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Table of Contents
Year : 2018  |  Volume : 22  |  Issue : 7  |  Page : 17-93

ESICON 2018 Abstracts

Date of Web Publication9-Nov-2018

Correspondence Address:
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2230-8210.245110

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How to cite this article:
. ESICON 2018 Abstracts. Indian J Endocr Metab 2018;22, Suppl S1:17-93

How to cite this URL:
. ESICON 2018 Abstracts. Indian J Endocr Metab [serial online] 2018 [cited 2021 Mar 8];22, Suppl S1:17-93. Available from: https://www.ijem.in/text.asp?2018/22/7/17/245110

   Diabetes Top

   Unsupervised “googling” improves glycemic control and QoL in type 1 diabetes patients Top

Ravindra Shukla, Divyangi Mishra1

Departments of Endocrinology & Meatbolism and 1Radiodiagnosis, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India.

E-mail: [email protected]

Objective: To delineate the effect of self gained information through internet on glycemic control and overall QoL in type 1 diabetes patient. Materials and Methods: 35 type 1 diabetes patients, who had reasonably good glycemic control were classified by a single clinician into net-savvy and ordinary based on their behaviour towards use of internet to gather information regarding health queries and their glycemic control and QoL analysed. WHO-5 questionnaire which is used in clinical practise was applied. Result: Of net savvy group (n = 18), 14 (82%) had WHO-5 score greater than 13 while among ordinary (n = 17) only 7 had WHO5 of same range. Thus, those who surfed internet were in general likely to have better QoL. Among net savvy group all had individual smart phones and used google as search engine. Among ordinary, 40% (9/17) had smart phones. The mean HbA1c of net savvy group was 7.2 which was lower than that of ordinary group mean HbA1c of 7.6. Those of net savvy group were more likely to agree to increase in number of s.c. insulin injections (12/18) as compared to ordinary group (4/17). The self reported hypoglycemia episodes were also more in net savvy group (6/person-week) as compared to ordinary (2/person-week). Conclusion: Use of smart search engines like google (with strong in built Artificial Intelligence (AI) systems), even if unsupervised, should be encouraged as part of DSME in type 1 Diabetes patients for optimizing glycemic control and detecting hypoglycemic episodes.

Keywords: Diabetes education, Google, type 1 diabetes

   Efficacy of Epalrestat in Diabetic Symmetrical Peripheral Neuropathy - A Clinical and Biothesiometric Evaluation Top

Rujul Jain, S. K. Singh

Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

E-mail: [email protected]

Aims and Objectives: Peripheral Neuropathy is the most common and most disabling long term complication of Diabetes Mellitus. This study was designed to evaluate the therapeutic efficacy of Epalrestat in Diabetic Peripheral Neuropathy. Materials and Methods: 50 subjects with symptoms of Neuropathy whose Diabetic Neuropathy Symptom Score (DNSS) ≥1 and Vibration Potential Threshold (VPT) ≥25 V by Biothesiometer were enrolled. Study population was divided into two groups: each patient of first group (25 patients) was administered Epalrestat (150 mg) once a day while patients of second group (25 patients) were administered placebo (multivitamin tablet). Components of Diabetic Neuropathy Symptom Score (DNSS), Numeric Pain Intensity Scale, Monofilament score and VPT measurements were done at baseline and at 12 weeks. Analysis was done using SPSS version 21.0. Result: DNSS score (out of 4) improved by 2.36 ± 1.11 (from 3.24 ± 0.88 at baseline to 0.88 ± 0.88 at 12 weeks) as compared to 0.56 ± 1.04 (from 2.8 ± 0.82 to 2.24 ± 1.3) for Epalrestat and placebo group respectively (P < 0.0001). Similarly the improvement in monofilament score (out of 10) was 2.8 ± 1.41 vs. 0.12 ± 0.93 (P < 0.0001), pain score (out of 10) was 2.6 ± 1.26 vs. 0.4 ± 0.82 (P < 0.0001) in Epalrestat and placebo group respectively. Average VPT score improved by 3.12 ± 1.53 vs. 0.33 ± 1.44 (P < 0.0001) in Epalrestat and placebo groups respectively. [Figure 1] and [Figure 2] Hence Epalrestat is useful in ameliorating symptoms of Diabetic Peripheral Neuropathy.
Figure 1: Showing comparison of improvement in various parameters in both study groups

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Figure 2: Box Whisker plot of mean improvement in various parameters in both study groups

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Keywords: Diabetic symmetrical peripheral neuropathy, epalrestat, vibration potential threshold

   Safety and efficacy of teneligliptin on qt/qtc Interval in indian type 2 diabetic patients Top

Soumya Sengupta, A. Rathod1, S. Suryawanshi1

Director, Dr Soumya Sengupta's Diabetic Clinic, Amlatola, P.O. Chaibasa, Singhbhum, Jharkhand, 1Medical Advisor's, Glenmark Pharmaceutical, Mumbai, Maharashtra, India.

E-mail: [email protected]

Aim: To evaluate the effectiveness and safety of Teneligliptin in Type 2 Diabetic patients with respect to QT prolongation. Materials and Methods: A retrospective data was collected from T2DM patients with ECG records who were treated with teneligliptin along with ongoing treatment. Mean daily dose (MDD) of anti-diabetic drugs and, HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) and QTc interval were compared from the baseline at 3 months of teneligliptin therapy. Results: Total of 20 patients data were collected and analyzed with a mean age of 55.5 years and duration of 10.8 years. Hypertension and dyslipidemia was the most common co-morbid disease (90.5% and 52.4% respectively) along with diabetes for a duration of 10.1 and 8.5 years respectively. Metformin and Glimepiride were the most prescribed dual drugs along with Teneligliptin with a MDD of Metformin was 1125 mg, Glimepiride was 2.3 mg. Significant reduction with FPG and PPG at 3 months were 57.85 mg/dL (P < 0.0001) and 107.1 mg/dL (P < 0.0001) from the baseline. Significant changes in the HbA1c from the baseline at 3 months was 0.85% (P < 0.0003). There was no significant increase in the Mean QTc interval from baseline to 3 months. No serious adverse events were reported. Conclusion: Teneligliptin was well tolerated and effective in significantly reducing the FPG, PPG and HbA1c at 3 months from the baseline with no adverse events. There was no increase in the mean QT interval.

Keywords: Diabetes, QT interval, teneligliptin

   From guidelines to clinical practice, reflections on the multinational randomised trial investigating the efficacy and safety of insulin degludec/insulin aspart and biphasic aspart 30 in patients with Type 2 diabetes before, during and after Ramadan Top

Sanjay Kalra, M. Hassanein1, E. G. Fita2, M. Ekelund3

Department of Endocrinology, Bharti Hospital, Karnal, Haryana, India, 1Department of Endocrine, Dubai Hospital, Dubai, UAE, 2Global Medical Affairs, 3Medical and Science, Novo Nordisk A/S, Søborg, Denmark.

E-mail: encoregroup [email protected], [email protected]

Aims: To provide clinical evidence reinforcing practical guidance concerning titration algorithm and dose modification for patients with Type 2 diabetes fasting during and/or outside Ramadan. Materials and Methods: Data were retrieved from a multinational, randomised, treat-to-target trial of insulin degludec/insulin aspart (IDegAsp) twice-daily (BID) (n = 131) vs biphasic aspart 30 (BIAsp 30) BID (n = 132) before, during and after Ramadan in fasting patients with Type 2 diabetes. A structured titration algorithm and dose modification, based on IDF – Diabetes and Ramadan 2016 guidelines, were applied during treatment (8- to 20-week initiation, 4-week Ramadan, 4-week post-Ramadan). Hypoglycaemia was analysed as overall (severe or blood glucose confirmed [<3.1 mmol/l]) symptomatic, nocturnal (00:01 to 05:59) overall symptomatic or severe (requiring third-party assistance). Results: Glycaemic control was maintained in both arms during and after Ramadan, regardless of treatment initiation duration. Total daily doses rose during titration, and as per protocol (30% to 50% reduction of latest pre-Ramadan breakfast/lunch or evening dose), decreased when Ramadan began and increased to pre-Ramadan level after Ramadan. During Ramadan, IDegAsp was associated with 62% lower overall hypoglycaemia rate (estimated rate ratio [ERR] 0.38 [0.19, 0.77], P = 0.0070) and 74% lower nocturnal hypoglycaemia rate (ERR 0.26 [0.08, 0.88], P = 0.0304), vs BIAsp 30. Post-Ramadan, overall, nocturnal and severe hypoglycaemia rates were IDegAsp: 78.6, 44.9 and 0.0 per 100 patient-years of exposure (PYE) respectively; BIAsp 30: 821.7, 142.4 and 32.9 per 100 PYE respectively. Conclusions: This study provides clinical evidence that reinforces recent practical guidance for patients with Type 2 diabetes who fast during and/or outside Ramadan.

Keywords: Insulin degludec/insulin aspart, insulin therapy during Ramadan, type 2 diabetes

   The cardiovascular benefits associated with liraglutide in the LEADER trial are sustained when analysing both first and recurrent MACE Top

Arthur J. Asirvatham, Subodh Verma1, Stephen C. Bain2, Thomas Idorn3, Søren Rasmussen3, David D. Ørsted3, Michael A. Nauck4, The LEADER Publication Committee on behalf of the LEADER Trial Investigators

Department of Diabetology, Arthur Asirvatham Hospital, Madurai, Tamil Nadu, India, 1Division of Cardiac Surgery, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Toronto, Canada, 2Department of Diabetes, Swansea University Medical School, Swansea, UK, 3Medical Affairs, Novo Nordisk A/S, Søborg, Denmark, 4Diabetes Center Bochum-Hattingen, St Josef Hospital (Ruhr-Universität Bochum), Bochum, Germany.

E-mail: [email protected]

Aims: In patients with type 2 diabetes and high risk for cardiovascular (CV) events, the LEADER CV outcomes trial (N = 9340) showed risk of a first major adverse CV event (MACE) was reduced with liraglutide vs placebo when added to standard of care. Here we further examined liraglutide treatment effects on both first and recurrent (“total observed”) CV events, including: 1) a composite MACE endpoint: CV death, non-fatal stroke or non-fatal myocardial infarction; 2) expanded MACE (also included coronary revascularisation and hospitalisation for heart failure or unstable angina); and 3) individual CV endpoints. Materials and Methods: A post hoc analysis utilising an extension of Cox regression modelling of time to event data, with additional sensitivity analyses. Results: In total, 1302 first and 303 recurrent MACEs occurred: liraglutide, 735 events; placebo, 870 events. Risk for total observed MACEs was reduced by 14% with liraglutide vs placebo (HR = 0.86, 95% CI 0.78–0.95). Corresponding analyses for all other CV endpoints suggested risk reductions with liraglutide, with the exception of hospitalisation for unstable angina [Table 1]. Sensitivity analyses using other regression models confirmed the results [Table 1]. Conclusion: The reduction in risk of first event with liraglutide in LEADER was sustained in this post hoc analysis; this is of clinical relevance to individuals who are at risk of or who have experienced a MACE, and confirms the robustness of the data.
Table 1: Risk of CV end points with Liraglutide vs placebo

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Keywords: Cardiac complications, cardiovascular events, LEADER trial, liraglutide, MACE

   No increased risk of heart failure hospitalization or major cardiovascular events observed with liraglutide in patients with or without a history of New York heart association class II-III heart failure: Results from the leader trial Top

Mala Dharmalingam, Mansoor Husain, Stephen C. Bain, Johannes F. E. Mann, Michael A. Nauck, Neil Poulter, Florian M. M. Baeres, Bryan Goldman, Anne B. Thomsen, Steven P. Marso, LEADER Publication Committee on behalf of the LEADER Trial Investigators, Novo Nordisk A/S, Søborg, Denmark

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Background: Some type 2 diabetes (T2D) therapies are associated with an increased risk of heart failure (HF).[1] In the LEADER trial (NCT01179048), liraglutide significantly reduced the risk of major adverse cardiovascular (CV) events (MACE) by 13% vs placebo (PBO) when added to standard care in people with T2D and high CV risk.[2] Here, we report post hoc analyses conducted to assess the risk of CV events, including HF hospitalization, in LEADER participants with or without a history of NYHA II-III HF. Materials and Methods: In LEADER, 9,340 patients with T2D and high CV risk were randomized 1:1 to add liraglutide or PBO to standard care, and followed for 3.5-5 years. Chronic NYHA IV HF was an exclusion criterion. Results: At baseline, 18% of patients in both treatment arms had a history of HF (NYHA I-III); 14% had a history of NYHA II-III HF. Overall, fewer patients were hospitalized for HF with liraglutide vs PBO during the trial (hazard ratio [95% confidence interval]: 0.87 [0.73-1.05], P = 0.14; [Table 1]). There was no interaction between treatment and history of NYHA II-III HF for the risk of the primary CV endpoint, an expanded CV endpoint or HF hospitalization [Table 1]. Conclusion: Non-significant reductions in the risks of HF hospitalization and MACE were observed with liraglutide vs PBO in LEADER participants with a history of NYHA II-III HF. Fewer patients experienced these events with liraglutide vs PBO, regardless of baseline NYHA II-III HF status.
Table 1: Risk of CV events with liraglutide or placebo by NYHA II-III HF status at baseline

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Keywords: GLP-1 RA, heart failure, liraglutide, MACE

   References Top

  1. Diabetes Metab 2017;43(Suppl 1):2S13-19
  2. N Engl J Med 2016;375:311-22.

   Evaluation of safety and effectiveness of teneligliptin when shifted from other gliptins uncontrolled with other OHA'S Top

Vipul Gupta, Girish Khurana1, Ameet M. Rathod2, Sachin Suryawanshi2

Medical Director, Gupta Ultrasound and Heart Care Centre, New Delhi, 1Medical Director, Vidya Medicare Centre, Bahadurgarh, Haryana, 2Medical Advisor, Glenmark Pharmaceutical Mumbai, Mumbai, Maharashtra, India.

E-mail: [email protected]

Aim: To evaluate effectiveness and safety of teneligliptin when switched from other gliptins in patients not controlled on oral Antidiabetic drugs in T2DM. Materials and Methods: Data of T2DM patients who were switched from other gliptin to Teneligliptin uncontrolled by dual or triple drug therapy. Data of at least 3 months was collected from hospital records and analyzed. Efficacy was evaluated by the changes in FPG, PPG and HbA1c from the baseline. Results: Total of 97 patients' data was collected and was analyzed. The mean age of the patients was 59.9 years and mean duration of diabetes was 16 years. Hypertension (61.9%) was the common comorbid condition with diabetes. Sitagliptin was most prescribed DPP-4 inhibitors with 65 (67%) patients with a mean dose of 88.5 mg, followed by Vildagliptin with 10 (10.3%) patients were prescribed with a mean dose of 95 mg. Metformin and Glimepiride were most common combination used with these DPP-4 inhibitors were 91 (93.8%) patients and 69 patients (71.1%) were prescribed respectively. There was significant reduction in FPG, PPG and HbA1c from the baseline with a differences of 45 mg/dL, 102 mg/dL and 1.6% respectively after switching to Teneligliptin from other gliptins. Teneligliptin was well tolerated and no serious adverse events were reported. Conclusion: Teneligliptin was effective in significantly reducing FPG, PPG and HbA1c when switching from other gliptins in T2DM patients not controlled with other anti-diabetic agents. The drug was well tolerated and no Serious Adverse events were reported.

Keywords: Diabetes mellitus, gliptins, glycated haemoglobin, teneligliptin

   Efficacy and Safety of Faster Aspart Compared with Insulin Aspart both with Insulin Degludec in Adults with T1D Top

Anil Bhansali, J. Buse1, A. Carlson2, M. Komatsu3, O. Mosenzon4, L. Rose5, B. Liang6, H. Horio7, T. Kadowaki8

Department of Endocrinology, PGIMER, Chandigarh, India, 1Department of Diabetes, University of North Carolina School of Medicine, Chapel Hill, NC, 2International Diabetes Center, Minneapolis, MN, USA, 3Department of Internal Medicine, Division of Diabetes, Endocrinology and Metabolism, Shinshu University School of Medicine, Nagano, 7Medical Affairs, Novo Nordisk Pharma Ltd, 8Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan, 4Department of Diabete, Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel, 5Department of Diabetes, Institute of Diabetes Research, Münster, Germany, 6Medical Affairs, Novo Nordisk A/S, Søborg, Denmark.

E-mail: encoregroup [email protected], [email protected]

Aim: To assess the effect and safety of Fast-acting insulin aspart (FA) in improving glycemic control in subjects with T1D. Materials and Methods: Multicenter, treat-to-target, 26-week trial (onset 8) randomized subjects with T1D to double-blind mealtime FA (n = 342), or insulin aspart (IAsp; n = 342), or open-label post-meal FA (n = 341), each with insulin degludec. All available information regardless of treatment discontinuation was used for the evaluation of effect. Results: Non-inferiority for the primary endpoint, change from baseline in A1C, was confirmed for mealtime and post-meal FA vs. IAsp [Figure 1]. Mealtime FA was superior to IAsp for 1-h PPG increment using a standard meal test (ETD: −0.90 [−1.36; −0.45] mmol/L; −16.24 [−24.42; −8.05] mg/dL). Self-measured 1-hr PPG increment favored FA at breakfast (ETD: −0.58 [−0.99; −0.17] mmol/L; −10.43 [−17.85; −3.02] mg/dL) and across all meals (ETD: −0.48 [− 0.74; −0.21] mmol/L; −8.58 [−13.35; −3.81] mg/dL). No significant differences were observed in treatment-emergent adverse events or overall rate of severe or confirmed hypoglycemic episodes (PG < 3.1 mmol/L [56 mg/dL]), but significantly less hypoglycemia was seen 3 to 4 h after meals with mealtime FA. Conclusion: In summary, mealtime FA provided superior PPG control to IAsp with a similar overall improvement in A1C and no increased safety risk. These findings were consistent with those previously reported in subjects with T1D.
Figure 1: Mean A1C over time

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Keywords: Efficacy, faster aspart, type 1 DM

   Effectiveness of teneligliptin in T2DM patients uncontrolled on metformin and sulfonylurea Top

Amiya K. Paul, Ameet M. Rathod1, Sachin Suryawanshi1

Medical Director, National Medical, Kharangajhar Market, Jhamshedpur, Jharkhand, 1Medical Advisor's, Glenmark Pharmaceutical Mumbai, Mumbai, Maharashtra, India.

E-mail: [email protected]

Objective: To evaluate the effectiveness of Teneligliptin in Type 2 Diabetes Mellitus T2DM uncontrolled on therapy of Metformin and Glimepiride. Study Design: A Retrospective data of patients treated with Teneligliptin as an add-on to ongoing Metformin and Sulfonylurea therapy at least three months in Jhamshedpur, India was collected and analyzed. Effectiveness of Teneligliptin assessed by analyzing the mean changes in fasting (FPG), Post-prandial (PPG) plasma glucose and Glycosylated Haemoglobin (HbA1c) after 3 months of duration. Results: Data of eligible 39 patients was used for this study; wherein teneligliptin 20 mg once daily was prescribed to the T2DM patients uncontrolled on metformin and Sulfonylurea therapy. The Mean average age of the patients was 51.1 years with a mean duration of diabetes of 7.4 years. Hypertension was the most common comorbidities with 66.7% with a mean duration of 8.1 years followed by dyslipidemia and stroke. Metformin glimepiride (66.7%) combination was the most preferred combination with mean dose of 1682.9 and 3.9 mg respectively. Statistically significant reduction was seen in HbA1c, FPG and PPG at the end of three months by 1.4 ± 0.3%, 65.1 ± 22.5 mg/dl and 115.4 ± 30.8 mg/dl from the baseline of 7.8 ± 0.5%, 165.8 ± 28.8 mg/dl and 261.9 ± 44.0 mg/dl respectively. At the end of three months HbA1c target of < 7% was achieved by 97.43% of patients on Teneligliptin. No safety related event was reported during three month duration. Conclusion: Teneligliptin found to be effective in the management of T2DM uncontrolled on metformin and sulphonylurea therapy and was well tolerated.
Figure 1: Glycemic Parameter after 3 months of Teneligliptin

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Keywords: Diabetes mellitus, metformin, sulfonylurea, teneligliptin

   Hypoglycemia with mealtime fast-acting insulin aspart versus insulin aspart across two large type 1 diabetes trials Top

Bipin Kumar Sethi, A. De Block1, A. Carlson2, L. Rose3, T. Gondolf4, A. Gorst-Rasmussen4, W. Lane5

Department of Endocrinology, CARE Hospital, Banjara Hills, Hyderabad, Telangana, India, 1Department of Endocrinology-Diabetology-Metabolism, Antwerp University Hospital, Antwerp, Belgium, 2Department of Endocrinology, International Diabetes Center, Minneapolis, MN, USA, 3Department of Endocrinology, Institute for Diabetes Research, Münster, Germany, 4Medical Affairs, Novo Nordisk A/S, Søborg, Denmark, 5Department of Endocrinology, Mountain Diabetes and Endocrine Center, Asheville, NC, USA.

E-mail: encoregroup [email protected], [email protected]

Hypoglycemia is a ubiquitous challenge with insulin treatment in type 1 diabetes (T1D), with nocturnal episodes of particular concern. Severe (as defined by the ADA) or blood glucose-confirmed (<56 mg/dL [3.1 mmol/L]) hypoglycemia was investigated across two double-blind, treat-to-target, randomized trials assessing the efficacy and safety of mealtime fast-acting insulin aspart (FA) vs insulin aspart (IAsp) by multiple daily injections in adults with T1D: a 52-week trial in combination with insulin detemir (onset 1; n = 761), and a 26-week trial in combination with insulin degludec (onset 8; n = 684). FA was confirmed to be non-inferior to IAsp regarding change from baseline in A1C in both trials, with a statistically significantly greater A1C reduction with FA in onset 1. Importantly, nocturnal hypoglycemia rates were consistently lower with FA vs IAsp in both trials (pooled estimated treatment rate ratio [ETR] 0.84 [95% CI 0.72;0.98]; P = 0.02) [Figure], while no significant difference was observed for overall (pooled ETR 0.94 [95% CI: 0.85;1.05]) and diurnal hypoglycemia (pooled ETR 0.96 [95% 0.86;1.07]) [Figure] with some heterogeneity across trials. In summary, analysis across two large trials supports the safety of mealtime FA, with lower rates of nocturnal hypoglycemia with FA vs IAsp. The lower rates of hypoglycaemia is most probably due to the pharmacological properties of FA.

Keywords: Diabetes management, faster aspart, type 1 DM

   Cardiovascular (CV) Safety and Severe Hypoglycemia Benefit of Insulin Degludec vs Insulin Glargine U100 in Older Patients (≥65 years) with Type 2 Diabetes (T2D): Observations from DEVOTE Top

Ambrish Mithal, Richard E. Pratley1, Scott S. Emerson2, Edward Franek3, Matthew P. Gilbert4, Steven P. Marso5, Darren K. McGuire6, Thomas R. Pieber7, Neil R. Poulter8, Charlotte T. Hansen9, Melissa V. Hansen9, Thomas Mark9, Alan C. Moses10, Bernard Zinman11, on behalf of the DEVOTE Study Group

Division of Endocrinology and Diabetes, Medanta-The Medicity, Sector 38, Gurgaon, Haryana, India, 1Department of endocrinology, Florida Hospital, Orlando, Florida, USA, 2Department of endocrinology, University of Washington, Seattle, Washington, USA, 3Department of endocrinology, Central Clinical Hospital MSWiA, Warsaw, Poland, 4Department of endocrinology, Larner College of Medicine, South Burlington, VT, USA, 5Department of endocrinology, HCA Midwest, Kansas City, MO, USA, 6Department of endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA, 7Department of endocrinology, Medical University of Graz, Graz, Austria, 8Department of endocrinology, Imperial Clinical Trials Unit, Imperial College London, London, UK, 9Department of Medical Affairs, Novo Nordisk A/S, Søborg, Denmark, 10Department of Medical Affairs, Novo Nordisk Inc., Plainsboro, NJ, USA, 11Department of endocrinology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.

E-mail: [email protected]

There is limited comparative evidence for the CV safety and hypoglycemia risk of basal insulins in older patients with T2D. This secondary analysis from DEVOTE investigated the CV safety and severe hypoglycemia risk of insulin degludec (degludec) vs insulin glargine 100 units/mL (glargine U100) in older patients (65–74 and ≥75 years age groups). Data from DEVOTE (a treat-to-target, randomized, double-blind trial evaluating 7637 patients with T2D over a median period of 2 years at high risk of CV events) were stratified by three age groups. At baseline, A1C, fasting plasma glucose and estimated glomerular filtration rates decreased with increasing age. Older patients had a higher risk of major adverse cardiovascular events (MACE), all-cause mortality and severe hypoglycemia, regardless of treatment. Treatment differences for MACE, all-cause mortality and severe hypoglycemia were similar across age groups [Figure 1], with no significant interactions between treatment and age group. Degludec was associated with a lower risk of severe hypoglycemia vs glargine U100, regardless of age. This analysis supported the CV safety of degludec and demonstrated a lower risk of severe hypoglycemia vs glargine U100 in older patients with T2D.
Figure 1: Treatment effects in terms of key end-points by age-group

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Keywords: CV safety, degludec, diabetes management, hypoglycemia

   Efficacy and safety of an expanded dulaglutide dose range: A phase 2, placebo-controlled trial in T2D patients on metformin Top

Juan Frias1, Alan Wynne2, Beata Matyjaszek-Matuszek3, Dagmar Bartaskova4, David Cox5, Brad Woodward5, Ying Grace Li5, Zvonko Milicevic5

1National Research Institute, California, USA; 2Cotton O'Neil Diabetes and Endocrinology Center, USA; 3Department of Endocrinology, Medical University, Lublin Poland; 4Diabetologická ambulance, Czech Republic; 5Eli Lilly and Company, Indianapolis, USA.

E-mail: [email protected]

Aims and Objectives: In this study, 3 and 4.5 mg doses of dulaglutide were evaluated for safety/efficacy after 18 weeks (wks) of treatment, including an initial 6-wk dose escalation. The primary objective was superiority of dulaglutide doses over placebo in HbA1c reduction at 18 wks. Materials and Methods: Patients (N = 318) on ≥1500 mg daily metformin, were randomized (1:1:1:1) to placebo (n = 82), dulaglutide 1.5 mg (n = 81), dulaglutide 3 mg (n = 79), dulaglutide 4.5 mg (n = 76).Result: For HbA1c, the least square mean changes from baseline in patients receiving dulaglutide 1.5 mg [−1.24% (SE: 0.09)], dulaglutide 3 mg [−1.77% (SE: 0.10)] or dulaglutide 4.5 mg [−1.50% (SE: 0.10)] were statistically significant compared with placebo [−0.42% (SE: 0.10)] (P < 0.001). Similarly, for body weight, the least square mean changes from baseline in patients receiving dulaglutide 1.5 mg [−2.9 kg (SE: 0.40)], dulaglutide 3 mg [−4.2 kg (SE: 0.41)] or dulaglutide 4.5 mg [−4.4 kg (SE: 0.10)] were statistically significant compared with placebo [−1.6 kg (SE: 0.41)] (P < 0.001). Incidence of gastrointestinal events (mostly mild to moderate) were dose-dependent for nausea (placebo, 4.9%; dulaglutide 1.5 mg, 22.2%; dulaglutide 3 mg, 24.1%; dulaglutide 4.5 mg, 30.3%) but not for vomiting (placebo 4.9%; dulaglutide 1.5 mg, 11.1%; dulaglutide 3 mg, 10.1%; dulaglutide 4.5 mg, 13.2%). No patients experienced severe hypoglycemia. This trial shows that 3 mg and 4.5 mg dulaglutide doses, compared to 1.5 mg, may provide additional glycemic benefit and weight reduction with an acceptable safety profile in T2D patients, providing support for phase 3 development.

Keywords: Diabetes type II, dulaglutide expanded dose, phase 2

   Recurrent spontaneous hypoglycemia due to insulin autoimmune syndrome Top

Savita Jain, Chandar Mohan Batra1

Department of Endocrinology, Deep Hospital, Ludhiana, Punjab, India, 1Department of Endocrinology, Indraprastha Apollo Hospital, New Delhi, India.

E-mail: [email protected]

Background: Insulin autoimmune syndrome is a rare disease characterized by recurrent spontaneous hypoglycemias. We present here two cases of insulin auto-immune syndrome. Both the patients presented with episodes of spontaneous hypoglycemia. Case Reports: Two patients, 82 year female and 61 year female presented with history of recurrent spontaneous hypoglycemic episodes. Both of them did not have any other significant history or physical finding. Biochemistry revealed normal kidney function, liver function, thyroid function, cortisol and blood counts. Serum insulin levels were high in both (9470 μIU/ml and 700 μIU/ml) respectively. First patient also showed a 4 mm hypoechoic lesion in the distal body of pancreas on endoscopic ultrasound. She underwent surgery and remained asymptomatic for 4 years. After 4 years, she started having recurrent hypoglycemic attacks. Serum insulin levels were high and Insulin antibody level was >100 μ/ml (normal <1 μ/ml) with normal MRI abdomen. Second patient had normal CT abdomen. Highly sensitive insulin antibodies were positive (36 nmol/L, normal 0-0.02 nmol/L). Both patients responded to a course of oral steroids. Discussion: Insulin autoimmune syndrome is a rare disease occurring due to polyclonal insulin antibodies, precipitated by drugs containing sulphydryl group and characterized by recurrent spontaneous hypoglycemias, elevated insulin levels and high levels of insulin antibodies in individuals never exposed to insulin therapy. Association with other diseases has been reported, notably plasma cell dyscrasias and other auto-immune diseases. Treatment consists of dietary modification including small, frequent meals and avoiding direct sugars, corticosteroids, plasmapheresis and immunosuppressants. Discontinuing the incriminating drug is very important.

Keywords: Insulin autoimmune syndrome, recurrent hypoglycemia, spontaneous hypoglycemia

   A study of cutaneous complications of insulin therapy in diabetic patients Top

Saurabh Arora, N. K. Agrawal, Ashish Verma1, SCU Patne2, Prem Narayanan, Jitendra Chauhan, Rujul Jain, Dhananjaya MS

Departments of Endocrinology and Metabolism, 1Radiology, 2Pathology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, UP, India.

E-mail: [email protected]

Objective: The aim of the study is to evaluate the possible role of ultrasonography in the detection of insulin induced local dystrophies and to assess the prevalence of insulin associated amyloidosis in diabetic patients. Materials and Methods: The study included 250 patients injecting insulin who underwent ultrasonography of dermis and subcutaneous tissue in the areas of insulin injection. Images were obtained and characterized by a single team and confirmed by a radiologist. All cases with radiological evidence of local site complications underwent punch biopsy from the lipohypertrophic area followed by congo red and anti insulin antibody staining to confirm the diagnosis of insulin associated amyloidosis. Results: The ultrasonographic signature for lipohypertrophy consists of increase in thickness of subcutaneous tissue layer which was associated with 1) heterogenous echotexture compared with surrounding tissue 2) variety of nodular shaped or diffuse hyperechogenecity 3) distortion of the surrounding connective tissue 4) absence of vascularity and 5) absence of capsule. Ultrasonography identified individuals with lipohypertrophy significantly more frequently than clinical examination. An abdominal subcutaneous tissue biopsy performed on seventy patients with radiological evidence of lipohypertrophy was negative for congo red stain. Conclusions: Ultrasonography is an emerging tool in the diagnosis of lipohypertrophy and is especially helpful in detecting lipohypertrophy at an early stage. Our study reinforces the fact that insulin associated amyloidosis is a rare complication of insulin therapy.

Keywords: Cutaneous complications, insulin associated amyloidosis, insulin therapy, lipohypertrophy

   Serum levels of B lymphocyte activating factor (BAFF) in patients with gestational diabetes mellitus (GDM) Top

Sudipta Banerjee, Pieu Adhikary, Amitabh Sur, Hajekul Alam1, Subhankar Chowdhury, Rana Bhattacharjee

Departments of Endocrinology and Metabolism, 1Obstetrics and Gynecology, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India.

E-mail: [email protected]

Objectives: To look into possible association of BAFF in pathogenesis of GDM. Materials and Methods: This cross-sectional study was performed at Outpatient department of department of Endocrinology and Metabolism of Institute of post graduate of medical education and research, Kolkata. We included 65 subjects in 2 study groups including 35 patients with GDM (group 1), 30 euglycemic pregnant individuals (group 2). Serum levels of BAFF were measured by ELISA and compared between groups. Result: The mean gestational age of the participants was 26.72 ± 4.18 years. There was no significant difference between two study groups regarding the clinical characteristics. After adjusting for age and BMI, serum levels of BAFF were significantly higher in those patients with GDM compared to euglycemic pregnant individuals (4586.57 ± 862.72 vs. 2845.87 ± 579.08 pg/ml; P = <0.001). Conclusion: Our findings demonstrate that serum levels of BAFF are higher in those with GDM compared to euglycemic pregnant individuals.

Keywords: BAFF, ELISA, GDM

   Demographic and clinical characteristics of young onset diabetes mellitus Top

Dhananjaya M S, Surya K. Singh, N. K. Agrawal, Prem Narayanan, Jitendra Chauhan, Saurabh Arora, Rujul Jain

Department of Endocrinology and Metabolism, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India.

E-mail: [email protected]

Objectives: To describe the demographic and clinical characteristics of young onset Diabetes Mellitus patients attending Endocrine service. Materials and Methods: A retrospective analysis of young patients of age less than 20 years with diabetes mellitus attending the endocrine unit of the university hospital in Varanasi during year 2016-2017. Results: One hundred patients (male: 71%, female: 29%) with young onset diabetes mellitus were included in the study. Ninety five patients were having type 1 Diabetes Mellitus. Pancreaticogenic diabetes was seen among 5 patients. Average BMI among patients was 15.71 kg/m2. No correlation was seen between BMI and total insulin dose required. Growth retardation was seen in 4 (4%) patients with height less than 3rd centile. Anemia was the most common (78%) comorbidity seen among the patients. Type of anemia was predominately microcytic hypochromic. Average haemoglobin among patients was 11.41 gm%. Discussion: Prevalence of anaemia was high among patients (78%). Age matched anaemia prevalence data for non-diabetic patient in Uttar Pradesh suggested a prevalence of 23.7%.(NFHS 4). Pancreatogenic diabetes was not infrequent. Growth retardation was uncommon among the patients suggesting short duration and early diagnosis of the condition. Conclusion: Type 1 DM was most common amongst patients with young onset diabetes. BMI was low but height was normal in these patients. Increased association of anemia with type 1 diabetes needs further evaluation to know about casual relation between both condition in this region.

Keywords: Anaemia, demography, diabetes, growth retardation

   Clinico-pathological, demographic and microbiological profile of chronic diabetic foot ulcers with special reference to factors governing their outcome Top

Subrata Chakrabarti, Satinath Mukhopadhyay, Subhankar Chowdhury

Endocrinology and Metabolism, IPGMER, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: Diabetic Foot ulcer (DFU) is a common and significant problem in people living with diabetes mellitus. There is under-appreciation of the role of biofilm in modulating the outcome of foot ulcer. Knowledge concerning clinico-demographic variables as well as laboratory parameters influencing the healing status is incomplete. Finally there are limitations of Culture based identification of pathogens from DFUs.

Aims and Objectives:

  • Determine the clinical characteristics and pathological parameters associated with chronic DFU.
  • Evaluate the Microbiological profile including antibiotic sensitivity patterns.
  • Assess pattern of biofilm formation.
  • Identify the risk factors behind non-healing.

Materials and Methods:

  • Observational, longitudinal hospital based study.
  • Study setting - DFU clinic; IPGMER.
  • 70 cases (>18 years) with DFU in different Texas grades.
  • A wound swab for c/s and Tissue samples for detection of biofilm (microscopy and FISH) and microbiome analysis (NGS).
  • standard treatment for DFUs.
  • cases followed up weekly for 6 months.


  • neuro-ischemic (67.1%); pure neuropathic (32.9%).
  • Site - base of great toe (35.7%).
  • grade 3 (85.7%); osteomyelitis (32.9%).
  • biofilm (+) 63.2%; no significant association with clinical or laboratory parameters.
  • Mean time to healing - 11.2 (±2.3) weeks.
  • 187 pathogens isolated from 70 cases; polymicrobial (71.3%).
  • Gram-negative aerobes (42.4%); anaerobes (19.8%).
  • S. aureus (23,1%); E. coli (21.5%); B. fragilis (16.7%).
  • Most common organisms for moderate or strong biofilm formation -Staphylococcus aureus (31.6%), Enterococcus (23.1%).
  • Multi-drug resistance in 38.9%; associated with nephropthy, ulcer size > 3.5 cm2, IHD, insulin usage.
  • healing time and non-healing status correlated with Biofilm, grade of ulcer, IHD, nephropathy, raised ESR, decreased albumin, high HbA1C, PPBS values.
  • Microbiome analysis- organisms grossly underrepresented by culture; Non-healing DFUs showed increase in fastidious organisms and anaerobes like Fusobacterium and Bacteroides and decrease in aerobes post antibiotic treatment; healing ulcers opposite scenari

Keywords: Diabetic foot ulcer, outcome

   Personalized health education in achieving better glycemic control Top

Jibily Joy, Sherin S. Mathew, Dijo E. George, George Thomas, Anulekha M. John

Department of Endocrinology and Metabolism, Believers church medical college hospital, Thiruvalla, Kerala, India.

E-mail: [email protected]

Background: Diabetes Mellitus, is an ever growing global problem with lot of economic, social and health impact. Providing a structured and personalized health education on various aspects of diabetes goes a long way in achieving better glycemic control. Aim: To assess the impact of structured health education, delivered in a personalized manner in adult patients suffering from type two diabetes. Materials and Methods: This prospective observational study was conducted in type-2 Diabetes mellitus patients who were seen in an outpatient clinic in the southern state Kerala, India, during the period January to April 2014. A total of 184 patients were given personalized, structured education about all aspects of diabetes and management. Glycosylated Hemoglobin (HbA1c) was performed before education, 3 months and 6 months after health education. No new medications were added on during this period. Student's t-test was used to ascertain the significance of differences between mean values. Chi-square test was performed to test for differences in proportions. Results: There was significant improvement in glycemic control after the education with 70.65% of patients achieving HbA1c reduction and 40.76% achieving target glucose levels. Mean HbA1c reduction by the addition of health education alone was 1.283 ± 1.336 at 3 months and 1.917 ± 1.313, at 6 months, which is higher than any other single oral therapy. The reduction achieved was statistically significant and clinically meaningful. The HbA1c reduction persisted at 6 months follow up.

Keywords: Diabetes mellitus, glycemic control, HbA1c, personalized health education

   Hirata's disease due to alpha lipoic acid in an Indian patient Top

Karthik Prabhakar, Ashwitha Shruti Dass

Department of Diabetes and Endocrinology, Manipal Hospital, Bengaluru, Karnataka, India.

E-mail: [email protected]

Case Report: A 59-year-old female complained of episodic sudden severe fatigue, profuse sweating and palpitations for 3 days that responded to sugar-intake. Symptoms occurred predominantly post-meals. Past history: Non-Diabetic; Recent bilateral knee-pain for which “Multivitamins” were prescribed by an Orthopaedic-doctor 11 days previously. Prolonged Oral-Glucose-Tolerance-Test with 75-gms glucose showed following plasma glucose-levels; Fasting: 70 mg/dL, 60 min: 275 mg/dL, 120 min: 202 mg/dL, 180 min: 190 mg/dL, 240 min: 105 mg/dL, 300 min: 45 mg/dL). Severe symptomatic hypoglycaemia (plasma-glucose 50 mg/dL) was demonstrated following mixed-meals too. Whipple's triad was confirmed. Further tests: Plasma Glucose: 45 mg/dL, Plasma Insulin >10000 mIU/ml (3-28), C-peptide: 18.45 ng/ml (0.9-7.1), Serum Cortisol: 567 nmol/L. TFT, LFT, CBC, renal-functions were normal. Triphasic-CT-Pancreas excluded insulinoma. Anti-Insulin-Antibodies were positive. Anti-Nuclear-Antibodies negative. A diagnosis of Insulin Autoimmune Syndrome (IAS) due to Alpha Lipoic Acid (ALA) in her multivitamin-capsules was made. The drug was discontinued. HLA Class II typing later revealed DRB1*04, DRB1*15, DRB4, DRB5. She was treated with IV Hydrocortisone initially, then Prednisolone orally. She recovered with dietary-modifications and steroids, which were tapered off over 8 weeks. She remains well 4-years since. Discussion: Hirata's disease or IAS is diagnosed when spontaneous hypoglycaemia, elevated insulin, anti-insulin-antibodies are present together, in the absence of exogenous insulin. Post-prandially, these anti-insulin-antibodies bind to endogenous insulin, but later dissociate from the complex causing hyperinsulinemic hypoglycaemia. Case-reports suggest exposure to sulfhydryl-containing-compounds such as ALA, Methimazole, Imipenem, Pantoprazole, etc., can trigger IAS in individuals with genetic-predisposition (DRB1 * 04 allele is commonly associated with IAS in Japanese population). To our knowledge, this is the first case-report of Hirata's Disease due to ALA from India.

Keywords: Alpha lipoic acid, insulin autoimmune syndrome, Hirata's disease

   A comparative analysis of patients with and without type 2 diabetes undergoing coronary artery bypass grafting at a tertiary care centre Top

Harsha Pamnani, Subhash K. Wangnoo

Apollo Centre for Obesity, Diabetes and Endocrinology, Indraprastha Apollo Hospital, New Delhi, India.

E-mail: [email protected]

Objective: To compare the clinical features and complications of diabetic and non-diabetic patients undergoing coronary artery bypass surgery at a tertiary care hospital. Materials and Methods: This is an observational study carried out for a period of 1 year. Clinical data and 3 months outcomes of patients with and without type 2 diabetes who underwent coronary artery bypass surgery were analyzed. Results: Of the 1122 patients who underwent CABG; 37% of them had diabetes, their mean age was 62.1 ± 9.49 years and 76% of them were men. Mean HbA1c was 7.82 ± 1.77%. Patients with diabetes were younger (57 ± 4.7 years vs. 63 ± 8.9 years; P < 0.001), more often obese (65.7% vs. 54.5%; P < 0.001), dyslipidemic (59.4% vs. 44.4%; P < 0.001), hypertensive (89.2% vs. 71.7%; P < 0.001), and presented with chronic renal failure (8.3% vs. 1.5%; P < 0.001). Diabetic patients had a higher incidence of multi-vessel disease and complicated coronary anatomy. They also presented with higher rates of post-op acute renal failure (5.6% vs. 1.9%, P < 0.001), infections (9.3% vs. 5.2%, P < 0.001) and longer hospital stay including ICU stay. Pneumonia and sternal wound infections were more common among patients with diabetes (5.3% vs. 1.4%, P < 0.001). Conclusion: Patients with diabetes were younger, had a higher incidence of dyslipidemia and hypertension, multi-vessel disease on CAG and had a higher risk for postoperative complications compared to non-diabetics.

Keywords: Coronary artery bypass, diabetes complications, diabetes mellitus

   Evaluation of eating disorders and their association with metabolic parameters and glycemic control in adult patients with diabetes mellitus type 2 Top

Aishwarya Krishnamurthy, Nikhil Tandon, Yashdeep Gupta, Pratap Sharan1, Rachana Bhargava2, Viveka P. Jyotsna

Departments of Endocrinology and Metabolism, 1Psychiatry, 2Psychiatry and NDDTC, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected], [email protected]

Aims and Objectives: Data regarding eating disorders (ETD) in type 2 Diabetes Mellitus (T2DM) is scarce, in contrary to clear demonstration of poorer glycemic control and short/long term complications in T1DM patients with ETD. Our aim is to evaluate the frequency of ETD in T2DM and its association with glycemic control and metabolic parameters. Materials and Methods: T2DM patients and non-diabetic attenders of patients availing Endocrinology services at All India Institute of Medical Sciences, Delhi, were recruited and screened with EAT-26 and Binge Eating Scale (BES), followed by psychiatric assessment if positive. Socio demographic and biochemical parameters were recorded. Results: Of the calculated total sample size of 500 subjects (1:1 T2DM and controls), 177 T2DM subjects and 50 controls have been recruited till June 2018. Compared to controls, more T2DM subjects screened positive in BES and EAT-26 scales: 12% and 48% inT2DM vs. 9% and 25% in controls. Characteristics of T2DM and controls were as follows: mean age (49 vs. 39 yrs), body mass index (28.9 vs. 30.4 kg/m2), HbA1c (8.5% vs. 5.5%) and fasting plasma glucose (167 vs. 90 mg/dl) of T2DM and controls and respectively. Mean HbA1c of T2DM patients who screened positive on BES and EAT-26 vs. those who screened negative were 12%, 8.4% and 8.45% respectively. Conclusions: Recruitment is ongoing and final analysis will be presented. Psychological attributes and eating behavior in T2DM patients have not been adequately explored, we hope to shed light on the magnitude of the problem and spur further research in this area.

Keywords: Binge eating scale, binge eating syndrome, EAT-26, eating disorders

[TAG:2]An open label 3 arm Randomised Control Trial to evaluate the effect of different modalities of lifestyle intervention (videos educating on lifestyle modification, yoga and standard care) on HbA1C in individuals with Type 2 Diabetes Mellitus on stable oral anti-hyperglycemic drugs for at-least 3 months[/TAG:2]

Uttio Gupta, Yashdeep Gupta, Viveka P. Jyotsna, Gautam Sharma1, Nikhil Tandon

Departments of Endocrinology and Metabolism, 1Cardiology, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Introduction: Effective strategies for glycemic control in patients with type 2 diabetes (T2DM) include strict compliance to medications, diet and physical activity.Data on lifestyle intervention trials in known cases of T2DM is sparse in India. Aim: To evaluate the effect of different modalities of lifestyle intervention [Group 1: 4 Videos educating on lifestyle modification with sessions modulated by trainee endocrinologist [VBLI]; Group 2 yoga based lifestyle intervention [YBLI]]as compared to usual care [group 3] on glycemic and metabolic parameters. Materials and Methods: T2DM patients with HbA1C of 7.5-10% on stable OADs were randomized in 1:1:1 ratio in VBLI, YBLI and standard care. Assessment was done at baseline and after 4 months. For difference of 0.5% in HbA1c between intervention and usual care group, with power of 90%, drop out rates of 10%, the estimated sample size was 120 patients. Mixed block randomization with allocation concealment using sequentially numbered, opaque, sealed envelopes (“SNOSE”) has been used. Result: Recruitment of study is complete. 52 patients have undergone post-intervention follow up. 18 had been randomized in VBLI, 16 to YBLI and 18 to usual care. The preliminary results for HbA1C reduction [Baseline minus post-intervention] in VBLI, YBLI and usual care arm are 0.57, 0.03 and −0.23% respectively. Conclusions: VBLI have significant benefit in reduction of HbA1C in addition to usual care. Preliminary results for YBLI suggests potential role in preventing rise of HbA1C from baseline. Full results ready before the conference will shed further insights.

Keywords: HbA1C, lifestyle intervention, yoga

   Clinical profile of patients developing new onset diabetes after transplantation (NODAT) in renal transplant recipients Top

Partha Sarathi Choudhury, Pradip Mukhopadhyay, Arpita RayChaudhury1, Sujoy Ghosh

Departments of Endocrinology and Metabolism, 1Nephrology, IPGME and R, Kolkata, West Bengal, India.

E-mail: [email protected]

Aims and Objectives: The study objectives were to determine the prevalence of NODAT in renal transplant recipients attending post renal transplantation clinic in a tertiary hospital of Eastern India, to identify the risk factors of NODAT and to assess its clinical response to treatment received. Methodology: All renal transplant recipients coming for follow up were screened for the presence of NODAT and 43 out of 250 patients were found to be having NODAT. Of the rest renal transplant recipients, 90 patients were recruited as controls. Renal transplant recipients aged less than 18 yrs and those who were having diabetes mellitus prior to transplantation were excluded from this study.Results: Prevalence of NODAT in renal transplant recipients was 17.2%. Pretransplant BMI, waist circumference, pretransplant total cholesterol and triglyceride, pretransplant FBS and use of tacrolimus as immunosuppressant were important risk factors of NODAT of which independent predictors of NODAT were waist circumference and trough tacrolimus level. HOMA Beta c peptide was found to be significantly decreased in NODAT group compared to Non NODAT group [P = 0.03]. 9.3% of NODAT patients was treated by lifestyle modification, 67.4% by oral antidiabetic drugs (OADs), 11.6% by insulin and rest 11.6% by combined insulin and OADs. All NODAT patients managed by lifestyle modification and majority of those treated with OAD, insulin or combined insulin and OAD were having HbA1c < 7%.

