Autoimmune polyglandular syndrome type III in monozygotic twins: a case report

Autoimmune polyglandular syndrome is characterized by the coexistence of several autoimmune diseases, affecting predominantly the endocrine glands. Autoimmune polyglandular syndrome type III, as a subdivision of autoimmune polyglandular syndrome type II, is the co-occurrence of autoimmune thyroid disease with other autoimmune disorders without Addison disease. We present a rare case of autoimmune polyglandular syndrome type III in monozygotic twins. One of the twins also had autoimmune leukopenia. To our knowledge, leukopenia is the first mentioned coexistence in the literature of autoimmune polyglandular syndrome.     

Hyperparathyroidism in a patient with autoimmune polyglandular syndrome

Autoimmune hypercalcemia has been reported in only a few cases, and never in the context of autoimmune polyglandular syndrome. A patient with type 1, insulin-dependent diabetes mellitus, Graves' disease, and antiparietal cell antibodies presented with persistent hypercalcemia with inappropriate PTH secretion. Other causes of hypercalcemia were excluded. In this context of two associated organ-specific autoimmune diseases we searched for autoantibodies directed to parathyroid tissue and to calcium-sensing receptor. Anti-parathyroid autoantibodies were detected by indirect immunofluorescence on parathyroid adenomas, and autoantibody against a peptide of the extracellular domain of the calcium-sensing receptor were detected by immunoblotting. Autoimmune hypercalcemia may be another organ-specific feature of autoimmune polyglandular syndrome.     

Update in endocrine autoimmunity

CONTEXT: The endocrine system is a common target in pathogenic autoimmune responses, and there has been recent progress in our understanding, diagnosis, and treatment of autoimmune endocrine diseases. SYNTHESIS: Rapid progress has recently been made in our understanding of the genetic factors involved in endocrine autoimmune diseases. Studies on monogenic autoimmune diseases that include endocrine phenotypes like autoimmune polyglandular syndrome type 1 and immune dysregulation, polyendocrinopathy, enteropathy, X-linked have helped reveal the role of key regulators in the maintenance of immune tolerance. Highly powered genetic studies have found and confirmed many new genes outside of the established role of the human leukocyte antigen locus with these diseases, and indicate an essential role of immune response pathways in these diseases. Progress has also been made in identifying new autoantigens and the development of new animal models for the study of endocrine autoimmunity. Finally, although hormone replacement therapy is still likely to be a mainstay of treatment in these disorders, there are new agents being tested for potentially treating and reversing the underlying autoimmune process. CONCLUSION: Although autoimmune endocrine disorders are complex in etiology, these recent advances should help contribute to improved outcomes for patients with, or at risk for, these disorders.     

Islet cell autoimmunity in youth onset diabetes mellitus in Northern India

We characterised a consecutive cohort of 132 youth onset diabetic individuals (age at onset<30 years, mean duration of disease 5.5+/-6.0 years) from North India, by serological determination of the determination of the islet cell autoantibodies, GAD(65) and IA2, and clinically for coexisting autoimmune thyroid disease, malnutrition and pancreatic calcification. Five types of diabetes were delineated: Type 1 (37%), ketosis resistant (32%), Type 2 (13%), fibrocalculous pancreatopathy (11%) and autoimmune polyglandular syndrome (7%). C-peptide response to glucagon was assessed in a representative subset of 50 patients with Type 1, ketosis resistant, and autoimmune polyglandular syndrome. A total of 22.4% of Type 1 and 30% of autoimmune polyglandular syndrome subjects showed both GAD(65) plus IA-2 autoantibody positivity, significantly more than the 4.7% positivity shown by the ketosis resistant type. However, GAD(65) antibody positivity alone was seen in 38% of ketosis resistant subjects which was significantly more than the 14.2 and 10% positivity seen in Type 1 and autoimmune polyglandular groups, respectively. The fibrocalculous pancreatopathy group showed GAD(65) plus IA-2 autoantibody positivity in 14.2% and GAD(65) autoantibody alone positivity in 7.1%. 26 and 60%, respectively, of the Type 1 and autoimmune polyglandular syndrome groups had thyroid microsomal autoantibody positivity. Type 1 showed significantly less C-peptide response to glucagon when compared to the ketosis resistant and autoimmune polyglandular syndrome groups. The controls and Type 2 diabetic individuals tested negative for islet cell autoimmunity markers. These findings demonstrate a role of islet cell autoimmunity in the pathogenesis of four out of the five clinical types of youth onset diabetes seen in North India.     

Case Report: Autoimmune Polyglandular Syndrome Type 2 Complicated by Acute Adrenal Crisis and Pericardial Tamponade in the Setting of Normal Thyroid Function

We describe herein a 48-year-old Caucasian woman with a history of autoimmune polyglandular syndrome type 2 who presented with pericarditis, pericardial effusion, and pericardial tamponade preceded by acute adrenal crisis in the setting of normal thyroid function. The case highlights the importance of a rare yet important complication of autoimmune polyglandular syndrome type 2 that mandates early recognition and intervention.     

