AIRE gene mutation in polyglandular syndrome type 1

Autoimmune polyglandular syndrome type 1 (APS-1) is an autosomal recessive disorder characterized by chronic mucocutaneous candidiasis, autoimmune hypoparathyroidism, and primary adrenal insufficiency. It has recently been associated with mutations of a single gene found on chromosome 21, designated AutoImmune Regulator (AIRE). We report two patients with APS-1 referred to our hospital for evaluation. The first patient was an 11-year-old girl with hypoparathyroidism, infectious or immunological malabsorption, and autoimmune hepatitis. Hypoparathyroidism associated with other processes with a probable autoimmune origin suggested APS-1. Genetic study was performed revealing deletion of 13 base pairs in exon 8 of the AIRE gene. The second patient was a 17-year-old girl with autoimmune hepatitis, hypoparathyroidism, mucocutaneous candidiasis, nail dystrophy, and obliterating bronchiolitis with a probable autoimmune origin. We suspected APS-1 and genetic study was performed. The only finding was an AIRE gene polymorphism. In conclusion, the presence of a single disease criterion is sufficient to suspect APS-1 and to indicate genetic study. Further studies are required to confirm the involvement of other genes in the development of this disease.     

Propylthiouracil-associated liver failure presenting as probable autoimmune hepatitis in a child with Graves' disease

This case describes a young girl with Graves' disease, who presented with fulminant hepatic failure 9 months into propylthiouracil (PTU) therapy. Her clinical presentation was consistent with 'probable autoimmune hepatitis,' as defined by the International Autoimmune Hepatitis Group scoring system. Despite discontinuation of PTU and high-dose steroid therapy, she required liver transplantation. Subsequent pathology could not definitively rule out autoimmune hepatitis. PTU is an important cause of drug-related liver failure in children, and clinicians should be mindful that it is frequently used in patients who already have an underlying risk of autoimmune liver disease.     

Seronegative autoimmune hepatitis in childhood

Comprehensive guidelines on seropositive autoimmune hepatitis have been published for both adults and children, although these guidelines comprise only limited knowledge about seronegative autoimmune hepatitis. Autoimmune hepatitis presents as an acute or chronic progressive disease and poor outcomes are inevitable if left untreated. The absence of autoantibody positivity, hypergammaglobulinemia and lack of comprehensive algorithms makes seronegative autoimmune hepatitis a mysterious disease. In general, seronegative autoimmune hepatitis often presents with acute hepatitis, and its treatment and prognosis similar to seropositive autoimmune hepatitis. The present review focuses on the known characteristics of seronegative autoimmune hepatitis in childhood, and those of which current knowledge is vague.     

Successful treatment of de novo autoimmune hepatitis and cirrhosis after pediatric liver transplantation

Over a 15-yr period of observation, among the 205 children who underwent liver transplantations, one of them developed a particular type of late graft dysfunction with clinical and histological similarity to autoimmune hepatitis. The patient had alpha1-antitrypsin deficiency and did not previously have autoimmune hepatitis or any other autoimmune disease before transplantation. Infectious and surgical complications were excluded. After repeated episodes of unexplained fluctuations of liver function tests and liver biopsies demonstrating reactive or a biliary pattern, without any corresponding alteration of percutaneous cholangiography, a liver-biopsy sample taken 4 yr after the transplant showed active chronic hepatitis progressing to cirrhosis, portal lymphocyte aggregates, and a large number of plasma cells. At that time, autoantibodies (gastric parietal cell antibody, liver-kidney microsomal antibody, and anti-hepatic cytosol) were positive and serum IgG levels were high. Based on these findings of autoimmune disease, a diagnosis of 'de novo autoimmune hepatitis' was made. The treatment consisted of reducing the dose of cyclosporine, reintroduction of corticosteroids, and addition of mycophenolate mofetil. After 19 months of treatment, a new liver-biopsy sample showed marked reduction of portal and lobular inflammatory infiltrate, with regression of fibrosis and of the architectural disruption. At that time, serum autoantibodies became negative. The last liver-biopsy sample showed inactive cirrhosis and disappearance of interface hepatitis and of plasma cell infiltrate. Presently, 9 yr after the transplantation, the patient is doing well, with normal liver function tests and no evidence of cirrhosis. Her immunosuppressive therapy consists of tacrolimus, mycophenolate mofetil, and prednisolone. In conclusion, the present case demonstrates that de novo autoimmune hepatitis can appear in liver-transplant patients despite appropriate anti-rejection immunosuppression, and triple therapy with tacrolimus, mycophenolate mofetil, and prednisolone could sustain the graft and prevent retransplantation.     

