|Year : 2019 | Volume
| Issue : 4 | Page : 468-472
Surgical management of primary hyperparathyroidism in the era of focused parathyroidectomy: A study in tertiary referral centre of North India
Sanjay K Yadav, Saroj K Mishra, Anjali Mishra, Sabaretnam Mayilvagnan, Gyan Chand, Gaurav Agarwal, Amit Agarwal, Ashok K Verma
Department of Endocrine Surgery, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Raebareli Road, Lucknow, Uttar Pradesh, India
|Date of Web Publication||3-Oct-2019|
Saroj K Mishra
Department of Endocrine Surgery, Nodal Officer, SGPGI Telemedicine Program, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow - 226 014, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Despite the benefits of focused parathyroidectomy (FPTx), few studies have questioned its durability with lower long-term cure rates than bilateral or conventional parathyroidectomy (CPTx). The objective of this study is to bring out the information on the type of surgical management versus cure rate, recurrence, and role of intra-operative parathyroid hormone (IOPTH) level monitoring of PHPT patients. Material and Methods: This was a retrospective study of all PHPT patients treated at our center based on operative approach (CPTx vs FPTx) or use of IOPTH. Treatment failure was divided into persistent or recurrent disease, based on documentation of hypercalcemia in combination with an inappropriate PTH within 6 months or more of surgery, respectively. Results: Overall, 50.78% patients underwent CPTx and 49.32% FPTx. 29 FPTx were converted to CPTx. Intention to treat analysis between CPTx and FPTx showed that the persistence rate was not statistically different at 2.54% and 4%, respectively (P = 0.98). Furthermore, when the persistence rate was scrutinized by a treatment received (TR) instead of ITT analysis, the persistence rate was higher for the patients who underwent TR-CPTX than for the patients subjected to TR-FPTX (3.22% vs 1.08%) but not significant statistically. We further analyzed the outcome of FPTx with IOPTH (n = 213) and FPTx without IOPTH (n = 28). The outcome did not differ between two groups statistically. Conclusion: FPTx yields a similar success rate as compared to CPTx even in symptomatic PHPT patients and can be performed safely even without intra-opeartive adjunct IOPTH in selected patients.
Keywords: Intra-operative PTH, parathyroidectomy, primary hyperparathyroidism
|How to cite this article:|
Yadav SK, Mishra SK, Mishra A, Mayilvagnan S, Chand G, Agarwal G, Agarwal A, Verma AK. Surgical management of primary hyperparathyroidism in the era of focused parathyroidectomy: A study in tertiary referral centre of North India. Indian J Endocr Metab 2019;23:468-72
|How to cite this URL:|
Yadav SK, Mishra SK, Mishra A, Mayilvagnan S, Chand G, Agarwal G, Agarwal A, Verma AK. Surgical management of primary hyperparathyroidism in the era of focused parathyroidectomy: A study in tertiary referral centre of North India. Indian J Endocr Metab [serial online] 2019 [cited 2019 Nov 22];23:468-72. Available from: http://www.ijem.in/text.asp?2019/23/4/468/268492
| Introduction|| |
Primary hyperparathyroidism is classically a symptomatic disease with “stones, bones, moans and groans”. However, the advent of a multichannel biochemical screening test in the early 1970s led to the clinical revolution of PHPT with recognition of a new entity of asymptomatic PHPT in the west. In the developing world most of the cases are still diagnosed only in symptomatic stage.,,,, Surgery is the only curative treatment available since the time of first successful parathyroidectomy performed by Felix Mandl in Vienna in 1925. This first surgery was a bilateral neck exploration (CPTx) and excision of single enlarged gland was performed, but patient had recurrent disease 6 years later and succumbed to the hypercalcaemic crisis. Surgery for PHPT has evolved over the time and also evolved back at few centers.
CPTx is considered the gold standard for PHPT. With the cure rate of 99.5%, the operative mortality 0.3%, persistent vocal cord paralysis 0.8%, and permanent hypocalcemia 0.3%, it was surgery of choice till 1990s. Unilateral neck exploration (UNE) came into picture in 1980s, but initially it was not accepted widely due to less reliable localization studies. Minimally invasive surgical approach is now possible with the quality of non-invasive preoperative imaging techniques and rapid intra-operative PTH assays.,,,, It was reported that CPTx for all parathyroid patients is an operation for the history books. Focused approach became the standard of care in 2000s. Despite the benefits of focused parathyroidectomy (FPTx), few studies have questioned its durability with lower long-term cure rates than bilateral or conventional parathyroidectomy (CPTx).
