Primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune cholangitis

Primary biliary cirrhosis (PBC), and autoimmune cholangitis are presumed to be autoimmune cholestatic diseases, but the relevant antigens are unknown. Primary biliary cirrhosis is diagnosed by a positive serum mitochondrial antibody test. It usually affects women and has a very long course, culminating in liver transplantation or death. Ursodeoxycholic acid is probably the appropriate treatment. Primary sclerosing cholangitis (PSC) is marked by progressive destruction of extrahepatic and intrahepatic bile ducts. There is no specific diagnostic test or treatment. Cholangiocarcinoma is the dreaded complication and precludes liver transplantation, the only chance of a cure. Autoimmune cholangitis overlaps PBC and autoimmune chronic hepatitis. It is a rare condition, resembling PBC but with a negative serum mitochondrial antibody test; however, serum antinuclear antibodies and smooth muscle antibodies are present in high titers.     

Variant syndromes in autoimmune hepatic diseases

Some autoimmune hepatic diseases patterns can be of difficult classification, sometimes as overlap of autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis and chronic viral hepatitis. The recognition of these forms is not so easy, but it is necessary for an effective therapeutic approach. At present, the specificity in these cases of the score system done and revised by the International Autoimmune Hepatitis Group is being discussed. Patients showing such diseases have different modalities of presentation of their hepatic disease and different courses. The role of histology appears to be important, but often the overlap of more manifestations is not helpful to a correct diagnostic definition. The variant syndromes could be classified as intermediate patterns of cholestatic forms and of autoimmune hepatic diseases or cholestatic forms of autoimmune hepatitis or hepatitic forms of cholestatic syndromes.     

Case Report: Treatment of Autoimmune Cholangitis

Autoimmune cholangitis has recently beendescribed as a rare, chronic cholestatic liver diseasewith clinical, biochemical, and immunological featuresof both primary biliary cirrhosis (PBC) and chronic autoimmune hepatitis (CAH) (1). In autoimmunecholangitis, increased levels of-glutamyltransferase (GGT) and alkalinephophatase (AP) are disproportionate in comparison withthe elevation in transaminases (AST/ALT), suggesting cholestatic liverdisease. Although the histological changes are similarto those in PBC, anti-mitochondrial antibodies (AMA),the serological hallmark of PBC, are not detectable. However, as in type-1 autoimmune hepatitis,high titers of anti-nuclear (ANA) and smooth muscleantibodies (ASMA) are features of autoimmunecholangitis. The diagnostic differentiation between PBC,CAH, and autoimmune cholangitis is important becauseof the different therapeutic strategies. In PBC, mostpatients do not benefit from immunosuppressive therapy(2), whereas ursodeoxycholic acid can slow disease progression (3-7). In contrast, most patientswith autoimmune hepatitis show a rapid response toimmunosuppressive treatment (8). There is no consensustherapy for autoimmune cholangitis because controlled prospective clinical trials have not beenconducted. Controversial responses to immunosuppressivetherapy and treatment with ursodeoxycholic acid havebeen reported for small numbers of patients (1, 9-13). Here we report a patient with autoimmunecholangitis who failed to respond to immunosuppressivetherapy but showed rapid and sustained response totreatment with ursodeoxycholic acid, and we review the literature on diagnosis and therapy ofautoimmune cholangitis.     

Anti-mitochondrial antibody positive autoimmune hepatitis triggered by EBV infection in a young girl

Autoimmune hepatitis (AIH) is rare in children. Two types of childhood autoimmune hepatitis are recognized: AIH type 1 which is characterized by the presence of smooth muscle (SMA) and/or antinuclear (ANA) antibodies; and AIH type 2 which is positive for anti-liver kidney microsomal type 1 (anti-LKM-1) antibody. Anti-mitochondrial antibody (AMA) is considered the hallmark for primary biliary cirrhosis (PBC) that occurs primarily in adult women and is characterized by destruction of the intralobular bile ducts and progression to cirrhosis and liver failure. Antimitochondrial-antibody-positive AIH is extremely rare in children. We report a 13 year old Saudi girl with type-1 AIH who had a strongly positive anti-mitochondrial antibody and no evidence of small bile duct disease in the liver biopsy.     

Autoimmune liver disease - are there spectra that we do not know?

