Thyroid Function Analysis in 50 Patients with COVID-19: A Retrospective Study

Abstract

Background:

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, it has affected >200 countries, areas, or territories in 6 continents. At present, whether COVID-19 has an effect on thyroid function is unclear. The aim of this study was to evaluate thyroid function in patients with COVID-19.

Methods:

Clinical manifestations, laboratory results, and chest computed tomography scans were retrospectively reviewed for 50 patients with laboratory-confirmed COVID-19 without a history of thyroid disease who underwent thyroid function testing during their course of COVID-19 infection and after recovery. They were admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, between January and March 2020. Healthy participants who underwent routine physical checkups and non-COVID-19 pneumonia patients with a similar degree of severity during the same period were included in the study as the control group. Thyroid hormone and thyrotropin (TSH) levels were analyzed and compared between the COVID-19 and control groups.

Results:

TSH lower than the normal range was present in 56% (28/50) of the patients with COVID-19. The levels of TSH and serum total triiodothyronine (TT3) of the patients with COVID-19 were significantly lower than those of the healthy control group and non-COVID-19 pneumonia patients. The more severe the COVID-19, the lower the TSH and TT3 levels were, with statistical significance (p < 0.001). The degree of the decreases in TSH and TT3 levels was positively correlated with the severity of the disease. The total thyroxine (TT4) level of the patients with COVID-19 was not significantly different from the control group. All the patients did not receive thyroid hormone replacement therapy. After recovery, no significant differences in TSH, TT3, TT4, free triiodothyronine (fT3), and free thyroxine (fT4) levels were found between the COVID-19 and control groups.

Conclusions:

The changes in serum TSH and TT3 levels may be important manifestations of the courses of COVID-19.

Introduction

Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, it has continued to spread worldwide. As of July 4, 2020, the global total number of confirmed cases of COVID-19 reached 10,922,324 (1). It has been recognized that the main target organs attacked by SARS-CoV-2 are the lungs and immune system, but it is unclear whether SARS-CoV-2 has an effect on thyroid function. In this study, the thyroid hormone and thyrotropin (TSH) of patients with COVID-19 were compared with those in a control group.

Materials and Methods

This retrospective study was approved by the Clinical Research Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University (reference number: 2020-129). The research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki.

The medical records of 104 patients with laboratory-confirmed COVID-19 admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University between January 2020 and March 2020, were retrospectively examined. After exclusion of patients with a history of thyroid disease, with pregnancy, or without assessment of thyroid function, 50 (48.1%) patients who had undergone thyroid function testing during the course of COVID-19 and after recovery were included. All the confirmed cases tested positive for SARS-CoV-2 in quantitative reverse transcriptase polymerase chain reaction of samples from the respiratory tract. All the cases were nonmild and divided into three clinical classifications: moderate, severe, and critical, based on clinical symptoms, laboratory results, and chest computed tomography scans, in accordance with the diagnosis and treatment plan for COVID-19 (Trial Version 7) issued by National Health Commission of China (2). The clinical classifications were mild cases, the clinical symptoms are mild and no pneumonia manifestations can be found on imaging; moderate cases, patients have symptoms such as fever and respiratory tract symptoms, and pneumonia manifestations can be seen on imaging; severe cases, adults who meet any of the following criteria: respiratory rate ≥30 breaths/min, oxygen saturation ≤93% at rest, and arterial partial pressure of oxygen (PaO₂)/oxygen concentration (FiO₂) ≤300 mmHg. Patients with >50% lesions progression within 24 to 48 hours on lung imaging were also classified as severe cases; critical cases, meeting any of the following criteria: occurrence of respiratory failure requiring mechanical ventilation, presence of shock, and other organ failure that requires monitoring and treatment in the intensive care unit (2). The 50 patients had their thyroid function tested, including serum total thyroxine (TT4), total triiodothyronine (TT3), and TSH within 3 days after admission. Their thyroid functions, including TT3, TT4, free triiodothyronine (fT3), free thyroxine (fT4), and TSH, were re-evaluated after recovery (i.e., nucleic acid tested negative for respiratory tract pathogen twice consecutively, respiratory symptoms had significantly improved, and lung image showed obvious improvement in lesions). Healthy participants of similar ages (48.4 ± 13.7 years old) and sex (33 male and 21 female) who underwent routine physical checkup during the same period were included as the control group. They had no thyroid diseases and no other medical history that could affect thyroid function. To determine whether there are any unique effects of COVID-19 on thyroid function, we included another control group of non-COVID-19 pneumonia patients with a similar degree of severity. The immunoluminescent method (Abbott i2000, Wiesbaden, Germany) was used for thyroid function testing. The thyroid hormone and TSH levels were analyzed and compared between the COVID-19 and control groups.

