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 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.     

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.     

Autoimmune hepatitis from the paediatric perspective

Autoimmune hepatitis (AIH) is an important entity within the broad spectrum of autoimmune hepatobiliary disease comprised of AIH, primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Since the 1960s, AIH has been investigated with extensive clinical research aimed at effective therapeutic intervention. It was one of the first liver diseases where treatment was demonstrated to prolong survival. AIH occurs in children, as well as in adults. Its clinical manifestations in children may differ from classic adult AIH. These differences have elucidated certain aspects of AIH and hepatobiliary disease in general. There are two major patterns of AIH: type 1, with anti-smooth muscle antibodies and type 2, with anti-liver/kidney microsomal antibodies. The second type of AIH was first identified in children and is more common in younger patients. AIH often presents as acute disease in children and also in adults: the nomenclature has dropped the allusion to chronicity. Some children who have sclerosing cholangitis present with clinical disease closely resembling AIH; this AIH-like PSC, termed autoimmune sclerosing cholangitis (ASC), is also found in adults. Children with AIH may have identifiable monogenic disorders of immune regulation such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Like adults with AIH, children with AIH usually respond very favourably to immunosuppressive treatment with corticosteroids ± azathioprine. True cures seem to be rare, although many children achieve a stable remission. Nonetheless children with AIH may develop cirrhosis and some require liver transplantation. Early diagnosis and improved treatment strategies may further improve the outlook for children with AIH.     

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.     

Paediatric autoimmune liver diseases: A descriptive study of patients from Saudi Arabia

Background and study aimsAutoimmune liver diseases (ALDs) are a clinico-pathologic spectrum of disorders that share some similarities. They are formally classified as autoimmune hepatitis (AIH), isolated autoimmune sclerosing cholangitis (ASC), and the overlap syndrome of these. We describe the clinical, biochemical, and outcomes data of a cohort of autoimmune ALDs patients in a tertiary care centre.Patients and methodsThis is a cross-sectional study conducted at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. Data were collected in 2007–2018. All cases were 18 years old or younger at the time of diagnosis. The data collection comprised clinical, laboratory, imaging, treatment, and longitudinal follow-up data.ResultsTwenty-five patients were identified; 14 (56%) were females. Twenty-one patients (84%) had AIH-1,1 patient (4%) had AIH-2, and 3 patients (12%) had autoimmune sclerosing cholangitis (ASC). An insidious course was found in 21 (84%) cases. Acute hepatitis and fulminant hepatic failure was found to be very rare. Eight cases (32%) had cirrhosis at diagnosis. A total of 20 cases (80%) had complete remission following therapy. The median follow-up period was 45 months. There was no mortality, and only one patient was referred for transplant. Thus, the transplant-free survival was 96%.ConclusionsOur study showed predominance of AIH-1 over AIH-2. Response to treatment in our cohort was found to be similar to the results found in some other key studies. Prognosis and transplant-free survival is better than many published paediatric studies.     

自身免疫性肝病活检组织病理学特征分析109例

目的:分析比较自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)及其重叠综合征的组织病理学变化,提高对自身免疫性肝病(AILD)的认识.方法:对27例AIH、67例PBC、4例PSC、1例AIH-PSC重叠综合征和10例AIH-PBC重叠综合征患者的肝穿组织病理资料进行回顾性分析.结果:AILD患者多发于中年女性(73.3%),肝组织病理变化以界面性肝炎为主(77.7%),在重度患者则出现重度界面性肝炎、桥样坏死等.PBC患者早期(Ⅰ、Ⅱ)占28.3%,而晚期(Ⅲ、Ⅳ)占71.7%,肝组织病理变化以小胆管减少甚至消失为主(62.6%).AIH-PBC重叠综合征患者并非罕见,他的肝组织病理学具有AIH和PBC的双重特征.结论:AILD是非病毒性肝病的重要组成部分,其诊断需综合临床表现、生化、免疫指标和组织学变化.     

