Interferon-induced thyroid dysfunction in chronic hepatitis C

Background:  Treatment of chronic hepatitis C with interferon is known to be associated with thyroid dysfunction (TD) in 5–14% of patients. We studied the incidence, types, outcome and risk factors predictive of thyroid dysfunction.
Methods:  A retrospective analysis was performed on all patients treated with interferon alpha (IFN) or pegylated interferon alpha (PEG-IFN) ± ribavirin (RBV), who developed abnormal thyroid function tests (TFTs). These cases were compared with treatment-matched controls to identify factors predictive of thyroid dysfunction. Statistical methods consisted of: χ² test, Fischer's exact test, Welch's t -test, and multivariate analysis.
Results:  From a total of 511 patients, 45 cases with TD were identified (8.8%). Pegylated interferon alpha was associated with higher rates of TD than IFN (14.1% vs 6.0%, P  = 0.0029). Female sex (OR 5.6, 95% CI 1.1–7) and Asian ethnicity (OR 2.7, 95% CI 1.4–22) were independent predictors of developing TD. Cytology was obtained in 13 patients: benign follicular pattern (8); thyroiditis (3); and normal (2). Thyroid peroxidase (TPO) antibodies ( P  = 0.004) and earlier onset of dysfunction ( P  = 0.03) were associated with need for treatment. Sixteen patients had persistent TD by the end of the follow-up period, predicted by female sex, non-Asian ethnicity, prior history of TD and TPO antibodies.
Conclusions:  Pegylated interferon alpha, female sex and Asian ethnicity are independent risk factors for TD. Thyroid peroxidase antibodies and earlier TD within the course of IFN are associated with the requirement for treatment. Thyroid function tests should be monitored during and after IFN-based therapy. The most common cytological finding is a benign follicular pattern.     

Thyroid dysfunction in patients with chronic hepatitis C receiving a combined therapy of interferon and ribavirin: Incidence, associated factors and prognosis

Abstract Background and Aims: Interferon (IFN) plus ribavirin therapy for chronic hepatitis C (CHC) virus infection has been associated with thyroid dysfunction. The goal of our current study was to elucidate predictive factors of: (i) thyroid dysfunction associated with combination therapy; and (ii) long‐term reversibility of thyroid dysfunction. Methods: In total, 461 patients with CHC and normal baseline thyroid functions were enrolled. All patients received IFN‐α‐2b, 3 or 5 million units thrice weekly, or pegylated (PEG)‐IFN‐α‐2b 80 or 100 µg weekly combined with ribavirin 1–1.2 g daily for 24–48 weeks. Assays for serum thyroid stimulating hormone (TSH) and free thyroxine were performed. Results: By the end of the treatment, thyroid dysfunction (TSH <0.1 or >5 mU/L) had developed in 58 patients (12.6%). Female gender was significantly associated with thyroid dysfunction (P < 0.001 odds ratio (OR) = 2.85; 95% confidence interval (CI) = 1.6–5.1). The incidence of thyroid dysfunction was similar for standard IFN and PEG‐IFN‐treated patients (49/391 vs 9/70; P = 1.00). Under a nested case‐control design, detailed laboratory assessment was carried out on frozen serum samples from patients and age‐ (± 5 years) and sex‐matched controls (n = 58). Multivariate analysis revealed significant association between higher positive rates of pretreatment TMA and patients who developed thyroid dysfunction (OR = 5.8, 95% CI = 1.2–27.9). Ten patients (～2%) remained thyroid dysfunctional at the end of follow up (median, 26.5 months). For these patients, no risk factor can predict the reversibility of thyroid function. Conclusions: Female gender and pretreatment TMA positivity are associated with thyroid dysfunction. Long‐term thyroid dysfunction may persist in a small group of patients (～2%).     

Phenotypes of Interferon-α-Induced Thyroid Dysfunction among Patients Treated for Hepatitis C Are Associated with Pretreatment Serum TSH and Female Sex

