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.     

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.     

Kinetics and risk of de novo hepatitis B infection in HBsAg-negative patients undergoing cytotoxic chemotherapy

BACKGROUND & AIMS: De novo hepatitis B virus (HBV)-related hepatitis after chemotherapy results in high morbidity and mortality. We evaluate the clinical course of de novo HBV-related hepatitis after chemotherapy. METHODS: Two hundred forty-four consecutive hepatitis B surface antigen (HBsAg)-negative lymphoma patients treated with chemotherapy were followed up for a median of 12.4 (range, 0.1-65.0) months. Serially collected serum samples were analyzed for hepatitis, serum HBV DNA, and HBsAg seroreversion. RESULTS: Eight of the 244 patients (3.3%) developed de novo HBV-related hepatitis. A 100-fold increase in serum HBV DNA preceded de novo HBV-related hepatitis by a median of 18.5 (range, 12-28) weeks. All 8 patients had normal serum alanine aminotransaminase level when the 100-fold increase in serum HBV DNA occurred. Patients with de novo HBV-related hepatitis were more likely to have occult HBV infection before chemotherapy. Direct sequencing results showed that these 8 patients had de novo HBV-related hepatitis from reactivation of occult HBV infection. Three of the 8 patients with de novo HBV-related hepatitis compared with 6 of the 236 patients without de novo HBV-related hepatitis developed fulminant hepatic failure (37.5% vs 2.5%, respectively, P < .001). On multivariate Cox analysis, de novo HBV-related hepatitis was independently associated with a higher risk of fulminant hepatic failure (relative risk, 29.854; 95% confidence interval: 4.844-183.980; P < .001). CONCLUSIONS: Close surveillance for a 100-fold increase in HBV DNA is recommended for HBsAg-negative patients treated with chemotherapy so that early commencement of antiviral therapy can be initiated before the occurrence of de novo HBV-related hepatitis.     

De novo autoimmune hepatitis after liver transplantation

Allograft dysfunction with clinical, serologic, and histologic features resembling autoimmune hepatitis (AIH) may develop in pediatric and adult patients who have received a liver transplant (LT) for end-stage diseases other than AIH. This condition is now known as de novo AIH, although its pathophysiology is still uncertain and whether it represents a specific type of rejection or a genuine form of AIH is under debate. The occurrence of de novo AIH seems to be unrelated to the etiology of the disease necessitating liver transplantation, but it has been correlated with antiviral treatment in cases of hepatitis C virus (HCV) infection recurring after LT. Several investigators have reported adverse outcome of de novo AIH, including graft failure, particularly in cases with late diagnosis. Prompt treatment with prednisone, with or without azathioprine (in addition to the basic immunosuppressive regimen), seems to be the best option. The histology of de novo AIH is characterized by an infiltrate rich in plasma cells with significant interface hepatitis and perivenular necro-inflammatory activity. These features are not specific for autoimmune damage; therefore, other causes of graft dysfunction must be excluded. The final diagnosis may be a challenge in patients with recurrent hepatitis C, and requires careful clinical and pathologic assessment.     

A case of acute liver failure due to hepatitis E virus,liver transplantation,and development of de novo autoimmune hepatitis

Acute hepatitis E virus (HEV) infection could lead to acute liver failure (ALF), which requires liver transplantation (LT). HEV infection could progress to chronic infection in an immunosuppressed host. De novo autoimmune hepatitis (AIH) is a rare occurrence of AIH during post‐LT immunosuppressive therapy in patients who underwent LT due to not AIH but some other etiology. Here, we report the first case of ALF due to HEV infection, the recurrence of HEV after LT that responded to ribavirin therapy, and then the development of de novo AIH showing a complete response to glucocorticoid therapy but multiple relapses after steroid withdrawal. This peculiar case suggests that HEV could have a pathogenic role in the development of the de novo AIH; additionally, this case report could help clinicians make therapeutic decisions in the post‐LT condition.     