Keywords: HOMA Beta C peptide, new onset diabetes after transplantation, renal transplant recipients, tacrolimus

   Study to assess insulin resistance in patients of chronic psoriasis in a tertiary care centre Top

Ranajit Bari, Subhankar Chowdhury

Department of Endocrinology and Metabolism, IPGME and R, Kolkata, West Bengal, India.

E-mail: [email protected]

Background: Psoriasis patients were shown to be associated with higher insulin resistance where obesity was a contributing factor. Whether insulin resistance in psoriasis is contributed by obesity, disease severity or both; needs further evaluation. Objective: To assess insulin resistance and its possible correlation with disease severity and inflammation in patients of psoriasis. Materials and Methods: Forty eight consecutive non diabetic patients of psoriasis vulgaris and 40 age, sex, Body mass index (BMI) matched healthy control were studied for following parameters: waist circumference, waist hip ratio, psoriasis area severity index (PASI, in case only), fasting glucose, fasting insulin, HOMA-IR, hsCRP, Triglyceride, HDL, LDL, Lipoprotein (a). Results: Psoriasis was associated with higher levels of HOMA-IR [median 2.02, IQR (1.72-2.82) vs median 0.88, IQR (0.72-1.2), P < 0.001], hsCRP [1.01 ± 1.71, median 0.68, IQR (0.3-1.3) vs 0.42 ± 0.18, median 0.3, IQR (0.3-0.52), P = 0.047] and Lipoprotein (a) [30.4 ± 18, median 29.85, IQR (1.41-38.4) vs 21.95 ± 14.1, median 18.4, IQR (10.8-26.3), P = 0.016]. HOMA-IR in psoriasis was significantly correlated with disease severity score (PASI) (rho = 0.469, P = 0.001), BMI (rho = 0.331, P = 0.022), waist circumference (rho = 0.415, P = 0.003) and waist hip ratio (rho = 0.383, P = 0.007). Taking HOMA-IR cut off value of 2.5, 29.17% of case and 7.5% of the control were insulin resistant (P = 0.01). Conclusion: Patients with chronic plaque psoriasis are more insulin resistant compared to age, sex, BMI matched healthy control. HOMA-IR is significantly correlated with disease severity index (PASI). HOMA-IR is significantly correlated with BMI, waist circumference and waist hip ratio, suggestive of central adiposity as one of the contributory factor for insulin resistance.

Keywords: HOMA-IR, insulin resistance, Psoriasis

   Treatment of type 2 diabetes with teneligliptin: A pharmacoeconomic evaluation Top

Navpreet Kaur, Diksha Sharma, Gurleen Kaur, Richa Prajapat, Inderjeet Verma, B. K. Agrawal1

Maharishi Markandeshwar College of Pharmacy, MM Deemed to be University, Mullana, 1MM Institute of Medical Sciences and Research, MM Demmed to be University, Mullana - Ambala, Haryana, India.

E-mail: [email protected]

Aim: The aim of this prospective, observational study was to analyze the cost-effectiveness of teneligliptin in treatment-naive T2DM patients in absence of traditional cardiovascular risk factors. Methodology: 80 newly diagnosed T2DM (HbA1c ≥ 6.5) were recruited and divided into Group A (teneligliptin + oral hypoglycemic agents [OHA]) and Group B (OHA except for DPP-4 inhibitors). The efficacy was assessed by analyzing the HbA1c and FBS at baseline and after 12 weeks therapy. Incremental cost-effectiveness ratio (ICER) and quality of life were assessed by using WHOQOL-BREF. Results: 37 patients in group A and 35 patients in group B completed the 12 weeks follow-up. We found that there was no statistically significant difference between both the groups at baseline (P > 0.05). HbA1c and FBS declined significantly in both the treated groups. Net change from the baseline in Group A vs Group B for HbA1c was − 1.77 ± 0.18 vs − 1.13 ± 0.18% (P = 0.01) and for FBS was − 65.03 ± 4.91 vs − 37.69 ± 4.15 mg/dl (P < 0.0001). The ICER was INR. 269.85 per unit of HbA1c reduced. Among the four domains of WHOQOL, the highest mean satisfaction rating was found in teneligliptin treated patients (Group A) compared with Group B. Net change in HDL from the baseline was 1.27 ± 0.30 vs − 0.37 ± 0.21 mg/dl (P = 0.02) in group A and group B, respectively. Conclusion: This is the first study to demonstrate pharmacoeconomic evaluation of teneligliptin. The study results suggest that treatment with teneligliptin adjunct with other hypoglycemic agents may be safe, economical therapeutic option for good glycemic control and improved quality of life in T2DM patients.

Keywords: Pharmacoeconomic evaluation, quality of Life, teneligliptin, type 2 Diabetes mellitus

   Correlation between subfractions of human adult hemoglobin and HbA1c Top

Vikas Malineni, K. Ramalingam1, Sunanda Tirupati, Vijaya Sarathi, Dileep Kumar

Departments of Endocrinology, 1Biochemistry, Narayana Medical College and Hospital, Nellore, Andhra Pradesh, India.

E-mail: [email protected]

Background: There is limited data on the correlation of other subfractions of human adult haemoglobin (HbA) with HbA1c. Aim: To find correlation of HbA1c by HPLC with other subfractions of HbA. Materials and Methods: This retrospective study was conducted at a tertiary health care centre from south India. The study included 4065 adult subjects in whom HbA1c was tested by high performance liquid chromatography using Biorad-D10, HPLC results were analysed for area and percentage of HbA1a, HbA1b, HbA1c and P3 fraction (degraded haemoglobin). Patient data was divided into five groups based on HbA1c level (group I: <5.7%, group II: 5.7-6.4%, group III: 6.5-7.9%, group IV: 8-9.9%, group V: ≥10%). Result: HbA1c had significant positive correlation with P3 fraction (r = 0.407, P < 0.0001), HbA1a (r = 0.17, P < 0.0001) and HbA1b (r = 0.031, P = 0.047). P3 fraction increased constantly as the severity of hyperglycaemia increased whereas HbA1a was not different between group I (euglycemia) and II (prediabetes range) but increased constantly with increasing severity of hyperglycaemia in diabetics. HbA1b increased from euglycemia to moderate hyperglycemia (6.5-7.9%) but decreased with further increase in hyperglycemia. Conclusion: Of all the subfractions of HbA, P3 fraction had the strongest positive correlation with HbA1c. This finding may represent detrimental effects of hyperglycemia on haemoglobin structure.

Keywords: HbA1a, HbA1b, HbA1c, P3

   A review on the effect of SGLT2i and GLP 1 analogues on hospitalization for heart failure in adults with type 2 diabetes mellitus Top

Sagar Panchal, Ashwani Mehta1, Subodh Chandra2, Anil Rajani, Amey Mane

Janssen Medical Affairs, Mumbai, Maharashtra, 1Department of Cardiology, Sir Gangaram Hospital, Delhi, 2Department of Medicine, Kailash Hospital, Noida, Uttar Pradesh, India.

E-mail: [email protected]

Aims and Objectives: To analyze the effect of SGLT2i and GLP 1 analogues on risk of hospitalization for heart failure (HHF) seen in CVOTs as well as some observational studies. Methodology: Search terms like SGLT2 inhibitors, GLP 1 analogues, hospitalization for heart failure were used in pubmed which showed 22 articles. Out of that, 8 articles were selected according to inclusion criteria of study. Results: CVOTs of two SGLT2 i have shown statistically significant risk reduction of HHF - CANVAS program [33%] HR 0.67 (0.52 – 0.87), EMPA REG [35%] HR 0.65 (0.50 – 0.85).GLP1 analogues did not show statistically significant effect on the risk of HHF. Numerical difference from placebo in the risk of HHF was (-) 13% for liraglutide (LEADER), (−) 4% for lixisenatide (ELIXA), and (+) 11% for semaglutide (SUSTAIN 6). A retrospective, observational studies comparing SGLT2 i against other glucose lowering agents in real world settings also showed statistically significant reduction in risk of HHF - CVD REAL (39%) (HR 0.61), CVD REAL 2 (36%) (HR 0.64), EASEL (43%) (HR 0.57). Conclusion: CVOTs as well as real world studies of SGLT2 I suggest significant CV beneficial effects by reducing risk of HHF as compared to standard of care.

Keywords: Canagliflozin, liraglutide, T2DM

   Positive cardiovascular outcome trials- Review on risk reduction of cardiometabolic risk factors and applicability to clinical practice Top

Sagar Panchal1, Richa Chaturvedi2, Neeraj Pandit3, Mayuresh Fegade1, Amey Mane1

1Janssen Medical Affairs, Mumbai, Maharashtra, 2Department of Endocrinology, Indraprastha Apollo Hospital, 3Department of Cardiology, Dr. Ram Manohar Lohia Hospital, Delhi, India.

E-mail: [email protected]

Aims and Objectives: To compare and analyze risk reduction of cardiometabolic risk factors seen in positive cardiovascular trials of antidiabetic drugs and applicability of the results to clinical practice of T2DM. Materials and Methods: Relevant articles on 4 positive CVOTs (CANVAS program, EMPA REG OUTCOME, LEADER, SUSTAIN 6) were searched on pubmed and google scholar and data on (HbA1C, weight, SBP, DBP, LDL-C, HDL-C, HR) obtained was compared and analyzed. Results: All 4 trials have shown significant reduction in HbA1C (semaglutide [−1.5%], canagliflozin [0.58%], liraglutide [−0.4%], empagliflozin [-0.3%]) and weight (semaglutide [−4.4 kg], liraglutide [−2.3 kg], empagliflozin [−2 kg], cana [−1.6 kg]). Both SGLT2i have shown significant reduction in SBP (cana [−3.93 mm Hg], empa [4 mm Hg]) and DBP (cana [−1.93 mm Hg], empa [−1 mm Hg]). Both cana and empa have shown a numerical increase in level of LDL-C (empa [+5.3 mg/dl], cana [+4.68 mg/dl]). Both GLP-1 analogues have shown a moderate increase in heart rate (liraglutide [+3 beats/min], semaglutide [+2.5 beats/min]). Conclusions: All 4 positive CVOTs have shown decrease in cardiometabolic risk factors except few parameters (LDL- C and HR). CANVAS program had broader patient population compared to other CVOTs.

Keywords: Canagliflozin, SGLT2I, T2DM

   Management of cognitive decline in T2DM - SGLT2 inhibitors at horizon Top

Sagar Panchal, Sudhir Chhabra1, Brij K. Prasad2, Biswajit Aich, Anil Rajani

Janssen Medical Affairs, Mumbai, 1Department of Medicine, Mata Chanan Devi Hospital, Delhi, 2B K Prasad Clinic, Faridabad, Haryana, India.

E-mail: [email protected]

Aims and Objectives: To review data available on different mechanisms by which SGLT2 inhibitors can be found to be effective in the management of cognitive decline in patients with T2DM. Materials and Methods: Relevant articles were searched on Pubmed using search terms like dementia, cognitive decline, SGLT2I in dementia. We got 22 articles, out of which 4 articles were selected according to inclusion criteria of this study. Results: In an experimental study by Arafa et al., canagliflozin significantly changed balance of cortical neurotransmitters by inhibiting AchE and increasing monoamine and amino acid levels. Sg-Nguuanmoo et al. in experimental study, therapy with dapagliflozin improved peripheral insulin sensitivity, brain mitochondrial function, CNS insulin signaling, apoptosis and prevented cognitive decline in HFD induced rat model. In Rizvi et al. enzoinformatics study, canagliflozin inhibited AchE enzymes levels, elevated levels of which are considered to be main culprit in alzheimers disease. Arafa et al. showed that canagliflozin significantly decreases AChE levels and increases monoamine levels compared to galantamine in scopolamine induced memory dysfunction in rats. Conclusion: Pre-clinical studies suggest that SGLT2 Inhibitors might be a novel therapeutic approach for preventing and treating cognitive decline in T2DM but translational clinical trials are needed to further support this hypothesis.

Keywords: Alzheimers, canagliflozin, memory

   Clinical effectiveness of combination therapy with dulaglutide, SGLT2 inhibitor and metformin with or without insulin in Indian adults with type 2 diabetes: A real-world retrospective study Top

Supratik Bhattacharyya

Department of Endocrinology and Diabetes, AMRI Hospital, Salt Lake, Kolkata, West Bengal, India.

E-mail: [email protected]

Objectives: This study examined real-world clinical effectiveness of combination therapy including dulaglutide, higher doses of SGLT2i and metformin with or without insulin in patients with inadequately controlled type 2 diabetes mellitus (T2DM). Materials and Methods: This retrospective, real-world, single-centre study included 15 patients (men, 9; mean age: 49.47 years; mean BMI: 32.27 kg/m2) with inadequately controlled T2DM. The patients received a combination of dulaglutide, higher doses of SGLT2i (Canagliflozin, Empagliflozin or Dapagliflozin) and metformin with or without insulin. Changes in fasting blood glucose (FBG), post-prandial blood glucose (PPBG), HbA1c and body weight were examined for a follow-up duration of 3 months. Self-reported adverse events were noted. Statistical analysis was performed using paired t-test. Results: At 3-month follow-up, there was a significant reduction (P <.001) in FBG and PPBG from baseline with a mean reduction (MR) of 66.67 ± 40.05 mg/dL and 83.33 ± 64.11 mg/dL respectively. There was a significant (P <.001) reduction in HbA1c with MR of 1.78 ± 1.08%. In addition to improvement in the glycaemic parameters, there was a significant reduction (P <.001) in the body weight with MR of 6.40 ± 3.96 kg and corresponding BMI with MR of 2.67 ± 1.63 kg/m2. The therapy was well tolerated; however, self-reported gastrointestinal symptoms were reported in 5 patients, which subsided within 2 weeks of therapy initiation. In conclusion, combination therapy with dulaglutide, higher doses of SGLT2i and metformin with or without insulin improves glycaemic control and reduces body weight in inadequately controlled Indian patients with T2DM.

Keywords: Dulaglutide, inadequately controlled, SGLT2i, type 2 diabetes mellitus

   A review of the effect of different newer generation anti-hyperglycemic agents on heart rate Top

Biswajit Aich, Debasis Ghosh1, Debasis Basu2, Anil Rajani, Amey Mane

Janssen Medical Affairs, Kolkata, West Bengal, India, 1Departments of Cardiology, 2Endocrinology, Apollo Hospitals, Kolkata, West Bengal, India.

E-mail: [email protected]

Aims and Objectives: Type 2 diabetes mellitus (T2DM) and its complications cause a large and growing burden of disease around the world. Effective control of blood glucose levels is central to the management of symptoms and the prevention of complications. Cardiovascular Disease is one of the few diseases associated with T2DM. In patients with type 2 diabetes mellitus, higher heart rate (HR) is associated with an increased risk of death and cardiovascular complications. The newer generation Anti Hyperglycemic Drugs are known to be associated with changes in Heart Rate (HR). Materials and Methods: A PubMed search was performed using the following key words “GLP1 Agonists” or Dapagliflozin or Canagliflozin or Empagliflozin AND Heart Rate. Search revealed 52 articles. Data are collected from few major CVOT trials of GLP1 RA and other original phase 3 studies. Hence, we evaluate the effects on Heart Rate of different Anti hyperglycemic agents. Results: It has been found that the GLP1 receptor agonists increased Resting Heart Rate (RHR). Liraglutide is associated with an increase of 3 BPM as compared to Placebo in LEADER trial. Lixisenetide also increased HR of 1 beat per minute in ELIXA trial. Whereas Exenatide is associated with an increase of 2.51 BPM in EXSCEL, and semaglutide is associated with 2-2.5 BPM in SUSTAIN 6 trial. In a 12-week study, Exenatide-infusion increased RHR (+7.5 ± 0.9 BPM) while liraglutide increased RHR (+6.6 ± 2.1 BPM). SGLT2 inhibitors are not associated with rise in Heart Rate.

Keywords: Canagliflozin, dapagliflozin, empagliflozin, heart Rate

   Mauriac syndrome: A forgotten complication of type 1 diabetes Top

Krishna R. Thaduri, Vijay S. R. Danda, Sreedevi Patnala, Apsia Ruhi

Department of Endocrinology, Gandhi Medical College/Hospital, Secunderabad,Telangana, India.

E-mail: [email protected]

Introduction: This syndrome was first described by Mauriac, in 1930. It is characterised by poor glycaemic control, in a genetically susceptible individual, leading to glycogen deposition in liver with consequent hepatomegaly, associated with short stature and delayed puberty. Short stature in Mauriac syndrome is probably due to low GH, IGF 1, and hypercortisolemia. Case Report: 17-year-old male, type 1 DM diagnosed 8 years back, on premixed biphasic insulin twice daily, presented with progressive abdominal distension for 1 year, abdominal pain since 10 days. He had jaundice 2 months back, resolved spontaneously. On examination he had proportionate short stature (−3.95 SDS), wasted (weight −3.86SDS), Tanner pubertal staging G2P1A1, abdominal distension with hepatomegaly (15 cm). Investigations revealed high blood sugars 648 mg%, elevated HbA1C s/o poor glycaemic control, anemia (7.6 g/dl), mild elevation of AST (52 U/L). CT scan abdomen revealed hepatomegaly (19 cm) with increased attenuation-S/o Glycogen storage/pigment deposition. With strict glycaemic control over a period of 6 months his hepatomegaly regressed and improvement in stature noted (4.5 cm gain). Discussion: Mauriac syndrome is an infrequently encountered complication of Type 1 DM in the present day due to improved medical care. Majority of cases seen in patients with probable underlying genetic susceptibility, and in those managed with premixed insulin. Awareness of this entity will prevent undue extensive evaluation for glycogen storage disorders. Management is directed at good glycemic control with basal bolus therapy. Prognosis is good.

Keywords: Gycogen storage, mauriac, hepatomegaly, type 1 diabetes

   Saponins from the fruit of Solanum anguivi reverses hyperglycemia, hyperlipidemia and increase antioxidant status in stretozotocin induced diabetic rats Top

*Isaac Gbadura Adanlawo1, Oluwamodupe Cecilia Ejelonu2, Olusola Olalekan Elekofehinti3

1Department of Biochemistry, Ekiti State University, Ado Ekiti, Ekiti State, 2Department of Biochemistry, Adekunle Ajasin University, Akungba, Akoko, 3Bioinformatics and Molecular Biology Unit, Federal University of Technology, Akure, Ondo State, Nigeria.

E-mail: [email protected]

Objective: The aim of this work was to investigate the antihyperglycemic, antioxidant and antihyperlipidemic effects of saponins from the fruit of Solanum anguivi, a plant generally used in treatment of diabetes and hypertension and to compare its effect with metformin in streptozotocin (STZ)-induced diabetic rats. Materials and Methods: Diabetes was induced in albino rats by administration of STZ (65 mg/kg) intraperitoneally. Saponin (40 and 100 mg/kg) was administered by oral gavage once daily for 21 days. Metformin (200 mg/kg b.w.) was administered as the positive control. The effect of saponin on blood glucose, serum lipids and enzymatic antioxidants defence systems, like superoxide dismutase (SOD), catalase (CAT), as well as MDA levels in serum, liver and pancreas were studied. Results: Our results showed that saponins from Solanum anguivi fruit reduced the blood glucose, total cholesterol (TC), triglycerides (TG) and low-density lipoprotein (LDL) levels in STZ-diabetic rats. It also significantly abolished the increase in MDA level in serum, liver and pancreas. The activities of SOD and CAT in serum, liver and pancreas were significantly increased as well as concentration of HDL in the serum. Metformin had the same effect as saponin but saponins seems to be more potent in reducing serum TC, TG, LDL and MDA, and increasing SOD and CAT. Conclusions: These results suggest that saponins from S. anguivi fruit have anti-diabetic and antihypercholesterolemic, antihypertriglyceridemic antiperoxidative activities mediated through their antioxidant properties. Saponins have more hypolipidemic, antiperoxidative and antioxidant activity than metformin.

Keywords: Anti diabetic compounds, diabetes, medicinal plants, phytochemical, saponins

   Hormonal alterations as a function of insulin resistance (IR) in young males with untreated metabolic syndrome and diabetes Top

Warun Kumar MR, Praveen VP, Harish Kumar

Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.

E-mail: [email protected]

Background: Hormonal alterations in GH, IGF 1, testosterone and DHEAS resulting from insulin resistance and diabetes has been studied individually with conflicting conclusions. Aims and Objectives: To assess the relationship of metabolic and hormonal parameters to insulin resistance compared to controls with special emphasis on DHEAS. Materials and Methods: 17 adult males aged 30-45 years with metabolic syndrome and untreated type 2 diabetes and 12 age/sex matched controls were included. FBS, free fatty acids (FFA), Lipid profile, insulin, Growth hormone, IGF 1, total testosterone and DHEAS in controls were compared with metabolic syndrome/type 2 diabetes group. Insulin resistance was calculated by online HOMA2 tool. Results: Mean age was 36.5+/- 4.5 years. HOMA IR (1.7 vs 1.09, P 0.004) free fatty levels (0.89 vs 0.65 mmol/L, P 0.007) and insulin (11 vs 6.9 uIU/ml, P 0.016) were higher in the IR group whereas testosterone (14.7 vs 18.8 nmol/L, P value 0.003) was lower. Testosterone negatively correlated (−0.49, P 0.009) with FFA, but not with HOMA IR2. DHEAS was higher in IR (317 vs 230 ng/dl), but didn't achieve significance. However logistic regression showed a significant negative association between insulin levels and DHEAS (P value 0.01). Conclusion: Negative correlation between FFA and testosterone points towards mechanisms other than insulin resistance. DHEAS is influenced only by insulin resistance and not by other hormonal factors like GH axis alternations.

Keywords: DHEAS, free fatty acids, growth hormone, insulin resistance, testosterone

   Prevalence, clinical profile and follow up of asymptomatic bacteriuria (ASB) in patients with Type 2 Diabetes Top

Tauseef Nabi, Bashir A. Laway, Nadeema Rafiq1

Department of Endocrinology, SKIMS, Soura, 1Department of Physiology, GMC, Srinagar, Jammu and Kashmir, India.

E-mail: [email protected]

Background and Objectives: Patients with diabetes mellitus (DM) have asymptomatic bacteriuria (ASB) more often than those without DM. It is unclear, how the natural history of ASB in Type 2 Diabetes (T2D) patients behaves. The present study intended to study the prevalence, clinical profile, complications and follow up of ASB in T2D patients. Materials and Methods: This was a cross sectional prospective study done on 400 T2D patients with no symptoms of urinary tract infection (UTI) and 200 healthy controls. Various clinical, biochemical parameters and urine examination and culture were monitored. All the ASB T2D patients were followed for 6 months with respect to number of UTIs, glycemic control and renal parameters. Results: The prevalence of ASB at baseline was significantly higher in T2D (17.5%) as compared to controls (10%). E. coli was the most common organism. T2D ASB patients were mostly postmenopausal females, uncontrolled diabetes and long duration of diabetes. Presence of diabetic nephropathy, HTN, CKD, UTI in previous year, uncontrolled BP, obesity, lower eGFR, proteinuria and glycosuria increased the risk of ASB in T2D patients. Of the 64 T2D ASB patients followed till 6 months, 14 (21.8%) developed symptomatic UTI. Postmenopausal state, uncontrolled diabetes, longer diabetes duration, presence of diabetic nephropathy and glycosuria significantly increased the risk of development of symptomatic UTI. ASB in T2D patients who develop UTI leads to worsening of glycemic control with no effect on renal function on follow up. Interpretation and Conclusions: ASB in T2D patients can be consequences of or lead to uncontrolled glycemia. ASB patients who develop UTI leads to worsening of glycemic control but there was no effect on renal function on follow up.

Keywords: Asymptomatic bacteriuria, glycemic control, renal function, type 2 diabetes, urinary tract infection

   HbA1C at term in Indian women: Maternal and neonatal implications Top

R. V. Jayakumar, C. Jayakumari1, P. K. Jabbar1, C. Nirmala2, Abilash Nair1, Geena S. George1

Indian Institute of Diabetes, Thiruvananthapuram, Kerala, India, 1Departments of Endocrinology, 2Obstetrics and Gynaecology, Government Medical College, Trivandrum, Kerala, India.

E-mail: [email protected]

Introduction: Whether HbA1c can be used as an estimate of glycemic status in third trimester or not is still not clear as there is no consensus regarding the normal range of HbA1c during pregnancy and its relation with maternal and fetal outcome is very scantily studied. Aims: The aim of the present study was to find the normal range of HbA1c during the third trimester of pregnancy and to assess its relationship with the maternal and fetal outcomes. Materials and Methods: All consecutive patients admitted to the labour room of Govt Medical College Thiruvananthapuram during the study period were included after Informed written consent. Details about current pregnancy the obstetric history, comorbidities, previously diagnosed diabetes and details of were collected. Maternal blood in first stage of labour and fetal blood (cord) was collected from all participants. Maternal HbA1C was estimated using HPLC method (Biorad D10) and random blood glucose were estimated by glucose oxidase (GOD-POD) method fetal serum insulin estimated (excluding hemolysed samples) using Roche Eclisys 2000 (ECLIA) at the Indian Institute of Diabetes, Trivandrum. Results: Interim analysis of data from first 303 patients enrolled was done. Eighty seven had gestational diabetes mellittus and 2 had overt diabetes, 29 of them are on insulin and one patient was treated with Metformin. In the non diabetic subjects average HbA1c was 5.05 ± 0.33. Hence an upper limit of normal can be proposed to be mean ±2 SD i.e. 5.71%. Patients with an HbA1C above 5.5 had higher body weight and bmi at conception although the weight gain among the 2 groups was comparable. The placental weight was higher in the group with higher HbA1C. There is a trend towards higher birth weight in group with higher HbA1C and may assume significance when more patient results are available. Of all the available glucose readings throughout pregnancy 2 hour post glucose values in second trimester was associated with higher HbA1C at term. In this interim review the cord blood insulin did not correlate with the HbA1C values. Conclusion: The study defines the normal value of HbA1C in the third trimester of pregnancy in South Indian patients, and relates it with pregnancy outcomes although more information will be available once the study gets completed.

Keywords: HbA1c, maternal, neonatal, pregnancy

   Identifying predictive factors for development of Post Transplant Diabetes Mellitus (PTDM) in those undergoing renal transplant Top

Krithika D. Muralidhara1, Ram Mohan Bhat2, Krishna Kishore1, Subramanian Kannan2

1Departments of Nephrology, 2Endocrinology Diabetes and Metabolism, Narayana Health City, Bengaluru, Karnataka, India.

E-mail: [email protected]

Context: PTDM has various implications with regard to allograft function, cardiovascular morbidity and mortality and thus the quality of life. The data on the prevalence of PTDM in India comes from single centre retrospective studies. Indian data on newly identified risk factors for PTDM like trace element deficiency, pre-transplant inflammatory status and Post-transplant Transient Hyperglycemia are insufficient. Aims: To study the incidence of Post Transplant Diabetes Mellitus (PTDM) at 6 months post renal transplantation and identify the risk factors at a tertiary care centre with primary objective to study the incidence of PTDM at 6 months post renal transplant and secondarily study the pre-transplant C-reactive protein (CRP) level, trace element deficiencies and Home based Self Monitoring of Blood Glucose in the prediction and early diagnosis of PTDM. Settings and Design: Prospective observational cohort study in non-diabetic patients undergoing renal transplant for 6 months. Results: The incidence of PTDM in our study was 36.6%. The cumulative incidence was 20% at month 1, 30% at month 3 and 36.6% at month 6 of follow-up post transplant. The mean age of our patients was 36 years with males constituting majority of the study population. Among the patients undergoing transplant one patient received pre-emptive renal transplant. The rest were on either Hemodialysis or Peritoneal dialysis with an average dialysis vintage of 9 months. The predominant cause of ESRD due to Non Diabetic Kidney Disease was Chronic Glomerulonephritis in our study. In this cohort, only two patients received deceased kidney donation while the rest received live kidney donation. A higher degree of HLA mismatch was seen in two third of the patients who received induction therapy prior to transplant, while the rest one third underwent transplantation without induction therapy. The rejection episodes in our cohort was 22%. Zinc levels were found to be significantly low in those who developed PTDM (P < 0.05). The presence of Post Transplant Transient Hyperglycemia (PTTH) was found to have significant association with future development of PTDM. Post transplant, all the patients were followed up for a period of six months. During the follow up, we used gluometer based home monitoring of glucose to detect hyperglycemia early. We found a characteristic pattern of post prandial hyperglycemia with fasting euglycemia in those who developed PTDM. The glycemic excursions were found to happen at post-lunch and post- dinner time points. A diagnosis of PTDM in two thirds of our patients was made by home monitored glucose values meeting the ADA criteria. Conclusions: One third of patients undergoing renal transplant develop PTDM. Age, PTTH, Zinc deficiency and Post-Lunch hyperglycemia were predictors for development for PTDM.

Keywords: Home monitoring, PTDM, PTTH, Zinc

Key Messages: One third of patients undergoing renal transplant develop PTDM. Age, PTTH, Zinc deficiency and Post-Lunch hyperglycemia were predictors for development for PTDM.

   Risk factors and Clinical profile of Stroke in type 2 diabetes mellitus Top

Jyotula Siva Kalyani, B. Vivekanand, A. Mythili, Jayanthy Ramesh, K. A. V. Subrahmanyam

Department of Endocrinology, Andhra Medical College, King George Hospital, Visakhapatnam, Andhra Pradesh, India.

E-mail: [email protected]

Background: Diabetes Mellitus (DM) is one of the established risk factors for stroke and has an influence on the age and severity of presentation. Aim: To identify the risk factors and evaluate the clinical profile of stroke in patients with Type 2 DM. Materials and Methods: Included 54 stroke patients with Type 2 DM from King George Hospital, Visakhapatnam from July 2017 to May 2018. A detailed history, physical examination and estimation of HbA1c, lipid profile and Carotid Intima Media Thickness (CIMT) was performed. In patients with ischemic stroke, correlation of CIMT with Non-HDL Cholesterol, HbA1c, SBP and MAP was analyzed. Results: Out of 54 patients, 30 (55.56%) were males and 24 (44.44%) were females with a mean age of 46.5 years. 88.89% patients had ischemic stroke and 11.11% had hemorrhagic stroke. Hemiplegia/Hemiparesis (76%) was the most common presentation followed by hemisensory loss (11.11%). All hemorrhagic strokes involved MCA territory whereas, among ischemic strokes, 68.75% involved MCA, 25% PCA, 4.16% ACA and 2.08% ICA territories. Hypertension was present in 72.2% patients and smoking in 35.18% patients. Posterior circulation stroke was significantly high among non-smokers compared to smokers. Majority of patients with ischemic stroke had CIMT > 1 mm and CIMT showed a significant positive correlation with Non-HDL cholesterol but not with HbA1c, SBP and MAP. Conclusion: Majority of patients with Type 2 DM developed ischemic stroke. So, targeting modifiable risk factors such as hypertension and Non-HDL Cholesterol could reduce the stroke events.

Keywords: Carotid intima media thickness, non-HDL cholesterol, stroke, type 2 diabetes mellitus

   Chronic unpredictable environmental stress impairs biochemical and physiological homeostatsis: Role in diabetes mellitus Top

Alok Raghav1, Jamal Ahmad1, Imrana Naseem2

1Rajiv Gandhi Centre for Diabetes and Endocrinology, J.N Medical College, Aligarh Muslim University, 2Department of Biochemistry, Faculty of Life Sciences, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.

E-mail: [email protected]

Introduction: Chronic unpredictable environmental stress (CUES) may induce predisposition to diabetes mellitus. Aims and Objectives: This study investigates the role of CUES on impaired homeostasis. Methodology: Stressed group mice (n = 20) were exposed to CUES for 16 weeks. Weekly body weight, feed consumption, feed efficiency ratio, fasting blood glucose were monitored. Plasma HbA1c, plasma cortisol, plasma epinephrine and plasma insulin, serum lipids, antioxidants and carbohydrate metabolizing enzymes activity were assessed along with DNA damage and histopathological examination of liver, kidney, pancreas, spleen and skeletal muscles. Results: Fasting blood glucose levels and HbA1c in the stressed were significantly higher compared to control (P < 0.001). Serum lipids were found insignificantly higher in stressed mice compared to control. Body weights of the stressed mice and feed efficiency ratio were found significant (P < 0.001). Plasma corticosterone, plasma epinephrine, HOMA-IR was found to be significantly higher in the stressed group (P < 0.001). Plasma insulin level was found to be significantly lower in the stressed group (P < 0.001). Significant changes were observed in antioxidants level, carbohydrate metabolizing enzymes activity, peripheral tissues and DNA integrity. Conclusions: CUES initiates pathogenesis of diabetes.

Keywords: Antioxidants, carbohydrate metabolism, chronic unpredictable environmental stress, diabetes mellitus, ROS

   Study of efficacy and safety of SGLT2 inhibitor in comparison with DPP4 inhibitor in subjects with type 2 diabetes mellitus inadequately controlled on metformin-in Eastern Indian population Top

Arindam Ray, Pranab K. Sahana, Nilanjan Sengupta, Arjun Baidya, Soumik Goswami, Sreenath R

Department of Endocrinology, Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: We have insufficient data comparing efficacy and safety between sodium glucose co-transporter2 inhibitors (SGLT2i) and dipeptidyl peptidase 4 inhibitors (DPP4i) to chose as second anti diabetic agent after metformin. Objective: To evaluate efficacy (glycaemic control) and safety [genital mycotic infection (GMI), urinary tract infection (UTI), ketosis] of SGLT2 inhibitor (Canagliflozin) compared with DPP4 inhibitor (linagliptin) as add on therapy to metformin in T2DM subjects inadequately controlled on metformin and to study the effect of Canagliflozin on beta cell function and insulin resistance in T2DM subjects. Materials and Methods: • 12 wks open label longitudinal prospective interventional study (n = 41 in each arm). • Subjects recruited asper inclusion and exclusion criteria from patients attending diabetes OPD at Nilratan Sircar Medical College and Hospital, Kolkata using a random table during April, 2017 to June, 2018 and evaluated according to proforma. Results: At the end of 12 wks, statistically significant reduction of FPG (44.1 vs 27.71), PPPG (72.27 vs 42.17), HbA1c (0.7 vs 0.48) was observed in Canagliflozin arm compared to linagliptin arm (P < 0.05). There was also statistically significant increment of HOMA-beta (354.82 vs 219.3) with reduction of c-peptide (-0.43 vs -0.13), fasting insulin (-0.29vs -0.06), HOMA-IR (-0.37 vs -0.2) in Canagliflozin arm compared to linagliptin arm (P < 0.05). Single incidence of GMI was observed with no UTI or ketosis in canagliflozin arm, statistically not significant. Statistically significant reduction of weight, BMI, diastolic blood pressure in Canagliflozin arm compared to linagliptin arm (P < 0.05) had also seen. Conclusion: Canagliflozin can be superior anti diabetic agent than linagliptin from glycemic efficacy with insignificant increments of adverse effects like (GMI, UTI, ketosis) improving beta cell function and reduce insulin resistance at the same.

Keywords: DPP4i, GMI, ketosis, SGLT2i, UTI

   Tech-savvy type 2 diabetics spend more time on social media Top

Hariballav Mahapatra1,2, Susant Mishra2, Monalisa Khuntia1, Abhay K. Sahoo2, Laxminarayan Mahapatra1, Bikram K. Mishra1, Madhabananda Dash1

1Sevayan Diabetes Centre and Jyoti Diabetes Research Foundation, Puri, Odisha, India, 2IMS and SUM Hospital, SOA University, Bhubaneswar, Odisha, India.

E-mail: [email protected]

Background and Aim: India has world's second largest number of internet users. Getting connected with family and friends, social networking, professional communications and financial transactions are principal reasons behind the upraise of internet usage. Receiving and maintaining laboratory test records, keeping tracks of the trends of fluctuations, scheduling physicians' appointment, and pill and consultation reminder have been made possible by smart phone based applications. We studied the attitude of internet using type 2 diabetic (T2DM) subjects who attended a specialised diabetes centre in Eastern India. Methodology and Results: Internet-savvy T2DM subjects (n = 234, M126:F108) who responded to a semi-structured questionnaire administered during their regular office visit, were recruited. Majority of the cohorts were graduated and were jobholders. The participant-disclosed mean time spent in internet-surfing was 52.5 ± 10.3hours/month. High proportion (95.7%) of them had active social media account. Facebook was the most used platform followed by WhatsApp. Mobile phones (96%) and computers (42%) were the preferred devices for internet-surfing. More than one third (35.9%) of the subjects were subscribers of health related groups. While 7.9% sought or extended help on internet regarding health aspects, only 4.0% preferred to post the same. Despite the widespread penetration of internet, print media was the commonest search media (43.59%) for health followed by Facebook. Those who were not using internet described lack of time as the main obstacle. Conclusion: Internet-savvy T2DM subjects spend more than 50 hours per month in internet-surfing. They choose social interaction over health issues.

Keywords: Diabetes, internet, social media

   Can Diabetic Ketoacidosis occur in patients with Fibrocalcific Pancreatic Diabetes (FCPD)?- Evidence for a “glucagonocentric” approach based on Euglycaemic-Hyperinsulinemic clamp studies from a South Indian tertiary care hospital Top

Riddhi D. Gupta, Anneka Wickremanayake3, Shajith Anoop, Roshna Ramachandran, Padmanaban V, Flory Christina, Joe Fleming1, Roshan Livingstone2, Felix Jebasingh, H. S. Asha, Thomas V. Paul, Meredith Hawkins3, Nihal Thomas

Department of Endocrinology, Diabetes and Metabolism, CMC Vellore, Tamil Nadu, India, 1Departments of Biochemistry, 2Radiology, 3Endocrinology, Albert Einstein College of Medicine, New York, USA.

E-mail: [email protected]

Introduction: Fibrocalcific pancreatic diabetes (FCPD) has been traditionally regarded as ketosis-resistant due to lack of glucagon. However, recent studies suggest the possibility of increased glucagon secretion in FCPD. We hypothesized that hyperglucagonemia in FCPD will be lead to occurrence of Diabetic ketoacidosis and will affect their glucose and lipid metabolism significantly. Objectives: To identify the potential role of hyperglucagonemia in contributing to the occurrence of DKA in patients with FCPD. Materials and Methods: Patients admitted with DKA under Endocrinology over a period of 2015-2016 were screened for the presence of FCPD. A total of n =5 patients were identified. These were compared with n =15 FCPD patients without DKA and n =15 T1DM patients with definite history of DKA. 5-hr Mixed-meal-challenge tests to evaluate insulin, C-peptide and glucagon secretion rates, 1-H-NMR-spectroscopy of hepatic and myocellular lipids were done in all. The study subjects underwent 6-hr-Euglycemic-hyperinsulinemic-pancreatic-clamp studies to evaluate hepatic and peripheral insulin resistance. Results: C-peptide deconvolution showed suppressed Insulin secretion rates (P=0.2) in the three groups while glucagon secretion rates (AUC) were significantly higher (P <0.01) in FCPD with DKA (26686.9± 5175.5) than FCPD without DKA (8557.1± 2969.8) and T1DM with DKA (12222.6± 2459.8). NMR-spectroscopy revealed greater Hepatocellular lipid (P =0.01) content in FCPD with DKA, compared to the other two groups. Clamp-studies showed significantly higher hepatic insulin resisatnce (P =0.01) in FCPD with DKA compared to the other two groups. Glucagon levels were found to correlate with hepatic lipid content (P =0.02) and hepatic insulin resistance (P <0.01) amongst FCPD with DKA. Conclusions: This is the first study that identifies hyperglucgaonemia as a pathogenetic factor in FCPD patients with DKA. Further, this increased glucagon is associated with hepatic steatosis and hepatic resistance, thus providing a novel pathogenetic model.

Keywords: Clamp, DKA, FCPD, glucagon

   Does the noveL InsuTag index (fasting insulin X fasting triglyceride) perform better than established surrogates in predicting insulin resistance?-Insights from hyperinsulinemic-euglycaemic clamp studies in healthy normoglycaemic Asian Indians Top

Riddhi D. Gupta, Roshna Ramchandran, Shajith Anoop S, Grace Rebekah1, Ib Bygbjerg2, Nihal Thomas

Departments of Endocrinology, Diabetes and Metabolism, 1Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India, 2Department of International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.

E-mail: [email protected]

Introduction: There is a paucity of adequate surrogate markers of insulin resistance in Asian-Indian population. Objectives: To assess the predictive accuracy of InsuTag index as a novel surrogate of insulin resistance (IR) in comparison to Hyperinsulinemic-Euglycaemic-Clamp (HEC)-derived M-value in normoglycemic Asian-Indians. Further, the performance of InsuTag was compared to established surrogates of IR. Materials and Methods: HEC and 75-gm-OGTT were performed in a cohort of 117 normoglycemic men aged between 18-22 years.Insulin resistance was defined by the rate of glucose disposal (M-value) derived from HEC studies. InsuTag Index was defined as product of fasting serum insulin (uU/ml) and Triglyceride levels (mmol/L). Data were analysed using Pearson's correlations and stepwise multiple regression. The sensitivity and specificity of InsuTAG values were measured by constructing the Receiver operating characteristic curves (ROC) and Youden's Index. Results: InsuTag scores ranged from 1.33 to 177.6 (median: 14). InsuTagcorrelated significantly with BMI (P = 0.02) and waist-circumference (P = 0.001). InsuTag significantly correlated with the HEC-derived M-value (r = −0.230, P = 0.01). InsuTag also correlated with established surrogates of IR like Matsuda (r = −0.22, P = 0.01), QUICKI (r = −0.34, P = 0.001) and fasting glucose-insulin ratio (r = −0.35, P = 0.001). However it did not correlate with HOMA-IR, Disposition index and Insulinogenic index. AUC by ROC was highest for InsuTag (AUC = 0.80, P = 0.02) compared to other surrogates suggesting its higher IR predictive value.The optimal cut off value for InsuTag in predicting IR was derived as ≥ 19.1 using ROC analysis (Sensitivity: 80%, Specificity: 66.1%, PPV: 9.5%, NPV: 98.7%, LR: 2.36, Youden's index: 0.46). Further, IR could be predicted from InsuTag using the equation: M-value = 11.299- (0.040 × InsuTAG). Conclusion: This is the first study amongst Asian-Indians to successfully validate the predictive accuracy of the novel InsuTag index in comparison to the gold-standard HEC-technique. The superior performance of InsuTag compared to established surrogates can be utilized for early detection of insulin resistance in Asian Indians.

Keywords: Clamp, insulin resistance, novel, triglyceride

   Prevalence of asymptomatic pulmonary hypertension in patients of metabolic syndrome with obstructive sleep apnoea Top

Surabhi V. S. Krishna1,2

1Command Hospital (NC), Udhampur, Jammu and Kashmir, India, 2Secunderabad, Hyderabad, Telangana, India.

E-mail: [email protected]

Aim: To find out the prevalence of asymptomatic pulmonary hypertension in metabolic syndrome patients who have obstructive sleep apnoea. Objectives: 1. To find out presence of pulmonary hypertension by 2D ECHO who have metabolic syndrome by WHO diagnostic criteria (presence of insulin resistance plus any of the following two criteria, namely hypertension, hypertriglyceridemia, low HDL, BMI >30 mg/kgm2, urinary albumin: creatinine ratio >30 mg/dl) and obstructive sleep apnoea done by polysomnography. 2. To assess hyperglycemic status in patients of metabolic syndrome with obstructive sleep apnoea and asymptomatic pulmonary hypertension. Materials and Methods: 1. Study population: All patients attending tertiary care out patient department for type 2 diabetes/pre diabetes/dyslipedemia/hypertension/obesity were screened for presence of metabolic syndrome features. 2. Study design: Prospective Observational analytical study. 3. Methodology: Clinical and dermographic data of patients screened positive for metabolic syndrome was obtained and underwent polysomnography by expertised lab technician using Philips Respronics and validated by oto-laryngeal surgeon of our hospital after taking consent from the patients. Cases having co-morbid conditions like coronary artery disease, diagnosed pulmonary hypertension, chronic obstructive pulmonary disease, any pathological lung condition are excluded. All cases of mild, moderate and severe obstructive sleep apnoea are screened for pulmonary artery pressures by 2D Echocardiography by cardiologist of our hospital. Results: As a pilot study 34 consecutive patients were found to have Metabolic Syndrome (MS) by WHO diagnostic criteria. 28 (82%) of MS patients have Obstructive Sleep Apnoea (OSA). 14 (50%) of them have Pulmonary Hypertension (PHT) by 2D Echocardiography. Prediabetes is more prevalent, 22 (65%) among MS patients than diabetes (32%). All but one patient who has no OSA is found to have moderate pulmonary hypertension [Diabetes with more >10 yr duration, hence 2D ECHO done), remaining 05 patients are pre -diabetic with no evidence of OSA {2D ECHO was not done} pulmonary hypertension]. Asymptomatic PHT is found in 6/12 (50%) of diabetics and in 8/22 (36%) in prediabetes. Except one, diabetes duration of all is less than 10 yr and all prediabetes recently detected within one year.

Keywords: Diabetes mellitus, metabolic syndrome, obstructive sleep apnoea, pulmonary hypertension

   Development and validation of knowledge, attitude and practice questionnaire for prediabetes Top

Mohsina Hyder K, Raja Durai, Ponnusankar Sivasankaran

Department of Pharmacy Practice, JSS College of Pharmacy, Ooty, Tamil Nadu, India.

E-mail: [email protected]

Aim and Objectives: To develop and validate a knowledge, attitude and practice assessment questionnaire for prediabetes. To find out the prevalence of prediabetes in the selected districts of Kerala and Tamilnadu. Materials and Methods: A draft of 45 questions were generated on experts opinion, group discussions and review of existing literature covering all aspects of prediabetes. 15 items were removed as they were assessed outmoded information. This self administered questionnaire was subjected to readability tests like Flesch-Kincaid readability test, Gunning fog index, Coleman Liau Index, SMOG Grade and automated readability index. Test retest reliability was carried out on 40 respondents. Pilot test were conducted in 100 prediabetics to ensure that the items could be correctly understood and interpreted. Factor analysis and cronbach's alpha were used to establish validity and reliability of the questionnaire. Kaiser-Meyer-Olkin test to show attitude items meet the criteria required for factor analysis. SPSS version 22 was used for statistical analysis. This questionnaire is used in Prediabetes Education Program (PEP) to compare baseline and after education scores. Results: The questionnaire obtained a flesch Kincaid reading ease score of 71.6, Gunning fog score 7.9 Coleman Liau index 11.7 smog index 7.3 and automated readability index 2.1 which indicated a result of fairly easy to read questionnaire. Reliability analysis of the 30 items gave a Cronbach's alpha coefficient for each domain >0.70.

Keywords: Assessment, attitude, knowledge, practice, prediabetes, questionnaire

   Spousal concordance of glycemic and cardiometabolic traits: An opportunity to target the household Top

Alpesh Goyal, Yashdeep Gupta, Nikhil Tandon

Department of Endocrinology and Metabolism, AIIMS, New Delhi, India.

E-mail: [email protected]

Aims and Objectives: To study the concordance of dysglycemia (prediabetes or diabetes) and cardiometabolic traits among spouses of women with history of previous gestational diabetes mellitus (GDM). Materials and Methods: Using hospital medical records, women with GDM diagnosed between 2012 and 2016 and their spouses were invited in a fasting state. Sociodemographic, anthropometric, medical data were collected and 75 gm OGTT with serum insulin estimation, HbA1c and fasting lipid profile were done at the hospital visit. Prediabetes and diabetes were defined using ADA criteria and metabolic syndrome defined using IDF criteria. Results: A total of 214 couples participated in the study. Women were tested at a mean age of 32.4 ± 4.6 years and at a median (IQR) of 19.5 (11-44) months following the index delivery while men were tested at a mean age of 36.4 ± 5.4 years. 72 (33.6%) couples showed concordance for dysglycemia while 99 (46.3%) and 51 (23.8%) couples were concordant for overweight/obesity and metabolic syndrome respectively. On univariate analysis, presence of dysglycemia and metabolic syndrome in women correlated positively with dysglycemia in men. Conclusions: High degree of spousal concordance shown in the study suggests social clustering of glycemic and cardiometabolic traits among biologically unrelated individuals due to shared sociocultural and environmental factors. This provides us with an opportunity to target the behavioral interventions at the” household” as a whole, which may be a novel and cost-effective method of combating the current diabetes epidemic.

Keywords: Cardiometabolic traits, dysglycemia, family intervention trial, household, spousal concordance

   Clinical spectrum of insulin autoantibody (IAA) syndrome: Data from a South Indian tertiary care centre Top

Rony Ruben, Praveen VP, Nisha Bhavani, Tittu Oommen, Aswin Pankaj, Usha Menon, Arun S. Menon, Nithya Abraham, Vasantha Nair, Harish Kumar

Department of Endocrinology, Amrita Institute of Medical Sciences, Cochin, Kerala, India.