Autoimmune liver diseases (AILDs) are common leading causes for liver cirrhosis and terminal stage of liver disease. They have variable prevalence among patients with liver disease and have two major clinical and biochemical presentations. Autoimmune hepatitis (AIH) is the typical example of hepatocellular AILD, but it can also be presented under a cholestatic pattern. AIH has a scoring diagnostic system and respond in most cases to the treatment with prednisolone and azathioprine. Primary biliary cirrhosis (PBC) is the second most common AILD, with a cholestatic presentation and characterized by positive antimitochondrial antibody (AMA). It has an excellent response and long term outcome with the administration of ursodeoxycholic acid (UDCA). Another AILD that is thought to be a variant of PBC is the autoimmune cholangitis, being a disease that has biochemical and histological features similar to PBC; but the AMA is negative. Primary sclerosing cholangitis (PSC) is a rare entity of AILD that has a cholestatic presentation and respond poorly to the treatment, with the ultimate progression to advance liver cirrhosis in most patients. Other forms of AILD include the overlap syndromes (OS), which are diseases with mixed immunological and histological patterns of two AILD; the most commonly recognized one is AIH-PBC overlap (AIH-PSC overlap is less common). The treatment of OS involves the trial of UDCA and different immunosuppressants. Here we present three case reports of unusual forms of chronic liver diseases that most likely represent AILD. The first two patients had a cholestatic picture, whereas the third one had a hepatocellular picture at presentation. We discussed their biochemical, immunological and histological features as well as their response to treatment and their outcomes. Then, we compared them with other forms of AILD.     

Type II Autoimmune Hepatitis and Small Duct Sclerosing Cholangitis in a Seven Years Old Child: An Overlap Syndrome?

Introduction

Autoimmune hepatitis is an inflammatory disease with multifactorial ethiopatogenesis, characterized by lympho-monocytic infiltration of liver, presence of serum autoantibodies (ANA, SMA, LKM-1) and high levels of immunoglobulins. Overlap syndromes are defined as the association of autoimmune hepatitis with cholestatic diseases such as primary biliary cirrhosis and primary sclerosing cholangitis. The boundaries of these syndromes as distinct pathological entities are still matter of debate and they could be part of a major liver autoimmune disease. Furthermore, cholestatic diseases may present even with atypical features (AMA-negative primary cirrohosis, primary sclerosing cholangitis with normal cholangiography).

Case Presentation

We herein describe a case of a 7 year-old child affected by an overlap syndrome between type 2 autoimmune hepatitis and small duct primary sclerosing cholangitis. Although characterized by a severe onset, the disease showed a good response to treatment with prednisone and azathioprine.

Conclusions

The association of type 2 autoimmune hepatitis and small duct primary cholangitis has been rarely reported in literature and this report adds new data on this still unclear entity.     

Diagnosis of primary biliary cirrhosis

Primary biliary cirrhosis is the archetypal autoimmune liver disease, with the disease label describing a chronic granulomatous lymphocytic small bile duct cholangitis, which now most commonly presents asymptomatically and at an early pre-cirrhotic stage. Disease is more common than thought, with 1 in 1000 women over the age of 40 affected. Characteristic immunologic features of the disease assist clinicians in ready non-invasive diagnosis of patients, even if asymptomatic with only anicteric/cholestatic liver biochemical profiles. Over 90% of patients are anti-mitochondrial antibody positive, and for those negative, a significant proportion have highly specific anti-nuclear antibody profiles. Liver biopsy remains useful in certain settings where clarity is needed to confirm diagnosis, exclude alternative disease, and assess the relative contribution of PBC to other co-existent liver injury, and seeks to demonstrate in particular the classic bile duct lesions, as well as the degree of interface activity.     

Autoimmune cholangitis

Autoimmune cholangitis is the term that has been used to describe patients who have the clinical, biochemical, and histologic characteristics of primary biliary cirrhosis (PBC), but who are antinuclear antibody positive rather than anti-mitochondrial antibody (AMA) positive in their sera. The course of their disease is similar to AMA positive cases, and the associated nonhepatic autoimmune diseases are the same in both AMA-positive and AMA-negative PBC. Serial testing for AMA using highly sensitive and specific techniques over time suggests that in subjects with autoimmune cholangitis, their AMA negative status remains negative. The beneficial response to treatment with ursodeoxycholic acid is the same as for AMA-positive PBC. It may be preferable to use the term autoimmune cholangitis, further stratified by AMA status, instead of the somewhat innapropriate term primary biliary cirrhosis.     

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.     

Hépatites auto-immunes : actualités diagnostiques et thérapeutiques

Autoimmune hepatitis is a disorder of unknown aetiology that occurs in children and adults of all ages with a female predominance. The spectrum of presentation is wide, ranging from no symptoms to acute liver failure. The diagnosis is based on high level serum gammaglobulins, characteristic circulating autoantibodies and histologic abnormalities (necrosis and inflammation). Autoimmune hepatitis is classified on the basis of the autoantibody pattern: type 1 (antinuclear and/or smooth muscle antibodies) is the classic form whereas type II (liver-kidney microsome 1 antibody) is much less common and occurs mainly in childhood. Mixed forms of autoimmune hepatitis that share features with other putative autoimmune liver diseases, primary biliary cirrhosis and primary sclerosing cholangitis, have been described. Because of therapeutic issues, it is important to distinguish autoimmune hepatitis from other forms of hepatitis and the use of diagnostic scoring systems may be helpful. The treatment of autoimmune hepatitis has not changed for the past 30 years. It consists of corticosteroids associated with azathioprine. This treatment is rapidly effective but usually only suspensive. Relapse after treatment withdrawal is the rule (80% of cases). The main risk factor of recurrence is the degree of residual inflammation on liver biopsy. The frequency of side effects justifies an attempt of drug discontinuation provided that criteria of clinical, biochemical and histological remission are achieved after at least 2 years of treatment.     

