Autoimmune thyroid disease and thyroid function test fluctuations in patients with resistance to thyroid hormone.

OBJECTIVE: Resistance to thyroid hormone beta (RTHß) is an inherited syndrome caused by mutations in the thyroid hormone receptor ß (THRB) gene. Patients with RTHß typically have elevated thyroid hormone levels with non-suppressed serum thyroid-stimulating hormone (TSH). We aimed to elucidate the clinical, laboratory, and imaging findings of RTHß patients and further to explore their association with THRB gene mutations. DESIGN AND METHODS: We retrospectively reviewed the clinical charts and compared the clinical findings of 68 RTHß patients (45 probands and 23 relatives) and 30 unaffected relatives in Kuma Hospital. RESULTS: Genetic testing revealed 35 heterozygous THRB gene mutations. Among all RTHß patients, autoimmune thyroid disease (AITD) was detected in 42.1% of men and 40.9% of women, showing that the prevalence of AITD in affected males was significantly higher than in unaffected relatives (P = 0.019). During the follow-up of 44 patients, 13 patients (29.5%; 8 (42.1%) with AITD and 5 (20%) without AITD) temporarily showed thyroid function test results inconsistent with RTHß. Two patients with the R383H mutation, which has little dominant-negative effect, temporarily showed normal thyroid hormone and TSH levels without AITD. CONCLUSIONS: The frequency of AITD in male RTHß patients was significantly higher compared to unaffected relatives. More than 20% of RTHß patients temporarily showed laboratory findings atypical of RTHß during their follow-up, and patients with AITD and specific THRB mutations were prone to display such findings. Therefore, genetic testing should be performed even for patients with fluctuations in thyroid function test results to avoid misdiagnosis and inappropriate treatment.

Severe primary hypothyroidism in an apparently asymptomatic 19-year-old woman: a case report.

BACKGROUND: Hypothyroidism is diagnosed on the basis of laboratory tests because of the lack of specificity of the typical clinical manifestations. There is conflicting evidence on screening for hypothyroidism. CASE PRESENTATION: We report a case of an apparently healthy 19-year-old Kuwaiti woman referred to our clinic with an incidental finding of extremely high thyroid-stimulating hormone (TSH), tested at the patient's insistence as she had a strong family history of hypothyroidism. Despite no stated complaints, the patient presented typical symptoms and signs of hypothyroidism on evaluation. Thyroid function testing was repeated by using different assays, with similar results; ultrasound imaging of the thyroid showed a typical picture of thyroiditis. Treatment with levothyroxine alleviated symptoms and the patient later became biochemically euthyroid on treatment. CONCLUSION: There is controversy regarding screening asymptomatic individuals for hypothyroidism; therefore, it is important to maintain a high index of suspicion when presented with mild signs and symptoms of hypothyroidism especially with certain ethnic groups, as they may be free of the classical symptoms of disease.

Immunomodulatory Function of Vitamin D and Its Role in Autoimmune Thyroid Disease.

Vitamin D is one of the most important nutrients required by the human body. It is a steroid hormone that plays an important role in regulating calcium and phosphorus metabolism, and bone health. Epidemiological studies have revealed a close correlation between vitamin D and many common chronic diseases. Additionally, vitamin D has recently been shown to act as an immunomodulatory hormone, and, accordingly, vitamin D deficiency was uncovered as a risk factor for autoimmune thyroid diseases, although the underlying mechanisms are still unknown. It is therefore necessary to disclose the role and mechanism of action of vitamin D in the occurrence and development of autoimmune thyroid diseases. This knowledge will help design intervention and early treatment strategies for patients with autoimmune thyroid diseases who present with low levels of vitamin D.

Thyroid complications of SARS and coronavirus disease 2019 (COVID-19).

