Review Postgrad Med J: first published as 10.1136/postgradmedj-2020-137934 on 11 June 2020. Downloaded from Endocrine changes in SARS- CoV-2 patients and lessons from SARS- CoV Shubham Agarwal ,1 Sanjeev Kumar Agarwal2 1Department of Internal ABSTRact for better risk stratification and management of Medicine, Rosalind Franklin Coronavirus infection outbreaks have occurred frequently patients with SARS- CoV-2 infection. University of Medicine and Science Chicago Medical School, in the last two decades and have led to significant North Chicago, Illinois, USA mortality. Despite the focus on reducing mortality by 2 METHODS Department of Cardiology, preventing the spread of the virus, patients have died All articles reporting endocrine changes in Rashid Hospital, Dubai, United due to several other complications of the illness. The Arab Emirates SARS- CoV-2 and SARS- CoV patients were consid- understanding of pathological mechanisms and their ered. Electronic database of PubMed was searched implications is continuously evolving. A number of Correspondence to using medical subject headings (MeSH) terms Dr Shubham Agarwal, Rosalind symptoms occur in these patients due to the involvement related to SARS- CoV-2, SARS-CoV and different Franklin University of Medicine of various endocrine glands. These clinical presentations hormones. Since the SARS- CoV outbreak occurred and Science Chicago Medical went largely unnoticed during the first outbreak of in 2002, search results were limited to January School, North Chicago IL 60064, severe acute respiratory syndrome (SARS) in 2002–2003. 2002 onwards to consider articles pertaining to Illinois, USA; A few of these derangements continued during the shubhamagarwaldr@ gmail.com the outbreaks of both the viruses. A considerable convalescence phase and sometimes occurred after number of articles were in the Chinese language and Received 22 April 2020 recovery. Similar pathological and biochemical changes were included after being translated into English. Revised 16 May 2020 are being reported with the novel coronavirus disease This was supplemented by handsearching refer- Accepted 26 May 2020 outbreak in 2020. In this review, we focus on these ence lists for additional studies and case reports. endocrine changes that have been reported in both Similarly, Google Scholar database was hand- SARS coronavirus and SARS coronavirus-2. As we battle searched. Studies listing type 2 diabetes mellitus as the pandemic, it becomes imperative to address these a risk factor of SARS-CoV -2 and SARS-CoV were underlying endocrine disturbances that are contributing excluded since they did not mention any biochem- towards or predicting mortality of these patients. ical changes. Articles about corticosteroid induced hyperglycaemia, audio interviews and articles detailing the renin- angiotensin aldosterone system (RAAS) inhibitors were excluded. An initial search INTRODUCTION showed 1585 articles; finally, 17 of them were On 31 December 2019, the WHO office in China included (figure 1). was informed of a few cases of pneumonia of unknown cause originating from the city of Wuhan, http://pmj.bmj.com/ Hubei in China.1 Over the next 3 months, the DISCUSSION severe acute respiratory syndrome coronavirus-2 Coronavirus infections cause a systemic disease (SARS- CoV-2) illness commonly called COVID-19 that injures many organs. These patients mani- has affected more than four million people glob- fest many hormonal and metabolic disturbances. ally with over 1.4 million cases in the USA itself, Changes in thyroid, pancreas and adrenal glands making it the new epicentre of the illness followed have been reported in detail in both SARS-CoV and by much of Western Europe. The mortality rates the current SARS- CoV-2 infections. The pathology on September 26, 2021 by guest. Protected copyright. from different parts of the world show vast differ- data, clinical features, management and outcome ences but studies have consistently shown that the of these endocrinopathies are highlighted below presence of comorbidities, specially type 2 diabetes (figure 2). mellitus significantly increases mortality in patients with SARS- CoV-2 with an OR of 2.85.2–5 A study Thyroid changes from China also showed that patients in the inten- A detailed histopathological study on the effects sive care unit with SARS-CoV -2 infection were of SARS infection on the thyroid gland was done more likely to have underlying diabetes (22.2% during the SARS- CoV outbreak.7 There was exten- vs 5.9%) than others.6 Certain forms of hypoph- sive injury of the parafollicular cells and follicular © Author(s) (or their ysitis, thyroiditis and adrenalitis have viral aetiol- epithelium with the destruction and exfoliation employer(s)) 2020. No ogies. Changes in endocrine functions observed of epithelial cells into the follicle leading to its commercial re- use. See rights and permissions. Published during the previous coronavirus outbreak with disruption. These changes were responsible for by BMJ. SARS-CoV , led to considerable morbidity and were lower levels of thyroid hormones noted in clin- important