Variation in phenotypic appearance of Graves' disease: effect of genetic anticipation and duration of complaints

Abstract

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.

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

“…Therefore, the biochemical switch from normal TSH and FT 4 values to the suppressed TSH and elevated FT 4 values must have occurred in the year before hyperthyroidism was diagnosed, suggesting that the transition from euthyroidism to overt autoimmune hyperthyroidism develops fast in terms of months rather than years. This observation is in agreement with a recent cross-sectional multicenter observational study (16), which investigated the duration of thyrotoxic symptoms until Graves' hyperthyroidism was diagnosed. The median duration of Graves' disease symptoms until diagnosis is 4 months.…”

Genotypes in relation to phenotypic appearance and exposure to environmental factors in Graves' hyperthyroidism

“…The age difference in our cohort is in the same range: 7 years for the difference between homozygotes and the wild type of CTLA4 49A/G, and 8 years for that of CTLA4 CT60. These values are in the same order of magnitude when the age of onset is related to a family history of thyroid disease (33). A positive family history is associated with a younger age of onset when compared with no family history (difference: 6 years in males and 5 years in females) (34).…”

Predictive score for the development or progression of Graves’ orbitopathy in patients with newly diagnosed Graves’ hyperthyroidism

“…It is not immediately clear why a longer duration of hyperthyroid symptoms is a predictor of GO. In a previous study among 251 consecutive patients with newly diagnosed GH, duration of symptoms >4 months was associated with younger age, higher TPOAb (thyroid peroxidase antibodies) levels, larger goiter size, but not with higher TBII (TSH-binding inhibitor immunoglobulins) or higher prevalence of GO (although the prevalence of GO was 19% at symptoms duration ≤4 months and increased to 28% at a duration ≥12 months, the trend was not significant) (26). One may hypothesize that longer duration of symptoms means longer exposure to TBII, which is associated with larger goiter size and by analogy may also lead to larger size of extraocular muscles and orbital fat.…”