Context: Thyroid dysfunction is a common complication of interferon-α (IFNα) therapy, with many phenotypic patterns and the potential for significant morbidity. Objective: Our objective was to gain mechanistic insight and predict clinical presentations by determining the risk factors for distinct subtypes of IFNα-induced thyroid dysfunction. Design: ACHIEVE-1, a randomized trial conducted from 2005-2009, compared long-acting preparations of IFNα in 1323 patients with hepatitis C, genotype 1. Setting: A total of 149 outpatient clinics in North America, Europe, and Australia participated. Patients: We studied 1233 patients who were euthyroid at baseline. This population is 60% male and 82% Caucasian. Interventions: Patients were treated with pegylated IFNα2a weekly or albumin-IFNα2b every 2 wk for 48 wk. Serum TSH and free T(4) were measured before therapy and 12 or more times over 60 weeks. Main Outcome Measures: Thyroid dysfunction was defined as a TSH outside the normal range during the course of therapy. Low serum TSH indicated thyrotoxicosis, elevated TSH indicated hypothyroidism, and both abnormalities occurred in biphasic thyroiditis. Results: Of previously euthyroid patients, 16.7% developed abnormal TSH values during therapy, including 24 with TSH below 0.1 mU/liter, 69 with TSH over 5.5 mU/liter, and 76 with biphasic thyroiditis. Biphasic thyroiditis was over 8-fold more common among women than men using multivariate logistic regression analysis [odds ratio (OR) = 8.4; 95% confidence interval (CI) = 4.5-15.8]. Thyrotoxicosis was most strongly associated with a lower pretreatment TSH (OR = 4.1 per -1 mU/liter decline; 95% CI = 1.9-9), whereas hypothyroidism was strongly associated with higher pretreatment TSH (OR = 3.9 per 1 mU/liter increase; 95% CI = 3-5.2). Conclusions: Biphasic thyroiditis is common among women treated for hepatitis C with IFNα. Lower and higher pretreatment serum TSH are associated with greater likelihood of thyrotoxicosis and hypothyroidism, respectively. Antithyroid antibody levels were not available for the cohort, and thus we cannot clarify the role of pretreatment thyroid autoimmunity as a risk factor. Our results do show that readily identifiable patient characteristics are risk factors for specific patterns of IFN-induced thyroid dysfunction. These findings suggest that distinct mechanisms may underlie subtypes of thyroid dysfunction associated with immune-modulatory therapy for hepatitis C.     

Thyroid dysfunction in Chinese hepatitis C patients: Prevalence and correlation with TPOAb and CXCL10

AIM: To investigate the relationship among pretreatment serum CXC chemokine ligand 10(CXCL10),thyroid peroxidase antibody(TPOAb) levels and thyroid dysfunction(TD) in Chinese hepatitis C patients.METHODS: One hundred and thirty-nine treatmentnaive genotype 1 chronic hepatitis C patients with no history of TD or treatment with thyroid hormones were enrolled in this study.Patients underwent peginterferon alfa-2a/ribavirin(Peg IFNα-2a/RBV) treatment for 48 wk,followed by detection of clinical factors at each follow-up point.Hepatitis C virus(HCV) antibodies were analyzed using microsomal chemiluminescence,and serum HCV RNA was measured by real-time PCR assay at 0,4,12,24 and 48 wk after the initiation of therapy and 24 wk after the end of therapy.To assess thyroid function,serum thyroid stimulating hormone(TSH),free thyroxine(FT4),free triodothyronine(FT3) and TPOAb/thyroglobulin antibody(TGAb) levels were determined using chemiluminescent immunoassays every 3 mo.Serum CXCL10 levels were determined at baseline.RESULTS: The prevalence of TD was 18.0%.Twentyone(84.0%) out of twenty-five patients exhibited normal thyroid function at week 24 after therapy.The rate of sustained virological response to Peg IFNα-2a/RBV in our study was 59.0%(82/139),independent of thyroid function.Pretreatment serum CXCL10 levels were significantly increased in patients with euthyroidstatus compared with patients with TD(495.2 ± 244.2 pg/m L vs 310.0 ± 163.4 pg/m L,P = 0.012).Patients with TD were more frequently TPOAb-positive than non-TD(NTD) patients(24.2% vs 12.3%,P = 0.047) at baseline.Three of the one hundred and fifteen patients without TPOAb at baseline developed TD at the end of treatment(37.5% vs 2.6%,P = 0.000).Female patients exhibited an increased risk for developing TD compared with male patients(P = 0.014).CONCLUSION: Lower pretreatment serum CXCL10 levels are associated with TD,and TD prevalence increases in female patients and patients who are positive for TPOAb at baseline.     