Histology of autoimmune hepatitis and its variants

Autoimmune hepatitis does not have a pathognomonic feature, and its laboratory, serologic, and histologic manifestations are shared with a variety of acute and chronic liver diseases. The disease has active and quiescent phases and thus variable histologic appearances. This article outlines the many histologic faces of autoimmune hepatitis. It discusses the fulminant and acute forms, as well as the chronic hepatitic forms. Overlap syndromes with primary biliary cirrhosis and primary sclerosing cholangitis are described. The role of the pathologist in reporting the biopsies is discussed.     

Lipids and lipid-activated vitamins in chronic cholestatic diseases

Primary biliary cirrhosis, primary sclerosing cholangitis and autoimmune cholangiopathy are cholestatic liver diseases of unknown cause. Destruction of small to medium bile ducts (in primary biliary cirrhosis and autoimmune cholangiopathy) and large bile ducts (in primary sclerosing cholangitis) leads to progressive cholestasis, liver failure and end-stage liver disease. A variety of abnormalities in lipid metabolism have been described in primary biliary cirrhosis, and range from alterations in serum lipid levels and lipoprotein subsets to deranged metabolism of cholesterol. Progressive cholestasis and, consequently, decreased small intestinal bile acid concentrations in these cholestatic liver disease can also lead to impaired absorption of fats and fat-soluble vitamins, resulting in steatorrhea and deficiencies in vitamins A, D, E, and K. This article focuses on abnormalities in lipid metabolism in primary biliary cirrhosis and primary sclerosing cholangitis, and on lipid-activated vitamin deficiencies in these disorders.     

The Overlap Syndromes of Autoimmune Hepatitis

Autoimmune hepatitis has two major variant phenotypes in which the features of classical disease are co-mingled with those of primary biliary cirrhosis or primary sclerosing cholangitis. These overlap syndromes lack codified diagnostic criteria, established pathogenic mechanisms, and confident management strategies. Their clinical importance relates mainly to the identification of patients who respond poorly to conventional corticosteroid treatment. Scoring systems that lack discriminative power have been used in their definition, and a clinical phenotype based on pre-defined laboratory and histological findings has not been promulgated. The frequency of overlap with primary biliary cirrhosis is 7–13 %, and the frequency of overlap with primary sclerosing cholangitis is 8–17 %. Patients with autoimmune hepatitis and features of cholestatic disease must be distinguished from patients with cholestatic disease and features of autoimmune hepatitis. Variants of the overlap syndromes include patients with small duct primary sclerosing cholangitis, antimitochondrial antibody-negative primary biliary cirrhosis, autoimmune sclerosing cholangitis, and immunoglobulin G4-associated disease. Conventional corticosteroid therapy alone or in conjunction with ursodeoxycholic acid (13–15 mg/kg daily) has been variably effective, and cyclosporine, mycophenolate mofetil, and budesonide have been beneficial in selected patients. The key cholestatic features that influence the prognosis of autoimmune hepatitis must be defined and incorporated into the definition of the syndrome rather than rely on designations that imply the co-mingling of different diseases with manifestations of variable clinical relevance. The overlap syndromes in autoimmune hepatitis are imprecise, heterogeneous, and unfounded, but they constitute a clinical reality that must be accepted, diagnosed, refined, treated, and studied.     

Overlap syndromes

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.     

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。     

Overlap Syndromes of Autoimmune Hepatitis: An Open Question

The headword “overlap syndromes” of liver diseases includes the coexistence of autoimmune hepatitis, primary biliary cirrhosis, and primary sclerosing cholangitis. These syndromes often represent a diagnostic and therapeutic challenge for hepatologists; it remains unclear whether these overlap syndromes form distinct entities or they are only variants of the major autoimmune liver diseases. The most frequent reported association occurs between autoimmune hepatitis and primary biliary cirrhosis, whereas the overlap between autoimmune hepatitis and primary sclerosing cholangitis is less frequent, typically at young age and often attendant with an inflammatory bowel disease. The choice therapy is based on ursodeoxycholic acid and immunosuppressive drugs, used at the same time or consecutively, according to the course of disease. The diagnostic scores for autoimmune hepatitis can help for diagnosis, even though their definitive soundness is lacking.     

