Does COVID-19 infection change thyroid hormone levels? A comparative cross-sectional study in Iran

doi:10.21203/rs.3.rs-1538510/v1

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Does COVID-19 infection change thyroid hormone levels? A comparative cross-sectional study in Iran

https://doi.org/10.21203/rs.3.rs-1538510/v1

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Background: Given the paucity of research investigating the changes of thyroid hormones in people affected with COVID-19, this study aimed to evaluate the levels of thyroid hormones in people affected by COVID-19 infection in Ahvaz, Iran.

Methods: This was a comparative cross-sectional study on 78 patients with COVID-19 infection and 80 individuals without infection. Thyroid stimulating hormone (TSH), Triiodothyronine (TT3) and tetraiodothyronine (TT4) were measured in hospitalized patients and one month after recovery and in participants without infection. Data were analyzed using paired t-test, Wilcoxon test, and ANCOVA.

Results: The level of TSH at baseline in the hospitalized patients was significantly lower than that in the control group (1.24±1.08 vs. 2.05± 1.02 mlU/L, respectively, p<.0001). The mean level of TT3 was 1.20±0.24 and 1.28 ± 1.25 ng/dL in the case and control groups respectively (p=.188). The level of TT4 in the case group was high at baseline in comparison to the control group (8.48±2.27 vs. 7.76 ± 1.43 ng/dL, p=.076) that was reduced in the follow-up period. Thirty-five (44.8%) patients had severe disease and were admitted to ICU, that nine of them have died. The level of TSH was non- significantly lower in patients with severe disease compared to those with moderate disease.

Conclusion: Patients with COVID-19 infection showed abnormalities in thyroid hormones such as decreased levels of TSH. Patients with severe disease had a lower level of TSH. More investigation about thyroid function in patients with COVID-19 are recommended.

COVID-19 infection

Thyroid stimulating hormone

Triiodothyronine

Tetraiodothyronine

Thyroid dysfunction

COVID-19 infection was detected in late 2019 in Wuhan (China), and so far, 203, 944,144 confirmed cases and 4,312,902 deaths from this disease have been recorded. Meanwhile, about five million cases of COVID-19 have been diagnosed in Iran, and more than 100,000 people have died so far in this country [1].

The effect of COVID-19 infection on the level of endogenous hormones in the body recently attracted much scholarly attention. One group of these hormones are thyroid hormones. Despite the importance of this topic, few studies have evaluated the changes of thyroid hormones in people affected with COVID-19. For instance, Chen et al. studied 50 people affected with COVID-19 and found that the levels of Thyroid Stimulating Hormone (TSH) and Triiodothyronine (T3) were significantly lower than those in healthy people [2]. Confirming Chen et al’s findings, Wang et al. also, reported that even TSH level was much lower in patients with severe COVID-19 infection compared with other patients [3]. Lania et al. found that the function of thyroid in most cases who were affected with COVID-19 infection remained normal, some cases showed thyrotoxicosis, and only minority of the patients showed hypothyroidism [4]. A systematic review including seven studies and 1237 patients, showed that the prevalence of thyroid dysfunction was varied from 13–64% in patients affected with COVID-19 infection [5]. Wang et al. in their study on 84 hospitalized patients with COVID-19 infection found that the level of total triiodothyronine (TT3) and thyroid stimulation hormone (TSH) were significantly lower in the patients than that in the healthy people, and 61.9% of patients showed thyroid function abnormalities [3]. Also, Xu et al. in a systematic review on 11 studies and 2,995 COVID-19 patients found that thyroid dysfunction was associated with severe COVID-19 infection, with the hypothyroidism had a grater relationship with severe COVID-19 infection [6]. According to evidence, non-thyroid illness (NTI) syndrome are the most hormonal alteration that observed in COVID-19 patients, and most changes in thyroid hormones are caused by cytokine storm (7). Most studies classified thyroid disorders during COVID-19 infection as euthyroid sick syndrome (ESS) or destructive thyroiditis [8–9].

Although a number of studies have examined the association of COVID-19 infection with thyroid hormones, this association is not yet fully understood. Moreover, no study has yet been conducted on this topic in Iran. Therefore, this study was conducted to evaluate the effect of COVID-19 infection on thyroid hormones in hospitalized patients in Ahvaz, Iran.