We have reviewed the available literature on thyroid diseases and coronavirus disease 2019 (COVID-19), and data from the previous coronavirus pandemic, the severe acute respiratory syndrome (SARS) epidemic. We learned that both SARS and COVID-19 patients had thyroid abnormalities. In the limited number of SARS cases, where it was examined, decreased serum T3, T4 and TSH levels were detected. In a study of survivors of SARS approximately 7% of the patients had hypothyroidism. In the previous evaluation evidence was found that pituitary function was also affected in SARS. Others suggested a hypothalamic-pituitary-adrenal axis dysfunction. One result published recently indicates that a primary injury to the thyroid gland itself may play a key role in the pathogenesis of thyroid disorders in COVID-19 patients, too. Subacute thyroiditis, autoimmune thyroiditis and an atypical form of thyroiditis are complications of COVID-19. Thyroid hormone dysfunction affects the outcome by increasing mortality in critical illnesses like acute respiratory distress syndrome, which is a leading complication in COVID-19. Angiotensin-converting enzyme 2 is a membrane-bound enzyme, which is also expressed in the thyroid gland and the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) uses it for docking, entering as well as replication. Based on the available results obtained in the SARS-CoV-2 pandemic, beside others, we suggest that it is necessary to monitor thyroid hormones in COVID-19.

Hipotiroidismo consuntivo en paciente con hipotiroidismo primario previo / Consumptive hypothyroidism in patient with previous primary hypothyroidism

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Exposure to the Chinese Great Famine in Early Life and Thyroid Function and Disorders in Adulthood: A Cross-Sectional Study.

Background: Malnutrition in early life may permanently change the structure and function of the body, which lead to a number of diseases in adulthood. The effect of famine exposure during the early life on thyroid function and disorders remains unclear. This study investigated the association between exposure to the Great Chinese Famine (1959-1961) in early life and thyroid function and disorders in adulthood. Methods: Nine thousand eight hundred eighty-one subjects with appropriate birth dates derived from the Thyroid disorders, Iodine status, and Diabetes Epidemiological survey were included. Thyroid function and disorders were defined by the test results of blood sample and ultrasonography of all participants. Associations between famine exposure in early life and thyroid function and disorders in adulthood were assessed with binary logistic regression and linear regression. Results: Participants exposed to the Great Chinese Famine during the fetal stage was associated with a higher thyrotropin (TSH) level in adulthood (ß = 0.024; p = 0.038), compared with the nonexposed participants. The association was significant among rural participants (ß = 0.039; p = 0.02) but not in urban participants (ß = 0.005; p = 0.77). Fetal-exposed group did not show a higher risk of thyroid disorders than the age-matched balanced control group, including overt hyperthyroidism, subclinical hyperthyroidism, overt hypothyroidism, subclinical hypothyroidism, autoimmune thyroiditis, and thyroid nodules (p > 0.05). Conclusions: Famine exposure during the fetal stage was associated with a higher TSH level in adulthood. The fetal stage could be the critical period for programming the pituitary-thyroid axis.

Does thyroid autoimmunity affect the reproductive outcome in women with thyroid autoimmunity undergoing assisted reproductive technology?

PROBLEM: Our study aims to investigate whether the anti-thyroperoxidase antibody (TPO-Ab) and TSH level in euthyroid women have any association with reproductive outcomes after the ART cycle. METHODS OF STUDY: A total of 1107 patients who were enrolled in the study were divided into four groups based on serum TSH level and TPO-Ab status: group A, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab- ; group B, 0.3 ≤ TSH < 2.5 mIU/L and TPO-Ab+ ; group C, 2.5 ≤ TSH < 4.2 mIU/L, and TPO-Ab- ; and group D, 2.5 ≤ TSH < 4.2 mIU/L, TPO-Ab+ . The differences in ART cycles and pregnancy outcomes were analyzed between study groups. RESULTS: The fertilization rate in group D (73%) was significantly lower than that in groups A (83% P < .001), B (84% P = .001), and C (82% P = .002). The biochemical pregnancy rates of groups B (7%) and D (12%) were significantly higher than those of group A (2%) (P = .028 and P = .017, respectively). TPO-Ab was related to a higher biochemical pregnancy rate (P = .002, OR = 5.311, 95% CI 1.859-15.169) and TSH over 2.5 mIU/L was related to higher ICSI rate (P = .001, OR = 1.759, 95% CI 1.250-2.476) by logistic regression analysis. The receiver operating characteristic (ROC) also verified the results. CONCLUSION: The impacts of TSH ≥ 2.5 mIU/L on the intracytoplasmic sperm injection (ICSI) rate, TSH ≥ 2.5 mIU/L and TPO-Ab+ on the fertilization rate, and TPO-Ab+ on the biochemical pregnancy rate, rather than the effect on abortion, clinical pregnancy, and live birth, were emphasized.

