Autoimmune paediatric liver disease

Liver disorders with a likely autoimmune pathogenesis in childhood include autoimmune hepatitis（AIH）,autoimmune sclerosing cholangitis（ASC）,and de novo AIH after liver transplantation.AIH is divided into two subtypes according to seropositivity for smooth muscle and/or antinuclear antibody（SMA/ANA,type 1） or liver kidney microsomal antibody（LKM1,type 2）.There is a female predominance in both.LKM1 positive patients tend to present more acutely,at a younger age,and commonly have partial IgA deficiency,while duration of symptoms before diagnosis,clinical signs,family history of autoimmunity,presence of associated autoimmune disorders,response to treatment,and long-term prognosis are similar in both groups.The most common type of paediatric sclerosing cholangitis is ASC.The clinical,biochemical,immunological,and histological presentation of ASC is often indistinguishable from that of AIH type 1.In both,there are high IgG,non-organ specific autoantibodies,and interface hepatitis.Diagnosis is made by cholangiography.Children with ASC respond to immunosuppression satisfactorily and similarly to AIH in respect to remission and relapse rates,times to normalization of biochemical parameters,and decreased inflammatory activity on follow up liver biopsies.However,the cholangiopathy can progress.There may be evolution from AIH to ASC over the years,despite treatment.De novo AIH after liver transplantation affects patients not transplanted for autoimmune disorders and is strikingly reminiscent of classical AIH,including elevated titres of serum antibodies,hypergammaglobulinaemia,and histological findings of interface hepatitis,bridging fibrosis,and collapse.Like classical AIH,it responds to treatment with prednisolone and azathioprine.De novo AIH postliver transplantation may derive from interference by calcineurin inhibitors with the intrathymic physiological mechanisms of T-cell maturation and selection.Whether this condition is a distinct entity or a form of atypical rejection in individuals susceptible to t     

Overlap syndromes among autoimmune liver diseases

The three major immune disorders of the liver are autoimmune hepatitis（AIH）,primary biliary cirrhosis（PBC） and primary sclerosing cholangitis（PSC）.Variant forms of these diseases are generally called overlap syndromes,although there has been no standardised definition.Patients with overlap syndromes present with both hepatitic and cholestatic serum liver tests and have histological features of AIH and PBC or PSC.The AIH-PBC overlap syndrome is the most common form,affecting almost 10% of adults with AIH or PBC.Single cases of AIH and autoimmune cholangitis（AMA-negative PBC） overlap syndrome have also been reported.The AIH-PSC overlap syndrome is predominantly found in children,adolescents and young adults with AIH or PSC.Interestingly,transitions from one autoimmune to another have also been reported in a minority of patients,especially transitions from PBC to AIH-PBC overlap syndrome.Overlap syndromes show a progressive course towards liver cirrhosis and liver failure without treatment.Therapy for overlap syndromes is empiric,since controlled trials are not available in these rare disorders.Anticholestatic therapy with ursodeoxycholic acid is usually combined with immunosuppressive therapy with corticosteroids and/or azathioprine in both AIH-PBC and AIH-PSC overlap syndromes.In end-stage disease,liver transplantation is the treatment of choice.     

Autoantibodies in primary sclerosing cholangitis

The aetiology of primary sclerosing cholangitis （PSC） is not known and controversy exists as to whether PSC should be denominated an autoimmune disease. A large number of autoantibodies have been detected in PSC patients, but the specificity of these antibodies is generally low, and the frequencies vary largely between different studies. The presence of autoantibodies in PSC may be the result of a nonspecific dysregulation of the immune system, but the literature in PSC points to the possible presence of specific antibody targets in the biliary epithelium and in neutrophil granulocytes. The present review aims to give an overview of the studies of autoantibodies in PSC, with a particular emphasis on the prevalence, clinical relevance and possible pathogenetic importance of each individual marker.     

Overlap syndrome consisting of PSC-AIH with concomitant presence of a membranous glomerulonephritis and ulcerative colitis

The association of primary sclerosing cholangitis(PSC)and autoimmune hepatitis(AIH)is known as an overlap syndrome(OS).OS can also be described in the setting of concomitant presence of AIH and PSC.These diseases can in some cases be associated with ulcerative colitis.In this case report we describe,to our knowledge,the first case in the literature of a young Caucasian male suffering from ulcerative colitis and an overlap syndrome consisting of an association betweenPSC-AIH,with the concomitant presence of a membranous glomerulonephritis.     