Statistical analysis

Data were analyzed with the statistical software package PASW Statistics version 18 (International Business Machines Corp., Armonk, NY). As the data were not normally distributed, the total number (proportions) of categorical variables and median [first quarter, third quarter] of the continuous variables were used. For comparison between the two groups, the Wilcoxon rank sum test was used for continuous variables. The Kruskal–Wallis test was used for comparison among more than three groups. Chi-square test was used for the categorical variables. Differences were considered statistically significant when the p value was <0.05.

Results

During the course of COVID-19, our examination of thyroid function indicated that 64% (32/50) of the patients had abnormal thyroid function parameters, including 34% (17/50), 6% (3/50), 18% (9/50), 2% (1/50), and 4% (2/50) with lower-than-normal values in only TSH, TT3, TSH and TT3, TT3 and TT4, and TSH, TT3 and TT4 levels, respectively. Of the patients with COVID-19, 56% (28/50) had lower-than-normal TSH levels, with a p value of <0.01 compared with the control group. The serum TSH and TT3 levels of the patients with COVID-19 were significantly lower than those of the healthy control group and non-COVID-19 pneumonia patients. The TT4 levels of the patients with COVID-19 were not significantly different from those of the controls (Table 1). The clinical classification of the 50 confirmed COVID-19 cases was moderate in 15, severe in 23, and critical in 12 cases. The more severe the COVID-19 infection was, the lower the TSH and TT3 levels, with statistically significant differences (p < 0.001). The degree of the decrease of TSH and TT3 was positively correlated with the severity of the disease (Table 2). As compared with non-COVID-19 pneumonia patients with a similar degree of severity, the serum TSH levels of the patients with COVID-19 were significantly lower in the severe and critical ill, while it was not different in the moderate group. TT3 and TT4 were not different between COVID-19 and non-COVID-19 with a similar degree of severity (Table 3). None of the patients received thyroid hormone replacement therapy, and the levels of all the thyroid hormones returned to normal after recovery (Supplementary Table ).

Table 1.

Comparison of Serum TSH, TT3, and TT4 Between COVID-19 and Healthy Control Group and Non-COVID-19 Pneumonia Patients

	COVID-19 (n = 50)	Healthy control (n = 54)	Non-COVID-19 (n = 50)
Alb (g/L)	38.15 [34.57, 43.10]^**	46.15 [43.98, 48.05]	38.70 [33.67, 40.95]
TSH (mIU/L)	0.30 [0.15, 0.86]^** ^,##	1.57 [1.03, 1.97]	1.18 [0.68, 1.91]
TT3 (nmol/L)	0.98 [0.84, 1.22]^** ^,#	1.58 [1.49, 1.73]	1.28 [0.82, 1.43]
TT4 (nmol/L)	97.41 [78.71, 113.73]	97.11 [85.73, 108.76]	90.37 [69.16, 105.83]

p < 0.01 compared with healthy control.

p < 0.05, ^## p < 0.01 compared with non-COVID-19 pneumonia patients.

The median [first quarter, third quarter] of continuous variables was used.

Alb, albumin; COVID-19, coronavirus disease 2019; non-COVID-19: non-COVID-19 pneumonia patients; TSH, thyrotropin; TT3, total triiodothyronine; TT4, total thyroxine.

Table 2.

Comparison of Serum TSH, TT3, and TT4 Among Different Clinical Classification of COVID-19 According to Severity

	TSH (mIU/L)	TT3 (nmol/L)	TT4 (nmol/L)
Control (n = 54)	1.57 [1.03, 1.97]	1.58 [1.49, 1.73]	97.11 [85.73, 108.76]
Moderate (n = 15)	0.50 [0.22, 1.58]	1.33 [1.02, 1.53]	98.67 [85.59, 112.63]
Severe (n = 23)	0.286 [0.13, 0.77]	0.95 [0.88, 1.12]	100.98 [72.73, 114.27]
Critical (n = 12)	0.23 [0.085, 0.42]	0.83 [0.68, 0.96]	85.05 [78.33, 118.70]
p-value^*	<0.001	<0.001	0.756
p-trend^#	<0.001	<0.001	—

Moderate: moderate COVID-19; severe: severe COVID-19; critical: critical COVID-19; The median [first quarter, third quarter] of continuous variables was used.

The p-value means that there is difference as compared among all the groups.

p-trend means that there is a trend for the more severe the COVID-19, the lower the TSH and TT3 levels were.

Table 3.

