Thyroid Dysfunction in COVID-19 Patients: A Study at Imam Reza Hospital, Sirjan

BackgroundLow free triiodothyronine (FT3) levels are related to a poor prognosis deterioration in patients with COVID-19 presenting with non-thyroidal illness syndrome (NTI). This study was designed to explore whether free thyroxin (FT4) or thyroid stimulating hormone (TSH) levels affected the mortality of patients with COVID-19 presenting with NTI.MethodsPatients with COVID-19 complicated with NTI who were treated at our hospital were included in this retrospective study. Patients were divided into low TSH and normal TSH groups, as well as low and normal-high FT4 group, according to the reference range of TSH or FT4 levels. The 90-day mortality and critical illness rates were compared among patients with low and normal TSH levels, as well as among patients with low FT4 levels and normal-high FT4 levels; in addition, differences in demographic and laboratory data were compared. A Kaplan-Meier analysis and Cox proportional hazards models were used to assess the associations of TSH and FT4 levels with mortality.ResultsOne hundred fifty patients with low FT3 levels and without a history of thyroid disease were included, 68% of whom had normal FT4 and TSH levels. Critical illness rates (74.07% VS 37.40%, P = 0.001) and mortality rates (51.85% VS 22.76%, P = 0.002) were significantly higher in the low TSH group than in the normal TSH group. Although no significant difference in the critical illness rate was found (P = 0.296), the mortality rate was significantly higher in the low FT4 group (P = 0.038). Low TSH levels were independently related to 90-day mortality (hazard ratio = 2.78, 95% CI:1.42–5.552, P = 0.003).ConclusionsLow FT4 and TSH concentrations were associated with mortality in patients with COVID-19 presenting with NTI; moreover, low TSH levels were an independent risk factor for mortality in these patients.

Purpose: To investigate the serum levels of uric acid (UA) in obese acanthosis nigricans (AN) patients with different thyroid hormones (THs) levels within the normal range. Methods: We investigated 834 obese patients (385 females and 449 males) with euthyroid function in the department of endocrinology of shanghai 10th people’s hospital from 2011 to 2019 with the median age of 29 years (interquartile range 22-36 years) for this study. 343 patients were diagnosed of AN. The cut-offs for thyroid-stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4) were 2mIU/L, 16mIU/L and 5mIU/L, respectively. Results: In male obese patients, AN patients with high TSH and FT4 had higher levels of UA compared to those with high TSH and low FT4 (523.20±120.98 vs. 477.56±86.92umol/L, P=0.036) and showed a correlation with fasting C-peptide (FCP) (r=0.330, P=0.029). The TSH, FT3, and FT4 alone did not showed any predictive value in male patients. In female patients, high FT3 was associated with higher levels of UA (388.47±100.95 vs. 366.33±82.40umol/L, P=0.019). However, the predictive value of FT3 in female was obtained only in low TSH subgroup (low TSH+ high FT3 vs. low TSH+ low FT3, P=0.033) not in high TSH patients. The levels of fasting insulin, 2h-insulin, FCP, 2h C-peptide, total cholesterol, triglyceride and testosterone were in correlation with higher UA levels in female obese patients with low TSH and high FT3(all P<0.05). Conclusion: The metabolic characteristics of UA are found to differ in obese patients with euthyroid function, in which AN plays an important role for male obese patients with high TSH and high FT4. But in the case of female, a combination of THs instead of AN showed it’s unique in UA metabolism. Disclosure J. Zhang: None. G. Li: None. X. Cheng: None. X. Wang: None. M. Jayachandran: None. Y. Huang: None. S. Qu: None. Funding National Key Research and Development Program of China (2018YFC1314100); National Natural Science Foundation of China (81970677); Shanghai Pujiang Program (2019PJD040); Effect of ApoC3 High Expression on Islet Cells and Related Molecular Mechanism (03.05.18.002)

