Post-COVID-19 Painless Thyroiditis: A Case Study on Thyrotoxicosis Management

Introduction

COVID-19, caused by the SARS-CoV-2 virus, has been linked to a wide spectrum of extrapulmonary manifestations that extend beyond its primary respiratory involvement. These manifestations encompass nearly every body system and include cardiac arrhythmia, acute kidney injury, venous thromboembolism, hyperglycemia, ketosis, diarrhea, myocardial infarction, ischemic stroke, and acute limb ischemia, among many others [1]. The immune dysregulation and hyperinflammatory state induced by SARS-CoV-2 have been implicated in exacerbating several autoimmune disorders, such as insulin-dependent diabetes mellitus [1], Guillain-Barré syndrome [2], cold agglutinin syndrome, rheumatoid arthritis, systemic lupus erythematosus [3], vasculitis [4], immune thrombocytopenic purpura and myasthenia gravis [5], Graves’ disease, and Hashimoto’s thyroiditis [6]. However, development of new-onset thyroiditis has been uncommon.

Thyroiditis refers to diverse disorders characterized by inflammation of the thyroid gland. It can be caused by various autoimmune disorders, infections, and medications. The condition is commonly classified into 2 types based on presence or absence of features of inflammation: (1) painless thyroiditis (silent thyroiditis), including Hashimoto’s thyroiditis, drug-induced thyroiditis, post-partum thyroiditis, and fibrous thyroiditis; and (2) painful thyroiditis (subacute thyroiditis), including de Quervain’s thyroiditis, suppurative thyroiditis, and radiation-induced thyroiditis.

Painless or silent thyroiditis is marked by the presence of anti-thyroid autoantibodies (eg, Hashimoto’s thyroiditis), a normal erythrocyte sedimentation rate (ESR), a painless goiter, history of parturition (eg, postpartum thyroiditis), and use of certain drugs (eg, tyrosine kinase inhibitors, amiodarone, immune checkpoint inhibitors) [7].

Subacute thyroiditis – a type of painful thyroiditis – is triggered by a viral infection. It is characterized by pain, tenderness, and swelling of the thyroid, and an elevated ESR. Coxsackie virus, mumps, measles, and adenovirus [8] are commonly the cause. Typically, it progresses through an initial phase of thyrotoxicosis due to the release of pre-formed thyroid hormones, followed by a hypothyroid phase and a recovery phase. The clinical presentation is mild, and may need symptomatic treatment only (eg, non-steroidal anti-inflammatory drugs). Although post-viral painful thyroiditis has been widely reported due to COVID-19 [9], an atypical form of post-viral thyroiditis, which is painless, has rarely been described. We present a case of a man who presented with painless thyroiditis leading to thyrotoxicosis after recent COVID-19 illness to discuss the presentation and management of this unique entity.

Case Report

A 67-year-old man with pre-existing hypertension, non-insulin-dependent diabetes, and myocardial infarction presented to the emergency room with a 4-week history of decreased appetite, nausea, vomiting, and 18 kg weight loss. He also experienced associated weakness and upper-extremity tremors. The patient denied fever, chills, cough, shortness of breath, diarrhea, dizziness, headaches, or sleep disturbances. He reported having COVID-19 diagnosed through PCR-based testing about 2 months before the current presentation, which had resolved. In the emergency department, he was lethargic. Assessment of vital signs revealed tachycardia (106/min), normotension (122/64 mmHg), and normal respiration (18/min, oxygen saturation of 99% on room air). A physical exam was significant for warm and dry skin. There was no proptosis, cervical lymphadenopathy, thyroid tenderness, or goiter. The patient was oriented to time, place, and person. There were no sensory, motor, or cranial nerve deficits. Cardiovascular and abdominal exam results were normal. He reported regular use of metformin and glimepiride for diabetes, carvedilol and enalapril for hypertension, and clopidogrel for myocardial infarction. He did not report prior use of amiodarone, lithium, or any tyrosine kinase inhibitors.

The laboratory investigation (Table 1) revealed anemia and features of intravascular volume depletion. Thyroid function tests were notable for a thyroid-stimulating hormone (TSH) of 0.01 mIU/L and free T4 of >7.7 μg/dL, suggestive of thyrotoxicosis. Tests for thyroid-stimulating immunoglobulins (TSI) and anti-thyroid peroxidase antibodies (anti-TPO) were negative, making autoimmune thyroid disorders less likely. The patient’s SARS-CoV-2 spike antibody IgG titers were high at 441 U/mL, but he denied being vaccinated. A neck ultrasound showed a normal thyroid gland with normal-intensity vasculature, without thyromegaly or nodules (Figure 1). A chest X-ray showed no acute findings. The patient was diagnosed with post-viral painless thyroiditis secondary to COVID-19 and was admitted to the hospital for further management.

