Genotyping increases the accuracy of a clinical score (based on pretreatment age, goiter size, FT4, TBII) for predicting recurrence of Graves' hyperthyroidism after a course of antithyroid drugs: a prospective study.

The prevalence of TBII-seronegativity in untreated patients with GH is 5.4% using a second generation assay. TBII-seronegative patients have biochemically less severe thyrotoxicosis and no Graves' orbitopathy. TBII-seronegative and TBII-seropositive patients apparently belong to the same population of GH, albeit the severity of the autoimmune attack is less in TBII-seronegative patients.

Leptin administration selectively restores starvation-induced increased hepatic D3 expression independently of serum thyroid hormone concentrations. The present study shows that fasting-induced changes in mRNA expression of genes involved in hepatic hormone metabolism are influenced not only by decreased serum thyroid hormone levels but also by serum leptin.

Profound changes in thyroid hormone metabolism occur in the central part of the hypothalamus-pituitary-thyroid (HPT) axis during fasting. Hypothalamic changes are partly reversed by leptin administration, which decreases during fasting. It is unknown to what extent leptin affects the HPT axis at the level of the pituitary. We, therefore, studied fasting-induced alterations in pituitary thyroid hormone metabolism, as well as effects of leptin administration on these changes. Because refeeding rapidly increased serum leptin, the same parameters were studied after fasting followed by refeeding. Fasting for 24 h decreased serum T 3 and T 4 and pituitary TSHb, type 2 deiodinase (D2), and thyroid hormone receptor b2 (TRb2) mRNA expression. The decrease in D2 and TRb2 mRNA expression was prevented when 20 mg leptin was administered twice during fasting. By contrast, the decrease in TSHb mRNA expression was unaffected. A single dose of leptin given after 24 h fasting did not affect decreased TSHb, D2, and TRb2 mRNA expression, while 4 h refeeding resulted in pituitary D2 and TRb2 mRNA expression as observed in control mice. Serum leptin, T 3 , and T 4 after refeeding were similar compared with leptin administration. We conclude that fasting decreases pituitary TSHb, D2, and TRb2 mRNA expression, which (with the exception of TSHb) can be prevented by leptin administration during fasting. Following 24 h fasting, 4 h refeeding completely restores pituitary D2 and TRb2 mRNA expression, while a single leptin dose is ineffective. This indicates that other postingestion signals may be necessary to modulate rapidly the fasting-induced decrease in pituitary D2 and TRb2 mRNA expression.

Objective: The evidence that stress may provoke Graves' hyperthyroidism in genetically susceptible subjects is substantial. Whether exposure to stress is related to the severity of thyrotoxicosis has not been studied. Advancing age is associated with not only less severe Graves' hyperthyroidism but also self-reported stress. We tested the hypothesis whether advancing age is associated with less exposure to stress, resulting in a lower immunological response, and less severe Graves' hyperthyroidism. Design: Cross-sectional multicenter study. Patients: Two hundred and sixty-three consecutive untreated patients with a first episode of Graves' hyperthyroidism were included. The severity of Graves' hyperthyroidism was evaluated biochemically (freeT 4 -index and freeT 3 -index, thyrotropin-binding inhibitory immunoglobulin (TBII)) and clinically by the hyperthyroid symptom scale score (HSS score). Stress exposure was quantitated by three questionnaires. Results: Advancing age was associated with less severe Graves' hyperthyroidism, both biochemically by lower serum freeT 3 -index and freeT 4 -index (P!0.01), lower serum TBII (PZ0.05), and clinically by lower HSS scores (PZ0.04) and smaller goiter size (P!0.01). FreeT 3 -index and freeT 4 -index were directly associated with HSS scores (P!0.01). Stress scores were associated with HSS scores (P!0.01) but not with biochemical severity of Graves' hyperthyroidism. Advancing age was associated with lower scores for stress exposure. Multivariate regression analysis showed that HSS score was independently related to the tendency to report negative feelings (P!0.01) but not to other stress scores and also not to age. Conclusion: Advancing age is associated with less exposure to stress, lower serum TBII and less severe clinical and biochemical Graves' hyperthyroidism. Because no direct relationship exists between stress exposure and TBII or freeT 3 -index and freeT 4 -index, we reject our hypothesis that less stress is causally related to biochemically less severe Graves' hyperthyroidism in old age. HSS score is primarily determined by negative feelings and not by age.

