Autoimmune hypophysitis: an underestimated disease in search of its autoantigen(s).

Autoimmune diseases encompass about 85 conditions in which the patient’s own immune system attacks itself, rather than foreign, antigens and directly causes pathology. These diseases can affect virtually any site in the body and are now among the top 10 causes of morbidity in women (1). Some autoimmune diseases, such as Hashimoto’s thyroiditis, rheumatoid arthritis, Graves’ disease, and systemic lupus erythematosus are common, with an estimated population prevalence of approximately 0.5% (2). Others such as birdshot retinochoroidopathy, autoimmune hypoparathyroidism, and relapsing polychondritis are true rarities. Autoimmune diseases tend to cluster in certain families and even occur together, so the presence of one disorder increases the patient’s risk of developing a second or a third disorder (3). The common denominator in autoimmune diseases is the mononuclear (mainly lymphocytic) infiltration of the target organ, ultimately leading to destruction of the normal architecture and loss of function. Also common is the presence of circulating autoantibodies, which are much more numerous than autoimmune diseases and are constantly being discovered. Autoantibodies are at present the only immunological assessment performed in the clinical laboratory to diagnose and monitor autoimmune diseases, because assays aimed at T lymphocytes, often the key pathogenic players, have yet to become mainstream. More recently, autoantibodies have been used to identify individuals at risk for developing a particular autoimmune disease (4). This concept of predictive autoantibodies, now well established for type 1 diabetes, is finding application in an increasing number of autoimmune diseases, opening new opportunities and challenges. Autoantibodies can be measured by a variety of technologies, including immunofluorescence, immunoblotting, ELISA, fluid phase radioassays, and, more recently, antigen arrays. Immunofluorescence, one of the oldest technologies, is not very sensitive and is based on a subjective and weakly quantitative interpretation of the results. It is useful, however, when the autoantigen(s) recognized by the autoantibodies are not yet known. Immunofluorescence reveals the presence in the patient serum of “histological autoantibodies” that bind to a normal organ or tissue used as substrate. For example, in the mid 1970s autoantibodies reacting against normal human pancreatic islets were found in the serum of patients with type 1 diabetes (5, 6). Subsequently, it was discovered that key autoantigens were the 65-kDa form of glutamic acid decarboxylase and the protein tyrosine phosphatase ICA512. Identification of such autoantigens and “biochemical autoantibodies” has made it possible to develop assays that are objective, sensitive, quantitative, and with high throughput. This issue of the journal includes a study from the University of Pisa, one of the largest endocrine clinics in Europe, on the prevalence and functional significance of pituitary autoantibodies in patients with autoimmune thyroid diseases. Manetti et al. (7) recruited a large number of cases with autoimmune thyroiditis (707 with Hashimoto’s thyroiditis and 254 with Graves’ disease) and an adequate number of controls (269 nontoxic nodular goiters, 60 toxic nodular goiters, and 135 healthy subjects), and measured cross-sectionally the presence and titer of pituitary autoantibodies by immunofluorescence. They found that pituitary autoantibodies are 12 times more common in thyroiditis patients than in controls (11% vs. 0.9% prevalence). The Pisa study confirms with greater power the findings of six other similar studies (8–13). A meta-analysis of these seven studies shows that pituitary antibodies are, on average, present in about 20% of autoimmune thyroiditis patients. The Mantel-Haenszel pooled estimate indicates that the risk of having pituitary antibodies in patients with autoimmune thyroiditis is 5-fold higher than in controls (95% confidence interval between 3.4and 7.2-fold). Some study heterogeneity is observed (P 0.084), with one study indicating a 35-fold risk (10) and another a 2.8-fold risk (13), likely due to the use of different methodologies. This heterogeneity is higher when only the Hashimoto’s thyroiditis cases are analyzed (P 0.002) and lower when only the Graves’ cases are included (P 0.400), perhaps reflecting the fact that the diagnostic criteria of Graves’ disease are more uniform than those of Hashimoto’s thyroiditis. The Pisa study also highlights the increasing complexity of pituitary autoimmunity. In their patients, only GH secretion was impaired, whereas the other anterior pituitary hormones (ACTH, TSH, gonadotropins, and prolactin) were unaffected. In contrast, in the classic form of pituitary autoimmunity, called autoimmune (or lymphocytic) hypophysitis, there are typically multiple pituitary defects. Three hundred seventy-nine patients with primary autoimmune hypophysitis have been reported from the original description in 1962 to October 2004 (reviewed in Ref. 14), and 81 additional patients have been identified since then (15). In the total 460 patients, ACTH deficiency is the most common abnormality (present in 57% of the cases), followed by TSH (49%), gonadotropins (52%), GH (39%), and prolactin deficiencies (23%). Patients with histologically proven hypophysitis rarely have isolated deficiencies, such as lacking only ACTH (16, 17) or only TSH (18, 19). In recent years, however, the presence of pituitary antibodies in patients with idiopathic GH deficiency (8) and secondary hypogonadism (20) has been reported, suggesting that the spectrum of autoimmune hypophysitis is wider than previously appreciated. The Pisa JCEM is published monthly by The Endocrine Society (http://www. endo-society.org), the foremost professional society serving the endocrine community. 0021-972X/07/$15.00/0 The Journal of Clinical Endocrinology & Metabolism 92(6):2038–2040 Printed in U.S.A. Copyright © 2007 by The Endocrine Society doi: 10.1210/jc.2007-0808