Intravenous fluids and anti-thyroid medications were initiated and enalapril and metformin were held. Following regular administration of propranolol 60 mg daily, methimazole 20 mg twice a day, and prednisone 40 mg daily, he showed improvement in strength, tremors, and appetite. His free T4 declined to 2.3 ng/dL from >7.7 after 7 days of therapy. Subsequently, he was discharged home in a stable condition on prednisone 10 mg daily, propranolol 60 mg daily, and methimazole 20 mg daily for 3 weeks. Outpatient follow-up with his primary care physician was advised to monitor for development of a possible hypothyroid state. Ultimately, he achieved resolution of all symptoms and returned to the euthyroid state without overt hypothyroidism.

Discussion

Post-viral subacute thyroiditis is mostly painful and presents with thyrotoxicosis. Following a viral infection, an immune response against the thyroid gland causes lymphocytic infiltration, leading to release of pre-formed thyroid hormone, causing thyrotoxicosis. An uncommon form of post-viral subacute thyroiditis can present with a painless thyroid gland. It is hypothesized that the absence of inflammatory infiltration into the thyroid’s interfollicular spaces reduces tension on the thyroid capsule, leading to a non-painful form of thyroiditis. Although painful thyroiditis has been widely reported due to COVID-19 [9], an atypical form of post-viral painless thyroiditis, as is depicted by our case, is quite rare. COVID-19-associated subacute painless thyroiditis is more frequently seen in male patients and typically presents within 4 to 8 weeks after COVID-19 illness [10]. It is characterized by low concentrations of TSH and normal or elevated concentrations of T4. Thyroid-stimulating and thyroid peroxidase antibodies, as well as thyroid ultrasound results, are usually normal [11].

The presented case adds to the limited existing evidence of an association between COVID-19 and atypical painless thyroiditis. A retrospective study in Italy on hospitalized patients with severe COVID-19 showed that 20.2% of this population had some form of thyrotoxicosis secondary to destructive or inflammatory thyroiditis [12]. Muller et al reported a high prevalence of thyrotoxicosis (15%) in COVID-19 patients hospitalized in high-intensity care units for severe lung disease. Clinically, none of the patients in the case series had pain, leading to a diagnosis of atypical/painless thyroiditis [11]. However, symptomatic but painless thyroiditis requiring hospitalization, as in our case, has not been previously described.

Evidence suggests that the SARS-CoV-2 virus induces thyroid inflammation through several mechanisms. Molecular mimicry impairs the physiological immune response to infection, potentially triggering autoimmunity [13–15]. Another plausible mechanism involves the interaction of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) receptors, which are abundantly expressed in thyroid tissue and to which the virus has a high affinity [16–18]. A third mechanism involves the induction of a massive inflammatory response characterized by inflammatory infiltration and apoptotic cells within the thyroid gland. This systemic immune and inflammatory response activates the coagulation and complement systems and elevates inflammatory cytokines such as IL-6, IL-1β, and TNF-α [19]. The inflammation-mediated destruction of the thyroid gland, specifically the acinar cells, leads to the release of pre-formed T4 into the bloodstream. Notably, COVID-19 vaccination has also been implicated in the development of cutaneous small-vessel vasculitis, with molecular mimicry of the SARS-CoV-2 spike protein and activation of autoreactive lymphocytes proposed as potential mechanisms [20], but our patient denied receiving vaccination.

Post-viral thyroiditis is usually mild, and symptomatic treatment is sufficient. Debilitating symptoms requiring hospitalization, as occurred in our case, are uncommon. The existing literature on COVID-19-induced thyroiditis indicates that all cases ultimately progress to a euthyroid state after resolution of the inflammation [11]. Treatment for severe thyrotoxicosis involves the use of beta blockers to reduce peripheral deiodination of T4 to T3 and help with symptomatic relief from palpitation and tremors. Anti-thyroid drugs to inhibit the production of T4, and systemic corticosteroids to reduce inflammation are seldom required [21]. Our patient had debilitating symptoms and ultimately required treatment with beta blockers, anti-thyroid medications, and steroids to achieve significant symptomatic resolution.

Conclusions

An atypical form of subacute post-viral thyroiditis after COVID-19 illness can present in a painless form within 4 to 8 weeks after infection. Prompt recognition of this uncommon condition is important considering the scale of the COVID-19 pandemic. Most cases are mild and need only symptomatic treatment. Close follow-up after resolution is crucial to monitor for development of hypothyroidism, but most patients show resolution to the euthyroid state.