Genetic factors play an important role in the pathogenesis of autoimmune thyroid disease (AITD) and it has been calculated that 80% of the susceptibility to develop Graves' disease is attributable to genes. The concordance rate for AITD among monozygotic twins is, however, well below 1 and environmental factors thus must play an important role. We have attempted to carry out a comprehensive review of all the environmental and hormonal risk factors thought to bring about AITD in genetically predisposed individuals. Low birth weight, iodine excess and deficiency, selenium deficiency, parity, oral contraceptive use, reproductive span, fetal microchimerism, stress, seasonal variation, allergy, smoking, radiation damage to the thyroid gland, viral and bacterial infections all play a role in the development of autoimmune thyroid disorders. The use of certain drugs (lithium, interferon-a, Campath-1H) also increases the risk of the development of autoimmunity against the thyroid gland. Further research is warranted into the importance of fetal microchimerism and of viral infections capable of mounting an endogenous interferon-a response.European Journal of Endocrinology 150 605-618

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.

The onset of behavioral problems starts in early life. This study examined whether excessive infant crying (maternal ratings) is a determinant of emotional and behavioral problems at age 5–6 years. In the Amsterdam Born Children and their Development (ABCD) study, a large prospective, observational, population-based multiethnic birth cohort, excessive infant crying (crying for three or more hours per 24 h day over the past week) during the 13th week after birth (range 11–25 weeks, SD 2 weeks), maternal burden of infant care and maternal aggressive behavior (either angry speaking, or physical aggression) was assessed using a questionnaire. Children’s behavioral and emotional problems at the age of 5–6 were assessed by Goodman’s Strengths and Difficulties Questionnaire (SDQ), by the subscale of generalized anxiety of the preschool anxiety scale (PAS), and by the Short Mood and Feelings Questionnaire (SMFQ). Inclusion criterion was singleton birth. Exclusion criteria were preterm born babies or congenital disorders. Among 3389 children, excessive infant crying (n = 102) was associated with a twofold increased risk of the overall problem behavior, conduct problems, hyperactivity, and mood problems at the age of 5–6 [ORs between 1.75 (95 % CI 1.09–2.81) and 2.12 (95 % CI 1.30–3.46)]. This association was mediated by maternal burden of infant care (change in odds’ ratio 1–17 %) and maternal aggressive behavior (change in odds’ ratio 4–10 %). There was no effect modification by the child’s gender or maternal parity. Excessive infant crying was not associated with general anxiety problems. Excessive infant crying doubles the risk of behavioral, hyperactivity, and mood problems at the age of 5–6, as reported by their mother. Maternal burden of infant care partially mediates the association between excessive crying and behavioral and mood problems. Special care for mothers with a high burden of care for their excessive crying infant, notwithstanding their own good health, can be a feasible strategy for possible prevention of mood and behavioral problems in their children later in life.

Background: Genetic and environmental factors are involved in the pathogenesis of autoimmune thyroid disease (AITD). Family members of patients with AITD are at increased risk for AITD, but not all will develop overt hypothyroidism or hyperthyroidism. Our goal was to develop a simple predictive score that has broad applicability and is easily calculated at presentation for progression to overt hypothyroidism or hyperthyroidism within 5 years in female relatives of patients with AITD. Methods: We conducted a prospective observational cohort study of 790 healthy first-or second-degree female relatives of patients with documented Graves or Hashimoto disease in the Netherlands. Baseline assessment included measurement of serum thyrotropin (TSH), free thyroxine (FT 4), and thyroid peroxidase (TPO) antibody levels as well as evaluation for the presence and levels of Yersinia enterocolitica antibodies. We also gathered data on family background, smoking habits, use of estrogen medication, pregnancy, and exposure to high levels of iodine. In follow-up, thyroid function was investigated annually for 5 years. As main outcome measures, termed events, we looked for overt hypothyroidism (TSH levels Ͼ5.7 mIU/L and FT 4 levels Ͻ0.72 ng/dL) or overt hyperthyroidism (TSH levels Ͻ0.4 mIU/L and FT 4 levels Ͼ1.56 ng/dL). Results: The cumulative event rate was 7.5% over 5 years. The mean annual event rate was 1.5%. There were 38 hypothyroid and 13 hyperthyroid events. Independent risk factors for events were baseline findings for TSH and TPO antibodies in a level-dependent relationship (for TSH the risk already starts to increase at values Ͼ2.0 mIU/L) and family background (with the greatest risk attached to subjects having 2 relatives with Hashimoto disease). A numerical score, the Thyroid Events Amsterdam (THEA) score, was designed to predict events by weighting these 3 risk factors proportionately to their relative risks (maximum score, 21): low (0-7), medium (8-10), high (11-15), and very high (16-21). These THEA scores were associated with observed event rates of 2.7%, 14.6%, 27.1%, and 76.9%, respectively. Conclusions: An accurate simple predictive score was developed to estimate the 5-year risk of overt hypothyroidism or hyperthyroidism in female relatives of patients with AITD. However, in view of the small number of observed events, independent validation of the THEA score is called for.

Objective: To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism. Subjects and methods: The design is that of a nested case-control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism -TSHO 5.7 mU/l and free thyroxine (FT 4 )!9.3 pmol/l and overt hyperthyroidism -TSH!0.4 mU/l and FT 4 O20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up). Results: At baseline, the 38 hypothyroid cases had already higher TSH and lower FT 4 concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT 4 values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (PZ0.083) and more common in the postpartum period (PZ0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (PZ0.063). Conclusions: The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months.