Celiac disease markers in patients with liver diseases: A single center large scale screening study

AIM:To study the coincidence of celiac disease, we tested its serological markers in patients with various liver diseases.METHODS:Large-scale screening of serum antibodies against tissue transglutaminase (tTG), and deamidated gliadin using enzyme-linked immunosorbent assay and serum antibodies against endomysium using immunohistochemistry, in patients with various liver diseases (n = 962) and patients who underwent liver transplantation (OLTx, n = 523) was performed. The expression of tTG in liver tissue samples of patients simultaneously suffering from celiac disease and from various liver diseases using immunohistochemistry was carried out. The final diagnosis of celiac disease was confirmed by histological analysis of small-intestinal biopsy. RESULTS:We found that 29 of 962 patients (3%) with liver diseases and 5 of 523 patients (0.8%) who underwent OLTx were seropositive for IgA and IgG anti-tTG antibodies. However, celiac disease was biopsy-diagnosed in 16 patients:4 with autoimmune hepatitis type Ⅰ, 3 with Wilson's disease, 3 with celiac hepatitis, 2 with primary sclerosing cholangitis, 1 with primary biliary cirrhosis, 1 with Budd-Chiari syndrome, 1 with toxic hepatitis, and 1 with non-alcoholic steatohepatitis. Unexpectedly, the highest prevalence of celiac disease was found in patients with Wilson's disease (9.7%), with which it is only rarely associated. On the other hand, no OLTx patients were diagnosed with celiac disease in our study. A pilot study of the expression of tTG in liver tissue using immunohistochemistry documented the overexpression of this molecule in endothelial cells and periportal hepatocytes of patients simultaneously suffering from celiac disease and toxic hepatitis, primary sclerosing cholangitis or autoimmune hepatitis type Ⅰ. CONCLUSION:We suggest that screening for celiac disease may be beneficial not only in patients with associated liver diseases, but also in patients with Wilson's disease.     

Recurrence of autoimmune hepatitis after liver transplantation without elevation of alanine aminotransferase

It is controversial whether steroid therapy should be continued to prevent the recurrence of autoimmune hepatitis(AIH)in patients who have undergone liver transplantation(LTx)due to AIH.We report a case of recurrent autoimmune hepatitis after LTx despite a persistently normal range of alanine aminotransferase(ALT).A 50-year-old woman was admitted to our hospital because of jaundice and severe liver dysfunction,where she was diagnosed with liver failure due to AIH.Steroid therapy was not effective enough and the patient received living-donor LTx in 1999.Following the operation,the level of ALT was maintained within a normal range and anti-nuclear antibody(ANA)became negative,however,the serum level of IgG gradually elevated and ANA became positive,while platelets decreased.A liver biopsy performed 6 years after LTx showed histological findings of AIH and she was diagnosed with recurrent AIH.A recurrence of AIH may occur after LTx even if the level of ALT remains within a normal range.We consider that a protocol liver biopsy should be performed in patients who undergo LTx due to AIH to decide the indication for steroid therapy.     

Etiopathogenesis of primary sclerosing cholangitis

Primary sclerosing cholangitis（PSC） is a chronic cholestatic liver disease of unknown etiology but lymphocytic portal tract infiltration is suggestive of an immune-mediated basis for this disease.Associations with inflammatory bowel disease（IBD） especially ulcerative colitis（UC）,and with particular autoimmune diseases,as well as the genetic associations further suggest PSC may be an immune-mediated disease.The immunogenetics of PSC have been the subject of active research and several HLA and non-HLA associated genes have been implicated in the development of the disease.Lymphocytes derived from the inflamed gut may enter the liver via the enterohepatic circulation to cause hepatic disease.PSC may be triggered in genetically susceptible individuals by infections or toxins entering the portal circulation through a permeable colon and hence evoking an abnormal immune response.     