Pegylated interferon-alpha2beta in combination with ribavirin does not aggravate thyroid dysfunction in comparison to regular interferon-alpha2beta in a hepatitis C population: meta-analysis

BACKGROUND: Interferon (IFN) has been well documented to cause thyroid dysfunction, especially in high risk patients and when combined with ribavirin (RBV). There is very sparse data to assess if pegylated IFN will further aggravate the thyroid disease risk in comparison to regular IFN. The purpose of this study was to assess the risk of developing thyroid disease with pegylated IFN (pIFN) versus regular IFN (rIFN) therapy (in combination with RBV). We also pooled our results with previous studies in a meta-analysis. METHODS: An observational study was made retrospectively of 24 patients who underwent a combination of rIFN and RBV therapy for hepatitis C virus (HCV) infection. As these patients failed to obtain an initial satisfactory response, they were retreated using pIFN and RBV. Monthly thyrotropin (TSH) levels were assessed while undergoing both treatment regimens. A meta-analysis was performed using available published data in PubMed. RESULTS: No difference in TSH levels was observed when comparing rIFN/RBV with pIFN/RBV. None of the patients developed hypo- or hyperthyroidism. TSH levels fluctuated during the treatment but did not extend outside the reference range. No further investigation was carried out in the absence of clinical and biochemical thyroid disease. The result of the meta-analysis failed to find any excess risk of thyroid dysfunction using pIFN above that of rIFN. CONCLUSIONS: The pegylation of IFN, in combination with RBV, did not aggravate thyroid diseases in the hepatitis C population. This finding is reassuring and dictates that no deviation from current practice regarding thyroid surveillance is required whilst undergoing HCV treatment.     

The prevalence of affective disorder and in particular of a rapid cycling of bipolar disorder in patients with abnormal thyroid function tests

OBJECTIVE Cognitive and affective functioning is sensitive to changes in thyroid hormones. We have sought to determine: (1) the prevalence of thyroid function abnormalities in a psychiatric population on admission (as compared to the prevalence in a normal population), and (2) whether such thyroid function abnormalities are associated with the occurrence or development of cognitive and affective disorders. DESIGN Serum was collected 2–3 weeks after hospitalization in 3 major clinics from 3756 psychiatric patients in 1987–1990, stored, and assayed in 1993 for the presence of antibodies against the TSH-receptor and thyroperoxidase (TPO-Ab) and for TSH levels. The psychiatric cohort was matched with a control population of healthy individuals living in the same area (n = 1877). The prevalence study was followed by a case-control study involving patients from one clinic that had routinely assigned a DSM-IIIR classification to its patients. Cases were those admissions with thyroid abnormalities and three subgroups of cases were randomly formed demonstrating either TSH less than 0.4 mU/l (n = 44) or over 4.0 mU/l (n = 44), or TPO-Ab positivity (n = 50). Cases were compared to random controls from the same psychiatric population, viz patients without thyroid abnormalities (n = 83). Comparison was with respect to their psychiatric follow-up diagnosis (the investigator was blinded to the thyroid test results). RESULTS Prevalence study. The percentage of patients positive for TSH-receptor-Ab was 0.26 (9/3504), for TPO-Ab was 10.0 (331/3316) and outside the TSH range of 0.4–4.0 mU/l was 10.0 ((332/3316): 5.9% (198/3316) >4.0 mU/l and 4.1% (134/3316) <0.4 mU/l). Abnormal total thyroxine levels were found in only 9.8% of subjects with abnormal TSH, indicating the predominantly subclinical character of the thyroid alteration. In comparison, the healthy area controls over 55 years of age showed the same prevalence of positive TPO-antibodies and TSH under 0.4 mU/l, but a higher prevalence of TSH over 4.0 mU/l. Case-control study. In the case control analysis differences could not be noticed with regard to prevalences of dementia, schizophrenia or other psychiatric illnesses apart from the prevalence of affective disorders which were more prevalent in TPO-Ab positive patients and patients with a low serum TSH. Since prior use of lithium, carbamezapine, carbimazole and/or thyroxine could be a factor of importance in this association, analyses were also carried out excluding patients with such prior drug use. In these analyses affective disorders were still more prevalent in patients with a low serum TSH (particularly in males, 40% in cases vs 9% in controls, P < 0.05). The most significant association was however between TPO-antibody positivity (and in particular with high titre and/or with TSH > 4.0 mU/l) and a subgroup of the affective disorders, viz with a rapid cycling of bipolar disorder (18% in cases vs 0% in controls, P < 0.001). CONCLUSION Thoug h causal relations cannot be determined from this cross-sectional study, this admission survey found early forms of autoimmune thyroid disease, sometimes characterized only by TPO-Abs, highly significantly associated with rapid cycles of a bipolar disorder. It also found a weak association between subclinical hyperthyroidism (low serum TSH without TPO-Ab positivity) and affective disorder.     

