A 25-year-old woman, Mrs WG, was referred to the local endocrine clinic. She had visited her GP complaining of increasing tiredness and fatigue and, over the 4 weeks prior to presentation, had noticed she felt giddy at times, particularly when she got out of bed in the morning or on standing up from a chair. Mrs G was known to have primary hypothyroidism, on thyrox-ine replacement therapy and vitiligo over her forearms and chest. Her most recent set of thyroid function tests were in the normal range. The GP had noted her blood pressure to be 90/45. At the clinic the hypotension was confirmed and on questioning she had noticed increased pigmentation over her knees and around her waistband. A short Synacthen test was performed during which her basal plasma cortisol level was found to be 75 nmol/L and 100 nmol/L 30 minutes after injection of 250 μg of synthetic ACTH (Synacthen). Later her basal ACTH concentration was reported at 550 ng/L and adrenal antibodies were positive, confirming the diagnosis of primary adrenal failure. She was started on glucocorticoid replacement in the form of hydrocortisone and mineralocorticoid replacement with fludrocortisone, following which her symptoms rapidly improved.
Many endocrine conditions have an autoimmune aetiology and patients frequently exhibit antibodies to multiple endocrine organs and have evidence of associated autoimmune disease such as pernicious anaemia, depigmentation of the skin (vitiligo; Fig. 22a) or coeliac disease. Two specific autoimmune polyglandular syndromes are recognized in which there are two or more affected endocrine glands as well as non-endocrine manifestations (Table 22.1):
· PGA 1 presents in children and is an autoimmune recessive disorder;
· PGA 2 (also known as Schmidt’s syndrome) is a familial disorder most commonly seen in women and thought to be HLA DR3 linked.
Autoimmunity may be defined as an attack by the host’s immune system on the host’s own tissues. These attacks may be transient immune reactions to infection, for example, which resolve spontaneously. They may, however, become chronic, with pathological consequences. Endocrine autoimmunity often involves an immune attack on specific endocrine glands, for
example Addison’s disease, Graves’ disease, Hashimoto’s thyroiditis and insulin-dependent diabetes mellitus, where the gland is damaged or destroyed altogether. These are examples of mainly organ-specific autoimmune diseases (Fig. 22b). In systemic autoimmune disease, on the other hand, the immune system attacks several tissues that may be anatomically distant from each other. Examples of systemic autoimmune disease include rheumatoid arthritis, scleroderma and systemic lupus erythematosus (SLE). There may be both organ-specific and systemic components in most, if not all, autoimmune diseases. Some autoimmune diseases may have genetic and/or endocrine components, since some, notably Graves’ disease (thyrotoxicosis), Hashimoto’s thyroiditis, rheumatoid arthritis (RA) and SLE, are more prevalent in women, and the sex hormones, especially estrogens, may be important mediating factors.
Mechanisms of autoimmunity. These are not well understood at the moment, but three important mechanisms have been defined so far: (i) direct antibody-mediated; (ii) T cell- mediated; and (iii) immune complex-mediated (Fig. 22c). While autoimmune diseases might tentatively be classified in terms of these three mechanisms, it is possible that all three are involved in an autoimmune disease.
1. Direct antibody-mediated disease: Graves’ disease is an example of direct antibody action on a gland causing damage. The disease can be passively transferred from a diseased to a healthy organism by the transfer of IgG antibodies. For example, babies born of mother swho have untreated Graves’diseas eexhibit symptoms of thyroiditis until the baby’s system destroys the IgG which had been transferred via the placenta. In severe cases, the baby may be successfully treated using plasma exchange.
2. T cell-mediated disease: Hashimoto’s thyroiditis is an example of this type of endocrine autoimmunity (Fig. 22d). In these patients, autoreactive T cells cause tissue damage in the thyroid by two main mechanisms: (i) they recruit and activate macrophages, which destroy tissues; and (ii) T cells release cytokines, for example tissue necrosis factor (TNF). Possibly, suppressor T-cell function is impaired in these patients, and helper T cells inappropriately stimulate autoantibody production in B cell, including the production of TSH receptor antibod- ies, which bind to the TSH receptor on thyrocytes. In addition to these T cell-mediated effects, iodine uptake and thyroglobulin binding may be directly interfered with by autoreactive antibodies. Furthermore, the inflammation caused by autoimmune reactions may trigger apoptosis in thyrocytes. Thyrocytes, unusually, constitutively express the FAS receptor ligand, which combines with the FAS receptor to cause apoptosis of the thyrocytes.
3. Immune complex-mediated disease: systemic autoimmune diseases, such as SLE, are most probably caused by immune complex-mediated reactions. Patients with SLE have several circulating autoantibodies to both cytoplasmic and nuclear constituents, for example IgG directed against double-stranded nuclear DNA. The cytoplasmic and nuclear antigens may not themselves be pathogenic; a major pathogenic event is the deposition of the immune complexes in tissues such as the kidneys.
Genetic factors. Epidemiological and familial studies of virtually all autoimmune diseases point to a genetic susceptibility. The most important genetic determinant appears to be the major histocompatibility complex (MHC), a series of genes on chromosome 6 that code for antigens, including the human leukocyte antigen (HLA) system. Recent research suggests that there are multiple genetic loci that contribute to autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM). In the case of IDDM, the gene encoding preproinsulin may be a locus for genetic polymorphism that may be associated with susceptibility to IDDM.
Endocrine factors. The possible role of endocrine hormones, for example estrogens, in the aetiology of autoimmune disease is unknown at present, but the sexual dimorphism of the distribution of several autoimmune diseases points to the involvement of the sex hormones. This putative role for sex hormones is given support from the well-known phenomenon of RA remission during pregnancy, and the rebound exacerbation or ‘flare’ of disease after parturition. SLE, as mentioned above, is far more common in women, especially during the reproductive years, and often flares up during pregnancy and after parturition. SLE may be precipitated or flare after commencement of oral contraceptive use. It has been reported that patients with SLE and their first-degree relatives had elevated serum levels of 16α-hydroxyestrone, which is an actively feminizing metabolite of estradiol.