This was a comparative cross-sectional study on 78 hospitalized patients with COVID-19 infection and 80 individuals without COVID-19 infection. The design of this study was approved by the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences (Ref No: IR.AJUMS.REC.1399.541). Individuals with the following criteria were recruited for the study: age up to 55 years for males and up to 45 years for females (to avoid the effect of perimenopause on thyroid hormones), and confirmed infection with COVID-19 based on PCR test or lung CT-scan for the groups with COVID-19 infection. Menopausal women, and people with known hormonal dysfunction were excluded from the study. All participants provided written informed consent for participation in the study.

Measurements

A demographic questionnaire and a check list were used to collect the data. All patients with confirmed COVID-19 infection who were hospitalized in Razi Hospital of Ahvaz, Iran were screened for eligibility. Razi Hospital is a university hospital with 200 beds that was designated for the admission of patients with COVID-19 infection from the early days of COVID-19 pandemic in Iran.

Eligible hospitalized patients were requested to fill-up a demographic questionnaire. Then, 5mL venous blood sample was collected from all patients, and placed into gel tubes, and transferred to a reference laboratory (Novin Lab, Ahvaz). The blood samples were centrifuged for 10 minutes. Then the sera were separated in gamma tubes with a lid and stored in a freezer (-20 C°) until the time of evaluation. The measurement technique was based on quantitative luminescence, which has a much higher sensitivity and specificity than the enzyme-linked immunoassay (ELISA). A severe disease was defined when around 50% of the lung had been affected with virus, or if the level of blood oxygen was less than 93%. Patients with severe disease were transferred to intensive care unit (ICU).

Thyroid function was assessed using measurement of thyroid stimulating hormone (TSH), total Triiodothyronine (TT3) and total tetraiodothyronine (TT4). The same thyroid hormones were measured in the control group that had these tests for routine checkups [10]. The results of laboratory tests were recorded in a checklist.

Statistical Analyses

All data were entered into SPSS version 22 (IBM SPSS Statistics for Windows). Results were presented as mean ± SD or number and frequency. The independent t-test, Chi-square test, Mann-Whitney, and Wilcoxon test were used to compare variables between groups. Because age between two groups was significant, the ANCOVA test was used to adjust this effect. P < 0.05 was considered statistically significant.

Blood samples from 78 hospitalized men and women with COVID-19 infection of whom 30 (18.5%) were in the intensive care unit (ICU) were initially tested. One month after discharge from the hospital, nine patients died because of COVID-19 infection (six males and three females), and four patients from those admitted to ICU died because of disease severity.

Demographic characteristics of participants are presented in Table 1. As evident from this table, participants in the control group were significantly younger than that in the case group (p < .001). Participants did not show any significant difference regarding sex, occupation, educational attainment, and marital status. Most participants in the CVID-19 group had a complex of symptoms of infection, while 26.9% of them had only one symptom.

Table 1

Demographic characteristics of participants in the case and control groups
Variable	Participants n = 78	Control group n = 80	P value
	Mean ± SD
Age (y)	38.94 ± 6.68	32.27 ± 6.84	< .001
	n (%)
Sex
Female	39(50.0)	40 (50.0)	< .99
Male	39(50.0)	40(50.0)	< .99
Occupation
Unemployed	6(7.7)	6(7.5)	.99
Housewife	31(39.7)	32(40)
Manual worker	3(3.8)	4(5)
Employed	18(23.1)	17(21.3)
Self-employee	20(25.6)	21(26.3)
Education
Primary	20(25.6)	19(23.8)	.99
High school	11(14.1)	13(16.3)
Diploma	27(34.6)	26(32.5)
University education	20(25.6)	22(27.5)
Marital status
Single	10(12.8)	12(15)	.91
Married	68(87.2)	68(85)	.91
Signs and symptoms of COVID-19 infection
Fever + chills + shortness of breath and pain in the body	11(14.1)	-
Fever + shortness of breath + chills and headache	16(20.5)	-
All symptoms	30(38.5)	-
One of the following symptoms such as fever, cough, headache, or shortness of breath	21(26.9)	-

Table 2 shows the level of thyroid hormones in participants with COVID-19 infection and in the control group. As this table shows, the level of TSH at baseline in the hospitalized patients was significantly lower than that in the control group (p < .0001). The level of this hormone increased one month after discharge from hospital (p = .0001).

