Bimodal Distribution of Thyroid Dysfunction Triggered by Covid-19 Infection. An Experience From a Single Endocrine Centre. A Short Report & Literature Review

Purpose: Covid-19 infection has been spreading across the globe since the end of 2019 and it continues to cause chronic multi-system sequalae, of which thyroid dysfunction appears to be a major one. We aim to present cases Methods: Case series report. Results: Over the period from October 2020 to July 2021, a series of 10 cases of thyroid dysfunction due to Covid-19 infection were seen and managed in a single outpatient endocrine centre in Doha, Qatar. These are 6 cases of Graves hyperthyroidism, two cases of chronic primary hypothyroidism including one with GD treated by RAI therapy, two cases of subacute thyroiditis and one case with ‘Thyroxin Thyrotoxicosis’, and nally one case of central hypothyroidism. Conclusion: This report is the largest to be reported from a single centre so far, and it points to a bimodal distribution of thyroid dysfunction in patients with covid-19 infection. A review of the literature and discussion of possible pathophysiological mechanisms is presented. We stress the importance of screening for thyroid dysfunction in post-Covid cases, as the prevalence may be underestimated.


Introduction
For over two years the world has been battling the health impact stemming from the Severe Acute Respiratory Syndrome Coronavirus 2, (SARS-CoV-2,), also known as Covid-19, which was rst witnessed in Wuhan in 2019/2020 winter. The virus classically presents with respiratory symptoms but could well be asymptomatic or may even present with atypical presentation with non-pulmonary complications that include neurological disorders, cardiac abnormalities, renal failure, liver disease, rhabdomyolysis, coagulopathy and thrombosis, and endocrine dysfunction. SARS-CoV-2 uses ACE-2 receptor and transmembrane protease serine 2 (TMPRSS2), and Cathpesin to gain access and infect human cells (1). Infection or entry will trigger a cascade of virus replication and release of virus with resultant cell damage. This process is called pyroptosis, an abrupt form of programmed cell death (2), with subsequent cascade of events that include a release of an array of cytokines (e. g. interleukins, TNF & INF), in addition to intracellular molecules, like ATP, nucleic acids and damage associated nuclear patterns (PAMPs). The proin ammatory cytokines (IL-β, TNFα-, INF-, etc), may lead to immune response hyperactivity and uncontrolled systemic in ammatory response (2). Enhanced Th1/Th17 immune responses and cytokine pathways involved in SARS resemble in some way the immune activation that occurs in immune mediated thyroid disease (3). ACE-2 & Transmembrane protease serine 2 (TMPRSS2) expression is very high in the thyroid more than in the lungs (4).
Uptake by host cells of SARS-Covid-2 is thought to be mediated by other cellular proteases and molecules.
One main group of cellular membrane protein involved was found to be the integrins, and ACE2 binds to integrins to modulate downstream signal transduction. T4 regulates expression of genes for the monomeric protein that makes up integrins (5). Thyroid hormones regulate genes for the monomeric protein that makes up integrins and they are also deemed to promote internalization of the integrins (6, 7). Worth noting is that olfactory receptors (ORs) are co-expressed with ACE2 and TMPRSS2. ORs are widely expressed in the thyroid (8). Impairment of the cellular function at the neuro-epithelium of the Olfactory bulb constitutes the molecular mechanism that underlies the anosmia observed in Covid victims (9). The damage to ORs is postulated to be contributing to the impairment of other organs expressing OR not excluding the thyroid (8).
Viruses has been well recognized to trigger thyroid autoimmunity (10). Thyroid disease in the context of Covid-19 infection has been shown in a recent systematic review and metanalysis to be associated with poor outcome (11). However, the relationship of the two has been described as bidirectional (12). In this short report, we present a esta of a diverse 8 cases of thyroid dysfunction associated with Covid-19 infection that were diagnosed and managed in a single endocrine centre in Qatar. We have also reviewed the literature related to the subject.