Clinical features and management of primary sclerosing cholangitis

Primary sclerosing cholangitis is a chronic cholestatic liver disease characterized by inflammation and fibrosis of the bile ducts,resulting in cirrhosis and need for liver transplantation and reduced life expectancy.The majority of cases occur in young and middle-aged men,often in association with inflammatory bowel disease.The etiology of primary sclerosing cholangitis includes immune-mediated components and elements of undefined nature.No effective medical therapy has been identified.The multiple complications of primary sclerosing cholangitis include metabolic bone disease,dominant strictures,bacterial cholangitis,and malignancy,particularly cholangiocarcinoma,which is the most lethal complication of primary sclerosing cholangitis.Liver transplantation is currently the only life-extending therapeutic alternative for patients with end-stage disease,although recurrence in the allografted liver has been described.A PSC-like variant attracting attention is cholangitis marked by raised levels of the immunoglobulin G4 subclass,prominence of plasma cells within the lesions,and steroid responsiveness.     

Primary sclerosing cholangitis： Updates in diagnosis and therapy

Primary sclerosing cholangitis (PSC) is a chronic cholestatic syndrome of unknown origin mostly found in males, and characterized by diffuse inflammation and fibrosis of both intra-and extra-hepatic bile ducts. So far, PSC is considered as an autoimmune hepatobiliary disease. In most cases the progression of PSC towards liver cirrhosis and liver failure is slow but irreversible, and liver transplantation is currently the only definitive treatment. In recent years, PSC has been an area of active research worldwide with great interest in etiology, pathogenesis, diagnosis, and therapeutic options such as hydrophilic ursodeoxycholic acid and immunosuppressive agent tacrolimus. Recent updates on clinical and therapeutic aspects of PSC are discussed in the present review.     

慢性肝病中抗肝抗原自身抗体的检测

目的　探讨中国人不同病因所致慢性肝病患者中抗肝抗原自身抗体的存在状况及自身免疫性肝病的自身抗体特征。方法　 166例肝功能异常患者分为 6组 :自身免疫性肝炎 (AIH ) 12例、原发性胆汁性肝硬化 (PBC) 2 0例、原发性硬化性胆管炎 (PSC)13例、HBV组 66例、HCV组 2 2例、肝豆状核变性 (HDL) 3 9例。用间接免疫荧光法检测抗核抗体 (ANA)、平滑肌抗体 (SMA)、抗肝肾微粒抗体I型抗体 (anti LKM1)、抗线粒体抗体 (AMA)和抗中性粒细胞胞浆抗体 (ANCA) ,免疫印迹法检测抗肝细胞胞溶质抗原 1型抗体 (anti_LC1)、抗可溶性肝抗原 /肝胰抗原抗体 (anti_SLA/LP)、抗肝肾微粒抗体 1型 (anti_LKM1)、AMA_M2亚型等多种肝抗原自身抗体。结果　 166例中ANA、AMA、M_2、pANCA阳性率在 7组中有显著差异 (P <0 .0 1)。PBC中AMA、M 2阳性检出率均为 10 0 % ,PSC中pANCA阳性检出率为 5 3 8% ,Fisher精确检验在a =0 .0 0 2水准与其他各组比较有显著差异。AIH与PBC的ANA阳性率分别为10 0 %和 60 % ,Fisher精确检验在a =0 .0 0 2水准二者无显著差异。与其他各组比较有显著差异。在AIH组SMA阳性率为 2 5 % ,LKM 1、LC 1、SLA/LP阳性率均为 8.3 % ,统计学处理与其他组无显著差异 (P >0 0 5 ) ,可能与病例少有关。PBC中分别有 1     