Table 2

Thyroid hormone levels in the case and control group before and after COVID-19 infection
Variables	Case N = 78	Control N = 80	P value*
	Mean ± SD
TSH (mlU/L)
Baseline	1.24 ± 1.08	2.05 ± 1.02	< .0001
Follow-up	1.87 ± 1.26	-
P-value	.0001	-
TT₃ (ng/dL)
Baseline	1.20 ± 0.24	1.28 ± 1.25	.188
Follow-up	1.00 ± 0.27	-
P-value	< .0001	-
TT₄ (ng/dL)
Baseline	8.48 ± 2.27	7.76 ± 1.43	.076
Follow-up	7.31 ± 1.83	-
p-value	< .001	-
*ANCOVA test was used adjusted for age.

The mean level of T3 was 1.20 ± 0.24 and 1.28 ± 1.25 in the case and control groups respectively that did not show statistically significant after adjusting for age (p = .188). The level of this hormone decreased after recovery from the disease (p < .0001). The level of T4 in the case group was high in the baseline in comparison to the control group (8.48 ± 2.27 vs. 7.76 ± 1.43, p = .076) that was reduced in the follow-up period (7.31 ± 1.83, p < .001).

Table 3 was designed to show the differences between two groups of patients with moderate and severe infection. As this table shows, at baseline the mean of TSH was non-significantly lower in the group with severe infection (1.02 ± .83 vs. 1.42 ± 1.22, mlU/L, p = .27). The increase in the level of this hormone in the group with severe disease was more dominant in the follow-up period (p = .024). The level of TT3 and TT4 at baseline did not show any significant difference, but in the follow-up the mean of TT4 was decreased more than that in the patients with the moderate disease (p = .014).

Table 3

Comparison of thyroid hormones levels between two groups with severe and moderate disease
	Disease severity
Outcomes	Moderate n = 43	Severe n = 35	P-value
	Mean ± SD
TSH(mlU/L)
Baseline (n = 78)	1.42 ± 1.22	1.02 ± 0.83	0.27*
Follow-up (n = 69)	1.55 ± 1.06	2.27 ± 1.38	.024*
TT₃ (ng/dL)
Baseline (n = 78)	1.19 ± .26	1.20 ± .21	.513*
Follow-up (n = 69)	1.04 ± .25	.95 ± .29	.146*
TT₄ (ng/dL)
Baseline (n = 78)	8.48 ± 2.46	8.48 ± 2.04	.99**
Follow-up (n = 69)	7.80 ± 1.65	6.72 ± 1.90	.014**
Mann-Whitney *Independent t-test

This study was designed to evaluate the levels of thyroid hormones in COVID-19 patients during the active period of the disease and one month after recovery. Our results showed that the levels of TSH in both males and females decreased during the active period of COVID-19 infection in comparison to the control group, while in the follow-up period, an increase was observed in the level of this hormone. In line with our study, Wang et al. studied 84 hospitalized COVID-19 patients and found that the levels of TT3 and TSH in these patients were lower compared with healthy people (p < 0.001) [3]. Few cases of subacute thyroiditis (SAT) accompanying COVID-19 infection have been reported since the onset of the COVID-19 pandemic [11]. Khatri et al. in their study explained a case of COVID-19 infection that manifested SAT without any clinical, or radiological cause of this other than COVID-19 were negative [12]. Furthermore, Muller et al. in their study in hospitalized patients who affected with COVID-19 infection found that patients with more severe disease showed thyrotoxicosis and low level of TSH that might be resulted from SAT induced by COVID-19 infection [13]. Our results are line with above-mentioned studies.

Our results showed that the levels of TT3 and TT4 were high during the active period of infection which fell significantly in the follow-up period. Similar to our results, Weiwei et al. in their study on 1395 individuals found that the level of FT4 increased and level of TSH and FT3 decreased significantly in patients with COVID-19 infection [14].

Chen et al. conducted a retrospective study on 50 patients and found that lower TSH was present in 56% of COVID-19 patients, and their levels of TT3 was lower compared with healthy people. Based in their results, the more severe the disease, the lower the level of thyroid hormones. They concluded that thyroid hormone levels were more likely to change in people with severe COVID-19 disease [2]. Also, Wang et al. conducted a study on 84 hospitalized COVID-19 patients and found that the level of TT3 and TSH were significantly decreased during the active period of COVID-19 infection [3]. Our results are similar to Chen et al. and Wang et al. except for that the level of TT3 in our study was higher in the active period of the disease and then reduced. The increase in the level of TT3 was negligible and even was much closed to the level of this hormone in the healthy individuals (1.20 ± 0.24 vs. 1.28 ± 1.25, p = .188). In our study, patients underwent corticosteroid therapy from the admission to hospital that may cause these manifestations.