Case Presentations 1-Case 1: A young 49-year-old Sudanese gentleman, with history of bronchial asthma, hypertension, prediabetes and gout, was tested positive for Covid on 24 November 2020. He had PCR as mandatory screening, which was done upon arrival to Qatar as a part of preventive measures to curb the spread of the coronavirus. Upon questioning, he gave history of headache and fever over the preceding few days along with multiple episodes of vomiting and diarrhea (around 4 times a day). However, these subsided two days later. On questioning, patient denied any cough, shortness of breath or sore throat. He was diagnosed with Covid pneumonia and was started on the anti-retroviral favipiravir and transferred to a quarantine facility. No thyroid function tests (TFTs) was done during this time. He had TFT in May 2019, and that was normal. He made an uneventful recovery from Covid. Two months later, the patient had general checkup as he complained of slight increase in body weight. Here, TFT showed TSH of 33.49 mu/l (NRR 0.4-4.5mu/l), and free T4 of 8pmol/l (NRR 8-18pmol/l). Repeat TFTs done 6 weeks later revealed TSH of 34.22mu/l and T4 dropped further to 7.4 pmol/l. At this point he was referred to our endocrine clinic.
When reviewed at our clinic, he denied any history of tiredness, fatigue, sleepiness or other symptoms of hypothyroidism other than weight gain. He has no family history of goitre or thyroid dysfunction. He was not on any medication which may cause perturbation of thyroid function. On examination; BP: 128/84, Pulse: 74, BMI: 29.06 Kg/m 2 . He was clinically euthyroid with no neck swelling, and unremarkable physical exam. Tests done showed TSH 49 mU/l, FT 11 pmol/l. Anti-TPO Ab was 423 IU/ml (Normal <30), TSH-RAb was negative.
Neck US showed heterogenous thyroid with minimally increased vascularity and a small hyperechoic nodule measuring 5x4 mm. Thyroid uptake scan showed normal morphology and function except for a cold nodule in the postero-inferior part of the right lobe.
After discussion with the patient, it was decided to wait and see policy. Repeated TFT after 6 weeks showed TSH has risen to 61 mIU/l and FT 4 pmol/l. He was started on levothyroxine 100mcg daily and TFT normalized after 6 weeks.

2-Case 2:
A 50-year-old Filipino male, with past medical history of asthma and hypertension, presented with respiratory symptoms and he tested positive for Covid-19 infection. Chest x-ray showed bilateral lung in ltrates. He was treated as Covid-19 pneumonia and started on treatment as per hospital protocol (azithromycin: 500mg daily, ceftriaxone 2gm IV once daily, hydroxychloroquine 400mg daily, lopinavir/ritonavir 200/50mg bid, ribavirin and oseltamivir 150 mg bid). His hospital course was complicated by ARDS requiring ICU admission. He received Tociluzimab and methylprednisolone but did not require endotracheal intubation or mechanical ventilation. TFTs were done because of persistent tachycardia, and that showed TSH; 0.08 mu/l, FT3 3.4 pmol/l (NRR 3-6), FT4 23. When TFT was repeated few weeks later it showed resolution of thyroid dysfunction with TSH 0.47, and FT4 18.8pmol/l, suggesting 'Thyroxine Thyrotoxicosis' due to Covid-19 related thyroiditis. Subsequent follow up over 6 months revealed no further abnormality.
3-Case 3: 32 years old female Sudanese patient had hypothyroidism during adolescence for which she was treated with levothyroxine till the age of 16 years. She has been euthyroid since then. She also has previous history of thyroid nodule in 2016 for which she had no follow up since then. In September 2020, she was diagnosed with Covid-19 infection following a mild respiratory illness. She made uneventful recovery, but 3 months later in December 2020, she presented with symptoms of tiredness, fatigue, bilateral hand tremors, palpitations, increased sweating, shortness of breath and irregular periods. Physical examination was consistent with hyperthyroid state with a small diffuse goitre. TFTs showed TSH<0.01, FT4: 72.3 mIU/l, TSH-RAb 28 U/l (Normal<0.75). Thyroid nuclear uptake scan with technetium revealed enlarged thyroid with overall picture suggestive of diffuse Grave's disease. She was started on carbimazole 30 mg daily along with propranolol 40mg bid and she improved. Repeated TFT after 2 months showed TSH<0.01, FT3: 7.6 and FT4: 24.0. Subsequent repeat TFTs showed normal level. She is being followed up in the Endocrinology clinic for her Grave's disease, and latest TFTs done in January 2022 showed persistent remission with carbimazole.