LIVER DISEASE IN POLYGLANDULAR AUTOIMMUNE DISEASE TYPE ONE: Clinicopathologic Study of Three Patients and Review of the Literature

We report the findings from liver biopsies of three patients with polyglandular autoimmune disease type 1. The livers in two patients had histologic features of chronic hepatitis that eventuated in bridging fibrosis and cirrhosis over a period of several years. Nonspecific lobular and portal tract inflammation was present in the liver biopsy of the third patient. Although these patients did not have liver-specific autoantibodies, the liver disease in polyglandular autoimmune disease type 1 possibly represents an expression of autoimmune hepatitis.     

Detection of autoimmune regulator gene mutations in children with type 2 autoimmune hepatitis and extrahepatic immune-mediated diseases

Autoimmune regulator gene mutations were identified in 3 children with type 2 autoimmune hepatitis and extrahepatic immune diseases, including 1 child with immune hepatitis recurrence after liver transplantation. These findings suggest that autoimmune regulator gene variants might predispose children to systemic autoimmune disease, a recurrence of immune disease, or both.     

Prevalence of Celiac Disease in Children with Autoimmune Hepatitis and vice versa

Objective:

Celiac disease is an autoimmune disorder in which the risk of autoimmune liver disease is high. Autoimmune hepatitis is a chronic and progressive entity and the risk of its being associated with other autoimmune disorders such as celiac disease is high also. The aim of this study was to determine the prevalence of celiac disease in patients with autoimmune hepatitis and vice versa.

Methods:

In a cross-sectional study children with autoimmune hepatitis underwent serological screening and endoscopy for celiac disease. In patients with celiac disease, serum aminotransferases were measured and, if abnormal, autoantibodies related to autoimmune hepatitis were checked and needle liver biopsy was performed.

Findings:

Of the 96 patients, 64 had autoimmune hepatitis and 32 celiac disease. Among patients with autoimmune hepatitis only three (4.7%) were compatible with celiac disease. In the group of patients with celiac disease, autoimmune hepatitis was confirmed in four (12.5%) cases. We consider important to state that 3.1% of this group had celiac hepatitis.

Conclusion:

Autoimmune liver disease is sometimes associated with latent celiac disease. Serological screening for celiac disease should be routinely done in patients with abnormal serum aminotransferases, particularly those with chronic liver disease. On the other hand, celiac disease is often accompanied by other autoimmune diseases, including autoimmune hepatitis.     

儿童自身免疫性肝炎11例临床分析

目的 了解儿童自身免疫性肝炎(AIH)的临床特点,以提高对该病的认识.方法 提取2004至2008年临床诊断为AIH的12例病史及随访资料,参照AIH国际诊断评分标准对每个病例重新予以治疗前和治疗后评分,符合AIH诊断标准的资料进行回顾性分析.结果 11例符合确诊标准,临床表现为急性肝炎者7例(63.6%),其中2例进展为亚急性重症肝炎,隐匿起病3例(27.3%),肝硬化并发症起病1例(9.1%).10例为Ⅰ型AIH,1例未分型.平均确诊时间(7.5±7.4)个月.血清球蛋白和IgG升高10例(90.9%),抗核抗体阳性10例,其中1例合并平滑肌抗体阳性,肝肾微粒体抗体、抗线粒体抗体均阴性.11例病理符合慢性和急性炎症型者分别为6例和5例,肝细胞亚大块坏死等重度炎症表现3例,肝硬化3例,淋巴细胞浆细胞浸润9例(81.8%),界面性肝炎4例(36.4%),玫瑰花环2例(18.2%).11例均经糖皮质激素或联合免疫抑制剂治疗,3例死于继发感染,2例恶化后失访,1例部分缓解,1例缓解,4例复发.除死亡和失访者外平均随访2.25年(1.5～3.5年).结论 儿童AIH临床表现多样;部分进展快、病情重;病理表现典型者少;早期易误诊;需要长期随访治疗.     