E-mail: [email protected]

Aim and Objective: In this case series we describe the wide spectrum of presentations associated with IAA syndrome in patients with and without diabetes. Materials and Methods: Retrospective data of patients from hospital information system, with confirmed IAA syndrome in the time period 2008 to 2018 was used in this case series. The data included 19 (4 diabetic and 15 non diabetic) patients with varied presentations. Supervised fasting followed by estimation of venous plasma glucose values at the time of symptoms with estimation of Insulin (CMIA), C peptide (ECLIA) and Insulin autoantibody were done in all patients. Use of treatment modalities like steroids and plasmapheresis was also noted. Statistical analysis for various parameters was performed with SPSS Version 20 using standard techniques. Results: We came across 3 distinct presentations: 1. Hyperinsulinemic hypoglycaemia with (8 patients) or without post prandial hyperglycemia (7). 2. Initial presentation as Hyperglycemia progressing to Hypoglycaemia (1). 3. Extreme glycemic variability in patients with diabetes which responded to steroid therapy (3). Female preponderance (10:9), median age 62 years (17-73) and median duration of symptoms 3 months (0.5-6) was noted in our series. Median Insulin, C peptide and Insulin antibody titres were 300 uIU/ml (13-18200), 10.15 ng/ml (2.3-32.4) and 50 (18-300) respectively. 9 patients were initiated on steroids. Median duration of steroid use and time to resolution were both 3 months. Conclusion: IAA syndrome is an under recognized entity which can present with modest insulin levels and isolated postprandial hypoglycaemia.

Keywords: Dysglycemia, hyperinsulinemic hypoglycemia, insulin auto antibody, postprandial hypoglycemia

   A SMART and supportive digital tool for monitoring and managing diabetes: An Apollo Sugar app Top

Sambit Das, Sanjiv Shah1, Rabindera N. Mehrotra2, Ravi Sankar E2, Surya P. Reddy2, Jayaprakash Sai2, Kalpana Dash3, Balaji Jaganmohan4, Usha Ayyagari5, Surekha Tippisetty2, Vamsi K. Kolukula2, Shashank R. Joshi1

Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Bhubaneswar, Odisha, 1Apollo Sugar Clinics, Mumbai, Maharashtra, 2Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Hyderabad, Telangana, 3Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Raipur, Chhattisgarh, 4Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Bangalore, Karnataka, 5Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Chennai, Tamil Nadu, India.

E-mail: [email protected]

Aim: To evaluate the impact of health interactions through unique Apollo Sugar mobile app on glycaemic outcomes of T2DM patients. Materials and Methods: Apollo Sugar app is the brain child of Apollo Sugar Clinics an innovative centre of excellence for managing diabetes and endocrine disorders. It captures health coach and patient interactions, self-monitoring of blood glucose (SMBG) of patients, prescription and diet, and a 24/7 sugar buddy to resolves any kind of queries. The analysis was performed on meaningful health interaction on diet, insulin, medication, SMBG, hypoglycemia, blood glucose, and exercise between health coach and patients though app. Descriptive statistics was applied to analyse the data and to assess clinical outcomes. Results: Of 13447 app downloads 18500 interactions were captured of which 6000 were meaningful (883 patients) which includes on diet (24%), exercise (2%), medication change (18%), insulin dose (4%), hypoglycaemia (2%), SMBG based diabetes counselling (20%), and diabetes education (20%). 250 patients were regularly monitoring their SMBG, 65% of patients did > 2 times/week and 81% at least once/week. Nearly 40% of patients have achieved Pre-meal (70-130 mg/dL) and 25% achieved post-meal (<180 mg/dL) blood glucose and only 14% of patients recorded hypoglycaemic blood glucose values. Clinical outcomes were evaluated for only those patients who had followup HbA1c. At baseline mean HbA1c was 9.3% and at follow up HbA1c reduced to 8.2% with a mean difference of -1.1%; Baseline fasting and prandial blood glucose were 180 mg/dL and 268 mg/dL, at follow up 132 mg/dL and 229 mg/dL, with mean difference of − 48.1 mg/dL and − 39.1 mg/dL. Conclusion: Our analysis indicates that most of the patients are cautious about diabetes condition and hence would want to be always engaged remotely with their health experts to manage diabetes efficiently. However, more studies are recommended to establish the current findings.

Keywords: Apollo Sugar app, diabetes, management

   Apollo sugar pan India diabetes surveillance and counselling for high risk diabetes patients Top

Vamsi K. Kolukula, Surekha Tippisetty, Poornima A. Chivukula, Sravani Popuri

Apollo Sugar Clinics Limited, Banjara Hills, Hyderabad, Telangana, India

E-mail: [email protected]

Aims: We aimed to evaluate screening data that gives insights to build a strong inclinic and beyond clinic diabetes management strategies. Materials and Methods: A retrospective analysis of individuals who attended surveillance camps conducted by Apollo Sugar Clinics across India. So far 362000 people were screened from different corners of the nation through camps from Jan 16 to March 18. A minimum demographics, family background and current health status of the individual was collected, during the camp every person does random blood glucose test to understand their clinical status and risk. The data is captured in Apollo Sugar clinics electronic medical records data bank. Descriptive statistics was used to present the data. Results: Total 362000 people were screened (75% male and 25% female) across India. The individuals screened were majorly from South India (77%), followed by North India (23%). Of the screened population 85% were known diabetic, of these 14% were uncontrolled as their RBG was > 200 mg/dl and 20% had RBG between 140-200 mg/dL. With the known diabetic 84% were aged > 40 years and 26% had positive family history. During screening 20% of them were self-motivated to visit the clinic and they were privileged to receive tailored SMS alerts based on their risk score, diabetes pocket guide and a mobile App to monitor diabetes. App plays an important role in conjoining patients and health coach. A two-way interactions in Apollo Sugar app is a unique feature that indirectly aids in better management. Non-diabetic individuals with RBG > 200 mg/dl were confirmed on diabetes status at Apollo Sugar clinics. Therefore during screening individuals identified with known diabetes and RBG > 200 mg/dl, Apollo Sugar through health interactions, diabetes education calls and SMS alerts had helped patients to adhere to medication and diet. Unlike in-clinic doctor consultation, beyond clinic activities of Apollo Sugar benefits patients to efficiently manage diabetes.

Keywords: Diabetes, random blood glucose, screening

   HbA1c as a marker of HDL cholesterol in Odia subjects with type 2 diabetes Top

Hariballav Mahapatra1,2, Susant Mishra3, Monalisa Khuntia1, Biswaranjan Jena1, Rajesh K. Padhi4, Abhay K. Sahoo2, Syed Abuthaahir5, Apurba R. Jena1, Ajay Patwari6, Ranjit K. Khatua7

1Sevayan Diabetes Centre and Jyoti Diabetes Research Foundation, Puri, Departments of 2Endocrinology, 3Plastic Surgery, 4Nephrology, Institute of Medical Sciences and SUM Hospital, SOA University, Bhubaneswar, Odisha, 5Apollo First Med Hospitals, Chennai, Tamil Nadu, 6Jharkhand Diabetic and Eye Centre, Dhanbad, Jharkhand, 7Dr. Ranjit's Diabetes Speciality Clinic, Bhadrak, Odisha, India.

E-mail: [email protected]

Introduction: HbA1c is the gold standard means of accessing long term glycemia and for diagnosing diabetes. Cardiovascular disease (CVD) is the leading cause of death in type 2 diabetes (T2DM). HDL-c has been considered as a surrogate marker of CVD. In this study we aimed to find the relationship between HbA1c and HDL-c in Odia subjects with T2DM. Method: T2DM adults, who visited Sevayan Diabetes Centre, Puri (March 2018 to June 2018) were requested to participate. Subjects with type 1 diabetes, secondary diabetes, GDM, nourishing mothers, pregnant women, as well as individuals who were on lipid lowering medicines, thyroid hormone therapy, steroids, immunosupressants were excluded. Comprehensive medical and drug history were recorded. After consent, participants underwent overnight fasting for estimation of HbA1c and lipid panel measurement. Results: Mean age and duration of diabetes for the sample (n = 1352, M/F = 832/520) were 51.8 ± 10.5 and 9.8 ± 6.0 years respectively. Mean HbA1c and HDL-c values were 8.7 ± 2.4% and 40.6 ± 8.7mg/dl in order. The prevalence of low HDL (n = 697, 51.6%) and hypertriglyceridemia (n = 689, 51.0%) were almost similar. Uncontrolled HbA1c (≥7%) was documented in two third (66.7%) of persons with low HDL. While HDL was seen to be inversely related to HbA1c values, triglyceride level was found to be proportionate to HbA1c. Conclusion: The study shows that elevated HbA1c is associated with low HDL and high triglyceride levels in Odia T2DM subjects and warrants the use of statins for prevention of cardiovascular events in this resource restricted community.

Keywords: Diabetes, HbA1c, HDL, Odia

   The use of the Problem Areas in Diabetes (PAID) scale amongst patients with Type 2 diabetes: An experience from a tertiary care hospital in southern India Top

Hesarghatta Shyamasunder Asha, Lydiya Thomas3, Raja Edwin Amalraj5, Prakash R1, Prakash Abraham4, Nihal Thomas2

Departments of Endocrinology, 1Biostatistics, 2Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India, 3Aberdeen Royal Infirmary, Foresterhill, Aberdeen, 4JJR Macleod Centre for Diabetes, Endocrinology and Metabolism, David Anderson Building, Aberdeen Royal Infirmary, Foresterhill, Aberdeen AB25 2ZP, UK, 5Division of Applied Health Sciences, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, UK.

E-mail: [email protected]

Objectives: The purpose of this study was to establish the prevalence of Diabetes-Specific Psychological Distress (DSPD) among patients with Type 2 diabetes Mellitus (T2DM) using the “Problem areas in diabetes” (PAID) scale at a tertiary hospital in south India. We also intended to assess the level of acceptance of the PAID scale by Asian Indian patients. Methods: Patients with T2DM aged more than 18 years attending the diabetes outpatients were recruited. They completed two sets of questionnaires; PAID and a satisfactory questionnaire, which included socio-demographic characteristics and questions relating to the acceptance of PAID. Statistical analysis was performed using Stata 13.1 and Excel. Ethical approval was obtained from the institutional review board and the ethics committee of Christian Medical College, Vellore. Results: 253 questionnaires were completed including 157 (62.1%) male patients. The prevalence of DSPD was 32.8% (83/253); younger age (OR 3.65 (95% CI 1.36-9.80)) and presence of retinopathy (OR 2.60 (95% CI 1.12-6.04)) significantly predicted DSPD. However, it was observed that one-third of the patients had elevated distress regardless of socio-demographic or clinical factors. PAID was well-accepted by the participants and 84.6% (214/253) were pleased to complete it again. Conclusion: About one-third of T2DM patients had DSPD. Psychological distress was higher in the younger age group and those with retinopathy. PAID is an easy, well-accepted questionnaire, and would serve as a useful tool to screen for DSPD.

Keywords: Diabetes specific distress

   Are complications of diabetes a risk factor for hypoglycemia? Real world data from a tertiary care setting in Sri Lanka Top

Wijetunga W M U A, Uditha Bulugahapitiya, Gowri M. Ratnayake, Madushani K P L, Jayasuriya C A, De Silva G C H.

Endocrinology Unit, Colombo South Teaching Hospital, Sri Lanka.

E-mail: [email protected]

Introduction: Hypoglycemia is a major barrier in achieving good glycemic control in patients with diabetes and affects quality of life. Objectives: To describe the association of diabetes complications with hypoglycemia in patients with type 2 diabetes. Materials and Methods: A sample of 114 patients with type 2 diabetes was randomly selected from the diabetes clinic at the Colombo South Teaching Hospital and details on hypoglycemia and complications of diabetes were recorded. Data were analyzed by independent sample t test. Results: Out of 114 patients, 83.3% were females. Mean age and mean duration of diabetes were 56.5 (±12.4) years and 11.5 (±7.5) years respectively. The incidence of minor hypoglycemia during the previous month and major hypoglycemia during the previous year were 1.6 ± 3.5 and 0.13 ± 0.56 episodes per patient. Minor hypoglycemia was more frequent in patients with retinopathy (2.5 vs 1.3 episodes/month, P = 0.26), nephropathy (4.3 vs 1.4, P < 0.05), neuropathy (2.3 vs 1.2, P = 0.12), ischemic heart disease (3.1 vs 1.3, P = 0.24) and stroke (5.0 vs 1.5, P = 0.56). Major hypoglycemia was also more frequent in patients with retinopathy (0.29 vs 0.07 episodes/year, P = 0.20), nephropathy (0.33 vs 0.12, P = 0.36), neuropathy (0.22 vs 0.08, P = 0.27), ischemic heart disease (0.45 vs 0.06, P = 0.15) and stroke (0.33 vs 0.13, P = 0.53). Conclusion: Hypoglycemia is seen more frequently in patients with microvascular and macrovascular complications. Thus, less stringent glycemic targets should be advocated in patients with established microvascular or macrovascular complications.

Keywords: Diabetes, diabetes complications, hypoglycemia

   A real world analysis of clinical effectiveness of DPP4 inhibitors from a large data set in India Top

Venkataraman S, Sanjiv J. Shah1, Balaji Jaganmohan2, Vikranth Tari1, Dwarakanath CS2, Anish Behl3, Manikandan RM, Boochandran TS, Mahesh Chavan1, Shantharam D, Vamsi K. Kolukula4, Krishna G. Seshadri1

Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Chennai, Tamil Nadu, 1Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Mumbai, Maharashtra, 2Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Bengaluru, Karnataka, India, 3Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Mysore, Karnataka, 4Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Hyderabad, Telangana, India.

E-mail: [email protected]

Objective: To evaluate clinical effectiveness of DPP4 inhibitors (DPP4i) as add on agent in patients with type 2 diabetes mellitus (T2DM). Methods: A cross-sectional retrospective analysis of T2DM patients initiated on DPP4i registered at Apollo Sugar Clinics India. Apollo Sugar is a large community based clinic practice system with over 35 clinics, 90 health care providers and serving more than 75000 patients. A total of 4507 patients initiated on DPP4i as add on to either oral anti-hyperglycaemic agents or insulin were screened. Among these 1138 patients with baseline and follow up HbA1c were included for the analysis. Appropriate statistics was applied and tested for significance at P ≤ 0.05. Results: Mean (SD) age of the patients initiated on DPP4i was 53.7 (10.2) years, of these 66% were males and 34% were females. In 430 (38%) patients DPP4i were added to MF (Group 1) or other monotherapy. In 221 (19%) DPP4i were added to two or more agents (Group 2) and in 69 (6%) patients DPP4i were added to insulin (Group 3). The mean (SD) HbA1c in patients at initiation was 8.7 (1.9) in the whole group, 8.4 (1.8) in Group 1, 8.7 (2.0) in Group 2, and 9.5 (2.0) Group 3. The HbA1c at follow up was 8.3 (Δ: 0.4; 95% CI [0.30 – 0.49]) in the whole group, 7.9 (Δ 0.5; 95% CI [0.31-0.61]) in Group 1; 8.5 (Δ 0.2; 95% CI [0.01- 0.39]) in Group 2; and 9.0 (Δ 0.5; 95% CI [0.06-1.08]) in Group 3. 26% (293 of 1138; Δ 1.1; 95% CI [0.94- 1.34]) of patients reached HbA1c < 7% in the whole group with 30% (129 of 430), 21% (46 of 221) and 7% (5/69) in Groups 1, 2 and 3 respectively. Conclusion: We present real world evidence of the efficacy of DPP4i in a large dataset from India. The overall efficacy of these drugs and their ability to help about a third of patients reach therapeutic targets ensure their continued relevance in the therapeutic armamentarium. The greater efficacy of these agents as a second line than later in therapy provides clues to their appropriate positioning.

Keywords: Clinical effectiveness, diabetes, DPP4 inhibitors, HbA1c

   Effect of hypoglycemia on poor medication adherence Top

W. M. Udai A. Wijetunga, Uditha Bulugahapitiya, K. P. L. Madushani, Gowri M. Ratnayake, C. Anuradha Jayasuriya, G. Charini H. De Silva

Endocrinology Unit, Colombo South Teaching Hospital, Sri Lanka.

E-mail: [email protected]

Introduction: Poor medication adherence is a major cause of suboptimal glycemic control in patients with diabetes. Objectives: To describe the association of hypoglycemia with poor medication adherence in patients with type 2 diabetes. Materials and Methods: A sample of 114 patients with type 2 diabetes was randomly selected from the diabetes clinic at the Colombo South Teaching Hospital and details on hypoglycemia and medication adherence were recorded. Data were analyzed by independent sample t test. Results: Out of 114 patients, 83.3% were females. Mean age was 56.5 (±12.4) years. During the previous week 21.9% of patients had at least missed one medication dose. The mean number of missed medication doses during a week was 1.46 (±4.78). In patients experiencing more than 2 episodes of minor hypoglycemia per month, 33.3% miss at least one medication dose per week while this figure is 18.9% in patients with less frequent hypoglycemia (P = 0.12). Patients who had missed at least one medication dose during the previous week, had higher frequency (statistically insignificant) of minor hypoglycemia (2.2 vs 1.4 episodes/month, P = 0.30) but not major hypoglycemia (0.04 vs 0.16 episodes/year, P = 0.35) than patients who hadn't missed any medication doses. Conclusion: More than 1 in 5 patients with type 2 diabetes miss at least one medication dosage during a week. This figure rises up to 1 in 3 in patients with frequent hypoglycemia. Prevention and minimizing minor hypoglycemia is very important in improving medication adherence. Further studies with larger patient samples is recommended.

Keywords: Diabetes, hypoglycemia, medication adherence

   A case series of Werner syndrome in Kashmir Valley – Likelihood of high prevalence in this population Top

Vishnu Vasudevan, Raiz A. Misgar, Javaid Rasool

Department of Endocrinology, SKIMS, Srinagar, Jammu and Kashmir, India.

E-mail: [email protected]

Aim and Objectives: To describe the clinical features of 9 patients diagnosed as Adult progeria (premature ageing) – Werner syndrome, who presented to the endocrinology department of SKIMS, Srinagar during the past 2 years. Materials and Methods: Descriptive case series and literature review. Results: Werner Syndrome, the canonical autosomal recessive adult progeria syndrome, was first described around a century earlier. It is a rare disease involving all the organ systems of the affected individual. During the past 2 years, we have diagnosed Werner syndrome clinically in nine patients who presented with young onset diabetes and progeroid features. The clinical features of these patients were compared and an extensive literature review was done. Most of the patients were worked up for suspected connective tissue disorder like systemic sclerosis and premature cataract, but the correct diagnosis was overlooked for many months to years. Importance of early diagnosis and treatment of co-morbidities is highlighted. Only a few case reports have been published from India previously, and such a large number of patients from a comparatively small population lead us to speculate a higher than average prevalence of this condition in Kashmir Valley. An International registry of Werner syndrome cases at Seattle, USA was contacted for genetic studies and mutation analysis of WRN gene is under pipeline for these patients in our registry.

Keywords: Adult progeria, Kashmir, Werner syndrome

   Efficacy of SGLT2i as add on therapy to oral hypoglycemic agents or insulin in patients with type 2 diabetes Top

Krishna G. Seshadri, Venkataraman S, Dwarakanath C Suryanarayana1, Manikandan RM, Boochandran TS, Narayanan NK, Jayashree Gopal, Shantharam D, Balaji Jaganmohan1, Vamsi K. Kolukula2

Apollo Sugar Clinics, Chennai, India, 1Apollo Sugar Clinics, Bangalore, 2Apollo Sugar Clinics, Hyderabad, India.

E-mail: [email protected]

Objective: To assess glycemic outcomes of SGLT2 inhibitors (SGLT2i) as an add on to oral hypoglycemic agents or insulin anti-diabetes drugs in patients with type 2 diabetes mellitus (T2DM). Materials and Methods: A cross-sectional retrospective data analysis of T2DM patients initiated on SGLT2i registered at Apollo Sugar Clinics Limited, India. The Apollo Sugar Group is a large community based clinic practice with over 35 clinics, 90 health care providers and serving more than 75000 patients across nation. A total of 750 T2DM patients were initiated on SGLT2i from Jun 2016 to Dec 2017. Patients were categorized into two groups, G1 is SGLT2i added to oral and G2 added to oral + insulin. Appropriate statistics were applied for analysis and P ≤ 0.05 is considered to be significant. Results: Of 750 patients on SGLT2i, 72% of patients were prescribed with SGLT2 inhibitors along with other oral drugs vs. 28% along with insulin. Overall mean (SD) HbA1c was 8.4%; FBG was 165 mg/dL and PPBG was 240 mg/dL. The most common drugs prescribed along with SGLT2i were biguanides (62%), followed by DPP4 (55%), SUs (43%) and Insulin (28%). The most commonly used SGLTi is empagliflozin (39%) followed by canagliflozin (33%), and dapagliflozin (28%). Of 750 patients, follow-up HbA1C data was available in 181 patients and these were chosen for efficacy analysis. The mean HbA1c at initiation and at follow-up was 8.5% and 7.9% with a significant mean difference of 0.61% (95% CI: 0.38-0.83; P < 0.001). The HbA1c reduction in G1 was 0.59% and G2 was 0.66%. The difference between the groups was numerical and has no statistical significance. At follow up 31.5% of patient in overall and 38.6% of patients in G1 and 12.2% in G2 were able to reach a target goal of <7% HbA1c. At follow up 5 patients reported hypoglycemia and one patient had urinary tract infection. Conclusion: Indian patients initiated on SGLT2i have clinically meaningful reduction in HbA1c in combination with OHAs or insulin with low morbidity.

Keywords: Clinical effectiveness, diabetes, HbA1c, SGLT2 inhibitors, type 2 diabetes

   Impact on monotherapy and combination therapy in achieving target HbA1c in large health care system Top

Krishna G. Seshadri, Venkataraman S, Jayaprakashsai Jana1, Dwarakanath C. Suryanarayana2, T. S. Boochandran, N. K. Narayanan, Balaji Jaganmohan2, Sanjoy Paul1

Department of Diabetes and Endocrinology, Apollo Sugar Clinic, Chennai, Tamil Nadu, 1Department of Diabetes and Endocrinology, Apollo Sugar Clinic, Hyderabad, Telangana, 2Department of Diabetes and Endocrinology, Apollo Sugar Clinic, Bengaluru, Karnataka, India.

E-mail: [email protected]

Objective: The Purpose was to analyse the prescribing patterns of medical practitioners based on the HbA1C of patients at the time of presentation. Materials and Methods: Apollo Sugar is a diabetes health care system 20 stand-alone clinics and also 15 of ambulatory care centres attached to secondary and tertiary health care institutions across the country. Providers in these institutions are endocrinologists, or Diabetologist with a computerised prescription entry. Till date an overall 75000 EMR penetrance is observed across the clinics. Glycated haemoglobin (HbA1c) is used as the deciding factor for treatment strategy. Results: A total of 2774 prescriptions available between January 2016 and 2017 were included for the analysis. The mean age of the patients was 54.5 years, 63% were males and 37% were females. While Biguanides were the single largest monotherapy (53.7%) used, monotherapy with sulphonylureas (13.8%) or DPPIV inhibitors (11.3%) was not uncommon. Initial combination therapy was used in 51.5% of patients with HbA1C ≤8. The most common combinations used were biguanides and DPP4 inhibitors. Initial combinations were used with greater frequency in patients with HbA1C >8%. These include OHAS (69.3%), OHAS+ insulin (23.0%) and Insulin alone (7.7%). At follow-up 40% of the patients on one OHA at start reached HbA1c <7% and 54% on two OHAs reached <8%. In patients whose HbA1c is <8 at start the reduction in HbA1c using monotherapy or dual therapy was 0.57% and 0.54% respectively in an average time interval of 78 days. Conclusion: The similarity of results in this large sample for mono and dual therapy is surprising. There could be background issues including duration of diseases, comorbidities, and other influencing factors. However, such large prescription analysis from electronic medical records (EMR) to our knowledge has never been published from India. We hope to evaluate with controlled prospective studies on prescription patterns.

Keywords: Combination, HbA1c, insulin, monotherapy, orals, therapy

   Chorea as first presentation of Diabetes mellitus in an elderly male: A case Report Top

Danendra Sahu, Vishnu Vasudevan, B. A. Laway

Department of Endocrinology, SKIMS, Srinagar, Jammu and Kashmir, India.

E-mail: [email protected]

Objective: To report an unusual case of Chorea (diabetic-striatopathy) as first presentation of diabetes mellitus in an elderly male. Case Report: A 64 year old male, known case of hypertension but with no history of diabetes, noticed sudden onset of choreo-ballistic movements of the right upper and lower extremities for the past three months which occurred even during sleep. He was given trihexiphenidyl but with minimal improvement in symptoms He also had osmotic symptoms for few weeks. On examination, he had hypotonia with uncontrollable involuntary chorea like movements more in his right lower than upper limb. His muscle power was normal and systemic examination was unremarkable. Investigations revealed initial plasma glucose of 490 mg/dl, and HbA1c of 14.4%. A review of NCCT-brain done 3 months back initially reported as normal, revealed subtle hyperdensity in the basal ganglia. MRI-brain showed T1-hyperintense and T2-hypointense lesion in the left caudate nucleus and putamen. His diabetes was managed with insulin and also started on haloperidol. Within five days of admission, he showed marked improvement in symptoms and choroid movements disappeared during his sleep. Discussion: The patho-physiological mechanisms in diabetic-striatopathy involve hyperviscosity leading to local tissue hypoperfusion, depletion of gamma amino-butyric acid, and accumulation of manganese-containing gemistocytes in the basal ganglia which typically appear as T1 hyperintense lesions. Conclusion: In a patient of diabetes with non-ketotic hyperglycemia, high signal intensity lesions on T1-weighted MR imaging confined to basal ganglia and contra lateral chorea is a unique syndrome often termed as diabetic-striatopathy.

Keywords: Basal ganglia, chorea, diabetic striatopathy

   Prevalence of glucose intolerance among Kashmiri tribal population – A cross sectional study Top

Sheikh A. Ali1, Imtiyaz Wani1, Danendra Sahoo1, Wajid Rafi3, Aafia Rashid1, Tajali Sahar1, Ishfaq Wani1, Irfan Robbani4, Sobia Nisar2, Nandita Gupta3, Mohd A. Ganie1

1Departments of Endocrinology, 4Radiodiagnosis, Sher-i-Kashmir Institute of Medical Sciences Srinagar, Jammu and Kashmir, India, 2Department of Internal Medicine, GMC, Srinagar, Jammu and Kashmir, India, 3Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Background: An increase in the prevalence of type 2 diabetes mellitus (T2DM) has been observed in all ethnic groups in India. Data on glycemic disorders in various tribal populations in the country is scanty. Objective: To study the prevalence of abnormal glucose tolerance on the basis of hemoglobin A1C (HbA1c) among Kashmiri tribal population. Materials and Methods: A total of 4500 subjects (n = 1923 men and n = 2577 women) were recruited using multistage cluster sampling technique involving 5 of 10 districts of Kashmir valley. An informed consent was obtained and a pre-designed questionnaire was used to collect data on socio-demographic characteristics, family history of DM, anthropometric and biochemical measurements. Random blood sample was collected, centrifuged on the study site and the aliquots were transported in cold boxes to storage sites. The assays included haemogram, biochemistry, random blood glucose and glycated hemoglobin A1C. Data was analyzed by STATA version 13. Results: The mean age of subjects was 36.23± 11 years and the mean BMI of 25.16 kg/m2. The average systolic and diastolic BP was 119.51 mmHg and 80.47 mmHg respectively. The mean HbA1C was 5.27% with random plasma glucose of 109.08± 7 mg/dl. On the basis of HbA1c estimation, the prevalence DM was 5.9% as compared to 22.44% of prediabetes. BMI correlated positively with DM. Conclusion: Although the prevalence of DM among tribals of Kashmir valley is lower than general population, the higher prediabetes may indicate rising trend in future.

Keywords: Diabetes, glucose intolerance, HbA1c, Kashmir, tribal population

   Health Related Quality of Life and Treatment Satisfaction in Patients with Diabetes Mellitus Top

Sourav Misra, Ksh Shilpa, M. Bijoy Singh, Anand Sonwane, Chongtham D. Singh, Salam Ranabir

Department of Medicine, Regional Institute of Medical Sciences (RIMS), Imphal, Manipur, India.

E-mail: [email protected]

Background: Diabetes Mellitus requires continuous medical care and patient's self-management education to prevent or reduce risks of complications. Emotional coping with the diagnosis, treatment, improvement and complications has great impact on well-being and treatment satisfaction of diabetic patients. Aim: To assess the health related quality of life and treatment satisfaction in diabetes mellitus patients and different factors affecting these. Materials and Methods: this was a cross-sectional observational study with a calculated sample size of 430 conducted over 2 years in the Medicine department of RIMS, Imphal. Patients with both type 1 and type 2 diabetes mellitus were included. Those having other chronic diseases, GDM or secondary diabetes were excluded. Data for age, sex, BP, BMI, treatment modality, complications, FBG/PPBG, HbA1c, creatinine, lipid profile, and fundus examination report were obtained and analysed with the patient given scores on WHO-5 well-being questionnaire and Diabetes Treatment Satisfaction Questionnaire. Scores of these two questionnaires were also compared for association. Result: There are 229 male and 201 female in the present primary sample of 430 diabetes mellitus patients with respective percentage of 53.3 and 46.7. Average age of the patient is 53.34 ± 15.70 years. Increasing age and male gender was found to have poor quality of life and less treatment satisfaction. Both well-being status and treatment satisfaction were found to have correlation with all the variables except BMI. Quality of life and treatment satisfaction are found to be significantly correlated. Conclusion: It is found from the study that both the domains have correlation with the study variables and females and younger people lead a better quality life and are more satisfied to the treatment reflecting the need for special care for people with prediction to have lower quality and poor adherence.

Keywords: Diabetes, quality of life, treatment satisfaction

   Statin use in patients with T2DM in developing country: How to improve statin use in uncontrolled patients Top

Sanjiv Shah, T. S. Boochandran1, N. K. Narayanan1, C. S. Dwarakanath2, S. Venkataraman1, Jayashree Gopal1, R. M. Manikandan1, Anish Behl2, Usha Ayyagari1, Sambit Das3, Shashank R. Joshi

Department of Diabetes and Endocrinology, Apollo Sugar Clinic, Mumbai, Maharashtra, 1Department of Diabetes and Endocrinology, Apollo Sugar Clinic Chennai, 2Department of Diabetes and Endocrinology, Apollo Sugar Clinic Bangalore, 3Department of Diabetes and Endocrinology, Apollo Sugar Clinic Bhubaneswar, India.

E-mail: [email protected]

Aim: To evaluate the lipid profiles of patients with T2DM aged >40 years and treatment with statins- a multi-chain management of lipids. Materials and Methods: A cross-sectional retrospective analysis of lipid profiles of T2DM patients register at Apollo Sugar Clinics, India. A total of 15302 patients with lipid profiles, HbA1c >6.5% and on statin therapy from EMR records from Jan 2016 to July 2017 were selected for the analysis. As per ADA guidelines patients at target were categorized as controlled (LDL <100) and not at the target as uncontrolled (LDL ≥100) patients to correlate with HbA1c. Descriptive statistics were used to report the results and to test the significance between the groups an appropriate statistical test was applied with P < 0.05 set as significant. Results: Of 15302 patients, males were 65.6% and females were 34.4%. Mean age was 55 years and mean HBA1c was 8.7%. Patients at target LDL <100 and <70 was 53.1% and 20% respectively. Nearly 12.3% of these patients were on moderate to a high-intensity type of statins. Among patients who were on statins nearly 43% of patients are at controls and 57% were still uncontrolled this indicates for improvements in statin dosage along with lifestyle management. Surprisingly in untreated patients, 54.6% of patients were at target, this could be due to lifestyle management through Apollo Sugar app interactions with a health coach. There was a significant decrease in the proportion of LDL <100 patients with increasing in HbA1c (P < 0.001). Mean HbA1c was significantly low in controlled patients compared to uncontrolled patients (LDL: 8.51 vs. 8.96; P < 0.001). Most commonly used statin was rosuvastatin (64%) and atorvastatin (36%). Conclusion: We observed that nearly 43% of patients who were on statins were successful in achieving LDL target. However, patients who were on statins and not achieved the target right statin with right dose along with lifestyle management may bring meaningful clinical outcome.

Keywords: Diabetes, HbA1c, LDL, lipid profile, statins

   Comprehensive Apollo sugar diabetes management program: Adherence for better clinical outcomes Top

Sambit Das, R. M. Manikandan1, T. S. Boochandran1, Aftab Ahmed2, Dwarakanath C. Suryanarayana3, Balaji Jaganmohan3, Jayaprakashsai Jana2, Richa Chaturvedi4, S. Venkataraman1, Surekha Tippisetty2, Vamsi K. Kolukula2, Shashank R. Joshi5

Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Bhubaneswar, Odisha, 1Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Chennai, Tamil Nadu, 2Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Hyderabad, Telangana, 3Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Bangalore, Karnataka, 4Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Delhi, 5Department of Diabetes and Endocrinology, Apollo Sugar Clinics, Mumbai, Maharashtra, India.

E-mail: [email protected]

Aims: To compare glycemic outcomes of type 2 diabetes mellitus (T2DM) patients enrolled in comprehensive diabetes management program (DMP) at Apollo Sugar Clinics, Pan India. Materials and Methods: A cross sectional retrospective analysis of glycemic control of T2DM patients enrolled in DMP program at Apollo Sugar Clinics, Pan India (June 2017 to December 2017). DMP is a structured long term comprehensive care model to achieve glycemic goals and reduce complications burden. It consists of in-clinic physician and diet consultation and beyond clinic support includes counselling by health coach on medication, diet and exercise, SMBG monitoring, diet and exercise tips through Apollo sugar mobile app. Mean HbA1c reduction was considered to compare between the DMP and NoDMP. Appropriate statistics were applied to test the significant difference between the groups at a P < 0.05. Results: A total of 200 (No DMP = 100; DMP = 100) uncontrolled T2DM patients were selected for the analysis. Mean age was 51.9 (13.1) years and 63% were males. Mean HbA1c at baseline was 9.8% and at followup was 8.9% and a mean reduction of 0.9% (95% CI: 0.69-1.02; P < 0.001). Further, there was also a significant difference in mean HbA1c (9.5% to 8.9% vs. 10.1% to 9.0%) in No DMP and DMP patient groups from baseline to followup. The mean difference in HbA1c is statistically significant in both DMP (Δ: 1.1%, 95% CI: 0.80-1.41, P < 0.001) and No DMP (Δ: 0.6%; 95% CI: 0.48-0.74, P < 0.001) patient, and the reduction is significantly greater in DMP compared to No DMP. Further in DMP at follow up 10% of patients with > 8% HbA1c achieved < 7% of HbA1c goal. Conclusion: Our current analysis reveal patients on DMP had better glycemic outcomes than NoDMP patients, suggesting a comprehensive care should be recommended to have a good control over diabetes and prevent from complications burden. However, further prospective studies are required to come up with more tangible data to support DMP.

Keywords: Diabetes, glycemic control, HbA1c, management

   Validity of Sri Lankan Diabetes Risk Score (SLDRISK) as a screening tool for high-risk population Top

Prasad Katulanda1, Gaya Katulanda2, Gowri M. Ratnayake3, G. R. Constantine1, P. C. Karunananda1, P. K. Amarasinghe1, M. M. R. Nishadi1, A. P. M. Weerasinghe1, I. A. Maharambe1, S. P. Anthonis1, C. Senevirathna1, R. Kumarage1, T. Gangodawila1, D. R. Samaratunge1, S. S. Madawanarachchi1, B. A. V. S. Bamunuarachchi1

1Diabetes Research Unit,Department of Clinical Medicine, University of Colombo, Sri Lanaka, 2Medical Research Institute, Colombo, 3University Medical Unit, National Hospital of Sri Lanka, Sri Lnaka.

E-mail: [email protected]

Introduction: Screening for undiagnosed diabetes is not widely undertaken due to the high costs and invasiveness of blood sampling. Simple non-invasive tools to identify high risk individuals can facilitate screening. The main objectives of this study are to find the effectiveness of SLDRISK score as a non-invasive screening tool in a high risk Sri Lankan adult population. Materials and Methods: SLDRISK score was calculated for all the participants selected through randomized cluster sampling and categorized into two groups according to the cutoff of 31. Score >31 were considered having a 10% chance of having diabetes at present and <31 were considered having a risk of diabetes less than 2%. Then sample was tested for diabetes using HbA1c, FBS and PPBS. Patients were considered as having Diabetes if either one of the test is positive according to ADA 2017 diagnostic criteria. The relationship between SLDRISK and the diabetes was analyzed to obtain sensitivity, specificity, positive predictive value, negative predictive values. Results: In a sample of 912, there were 749 (82.1%) individuals with SLDRISK score >31. Among these 284 (31.1%) were diagnosed to have diabetes mellitus. Of the 163 who had a SLDRISK score <31, 39 (23.9%) were diagnosed to have diabetes mellitus. Therefore SLDRISK score showed low specificity (19.74%) but high sensitivity (82.26%) in this population. The positive and negative predictive values of the SLDRISK score were 32.71 and 76.07% respectively. Conclusion: SLDRISK score is not a good screening tool for screening high-risk populations as it gives high false positive value.

Keywords: Diabetes risk score, diabetes screening, diabetes prevention

   Making diabetes care more efficient through the use of a digital clinical assistant application Top

Subramanian Kannan, Shivaprasad KS, Kranti Khadilkar, Alben Sigamani, Vellaichamy M. Annapandian, Samir Mitra1, Simona Brusa Pasque1, Deviprasad Shetty

Department of Endocrinology, Diabetes and Metabolism, Narayana Health City, Bangalore, Karnataka, India, 1Cura Technologies Inc., SanFrancisco Bay Area, USA.

E-mail: [email protected]

Background and Aim: Streamlined clinical workflow technology has been shown to improve clinical outcomes and efficiency for diabetes and other diseases. Aims and Objectives: The goal of this study is to determine the impact of implementing a new physician workflow tool on documentation of diabetes data points and clinical efficiency. Material and Methods: A retrospective analysis was conducted on adult patients (>18 years) under the Endocrinology department at Narayana Health City, Bangalore between Nov-2016 to Nov-2017. Patients with clinical documentation of diabetes mellitus who have been visited diabetic clinic at least 2 times over 12 months period were included. A digital clinical assistant application (CURA) system were used during the study period. Data-points including HbA1C, fasting and post-prandial blood sugar, LDL cholesterol, and serum creatinine levels were collected from hospital information system and CURA clinical application records. Results: A total of 5083 patients were studied, out of whom 59% were males, the median age of 54 years. Following implementation, the Cura diabetes application made it mandatory to collect the weight, BP, smoking history at every visit, and medication reconciliation was done at every visit. In the 1 year period, about 50% of of patients achieved the clinical targets of HbA1c < 8.0% and LDL-cholesterol < 100 mg/dL. Additionally BP targets < 140/80 mmHg was achieved in 46% of patients. Conclusions: We propose a new clinical application for diabetes care which significantly improves the effectiveness and efficiency of outpatient diabetes care.

Keywords: Clinical work flow, CURA, Diabetes management, Digital clinical application

   A comparative analysis of spectrum and outcome of common bacterial infections in patients with and without diabetes - A prospective hospital based study Top

Moomin H. Bhat1, Fayaz A. Bhat2, Shariq R. Masoodi1, Mona Sood1, Arshad Iqbal Wani1, Mir Iftikhar Bashir1, M. Ashraf Ganie1, Abdul Hamid Zargar1

1Department of Endocrinology, SKIMS, 2Department of Medicine, SKIMS, Srinagar, Jammu and Kashmir, India.

E-mail: [email protected]

Background and Aims: Though the association between diabetes mellitus and increased susceptibility to infection in general is not supported by strong evidence, many specific infections are more common in diabetic patients, and some occur almost exclusively in diabetic patients. Aim of this study was to look at the clinical spectrum and outcome of infections in patients with diabetes mellitus in comparison to that of non-diabetic controls. Materials and Methods: 142 consecutive diabetic patients and 100 non-diabetic controls, admitted to a tertiary care hospital because of various bacterial infections studied. Recruited subjects were classified to have an infection as Definite or Probable; depending on culture evidence or clinical suspicion of infection. Patients were mortality, and re-infection at follow up. Results: The mean age of study subjects was 52.7 ± 14.0 and 49.1 ± 20.6 years in diabetic and non-diabetic controls respectively. Fever was observed in only 45% of diabetic compared to 82% in non-diabetic subjects. The mean hospital stay for diabetic and non-diabetic controls was 14.2 ± 5.4 and 14.9 ± 8.9 days respectively; when adjusted for severity of illness in terms of APACHE (Acute Physiology and Chronic Health Evaluation) II score, the stay was significantly longer in diabetic subjects. Certain infections like skin, soft tissue and foot infections were seen mostly in diabetic subjects [Table 1]. Urinary tract infections were the commonest infection observed in both groups (36% in diabetic; 30% in non-diabetic) though emphysematous pyelonephritis occurred exclusively in diabetic subjects (3). Staph aureus was the most frequently isolated organism in both the groups 45 (31.7%) vs 19 (19) followed by E coli and Klebsiella. In-hospital mortality was similar in both groups [6% vs 11%; P > 0.08]. Re-infections on follow-up occur significantly more in diabetics compared to non-diabetics (15% vs. 2.6%; P = 0.005). Conclusions: Though Infections generally behave similarly in diabetic and non-diabetic subjects, there are certain differences like, less inflammatory response (fever and leukocytosis), and more chances of soft tissue and atypical infections like emphysematous pyelonephritis in diabetic subjects. Also, diabetics stay longer in hospital when adjusted for severity of illness.
Table 1

Click here to view

Keywords: Bacterial infections, diabetes, Urinary tract infection, Emphysematous pyelonephritis

   An interesting case of insulin induced hypoglycemia-More than meets the eye Top

Swayamsidha Mangaraj, Arun Kumar Choudhury, Anoj Kumar Baliarsinha

Department of Endocrinology, S.C.B Medical College Cuttack, Odisha, India.

E-mail: [email protected]

Objectives: Millions of individuals take insulin on a routine basis for managing their hyperglycemia. Usual complications of insulin therapy include hypoglycemia, weight gain and insulin injection site lipohypertrohy. We aim to report a very rare complication of insulin therapy that is immunological hypoglycemia. In this form of autoimmune hypoglycemia insulin antibodies are induced by exogenous insulin administration and result in unexplained and severe hypoglycemia. Case Description: A 60 year old male presented with repeated episodes of hypoglycemia. He was a known case of type 2 diabetes mellitus for last 14 years. Due to poor glycemic control, he was switched to multiple subcutaneous doses of human insulin. However, after one month of insulin initiation, he started developing frequent episodes of hypoglycemia. During hospitalization, the patient continued to have such episodes even after complete stoppage of insulin therapy. Subsequent evaluation as per hypoglycemia work up protocol revealed significantly elevated serum insulin (>600 mIU/ml) and detectable C peptide (2.24 ng/mL) in presence of documented hypoglycemia. No lesion was identified in pancreas after contrast enhanced computed tomography. Anti Insulin antibody (>100 IU/ml) was strongly positive. Hypoglycemia may persist in such cases even after insulin withdrawal for some days. The diagnosis also has a significant bearing on issue of future use of insulin in these patients due to possibility of recurrence of symptoms. Conclusions: Hence, autoimmune hypoglycemia though very rare, should be explored as a potential cause in cases of recurrent and refractory hypoglycemia in insulin treated patients when other causes are ruled out.

Consent: Written informed consent was obtained from the study subject for publication of study.

Keywords: Autoimmune hypoglycemia, hypoglycemia, insulin

   How safe is metformin when initiated in early pregnancy ? A retrospective 5-year study of pregnant women with Gestational Diabetes mellitus from India Top

Riddhi Dasgupta, Vanlal Hruaii, Roshna Ramachandran, Jiji. E. Mathews1, Annie Regi1, Niranjan Thomas2, Vijay Gupta2, Visalakshi P3, Asha HS, Thomas Paul, Nihal Thomas

Departments of Endocrinology, Diabetes and Metabolism, 1Obstetrics and Gynecology, 2Neonatology, 3Statistics, Christian Medical College (CMC), Vellore, Tamil Nadu, India.

E-mail: [email protected]

Background: The initiation of metformin in early pregnancy in Gestational Diabetes Mellitus (GDM) remains controversial. Aims and Objectives: The aim of our study was to assess the influence of Metformin on maternal and fetal outcomes when initiated within the first trimester of pregnancy in GDM. Methods and Materials: A retrospective analysis of 540 women with diabetes complicating pregnancy (IADPSG criteria) over five years (January 2011 to May 2016) was done. The study population comprised of patients initiated on a) metformin within the first trimester (Group A: n = 186), b) metformin after the first trimester (Group B: n = 203) and c) insulin at any time during their pregnancy (Group C: n = 151). The primary outcomes compared were prematurity, respiratory distress, birth trauma, 5-minute APGAR score, neonatal hypoglycaemia and need for phototherapy, while secondary outcomes compared were neonatal anthropometric measurements, maternal glycemic control, maternal hypertensive complications, postpartum glucose tolerance. Results: Individual and composite primary or secondary outcomes in group A were similar to Groups B and C, though numerically higher premature births were seen in Group A. There was a 1.3% overall incidence of stillbirths/IUD, while 1.11% congenital anomalies were noted of which 2.15% were in group A and 1.32% were in Group C (P = 0.16). Conclusions: The initiation of metformin within the first trimester of pregnancy has no significant adverse maternal or fetal outcomes. However, vigilance for premature births is recommended in women exposed to metformin in early pregnancy.

Keywords: Early, estational, metformin, pregnancy

   Study on Cognitive impairment in patients with type 2 diabetes mellitus: Assessed by Montreal cognitive assessment scale Top

Seena TP, P. K. Jabbar, Abilash Nair, C. Jayakumari

Department of Endocrinology, Government Medical College, Thiruvananthapuram, Kerala, India.

E-mail: [email protected]

Background: Cognitive assessment in diabetic patients is useful for early detection of diabetes dependent cognitive dysfunction (DDCD). The present study evaluated cognitive impairment using Malayalam version of Montreal Cognitive Assessment (M-MoCA) in patients with diabetes and compared it with the score in normal subjects. Objective: The primary objective of the study was to assess the presence of cognitive impairment in type 2 diabetes patients compared with non - diabetes subjects. Methods: This cross-sectional study was done in the Department of Endocrinology in Govt. Medical College, Thiruvananthapuram. Study population included both male and female subjects between 25 and 60 years of age. The socio-demographic, and disease related details were noted. Type 2 patients having HbA1c level less than 7.0% and control subjects having HbA1c more than 5.4% were excluded from the study population. The 10 minutes M-MoCA test was performed in both the patients and control subjects. Results: 49 controls and 46 cases were evaluated in the final analysis. There was a significant difference in the age of the subjects included in the two groups. Diabetic subjects had a lower median M-MoCA score (23 [IQR 21-25]) than the control subjects (26 [IQR 24-26]). Within the diabetic group, patients with higher diastolic blood pressure and a higher pulse rate were more likely to have a lower M- MoCA score. Conclusion: Patients with diabetes have a higher risk of having cognitive impairment than the normal population and it may have a relation with increased diastolic blood pressure and a higher pulse rate. Larger studies are indicated for better characterisation of risk factors.

Keywords: Mild cognitive impairment, montreal cognitive assessment scale, type 2 diabetes

   A Hospital based comparative study on factors associated with hypoglycemia in diabetic patients, and their knowledge, attitude and practices related to hypoglycemia Top

Dayakshi D. K. Abeyaratne1, C. Lakmal Fonseka2, Chathuri Liyanapathirana3, Maathuri Sivapalan3, Piumi Hettiarachchi1, B. G. Anushka Rathnamali4, Noel P. Somasundaram1, P. W. M. C. Sanjeewa B. Wijekoon5

1Department of Endocrinology, National Hospital of Sri Lanka, Colombo, 2Department of Medicine, Faculty of Medicine, University of Ruhuna, Matara, 3University Medical Unit, Colombo South Teaching Hospital, 4Medical Unit, National Hospital of Sri Lanka, Colombo, 5Department of Medicine, Faculty of Medicine, University of Sri Jayawardanapura, Nugegoda, Sri Lanka.

