High prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis

BackgroundOverlap syndrome is a term used for overlapping features of autoimmune hepatitis and primary sclerosing cholangitis or primary biliary cirrhosis and for autoimmune cholangitis. We describe a high prevalence of small duct primary sclerosing cholangitis among patients with overlapping autoimmune hepatitis and primary sclerosing cholangitis.MethodsWe sought to retrieve all patients with overlap syndrome between primary sclerosing cholangitis and autoimmune hepatitis in six university hospitals in Sweden. The revised autoimmune hepatitis scoring system proposed by the International Autoimmune Hepatitis Group was used to establish the diagnosis autoimmune hepatitis. Endoscopic retrograde cholangiography and/or magnetic resonance cholangiography were used to separate the primary sclerosing cholangitis cases diagnosed through liver biopsy into small and large primary sclerosing cholangitis. A histologocial diagnosis compatible with both autoimmune hepatitis and primary sclerosing cholangitis was required for inclusion.Results26 patients fulfilled our criteria for histological overlap of autoimmune hepatitis and primary sclerosing cholangitis, 7 (27%) of which had small duct primary sclerosing cholangitis. The reliability of the diagnosis small duct primary sclerosing cholangitis was supported by a very close similarity between small and large duct primary sclerosing cholangitis patients in clinical and laboratory data, and by a poor response to immunosuppressive therapy in the small duct primary sclerosing cholangitis patients. Patients with large duct overlap syndrome had a good response to immunosuppressive therapy. In both groups, our limited experience from ursodeoxycholic acid was largely poor.ConclusionsSmall duct primary sclerosing cholangitis is prevalent in the overlap syndrome between autoimmune hepatitis and primary sclerosing cholangitis.     

Clinical course of inflammatory bowel disease and impact on liver disease outcomes in patients with autoimmune sclerosing cholangitis

Background & AimsAutoimmune sclerosing cholangitis (ASC) is a childhood sclerosing cholangitis frequently associated with inflammatory bowel disease (IBD). We describe the IBD phenotype in ASC patients and associated liver disease outcomes.MethodsSingle center retrospective observational review of ASC patients, with a control population of pediatric IBD. Demographic and clinical parameters were obtained. Clinical endpoints were escalation of IBD therapy (biologic or colectomy) and transplant-free survival.ResultsIn 93 ASC patients (53.8% female) and median follow up of 172 months: 70% had IBD, 25.8% underwent liver transplant. Median age at liver transplant was 21.7 years, at 131 months from ASC diagnosis. There was no association between presence of IBD and transplant-free survival, whilst those requiring second-line immunomodulators for ASC had poorer long-term liver prognosis. During follow-up 22 (33.8%) ASC-IBD required biologic or colectomy. On multivariate analysis ASC was associated with a lower risk of escalation of IBD therapy (HR 0.14, 95% CI 0.05–0.42; P=.001), including biologic therapy (HR 0.21, 95% CI 0.08–0.55, P=.002), but not colectomy on univariate analysis (HR 1.54, 95% CI 0.43–5.44, P=.51).ConclusionsIBD is common in ASC and during longterm follow up a third of ASC-IBD required escalation of IBD therapy; however ASC-IBD was lower risk compared to IBD alone. IBD does not appear to impact on transplant-free survival in patients with ASC, however second-line immunomodulators for ASC are associated with poorer IBD and liver outcomes.     