Background: Thyroid dysfunction, including non-thyroidal illness syndrome (NTIS), is commonly observed in critically ill patients and has been reported in COVID-19, particularly in those with severe disease. NTIS is defined by low free triiodothyronine (fT3) with normal or low thyroid-stimulating hormone (TSH) and free thyroxine (fT4) levels. Thyroid autoantibodies may also reflect immune system activation. The relationship between thyroid hormone alterations, autoimmunity, and clinical severity in COVID-19 remains incompletely understood. Methods: We conducted a retrospective study of 276 patients hospitalized with COVID-19, including 138 in the intensive care unit (ICU) and 138 in general wards. A control group of 110 hospitalized, non-infected patients was also analyzed. Serum concentrations of TSH, fT3, fT4 and reverse T3 (rT3) were measured. The presence of anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-Tg), and thyrotropin receptor antibodies (TRAb) was assessed. Results: NTIS was observed in 44.2% of ICU patients, 18.1% of non-ICU patients, and 1.8% of controls. The fT3/rT3 ratio was lowest in ICU patients (median 0.11 vs. 0.16 in non-ICU and 0.22 in controls). Thyroid autoantibodies were significantly more prevalent in COVID-19 patients than in controls, with anti-TPO antibodies being the most frequently detected. Their presence, even in patients without known thyroid disease, may reflect immune activation associated with SARS-CoV-2 infection. Conclusions: NTIS and thyroid autoimmunity are frequent in hospitalized COVID-19 patients and may reflect disease severity and immune activation. Our study highlights the prognostic relevance of routine thyroid testing, including the fT3/rT3 ratio and combined autoantibody positivity (notably the triple-positive pattern), by directly comparing ICU and non-ICU patients with a non-COVID control group.

Background: Thyroid-stimulating hormone (TSH) concentrations are frequently altered in acute ischemic stroke patients. It is becoming increasingly apparent that various hormones in the hypothalamus-pituitary-thyroid axis may be associated with functional stroke outcome. We have previously shown that white matter hyperintensities (WMH) of presumed vascular origin are strong indicators of functional outcome. It is unclear whether an association exists between WMH and TSH. We therefore sought to determine whether TSH levels, measured in acute ischemic stroke patients, are associated with WMH and functional outcome. Methods: We analyzed all first ischemic stroke patients who participated in the Berlin ‘Cream & Sugar' Study (NCT 01378468) and completed a 1-year follow-up assessment from January 2009 to March 2013. Patients were stratified into 3 groups: (1) low TSH (0.1-0.44 μU/ml); (2) normal TSH (0.44-2.5 μU/ml), and (3) high TSH (2.5-20 μU/ml). WMH were assessed using the Fazekas and Wahlund visual rating scales. Functional outcome was assessed using the modified Rankin Scale and was performed via telephone at 1 year by a certified rater. Results: 183 patients were included [median age 66, interquartile range (IQR) 54-75; 33% females; median National Institute of Health Stroke Scale 3, IQR 1-4, range 0-24]. Venous samples were collected a median of 4 days (IQR 3-5) following initial symptom onset between 8 and 9 a.m. following a 10-hour fast. Patients with normal TSH levels (n = 132; 72%) had significantly higher rates of prestroke diabetes than patients with high TSH levels (normal TSH 17%; high TSH 1%; p = 0.03). Additionally, patients with normal TSH levels tended to have higher estimated glomerular filtration rates than patients with high and low TSH concentrations (normal TSH median estimated glomerular filtration rates: 83 ml/min/1.73 m²; high TSH median estimated glomerular filtration rates: 76 ml/min/1.73 m²; low TSH median: 78 ml/min/1.73 m²; p = 0.068). Logistical regression analysis force-adjusted for age (quartiles), NIHSS (quartiles), prestroke diabetes status, and stroke subtype revealed significant associations between WMH and TSH [Wahlund scores: odds ratio 2.547, 95% confidence interval (CI) 1.159-5.598, p = 0.020; Fazekas scores: odds ratio 2.530, 95% CI 1.115-5.741, p = 0.003]. Functional outcome was not significantly associated with TSH levels in univariate or multivariate models. Conclusion: TSH levels are independently associated with WMH in acute ischemic stroke patients. Based on our findings, we cannot recommend assessing TSH to estimate the 1-year functional outcome following ischemic stroke.