The role of thyroid autoantibodies in the development of thyroid dysfunction in Taiwanese chronic hepatitis C patients with interferon-alpha and ribavirin combination therapy

Summary. To investigate the role of thyroid autoantibodies in the development of thyroid dysfunction among chronic hepatitis C (CHC) patients receiving interferon‐alpha (IFN‐α) plus ribavirin (RBV) combination therapy, 95 Taiwanese naïve patients with baseline euthyroidism were enrolled. They were treated with IFN‐α2b, 6 million units thrice weekly, plus RBV 1000–1200 mg daily for 24 weeks. Thyroid function, anti‐thyroglobulin and antiperoxidase autoantibodies were tested at enrolment (M0), at the end‐of‐treatment (M6) and 6 months after end‐of‐treatment (M12). The percentages of thyroid autoantibodies were 8.4%, 11.6% and 9.5%, at M0, M6 and M12 respectively. Fourteen (14.7%) patients developed thyroid dysfunction at M6 or M12. Thyroid dysfunction occurred during treatment in five (62.5%) of the eight patients with baseline thyroid autoantibodies, which was significantly higher than nine (10.3%) of 87 patients without baseline thyroid autoantibodies (P = 0.0001). Among 14 patients who developed thyroid dysfunction, four (80.0%) of five patients with baseline thyroid autoantibodies recovered at M12, in contrast to two (25%) of eight without baseline thyroid autoantibodies recovered at M12 (P < 0.05). In conclusion, thyroid autoantibodies, either occurred before or during IFN‐α plus RBV combination therapy, carry a high prediction of subsequent thyroid dysfunction. There also exists difference in the clinical manifestations of thyroid dysfunction in CHC patients treated with combination therapy.     

Five‐year incidence and progression of thyroid dysfunction in an older population

Background: Very few studies have assessed both the incidence and progression of thyroid dysfunction in a single older population‐based cohort. In this study, we aimed to assess the 5‐year incidence, progression and risk factors for development of thyroid dysfunction in an older Australian population. Methods: The Blue Mountains Eye Study is a longitudinal population‐based cohort study. During 1997–1999, 1768 participants (≥55 years) had thyroid function assessed. After excluding participants reporting any form of treatment for their thyroid condition at baseline, 951 participants (91.4%) without thyroid dysfunction and 54 (5.4%) with thyroid dysfunction were re‐examined 5 years later. Thyroid dysfunction was defined using serum thyrotropin (thyroid stimulating hormone (TSH)) screen, followed by serum free T4 assessment. Results: The overall 5‐year incidence of thyroid dysfunction was 4.7% (95% confidence interval (CI) 3.4–6.1). Obesity (body mass index ≥ 30 kg/m²) and serum TSH > 2 mIU/L at baseline predicted incident overt hypothyroidism (odds ratio (OR) 4.05, CI 1.74–9.41) and (OR 5.46, CI 1.16–25.67) respectively. The 5‐year incidence of subclinical hypothyroidism was significantly higher in women than in men, 2.5% versus 0.7% (P= 0.03). Progression to overt hypothyroidism was observed in 17.9% of subjects with subclinical hypothyroidism over 5 years. Conclusions: The 5‐year incidence of thyroid dysfunction in this older population was relatively low, and was associated with obesity and serum TSH level > 2 mIU/L at baseline. Over one in six persons with subclinical hypothyroidism progressed to overt thyroid dysfunction over the 5‐year period. Our findings highlight the need for appropriate management of subclinical hypothyroidism among older people.     

Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration

CONTEXT: Thyroid nodules and goiter are common, and fine-needle aspiration biopsy (FNAB) is the first investigation of choice in distinguishing benign from malignant disease. OBJECTIVE: The objective of the study was to assess whether simple clinical and biochemical parameters can predict the likelihood of thyroid malignancy in subjects undergoing FNAB. DESIGN: The design was a prospective cohort. SETTING: The study was conducted at a single secondary/tertiary care clinic. PARTICIPANTS: One thousand five hundred consecutive patients without overt thyroid dysfunction (1304 females and 196 males, mean age 47.8 yr) presenting with palpable thyroid enlargement between 1984 and 2002 were evaluated by FNAB of the thyroid. INTERVENTION(S): There were no interventions. MAIN OUTCOME MEASURES: Goiter type was assessed clinically and classified as diffuse in 183, multinodular in 456, or solitary nodule in 861 cases. Serum TSH concentration at presentation was measured in a sensitive assay in patients presenting after 1988 (n = 1183). The final cytological or histological diagnosis was determined after surgery (n = 553) or a minimum 2-yr clinical follow-up period (mean 9.5 yr, range 2-18 yr). RESULTS: The overall sensitivity and specificity of FNAB in predicting malignancy were 88 and 84%, respectively. The risk of diagnosis of malignancy rose in parallel with the serum TSH at presentation, with significant increases evident in patients with serum TSH greater than 0.9 mU/liter, compared with those with lower TSH. Binary logistic regression analysis revealed significantly increased adjusted odds ratios (AORs) for the diagnosis of malignancy in subjects with serum TSH 1.0-1.7 mU/liter, compared with TSH less than 0.4 mU/liter [AOR 2.72, 95% confidence interval (CI) 1.02-7.27, P = 0.046], with further increases evident in those with TSH 1.8-5.5 mU/liter (AOR 3.88, 95% CI 1.48-10.19, P = 0.006, compared with TSH < 0.4 mU/liter) and greater than 5.5 mU/liter (AOR 11.18, 95% CI 3.23-8.63, P < 0.001, compared with TSH < 0.4 mU/liter). Males (AOR 1.8, 95% CI 1.04-3.1, P = 0.04), younger patients (AOR 1.1, 95% CI 1.01-1.15, P = 0.025), and those with clinically solitary nodules (AOR 2.53, 95% CI 1.5-4.28, P = 0.001) were also at increased risk. Based on these findings, a formula to predict the risk of the diagnosis of thyroid malignancy in individual patients, taking into account their gender, age, goiter type determined clinically, and serum TSH, was calculated. CONCLUSIONS: The risk of malignancy in a thyroid nodule increases with serum TSH concentrations within the normal range. In addition to patient's gender, age, and goiter type, the serum TSH concentration at presentation is an independent predictor of the presence of thyroid malignancy. We propose that these simple clinical and biochemical factors can serve as an adjunct to FNAB in predicting risk of malignancy.     

The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized,double blind,cross‐over study in thyroidectomized patients

Context The substitution of liothyronine (L‐T3) for levothyroxine (L‐T4) is commonly employed during thyroid hormone (TH) withdrawal in preparation for diagnostic and therapeutic interventions on thyroid cancer patients. Presently, only limited data are available on the L‐T3 for L‐T4 therapeutic substitution. Objective To characterize the pharmcodynamic equivalence of L‐T3 and L‐T4. Design Randomized, double‐blind, cross‐over intervention study. Setting NIH clinical center. Patients Ten thyroidectomized patients. Interventions Study participants were treated with L‐T3 or L‐T4 with a target TSH ≥ 0·5 ≤ 1·5 mU/l for at least 30 days before undergoing inpatient testing. Following testing, subjects crossed‐over according to the same scheme. Main outcome measures Area under the serum concentration–time curve of TSH from 0 to 60 min (AUC_0–60) and peak TSH serum concentration (C_max) following thyrotropin‐releasing hormone (TRH) stimulation test, total L‐T4 and L‐T3 dose (mcg/kg), and L‐T4/L‐T3 ratio. Results No difference was observed for time 0 TSH values between L‐T3 and L‐T4 replacement phases (1·48 ± 0·77 vs. 1·21 ± 0·62 mU/l, P = 0·293) at average daily doses of 40·3 ± 11·3 mcg L‐T3 and 115·2 ± 38·5 mcg L‐T4, L‐T3: L‐T4 ratio 0·36 ± 0·06. TRH stimulation test resulted in similar L‐T3 vs. L‐T4 TSH responses with AUC_0–60 of 326·1 (95% CI 232·6–457·1) and 247·1 (95% CI 153·8–397·1) mU* min/l (P = 0·285); and C_max of 6·83 (95% CI 4·88–9·55) and 5·23 (95% CI 3·31–8·3) mU/l (P = 0·383). Conclusions This is the first study addressing the equivalency between L‐T3 and L‐T4 therapy measured by baseline and TRH‐stimulated TSH. The therapeutic substitution of L‐T3 for L‐T4 was achieved at approximately 1:3 ratio.     