自身免疫性肝炎患儿临床特点与预后

目的了解自身免疫性肝炎(AIH)患儿临床特点与预后。方法回顾性分析2016年8月至2019年8月于湖北省襄阳市中心医院收治的138例AIH患儿的临床资料,分析临床特征及治疗、预后。结果138例患儿中AIH-1型96例(69.57%),AIH-2型42例(30.43%)。发热6例(4.35%),恶心、乏力12例(8.70%),转氨酶异常39例(28.26%),黄疸81例(58.70%)。AIH-1型患儿合并炎症性肠病、原发性硬化性胆管炎、系统性红斑狼疮、原发性胆汁性胆管炎分别为6例(4.35%)、9例(6.52%)、3例(2.17%)、3例(2.17%)。入院时所有患儿均有肝功能异常,AIH-1型者γ球蛋白、免疫球蛋白G显著高于AIH-2型者(P<0.05)。117例行肝活组织检查,提示界面性肝炎108例(92.31%),玫瑰花结9例(7.69%),浆细胞或淋巴细胞浸润69例(58.97%);肝脏炎症分级G≥3级66例(56.41%),纤维化分期S≥3级78例(66.67%)。120例行糖皮质激素规范治疗,完全缓解87例(72.50%),部分缓解30例(25.00%),无应答3例(2.50%)。完全缓解后激素减量期45例(51.72%)复发。结论儿童AIH多见于AIH-1型,临床表现复杂,发病时多数患儿肝脏炎症及纤维化已明显进展,激素单用或联合硫唑嘌呤治疗后可改善患儿生化指标及病理,但易复发。     

Clinical analysis of liver transplantation in autoimmune liver diseases

Background: Autoimmune liver diseases(ALDs) consist of autoimmune hepatitis(AIH), primary biliary cirrhosis(PBC), primary sclerosing cholangitis(PSC), Ig G4-associated cholangitis and overlap syndromes.Patients with these diseases may gradually progress to end-stage liver diseases and need liver transplantation. The present study aimed to explore the prognosis of patients with ALDs after liver transplantation.Methods: The clinical data of 80 patients with ALD(24 cases of AIH, 35 of PBC, 15 of PSC and 6 of AIHPBC overlap syndromes) who underwent liver transplantation in Renji Hospital, Shanghai Jiao Tong University School of Medicine from June 2004 to September 2016 were collected retrospectively. The causes of death were analyzed and the postoperative cumulative survival rate was estimated by the Kaplan–Meier method. Recurrence and other complications were also analyzed.Results: Of the 80 patients, 18 were males and 62 were females. The average age was 50.5 years and the average Model for End-stage Liver Disease(MELD) score was 14.1. After a median follow-up of 19.8 months, 8 patients died. The 1-, 3-and 5-year cumulative survival rates were all 89.0%. Three cases of recurrent ALDs were diagnosed(3.8%) but they were not totally consistent with primary diseases. Biliary tract complication occurred in 10 patients(12.5%). The new onset of tumor was observed in 1 patient(1.3%). De novo HBV/CMV/EBV infection was found in 3, 8 and 3 patients, respectively.Conclusion: Liver transplantation is an effective and safe treatment for end-stage ALD.     

Autoimmune liver serology：Current diagnostic and clinical challenges

Liver-related autoantibodies are crucial for the correct diagnosis and classification of autoimmune liver diseases（AiLD）,namely autoimmune hepatitis types 1 and 2（AIH-1 and 2）,primary biliary cirrhosis（PBC）,and the sclerosing cholangitis variants in adults and children.AIH-1 is specified by anti-nuclear antibody（ANA） and smooth muscle antibody（SMA）.AIH-2 is specified by antibody to liver kidney microsomal antigen type-1（anti-LKM1） and anti-liver cytosol type 1（anti-LC1）.SMA,ANA and anti-LKM antibodies can be present in de-novo AIH following liver transplantation.PBC is specified by antimitochondrial antibodies（AMA） reacting with enzymes of the 2-oxo-acid dehydrogenase complexes（chiefly pyruvate dehydrogenase complex E2 subunit） and disease-specific ANA mainly react-ing with nuclear pore gp210 and nuclear body sp100.Sclerosing cholangitis presents as at least two variants,first the classical primary sclerosing cholangitis（PSC） mostly affecting adult men wherein the only（and non-specific） reactivity is an atypical perinuclear antineutro-phil cytoplasmic antibody（p-ANCA）,also termed perinuclear anti-neutrophil nuclear antibodies（p-ANNA） and second the childhood disease called autoimmune sclerosing cholangitis（ASC） with serological features resembling those of type 1 AIH.Liver diagnostic serology is a fast-expanding area of investigation as new purified and recombinant autoantigens,and automatedtechnologies such as ELISAs and bead assays,become available to complement（or even compete with） traditional immunofluorescence procedures.We survey for the first time global trends in quality assurance impacting as it does on（1） manufacturers/purveyors of kits and reagents,（2） diagnostic service laboratories that fulfill clinicians＇ requirements,and（3） the end-user,the physician providing patient care,who must properly interpret test results in the overall clinical context.     