45 Validation of a Clinical Decision Rule to Predict Abnormal Thyroid-Stimulating Hormone Levels in Patients Presenting to the Emergency Department With Atrial Fibrillation

Many practitioners perform a thyroid stimulating hormone (TSH) assay as a screening test in older patients. The introduction of sensitive TSH assays with lower normal limits has created a laboratory abnormality that is often of uncertain significance. Mechanisms include autonomous overproduction of thyroid hormone, nonthyroidal illness including medication effects, and hypothalamic/pituitary dysfunction. To characterize the clinical status and course of nursing home residents with low TSH and normal total T4 levels in the absence of treatment with thyroid hormone. Retrospective chart review was performed to determine participants status at the time of low TSH level, with additional recording of follow-up thyroid hormone levels, cardiac rhythm, and mortality. Mortality was compared with that of a control group matched for age and sex. A nursing home for veterans and their spouses. Forty subjects with low TSH and initially normal total T4 were identified. Only three subjects were subsequently diagnosed as hyperthyroid. TSH levels of 18 subjects subsequently normalized, and four additional subjects had low total T3 levels suggesting a nonthyroidal mechanism. Seven subjects died during the first 4 months of follow-up compared with three in a control group (P < .001). Nine of the 40 subjects had a history of or current atrial fibrillation. No new atrial fibrillation was documented during 388 months of EKG follow-up. Low total T3 levels, TSH normalization, and excess mortality suggest that nonthyroidal illness plays a role in the pathogenesis of low TSH determinants in the nursing home. Autonomous production of thyroid hormone also plays a role. We believe that the term "subclinical hyperthyroidism" should be used only if the clinician believes that autonomous overproduction of thyroid hormone is the cause of a low TSH level. If subsequent research shows correctable adverse consequences associated with subclinical hyperthyroidism from autonomous overproduction of thyroid hormone, a more aggressive diagnostic approach will be needed to define the mechanism of a low TSH level at the time of its discovery.

Sirs, We read with interest the recently published study in Pediatric Nephrology titled “Steroids combined with levothyroxine to treat children with idiopathic nephrotic syndrome (NS): a retrospective single-centre study,” by Guo et al. [1]. In their retrospective study, 73 of 164 nephrotic children had thyroid dysfunction, of who 40 were treated with steroids and levothyroxine. First, the authors observed that time to proteinuria remission was significantly shorter in the levothyroxine plussteroid group than in the group treated with steroids alone (21.05±11.00 vs 26.67±11.82, p<0.05). However, the mean time to remission in either group was much longer than that observed in most studies. This was probably due to the inclusion of both steroid-sensitive NS (SSNS) and steroid-resistant NS (SRNS) patients in a single group in the present study. Second, subclinical hypothyroidism is defined as a state of increased serum thyroid-stimulating hormone (TSH) concentration, with circulating thyroxine and triiodothyronine (TT3) within the population reference range [2]. Forty-four percent of patients were reported to have subclinical hypothyroidism. In groups A and B, there were 25 cases of low T3 syndrome (low TT3 and normal TSH), 11 cases of low T4 syndrome [low total thyroxine (TT4) and normal TSH], 27 cases of hypothyroxinemia (low TT3 and TT4 but normal TSH), and ten cases of hypothyroidism [low free thyroxine/free triiodothyronine (FT3/FT4) and high TSH]. None of the categories of thyroid dysfunction had increased TSH and normal T3/T4. Third, subclinical hypothyroidism is known to be due to reduced glomerular filtration rate (GFR), and as GFR decreases, there is further decrease of thyroid hormones levels. Guo et al. did not mention estimated GFR (eGFR) of the patients in their study, whichmay confound their results [1]. Finally, decrease in thyroid hormones and increase in TSH is transient in patients with SSNS, and they return to normal on remission; however, this may be persistent in patients with congenital NS and those with SRNS due to massive prolonged proteinuria [3]. We studied thyroid functions in 20 children with SRNS (14 in complete remission and six in partial remission) and found six of them to have nonautoimmune subclinical hypothyroidism [3]. Four of six children with grade 2–3 subclinical hypothyroidism received thyroid hormone replacement therapy, and levels of TSH normalized in all patients on therapy. In conclusion, thyroxine replacement therapy in children with SSNS who have proteinuria for a short duration (i.e., 2– 3 weeks) may not prove beneficial in terms of the transient nature of thyroid dysfunction. The final answer would come from a double-blind placebo-controlled trial on carefully selected patient groups.

BackgroundBoth lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated.MethodsWe included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission.ResultsA total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001).ConclusionTSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.