predictors of mortality. Therefore, it is ical studies. Parafollicular cells are responsible for To cite: Agarwal S, Agarwal imperative to know the endocrinopathic impact of calcitonin production and they could not be iden- SK. Postgrad Med J Epub ahead of print: [please SARS-CoV -2 illness. The purpose of this review is tified on H&E sections in the tissue sample from include Day Month Year]. to highlight the available data on endocrine changes patients with SARS. Damage to interfollicular tissue doi:10.1136/ in such patients and to recapitulate the existing including parafollicular cells may adversely affect postgradmedj-2020-137934 knowledge from previous coronavirus outbreaks calcitonin production. An interesting finding was Agarwal S, Agarwal SK. Postgrad Med J 2020;0:1–5. doi:10.1136/postgradmedj-2020-137934 1 Review Postgrad Med J: first published as 10.1136/postgradmedj-2020-137934 on 11 June 2020. Downloaded from Figure 1 Flow chart of literature search and selection of studies. RAAS, renin- angiotensin aldosterone system. the absence of inflammatory infiltrate and features of cellular showed that thyroid stimulating hormone (TSH) and free necrosis, supporting the hypothesis of extensive apoptosis triiodothyronine (T3) concentrations were significantly lower in responsible for thyroid injury. deceased patients (0.7 mIU/mL and 2.8 pmol/L) than in recov- The pathology data of the thyroid gland in patients with ered patients (1.4 mIU/mL and 4.3 pmol/L). The difference in SARS- CoV-2 infection have been published by Yao et al. They the thyroxine (T4) levels was not statistically significant.9 conducted minimally invasive autopsies from different organs A study by Wang et al reported that serum levels of T3 and T4 in patients who had died of SARS-CoV -2 and investigated the in patients with SARS-CoV were significantly lower than those pathological changes.8 They reported no abnormalities in the in the control group, and low T3 levels correlated with disease thyroid follicular morphology but did note lymphocytic infiltra- severity. Serum T3 and T4 levels were decreased, respectively, in tion in the interstitium. None of the tissue immunohistochemistry 94% and 46% of 48 patients with SARS-CoV during the acute and PCR analyses detected SARS- CoV-2 in the thyroid gland. phase and 90% and 38% during the convalescent phase of the These findings are at variance with those reported in SARS-CoV disease.10 The authors also noted lower levels of TSH in these though the patient characteristics in the two studies were nearly patients. Dysfunction of the HPT axis caused a diminished level the same. However, irrespective of pathological findings, most of serum TSH in patients with SARS-CoV despite low serum T3 of the studies found a similar pattern of biochemical changes. and T4. No significant difference in serum parathyroid hormone Limited data suggest that the thyroid gland and the hypo- level was observed between patients with SARS-CoV and the thalamo–pituitary–thyroid (HPT) axis are directly affected in control group, during the acute or convalescent phases of the SARS- CoV-2 illness. A study of 274 patients with SARS-CoV -2 illness. http://pmj.bmj.com/ Changes in thyroid hormone levels may persist after clinical recovery. Leow et al studied SARS-CoV survivors for hormonal derangements 3 months after recovery and noted that 6.7% of the patients had developed biochemical hypothyroidism.11 The majority of these patients (75%) had a central aetiology and only 25% developed primary hypothyroidism with positive antibodies and continued to receive thyroid hormone replace- on September 26, 2021 by guest. Protected copyright. ment at the end of the study. On follow-up, changes in the thyroid profile of the patients with central hypothyroidism had normalised. Central hypocortisolism was also present in 66% of patients who had central hypothyroidism. The authors suggested a dysfunctional HPT axis as evidenced by the results of thyroid hormones and the coexistence of central hypocortisolism. These studies suggest for the monitoring of thyroid func- tion tests during acute illness as well as during convalescence of SARS-CoV -2 with the possibility of replacement therapy as indicated. There were reports of recovery of thyroid function in 3– 6 months in SARS-CoV patients, implying reassessment of survivors of the current pandemic.11 Figure 2 Schematic representing endocrine changes seen in Endocrine pancreas changes and diabetes SARS- CoV infections. ACTH, adrenocorticotropic hormone; DHEA- S, Many viruses, such as enteroviruses, Coxsackie B virus,12 retro- dehydroepiandrosterone sulfate; HPA, hypothalamic–pituitary–adrenal; viruses, rubella, mumps, cytomegalovirus, Epstein- Barr and vari- HPT, hypothalamo–pituitary–thyroid; SARS- CoV, severe acute respiratory cella zoster virus have been implicated in the development of syndrome coronavirus; TSH, thyroid stimulating hormone. diabetes mellitus in humans.13 2 Agarwal S, Agarwal SK. Postgrad Med J 2020;0:1–5. doi:10.1136/postgradmedj-2020-137934 Review Postgrad Med J: first published as 10.1136/postgradmedj-2020-137934 on 11 June 2020.