COVID-19-associated thyroid diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mitra Chitsazan, M.D.[2]

Overview

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus named for the similarity of its symptoms to those caused by the severe acute respiratory syndrome. Coronavirus disease 2019 (COVID-19) has been considered a global pandemic since its first emergence in Wuhan, China. On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.COVID-19 has been found to affect several organs and body systems, including the endocrine system, with short-term and possible long-term consequences. Recent data shows that COVID-19 patients have experienced a range of thyroid diseases.

Historical Perspective

• Coronavirus disease 2019 (COVID-19) has been considered as a global pandemic since its first emergence in Wuhan,China.
• On March 12, 2020, the World Health Organization declared the COVID-19 outbreak a pandemic.
• In March 2020, the first case of subacute thyroiditis in an 18-year-old woman with COVID-19 was described.

Classification

There is no established system for the classification of COVID-19-associated thyroid disorders.

Pathophysiology

The exact pathogenesis of COVID-19-associated thyroid diseases is not fully understood. However, the following hypotheses have been suggested for the development of thyroid dysfunction in COVID-19 patients.

• Angiotensin-converting enzyme 2 (ACE2) receptors are essentially involved in SARS-CoV-2 internalization into host cells. The thyroid gland is amongst the organs which have the highest levels of ACE2 expression and activity. Therefore, following SARS-CoV-2 infection, thyroid damage could result from either a direct or immune-mediated injury.
• COVID-19 may also cause an immune system imbalance and, in severe cases, a cytokine storm, which may break immunotolerance in susceptible patients, leading to new onset of immune-mediated thyroiditis, exacerbating a previous thyroid disease, or inducing a recurrence of thyroid disease.
• The other potential pathophysiology for the development of thyroid disease in COVID-19 could be an underlying euthyroid sick syndrome, also known as nonthyroidal illness syndrome (NTIS), caused by critical illness. Patients with the euthyroid sick syndrome are often characterized by low T3 concentration, along with a normal or low serum TSH. T4 concentration may be low in more severe or prolonged illnesses.
• The fourth hypothesis is that hypothalamic-pituitary-thyroid (HPT) axis dysfunction in COVID-19 Patients results in a decresaed level of serum TSH in patients with SARS-CoV-2, causing secondary causes of hypothyroidism (central hypothyroidism).

Causes

Coronavirus disease 2019 (COVID-19) caused by a novel coronavirus called SARS-CoV-2 is the cause of COVID-19-associated thyroid diseases. To read more click here

Differentiating COVID-19-associated thyroid diseases from other Diseases

• Differential diagnosis of hyperthyroidism in COVID-19 patients may include:
  • Graves' disease
  • Subacute thyroiditis
  • Painless thyroiditis

• Differential diagnosis of hypothyroidism in in COVID-19 patients may include:
  • Primary hypothyroidism:
    • Autoimmune thyroiditis(Hashimoto's thyroiditis)
    • Subacute granulomatous (de Quervain’s) thyroiditis
  • Secondary hypothyroidism
    • Central Hypothyroidism]
• For a complete list of differential diagnoses of hyperthyroidism, please click here.
• For a complete list of differential diagnoses of hypothyroidism, please click here.
• For a complete list of differential diagnoses of the euthyroid sick syndrome, please click here.

Epidemiology and Demographics

• Data on the exact epidemiology and demographics of thyroid diseases in COVID-19 patients are lacking.
• Several cases of subacute thyroiditis, Hashimoto thyroiditis, myxedema coma, Grave's disease, atypical thyroiditis, thyrotoxicosis, sick euthyroid syndrome have been reported in COVID-19 patients worldwide.

Risk Factors

There are no established risk factors for COVID-19-associated thyroid diseases.

Screening

There is insufficient evidence to recommend routine screening for COVID-19-associated thyroid diseases.

