A new metanalysis study conducted by researchers from Xiamen University-China, Fujian Medical University-China and Peking Union Medical College-China has found that SARS-CoV-2 infections causes fluctuations in thyroxine fluctuations which can lead to health issues.
The study findings were published in the peer reviewed journal: Frontiers In Endocrinology.
SARS-CoV-2 can damage multiple organs, including the lungs, liver, heart, brain, and kidneys, leading to systemic symptoms.
The thyroid gland highly expresses the ACE2 receptor.
Thus, the hypothalamic–pituitary–thyroid axis may be susceptible to the disturbance in patients with COVID19 (22, 34, 41, 51, 52). SARS-CoV, a coronavirus related to SARS-CoV-2, injures thyroid parafollicular and follicular cells (53). Lui et al. found that high SARS-CoV-2 viral loads were associated with small thyroid volumes (37).
This association suggested a direct viral effect on the thyroid gland. Lania et al. revealed that COVID-19 might be associated with the high risk of thyrotoxicosis (n = 31, 10.8%) in a retrospective study that enrolled 287 patients (54). However, the autopsy results suggested the absence of the virus was in thyroid tissues (55–57).
The number of reported thyrotoxicosis cases in literature did not exponentially increase, including critically ill patients (13, 15, 28, 32, 34). Thyrotoxicosis may be a rare complication of COVID-19 (51).
Many studies revealed that thyroid function significantly changes during COVID-19 infection.
The trends of thyroxine level fluctuations in patients with COVID-19 and non-COVID-19 pneumonia were similar (decreased TSH and FT3 levels and increased FT4 levels). This similarity suggests that COVID-19 and non-COVID-19 pneumonia affect the thyroid gland through similar mechanisms.
In addition, thyroxine levels during follow-up indicated progressive improvement and transient hormone changes (17, 34). Patients suffering from COVID-19 and thyroxine fluctuation potentially encountered non-thyroidal illness syndrome (NTIS) induced by systemic inflammation (58, 59).
NTIS is an adaptive response to stress, critical illness, and malnutrition, manifested by a decrease in FT3 levels or decreases in TSH, FT3, and FT4 levels in severe disease (58, 60). Since systemic inflammation potentially impacts the de-iodinase activity, it inhibits T4–T3 conversion decreases FT3 levels and increases FT4 levels (17, 61, 62).
Elevated FT4 level upon admission tends to be mistaken for thyrotoxicosis. Most studies have investigated thyroxine changes in COVID-19 at admission. NTIS in patients with long-term critical illness shows symptoms similar to hypothyroidism (59, 63, 64). Unlike thyrotoxicosis, treatment with thyroid hormone is not recommended without clinical signs of hypothyroidism.
Even mild hypothyroidism can be considered a physiologically favorable condition that can suppress energy expenditure and eventually restrict catabolism by decreasing thyroid hormone activity (63). Thyroid function can recover in patients without intervention (18, 58, 65, 66).
Immunoassays for thyroxine can be affected by alterations in serum binding protein that occurs in various physiological states (20). Decreased TSH and increased FT4 levels were reported in the healthy cohort during the COVID-19 outbreak (67). During the pandemic, relationships were found between thyroid diseases and psychiatric factors, such as anxiety and depression (68, 69).
The pandemic socio-psychological sequelae can constitute stressors for the population, potentially affecting the thyroid gland. Collectively, patients with COVID-19 are at risk of thyroid diseases and require attention.
Thyroid function parameters have clinical significance in determining disease severity and prognosis of COVID-19. Whether the severity of COVID-19 is associated with thyroid function remains unclear. Some studies reported no significant relationship between COVID-19 severity and thyroid function, whereas other studies have suggested that only some statistically significant indicators compare disease severity (7, 13, 14, 28, 45, 47).
It may be related to multiple factors, including different criteria adopted in different regions. The classifications of COVID-19 severity vary. The WHO uses SpO2 of less than 90% as a cutoff between severe and non-severe COVID-19. By contrast, the United States, China, and Japan use 93% or 94% as a division basis in diagnosis and treatment guidelines (14, 19, 47, 70).
In the present study, the single-arm meta-analysis results revealed that only TSH and FT3 levels were significantly different compared to patients with severe-critical and non-severe COVID-19. The case-control study showed that although the FT4 levels differed significantly, the difference was only 0.18, with minor practicality. In the acute phase, TSH and FT3 levels at admission in COVID-19 patients can be used in assessing patient severity.
Thyroid function is not a routine test indicator in patients infected with COVID-19. Some studies have suggested that thyroid function cannot be used in evaluating the prognosis of patients, or only some indicators can be used in the prognostic analysis (13, 32, 48, 71). In the present study, TSH, FT3, and FT4 levels presented significant differences between survivors and deceased patients at admission.
The results of the single-arm meta-analysis suggested that only TSH and FT3 levels were heterogeneous between survivors and non-survivors. The controlled studies showed statistically significant differences in the three thyroid function parameters. However, we found that differences in TSH (SMD = 0.29) and FT4 (SMD = 0.22) levels were limited for assessing prognosis.
Compared with TSH and FT4, FT3 levels may be more effective (SMD = 0.79). A low FT3 level is an outcome predictor, especially in severe patients (5). The excessive production of proinflammatory cytokines during SARS-CoV-2 infection aggravates ARDS and tissue damage resulting in multi-organ failure and death (72, 73).
In patients with COVID-19, FT3 levels decrease with the increasing levels of inflammatory cytokines. Some studies have suggested that improving thyroid function can improve patient outcomes. However, a reduction in FT3 levels occurs before clinical symptoms worsen. This reduction can be used in assessing changes in patient condition and prognosis (74).
Survivor bias may have been present when prognostic thyroid function was being determined. Thyroid function is an unconventional test indicator for patients with COVID-19. Medical centers tend to assess the thyroid function in patients with underlying thyroid diseases or other severe illnesses.
Moreover, the pharmacological doses of steroids in severe COVID-19 can affect thyroid function. Therefore, comprehensive extensive clinical studies are needed to evaluate the significance of thyroid function assessment for patients with COVID-19.
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