E-mail: [email protected]

Introduction: Hypoglycemia is an important complication to look for when managing patients with diabetes with stringent glycemic targets. We opt to assess common presentations and factors associated with hypoglycemia in patients who gets severe hypoglycemic episode and to compare their knowledge attitudes and practices with a diabetic population who haven't had hypoglycemia. Methods: Patients admitted with severe hypoglycemia (SH) to medical wards of a Teaching Hospital over 1 year period were recruited. Comparison group was selected randomly from diabetic patients admitted to wards who never had hypoglycemia (NH). Data on basic factors, knowledge, attitude and practices on hypoglycemia were compared. Results: 70 patients for each group were recruited (Males 58%). Both had a mean age of 60yrs. All had poor knowledge on hypoglycemic symptoms. 80% of patients had admitted with loss of consciousness. 45% had hypoglycemic unawareness. 48% had past admissions with hypoglycemia. 30% had a blood sugar level <40 mg on admission. In 88% missed meals was the most likely cause. In comparison of groups, there was no statistically significant difference with regard to educational status, duration of diabetes or insulin therapy, presence of macro or microvascular complications, clinic visits per year, medications, glucometer use. However, the immediate carer of the SH group were less aware on home management of hypoglycemia (P = 0.003). Conclusions: All diabetic patients and at least the immediate carer of family should be regularly educated on importance of meal pattern, common and uncommon hypoglycemic symptoms and home management of hypoglycemia.

Keywords: Causative factors, hypoglycemia, diabetes, knowledge, practices

   Type 2 diabetes and physical activity: Barriers and enablers to diabetes control in Eastern India Top

Sanghamitra Pati, Eunice Lobo1, Sandipana Pati2, Shyama Desaraju1, Pranab Mahapatra3

Department of Health Research, ICMR - Regional Medical Research Centre, Government of India, 1Indian Institute of Public Health Bhubaneswar, Public Health Foundation of India, 2Department of Health and Family Welfare, Directorate of Public Health, Government of Odisha, 3Department of Psychiatry, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India.

E-mail: [email protected]

Introduction: Type 2 diabetes has tremendous morbidity burden due to disease management and complication prevention. Behaviour modification identified as a key to management includes healthy diet and regular physical activity (PA). This study aims to identify patterns and preferences of PA of Type 2 diabetes patients and explore perceived enablers and barriers for diabetes control in Bhubaneswar. Materials and Methods: Cross-sectional, facility-based study conducted in the private sector from June-August 2014 recruited 321 Type 2 diabetes patients using semi-structured questionnaires. Descriptive statistics and associations of PA were computed. Results: Almost two-third patients (59%) reported performing PA frequently. Majority patients cited walking as most preferred mode of PA (79%) with 41% performing PA daily. Actual versus perceived weight was a complete mismatch with most patients misjudging their weight. Reasons for enabling PA included “controlling diabetes” and “doctors' advice” as key factors; while “lack of time” and “unwillingness” were main barriers among inactive patients. Conclusion: Counseling on PA by physicians during routine visits, along with tailored or patient-specific interventions should be considered. Focus on social support for positive behavioral changes and motivation play a central role in diabetes control.

Keywords: Active patient, diabetes control, internal and external barriers, Odisha, personal enablers

   Evaluation of Demographic, Clinical and Tumour Characteristics of a Group of Patients with Cushings Disease – 8 year Experience from a Tertiary Care Unit in Sri Lanka Top

Ishara Ranatunga, S. S. C. Gunatilake1, D. D. K. Abeyaratne, P. Hettiarachchi, T. D. R. Rathnayake, Joseph P. Naveenkumar, Chaminda Garusinghe, M. Sumanatilake, N. P. Somasundaram

Diabetes and Endocrinology Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka, 1Oxford Centre for Diabetes, Endcorinology and Metabolism, Oxford, England

Address for correspondence:

Dr. Ishara Ranatunga, Diabetes and Endocrinology Unit, National Hospital of Sri Lanka, Colombo 8, Sri Lanka.

E-mail: [email protected]

Background and Objectives: Cushing's Disease is a disorder caused by prolonged hypercortisolism as a result of pituitary hypersecretion leading to increased morbidity and mortality. It is a rare disorder with variable presentations. The incidence is 1–3 cases per million, whereas prevalence is about 40 cases per million. Methods: Study was conducted at the Endocrinology Unit of the National Hospital of Sri Lanka. Data were collected retrospectively from the patient data base on pituitary diseases who were in follow up at the National hospital of Sri Lanka. Results: 12 patients were identified with Cushing's disease with follow up. Majority belonged to age category of more than 40 years (58.33%) and 91% of population were females. The commonest presentation was excessive weight gain (91.66%) while the commonest specific presentation was easy bruising 41.66%. On examination majority had hypertension (83.33%). Facial plethora was seen in 75% while 58.33% had proximal myopathy and 25% had dorso-cervical fat pad. 8.33% had visual field defects. All had one or more positive screening tests and high dose dexamethasone suppression test was positive in all. Adrenocorticotrophic hormone (ACTH) levels were high in all and out of them 25% had values had a level more than 100 pg/ml. On further investigation with magnetic resonance imaging of the brain, 66.66% patients were found to have a detectable pituitary micro-adenoma. Only 20% underwent inferior petrosal sinus sampling and out of that 66.66% had evidence for central tendency. 83.33% patients underwent pituitary surgery and there was no complication during the intra or post-operative period. Conclusion: In conclusion, Cushing's disease is a rare disease that is more common in females. The commonest presentations are nonspecific and thus the diagnosis is difficult. Accurate and early diagnosis can reduce the disease associated morbidity and mortality and improve the prognosis.

Keywords: Clinical features, Cushing's disease, investigation

   Maternal and neonatal outcomes in gestational diabetes treated with metformin Top

Patanjali CP, Vageesh Ayyar, Ganapathi Bantwal, Belinda George, Nandhini Perumal

Department of Endocrinology, St Johns Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Introduction: Metformin is increasingly being used a therapeutic option for the management ofgestational diabetes mellitus (GDM). A number of studies have demonstrated that treatment of GDM with metformin can leadto adequate glycaemic control and does not increase the risk of adverse perinatal outcomes. But still use of metformin for the treatment of hyperglycaemia inpregnancy is not universally implemented and there is a lack of consensus in GDM managementguidelines. Aims and Objectives: The aim of this study was to compare the maternal and neonatal outcomes of women with GDM treated with metformin (with or without supplementalinsulin) with those treated with only insulin or diet. Materials and Methods: This was a retrospective analysis of women with diabetes complicating pregnancy (IADPSG criteria) over one year (July 2017 to July 2018) who had delivered in St John's Hospital, Bangalore. Study population comprised of patients with GDM treated with Metformin with and without insulin and patients managed with diet alone. We compared maternal outcomes such as mode of delivery, glycemic control before delivery, incidence of preeclampsia in the groups. We also compared neonatal outcomes such as prematurity, macrosomia, 5 minute APGAR score, intrauterine growth restriction, hypoglycemia and incidence of congenital anomalies. Results: We went through records to find a total of 2381 pregnancies and found 288 GDM pregnancies. Prevalence of GDM in our population was 12.09%. 62.1% (n = 179) of GDM patients were managed with diet alone, 20.1% (n = 58) received insulin, 8% (n = 23) received only Metformin and 9.7% (n = 28) required insulin with Metformin. Associated hypothyroidism was seen in 15.9% (n = 46) of patients. The groups were comparable with respect to age, parity, past history of GDM and family history of diabetes. Women managed with diet and lifestyle modification hada significantly lower fasting plasma glucose (P <0.01) at diagnosis and HbA1c (P <0.01) at 37 weeks of gestation. Caesarean deliveries were significantly more likely in women treated with insulin (66%) and metformin (57%) than in the diet group (40%). Incidence of prematurity was significantly higher in patients treated only with insulin (37.9%) (P =0.04) compared to other two groups. There was no significant difference in other neonatal outcomes such as birth weight, jaundice, respiratory distress and neonatal hypoglycemia between the groups. Conclusion: Metformin is a useful alternative to insulin in the management of mild GDM, and also as a supplement to insulin. Its use is associated with similar neonatal outcomes as insulin.

   Abstract: A rare complication of diabetic polyneuropathy: The diabetic hand Top

S. Lodha, D. N. Singh, R. Kasliwal1, S. Mukul2

Department of Endocrine Sciences, Eternal Hospital, 1Department of Endocrinology, MG Hospital, 2Department of Plastic Surgery, Fortis Hospital, Jaipur, India.

E-mail: [email protected]

Introduction: Neuropathy in diabetes mellitus (DM) is mainly axonal which follows a length-dependent pattern with sensory symptoms and signs predominating over motor manifestations. We are reporting a case of type 2 diabetic with severe distal sensory neuropathy in both feet and hands with cigarette burns. Description of the Case: A 59-years male, type 2 diabetic since last 16 years with poor glycemic control, severe non-proliferative retinopathy, and severe depression with nicotine dependence; was admitted with bilateral symmetrical peripheral neuropathy involving the feet, legs and hands. He also had autonomic neuropathy -gastroparesis, fecal incontinence, difficulty in voiding and dry skin. The right middle finger had deep burns which was completely disorganized in architecture and infected along with distal burns and necrosis of thumb and index finger [Figure 1]. In left hand middle finger had an abscess and pulp necrosis of ulnar side with distal burn and necrosis of thumb and index finger. Nerve conduction studies of both lower and upper limbs reveled axonal neuropathy and arterial doppler study was normal. Ray amputation of right middle finger with debridement of left middle finger was done. Discussion: Peripheral neuropathy involving hands is rare. The adjoining area of middle and index finger of insensate hands corresponds to the cigarette holding in both hands and thumb pulp burn occurred due to repeated touch to the burning end of cigarette. This was further aggravated by depression and retinopathy. Conclusions: Peripheral neuropathy involving hands is rare, can develop in longstanding diabetes. It can be complicated by depression and smoking.
Figure 1: Hands showing cigarette burns and deformities indicating sensory motor distal polyneuropathy

Click here to view

Keyword: Diabetic hand

   Comprehensive Apollo sugar diabetes management programs: Adherence for better clinical outcomes Top

Sambit Das, R. M. Manikandan1, T. S. Boochandran2, Aftab Ahmed3, Dwarakanath CS4, Balaji Jaganmohan4, Jayaprakash Sai3, Richa Chaturvedi5, S. Venkataraman2, Surekha Tippisetty3, Vamsi Krishna Kolukula3, Shashank R. Joshi6

Apollo Sugar Clinic, Apollo Hospital, Bhubaneswar, Odisha, 1Apollo Sugar Clinic, Apollo Hospital, Madurai, 2Apollo Sugar Clinic, Apollo Hospital, Chennai, Tamil Nadu, 3Apollo Sugar Clinic, Apollo Hospital, Hyderabad, Telangana, 4Apollo Sugar Clinic, Apollo Hospital, Bangalore, Karnataka, 5Apollo Sugar Clinic, Apollo Hospital, Delhi, 6Apollo Sugar Clinic, Mumbai, Lilavati Hospital and Research Centre, Mumbai, Maharashtra, India.

E-mail: [email protected]

Aims: To compare glycemic outcomes of type 2 diabetes mellitus (T2DM) patients enrolled in comprehensive diabetes management program (DMP) at Apollo Sugar Clinics, Pan India. Materials and Methods: A cross sectional retrospective analysis of glycemic control of T2DM patients enrolled in DMP program at Apollo Sugar Clinics, Pan India (June 2017 to December 2017). DMP is a structured long term comprehensive care model to achieve glycemic goals and reduce complications burden. It consists of in-clinic physician and diet consultation and beyond clinic support includes counselling by health coach on medication, diet and exercise, SMBG monitoring, diet and exercise tips through Apollo sugar mobile app. Mean HbA1c reduction was considered to compare between the DMP and NoDMP. Appropriate statistics were applied to test the significant difference between the groups at a P < 0.05. Results: A total of 200 (No DMP = 100; DMP = 100) uncontrolled T2DM patients were selected for the analysis. Mean age was 51.9 (13.1) years and 63% were males. Mean HbA1c at baseline was 9.8% and at followup was 8.9% and a mean reduction of 0.9% (95% CI: 0.69-1.02; P < 0.001). Further, there was also a significant difference in mean HbA1c (9.5% to 8.9% vs. 10.1% to 9.0%) in No DMP and DMP patient groups from baseline to followup. The mean difference in HbA1c is statistically significant in both DMP (Δ: 1.1%, 95% CI: 0.80-1.41, P < 0.001) and No DMP (Δ: 0.6%; 95% CI: 0.48-0.74, P < 0.001) patient, and the reduction is significantly greater in DMP compared to No DMP. Further in DMP at followup 10% of patients with >8% HbA1c achieved <7% of HbA1c goal. Conclusion: Our current analysis reveal patients on DMP had better glycemic outcomes than NoDMP patients, suggesting a comprehensive care should be recommended to have a good control over diabetes and prevent from complications burden. However, further prospective studies are required to come up with more tangible data to support DMP.

Keywords: Diabetes, glycemic control, HbA1c, management

   Stability of insulin at high temperature Top

Siddhi Singh, Arunkumar R. Pande1, Ashwani K. Thakur

Biological Sciences and Bioengineering Department, Indian Institute of Technology, Kanpur UP, 1Department of Endocrinology, Sahara Hospital and LEDTC Clinic, Lucknow, UP, India.

E-mail: [email protected]

Introduction: According IDF, at least 33% of families with children with diabetes lack access to refrigeration.As per State of Electricity Access Report (SEAR)-2017 by World Bank; in 2014, globally 1.06 billion people lived without electricity access. India has the world's largest electricity deficit which makes insulin storage difficult. Aims and Objectives: To assess stability of insulin by pot in pot method and FDA-approved FRIO® cooling pouch. Materials and Methods: Stability of commercial insulin was seen prior to the experiment insulin was stored in 4°C. Insulin vials were placed inside each device. These devices were kept inside incubator at 37°C. For Stability assessment, Light scattering and Reverse Phase-High performance liquid chromatography (RP-HPLC) was performed. Result and Conclusion: Insulin stored in pot-in-pot cooler is stable (based on RP-HPLC and Light scattering data) for at least first 14 days at 37°C. Efficacy of pot-in-pot cooler is same as that of Frio cooling pouch. Future Prospects: Inclusion of more indigenous devices under diverse climatic conditions. Bioassay on Type-1 diabetic cell lines and mouse models to assess its functional activity.

   Thyroid Top

   Life-threatening cardiac presentation of recurrent subacute thyroiditis: A case report Top

Arpit Garg1, Manas K. Sahoo2, Ambrish Mithal1

1Division of Endocrinology and Diabetes, 2Department of Nuclear Medicine, Medanta The Medicity, Gurugram, Haryana, India.

E-mail: [email protected]

Objective: We aimed to present a unique case of recurrent subacute thyroiditis presenting as life-threatening cardiac manifestations. Materials and Methods: Clinical features, disease course, laboratory parameters, imaging studies and treatment of the patient have been reported. We have also reviewed the literature containing reports of recurrent subacute thyroiditis with cardiac presentations. Results: A 35-year-male presented to our hospital with recurrent episodes of thyrotoxicosis for the past five years. In the first episode, patient developed thyrotoxicosis with atrial fibrillation (AF) with cardiovascular collapse requiring DC cardioversion. He was treated with anti-thyroid drugs. Patient became hypothyroid after one month of treatment followed by euthyroidism for six months after stopping the treatment. Patient had similar cycles of thyrotoxicosis, hypothyroidism followed by euthyroidism twice before the fourth episode in which the patient again had thyrotoxicosis with life threatening AF. 99mTc thyroid scan showed negligible uptake during thyrotoxicosis phase and TSH receptor antibody levels were low. Confirming the diagnosis of thyroiditis, radioactive iodine uptake also revealed low value, which excluded the treatment option with radioactive iodine (RAI). Total thyroidectomy was done as the definitive management and histopathology report showed lymphocytic thyroiditis. To the best of our knowledge, this is the first case report describing episodic AF with cardiac collapse requiring DC cardioversion, following episodes of recurrent subacute thyroiditis. Conclusion: Recurrent subacute thyroiditis with life threatening cardiac manifestations is a rare condition. Definitive therapy in the form of thyroidectomy may be required in such cases.

Keywords: Cardiac manifestation, recurrent subacute thyroiditis, thyroidectomy, thyrotoxicosis

   Palmoplantar keratoderma: A rare presentation of primary hypothyroidism Top

Bharat Panigrahy

Department of Medicine and Rheumatology, CARE, AMRI and LVPEI, Bhubaneswar, Odisha, India.

E-mail: [email protected]

Introduction: Hypothyroid state is associated with a wide variety of cutaneous findings; however, its association with palmoplantar keratoderma is seldom described in the medical literature. Case: A 53-year-old woman presented with a 6-month history of symmetric, diffuse and hyperkeratosis of palms and soles. Plantar surfaces were the most affected, with painful fissures. The remainder physical examination was normal. Asthenia, constipation were present for the last 4 months. Her past medical history was unremarkable. She denied the use of any medication. Family history was negative for dermatological diseases. No improvement after prior Treatment with topical antifungals, oral terbinafine and topical corticosteroids. Routine laboratory tests were normal. Thyroid function test revealed TSH-63.9. μIU/ml, T4- 4.0 μg/dl (5.10-14.10), T3-74 ng/dl (80-200). Anti TPO antibody was positive. Hepatitis B, C and HIV were negative. Scrap cytology revealed acquired hyperkeratosis with nonspecific inflammation. She was treated with Levothyroxine 100 μg daily and there was significant improvement after 2 months. She is on follow up now. Discussion: Hypothyroidism has been rarely associated with palmoplantar keratoderma. Distinctive features include a yellowish hue, diffuse involvement of the soles and more limited palmar involvement, lack of response to topical corticosteroids and keratolytics and a rapid response to thyroid hormone replacement. Histopathological findings have been unspecific, with marked hyperkeratosis. Conclusion: Acquired palmoplantar keratoderma due to hypothyroidism is a rare and reversible condition and should be considered in the differential diagnosis of acquired palmoplantar keratoderma.

   References Top

  1. Case Rep Med 2010:3, Article ID 604890. Available from: http://dx.doi.org/10.1155/2010/604890.
  2. Patel S, Zirwas M, English III JC. Acquired palmoplantar keratoderma. Am J Clin Dermatol 2007;8:1-11.
  3. Puri N. A study on cutaneous manifestations of thyroid disease. Indian J Dermatol 2012;57:247-8.

   Prevalence of microalbuminuria in subclinical and overt hypothyroidism: A cross sectional study Top

Tapsi Akhoon, Suman Kotwal1

Intern, MBBS, Government Medical College and Hospital, 1Assistant Professor, Department of Internal Medicine, Government Medical College and Hospital, Jammu, Jammu and Kashmir, India.

E-mail: [email protected]

Introduction: Prevalence of Microalbuminuria can be used as a marker for the risk of developing Cardiovascular and Renal Disease in patients of Hypothyroidism. The aim of this ongoing study is to establish correlation between the two in Phase 1 and to document remission in patients on levothyroxine therapy in Phase 2, thereby guiding clinical management. Materials and Methods: A cross sectional survey was performed on 90 (77 females, 13 males) newly diagnosed cases of Hypothyroidism in the endocrinology OPD of Government Medical College and Hospital Jammu after doing all baseline tests. A spot urine sample was assessed for Albumin-Creatinine Ratio using Biosense ACR™/URS 2AC strips and a UChek™ device. Results: Subclinical hypothyroidism (TSH ~ 5-10 mIU/L) was found in 44 subjects and 46 had overt hypothyroidism (TSH >10 mIU/L). The prevalence of abnormal ACR in study population is 24.71% (95% CI between 15.8% to 33.6%). Out of all patients of subclinical hypothyroidism, 25%; out of all patients with overt hypothyroidism, 24.4% had abnormal ACR (≥30). Out of all patients of overt hypothyroidism with abnormal ACR, 63.7% had TSH >100 mIU/L. In the ongoing phase 2- so far -after 6 weeks of therapy, patients with abnormal ACR in phase 1 are being reassessed. Conclusion: The prevalence of microalbuminuria in the study population is comparable to presence of microalbuminuria in early diabetics according to some studies. The prevalence is similar among subclinical and overt groups, within the overt group it is high in patients with TSH >100 mIU/ml.

Keywords: Cardiovascular disorders, hypothyroidism, microalbuminuria, throid disorders

   Effect of metformin on thyroid function test in patients with subclinical hypothyroidism: An open-label randomized control trial Top

Rajan Palui, Sadishkumar Kamalanathan, Jayaprakash Sahoo, Kalyani Sridharan, Harsh Durgia, Henith Raj

Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.

E-mail: [email protected]

Objective: Most observational studies have shown that metformin can reduce serum thyrotropin (TSH) level in hypothyroidism patients with either diabetes or polycystic ovarian disease independent of thyroxine treatment. However, randomised control trials evaluating the effect of metformin on TSH and thyroid hormones (free T3 and free T4) in patients with isolated subclinical hypothyroidism are sparse. The primary objective of this study was to evaluate the effect of metformin on thyroid function test (TSH, free T4, and free T3) in patients with subclinical hypothyroidism. Methodology: In this open-label, randomised controlled trial, a total of 60 patients with subclinical hypothyroidism (TSH 5.5-10 mIU/L) were randomised to either metformin group or control group. Pregnant or lactating mothers, patients with diabetes or infertility, dyslipidemia, chronic liver or kidney disease, BMI >35 or <18.5 Kg/m2 were excluded. Patients in metformin group received tablet metformin 500 mg thrice daily for 6 months whereas patients in control group received nothing. Result: Baseline characteristics of both the groups were similar. A total of 46 patients (23 in each group) completed follow-up. There was no statistically significant difference in serum TSH, free T4, free T3 between metformin and control groups at the end of study period. There was no significant change in serum TSH (pre-and post-6 months) within the individual groups also. However, markers of insulin resistance had significantly improved in patients receiving metformin. Four patients had mild gastrointestinal adverse effects in metformin group. Conclusion: Metformin had no significant effect on serum TSH level in this randomised controlled trial.

Keywords: Metformin, subclinical hypothyroidism, thyroid function

   Correlation of cord blood thyroid hormone levels, serum testosterone of newborns and maternal βhcg with Anogenital diatance as a surrogate of fetal reproductive axis Top

Ipsita Mishra, S. Mangaraj, Arun K. Choudhury, A. K. Baliarsinha

Department of Endocrinology, S.C.B. Medical College and Hospital, Cuttack, Odisha, India.

E-mail: [email protected]

Objective: To study the correlation of cord blood thyroid hormones, serum testosterone of newborns and maternal βhcg with anogenital distance (AGD) of newborn babies and to determine if any sex difference exists in influence of these hormones on AGD. Material and Methods: This cross-sectional study was carried out in department of Endocrinology SCBMCH, Cuttack between January 2017 to January 2018. Newborn babies delivered in department of O and G, SCBMCH meeting the inclusion and exclusion criteria were enrolled in the study. All newborns underwent clinical examination and anogenital distance (AGD) were measured. Biochemical investigations included estimation of cordblood serum fT3, fT4, TSH, serum total testosterone of newborns and maternal βhcg. All newborns were divided into two groups of male and female. Appropriate statistical tests were applied and results were derived. Results: A total of one hundred and thirty three newborns were taken of which ninety were male and fortythree were female. The mean AGD in males (2.62 ± 0.0874 cm) was significantly greater than females (1.15 ± 0.048 cm) (P = 0.001). fT3 (P = 0.001) and βhcg (P = 0.001) was significantly high in male than females. Though mean S. Testosterone was high in males (1.707 ± 0.203 ng/ml) than females (0.799 ± 0.258 ng/ml) yet it was not significant (P = 0.16). Regression results of AGD and S. Testosterone, cord blood thyroid hormones, maternal βhcg stratified by sex revealed significant positive association of male AGD with S. Testosterone (β = 0.638, P = 0.001), fT3 (β = 0.664, P = 0.001), fT4 (β = 0.724, P = 0.001), TSH (β = 0.594, P = 0.0001) and βhcg (β = 0.564, P = 0.0001). Female AGD didnot have any significant association with S. Testosterone (β = 0.221, P = 0.154), fT3 (β=-0.057, P = 0.718), fT4 (β = 0.055, P = 0.725), TSH (β = −0.051, P = 0.743) or βhcg (β = 0.094, P = 0.543). Conclusion: AGD is significantly higher in male newborns. Among various hormones which play an important role during masculinization programming window, not only testosterone but also thyroid hormones and maternal βhcg significantly influence the AGD in male newborns.

Keywords: Anogenital distance, cord blood thyroid hormones, newborns, testosterone

   A study on aetiopathogenesis of Graves' orbitopathy with special reference to TSH Receptors in circulating fibrocytes Top

Madhurima Basak1, Subhankar Chowdhury1, Sudipta Banerjee1, Tamalika Sanyal2,3, Madhusudan Das2, Pritha Bhattacharjee3

1Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research and SSKM Hospital, 2Departments of Zoology, 3Environmental Science, University of Calcutta, Kolkata, West Bengal, India.

E-mail: [email protected]

Graves' orbitopathy (GO) is an inflammatory autoimmune disorder of the orbital connective tissue. These are extensively remodeled with enlargement of the extra ocular muscles (EOM) and retro orbital fat. It is not yet clearly understood as to why only a proportion of individuals with Graves' disease (GD) develop clinically significant orbitopathy and TSHR in circulating fibrocytes which also serves as the autoimmune target in Graves' hyperthyroidism may have a role. Our objectives are to look for the correlation between TSH Receptor Antibody (TRAb) and fT3, fT4, Goiter size, EOM thickness and the expression of TSHR in fibrocytes in GD and GO, with respect to control. GD [n = 30 (Age38.78 ± 9.30 years), GO [n = 12(Age 35.6 ± 8.58 years)] Patients and control [n = 10(Age 31.5 ± 8.57 years)] were included. Circulating fibrocytes were cultured from Peripheral Blood mono nuclear cells (PBMCs) and TSHR expression were observed and analyzed through immuno cytochemistry and western blot. TRAb value is positively correlated with fT3 (GD r = 0.23; P = 0.00012, GO r = 0.64; P = 0.0072), fT4 (GD r = 0.61; P = 0.00011, GO r = 0.66, P = 0.0205) and goiter size (GD r = 0.33; P = 0.0001, GO r = 0.62; P = 0.011) in GD and GO. TRAb value is also positively correlated with EOM thickness [Medial Rectus (MR) Inferior Rectus (IR)] in GO [(MR: r = 0.48; P = 0.01) (IR: r = 0.37; P = 0.03,) but no significant correlation has been found in GD. Qualitatively, there is a graded expression of TSHR in fibrorcytes and it is lowest in control, intermediate in GD and highest in GO. Quantitative data will be provided at presentation. From this study we can conclude that due to the change in expression level of TSHR in circulating fibrocytes may affect the binding of TRAb with TSHR and pathogenesis of GO.

Keywords: Fibrocytes, goiter, TRAb, TSHR

   Nivolumab, an immune check point inhibitor induced thyroid dysfunction Top

Ganavi Y.P., Chitra Selvan

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Introduction: Nivolumab, a human IgG4 monoclonal antibody is an immune checkpoint inhibitor used in the management of inoperable or metastatic squamous non-small cell lung carcinoma with its effects on thyroid gland being hypothyroidisn, hyperthyroidism, and thyroiditis. We report a case of nivolumab-induced thyroid dysfunction. Case Report: A 41-year-old man with adenocarcinoma lung with leptomeningeal metastasis received weekly nivolumab for 4 weeks following which he developed signs and symptoms of thyrotoxicosis without eye signs. Investigations revealed supressed TSH with T4 and T3 being elevated. Thyroid scintigraphy was suggestive of thyroiditis and was started on propranolol. After 10th cycle of nivolumab, patient developed giddiness, easy fatigability, swaying while walking, anorexia and reduced alertness with ankle oedema and bradycardia. Investigations done revealed primary hypothyroidism for which he received levothyroxine sodium at a dose of 50 mcg per day. But After 14 cycles of nivolumab, he presented with similar symptoms with a persistently elevated TSH. 8 am cortisol was normal. Hence nivolumab induced hypophysitis was ruled out and levothyroxine dose was increased to 100 mcg/day. Following use of levothyroxine at a dose of 100 mcg/day, a gradual resolution of all symptoms and signs related to hypothyroidism was noticed 2 months later with a TSH of 0.98 mcIU/ml. Conclusion: The mechanisms underlying immune-related thyroid dysfunction is not fully characterised. This can be ascribed to the disinhibition of CTLA-4 and PD-1 which might exacerbate hypothyroidism and/or thyroiditis. This is the first documented case of thyroiditis followed by hypothyroidism induced by nivolumab from India.

Keywords: CTLA4 inhibitor, hypothyroidism, nivolumab, thyroiditis

   Graves' disease presenting as bilateral hip fracture Top

Manoranjan Tripathy, Swayam S. Mangaraj, Arun K. Choudhury, Anoj K. Baliarsinha

Department of Endocrinology, S.C.B. Medical College and Hospital, Cuttack, Odisha, India.

E-mail: [email protected]

Objective: Hip fracture after trivial trauma usually occurs in elderly individuals. In young individuals hip fracture occurs only after severe trauma like road traffic accident or sports injury. Hyperthyroidism is associated with decrease in bone mineral density and increased fracture risk in elderly individuals. Fragility fracture in young individuals due to hyperthyroidism is rarely reported in literature. We are reporting a rare case of hyperthyroidism associated with bilateral hip fracture in a young girl. Methodology and Result: A 19 year old girl presented with pain in the left hip for 6 months and right hip for 3 months following which she was unable to walk. On enquiry, she gave history of trivial trauma prior to the onset of pain. On examination, her legs were externally rotated and tenderness over bilateral trochanteric area was present. MRI pelvis revealed bilateral transtrochanteric fracture of recent onset with old subcapital fracture of right femur with sclerosis. On detailed enquiry, she gave history of thyrotoxic symptoms for last 6 months. Clinical examination revealed presence of a grade two diffuse goitre with tachycardia, tremors and bilateral exophthalmos and inactive ophthalmopathy. Hormonal evaluation revealed elevated thyroid hormones with suppressed TSH. She also had vitamin D deficiency with normal serum calcium, phosphorous and raised alkaline phosphatase. She was started on carbimazole 30 mg and propranolol 40 mg per day with calcium and vitamin D supplementation. Conclusion: Though rarely reported, Graves' disease can present with pathological hip fracture in young individuals and should be sought as a potential reversible cause.

Keywords: Bilateral hip fracture, graves' disease, hip fracture, young patient

   Iodine status and trend of total T4 in pregnancy: A cross-sectional study from a tertiary center in Eastern India Top

Subhodip Pramanik, Rana Bhattacharjee, Pradip Mukhopadhyay, Sujoy Ghosh, Subhankar Chowdhury

Department of Endocrinology, IPGMER, Kolkata, West Bengal, India.

E-mail: [email protected]

Objective: Pregnancy is associated with elevated total thyroxin (T4) level during pregnancy due to rise of thyroxin binding globulin (TBG). Our aim was to determine the magnitude and timing of rise of T4 during pregnancy among women attending a tertiary center in Eastern India. Materials and Methods: Both pregnant and representative non-pregnant population was screened. Thyroid profile was done by chemiluminometry assay. Urinary iodine was done by Sandell–Kolthoff method. Those on levothyroxin supplement or having twin/hyperemesis graviderum were excluded. Results: 350 pregnant women and 80 non-pregnant women were screened. Mild urinary iodine deficiency (Urinary iodine 101-150 μg/L) was found in 12% pregnant population, but none of non-pregnant woman was found iodine deficient. Significant rise of total T4 occurred between 10-18th week of pregnancy and the elevation was only 20% in 18th week of gestation as compared with non-pregnant values. Conclusion: One out of eight women still suffers from mild iodine deficiency in pregnancy in Eastern India, however there is no moderate or severe iodine deficiency. The increment in total T4 in pregnancy is only 20% in this part of country.

Keywords: Cretinism, hypothyroidism, iodine deficiency


Prof Satinath Mukhopadhyay and Dr Dibakar Biswas for their help in patient recruitment.

   Encapsulated follicular variant of papillary thyroid carcinoma - A paradigm shift Top

Subramanian Kannan1, Sushma Mehta2, Nikita Oza2, Naveen Hedne2, Vijay Pillai2, Vivek Shetty2, Vidya Bhushan2, Trupti Kolur2, Moni A. Kuriakose2, Sunil H. V4, Vidita Powle4

Departments of 1Endocrinology Diabetes and Metabolism, 2Head and Neck Surgical Oncology, 3Pathology and Laboratory Services, Narayana Health City, Bangalore, 4Department of Nuclear Medicine, FDI, Narayana Health City Campus, Bangalore, Karnataka, India.

E-mail: [email protected]

Context: NIFTP (Non-invasive Follicular thyroid neoplasm with papillary nuclear like features) has replaced the previous term “Encapsulated follicular Variant of papillary thyroid cancer”. Aims: To determine the clinical behaviour of patients with encapsulated variant of follicular variant of PTC who could meet the diagnostic criteria of Non-invasive follicular thyroid neoplasm with papillary like features. Settings and Design: A retrospective analysis of patients with encapsulated follicular variant of papillary thyroid carcinoma was done from 2012 to 2017. A total of 21 patients were included which were microscopically evaluated for the specific features such as encapsulation or clear demarcation, follicular growth pattern with less than 1% papillae, absence of psammoma bodies, less than 30% solid/trabecular/insular growth pattern, a nuclear score of 2-3. Material and Methods: Retrospective chart review. Results: A total of 10 patients could be reclassified/re-diagnosed as NIFTP based on the features described above. Out of these, there were 7 females and 3 male patients. One patient had positive central compartment neck dissection (N1a), 3 were N0 and 5 patients were not subjected to neck dissection. Post-operative histopathology staging was assessed, the TNM staging was as follows: one T1N0, two T2N0, three T2Nx, two T3Nx, one T3N1a. Two patients had a size of more than 5 cm and two were above age of 55 years. 6 patients received RAI treatment post surgery; all of them with 50 mCi, 3 patients did not have any uptake following whole body iodine scan (WBS). None of these patients had lymph nodal uptake in the post op WBS scan. None of these patients have had residual or metastatic disease in the mean follow up of 36 months. Conclusions: Our review of patients with NIFTP seems to be consistent with low risk thyroid tumors and agree with de-escalating treatment protocols for these patients.

Keywords: Encapsulated variant follicular thyroid cancer, NIFTP, treatment

   Papillary thyroid carcinoma in a patient with Graves disease Top

Srinivas G. N. S. V. Kandula, K. D. Modi, Vaibhav V. Dukle

Department of Endocrinology, Care Hospitals, Banjara Hills, Hyderabad, Telangana, India.

E-mail: [email protected]

Background: Nodules in hyperthyroidism usually denote toxic multinodular goiter or adenoma. Non-functioning nodules of significant size in hyperthyroid patient always warrant further investigation. Case: A 35 year old female, known case of hyperthyroidism, on anti-thyroid medication since 1 ½ years presented with a swelling in front of neck, noticed 4 months back, progressively increasing in size with no associated pain or compressive symptoms like hoarseness of voice, dysphagia. Patient gives history of weight loss (5 kg in 3 months) associated with palpitations, increased sweating and tremulousness of hands. She gives no history of radiation exposure or any family history of thyroid disease. On examination, she was thin built, with a pulse rate of 116/min, fine tremors of both hands and absent eye signs. Oval shaped swelling of 5 × 4 cm noticed in front of neck more towards left side, moving with deglutition. Swelling is firm in consistency, non-tender, lower border felt and no palpable lymphnodes. On radioisotope scan, a hyper-functioning thyroid gland with a diffuse uptake of 7.1% (suggesting Graves disease) along with a non-functioning cold nodule in the inter-polar region of left lobe detected. Sonographic imaging suggested enlarged thyroid gland with a left-sided hypoechoic nodule of 4 × 5 cm with irregular margins and microcalcifations. FNAC of the swelling was suggestive of papillary carcinoma thyroid (BETHESDA category 5). After achieving euthyroid status with anti thyroid drugs, patient underwent near total thyroidectomy. Gross and histopathological examination showed a 4 cm Papillary carcinoma thyroid (oncocytic variant) with minimal extrathyroidal extension, absent angioinvasion and no lymphnode metastatsis. Conclusion: Thyroid nodules in the background of Graves disease have higher risk of being malignant and appropriate work-up is necessary in such cases.

Keywords: Cold-nodule, Graves disease, hyperthyroidism, papillary thyroid carcinoma

   Utility of thyroid blood flow parameters in evaluation of thyrotoxicosis Top

Swayamsidha Mangaraj, Pradosh K. Sarangi1, Arun K. Choudhury, Anoj K. Baliarsinha

Department of Endocrinology, 1Radiology, S.C.B Medical College Cuttack, Odisha, India.

E-mail: [email protected]

Objectives: To evaluate the utility of peak systolic velocity of superior thyroid artery (PSV-STA) and a novel parameter (ratio of peak systolic velocity of superior thyroid artery to peak systolic velocity of common carotid artery (STA-PSV/CCA-PSV ratio) in differentiation of Graves' disease and thyroiditis presenting with thyrotoxicosis. Materials and Methods: A total of 111 patients with newly diagnosed thyrotoxicosis without antithyroid medication or β-blockers use and 45 age and sex matched healthy subjects as control were included. Thyroid function tests and thyroid autoantibody titres were done. All subjects underwent a detailed color-flow Doppler ultrasonography of the thyroid gland and spectral flow analysis of thyroid and carotid arteries. Results: On Doppler study, the mean STA-PSV of patients with Graves' disease was significantly higher than thyroiditis and control group ((92.79 ± 44.95 cm/sec, 37.89 ± 15.33 cm/sec, 20.07 ± 6.77 cm/sec respectively (P < 0.001). Similarly, STA-PSV/CCA-PSV ratio was significantly higher in Graves' disease (0.65 ± 0.32) than thyroiditis (0.30 ± 0.11) (P < 0.001). STA-PSV greater than 54.275 cm/s had 82.9% sensitivity and 86.2% specificity in diagnosing Graves' disease. On the other hand, STA-PSV/CCA-PSV ratio (0.40) had a similar specificity (86.2%) albeit with a slightly lower sensitivity (80.5%) compared to STA-PSV. Conclusions: The mean STA-PSV and STA-PSV/CCA-PSV ratio have high sensitivity and specificity in differentiating Graves' disease from thyroiditis and should be used routinely in clinical practice. Consent: Written informed consent was obtained from the study subjects for publication of study.

Keywords: Graves' disease, peak systolic velocity, superior thyroid artery, thyroiditis

   Cognitive dysfunction and depression in primary hypothyroidism and post treatment follow up Top

Prashanth Poulose, Geetha Panarkandy

Department of Medicine, Government Medical College, Calicut, Kerala, India.

E-mail: [email protected]

Introduction: Thyroid hormone receptors are widely distributed in areas of brain critical to mood and higher order cognition. Hypothyroidism impairs learning, memory, behaviour and mood. Objectives: To find out the effect of hypothyroidism on cognitive and mood domains and assess post treatment cognition and depression status after thyroid functions have normalized. Materials and Methods: Cognition and Depression in newly detected Hypothyroid patients were assessed using Addenbrookes Cognition examination tool (ACE-R) and Patient Health questionnaire PHQ-9 and patients were reassessed following treatment after attainment of Euthyroid state with the same scales. Result: In this study 39% patients have cognitive dysfunction. Depression was present in 82.6% of patients. All patients with Cognitive impairment had depressive symptoms also. Mood, Working memory, Recent episodic memory are the cognitive domains most affected in Hypothyroidism. These cognitive and mood domains showed statistically significant improvement post treatment. Language domain was not much affected in Hypothyroidism. There was statistically significant association between age, education, fatigue, TSH, Anti-TPO and Cognition. Depression severity had association with TSH and Anti-TPO positivity. Conclusion: Dorsolateral Prefrontal Cortex, Medial temporal lobe, Limbic system are the most affected areas in Hypothyroidism. Subclinical hypothyroidism causes cognitive dysfunction and depression. Dementia and depression due to hypothyroidism is reversible and it should be definitely treated with thyroid hormone supplementation.

Keywords: Addenbrookes cognition examination tool, patient health questionnaire

   Hürthle cell metaplasia in chronic lymphocytic thyroiditis: Role of age factor Top

Dilip K. Das

Department of Pathology, Faculty of Medicine, Kuwait University and Cytology Unit, Mubarak Al-Kabeer Hospital, Kuwait.

E-mail: [email protected]

Aims and Objective: Hürthle cell (HC) metaplasia is an important feature of chronic lymphocytic (Hashimoto) thyroiditis (HT); however, it rarely occurs in the juvenile form. In a study based on fine needle aspiration cytology, we aimed to study the cytomorphological differences between pediatric HT and it adult form, with special attention on HC metaplasia and its pathogenesis. Materials and Methods: The frequency of following 12 cytomorphological features in 16 pediatric and 104 adult HT cases were compared: follicular cells, lymphoid cells, Hürthle cells, plasma cells, lympho-histiocytic aggregates, epithelioid histiocytes, multinucleated giant cells, fire-flare appearance, colloid, intracytoplasmic lumen (ICL) with or without colloid inclusion (CI), paravacuolar granules and cyst cells. The age decade distribution of cases with HC metaplasia was analysed. Results: Significant difference was observed between pediatric HT and its adult form in respect of HC metaplasia and ICL with CI in HC. HC were present in 7 (43.8%) of pediatric and 94 (90.4%) of adult HT cases (P = 0.00006). 1 (6.3%) pediatric and 35 (33.7%) adult HT cases had ICL with CI in HC (P = 0.03698). As compared to first two decades of life, significantly higher number of cases revealed HC metaplasia in every decade from 3rd decade onwards (P = 0.01290 to 0.00009); however, the difference in respect of ICL with CI attained significance during 6th decade only (P = 0.00235). Thus, Hürthlization, which appears to be survival response, is rare in pediatric HT and becomes more pronounced starting from 3rd decade onwards; significant increase in ICL with CI is a much more delayed phenomenon.

   Case of Van-Wych Grumbach syndrome Top

V. B. Nagapriya, Smitha Nalla, Prasun Deb, Ashish Kumar

Department of Endocrinology, KIMS Hospitals, Secunderabad, Telangana, India.

E-mail: [email protected]

Primary hypothyroidism usually leads to retardation of linear growth and delay or even arrest of puberty in juvenile patients. In rare cases, pediatric patients with long standing hypothyroidism may present with precocious puberty. This is associated with delayed bone age and growth retardation. Van Wyk-Grumbach syndrome (VWGS) was termed in 1960 which includes juvenile hypothyroidism, delayed bone age and pseudo precocious puberty. Here we are describing case of a 7-year-old girl with presenting with bleeding per vagina, facial puffiness and short stature. Found to have features of iso-sexual precocious puberty (ISP) with bleeding per vagina, thelarche and height below 3rd centile. Investigations showed normal baseline investigations with raised FSH, prepubertal LH and very high TSH, ultrasound abdomen and pelvis showed multi- cystic ovaries and uterus of pubertal size. Diagnosis of juvenile hypothyroidism with precocious puberty and short stature was made and she has been started on Levothyroxine supplementation. Recognizing this condition is important to avoid costly investigations and unnecessary surgeries in children with precocious puberty.

   Pituitary Top

   A rare case of pituitary hemangiopericytoma masquerading as macroprolactinoma Top

Shalin Shah, Mohammad S. Kuchay, Sunil K. Mishra, Ambrish Mithal, Jay P. Sharma1

Division of Endocrinology and Diabetes, 1Department of Radiology, Medanta The Medicity Hospital, Gurugram, Haryana, India.

E-mail: [email protected]

Objectives: We aimed to present a rare case of pituitary hemangiopericytoma masquerading as macroprolactinoma. Materials and Methods: We report clinical features, laboratory parameters and imaging studies of the patient, before and after surgery. Results: A 29-year-female presented with oligomenorrhea for the past six months, galactorrhea for 4 months; headache and gradual vision loss for the last 15 days. Biochemical evaluation revealed hyperprolactinemia. Patient was treated with cabergolin but showed only partial normalization of serum prolactin levels. Patient was referred to our department for further management. Hormonal evaluation revealed hypopituitarism and persistent prolactinemia. Dynamic contrast enhanced MRI pituitary revealed sellar mass with suprasellar extension and intralesional hemorrhage mimicking pituitary macroadenoma. Endonasal Transphenoidal Excision of pituitary mass was done. Histopathology and Immunohistochemistry revealed features suggestive of hemangiopericytoma (WHO Grade 3). Subsequently patient underwent right pterional craniotomy and tumour excision followed by radiotherapy and chemotherapy. On follow-up, her vision improved significantly and her prolactin levels normalized. Conclusions: Pituitary hemangiopericytoma is a rare condition and may sometimes mimic pituitary adenoma. High degree of suspicion is needed to diagnose this condition.

Keywords: Craniotomy, intacranial hemangiopericytoma, macroadenoma, prolactinoma, spindle cell tumour

   Herniation of optic chiasma into secondary empty sella, after transphenoidal surgery and cabergoline therapy for a macroprolactinoma resulting in field defects corrected by chiasmopexy Top

Chandar M. Batra, V. P. Singh, Savita Jain

Department of Endocrinology and Neurosurgery, Indraprastha Apollo Hospital, New Delhi, India.

E-mail: [email protected]

Herniation of the optic chiasma is a rare complication of transphenoidal pituitary surgery and cabergoline therapy in a macroprolactinoma. This results in defects in acuity of vision and bitemporal heminopia. The treatment for this defect is chiasmopexy, a neurosurgical technique by which the sella is pushed up and the sellar floor is repaired resulting in correction of visual field defects. Only 11 cases of chiasmopexy have been reported so far, this is the 12th case. AIIMS and Objectives: To describe the clinical, biochemical, radiological and pathological parameters and result of treatment of a case of macoprolactinoma who underwent transphenoidal surgery and cabergoline therapy resulting in herniation of the optic chiasma into a secondary empty sella with decrease in visual acuity and field defects which were corrected by chiasmopexy. Case Report: Mrs KS a 41 year resident of nepalpresented with history of headache and bilateral galactorrhoea and secondary amenorrhoea for 6 months. The headache was of gradual onset, progressive, bilateral in the temporoparietal region and was not associated with any visual complaints [Figure 2]. On evaluation her MRI sella revealed a giant pituitary tumor which was sellar and suprasellar but not touching the optic chiasma [Figure 1]. The hormone analysis revealed a very high serum prolactin of 9031 ng/ml with normal thyroid functions and normal adrenocortical functions. She underwent a translabial transphenoidal pituitary adenectomy in Nepal. The histopathology was suggestive of pituitary adenoma. The post operative hormonal analysis showed a serum prolactin of 200 ng/ml and secondary hypothyroidism and secondary adrenocortical failure. The visual acuity and field of vision in both eyes was normal. She was started on bromocriptine 2.5 mg daily followed by cabergoline 0.5 mg weekly. She was also put on replacement therapy of wysolone 5 mg daily and thyroxine 50 ug daily. Her headache and galactorrhoea resolved but amenorrhoea persisted. 3 months postop she started having progressive decrease in visual acuity and perimetry showed bitemporal hemianopia. (Vision RE6/8 LE6/30) [Figure 4]. MRI sella showed herniation of optic chiasma into a secondary empty sella [Figure 3]. She was diagnosed as secondary empty sella with panhypopituitarism and bilateral hemianopia due to herniation of optic chiasma into sella. She underwent transphenoidal chiasmopexy in which her sell was filled up wih fat, fasciaglue and the floor was repaired with fat, fascia and bone. Her field of vision normalized [Figure 6] a week after surgery and a post operative MRI done demonstated [Figure 5] elevation of optic chiasma.
Figure 1: Preoperative mri sella showing massive macroprolactinoma

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Figure 2: Preoperative perimetry, normal fields

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Figure 3: Mri sella 3 months post transphenoidal adenectomy

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Figure 4: Perimetry 3 months post transphenoidal pituitary adenectomy

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Figure 5: Post chaismopexy MRI

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Figure 6: Post chiasmopexy perimetry

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Keywords: Chiasmopexy, herniation, optic chiasma

   Pituitary metastasis from follicular carcinoma thyroid Top

C. M. Batra, V. P. Singh, Pratima Goyal, Nikhil Tandon1

Department of Endocrinology and Neurosurgery, Indraprastha Apollo Hospital, New Delhi, India, 1Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Pituitary metastasis from thyroid gland is a rare disorder, there are only 22 reported cases so far. They are found in only 1% of all pituitary resections and only 2% of these are from thyroid carcinoma. Aims and Objectives: To describe the clinical, biochemical, radiological and pathological parameters and result of treatment of a case of a case of pituitary metastases from follicular carcinoma thyroid. Case Report: Mrs R V a 26 year old housewife was admitted on 28/9/17 with complaints of a small nodule on the left side of neck since 4 years, severe headache since 10 days and decreased vision of left eye since 8 days. The examination findings were a firm to hard, nodular, swelling 6cm in diameter on anterior side of neck. The visual acuity on left side was only finger counting at 1 feet and there was a left temporal field defect whereas the right eye was normal. Investigations of thyroid nodule revealed subclinical hypothyroidism and FNAC of thyroid showed follicular epithelial cell so it was labelled a adenomatous thyroid nodule. CT head was normal but MRI of cranium on 25.9.17 showed a 30 mm diameter expansile lesion involving body and left lateral wing of sphenoid bone reaching upto left orbital apex [Figure 1]. A diagnosis of invasive pituitary macroadenoma compressing the optic chiasma with loss of vision left eye, primary hypothyroidism and benign multinodular goitre was made. Transnasal transsphenoidal microsurgical decompression was done on 29.9.17. Postoperatively vision in her left eye improved but post operative NCCT head revealed a large residual tumor. Histopathology was suggestive of a beningn epithelial neoplasm but immunostaining for GH, prolactin, synaptoyophysin was negative. Immunohistochemistry for pancytokeratin (AE1/AE3), thyroglogulin and TTF-1 was positive diffusely. On this basis a diagnosis of Follicular carcinoma of thyroid with metastases to the pituitary was made. The patient underwent total thyroidectomy. Histopathological report was follicular carcinoma thyroid. Subsequently she was given 100 millicurie of I-131. Radiotherapy for the residual mass is planned.
Figure 1: MRI of cranium with contrast(25/09/17): 35/35/30 mm expansile ill defined lesion involving body and left greater wing of sphenoid bone, breech of left lateral wing of sphenoid sinus with intracranial extradural soft tissue component causing mass effect on the pre chiasmatic part of B/L optic nerves, extension into left ethmoid air cells reaching upto left orbital apex

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Keywords: Follicular carcinoma thyroid, immunohistochemistry, metastasis, pituitary

   Rise of sphinx – Two cases of cushing's disease diagnosed several years after excision of non functioning macroadenoma Top

Amrutha Gopalakrishnan, Sujay Rao1, Sudeep Putta-Manohar2

Department of Family Medicine, 1Consultant Neurosurgeon, Neurosurgery, 2Consultant Endocrinologist, Endocrinology, ST Philomenas Hospital, Bangalore, Karnataka, India.