Overlap syndromes from pediatrics to adulthood

Abstract   Overlap syndromes are autoimmune conditions with mixed immunological, clinical and histological features. The most frequent overlaps are between primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH), and between AIH and sclerosing cholangitis (SC). True AIH/PBC overlap syndrome is rare and characterized by elevation of transaminases and immunoglobulin G (IgG), positive anti-smooth muscle antibodies and a liver biopsy showing interface hepatitis as well as changes typical of PBC. These patients respond to immunosuppressive treatment that must be given promptly, to avoid progression to liver failure. The so-called 'autoimmune cholangitis' defines a small group of patients with cholestatic and histological features of PBC but negative for anti-mitochondrial antibody (AMA) and positive for PBC-specific anti-nuclear antibody (ANA). The positivity for ANA in these patients is a consequence of the AMA negativity, since AMA masks ANA on immunofluorescence. These patients' clinical course and response to treatment resemble that of classical PBC. AIH/ASC overlap syndrome is characterised by elevated levels of IgG and circulating autoantibodies, including ANA, SMA and atypical perinuclear anti-neutrophil cytoplasmic antibody, in association with cholangiographic changes typical of SC. This condition affects in particular children and young adults and may represent the early stage of adult primary SC. The parenchymal liver inflammation responds satisfactorily to immunosuppression, while the bile duct damage may progress despite treatment.     

儿童自身免疫性肝炎的诊治进展

自身免疫性肝炎(AIH)是一种进行性炎症性肝病,儿童AIH发病率近年来逐步上升。AIH可分为两种类型:抗核抗体和(或)平滑肌抗体和(或)抗可溶性肝抗原抗体阳性的AIH-1、抗肝-肾微粒体1型和(或)抗肝细胞溶质1型抗体阳性的AIH-2,AIH-2主要见于儿童。正常儿童少见自身抗体阳性,因此儿童AIH诊断时对自身抗体滴度的要求低于成人标准,但儿童AIH疾病进展比成人期更快,因此确诊后应该立即开始治疗。成人AIH诊断评分系统不适用于儿科患者,尤其不适于区分AIH和自身免疫性硬化性胆管炎。     

Autoantibodies and defined target autoantigens in autoimmune hepatitis: an overview

Autoimmune hepatitis (AIH) is a disease of unknown aetiology characterised by hypergammaglobulinaemia, non-organ and liver-related autoantibodies, association with HLA-DR3 or DR4 and a favourable response to immunosuppression. The current classification of AIH and the several autoantibodies/target autoantigens found in this disease are reported. The importance of these markers in the differential diagnosis and the study of pathogenesis of AIH is also given. AIH is subdivided into two major types: AIH type 1 (AIH-1) and AIH type 2 (AIH-2). AIH-1 is characterised by the detection of smooth muscle autoantibodies (SMA) and/or antinuclear antibodies (ANA). Antineutrophil cytoplasmic autoantibodies (ANCA), in most cases of perinuclear pattern (p-ANCA), by the indirect immunofluorescence assay, antibodies against the asialoglycoprotein receptor (anti-ASGP-R) and antibodies to soluble liver antigens or liver-pancreas (anti-SLA/LP) may be useful for the identification of individuals who are seronegative for ANA/SMA. AIH-2 is characterised by the presence of specific autoantibodies against liver and kidney microsomal antigens (anti-LKM type 1 or infrequently anti-LKM type 3) and/or autoantibodies against liver cytosol 1 antigen (anti-LC1). Anti-LKM-1 and anti-LKM-3 autoantibodies are also detected in some patients with chronic hepatitis C (HCV) and chronic hepatitis D (HDV). For these reasons, the distinction between AIH and chronic viral hepatitis is of particular importance. Cytochrome P450 2D6 (CYP2D6) is the major target autoantigen of anti-LKM-1 autoantibodies in both conditions (AIH-2 and HCV infection). Recent data have demonstrated the expression of CYP2D6 on the surface of hepatocytes, suggesting a pathogenetic role of anti-LKM-1 autoantibodies in liver injury. Family 1 of UDP-glycuronosyltransferases has been identified as the target autoantigen of anti-LKM-3. The molecular target of anti-SLA/LP autoantibodies has been identified recently as a 50 kDa protein with unknown structure and function. A liver-specific enzyme, the formiminotransferase cyclodeaminase, was identified as the target autoantigen of anti-LC1 autoantibodies. Anti-ASGP-R and anti-LC1 autoantibodies appear to correlate better with the severity of AIH and the response to treatment. The latter may suggest a pathogenic role of these autoantibodies in the hepatocellular damage in AIH. In general, however, autoantibodies should not be used to monitor treatment or to predict AIH activity or outcome. Finally, current knowledge concerning a specific form of AIH that may develop in some patients with a rare genetic syndrome, the autoimmune polyglandular syndrome type-1 (APS-1), is also discussed. Autoantibodies against liver microsomes (anti-LM) are the specific autoantibodies found in AIH as a disease component of APS-1. However, anti-LM autoantibodies have also been described in cases of dihydralazine-induced hepatitis. Cytochrome P450 1A2 has been identified as the target autoantigen of anti-LM autoantibodies in both disease entities.     

