Indian Journal of Endocrinology and Metabolism

EDITORIAL
Year
: 2021  |  Volume : 25  |  Issue : 1  |  Page : 1--3

COVID-19 and endocrine disorders – Emerging links in this puzzle


SV Madhu, Nishant Raizada 
 Department of Endocrinology, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi, India

Correspondence Address:
S V Madhu
Department of Endocrinology, Center for Diabetes Endocrinology and Metabolism, University College of Medical Sciences and Guru Teg Bahadur Hospital, New Delhi - 110 095
India




How to cite this article:
Madhu S V, Raizada N. COVID-19 and endocrine disorders – Emerging links in this puzzle.Indian J Endocr Metab 2021;25:1-3


How to cite this URL:
Madhu S V, Raizada N. COVID-19 and endocrine disorders – Emerging links in this puzzle. Indian J Endocr Metab [serial online] 2021 [cited 2021 Jul 25 ];25:1-3
Available from: https://www.ijem.in/text.asp?2021/25/1/1/322027


Full Text



The COVID-19 pandemic is well into its second year of existence and our knowledge about this novel infection has increased substantially in this period. The causative agent of COVID-19, the SARS CoV-2, has demonstrated that it is capable of involving multiple organ systems rather than being just a respiratory pathogen. The link with endocrine disorders was noticed quite early when it was found that patients with diabetes and uncontrolled hyperglycemia were at an increased risk of severe disease as well as mortality from COVID-19.[1] However, the other endocrine manifestations of COVID-19 probably were more subtle and information about them emerged more gradually over a period of time. In this issue, Kumar et al. have reported endocrine abnormalities in COVID-19 patients with a focus on thyroid and adrenal function.[2]

Thyroid diseases are common endocrine disorders; and accordingly, a lot of attention has gone into the study of how COVID-19 affects the thyroid. Although the majority of mild to moderate COVID-19 patients remain euthyroid, a significant proportion of those with severe disease manifest with abnormalities in thyroid function. These manifestations include low TSH and low T3 levels, whereas low T4 levels were observed less commonly.[3] Kumar et al. also found that nearly a quarter of their study population had low T3 syndrome, whereas low T4 was seen in 5%. This picture has been likened to the non-thyroidal illness pattern of thyroid dysfunction. The prognostic implications of these manifestations have also been investigated.[4] Apart from this, several reports of subacute thyroiditis following COVID-19 have also been published.[5] Although direct causality has not been proven, no other causative factor was identified in these reports. COVID-19 related thyroiditis has been proposed as a novel entity.[6] Similarly, Graves' disease has been reported to occur in patients who had recovered from COVID-19.[7]

In a large study, thyrotoxicosis occurred in 20% of COVID-19 patients suggesting the role of systemic immune activation.[8] Hypothyroidism, predominantly subclinical, has been found in few patients, a finding corroborated by the study published in this issue.[2],[8] A possibility of central hypothyroidism, which improved after recovery from COVID-19, has been reported in a few cases in one study.[9]

Adrenal dysfunction in COVID-19 has now been reported in several studies. The receptors for the SARS-CoV-2, angiotensin-converting enzyme 2(ACE2), and transmembrane serine protease 2 (TMPRSS2) have been localized in adrenals providing a pathway for the virus to affect the gland.[10] Low basal serum cortisol and plasma adrenocorticotropic hormone (ACTH) have been documented in COVID-19 patients mimicking a picture of central adrenal insufficiency. The levels are found to be lower in patients with more severe disease, and critically ill COVID-19 patients have lower cortisol levels than those with critical illness without COVID-19.[11] In this respect, the present study by Kumar et al. differs – severe cases appeared to have higher basal and stimulated serum cortisol than mild cases; although, critical illness-related corticosteroid insufficiency (CIRCI) was reported by Kumar et al. also.[2] Interestingly, Kumar et al. found evidence of adrenal insufficiency mainly in asymptomatic and mild COVID-19 patients. This finding is not surprising as the adrenal crisis has been reported in asymptomatic COVID -19 patients.[12]