E-mail: [email protected]

Introduction: Cushing's disease is rare with incidence of about 5 to 10/million/year. Only 5% of these are due to a macroadenoma. Cushing's disease has a high rate of recurrence post surgery. We present 2 young females who had macroadenoma resection which were considered nonfunctioning lesions but presented back after a few years with symptomatic cushing's disease. Case 1. 31 yr/F presented with classical symptoms of pituitary apoplexy in 2007. She underwent emergency decompression and Transphenoidal resection of a pituitary macroadenoma. She represented in 2011 with obesity, diabetes and hypertension and on evaluation was found to have ACTH dependent cushing's syndrome with recurrence of pituitary macroadenoma. Case 2. 32 y/F had undergone resection of a non-functioning pituitary macroadenoma in 2012 and represented back in 2016 for consideration of bariatric surgery for morbid obesity. On pre-operative workup she was found to have ACTH dependent cushing's syndrome with recurrence of pituitary macroadenoma. In both our cases we noted that Immunohistochemistry for ACTH staining was not obtained post-operatively. Conclusion: Our cases emphasizes the need for thorough pre-operative and post-operative evaluation of pituitary adenoma with multidisciplinary team involvement.

Key words: Cushing's disease, pituitary apoplexy, pituitary macroadenoma

   Idiopathic intracranial hypertension precipitated by ketoconazole therapy in an adult patient with persistent (post trans-sphenoidal surgery and radiotherapy) Cushing's disease Top

Ayan Roy, Sadishkumar Kamalanathan, Jayaprakash Sahoo, Pradeep P. Nair1, Niya Narayanan

Departments of Endocrinology, 1Neurology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.

E-mail: [email protected]

Introduction: Idiopathic intracranial hypertension (IIH), also known as benign intracranial hypertension or pseudotumor cerebri usually presents with headache and visual blurring and can be vision threatening if not treated promptly. In Cushing's syndrome (CS), IIH is reported commonly in children following pituitary surgery. IIH in an adult with CS precipitated by medical therapy has not been reported. Case Report: A 19 year old female, known case of ACTH dependent Cushing's disease with history of twice trans-sphenoidal surgery (2015) and gamma knife surgery (2016) came with persistent disease. She was started on oral ketoconazole (50 mg BD) in February 2018 as a rescue therapy till the radiothearpy effect comes. The dose of ketoconazole was increased to 100 mg BD in May 2018 based on persistant high urinary free cortisol. Then, she presented with headache, dizziness, and recurrent vomiting along with visual blurring and diplopia after four weeks.There was no fever or meningeal signs. She had bilateral papilloedema along with sixth cranial nerve palsy. The CSF opening pressure was also very high suggestive of raised intracranial tension. Both CSF studies and CT venogram were normal ruling out meningitis and cortical venous thrombosis. So, the diagnosis of IIH was made and she was started on oral acetazolamide (250 mg thrice daily). There was a considerable improvement within a week of initiation of treatment. Conclusion: IIH should be kept as a differental diagnosis of headache with visual symptoms in a patient with CS following cortisol lowering medical therapy.

Keywords: Cushing's disease, IIH, ketoconazole

   Short stature and delayed puberty in a non-syndromic patient of hypothalamic hamartoma with panhypopituitarism Top

Henith Raj, Ayan Roy, Harsh Durgia, Rajan Palui, Jayaprakash Sahoo, Sadishkumar Kamalanathan

Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India

E-mail: [email protected]

Background: Hypothalamic hamartoma (HH) usually presents with precocious puberty. This is attributed to premature activation of HPG axis. Other associated endocrine features in HH include diabetes insipidus, growth hormone deficiency and hypogonadotrophic hypogonadism. In children with Pallister-Hall syndrome, HH is associated with panhypopituitarism and can have presentation with short stature along with other features of this syndrome. Case Report: A 14-year old boy presented with delayed puberty and short stature. He was born out of non-consanguineous marriage and the perinatal history was unremarkable. No history of seizures or abnormal behaviour was present. No auditory or visual complaint or any abnormality in smell was noted. There was no family history of delayed puberty. His height was −2.7 SDS and bone age was 11.5 years. His SMR was P1, bilateral testicular volume 3 ml and axillary hair was absent. Clinical examination revealed no other abnormality. Routine biochemical tests were within normal limits. His freeT4 was 0.73 (0.89-1.76 ng/dl) and TSH 2.01 (0.5-5.5 IU/ml) suggesting central hypothyroidism whereas the HPA axis was normal. Serum IGF1 was low (<25 ng/ml) and clonidine stimulation test revealed peak GH level less than 1 mcg/dl suggesting severe growth hormone deficiency. His LH was 0.03 mIU/ml, FSH was 0.09 mIU/ml and Testosterone was 3.35 ng/dl). Leuprolide stimulation test revealed peak LH and FSH response of 0.42 and 3.46 mIU/ml respectively. MRI showed a hypothalamic hamartoma with hypoplastic anterior pituitary. Conclusion: We describe an unique case of hypothalamic hamartoma with concomitant panhypopituitarism presenting as delayed puberty with short stature.

Keywords: Hypothalamic hamartoma, nonsyndromic cause, panhypopituitarism

   Genetic, clinical and histopathological findings in patients with sporadic anterior pituitary adenoma Top

Ekta Malik, Viveka P. Jyotsna1, Mehar Chand Sharma2, Shipra Agarwal2, Devasenathipathy Kandasamy3, Arundhati Sharma

Departments of Anatomy, 1Endocrinology and Metabolism, 2Pathology, 3Radio Diagnosis, AIIMS, New Delhi, India

E-mail: [email protected]

Objective: To screen the MEN1, AIP, GNAS1 and PRKAR1A genes in sporadic Anterior Pituitary Adenoma (APA) patients. Materials and Methods: 100 clinically diagnosed sporadic APA patients from the outpatient department of Endocrinology and Metabolism and 40 healthy individuals from the general population were recruited. Detailed clinical and family history and 5 ml blood was collected after taking informed consent. PCR amplification of MEN1, AIP, GNAS1, and PRKAR1A was done followed by direct sequencing. Results were compared with reference sequences in the public databases and in–silico analysis was done using bioinformatics tools Mutation [email protected] and Human Splicing Finder (HSF). Results: Out of 100 patients (75 functioning and 25 non-functioning), 55 were females and 45 males. Magnetic Resonance Imaging reported macroadenoma in 64 and microadenoma in 36 patients. Genetic screening revealed 3 intronic and 1 exonic MEN1 variations and 2 intronic changes in AIP gene. MEN1 changes were variation L404L (1 patient), reported intronic variations c. 913-79T>A (2 patients), c. 913-42G>C (2 patients) and c. 784-129T > A (1 patient) and SNP rs669976 in 32 patients. These changes were not identified in the controls. SNPs rs654440 (30% cases; 60% controls) and rs2071313 (35% cases; 70% controls) were also found. AIP screening revealed intronic splice site variations c. 100-6C>A and c. 100-18C>T in 1 patient each, SNPs rs2276020 (22 patients), rs641081 (51 patients) and rs4084113 in 55 patients. Variations c. 913-42G>C (MEN1) and c. 100-6C>A (AIP) were predicted to be damaging and MEN1 variations c. 913-79T>A, c. 784-129T>A, c. 913-42G>C and variation c. 100-6C>A of AIP were found to modify the splice site predicted by HSF. No variations were found in the GNAS1 and PRKAR1A. Histopathology in a patient with MEN1 variation c. 784-129T>A was associated with a higher MIB-1 labeling index. Conclusion: Intronic variants may lose or acquire downstream regulatory elements which may affect gene regulation. The study suggests that intronic MEN1 and AIP variations may alter the splicing mechanism resulting in altered protein thereby leading to disease causation.

Keywords: AIP, MEN1, mutation, pituitary adenoma, screening, variations

Support: The work was supported by funding from the All India Institute of Medical Sciences (AIIMS), New Delhi, India (Project Code - A-12).

   A case of septo-optic dysplasia Top

Apsia Ruhi, Vijay S. R. Danda, Srinivas Rao P, Madhavi Verpula

Department of Endocrinology, Gandhi Medical College/Hospital, Secunderabad, Telangana, India.

E-mail: [email protected]

Introduction: Septo-optic dysplasia, also referred to as de Morsier syndrome, is a congenital condition characterized by classic triad of, midline brain abnormalities, optic nerve hypoplasia and hypothalamo-pituitary dysfunction. Case Presentation: A seven-and-a-half-year-old male child, brought by parents with the complaints of decreased height gain over past 3 years. Born of non consanguineous union, birth weight of 2 kg, with prolonged neonatal jaundice. Normal developmental milestones, with average scholastic performance. No significant medical illness in the past. No significant family history. On examination he had midfacial hypoplasia, short stature (−3.09 SDS), weight of − 2.85 SDS. Systemic examination unremarkable. He had normal visual acuity and fundus examination was normal. Baseline investigations were within normal range and TFT, cortisol and prolactin were normal. Posterior pituitary function was normal. Bone age is of 4 years (G-P chart) and low IGF1. Clonidine stimulation test was done with stimulated levels were < 10 ng/ml suggesting growth hormone deficiency. Magnetic resonance imaging showed absent septum pellucidum, pituitary hypoplasia and partial corpus callosum. A diagnosis of Septo-optic dysplasia was made. Conclusion: Septo-optic dysplasia is a rare cause of short stature. A proper diagnosis will enable holistic approach towards management of the multiple components of condition.

Keywords: Midfacial hypoplasia, septo-optic dysplasia

   Acromegaly with pituitary microadenoma – Case report Top

Chhavi Agrawal, Asish K. Basu, Anirban Sinha, Animesh Maiti, Saurav Shishir, Sayan Ghosh, Somnath Raghuvanshi

Department of Endocrinology, Medical College Kolkata, Kolkata, West Bengal, India

E-mail: [email protected]

Introduction: Acromegaly is a rare condition predominantly caused by a growth hormone secreting pituitary adenoma. Long-term presence of elevated GH and insulin like growth factor I (IGF-I) levels is associated with complications such as heart failure, cerebrovascular disease, diabetes mellitus, sleep apnoea and arthropathy. Case Report: A 50 year old male patient complained of progressive acral enlargement for 6 years associated with coarsening of facial features [Figure 1]. He had complaints suggestive of peripheral neuropathy for last 3 years and was diagnosed with diabetes mellitus 3 years back, poorly controlled on insulin. There was history of snoring, change of voice and reduced libido. On examination he had features of acral enlargement [Figure 2] and clinical evidence of symmetric peripheral sensory neuropathy in bilateral upper and lower limbs. Fundus examination revealed changes of non proliferative diabetic retinopathy with macular edema. Investigations revealed normal CBC, LFT, KFT with FPG of 160 (on insulin) and IGF1 levels of 848 ng/ml (high for age). Other hormonal investigations were normal. X ray skull revealed thickened calvaria and enlarged frontal sinuse [Figure 3]. Glucose suppression test was positive for acromegaly and MRI revealed pituitary microadenoma on left side [Figure 4]. Diagnosis of acromegaly with pituitary microadenoma was made, glycemia was adequately controlled and patient was referred for neurosurgery. Discussion: Acromegaly in most cases is due to pituitary macroadenoma, easily identified on MRI sequences. Rarely, it can be caused by occult pituitary microadenomas. Although medical therapy achieves disease control in many patients, surgical removal of the microadenoma can obtain a definitive cure.
Figure 1: Coarse facial features with prominent supraorbital ridges and prognathism

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Figure 2: Spade like hands

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Figure 3: Thickened calvaria and enlarged frontal sinuse

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Figure 4: Pituitary MRI suggestive of microadenoma on left side

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Keywords: Acromegaly, diabetes mellitus, microadenoma

   A rare case of familial primary empty sella syndrome with panhypopituitarism Top

Kumari Archana, Gaurav Kumar, Manjunath Hiremath, Zorinpuii Khiangte, Kumar Himanshu, Israrul Haque, Pankaj Hans, Rajan Kumar, Madan P. Singh, Surendra Kumar1

Departments of General Medicine, 1Endocrinology, Patna Medical College and Hospital, Patna, Bihar, India.

E-mail: [email protected]

Introduction: Primary Empty Sella Syndrome (ESS) is caused due to herniation of arachnoid into the sella turcica through an incompetent sellar diaphragm leading to flattening of pituitary. The sella gets filled with CSF. It is a rare entity in children and adolescents with usually benign clinical picture although GH deficiency has been found leading to skeletal abnormalities and increased familial incidence is associated in such cases. We report here a rare case of Familial Primary Empty Sella Syndrome in an adolescent with panhypopituitarism. Case Report: A 17 years old girl presented with pain abdomen and constipation for 3 days, altered sensorium for one day. She had history of headache, pain abdomen and constipation, generalized swelling of body on an off with short stature and primary amenorrhoea. In her family, her mother and brother also had short statures. On examination:-her height was: -126 cm. Absence of secondary sexual characters. Her blood pressure was 100/60 mmHg. Relevant investigations:- Hb-9.1 g/dl, Na + 102 mmol/L, K+ -3.3 mmol/L, TSH- 16.8 mIU/ml, FSH-0.6 mIU/ml, LH-<0.07 mIU/ml, prolactin-3.75 ng/ml, Serum Cortisol-5.10 mcg/dl at 6 a.m. USG-Hypoplastic uterus and absence of ovaries. MRI brain showed empty sella. Her mother and brother were short statured with empty sella but without hormonal deficiency. Results: A diagnosis of Empty Sella Syndrome with panhypopituitarism was made, electrolytes were corrected. She was started with thyroxine, estrogen, fludrocortisone and hydrocortisone. She recovered and is doing well. Conclusion: This case is an extreme end of a disorder considered benign. Thus primary ESS can present with panhypopituitarism. So, a meticulous work up is required in suspected cases. And hormone replacement helps the patients to lead a normal life.

Keywords: Empty sella syndrome, panhypopituitarism, sella turcica

   Pituitary hormonal profile in vasculotoxic snake bite patients who develop acute kidney injury Top

Sowrabha Bhat, Subhankar Chowdhury, Sujoy Ghosh

Department of Endocrinology and Metabolism, IPGMER, Kolkata, West Bengal, India.

E-mail: [email protected]

Objectives: Hypopituitarism has been found to occur following vasculotoxic snake bite. The time of its development in relation to the snake bite and any possible predictors are not known although it has been observed to happen more commonly in those patients who develop acute kidney injury post snake bite. The aim of this study was to evaluate the pituitary hormonal profile of snake bite patients admitted in our institute and to look for any factors that may predict subsequent development of hypopituitarism. Materials and Methods: 50 patients of viper bite who developed acute kidney injury, admitted in the inpatient department of SSKM hospital and Sambhunath Pandit hospital, Kolkata between January 2017 and June 2018 were included in the study. Clinical and biochemical evaluation was done for these patients within a week of the snake bite, at 6 weeks and 3 months post the snake bite. Results: Of the 50 patients included in the study, 11 patients developed hypopituitarism. 10 of these patients developed hypopuitarism at baseline i.e within a week of the snake bite, while one patient had low hormone levels only at 3 months post the bite. This study found that hypopituitarism more commonly occurred in younger patients, in those who needed a higher number of hemodialysis cycles for the acute kidney injury. Conclusion: In this study, most patients of viper bite developed hypopituitarism at baseline i.e within a week. An association was found between age of the patient, number hemodialysis sessions needed and the subsequent development of hypopituitarism. These factors could possibly be used to estimate the likelihood of development of hypopituitarism in vasculotoxic snake bite patients with acute kidney injury. Such patients would warrant more close clinical and biochemical follow up for early diagnosis of hormone insufficiency and institution replacement therapy.

Keywords: Acute kidney injury, hormones, pituitary, snake bite

   Assessment of quality of life in patients with Sheehan's syndrome attending a tertiary care hospital Top

Soumita Mandal, Sujoy Ghosh, Pradip Mukhopadhyay, Rana Bhattacharjee, Subhankar Chowdhury

Department of Endocrinology, IPGME & R, Calcutta, West Bengal, India.

E-mail: docsoumita @gmail.com

Objectives: To assess the quality of life in patients with Sheehan's syndrome (SS). Materials and Methods: 20 patients, diagnosed as SS, who are on optimal hormone replacements [L- thyroxine, glucocorticoid, oestrogen and progesterone at appropriate doses] were asked to fill-up the standard Bengali or Hindi version of WHOQOL- BREF questionnaire for quality of life either by themselves or by interview method. Collected Data were analysed by standard statistical methods. Results: There is strong and statistically significant correlation found in between psychological health and overall QOL as well as environmental health with overall QOL (CC- 0.560 and 0.484 respectively). Similar correlations were found both in Psychological health and social relationships with environmental health (CC-0.584 and 0.620 respectively). Overall health and Physical health are found to be affected by age as an independent variable (mean score in ≤40 yrs vs >40 yrs-3.33 ± 0.86 and 2.45 ± 0.65 respectively for overall health; P Value 0.02; 14.33 ± 1.1 and 11.27 ± 2.3 respectively for Physical health) P Value 0.002. However, level of education was found not to have any influence on any of the domain of QOL. The Chronbach's alfa (Internal Consistency Index) for this study was 0.765 which is more than recommended 0.7 which means there are good correlations within the data for the items in each domain of the questionnaire. Conclusion: Psychological and environmental health both have independent impact on overall QOL in patients with SS; on the other hand age can also affect physical as well as overall health of these patients despite being hormonally sufficient.

Keywords: Quality of life, Sheehan's syndrome, WHOQOL- BREF

   Pituitary stalk interruption syndrome: A case series from tertiary care centre Top

Sonali Appaiah, Dipti Sarma, Uma K. Saikia, Bipul K. Choudhury, Ashok K. Bhuyan

Department of Endocrinology, Gauhati Medical College, Guwahati, Assam, India.

E-mail: [email protected]

Objectives: To study the clinical spectrum of presentation in patients with multiple pituitary hormone deficiency (MPHD) due to Pituitary stalk interruption syndrome (PSIS). Materials and Methods: Six children diagnosed with MPHD due to PSIS at Guwahati medical college and hospital, in past one year were evaluated. PSIS was diagnosed radiologically by the triad of absent or hypoplastic anterior pituitary gland, thin or absent infundibulum and ectopic or absent posterior pituitary. Detailed medical history, clinical examination, biochemical tests and radiological imaging were done in all patients. Results: The age at presentation ranged from 11.4 to 22 years (mean 15.5 ± 4 years). The male: female ratio was 2:1. Lag period between onset of clinical features and presentation was 11 ± 4.8 years. The most common presentation was short stature (100%), followed by delayed puberty (66.6%) and symptoms of hypothyroidism in (33.3%). Breech delivery with postnatal hypoxia was present in one patient. Delayed developmental milestones were seen in 33.33%, and all these patients had symptoms of hypothyroidism. On hormonal evaluation, growth hormone (GH) deficiency diagnosed by Clonidine stimulation test (CST), was seen in all with a 60 and 90 minute post CST, mean GH level of 0.5 ± 0.25 ng/ml and 0.37 ± 0.12 ng/ml. Hypogonadotrophic hypogonadism was seen in all children in pubertal age, with the mean values of FSH of 2.1 ± 2.1 mIU/ml, LH was 1.1 ± 1.2 mIU/ml, total testosterone of 9 ± 8 ng/dl in boys and estradiol level of <5 pg/ml in girls. Central hypothyroidism was seen in 66.6% and secondary adrenal insufficiency in 33.3% at diagnosis, with a mean serum fT4 (thyroxine) of 67.6 ± 28 nmol/lt and a mean 8:00 am serum cortisol of 2.28 ± 2.2 ug/dl. None of the patients had Diabetes insipidus. Conclusion: PSIS can present with varying spectrum of single or MPHD in children. Early diagnosis, adequate treatment, and monitoring for progressive loss of anterior pituitary hormone function ensure normal physical and cognitive development of children with PSIS.

Key words: Multiple pituitary hormone deficiency, pituitary stalk interruption syndrome

   Delayed hypopituitarism following Russell's viper envenomation - A case series of eight patients Top

Shivaprasad Chennabasappa

Department of Endocrinology, Vydehi Institute of Medical Sciences, Bangalore, Karnataka, India.

E-mail: [email protected]

Introduction: Snake bite is a significant health hazard for rural farmers of tropical countries. Russell's viper (Daboia russelii) and saw scaled viper inhabit most of the Indian states and the former is a leading cause of fatal snake bite in India. Hypopituitarism is an uncommon consequence and delayed hypopituitarism (DHP) presents months to years after the recovery from snake bite and manifestations are subtle and insidious. Aims and Objective: Retrospective case series of eight cases of delayed hypopituitarism due to Russell's viper envenomation to outline the presentation, manifestations, hormonal profile and radiological features. Materials and Methods: This case series is based on 8 patients with delayed presentation of hypopituitarism following Russell viper snake bite. Patients presented to or were referred to our clinic for endocrine issues, several months after snake bite. We defined hypopituitarism as deficiency of one or more pituitary hormones as follows: secondary hypothyroidism defined as low free thyroxin with low or normal thyroid stimulating hormone. Secondary adrenal insufficiency and growth hormone deficiency were defined as a peak stimulated cortisol of <18 mg/dl and peak GH <3.0 μg/L respectively during insulin tolerance test. Hypogonadotropic Hypogonadism was defined as low testosterone (<2.5 ng/ml) or low estradiol (<15 pg/ml) with low or normal gonadotropins. Results: The mean BMI was 19.5 ± 2.92. Mean age at diagnosis was 39.5 ± 11.6 and mean duration between snake bite and diagnosis of hypopituitarism was 8.1 ± 3.6 years. Mean duration of symptoms that led to the diagnosis of hypopituitarism was 4 ± 2.6 years. Fatigue and loss of libido were the most common symptoms among males. Among females, secondary amenorrhea was present in all patients. Secondary hypothyroidism and hypogonadotropic hypogonadism was present in all patients. GHD and secondary hypocortisolism were present in 6 (75%) patients. MRI sella was empty sella and partial empty sella in three patients each and normal in two patients. Conclusions: Delayed hypopituitarism is an important complication of RVE and delay in diagnosis is associated with significant morbidity and impaired quality of life. Patients with RVE require long term follow-up to identify DHP. Fatigue, reduced libido, amenorrhea, hypoglycemia or hypotension should prompt evaluation for DHP in patients with history of RVE.

Keywords: Delayed hypopituitarism, russell's viper, snake bite

   Microstructural white matter changes using diffusion tensor imaging in patients with Cushing disease Top

Suvrit Jain, Sunil Jain1, Rajesh Kumar2, Eesh Bhatia

Departments of Endocrinology and 1Radiodiagnosis, SGPGIMS, Lucknow, Uttar Pradesh, India, 2Department of Anesthesiology, Radiological Sciences and Bioengineering, University of California, California, USA.

E-mail: [email protected]

Background: Cushing disease results in chronic exposure to increased levels of cortisol. Cortisol excess causes profound alterations in white matter microarchitecture and adversely affects cognitive functioning. Diffusion tensor imaging (DTI) is a novel technique used to evaluate the integrity of white matter (WM) architecture. There is little information on DTI changes in Cushing disease (CD). Aims and Objectives: To study WM changes in patients with Cushing disease using diffusion tensor imaging and compare this with healthy controls. Materials and Methods: 16 patients with Cushing disease and 16 healthy controls matched for age, sex and educational status were analysed through DTI (Voxel based analysis) for fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity. All patients with CD were evaluated by cortisol suppression testing and salivary cortisol to ensure disease activity. Results: There were widespread alterations (reduced fractional anisotropy, increased mean diffusivity, axial diffusivity and radial diffusivity) in patients with CD as compared with controls. Areas of the brain which are involved in cognitive function were affected including the uncinate fasiculus, hippocampus, cingulum and corpus callosum. Preliminary results of cognitive assessment revealed impaired cognitive functioning in various domains in patients with Cushing disease. Conclusions: White matter alterations are seen in areas associated with cognitive functioning. Further analysis is needed to identify correlations between DTI findings and cognition.

Keywords: Cushing disease, diffusion tensor imaging, microstructural, white matter changes

   Thyrotropin-secreting pituitary macroadenoma Top

Awesh Shingare, Manoj Chadha, Phulrenu Chauhan, N. F. Shah, Ameya Joshi1

Department of Endocrinology, P. D. Hinduja Hospital Mumbai, Maharashtra, India, 1Department of Endocrinology, Bhaktivedanta Hospital, Mumbai, Maharashtra, India.

E-mail: [email protected]

Background: Thyrotropin-secreting pituitary tumors [TSH-oma] are rare and account for <1% of all pituitary tumors and <1% of hyperthyroidism cases. It is essential but difficult to differentiate TSH-oma from resistance to thyroid hormones [RTH].Case: 30 years male presented with recurrent sore throat since 4 months. Previously he was treated for hyperthyroidism for 1 month. He was clinically euthyroid. General and systemic examinations were normal with no goiter or eye signs. Laboratory test showed elevated T3 [193 ng/dl], T4 [12.6 ugm/dl] and TSH [10.35 mIu/L]. On inquiry patient had mild headache since few months but no visual or pituitary hormonal insufficiency symptoms. Thyroid scan demonstrated mild thyromegaly with increased trapping function suggesting TSH induced hyperplasia [Figure 3]. MRI brain showed a pituitary macroadenoma of size 1.9 × 1.7 × 1.7 cms in right half abutting against cavernous portion of right internal carotid artery [Figure 1] and [Figure 2]. 5 hours post Octreotide [100 mcg subcutaneous], TSH decreased from 6.83 mIU/l to 3.86 mIU/l. Other pituitary hormonal evaluation was normal. Pituitary adenoma was excised endonasally. Histopathology confirmed adenoma. On immunohistochemistry cells were positive for TSH and GH. Post operation TSH [0.5 mIU/L] and T4 [8.08 ugm/dl] normalized while T3 [47.6 ng/dl] was low which normalized later. Conclusion: TSH-oma are usally macroadenomas and mostly present with symptoms due to thyrotoxicosis or tumor growth. The combination of high T4, T3, and α-subunit; high or inappropriately normal TSH; and a pituitary tumor strongly confirm the diagnosis of TSH-oma. Surgery is first line of treatment and results in clinical and biochemical improvement in most patients.
Figure 1: MRI pituitary: Sagittal view

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Figure 2: MRI pituitary: Axial view

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Figure 3: Technicium thyroid scan

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Keywords: Thyrotropinoma, TSH-OMA, TSH-secreting tumor

   Poems syndrome Top

Madhur Maheshwari, Nishit F. Shah, Phulrenu Chauhan, Manoj Chadha, Awesh Shingare

Department of Endocrinology, P. D. Hinduja Hospital, Mumbai, Maharashtra, India.

E-mail: [email protected]

Background: POEMS syndrome is rare multisystem paraneoplastic syndrome representing polyneuropathy, organomegaly, endocrinopathy, M-band and skin changes. Other manifestations: volume overload, sclerotic and lytic bone lesion and pulmonary hypertension. Case: 64 years male with diabetes and hypertension, presented with anasarca and breathlessness. Evaluation revealed right adrenal mass [Figure 1] 4 × 3.5 × 3 cm. PET showed increased metabolic activity in lymph nodes and lytic lesions in right ilium and vertebrae. Right adrenalectomy done. Histopathology showed hemorrhage and necrosis, but no tumor. Antidiabetics and antihypertensives gradually withdrawn. Preoperative and postoperative hormonal evaluation was unavailable. Steroid replacement was started but patient wasn't compliant. Few months later patient presented to our hospital with giddiness and anasarca. Investigations showed hyponatremia and hyperkalemia. 8 am cortisol 0.6 mcg/dl, ACTH 31.6 pg/ml and DHEAS <15 mcg/dl. Renin and aldosterone normal. On enquiry, patient gave history of numbness in lower limbs, weak erections and hyperpigmented patches. Pituitary hormonal evaluation showed low TSH [0.87 mIU/l], FT3 [1.19 pg/ml], FT4 [ 0.87 ng/dl], Prolactin [2.73 ng/dl], Testosterone [74 ng/dl], LH [2.01 mIU/ml] and FSH [3.5 mIU/ml]. Severe sensory motor peripheral neuropathy on nerve conduction in all four limbs. Protein electrophoresis showed M band. Bone marrow showed 5% plasma cells. Hence diagnosis of POEMS was made. Patient responded to steroid, levothyroxine and testosterone replacement. Specific treatment for plasma cell dyscrasias [lenalidomide] planned on follow up. Conclusion: Endocrine manifestations such as hypogonadism [most common], diabetes mellitus, hypothyroidism, hyperprolactinemia, adrenal insufficiency, gynecomastia, breast engorgement in women and hypoparathyroidism are described in POEMS. High index of suspicion about multiple endocrine involvements is essential for diagnosis.
Figure 1: Right adrenal mass. Left adrenal appears normal

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Figure 2: Pituitary appears normal

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Keywords: Endocrinopathy, hypopituitarism, poems

   Evaluation of demographic, clinical and tumour characteristics of a group of patients with prolactinoma – 5 year experience from a tertiary care unit Top

Dayakshi D. K. Abeyaratne, Sonali S.C. Gunatilake1, Ishara Ranatunga1, Piumi Hettiarachchi, Tharindu D. R. Rathnayake, Joseph P. Naveenkumar, Chathuranga. L. Fonseka2, Chaminda Garusinghe, Manilka Sumanatilake, Noel P. Somasundaram

Diabetes and Endocrinology Unit, National Hospital of Sri Lanka, 1Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, United Kingdom, 2Department of Medicine, Faculty of Medicine,University of Ruhuna, Sri Lanka.

E-mail: [email protected]

Background: Prolactinoma is the most common hormonr-secreting pituitary tumour and usually responds to medical therapy. The aim was to determine demographic characteristics, type of presentation, clinical and tumour characteristics and treatment aspects of patients with prolactinomas. Methods: This study was conducted at Endocrinology Unit at the National Hospital of Sri Lank. Details obtained from consecutive records of 31 patients with prolactinoma over 5 years. Results: Out of 31 patients, 65% were females. While, in males 81% of them belong to more than 40 years age group at first presentation, majority of the females belonged to less than 40 age group (55%) at first presentation. The most common symptoms at presentation were headache (61%), galactorrhea (58%), amenorrhea (55%), infertility (16%) and visual impairment (41%). Majority of analyzed patients had macroprolactinomas (58%) while microprolactinomas were 42%. Giant resistant prolactinomas was seen in 13% of patients. One patient was detected with prolactin secreting carcinoma with distant metastasis. In majority of macroprolactinomas, initial prolactin value detected was 2000-20,000 mIU/l (38%), while all microprolactoma patients had a level less than 2000 mIU/L. A reducing trend of prolactin level was noted after initiation of treatment. 19% have undergone debulking surgery while 12% were given radiotherapy. Conclusions: Majority of prolactinomas occur in females and presents commonly with headache. The decreasing trend of serum prolactin and tumour size reduction occurs with medications. Despite medical therapy some may need surgery or radiotherapy.

Keywords: Clinical characteristics, demographic characterisitics, prolactinoma

   Phosphorylation of Beta-Catenin on Serine 552: A Prognostic Marker of Recurrent Nonfunctioning Pituitary Adenoma Top

Ashutosh Rai, Pinaki Dutta1, Kanchan K. Mukherjee2, Bishan Das Radotra3

Departments of Translational and Regenerative Medicine, 1Endocrinology, 2Neurosurgery and 3Histopathology, PGIMER, Chandigarh, India

Address for correspondence:

Dr. Ashutosh Rai, Department of Translational and Regenerative Medicine, PGIMER, Chandigarh, India.

E-mail: [email protected]

Introduction: Non-functioning pituitary adenomas (NFPA) usually present as macroadenomas and 42% shows invasion of the adjacent structures, such as cavernous sinus, sphenoid bone or nasopharynx and some recur locally. The incomplete removal of invasive NFPAs carries the increased risks of recurrence and requires adjuvant radiotherapy and surgeries. It is necessary to clarify the molecular mechanisms and markers of invasiveness to guide the management of NFPA patients. Here we describe a comprehensive phosphoproteomics evaluation of 20 NFPAs followed by validation in a large cohort. Materials and Methods: Peptides from 20 tumors were enriched with TiO2 beads, fractionated using bRPLC and subjected to high-throughput LC-MS/MS-orbitrap fusion tribrid mass spectrometer. Upto 5 precursor ions were chosen for MS/MS analysis. Following Mascot and SEQUEST analysis our bioinformatics pipeline (Phosphosite Plus, Gene Ontology, DAVID, and KEGG) identified 2233 unique phosphopeptides corresponding to 1345 phosphoproteins. Eight candidate phosphoproteins involved in cell proliferation and growth were selected for validation using immunoblotting (n = 18) and immunohistochemistry (tissue microarray containing 200 NFPA samples). Histoscore (H-score) was calculated by a semi-quantitative assessment of both the intensity of staining (graded as: 0, non-staining; 1, weak; 2, median; or 3, strong using adjacent normal mucosa as the median) and the percentage of positive cells. The range of possible scores was from 0 to 300. Results and Discussions: CTNNB1 phospho-Ser552 was found 1.9 fold hyper phosphorylated in recurrent group while in our mass spectrometry experiment. Immunohistochemistry revealed 2.1-fold up regulation (P < 0.0001) in the recurrent and 1.6 (P < 0.01) fold up regulation in invasive NFPA. In agreement with the mass spectrometry and IHC data, immunoblotting also revealed significantly up regulated CTNNB1 phospho-Ser 552 in invasive and recurrent group. CTNNB1 phospho-Ser552 translocate to the nucleus and act as transcription factor and increase the expression of cyclin D and hence play significant role in tumorigenesis. Conclusion: CTNNB1 phospho-Ser552 is significantly associated with NFPA invasion and recurrence. It provides a roadmap for patient stratification, and prognostication for recurrence and trials for targeted therapy.

   Adrenals and Neuroendocrine Tumors Top

   Cushing's syndrome due to ectopic ACTH secretion from neuroendocrine tumors Top

Chandar M. Batra1, Alok Agarwal2, Monika Goyal1

Departments of 1Endocrinology and 2Internal Medicine, Indraprastha Apollo Hospitals, New Delhi, India.

E-mail: [email protected]

Ectopic ACTH syndrome (AES) is rare, 1 in a million patient years and is the cause of 15% of cushings syndrome. The common causes of AES is carcinoma lung 50%, endocrine tumors of foregut origin 35% and pheochromocytoma 5% and rarely the thymic tumors. Neuroendocrine tumors (NETS) are tumors arising from entero chromaffin cells located in neuroendocrine tissue throughout the body. Aims and Objectives: To present the clinical, biochemical, radiological features and the management of 2 cases of AES which were due to NETS. Case Reports: These patients were young a 16 year old boy [Figure 1] and a 39 year female [Figure 2] with rapid onset of symptoms 3 months and 12 days. They presented with a facial and abdominal rash, hyperpigmentation, severe muscle weakness, proximal myopathy, facial puffiness and hypertension. The biochemical picture was similar. Very high serum cortisols non suppressible with low and high dose dexamethasone suppression, high midnight cortisols, high ACTH levels, severe hypokalemia resistant to treatment. MRI of sella were normal, CT scans of adrenals showed adrenal hyperplasia, CT of chest and abdomen in the male patient revealed a large thymic tumor [Figure 3] with hepatic metastases and FNAC of the thymic mass [Figure 4] confirmed NET. This patient left against medical advice. The female patient was subjected to whole body PET CT which revealed FDG avidity [Figure 5] and [Figure 6] in the bone marrow. Bone marrow biopsy confirmed NET [Figure 7] and [Figure 8]. Primary tumor could not be found and she was started on chemotherapy of 4 cycles of inj Etopside, cisplatin and sandostatin Lar 30, to which she is responding.
Figure 1: Patient 1

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Figure 2: CT chest showing the thymic mass

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Figure 3: CT guided fnac from anterior mediastinal mass (low power) numerous small loose clusters and dispersed fairly uniform, moderate sized cells, lacking cytoplasm. Nuclei show occasional mounding and irregular margins and have stippled chromatin Positive for malignant cell Consistent with round cell lesion morhologically resembling neuroendocrine tumor

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Figure 4: Patient 2

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Figure 5: Enhancing marrow lesions with varying degree of FDG uptake are seen extensively involving multiple vertebrae of the spine including sacrum, bilateral pelvic bone and femori on right side was present consistent with FDG avid lesions? Could be metastatic

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Figure 6: In abdomen diffuse hyperplasia of bilateral adrenals with increased intake with no demonstrable mass lesion

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Figure 7: Bone marrow BMBx. Infiltrating on marrow spaces are small ball like cohesive cluters neoplastic cells having uniform eccentric nuclei and moderate amount of cytoplasm

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Figure 8: Bone marrow BMBx.The cells were positive for synaptophrin with CKAE1/AE3, CK20 and CK 7 are negative: Suggestive of metastatic tumor of neuroendocrine origin

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Keywords: Cushings, Ectopic ACTH, NET

   Insulin resistance and quality of life assessment in children with congenital adrenal hyperplasia Top

Roopa Vijayan, Nisha Bhavani, Praveen Pavithran, Harish Kumar

Department of Endocrinology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.

E-mail: [email protected]

Aims and objectives: To assess insulin resistance and quality of life in children with congenital adrenal hyperplasia (CAH) and compare with age and sex matched controls and to see the correlation between the two. Materials and Methods: This is an ongoing study on 39 children aged 3-18 years diagnosed with CAH. Fasting blood sugar and insulin were done for calculating insulin resistance by homeostatic model assessment in 14 children. Quality of life was assessed in 39 children and their parents using a validated PedsQL questionnaire. Insulin resistance was done in 22 age and sex matched controls. Quality of life in the control population is already published (n =584). Results: Of the 39 CAH children, 10 were males and 29 were females. Mean age was 11.28± 5.5 years. HOMA IR was significantly higher among the cases when compared to age matched controls (2.97± 2.27 vs 0.93± 0.66; P 0.001). Insulin resistance showed a significant negative correlation with total and psychosocial scores(r = −0.529, P 0.05 and r = −0.585, P 0.04 respectively). PedsQL scores showed significant reduction in quality of life in all domains as per parents assessment when compared to controls (79.86± 15.17 vs 90.09± 9.47; P <0.001). Children themselves had comparable scores compared to controls. Conclusion: Insulin resistance was significantly higher in CAH compared to controls and had significant negative correlation with quality of life. The study also showed a significant reduction in quality of life of CAH children from the parents' perspective.

Keywords: Congenital adrenal hyperplasia, insulin resistance, quality of life

   Adrenals and Neuroendocrine Tumors Rare endocrine manifestation of Neurofibromatosis type 1- A study of two cases Top

Ipsita Mishra, S. Mangaraj, A. K. Choudhury, A. K. Baliarsinha

Department of Endocrinology, S.C.B. Medical College and Hospital, Cuttack, Odisha, India.

E-mail: [email protected]

Background: Neurofibromatosis 1 (NF1), is an autosomal dominant disorder caused by mutation in NF1 gene. Common endocrine manifestations of NF1 include GH hypersecretion, GH deficiency, central precocious puberty, phaeochromocytoma and gynaecomastia. Objective: We present here two cases of NF1 diagnosed at different ages by clinical suspicion with different modes of clinical presentation to us. Methods and Results: Case 1: 27 yr male presented with c/o pain in right loin and adrenal incidentoloma. He had no history of phaeo like spells, proximal muscle weakness or easy bruisability. O/E was found to be normotensive with, multiple neurofibroma, cafe-au-lait spots with history of NF1 in father. Biochemical parameters revealed elevated 24 hour urinary metanephrines. Radiologial imaging revealed large heterogeneously enhancing right suprarenal lesion. After adequate alpha blockade, transabdominal right adrenalectomy was done. Histopathology revealed presence of phaeochromocytoma with a component of cellular schwammoma and low grade MPNST. Case 2: 6 yr child reared as female, presented with c/o phallus like structure noted since birth. She was born from a non-consangineous marriage without any post natal complication, but h/o NF1 in father and grandmother. O/E she had height on 3rd centile, weight <3rd centile, SMR A1B1P1, boneage of 6 yrs and multiple hyperpigmented macules over body. Prader stage 1 genitalia with phallus of length 3.5 cm was present. USG revealed presence of mullerian structures and absence of wollfian structures. Karyotype was 46XX. Hormonal parameters were normal (S. Testo, DHEAS and 17OHP). She was subjected to clitoroplasty with nerve sparing. Histopathology revealed presence of neurofibroma. Conclusion: Though NF1 has common endocrine and non-endocrine manifestations, yet they can present with rare endocrine disorders.

Keywords: Clitoral neurofibroma, composite phaeochromocytoma, neurofibromatosis 1

   Primary hyperaldosteronism: Experience at a tertiary care hospital Top

Nandini Prasad, P. K. Jabbar, C. Jayakumari, Abilash Nair, Geena S. George

Department of Endocrinology, Government Medical College, Thiruvananthapuram, Kerala, India.

E-mail: [email protected]

Aims: To study the clinical, biochemical and imageological profile of primary hyperaldosteronism. Materials and Methods: Patients who were referred for endocrine hypertension and adrenal incidentaloma were evaluated over a period of 11 months from August 2017. All patients underwent clinical and biochemical investigations including S. potassium, RFT, Serum Aldosterone, Plasma Renin Activity. Of the 13 patients who had an Aldosterone Renin Ratio >20 ng/dl/ng/ml/hr, saline infusion test was done in 11 patients. CT with adrenal protocol or MRI was done in all patients. Results: Of the 13 cases 5 (39%) were having (APA) whereas 8 (61%) were having (IHA) The mean age of presentation was 41.6 yrs for APA and 39.13 yrs for IHA. IHA was more common in males (80%). The mean blood pressure in APA was 165/98 mmHg whereas in IHA it was 182/102 mmHg. 61% of the patients had evidence of target organ damage. The mean S. potassium in both the groups was 3.4 mmol/l (range 1.7-4.3). Mean Aldosterone values in APA group was 58.47 ng/dl (Range: 19-191.6) and in IHA group was 44.2 ng/dl (Range: 29.2-50.3). Mean ARR in APA group was 16.8 ng/dl/ng/ml/hr whereas in IHA group was 67.8 ng/dl/ng/ml/hr. Saline infusion test was positive in all the cases with a mean value of 30.7 ng/dl. The mean HU on unenhanced CT and mean absolute washout was 28.9 and 57% respectively. One patient had an isolated aldosterone secreting ACC and presented with hypokalemic periodic paralysis and one had a plurihormonal (aldosterone and corticosteroid cosecreting) atypical adenoma confirmed by histopathology, both of which are extremely rare. All the patients had a reduction in the number and dose of antihypertensives following surgery. Conclusion: It is important to identify primary hyperaldosteronism and provide appropriate management so as to prevent further target organ damage.

Keywords: Adrenal incidentaloma, aldosterone producing adenoma, hyperaldosteronism

   An unusual cause of uncontrolled diabetes mellitus - Pheochromocytoma Top

V. B. Nagapriya, Francis Sridhar K1, Smitha Nalla, Prasun Deb

Departments of Endocrinology, 1Urology, KIMS Hospitals, Secunderabad, Telangana, India.

E-mail: [email protected]

A 64 year old female with a known history of hypertension, well controlled with Telmisartan 40 mg and hydrochlorthiazide 12.5 mg, and Type 2 Diabetes Mellitus poorly controlled on oral hypoglycaemic agents, presented with dragging pain in the right side of the abdomen since 2 months. Ultrasound abdomen showed mass lesion in the right adrenal gland with heterogeneous echotexture of 8.0 * 6.0 cm. On examination, she was normotensive without postural hypotension, tachycardia, tenderness or palpable abdominal mass. Investigations showed poor glycaemic control with HbA1c of 12%, normal cortisol, serum electrolytes and elevated 24 hour urinary metanephrines and normetanephrines. Diagnosis of giant pheochromocyotma was made and she was planned for surgical removal. Preoperative alpha blockade with Prazosin was commenced after stopping telmisartan. Hypertension was difficult to control with prazosin alone and beta blockade was added after adequate alpha blockade, for persistent tachycardia. Optimal glycaemic control was achieved with Insulin. She underwent laparoscopic right adrenalecteomy and peri-operatively developed hypertensive crisis requiring Nitroprussides. Histology was confirmative of pheochromocytoma of size 9.0 * 6.0 * 4.5 cm with PASS score 5. Post operatively, she had persistent tachycardia but achieved significant improvement in glycaemic control not requiring insulin. Follow up metanephrines at 3 months were within normal limits and she remains on oral hypoglycaemic agents. In conclusion we present a case of a large asymptomatic phaeochromocytoma with poorly controlled diabetes but well controlled hypertension. We strongly recommend investigation of all such lesions pre-operatively inspite of lack of symptoms. Given the high PASS score, we recommend ongoing surveillance for residual/malignant phaeochromocytoma.

Keywords: Diabetes mellitus, hypertension, pheochromocytoma

   Neonatal adrenal hemorrhage presenting as hypertension with adrenal insufficiency Top

Justin E. Sam, K. M. Suryanarayana

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Introduction: Adrenal hemorrhage is an uncommon condition during the neonatal period with the manifestations being mild anemia, unexplained jaundice associated with an abdominal mass. Adrenal hemorrhage presenting as neonatal hypertension is extremely rare and this is the first case report from India. Case Report: Thirty-two days old male child born out of full-term normal delivery with a birth weight of 3.7 kg and with right hand Erb's palsy was detected to have high BP on day 3 of life. Antenatal USG scan had revealed fetal macrosomia (>99th percentile) and slightly enlarged kidneys. NIBP showed BP >99th percentile (>90/72) with MAP >77 and treated with tablet labetalol-4 mg/kg/day. MRI abdomen done on day 5 of life revealed a well-defined mass lesion in the right adrenal gland region causing mass effect on upper pole of right kidney with normal sized kidneys. On examination, the baby was found to have bilateral palpable testes and scrotum and evaluation revealed, low serum 8 am cortisol of 1.86 μg/dl, serum potassium of 5.5 mEq/L, serum sodium of 131 mEq/L with normal serum levels of total testosterone, DHEAS, metanephrines, and normetanephrines. In view of low serum cortisol, the baby was initiated on replacement dose of hydrocortisone-15 mg/m2. After 4 weeks, blood pressure normalized and labetalol was withdrawn. The baby continues to have adrenal insufficiency and on regular hydrocortisone replacement. Conclusion: Adrenal hemorrhage must be considered as a rare cause of neonatal hypertension.

Keywords: Adrenal, insufficiency, hemorrhage, hypertension

   Normotensive primary aldosteronism with non sustained polymorphic ventricular tachycardia: Case report Top

Sahu Sandeep Kumar, Mangaraj S, Choudhury AK, Baliarsinha AK

Department of Endocrinology, SCB Medical College and Hospital, Cuttack, Odisha, India.