Autoimmune hepatitis in the Indian subcontinent: 7 years experience

BACKGROUND: Autoimmune hepatitis (AIH) is presumed to be rare in India. The present prospective study was carried out to determine the prevalence, clinical, biochemical and histological profile of patients with AIH in India. METHODS: Consecutive patients with chronic liver disease suspected to be AIH, were screened for antinuclear antibodies (ANA), antismooth muscle antibodies (ASMA), antimitochondrial antibody (AMA), and anti-liver kidney microsomal antibodies (anti-LKM-1). Serum protein electrophoresis and liver biopsy were done. Autoimmune hepatitis was diagnosed according to the International Autoimmune Hepatitis Group criteria. RESULTS: Fifty of 1358 (3.43%) patients with chronic liver disease were diagnosed as autoimmune liver disease; 39 with AIH, two with overlap syndrome, five with primary sclerosing cholangitis, and four with primary biliary cirrhosis. Twenty-nine patients were categorized as definite AIH and 10 as probable AIH. Autoimmune hepatitis was common in females (males : females 1:3), with a mean age of 31 +/- 17 years. Patients often presented with fatigue, jaundice and anorexia. Skin lesions (58%), joint symptoms (30%), and menstrual abnormalities (26%) were not uncommon. Mildly elevated alkaline phosphatase and hyper gamma globulinemia were seen in 78 and 91% patients, respectively. Eighty percent of patients were type I AIH, while 20% of cases remained unclassified. Histopathological changes included piecemeal necrosis (100%), plasma cell infiltration (91%), rosette formation (82%), and cirrhosis (76%). Overall mortality was 25% during a mean follow up of 15.7 +/- 17.0 months. CONCLUSIONS: Our results clearly demonstrate that: (i) AIH is not uncommon in India; and (ii) while the profile and spectrum of AIH resembles that seen in the West, Indian patients present late, often in a cirrhotic state.     

Intrahepatic IgG/IgM plasma cells ratio helps in classifying autoimmune liver diseases

Background/AimPlasma cells infiltrate in the liver is a prototype lesion of autoimmune liver diseases. The possible role of plasma cells isotyping (IgM and IgG) in the liver in the diagnostic definition of autoimmune liver disease, and particularly in variant syndromes such as autoimmune cholangitis and the primary biliary cirrhosis/autoimmune hepatitis overlap syndrome, is less defined.MethodsWe analysed the clinical, serological and histological features of 83 patients with autoimmune liver disease (40 primary biliary cirrhosis, 20 autoimmune hepatitis, 13 primary sclerosing cholangitis, 4 autoimmune cholangitis and 6 overlap syndrome) compared to 34 patients with chronic hepatitis C and evaluated the expression of IgM and IgG plasma cells in their liver by immunostaining.ResultsBy Spearman's correlation, the mean-counts of IgM plasma cells in portal tracts were significantly correlated with female gender, serum alkaline phosphatase, gamma-glutamyl transferase and IgM values, positivity for anti-mitochondrial antibody-M2 and, on liver biopsy, with bile duct changes, orcein-positive granules and granulomas. Whereas IgG plasma cells resulted more correlated with alanine aminotransferase levels. IgG/IgM ratio lower than 1 was found no only in primary biliary cirrhosis but also in all patients with autoimmune cholangitis. Conversely, all patients with overlap syndrome showed IgG/IgM ratio higher than 1.ConclusionImmunostaining for IgM and IgG plasma cells on liver tissue can be a valuable parameter for better diagnosis of autoimmune liver disease and also for variant or mixed syndromes.     

Sclerosing Cholangitis: Pediatric Perspective

Sclerosing cholangitis is a rare progressive cholestatic liver disease affecting the biliary tract. It may be associated with other diseases including autoimmune hepatitis, immunodeficiencies, cystic fibrosis, and sickle cell disease. Sclerosing cholangitis not associated with other diseases is termed “primary sclerosing cholangitis,” which has a strong association with male gender, Caucasian race, and inflammatory bowel disease. Diagnosis is based on typical biochemical, radiologic, and histologic features. Medical management is directed mainly at managing complications (pruritus, cholangitis, strictures, and nutritional deficiencies). Administration of ursodeoxycholic acid results in biochemical improvement, but has not been proven to prolong transplant-free survival. Patients with autoimmune overlap respond to immunosuppression. The disease is typically progressive and evolves to biliary cirrhosis and possibly cholangiocarcinoma. Orthotopic liver transplantation remains the only life-extending alternative for patients with sclerosing cholangitis, with good long-term patient and graft survival, and recurrent graft primary sclerosing cholangitis in about 10% of children.