4-Case 4:
A 40 year old Filipina lady with history of asthma on salbutamol inhaler, was admitted to hospital with Covid-19 pneumonia of mild to moderate severity. She was started on COVID treatment as per hospital protocol (Hydroxychloroquine, oseltamivir and azithromycin). She was noticed to have persistent tachycardia, so TFT done, and that showed hyperthyroidism with TSH <0.01, FT3 30.8 pmol/l, and FT4 83.3 pmol/l. Anti-TPO Abs; 494 IU/ml. TRAb was elevated at 8.7 iu/l. She was started on carbimazole, however, she stopped it after discharge thinking that it is a Covid medication. 8 months later she presented to the ER with severe abdominal pain and vomiting. On exam, BP: 211/110. Heart rate: 136/min, with small goitre, otherwise no other signs of hyperthyroidism. CT abdomen showed intestinal obstruction. Labs: TSH<0.01, FT3: 32.9pmol/l, FT4 >100pmol/l, and TSH-RAb elevated at 7.7 u/l. Her Bursch Wartofsky's score was 35, so she was treated as impending thyroid storm. Neck US revealed enlarged thyroid lobes with increased vascularity. The intestinal obstruction was managed conservatively. She improved and was discharged home on carbimazole 20mg bid and metoprolol 75mg bid. On follow up, she remained euthyroid.

5-Case 5:
A 40 year old male referred to Endocrine clinic for hyperthyroidism. He stated that he had symptoms of loss of taste and smell, muscle aches and pains 3 months ago, however, he didn't get tested for COVID. Later after 2 to 3 months, he developed symptoms of weight loss and anxiety and was referred to endocrinology clinic. His TSH was <0.01, FT4; 100 pmol/l. He was started on carbimazole 40mg/day, and on follow up his TFTs normalized. The presumptive diagnosis is Grave's disease precipitated by COVID. 6-Case 6: A 14-year-old Qatari girl was referred to the endocrine clinic in November 2020, for possible hyperthyroidism. All family including the patient suffered mild Covid-19 infection, and all made uneventful recovery. On assessment, she was noted to be tremulous, and mentioned that she had lost some weight of around 6-8 Kg and then she began to have palpitations. TFTs showed TSH <0.02 mU/l, T4, 35pmol/l. She was given propranolol, 10mg tid. Repeat TFTs, 5 weeks later in January 2021, showed TSH 5.6 mu/l, and She had TFTs in November 2020 which was normal with TSH 0.92 mu/l, FT4 19pmol/l. Was started on carbimazole and that resulted in good response with remission in the following 2 months. Latest TFTs showed persistent remission on maintenance carbimazole. Table 1 summarizes the above 10 cases of thyroid dysfunction related to COVID-19 infection.

Discussion
Covid-19 infection continues to ravage the world population, and its effect proved to have diverse with multisystem consequences. Covid-induced thyroid dysfunction is emerging as well established and common aftermath of the disease. As is shown by our cases, the clinician in endocrine practice could well be faced by protean and diverse presentations. Four of our eight cases presented with immune mediated hyperthyroidism, and the remaining four all had virus-induced destructive thyroiditis, which proved to be transient in two cases, and have a permanent effect in the other two. Triggering of various autoimmune disease in general by Covid-19 has been recognized, that includes anti-phospholipid syndrome, autoimmune thrombocytopenia, haemolytic anaemia, Gillian Barre, syndrome, to name but a few (13). This may persist long after the resolution of Covid-19.
