|Year : 2020 | Volume
| Issue : 3 | Page : 161-165
COVID-19 and endocrinopathies
Subhash Kumar Wangnoo1, Radhika Jindal2, Mohammad Asim Siddiqui1
1 Apollo Centre for Obesity, Diabetes and Endocrinology, Indraprastha Apollo Hospital, New Delhi, India
2 Department of Endocrinology, Safdurjung Hospital and Vardhman Mahavir Hosipital, New Delhi, India
|Date of Submission||23-Jun-2020|
|Date of Acceptance||03-Jul-2020|
|Date of Web Publication||29-Jul-2020|
Subhash Kumar Wangnoo
Apollo Centre for Obesity, Diabetes and Endocrinology, Indraprastha Apollo Hospital, New Delhi
Source of Support: None, Conflict of Interest: None
In general, it is rare for an endocrine physician to be at the fore-front of any pandemic, as most of the acutely ill patients are managed by first responders and emergency physicians. With increasing evidence that patients having endocrine and metabolic disorders, especially uncontrolled, are the ones expected to have poorer outcomes during the ongoing coronavirus disease 2019 (COVID-19) pandemic, it has brought the endocrine physician to the fore-front of management. Several publications have reported the endocrine and metabolic conditions that may be considered risk factors for acquiring the new coronavirus (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) infection, but the direct evidence whether SARS-CoV-2 may directly lead to endocrinopathies causing disorders that make the prognosis of affected patients worse, are lacking. Most of the endocrine disorders, but their etiopathogenesis or treatment thereof alter the way the body's immune defense mechanisms are triggered. Furthermore, in specific scenarios, ongoing treatment may have to be discontinued/modified. There is still paucity of data to alter the already available “best practices or clinical recommendations” statements. In the absence of any specific recommendations, it is the left to the judgment of the treating endocrine physician to adapt the available recommendations/guidelines on the basis of the clinical judgment.
Keywords: COVID-19, endocrine physician, endocrinopathies, immune mechanisms, poorer outcomes
|How to cite this article:|
Wangnoo SK, Jindal R, Siddiqui MA. COVID-19 and endocrinopathies. Apollo Med 2020;17:161-5
| Introduction|| |
The entire planet is encountering an unexpected situation due to coronavirus disease 2019 (COVID-19). In December 2019, the China National Health Commission reported that cases of pneumonia with an unknown cause had been detected in Wuhan in Hubei Province. Over the succeeding months, the disease then rapidly spread from Wuhan to throughout the world. The novel coronona virus - severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) was first isolated from patients of pneumonia at the epicentre of outbreak in Wuhan, China, in January this year. On March 11, 2020, the World Health Organization declared COVID-19 a public health emergency of international concern. In the absence of any treatment, this pandemic has put a remarkable strain on the health-care services, with even countries with excellent health-care systems feeling the strain. The situation in the countries with limited or no access to public health-care systems is even worse. The patients with endocrine disorders, especially if uncontrolled, are liable to be the most affected.
| The Relationship between Covid-19 and Endocrine System|| |
It is understandable health-care professionals who are involved in treating and caring for patients with COVID-19 are prioritizing data analysis, a situation exacerbated by the risk of contracting COVID-19. There is still a paucity of the data and it is expected that the understanding maybe undergo revision as more evidence is available. According to genome sequencing, SARS-CoV-2 is a beta-coronavirus of the same subgenus as SARS-CoV, with which it shares a sequence identity of approximately 80%. It enters the human body through the respiratory droplets through the respiratory tract, where it enters the cells through the angiotensin-converting enzyme 2 (ACE2) receptor. The clinical course of the disease varies, and risk factors for severe illness are advanced age, living in long-term care facility, chronic lung disease, cardiac conditions, immunocompromised, severe obesity, diabetes especially uncontrolled, chronic kidney disease treated with dialysis, and liver disease. A number of endocrine organs express ACE2, namely pancreas, thyroid, testis, ovary, adrenal glands, and pituitary. The role of ACE2 expression on endocrine system is presently unknown; currently, there are no clinical/preclinical data to preclude any such conclusions. The extrapolation is mostly based on observations drawn partly from studies pertaining to the prior SARS outbreak (in 2003) and partly from animal models. The immune response from the virus-infected lung epithelial cells produced interleukin (IL)-8 in addition to IL-6. IL-8 is a well-known chemoattractant for neutrophils and T cells. The majority of the observed infiltrating adaptive immune cells were likely T cells, considering that the significant reduction in circulating T cells was reported. CD14 + CD16 + inflammatory monocyte subsets, which seldom exist in healthy controls and are also found at significantly higher percentage in COVID-19 patients. These inflammatory CD14 + CD16 + monocytes had high expression of IL-6, which likely accelerated the progression of systemic inflammatory response. These inltereukins are also involved in the generation of endocrine autoimmune response, both in newly diagnosed patients and also amplifying the response in under-treatment patients.