E-mail: [email protected]

Objectives: The cardinal manifestations of primary aldosteronism is the combination of resistant hypertension and hypokalemia. However, the disease can evade clinical diagnosis in case of absence of hypertension if clinical vigil is not high. We report a case of primary aldosteronism who presented with recurrent episodes of arrhythmia and was subsequently diagnosed with aldosterone producing adenoma. Materials and Methods: A 34 year old female presented with palpitations and syncopal attacks for 2 weeks. During initial cardiological evaluation, she was found to have hypokalemia and non sustained polymorphic ventricular tachycardia. She had no evidence of hypertension and her blood pressure was normal on repeated measurements during hospitalization. During routine evaluation for pain abdomen, she was found to have right adrenal incidentaloma on CT abdomen and hence referred for endocrine evaluation. Results: After correction of hypokalemia, screening tests for primary aldosteronism was done, which revealed raised serum aldosterone and suppressed PRA and elevated ARR ratio of 32.42. Following saline loading test, PAC was not suppressed (16.5 ng/dl). CECT adrenal revealed a lesion of 14 × 10 mm consistant with adrenal adenoma. Based on these findings, a diagnosis of Primary aldosteronism due to possible right adrenal adenoma was made. Conclusion: Arrythmia can be a rare presentation of underlying primary aldosteronism. It should also be borne in mind that such patients may be normotensive.

Keywords: Incidentaloma, non sustained VT, primary aldosteronism

   Pheochromocytoma - Extended case series of patients in last 3 years in IPGMER, Kolkata with genotyping Top

Subhankar Chowdhury, Satinath Mukhopadhyay, Sujoy Ghosh, Pradip Mukhopadhyay, Rana Bhattacharya, Debarati Bhar

Department of Endocrinology and Metabolism, Ronald Ross Building, Institute of Post Graduate Medical Education and Research (IPGMER), Seth Sukhlal Karnani Memorial Hospital (SSKMH), Kolkata, West Bengal, India.

Email: [email protected]

Pheochromocytoma, a rare catecholamine producing neuroendocrine tumour (sometimes biochemically silent), a must exclude cause of secondary hypertension due to adverse fatal cardiovascular outcomes, was endorsed for genetic testing in all proven cases of PPGL at joint meeting of the International Congress of Endocrinology and Endocrine Society in 2014. At least 9 pathogenic mutations implied - RET, VHL, NF 1, SDHA, SDHB, SDHC, SDHD, SDHAF2 or SDH 5 and TMEM127. Results: Our case series of 16 patients of PPGL, found mean age 35.5 yrs (range 2.5-70 yrs), gender M:F ratio 3:2, familial-6.3% (1 medullary thyroid cancer), no hypertension-31.3%, lack of classic spells -62.5%, lack of syndromic features-93.8% (1 von Hippel Lindau disease), noradrenergic -92.8% (VHL heterozygous mutants), adrenergic-6.3% (single RET mutant), metastasis to liver, pleura, bone -14.3% (VHL mutant, SDH-negative), mean tumor size-6.6 cm (largest-12.8 cm), mean 24 hours urine normetanephrine-4055 mcg (maximum- 7996 mcg, 6.7 fold upper normal limit). Genetic test VHL positive-68.8% (11 of 16), RET -6.3%(1). No SDH mutation, extra-adrenal location was found. Conclusion: Our case series highlights single VHL gene directed genetic screen may suffice in all noradrenergic bilateral adrenal pheochromocytoma, in any age, without syndromic/familial clues, even in presence of metastasis.

Keywords: Metanephrines, normetanephrines, pheochromocytoma, PPGL, SDH gene, VHL

   Varied presentations of Von Hippel-Lindau disease and their outcomes Top

Kanhaiya Agrawal, Ashu Rastogi, Anil Bhansali

Department of Endocrinology and Metabolism, Post Graduate Institute of Medical Education and Research, Nehru Hospital, Chandigarh, India.

E-mail: [email protected]

Background: Von Hippel-Lindau (VHL) disease is a rare autosomal dominant disorder characterized by the formation of endocrine and non-endocrine, benign and malignant tumors in different parts of the body. We aim to describe various endocrine presentations of VHL and outcomes on follow-up. Materials and Methods: We describe a cohort of patients with pheochromocytoma and VHL disease being followed up at PGIMER, Chandigarh. A detailed family history (first and second degree family members), presenting manifestations, biochemical and radiological screening data was obtained and compared with the historical controls. Results: A total of four cases of pheochromocytoma and 9 other affected family members with VHL associated tumors on pedigree analysis were identified. The prevalence of pheochromocytoma is 30.7%. The mean age of presentation was 30.23 ± 9.47 years (male to female ratio of 1.17). The most common presentation amongst the index cases was abdominal pain (three of the four cases). Phaechromocytoma was bilateral in three and unilateral in one. Cerebellar hemangioblastoma was seen in 9 (69.2%) subjects and brain stem/spinal cord hemangioblastomas in 4 (30.7%). One patient had an unusual presentation with dysphagia attributed to a large spinal syrinx extending from medulla to D11 with cord edema. Renal cell carcinoma was seen in 4 (30.7%) cases. Pancreatic cysts were seen in 4 (30.7%), renal cysts in 2 (15.3%) and retinal angiomas in 2 (15.3%) cases. Among seven males, one (14.2%) had bilateral epididymal cysts. Two individuals (15.3%) had mortality due to non-operable CNS hemagioblastoma associated with hydrocephalous. Conclusions: Non-endocrine tumors i.e. hemangioblastoma are the most common tumors in VHL followed by phaechromocytoma and renal cell carcinoma. However headache was the most common presenting complaint in other individuals.

Keywords: Cerebellar hemangioblastoma, pheochromocytoma, Von Hippel-Lindau (VHL) disease

   Rare endocrine manifestation of neurofibromatosis type 1 - A study of two cases Top

Ipsita Mishra, S. Mangaraj, Arun K. Choudhury, A. K. Baliarsinha

Department of Endocrinology, S.C.B. Medical College and Hospital, Cuttack, Odisha, India.

E-mail: [email protected]

Background: Neurofibromatosis 1(NF1), is an autosomal dominant disorder caused by mutation in NF1 gene. Common endocrine manifestations of NF1 include GH hypersecretion, GH deficiency, central precocious puberty, phaeochromocytoma and gynaecomastia. Objective: We present here two cases of NF1 diagnosed at different ages by clinical suspicion with different modes of clinical presentation to us. Methods and Results: Case 1: 27 yr male presented with c/o pain in right loin and adrenal incidentoloma. He had no history of phaeo like spells, proximal muscle weakness or easy bruisability. O/E was found to be normotensive with, multiple neurofibroma, cafe-au-lait spots with history of NF1 in father. Biochemical parameters revealed elevated 24 hour urinary metanephrines. Radiologial imaging revealed large heterogeneously enhancing right suprarenal lesion. After adequate alpha blockade, transabdominal right adrenalectomy was done. Histopathology revealed presence of phaeochromocytoma with a component of cellular schwammoma and low grade MPNST. Case 2:- 6 yr child reared as female, presented with c/o phallus like structure noted since birth. She was born from a non-consangineous marriage without any post natal complication, but h/o NF1 in father and grandmother. O/E she had height on 3rd centile, weight <3rd centile, SMR A1B1P1, boneage of 6 yrs and multiple hyperpigmented macules over body. Prader stage 1 genitalia with phallus of length 3.5 cm was present. USG revealed presence of mullerian structures and absence of wollfian structures. Karyotype was 46XX. Hormonal parameters were normal (S. Testo, DHEAS and 17OHP). She was subjected to clitoroplasty with nerve sparing. Histopathology revealed presence of neurofibroma. Conclusion: Though NF1 has common endocrine and non-endocrine manifestations, yet they can present with rare endocrine disorders.

Keywords: Clitoral neurofibroma, composite phaeochromocytoma, neurofibroma

   Rare case of 4A syndrome: Case report Top

Debasish Patro, Swayam S. Mangaraj, Arun K. Choudhury, Anoj K. Baliarsinha

Department of Endocrinology, SCB Medical College and Hospital, Cuttack, Odisha.

E-mail: [email protected]

Objectives: Triple A or Allgrove's syndrome is characterized by three main conditions: achalasia, alacrimia and Addison's disease. When this is associated with autonomic neuropathy it is termed is 4A syndrome. We report a case of 4A syndrome who presented with predominant neurological manifestations. Materials and Methods: A 25 years old male who was a diagnosed case of Addison's disease since 4 years of age (on steroid replacement) presented with progressive weakness in hands and dysphagia. On enquiry he gave history of decreased lacrimation. Results: On examination he was found to have hypotension along with palmo-plantar and mucosal hyperpigmentation. He had normal sexual maturity. Neurologic examination revealed wasting of small muscles of hand, hypernasality of voice, exaggerated deep tendon reflexes, extensor plantar and normal sensation. Test for autonomic function revealed autonomic dysfunction. Schirmer's test suggestive of alacrimia. Upper GI endoscopy and Barium swallow was suggestive of Achalasia cardia. Hormonal evaluation confirmed adrenal insufficiency. MRI of Brain and spine was normal. Taken together a diagnosis of 4A syndrome was made. Conclusion: Allgrove's syndrome is a rare cause of childhood adrenal insufficiency. A high index of suspicion is required when patients present with complex symptoms as dysphagia, alacrimia, nasal speech and seizures in addition to adrenal insufficiency.

Keywords: Achalasia cardia, addisons disease, allgrove syndrome, autonomic dysfunction

   How common is a positive Aldosterone Renin Ratio? A review of data from a tertiary referral laboratory and tertiary hospital in Southern India Top

Subramanian Kannan, Shriraam Mahadevan1

Department of Endocrinology, Diabetes and Metabolism, Narayana Health City, Bangalore, Karnataka, 1Department of Endocrinology, Diabetes and Metabolism, Sri Ramachandra Medical College, Porur, Chennai, Tamil Nadu, India.

E-mail: [email protected]

Background: The prevalence of primary Hyperaldosteronism (PHA) ranges from 5-10% and there is a push to screen for this disorder routinely in hypertensive clinics. The exact prevalence of this disorder in the Indian setting is not known and the positive predictive value (PPV) of the screening test, the Aldosterone-Renin ratio (ARR) is not known. Aim and Hypothesis: To make a preliminary evaluation on the number of times, ARR is positive using data from a randomly obtained tertiary referral laboratory and a tertiary hospital data set. Materials and Methods: A retrospective review of data from a tertiary laboratory (catering to multiple hospitals in Chennai) from Nov 2016 to July 2018 (1.8 yr) and from a single tertiary care hospital (Narayana Hrudhalaya, Bangalore) from Jul 2015 to July 2018 (3 years). The assumption was the ARRs were typically done in adult (>18 years) patients with high pre-test probability (hypertension with either hypokalemia or adrenal mass or difficult to control blood pressures). A suppressed Renin (either Plasma Renin Activity (PRA) <1 ng/ml/hr or Direct Renin Concentration (DRC) <4 mIU/ml) and an ARR >20 was considered as a positive screen. Plasma Aldosterone (ALDO) and DRC was measured by chemiluminescence while PRA was estimated using radioimmunoassay. Results: We had data of 290 patients who had underwent either aldosterone or renin, out of which 95 patients had data on renin (54 had PRA while 41 had DRC). We divided these patients into those with suppressed Renin (29%) or non-suppressed Renin (71%). Among those with suppressed Renin, the mean (SD) age was 36 (21) years with 53% males. After excluding 6 patients who did not have simultaneously recorded ALDO levels, 17 patients (19%) had ARR >20. The median ARR ratio is this group was 177 (IQR 35-430). In comparison, the non-suppressed Renin group had a mean (SD) age was 36 (19) years with 75% males and had a median ARR of 4.4 (IQR 0.4-18) (P = 0.01 for comparison between the groups). The median ALDO levels were 87 pg/ml (IQR 33-182) suggesting a high pre-test probability of the patients in those these tests were done. Even if an conservative estimate of a pre-test probability of a positive ARR is around 50% in the samples tested, a positive ARR was noted in 19%. If the pre-test probability of a positive ARR on a routine hypertensive patient is about 1%, the positive rates of ARR are likely to be < than 0.3%. Given a high prevalence of essential hypertension in India of about 30%, this would be mean a wasteful expenditure of lab resource. Conclusions: Routine testing for PA using ARR in low pre-test probability hypertensive patients is unlikely to result in more positive ARR reports.

Keywords: Aldosterone renin ratio, Direct renin concentration, Primary Hyperaldosteronism

   A single centre experience with vasopressin stimulated bilateral inferior petrosal sinus sampling in ACTH dependent Cushing's syndrome Top

Rajeev Kasaliwal, Gaurav Goyal1, Ankur Gahlot2, Lonika Lodha3

Departments of Endocrinology and 1Neurology, Mahahtam Gandhi Hospital and Mrdiacl College, 2Conultant Endocrinologist, Rukmani Birla Hospital, Jaipur, Rajasthan, India, 3Diabetes, Endocrinology and Andrology Research Society

E-mail: [email protected]

Context: CRH stimulated bilateral inferior petrosal sinus sampling (BIPSS) is currently considered as the'gold standard' test for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS). However, scarce availability of CRH in resource limited countries like India is a major obstacle in widespread use of IPSS for this purpose. Literature on use of vasopressin during IPSS for differentiation of peripheral versus central Cushing's syndrome is scarce. Objective: To study the diagnostic accuracy of vasopressin stimulated BIPSS in differentiating peripheral versus central Cushing's syndrome. Patients and Methods: Prospective observational study of 7 patients with ACTH dependent cushing's syndrome who underwent vasopressin stimulated BIPSS were included in the study. Results: BIPSS correctly localized the source of ACTH excess in 7/7 of the ACTH dependent cushing's syndrome (4-Cushing's disease, 3-ectopic CS; 6 confirmed on histopathology, 1 occult). Conclusion: BIPSS using vasopressin localised the source of ACTH excess correctly in all the patients with ACTH dependent Cushing's syndrome.

Keywords: Cushing's syndrome, IPSS, vasopressin

   Sympathetic paraganglioma (sPGL): A single centre experience from western India Top

Sanjeet K. Jaiswal, Vijaya Sarathi HA, Tushar R. Bandgar, Swati Jadhav, Anurag R. Lila, Nalini S. Shah

Department of Endocrinology, Seth GS Medical College and KEM College, Mumbai, Maharashtra, India.

E-mail: [email protected]

Aims and Objective: To study clinical, biochemical, radiological and genotype of Sympathetic paraganglioma and also compare the sPGL from pheochromocytoma from our institute. Materials and Methods: Data of 75 patients of sPGL from 2005-2017 was analyzed retrospectively. Details regarding demographic, clinical, biochemistry were noted. The sPGL was considered secretory if PFNMN neither (Plasma free nor metanephrine) >180 pg/ml or PFMN (Plasma free-metanephrine). Anatomical localization of tumor was done with contrast enhanced CT (CECT) of abdomen and thorax (n = 73) or MRI (n = 2) in patients with contraindication to CT. Genetics were done with Sanger sequencing for five susceptibility gene RET, VHL, SDHB, SDHD and SDHC) and multiplex ligation-dependent probe amplification for genetic rearrangement were done for VHL and SDHX. Results: Total 75 index patient (M: F, 30:45) with mean age 32.9 ± 14.16 years. 60 (80%) patient had single sPGL, 10 (13%) had multifocal (sPGL with PCC) PGL, five (7%) had multiple PGL. In 37 (49%) sPGL located at OOZ, 20 (27%) at infra-diaphragmatic (above the OOZ), 4 (5%) at urinary bladder, 4 (5%) at mediastinum and 10 (13%) at other sites (Perihilar, pelvic, para-testicularetc.) sites. pg/ml). In CECT 59 (84%) patients showed percentage arterial enhancement (PAE) >100% with enhancement >100 Hounsfield units (HU). Nineteen patients had metastatic disease. 12 (63%) had metastasis at presentation (synchronous), whereas seven (37%) developed metastasis during follow up (metachronous metastasis). Most common site for metastasis was bone. Genotype was available for 35 patient with SDH-B in 8 (11.4%), VHL in 6 (2.8%), RET in 1, and in 20 patients, sequenced genes were negative. Compare to pheochromocytoma sPGL mainly presented as incidentaloma (38 vs 58 P = 0.0068) and had high risk of metastasis (10 vs 26 P = 0.0025).

Keywords: Organ of zuckerkandl, Paraganglioma, SDHB

   Gonads Top

   Two ends of the Rainbow of DSD Top

Deepa Kulkarni, Madhukar Mittal, Pratishtha Mishra, Sudhanshu Tiwari, Naresh K. Maurya

Department of Endocrinology, King George's Medical University, Lucknow, Uttar Pradesh, India.

E-mail: [email protected]

Aim and Objective: To report two cases presenting at two extreme ends of the spectrum of Disorder of Sexual Differentiation (DSD). Materials and Methods: Two cases of DSD presented in our Endocrinology OPD in recent past with their sexual phenotype completely opposite to their karyotype. Both were in the 2nd-3rd decade of life. Results: Case1: 16-year female presented with primary amenorrhea. Examination showed Tanner's stage B3P2, clitoromegaly and blind vagina. USG-abdomenwas suggestive of Mullerian agenesis with no visible gonads. Bilateral gonads were visualised on CECT-abdomen in high inguinal region. Estradiol levels were 54.05 pg/ml, FSH 20.67 mIU/mL, Prolactin 6.2 ng/mL, Testosterone 86.60 ng/dL, and 17(OH) P 5.89 ng/mL. Karyotype was 46XY. Bilateral gonadectomy was done. Histopathology confirmed tissue as testes. Estrogen therapyhas been started with plan of vaginal reconstruction. Case2: 24-year male presented with absent beard. Examination showed bilateral gynaecomastia and empty scrotal sacs. USG-scrotum was able to identify bilateral small testes. Hormonal analysis showed serum Estradiol 33 pg/mL, Prolactin 18.5 ng/mL, Beta-HCG 2.44 mIU/mL, LH 22.29 mIU/mL, FSH 82.01 mIU/L, Testosterone 90.17 ng/dL. However, to our surprise Karyotype came46XX which was reconfirmed. Androgen replacement therapy has been initiated. Conclusion: Androgen Insensitivity Syndrome (AIS) is a rare disorder with46XY karyotype presenting with failure to start menses. Partial forms may present earlier. De La Chapelle syndrome or 46XX male is a disorder with microorchia and normal-sized penis. Majority patients bear SRY-gene on one X-chromosome, thus explaining male phenotype. In the 2 cases seen by us, Karyotype was pivotal for diagnosis. In India patients of DSD come late when patients approach marriageable age.

Key words: Androgen insensitivity syndrome, De La Chapelle syndrome, karyotype

   Clinical and biochemical characterization of non-obese PCOS patients and its relation with lean-NAFLD Top

Kaushik Sen, Kausik Das1, Chaitali Datta Ray2, Sujoy Ghosh

Departments of Endocrinology and Metabolism and 1Hepatology, IPGMER and SSKM Hospital, Kolkata, 2Department of Gynecology and Obstetrics, Raiganj Govt Medical College, West Bengal, India.

E-mail: [email protected]

Background: PCOS is the most common endocrine abnormality in reproductive age women. There has been scarcity of data regarding the details of clinical phenotypes and laboratory parameters of non-obese PCOS women. Material and Methods: It was a cross-sectional, observational study. Women below 18 years and after menopause were excluded. There were four groups viz. Non-obese PCOS, overweight/obese PCOS, overweight/obese non-PCOS and non-obese non-PCOS. We performed Transient Elastography (Fibroscan), in addition to routine biochemical tests and ultrasonography. Results: 11.5% non-obese PCOS women had waist-hip ratio more than 0.81 although none of them had waist circumference more than 80cm. Non-obese PCOS women had significantly higher prevalence of menstrual irregularity compared to their overweight/obese counterparts (96.2% vs 74.1% P < 0.001). USG evidence of fatty liver was found in 26.9% of non-obese PCOS women as opposed to 4.5% of non-obese non-PCOS women (P = 0.038), but there was no significant difference between non-obese PCOS and overweight/obese PCOS women (26.9% vs 48.1% P 0.11). None of the women in the PCOS and non-PCOS groups had evidence of fibrosis in Fibroscan. There was a graded increase in fasting insulin as well as the HOMA-IR values from non-obese non-PCOS women, through overweight/obese non-PCOS and overweight/obese PCOS to non-obese PCOS women. Although the absolute mean values of AMH and Testosterone were higher in non-obese PCOS women than those in overweight/obese PCOS women, they failed to reach statistical significance. Conclusion: Significant hirsutism, as defined presently, may not be present in PCOS. Biochemical and morphological alterations of liver are similar in non-obese PCOS and overweight/obese PCOS. Hepatic fibrosis is not a feature of PCOS. Non-obese PCOS patients are more insulin resistant compared to overweight/obese subjects irrespective of presence or absence of PCOS.

Keywords: Fibroscan, insulin resistance, non-obese PCOS

   A rare case of 46 XY disorder of sexual differentiation Top

Sayan Ghosh, Asish K. Basu, Anirban Sinha, Animesh Maiti, Somnath Raghuvanshi, Saurav Shishir, Chhavi Agrawal

Department of Endocrinology, Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: DSD is a congenital disorder associated with discordant chromosomal, gonadal and phenotypic sex affecting urogenital differentiation. 46 XY DSD is nothing but a new terminology of Male pseudo-hermaphroditism. It can leads not only to medical emergency but can also leads to social emergency to the parents, when ascribing a sex to their newborn child. So, etiological diagnosis of DSD is compulsory to clear all those matters. Case Report: 2 year 2 month old phenotypically female child born out of consanguineous marriage presented with bilateral palpable inguinal swelling since 2 months of age. Family history reveals similar history in elder sister. On examination, Palpable Labial swelling about 1 cc in diameter, Prader stage II, External Masculinisation Score 3/12, clitoral index 35 cm2, clitoral length 15 mm, mild posterior labial fusion, Anogenital Ratio 0.6 and two opening at perineum. Her karyotype was 46 XY. USG shows Testes like structure in both side with visible prostate. β HCG stimulation (1500 IU IM) Revealed Basal and stimulated Testosterone <20 ng/dl and 79.1 ng/dl respectively, basal and stimulated Androstenedione <0.30 ng/ml and 2.82 ng/ml respectively. Stimulated DHT value was 225.01 pg/ml. So, T/A ratio was 0.28 (low) and T/DHT ratio was 3.51 (normal), that is suggestive of 17 β HSD3 deficiency, though genetic testing report is still pending. Conclusion: 17 β HSD3 deficiency is a rare cause of DSD and it requires urgent diagnosis for urgent decision making about sex of rearing and consideration of potential fertility. Features of virilisation may not be apparent by parents in prepubertal period. Gonadal biopsy is not required for detection of the case. Only requirement is the biochemical stimulation testing and finally genetic testing for confirmation, though not mandatory.

Keywords: A (Androstenedione), β HCG (Beta Human Chorionic Gonadotropin), DSD (Disorders of Sexual Differentiation), T (Testosterone), 17 β HSD3 (17 beta-hydroxysteroid dehydrogenase type 3)

   A rare variant of turner syndrome - Case report Top

Sayan Ghosh, Asish K. Basu, Anirban Sinha, Animesh Maiti, Somnath Raghuvanshi, Saurav Shishir, Chhavi Agrawal

Department of Endocrinology, Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: Turner syndrome is a chromosomal disorder of female, characterized by complete or partial absence of X chromosome. Genotypically around 50% cases shows typical Monosomy X (45, X), 5-10% have Isochromosome of Xq [46, Xi (Xq)] and rest 30% are Mosaic, Ring X-chromosome and Deletion of Xp/Xq. Variant Turner syndrome is usually associated with less phenotypic features. Even in absence of growth hormone deficiency rhGH can be used to accelerate the growth velocity. Case Report: 15 years old girl presented with short stature and primary amenorrhea with no similar family history. On examination, her initial height was 124 cm (Height SDS = −3.7 SD), weight was 30 kg (5rd - 10th percentile), US: LS ratio was 0.98:1. Patient was having short neck, low posterior hair line, carrying angle >15 degree. Initially SMR was B3P2. On investigation low Estradiol with high FSH and LH was found. She was Euthyroid. Echocardiography, USG Abdomen was unremarkable. USG Pelvis revealed Infantile uterus with 1.4 × 1.6 cm right ovary and 1.2 × 1.3 cm left ovary with two follicles in each. On Karyotype she was found to have Isochromosome Mosaic Turner Syndrome with inversion chromosome 9 [MOS 46, X, i (X) (q10) inv (9) (p11q12)/45×]. After 3 months of treatment with rhGH 1.6 mg/day s/c and 0.5 mg Estradiol valerate, her height increased to 128 cm (Height SDS = −3.10 SD) and Tanner stage progress to B4P3. Conclusion: Isochromosome Mosaic Turner Syndrome (IMTS) is a rare genotype found in <5% cases of Turner Syndrome. Mosaic TS with inv (9) of normal cell line is reported, but inv (9) in both 45X and 46, X, i (X) cell type of IMTS is not reported till now. Spontaneous puberty can occur in Mosaic Turner Syndrome in 30% of cases. Inversion of chromosome 9 is one of the frequent rearrangement (13%), usually not associated with phenotypic abnormality in normal population. Few reports shows association of single inv (9) without sex chromosome abnormality can leads to infertility, abortion and growth failure. So in our case presence of inv (9) along with Isochrosome can be the cause of more severe short stature (<50th percentile of Turner specific growth chart).
Figure 1: Phenotypic features

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Figure 2: Karyotype (30 cells)

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Figure 3: Standard IAP Growth Chart

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Figure 4: Turner specific Growth Chart

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Keywords: IMTS (Isochromosome Mosaic Turner Syndrome), isochromosome, rhGH (Recombinant Human Growth Hormone)

   Efficacy and outcome of gonadotropin vs gonadotropin and testosterone therapy in the male congenital hypogonadotropic hypogonadism: A clinical experience Top

Somnath Raghuvanshi, Asish K. Basu, Animesh Maiti, Anirban Sinha, Sayan Ghosh, Saurav Shishir, Chhavi Agrawal

Department of Endocrinology, Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Gonadotropin induces masculinization and spermatogenesis in men with congenital hypogonadotropichypogonadism (CHH) via intra testicular androgen production. However, for the induction of puberty with gonadotropin therapy is cumbersome due to frequent injection, high cost, and compliance issue as compare to testosterone therapy. The testosterone is used in male with delayed puberty to induce secondary sex character but the effect of testosterone on future spermatogenesis not established and large cohort studies to be conducted to show the efficacy and reliability of this therapy. Aim: The aim of this present therapy was to evaluate the efficacy of gonadotropin vs testosterone followed by gonadotropin treatment in a cohort of male CHH patients and its effect on the spermatogenesis. Materials and Methods: In this study we included 7 CHH azoospermic patients without pubertal development and patient were treated between 2015 and 2018 at medical college Kolkata. All patients received combined human chorionic gonadotropin (HCG) and human recombinant Follicular stimulating hormone (FSH) and out of 7 three patient received testosterone followed by gonadotropin (TFGT), the testosterone therapy was omitted at least 3 month before the gonadotropin therapy (GT) and were followed up for 1 year. Serum total testosterone level, testicular volume, spermatogenesis, were recorded at each visit. Statistical Analysis: The data were represented as Mean ± SD, student t test applied for paired data, Chi-square test done for nonparametric. Results: The [Table 1] showed baseline characteristics and both the group had small testicular volume, azoospermia, low gonadotropin and serum testosterone [Table 2]. The mean Age were 23 ± 2.48 and 25.3 ± 1.45 in GT and TFGT group respectively which has the P value of > 0.05. After gonadotropin therapy, testicular size was enlarged from 2.03±0.20 to5.93 ± 1.36 mL (P < 0.0001) in GT and 8 ± 1.6 ml (P 0.0001) in TFGT and the serum total testosterone was elevated from 14.95 ± 0.97 to 364 ± 129 ng/dl/L (P < 0.001) in GT and 588 ± 233 (P 0.0001) ng/dl in TFGT [Table 3]. There were no significant difference in TV and testosterone among T and TGT patients. Spermatogenesis occurred in both group with a mean value of 0 (P 0.00001), 12.5 (P > 0.05), 22.6 (P > 0.05) million/ml at baseline, GT and TFGT groups respectively. It was statistically significant in comparision to baseline but not among GT & TFGT (P 0.65) [Table 4]. Conclusion: In this scenario the TFGT therapy associated with numerically more increase in the testicular size and spermetogenesisas compared to GT arm and it may be due to more testicular volume in TFGT at the beginning of therapy but this difference is not statistically significant. We found no adverse effect of testosterone therapy on the spermatogenesis.
Table 1: Baseline characteristics GT Group patient no 1 to 4 and TFGT group patient no 5 to 7

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Table 2: Effect of GT and TFGT on the testicular volume, pubic hair staging, serum testosterone and sperm count

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Table 3: Serum testosterone and testicular volume after treatment

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Table 4: Sperm count after treatment

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Keywords: Gonadotropin, spermatogenesis, testicular volume, testosterone

   Study of karyotype-phenotype correlation in Turner's syndrome Top

Sunetra Mondal, Satinath Mukhopadhyay, Rana Bhattacharya, Subhankar Chowdhury

Department of Endocrinology, IPGME and R, Kolkata, West Bengal, India.

E-mail: [email protected]

Aim: To study correlation between karyotype and phenotype in patients with TS. Materials and Methods: 72 patients with TS (based on phenotype and 30-cell karyotype) from Eastern India were assessed clinically and investigated. Differences among the karyotype-groups were analysed statistically using ANOVA or Kruskal Wallis (for quantitative parameters) and Chi-square (for qualitative parameters). Results: Most common karyotype was 45, XO (52.78%) > XO/X, iXq (15.28%) > XO/XX (13.89%) > XO/XY (8.5%) >46, iXq (6.94%) > structural anomalies. 5 patients had marker chromosomes the origin of which was determined using FISH for X and Y specific probes. Isodicentric Xq was a particularly common finding among isochromosomes (62.5%). No significant differences in height/Ht-SDS were found. Of the Turner's stigmata, prevalence of low posterior hairline, low set ears, lymphedema and shield chest was significantly higher in the XO group. The groups differed significantly in the prevalence of spontaneous the thelarche, spontaneous menarche (both higher in the XO/XX and isochromosomes). No significant differences in the prevalence of cardiovasacular and urinary-tract anomalies. Anti-TPO-antibody positivity was significantly higher in isochromosomes but prevalence of overt/subclinical thyroid dysfunction wasn't. Although TS patients are known to be prone to metabolic syndrome, upto 25% were underweight while only 8% were overweight-obese. There was an increased prevalence of transaminitis in those with isochromosomes and dyslipidemia in mosaics although majority of patients in these groups were underweight.” instead of the sentence “ Isochromosomes had higher prevalence of hepatic dysfunction and mosaics of dyslipidemia but both these groups had higher prevalence of underweight patients. Isochromosomes had higher prevalence of hepatic dysfunction and mosaics of dyslipidemia but both these groups had higher prevalence of underweight patients. XO/XX mosaics had the lowest scores on performance IQ and arithmetic subsets and XO/XY mosaics the highest. A previously unreported higher prevalence of MVP, mitral and tricuspid regurgitation and of PUJ obstruction was noted” instead of the sentence “ A high prevalence of MVP<mitral and tricuspid regurgitations a d PUJ obstruction was noted which was previously not reported. A high prevalence of MVP, mitral and tricuspid regurgitations and PUJ obstruction was noted that is previously not reported. Few unusual phenotypes were encountered like agenesis of leg, pediatric Graves' disease, EHPVO and twins with TS. Conclusion: This is the largest reported cohort of TS from Eastern India and reestablishes some known correlations like increased autoimmunity in isochromosomes, spontaneous puberty in mosaics. No significant increase in severity of short stature, stigmata, CV/UT anomaly/metabolic syndrome in any group. Some novel associations were found.

Keywords: Isochromosomes, karyotype groups, mosaics

   Aromatase deficiency-two different families-clinical and mutation studies Top

Rabindera Nath Mehrotra, U. Jyanthi1, R. Sinha2

Department of Endocrinology and Metabolism, Apollo Health City, Jubilee Hills, 1Chief (Former), Sandor Life Sciences, 2Department of Obstetrics and Gynaecology, Apollo Health City, Jubilee Hills, Hyderabad, Telangana, India.

E-mail: ravinm1rediffmail.com

Aromatatase (CYP19A) deficiency is a uncommon autosomal recessive disorder. Aromatase is the only P450 enzyme which would catalyze the conversion of androgens to estrogens. Aroamatase expression in various tissues is responsible for the systemic and local effects of estrogen.

We report aromatase deficiency in two families.

  • Family-1-32 year old male had presented with progressive valgus deformity and kyphoscoliosis. He was tall, had acanthosis, skin tags. Androgenisation was normal. Xray of knee and wrist showed open epiphysis. Testosterone was normal, but Estradiol was low. BMD-Z scores were less than − 2.0 at both hips and spine. He had 2 Sisters:- (A) Had primary amenorrhea, Normal stature, Hisrsutism, hypoplastic uterus with enlarged and cystic ovaries, She had no Progestrone with drawl bleed, but had regular cycles on estrogen and progesterone. Second sister had spontaneous menarche, but had cycles only for a year, later she had prolonged amenorrhea. Had vaginoplasty. Family was detected to have Homozygous mis sense mutation c.628G>A (p. 210) in exon 5.
  • Family-2-25 year old male had presented with progressive valgus deformity. He was tall and had noticed increase in height in last couple of years. Had prognathisim, acanthosiss and skin tags. X ray showed open epiphysis. His 18 year old sister had not attained menarche, had clitromegaly, significant ovarian cysts. The patient was detected to have - -Hetrozygous Mutation-c295A>T-(p.k99) in exon 2, and Heterzygous mutation c.628G>A-(p.E2210K) in exon 4.

Keywords: Amenorrhea with virilization, aromatase deficiency, open epiphysis

   46 XX male sex reversal syndrome: A report of three cases and review of literature Top

Rahul Gupta, Ashu Rastogi, Anil Bhansali

Department of Endocrinology and Metabolism, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

E-mail: [email protected]

Aims: to study the clinical, hormonal and cytogenetic profile of patients with 46 XX male sex reversal syndrome. Materials and Methods: From a cohort of patients with disorder of sex development who are under OPD follow up at Department of Endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh cases with 46 XX male sex reversal syndrome were retrospectively identified. A detailed history and physical examination was performed. Hormonal analysis was performed using ECLIA. Karyotyping was performed in all and those showing 46 XX karyotype with male phenotype were subjected to FISH analysis for SRY gene using Vysis probes. Result: A total of three cases were identified. The mean age of presentation was 25.7 ± 5.7 years. Two presented with primary infertility and one with poor development of secondary sexual characteristics. One had glandular hypospadias, the rest had EMS of 12 and all three had testicular volume of less than 4 ml. Mean LH, FSH and testosterone were 21.8 ± 13.2 mIU/ml, 35.86 ± 19.23 mIU/ml and 5.26 ± 2.23 nmol/l respectively. Karyotyping showed a 46 XX karyotype in all three and FISH analysis for SRY gene was positive in two. Conclusion: 46 XX male reversal syndrome is caused by the presence of a small Y-chromosome fragment in a karyotypic XX genome which can contain genes that mediate male sex determination. It presents in adulthood with primary infertility or poor development of sexual characteristics. The consistent biochemical finding is an elevated FSH with variable LH and testosterone. Based on FISH analysis they can be divided into SRY positive and SRY negative groups, with SRY negative patients more likely to show abnormality of gentiles.

Keywords: 46 XX male, sex reversal syndrome, SRY gene

   References Top

  1. Ergun-Longmire B, Vinci G, Alonso L, Matthew S, Tansil S, Lin-Su K, et al. Clinical, hormonal and cytogenetic evaluation of 46, XX males and review of the literature. J Pediatr Endocrinol Metab 2005;18:739-48.
  2. Liu L, Feng LN, Yang LL. The phenotype and genetics of 46, XX male syndrome. Endocrinol Foreign Med Sci 2005;25:283-5.

   Vegetarian dietary practices elevate adipocytokines among Indian women with PCOS Top

Tajali Sahar, Aafia Rashid, Rubana Aashiq, Sobia Nisar1, Nisar Ahmed, Nikhil Tandon2, Alka Kriplani3, Nandita Gupta2, Mohd Ashraf Ganie

Department of Endocrinology, Sheri-Kashmir Institute of Medical Sciences, Srinagar, 1Department of Internal Medicine GMC Srinagar, Srinagar, Kashmir, 2Departments of Obstetrics and Gynecology, 3Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Objective: To evaluate the serum inflammatory markers and their association with dietary habits in North Indian women with PCOS. Materials and Methods: Women diagnosed with PCOS as per the NIH 1990 criteria were evaluated using a common presdesigned proforma about details of mestrual history, dietary practices, anthropometry, FG score, biochemical, hormonal, and cytokine profile after a written informed consent. A total of 144 PCOS subjects were recruited from two participating centres (n = 82 women vegetarian from AIIMS, New Delhi and n = 62 women non-vegetarian diet from SKIMS, Srinagar). Results: The mean age of vegetarian and non-vegetarian subjects was 25.87 ± 4.2 years vs. 26.13 ± 4.3 years with mean BMI of 24.83 ± 4.2 kg/m2 vs 24.67 ± 3.4 kg/m2. The mean number of cycles per year and mean FG scores were comparable (P > 0.05). The mean waist circumference of vegetarian women was significantly higher (P < 0.05) whileas serum total testosterone levels were marginally higher in non-vegetarian subjects. Intersetingly resistance (HOMA-IR and QUICKI) and pro-inflammatory markers (serum TNF-α, IL-6, hs-CRP and resistin) were found to be significantly elevated among vegetarian subjects than their non-vegetarian counterparts (P < 0.05). However, serum IL-10 levels did not differ significantly between two groups (P > 0.05). Dietary evaluation indicated lower daily energy (1344.49 ± 367.41 kcal vs. 1792.21 ± 366.9 kcal) and protein intake (39.83 ± 12.04 gm vs. 52.83 ± 12.17 gm) among vegetarian subjects as compared to non-vegetarians respectively (P < 0.05). Conclusion: Vegetarian women with PCOS have higher waist circumference, proinflammatory markers, insulin resistance despite of low calorie and protein intake as compared to age and BMI matched women with PCOS.

Keywords: Diet, inflammation, insulin sensitivity, PCOS, testosterone

   Potential benefits of high dose of cholecalciferol supplementation on efficacy of spironolactone in women with polycystic ovary syndrome (PCOS) - A six month open label randomized study Top

Aafia Rashid, Ishfaq A. Wani, Mudasir Makhdoomi, Sobia Nisar1, Tajali Sehar, Nandita Gupta2, Neena Malhotra3, Mohd Ashraf Ganie

Department of Endocrinology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, Departments of 1Internal Medicine GMC Srinagar, 2Endocrinology and Metabolism and 3Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Aims and Objectives: The study was designed to assess the effect of vitamin D supplementation in co-prescription with anti-androgen drug like spironolactone on clinical, hormonal, metabolic and insulin sensitivity parameters in women with PCOS. Materials and Methods: A total of 150 women were screened for PCOS, out of which 104 womenwith PCOS qualified a diagnosis (AE-PCOS 2009 criteria) of PCOS and were assigned to two treatment groups-Group I (n = 52, spironolactone 50 mg/day in combination with cholecalciferol 4000 IU/day) and Group II (n = 52, spironolactone 50 mg/day alone). Vitamin D supplementation was given as 60,000 units every two weeks for 24 weeks. All Subjects were routinely evaluated for clinical, biochemical, hormonal and insulin sensitivity parameters in addition to various safety parameters especially serum calcium levels at baseline and after 24 weeks of treatment. Results: The mean age of subjects who completed the study (n = 60) was 23 ± 5 yrs with mean BMI of 22.9 ± 4 kg/m2. After 24 weeks of cholecalciferol administrationserum 25 (OH) D levels increased significantlyin group I without any adverse effects and remained unchanged in group II (P < 0.001).By 6 months, number of menstrual cycles increased significantly (P < 0.001) in both the groups, however the difference between the two groups was not significant as was FG score. Serumtotal testosterone levels decreased significantly (P < 0.01) in the cholecalciferol arm as was HOMA-IR and QUICK. No significant beneficial changes were observed in weight, BMI, blood pressure, glucose tolerance and serum lipids in treatment group supplemented with cholecalciferol. Conclusions: We conclude that daily dose of 4000 IU cholecalciferol might be a useful adjunct in complex treatment of PCOS with fewer adverse events.

Keywords: Cholecalciferol, HOMA –IR, PCOS, testosterone

   Demographic, clinical, psychological, and social profile of transgenders Top

Ashok C. Makineni, B. Vivekananda, A. Mythili, J. Ramesh, K. A. V. Subrahmanyam

Department of Endocrinology, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India.

E-mail: [email protected]

Introduction: Transgender is a high socioeconomic and cultural problem. Aim: To Study the Demographic, clinical, psychological and social profile of transgenders. Subjects and Methods: 109 cases of transgenders who attended Department of Endocrinology from January 2018 to July 2018 were studied with psychiatry questionnaire, genital examination, features of virilization and reasons for gender change. Results: All 109 were transgender females. 70% were from urban area and 30% were from rural area. Around 3% have lower education whereas secondary school education is 59.6%. 9.17% up to 12th class, 3.6% were graduates. 26.6% gender change was based on religious belief. 73.3% change their gender identity as their choice, of whom only 1% were accepted by parents. All were born with normal male genitalia, assigned and reared as male. Mean age of change in gender identity was 10 years and mean age of sexual orientation towards male was 16 years. 18.34% underwent sex reversal surgery and 8.25% were on hormonal therapy. 71.1% were residing in the transgender community, 7% with family members and 14% were alone. Source of income was begging in 23%, begging and prostitution in 60%, daily labour work in 17%. 97% had multiple sexual partners. Conclusion: This study highlights the psychological factors, high risk of sexual behaviour. Strategies need to be devised to protect from sexual, psychological and physical harassment, besides social neglect and being ostracised by the society.

Keywords: Transgender issues in India

   Relationship between total testosterone and vitamin D levels in males with erectile dysfunction Top

Samiran Das, Dipti Sarma, Ashok K. Bhuyan, Uma K. Saikia, Bipul K. Choudhury

Department of Endocrinology, Gauhati Medical College, Guwahati, Assam, India

E-mail: [email protected]

Aim: To evaluate the association between serum testosterone and Vitamin D status in apparently healthy males presenting with erectile dysfunction (ED) and to see the correlation of Vitamin D status with ED score (IIEF-5). Materials and Methods: After adequate exclusion criteria 188 subjects (>18 yrs) presenting with erectile dysfunction as per IIEF-5 criteria (International Index of Erectile Function) were included in the study. Serum total testosterone and Vitamin D were essayed using ectrochemiluminescence immunoassay. Association between Testosterone and Vitamin D levels and IIEF-5 score with Vitamin D levels were examined using linear regression analysis. Results: Mean age for the study population is 46.03 ± 7.28 (2 SD) yrs. Mean total testosterone and vitamin D were 3.93 ± 1.1 (2 SD) ng/ml and 31.2 ± 8.3 (2 SD) ng/ml respectively. According to IIEF-5 scoring 10.6% subjects had severe ED, 46.2% had moderate ED, 33.5% mild-moderate ED and rest had mild ED. A significant positive correlation was seen between total testosterone levels and vitamin D (r = 0.58; P < 0.05) as well as between vitamin D and IIEF-5 score (r = 0.43; P < 0.05) among the study population. Linear regression analysis showed a significant association between Vitamin D and total testosterone (P < 0.05) as well as between vitamin D and IIEF-5 score (P < 0.05). Conclusion: Vitamin D levels may be a determinant factor for testosterone levels in males. Unexplained erectile dysfunction in an apparent healthy male may be attributed to a low vitamin D level.

Keywords: Erectile dysfunction, testosterone, vitamin D

   Rare case of a primary amenorrhea Top

Madhava R. Vupputuri, Hari K. Reddy2, Madhurima Kandepu1

Departments of Endocrinology and 1Pediatrics, GIDE Hospital, Bhaskar Nagar, Kakinada, 2Department of Endocrinology, Devireddy Diabetes and Hormone Centre, Kadapa, Andhra Pradesh, India.

E-mail: [email protected]

Aims: To present a rare case of primary amenorrhea. Objectives: To describe the clinical and biochemical details of a young lady with primary amenorrhea and hypertension. Materials and Methods: We elicited careful history followed by biochemical workup. This 23 yr old lady is first of 2 issues of a consanguineous marriage. Her Ht is 166.5 cm (tallest in the family). At the age of 13 yrs she was evaluated by a gynecologist and put on Estradiol therapy for primary amenorrhea. After 6 months of therapy she attained menarche and subsequently she was put on combination oral contraceptive therapy with regular cycles. She was recently detected to have hypertension (BP = 146/114 (Rt), 148/120 mm of Hg (Lt)). Result: Karyotype was 46 XX. USG Pelvis showed hypoplastic uterus (31 × 18X13 mm), small left ovary (15 × 9 mm) and right ovary was not visualized. Her LH/FSH were 31.03/123.36 IU/mL. In view of hypertension we suspected 17 hydroxylase deficiency. We measured her Cortisol/Testosterone/Estradiol/Progesterone and they were <0.5 mcg/dL/0.03 ng/mL/<10 pg/mL/3.14 ng/mL respectively. Plasma Renin Activity was 0.48 ng/mL/hr (NR in standing position - 0.10-6.56 ng/mL/hr). Her serum Na/K were 140/4.1 mmol/L. ECG showed LVH. Her hand X-ray done at the age of 23 years showed unfused distal radius and ulna. This combination of hypergonadotropic hypogonadism, low testosterone, low cortisol, low estradiol, low renin hypertension strongly goes in favor of 17 hydroxylase deficiency as the underlying etiology. Genetic analysis is awaited for the confirmation of diagnosis.

Keywords: 17 hydroxylase deficiency, hypergonadotropic hypogonadism, low renin hypertension, primary amenorrhea

   Dihydrotestosterone (DHT): A potential biomarker of hyperandrogenaemia in polycystic ovary syndrome Top

Ashutosh Halder, Hemant Kumar, Amanpreet K. Kalsi, Manish Jain

Departments of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Objective: To assess various androgens to identify best available biomarker of hyperandrogenaemia in polycystic ovary syndrome. Materials and Methods: Prospective study on 175 polycystic ovary syndrome cases (after exclusion of secondary causes) and 50 control women from North India. Serum basal testosterone, FAI (free androgen index), dehydroepiandrosterone sulphate (DHEAS), androstenedione and dihydrotestosterone (DHT) were measured besides assessment of clinical hyperandrogenism (Ferriman-Gallwey/FG score). Predictive values were also evaluated with the use of the receiver operating characteristic (ROC) curve analysis. Results: Clinical hyperandrogenism (FG score ≥9) was observed in 76.3% cases. High levels (>mean + 2SD with <10% false positive rate) of testosterone (>0.5 ng/ml), FAI (>2.5), DHEAS (>308 ug/dl), androstenedione (>2.1 ng/ml) and dihydrotestosterone (>460 pg/ml) were observed in 35.9%, 57.14%, 11.1%, 17.3% and 57.6% cases respectively in PCOS cases. Mean DHT value was 562 pg/ml in study group whereas in control was 257 pg/ml (P < 0.00001) and area under ROC curve was 0.873 (95% specificity and 65% sensitivity with an accuracy of >72%; lower and upper bound 95% Conf. Interval 0.819-0.927; P value <0.0001). The area under the ROC curve assay yielded highly satisfactory result in phenotype A (hyperandrogenism, oligo-anovulation and polycystic/enlarged ovaries); ROC as 0.953 (P < 0.00001). The best compromise between >95% specificity and >82% sensitivity with an accuracy of >88% was obtained with a cut-off value of 400 pg/mL for PCOS diagnosis. Conclusions: Serum DHT measurement is best available single marker of hyperandrogenemia in PCOS women from north India, in particular with phenotype A. The serum DHT level is a useful diagnostic tool of hyperandrogenemia in PCOS.

Keywords: DHT, Hyperandrogenemia, PCOS

   TAK1 is involved in regulation of TGFβ-induced Smad signaling and promotes the growth and inflammatory responses in endometriotic cells Top

Jyoti B. Kaushal1,2, Pushplata Sankhwar3, Vinay Shukla1,2, Rajesh K. Jha1, Anila Dwivedi1,2

1Division of Endocrinology, 2Academy of Scientific and Innovative Research (AcSIR), CSIR-Central Drug Research Institute Campus, 3Department of Obstetrics and Gynaecology, King George's Medical University, Lucknow, Uttar Pradesh, India.

