Polyglandular autoimmune syndrome, type 2

We have described two patients with Addison's disease and associated endocrinopathies, a condition termed polyglandular autoimmune (PGA) syndrome, type 2. One of our patients also had autoimmune hypothyroid disease, and the other had premature gonadal failure and Hashimoto's thyroiditis. This syndrome shows that glandular disorders tend to occur together. It has been suggested that an HLA-associated genetic predisposition coupled with environmental factors triggers an autoimmune process resulting in glandular hypofunction or hyperfunction. We stress the necessity for evaluation of every individual with idiopathic Addison's disease for associated endocrinopathies.     

Diffuse toxic goiter]

Diffuse toxic goiter is a common disease of the thyroid gland. As organospecific autoimmune condition the disease is not infrequently combined with endocrine ophthalmopathy and in this connection a more precise preparation of the patients to surgery is found to be mandatory. Elderly persons demonstrate atypical patterns of the disease course (insignificant enlargement of the gland, manifest depression, isolated cardial disorders without other symptoms of thyrotoxicosis, resistance to thyrostatic treatment). The patients need a life-long dispensary follow-up as diffuse toxic goiter is a condition of a relapsing type.     

POLYSEROSITIS AS A RARE COMPONENT OF POLYGLANDULAR AUTOIMMUNE SYNDROME TYPE II

Polyglandular autoimmune (PGA) syndromes (types I and II) may affect various endocrine and non-endocrine organs in the body. In the commoner PGA type II, primary adrenal insufficiency, autoimmune thyroid disease and type I diabetes mellitus are the most frequent manifestations. Serositis with pericardial or pleural involvement is not a well known component of the disease. Here, we report a 21-year-old man who first presented with a pleuropericardial effusion and Graves' disease, and who then developed type I diabetes mellitus.     

Autoimmune polyglandular syndrome, type II

The combination of autoimmune adrenal insufficiency with autoimmune thyroid disease and/or type 1 autoimmune diabetes mellitus defines autoimmune polyglandular syndrome, type II. The conditions may occur in any order, and diagnosis is confounded by the nonspecific nature of the symptoms of adrenal insufficiency and hypothyroidism. The disorder is not common, but consequences can be life threatening when the diagnosis is overlooked. The conditions usually present in midlife, and women are affected more often than men. The cosyntropin test is recommended for diagnosing adrenal insufficiency, which must be present to diagnose this syndrome. Hormone therapy for each condition is similar to treatment that would be provided if the conditions occurred separately, except that treatment for adrenal insufficiency must be given before thyroid therapy is started when the conditions occur together.     

Receptors, antibodies, and disease

Abnormal antibody production is now recognized as the basis of specific endocrine and neurological diseases and their complications. Among the autoimmune diseases, the best understood from a mechanistic point of view are myasthenia gravis, Graves' disease, several variants of insulin resistance, and a variant of bronchial asthma. In each of these human disorders, the clinical symptoms can be traced to the actions of antireceptor antibodies produced by a deranged immune system. The autoantibodies produced in these diseases are functionally heterogeneous. They may produce the clinical symptoms of hormone or neurotransmitter insufficiency either by blocking the binding of these agents to target cell surface receptors or by accelerating the internalization and degradation of these receptors. In other cases, the autoantibodies may produce the clinical signs of hormone excess by mimicking the actions of the hormone, in an uncontrollable fashion. In some cases, functionally different types of autoantibodies will appear in the same patient at different stages of the disease. For all of these autoantibodies, of whatever function, assays for their presence in serum are available, in forms suitable for clinical chemists, as well as for researchers; these will be described in this review. In addition to the known anti-receptor autoimmune diseases, there are a large number of other autoimmune diseases for which there is fragmentary evidence that their clinical symptoms have an anti-receptor autoantibody etiology. Several examples of this group will be discussed, and assays suitable for establishing the presence of anti-receptor antibodies in the sera of such patients will be provided. The disorders to be considered are: type I diabetes mellitus, chronic atrophic gastritis, autoimmune Addison's disease, autoimmune hypoparathyroidism, type II pseudohypoparathyroidism, resistant ovary syndrome, connective tissue diseases, and the HLA-B8/DR3 antigen haplotype as a potential marker for autoimmune diseases of the anti-receptor type.     