Common carotid pulsatility is deteriorated by autoimmune thyroiditis in children with type 1 diabetes mellitus - A pilot study.

Autoimmune thyroiditis (AIT) frequently coexists with type 1 diabetes (DM1) and additionally increases the extent of microcirculatory complications due to DM1. We hypothesized that in pediatric patients with DM1, impairment of macrocirculation could be further augmented by a coexisting autoimmune process. Therefore, we investigated the influence of AIT on large arteries in DM1 pediatric patients. Our group consisted of 19 DM1, 19 DM1 + AIT patients and 29 control subjects. The groups were comparable regarding age and gender. The DM1 and DM1 + AIT patients were matched for age at onset of DM1 and diabetes duration. Macrocirculation was described using pulsatility indices (PIs) determined for common carotid (CCA) and peripheral arteries of upper and lower limbs. CCA resistance index (RI) and ABI were also assessed. Children with DM1 + AIT had only significantly lower CCA_PI and CCA_RI in comparison with controls whereas in the absence of AIT such difference was not found. The diabetes duration and age of onset did not correlate with carotid indices. Total cholesterol level was higher both in DM1 + AIT and DM1 groups than in the control group. For low density lipoproteins cholesterol, a significant difference was found between DM1 + AIT and control groups. Age-independent impact of AIT on CCA_PI was confirmed by multivariate analysis. Common carotid pulsatility is deteriorated by autoimmune thyroiditis independently of age in children with type 1 diabetes mellitus.

Long-Term Follow-Up and Outcomes of Autoimmune Thyroiditis in Childhood.

Background: Autoimmune thyroiditis (AIT) is the most common cause of acquired hypothyroidism in children. The natural outcome of AIT in childhood has been reported previously however follow-up duration is generally short and results variable. Objectives: To characterize clinical and biochemical findings at presentation of AIT, evaluate long-term outcomes and assess which factors at presentation predict evolution over time. Study cohort: 201 children under 18 years of age at presentation (82% female) were enrolled. Subjects were divided into five subgroups according to thyroid stimulating hormone (TSH) level at referral. Results: Mean follow-up was 8.1 years (range 0-29 years). At presentation, 34% of patients had overt hypothyroidism, 32% subclinical hypothyroidism (SCH), 16% compensated hypothyroidism, 14% were euthyroid, and 3.7% had Hashitoxicosis. Children with overt hypothyroidism were younger (10.6 vs. 13.2 years) and had higher thyroid peroxidase antibody titers. At the time of the study, levothyroxine (LT4) therapy was required in 26% of children who were euthyroid at presentation, 56% of SCH patients, 83-84% of those with TSH above 10 mIU/L, and 57% of those with Hashitoxicosis. Over the years, 16% of children presenting with overt hypothyroidism stopped therapy. Free T4 at presentation was the only predictor of outcome over time. Conclusions: Our findings suggest that only 26% children who were euthyroid at presentation developed hypothyroidism, whereas over 50% of those with SCH went on to require treatment. Of those presenting with overt hypothyroidism, 16% recovered with time. The only predictive parameter for LT4 therapy at the end of the study was free T4 levels at presentation. Long-term follow-up is required to determine ongoing therapy needs and screen for additional autoimmune diseases.

Autoimmune Thyroid Disease is Associated with a Lower Prevalence of Diabetic Retinopathy in Patients with Type 1 Diabetic Mellitus.