Immune-mediated complications of the graft in interferon-treated hepatitis C positive liver transplant recipients

Hepatitis C virus (HCV) re-infection of the graft is universal and interferon based antiviral therapy remains at present the treatment of choice in HCV liver transplant recipients. Apart from the antiviral effects, interferon and ribavirin have both potent immunomodulatory properties resulting in a broad range of immune-related disorders including acute cellular rejection and chronic ductopenic rejection as well as de novo autoimmune hepatitis. Further complicating the picture, HCV infection per se is associated with a variety of autoimmune phenomena. We discuss here the immune-mediated complications and their relationship to chronic HCV and interferon based antiviral therapy.     

Autoimmune hepatitis-primary biliary cirrhosis concurrent with biliary stricture after liver transplantation

Although the development of de novo autoimmune liver disease after liver transplantation(LT)has been described in both children and adults,autoimmune hepatitis(AIH)-primary biliary cirrhosis(PBC)overlap syndrome has rarely been seen in liver transplant recipients.Here,we report a 50-year-old man who underwent LT for decompensated liver disease secondary to alcoholic steatohepatitis.His liver function tests became markedly abnormal 8 years after LT.Standard autoimmune serological tests were positive for anti-nuclear and antimitochondrial antibodies,and a marked biochemical response was observed to a regimen consisting of prednisone and ursodeoxycholic acid added to maintain immunosuppressant tacrolimus.Liver biopsy showed moderate bile duct lesions and periportal lymphocytes infiltrating along with light fibrosis,which confirmed the diagnosis of AIH-PBC overlap syndrome.We believe that this may be a case of post-LT de novo AIH-PBC overlap syndrome;a novel type of autoimmune overlap syndrome.     

Immune-mediated liver dysfunction after antiviral treatment in liver transplanted patients with hepatitis c: Allo or autoimmune de novo hepatitis?

BackgroundThe recurrence of hepatitis C after liver transplantation is extremely frequent. Antiviral therapy combining pegylated-interferon with ribavirin is therefore increasingly used in these patients. It has been recently reported, however, that during antiviral treatment a hepatic immune-mediated liver dysfunction, similar to “de novo” autoimmune hepatitis, may develop in a few transplanted patients.Patients and methodsThree patients, treated with pegylated-interferon α-2a and ribavirin for recurrent hepatitis C after liver transplantation, developed an aggressive hepatitis with clinical, biochemical, and histological features similar to those of autoimmune hepatitis.ResultsIn all three patients, a liver enzymes increase was evident after hepatitis C virus-RNA had become undetectable. Diagnosis of “de novo” autoimmune hepatitis was proposed, based on the presence of high-titre circulating autoantibodies and liver histology features. Following the introduction of a steroid therapy, clinical and biochemical parameters progressively improved. Hepatitis C virus infection, however, relapsed after a few months in all the patients.ConclusionsFollowing liver transplantation, antiviral therapy with pegylated-interferon α-2a and ribavirin for recurrent hepatitis C may be associated, in a few patients, with severe immune-mediated graft dysfunction similar to autoimmune hepatitis.     

Autoimmune hepatitis after liver transplantation

Liver transplantation is an effective treatment for patients with end-stage acute and chronic autoimmune hepatitis. However, despite the good outcomes reported, disease recurrence is relatively common in the allograft. In addition, autoimmunity and autoimmune liver disease can arise de novo after transplantation for non-autoimmune liver disorders. Little is known about the mechanisms by which autoimmune diseases develop after liver transplantation, but genetic factors, molecular mimicry, impaired regulatory T-cell responses, and exposures to new alloantigens might be involved. Regardless of the pathogenic mechanisms, it is important to remain aware of the existence of recurrent and de novo autoimmune hepatitis after liver transplantation; these disorders are similar to classic autoimmune hepatitis and are therefore not treated with standard antirejection strategies.     

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     

What is the long-term outcome of the liver allograft?