The objective of this study is to bring out the relevant information on type of surgical management versus cure rate, recurrence, and role of intra-operative parathyroid hormone level monitoring of PHPT patients managed at our Institute over last 28 years.
| Material and Methods|| |
This was a retrospective study of all PHPT patients treated in the Department of Endocrine surgery, SGPGIMS, Lucknow between January 1990 to December 2017. The evaluation and diagnostic protocol at our institute has been published in our previous publications,, and [Doc S1]. The patient cohort was divided into 2 groups, based on operative approach (CPTx vs FPTx) or use of IOPTH (Intraoperative parathyroid harmone monitoring) vs. no use of IOPTH. All Patients with PHPT with a minimum follow up of 6 months between January 1990 and December 2016 were included and patients for whom all required data were not available, parathyroid adenomas detected incidentally during thyroidectomy, Multiple endocrine neoplasia patients, parathyroid carcinoma patients, secondary primary hyperparathyroidism, and tertiary hyperparathyroidism patients were excluded. All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval from Institutional ethics committee was obtained on 3rd Feb 2017.
All statistical analyses were performed using SPSS (version 16.0; SPSS Inc, Chicago, Illinois). The data are expressed as means SD, except for data those do not have a normal distribution, which are expressed as median (range). Variables were tested for normality using the Kolmogorov-Smirnov Z statistic. Parametric and nonparametric tests were used as required to see the significance.
| Results|| |
A total of 408 patients underwent parathyroidectomy in our department during the study period, and 373 of them were included in the present study. Patients with parathyroid carcinoma, parathyroid adenomas detected incidentally during thyroidectomy and multiple endocrine neoplasia were excluded.
Prevalence and clinical presentation
Over the past 27 years 265 women (median age 49 years; range 12–70 years) and 108 men (median age 52 years; range 13–75 years) underwent parathyroidectomy. The clinical profile of the patients is summarized in [Table S1]. Symptomatic patients (n = 341, 91.42%) still predominate in Indian setting and most of the patients present with bony pain (88.26%) followed by proximal myopathy (n = 277, 81.23%), renal stones (n = 134, 39.29%), and fractures (n = 101, 29.61%). Palpable neck mass was present in 17.59% of the patients and 54 patients (15.83%) presented with hypercalcaemic crisis.
Some form of localization was undertaken in all patients. Overall, 358 patients had high resolution ultrasonography of the neck, 347 patients underwent SestaMIBI scan and six patients had contrast enhanced computed tomography of the neck. The sensitivity and positive predictive value for sestamibi scintigraphy were 86% and 94%, respectively, whereas ultrasonography had 80% and 88%, respectively.
50.78% (n = 189) patients underwent CPTx and 49.32% (n = 184) FPTx. 29 FPTx were converted to CPTx. Eight procedures were performed under regional anesthesia and frozen section biopsy was utilized in 58.98% (n = 220) cases. Rate of temporary recurrent laryngeal nerve palsy (RLN) was 3.21% and permanent RLN palsy was 0.53%. The median hospital stay was 8.6 +/- 4 days [Table 1]. The overall cure rate was 97.31% (n = 363). Eight patients had persistent disease and two patients had recurrent disease.
Surgical approach and outcome
To investigate outcome based on operative approach, 2 groups was formed on the basis of ITT (Intention to treat) analysis and they comprised 213 ITT-FPTX cases, including 29 conversions, and 157 ITT-CPTX cases. Baseline characteristics and operative data showed that the patient age was similar between the 2 groups, mean serum calcium and ALP levels were higher in the ITT-CPTX group. This analysis showed that the persistence rate was not statistically different at 2.54% and 4%, respectively (P = 0.98) [Table 2]. Furthermore, when the persistence rate was scrutinized by a treatment received (TR) instead of ITT analysis, rate of persistent PHPT was higher for the patients who underwent TR-CPTX than for the patients subjected to TR-FPTX (3.22% vs. 1.08%) but the difference was not significant statistically [Table 3].
|Table 3: Persistent disease according to actual treatment received group|
Click here to view
IOPTH and outcome
Cure rate did not differ significantly whether IOPTH was used or not. Out of 247 cases when IOPTH was used, 233 had curative fall, according to Miami criteria. But one patient out of this 233 continued to have hypercalcaemia (persistent disease). Fourteen patients did not have a curative fall in IOPTH, out of which 10 patients were cured [Figure 1]. Overall sensitivity, positive predictive value and accuracy was 95.87%, 99.57%, and 95.55% respectively. IOPTH was false negative in 10 cases and true positive in 04 cases. IOPTH correctly predicted cure in 95.5% and persistence in 1.6%. Overall three cases had unnecessary conversions due to non-curative fall in IOPTH and four cases were converted and cured due to non-curative fall in IOPH.
