The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has profoundly impacted society since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Generally, the SARS-CoV-2 infection can present from mild to severe disease and death. It continues to have adverse effects including damage to the endocrine systems. The route of entry of SARS-CoV-2 is mainly via angiotensin-converting enzyme 2 (ACE2). ACE2 is not only a receptor for SARS-CoV-2, but also has protective roles against organ damage by converting angiotensin II into angiotensin 1–7 and down regulating the renin-angiotensin system (1, 2). However, the increased expression of ACE2 and its cofactors, the host proteases transmembrane protease, serine 2 (TMPRSS2) and A Disintegrin and Metalloproteinase 17 (ADAM17), in human tissues can facilitate SARS-CoV-2 entry into human cells, and therefore, increase the risk of organ damage following SARS-CoV-2 infection, including the thyroid gland (1, 3).

The first case of COVID-19 with thyroid dysfunction was reported in May 2020 by Brancatella et al., which was a case of subacute thyroiditis (SAT) following mild, symptomatic SARS-CoV-2 infection (4). There is also an association between COVID-19 and autoimmune diseases, which raises concern regarding a causal relationship between SARS-CoV-2 infection and autoimmune thyroid diseases (5). Basically, the expression of ACE2 and TMPRSS2 on the thyroid follicular cells enables SARS-CoV-2 to invade thyroid cells, and increases the susceptibility of the thyroid gland to SARS-CoV-2 related injuries (6). Furthermore, long COVID is a debilitating complication of acute SARS-CoV-2 infection, possibly due to persistent SARS-CoV-2 reservoir or immune activation (7). Therefore, long COVID can also be associated with further organ damage, such as endocrine organs including the thyroid gland. Although there are studies reporting almost complete recovery of thyroid function following acute SARS-CoV-2 infection, the overlapping symptoms between long COVID and thyroid dysfunction highlight the point that subtle organ damage should be investigated more carefully with pertinent clinical presentations (8).

Preventive and therapeutic strategies may improve the clinical outcomes of acute SARS-CoV-2 infection. However, differences in race and ethnicity, in addition to social and political factors such as economic inequalities, accessibility to healthcare resources, and vaccine hesitancy, were potential drivers of outcome inequalities in different regions of the world (9, 10). There is a concern exists for SARS-CoV-2 mutations, with resistance to antiviral therapy (11). Therefore, proposing a therapeutic approach that is effective against new strains of SARS-CoV-2, and that can be implemented in developing countries is important to prevent acute and chronic complications of COVID-19 infection.

This review summarizes the incidence of thyroid dysfunction following acute SARS-CoV-2 infection, including outcomes in different countries. Gender and vaccine status are other variables that are considered in this review, and may play a role in susceptibility to thyroid disorders. Finally, this article will discuss the pros and cons of current therapeutic approaches, and introduce a new strategy to mitigate SARS-CoV-2-related complications.

A total of thirty-two studies were carefully chosen during the selection process (14–45). The eligible manuscripts include 13 prospective and 19 retrospective or cross-sectional studies. An observational study by Fallahi et al. from Italy during the first phase of the pandemic in 2020, reported that patients with autoimmune thyroid disease have higher prevalence of SARS-CoV-2 infection (46). The prevalence of thyroid dysfunction was reported as 15% in a systematic review that evaluated 30 cohort studies and included 9,707 COVID-19 cases. Noticeably, thyroid dysfunction prevalence correlated with severity of COVID-19 (6.2% among mild to moderate cases and 20.8% among sever cases) (47). Another meta-analysis by Ashrafi in January 2024, reported 26% prevalence of non-thyroidal illness syndrome (NTIS) and 10% prevalence of thyrotoxicosis. The aforementioned study selected 8 out of 1,256 studies and included 1,654 participants. The prevalence of hypothyroidism (3%), isolated elevated FT4 (2%), and isolated low FT4 (1%) were unremarkable (48). NTIS is the most common abnormality seen in the literature following acute SARS-CoV-2 infection. Typical findings in NTIS include reduced triiodothyronine (T3) with normal or decreased thyroid stimulating hormone (TSH). The prevalence of NTIS in patients with COVID-19 ranges from 5 to 58 percent in the literature (21, 27). NTIS is also referred to as isolated low T3 syndrome and sick euthyroid syndrome. NTIS is reported from various areas, including Bangladesh (14), China (18–22), Hong Kong (24, 25), India (27, 28), Qatar (35), Saudi Arabia (37), and the United Kingdom (40–42).