Coeliac disease and autoimmune Addison's disease: a clinical pitfall

BACKGROUND: Coeliac disease has an increased prevalence in a number of autoimmune endocrine conditions. An association between coeliac disease and Addison's disease has been proposed in isolated case reports, but has not been formally studied. AIM: To investigate the extent of this association. DESIGN: Prospective screening of patients with confirmed Addison's disease. METHODS: From central computerized records, we identified all living patients with a diagnosis of autoimmune Addison's disease in the past 30 years and presently attending our affiliated hospitals. After exclusions, 44 were invited to attend for screening. RESULTS: Of 41 patients screened, five (12.2%) had coeliac disease: Three were previously diagnosed coeliacs and this was confirmed on review, including examination of biopsy material. A further two had positive IgA-endomysial antibodies. Histological confirmation was obtained in both cases. Neither had laboratory or clinical evidence of malabsorption. DISCUSSION: In this series of patients with Addison's disease, a higher co-morbidity with coeliac disease was observed than in any previously studied endocrine condition. We recommend that coeliac serology (anti-endomysial and tissue transglutaminase antibody) testing be incorporated routinely into the autoimmune screen for other conditions in patients with Addison's disease.     

Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects

OBJECTIVE: In type 1 diabetes the coexistence with other endocrine diseases and organ-specific autoantibodies has been frequently reported leading to the concept of autoimmune polyendocrine syndrome (APS). In addition, an association of type 1 diabetes with celiac disease has been described. These disorders share a similar genetic background, and first-degree relatives of type 1 diabetic patients may also be affected significantly. Screening for specific antibodies allows early diagnosis of these disorders. RESEARCH DESIGN AND METHODS: In the present cross-sectional study, we analyzed sera from 197 recent-onset type 1 diabetic patients at the time of diagnosis, 882 first-degree relatives, and sera of 150 healthy control subjects for prevalence and co-occurence of the following antibodies (method): insulin autoantibodies (radioimmunoassay); GAD and IA-2 antibodies (radioligand assay); islet cell antibody, anti-adrenal cortex antibodies, and anti-gastric parietal cell antibodies (indirect immunofluorescence); anti-thyroglobulin and anti-thyroid peroxidase antibodies; and gliadin IgG/A and tissue-transglutaminase IgA (enzyme-linked immunosorbent assay). RESULTS: The overall frequency of gastric patietal cell antibodies and adrenal antibodies did not differ significantly among groups. In contrast, type 1 diabetes-associated antibodies and thyroid antibodies were significantly more frequent both in recent-onset type 1 diabetic patients and in the group of first-degree relatives (P < 0.05). The prevalence of gliadin IgG/IgA and transglutaminase IgA was significantly higher in the group of recent-onset type 1 diabetic patients (P < 0.05), but the difference between first-degree relatives and control subjects did not reach statistical significance. Focusing on the coexistence of antibodies, the group of recentonset type 1 diabetic patients presented with 27.4% of the subjects testing antibody-positive-specific for two or more of the envisaged disorders (i.e., type 1 diabetes, autoimmune thyroiditis, and celiac disease) compared with 3.1% in the group of first-degree relatives and 0 of 150 in the control population (P < 0.05). CONCLUSIONS: We conclude that, in an active case-finding strategy, recent-onset type 1 diabetic patients should be routinely screened at least for concomitant autoimmune thyroid disease and additionally for celiac disease. Screening in their first-degree relatives should include at a minimum the search for thyroid autoimmunity in addition to screening for pre-type 1 diabetes.     

Hirschsprung disease: A component of the familial cancer syndrome multiple endocrine neoplasia type 2a

Hirschsprung disease is a congenital condition characterized by a mechanical obstruction caused by inadequate motility in parts of the intestine. This condition can result from mutations in any one of several different genes operating either alone or in combination. Hirschsprung disease has been identified in families with the cancer syndrome multiple endocrine neoplasia type 2a, and it may be the first presentation of the syndrome. Parents of newborns diagnosed with Hirschsprung disease should be counseled on the possible presence of a genetic mutation to therearrangedtransfection (RET) gene on chromosome 10 that predisposes individuals to this hereditary cancer. Risk management strategies can begin early in life to prevent cancer morbidity and mortality. Copyright 2002, Elsevier Science (USA). All rights reserved.     

Is pancreatic diabetes (type 3c diabetes) underdiagnosed and misdiagnosed?