We further analyzed the outcome of FPTx with IOPTH (n = 213) and FPTx without IOPTH (n = 28). The outcome did not differ between two groups statistically. Two patients had persistent disease and one had recurrent disease in the group where IOPTH was used as compared to no failures in the group without IOPTH [Table S2]. However, patients who underwent FPTx without IOPH had 100% concordance (anatomical and functional) as compared to the group who underwent FPTx with IOPTH which had 78% concordance rate.
| Discussion|| |
We have previously reported the unique clinical characteristics of PHPT from India. Indian primary hyperparathyroidism patients with parathyroid carcinoma do not differ in clinico-investigative characteristics from those with benign parathyroid pathology. Similar findings have been reported from other centers from developing countries.,,, This study too has brought out similar findings with regard to younger age of presentation, high rate of palpable neck mass (17.59%), and the high incidence of hypercalcaemic crisis (15.83%) in benign PHPT. The exact cause of this type of presentation is still elusive. Suboptimal Vitamin D nutrition is linked with parathyroid adenoma growth and vitamin D deficiency in this part of the world may be a causative factor. Another theory is increased awareness in western countries but only increased awareness cannot explain the drastically opposite presentation of PHPT in developing countries.
There are no two thoughts on the surgical management as the only curative modality for the symptomatic PHPT. However, world literature is somewhat divided on the extent of surgical exploration. Norman et al. have questioned the utility of limited explorations and pointed it to be suitable for only a minority of PHPT cases. Their long term follow up study showed that Regardless of surgical adjuncts (scanning, intra-operative parathyroid hormone), unilateral parathyroidectomy will carry a 1-year failure rate of 3% to 5% and a 10-year recurrence rate of 4% to 6%. Allowing rapid analysis of all 4 glands through the same 1-inch incision has caused them to abandon unilateral parathyroidectomy. Norlen et al. performed a multicenter retrospective study to look for the best surgical approach for PHPT. The patient cohort was divided into 2 groups, FPTx and CPTx, based on intention-to-treat analysis the primary outcome measure was the persistence of PHPT. A total of 4569 patients (3585 females) were included. The overall persistence and recurrence rates were 2.2% and 0.9%, respectively, after a median follow-up of 6.5 years. There were 2531 FPTx cases and 2038 CPTx cases. The long-term recurrence rate was not different (5-year, 0.6% vs. 0.4%, log-rank P = 0.08). However, complications were more common in CPTx than in FPTX (7.6% vs. 3.6%, P < 0.001). In our study the overall persistence and recurrence rates were 2.14% and 0.53%, which is similar to the world literature. Surgical outcome did not differ between CPTx and FPTx groups and complication rates were also non-significant. Several other groups have also examined their results with surgical exploration and outcomes and their results are similar to our findings.,,, Most of these studies are from developed countries where the clinical profile of PHPT patients is totally different as compared to developing world. Although clinical profile of PHPT is changing in the developing world but it continues to be a symptomatic disorder with skeletal, renal and metabolic complications at a much younger age.,,,,,,,, Most of the studies demonstrating non-superiority of CPTx over FPTx have been done in a patient population where the majority of the cases are asymptomatic screen detected PHPT. Our study is probably the first study done in symptomatic PHPT with severely deranged biochemical profile, showing comparable results with CPTx and FPTx. Additionally, use of IOPTH did not influence the outcome in FPTx group. FPTx can be safely performed in resource limited settings where IOPTH is not available.
Reason for prolonged hospital stay at our center (8.6+/-4.7 days) as compared to developed countries is lack the of robust primary health care system. We discharge our patients only when their serum calcium comes up to within normal limits with oral calcium supplements.
| Conclusion|| |
FPTx yields a similar success rate as compared to CPTx even in symptomatic and young PHPT patients and can be performed safely even without intra-operative adjunct IOPTH in selected patients.