Liver transplantation in autoimmune liver diseases

Liver transplantation is indicated for terminal phases of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. Indications for transplantation in autoimmune liver diseases are similar to those used in other acute or chronic liver diseases. Therapeutic advances have reduced the need for transplantation for autoimmune hepatitis and primary biliary cirrhosis but not for primary sclerosing cholangitis. Overall, outcomes of transplantation for autoimmune liver diseases are excellent. However, recurrence of autoimmune liver diseases in the allograft has variable impacts on graft and patient survivals. Treatment of recurrent diseases requires changes in immunosuppression or addition of ursodeoxycholic acid. Among autoimmune liver diseases, only autoimmune hepatitis occurs de novo in recipients transplanted for other diseases. Patients transplanted for autoimmune hepatitis or primary sclerosing cholangitis are at risk for reactivation or de novo onset of ulcerative colitis. Better understanding of the pathogenesis of recurrent autoimmune liver diseases is needed to devise effective means of prevention and treatment.     

Autoimmune hepatitis in children

AIH, ASC, and de novo AIH after liver transplantation are childhood liver diseases of an autoimmune nature. The mode of presentation of AIH in childhood is variable, and the disease should be suspected and excluded in all children presenting with symptoms and signs of prolonged or severe acute liver disease. Although corticosteroids are effective in all types of childhood AIH, patients with LKM1 have a higher frequency of acute hepatic failure and relapse after corticosteroid withdrawal than do patients with ANA/SMA. ASC occurs commonly in the absence of inflammatory bowel disease, requires cholangiography for diagnosis, and improves during corticosteroid therapy. The development of AIH de novo in children who undergo liver transplantation for nonautoimmune liver disease may reflect interference with the maturation of T cells by immunosuppressive drugs.     

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.     

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.     

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.     

Recurrence of autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis after liver transplantation

Liver transplantation (LT) is the standard therapeutic approach for the treatment of end-stage acute and chronic autoimmune liver disease as autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Results of liver transplantation in these indications are good with a patient survival after LT at 5 years of 85%. However several series have reported a possible recurrence of primary autoimmune liver disease after liver transplantation. Concerning all these three autoimmune liver diseases, recurrence of the disease on the graft may have multiple clinical, biochemical, histological and radiological expression influenced by different factors as the diagnostic methods used, the degree of immunosuppression and the genetic background of the recipient. We would like with this overview to describe the different pattern of recurrence of these autoimmune liver disease, their potential influence on the liver graft and their therapeutic management.     

Sequential occurrence of primary sclerosing cholangitis and autoimmune hepatitis type III in a patient with ulcerative colitis: a follow up study over 14 years

In 1983, a female patient born in 1963 presented with symptoms of ulcerative colitis and typical clinical and histological signs of primary sclerosing cholangitis (PSC). At this time only pANCA were positive while other marker antibodies for autoimmune liver disorders could not be detected. In summer 1987 the clinical picture changed and was replaced by laboratory and histological signs typical of autoimmune hepatitis (AIH). Thus, IgG levels increased considerably and cholestatic enzymes became normal. For the first time, anti-liver-pancreas antibodies (LP), a diagnostic marker for AIH type III could be detected. In the following years several relapses occurred also induced by repeated discontinuation of immunosuppressive therapy. Symptoms of colitis persisted but signs of cholestasis remained absent for the following ten years. In 1997, colitis exacerbated again and colectomy had to be performed together with liver transplantation. Surprisingly, histology of the explanted liver now showed the typical features of PSC stage III/IV while the significant criteria for AIH were now lacking. Thus, progression to cirrhosis was, probably, mainly induced by the biliary destructive and fibrotic process although biochemical and serological data were clearly indicative of an autoimmune, i.e. AIH-related manifestation.     

Liver transplantation and autoimmunity.