| Covid-19 and Diabetes|| |
As per the 9th diabetes atlas from the International Diabetes Federation, 463 million people in the world have diabetes, with India being in second place if sheer numbers are to be taken into account. This humongously high prevalence of diabetes makes it an especially concerning risk factor as the COVID-19 pandemic progresses, especially in the rural areas where the access to quality health care is an issue. Furthermore, the situation is complicated by the younger population with diabetes, a large majority not having an adequate control of diabetes and having chronic complications. The earlier experience with SARS and Middle East respiratory syndrome, the two previous worldwide fatal respiratory infections caused by coronaviruses in the last decades, had increased fatalities in patients with diabetes.,
The mechanism that increases susceptibility to COVID-19 in patients with diabetes has not been conclusively established, but several mechanisms have been proposed. The expression of ACE2 is seen on the exocrine pancreas as well as on the islets, with pancreas having numerically higher expression compared to lungs. Exocrine pancreatic injury is manifested as elevated serum amylase and/or lipase in 1%–2% and 17% of patients with nonsevere and severe COVID-19, respectively. Immunohistochemistry and in situ hybridization have identified SARS-CoV in the pancreas of patients who died of SARS. Because of the immunological cascade it portends, it maybe a trigger for potentiating autoimmune endocrine pancreatic damage through release of mediators such as tumor-necrosis factor-α (TNFα) and interferon-γ. Elevated levels of IL-1β, monocyte chemoattractant protein-1 (MCP-1) and inducible protein-10 even in patients with mild COVID-19 might play an additional role to accentuate the process. Hypokalemia associated with the direct infection or as a consequence of treatment may lead to downregulation of pulmonary ACE2, reduced angiotension-II degradation, and subsequent increased aldosterone secretion. Hypokalemia, in turn, can worsen glucose control in preexisting diabetes. Associated obesity has also been found to be related to severe disease in COVID-19. Adipose tissue express ACE2; with higher adipose tissue, more would be the overall ACE2 expression that would act as receptors for SARS-CoV-2; also obesity is a pro-inflammatory state with patients have a higher concentration of several pro-inflammatory cytokines such as TNF-α, IL-6, and MCP-1, produced by visceral and subcutaneous adipose tissue. This may predispose an obese individual to an exaggerated cytokine response in the presence of SARS-CoV-2, manifesting as severe disease, and acute respiratory distress syndrome.
With the limited data that are available, male gender, advanced age, smoking, presence of cardiovascular, and kidney disease has a poorer outcome. Preexisting diabetes maybe affected with worsening glycemic control perhaps due to increases in serum levels of fetuin A, a glycoprotein that has been linked with impaired insulin sensitivity. However, there is a paradox - it has not yet been established whether poor glycemic control in uninfected patients with diabetes could increase their susceptibility to COVID-19. Furthermore, there are limited data on the association between good glucose control and a favorable prognosis.
Institutional protocols should include mandatory to check glucose and HbA1c levels in COVID-19 patients with diabetes and also in every patient who is admitted with COVID19.