The retrospective nature of the study is a major limitation in itself and lack of long-term follow up data for patients operated in the current decade is another limitation. Results of FPTx has been compared with CPTx group which includes a retrospective cohort when FPTx was not being performed at our center. This may introduce an inherent bias.
Informed written consent was obtained from the patient.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| Supplemental Doc S1|| |
Surgical management protocol
Over the past 28 years total seven surgeons have been operating on these patients, but the usual departmental protocol is followed by them regarding the extent of exploration. Our departmental protocol prior to the year 2000 was conventional four gland exploration. This involved visual identification of at least four parathyroids and excision of enlarged glands. No intraoperative adjuncts were used during this time period. After the year 2000 departmental protocol changed to conventional four gland exploration only if both the anatomical and functional imaging (ultrasound/computerized tomography [CT] and Tc99 m sestamibi scans) of the neck were discordant. If the results of these two imaging techniques are concordant, we use a focused, lateral, minimally invasive approach, except when large palpable tumors are detected, in which case standard unilateral exploration is done. A few endoscopic (total endoscopic and video assisted) procedures were carried out as part of surgical workshop; hence, such procedures are not part of department protocol. The follow-up protocol included biochemical evaluation (S calcium, phosphorus, and alkaline phosphatase). All the patients who attained postoperative normocalcemia were defined as cured. Persistent disease was defined as failure to attain normocalcemia, postoperatively. Patients who became hypercalcemic 6 months after a curative surgery were defined as having recurrent disease.
| References|| |
Bilezikian JP, Silverberg SJ. Asymptomatic primary hyperparathyroidism. N
Engl J Med 2004;350:1746-51.
Harinarayan CV, Gupta N, Kochupillai N. Vitamin D status in primary hyperparathyroidism in India. Clin Endocrinol (Oxf) 1995;43:351-8.
Mishra SK, Agarwal G, Kar DK, Gupta SK, Mithal A, Rastad J. Unique clinical characteristics of primary hyperparathyroidism in India. Br J Surg 2001;88:708-14.
Arya V, Bhambri R, Godbole MM, Mithal A. Vitamin D status and its relationship with bone mineral density in healthy Asian Indians. Osteoporos Int 2004;15:56-61.
Muthukrishnan J, Jha S, Modi KD, Jha R, Kumar J, Verma A, et al
. Symptomatic primary hyperparathyroidism: A retrospective analysis of fifty one cases from a single centre. J Assoc Physicians India 2008;56:503-7.
Soin AS, Gupta S, Kochupillai N, Sharma LK. Primary hyperparathyroidism-An Indian study. Indian J Cancer 1994;31:72-7.
Mandl F. Therapeutisher versuch bein falls von ostitis fibrosa generalisata mittles. Extirpation eines epithelkörperchen tumors. Wien Klin Wochenshr Zentral 1926;143:245-84.
Carney JA. The glandulae parathyroideae of Ivar Sandstrom. Am J Surg Pathol 1996;20:1123-44.
van Heerden JA, Grant CS. Surgical treatment of primary hyperparathyroidism: An institutional perspective. World J Surg 1991;15:688-92.
Tibblin S, Bondeson AG, Ljungberg O. Unilateral parathyroidectomy in hyperparathyroidism due to a single adenoma. Ann Surg 1982;195:245-52.
Russell C. Unilateral neck exploration for primary hyperparathyroidism. Surg Clin North Am 2004;84:705-16.
Mazzeo S, Caramella D, Lencioni R, Molea N, De Liperi A, Marcocci C, et al
. Comparison among sonography, double-tracer subtraction scintigraphy, and duoble phase scintigraphy in the detection of parathyroid lesions. AJR 1996;166:1465-70.
Irvin GL, Carneiro DM. Rapid parathyroid hormone assay guided exploration. Op Tech Gen Surg 1999;1:18-27.
Miura D, Wada N, Arici C, Morita E, Duh QY, Clark OH. Does intraoperative quick parathyroid hormone assay improve the results of parathyroidectomy? World J Surg 2002;26:926-30.
Denham DW, Norman J. Bilateral neck exploration for all parathyroid patients is an operation for the history books. Surgery 2003;134:513.
Duh QY. Presidential address: Minimally invasive endocrine surgery-standard of treatment or hype? Surgery 2003;134:849-57.