Longitudinal study of pituitary-thyroid axis in pregnancy

The thyroid undergoes important changes during pregnancy. In order to evaluate changes of the hypophyseal-thyroid axis during this period we studied the thyroid function in 587 pregnants by determining serum TSH, free T4, TPO antibodies and betahCG in the 1st trimester and serum TSH, free T4 and TPOAb in to 2nd and 3rd. We observed a progressive rise in average serum TSH in the 2nd (2.14 mU/L) and 3rd (2.96 mU/L) trimesters when compared to the 1st (1.39 mU/L). Serum TSH values in the 1st trimester were inversely correlated with betahCG levels in as much as TSH levels below 0.4 mU/L corresponded to average betahCG levels of 129,000 UI/L whereas these were 34,200 UI/L in the normal TSH group. A slight decrease in free T4 levels was also observed in the 2nd and 3rd trimesters (averages 1st: 1.15; 2nd: 0.99; 3rd: 0.94 ng/dl). Thyroid autoimmunity defined as positive TPOAb occurred in 13.9% of our patients during pregnancy. No significant differences in TSH and free T4 medium values were found between patients with positive TPOAb and those without. However, a significantly higher proportion of pregnants had abnormal hormonal values throughout the trimesters. We conclude that thyroid function is affected by pregnancy with a tendency for decline as it progresses, a feature more easily observed in positive TPOAb group.     

Recovery of thyroid function with a decreased titre of antimicrosomal antibody in a hypothyroid man with Hashimoto's thyroiditis

A 36 year old man with a diffuse goitre, signs of mild hypothyroidism, strikingly low levels of T4 (0.9 micrograms/dl) and T3 (24 ng/dl), elevated TSH (140 microU/ml) and elevated microsomal haemagglutination antibody (MCHA, 1:409 600), subsequently became non-goitrous and euthyroid with a decreased titre of antimicrosomal antibody without any medication. At the time of surgical biopsy, serum levels of T4 and T3 had risen to the normal range (4.6 micrograms/dl and 73 ng/dl, respectively), serum TSH had decreased to 30 microU/ml and the titre of MCHA to 1:25 600. Thyroid specimens showed Hashimoto's thyroiditis. The activity of thyroid peroxidase (TPO) was normal. The latest examination, 1 year and 3 months after initial evaluation, showed that the patient remained euthyroid with no goitre, that serum thyroid hormones were within the normal range (T4 7.7 micrograms/dl and T3 97 ng/dl), and that TSH was not detectable. The titre of MCHA decreased strikingly to 1:400.     

Smoke exposure is associated with a lower prevalence of serum thyroid autoantibodies and thyrotropin concentration elevation and a higher prevalence of mild thyrotropin concentration suppression in the third National Health and Nutrition Examination Survey (NHANES III)

Few modifiable exposures influencing autoimmune thyroid disease have been identified. Studies evaluating cigarette smoke and thyroid disorders have yielded conflicting results. The relationship between smoking and thyroid abnormalities was evaluated in the 1988-1994 Third National Health and Nutrition Examination Survey (NHANES III), a cross-sectional study that used a complex, multistage, stratified, clustered sampling approach to reflect the entire noninstitutionalized United States population. Among 18,148 persons who underwent thyroid testing, data regarding age, gender, iodine status, smoke exposure, and thyroid tests were complete for 16,046 persons. After excluding those taking thyroid-altering medications, 15,592 remaining subjects were analyzed. Subjects with serum cotinine levels greater than 15 ng/ml were classified as smokers. Outcome measures included the presence of 1) antithyroperoxidase antibody levels of 0.5 IU/ml or more or antithyroglobulin antibody levels of 1.0 IU/ml or more, 2) TSH concentration greater than 4.5 mU/liter, 3) TSH concentration less than 0.1 mU/liter, and 4) TSH concentration of 0.1-0.4 mU/liter. Fewer smokers (11%, 95% confidence interval (CI) = [10-13%]) had thyroid autoantibodies compared with nonsmokers (18%, 95% CI = [17-19%]). Prevalence in smokers after adjustment for age, gender, race-ethnicity, and iodine status was 13%, 95% CI = [12-15%]. Fewer smokers (2.6%, 95% CI = [2.0-3.2%]) had elevated TSH compared with nonsmokers (5.5%, 95% CI = [4.7-6.3%]). The adjusted rate in smokers was 3.4%, 95% CI = [2.6-4.3%]). Among persons with thyroid autoantibodies, smokers had 40% lower odds of TSH elevation compared with nonsmokers (adjusted odds ratio [95% CI] = 0.6 [0.4-0.97]). Among persons without TSH elevation, smoke exposure was associated with 200% greater odds of low normal TSH 0.1-0.4 mU/liter (adjusted odds ratio [95% CI] = 2.0 [1.3-2.9]). Smoking appears to be negatively associated with serological evidence of thyroid autoimmunity and hypothyroidism and positively associated with mild TSH decreases. Eliminating smoke exposure may help prevent the low normal TSH measurements that are characteristic of mild hyperthyroidism. Understanding the underlying mechanism could help identify potential pathways for the prevention of autoimmune thyroid disease.     