Exocrine pancreatic insufficiency is frequently associated with diabetes, with high prevalence in both insulin-dependent or insulin-independent patients. Exocrine pancreatic failure has often been perceived as a complication of diabetes. In contrast, recent clinical observations lead to the notion that nonendocrine pancreatic disease is a critical factor for development rather than a sequel to diabetes. The incidence of diabetes caused by exocrine pancreatic disease appears to be underestimated and may comprise 8% or more of the general diabetic patient population. Nonendocrine pancreas disease can cause diabetes by multiple mechanisms. Genetic defects have been characterized, resulting in a syndrome of both exocrine and endocrine failure. Regulation of beta-cell mass and physiological incretin secretion are directly dependent on normal exocrine function. Algorithms for diagnosis and therapy of diabetes should therefore address both endocrine and exocrine pancreatic function.     

Primary hyperparathyroidism with multiple parathyroid gland enlargement: review of 53 cases.

Of 53 patients who had hyperparathyroidism assocated with multiple parathyroid gland enlargement, 39 (74%) had primary hyperparathyroidism without clinical or laboratory evidence of associated endocrine gland dysfunction, 2 had documented familial primary hyperparathyroidism, and 12 had hyperparathyroidism as part of the multiple endocrine neoplasia syndrome. When last studied, 31 of the 39 patients with nonfamilial hyperparathyroidism had normal serum calcium levels, 3 had permanent hypoparathyroidism, 2 had recurrent hyperparathyroidism, and 3 were lost to follow-up. The two patients with familial hyperparathyroidism were treated by removal only of enlarged parathyroid glands, and in each, hyperparathyroidism recurred. Five patients with multiple endocrine neoplasia, type 1, were treated by removal only of enlarged parathyroid glands, and hyperparathyroidism recurred in four. Four patients with multiple endocrine neoplasia, type 1, were treated by removal of three or more parathyroid glands, and there were no instances of recurrent hyperparathyroidism. In one patient, permanent hypoparathyroidism developed. Three patients with multiple endocrine neoplasia syndrome, type 2, had total parathyroidectomies as a part of thyroidectomy for medullary thyroid carcinoma. In each patient, permanent hypoparathyroidism developed. When primary hyperparathyroidism occurs in the absence of a definite history of polyendocrine or familial disease, only the glands that are definitely enlarged should be removed, and normal-appearing glands should be tagged rather than risk the possibility of permanent hypoparathyroidism that may attend routine subtotal parathyroid gland excision.     

Chronic fatigue syndrome: an endocrine disease off limits for endocrinologists?

Endocrinologists were not included in the multidisciplinary working groups that prepared two recent reports on chronic fatigue syndrome, despite its unequalled clinical overlap with Addison's disease, which is a classic endocrine disorder. The failure to include at least one endocrinologist in those panels may explain why in their extensive reports there is not a single word about the 42 clinical features that chronic fatigue syndrome shares with Addison's disease, including all the signs and symptoms listed in the case definition of this syndrome.     

Reactivation of Epstein-Barr virus in Sjögren’s syndrome

Summary Sj?gren’s syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration and destruction of salivary and lacrimal glands. This condition may be limited to glandular tissues or may be associated with other autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosus. Since the environmental factors that initiate SS are unknown, we have investigated the potential role of Epstein-Barr virus (EBV), cytomegalovirus (CMV) and other viruses. We observed that epithelial cells in salivary gland biopsies of SS patients contained antigens reactive with monoclonal antibodies against EBV-associated antigens. These antigens were not found in other tissues of SS patients and were absent in salivary gland biopsies from normals and patients with other autoimmune diseases lacking SS. Also, the content of EBV DNA in the saliva of SS patients was significantly greater than in age and sex-matched controls or individuals with other autoimmune disorders. These studies provide one of the first examples where a specific viral agent may be implicated in perpetuating a chronic autoimmune disease. However, great caution must be used before an etiologic role can be attributed to an ubiquitous agent such as EBV. This is publication 4923BCR of the Research Institute of Scripps Clinic, La Jolla, CA. Supported by grants AR33983 and RR00833 and gifts from the Josephine Scripps and Kieckhefer Foundations.     

Atypical autoimmune polyglandular syndrome type 3 overlapped by chronic HCV infection resulting in carcinogenesis and fatal infection

The case of a woman with insulin-dependent diabetes mellitus, autoimmune thyroiditis, atrophic gastritis, pernicious anemia, and immunologic thrombocytopenic purpura consisting of autoimmune polyglandular syndrome type 3 associated with a history of gonadal failure is reported. Hepatitis C viral infection added xerophthalmia, lymphocytic sialadenitis, and exacerbation of idiopathic thrombocytopenic purpura. This unique disease constellation was complicated with splenic marginal zone lymphoma and gastric carcinoids. A lung infection, initially treated on an outpatient basis, proved fatal to the patient.     