Current evidence does not support any change in the ongoing medications and follow-ups. Similarly, international organizations recommend patients on ACEi/ARBs to carry on with their medications.
| Covid-19 and Thyroid|| |
The data on thyroid function or thyroid pathology are yet not available. It is also not known whether COVID-19 patients, symptomatic or without symptoms, develop thyroid dysfunction after infection. A possible localization of SARS-CoV-2 at the thyroid level cannot be excluded; the anatomical localization of thyroid gland may make it more prone toward direct infection. The generation of inflammatory cytokines may also make the susceptible individuals more prone for autoimmune thyroid disease. There have been case reports of COVID-19 patients mention suffering from ear pain (which may be a symptom of subacute thyroiditis) and one of the most common cardiovascular complications of these patients is tachyarrhythmia. Thyrotoxicosis may worsen the cardiovascular conditions, leading in some cases to tachyarrhythmia. In a recently published series of COVID-19 critically ill COVID-19 patients admitted to the intensive care unit, no preexisting thyroid problems were reported (even though the majority of patients had chronic illnesses before their admission to intensive care, most commonly, it was diabetes mellitus and chronic kidney disease), and it seems that no new thyroid issues have been reported during the COVID-19 illness in this patients cohort.
It is too early to suggest for routine evaluation of thyroid hormones in each and every patient, but admitted patients with preexisting disease should undergo evaluation promptly, especially those on the treatment of hyperthyroidism.
The British Thyroid Association and the Society for Endocrinology have issued a consensus statement regarding issues specific to thyroid dysfunction during COVID-19 pandemic. Patients with underlying hypothyroidism or hyperthyroidism are advised to continue their prescribed medications as usual. Special attention should be paid to patients on anti-thyroid drugs because they are at a risk of agranulocytosis, although its quite rare in general, symptoms of agranulocytosis often overlap with those of COVID-19, hence, often making it difficult to differentiate one from the other clinically. It is recommended that patients on ATDs who develop symptoms suggestive of agranulocytosis should immediately discontinue the drug and get a full blood count done at the earliest.
| Covid-19 and Pituitary|| |
There is no evidence that COVID-19 directly involves the pituitary gland. Hypothalamic and pituitary tissues do express ACE2 and can theoretically be the viral targets. Expression of ACE2 by the olfactory epithelial supporting cells could explain much hyposmia like symptoms. Autopsy studies, edema, and neuronal degeneration along with the identification of SARS genome have been shown in the hypothalamus. There is evidence of hypohysitis, but it recovers on follow-up. Currently, there is no data with regard to patients with COVID-19; but there is a theoretical possibility of immune-mediated hypophysitis. Clinicians should have a low threshold to suspect central hypocortisolism and central hypothyroidism in COVID-19 survivors, especially those complaining of unexplained fatigue, lassitude, malaise, orthostatic dizziness, anorexia, and apathy on follow-up. Patients with pituitary–hypothalamic disorders often have underlying diabetes insipidus (DI); COVID-19 in patients with DI can lead to insensible water loss due to fever and tachypnea ultimately resulting in hypernatremia.
| Covid-19 and Adrenals|| |
There is no evidence or data for the interaction of COVID-19 and adrenal dysfunction. The evidence available from molecular studies indicate that one of the strategies utilized by the SARS-CoV is to knock down the host's cortisol stress response, probably due to molecular mimicry of certain amino acid sequences with adrenocorticotropic hormone (ACTH). This blunts the stress-induced cortisol rise, as antibodies produced against the viral particles will inadvertently destroy the circulating ACTH. The use of high-dose steroids, and the recent evidence that dexamethasone in critically ill patients with severe COVID-19 may be helpful, may mask underlying relative adrenal insufficiency. Patients with underlying primary adrenal insufficiency are at a high risk of lower-respiratory tract infections and should be made aware of sick-day guidelines and be explained about regulating the dose of corticosteroids.