Thyroiditis is another complication of SARS-CoV-2 infection, and includes SAT, painless thyroiditis, autoimmune thyroiditis and atypical thyroiditis (21, 49, 50). There is generally an increased risk of thyroiditis, thyroid autoimmunity, and autoimmune thyroiditis following acute SARS-CoV-2 infection, which is unlikely associated with persistent thyroid dysfunction, but may result in new-onset thyrotoxicosis or hypothyroidism (25–27, 31, 35, 36, 39, 51, 52). The reported incidence of thyroiditis and outcomes following acute SARS-CoV-2 infection varies by country, which could be due to the differences in population characteristics, severity of infection, and therapeutic interventions.

SAT typically present with fever, neck pain and symptoms and signs of thyrotoxicosis. The clinical manifestations of SAT following SARS-CoV-2 infection appear similar to the typical SAT (53). If acute SARS-CoV-2 infection is considered as a risk factor for SAT, then the incidence of SAT would be expected to rise after the pandemic. A nationwide study from South Korea found an increased incidence of SAT during the early phase of COVID-19 in 2020 (38). However, retrospective single-center studies reported that the incidence of SAT was not increased in Italy (32, 54) and Turkey (55, 56) during the COVID-19 pandemic. In addition, a multicenter nationwide study reported no differences in clinical characteristics or outcomes of SAT in Turkey (39) and no significant increase in thyroiditis in Hong Kong (25) after the pandemic. Finally, it seems that SARS-CoV-2 infection does not affect the onset, progression, and outcome of SAT as demonstrated by a multicenter prospective study from Italy that included 52 patients (7 COVID+ and 45 COVID-) (44).

Painless thyroiditis and autoimmune thyroiditis have also been reported following SARS-CoV-2 infection. In Hungary, rates of autoimmune thyroiditis were higher in the pediatric population with a history of SARS-CoV-2 infection (26). Data from Italy described an increased, almost doubled, rate of autoimmune thyroid disease prevalence in COVID-19 survivors, but a minority demonstrate thyroid function test abnormalities (31). SARS-CoV-2 infection can generally trigger autoimmunity as reported from Bulgaria (16), Columbia (23), Italy (31), Qatar (35), and Romania (36).

Atypical thyroiditis was reported by Muller et al. in 2020. It was reported in ICU patients with COVID-19 who presented with low TSH and T3 accompanied by normal or elevated thyroxine (T4) (50). This presentation is a combination of NTIS and thyrotoxicosis, which has been reported as T4 thyrotoxicosis previously (57).

Graves’ disease and Hashimoto’s thyroiditis are other possible complications of SARS-CoV-2 infection. There is a link between acute SARS-CoV-2 infection and Graves’ disease (17, 29). The first two cases of Graves’ disease after COVID-19 were reported in October 2020 (58). The epidemiologic studies about the prevalence of Graves’ disease during the COVID-19 pandemic are limited. An observational study from Spain described a significant increase in the incidence of Graves’ disease during the pandemic (17). In the United States reported an increased incidence of new-onset pediatric Graves’ disease during the first 2 years of COVID-19 (43). A retrospective cohort study from Taiwan that included 1,379,311 COVID-19 patients and 6,896,814 non-COVID-19 patients, reported an increased risk of thyroid dysfunction, including thyrotoxicosis and hypothyroidism, secondary to COVID-19. The risk of thyroid dysfunction, both thyrotoxicosis and hypothyroidism, following COVID-19 infection appears to be higher in older patients (aged 65 and above) and female (52). There is also a connection between SARS-CoV-2 infection and complications of Graves’ disease, such as orbitopathy (59, 60), thyrotoxic periodic paralysis (61–64) and thyroid storm (65–67). In terms of hypothyroidism, a bi-directional Mendelian randomization study supports a causal relationship between the host response to SARS-CoV-2 infection and increased risk of hypothyroidism (51). There are also studies from Bosnia and Herzegovina (15), Bulgaria (16), Hong Kong (25), India (27), Italy (30), Nepal (33), and Qatar (35) that reported development or increased risk of hypothyroidism after SARS-CoV-2 infection.