Relationships between Glycemic and Lipid Control and TSH in Euthyroid Latinx Adults- a Community-Based Study

Objective: Thyroid hormones are essential for fetal growth and neurodevelopment, however, data on cord blood thyroid hormones are sparse in China where maternal age at childbearing is increasing in recent decades. We aimed to assess cord blood levels of free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) in full-term Chinese newborns, and examine potential related perinatal factors.Methods: This study included 922 mother-newborn pairs from a prospective birth cohort enrolled in 2012–2013, Shanghai, China. Cord serum concentrations of FT3, FT4, TSH, and TPOAb were measured in newborns.Results: Newborns born via cesarean section had higher cord serum FT3 (mean ± SD: 1.90 ± 1.16 pmol/L) and lower cord serum TSH (5.15 ± 2.60 mIU/L) than those born via vaginal delivery (FT3: 1.62 ± 0.93 pmol/L; TSH: 9.27 ± 6.76 mIU/L). In cesarean section deliveries, the concentration of cord serum FT3 was 0.15 (95%CI: −0.03, 0.33; p = 0.10) pmol/L lower in infants of mothers aged 30–34 years, and 0.57 (95%CI: 0.22, 0.92; p = 0.002) pmol/L lower in infants of mothers ≥35 years compared to infants of mothers <30 years. Large-for-gestational-age (birth weight >90th percentile) was associated with higher TSH (p = 0.02). Similar results were also found in vaginal deliveries.Conclusions: In this Chinese term birth cohort, newborns born via cesarean section had higher cord serum FT3 and lower TSH than those born via vaginal delivery. Advanced maternal age was associated with lower fetal FT3. Further research is needed to understand whether this association may mediate the adverse impact of advanced maternal age on neurodevelopment in early life.

Purpose Maintaining an optimal thyroid stimulating hormone (TSH) level is important in the postoperative management of papillary thyroid carcinoma (PTC). However, there is little evidence for TSH target levels in patients undergoing radiofrequency ablation (RFA). This study aimed to determine the optimal TSH level for management in low-risk patients who underwent RFA. Methods This retrospective propensity score-matched cohort study included patients with low-risk PTC who underwent RFA from January 2014 to December 2018. The patients were categorized into two groups based on the range of TSH levels: low (≤2 mU/L) and high (>2 mU/L) TSH levels. Local tumor progression and disease-free survival (DFS) were compared between the low TSH and high TSH groups, using propensity score analyses based on patient- and tumor-level characteristics. Univariate analyses were performed to select risk factors for tumor progression. Results Overall, our study included 516 patients with low-risk PTC who underwent RFA with a long-term follow-up of 5-years. During follow-up, the overall incidence rate of local tumor progression was 4.8% (25/516), with no significant difference between the matched groups (7/106 [6.6%] vs. 5/53 [9.4%], p = 0.524). DFS did not differ between the two groups (p = 0.5). Moreover, TSH level was not regarded as a significant predictor of tumor progression after Cox analysis; primary tumor size was the only relevant risk factor. Conclusion This large propensity-matched study revealed no association between TSH levels and tumor progression. Thus, for patients with low-risk PTC who underwent RFA, the optimalTSH level is recommended at the euthyroid range.

The growth processes in children depend on the proper functioning of some hormones and growth factors. Recently, a positive correlation between ghrelin and TSH (thyroid stimulating hormone) in patients with hyper- and hypothyroidism was proved. Moreover, in hypothyroid rats with high ghrelin concentration, growth hormone (GH) and insulin-like growth factor I (IGF-I) secretion was suppressed. We analyzed these relationships in euthyroid prepubertal children with idiopathic short stature (ISS). The analysis comprised concentration of ghrelin, GH in stimulating tests and during the night, as well as IGF-I, TSH, free thyroxine (FT4) and free triiodothyronine (FT3) in 85 children with ISS (36 girls, 49 boys) aged 9.65 ± 3.02 years (mean ± SD). A strong positive correlation between ghrelin and TSH was confirmed (r = +0.44, p < 0.05). A higher ghrelin but lower nocturnal GH and lower IGF-I were observed in children with higher normal TSH concentration than those in children with lower normal TSH. Interestingly, alterations of TSH level were without any impact on FT4 and FT3 concentrations. Summing up, in ISS prepubertal euthyroid children, ghrelin and TSH secretion are closely related. On the other hand, the higher the TSH, the lower the nocturnal GH and IGF-I levels. The contribution of the above findings in deterioration of growth processes requires further studies.

Epidemiology of Thyroid Cancer.