| Covid-19 and Gonads|| |
The testicular expression of mRNA and ACE2 in the testis is almost the highest in the human body. The Leydig cells, Sertoli cells, and the spermatogonia all express ACE2. A new study (although still to go into peer review at time of writing this article) provides the first direct evidence that the COVID-19 virus affects male sex hormones, drawing more attention to the evaluation of gonadal function among patients who have recovered from the infection, especially reproductive-age men. The study found a significant increase in serum luteinizing hormone in males with COVID-19, while there was a decrease in their ratio of testosterone to luteinizing hormone and the ratio of follicle stimulating hormone to luteinizing hormone. Besides, multivariable regression analysis indicated that c-reactive protein level was significantly associated with serum testosterone to luteinizing hormone ratio in such patients. In another study, testosterone in comparison to estrogen may predispose men to a widespread COVID-19 infection. Low serum levels of testosterone, which should be supposed to characterize the hormonal milieu in seriously ill individuals, may predispose men, especially aged men, to poor prognosis or death. Further studies are needed to confirm these pathophysiological assumptions and to promptly identify adequate therapeutic strategies. There is no data on effects on the female reproductive system.
| Covid-19 and Bone and Mineral Metabolism|| |
At present, there is no evidence that patients undergoing treatment for mineral and metabolic bone conditions may have any effects as regards to treatment for COVID-19. Observational studies have hypothesized an increased risk of hospitalization due to infections in patients with hypoparathyroidism. It is, however, unknown whether a causal relationship exists, and no data are available on risk of COVID-19 infections in hypoparathyroidism. It has been proposed that Vitamin D may play a role in reducing the risk of respiratory infections, such as seasonal influenza, through modulation of inflammatory cytokine profiles and induction of cathelicidins and defensins., Previous observational research has identified Vitamin D deficiency as a risk factor for ARDS and severity of ARDS, which can be a life-threatening complication of COVID-19. There is heterogeneity in outcomes and confounding factors in previous observational and RCT studies in this area. Vitamin D deficiency should be corrected based on available guidelines. Ongoing treatments for osteoporosis maybe delayed till the patient stabilizes. In patients newly diagnosed with primary hyperparathyroidism, medical management should be preferred unless indicated otherwise.
| Conclusions|| |
In the absence of meaningful data regarding COVID-19 and its acute effects on endocrinopathies, the available best practice guidelines should be followed. The treatment planning should involve multidisciplinary efforts to prioritized best outcomes. This further confounded by the failure up until now to exactly characteristics of the virus. It will take some time to clearly understand the immune reaction to SARS-CoV-2, antibody formation, and the rate of mutation of SARS-CoV-2. Until then, the adage of “Prevention is better than Cure” is apt for the current scenario.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, et al
. Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 2020;395:565-74.
Rabi FA, Al Zoubi MS, Kasasbeh GA, Salameh DM, Al-Nasser AD. SARS-CoV-2 and coronavirus disease 2019: What we know so far. Pathogens 2020;9:231.
Bosch BJ, van der Zee R, de Haan CA, Rottier PJ. The coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex. J Virol 2003;77:8801-11.
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, et al
. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-4.
Chen Y, Guo Y, Pan Y, Zhao ZJ. Structure analysis of the receptor binding of 2019-nCoV [published online ahead of print, 2020 Feb 17]. Biochem Biophys Res Commun 2020;525:135-40.
Walls AC, Park YJ, Tortorici MA, Wall A, McGuire AT, Veesler D. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 2020;181:281-92.
Williams R, Karuranga S, Malanda B, Saeedi P, Basit A, Besançon S, et al
. Global and regional estimates and projections of diabetes-related health expenditure: Results from the International Diabetes Federation Diabetes Atlas, 9th
edition. Diabetes Res Clin Pract 2020;162:108072.
India State-Level Disease Burden Initiative Diabetes Collaborators. The increasing burden of diabetes and variations among the states of India: The Global Burden of Disease Study 1990-2016. Lancet Glob Health 2018;6:e1352-e1362.
Hussain A, Bhowmik B, do Vale Moreira NC. COVID-19 and diabetes: Knowledge in progress. Diabetes Res Clin Pract 2020;162:108142.
Tang D, Comish P, Kang R. The hallmarks of COVID-19 disease. PLoS Pathog 2020;16:e1008536.
Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. Am J Physiol Endocrinol Metab 2020;318:E736-41.
Tay MZ, Poh CM, Rénia L, MacAry PA, Ng LF. The trinity of COVID-19: Immunity, inflammation and intervention. Nat Rev Immunol 2020;20:363-74.