E-mail: [email protected]

Background: Transforming growth factor (TGFβ) plays a major role in establishment and maintenance of endometriosis, however, the underlying mechanism remains unclear. Objectives: The current study was undertaken to decipher the role of TAK1 in TGFβ -mediated NFκB/Smad7 signaling in endomeriotic cellular responses. Materials and Methods: The primary culture of human endometriotic tissue, normal endometrial tissue and also the cell lines CRL-7566, CRL-4003 were used. Western blotting, confocal microscopy, FACS, were done for protein expression study. Cell viability assay, BrdU labeling and NFκB -luc transcriptional activation were done to assess growth responses. Results: Exposure of TGFβ1 in endometriotic stromal cells (ESCs) induced the expression of various TGFβ signaling- target molecules that provided evidence that TGFβ1 is implicated in Tak1/NFκB/Smad7 cascade commencement via both canonical and non-canonical mechanisms. The silencing of TAK1 in ESCs significantly attenuated the TGFβ -stimulated NFκB -luc transcriptional activation and nuclear translocation of NFκB (p65) subunit similar to that seen with NFκB inhibitor (QNZ). The blockage of NFκB or knockdown of TAK1 caused reduced Smad7 and Cox 2 expression and showed low BrdU incorporation even in the presence of exogenous TGFβ1. Further, celestrol attenuated the expression of TGFβ signaling downstream molecules corroborating that TAK1 is crucial mediator for TGFβ1 action. Exposure to celastrol resulted in the activation of caspase-3 and -9 that led to PARP cleavage and triggered apoptosis as well as autophagy via increased expression LC3BII, Beclin along with the reduced expression of mTOR and P70 S6K1 in ESCs. Conclusion: Overall, our study provided evidence that functional cross-talk between TGFβ and NFκB is mediated via TAK1 and thus contributed towards understanding the molecular mechanism involved in TGFβ-stimulated inflammatory response and proliferation in ESCs.

Keywords: Apoptosis, autophagy, endometriosis, transforming growth factor

   46 XX male: A case report Top

Avinash Patil, Praveen Ganji, V. Suresh, Alok Sachan

Department of Endocrinology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India.

E-mail: [email protected]

Introduction: The 46 XX testicular disorder of sex development (DSD), previously known as de la Chapelle syndrome is a rare condition occurring in about 1:20000 males and characterized by a variable degree of mismatch between the phenotype and the genotype of the affected individual. Patients may present seeking fertility with normal male internal and external genitalia, or may present at an earlier age because of ambiguous genitalia. Abstract: We present a case report of 33 yr old male who attended our endocrinology clinic with complaints of bilateral gynecomastia for the last 2 years. On examination his height was 148 cm and weight 53 kg (BMI: 24.20 kg/m2). His Sexual Maturation Rate was A3P4, stretched penile length being 9.5 cms. Lab reports showed FSH-37 IU/L and LH-18.5 IU/L, with low concentrations of Testosterone levels of 1.1 ng/mL. Ultrasound scortum showed bilateral small testes with no varicocele or hydrocele. Abdominal pelvic ultrasonography (USG) showed normal seminal vesicles and prostate without any mullerian derivatives. Semen analysis showed azoospermia. Chromosomal analysis revealed 46XX karyotype. Conclusion: The 46XX testicular DSD is a rare form of sex reversal with complex mechanisms leading to a large spectrum of clinical manifestations ranging from ambiguous genitalia in the newborn to normal male phenotype.

Keywords: Disorders of sexual development, XX male

   A rare case of 46XY DSD Top

Sandeep Ganta, Praveen Ganji, Suresh V, Alok Sachan

Department of Endocrinology, SVIMS, Tirupathi, Andhra Pradesh, India.

E-mail: [email protected]

Introduction: 46XY DSD rarely present with unambiguously female external gentalia. Case Report: We present case of 16 years old child reared as female who came for evaluation of primary amenorrhea. On examination Sexual maturity rating was B1A1P1, height was 153 cms, Upper Segment 72 cms and Lower Segment was 81 cms. She had a single urethral opening, blind vaginal pouch with posterior labial fusion. Her FSH was 27.4 IU/L, LH 64 IU/L and testosterone 0.18 ng/ml. Serum stimulated cortisol, 17 hydroxy progesterone, andostenodione, 11 deoxy cortisol and DHEA were normal. MRI abdomen was suggestive of absent uterus, ovaries, vagina with left testis in left inguinal ring and right testis in right deep inguinal ring. Her karotyping was 46XY. Conclusion: Our patient was 46XY DSD, female phenotype, elevated gonadotropins, low testosterone, normal intermediates and without atrophic testis, suggestive of leydig cell hypoplasia.

Keywords: Disorders of sexual development, leydig cell hypoplasia

   Epidemic of Polycystic Ovary Syndrome (PCOS) among Indian women: A cross-sectional questionnaire-based survey Top

Danendra Sahu, Aafia Rashid, Nishat Fatima, Ishfaq A. Wani, Gul Mehraj, Garima Rana1, Mohd A. Ganie

Department of Endocrinology, Sher-i-kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, 1Department of Endocrinology, All India Institutes of Medical Sciences (AIIMS), New Delhi, India.

E-mail: [email protected]

Background: Estimates of prevalence of PCOS in Asian women ranged from 3.9-22.5%. Few studies have reported the prevalence of this disorder in Indian communities and the variation in prevalence is remarkable. Objectives: This study was conducted to estimate the prevalence of PCOS among women in Kashmir valley. Materials and Methods: Eligible women in the age group 15 to 40 years from various educational institutions were screened through a brief questionnaire in a staged manner. Using a multistage random selection process involved selection, 5 out of 12 districts in turn housing 14 educational institutions having total of 3300 eligible subjects were included. After obtaining a written informed consent,418 subjects underwent detailed clinical (menstrual details, quantitation of hair growth, severe acne, weight gain, drug intake, anthropometry, FG scoring etc.), biochemical (liver, kidney functions, lipids), hormonal (T4, TSH, PRL, LH, FSH and total testosterone) and sonographic evaluation to satisfy Rotterdam 2003 criteria. The subjects were also evaluated using NIH and AE-PCOS criteria. Results: Out of a total of 3300 eligible women, 962 women were evaluated using a structured questionnaire. Among these 446 (46.4%) were identified as 'probable PCOS' cases. Out of 171 probable PCOS women who completed all biochemical, hormonal and sonologic assessment, 35.3% qualified a diagnosis of PCOS using Rotterdam criteria. The prevalence of PCOS was 28.7% by NIH criteria, and 34.2% by AE-PCOS criteria. Conclusion: The prevalence of PCOS is high among Kashmiri women and is probably the highest in published series globally. A countrywide systematic prevalence study is warranted to reconfirm the findings.

Keywords: AE-PCOS criteria, NIH criteria, prevalence, Rotterdam criteria

   Evaluation of pregnanediol glucuronide levels in three urine samples to assess ovulatory status and corpus luteum deficiency Top

M. I. Khatkhatay, M. Desai, S. Kadam, S. C. Vadakhathil1, S. Balakrishnan2, B. S. Lakshami2

ICMR-National Institute for Research in Reproductive Health, J M Street, Parel, Mumbai, Maharashtra, 1NIRRH Field Units, 2SAT Hospital, Thiruvananthapuram, Kerala, India.

E-mail: [email protected]

Aim: To compare interpretations based on pregnanediol glucuronide (PDG), a urinary metabolite of progesterone (P), with those based on serum P levels and ovarian ultrasonography (OU) in the diagnosis of ovulatory disorders. Materials and Methods: PDG was estimated by indigenous kit in 3 mid luteal phase urine samples (3MLPS) obtained from 25 women attending infertility clinic. Ovulation status and corpus luteum function was confirmed by OU and serum P levels measured thrice during the cycle. PDG levels in urine were expressed as μg/mg Creatinine content (μg/mgC). Based on values established previously, a sum PDG values in any 3 MLPS ≤8μg/mgCwas considered as indicative of anovulation whereas values ranging between 8-16 μg/mgC were considered as cycles with corpus luteum deficiency (CLD) and value ≥16 μg/mgCwas considered cycles with corpus luteum adequacy (CLA). Results: 21 cycles were ovulatory and 4 cycles were anovulatory. In 20 out of 21 ovulatory cycle, sum of 3 MLPS PDG values were >8 μg/mgC indicating occurrence of ovulation and 3 out of 4 anovulatory cycles these values were ≤8 μg/mgC and indicated anovulation. Thus PDG test gave sensitivity of 95.24%, specificity of 75% and accuracy of 92%. Urinary MLP PDG values (>17 μg/mgC) were indicative of CLA in 10 out of 12 cases in all CLD cases PDG levels were ≤17 μg/mgC giving sensitivity of 100%, specificity of 81.82% and accuracy of 90.48. Conclusion: Estimating PDG in 3 MLPS for detection of occurrence of ovulation and assessment of CLD is adequately reliable and is cost effective and patient friendly.

   Pediatric and Adolescent Endocrinology Top

   Rare case of anemia with Endocrinopathies: Fanconi's Anemia Top

Jaideep Khare, Prachi Srivastava1, Prasun Deb2

Departments of Medicine, 1Dermatology, MGM Medical College, Mumbai, Maharashtra, India, 2Department of Endocrinology, Krishna Institute of Health Sciences, Secunderabad, Telangana, India.

E-mail: [email protected]

Fanconi Anemia is a rare chromosomal disorder characterized by congenital, hematological and endocrine disorder. We hereby report a rare case of Fanconi Anemia with multiple endocrinopathy. A 12-year-old boy, resident of Hyderabad, born of non- consanguineous marriage presented with complains of not gaining weight and height, progressively increasing pigmentation all over body since 2 years, generalized weakness and easy fatigability since 3-4 months. Had history of bilateral cataract surgery at the age of 2 years. Rest in history was not significant. On general examination his vitals were stable, height and weight were below 3rd percentile with upper to lower segment ratio of 0.93. He had low set ears, retrognathia, acanthosis nigricans, cafe au late spot, generalized hyperpigmentation with few hypopigmented spots. On systemic examination he had mild hepatomegaly and rest was within normal limit. On Investigations CBC showed severe anemia with hemoglobin of 6.4 mg/dl and retic count of 0.6%. His blood sugars were high with fasting 247 mg/dl and post lunch 326 mg/dl. Thyroid profile was deranged with TSH of 64 IU/L. Bone marrow showed hypocellular bone marrow with suppressed erythromegakaryopoisis. Initially for high blood sugars insulin therapy was used but later well maintained on metformin. Hematenic and thyroxine replacement was started. Diagnosis of Fanconi Anemia was suspected which was confirmed by chromosomal fragility analysis and patient was advised for bone marrow transplantation. Thus we would like to present this case for its rarity and raise the index of suspicion of Fanconi's Anemia in patients presenting with pancytopenia with endocrine abnormalities.

Keywords: Diabetes, Fanconi's Anemia, hypothyroidism, short stature

   A rare case of Liddle syndrome with hypercalciuria and nephrocalcinosis Top

Aashish R. Bande, Pramila Kalra

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Background: Liddle syndrome is a rare cause of secondary hypertension. It is characterised by early onset, hypertension, hypokalemia, metabolic alkalosis, low plasma renin activity and hypoaldosteronism. We report a rare case of Liddle syndrome, associated with medullary nephrocalcinosis and hypercalciuria. Case Report: A 16 year old boy presented with uncontrolled hypertension not responding to amlodipine 5 mg BD, prazosin 5 mg OD and spironolactone 50 mg BD. On examination his blood pressure was 170/110 mm of Hg. Investigations showed serum sodium of 142 meq/l, serum potassium of 1.61 meq/l. ABG showed metabolic alkalosis. Serum creatinine was 1.1 mg/dl. Urine potassium was 28.1 meq/l. Serum aldosterone was 2.17 ng/ml, plasma direct renin was 3.20 uIU/ml. Abdominal CT scan showed normal adrenal glands with medullary calcification in both kidneys. His 24 hour urinary calcium was 160.6 mg/24 hr and urine calcium creatinine ratio was 5.44 mg/kg/day. The patient was started on amiloride. On follow up patients BP was 98/70 mm Hg and serum potassium was 3.6 meq/l. Discussion: In view of hypertension with metabolic alkalosis, hypokalemia, hyporeninemic hypoaldosteronism with normal adrenal glands on CT, diagnosis of Liddle syndrome was considered. Therapeutic response to amiloride and lack of any response to spironolactone strongly favoured the diagnosis of Liddle syndrome. This patient had hypercalciuria and evidence of medullary nephrocalcinosis on abdominal CT scan which is very rare. Conclusion: Hypercalciuria and medullary nephrocalcinosis is very rarely seen in Liddle syndrome and is not reported from India till now.

Keywords: Hypercalciuria, Liddle syndrome, medullary nephrocalcinosis

   Clinical heterogeneity in noonan syndrome - A case series Top

Ashu Goyal, Pranab Kumar Sahana, Nilanjan Sengupta, Arjun Baidya, Soumik Goswami, Rahul Valsaraj

Department of Endocrinology, N.R.S. Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: Noonan Syndrome is a rare, autosomal dominant disorder (prevalence of 1 in 1000-2500) characterized by short stature, facial dysmophism, congenital heart defects and urogenital malformations. Ocular changes occur in 95% of patients and usually include hypertelorism, ptosis, refractive errors, strabismus, amblyopia, rarely nystagmus, colobomas. NS is a RASopathy, caused by a disruption of RAS-MAPK signaling pathway (most common gene PTPN11 on chromosome 12). Aims and Objectives: To study the varied clinical presentation of patients with Noonan syndrome. Material and Methods: Four patients who presented to our department between July 2017-July2018 were subjected to a complete history and physical examination, biochemical, hormonal investigations and imaging along with karyotype. Results: (male:female ratio 3:1). Age of presentation was between 8-15 year (mean age: 11.25 years). Short stature (mean HtSDS: - 2.19) and craniofacial dysmorphic feature were the commonest clinical presentation. All the patients had facial dysmorphism with, hypertelorism, short neck, low set ears, dental overcrowding with malocclusion and high arch palate. Out of the four, low (n = 2), pectus excavatum (n = 2) and carinatum (n = 1), ptosis (n = 2) strabismus (n = 1). MRI pelvis intelligence (n = 3), pterigium colli (n = 2), wide carrying angle (n = 2), kyphoscoliosis (n = 2) cryptorchidism (could not localize the gonads in two patients who had cryptorchidism. Bone age was delayed in all the patients. one patient had severe pulmonary stenosis and one had mild pulmonary regurgitation. Karyotype was normal in all the patients. Conclusion: This series reflects the importance of phenotypic variability in patients of noonan syndrome. craniofacial dysmorphism and pectus deformities are the tellale sign of noonan syndrome.

Keywords: Cryptorchidism, noonan syndrome, pectus deformities, short stature

   A rare case of male precocious puberty Top

Geena S. George, P. K. Jabbar, C. Jayakumari, Abilash Nair, Nandini Prasad

Department of Endocrinology, Government Medical College, Thiruvananthapuram, Kerala, India.

E-mail: [email protected]

Introduction: Familial male precocious puberty is a form of isosexual precocious puberty with an autosomal dominant inheritance although sporadic cases have been reported. The pathogenesis is due to a heterozygous mutation in the gene that encodes the LH receptor resulting in its constitutive activation resulting in autonomous sex steroid secretion and early pubertal development. Case Report: We report a case of 7 year old male child whose chief complaints were penile enlargement for past 1 year, change in voice and pubic hair growth for past 3 months and priapism for 2 months with rapid increase in height and weight. He didn't have headache, cold intolerance, hypersomnolence, fractures, bony swelling or inadvertent drug exposure. No family history of neonatal death, abortion, infertility or short stature. Father and elder brother had history of early penile enlargement. On examination child has a masculine habitus with no thyromegaly, café – au –lait macule, or bony swelling. Height was 126 cm (75th centile) and weight 20 kg (75th centile). Size of testis was 4 ml bilaterally with a stretched penile length of 12 cm with glans and pubic hair stage 2. Routine blood investigations were normal. Hormonal analysis showed the following results. S. Testosterone- 8.8 ng/ml (0.03-0.32), Lh -<0.1 uiu/ml (<0.3), Fsh- 0.31 uiu/ml (1.5-12.4), 17 OHP – 1.43 ng/ml (0.07-1.7), DHEAS – 41.18 uiu/ml, 8 am cortisol – 5 ug/dl, Dexamethasone suppression test - 0.5 ug/dl, Beta HCG – 15 uiu/ml (<3), AFP – 0.70 ng/ml (<3). MRI brain, CT chest and abdomen and USG testis were normal. Patient was started on Tab. Bicalutamide 50 mg and Tab. Letrozole 2.5 mg once daily to arrest the pubertal progression and epiphyseal closure.

Keywords: Bicalutamide, familial male limited precocious puberty, letrozole

   Clinical and hormonal profile of 46 XY DSD Top

Riyas RS, Nilanjan Sengupta, Pranab K. Sahana, Arjun Baidya, Saumik Goswami

Department of Endocriology, NRS Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Disorders Of Sexual Development (DSD) can have a wide range of presenting phenotypes depending on the underlying condition and its severity.Defects in androgen production or action lead to the formation of hormone-dependentDSD, consisting of lack of virilization, without persistence of Mullerian derivatives inpatients with a Y chromosome. Diagnosis and subsequent management of these patients depends on the cause of DSD, degree of feminisation, age at presentation and gender orientation. Aims and Objectives: To find out the aetiology of androgen synthesis and action in patients of 46 XY DSD. Materials and Methods: All patients of 46 XY DSD attended the endocrinology department NRS Medical College (May 2016-July 2018) included in this study. Clinical examination, hormonal and karyotype analysis were done to identify the cause. Results: Among 20 patients, 10 patients (50%) are found to have 5 alpha reductased efficiency, 6 patients (30%) were 17 beta HSD type 3 deficient and remaining 4 patients (20%) were partial androgen insensitivity syndrome. Mean age at presentation was 4 years. 16 patients (80%) had micropenis, 15 patients (75%) presented with hypospadias. 10 patients had cryptorchidism. Conclusion: 5 alpha reductase was the most common cause followed by 17 beta HSD in our patients.

Keywords: 5 alpha reductase, DSD, hypospadias

   Profile of karyotyping variability in Turner syndrome – A Single centre study Top

Kadiyala Hinduja, B. Vivekananda, A. Mythili, Jayanthy Ramesh, K. A. V. Subrahmanyam

Department of Endocrinology, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India.

E-mail: [email protected]

Aim and Objectives: To study the clinical profile of Turner syndrome based on the karyotype. Materials and Methods: 12 cases of karyotype proven Turner syndrome who attended the Department of Endocrinology, King George Hospital, Andhra Medical college from June 2016 to May 2018 were studied. Results: Out of 12 cases – 5 had Classic Turner karyotype, 7 had Mosaic karyotype. In mosaic group 2 had isochromosome, 2 had inversion, 1 had 46 × x mosaic, 1 had deletion, 1 had heterodimerization. Mean age of presentation was 14.27 years. Mode of presentations were Short stature 41.6% (n = 5), Delayed puberty 33.3% (n = 4) and both 25% (n = 3). In mosaic – most common presentation is delayed puberty, two had primary hypothyroidism and median TSH level was lower than classic turner. One had horse shoe kidney, one had foveal aplasia, two had deafness, five had hypoplastic uterus and ovaries, two are receiving growth hormone treatment. No one had spontaneous puberty. Conclusion: Clinical profile of Turner syndrome is varied among various karyotypes.

Keywords: Hypothyroidism, karyotype, mosaic, turner

   Newborn 17OHP screening-an institutional review Top

Leena Priyambada, Nalinikant Panigrahy, Rohit Kariappa1

Rainbow Children's Hospital, Hyderabad, Telangana, 1Neogen Labs, Bengaluru, Karnataka, India.

E-mail: [email protected]

Background: 17hydroxyprogesterone 17OHP levels has been used for congenital adrenal hyperplasia screening in newborns in many parts of the world. The need for 17OHP screening has been debated, and the screening cut-offs have been debated. Indian population studies are practically non-existent. Aims: To review newborn 17OHP levels in a tertiary care hospital across various gestational and birth weight categories of Indian babies. Materials and Methodology: Retrospective data for newborns related to 17-OHP screening for 2 years (2016-2018) was analysed. Results: Data for 6634 (54% males) babies was analysed. The mean 17OHP value was 4.41 ± 5.92 ng/ml. The mean age of gestation was 37.7 ± 1.7 weeks (23-43 weeks, 15% preterm). The mean birthweight was 2926.64 ± 522.764 gms (600-4998 gms, 17% <2500 gms). The mean day of sampling was 4.4 ± 5.9 days. A single cut-off of 20 ng/ml was used to report abnormal results. 3 babies were true positives and 10 babies were false positive. 9/10 babies who were false positive were preterm. Gestational age and birth weight were inversely related and between-group analysis in various categories of weight and gestation were statistically significant. 99 percentile of 17OHP values gestational age-wise, birth weight-wise according to day of sampling is presented. Conclusions: Birth weight and gestational age have a significant influence on the newborn 17OHP values and appropriate screening-cut offs need to be designed.

Keywords: 17OHP, congenital adrenal hyperplasia, newborn screening

   A clinical, auxiological and radiological profile of 12 growth hormone deficiency children Top

M. Madhu Babu, B. Vivekanand, A. Mythili, Jayanthy Ramesh, K. A. V. Subrahmanyam

Department of Endocrinology, Andhra Medical College, King George Hospital, Visakhapatnam, Andhra Pradesh, India.

E-mail: [email protected]

Background: Growth hormone deficiency is one of the important and treatable endocrine causes of severe short stature in children. Knowing the varied presentations of growth harmone deficiency in respect to clinical and anthropometric variates and radiographic correlation by MRI sella is of paramount importance. Aim: To delineate anthropometric, clinical and radiographic presentation of GH deficiency affected children. Materials and Methods: 12 GH deficiency children with age ≤12 years, diagnosed from January 2017 to May 2018, at King George Hospital, Visakhapatnam. Their anthropometric data was collected. All have undergone ITT for the diagnosis along with other hormone evaluation. X-ray of left hand for bone age and Mri sella was performed in all patients. Results: Mean age of study group is 8.6 years. Out of the 12 children 6 had isolated GH deficiency and 6 had panhypopituitarism (hypocortisolism plus GH deficiency). Mean height SDs of isolated GH deficiency was −4.2, and −3.9 in panhypopituitarism children. Mean bone age in isolated GH deficiency group was 4.5 years while 5.1 years in panhypopituitarism group. Mean peak stimulated serum GH value in isolated GH deficiency group was 2.04 ng/dl vs 1.70 ng/dl in panhypopituitartism group. 2 children had anterior pituitary hypoplasia and one had J shaped sella on MRI. Conclusion: These findings suggest that when compared with isolated GH deficiency, children with panhypopituitarism had a low GH reserve and had a lower mean height sds and majority of study group had normal pituitary imaging.

Keywords: GH deficiency, MRI sella, HT SDs, bone age, panhypopituitarism

   Hypertriglyceridemia in hypernatremia: Coincidence or consequence?? Top

Ganesh Namani, Rakesh Sahay, K. Neelaveni

Department of Endocrinology, Osmania Medical College, Hyderabad, Telangana, India.

E-mail: [email protected]

Introduction: Hypertriglyceridemia in children can be hereditary or secondary to other disorders. It is usually associated with apparently low serum sodium levels/Pseudohyponatremia. Rarely Hypertriglyceridemia can occur as a consequence of high serum sodium levels as reported rarely by few authors. Case Report: 18 month male child was brought with history of recurrent respiratory tract infections and failure to thrive. He was diagnosed to have hypertriglyceridemia at the age of 8 months and was on Omega 3 fatty acids and Medium chain triglycerides since then. His Triglycerides decreased from initial level of 1200 mg/dl to 700 mg/dl at current admission. Child had polyuria and polydipsia with 3 litres of urine output/day. Sodium was 170 meq/l and serum osmolality was 350 mosmol/l with urine osmolality of 80 mosmol/l. Desmopressin nasal spray was tried without any success. MRI brain showed normal posterior pituitary bright spot and normal pituitary stalk without any other abnormality. Child has been started on hydrochlorothiazide and serum sodium decreased to 140 meq/l and urine osmolaity increased to 180 mosmol/l after 2 weeks. Child is stable and accepting feeds normally now. His triglyceride level also decreased to 270 mg/dl without omega 3 fatty acids and medium chain triglycerides for 1 month. The possible link between high sodium levels and hypertriglyceridemia will be discussed. Conclusion: Serum sodium levels should be assessed in children with high Triglyceride levels. Presence of high sodium levels indicate that hypernatremia could be the cause for Hypertriglyceridemia and it should be treated promptly with appropriate evaluation of underlying cause which would resolve the lipid abnormality without the need for other medication.

Keywords: Consequence, hypernatremia, hypertriglyceridemia

   References Top

  1. Ben-Amitai D, Rachmel A, Levy Y, Sivan Y, Nitzan M, Steinherz R. Hypodipsic hypernatremia and hypertriglyceridemia associated with cleft lip and cleft palate: A new hypothalamic dysfunction syndrome? Am J Med Genet 1990;36:275-8.
  2. Crook M, Robinson R, Swaminathan R. Hypertriglyceridemia in a child with hypernatremia due to a hypothalamic tumor. Ann Clin Biochem 1995;32:226-8.
  3. Hayek A, Bryant PD, Wooside WF. Hypernatremia induces hyperlipidemia and fatty liver. Metabolism 1983;32:1-3.

   Secular trends in age at menarche in an Indian population: An observational study Top

Sphoorti P. Pai, Vageesh Ayyar, Ganapathi Bantwal, Belinda George, Nandhini L. P

Department of Endocrinology, St John's Medical College, Bangalore, Karnataka, India.

E-mail: [email protected]

Introduction: Attainment of menarche sets a major milestone in a woman's life. It is the prime indicator of reproductive capability in females. It is multifactorial, with influences noticed even from prenatal period in a female. Even though it seems rather simple, there are very few studies examining the possible factors involved in the same. To name a few factors responsible: - maternal age at menarche, socioeconomic status, diet, exercise, prenatal growth, birth size, BMI etc., Earlier age at menarche has following consequences-Increased risk of future breast cancer: Social reasons including mismatch between mental age and physical maturity leading to problems such as teenage pregnancy, sexual abuse, suicide rates. Aim of our Study: 1) To assess relationship of factors such as maternal age at menarche, socioeconomic status of family, anthropometric measures of subjects, birth order, birth weight. 2) To assess whether secular trend is a reality among Indian population. Materials and Methods: It is questionnaire based observational study. The questionnaire includes - age at menarche; number of siblings and birth order; height, weight; maternal age at menarche, daughter's age at menarche; family income; educational qualification. The questionnaire would be allotted randomly to females in our hospital falling within the inclusion criteria which they would self-report. Results: Average age of menarche in daughters was 13.35 ± 1.53 years. Average age of menarche in mothers was 13.76 ± 1.68 years. However on comparing, though average age of daughters was lesser than mothers' age of menarche, P value was 0.07 which was not statistically significant. On correlating mothers age with daughters' age of menarche r = 0.26 showing weak correlation. On correlating other parameters, also showed correlation which was weak. Conclusion: There was a reduction in the age of menarche of daughters compared to mothers, however it did not reach statistical significance.

   Bone and Mineral Metabolism Top

   Tumor induced osteomalacia and primary hyperparathyroidism - A rare coexistence Top

Arpit Garg1, Mohammad S. Kuchay1, Sunil K. Mishra1, Alka A. Singhal2, Ambrish Mithal1

1Division of Endocrinology and Diabetes, 2Department of Radiology, Medanta the Medicity Hospital, Gurugram, Haryana, India

E-mail: [email protected]

Objective: We aimed to present a rare case of tumor-induced osteomalacia (TIO) and primary hyperparathyroidism (PHPT) existing in a same patient. Materials and Methods: We report clinical features, laboratory parameters and imaging studies of the patient, before and after surgical excision of the parathyroid lesion and radiofrequency ablation of the TIO culprit lesion. Results: A 62-year-male presented with severe bony and muscle pains for the past one year along with proximal muscle weakness. Biochemical profile revealed hypophosphatemia, phosphaturia, elevated parathyroid hormone (PTH) and serum total albumin-corrected calcium in upper range of the normal limit. A diagnosis of normocalcemic PHPT was made. Imaging revealed left inferior parathyroid lesion. The lesion was excised. Intraoperative PTH declined significantly and histopathology confirmed parathyroid adenoma. At 6-months follow-up, persistence of partial symptoms, hypophosphatemia and renal phosphate wasting raised the suspicion of another coexisting phosphaturic condition. Ga68 DOTANOC imaging and; histopathology and immunohistochemistry revealed mesenchymal tumor of mixed connective tissue variant in right ramus and angle of mandible. Radiofrequency ablation of the same lesion led to resolution of clinical symptoms and phosphate abnormality. Conclusions: The co-existence of PHPT and TIO is a rare occurrence. The diagnosis and management of the patient could be challenging. High index of suspicion is needed to diagnose these conditions in the same patient.

Keywords: Oncogenic osteomalacia, radiofrequency ablation, phosphatonin, renal phosphate wasting, tumor induced osteomalacia

   Tumor induced hypophosphatemic osteomalacia Top

Chandar M. Batra, Savita Jain, Sandip Uphadhya, Vikram Pratap Singh

Departments of Endocrinology, Rheumatology and Oncosurgery, Indraprastha Apollo Hospital, New Delhi, India.

E-mail: [email protected]

Tumor induced osteomalacia is a rare paraneoplastic syndrome caused by small usually benign endocrine tumors that secrete phosphaturic hormones FGF23. The biological hallmarks of this syndrome are severe hypophosphatemia due to renal phosphate wasting, normal or low 1,25(OH) 2 vitamin D and elevated FDF23 levels. Aims and Objectives: To describe the clinical, biochemical, radiological and pathological parameters of a case of hypophosphatemic osteomalacia which was due a small mesenchymal maxillary tumor on the left side. Case Report: Our patient was a 23 years old male from Kashmir who came on a wheel chair, presenting with bony pains and proximal myopathy, hypophosphatemia (serum phosphorous 1.2-1.4 mg/day), 24 hours urinary phosphate of (165-171 mg/day), TMP/GFR 1.04. PET-CT revealed a small FDG avid tumor in the left maxilla [Figure 1]. The patient was operated a left maxillectomy was done and the tumor removed with a wide rim of normal tissue. The patient showed remarkable improvement. The phosphorous levels normalized in 1 week and the patients muscle strength improved gradually to normal within a month of surgery.
Figure 1: PET CT of the patient histological slides of the tumor

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Keywords: Hypophosphatemia, phosphaturia, tumor osteomalacia, F9F23

   Functional hypoparathyroidism in Vitamin D deficient type 2 diabetics-effect on bone health Top

Savita Jain, Chandar Mohan Batra1

Department of Endocrinology, Deep Hospital, Ludhiana, Punjab, India, 1Department of Endocrinology, Indraprastha Apollo Hospital, New Delhi, India.

E-mail: [email protected]

We studied the status of intact parathyroid hormone levels and the parameters of calcium homeostasis and effect on bone health in vitamin D deficient type 2 diabetic subjects. Objectives of the Study: To find proportion of patients having functional hypoparathyroidism in vitamin D deficiency, compare bone mineral density and assess the role of smoking, alcohol, obesity, HbA1c and physical activity in patients having functional hypoparathyroidism versus secondary hyperparathyroidism. Materials and Methods: The study was conducted in a tertiary care hospital. 65 type 2 diabetic patients were enrolled. Detailed history and physical examination was done. Serum calcium (and albumin), phosphorus, alkaline phosphate, 25(OH) D, magnesium, parathyroid hormone levels, HbA1c and 24 hour urine calcium and phosphorus were measured for all the patients. Observation and Results: Vitamin D deficiency was common in the population studied. The proportion of patients having functional hypoparathyroidism was 43% and secondary hyperparathyroidism was 57%. Baseline mean age, sex distribution, duration of diabetes mellitus, treatment being taken, HbA1c levels and 25(OH) D levels in two groups were not statistically different. Both the groups were similar with respect to serum calcium, phosphorus, magnesium, history of fractures and physical activity score. There was no difference in both the groups in terms of number of patients having osteopenia or osteoporosis. Conclusion: Functional hypoparathyroidism, though common in vitamin D deficiency in type 2 diabetic patients as shown in the study, is not protective for bone health. There is no relation of parathyroid hormone response with smoking, alcohol, obesity, HbA1c and physical activity.

Keywords: Bone health in type 2 diabetes, functional hypoparathyroidism, vitamin D deficiency

   An interesting and rare case of short stature Top

Dwijaraj G. Hegde, Beena Bansal, Ganesh Jevalikar, Jai P. Sharma1, Ambrish Mithal

Division of Endocrinology and Diabetes, 1Department of Radiology, Medanta The Medicity Hospital, Gurugram, Haryana, India.

E-mail: [email protected]

Objective: We aimed to present a rare and interesting case of short stature – a case of skeletal dysplasia. Materials and Methods: We report clinical features, laboratory parameters and imaging studies of the patient. Results: 22 yrs old hailing from Iraq, born out of non – consanguinous marriage, referred from neurosugery OPD with past history of operation for nasal obstruction and gamma knife therapy for CNS tumor in 2010, for evaluation of skeletal lesions. His chief complaints were bleeding from skin lesions over chest and difficulty swallowing. Family history was significant, his great grand father had similar complaints. On examination patient had short stature, scoliosis (convexity to left), ankylosis of elbow joints, limb Length discrepancy (L > R), multiple hemangiomas all over the body, fibroma over right wrist, large fingers and toes. Skeletal survey showed enchondromas in both short bones and long bones, scoliosis. Laboratory investigations were unremarkable except elevated PTH level. Genetic analysis was done which confirmed maffucci syndrome.Conclusions: Maffucci syndrome is rare cause of short stature and skeletal dysplasia.

Keywords: Eenchondroma, fibroma, hemangioma, maffucci syndrome

   Response to zoledronic acid in patients with active Paget's disease of bone in a tertiary care centre – A retrospective study Top

Harsh Durgia, Rajan Palui, Kalyani Sridharan, Henith Raj, Jayaprakash Sahoo, Sadishkumar Kamalanathan

Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry, India.

E-mail: [email protected]

Aims and Objectives: The objective of this study was to retrospectively analyze the effect of intravenous zoledronic acid in 13 patients with this condition in a tertiary care center of South India. Materials and Methods: Retrospective data of 13 patients with active Paget's disease of bone who received intravenous zoledronic acid at our institute from January 2011 to June 2017 was reviewed. Response to therapy was monitored clinically, biochemically by serum alkaline phosphatase (ALP) and scintigraphically by 99m-Technetium methylene diphosphonate bone scan. Results: Bone pain was relieved in all the patients. Serum ALP levels reduced significantly from 1190.9 ± 666.1 IU/L (n = 13) at baseline to 200.5 ± 68.4 IU/l (n = 13) at 6 months (P < 0.001). ALP level at 1 year was 174 ± 33.6 IU/L (n = 12) which remained stable till 36 months at 176.5 ± 50 IU/L (n = 8). This indicates that remission achieved by 6 months post zoledronic acid was sustained for at least 3 years. Scintigraphic ratio (SR) reduced from 9.6 (interquartile range 5.25-18.2) at baseline to 2.7 (interquartile range 1.20-4.05) at follow-up (P < 0.001). Similarly, scintigraphic index of involvement (SII) reduced from 9.9 (interquartile range 5.6-28.5) at baseline to 3 (interquartile range 2-4) at follow-up (P = 0.018). Two of our patients had stress fractures which healed with single dose of zoledronic acid. Conclusion: A 4 mg single dose of intravenous zoledronic acid results in clinical, biochemical and scintigraphic response that is sustained for at least 3 years.

Keywords: Bisphosphonates, Paget's disease of bone, zoledronic acid

   Primary hyperparathyroidism presenting as metatstatic bone disease: Case report Top

Debasish Patro, Swayam Sidha Mangaraj, Arun Kumar Choudhury, A. K. Baliarsinha

Department of Endocrinology, SCB Medical College and Hospital, Cuttack, Orisa.

E-mail: [email protected]

Objectives: Multiple osteolytic lesions are usually associated with metastatic involvement of the bone, however, metabolic bone diseases should also be included in the differential diagnosis. We report a case of primary hyperparathyroidism presenting as metatstatic bone disease. Materials and Methods: A 50 year old female who was evaluated for pain in b/l thigh region and limping gait for 15 days. She was evaluated for her complains and found to have multiple osteolytic lesions that was diagnosed initially as having metastatic bone involvement by FDG PET Scan. After ruling out the causes of multiple lytic lesions and proper skeletal survey, imaging, biochemical, hormonal assay, a diagnosis was reached. Results: Skeletal survey revealed multiple osteolytic lesions and brown tumors in long bones, ribs and pelvic bones. The laboratory results showed hypercalcemia and raised alkaline phosphatase, normal serum protein electrophoresis. The parathyroid hormone levels were high, which pointed toward a diagnosis of PHPT. USG of Neck revealed hypocellular lesion of noted posteromedial to right lobe of thyroid with internal vascularity. Sestamibi scan revealed uptake at the level of the right upper and left upper parathyroid region suggestive of adenoma. Based on these findings diagnosis of Primary hyperparathyroidism due to b/l parathyroid adenoma was made. Conclusion: The possibility of hyperparathyroidism should be kept in mind when a patient presents with multiple osteolytic lesions and hypercalcemia.

Keywords: Brown tumors, multiple osteolytic lesions, primary hyperparathyroidism

   Inadequate awareness about osteoporosis among postmenopausal South Indian women Top

Senthil Raja, H. S. Asha, Nitin Kapoor, Thomas V. Paul

Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India.

E-mail: [email protected]

Background: Osteoporosis has emerged as a common health problem in postmenopausal women (PMW). Awareness about osteoporosis and its consequences in PMW improves preventive measures and adherence to treatment. Aims: This study was undertaken to assess the level of awareness about osteoporosis in South Indian PMW using the Osteoporosis Knowledge Assessment Tool (OKAT). Subjects and Methods: This was a cross sectional study of 302 consecutive PMW referred for assessment of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) at a tertiary care centre in Southern India. The OKAT questionnaire was administered by a technician. Those who answered >50% of the questions correctly were considered to have adequate knowledge about osteoporosis. Results: Mean (SD) age of the subjects included in this study was 58.8 (±6) years. The mean age of menopause was 46 (±5.5) years, mean BMI was 27.05 (±5.2) kg/m2. One hundred and six subjects (35%) were found to have osteoporosis at any site. On average, 42% of the questions (8.3/20) were correctly answered. Only 50 out of 302 (16%) PMW had adequate knowledge about osteoporosis. Conclusions: A large proportion of postmenopausal Indian women have insufficient awareness and knowledge about osteoporosis. This study emphasizes the need to improve awareness about osteoporosis among them through education via mass media and risk based individual education to recognize and manage osteoporosis appropriately to prevent fragility fractures.

Keywords: Bone mineral density (BMD), dual-energy X-ray absorptiometry (DXA), osteoporosis knowledge assessment tool (OKAT), postmenopausal women (PMW)

   Utility of trochanter Bone Mineral Density for the diagnosis of postmenopausal osteoporosis in subjects with or without femoral neck fracture – A cross-sectional study from southern India Top

Shivendra Verma, H. S. Asha, Thomas V. Paul, Nitin Kapoor

Department of Endocrinology, Diabetes and Metabolism, Christian Medical College, Vellore, Tamil Nadu, India.

E-mail: [email protected]

Background: Hip Bone Mineral Density (BMD) is a known predictor of major osteoporotic fracture; however its measurement may be inaccurate due to degenerative changes in the joints or artefacts from metallic implants. Objectives: To assess the agreement between BMD measurements among different sites- femoral neck, trochanter and total hip in postmenopausal women with or without hip fracture. Materials and Methods: This was a cross-sectional study of 674 postmenopausal women including thirty-two women with fracture at femoral neck who underwent dual energy X-ray absorptiometry (DXA) scan for assessment of BMD at the hip and lumbar region at a South Indian tertiary care institution. Agreement between different sites was estimated using kappa statistic. Results: The mean (SD) age of subjects was 60.3 ± 7.1 years. The prevalence of osteoporosis was 24.4%, 14.83%, 15.1% at the femoral neck, trochanter and total hip respectively. There was almost perfect agreement between trochanter and total hip for the diagnosis of osteoporosis in fracture subjects (kappa = 0.9) but it was only moderate in non-fracture subjects (kappa = 0.7), agreement between trochanter and neck of femur was weak in subjects with and without fracture (kappa = 0.5 and 0.4). The agreement was moderate between total hip and femoral neck in fracture subjects (kappa = 0.6). Conclusion: An almost perfect agreement observed in this study between trochanter and total hip in subjects with hip fracture may suggest the utility of trochanter BMD in prediction of hip fracture when total hip BMD cannot be interpreted.

Keywords: Bone mineral density (BMD), dual energy X-ray absorptiometry (DXA), postmenopausal women (PMW)

   Which is best for estimation of Hip BMD: Both or either hip? Top

Sindhu Sree Rallapalli, Sunanda Tirupati, M. V. Rama Mohan, Vijaya Sarathi, K. Dileep Kumar

Department of Endocrinology, Narayana Medical College and Hospital, Nellore, Andhra Pradesh, India.

E-mail: [email protected]

Background: ISCD recommends use of either hip bone mineral density (BMD) T scores for diagnosis of osteoporosis. Use of BMD in either hip may underestimate osteoporosis. Objectives: To compare the prevalence of osteoporosis or low BMD (osteoporosis or osteopenia) by using either hip versus both hips. Methodology: It is a cross sectional, retrospective study done at a tertiary care center. A total of 425 subjects underwent BMD testing at both hips during the previous 3 years, of whom 303 men aged more than 50 years and postmenopausal women were included in the analysis. Either femoral neck or total hip which had the lower BMD T score was used to define osteoporosis/osteopenia according to WHO criteria. For both hips, T score that was lower between right or left hip was used to define osteoporosis/osteopenia. Results: Using either hip there were 65 and 228 cases of osteoporosis and low BMD respectively. When compared to both hips prevalence of osteoporosis using right hip (100% vs 74.5%, P = <0.0001) or left hip (100% vs %, 81.5%, P = 0.0003) were significantly lower. Similarly, prevalence of low BMD (osteoporosis or osteopenia) were also significantly lower using right hip (100% vs 96.9%, P = 0.015) or left hip (100% vs 95.6%, P = 0.002) when compared to both hips. However, the prevalence of osteoporosis (P = 0.82) or low BMD (P - 0.6) were not significantly different between right and left hip. Conclusion: Use of either (right or left) hip alone would significantly underestimate BMD when compared to use of both hips.
Table 1: Comparison of BMD of right and left hip

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Keywords: Best site, BMD, hip

   Effect of using Ward's area and greater trochanter T scores on the prevalence of osteoporosis/osteopenia Top

Sindhu Sree Rallapalli, Sunanda Tirupati, N Rajendra Prasad, Vijaya Sarathi HA, Dileep Kumar

Department of Endocrinology, Narayana Medical College and Hospital, Nellore, Andhra Pradesh, India.

E-mail: [email protected]

Background: Use of Ward's area and greater trochanter T scores are considered to overestimate the prevalence of osteoporosis or low BMD (osteoporosis or osteopenia). Objective: To quantify the effect of using Ward's area and greater trochanter T scores on the prevalence of osteoporosis or low BMD in routine clinical practice. Materials and Methods: It is a retrospective study done at a tertiary health care center in South India. Database of DXA machine at our center was reviewed. A total of 425 subjects had undergone BMD testing at both hips during the previous 3 years of whom men aged more than 50 years and postmenopausal women (n = 303) were included in the study. The lower T score at femoral neck or total hip was used to define osteoporosis or low BMD as per the position statement by international society for clinical densitometry (ISCD). Results: In both right and left hips prevalence of osteoporosis and low BMD were significantly lower in total hip and significantly higher at Ward's area but were not significantly different at femoral neck than those diagnosed by ISCD criteria [Table 1]. At left trochanter both osteoporosis and low BMD were significantly lower but not different at right hip than those by ISCD criteria. Conclusion: Use of Ward's area T score overestimates prevalence of osteoporosis or low BMD but not the trochanter T score. Rather, trochanter T scores at left hip may underestimate osteoporosis and low BMD.
Table 1: Prevalence of osteoporosis, osteopenia and normal BMD at various sites of right and left hip

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Keywords: BMD, greater trochanter, Ward's area

   Effect of mislabelling T12 as L1 on prevalence of osteoporosis and osteopenia Top

Venkatarakesh Chintala, T. Sunanda, Vijaya Sarathi, P. Sudhakar Reddy, K. Dileep Kumar

Department of Endocrinology, Narayana Medical College and Hospital, Nellore, Andhra Pradesh, India.

E-mail: [email protected]

Introduction: Mislabelling of T12 as L1 has been showed to reduce L1-L4 BMD. However, the effect of such mislabelling on the L1-L4 BMD and prevalence of osteoporosis/osteopenia is not known. Objective: To study the effect of mislabelling of T12 as L1 on the L1-L4 BMD and prevalence of osteoporosis/osteopenia. Materials and Methods: It is a retrospective study done at a tertiary health care center in South India. Database of DXA machine at our centre was reviewed and BMD data of men aged more than 50 years and postmenopausal women who underwent BMD during the last 3 years was included in the analysis. A total of 498 subjects had undergone BMD testing at lumbar spine of whom images of the T12 and lower part of the T11 were available for 126 subjects. The BMD data of these subjects was noted. Later T12 was labelled as L1 and a new set of BMD data was collected. Results: L1-L4BMD (0.97 ± 0.186 vs 0.99 ± 0.18, P < 0.0001) and T-scores (−1.77 ± 1.48 vs − 1.59 ± 1.52, P < 0.0001) were significantly lower with mislabelling than correct labelling. Prevalence of osteoporosis (30.95% vs 27.7%, P = 0.88), and low BMD (71.43% vs 67.47%) were not significantly different between correct and wrong labelling. Inter-rater agreement between the two scenarios for the diagnosis of osteoporosis, osteopenia and normal BMD was substantiate (Cohen's Kappa coefficient: 0.772, P < 0.001). Conclusion: Mislabelling of T12 as L1 significantly reduces L1-L4 BMD but has no significant effect on the prevalence of osteoporosis or low BMD.

Keywords: L1, mislabelling, osteopenia, osteoporosis, T12

   Fanconi's syndrome: A case of refractory rickets Top

Chaitanya Konda, Vijay S. R. Danda, Srinivas Rao P, Krishna R. Thaduri

Department of Endocrinology, Gandhi Medical College/Hospital, Secunderabad, Telangana, India.

E-mail: [email protected]

Background: Fanconi's syndrome can be caused by various underlying congenital or acquired diseases and is characterised by various molecules being excreted in the urine instead of being reabsorbed from the proximal tubule (for example glucose, amino acids, uric acid, phosphate and bicarbonate). Inability to reabsorb HCO3 in the proximal tubule leads to urinary bicarbonate wasting, subsequent acidemia and hypokalemia. The loss of phosphate results in rickets (children) and osteomalacia (adults) because phosphate is necessary for bone development and bone metabolism. We present a case of Fanconi's syndrome presenting as hypophostemic rickets. Case History: A 9 year-old boy, presented with disproportionate short stature (-4SD), genu valgum deformity. He had delayed motor milestones. No significant family history. On evaluation, he was found to have hypophosphatemia and hypokalemia, hyperphosphaturia, glycosuria, aminoaciduria with elevated serum alkaline phosphatase. Serum calcium, 25(OH) vitamin D, intact PTH were within normal range. 24 hr urinary calcium was WNL. ABG analysis revealed metabolic acidosis with corresponding Urine pH of 5.0. Clinical and X-ray findings consistent with rickets. Treatment started with phosphorus, potassium citrate, calcitriol and bicarbonate replacement were done. Serum Alkaline phosphatase, potassium, phosphorus and bicarbonate levels reached the target goal with disappearance of X-ray signs of the active rickets. Linear growth improved. Conclusion: Fanconi's syndrome is one of important causes of refractory rickets. Early identification of disease will prevent the bone deformities and growth retardation.

Keywords: Fanconi, hypophosphatemic rickets, rickets

   VDDR type 2: A rare form of rickets Top

Madhavi Verpula, Vijay S. R. Danda, Sreedevi P, Chaitanya Konda

Department of Endocrinology, Gandhi Medical College/Hospital, Secunderabad, Telangana, India.