Background and objectives: The aim of the study was to assess the correlation of autoimmune thyroid diseases (AITD) in patients with diabetes mellitus type 1 (DM1) with the occurrence of diabetic retinopathy (DR). Materials and Methods: The inclusion criteria for the study were: type 1 diabetes diagnosed on the basis of WHO criteria lasting at least a year, presence of AITD for at least a year, and age over 18 years. The control group consisted of patients without diagnosed AITD (DM1noAITD), selected according to age, BMI and DM1 duration. Anthropometric parameters, metabolic risk factors such as glycated hemoglobin (HbA1c), lipids and blood pressure, thyroid status and the presence of DR were assessed. Results: The study involved 200 patients with type 1 diabetes aged 36 ± 12 years, 70 men and 130 women. Patients from the study group (DM1AITD) had significantly lower creatinine concentration, significantly lower systolic blood pressure (SBP), glycated hemoglobin (HbA1c) percentage and triglyceride (TG) concentration, and higher high-density lipoprotein (HDL-cholesterol) concentration than the control group (DM1noAITD). There was a significantly lower chance of non-proliferative diabetic retinopathy (NPDR) among DM1AITD than in the control group. Conclusions: Patients with DM1 and AITD were metabolically better balanced, as evidenced by a significantly lower SBP, percentage of HbA1c and TG, as well as significantly higher HDL-cholesterol in this group. Patients with DM1 and AITD were significantly less likely to have NPDR than the control group.

Predictive and sensitive biomarkers for thyroid dysfunctions during treatment with immune-checkpoint inhibitors.

Immune-related adverse events (irAEs) are often seen during immune-checkpoint inhibitor (ICI) treatment of various malignancies. Endocrine irAEs including thyroid dysfunctions are the most common irAEs, but their biomarkers remain unclear. In order to identify individuals who are susceptible to thyroid irAE for earlier diagnosis and appropriate follow-up, the current study is aimed to investigate biomarkers of thyroid irAE. Herein, patients with advanced malignant diseases who received ICIs treatment were prospectively studied. Clinical and laboratory examination, thyroid function, and autoantibodies were evaluated at baseline, and every 4 wk after first treatment with ICIs. Cytokines/chemokines were measured at baseline and at 4 wk. In vivo effects of ICIs on experimental autoimmune thyroiditis were evaluated. Twenty-six patients with malignant diseases who received ICIs treatment were enrolled in the study. Patients were divided into two groups: those who developed thyroid irAE, and those without irAEs. Comparing the two groups, early increase (≤4 wk) in serum thyroglobulin (Tg) levels and thyroid autoantibodies was seen in thyroid irAE (P < .05). Notably, higher levels of serum IL-1ß, IL-2, and GM-CSF at baseline, and early decrease of IL-8, G-CSF, and MCP-1 were significantly associated in the development of thyroid irAE (P < .05). In vivo effects of anti-PD-1 antibody on deterioration of mice experimental thyroiditis were seen. In conclusion, early change in Tg, thyroid autoimmunity, and cytokine levels might indicate development of thyroid irAE. Pre-existing thyroid autoimmunity might be involved with the development of thyroid irAE. Potential application of these factors as surrogate biomarkers for tumor therapy was indicated.

The role of protein disulphide-isomerase A3 as autoantigen in the pathogenesis of autoimmune thyroiditis and related brain damage in adult mice.

Autoimmune thyroiditis (AIT)-related brain damage is one of most severe extrathyroidal manifestations of AIT, but the mechanism remains unclear. In this study, we confirmed that protein disulfide-isomerase A3 (PDIA3) is expressed in both thyroid and brain tissues of mouse, and found the significantly increased serum levels of anti-PDIA3 antibody (PDIA3Ab) in classical mouse models of thyroiditis. In addition, we investigated the PDIA3-specific autoimmune reaction in thyroid and brain tissues in a mouse model with high-serum PDIA3Ab induced by immunization with recombinant PDIA3 protein. PDIA3-immunized mice had elevated serum thyrotropin and impaired learning and memory. PDIA3-expressing cells had IgG deposition, and IgG colocalized with C3 in the thyroid and brain tissues of PDIA3-immunized mice, resulting in membrane attack complex formation. Our results suggest that PDIA3 protein may be a common autoantigen shared by the thyroid and brain tissues and involve in the thyroidal and intracerebral damage through activating complement system.