Kadkhoda K. COVID-19: An Immunopathological View. mSphere 2020;5:e00344-20.
Collins AJ, Pitt B, Reaven N, Funk S, McGaughey K, Wilson D, et al
. Association of serum potassium with all-cause mortality in patients with and without heart failure, chronic kidney disease, and/or diabetes. Am J Nephrol 2017;46:213-21.
Dietz W, Santos-Burgoa C. Obesity and its Implications for COVID-19 Mortality. Obesity (Silver Spring) 2020;28:1005.
Marhl M, Grubelnik V, Magdič M, Markovič R. Diabetes and metabolic syndrome as risk factors for COVID-19. Diabetes Metab Syndr 2020;14:671-7.
Guo VY, Cao B, Cai C, Cheng KK, Cheung BMY. Fetuin-A levels and risk of type 2 diabetes mellitus: A systematic review and meta-analysis. Acta Diabetol 2018;55:87-98.
Patients Taking ACE-i and ARBs who Contract COVID-19 Should Continue Treatment, Unless Otherwise Advised by Their Physician; 2020. Available from: http://heart.org
. [Last accessed on 2020 Mar 17].
Dworakowska D, Grossman AB. Thyroid disease in the time of COVID-19. Endocrine 2020;68:471-4.
Ippolito S, Dentali F, Tanda ML. SARS-CoV-2: A potential trigger for subacute thyroiditis? Insights from a case report. J Endocrinol Invest 2020;43:1171-2.
Brancatella A, Ricci D, Viola N, Sgrò D, Santini F, Latrofa F. Subacute thyroiditis after Sars-COV-2 infection. J Clin Endocrinol Metab 2020;105:dgaa276.
Boelaert K, Visser WE, Taylor PN, Moran C, Léger J, Persani L. ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of hyperthyroidism and hypothyroidism. Eur J Endocrinol 2020;183:G33-9.
Pal R, Banerjee M. COVID-19 and the endocrine system: Exploring the unexplored. J Endocrinol Invest 2020;43:1027-31.
Mongioì LM, Barbagallo F, Condorelli RA, Cannarella R, Aversa A, La Vignera S, et al
. Possible long-term endocrine-metabolic complications in COVID-19: Lesson from the SARS model. Endocrine 2020;68:467-70.
Fleseriu M, Buchfelder M, Cetas JS, Fazeli PK, Mallea-Gil SM, Gurnell M, et al
. Pituitary society guidance: Pituitary disease management and patient care recommendations during the COVID-19 pandemic-an international perspective. Pituitary 2020;23:327-37.
Christ-Crain M, Hoorn EJ, Sherlock M, Thompson CJ, Wass JAH. Endocrinology in the time of COVID-19: Management of diabetes insipidus and hyponatraemia. Eur J Endocrinol 2020;183:G9-15.
Bornstein SR, Dalan R, Hopkins D, Mingrone G, Boehm BO. Endocrine and metabolic link to coronavirus infection. Nat Rev Endocrinol 2020;16:297-8.
Theoharides TC, Conti P. Dexamethasone for COVID-19? Not so fast [published online ahead of print, 2020 Jun 4]. J Biol Regul Homeost Agents 2020;34:10.
Puig-Domingo M, Marazuela M, Giustina A. COVID-19 and endocrine diseases. A statement from the European Society of Endocrinology. Endocrine 2020;68:2-5.
Fu J, Zhou B, Zhang L, Balaji KS, Wei C, Liu X, et al
. Expressions and significances of the angiotensin-converting enzyme 2 gene, the receptor of SARS-CoV-2 for COVID-19. Mol Biol Rep 2020;47:4383-92.
Giagulli 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? [published online ahead of print, 2020 Jun 11]. Andrology. 2020;10.1111/andr.12836.
Grant WB, Lahore H, McDonnell SL. Evidence that Vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020;12:988.
Martineau AR, Jolliffe DA, Hooper RL, Greenberg L, Aloia JF, Bergman P, et al
. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017;356:i6583.
Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, et al
. Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Thorax 2015;70:617-24.