Natural History, Complications, and Prognosis

A number of observational studies have shown that COVID-19 infection may be linked to some thyroid diseases, including:

• Subacute thyroiditis
• Graves’ disease
• Non-thyroidal illness or euthyroid sick syndrome
• Thyrotoxicosis
• Hashimoto’s thyroiditis

• Prognosis has generally been good in most cases of COVID-19 patients with hyperthyroidism/hypothyroidism.
  • In a patient with subacute thyroiditis, the thyroid function and inflammatory markers normalized in 40 days.
• In a study on 154 COVID-19 patients, Low fT3 (i.e., euthyroid sick syndrome) was associated with higher mortality and increased IL-6, suggesting poor prognosis in these patients.

Diagnosis

Diagnostic Study of Choice

The diagnosis of COVID-19-associated thyroid diseases is made based on the thyroid function test (TFT), which measures serum levels of triiodothyronine (T3), thyroxine (T4), and thyroid stimulating hormone (TSH).

History and Symptoms

The symptoms of clinical hyperthyroidism in COVID-19 patients are similar to hyperthyroidism in the general population. The most common symptoms include:

• Palpitations
• Insomnia
• Anxiety
• Weight loss
• Heat intolerance
• Diarrhea

The symptoms of clinical hypothyroidism in COVID-19 patients are similar to hypothyroidism in the general population. The most common symptoms include:

• Fatigue
• Cold intolerance
• Decreased sweating
• Hypothermia
• Coarse skin
• Weight gain
• Hoarseness
• Depression
• Emotional lability
• Attention deficit
• Puffiness
• Hair loss
• Constipation
• Slowed speech and movements
• Hyperlipidemia
• Galactorrhea
• Myxedema coma (with non-pitting edema)

If accompanied by thyroiditis:

• Sore throat
• Periorbital edema

Physical Examination

The most common physical examination findings in patients with hyperthyroidism include:

• Tachycardia
• Stare
• Eyelid lag
• Resting tremor
• Hyperreflexia
• Warm, moist, and smooth skin
• In patients with Graves's disease:
  • Localized dermopathy (i.e., pretibial myxedema)
  • Proptosis (exophthalmos)
  • Goiter

The most common physical examination findings in patients with hypothyroidism include:

• Myxedema: in patients with Hashimoto's thyroiditis
• Bradycardia
• Dry skin
• Coarse hair
• Enlarged thyroid gland or presence of goiter
• Small or shrunken thyroid gland (late in the disease)
• Bradypnea
• Slowed speech
• Slowed reflexes

Laboratory Findings

The laboratory findings in hyperthyroidism are:

• Elevated levels of serum thyroxine (T4) and triiodothyronine (T3).
• Undetectable serum TSH.
• Total T4 and T3 measurements are influenced by multiple conditions affecting serum thyroxine-binding globulin (TBG). Thus, the measurement of free thyroid hormones; free T4 (FT4) and free T3 (fT3), is the gold standard for the diagnosis of Graves' disease.
• Antibodies against the TSH receptor (TRAbs) are pathognomonic for Graves' disease. They are detectable in the serum of about 98% of untreated patients. Detection of TRAbs rules out other causes of thyrotoxicosis.
• Anti-thyroid peroxidase (TPO) and antithyroglobulin (Tg) antibodies are also detectable in many patients with Graves' disease, but it is not recommended to measure these antibodies for diagnosis in all patients.

The laboratory findings in hypothyroidism are:

• Increased Thyroid-stimulating hormone (TSH)
• Decreased Free T3 and Free T4
• TSH may be decreased in the transient hyperthyroid state
• Thyroid antibodies are usually positive in patients with Hashimoto's thyroiditis:
  • Anti-thyroid peroxidase antibodies (anti-TPO) (correlates with the disease severity)
  • Anti-thyroglobulin antibodies (anti-Tg)
  • Anti-microsomal antibodies can help obtain an accurate diagnosis

The laboratory findings in euthyroid sick syndrome are:

Euthyroid sick syndrome	T3 (80-180 ng/dl)	T4 (4.6-12 ug/dl)	FT4 (0.7-1.9 ng/dl)	TSH (0.4 to 4.0mIU/L)	Reverse T3 (90 to 350pg/mL)
Mild euthyroid sick syndrome	↓	N	N	N	↑
Moderate euthyroid sick syndrome	↓	N	N/↓	N/↓	↑
Severe euthyroid sick syndrome	↓	↓	N/↓	↓	↑
Recovery	N/↓	N	N	N	N/↑

Electrocardiogram

• There are no ECG findings associated with COVID-19-associated thyroid disease.
• However, the following findings may be seen on ECG in patients with hyperthyroidism and thyrotoxicosis:
  • Sinus tachycardia
  • Atrial fibrillation (often in elderly patients)
  • Complete heart block (rare)
  • Changes in QT interval
• The following findings may be seen on ECG in patients with hypothyroidism:
  • Sinus bradycardia
  • Prolonged QTc interval
  • Changes in the morphology of the T-wave and QRS duration
  • Low voltage.

X-ray

• There are no x-ray findings associated with COVID-19-associated thyroid diseases.

Echocardiography or Ultrasound

• There are no echocardiographyfindings associated with COVID-19-associated thyroid diseases.
• Thyroid ultrasoongraphy

CT scan

• There are no CT scan findings associated with COVID-19-associated thyroid diseases.

MRI

• There are no MRI findings associated with COVID-19-associated thyroid diseases.

Other Imaging Findings

Thyroid ultrasound

• Thyroid ultrasound may help diagnose Graves's disease. Typically, the thyroid pattern in Graves' disease is hypoechoic. Thyroid ultrasound gives an accurate estimation of the thyroid size, which is important in planning the therapeutic management and allows the detection of thyroid nodules that may not be palpable on physical examination.

Color flow Doppler

• Color flow Doppler (CFD) estimates the blood flow which, in hyperthyroid Graves' disease patients, is typically increased within the thyroid gland.
• CFD can be useful in the differential diagnosis of Graves' disease and other causes of thyrotoxicosis characterized by a low blood flow to the thyroid, such as factitious thyrotoxicosis, painless and subacute thyroiditis.

Other Diagnostic Studies

Radioactive iodine uptake

• 24-hr radioactive iodine uptake (RAIU) is a diagnostic measure for Graves' disease, which shows increased homogeneous uptake.
• RAIU is generally increased in Graves' disease because of the action of stimulating TRAbs.
• Normal values for RAIU 24 h after the administration of a tracer dose of radioiodine are 20% in iodine sufficient and 40% in iodine-deficient areas.

Thyroid Disease	TSH receptor antibodies	Thyroid Ultrasound	Color flow Doppler	Radioactive iodine uptake/Scan	Other features
Graves' disease	+	Hypoechoic pattern	↑	↑	Ophthalmopathy, dermopathy
Toxic nodular goiter	-	Multiple nodules	-	Hot nodules at thyroid scan	-
Toxic adenoma	-	Single nodule	-	Hot nodule	-
Subacute thyroiditis	-	Heterogeneous hypoechoic areas	Reduced/absent flow	↓	Neck pain, fever, and elevated inflammatory markers
Painless thyroiditis	-	Hypoechoic pattern	Reduced/absent flow	↓	Symptoms and signs of hypothyroidism
Hashimoto's thyroiditis	-	Diffusely enlarged thyroid gland with a heterogeneous echotexture	Normal	early stages: may show increased uptake, late stages: single or multiple areas of reduced uptake (cold spots)	-

• To view other diagnostic studies for COVID-19, click here.
  

Treatment

Medical Therapy

• Treatment of COVID-19-associated thyroid diseases generally depends on the presentation of thyroid disease.
• No specific treatment has been reported for COVID-19-associated thyroid disease.

Surgery

Surgery is not a treatment option for patients with COVID-19-associated thyroid diseases.

Primary Prevention

There are no established measures for the primary prevention of COVID-19-associated thyroid diseases.

Secondary Prevention

There are no established measures for the secondary prevention of COVID-19-associated thyroid diseases.