The mechanism of change in thyroid hormones in infectious diseases is unknown. Studies have shown that the cause of changes in the level of thyroid hormones especially TSH during infectious diseases may not related to the pituitary origin, and may result from outside of pituitary such as bone marrow [15]. At the present time there is no evidence in favor of direct thyroid effect of cytokines on thyroid hormones [7]. Other studies explained the role of angiotensin-converting enzyme 2 (ACE2) receptors in the entry of viruses into the thyroid cells and cytokine storm [16]. Also, apoptosis may play a role in the thyroid dysfunction associated with SARS disease [17].

In our study, 35 patients (44.8%) had a severe form of disease and were admitted to ICU, that none of them died. Patients with severe disease had non-significant lower levels of TSH at baseline. These results are in line with those of Chen et al [2]. Also, Beltrao et al. reported that FT3 levels were lower in patients with severe disease, while the serum reverse triiodothyronine (rT3) was elevated in patients with severe disease. They drew the conclusion that thyroid hormones have a correlation with severity of the disease [18]. The results of the present study are in line with those of Beltrao et al’s. In line with our study, Yazan et al. found that there is a relationship between changes of thyroid hormones and mortality in patients with COVID-19 infection, in this way that patients with higher reduction in TSH, FT3, and higher level of FT4 were more likely to admit to ICU or die [19].

This is the first study in Iran to prospectively follow up hospitalized patients with COVID-19 infection one month after recovery from the disease. The steroid therapy regularly starts for any COVID-19 patient that admit to hospital in Iran. Therefore, the changes in thyroid hormones may partly due to steroid therapy and not COVID-19 infection.

According to the results of this study, patients with COVID-19 infection showed abnormalities in thyroid hormones such as decreased levels of TSH which returned to normal ranges after recovery. Patients with severe cases of COVID-19 showed higher levels of TSH and lower levels of TT3 and TT4. More investigations about thyroid function in patients with COVID-19 are recommended.

TSH

Thyroid stimulating hormone

TT3

Triiodothyronine

TT4

Tetraiodothyronine

ANCOVA

Analysis of Covariance

NTI

Non-thyroid illness

ESS

Euthyroid sick syndrome

ELISA

Enzyme-linked immunoassay

ICU

Intensive care unit

SAT

Subacute thyroiditis

FT4

Free thyroxine

Ethics approval and consent for participate: The design of this study was approved by the Ethics Committee of Ahvaz Jundishapur University of Medical Sciences (Ref No: IR.AJUMS.REC.1399.541). All participants provided written informed consent prior to data collection.

Consent for publication: Not applicable

Availability of data and materials: Data of this study will be available upon the reasonable request from corresponding author.

Competing interest: Authors declare that they do not have any competing interest.

Funding: This study was financially supported by Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran (Ref No: RHPRC-9925(. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authors’ contributions

Conception of the study: Poorandokht Afshari, Mehrnoosh Zakerkish,Parvin Abedi, Hossein Meghdadi, Maryam Beheshtinasab

Data collection: Maryam Beheshtinasab

Data analyzing and interpretation: Elham Maraghi

Writing the manuscript: Parvin Abedi

Editing and approval of final version of paper: All authors

Acknowledgements: We would like thanks all participants who participated in this study.