Norman J, Lopez J, Politz D. Abandoning unilateral parathyroidectomy: Why we reversed our position after 15,000 parathyroid operations. J Am Coll Surg 2012;214:260-9.
Agarwal G, Prasad KK, Kar DK, Krishnani N, Pandey R, Mishra SK. Indian primary hyperparathyroidism patients with parathyroid carcinoma do not differ in clinicoinvestigative characteristics from those with benign parathyroid pathology. World J Surg 2006;30:732-42.
Yadav SK, Mishra SK, Mishra A, Mayilvagnan S, Chand G, Agarwal G, et al
. Changing profile of primary hyperparathyroidism over two and half decades: A study in tertiary referral center of North India. World J Surg 2018;42:2732-37.
Ohe MN, Santos RO, Barros ER, Lage A, Kunii IS, Abrahão M, et al
. Changes in clinical and laboratory findings at the time of diagnosis of primary hyperparathyroidism in a University Hospital in Sao Paulo from 1985-2002. Braz J Med Biol Res 2006;38:1383-7.
Biyabani SR, Talati J. Bone and renal stone disease in patients operated for primary hyperparathyroidism in Pakistan: Is the pattern of disease different from the west? J Pak Med Assoc 1999;49:194-8.
Gopal RA, Acharya SV, Bandgar T, Menon PS, Dalvi AN, Shah NS. Clinical profile of primary hyperparathyroidism from western India: A single center experience. J Postgrad Med 2010;56:79-84.
] [Full text]
Shah VN, Bhadada SK, Bhansali A, Behera A, Mittal BR. Changes in clinical and biochemical presentations of primary hyperparathyroidism in India over a period of 20 years. Indian J Med Res 2014;139:694-9.
] [Full text]
Ingemansson SG, Hugosson CH, Woodhouse NJ. Vitamin D deficiency and hyperparathyroidism with severe bone disease. World J Surg 1988;12:517-21.
Silverberg SJ, Bilezikian JP. Primary hyperparathyroidism: Still evolving? J Bone Miner Res 1997;12:856-62.
Norlén O, Wang KC, Tay YK, Johnson WR, Grodski S, Yeung M, et al
. No need to abandon focused parathyroidectomy: A multicenter study of long-term outcome after surgery for primary hyperparathyroidism. Ann Surg 2015;261:991-6.
Venkat R, Kouniavsky G, Tufano RP, Schneider EB, Dackiw AP, Zeiger MA. Long-term outcome in patients with primary hyperparathyroidism who underwent minimally invasive parathyroidectomy. World J Surg 2012;36:55-60.
Hodin R, Angelos P, Carty S, Chen H, Clark O, Doherty G, et al
. No need to abandon unilateral parathyroid surgery. J Am Coll Surg 2012;215:297; author reply 297-300.
Slepavicius A, Beisa V, Janusonis V, Strupas K. Focused versus conventional parathyroidectomy for primary hyperparathyroidism: A prospective, randomized, blinded trial. Langenbecks Arch Surg 2008;393:659-66.
Westerdahl J, Bergenfelz A. Unilateral versus bilateral neck exploration for primary hyperparathyroidism: Five-year follow-up of a randomized controlled trial. Ann Surg 2007;246:976-80; discussion 980-1.
Sosa JA. How best to approach surgery for primary hyperparathyroidism-Can we all agree? JAMA Surg 2016;151:969.
Bhansali A, Masoodi SR, Reddy KS, Behera A, das Radotra B, Mittal BR, et al
. Primary hyperparathyroidism in north India: A description of 52 cases. Ann Saudi Med 2005;25:29-35.
] [Full text]
Bilezikian JP, Meng X, Shi Y, Silverberg SJ. Primary hyperparathyroidism in women: A tale of two cities-New York and Beijing. Int J Fertil Womens Med 2000;45:158-65.
Zhao L, Liu J-M, He X-M, Zhao H-Y, Sun L-H, Tao B, et al
. The changing clinical patterns of primary hyperparathyroidism in Chinese patients: Data from 2000 to 2010 in a single clinical center. J Clin Endocrinol Metab 2013;98:721-8.
Prasarttong-Osoth P, Wathanaoran P, Imruetaicharoenchoke W, Rojananin S. Primary hyperparathyroidism: 11-year experience in a single institute in Thailand. Int J Endocrinol 2012;2012:952426.
[Table 1], [Table 2], [Table 3]