Background: Genetic polymorphisms and environmental factors are both involved in the pathogenesis of Graves' disease, but their interaction and effect on Graves' phenotypes have scarcely been investigated. Objective: To test the hypothesis that subjects with susceptibility genotypes develop more severe Graves' hyperthyroidism at a younger age and after less exposure to environmental factors, with attention to gender differences. Study design: A prospective observational multicenter study in 205 adult Caucasian patients with untreated first episode of Graves' hyperthyroidism. Methods: Evaluation of genotypes (HLA DRB1*03, DQA1*05, DQB1*02; CTLA4 49A/G, CT60 A/G; PTPN22 C/T) in relation to phenotypes (age, sex, severity (clinical, biochemical, and immunological)) of hyperthyroidism and environmental factors (smoking, stress questionnaires). Results: G-alleles in CTLA4 single nucleotide polymorphisms were dose-dependently associated with younger age at the time of diagnosis and less exposure to daily hassles. In gender-specific analysis, this association is enhanced in men and attenuated in women. Males (but not females) in HLA linkage disequilibrium had more severe (biochemical and immunological) hyperthyroidism and a tendency to younger age at diagnosis, compared with those not in linkage disequilibrium. Conclusion: Graves' hyperthyroidism occurs at a younger age with less exposure to environmental factors in subjects carrying susceptibility genotypes. The impact of genotypes seems to be greater in males than in females.

Objective: Both genetic and environmental factors contribute to susceptibility of Graves' disease. In this study, we evaluated whether the duration of symptoms or a positive family history of autoimmune thyroid disease (AITD) are related to specific phenotypes in patients with a first episode of Graves' hyperthyroidism (GH). Design: Cross-sectional multicentre observational study. Patients: Two hundred and sixty-three consecutive untreated patients (mean age (GS.D.) 42.6G12.4 years; range 16-79 years) with a first episode of GH were included. Biochemical and clinical severity of GH was evaluated. Participants were asked to complete questionnaires about environmental factors (smoking behavior, use of estrogens, stress etc.), the duration of symptoms (interval between start of symptoms and date of referral) and family history for AITD. We ascertained the autoimmune nature of thyroid disease in affected relatives. Family history scores (FHS; high score indicating a close genetic relationship and/or a large number of affected relatives) were calculated for patients with a positive family history for AITD. Results: The peak incidence for the diagnosis of GH was 2-3 months after onset of symptoms (32% of patients). Duration of symptoms was negatively associated with age (P for trendZ0.04). A positive family history for AITD was present in 42.6% of patients. Patients with the highest FHS were more often male (PZ0.01) while age at onset was lower (PZ0.02) compared to patients with a lower FHS. Among patient groups with different FHS, no differences were found in exposure to environmental factors, nor in clinical or biochemical severity of hyperthyroidism. Conclusion: Our study does not support the hypothesis that a short duration of thyrotoxic symptoms until diagnosis is related to more severe hyperthyroidism in Graves' disease. We have found supporting evidence for the existence of genetic anticipation in Graves' disease by means of a lower age of onset in the group with the highest FHS.

We here present the case of a 22-year-old female of Suriname ethnicity with ulcerative colitis who received treatment with mercaptopurine and infliximab. She presented herself with a severe necrotizing tonsillitis due to herpes simplex virus type-1 (HSV-1). Combination therapy consisting of immunomodulators and anti-tumor necrosis factor (TNF) agents is increasingly being used. Anti-TNF therapy is associated with an increased risk of developing serious infections, and especially patients receiving combination treatment with thiopurines are at an increased risk. We here show that HSV infections can cause a severe tonsillitis in immunocompromised patients. Early recognition is essential when there is no improvement with initial antibiotic therapy within the first 24 to 72 h. HSV infections should be in the differential diagnosis of immunocompromised patients presenting with a necrotizing tonsillitis and can be confirmed by polymerase chain reaction. Early treatment with antiviral agents should be considered especially if antibiotic treatment fails in such patients.