Vascular complications in the adrenals can also occur. Both unilateral and bilateral adrenal hemorrhage has been reported.[13],[14] Furthermore, adrenal infarction has been known to occur.[15] Acute adrenal infarction has been reported as an incidental finding on CT scans in nearly a fourth of severe COVID-19 patients and may portend a poor prognosis.[16] A delayed onset central hypoadrenalism during recovery from COVID-19 has been reported.[17] Ischemic necrosis, lipid degeneration, hemorrhage, and adrenalitis have been found in autopsy studies of adrenals.[18]

The parathyroids appear to have been spared by the SARS CoV-2. A single case report of hypoparathyroidism due to COVID-19 has been published.[19] Additionally, serum calcium has been proposed as a biomarker of severity in COVID-19.[20]

Regarding pituitary dysfunction, data are again scanty. Apart from the involvement of the pituitary-thyroid and pituitary-adrenal axis by COVID-19, as discussed above, several case reports of pituitary apoplexy within pituitary adenomas in patients with COVID-19 have come to light.[21],[22],[23] In one case, apoplexy appeared to occur in the absence of a pituitary adenoma or other risk factors, raising the possibility of COVID-19 itself being the cause.[24],[25] Hyperprolactinemia has been reported in COVID-19 patients.[26] Kumar et al. have also reported hyperprolactinemia in around 9% of their patients.[2]

Gonadal function in COVID-19 has received some attention. Serum testosterone levels were found to be lower in patients with severe COVID-19 as compared to mild or moderate cases, but this effect may be entirely attributable to critical illness rather than a COVID-19 manifestation.[27] A systematic review also found low testosterone and high luteinizing hormone (LH) levels in COVID-19 patients.[28] Furthermore, autopsy studies have shown evidence of damage to seminiferous tubules, a reduction in Leydig cells, and infiltration by lymphocytes.[29] The male genital tract appears to express ACE2 and TMPRSS2 receptors at various sites, increasing its susceptibility to the SARS-CoV-2.[30] Overall, males seem to have a poor outcome from COVID-19, a phenomenon that may be linked to the different sex hormone milieu in males and females.[31] The female reproductive tract may not be rich in receptors like ACE 2 and TMPRSS2.[32] Accordingly, changes in female sexual function and hormone levels have been reported to be infrequent.[33]Although diabetes was the very first endocrine disorder to gain importance in the pandemic, the ability of the SARS-CoV-2 to affect pancreatic beta cells and cause diabetes is still a matter of debate. There were initial concerns regarding new-onset diabetes and ketoacidosis with COVID-19.[34] Some studies reported that the ACE 2 receptor was present on beta cells, whereas other studies found it to be absent.[35],[36] The incidence of type 1 diabetes does not appear to have increased in the pandemic which also does not support a direct toxic effect of the SARS-CoV-2 on beta cells.[37],[38] Factors such as undiagnosed pre-existing diabetes, stress hyperglycemia, and steroid-induced diabetes, make deciphering the impact of SARS-CoV-2 on diabetes a difficult task.[39]

The endocrine manifestations of COVID-19 can be likened to pieces of a puzzle – one which is slowly but surely coming together.