The literature shows that non-thyroidal illness (NTI) is the most common abnormality observed in Covid-19 patients. Up to 30% of Covid-19 patients, may suffer the syndrome of low TSH with low or normal T4, and low T3 (14). NTI may occur at all spectra of the illness. It commonly occurs with the 'Cytokine Storm' also known as Cytokine Release Syndrome (15,16), The degree of reduction of TSH and FT3 is proportional to the severity of Covid infection (17). Those with low T3, generally have low fT3/fT4 ratio (<0.3) suggesting a reduced 5-mono-deiodinase activity (both D1 & D2), that converts T4 to T3. There is also increased activity of D3 that catalyses deactivation of both T4 and T3. In our series, which is exclusively an outpatient activity, we have not seen this abnormality. All our cases had recovered from their acute Covid-19 infection, and whether they had an initial picture of NTI followed by a more orid presentation to speci c clinical phenotype could not be established, as none had been tested for thyroid dysfunction during their Covid-19 infection. Destructive thyroiditis, which could be subclinical or clinical, may take the form of either subacute thyroiditis (SAT, De Quervain thyroiditis), or painless thyroiditis. This is well recognized to be associated with many  (24), or during the few weeks to months following its resolution, as occurs in our cases as well as those of (31). Neither autoimmune nor non-immune thyroid disease are risk factors for SAT. Neck pain is the hallmark of the disease in SAT. The classical course includes an initial phase of hyperthyroidism followed by hypothyroidism, then euthyroidism, which unfolds over a period of 6 month. The outcome would be either complete resolution (30,32) or development of permanent hypothyroidism (31). Our series had two cases of SAT, one of them, the young girl, recovered completely, and the second one went on to develop permanent hypothyroidism requiring replacement thyroxine therapy. A variant of subacute thyroiditis, which occurs in 15% as a form of 'SAT' without neck pain, which is thought to be due to lymphopenia (33), which was rst recognized in critically ill patients admitted to ICU (34). The biochemical hallmarks comprise low TSH, low FT3 and normal or high FT4, hence the synonym 'Thyroxine thyrotoxicosis'. This is represented in our third case with thyroiditis. This variety is more frequent in males, which could be explained by the gender difference in the immune signatures associated with ACE2 at the thyroid level. Our last case falls in this category, which is not commonly seen. relationship between TSH and level of IL-6 in their cohort of 287 patients studied (24). This may suggest a role for the cytokine in perpetuating the thyroid dysfunction. On the other hand, an extensive injury to the 'follicular and parafollicular' cells by the virus were reported by some studies (40). This may shed some light for the captivating explanation of increased risk of osteonecrosis in Covid patients (41,42). Impairment of the hypothalamic-pituitary thyroid axis may play a role as SARS genomic sequence were detected in the hypothalamus, and immune-histochemistry of adenohypophysis revealed that both the number and immune reactivity of thyrotrope cells were reduced (43).
Postulated Mechanisms of the trigger of Graves' hyperthyroidism was reviewed by Murugan & Alzahrani (39). The appealing role of the Corona virus in triggering thyroid autoimmunity is supported by several cases of thyroid dysfunction triggered by the vaccines developed from these viruses (44,45,46), or worsening of pre-existing Graves' following vaccination (47). The phenotypic expression of thyroid autoimmunity has been thought that it is a balance between Th1 and Th2. A predominant Th1 mediated immune response is likely to trigger apoptopic pathway in the thyroid follicular cells resulting in destruction of thyroid cells. Th2 immune mediated activity is likely to activate antigen speci c B lymphocytes to make TSH-RAb that results in proliferation of thyroid cells and their hyperactivity of the gland. Stress has been shown to shift the balance towards Th2 that favours development of GD. Further, regulatory CD4+ T cells (Tregs) inhibit effector T cells, and these could differentiate into Th1, Th2 or Th17 and this is dependent on the cytokine milieu. Activity of these cells lines has been shown in animal models to augment cytokine production and activation of autoimmune diseases. SARS-Cov-2 has evidence to be associated with hyper-in ammation that induces Th17 (39). These suggest that viral-induced Graves' disease is likely to be mediated by Th17.
In conclusion, the evidence for Covid-19 virus in causing thyroid dysfunction is accumulating, with a bimodal distribution, occurring with the acute infection as well as during the recovery period. Our report gives further support to this notion. Despite that there are no well-de ned risk factors, with the possible exceptions that those with previous history of autoimmune thyroid disease may be more vulnerable, and those who are ethnically more vulnerable to thyroid dysfunction may be most at risk. However, this is only from observation of the few reported cases that accumulated so far. Further, the overall thyroid dysfunction is clinically meaningful to the extent that warrants more vigilance. Screening in the follow up period is therefore highly warranted in patients who recovered from Covid-19 infection, as thyroid dysfunction, as shown in our series may occur weeks to months after the acute phase of the disease. Further, as shown by clustering of cases among those who had previous history of thyroid autoimmunity, and also those who are generally ethnically or genetically predisposed, therefore it would be desirable to consider them as among the highest vulnerable group. This may help to elucidate the exact epidemiology of the thyroid disease in Covid-19 era. The other possible contributory mechanisms could be the role of anti-retroviral therapy, role of other factors as secondary modulators, family history, pre-existing thyroid disease/autoimmunity, sex, other environmental factors triggered by the pandemic needs to be also explored. Availability of supporting data: Data is protected in cerner under Hamad Medical Corporation Regulations.