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) represent good indications for orthotopic liver transplantation (OLT). While there is effective treatment for AIH (steroids with or without azathioprine) and PBC (ursodeoxycholic acid) no such treatment is currently established for PSC. The need of transplantation can be delayed for AIH and PBC with appropriate therapies, while treatment options for PSC are still controversially discussed. Although the time point for liver transplantation can be roughly estimated for AIH by failure of immunosuppressive therapy and for PBC by prognostic models, the prediction of survival in patients with PSC is more difficult, and further complicated by the risk of developing cholangiocellular carcinoma. Long term (5-year) outcome after liver transplantation approaches 80 to 90% for autoimmune liver diseases unless cholangiocellular carcinoma complicates PSC at the time of OLT. The risk of disease recurrence has been recognised for each of these entities although its clinical relevance is controversial and not exactly determined today. As survival after liver transplantation is steadily increasing, recurrent autoimmune liver disease may become a clinical problem in the future. Recently de novo autoimmune hepatitis after liver transplantation has been reported from several transplant centres, although its importance still needs to be established.     

自身免疫性肝病的组织病理学特点及其临床意义

自身免疫性肝病（AILD）可分为自身免疫性肝炎（AIH）、原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC）。肝活检对于AILD的诊断以及严重程度和预后判断至关重要。AIH-般以界面性肝炎（碎屑样坏死）、淋巴．浆细胞浸润和肝细胞玫瑰样花结为组织病理学特点．而PBC和PSC分别表现为胆管肉芽肿样破坏和胆管周围同心圆样纤维沉积（“洋葱皮样”）。除组织病理学证据外,AILD的诊断还需结合特征性临床、生化改变以及血清自身抗体和球蛋白水平综合判断。     

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.     

Budesonide induces complete remission in autoimmune hepatitis

AIM: Prednisone and azathioprine represent the standard treatment for autoimmune hepatitis (AIH). However, only 65% of the patients enter complete histological remission. Recently, budesonide (BUD) was reported to be a promising alternative. In this study we assessed the efficacy and safety of BUD in AIH. METHODS: Eighteen patients (12 women, 6 men; mean age 45.4±21 years) with AIH were treated with BUD (Budenofalk(?)) 3 mg thrice daily and followed up for at least 24 wk. Seven patients also had features of primary biliary cirrhosis (n=5) or primary sclerosing cholangitis (n=2). Advanced liver fibrosis or cirrhosis was present in 6 patients. RESULTS: Fifteen (83%) patients had a complete clinical and biochemical remission. Ten patients, including five with acute hepatitis, were given BUD as first-line therapy, of which seven enter remission. Three patients, two with liver cirrhosis, did not improve. All patients with second-line therapy experienced long-term remission. A histological remission was also seen in three patients. Clinically relevant BUD-induced side effects were recorded only in patients with liver cirrhosis (n=4). CONCLUSION: BUD is effective in remission induction in the majority of our patients with AIH. Side effects and treatment failure was mainly observed in patients with liver cirrhosis.     

Recurrence of autoimmune liver diseases after liver transplantation

Liver transplantation(LT) is the most effective treatment modality for end stage liver disease caused by many etiologies including autoimmune processes. That said, the need for transplantation for autoimmune hepatitis(AIH) and primary biliary cirrhosis(PBC), but not for primary sclerosing cholangitis(PSC), has decreased over the years due to the availability of effective medical treatment. Autoimmune liver diseases have superior transplant outcomes than those of other etiologies. While AIH and PBC can recur after LT, recurrence is of limited clinical significance in most, but not all cases. Recurrent PSC, however, often progresses over years to a stage requiring re-transplantation. The exact incidence and the predisposing factors of disease recurrence remain debated. Better understanding of the pathogenesis and the risk factors of recurrent autoimmune liver diseases is required to develop preventive measures. In this review, we discuss the current knowledge of incidence, diagnosis, risk factors, clinical course, and treatment of recurrent autoimmune liver disease(AIH, PBC, PSC) following LT.