Type 1 diabetes, autoimmune thyroid disease, and chronic urticaria

A 12-yr-old boy initially presented with chronic urticaria. Autoimmune thyroid disease was then diagnosed during routine evaluation. He developed type 1 diabetes shortly after thyroid hormone replacement was initiated. This case emphasizes the importance of routine screening for other autoimmune disorders in patients in whom one disorder is already present.     

Mechanisms of autoimmune hepatitis

Autoimmune hepatitis (AIH) is a progressive inflammatory liver disease with a female preponderance, responsive to immunosuppressive treatment. Two types of AIH are described: type 1 AIH is characterized by positivity for smooth muscle and/or antinuclear antibody, while type 2 AIH is positive for liver kidney microsomal type 1 antibody. The putative mechanisms leading to the development of this condition include genetic predisposition to autoimmunity through possession of specific human leukocyte antigen alleles, immune reactions to liver cell antigens, possibly triggered by a mechanism of molecular mimicry, where immune responses to external pathogens, e.g. viruses, become directed toward structurally similar self-components, and an impairment in immune regulation. AIH has been described to arise de novo after liver transplantation. The mechanisms leading to post-transplant autoimmunity remain to be defined.     

Autoimmune hepatitis as a late complication of liver transplantation

BACKGROUND: The development of de novo autoimmune hepatitis as a long-term complication after liver transplantation has been recently reported. The authors describe five liver allograft recipients who developed chronic hepatitis associated with autoimmune features. METHODS: Five of 155 liver transplant recipients at risk (2.5%) developed this particular form of graft dysfunction. The authors review the clinical records, liver histology, therapy, and outcome of these five patients. RESULTS: Patients included two boys and three girls. Median age at transplantation was 3.5 years (range, 0.5-14 years), median age at presentation was 9 years (range, 2-17 years), and median interval after transplantation was 5.1 years (range, 1.5-9 years). Indications for liver transplant included biliary atresia in four patients and primary sclerosing cholangitis in one patient. At the time of presentation, all patients were receiving cyclosporine as their primary immunosuppressive agent. Only one patient had a history of rejection, which had resolved. All patients presented with increased transaminase levels, and one had a mildly elevated conjugated bilirubin level. Only one patient had constitutional complaints. Acute and chronic rejection, viral hepatitis, vascular insufficiency, and biliary tract obstruction were excluded. Antinuclear antibody levels were elevated in four patients (titer range, 1:160-1:640), one of whom also had positive antismooth muscle antibody (titer 1:80) results. The fifth patient had an elevated serum total protein level. Histologic analysis of liver biopsy samples from the five patients showed findings consistent with chronic autoimmune hepatitis. All patients were treated with standard therapy for autoimmune hepatitis, which included daily steroids and azathioprine. Cyclosporine doses were reduced in three patients and eliminated in two. All patients responded with normalization (n = 2) or improvement (n = 3) of liver transaminases within the first 3 months of therapy. Histologic analysis of the 3-month follow-up liver biopsy was normal (n = 2) or showed improvement in inflammation (n = 2). Two patients developed acute allograft rejection within 6 to 12 months after discontinuation or reduction in cyclosporine. CONCLUSIONS: Autoimmune hepatitis occurs after liver transplantation in patients without a previous history of autoimmune hepatitis. The risk of developing autoimmune hepatitis appears to be greater in children after liver transplantation than in the general pediatric population. Standard therapy for autoimmune hepatitis is effective.     

Different mechanisms responsible for in vitro cell-mediated cytotoxicity to autologous hepatocytes in children with autoimmune and HBsAg-positive chronic liver disease

To investigate mechanisms of hepatocyte injury, lymphocytes from 41 children with chronic liver disease were incubated with autologous liver cells in a microcytotoxicity assay. Cytotoxicity was significantly increased in 18 of 25 patients with chronic hepatitis B virus (HBV) infection, in five of nine with "autoimmune" chronic active hepatitis (CAH), and in only one of seven with histologically inactive liver disorders. There was a good correlation between cytotoxicity and biochemical and histologic markers of disease activity in children with autoimmune CAH, whereas in HBsAg-positive disease a positive correlation was found only with serum alanine aminotransferase (SGPT). Children with autoimmune CAH receiving steroid treatment had normal cytotoxicity, whereas increased values were found in two of three HBsAg-positive patients receiving prednisolone. Fractionation studies revealed that non-T cells were cytotoxic in both autoimmune and HBcAg-positive chronic liver disease. T cell cytotoxicity was exclusively found in children with chronic HBV infection, particularly with HBc antigenemia. Blocking experiments showed that T-lymphocytes from HBsAg-positive children reacted with HBV core antigen on the hepatocyte surface. Non-T cells were directed against hepatocyte membrane antigens in both HBsAg-positive and HbsAg-negative children. These results suggest that different immune mechanisms of liver damage are involved in autoimmune and HBsAg-positive chronic liver disease.     