Metabolic syndrome and autoimmune diabetes: action LADA 3

OBJECTIVE—The purpose of this study was to estimate whether prevalence of metabolic syndrome in adult European diabetic patients is associated with type of diabetes.RESEARCH DESIGN AND METHODS—A consecutive series of patients attending hospital-based diabetes clinics were assessed for the frequency of metabolic syndrome and compared with population-based control subjects as part of the Action LADA study. In total, 2,011 subjects (aged 30–70 years) were studied, including 1,247 patients with recent-onset type 2 diabetes without glutamic acid decarboxylase autoantibodies (GADAs), 117 non–insulin-requiring patients with GADAs who had not received insulin therapy for at least 6 months after diagnosis (designated latent autoimmune diabetes of adults [LADA]), 288 type 1 diabetic patients, and 359 normal subjects.RESULTS—Frequency of metabolic syndrome was significantly different in patients with type 1 diabetes (31.9%) and LADA (41.9%) (P = 0.015) and in both conditions was less frequent than in type 2 diabetic patients (88.8%) (P < 0.0001 for each). Eliminating glucose as a variable, the prevalence of metabolic syndrome was similar in patients with autoimmune diabetes (type 1 diabetes and/or LADA) (17.3%) and control subjects (23.7%) but remained more common in type 2 diabetic patients (47.8%) (P = 0.001 for all groups). In both type 1 diabetic patients and those with LADA, individual components of metabolic syndrome were similar but less common than in type 2 diabetic patients (P < 0.0001 for each).CONCLUSIONS—The prevalence of metabolic syndrome is significantly higher in type 2 diabetic patients than in patients with LADA or adults with type 1 diabetes. Excluding glucose as a variable, metabolic syndrome is not more prevalent in patients with autoimmune diabetes than in control subjects. Metabolic syndrome is not a characteristic of autoimmune diabetes.Type 1 diabetes is an autoimmune disease in which insulin deficiency results from immune-mediated destruction of insulin-secreting islet cells. The majority of patients with type 1 diabetes have autoantibodies in their peripheral blood, and these autoantibodies can predict the disease. Autoimmune diabetes, as characterized by these autoantibodies, such as glutamic acid decarboxylase autoantibodies (GADAs), is the most prevalent form of diabetes in children and also occurs in a proportion of patients who initially present with adult-onset non–insulin-requiring diabetes, also called latent adult-onset autoimmune diabetes (LADA) (1).Because glucose disposal and blood glucose are determined by both insulin secretion and insulin action, it follows that insulin sensitivity could be important in the pathogenesis of autoimmune diabetes. Insulin sensitivity has not been studied in detail in autoimmune diabetes, although studies suggest that its loss may occur in established disease as well as in the pre-diabetic phase (2–5). Loss of insulin sensitivity is difficult to assess epidemiologically but is reflected in the cluster of metabolically related cardiovascular risk factors that together comprise the metabolic syndrome and include altered glucose levels, central obesity, dyslipidemia, and hypertension. Several groups, including the International Diabetes Federation (IDF) and the National Cholesterol Education Program (NCEP), with Adult Treatment Panel III (6), have proposed their own definitions for the metabolic syndrome.LADA is clearly distinct from type 2 diabetes, in that LADA is associated with histocompatability (HLA) genes, diabetes-associated autoantibodies, reduced insulin secretion, no need for insulin therapy initially after diagnosis, and less prevalence of metabolic syndrome (7–9). The key question is whether LADA is distinct from type 1 diabetes (1,10,11), that is, whether LADA is one end of a rainbow of pathophysiological variations encompassing autoimmune diabetes with a frequency of metabolic syndrome similar to that of childhood-onset type 1 diabetes or whether LADA is a distinct form of autoimmune diabetes that resembles type 2 diabetes, showing evidence of insulin resistance with a high frequency of metabolic syndrome (1). Therefore, the aim of this study was to test whether individuals with type 2 diabetes and autoimmune diabetes (incorporating type 1 diabetes and LADA) have a higher frequency of metabolic syndrome than normal subjects, and our hypothesis was that they would.     