Risk factors for and prevalence of thyroid disorders in a cross-sectional study among healthy female relatives of patients with autoimmune thyroid disease

OBJECTIVE: Autoimmune thyroid disease (AITD) is a common disorder especially in women, and both genetic and environmental factors are involved in its pathogenesis. We wanted to gain more insight into the contribution of various environmental factors. Therefore, we started a large prospective cohort study in subjects at risk of developing AITD, for example healthy female relatives of AITD patients. Here we report on their baseline characteristics. SUBJECTS: Only first- or second-degree female relatives of patients with documented AITD were included. MEASUREMENTS: Smoking habits, oestrogen use, pregnancy history and iodine exposure were assessed by questionnaires, and correlated to the thyroid function and antibody status. RESULTS: Of 803 subjects, 440 came from families with more than one patient with documented AITD. Of these families, 33% had documented cases of both Graves' disease and Hashimoto's thyroiditis. Although the subjects were in self-proclaimed good health, 3.6% were found to have hypothyroidism (overt disease in 1.3%) and 1.9% had hyperthyroidism (overt disease in 0.4%). These patients were older than the euthyroid subjects and were mostly positive for thyroid peroxidase (TPO) antibodies. Oestrogen use was associated with a lower rate of hyperthyroidism [relative risk (RR) 0.169; 95% confidence interval (CI) 0.06-0.52], whereas having been pregnant was associated with a higher relative risk for hyperthyroidism (RR 6.88; 95% CI 1.50-30.96). Of the 759 euthyroid subjects, 24% had TPO antibodies. Smoking and oestrogen use were negatively correlated with the presence of TPO antibodies. In the euthyroid subjects, TPO antibody titre correlated positively with TSH levels (r = 0.386; P < 0.001). CONCLUSIONS: The high prevalence of evidence for autoimmune thyroiditis at baseline supports the importance of genetic factors in its pathogenesis. The co-occurrence of Hashimoto's thyroiditis and Graves' disease within one family suggests a common genetic basis for these diseases. Oestrogen use is associated with a lower risk, and pregnancy with a higher risk for developing hyperthyroidism. The positive correlation between TPO antibody titres and TSH levels in euthyroid subjects suggests that TPO antibodies are indeed a marker of future thyroid failure.     

Anti-TPO antibodies and screening of thyroid dysfunction in type 1 diabetic patients

The diagnosis of thyroid dysfunction is often late in type 1 diabetic population. So, the aims of this study were 1) to evaluate the prevalences of thyroperoxydase (TPO) and thyroglobulin (Tg) autoantibodies detected by highly sensitive radioimmunological method in a cohort of 258 adult type 1 diabetic patients without evidence of clinical thyroid disease; 2) to determine whether or not measurement of TPO and/or Tg antibodies can identify subjects at risk of clinical or infraclinical thyroid dysfunction by measuring TSH in the entire group. TPO antibodies were found in 45 of the 258 diabetic patients (17%). The prevalence of TPO antibodies was not influenced by the following factors: gender, duration of disease, age at screening and at diabetes diagnosis, positivity of familial history. Tg antibodies were found in 19 patients (7%), including 13 cases with TPO antibodies. All patients without TPO antibody (n=213), including Tg-positive patients displayed TSH values in normal range. Among the 45 TPO-positive patients, 11 patients displayed infraclinical thyroid dysfunction. At the end of the 5-year follow-up, only 2/45 patients became anti-TPO negative. Thirteen of the 45 patients developed subclinical or clinical thyroid diseases (4 Graves'disease and 9 thyroiditis with hypothyroidism). By contrast, none of 45 TPO negative patients, sex and age matched with the TPO-positive patients, developed during follow-up anti-TPO positivity and/or infraclinical thyroid dysfunction. In conclusion, the determination of TPO antibodies by a highly sensitive method allows identifying diabetic patients with thyroid autoimmunity and at risk of subsequent impaired thyroid function, whatever age at diagnosis and diabetes duration. By contrast, anti-Tg determination did not give further information about subsequent thyroid dysfunction. In TPO antibody positive patients repeated thyroid clinical examination and TSH determination could be recommended to detect infraclinical thyroid dysfunction.     