Polyglandular autoimmune syndromes

Dysfunction of multiple endocrine glands may develop as the result of hypopituitarism, various infiltrative disorders, or an organ-specific autoimmune mechanism. When dysfunction of two or more endocrine glands occurs in association with circulating organ-specific antibodies directed against the involved glands, the term polyglandular autoimmune syndrome is applied. Characteristics of polyglandular autoimmunity include specific patterns of disease association and frequently a family history of similar involvement. The principal endocrine components of these syndromes are adrenal insufficiency, autoimmune thyroid disease, insulin-dependent diabetes mellitus, and premature gonadal failure. In addition, primary hypoparathyroidism is a key feature of one form of polyglandular autoimmunity that occurs in children. Several nonendocrine organ-specific autoimmune disorders are also associated with polyglandular autoimmunity, of which pernicious anemia is the most frequent. The underlying abnormality responsible for polyglandular autoimmunity is most likely a defect in T suppressor cell function, but there is evidence that aberrant expression of HLA DR antigens also plays an important role in the pathogenesis of these disorders.     

Autoimmune regulator AIRE: evidence for genetic differences between autoimmune hepatitis and hepatitis as part of the autoimmune polyglandular syndrome type 1

The mechanisms driving the immune-mediated destruction of hepatic tissues in autoimmune hepatitis (AIH) are unknown. Recently the autoimmune regulator (AIRE), a gene associated with the development of the autoimmune polyglandular syndrome type 1 (APS-1), was cloned. About 15% to 20% of APS-1 patients develop hepatitis. However, the role of AIRE mutations in AIH, primary sclerosing cholangitis (PSC), and primary biliary cirrhosis (PBC) is not known. To address this issue patients with AIH (n = 94), PSC (n = 60), and PBC (n = 30) were analyzed for the presence of mutations in exons 6, 8, and 10 of AIRE by single stranded conformation polymorphism and sequence analysis. Autoantibody patterns of patients with defects in AIRE were analyzed by indirect immunofluorescence, enzyme-linked immunosorbent assay and Western blot. Heterozygous mutations of AIRE were identified in 3 patients: a patient with PBC and a patient with AIH type 1 carried a R257X mutation, and a patient with AIH type 2, diabetes mellitus type 1 (IDDM), thyroid disease, and atrophic gastritis carried a G305S mutation in the first PHD ring finger domain of the AIRE protein. None of the 3 patients with a defective AIRE allele showed autoantibodies, which are known to associate with APS-1. These findings show a differential genetic association of autoimmune liver diseases and hepatitis in APS-1. The subgroup of patients with heterozygous mutations in AIRE does not represent patients with an incomplete APS-1 syndrome. However, the Aire gene defect showed that genes involved in the induction of immunologic tolerance provide candidates for etiologic factors in autoimmune liver diseases.     

Polyglandular autoimmune syndrome type II in patients with idiopathic Addison's disease

The frequency of polyglandular autoimmune syndrome Type II, (idiopathic or autoimmune Addison's disease associated with autoimmune thyroid disease, and/or insulin-dependent diabetes mellitus), was retrospectively investigated in 44 patients (26 females and 18 males) with idiopathic Addison's disease (median age at onset 32.5 years, range 8-62; median observation time 17 years, range 0.5-41) evaluated between 1966 and 1988 in the Department of Endocrinology, General Hospital, Malm?. Twenty-two patients (16 females and 6 males) fulfilled the criteria for polyglandular autoimmune syndrome Type II and of these 16 had autoimmune thyroid disease and 9 insulin-dependent diabetes mellitus. In 7 of 9 patients insulin-dependent diabetes mellitus developed prior to Addison's disease, whereas autoimmune thyroid disease was diagnosed before as well as after Addison's disease and with a similar age distribution as Addison's disease. In conclusion, the present study indicates that polyglandular autoimmune syndrome Type II occurs in about 50% of patients with idiopathic Addison's disease and that autoimmune thyroid disease is more common than insulin-dependent diabetes mellitus in these patients. The present study also indicates that insulin-dependent diabetes mellitus precedes Addison's disease in a majority of these patients and usually develops at a young age, whereas autoimmune thyroid disease precedes as well as succeeds Addison's disease and occurs at all ages in these patients.     