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目的分析儿童自身免疫性肝炎与药物性肝病的发病机制、临床特点和预后。方法2006年5月至2008年4月华中科技大学同济医学院附属同济医院收治儿童自身免疫性肝炎3例、药物性肝病5例,对其病因、临床表现、实验室检查、治疗方案和预后进行回顾性分析和总结,并复习相关文献进行临床比较。结果3例自身免疫性肝炎患儿病史6个月至3年、肝脾中至重度增大、血清IgG水平升高、自身抗体阳性、肝组织病理学检查示肝细胞水肿变性、间质及汇管区炎性细胞浸润、皮质激素治疗有效;5例药物性肝病患儿曾应用过相关药物、病史3～20d、4例肝脏轻至中度肿大、3例急性期天冬氨酸转移酶1000U/L以上、2例血清IgG水平升高、自身抗体阴性、4例对症处理好转、1例淤胆型肝病皮质激素治疗有效。结论儿童期急性或慢性严重肝病除外感染、代谢等因素者,应重点追踪患儿用药史、肝功能动态变化、免疫球蛋白、自身抗体及肝组织病理学检查,早期正确诊断和处理有利于疾病恢复,并可避免肝脏不可逆性损害。     

Life-saving immunosuppressive treatment in severe autoimmune chronic active hepatitis

A 13-year-old girl with a 1-year history of elevated serum alanine transferase was hospitalized because of liver failure. Low prothrombin time (12%) prevented needle liver biopsy. Because of a high titer of antismooth-muscle antibodies (1:500), a tentative diagnosis of "autoimmune" chronic active hepatitis was made and immunosuppressive therapy was started. Despite the severity of the liver disease, of her poor general condition, and of spontaneous bacterial peritonitis, she dramatically responded to treatment, prothrombin time returning to normal within 5 months. Diagnosis of chronic active hepatitis was later confirmed by liver biopsy. This report indicates that immuno-suppressive therapy can be life saving in children with severe chronic active hepatitis even when major signs of liver failure are present.     

Autoimmune hepatitis

Autoimmune hepatitis can present as either acute or chronic disease in children. Clinical and laboratory features, including association with extrahepatic autoimmune syndromes and prompt response to immunosuppressive treatment, circulating autoantibodies and hypergammaglobulinemia, suggest an immune etiology. However, the disease mechanism remains uncertain. Different types of autoimmune hepatitis are defined on the basis of which autoantibodies are present: anti-smooth muscle (type 1), anti-liver/kidney microsomal (type 2), or anti-soluble liver antigen (type 3). Diseases which may be clinically similar to autoimmune hepatitis must be excluded before the diagnosis of autoimmune hepatitis is established: Wilson’s disease, primary sclerosing cholangitis, chronic hepatitis B or C, and drug-induced liver disease are among the most important entities. Corticosteroids alone or with azathioprine constitute the usual treatment for autoimmune hepatitis. Although some children achieve a complete remission, or even recovery, and can stop immunosuppressive treatment, others require low-dose prednisone treatment indefinitely.     

mRNA expression of T-helper 1, T-helper 2 cytokines in autoimmune hepatitis in childhood

Background: In the pathology of autoimmune hepatitis the immunity mechanism of T-helper 1 (Th1) and Th2 cells was recently evaluated. The purpose of the present study was to measure the mRNA levels in peripheral mononuclear cells and serum cytokines obtained from children with autoimmune hepatitis for a better understanding of the mechanism.
Methods: Twenty-five patients with autoimmune hepatitis and seven controls were enrolled. mRNA levels in peripheral mononuclear cells and serum cytokines were measured using real-time polymerase chain reaction and immunoassay.
Results: Serum interferon-γ (IFN-γ) and interleukin-4 (IL-4) were rarely detected. In contrast the IFN-γ/β-actin mRNA levels were high.
Conclusion: Autoimmune hepatitis is a Th1-predominant state, therefore immune modulation therapies that target the control of Th1 cytokines should be used.     