References

1Barron E, Bakhai C, Kar P, Weaver A, Bradley D, Ismail H, et al. Associations of type 1 and type 2 diabetes with COVID-19-related mortality in England: A whole-population study. Lancet Diabetes Endocrinol 2020;8:813-22.
2Kumar B, Gopalakrishnan M, Garg MK, Purohit P, Banerjee M, Sharma P, et al. Endocrine dysfunction among patients with COVID-19: A single-center experience from a tertiary hospital in India. Indian J Endocr Metab 2021.
3Trimboli P, Camponovo C, Scappaticcio L, Bellastella G, Piccardo A, Rotondi M. Thyroid sequelae of COVID-19: A systematic review of reviews. Rev Endocr Metab Disord 2021;22:485-91.
4Lui DTW, Lee CH, Chow WS, Lee ACH, Tam AR, Fong CHY, et al. Thyroid dysfunction in relation to immune profile, disease status, and outcome in 191 patients with COVID-19. J Clin Endocrinol Metab 2021;106:e926-35.
5Khatri A, Charlap E, Kim A. Subacute Thyroiditis from COVID-19 infection: A case report and review of literature. Eur Thyroid J 2020;9:324-8.
6Dworakowska D, Morley S, Mulholland N, Grossman AB. Covid-19 related thyroiditis: A novel disease entity? Clin Endocrinol (Oxf) 2021. doi: 10.1111/cen. 14453.
7Harris A, Al Mushref M. Graves' thyrotoxicosis following SARS-CoV-2 infection. AACE Clin Case Rep 2021;7:14-6.
8Lania A, Sandri MT, Cellini M, Mirani M, Lavezzi E, Mazziotti G. Thyrotoxicosis in patients with COVID-19: The THYRCOV study. Eur J Endocrinol 2020;183:381-7.
9Chen M, Zhou W, Xu W. Thyroid function analysis in 50 patients with COVID-19: A retrospective study. Thyroid Off J Am Thyroid Assoc 2021;31:8-11.
10Mao Y, Xu B, Guan W, Xu D, Li F, Ren R, et al. The adrenal cortex, an underestimated site of SARS-CoV-2 infection. Front Endocrinol 2021;11:593179. doi: 10.3389/fendo. 2020.593179.
11Alzahrani AS, Mukhtar N, Aljomaiah A, Aljamei H, Bakhsh A, Alsudani N, et al. The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis. Endocr Pract Off J Am Coll Endocrinol Am Assoc Clin Endocrinol 2021;27:83-9.
12Castinetti F, Amodru V, Brue T. Adrenal crisis may occur even in patients with asymptomatic covid-19. Endocr Pract 2020;26:929-30.
13Sharrack N, Baxter CT, Paddock M, Uchegbu E. Adrenal haemorrhage as a complication of COVID-19 infection. BMJ Case Rep 2020;13:e239643.
14Frankel M, Feldman I, Levine M, Frank Y, Bogot NR, Benjaminov O, et al. Bilateral adrenal hemorrhage in coronavirus disease 2019 patient: A case report. J Clin Endocrinol Metab 2020;105:dgaa487. doi: 10.1210/clinem/dgaa487.
15Kumar R, Guruparan T, Siddiqi S, Sheth R, Jacyna M, Naghibi M, et al. A case of adrenal infarction in a patient with COVID 19 infection. BJR Case Rep 2020;6:20200075. doi: 10.1259/bjrcr. 20200075.
16Leyendecker P, Ritter S, Riou M, Wackenthaler A, Meziani F, Roy C, et al. Acute adrenal infarction as an incidental CT finding and a potential prognosis factor in severe SARS-CoV-2 infection: A retrospective cohort analysis on 219 patients. Eur Radiol 2021;31:895-900.
17Chua MWJ, Chua MPW. Delayed onset of central hypocortisolism in a patient recovering from COVID-19. AACE Clin Case Rep 2021;7:2-5.
18Santana MF, Borba MGS, Baía-da-Silva DC, Val F, Alexandre MAA, Brito-Sousa JD, et al. Case report: Adrenal pathology findings in severe COVID-19: An autopsy study. Am J Trop Med Hyg 2020;103:1604-7.
19Elkattawy S, Alyacoub R, Ayad S, Pandya M, Eckman A. A novel case of hypoparathyroidism secondary to SARS-CoV-2 infection. Cureus 2020;12:e10097.
20Sun J-K, Zhang W-H, Zou L, Liu Y, Li J-J, Kan X-H, et al. Serum calcium as a biomarker of clinical severity and prognosis in patients with coronavirus disease 2019. Aging 2020;12:11287-95.