Autoimmune thyroiditis--selected etiopathogenic mechanisms

Autoimmune thyroiditis occurs as organ specific autoimmune disease not only as an isolated impairment of thyroid gland, but also linked to many autoimmune endocrinopathies. Genetic predisposition in the area of HLA antigens was followed up by patients with autoimmune thyroiditis diagnosed in this way and it appeared that genetic predisposition in isolated autoimmune thyroiditis is different when compared to the occurrence linked to endocrine polyglandular disease. In selected groups of patients with autoimmune disease also the influence of extraneous factors on the development of the autoimmune process was followed up, namely the influence of heavy metals and the influence of infectious agent--Helicobacter pylori. These factors have a different character of activation of autoimmune thyroiditis too, depending on the character of its manifestation as isolated disorder or in link to autoimmune polyglandular syndrome type II, or in link to the group of polyglandular activation of autoimmunity. To conclude, this study leads to the assumption, that autoimmune thyroiditis is a set of clinical syndromes that depends on the activation of the autoimmune process, rather than a strictly genetically and epigenetically characterized nosological unit.     

An autoimmune polyglandular syndrome complicated with celiac disease and autoimmune hepatitis

Autoimmune polyglandular syndrome (APS) is a combination of different autoimmune diseases. The close relationship between immune-mediated disorders makes it mandatory to perform serological screening periodically in order to avoid delayed diagnosis of additional autoimmune diseases. We studied a patient with type 1 diabetes (T1D) who later developed an autoimmune thyroid disease (ATD) and was referred to our hospital with a serious condition of his clinical status. The patient was suffering from an advance stage of celiac disease (CD), the delay in its diagnosis and in the establishment of a gluten-free dietled the patient to a severe proteincalorie malnutrition. Later, the patient developed an autoimmune hepatitis (AIH). We consider that clinical deterioration in patients with APS should alert physicians about the possible presence of other immune-mediated diseases. Periodic screening for autoantibodies would help to prevent delayed diagnosis and would improve patient’s quality of life.     

Alopecia totalis, Hypotonie und erektile Dysfunktion bei einem 34-jährigen Mann

The occurrence of both autoimmune endocrinopathies and endocrinopathies caused by other reasons is called polyglandular autoimmune syndrome (PAS-syndrome). In a 34 years old man with weakness, weight loss and erectile dysfunction we found low cortisol caused by an autoimmune adrenalitis and low testosterone caused by a hypophysitis with impaired gonadotropin secretion. Thyroid autoantibodies and islet cell autoantibodies without any hormone deficiencies were further signs of a broad endocrine autoimmune syndrome. In the following 11 years the patient developed three autoimmune disorders: paradrenal glandular insufficiency, hypogonadism caused by hypophysitis, Diabetes mellitus type 1. In the same time several non endocrine autoimmune diseases became manifest: alopecia totalis, vitiligo, retrobulbar neuritis and keratoconjunctivitis.     

Pure red cell aplasia: further evidence of T cell clonal disorder

Summary. We report a patient with pure red cell aplasia and type I autoimmune polyglandular syndrome who also had an expansion of suppressor T lymphocytes in the peripheral blood. Southern blotting of DNA from these cells suggested T cell receptor (TCR) γ gene rearrangement. We confirmed true clonality of this by amplification of the gene rearrangement using the polymerase chain reaction and subsequent analysis of the product by gene cloning and DNA sequencing.     

Population genetics and functions of the autoimmune regulator (AIRE).

The autoimmune polyglandular syndrome type 1 (APS1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APS1), is a monogenic autosomal disease with recessive inheritance. It is characterized by chronic mucocutaneous candidiasis, multiple autoimmune endocrinopathies, and ectodermal dystrophies. The defective gene responsible for this disease has been identified and named "autoimmune regulator" (AIRE). The AIRE gene is located on chromosome 21q22.3. At least 45 different disease-causing mutations in AIRE have been discovered. This review summarizes the global distribution of AIRE mutations and the relevance of major mutations to the clinical disorders associated with APS1. We also will review studies on the structure and DNA-binding ability of the AIRE protein and the possible malfunctions of the AIRE protein as a result of major disease-causing mutations.     

Sekundäre Diabetesformen

Other types of diabetes include diabetes forms which are induced by diseases of the pancreas or liver as well as drug-induced diabetes. In this context endocrine disorders as the cause of secondary diabetes are of special clinical interest: On the one hand a chronically insufficient metabolic control of diabetes can change endocrine parameters (e.g. thyroid hormone, growth hormone), while on the other hand acute imbalance of glucose control in diabetic patients could be induced by endocrine diseases. Hyperthyroidism in diabetics leads to increased insulin resistance and reduced insulin secretion, resulting in pronounced hyperglycemia. In contrast, hypothyroidism leads to increased insulin sensitivity and greater risk of hypoglycemia, especially in insulin-dependent diabetes. Pathologically increased growth hormone secretion and diseases of the adrenal gland may have pronounced effects on glucose metabolism. Given the known association between type 1 diabetes and other autoimmune endocrinopathies (polyglandular autoimmune syndrome, PAS), annual screening for these patients and their near relatives is recommended.     