抗核抗体谱在自身免疫性疾病中的临床应用

目的 探讨抗核抗体谱在自身免疫病中的应用价值.方法 ANA 检测采用间接免疫荧光法,ENA多肽抗体谱用免疫印迹法.结果 729例患者中,有58例自身免疫病患者,其中SLE 31例,混合性结缔组织病12例,干燥综合征13例,硬皮病和皮肌炎各1例.所有自身免疫病患者的ANA均为阳性,但SLE患者的ENA抗体谱中可显示抗nRNP、抗Sm、抗SSA、抗SSB、抗dsDNA等抗体阳性;而干燥综合征患者仅抗SSA或抗SSB抗体阳性;皮肌炎患者仅显示抗Jo-1抗体阳性;硬皮病患者仪显示抗Scl-70抗体阳性.结论 ENA抗体谱对种自身免疫病的诊断具有重要意义.     

Endocrine autoantibodies

The autoantibody assays that exist and that are being refined are of increasing importance to a broad spectrum of endocrine disorders. This is particularly true for type IA diabetes, which is one of the best-studied organ-specific autoimmune diseases. Autoantibodies are used as valuable markers in prediction and prevention studies of type IA diabetes.Autoantibodies related to other endocrine organs are also important because multiple related autoimmune endocrine and non-endocrine disorders are increased in frequency in patients and their families with autoimmunity. The availability of highly sensitive and specific autoantibody assays for the various endocrine disorders can allow physicians to better diagnose and promptly treat these conditions.     

Antibodies against double-stranded DNA and development of polymyositis during treatment with interferon

Alpha interferons have become effective palliative treatments for patients with neuroendocrine tumours such as carcinoids and endocrine pancreatic tumours. However, several reports indicate an increased incidence of both autoantibodies and autoimmune diseases in patients treated with interferon-alpha (IFN-alpha). We studied the development of antibodies against double-stranded DNA (dsDNA) and clinical signs of autoimmune disease in 214 patients with malignant carcinoids or endocrine pancreatic tumours consecutively admitted for treatment with IFN-alpha. Seventeen patients (8%) developed antibodies against dsDNA, predominantly females (12 females and 5 males). One patient had clinical and laboratory signs of polymyositis. Among the other 16 patients, three developed hypothyroidism and in six patients the anti- dsDNA autoantibodies normalized despite continuing therapy. Although a significant number of patients developed autoantibodies against dsDNA, overt autoimmune disease related to these antibodies is a rare event and many patients spontaneously normalize these titres despite continuing IFN-alpha treatment.      

Autoimmune polyglandular syndromes

Autoimmune polyglandular syndromes are classified into three types. Type I occurs in childhood and is characterized by at least two of the following: chronic mucocutaneous candidosis, adrenal failure and hypoparathyroidism. There is also an association with chronic active hepatitis. Type II usually develops in adulthood and is characterized by adrenal failure plus hypothyroidism or diabetes mellitus, or both. Type III consists of thyroid disease and one other organ-specific autoimmune disorder. This classification has potential usefulness in patient management and family screening for autoimmune endocrine diseases.     

Comment prendre en charge les tumeurs carcinoïdes gastriques ?

Most gastric well-differentiated neuroendocrine tumors (NETs) are located in the corpus part of the stomach. Two types are frequent: type 1 which is associated with autoimmune fundic atrophic gastritis due to the pernicious anemia where hypergastrinemia triggers fundic endocrine cell hyperplasia then NETs and type 3 (sporadic NETs) without any underlying disease (no hypergastrinemia, no fundic atrophic gastritis, no fundic endocrine cell hyperplasia). Most type 1 gastric NETs are benign, multiple, small (<1 cm) and are either not resected or endoscopically resected. Morphological investigations (endoscopic ultrasound, somatostatin receptor scintigraphy) are only indicated for tumors >1 cm. Type 3 NETs are most often invasive, malignant and must be managed as cancers of similar size. Type 2 NETs associated with the Zollinger-Ellison syndrome and multiple endocrine neoplasia type 1 are very rare. These underlying diseases are always known before gastric NETs diagnosis. The main aims of the management of welldifferentiated NETs are first to differentiate types 1 and 3, i.e. to search for pernicious anemia, and secondly to be harmless due to the benignity of type 1 tumors.     

Diagnosis and differential diagnosis of hypergastrinemia

The most frequent conditions of hypergastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing unrestrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.