WHO Coronavirus (COVID-19) Dashboard. Available at: https://covid19.who.int/ Accessed date: 11 August 2021.
Chen M, Zhou W, Xu W. Thyroid Function Analysis in 50 Patients with COVID-19: A Retrospective Study. Thyroid. 2021; 31:8–11. Doi: 10.1089/thy.2020.0363.
Wang W, Su X, Ding Y, Fan W, Zhou W, Su J, et al. Thyroid Function Abnormalities in COVID-19 Patients. Front. Endocrinol. 2021; 11: 623792. https://doi.org/10.3389/fendo.2020.623792
Lania A, Sandri MT, Cellini M, Miran M, Lavezzi E, Mazziotti G. Thyrotoxicosis in patients with COVID-19: the THYRCOV study. Eur J Endocrinol. 2020; 183:381–387. Doi: 10.1530/EJE-20-0335.
Giovanella L, Ruggeri RM, Ovcaricek PP, Campenni A, Treglia G, Deandreis. Prevalence of thyroid dysfunction in patients with COVID-19: a systematic review. Clin Transl Imaging. 2021; 11: 1–8. Doi: 10.1007/s40336-021-00419-y [Epub ahead of print]
Xu J, Li Y, Xia Q, Shi Q. Association between thyroid disease and severe Coronavirus disease 2019 (COVID-19) infection: A meta-analysis. Iran J Public Health. 2021; 50: 1517–1525.
Croce L, Gangemi D, Ancona G, Liboa F, Bendotti G, Minelli L, Chiovato L. The cytokine storm and thyroid hormone changes in COVID-19. J Endocrinol Invest. 2021; 44: 891–904. https://doi.org/10.1007/s40618-021-01506-7
Guo J, Hong Y, Wang Z, Li Y. Analysis of the incidence of euthyroid sick syndrome in comprehensive intensive care units and related risk factors. Front Endocrinol (Lausanne). 2021; 9;12:656641. Doi: 10.3389/fendo.2021.656641.
Lui DTW, Lee CH, Chow WS, Lee ACH, Tam AR, Fong CHY, et al. Thyroid Dysfunction in Relation to Immune Profile, Disease Status, and Outcome in 191 Patients with COVID-19. J Clin Endocrinol Metab. 2021; 106:e926-e935. Doi: 10.1210/clinem/dgaa813.
Lewandowski K. Reference ranges for TSH and thyroid hormones. Thyroid Res. 2015; 8(Suppl 1): A17. Doi: 10.1186/1756-6614-8-S1-A17
Brancatella A, Ricci D, Cappellani D, Viola N, Sgrò D, Santini F, et al. Is Subacute Thyroiditis an Underestimated Manifestation of SARS-CoV-2 Infection? Insights From a Case Series. J Clin Endocrinol Metab. 2020; 105: dgaa537. Doi: 10.1210/clinem/dgaa537.
Khatri A, Charlap E, Kim A. Subacute thyroititis from COVID-19 infection: a cae report and review of literature. Eur Thyroid J. 2020; 9:324–328. https://doi.org/10.1159/000511872
Muller I, Cannavaro D, Dazzi D, Covelli D, Montovani G, Muscatello A. SARS-Cov-2-related atypical thyroiditis. The LANCET Diabetes Endocrinol. 2020; 8: 739–741.
Weiwei D, Bei W, Hong W, Cailan W, Hailin S, Donghong X, et al. Thyroid Hormone Changes in the Northern Area of Tianjin during the COVID-19 Pandemic. Int. J. Endocrinol. 2022; ID 5720875 | https://doi.org/10.1155/2022/5720875
Klein JR. The Immune System as a Regulator of Thyroid Hormone Activity. Exp Biol Med (Maywood). 2006; 231: 229–236. Doi: 10.1177/153537020623100301
Murugan AK, Alzahrani AS. SARS-CoV-2: Emerging Role in the Pathogenesis of Various Thyroid Diseases. J Inflamm Res. 2021; 14:6191–6221. Doi: 10.2147/JIR.S332705.
Wei L, Sun S, Xu CH, Zhang J, Xu Y, Zhu H, et al. Pathology of the thyroid in severe acute respiratory syndrome. Hum Pathol. 2007; 38: 95–102. Doi: 10.1016/j.humpath.2006.06.011
Beltrão FEDL, Beltrão DCDA3, Carvalhal G, Beltrão FEDL3, Brito ADS, Capistrano KHRD et al. Thyroid Hormone Levels During Hospital Admission Inform Disease Severity and Mortality in COVID-19 Patients. Thyroid. 2021; 31:1639–1649. Doi: 10.1089/thy.2021.0225.
Yazan CD, Ilgin C, Elbasan O, Apaydin T, Dashdamirova S, Yigit T. The Association of Thyroid Hormone Changes with Inflammatory Status and Prognosis in COVID-19. Int. J. Endocrinol. 2021: Article ID 2395212. https://doi.org/10.1155/2021/2395212

No competing interests reported.

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Does COVID-19 infection change thyroid hormone levels? A comparative cross-sectional study in Iran

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Abstract

Background

Methods

Measurements

Statistical Analyses

Results

Discussion

Limitations Of The Study

Conclusion

Abbreviations

Declarations

References

Additional Declarations

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