Summary
BACKGROUND AND OBJECTIVE The original Whlckham Survey documented the prevalence of thyroid disorders in a randomly selected sample of 2779 adults which matched the population of Great Britain in age, sex and social class. The aim of the twenty-year follow-up survey was to determine the Incidence and natural history of thyroid disease in this cohort.

DESIGN, PATIENTS AND MEASUREMENTS Subjects were traced at follow-up via the Electoral Register, General Practice registers, Gateshead Family Health Services Authority register and Office of Population Censuses and Surveys. Eight hundred and twenty-five subjects (30% of the sample) had died and, In addition to death certificates, two-thirds had Information from either hospital/General Practitioner notes or post-mortem reports to document morbidity prior to death. Of the 1877 known survivors, 96% participated in the follow-up study and 91 % were tested for clinical, biochemical and Immunological evidence of thyroid dysfunction.

RESULTS Outcomes in terms of morbidity and mortality were determined for over 97% of the original sample. The mean Incidence (with 95% confidence Intervals) of spontaneous hypothyroidism in women was 3.5/1000 survivors/year (2.8-4.5) rising to 4.1/1000 survivors/year (3.3-5.0) for all causes of hypothyroidism and in men was 0.6/1000 survivors/year (0.3-1.2). The mean incidence of hyperthyroidism In women was 0.8/1000 survivors/year (0.5.1.4) and was negligible in men. Similar incidence rates were calculated for the deceased subjects. An estimate of the probability of the development of hypothyroidism and hyperthyroidism at a particular time, i.e. the hazard rate, showed an Increase with age In hypothyroidism but no age relation in hyperthyroidism.

The frequency of goitre decreased with age with 10% of women and 2% of men having a goitre at follow-up, as compared to 23% and 5% in the same subjects respectively at the first survey. The presence of a goitre at either survey was not associated with any clinical or biochemical evidence of thyroid dysfunction. In women, an association was found between the development of a goitre and thyroid-antibody status at follow-up, but not initially.

The risk of having developed hypothyroidism at follow-up was examined with respect to risk factors Identified at first survey. The odds ratios (with 95% confidence Intervals) of developing hypothyroidism with (a) raised serum TSH alone were 8 (3-20) for women and 44 (19-104) for men; (b) positive anti-thyroid antibodies alone were 8 (5-15) for women and 25 (10-63) for men; (c) both raised serum TSH and positive anti-thyroid antibodies were 38 (22-65) for women and 173 (81-370) for men. A loglt model Indicated that Increasing values of serum TSH above 2mU/l at first survey Increased the probability of developing hypothyroidism which was further Increased in the presence of anti-thyroid antibodies. Neither a positive family history of any form of thyroid disease nor parity of women at first survey was associated with Increased risk of developing hypothyroidism. Fasting cholesterol and triglyceride levels at first survey when corrected for age showed no association with the development of hypothyroidism In women.

CONCLUSIONS This historical cohort study has provided Incidence data for thyroid disease over a twenty-year period for a representative cross-sectional sample of the population, and has allowed the determination of the importance of prognostic risk factors for thyroid disease Identified twenty years earlier.

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The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey

Subclinical thyroid disease (SCTD) is defined as serum free T4 and free T3 levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine t...

The clinical significance of subclinical thyroid dysfunction.

In 1912, Hashimoto described four women in whom the thyroid gland was enlarged and appeared to have been transformed into lymphoid tissue (“struma lymphomatosa”).1 Although the patients were not initially hypothyroid, they became so after thyroid surgery. Over 40 years later, the presence of antithyroid antibodies was reported in patients with this disorder.2 Hashimoto's disease, or Hashimoto's thyroiditis, is now recognized as a form of chronic autoimmune thyroiditis. There is no internationally accepted classification of autoimmune thyroid diseases.3 Some investigators consider autoimmune thyroiditis a histologic diagnosis that can be subdivided into lymphocytic thyroiditis, if only lymphocytic infiltration is present, and . . .

Chronic Autoimmune Thyroiditis

The revolution in molecular techniques has allowed dissection of the autoimmune response in a way impossible to imagine 10 yr ago. There have been spectacular advances in our understanding of self-tolerance mechanisms and how these may fail, combined with a detailed comprehension of antigen presentation, functional T cell subsets, and TCR utilization in autoimmunity, albeit usually in animal models that resemble, but do not exactly duplicate, human diseases. More gradually, these findings are being translated to thyroid autoimmunity, where the major achievement of the last decade has been the molecular characterization of the three main thyroid autoantigens. This in turn has allowed epitope identification, although again the only clear data so far have come from animal models of EAT. Another advance has been the recognition that the thyrocyte is not a helpless target of autoaggression, being capable of expressing a wide array of immunologically active molecules, which may exacerbate or diminish the autoimmune response. In 1983, there was considerable excitement at the discovery of the first of these phenomena, namely MHC class II expression, but its possible role in autoantigen presentation remains to be defined. By analogy with pancreatic beta-cells, and based on our own data, we believe that class II-expressing thyrocytes have little, if any, such role and suspect that instead this may be a mechanism for inducing peripheral tolerance. Defining the contribution of thyrocytes to the intrathyroidal autoimmune response, whether from released cytokines or surface-bound molecules, will be crucial to our future understanding, as well as holding the promise that these thyroid-derived products might be therapeutic targets. Despite molecular developments in HLA analysis, there have been no really major improvements in our understanding of the immunogenetics of thyroid autoimmunity, equivalent to those made in type 1 diabetes mellitus. The available data suggest strongly that non-MHC genes play an important role in susceptibility, and novel approaches will be required to identify these. On the other hand, we know more about the importance of environmental and endogenous (most probably hormonal) factors in thyroid autoimmunity. Understanding the basic immunological changes in the postpartum period is still poor, however, as most studies to date have concentrated on epidemiology and clinical delineation. As PPTD undergoes spontaneous remission, elucidation of these mechanisms has clear implications for treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Autoimmune thyroid disease: further developments in our understanding

▪ Objective: To determine the incidence of autoantibodies and autoimmune disease and their influence on therapeutic results during alpha-interferon treatment in patients with malignant midgut carci...

