Coronavirus as a Trigger Of Graves’ Disease

Abstract

Context

SARS-CoV-2 infection was declared a pandemic in 2020 and affected millions of people worldwide. Angiotensin-converting enzyme-2 receptors, through which coronavirus enters the cells of different organs, have been detected in the thyroid gland. The most common cause of thyrotoxicosis is Graves’ disease in which thyroid-receptors antibodies (TRAb) stimulate the TSH receptor, increasing thyroid hormone production and release.

Case presentation

A 22-year-old woman had symptoms of palpitation, tremor, muscle weakness, anxiety and sleep disturbance. 3 weeks before the onset of these symptoms, the patient suffered from COVID-19, which lasted 14 days and was characterized by a course of moderate severity with fever up to 38^°C, general weakness without shortness of breath. The patient had no pre-existing thyroid problems. Her TSH was <0.01 mU/L, FT4, FT3 and TRAb were increased. Antithyroid drugs, glucocorticosteroids and β-blockers were prescribed. During 3 months of treatment doses of methimazole, methylprednisolone and bisoprolol were gradually reduced due to the improvement of the patient’s condition and thyroid tests normalization.

Conclusions

COVID-19 infection can cause Graves’ disease and thyrotoxicosis. The onset of this disease after SARS-CoV-2 does not depend on the presence of pre-existing thyroid pathology and requires the appointment of glucocortisteroids.

Introduction

In March 2020, WHO declared SARS-CoV-2 a global pandemic. Currently, about 55.5 million people have been infected with coronavirus (1). The most susceptible populations are the elderly, pregnant women and people with chronic illnesses such as heart failure, asthma and cancer (2).

There are no data available about the pathogenesis of coronavirus disease and its consequences for the patients in the future (3, 4). The possible way for coronavirus to reach the cells are ACE-2 receptors, which are located in small intestine, lungs, kidneys, heart, adipose tissue, and thyroid gland (5). Therefore, it is logical to assume that not only the respiratory system may be a target for coronavirus, but also other above-mentioned organs.

A connection between αvβ3-integrin and coronavirus is being actively studied now. Integrins are a group of heterogeneous systemic proteins that are responsible for the interaction between cells and extracellular proteins, in particular, they can bind to ACE-2 receptors (3, 6, 7). Integrin αvβ3 has receptors to thyroid hormones on its surface, in particular T4 (8), which modulate an expression of genes responsible for the synthesis of integrin β3. Therefore, it is assumed that thyroid hormones may contribute to the entry of coronavirus into target organs. So, patients with thyrotoxicosis are a group at risk for SARS-Cov-2 infection (9) and coronavirus can influence thyroid function as numerous cases with destructive/subacute thyroiditis in patients infected by SARS-COV-2 have been described (10).

Thyrotoxicosis is most commonly due to Graves’ disease, the prevalence of which is>1% in the world population (11). GD is an autoimmune disorder in which TRAb stimulate the TSH receptor, increasing thyroid hormone production and release. Lately, two cases of COVID-19-related to Graves’ disease were reported by Mateu-Salat et al. (12). Besides, evidence of painless thyroiditis were found in patients after COVID-19 with pneumonia (13).

In the most cases, antithyroid drugs and β-blockers are prescribed to reduce the symptoms of thyrotoxicosis. Glucocortico should be prescribed in the case of thyroid storm, orbitopathy, precrisis or failure to control the thyrotoxicosis.