E-mail: [email protected]

Introduction: Vitamin D dependent type 2 rickets is a rare AR disorder. It is caused by end-organ resistance to calcitriol. 'Vitamin D Resistant Rickets' was first described by Albright et al., as a form of rickets requiring high doses of vitamin D for healing of rachitic changes. Spectrum of presentation varies widely, based upon residual vitamin D receptor activity. We present a case of Vitamin D Dependent Rickets type 2. Case History: 3-and-a-half-year-old child presented with irritability, constipation, pain and deformities of extremities. He has history of recurrent chest infection. He was 4th in birth order, born of non-consanguineous union. No similar history in family. On examination patient had latent tetany, bony deformities in the form of anterior bending of legs (saber shin), bowing of upper limbs, rachetic rosary. He had protuberant abdomen and alopecia. On investigation serum electrolytes, complete blood picture, ABG, LFT and Renal function tests were normal. He had low calcium level (6.9 mg/dl) and phosphorus levels (3.6 mg/dl), normal albumin levels and elevated alkaline phosphatase levels (1200 IU). 25 (OH) vit d level 30 ng/ml, Intact PTH level 134 pg/ml. 1,25(OH) Vit D level was highly elevated (185 pg/ml). Radiological changes are consistent with rickets. He was treated with high doses of calcitriol, calcium and Vitamin D3. Conclusion: Vitamin D Dependent Rickets Type II is rare form of disease, often fatal, with variable presentation and requires treatment with high doses of calcium and calcitriol. Severe cases may benefit with calcium infusions.

Keywords: Alopecia, rickets, VDDR type 2

   Multiple pathological fractures: A diagnostic dilemma Top

Saurav Shishir, Anirban Sinha, Asish Kumar Basu, Animesh Maiti, Chhavi Agrawal, Somnath Raghuvanshi, Sayan Ghosh

Department of Endocrinology, Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: We are reporting a case of Primary Sjogren's syndrome with distal renal tubular acidosis (RTA), presenting as hypokalemic paralysis and pathological fractures. All these features clustered together in a single case has rarely been described in literature. Case Report: A 30 year old female presented with bilateral thigh pain for last 8-9 months. She had an episode of quadriparesis 1.5 years back, treated with oral potassium. Examination was essentially normal except for an antalgic gait. Investigations revealed normal CBC, sodium - 139 mEq/L, potassium - 2.5 mEq/L, creatinine - 0.8 mg/dL, calcium – 8.4 mg/dL, phosphorus– 1.6 mg/dL, albumin -3.8 g/dl, ALP - 350 U/L. iPTH, Vitamin D and Thyroid function test were normal. ABG showed normal anion gap metabolic acidosis. Urinary pH was 6.5. Subsequently a diagnosis of distal RTA was made. USG abdomen was suggestive of nephrocalcinosis. Skeletal survey and CT Pelvis revealed fractures in left femoral metadiaphysis, inferior pubic rami, right femur neck and right 1st metacarpal [Figure 1], [Figure 2] and [Figure 3]. Schirmer test was < 5 mm in both eyes. Autoantibody profile revealed ANA – 4 + Coarse Speckled and positive anti SSA. Thus diagnosis of Primary Sjogren's syndrome (pSS) was made. She was started on Syrup Potassium citrate and citric acid combination and is under follow up. Discussion: Although Osteomalacia is a known complication of RTA associated with Sjogren's syndrome but patients presenting with multiple fractures as a first manifestation in pSS has rarely been reported. A high index of suspicion should be maintained in patients presenting with bone pains.
Figure 1: X-ray right hand showing linear undisplaced fracture of right 1st metacarpal base

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Figure 2: X-ray showing fracture in left femoral metadiaphyseal region

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Figure 3: CT Pelvis and lower limbs showing fracture in left femoral metadiaphysis and right femoral neck

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Keywords: Hypokalemia, renal tubular acidosis, Sjogren's syndrome

   Paget's disease: A case report Top

Saurav Shishir, Asish Kumar Basu, Anirban Sinha, Animesh Maiti, Chhavi Agrawal, Sayan Ghosh, Somnath Raghuvanshi

Department of Endocrinology, Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: We are presenting a case of Polyostotic Paget's disease with marked craniofacial deformity and neurological sequelae. Though it has been described in European population, it is relatively rarer in Africans, Asians and Middle East population. Case Report: A 46 year old lady presented with generalized bodyache and craniofacial bony deformity for last 2 years. She had continuous throbbing headache and diminished distant vision. Examination revealed generalized increase in head circumference (58 cm) along with bilateral maxillary prominence, frontal bossing and depressed nasal bridge [Figure 1]. She had bilateral decreased visual acuity (6/24) and sensorineural hearing loss. Investigations were normal except for LFT showed a markedly elevated alkaline phosphatase–1847 U/L (normal range- 40-125 U/L) with normal level of other enzymes. Skeletal survey of skull and pelvis revealed findings suggestive of Paget's disease of bone [Figure 2] and [Figure 3]. A 99mTc-MDP whole body scintigraphy revealed marked increase in tracer concentration in whole skull, bilateral pelvic bones, left scapula, cervical and lumbar vertebrae [Figure 4]. Thus final diagnosis of Polyostotic Paget's disease was made. She was given a single dose of 4 mg IV Zolendronic acid infusion after dental examination. Post treatment, her symptoms improved and ALP levels decreased to 330 U/L and further to 145 U/L after 1 year. Discussion: Symptomatic presentation of Paget's disease has been described rarely in literature, especially from Asian population. Our patient differed from these cases in having a relatively earlier age of presentation, presence of neurological complications, marked craniofacial deformity and a high level of alkaline phosphatase.
Figure 1: Patient having depressed nasal bridge, bilateral maxillary prominence, frontal bossing and increase in head circumference

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Figure 2: X-ray skull showing widening of diploic spaces, cotton wool spots and “Tam O Shanter” sign

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Figure 3: X-ray Pelvis showing thickening of ileopectineal and ileoischial lines

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Figure 4: Bone scan showing marked increase in tracer concentration in whole skull, bilateral pelvic bones, left scapula, cervical and lumbar vertebrae

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Keywords: Alkaline phosphatase, Paget's, skull

   Pachydermoperiostosis in a Patient with Primary Myelofibrosis Top

Chhavi Agrawal, Anirban Sinha, Asish K. Basu, Animesh Maiti, Saurav Shishir, Somnath Raghuvanshi, Sayan Ghosh

Department of Endocrinology, Medical College Kolkata, West Bengal, India.

E-mail: [email protected]

Introduction: Pachydermoperiostosis was first described by Friedreich in 1868. As per Borochowitz, diagnosis should only be made when at least two out of family history, clubbing, hypertrophic skin changes and radiographic changes are present. Estimated prevalence of disease is 0.16%. We report a case of pachydermoperiostosis in a patient of primary myelofibrosis. Case Report: A 34 year old male patient known case of primary myelofibrosis, on regular treatment, complained of enlargement of distal extremities of both upper and lower limbs with coarsening of facial features, starting at age of 13 years associated with arthralgia of large joints. There was no other significant history. On examination he had pronounced folds over forehead with symmetrical enlargement of bilateral hands and feet without any other significant findings [Figure 1] and [Figure 2]. Investigations revealed pancytopenia with other routine investigations and IGF1 being normal. X ray of the forearms revealed fluffy opacities in distal radii and along the medial border suggestive of periosteitis [Figure 3] MRI pituitary was normal [Figure 4]. Thus final diagnosis of pachydermatoperiostosis with myelofibrosis was made. Discussion: Pachydermoperiostosis is associated with peptic ulcer, gastric adenocarcinoma, Crohn disease and myelofibrosis. Myelofibrosis in pachydermoperiostosis is probably due to overgrowth of the normal marrow matrix. High levels of the same growth factors may lead to fibroblast expansion and collagen synthesis in bone marrow. The prevalence of pachydermatoperiostosis is low and in our patient diagnosis was delayed probably due to lack of clinical suspicion. This case highlights need for high clinical suspicion for diagnosis of the disease.
Figure 1: Pronounced folds in the area of forehead, between the eyes, on the chin

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Figure 2: Acral enlargement of hands and feet

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Figure 3: Fluffy opacities in distal radii suggestive of periosteitis

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Figure 4: Normal pituitary MRI

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Keywords: Growth factors, IGF1, pachydermoperiostosis

   Primary hyperparathyroidism-A case series Top

Sreenath Ravindranath, Nilanjan Sengupta, Pranab K. Sahana, Arjun Baidya, Soumik Goswami, Arindam Ray

Department of Endocrinology, Nilratan Sircar Medical College, Kolkata, West Bengal, India.

E-mail: [email protected]

The clinical presentation of primary hyperparathyroidism has evolved from a highly symptomatic disorder to one that is asymptomatic in the majority of patients. With the advent of automated serum chemistry autoanalyzer, the diagnosis of primary hyperparathyroidism became much more common. In the developed world symptomatic primary hyperparathyroidism is now the exception rather than the rule, with more than three fourths of the patients having no symptoms attributable to their disease, making primary hyperparathyroidism a disease that has “evolved” from its classic presentation. In developing countries the disease today still bears resemblance to the severe disorder of “stones, bones and groans” described by Fuller Albright and others in 1930s. Here we present five cases of primary hyperparathyroidism each one unique in its presentation. Patients presented with:

  1. Incidental hypercalcemia
  2. Renal calculi
  3. Pathological fracture
  4. Brown tumour of jaw
  5. Fibrocalculous pancreatic diabetes.

Primary hyperparathyroidism is a single disease entity with varied expressions, just like a view through kaleidoscope. We should be diligent in recognizing the diverse manifestations of primary hyperparathyroidism in our day to day clinical practice.

Keywords: Hypercalcemia, primary hyperparathyroidism

   Pseudohypoparathyroidism: A rare and often delayed diagnosis. A case series Top

Rahul Valsaraj, Nilanjan Sengupta, Pranab K. Sahana, Arjun Baidya, Soumik Goswami

Department of Endocrinology, Nilratan Sircar Medical College and Hospital, Kolkata, West Bengal, India

E-mail: [email protected]

Introduction: Pseudohypoparathyroidism is a rare sporadic or inherited genetic disorder characterized by parathyroid hormone (PTH) resistance. Aims and Objectives: To highlight the variable presentation of Pseudohypoparathyroidism and the challenges of an early diagnosis. Materials and Methods: Four patients who presented to our department between Jan-May 2018 were underwent a complete physical examination, biochemical and hormonal investigations. Results: Patients included two siblings (24 year old and his sister aged 36 years) and a 13 year boy and a 14 year old girl. All patients had short stature with a mean height of 136.7 cm (Mean SDS -4.24) however none were evaluated for the same. Two patients presented with seizures and came to our department with a delay of one year after soliciting medical attention. Albright Hereditary Osteodystrophy (AHO) phenotype were present in three patients. Symptoms and signs of hypocalcemia were present in all. One had subcutaneous calcifications. PTH Resistance was seen in all patients (Low Ionized Calcium, High Phosphate and Elevated PTH). Subclinical Hypothyroidism was seen in two and one had a low IGF1. All patients had a normal gonadal and adrenal axis. CT Brain imaging showed bilateral symmetrical calcification in basal ganglia and subcortical areas in all. All were managed with Calcitriol and Calcium Carbonate replacement following which symptoms improved. Conclusion: This series stress the importance of a good physical examination and a complete biochemical and hormonal evaluation in patients suspected to have hypocalcemia in order to avoid delayed diagnosis and treatment.

Keywords: Albright hereditary osteodystrophy (AHO), hypocalcemia, pseudohypoparathyroidism

   Clinical, biochemical and radiological profile of primary hyperparathyroidism at a tertiary health care centre in Kerala Top

Geena S. George, P. K. Jabbar, M. S. Sulfekar1, C. Jayakumari, Abilash Nair, Nandini Prasad

Departments of Endocrinology and 1General Surgery, Government Medical College, Thiruvananthapuram, Kerala, India.

E-mail: [email protected]

Introduction: Primary hyper parathyroidism (PHPT) has varied clinical presentation, however the predominant form is asymptomatic PHPT detected during routine biochemical investigations for unrelated cause. Recent data from Indian studies show that PHPT still presents with classic skeletal and renal manifestations. Aim: To study the clinical, biochemical and radiological profile of primary hyperparathyroidism. Materials and Methods: 24 patients were diagnosed to have primary hyperparathyroidism over a period of 11 months from August 2017. All patients underwent investigations including S. calcium, S. phosphorus, albumin, Alkpo4, PTH urine VMA and USG neck. Tc 99 Sestamibi scan was done in 23 patients and 4D CT scan of neck in 21 patients. Results: The mean age of presentation was 46 yrs with a M: F ratio of 1:1. Bilateral renal calculi was present in 58.3%, calcific pancreatitis in 12.5%. 2 patients had history of multiple fractures, 1 patient presented with bilateral slipped capital femoral epiphysis and 4 had psychiatric symptoms. 20.8% of patients were asymptomatic. Mean levels of S. calcium, S. phosphorus and PTH was 12.55 mg/dl, 2.54 mg/dl and 245.3 pg/ml respectively. Mean Z score at forearm was -3.12. The sensitivity of Usg neck, Sestamibi scan and 4D CT neck was 77.27%, 85.47% and 89.47% respectively when compared to the histopathology. 22 patients underwent parathyroid surgery and the postoperative resolution of hypercalcemia was 100 percent. Of the histologically studied specimens 2 were parathyroid carcinoma. Conclusion: Patients with PHPT present for the first time in different specialities although asymptomatic PHPT is most common. Bilateral slipped capital femoral epiphysis is a rare manifestation of PHPT. 4DCT is sensitive for the anatomical localisation when compared to other imaging modalities. Incidence of parathyroid carcinoma is quite high contrary to previous reports.

Key words: Parathyroid carcinoma, primary hyperparathyroidism, slipped capital femoral epiphysis

   References Top

  1. Bhansali A, Masoodi SR, Bhadada S, Mittal BR, Behra A, Singh P. Ultrasonography in detection of single and multiple abnormal parathyroid glands in primary hyperparathyroidism: Comparison with radionuclide scintigraphy and surgery. Clin Endocrinol (Oxf) 2006;65:340-5.
  2. AACE/AAES Task Force on Primary Hyperparathyroidism. The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism. Endocr Pract 2005;11:49-54.

   Tumor induced osteomalacia Top

Justin E. Sam, Pramila Kalra

Department of Endocrinology, Ramaiah Medical College, Bengaluru, Karnataka, India.

E-mail: [email protected]

Introduction: Tumor-induced osteomalacia, characterized by bone pain, muscle weakness and fractures, is a rare paraneoplastic syndrome of abnormal phosphate and vitamin metabolism caused by typically small endocrine tumors that secrete phosphaturic hormone FGF 23. Case Report: A 54-year- old female patient, on treatment for subclinical hypothyroidism presented with bilateral lower limb weakness predominantly involving proximal muscles which was insidious in onset and gradually progressive for past 4 years. On examination, power was 3/5 in the lower limb proximal muscles. Her serum calcium level was 8.91 mg/dl, serum phosphorus was 1.8 mg/dl, 25 hydroxy Vitamin D3 levels was 15 ng/dl, Serum PTH was 144.20 pg/ml and electrolytes were normal. The patient was started on phosphate supplementation and showed significant improvement. After normalization of vitamin D levels and in spite of normal calcium levels, she continued to require phosphate supplementation in a high dose for maintaining phosphate levels and normal muscle power. FGF 23 levels were assessed and found to be elevated which was 440 RU/ml (<180). Ga Dotatate whole-body PET CT scan was done to look for any tumor which showed abnormal somatostatin-expressing lesion in the right posterior nasal cavity. The patient is now being planned for surgery. Conclusion: Tumor-induced osteomalacia should be evaluated as a cause of adult-onset hypophosphatemia presenting with proximal muscle weakness. Prompt recognition and treatment leads to complete amelioration of symptoms.

Keywords: FGF 23, hypophosphatemia, proximal muscle weakness

   Effect of calcium deficiency on bone micro-architecture and strength and its reversibility on calcium supplementation Top

Shivmurat Yadav, N. Chattopadhyay1, R. Trivedi1, D. Singh1, S. Tiwari, Sushil Gupta

Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, 1Endocrinology Division, CSIR-Central Drug Research Institute, (CSIR-CDRI), Jankipuram Extension, Sitapur Road, Lucknow, India.

E-mail: [email protected]

Dietary calcium deficiency (CaD) deteriorates bone micro-architecture and bone mineral density which to some extent is reversible upon adequate Ca supplementation. In fact, the effect of CaD and supplementation on bone depends on the amount and time period of Ca consumption. In this study, we investigated the effect of dietary CaD in rat's femur, tibia and vertebrae micro-architecture, biochemical parameters and bone strength and its reversibility on adequate Ca supplementation at different time points. We used 0.1% Ca (as Ca Deficient) and 0.8% Ca (as Ca Replenished and Control) diet, obtained by modifying only Ca amount in the AIN-93G diet. We initiate feeding Ca deficient diet and control diet to P28 (P28, P = Postnatal) growing female Sprague-Dawley rats (10 rats/group) and investigate the effect of 0.1% Ca diet at P70, P150, and P210. Supplementation (0.8% Ca) was initiated to Ca Deficient-P70 rats and checks the effects at P150 and P210. Calcium deficiency decrease serum total and ionized calcium, at P70, P150, and P210. All micro-CT bone parameters were significantly impaired and three-point bending test of femur shows total energy, failure load, and stiffness were also significantly decreased in rats feeding 0.1% Ca feeding groups compared to control group at p70, P150, and P210. After Ca supplementation reversibility can be seen in serum parameters and micro-CT parameters but not in a three-point test at both time points P150 and P210. This study shows calcium replenish in calcium-deficient growing rats induces compromised bone strength despite recovery on micro-CT parameters.

Keywords: Bone strength, calcium deficiency, micro-architecture, micro-CT

   FRAX first: A pragmatic approach in resource poor settings Top

Adlyne Reena Asirvatham, Karthik Balachandran, Shriraam Mahadevan, Satish Kumar

Department of Endocrinology, Sri Ramachandra Medical College and Research Institute, Porur, Chennai, Tamil Nadu, India.

E-mail: [email protected]

Aims and Objectives: To determine if FRAX without BMD (FRAX) and FRAX with BMD (FRAX/BMD) would produce identical predictions for 10-year probability of hip fracture and major osteoporotic fracture. Materials and Methods: 239 subjects (men and women over 50 years of age) who underwent BMD measurement and found to have osteopenia or osteoporosis at one or more site were included in this retrospective study. Those who have already received treatment with USFDA approved drugs for osteoporosis were excluded. FRAX scores with BMD (FRAX/BMD) and without BMD (FRAX) were calculated using FRAX India tool. Subjects were separated on the basis of identical and different treatment recommendation. Comparison of group means was done using Student's t test and One way Anova in the case of three groups and correlation between the variables was tested using Spearman Correlation coefficient. Results: FRAX and FRAX/BMD made identical fracture risk prediction in 207 out of 239 subjects (86.61%) and different risk prediction in 32 (13.39%). In identical risk group, 18 (8.69%) subjects met treatment cut-off according to NOF recommendation whereas in different risk prediction group, 21 (65.62%) subjects met. Mean age was lower (P = 0.009) whereas BMI, Hip BMD, Spine BMD and history of previous fracture were higher (P = 0.005, P < 0.001, P < 0.001 and P = 0.02 respectively) in identical prediction group. Conclusion: FRAX predictions of fracture risk were identical to FRAX/BMD in most cases making it an useful tool when BMD is unavailable. Younger age and higher BMI may indicate identical prediction. Previous fractures would suggest different risk prediction.

Keywords: Fracture risk, FRAX, osteoporosis

   Vitamin D status in the tribal population of Kashmir valley: A cross sectional community based study Top

Ishfaq Wani, Shivani Sidana, Aabid A. Sheikh, Aafia Rashid, Lakshmy R1, Mohinder Kumar2, Nandita Gupta2, Mohd A. Ganie2

Department of Endocrinology, Sheri-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India, 1Departments of Cardiac Biochemistry, 2Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Background: Vitamin D deficiency (VDD) is reported in epidemic proportions (70-100%) in general population across India but studies on its prevalence among tribal populations are lacking. Objective: To assess the prevalence of VDD in the tribal population of Kashmir valley by measuring serum 25(OH) D levels. Materials and Methods: A total of 1266 apparently healthy tribal individuals (n = 588 men and 678 women) were sampled from five districts (Srinagar, Gandarbal, Anantnag, Pulwama and Kupwara) of Kashmir valley randomly selected by PPS method. Serum 25(OH) D levels were assessed and the status was classified as: deficiency (<20 ng/dl), insufficiency (20-30 ng/dl), sufficiency (>30 ng/dl) as per ES recommendations. Results: Out of 1266 subjects, 788 (62.2%) subjects had VDD, 230 (18.2%) subjects had insufficient serum 25(OH) D levels. VDD was equally prevalent in males (362;61.6%) and females (426;62.8%). Serum 25(OH) D levels correlated negatively with serum alkaline phosphatase, smoking, and education level but not with serum calcium, serum phosphorus, consumption of dairy products, meat and fish. Conclusion: VDD is high among tribal population of Kashmir valley despite their habit of outdoor activities and food habits. Further studies are required to see the impact of vitamin D supplementation with analysis of functional outcomes

Keywords: 25(OH) D, Vitamin D deficiency, tribal population

   Inverse relationship between Vitamin D and Parathormone: Are there two inflection points? Top

Mainak Banerjee, Pradip Mukhopadhyay, Sujoy Ghosh, Kingshuk Bhattacharjee, Subhankar Chowdhury

Institute of Postgraduate Medical Education and Research,

Kolkata, West Bengal, India.

E-mail: [email protected]

Context: There is no consensus about the inflection point for Vitamin D below which the intact PTH level increases. Objective: Determine the relationship/inflection point between Vitamin D and parathormone levels. Patients and Methods: We performed a population based analysis on a non obese cohort (N = 405). Results: Prevalence of vitamin D deficiency was 58.76% (n = 228). Vitamin D insufficiency was found in 34.56% (n = 140). An inverse relationship between Vitamin D and intact PTH does exist but strength of such relationship is weak (r = −0.17, P = 0.0009). Proportion of persons having high intact PTH was significantly higher in the cohort having lower Vitamin D levels compared to higher Vitamin D levels with respect to the linked cut offs mentioned by IOM as EAR (16 ng/ml) and RDA (20 ng/ml) (P = 0.005 for EAR linked cut off and P = 0.017 for RDA linked cut off). LOWESS method revealed two inflection points at which PTH levels change. A less conspicuous inflection point was found at 32 ng/ml (95% CI, 27-36) which reasonably corroborates with the current cut off of definition of Vitamin D sufficiency and the second, steeper inflection point was found at 16.5 (95% CI, 14.86-18.83) which corroborates with the IOM supported EAR linked value of Vitamin D level in general population and possible definition of Vitamin D deficiency. Conclusions: There are possibly two inflection points at which PTH levels change in relation to Vitamin D levels.

Keywords: Vitamin D deficiency, vitamin D insufficiency, inflection point

   An unusual case of Primary Hyperparathyroidism presenting as brown tumors Top

Tuhin Dubey, Subhash K. Wangnoo1, Mohammad A. Siddiqui1, Radhika Jindal2, Sajad Sumji3, Monika Sharma2

Department of Endocrinology, Medipulse Hospital, Jodhpur, Rajasthan, 1Departments of Endocrinology, Indraprastha Apollo Hospital, 2Department of Endocrinology, Safdarjung Hospital, New Delhi, 3Department of Endocrinology, Sher-e-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India.

E-mail: [email protected]

Objectives: We report a 62 year old man who presented with multiple lytic bone lesions and found to have primary hyperparathyroidism (PHPT). Materials and Methods: Serum parathyroid hormone levels using CLIA. Technetium-99 sestamibi scan for parathyroid adenoma. Case Report: A 62 year old man presented to orthopaedician with development of multiple bony swellings over limbs and spine over two years with pathological fracture of femur and spastic paraparesis. On evaluation was found to have anaemia (Hb 6.4 gm/dl), renal dysfunction (creatinine 3.5 mg/dl), and hypercalcaemia (corrected calcium 11.7 mg/dl). On skeletal survey there were multiple osteolytic bone lesions (brown tumors) [Figure 1], [Figure 2], [Figure 3] and bone scan revealed multiple hot spots (increased tracer uptake) [Figure 4]. He was misdiagnosed as metastatic bone disease and underwent fracture repair and decompression of spine.
Figure 1: Brown Tumor in Fibula

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Figure 2: Brown Tumors in Ulna and Phalanx

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Figure 3: Bone Scan Showing Multiple Hot Spots

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Figure 4: Brown Tumor in Humerus

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Endocrine reference for hypercalcaemia revealed PTH dependent hypercalcaemia with PTH levels of 2048 pg/ml (15-65 pg/ml). Technetium-99 sestamibi scan revealed left inferior parathyroid adenoma which was operated. Discussion and Conclusion: The incidence of bone lesions in patients with hyperparathyroidism has fallen from 80% to a current 15% due to early detection of hypercalcaemia. Incidence of brown tumors (osteitis fibrosa cystica) in PHPT is <2%. They are usually found in flat bones but can involve any part of skeleton and have no malignant potential. The lesions resolve once the abnormal metabolic conditions are controlled. Hence a diagnosis of hyperparathyroidism must be kept in mind while evaluating any patient with osteolytic bone lesions.

Keyword: Primary hyperparathyroidism

   A randomized double blind controlled trial to investigate the effects of vitamin D supplementation on maternal and new-born baby's vitamin D status in Asian-Indian subjects Top

Tarang Gupta, Harshna Sharma, Jaya Bajpai, Garima Kachhawa, Vidushi Kulshreshtha, Rajesh Khadgawat, Nandita Gupta, V. Sreenivas, Arul Selvi, Vandana Jain

Departments of Obstetrics and Gynecology, Endocrinology, Biostatistics, Pediatrics, and Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India.

E-mail: [email protected]

Background: Maternal vitamin D status has been linked to maternal and fetal outcomes. We planned a study to investigate the efficacy of vitamin D supplementation, given in early stage of pregnancy, on maternal, fetal and newborn parameters. Materials and Methods: Pregnant women attending antenatal clinic, AIIMS. Subjects were randomized into four groups in ratio of 1:1:1:1 (Group 1 - active control group received 600 units of vitamin D per day; Group 2-1000 units/day; Group 3 – 2000 units/day; Group 4-4000 Units/day). All groups received 1000 mg of elemental calcium. Doses of vitamin D were given orally, once a month. Safety of intervention was assessed by regular monitoring of urinary calcium creatinine ration and serum calcium levels. Results: High prevalence of vitamin D deficiency was seen in study population. Of total 257 subjects, 95.9% of subjects had VDD (S.VitD <20 ng/ml) while 98.8% subjects had S.VitD level <30 ng/ml. No significant difference was seen in S.VitD level among all four groups at Baseline. Improvement in S.VitD level after supplementation is shown in [Table 1]. At 24-28 week visit, at the time of delivery and cord blood, there is significance difference (P value- <0.001) seen within all four randomization group in S.25vitD level. Apart from S.VitD level, no significant difference was observed among all four groups in any other maternal, fetal and newborn parameters. Conclusion: Our study shows that supplementation of vitamin D in mother improves vitamin D status of newborn.
Table 1

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Keywords: Maternal parameter, newborn outcomes, vitamin D deficiency

   Primary hyperparathyroidism-Unusual presentations Top

Ganesh Namani, Rakesh Sahay, K. Neelaveni

Department of endocrinology, Osmania Medical College, Hyderabad, Telangana, India.

E-mail: [email protected]

Background: Hyperparathyroidism classically presents with bone disease, nephrolithiasis and hypercalcemia. Classsical phenotype is rarely seen today as more number of patients present with asymptomatic hyperparathyroidism. Here, we report 5 different uncommon presentations of hyperparathyroidism. Case Series: Case 1: 52 yr male known diabetic and hypertensive presented with acute pancreatitis, has hypercalcemia and elevated PTH. Found to have Ectopic parathyroid adenoma located in mediastinum on right side. Case 2: 40yr Male presented with proximal myopathy with background history of renal calculi 10yrs ago, has hypercalcemia with elevated PTH. He was found to have diabetes with calcifications in pancreatic parenchyma, has left inferior parathyroid adenoma. Diabetes resolved completely after surgical resection of the left inferior parathyroid. Case 3: 17 yr female presented with Proximal myopathy and genu valgum. Has hypercalcemia and elevated PTH. Has left superior parathyroid adenoma. Case 4: 23 yr female presented with Non healing fracture associated with deformity of left lower limb since 4 months, found to have hypercalcemia with increased PTH levels and has multiple osteolytic lesions. She has right inferior parathyroid adenoma. Case 5: 16 yr male presented with recurrent hypoglycemia and found to have hypercalcemia and elevated PTH in addition to inulinoma and prolactin secreting pituitary microadenoma. Conclusion: Hyperparathyroidism can have variable presentations. Caution should be exercised while evaluating patients with such presentations and hyperparathyroidism should be kept in mind as a differential diagnosis.

Keywords: Hyperparathyrodism, primary, unusual

   Bone biomarkers for the diagnosis and management of osteoporosis: An Indian perspective Top

Meena Desai, M. I. Khatkhatay

Department of Molecular Immunodiagnostics, ICMR- National Institute for Research in Reproductive Health, J. M. Street, Parel, Mumbai, India.

E-mail: [email protected]

Introduction: Bone biomarkers include formation, resorption and regulators released during the bone remodeling process. In the past decade these bone biomarkers have attracted much attention in the clinical assessment of osteoporosis. In conjunction with the bone mineral density measurements (BMD), the clinical applications of bone turnover markers (BTO) have provided comprehensive information for diagnosis and management of osteoporosis. However, the analytical approaches of the BTO are still the challenge for further clinical trials. Aim and Objectives: The aim of study is to present the functions of bone biomarkers and the recently developed techniques for their measurements which have been systematically integrated in an ELISA array for identifying women at risk for osteoporosis in early stage and assessment of bone health. Materials and Methods: In house assays developed for prominent bone markers osteocalcin (OC), Pro collagen n-terminal peptide (PINP), C-terminal telopeptide (CTX) and Deoxypyridinoline (DPD) were validated. The reference intervals were established in 500 apparently healthy Indian women (age 20-65 years) for each marker while cellular regulators RANKL and OPG estimated by commercial ELISAs. The age related changes in the biomarkers were correlated with BMD measurements and the hormonal levels. Results: The BTO markers provide a representative indicator of overall skeletal bone loss than the results obtained by BMD and reflect bone remodeling changes earlier within 3-6 months of therapy. The RANKL/OPG ratio can aid in identifying women at risk for osteoporosis. The in house developed assays for the biomarkers integrated in an ELISA array format for the assessment of bone health in Indian women is currently evaluated.

   Obesity and Lipid Metabolism Top

   Change in beta cell function, glucagon-like peptide-1, and calcitonin levels 2 weeks after bariatric surgery: An exploratory study Top

Kalyani Sridharan, Rajan Palui, Harsh Durgia, Henith Raj, Jayaprakash Sahoo, Sadish Kumar Kamalanathan

Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India.

E-mail: [email protected]

Aims and Objectives: The objective of this study was to measure the change in beta cell function, glucagon-like peptide-1 (GLP-1) and calcitonin before and 2 weeks after bariatric surgery. Materials and Methods: Patients >18 years who underwent either sleeve gastrectomy or Roux-en Y gastric bypass were recruited into the study. Clinical and biochemical data were recorded. Samples for blood glucose, insulin, GLP-1, and calcitonin were drawn during an oral glucose tolerance test at baseline and 2 weeks after surgery. Area under curve (AUC) was measured. Homeostatic model assessment for insulin resistance (HOMA2-IR), Matsuda index, and insulin secretion and sensitivity index (ISSI-2) were calculated. Results: In total, 28 patients completed the study. At baseline, 50% of patients were hypertensive and 46.4% had diabetes mellitus. At 2 weeks, there was a significant reduction of weight (8.8%) and requirement of antidiabetic and antihypertensive drugs. After surgery, HOMA2-IR was significantly lower, Matsuda index had improved but was not statistically significant, and ISSI-2 was significantly higher. Postprandial GLP-1 and AUC for GLP-1 were significantly higher. Serum calcitonin levels did not change and there was no correlation between change in GLP-1 and change in calcitonin levels after surgery. Conclusion: At 2 weeks following bariatric surgery, there was a significant decrease in weight, requirement of antidiabetic and antihypertensive medication, and hepatic insulin resistance, whereas beta cell function increased due to increased postprandial GLP-1.

Keywords: Bariatric surgery, beta cell function, calcitonin, glucagon-like peptide-1

   Body composition and lipid profile in euthyroid overweight vs hypothyroid patients and effect of levothyroxine replacement on these parameters in primary hypothyrodism Top

Sonal Singh, Muthukrishnan J, Vidushi Sharma, Sashindran VK

Department of Internal Medicine, AFMC, Pune, Maharashtra, India.

E-mail: [email protected]

Context: The beneficial effect of thyroxine replacement on weight, body composition and lipid parameters, is a matter of clinical importance. Aims: We aimed to study the effect of optimum thyroxine replacement on these parameters in patients with primary hypothyroidism. Settings and Design: Tertiary care centre in western India. Prospective cohort study with thyroxine replacement as intervention. Materials and Methods: Fifty-eight consecutive patients of the 18-65 years age with newly diagnosed primary hypothyroidism were included. Anthropometric data, body composition by DEXA scan and lipid profile was done. All patients received standard Diet and Exercise advice. The hypothyroid patients (TSH > 5 mIU/l) were started on thyroxine replacement as per baseline TSH. Follow up was done every 6-8 weeks of treatment and evaluation was repeated when the patient achieved euthyroid state. Thirty-five patients with overweight/obesity and normal thyroid function were also included for comparison. Statistical Analysis Used: Descriptive statistics and tests for comparison of mean (SD). Results: Forty out of 58 patients becoming euthyroid on thyroxine replacement were available for follow up evaluation after 6 weeks to 3 months of treatment. Mean change in weight was 0.85 kg (Range + 2 to − 3 kg). Lean mass increased by a mean of 0.7 kg (2%) and fat mass decreased by 1.2 kg (4%). A decrease in total and LDL cholesterol and a statistically significant fall in triglyceride levels was noted. HDL levels increased after achievement of euthyroid status. No difference in any of the parameters related to body composition or lipid profile was noted in the hypothyroid group between those with normal BMI and those with BMI in overweight-obese range. Conclusions: We noted that maximum weight loss was a modest 3 kg with some patients even gaining weight in this period. These patients showed decrease in fat mass and an increase in lean mass which may have contributed to the total weight remaining largely unchanged. There was overall improvement in the atherogenic lipid profile. Within the hypothyroid group, there was no difference between those with normal BMI and those overweight/obese suggesting that the impact of thyroid function on these parameters outweighs that of adiposity.

Keywords: Dyslipidemia, hypothyroidism, obesity

   Lipodystrophy – A diagnostic challenege Top

Neha Agrawal, Partha P. Chakraborty1, Rana Bhattacharjee, Subhankar Chowdhury

Department of Endocrinology and Metabolism, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, West Bengal, India, 1Department of Medicine, Midnapore Medical College and Hospital, Midnapore, West Bengal, India.

E-mail: [email protected]

Introduction: Lipodystrophy (LD), a rare group of metabolic disorders characterized by loss or abnormal distribution of body fat, is associated with insulin resistance (IR) and abnormal glucose homeostasis. It is classified as generalised, partial or localized, depending upon the extent of adipose tissue loss. Etiologically, subclassified as inherited or acquired; latter one usually arises secondary to infections or autoimmune conditions. Materials and Methods: 6 cases of LD with heterogeneous clinical presentation are being presented. IR, young onset diabetes, hypertriglyceridemia, NAFLD and absence of obesity were common for all. Markers of autoimmunity (C3, C4, ANA) and family history of LD were negative in all. Case 1-13YOF, pseudoacromegaly, generalized fat loss since birth without mechanical fat loss, clitoromegaly, mutilple lytic lesions over metacarpals and phalanges, TBF -DXA- 4%. Case2-6YOF, failure to thrive, both metabolic and mechanical fat loss seen by MRI, TBF- DXA 3% suggesting SEIP syndrome. Cases 3 to 6 had partial lipoatrophy with preserved facial fat. Case 3-5 YOF, fat loss since infancy, transaminitis. Case 4-16 YOF, oligomenorrhea, polycystic ovaries without hirsutism, TBF- DXA 19.7%. Case 5-22YOF, oligomenorhea, hirsutism, polycystic ovaries, TBF-DXA 14.4%. Case 6 – 28YOF, oligomenorrhea, hirsutism, polycystic ovaries, eruptive xanthomas, recurrent pancreatitis, TBF-DXA 23.5%. Results: Age (15 ± 8.9 yr), Female Preponderance, Acanthosis (66%), BMI (17.91 ± 3.60 kg/m2), FBS (146 ± 38.64 mg/dl), PPBS (233 ± 68.3 mg/dl), HbA1C (8.23 ± 0.86%), HDL (28.67 ± 6.52 mg/dl), TG (550 ± 726 mg/dl), Testosterone (135 ± 63.8 ng/dl), Fasting Insulin (32.61 ± 17.03 mIU/L), Prandial Insulin (146 ± 120.6 mIU/L). Conclusion: A high index of suspicion is the key to the early diagnosis of LD. One should carefully expose the patient for evidence of subcutaneous fat loss in any young, nonobese individual with diabetes, particularly in presence of acanthosis, hirsutism, hypertriglyceridemia or fatty liver. DXA and MRI are helpful in substantiating the diagnosis, which can be confirmed by genetic studies. No definitive treatment is available at present and the current treatment options are only symptomatic with Leptin-replacement therapy appears a promising tool in the metabolic correction.

Keywords: Insulin resistance, lipodystrophy, nonobese, Young onset diabetes

   Effect of laparoscopic sleeve gastrectomy and liraglutide on body composition, glucose homeostasis and intrapancreatic fat in obese individuals Top

Jimmy Pathak, Ashu Rastogi, Anil Bhansali, Rajesh Gupta1, Naveen Kalra2

Departments of Endocrinology, 1General Surgery, 2Radiodiagnosis, PGIMER, Chandigarh, India.

E-mail: [email protected]

Aim: To study the effect of Laparoscopic Sleeve Gastrectomy and Liraglutide on body composition, glucose homeostasis and intrapancreatic, intrahepatic fat in obese patients and to note if results are comparable to those achieved by the gold standard RYGB. Design and Setting: Prospective randomized placebo controlled study at a tertiary care centre. Materials and Methods: Patients undergoing Laparoscopic Sleeve Gastrectomy (LSG) were randomized at 6 weeks post-operatively to recieve Placebo (P) or Liraglutide (L) 0.6 mg subcutaneously daily up to maximum dose of 1.8 mg/day. Patients were assessed before and at 6 weeks, 12 weeks and 24 weeks after surgery for height, weight, waist and hip circumference, BMI, body composition (TANIKA, body composition analyzer). Fasting and stimulated levels of glucose, insulin, c-peptide, GLP-1 were obtained post 2 hour OGTT. MRI abdomen was done at baseline and at 24 weeks for intrapancreatic fat (IPF) and intrahepatic fat (IHF) content using MRS (Siemens). Results: Data was analysed for 16 patients for 6 months of follow-up post LSG. Patients in L (n = 8) group had statistically significant decline in weight, fat mass as compared to placebo [Δ weight (kg): −39.98(L) and − 22.13(P); P = 0.004; Δ fat mass (kg): −29.85(L) and − 18.22(P); P = 0.006}]. At 6 month post-op there was a non significant decline in fasting levels and AUC for glucose, insulin, c-peptide between the two groups. No significant increase in the fasting levels and AUC of GLP-1 was seen between both the groups. IHF and IPF declined in both the groups post intervention however inter group difference was insignificant. [Δ IHF and IPF (L): −2.197 and − 1.992 (P = 0.028 and 0.046 respectively); delta IHF and IPF (P): −2.366 and − 2.023 (P = 0.018 and 0.043 respectively)][intergroup difference P = 0.949 and 0.144 for IHF and IPF respectively]. Conclusion: Liraglutide added to LSG results in additional weight loss in obese subjects. There was a significant decline in intrahepatic and intrapancreatic steatosis post LSG but addition of Liraglutide did not lead to further benefits.

Keywords: Intrapancreatic fat, liraglutide, LSG

   References Top

  1. Palikhe G, Gupta R, Behera BN, Sachdeva N, Gangadhar P, Bhansali A. efficacy of laparoscopic sleeve gastrectomy and intensive medical management in obese patients with type 2 diabetes mellitus. Obes Surg 2014;24:529.
  2. Peterli R, Wolnerhanssen B, Peters T, et al. Improvement in glucose metabolism after bariatric surgery: Comparison of laparoscopic Roux-en-Y gastric bypass and laparoscopic sleeve gastrectomy: A prospective randomized trial. Ann Surg 2009;250:234-41.
  3. Petit JM, Cerceuil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes. The LIRANAFLD study. J Clin Endocrinol Metab 2017;102:407-15.
  4. Steven S, Hollingsworth KG, Small PK, Woodcock SA, Pucci A, Aribisala B, et al. Weight loss decreases excess pancreatic triacylglycerol specifically in type 2 diabetes. Diabetes Care 2016;39:158-65.
  5. Umemura A, Sasaki A, Nitta H, Baba S. Pancreas volume reduction and metabolic effects in Japanese patients with severe obesity following laparoscopic sleeve gastrectomy. Endocr J 2017;64:487-98.
  6. Gaborit B, Abdesselam I, Kober F, Jacquier A, Ronsin O, Emungania O, et al. Ectopic fat storage in the pancreas using H-MRS: Importance of diabetic status and modulation with bariatric surgery-induced weight loss. Int J Obes (Lond) 2014;39:480-7.

   Adipocytokines in obese and non-obese women with polycystic ovary syndrome Top

Anil Satyaraddi, Nitin Kapoor, Kripa E. Cherian, Sahana Shetty, Joseph D. Bondu1, Aleyamma T. K2, Mohan S. Kamath2, Nihal Thomas, Thomas V. Paul

Departments of Endocrinology, Diabetes and Metabolism, 1Clinical Biochemistry, 2Reproductive Medicine, Christian Medical College, Vellore, Tamil Nadu, India.

E-mail: [email protected]

Aims and Objectives: Dysregulation of adipocytokines play a key role in the pathogenesis of polycystic ovary syndrome (PCOS). This study aimed to compare serum adiponectin, osteocalcin and resistin levels in obese PCOS (BMI ≥25 kg/m2) and non-obese PCOS (BM <25 kg/m2) subjects and then to compare with their age and BMI matched controls. Materials and Methods: A total number of 81 PCOS subjects (Obese-42; Non-obese-39) and controls (Obese-42; Non obese-44) were recruited in the study. A Rotterdam criterion was used for the diagnosis of PCOS. All patients underwent detailed clinical, anthropometric, assessment of insulin resistance and adipocytokines (adiponectin, resistin and osteocalcin). Results: Forty percent of overall PCOS subjects (1/3rd non-obese PCOS and 2/3rd obese PCOS subjects) had features of either clinical or biochemical evidence of hyperandrogenism. Serum adiponectin levels were significantly (P < 0.05) lower in subjects with obese PCOS (4.3 ± 2.0 mcg/ml) when compared to its controls (5.5 ± 2.8 mcg/ml). Serum osteocalcin levels were significantly lower (P < 0.005) in non-obese PCOS subjects (14.4 ± 7.2 ng/ml) when compared to age and BMI matched controls (19.7 ± 8.4 ng/ml). Serum resistin was not significant in both the groups. Serum adiponectin and osteocalcin had significant negative spearman's correlation with free testosterone index and insulin resistance indices. Conclusion: Significant derangements in serum adipocytokines levels were noticed among the PCOS subjects. Significantly lower serum osteocalcin levels in non-obese PCOS and significantly lower serum adiponectin levels in obese PCOS were noticed when compared to their age and BMI matched controls. Serum resistin levels were not significantly different.

Disclosure statement: No, there is no multiplicity of interest that we should disclose.

Keywords: Adipocytokines, obese, polycystic ovary syndrome

   Secular trends in overweight and obesity in school children from Delhi over last decade Top

Aashima Dabas, Vandana Rastogi1, Rekha Ramot1, Raman Kumar Marwaha2, Rajesh Khadgawat1

Department of Pediatrics, Maulana Azad Medical College, 1Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, 2Scientific Advisor, International Life Sciences Institute, New Delhi, India.

E-mail: [email protected]

Objective: Recent lifestyle changes in India have led to a postulated increase in prevalence of overweight and obesity among children. Materials and Methods: Retrospective analysis was performed on growth data over last decade (2008, 2011, 2013 and 2015) of school-going boys and girls aged 4-18 years from Northern India. Standard procedures for measurement of weight, height and body mass index (BMI) were used. The BMI cut-offs were interpreted according to criteria given by IOTF and IAP, 2015. Results: The year-wise distribution of total 5244 boys and 6625 girls was: (2008) - 1881 boys, 1748 girls, (2011) - 300 boys, 403 girls, (2013) - 2832 boys, 3399 girls, (2015) - 431 boys and 1125 girls. BMI showed significant increase across successive age groups in respective years in both genders. The maximum BMI was recorded at 16-17 yr in boys at 21.30 ± 4.54 kg/m2. Mean BMI showed a significant secular trend across successive years in boys the age groups of 10-11 yr, 11-12 yr, 12-13 yr, 14-15 and 18-20 yr (P < 0.05). The maximum BMI was recorded at 17-18 yr in girls at 22.12 ± 4.70 kg/m2. Mean BMI showed a significant secular trend across successive years in girls in the age groups 4-5 yr, 10-11 yr, 11-12 yr, 12-13 yr, 13-14 yr, 14-15 yr, 16-17 yr and 18-20 yr (P < 0.05). The proportion of overweight and obese boys and girls was compared as per the IOTF and IAP criteria respectively. Conclusions: BMI showed a secular trend in both boys and girls in peripubertal years. Stricter lifestyle measures need to be enforced during adolescence to decrease the prevalence of overweight and obesity.

Keywords: Body mass index, growth, India, IOTF

   Effects of bariatric Surgery on cardiovascular risk factors; a single center, short term outcome study Top

Gowri M. Ratnayake1, C. A. Jayasooriya1, W. M. U. A. Wijethunga1, D. C. H de Silva1, Thejana Wijerathne2, Ranil Jayawardana3, Uditha Bulugahapitiya1

1Diabetes and Endocrinology Unit Colombo South teaching Hospital, 2University Surgical Unit, Colombo South Teaching Hospital, 3Department of Medicine, University of Colombo, Sri Lanka.

E-mail: [email protected]

Introduction and Objectives: Increased cardiovascular risk, is a major contributor to obesity related morbidity and mortality. Metabolic surgery is an important therapeutic modality in the management of obesity. Therefore assessing the effects metabolic surgery on cardiovascular risk is a timely research interest. The objective of this study was to assess the 10 year cardiovascular risk reduction at 6 and 12 months intervals following metabolic surgery. Materials and Methods: A cohort of patients undergoing metabolic surgery was assessed for cardiovascular risk pre-operatively and at 6 months and 12 months intervals post-operatively. Ten year cardiovascular risks were assessed using Q risk scores. Mean Q risk scores were calculated preoperatively and at 6 and 12 months post-operatively and analyzed using paired sample T tests. Results: A total of 86 patients who underwent Bariatric surgery were included in the study. Preoperative BMI ranged from 33.4-68.1 kg/m2 with mean of 44.9 kg/m2 (±2 SD = 12.8). The rates of Laparoscopic sleeve gastrectomy and of Mini-laparoscopic sleeve gastrectomy were 77.9% and 18.6% respectively. Preoperative Q risk score of the population ranged from 0.20 to 26.10 and mean was 6.22 (±2 SD = 12.02). At postoperative 6 and 12 months interval mean Q risk score were 4.96 (±2 SD = 10.48) and 4.90 (±2 SD = 10.62) respectively. There was statistically significant reduction of Q risk score at 6 months and 12 month (P < 0.01) postoperatively. Ten year cardiovascular risk reduction at 6months postoperatively was 21.22% and this remained the same at 12 months. Conclusions: Metabolic surgery causes a significant reduction of 10 years cardiovascular risk at short term, in obese individuals.

Keywords: Bariatric surgery, cardiovascular risk, obesity


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20], [Figure 21], [Figure 22], [Figure 23], [Figure 24], [Figure 25], [Figure 26], [Figure 27], [Figure 28], [Figure 29], [Figure 30], [Figure 31], [Figure 32], [Figure 33], [Figure 34], [Figure 35], [Figure 36], [Figure 37], [Figure 38], [Figure 39], [Figure 40], [Figure 41], [Figure 42], [Figure 43], [Figure 44], [Figure 45], [Figure 46], [Figure 47], [Figure 48], [Figure 49], [Figure 50]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10]

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