Coexistence of autoimmune polyglandular syndrome type 2 and diabetes insipidus in pregnancy

Autoimmune polyglandular syndromes are rarely diagnosed conditions characterized by the association of at least 2 organ-specific autoimmune disorders. Very few cases of these syndromes have been described during pregnancy. The authors report a case of a patient diagnosed with autoimmune thyroiditis and a history of HELLP (hemolysis, elevated liver enzymes and low platelet) syndrome in a prior pregnancy. After increasing the levothyroxine dose, she developed Addisonian crisis. Normalization of adrenal cortex function resulted in the appearance of diabetes insipidus. This report shows that pregnancy may influence the course of preexisting endocrine disorders and lead to their unmasking. Although the risk of the development of autoimmune polyglandular syndromes during pregnancy is small, they may pose a serious health problem. The possible presence of these clinical entities should be considered in every woman with 1 or more endocrine disturbances.     

Autoimmune Polyglandular Syndrome Type 2: A Rare Condition in Childhood

Autoimmune polyglandular syndrome type 2 is defined as the occurrence of Addison’s disease concomitantly with autoimmune thyroid disease and/or type 1 diabetes mellitus. An 11-year-old boy with Hashimoto’s disease, Addison’s disease, celiac disease and Langerhans islet cell autoimmunity is described in this case report. Treatment of an endocrine disease may also trigger the onset of another endocrine disease. This case report underlines the importance of early recognition and treatment of critical endocrine diseases as well as the necessity to investigate pediatric patients with autoimmune diseases for coexisting conditions. Furthermore, the role of psychological stress as an inducer of autoimmunity was also discussed.     

Autoimmune polyglandular syndrome type 2 induced by treatment with interferon alpha

Interferon α therapy has been reported to result in a variety of autoimmune side effects and to increase the risk of thyroid dysfunction. Autoimmune polyglandular syndromes are rarely described conditions characterized by the combination of at least 2 autoimmune endocrinopathies and nonendocrine autoimmunopathies, differing in the immunologic features of their pathogenesis. In light of research carried out in recent years, it seems that autoimmune polyendocrine syndromes occur much more frequently than previously estimated. In this article, the authors describe autoimmune polyglandular syndrome type 2 composed of autoimmune thyroid disease, Addison's disease and premature ovarian failure in a 37-year old woman after treatment of hairy cell leukemia with interferon α. Because of the underlying disorder, interferon α treatment had to be continued, and therefore the patient was prescribed with levothyroxine, hydrocortisone, fludrocortisone and oral contraceptives. Termination of interferon α therapy was associated with a spontaneous normalization of thyroid and adrenal functions, and therefore levothyroxine, hydrocortisone and fludrocortisone treatment was withdrawn.     

Target proteins in human autoimmunity: cytochromes P450 and UDP- glucuronosyltransferases.

Cytochromes P450 (CYPs) and UDP-glucuronosyltransferases (UGTs) are targets of autoantibodies in several hepatic and extrahepatic autoimmune diseases. Autoantibodies directed against hepatic CYPs and UGTs were first detected by indirect immunofluorescence as antiliver and/or kidney microsomal antibodies. In autoimmune hepatitis (AIH) type 2, liver and/or kidney microsomal (LKM) type 1 autoantibodies are detected and are directed against CYP2D6. About 10% of AIH-2 sera further contain LKM-3 autoantibodies directed against family 1 UGTs. Chronic infections by hepatitis C virus and hepatitis delta virus may induce several autoimmune phenomena, and multiple autoantibodies are detected. Anti-CYP2D6 autoantibodies are detected in up to 4% of patients with chronic hepatitis C, and anti-CYP2A6 autoantibodies are detected in about 2% of these patients. In contrast, 14% of patients with chronic hepatitis delta virus infections generate anti-UGT autoantibodies. In a small minority of patients, certain drugs are known to induce immune-mediated, idiosyncratic drug reactions, also known as 'druginduced hepatitis'. Drug-induced hepatitis is often associated with autoantibodies directed against hepatic CYPs or other hepatic proteins. Typical examples are tienilic acid-induced hepatitis with anti-CYP2C9, dihydralazine hepatitis with anti-CYP1A2, halothane hepatitis with anti-CYP2E1 and anticonvulsant hepatitis with anti-CYP3A. Recent data suggest that alcoholic liver disease may be induced by mechanisms similar to those that are active in drug-induced hepatitis. Autoantibodies directed against several CYPs are further detected in sera from patients with the autoimmune polyglandular syndrome type 1. Patients with autoimmune polyglandular syndrome type 1 with hepatitis often develop anti-CYP1A2; patients with adrenal failure develop anti-CYP21, anti- CYP11A1 or CYP17; and patients with gonadal failure develop anti-CYP11A1 or CYP17. In idiopathic Addison disease, CYP21 is the major autoantigen.