Comparison of Serum TSH, TT3, and TT4 Between Different Clinical Classification of COVID-19 and Non-COVID-19 Pneumonia Patients with a Similar Degree of Severity

	Moderate	p	Severe	p	Critical	p
Albumin (g/L)	43.40 [37.90, 44.90]	0.290	38.20 [35.60, 41.40]	0.462	34.40 [32.05, 37.45]	0.204
	41.40 [39.60, 43.10]		37.70 [35.20, 40.70]		33.50 [30.75, 37.35]
TSH (mIU/L)	0.50 [0.22, 1.58]	0.067	0.286 [0.13, 0.77]	0.000	0.23 [0.085, 0.42]	0.003
	0.99 [0.70, 1.90]		1.17 [0.51, 1.93]		1.42 [0.39, 1.92]
TT3 (nmol/L)	1.33 [1.02, 1.53]	0.281	0.95 [0.88, 1.12]	0.051	0.83 [0.68, 0.96]	0.707
	1.39 [1.29, 1.53]		1.28 [0.91, 1.42]		0.80 [0.69, 1.20]
TT4 (nmol/L)	98.67 [85.59, 112.63]	0.787	100.98 [72.73, 114.27]	0.097	85.05 [78.33, 118.70]	0.273
	95.74 [86.09, 105.85]		85.04 [68.10, 105.57]		83.31 [59.56, 100.61]

The upper line was for COVID-19, the lower line for non-COVID-19 pneumonia patients. The median [first quarter, third quarter] of continuous variables were used.

Discussion

Some patients with serious diseases other than thyroid disorders demonstrated abnormal levels of thyroid hormones, which are collectively called as nonthyroidal illness syndrome (NTI) or euthyroid sick syndrome (3,4). The most typical alterations are decreased plasma triiodothyronine (T3) level, low or normal plasma thyroxine (T4) level, and normal or slightly decreased TSH level (4). The common causes of NTI are mainly serious infections, liver and kidney failure, severe diabetic complications, malignant tumor, and severe malnutrition. However, in our study, 34% (17/50) of the patients showed lower-than-normal values only for TSH during the course of their COVID-19 infection, which may not be fully explained by NTI. SARS is a severe infectious illness, caused by SARS coronavirus (SARS-CoV), which is a systemic disease that has extensive effects on multiple organ systems. A previous study reported that the thyroid glands of patients with SARS were significantly affected by extensive injury to the follicular epithelial and parafollicular cells (5). Another previous study showed that the TT3, TT4, and TSH levels of patients with SARS were considerably lower than those of controls in both the progression and recovery phases (6). Moreover, Wei et al. found that the amount and staining intensity of TSH-positive cells were decreased in the pituitary of patients with SARS, which showed that the decreased TSH concentration might be associated with the changes in TSH-secreting cells in the pituitary (7). We also found that the patients with COVID-19 had low TSH and TT3 levels, and the degree of the decreases in their TSH and TT3 levels positively correlated with the severity of their COVID-19. The fact that the serum TSH levels of the patients with COVID-19 were significantly lower in the severe and critical group compared with non-COVID-19 pneumonia patients with a similar degree of severity also indicates there might be a unique effect of COVID-19 on TSH-secreting cells. Two possible mechanisms might account for these changes. One is a direct viral effect on the pituitary cells and another is an indirect effect wherein various systemic changes such as the activation of various proinflammatory cytokines caused by the virus infection (3,4) or its treatment led to hormonal changes in the pituitary–endocrine axis feedback loops. The observed decrease in TSH level in patients with COVID-19 could be induced by chronic stress from hypoxemia and the glucocorticoids with which most patients (31/50) were treated, though the dosage was low (57.3 mg methylprednisolone per day). SARS-CoV-2 is similar in structure and pathogenicity with SARS-CoV. Thus, we suspected that SARS-CoV-2 also might affect the TSH-secreting cells.

One of the shortcomings of this study was that fT3, fT4, and other pituitary hormones were not assessed at admission owing to the retrospective nature of the study. In addition, the thyroid hormones were tested while most patients (31/50) were receiving glucocorticoids. Therefore, excluding the effect of hormonal changes in the pituitary–endocrine axis feedback loops was difficult. Our hospital is a tertiary level hospital. The COVID-19 classification of the patients admitted in our hospital was higher than moderate. The patients with mild COVID-19 lacked thyroid function data, which is another shortcoming. Thus, changes in serum TSH and thyroid hormone levels may be important manifestations of the course of COVID-19.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

Funding Information

This study was supported by Zhejiang medical science and technology projects [Grant Nos. 2018KY056 and 2018KY363].

Supplementary Material

Supplementary Table S1

References

Coronavirus disease (COVID-19) pandemic. Geneva: World Health Organization. Available at https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports (accessed July 4, 2020 ).

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