Fetal nutrition and adult disease

Economic history has contributed significantly to the formulation of economic theory.* Among the economists who have found history an important source for their ideas are Smith, Malthus, Marx, Marshall, Keynes, Hicks, Arrow, Friedman, Solow, and Becker. Failure to take account of history, as Simon Kuznets (1941) stressed, has often led to a misunderstanding of current economic problems by investigators who have not realized that their generalizations rested upon transient circumstances. Nowhere is the need to recognize the role of long-run dynamics more relevant than in such pressing current issues as medical care, pension policies, and development policies.

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Economic growth, population theory, and physiology: the bearing of long-term processes on the making of economic policy

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

The thyroid gland is the most common organ affected by autoimmune disease. Other autoimmune diseases, most notably type 1 diabetes mellitus, are increasing in incidence. It is unknown whether autoimmune thyroid diseases are following the same pattern. This review summarizes studies of autoimmune thyroid disease incidence and prevalence since 1950, not only for these measures of occurrences, but also for commenting on identified risk factors for thyroid autoimmunity. We find that incidence of autoimmune thyroid disease is currently higher than in historic series although the studies are so variable in design, patient population, disease definition, and laboratory methods that it is impossible to tell whether this difference is real. Further research is required to assess the possibility of changing disease patterns of autoimmune thyroid disease as opposed to simple changes in diagnostic thresholds.

The incidence and prevalence of thyroid autoimmunity.

In order to determine whether the geographical distribution of autoimmune thyroid disease in Britain is influenced by the pattern of iodine intake, the prevalence of subclinical disease (detectable antithyroid antibodies in biochemically euthyroid individuals) has been measured in female blood donors from seven towns in England and Wales previously characterised in terms of past and present iodine intake. Thyroglobulin antibody and thyroid peroxidase antibody were measured by highly sensitive assays which are based on the direct interaction between antibody and radiolabelled antigen. Excluding cases of overt thyroid disease (biochemically hypo- or hyperthyroid with thyroid antibodies), the overall prevalences of the antibodies in sera from the 698 female blood donors were 17.8% for thyroglobulin antibody and 17.8% for thyroid peroxidase antibody. Both antibodies were found in 12.3% of the female blood donors. In contrast, the prevalences of thyroglobulin antibody and thyroid peroxidase antibody were 41 and 43%, respectively, in the 117 female relatives of 18 probands with autoimmune thyroid disease, but the highest prevalences were observed in groups of women patients with Graves' disease (N = 39) or Hashimoto's disease (N = 39) (51, and 97% for thyroglobulin antibody, respectively, and 72 and 97% for thyroid peroxidase antibody, respectively). Antibody prevalence increased with age in the female blood donors rising from 10.6% at age 18-24 to 30.3% at age 55-64 for thyroglobulin antibody and from 14.9% at age 18-24 to 24.2% at age 55-64 for thyroid peroxidase antibody. Geographical differences in the prevalences of both antibodies were not significant and did not correlate with either the previous goitre prevalence or with current differences in iodine intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Geographical distribution of subclinical autoimmune thyroid disease in Britain: A study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase

To determine whether fetal and infant growth could influence susceptibility to autoimmune disease in adults, the occurrence of thyroid autoantibodies and autoimmune thyroiditis was studied in 305 women, aged 60-71, born in Hertfordshire and for whom details of birthweight, infant growth, and feeding were routinely recorded. Thyroglobulin autoantibody was detected in 37% of the women, thyroid peroxidase autoantibody in 41%, and autoimmune thyroiditis, defined as biochemical or clinical hypothyroidism in association with thyroid autoantibodies, in 5.6%. The proportion of women with thyroglobulin and thyroid peroxidase autoantibodies fell with increasing birthweight but was not related to weight at 1 year of age or the method of infant feeding. The prevalence of both autoantibodies rose with increasing adult body mass index but fell as the waist to hip ratio increased. These results demonstrate the importance of early environment in determining the susceptibility to autoimmune thyroid disease. The contrasting effects of adult body mass index and waist to hip ratio on antibody prevalence could be explained by their associations with different hormonal environments.

Fetal growth and autoimmune thyroid disease

Recently the tendency to produce autoantibodies to thyroid peroxidase (TPO Ab) and thyroglobulin (Tg Ab) was shown to be inherited as an autosomal dominant characteristic in women but not in men. Because of potential bias in this study which was carried out in families with autoimmune thyroid disease (AITD), the inheritance of thyroid autoantibodies has been evaluated in 49 families unselected for autoimmune thyroid disease. Among these families (24 with facioscapulohumeral disease, 10 with Friedreich's ataxia, and 15 with schizophrenia) the prevalences of TPO Ab and Tg Ab were 27.8% and 26.7%, respectively, in women and 9.2% and 11.7%, respectively, in men. In 40 families where one or more individual had TPO Ab and/or Tg Ab, segregation analysis showed that the tendency to make antibodies was consistent with a Mendelian dominant trait in women but not in men. In young women, however, the prevalence of both TPO Ab and Tg Ab increased with age, rising from 14% and 10%, respectively, at age 15-24 to 35% and 40% at age 35-44. As this is inconsistent with a simple dominant hypothesis, a further segregation analysis by age was carried out in the families unselected for thyroid disease together with 16 pedigrees with AITD previously studied and two additional large AITD families. The results of the combined analysis provided strong support for the hypothesis of dominant inheritance but also showed significant reduction in gene expression among women aged 15-24 yr.

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease.

A panel of human monoclonal thyroglobulin (Tg) autoantibodies (TgAAb) has been used to analyze autoantigenic determinants on human Tg and to investigate the relationship between variable (V) region gene sequences and epitope specificity Two monoclonal TgAAb bound to the same (or closely related) epitope on Tg, and these were defined as type I TgAAb Three other monoclonals bound to a different site and were defined as type II TgAAb Inhibition studies with mixtures of type I and type II monoclonal TgAAb (Fab)2 preparations indicated that a mixture of the (Fab)2s almost completely inhibited (> 75%) labeled Tg binding to intact TgAAb in the sera of apparently healthy blood donors and patients with autoimmune thyroid disease (AITD) Type I TgAAb predominated in apparently healthy blood donors' sera, whereas type II TgAAb predominated in AITD sera Analysis of V region gene sequences of the TgAAb indicated that a range of light chain and heavy chain genes from different gene families was used Furthermore, the same germline genes that are used by TgAAb are also well represented in the genes coding for other self- and nonself-reactive antibodies No homology in terms of light chain and heavy chain gene families, germline gene usage, or complementarity determining region sequences was observed in TgAAb directed to the same or closely related epitopes Our studies show that TgAAb are directed to two major conformational epitopes on the Tg molecule and that the proportion of TgAAb directed to these epitopes in apparently healthy blood donors and that in patients with AITD appear to be different TgAAb derived from different germline genes and with different complementarity determining region sequences can display similar epitope specificity, and this indicates that AAb directed to the same or a closely related epitope show considerable heterogeneity at the molecular level

L. Prentice

Papers

Geographical distribution of subclinical autoimmune thyroid disease in Britain: A study using highly sensitive direct assays for autoantibodies to thyroglobulin and thyroid peroxidase

Fetal growth and autoimmune thyroid disease

Autosomal dominant inheritance of autoantibodies to thyroid peroxidase and thyroglobulin--studies in families not selected for autoimmune thyroid disease.

Monoclonal thyroglobulin autoantibodies: variable region analysis and epitope recognition.

Autosomal dominant inheritance of the tendency of develop thyroid autoantibodies.