There are multiple studies investigating the correlation between pre-existing autoimmune thyroid diseases and the outcomes of COVID-19 (45, 68–73). Underlying thyroid disorders, especially hypothyroidism, are reported to be associated with a worse prognosis of COVID-19 in two systemic reviews from Indonesia in 2021 (74) and 2022 (75). Moreover, a large retrospective cohort from Turkey (total n=14,966; hypothyroidism n=8813; hyperthyroidism n=1822; normal thyroid function n=4331) showed a positive correlation between pre-existing hyperthyroidism or hypothyroidism and COVID-19 mortality (72). However, a large observational cohort (20,366 adult patients; pre-existing hypothyroidism in 1,616) from the USA showed that pre-existing hypothyroidism in hospitalized COVID-19 patients was not associated with worse outcomes of acute SARS-CoV-2 infection (45). In addition, two large population-based cohort studies are reassuring and suggested that hypothyroidism or hyperthyroidism were not associated with an increased risk of infection or worse outcomes in COVID-19 patients (69, 71).

Finally, it is important to mention that thyroid function testing has relatively good prognostic value for illness severity and predicting mortality risk in hospitalized moderate-to-severe COVID-19 patients (76).

Although the mortality and morbidity seen during the height of the pandemic has diminished, the SARS-CoV-2 infection has both short and long-term complications. Further efforts to improve the outcomes of acute SARS-CoV-2 infection are necessary. Acute SARS-CoV-2 infection causes transient and permanent thyroid dysfunction. Transient thyroid dysfunction is associated with COVID-19 severity, hospitalization and even mortality (77, 78). Permanent thyroid dysfunction leads to long-term medication use and worsening of underlying medical comorbidities. COVID-19 also increases the risk of autoimmunity against the thyroid gland, which may lead to thyroiditis, hypothyroidism or hyperthyroidism (52).

The pathophysiologic and molecular mechanisms of thyroid dysfunction following acute SARS-CoV-2 infection have not been fully elucidated. SARS-CoV-2 enters into cells after attaching to cell receptor, predominantly ACE2. Subsequently, viral particle approximation, fusion and internalization are essential for viral RNA genome engulfment and viral replication in host cells. The processes of approximation and fusion are mediated by host proteases, such as TMPRSS2 and ADAM17 (11). There is evidence regarding the ability of SARS-CoV-2 to directly assault the thyroid gland including the presence of ACE2 and TMPRSS2 in the thyroid tissue (79), along with detection of SARS-CoV-2 infection in follicular thyroid cells (80) and upregulation of immune genes is the SARS-CoV-2-positive thyroid specimens (81). This evidence not only suggests the ability of SARS-CoV-2 to directly invade thyroid tissue, but also proposes another mechanism of tissue injury by heightening inflammation through pro-inflammatory cytokines (80–82). Therefore, SARS-CoV-2 may disrupt thyroid function by entering thyroid cells, replicating locally, and triggering autoimmunity (83). ACE2 and TMPRSS2 expression were also found in the hypothalamus and pituitary, which makes them susceptible to direct damage following acute SARS-CoV-2 infection (84). The presence of ACE2 on hypothalamus, pituitary and thyroid tissue could be associated with not only triggering autoimmunity against thyroid by SARS-CoV-2, but also affecting the hypothalamic-pituitary-thyroid (HPT) axis. Acute SARS-CoV-2 infection can also cause a hyper-inflammatory immune response or cytokine storm following pneumonia. The uncontrolled inflammatory response can damage host cells, which could potentially affect the function of thyroid gland or HPT axis too (82, 85). Moreover, it has been reported that pre-existing thyroid conditions may worsen COVID-19 outcomes. Therefore, a bidirectional relationship between acute SARS-CoV-2 infection and thyroid dysfunction may exist ( Figure 2 ).