Prevalence of autoimmune liver disease in Alaska Natives

OBJECTIVE: There is limited information on the prevalence of autoimmune liver disease in nonwhite populations. We conducted a population-based study on the prevalence of autoimmune liver diseases in Alaska natives. METHODS: Clinical records from 1984 to July, 2000 were reviewed to identify Alaska natives with autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis, autoimmune cholangitis, and overlap syndromes of two of the above. AIH was defined as definite or probable, based on criteria established by the International Autoimmune Hepatitis Group. The diagnosis of PBC was based on a positive antimitochondrial antibody of > or = 1: 40, biochemical evidence of cholestasis, and compatible liver biopsy. Autoimmune cholangitis was defined as PBC but without a positive antimitochondrial antibody. Primary sclerosing cholangitis was diagnosed on the basis of cholangiogram. RESULTS: Seventy-seven patients with possible autoimmune liver disease were identified. Of these, 42 had definite and seven probable AIH. At presentation, 34.7% of patients with AIH presented with acute icteric hepatitis, and 65.3% were asymptomatic. Persons presenting with mild or no symptoms were more likely to have moderate to severe fibrosis on liver biopsy than those presenting with jaundice. Eighteen persons were diagnosed with PBC, five with autoimmune cholangitis, five with overlap syndrome, and none with primary sclerosing cholangitis. The combined point prevalence of AIH Alaska natives was 42.9/100,000 (95% CI = 31-57.7). The prevalence of PBC was 16/100,000 (95% CI = 12.9-25.4). CONCLUSIONS: This population-based study demonstrates that the prevalence rates of AIH and PBC in Alaska natives are comparable with reported rates in other populations.     

Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study

To investigate whether sclerosing cholangitis with an autoimmune serology characteristic of autoimmune hepatitis (AIH) and AIH are distinct entities, we studied 55 consecutive children with clinical and/or biochemical evidence of liver disease and circulating antinuclear (ANA), anti-smooth muscle (SMA), and/or liver-kidney-microsomal type 1 (LKM1) autoantibodies. They underwent liver biopsy, direct cholangiography, sigmoidoscopy, and rectal biopsy at presentation. Twenty-eight were diagnosed as AIH in the absence and 27 autoimmune sclerosing cholangitis (ASC) in the presence of radiological features of cholangiopathy. Twenty-six ASC and 20 AIH had ANA and/or SMA; 1 ASC and 8 AIH LKM1 autoantibody. Similarities between the 2 conditions included most clinical and biochemical parameters and a lower frequency of HLA DR4. Inflammatory bowel disease and histological biliary changes were more common in ASC; coagulopathy, hypoalbuminemia, lymphocytic periportal hepatitis, and HLA DR3 were more common in AIH. Histological biliary changes were observed in 65% of ASC and 31% of AIH patients. Eighty-nine percent responded to immunosuppression. Follow-up liver biopsies from 17 ASC and 18 AIH patients had similarly reduced inflammatory activity and no progression to cirrhosis. Sixteen follow-up cholangiograms from AIH patients and 9 from ASC patients were unchanged, while 8 ASC patients showed a progressive cholangiopathy. One child with AIH and ulcerative colitis developed sclerosing cholangitis 8 years after presentation. At 2 to 16 years (median, 7 years) from presentation, all patients are alive, including 4 ASC patients who underwent liver transplantation. In conclusion, ASC and AIH are similarly prevalent in childhood; cholangiography is often needed to distinguish between these 2 entities, which are likely to lie within the same disease process.     

