A case of polyglandular autoimmune syndrome type III complicated with autoimmune hepatitis

A 58-year-old woman complaining of finger tremor was referred to our hospital. The diagnosis of Graves' disease was made based on increased free triiodothyronine (18.88 pg/ml) and free thyroxine (7.47 ng/dl), low TSH (<0.005 microIU/ml) and increased TSH receptor binding antibody activity (70.9%). Serum level of AST (62 U/l) and ALT (93 U/l) were increased and liver biopsy revealed linkage of adjacent portal areas by lymphoplasmacytic infiltrates and fibrosis with piecemeal necrosis. Although antinuclear antibody was negative, these findings indicated that she had autoimmune hepatitis (AIH) according to the criteria of the International Autoimmune Hepatitis Scoring System. Slowly progressive type 1 diabetes mellitus (DM) was confirmed by a diabetic response pattern due to 75 g-oral glucose tolerance test, and seropositivity towards anti-glutamic acid decarboxylase (725 U/ml) and islet cell (80 JDF Units) antibodies. This case exhibited an extremely rare combination of three different autoimmune diseases, including Graves' disease, slowly progressive type 1 DM and AIH, and had no known sensitive human leukocyte antigen (HLA) typing or haplotype for these disorders. Although it is common for patients with Graves' disease to exhibit abnormal liver function, it is important to make an accurate diagnosis of AIH because of this life-threatening disorder.     

Holmes-Adie syndrome, autoimmune hepatitis and celiac disease： A case report

A 35-year-old female patient presented with the following symptoms of Holmes-Adie syndrome: photophobia, enlargement of the left pupil unresponsive to light, Achilles areflexia. The pilocarpine test was positive. No tumor or other neurological abnormality was found. She had a 19-year history of autoimmune hepatitis. Flares up were observed following each 3 deliveries. At age of 31 she presented with diarrhea and weight loss. Abdominal tumor was detected by ultrasound. The surgically removed tumor was histologically a benign mesenteric multicystic lymphangioma. Simultaneously, celiac disease was diagnosed. Gluten-free diet resulted in a significant improvement of celiac disease, but not of autoimmune hepatitis. Autonomic neuropathy was proven by standard cardiovascular tests. The patient was a homozygous carrier for HLA DQ2 antigen characteristic for celiac disease and heterozygous for HLA DR3 B8 frequent in autoimmune liver diseases. Our novel observation on association of Holmes-Adie syndrome with autoimmune hepatitis and celiac disease is suggestive for a common immunological background for all three entities present in a patient with mesenteric multicystic lymphangioma.     

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.     

Animal models of autoimmune polyglandular syndrome.

Animal models for autoimmune polyglandular syndrome that are either spontaneous or induced by manipulations are presented. In addition, recent cloning of the autoimmune regulator (AIRE) gene responsible for autoimmune polyglandular syndrome type I, and its homologue in mice, Aire, provided the opportunity to study the effect of this gene on autoimmune diseases by producing knockout mice. These animal models make it possible to perform experiments that cannot be performed in humans, which will increase our understanding of the cause and molecular mechanisms of the autoimmune diseases and lead to the development of effective methods for their prevention and intervention.     

Erythropoietin-deficient anemia associated with autoimmune polyglandular syndrome type I

Autoimmune polyglandular syndrome type I (APS1), a relatively common disorder in some populations, is frequently associated with adrenal insufficiency, hypoparathyroidism, and other endocrine and skin abnormalities. We describe an 18-year-old male with APS1, as documented by genotyping, who presented with hypoparathyroidism and a normocytic, hypoproliferative, isolated anemia. An extensive hematological work-up revealed a low serum erythropoietin, without any other hematological abnormalities. His renal function was normal, and he did not have many of the laboratory or clinical findings associated with an anemia of chronic disease. His anemia was responsive to superphysiologic doses of erythropoietin. We thus suggest that erythropoietin deficiency may be one of the endocrine abnormalities associated with APS1, and clinicians should be cognizant of the association of treatable anemia in patients with APS1.     