Pediatric autoimmune liver disease and extra-hepatic immune-mediated comorbidities

Background

Autoimmune liver disease (AILD) includes autoimmune hepatitis (AIH) and autoimmune sclerosing cholangitis (ASC). AILD is often associated with other extra-hepatic immune-mediated disorders (EDs), but there are few pediatric studies available to date. In this study we evaluated the association between AILD and EDs in our pediatric series.

Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis

Background/Aims: Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are chronic liver diseases with probable autoimmune background. Overlapping features have been described for primary biliary cirrhosis and autoimmune hepatitis. In contrast, there have been only a few case reports on an overlap of autoimmune hepatitis and primary sclerosing cholangitis.Methods: We describe three male patients with clinical and histological overlapping features of primary sclerosing cholangitis and autoimmune hepatitis.Results: All initially asymptomatic patients had elevated levels of aminotransferases, alkaline phosphatase, γ-glutamyltranspeptidase and IgG. Anti-nuclear antibodies and/or smooth muscle antibodies were positive and anti-neutrophil cytoplasmic antibodies were detected in all patients. Retrograde endoscopic cholangiography showed bile-duct strictures characteristic for primary sclerosing cholangitis. Histopathology showed necro-inflammatory activity of portal tracts with bridging necrosis in all patients at the time of first diagnosis. Aminotransferase levels and the necro-inflammatory activity responded well to immuno-suppressive treatment. Predominant periductular fibrosis as a typical histopathological feature of primary sclerosing cirrhosis was seen to develop in all patients. Cholestatic serum parameters remained elevated and periductular fibrosis as endoscopic bile duct changes progressed despite immunosuppression.Conclusions: We suggest that these patients present an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis as they fulfill the diagnostic criteria for both conditions.     

Hepatitis autoinmune en niños: evolución de 20 casos del norte de México

BackgroundAutoimmune hepatitis (AIH) is a chronic inflammatory disease of the liver with nonspecific clinical manifestations that causes greater liver damage in children than in adults.AimsTo analyze the clinical progression, biochemical profiles, histopathologic changes, and treatment response in 20 children with AIH.Material and methodsA retrospective study was carried out on the variables associated with clinical progression, diagnosis, and treatment response in children seen at the the Unidad Médica de Alta Especialidad (UMAE) No. 71 IMSS in Torreón, Coahuila, Mexico, from 1992 to 2012.ResultsTwenty patients were analyzed, 75% with type 1 AIH (AIH-1) and 25% with type 2 AIH (AIH-2). Girls predominated with a 3:1 ratio of girls to boys. The mean age was 10.07 ± 6.53 years for the AIH-1 cases and 6.75 ± 3.77 years for the AIH-2 cases. There was an association with immunologic diseases in 40% of the patients.The patients in the AIH-2 group had greater biochemical profile alterations and IgA deficiency. Anti-nuclear antibody and anti-smooth muscle antibody were positive in 100% of the patients with AIH-1, and anti-liver kidney microsomal type 1 antibody was positive in 100% of the AIH-2 patients. Liver biopsy revealed interface hepatitis in both groups. The AIH-2 group responded more quickly to treatment, but had a higher recurrence rate.ConclusionsAutoimmune hepatitis in the pediatric patient should be suspected in order to make an early diagnosis and thereby establish opportune treatment. Determining the type of AIH is necessary for making adequate diagnosis and for achieving a better outcome in relation to recurrence and complication rates.     