原发性胆汁性肝硬化患者的免疫学特点分析

目的 分析原发性胆汁性肝硬化(PBC)出现的自身抗体等免疫学指标及其临床意义。 方法对3000例肝功能异常患者采用间接免疫荧光法检测抗核抗体(ANA)、抗线粒体抗体(AMA)、抗平滑肌抗体(SMA)和抗肝肾微粒体抗体(抗-LKM)等,并对ANA和AMA亚型及抗可溶性肝抗原/肝胰抗原(抗-SLA/LP)、LKM-1和抗肝特异性胞浆抗原型1抗体(抗-LC-1)等肝脏疾病相关的自身抗体进行了检测。结果 3000例肝病患者中,PBC 52例占1.7％。PBC患者的AMA和AMA-M2抗体均为阳性,52例PBC中,94.0％呈AMA高滴度(≥1:320)阳性,79.0％M2>200 RU/L,78.0％ANA阳性。ANA的主要荧光模式为细胞核膜型、细胞核点型和着丝点型。少见的荧光模式有抗干燥综合征A/B(SS-A/SS-B)、细胞核均质型、核仁型及颗粒型等。PBC患者免疫球蛋白M、碱性磷酸酶和γ-谷氨酰转肽酶高于乙型肝炎肝硬化患者;其白细胞介素(IL)-6、IL-10、肿瘤坏死因子α和干扰素γ水平高于正常人。5例表现为自身免疫性肝病重叠综合征,其中2例抗-SLA/LP阳性,提示PBC与自身免疫性肝炎(AIH)3型的重叠;1例抗-LKM-1阳性,提示PBC与AIH 2型的重叠;2例ANA阳性,且肝活体组织检查证实存在AIH和PBC的病理改变,提示为PBC与AIH 1型的重叠综合征。 结论 PBC在我国肝病患者中约占1％~2％。临床已出现典型症状者一     

Anti-liver cytosolic antigen type 1 (LC1) antibodies in childhood autoimmune liver disease

Antibodies to liver cytosol antigen type 1 (anti-LC1), which recognize a 60-kd peptide contained in the liver cytosolic fraction, have been reported to define a subset of autoimmune hepatitis (AIH) either negative for other autoantibodies or positive for anti-liver kidney microsomal antibody type 1 (LKM-1) and to be best detected in immunodiffusion. To analyze the prevalence of antiLC1 in childhood liver disease, we have tested the sera of 95 patients using immunoblot, indirect immunofluorescence, and immunodiffusion. Fifteen children had smooth muscle antibody (SMA) and/or anti-nuclear antibody (ANA)-positive AIH, 13 had anti-LKM-1-positive AIH, 14 had autoimmune sclerosing cholangitis (ASC) (all SMA and/or ANA positive), and 53 had non-autoimmune liver disease (10 had al-anti-trypsin deficiency [α1-ATD], 11 had Wilson's disease [wd], 14 had Alagille's syndrome, and 18 had chronic hepatitis B virus [HBV] infection). Twenty healthy children were studied as controls. Anti-LC1 positivity in immunodiffusion and strong reactivity in immunoblot were found in 4 LKM-1- and 2 SMA/ANA-positive patients with AIH and in 1 patient with ASC, but in none of the patients with other liver diseases nor in controls. A weak 60-kd band was detected by immunoblot in 6 more patients with AIH (2 were LKM-1- and 4 were SMA/ANA-positive) and 6 patients with ASC, all anti-LC1-negative by immunofluorescence and immunodiffusion. No distinct clinical features characterized the anti-LC1-positive patients. Our data show that, in pediatric age, LC1 reactivity, although associated with autoimmune liver disease, does not identify a distinct disease subset and that immunoblot is the most sensitive technique to detect anti-LC1.     

Diagnostic utility of IgG and IgM immunohistochemistry in autoimmune liver disease

AIM:To assess the role of IgM and IgG immunohistochemistry(IHC) in the evaluation of autoimmune liver conditions-autoimmune hepatitis(AIH),primary biliary cirrhosis(PBC),and primary sclerosing cholangitis(PSC).METHODS:Forty one biopsies from untreated patients diagnosed with autoimmune liver disease(AIH,n = 20;PBC,n = 13;PSC,n = 8) and fourteen biopsies of patients with chronic hepatitis C were selected.IgM and IgG-positive plasma cells were counted in each sample.RESULTS:A predominance of IgG-positive plas...