Modulation of differentiated function in cultured thyroid cells: thyrotropin control of thyroid peroxidase activity

The activity of thyroid peroxidase (TPO) in primary dog thyroid cell cultures was measured by both guaiacol oxidation and iodide oxidation assays. Whether cultures were initiated in the absence or presence of 50 mU/ml TSH, TPO activity fell in the first 24 h of culture to approximately 10% of the activity in freshly isolated follicles. After 5 days in culture, TPO activity almost completely disappeared in the absence of TSH, whereas in the presence of TSH, TPO activity rebounded to approximately 30% of that in freshly isolated follicles. TSH similarly induced TPO activity in cells that had lost this activity during a 1- to 6-day preincubation period in the absence of hormone. The half-time for the induction of TPO activity was approximately 3 days. Whether TSH was present from the start of culture or added after 5 days of culture without TSH, the half-maximal dose for reinduction of TPO activity was 0.3-0.4 mU TSH/ml. (Bu)2cAMP, 8-bromo-cAMP, forskolin, and cholera toxin all mimicked, either completely or in part, the ability of TSH to induce TPO activity in cells preincubated without hormone. We conclude that, in cultured dog thyroid cells, TPO activity is modulated by chronic TSH stimulation, and that this effect is mediated by cAMP. However, even though TSH stimulates TPO activity in cultured thyroid cells, the fact that there is no comparable restoration of organic iodine formation (as found in previous studies) makes it likely that other aspects of the iodide organification mechanism are altered.     

Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C

We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG‐IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty‐eight patients with genotype 1b high viral loads were treated with PEG‐IFN/RBV/TVR. Peg‐IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.     

NATURAL HISTORY OF THYROID FUNCTION IN DIABETICS WITH IMPAIRED THYROID RESERVE: A FOUR YEAR CONTROLLED STUDY

An attempt was made to compare the natural history of thyroid function in 80 diabetics having raised serum TSH concentrations (median 8.9 mU/l, range 5.8-46.3 mU/l) but serum T4 concentrations within the normal range (Group 1), and in 59 diabetics having normal serum TSH (median 1.9 mU/l, range 0.8-4.7 mU/l) and T4 concentrations (Group 2). Thyroid microsomal antibodies were present initially in 65% of patients in Group 1 and 15% of patients in Group 2. By 1981, 59 patients (74%) in Group 1 and 47 patients (80%) in Group 2 had been followed for a mean +/- SD duration of 4.2 +/- 1.8 and 4.2 +/- 1.5 years, respectively. Hypothyroidism developed in 9 patients in Group 1, but none from Group 2. Of patients in Group 1, hypothyroidism developed at a rate of 5% per annum in those with thyroid microsomal antibodies, but only 1% per annum in those without antibodies. Therefore, the risk of development of hypothyroidism is greatest in diabetics having both elevated serum TSH concentrations and thyroid microsomal antibodies and such patients should have regular review of thyroid function. Either risk factor alone appears to be a poor predictor of development of hypothyroidism.     

Serum TSH related to measures of body mass: longitudinal data from the HUNT Study, Norway

Objective Thyroid function and body mass are related, but the causal relationship remains unclear. Our objective was to investigate the longitudinal relationship between thyroid stimulating hormone (TSH) and body mass measures [body weight, body mass index (BMI), waist circumference (WC) and waist‐hip‐ratio (WHR)]. Design We used data from two waves of a population‐based study: HUNT 2 (1995–1997) and 3 (2006–2008). Average follow‐up time was 10·5 years. Multivariable general linear and logistic regression models were used to assess the relation between TSH and the body mass measures. Participants In total 9954 women and 5066 men without self‐reported thyroid disease and TSH within the reference range (0·5–3·5 mU/l) at baseline and <10 mU/l at follow‐up. Results For each mU/l increase in TSH among women, weight increased 0·9 kg (95% CI 0·8, 1·1), BMI 0·3 kg/m² (95% CI 0·3, 0·4) and WC 0·6 cm (95% CI 0·3, 0·8). In men, the corresponding figures were 0·8 kg (95% CI 0·5, 1·0), 0·2 kg/m² (95% CI 0·2, 0·3) and 0·5 cm (95% CI 0·2, 0·8). In line with this, a weight gain of more than 5 kg was associated with a TSH increase of 0·08 mU/l (95% CI 0·06, 0·11) in women and 0·15 mU/l (95% CI 0·12, 0·18) in men. Women who lost more than 5 kg decreased their TSH by 0·12 mU/l (95% CI 0·09, 0·16) and men by 0·03 mU/l (95% CI ?0.02, 0·09). Conclusion Weight gain is accompanied by increasing TSH, and weight loss in women is related to decreasing TSH.