Long-term follow-up of children and young adults with autoimmune hepatitis treated with cyclosporine

BackgroundCyclosporine (CSA) is an alternative treatment for autoimmune hepatitis (AIH), however, its unknown long-term safety and efficacy have limited its use.AimsExamine the long-term outcome of children and young adults with AIH treated with CSA for at least 4 years.MethodsTwenty patients were included in this retrospective study: 15 with classical AIH and 5 with autoimmune hepatitis/autoimmune sclerosing cholangitis overlap syndrome (ASC). CSA was administered as first (12 patients) or second-line (8 patients) treatment, alone or in combination with azathioprine or mycophenolate mofetil and/or prednisone.ResultsCSA determined initial clinical and biochemical remission in all patients. At the end of follow-up (median 8.6; range 4–20.4 years), all patients are alive with their native liver; 15 in complete remission (75%), 2 with incomplete response to treatment and 3 listed for liver transplant. Side effects were mild and transitory after dose tapering or, in 1 case, after CSA withdrawal. Hypertrichosis and moderate gingival hyperplasia were the most frequent. Two patients presented mild transient glomerular filtration rate (GFR) reduction. Median GFR at the beginning and end of treatment was not statistically different for all patients.ConclusionsCSA was effective and safe in the long-term treatment of our cohort of patients with AIH, tailoring the treatment remains key-points during CSA administration.     

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.     

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     

Waitlist mortality in patients with autoimmune liver diseases

Introduction and ObjectivesAutoimmune liver diseases such as autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis are the primary indication for ～24% of total liver transplants. The liver transplant allocation system is currently based upon the Model for End-Stage Liver Disease and it often underestimates the severity of autoimmune liver diseases. We aim to compare the rate of adverse waitlist removal among patients with all autoimmune liver diseases and other indications for liver transplant in the Model for End-Stage Liver -Na era.Materials and MethodsUsing the United Network for Organ Sharing database, we identified all patients listed for liver transplant from 2016 to 2019. The outcome of interest was waitlist survival defined as the composite outcome of death or removal for clinical deterioration. Competing risk analysis was used to evaluate the waitlist survival.ResultsPatients with autoimmune hepatitis had a higher risk of being removed from the waitlist for death or clinical deterioration (SHR 1.37, 95% CI 1.08–1.72; P<0.007), followed by primary biliary cholangitis (SHR 1.34, 95% CI 1.07–1.68; P<0.011).ConclusionsHigh waitlist death or removal for clinical deterioration was observed in patients with PBC and AIH when compared to other etiologies. It may be useful to reassess the process of awarding MELD exception points to mitigate such disparity.     

Autoimmune liver diseases in children - what is different from adulthood?

Autoimmune liver disorders in childhood include autoimmune hepatitis, autoimmune sclerosing cholangitis and de novo autoimmune hepatitis after liver transplant. These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels and serologically by autoantibodies and increased levels of immunoglobulin G. Autoimmune hepatitis is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment 80% of patients achieve remission and long-term survival. Autoimmune sclerosing cholangitis responds to the same treatment used for autoimmune hepatitis in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and higher transplantation requirement; it has a high recurrence rate post-liver transplant. De novo autoimmune hepatitis after liver transplant affects children transplanted for non-autoimmune conditions and responds well to the same treatment schedule used for autoimmune hepatitis, but not to the schedule used for acute rejection.     

Long-term follow-up of children and adoles-cents with primary sclerosing cholangitis and autoimmune sclerosing cholangitis

BACKGROUND: Sclerosing cholangitis (SC) is a chronic cho-lestatic hepatobiliary disease with uncertain long-term prog-nosis in pediatric patients. This study aimed to evaluate long-term results in children with SC according to the types of SC.
METHODS: We retrospectively followed up 25 children with SC over a period of 4-17 years (median 12). The diagnosis of SC was based on biochemical, histological and cholangio-graphic ifndings. Patients fuliflling diagnostic criteria for probable or deifnite autoimmune hepatitis at the time of diag-nosis were deifned as having autoimmune sclerosing cholangi-tis (ASC); other patients were included in a group of primary sclerosing cholangitis (PSC). The incidence of the following complications was studied: obstructive cholangitis, portal hy-pertension, advanced liver disease and death associated with the primary disease.
RESULTS: Fourteen (56%) patients had PSC and 11 (44%) had ASC. Patients with ASC were signiifcantly younger at the time of diagnosis (12.3 vs 15.4 years,P=0.032) and had higher IgG levels (22.7 vs 17.2 g/L,P=0.003). The mentioned compli-cations occurred in 4 (16%) patients with SC, exclusively in the PSC group: one patient died from colorectal cancer, one patient underwent liver transplantation and two patients, in whom severe bile duct stenosis was present at diagnosis, were endoscopically treated for acute cholangitis. Furthermore, two other children with ASC and 2 children with PSC had elevated aminotransferase levels. The 10-year overall survival was 95.8% in all patients, 100% in patients without complicated liver disease, and 75.0% in patients with complications.
CONCLUSION: In children, ASC is a frequent type of SC, whose prognosis may be better than that in patients with PSC.     