Furthermore, we must underscore the challenges in diagnosing thyroid complications after COVID-19, which are sometimes associated with overlapping symptoms and laboratory findings. Additionally, the increased risk of autoimmunity may precipitate development of long COVID syndrome (7). Long COVID is a multisystem condition that develops in almost 10% of infected patients, especially following a severe acute SARS-CoV-2 infection. Thyroid dysfunction appears unlikely, but has a possible correlation with long COVID. The heterogeneity of symptoms, and severity and duration of long COVID is sometimes associated with missed diagnosis and delayed treatment of potential preventable conditions such as thyroid dysfunction (7, 85). However, the data about correlation between thyroid dysfunction and long COVID are conflicting. It has been reported that there is a correlation between thyroid or pituitary dysfunction and long COVID (25, 86). However, multiple cohort studies reported that there is no meaningful correlation between long COVID and thyroid dysfunction (20, 22, 25, 41).

The current review has several limitations. Our review was limited to the studies written in the English language. The review excludes more recent publications completed after our initial review (March 31, 2024). We also reviewed information from different parts of the world, but there were still some missing areas, which limited the global applicability of the results. In addition, the differences in studies’ results may be caused by the evolution of treatment modalities for COVID-19 throughout the pandemic, the time of data collection in different studies and momentary incidence of the COVID-19 related complications.

The current recommendations for treating acute SARS-CoV-2 infection is primarily antivirals, such as remdesivir, molnupiravir and nirmatrelvir-ritonavir. Antivirals are designed to improve symptoms, reduce the duration of disease and prevent complications, such as hospitalization and post-acute sequelae of SARS-CoV-2 infection. However, SARS-CoV-2 continuously changes by altering the genetic codes, and routine usage of antivirals can induce new mutations too. For this reason, SARS-CoV-2 evolves gradually by accumulating mutations that can cause resistance to current antivirals and quicker spread of new variants with increased virulence (11, 87). Moreover, there are examples of hypothetical theories about the pathophysiology of post-acute sequelae of COVID-19, including sustained viral replication, presence of viral particles in organs, permanent inflammatory response, endothelial dysfunction, and altered immune function with a tendency toward autoimmunity (88, 89). Applying an alternative approach by targeting receptors, reducing virus engulfment and modulating immune response would be reasonable to improve COVID-19 outcomes.

Current literature supports the usefulness of dipeptidyl peptidase 4 inhibitors (DPP-4 inhibitors), metformin, spironolactone, and ursodeoxycholic acid (UDCA) in reducing virus entry into the cells and alleviating inflammatory responses (1). Each of the above medications has potential benefits to improve the clinical outcome of a patient with acute SARS-CoV-2 infection, and are not impacted by viral mutations. DPP-4 inhibitors are not only immunomodulators but also reduce SARS-CoV-2 interaction with receptors and diminish viral replication (11, 90). Spironolactone has anti-inflammatory and anti-thrombotic effects, and plays protective roles against SARS-CoV-2-mediated endothelial dysfunction by preventing damage to endothelial glycocalyx (91). Metformin reduces viral load, inflammation and thrombotic risks (92). Combining these medications can provide different valuable defenses against SARS-CoV-2 simultaneously, enhance the efficacy of treatment and further reduce complications of acute SARS-CoV-2 infection. In support of this statement, it has been shown that the combination of spironolactone and sitagliptin could reduce hospitalization of acute SARS-CoV-2 infection by almost 78 percent, which was superior to antivirals by some means (11, 93).

In conclusion, COVID-19 is associated with disruption of thyroid function, such as NTIS and thyroiditis. The preferred treatment options for COVID-19 may need to change as studies identify more promising medications that target the SARS-CoV-2 receptor. The use of antivirals seems inadvisable to prevent complications of acute SARS-CoV-2 infection. DPP-4 inhibitors, metformin, and spironolactone are relatively safe medications, which may be added to antivirals or used in combination for acute SARS-CoV-2 infection based on clinical judgment. It is crucial to evaluate these medications in clinical trials and produce more evidence to support their future use.