Case Presentation

A 22-year-old woman who is the resident in an iodine deficient area with no personal history of thyroid disease developed palpitations, hands tremor, muscle weakness, anxiety and sleep disturbance after 3 weeks of full recovery from COVID-19. In April 2020 she had fever up to 38°C and general weakness. COVID-19 was confirmed by a positive PCR test. The patient was managed with no specific treatment (no heparin/low molecular heparins, no glucocortico; CT scan was not performed) and recovered rapidly. Physical examination (05.05.2020): height - 1.68m, weight- 52 kg, heart rate (HR) - 110 beats/min., blood pressure (BP) - 110/79 mmHg, heart sounds rhythmic, respiratory rate (RR) - 18/min, hands tremor. Orbitopathy was not found. Blood cell count was with high lymphocyte percentage (48%) and increased erythrocyte sedimentation rate (25 mm/h). The thyroid function tests: TSH <0.010mU/L (normal values 0.4-4.0mU/L); FT3 was 12.55 pg/mL (n. v. 2.0–4.4); and FT4 was 17.77 ng/dL (n. v. 0.93–1.77). Thyroglobulin (Tg) was 421.5 pg/mL; (n.v. 3.5-77.0), whereas TRAbs were extremely increased - 32.72 mU/mL (n.v.<1.58 mU/mL). Neck ultrasonography showed a diffusely enlarged, hypoechogenic thyroid gland with markedly enhanced vascularization. Iodine uptake test was not performed. The patient was given antithyroid drugs (ATDs) – methymazole (10 mg 4 times per day) and β-blockers (bisoprolol 2.5 mg/d).

Within 2 weeks (20.05.2020), because of worsening of tremors, anxiety, and palpitations, treatment with oral methylprednisolone (12 mg/d) was given.

Figure 1.

Neck ultrasound (05.05.2020). Thyroid gland diffusely enlarged, hypoechogenic (a) with enhanced vascularization (b).

During two months of ATDs, ß-blockers and steroids therapy (20.05.-21.07.2020), the patient felt better. Physical examination: HR - 84 beats / min., BP - 115/75 mm Hg, RR - 16 / min., no tremor. Thyroid function test: TSH 0.12 mU/L; FT3 was 5.32 pg/mL; FT4 was 5.45 ng/dL, TRAbs were 12.37 mlU/L, Tg – 204.5 pg/mL. Liver transaminases were: alanine aminotransferase (ALT ) - 22.2 U/L (n.v.<33 U/L), aspartate aminotransferase (AST) - 20.2 U/L (<32 U/L). ATDs was reduced to 10 mg 3 times a day, methylprednisolone to 4 mg/day, bisoprolol remained unchanged.

Two weeks later (05.08.2020): HR - 82 beats/ min., BP- 112/76 mm Hg, RR - 19/min., ADTs was reduced to 20 mg/day and bisoprolol to 1.25 mg/d. Oral glucocorticosteroid was withdrawn.

At the last examination (21.09.2020) the patient did not have any symptoms. Thyroid function tests: TSH 2.89 mU/L; FT3 was 4.01 pg/mL; FT4 was 1.56 ng/dL, TRAbs were 4.2 mlU/L, Tg – 86.45 pg/mL. She was taking only ADTs 10 mg/d.

Discussion

SARS-COVID-19 infection has rapidly become a pandemic. Since the ACE-2 receptors have been detected on thyroid glands, they became a potential target for this virus. Lately there have been documented cases of subacute thyroditis, painless thyroiditis, and Graves’ disease in patients admitted to the hospital due to COVID-19. Subacute thyroiditis is caused by viral infection and has three phases in its course: thyrotoxicosis, hypothyroidism and euthyroidism. Its main symptom is neck pain, whereas painless (silent) thyroiditis is characterized by the absence of neck pain and any thyroid antibodies (TRAb, TgAb, TPOAb). Mateu-Salat et al. reported on two cases of Graves’ disease after COVID-19: one with previous history of Graves’ disease in remission for 30 years and another – without any history of problems with thyroid (12).

We report on a case of Graves’ disease associated with COVID-19 which required high-dose corticosteroids. The differential diagnosis was performed between subacute thyroiditis (our patient did not have neck pain and was positive for TRAb) and painless thyroiditis (TRAb positivity excluded this diagnosis). It has been suggested that the SARS-CoV-2 coronavirus may be a trigger mechanism in the onset of various thyroid diseases, including Graves’ disease which is accompanied by high levels of TRAbs as well as TG which emphasizes thyroid destruction. Therefore, we assume that patients with previous history of thyroid diseases have to raise a clinical suspicion since COVID-19 can be a trigger for new cases of Graves’ disease as well as its relapses.

In the days of coronavirus new methods of patients’ consultations are in high demand: care delivery via remote consultations is being increasingly used (over the telephone or video) worldwide. Video consultations have the advantage compared to telephone ones because clinical suspicion may arise from inspection/observation of the patient during the video.

Conflict of interest

The authors declare that they have no conflict of interest.