APS type II

This is usually defined as the occurrence of two or more of the major components listed in Table 1; some would widen this to encompass various other features such as pernicious anemia, whereas others would limit the syndrome to those patients who have Addison's disease with thyroid autoimmune disease (Graves' disease or autoimmune hypothyroidism) and/or type I diabetes mellitus. The clinical features of the individual components do not differ from the isolated disorders in their severity or age of appearance. APS type II seems to be inherited as an autosomal dominant condition with incomplete penetrance. There is considerable variation, both within and between families, in the expression of the various components. Affected siblings usually share one or both HLA haplotypes. There is a strong association with HLA-A1, -B8, -DR3, which varies according to the disease components, but is generally greater than with the individual isolated diseases. In addition, HLA-DR4 is increased in frequency in these patients, due to its association with type 1 diabetes mellitus. However, not all patients have these HLA alleles (suggesting that other loci are involved in the predisposition to develop polyendocrinopathy) and some diseases known to be associated with HLA-DR3, such as systemic lupus erythematosus, do not appear to be unusually frequent in APS type II patients.

It is important to be aware that these autoimmune endocrinopathies have a long prodromal phase and may remain subclinical throughout a patient's life; the presence of appropriate antibodies in such patients may be a marker for future endocrine dysfunction and for the presence of a more extensive autoimmune process than can be appreciated clinically. In particular, occult pernicious anemia/ atrophic gastritis may be more frequent than generally appreciated, as revealed by biopsy or achlorhydria after pentagastrin stimulation. Patients with pernicious anemia are especially prone to develop vitiligo.

When considering whether a patient has APS type II, those presenting with Addison's disease are the most likely to have another autoimmune endocrine disorder, 10-25% having gonadal failure, 10-25% type I diabetes mellitus, and 15-25% auto immune thyroid disease. In contrast, patients presenting with autoimmune thyroid disease (which is about 500 times commoner than Addison's disease) are much less likely to have the type II syndrome. This has implications for screening, since it is clearly worth testing patients with Addison's disease, but not thyroid autoimmunity, for the presence of other endocrinopathies. Since the separate components may occur 20 years apart in some individuals with the syndrome, there should be long-term follow-up. It is also essential to advise and, where appropriate, test family members for disease once a patient with type II APS has been identified. Apart from screening, the management of this syndrome is the same as that of patients presenting with the individual endocrine abnormalities.

There are no unique features of the T cell or antibody response against endocrine tissues in patients with APS type II compared to those with the isolated disorder. The major adrenal autoantigen in both APS type II and isolated Addison's disease is the 21-hydroxylase enzyme, although other P450 enzymes are also targets in a small proportion of patients. The closest animal models of APS type II are the non-obese diabetic (NOD) mouse and BB strain rat: both animals develop autoimmune diabetes mellitus and have a low but significant prevalence of autoimmune thyroiditis, but adrenalitis is absent. The obese strain (OS) chicken is a close model of Hashimoto's thyroiditis and adrenal and gastric autoantibodies have been reported although tissue destruction does not occur.

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