Chronological association between alopecia areata and autoimmune thyroid diseases: A systematic review and meta-analysis.

The association between alopecia areata (AA) and autoimmune thyroid diseases (AITD) has been suggested; however, the chronological relationship between AA and AITD remains elusive. A systematic review and meta-analysis were conducted to assess the association between AA and AITD focusing on the prevalence of thyroid antibodies, thyroid diseases and serological thyroid dysfunctions, respectively. Data collection was performed in October 2018 by searching for articles in two electronic databases: Medline and Embase. Case-control, cohort and cross-sectional studies were included. Meta-analysis of studies eligible for quantitative synthesis was performed to estimate pooled odds ratios of thyroid antibodies; thyroid peroxidase antibody (TPO-Ab) and thyroglobulin antibody (TG-Ab), diagnosed thyroid diseases and serological thyroid dysfunctions. Four hundred and eighty nine research papers were identified and 17 studies with 262 581 patients and 1 302 655 control subjects were included for quantitative synthesis. AA was significantly associated with both TPO-Ab and TG-Ab. In comparison, there was no significant association between AA and diagnosed hypothyroidism or hyperthyroidism and serological hypothyroidism or hyperthyroidism. In conclusion, AA is significantly associated with the existence of thyroid antibodies rather than with clinical or laboratory thyroid abnormality. Lack of long-term follow-up data is a limitation of the existing published work. Our findings do not support routine screening of thyroid diseases for asymptomatic AA patients but highlight the potential future risk of AITD particularly in severe and refractory AA.

The impact of autoimmune thyroiditis on skin microcirculation in children with non-complicated type 1 diabetes mellitus.

BACKGROUND: The impairment of endothelial function in type 1 diabetes mellitus (DM1) is considered as the basis of microvascular complications. In DM1 patients autoimmune thyroiditis is a frequent comorbidity which may be responsible for further deterioration of microcirculation function. In studies investigating the relationship between cardiovascular risk factors and microvascular function, skin microcirculation is widely used. The aim of our study was to evaluate the impact of coexisting autoimmune thyroiditis on skin microcirculation in children with type I diabetes mellitus. SUBJECTS: The study group consisted of 25 pediatric DM1 patients, 25 pediatric patients with type 1 diabetes and autoimmune thyroiditis (DM1 + AIT) and 29 control subjects matched for age and gender. The DM1 and DM1 + AIT patients were also matched for age at onset of DM and diabetes duration. METHODS: Performed capillaroscopy studies employed non-selective stimuli such as post-occlusive reactive hyperemia (PORH) and venous occlusion (VO) tests. The relative area covered by capillaries (coverage) and the distance between capillaries were assessed. These measurements were performed before tests as well as after PORH and VO. RESULTS: Coverage at baseline, after PORH and VO and distance after VO differ significantly between control subjects and the group DM1 + AIT. The coverage at baseline, after PORH and VO were significantly smaller in DM1 + AIT compared with the control group. Post-hoc analysis after controlling for lipids levels showed that differences between the DM1 + AIT and control group were remained only for coverage at baseline and after VO. Significant differences between DM1 + AIT and DM1 and control group for coverage after VO were also presented. CONCLUSIONS: Coexisting autoimmune thyroiditis significantly deteriorates skin microcirculation function in pediatric non-complicated type 1 diabetic patients. This process is independent of patient age, diabetes duration and age of diabetes onset.

l-selenomethionine supplementation in children and adolescents with autoimmune thyroiditis: A randomized double-blind placebo-controlled clinical trial.