Autoimmunity after Alpha-Interferon Therapy for Malignant Carcinoid Tumors

The significance of the characteristic lymphocytic infiltrate in the target organ in organ-specific autoimmune disease is unknown. We have demonstrated the production of thyroglobulin antibodies and immunoglobulins (IgG, IgM and IgA) by thyroid-derived lymphocytes in Graves' disease and Hashimoto's thyroiditis two plaque forming cell (PFC) assays. The thyroid appears to be an important site of thyroglobulin antibody production but the thyroid lymphocytes also contain many IgG PFCs of non-thyroglobulin specificity. Short-term culture and direct thyroglobulin antibody assay on micro-ELISA plates confirmed the results of the PFC assay. Therapies such as carbimazole may therefore be acting on a localized source of autoantibody production.

Thyroid antibodies are produced by thyroid-derived lymphocytes.

Several potential sites of thyroid autoantibody production have been investigated using tissue obtained at thyroidectomy for Graves' disease. Spontaneous thyroglobulin and microsomal antibody synthesis was measured using a plaque forming cell assay or a short term culture system coupled to a direct enzyme linked immunoassay (ELISA); these techniques allow the evaluation of lymphocyte populations which have been activated in vivo. Lymphocytes from the cervical lymph nodes, thyroid and bone marrow all contributed to autoantibody production; in contrast no synthesis was demonstrated using cells obtained from the thymus or peripheral blood. Long term culture of the lymphocytes confirmed these findings. The effect of anti-thyroid treatment, with radioiodine, drugs or surgery, on autoantibody production in Graves' disease must be viewed in the light of these results.

Extrathyroidal sites of autoantibody synthesis in Graves' disease.

Thyroid antibodies were measured by an enzyme-linked assay system (ELISA) on a random sample of 414 asymptomatic elderly people aged 70 years or more in a South Wales town in 1977. The prevalence of elevated titres of microsomal antibodies was 15.4% and of thyroglobulin antibodies 13.3%; 8.5% had an elevation of both antibodies. Five years later thyroid function was evaluated in 51 (66.6%) of those people with raised antibody titres in 1977 and compared with a control group of 46 old people drawn from the original population. Significant fluctuations of microsomal and thyroglobulin antibody titres were observed in two thirds of the antibody positive group. Three people in the control group developed positive thyroid antibodies during this period. Only 1 person in the antibody positive group became hypothyroid. The prognostic significance of raised thyroid antibodies with or without elevated TSH levels is less in the elderly than in middle aged or younger people. The significance of the fluctuating antibody levels as measured by a more sensitive method remains to be determined.

The prevalence and progression of autoimmune thyroid disease in the elderly.

Experimental autoimmune thyroid disease was induced in August rats by immunization with rat thyroglobulin in complete Freund's adjuvant. Disease severity, assessed by thyroid histology and circulating levels of anti-TG antibody measured by an enzyme immunoassay, was maximal between 30 and 60 days after the initial immunization and thereafter waned. Thyroid function through the duration of the disease, assessed by measurement of serum TSH levels by RIA, remained normal. Once the natural history of the disease was established, groups of rats received methimazole (MMI) with or without T4 in their drinking water, either before or after disease induction. The animals were bled at regular intervals and killed on day 49 for histological grading of their thyroids. MMI alone (group 3) or with T4 (group 4) before disease induction significantly reduced the severity of the disease, although the effect on circulating antibody levels was less marked in the animals in group 4. In animals given MMI alone (group 5) or with T4 (group 6) after establishment of the disease, MMI again significantly reduced the severity of the established disease, although this effect was less marked in the T4 supplemented animals. MMI significantly impaired the induction and reduced the severity of experimental autoimmune thyroid disease in August rats. The ability of MMI to influence the autoimmune process may have important implications for the use of this and other agents that act on the immune system in the management of human autoimmune disease.

The influence of methimazole on thyroglobulin-induced autoimmune thyroiditis in the rat.

Several studies have suggested that iodide may increase thyroiditis and autoantibody synthesis. We have investigated the effect of iodide in vitro at physiologically relevant concentrations on immunoglobulin synthesis by normal human peripheral blood lymphocytes stimulated with pokeweed mitogen. Both the number of cells which synthesised IgG and the amount of IgG released into the culture supernatant increased significantly after culture in a medium with added iodide compared to a medium with added chloride. No effect of increasing concentrations of the added iodide from 10(-3) mM to 10 mM was observed. These findings suggest that iodides may have a role in enhancing antibody synthesis which may be important when programmes of iodide supplementation are introduced into areas which are deficient.

A M McGregor

Papers

Thyroid antibodies are produced by thyroid-derived lymphocytes.

Extrathyroidal sites of autoantibody synthesis in Graves' disease.

The prevalence and progression of autoimmune thyroid disease in the elderly.

The influence of methimazole on thyroglobulin-induced autoimmune thyroiditis in the rat.

Iodide enhances IgG synthesis by human peripheral blood lymphocytes in vitro