Megaoesophagus in a patient with autoimmune polyglandular syndrome Type II

Dysphagia and vomiting are frequently present in untreated Addison's disease. These non-specific symptoms may be due either to the metabolic disorder and myopathy or to disorders associated with Addison's disease. We describe a patient with autoimmune adrenal failure as a feature of autoimmune polyglandular syndrome (APS) type II. This patient was referred initially because of megaoesophagus. The association of megaoesophagus with Addison's disease or any of the three types of APS has not previously been described in humans. The association of megaoesophagus and adrenal failure, however, is known to occur in Allgrove's syndrome, a disease with primary manifestation in childhood characterized by adrenal failure, achalasia and alacrimia. Moreover, there are several reports on the association of megaoesophagus with adrenocortical insufficiency and other autoimmune endocrine diseases in dogs.
Vomiting and dysphagia usually resolve with hormone substitution in patients with isolated Addison's disease. In our patient these symptoms disappeared in spite of the radiological persistence of megaoesophagus, which might have been overlooked if the diagnosis of Addison's disease had been made earlier. The occurrence of megaoesophagus might be more common than previously suspected and we suggest a systematic search for similar findings in other patients with autoimmune Addison's disease, even when minor dysphagia is present.     

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.     

The occurrence of polyglandular autoimmune syndrome type III associated with coeliac disease in patients with sarcoidosis

Abstract. Objectives. To study whether an association between polyglandular autoimmune (PGA) syndrome type III [including autoimmune thyroid disease (ATD) and insulin-dependent diabetes mellitus (IDDM)], coeliac disease and sarcoidosis, exists. Design. In patients with documented sarcoidosis, the presence of the disease constellation of ATD, IDDM and coeliac disease was examined. Setting. The patients were recruited at the Department of Pulmonary Medicine, and the study was conducted at the Department of Endocrinology, Lund University Clinics, General Hospital, Malmö, Sweden. Subjects. Of all patients (n = 89) with documented sarcoidosis attending the Department of Pulmonary Medicine between January 1980 and December 1991, 78 patients (44 males, 34 females; median age at the time of the study 48 years, range 22–81 years; median observation time since the diagnosis of sarcoidosis 120 months, range 1–468 months) were examined in the present study. Results. Amongst the 78 patients with documented sarcoidosis, one female patient was found with PGA syndrome type III, coeliac disease and sarcoidosis. Conclusions. This present patient further indicates the existence of an association between polyglandular autoimmune (PGA) syndrome type III, coeliac disease and sarcoidosis. To determine whether this disease constellation might constitute a new syndrome, further studies on larger groups of patients with sarcoidosis are demanded.     

自身免疫性多内分泌腺病综合征Ⅲ型1例

患者女,28岁,以T1DM、DKA就诊,伴白癜风和毒性弥漫性甲状腺肿（Grave’s病）的临床特点,最终确诊“自身免疫性多内分泌腺病综合征（APS）Ⅲ型”。提示T1DM和自身免疫性甲状腺疾病（AITD）同时发生时,应注意APS存在。     

自身免疫性多发内分泌腺病综合征Ⅰ型研究进展

自身免疫性多发内分泌腺病综合征Ⅰ型(APS Ⅰ)是一种罕见的由于自身免疫调节(AIRE)基因突变导致的常染色体隐性遗传病.其临床表现主要包括,原发性肾上腺皮质功能减退症、甲状旁腺功能减退症和慢性黏膜皮肤念珠菌病,三者中至少存在2个,同时也可能存在其他的内分泌或非内分泌疾病.其治疗主要包括激素替代、抗感染以及免疫抑制疗法,通常预后不佳.近30余年来中国共报道了17例APS Ⅰ患者,对其组成疾病种类及发病率、起病年龄、AIRE基因突变等进行总结,有助于为临床提供参考.     

Overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis complicated with hepatocellular carcinoma

Development of hepatocellular carcinoma (HCC) in patients with autoimmune liver disease is less common than in those with other types of chronic liver disease. Here we report a rare case of overlap syndrome consisting of autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC) that was subsequently complicated with HCC. A 72-year-old man was initially diagnosed as being in the cirrhotic stage of AIH on the basis of blood chemistry tests and histological examinations. Computed tomography and magnetic resonance cholangiography 20?months later showed diffuse stricturing of the intrahepatic bile duct with dilatation of the areas between the strictures, compatible with the findings of PSC, which resulted in a diagnosis of AIH/PSC overlap syndrome. The level of serum protein induced by vitamin K absence or antagonist II increased 22?months later, and HCC was diagnosed by radiological examinations. Four cycles of transarterial infusion therapy with cisplatin were performed, but the patient died one?year later. Sequential overlap of PSC may have played a part in accelerating AIH disease progression, leading to the development of HCC in this patient. Therefore, HCC surveillance may be important in advanced stages of autoimmune disease, especially in the cirrhotic stage.     

Primary biliary cirrhosis and type II autoimmune polyglandular syndrome.

A 45-year-old female was diagnosed with Hashimoto's thyroiditis in 1976 and Addison's disease in 1979. At that time, her antimitochondrial antibody (AMA) level was elevated at 1:32. She subsequently developed premature ovarian failure and type I diabetes mellitus. In 1996, she became jaundiced with a cholestatic enzyme pattern. AMA was positive at a titre of 1:256. A liver biopsy confirmed the diagnosis of primary biliary cirrhosis (PBC). She underwent a liver transplantation in January 1998. This is the first report of PBC in association with type II autoimmune polyglandular syndrome. The association of PBC with other organ-specific autoimmune diseases supports an immune-mediated pathogenesis and may have implications in further studies of PBC.     

A rare case of autoimmune polyglandular syndrome type 3

A 57-year-old female was admitted to our hospital suffering from a lower lip tumor, small ulcers in the arms and alopecia of the head. Because she had type 2 diabetes mellitus (DM) for the past 3 years, she was referred to our department of internal medicine for its treatment. Her endogenous insulin secretion was much decreased despite the short duration of diabetes. Glutamic acid decarboxylase antibodies (GADA) and islet cell antibodies (ICA) were both positive. Therefore, she was diagnosed as having slowly progressive form of type 1 DM. Type 1 DM is sometimes complicated with autoimmune disorders. After further examinations, she was diagnosed as having Sj?gren's syndrome, Graves' disease and autoimmune neutropenia (AIN). According to the histological examinations of the lip tumor and peripheral site of the skin ulcer, the patient was diagnosed as having carcinoma spinocellulare and chronic cutaneous lupus erythematosus. The examination also showed positive anti-intrinsic factor and anti-ribonucleoprotein (RNP) antibodies. She is a rare case of an autoimmune polyglandullar syndrome (APS) type 3 simultaneously manifesting these seven diseases with multiple autoimmune antibodies.     

An aged male patient with autoimmune hepatitis complicated by hepatocellular carcinoma.

An 82-year-old male patient was admitted for liver dysfunction. Laboratory test showed the following data; aspartate aminotransferase (AST) 79 IU/l, alanine aminotransferase (ALT) 28 IU/l, total bilirubin (T. Bil) 0.9 U, zinc sulfate turbidity test (ZTT) 48.9 U, gamma-globulin 4.9 g/dl, immunoglobulin G (IgG) 5,046 mg/dl, anti-nuclear antibodies x 320, anti-mitochondrial antibodies (-), hepatitis B virus surface antigen (HBsAg) (-), HBcAb (-), anti-hepatitis C virus (anti-HCV) (-), hepatitis C virus (HCV-RNA) (-), anti-hepatitis G virus (anti-HGV) (-), alpha-fetoprotein 306.8 ng/ml, carcinoembryonic antigen (CEA) 2.3 ng/ml, carbohydrate antigen (CA) 19-9 77.2 U/ml. Abdominal ultrasonography and computed tomography showed a large mass occupying most of the right lobe and portal thrombosis in the liver. Liver biopsy revealed cirrhosis with inactive hepatitis in the nontumorous lesion and well-differentiated hepatocellular carcinoma in the tumorous lesion. We report a rare case of an aged male patient with autoimmune hepatitis complicated by hepatocellular carcinoma.