WHAT IS KNOWN AND OBJECTIVE: Although a beneficial effect of selenium (Se) administration has been proposed in adults with autoimmune thyroiditis (AT), there is a paucity of similar data in children and adolescents. The purpose of the study was to investigate whether administration of a high dose of organic Se (200 µg daily as l-selenomethionine) has an effect on antithyroid antibody titres in children and adolescents with AT. METHODS: Seventy-one (71) children and adolescents, with a mean age of 11.3 ± 0.3 years (range 4.5-17.8), diagnosed with AT (antibodies against thyroid peroxidase [anti-TPO] and/or thyroglobulin [anti-Tg] ≥60 IU/mL, euthyroidism or treated hypothyroidism and goitre in thyroid gland ultrasonography) were randomized to receive 200 µg l-selenomethionine or placebo daily for 6 months. Blood samples were drawn for measurement of serum fT4, TSH, anti-TPO and anti-Tg levels, and thyroid gland ultrasonography was performed at the entry to the study and after 6 months of treatment. RESULTS AND DISCUSSION: At the end of the study, a statistically significantly higher reduction in anti-Tg levels was observed in the Se group compared to the placebo group (Δ: -70.9 ± 22.1 vs -6.7 ± 60.6 IU/mL, P = 0.021). Although anti-TPO levels were also decreased in the Se group, this change was not statistically different from that of the control group (Δ: -116.2 ± 68.4 vs +262.8 ± 255.5 IU/mL, P = 0.219). No significant difference in thyroid gland volume was observed between the two study groups (P > 0.05). WHAT IS NEW AND CONCLUSION: In this original study, organic Se supplementation appears to reduce anti-Tg levels in children and adolescents with AT.

Role of antithyroid autoimmunity as a predictive biomarker of chronic immune thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an acquired immune-mediated disorder characterized by isolated thrombocytopenia. Pediatric ITP patients are prone to develop autoantibodies such as antithyroglobulin (TG) and antithyroperoxidase (TPO), even in the absence of clinical signs of autoimmune disease. The aim of this multicenter retrospective study was to evaluate (1) the prevalence of positivity of antithyroid antibodies (TPO and TG) in a large cohort of pediatric patients with chronic ITP; (2) the role of autoimmune thyroiditis as a prognostic factor for chronicity of ITP. PROCEDURE: For this retrospective study, we collected data from patients diagnosed as affected by chronic ITP between 2011 and 2014 in six centers belonging to the Italian Association of Pediatric Haematology and Oncology (AIEOP). RESULTS: From the analysis of data, we found a significantly higher prevalence of antithyroid antibodies in children with chronic ITP (11.6%) than in the pediatric population (1.2%-1.3%). No correlation has been found between the platelet count and the prevalence of positive antithyroid antibodies at any detection time of the study. CONCLUSIONS: The results of our study demonstrated that (1) the prevalence of positivity for antithyroid antibodies (anti-TPO and anti-TG) in pediatric patients with chronic ITP results is significantly higher than in the pediatric population; (2) autoimmune thyroiditis does not seem to play a role as a prognostic factor for chronicity of ITP in pediatric patients.

Auto-immune Thyroiditis in an Infant Masquerading as Congenital Nephrotic Syndrome.

A seven-months-old girl under treatment for pneumonia presented with generalized edema, decreased urinary output and was found to have hypertension, muco-cutaneous fungal infection and pulmonary hypertension. Investigations revealed that she had heavy proteinuria, hypertriglyceridemia, hypoalbuminemia and elevated levels of free T3 and T4 with suppression of TSH levels in the serum. A diagnosis of autoimmune thyroiditis (AT) in thyrotoxic phase was made on the basis of clinical presentation and presence of anti-TPO antibodies and reduced uptake in thyroid (technetium) scintigraphy. The child responded to carbimazole therapy and propranolol. The case is presented to remind pediatricians about the rare occurrence of auto-immune thyroiditis in infancy with rare complications such as nephrotic syndrome and pulmonary hypertension.