21Ghosh R, Roy D, Roy D, Mandal A, Dutta A, Naga D, et al. A rare case of SARS-CoV-2 infection associated with pituitary apoplexy without comorbidities. J Endocr Soc 2021;5:bvaa203. doi: 10.1210/jendso/bvaa203.
22LaRoy M, McGuire M. Pituitary apoplexy in the setting of COVID-19 infection: A case report. Am J Emerg Med 2021. doi: 10.1016/j.ajem. 2021.02.045.
23Solorio-Pineda S, Almendárez-Sánchez CA, Tafur-Grandett AA, Ramos-Martínez GA, Huato-Reyes R, Ruiz-Flores MI, et al. Pituitary macroadenoma apoplexy in a severe acute respiratory syndrome-coronavirus-2-positive testing: Causal or casual? Surg Neurol Int 2020;11:304.
24Bordes SJ, Phang-Lyn S, Najera E, Borghei-Razavi H, Adada B. Pituitary apoplexy attributed to COVID-19 infection in the absence of an underlying macroadenoma or other identifiable cause. Cureus 2021;13:e13315.
25Kusmartseva I, Wu W, Syed F, Heide VVD, Jorgensen M, Joseph P, et al. Expression of SARS-CoV-2 entry factors in the pancreas of normal organ donors and individuals with COVID-19. Cell Metab 2020;32:1041-1051.e6.
26Kadihasanoglu M, Aktas S, Yardimci E, Aral H, Kadioglu A. SARS-CoV-2 pneumonia affects male reproductive hormone levels: A prospective, cohort study. J Sex Med 2021;18:256-64.
27Çayan S, Uğuz M, Saylam B, Akbay E. Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: A cohort study. Aging Male Off J Int Soc Study Aging Male 2020;23:1493-503.
28Khalili MA, Leisegang K, Majzoub A, Finelli R, Panner Selvam MK, Henkel R, et al. Male fertility and the COVID-19 pandemic: Systematic review of the literature. World J Mens Health 2020;38:506-20.
29Yang M, Chen S, Huang B, Zhong J-M, Su H, Chen Y-J, et al. Pathological findings in the testes of COVID-19 patients: Clinical implications. Eur Urol Focus 2020;6:1124-9.
30Sheikhzadeh Hesari F, Hosseinzadeh SS, Asl Monadi Sardroud MA. Review of COVID-19 and male genital tract. Andrologia 2021;53:e13914.
31Giagulli VA, Guastamacchia E, Magrone T, Jirillo E, Lisco G, De Pergola G, et al. Worse progression of COVID-19 in men: Is testosterone a key factor? Andrology 2021;9:53-64.
32Goad J, Rudolph J, Rajkovic A. Female reproductive tract has low concentration of SARS-CoV2 receptors. PloS One 2020;15:e0243959.
33Li K, Chen G, Hou H, Liao Q, Chen J, Bai H, et al. Analysis of sex hormones and menstruation in COVID-19 women of child-bearing age. Reprod Biomed Online 2021;42:260-7.
34Rubino F, Amiel SA, Zimmet P, Alberti G, Bornstein S, Eckel RH, et al. New-onset diabetes in Covid-19. N Engl J Med 2020;383:789-90.
35Fignani D, Licata G, Brusco N, Nigi L, Grieco GE, Marselli L, et al. SARS-CoV-2 receptor angiotensin I-Converting enzyme type 2 (ACE2) is expressed in human pancreatic γ-cells and in the human pancreas microvasculature. Front Endocrinol 2020;11. doi: 10.3389/fendo. 2020.596898.
36Coate KC, Cha J, Shrestha S, Wang W, Gonçalves LM, Almaça J, et al. SARS-CoV-2 cell entry factors ACE2 and TMPRSS2 are expressed in the microvasculature and ducts of human pancreas but are not enriched in γ cells. Cell Metab 2020;32:1028-40.e4.
37Rabbone I, Schiaffini R, Cherubini V, Maffeis C, Scaramuzza A, Diabetes Study Group of the Italian Society for Pediatric Endocrinology and Diabetes. Has COVID-19 delayed the diagnosis and worsened the presentation of type 1 diabetes in children? Diabetes Care 2020;43:2870-2.
38Tittel SR, Rosenbauer J, Kamrath C, Ziegler J, Reschke F, Hammersen J, et al. Did the COVID-19 lockdown affect the incidence of pediatric type 1 diabetes in Germany? Diabetes Care 2020;43:e172-3.
39Accili D. Can COVID-19 cause diabetes? Nat Metab 2021;3:123-5.