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.     

Appropriate steroid therapy for autoimmune pancreatitis based on long-term outcome

Objective. Because autoimmune pancreatitis (AIP) responds well to corticosteroids, many AIP patients are given this treatment. However, there is no consensus on the indications, dose, or duration of steroid treatment. The aim of this study was to establish the most appropriate steroid therapy regimen. Material and methods. We retrospectively reviewed morphological and serological improvement after steroid therapy and long-term outcome including relapse in 41 AIP patients who were given steroid therapy and were prospectively followed-up for more than 1 year. Results. All patients responded to steroid therapy, which was given because of bile duct stenosis secondary to sclerosing cholangitis in 34 AIP patients. Pancreatic enlargement normalized within one month; however, 13 patients had incomplete resolution of pancreatic duct narrowing, and 14 patients had incomplete resolution of bile duct stenosis. There was no correlation between the degree of morphological improvement and the initial prednisolone dose (30 mg and 40 mg/day). In 58% of 19 patients, serum IgG4 elevation failed to normalize. Glucose intolerance improved in 38% of the 21 patients with diabetes mellitus. Nine patients who had complete morphological and serological resolution, stopped their medication, and none have relapsed. Thirty-two patients continued maintenance therapy, and 4 of these patients suffered relapse. Conclusions. The indications for steroid therapy in AIP patients include bile duct stenosis caused by sclerosing cholangitis and other systemic diseases, such as retroperitoneal fibrosis and diabetes mellitus. We recommend that oral prednisolone be used at an initial dose of 30 mg/day; maintenance therapy is required in cases without complete morphological and serological resolution.     

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.     

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.     

Different immune mechanisms leading to autoimmunity in primary sclerosing cholangitis and autoimmune chronic active hepatitis of childhood

Children with primary sclerosing cholangitis or autoimmune chronic active hepatitis have similar high levels of immunoglobulin G and non-organ-specific autoantibodies and may have similar histological features. To investigate a possible immunopathogenesis of primary sclerosing cholangitis, we have studied a series of regulatory and/or effector immune mechanisms in eight children with primary sclerosing cholangitis, comparing them to 14 children with autoimmune chronic active hepatitis and 24 healthy children as controls. Antibodies to a liver membrane protein preparation were found in all children with autoimmune chronic active hepatitis tested and in seven of eight with primary sclerosing cholangitis, whereas antibodies against the hepatic asialoglycoprotein receptor were present in three of six patients with autoimmune chronic active hepatitis and in two of the eight with primary sclerosing cholangitis. Lymphocyte cytotoxicity values to autologous hepatocytes were similarly elevated in primary sclerosing cholangitis (median: 50%; range: 38 to 83%) and in autoimmune chronic active hepatitis (median: 52%; range 37 to 87%) compared to controls (median: 8%; range: 0 to 27%) (p less than 0.01 for both). In contrast, T suppressor cell number and function were normal in patients with primary sclerosing cholangitis (median: 23%; range: 19 to 28%; and median: 54%; range: 44 to 61%), but significantly decreased in patients with autoimmune chronic active hepatitis (median: 15%; range: 9 to 21%; and median: 9%; range: -40 to +21%) when compared to controls (median: 24%; range: 16 to 29%; and median: 53%; range: 8 to 77%) (p less than 0.01 for both).(ABSTRACT TRUNCATED AT 250 WORDS)     

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.