Background Globally, the COVID-19 pandemic inflicted considerable morbidity and mortality. It has become a systemic illness that affects several body organs. The primary pathway for the SARS-CoV-2 virus to enter cells is the angiotensin-converting enzyme 2 (ACE2) receptor, and it usestransmembrane serine protease 2 (TMPRSS2) for S protein priming. Thyroid follicular cells have been found to express ACE2 and TMPRSS2at even higher levels than those found in the lungs. The objective of the study was to assess and determine the six-month clinical outcome of thyroid dysfunction in COVID-19 patients. Methods This prospective, observational study was carried out in the COVID-19 unit of Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh. Forty-eight hospital-admitted COVID-19 reverse transcription-polymerase chain reaction (RT-PCR)-positive patients were included as per inclusion and exclusion criteria, and there was no control group. All admitted patients were classified into non-severe (mild, moderate) and severe (severe and critical) disease as per national guidelines. Baseline laboratory tests for thyroid-stimulating hormone (TSH), free T3, and free T4 were done on admission. The patients were again categorized according to their thyroid status. Further evaluation was done by performing autoantibody tests (TSH receptor Ab, anti-thyroid peroxidase Ab, anti-thyroglobulin Ab). The patients were followed up in the first month and sixth month to see disease progression and outcomes. Results Age and comorbidities were associated with an increased risk of severe disease. A total of 35 (73%) patients had comorbidities, 23 (49%) had multiple comorbidities, and 12 (24%) had single comorbidities. All patients (n=48) presented with fever and cough; 45 (94%) patients had fatigue, palpitations were present in 35 (73%) patients, and dyspnea in 32 (67%) patients. The difference in mean values of TSH, FT4, and FT3 among severe and non-severe groups was found to be significant. Most of the patients (n=36; 75%) were in a euthyroid state at baseline. Among the rest, 25%had thyroid dysfunction, including one (2.08%) who had subacute thyroiditis and eight (16.67%) who had euthyroid sick syndrome, which was higher in the severe group (14.59%). Three (6.24%) patients were autoantibody-positive and were diagnosed as having Hashimoto's thyroiditis in the form of primary hypothyroidism (2.08%; n=1) and subclinical hypothyroidism (4.16%; n=2). The Spearman correlation coefficient showed a strong negative correlation between severity and TSH (rs = -0.71) and moderate positive correlations between severity and free T3 (rs = 0.63) and free T4 levels (rs = 0.53).Follow-up at the first month showed that 44 (91.96%) returned to a euthyroid state, and at six months, 45 (93.7%) returned to a euthyroid state. Conclusion Thyroid hormone levels appear to change and recover gradually and spontaneously. Most patients have normal thyroid function status during COVID-19 infections, but a considerable number of patients can develop euthyroid sick syndrome in severe COVID-19 infections, from which they recover spontaneously.

ISEE-0440 Background and Objective: Infants are exposed to chemicals that might interfere with thyroid function, such as perchlorate, thiocyanate, and nitrate. There are no studies available with individual measures of these chemicals and thyroid function in infants. We examined whether urinary perchlorate, nitrate, or thiocyanate is associated with urinary thyroxine (T4) and thyroid stimulating hormone (TSH) in infants. Because background perchlorate exposure has been associated with changes in thyroid hormone levels in adults, we specifically examined whether perchlorate was associated with higher TSH in infants with low iodide and in infant girls, as was seen in US females over age 12 years. Methods: The study was conducted at the Children’s Hospital of Philadelphia, the Hospital of the University of Pennsylvania, and affiliated clinics, among 92 full term infants (47 males and 45 females) between birth and 1 year of age. We used data from the Study of Estrogen Activity and Development, which was a partly cross-sectional, partly longitudinal study designed to assess hormone levels of full term infants over the first 12 months of life. We analyzed urine samples collected in that study. Main Outcome Measures: Urinary perchlorate, thiocyanate, nitrate, iodide, TSH and T4, and blood TSH and T4. Results: In models with single chemical agents, infants with higher perchlorate had higher TSH and T4. In models with all three chemical agents, infants with low iodide and higher perchlorate had higher T4 and TSH; infants with higher urinary thiocyanate or higher urinary nitrate had higher urinary TSH and T4. Conclusions: The association of perchlorate exposure with increased urinary TSH in infants with low urinary iodide is consistent with previous findings in females aged 12 and older. Higher thiocyanate and nitrate exposure is also associated with higher urinary TSH in infants. (Supported in part by the intramural research program of NIH.)