胆道闭锁患儿自身免疫性肝病抗体的筛查分析

目的 分析自身免疫性肝病相关抗体在胆道闭锁(BA)患儿血清中检出情况,探讨其在BA临床诊断及致病机制中的意义.方法 采用线性免疫印迹法分别检测81例BA组、48例疾病对照组(DC)和40例正常对照组(NC)血清中自身免疫性肝病IgG抗体,包括原发性胆汁性胆管炎相关抗体(PBC相关抗体,含AMA-M2、抗M2-3E 、抗Spl00、抗PML和抗gp210抗体)、自身免疫性肝炎相关抗体(AIH相关抗体,含抗LKM-1、抗LC-1、抗SLA/LP抗体)以及抗Ro-52抗体.结果 BA组患儿中PBC相关抗体组合检出率为18.5%,单一检出率由高到低分别为抗M2-3E抗体(14.8%)、抗PML抗体(3.7%)、抗gp210抗体(2.5%),AMA-M2(1.2%)和抗sp100抗体(1.2%),其中,抗M2-3E抗体阳性率明显高于NC组((χ)2=5.025,P=0.025),但与DC组(4.2%)无统计学差异(P>0.05).AIH相关抗体在BA患儿中仅检出抗LC-1抗体(7.4%),与DC组(6.3%)、NC组(7.5%)的检出率差异,无统计学意义(P>0.05).抗Ro-52抗体在BA、DC和NC组的检出率分别为6.2%,4.2%和5%,组间无统计学差异(P>0.05).结论 BA患儿血清中存在不同程度检出率的自身免疫性肝病抗体,PBC相关抗体检出率较高,尤其是抗M2-3E抗体.自身抗体的检出提示BA存在针对靶抗原的体液免疫,可能参与BA的免疫致病过程,但其在BA的血清学诊断意义仍待进一步研究.     

Anti-liver-kidney microsome antibody-positive autoimmune hepatitis presenting as fulminant liver failure

A 17-month-old girl presented with acute hepatitis, which took a fulminant course leading to death 2 months after onset. No known cause of fulminant liver failure could be identified. Postmortem examination of the liver showed massive multilobular necrosis and areas of severe piecemeal necrosis. A high level of total serum gamma-globulins raised the possibility of autoimmune hepatitis. Search for anti-liver-kidney microsome antibody in the patient's serum was positive by immunofluorescence and enzyme-linked immunosorbent assay. Western blot analysis showed reactivity of the antibody with a 50-kDa protein identical to that observed in children with autoimmune hepatitis. This patient's history strongly suggests that autoimmune hepatitis can present as fulminant liver failure in children. Early diagnosis in such a patient could lead to early immunosuppressive therapy.     

Childhood common variable immunodeficiency with autoimmune disease

Clinical and laboratory findings in eight patients with childhood common variable immunodeficiency and autoimmune disease are described. Six of the eight patients had initial signs of the disease, persistent secretory diarrhea, recurrent upper respiratory tract infections, or both, in the first year of life. Autoimmune manifestations included idiopathic thrombocytopenia (4/8), hemolytic anemia (3/8), secretory diarrhea (4/8), arthritis (2/8), chronic active hepatitis (2/8), parotitis (2/8), and Guillain-Barré syndrome (2/8). In addition to the expected sinusitis, otitis, and pneumonia caused by encapsulated bacteria, these patients also had severe infections with viruses of the herpes group. Most of these patients had lymphadenopathy, splenomegaly, growth failure, and failure to develop secondary sexual characteristics. Laboratory studies demonstrated a significant increase in the ratio of T cells expressing the T helper phenotype (OKT4) to T cells expressing the T suppressor-cytotoxic phenotype (OKT8) (T4/T8). This increase could be attributed to a decrease in the absolute number of T8 cells. Additional findings included fluctuating levels of serum immunoglobulins and markedly diminished in vitro antibody production by B cells. The clinical course was relapsing and remitting, and dominated by the autoimmune manifestations of the disease. This group of patients constitutes a distinct subset of children with hypogammaglobulinemia, a subset with a complex, multisystemic disorder associated with significant morbidity and mortality.