With improved long-term survival following liver transplantation (LT), issues relating to the assessment of the liver allograft in long-term survivors are becoming increasingly relevant. Histological abnormalities are commonly present in late post-transplant biopsies, including protocol biopsies from patients who appear to be well with good graft function. Recurrent disease is the commonest recognised cause of abnormal graft histology, but may be modified by the effects of immunosuppression or interactions with other graft complications, resulting in complex or atypical changes. Other abnormalities seen in late post-transplant biopsies include rejection (which often has different appearances to those seen in the post-transplant period), de novo disease, "idiopathic" post-transplant hepatitis (IPTH) and nodular regenerative hyperplasia. In many cases graft dysfunction has more than one cause and liver biopsy may help to identify the predominant cause of graft damage. Problems exist with the terminology used to describe less well understood patterns of graft injury, but there is emerging evidence to suggest that late rejection, de novo autoimmune hepatitis and IPTH may all be part of an overlapping spectrum of immune-mediated injury occurring in the late post-transplant liver allograft. Careful clinico-pathological correlation is very important and the wording of the biopsy report should take into account therapeutic implications, particularly whether changes in immunosuppression may be indicated. This article will provide an overview of the main histological changes occurring in long-term survivors post-LT, focusing on areas where the assessment of late post-transplant biopsies is most relevant clinically.     

The impact of autoimmunity on hepatocytes

In this article, the impact of autoimmunity on the hepatocyte is analyzed in three distinct settings: classical autoimmune hepatitis, chronic hepatitis C virus infection with autoimmune manifestations, and de novo autoimmune hepatitis after liver transplantation. (1) Classical autoimmune hepatitis: Using as model autoimmune hepatitis type 2, whose main autoantigen is known, complementary aspects of the autoimmune response are revisited, including the targeting of discrete antigenic regions by humoral and cellular effectors of damage and a defect in the counterbalancing immunoregulatory mechanisms. (2) Chronic hepatitis C virus infection: This condition provides clues to the possible role of viruses as triggers of autoimmunity. The interaction between hepatitis C virus and its receptor on B lymphocytes is the likely trigger of a polyclonal activation leading to the production of autoantibodies. These appear not to be an epiphenomenon but to be markers of hepatocyte damage. (3) De novo autoimmune hepatitis after liver transplantation: The intriguing observation that autoimmune hepatitis can arise de novo after liver transplantation is presented and its possible pathogenic mechanisms are discussed.     

De Novo Superinfection of Hepatitis B Virus in an Anti-HBs Positive Patient with Recurrent Hepatitis C Following Liver Transplantation

A 60-year-old woman with end stage liver cirrhosis caused by genotype 2 hepatitis C virus (HCV) infection received an orthotopic liver transplantation (OLT). The patient was negative for the hepatitis B surface antigen (HBsAg) and positive for the anti-hepatitis B surface antibody (anti-HBs) prior to and one and a half months following the OLT. Due to reactivation of hepatitis C, treatment with interferon-alpha and Ribavirin started two months following the OLT and resulted in a sustained virological response. We performed a liver biopsy because a biochemical response was not achieved. Surprisingly, liver pathology showed HBsAg-positive hepatocytes with a lobular hepatitis feature, which had been negative in the liver biopsy specimen obtained one and a half months post-OLT. High titers of both HBsAg and HBeAg were detected, while anti-HBs antibodies were not found. Tests for IgM anti-hepatitis B core antibody and anti-delta virus antibodies were negative. The serum HBV DNA titer was over 1×10(7) copies/mL. A sequencing analysis showed no mutation in the "a" determinant region, but revealed a mixture of wild and mutant strains at an overlapping region of the S and P genes (S codon 213 (Leu/Ile); P codons 221 (Phe/Tyr) and 222 (Ala/Thr)). These findings suggest that de novo hepatitis B can develop in patients with HCV infection during the post-OLT period despite the presence of protective anti-HBs.     

Overlap syndrome of primary biliary cirrhosis and autoimmune hepatitis with unusual initial presentation as fulminant hepatic failure

Autoimmune hepatitis and primary biliary cirrhosis are generally easy to discriminate on the basis of clinical, laboratory, and histological findings. The presence of anti-mitocondrial antibodies seropositivity and cholestatic clinical, laboratory, and/or histological features in patients with autoimmune hepatitis indicates the overlap syndrome of autoimmune hepatitis and primary biliary cirrhosis. Fulminant hepatic failure is an unusual initial form of presentation of autoimmune hepatitis and primary biliary cirrhosis overlap syndrome. We report the case of a 50-year-old woman with autoimmune hepatitis and primary biliary cirrhosis overlap syndrome who presented with fulminant hepatic failure. Fulminant hepatic failure has a high mortality rate and may require liver transplant. Our patient revealed a good response to corticosteroid and ursodeoxycholic acid therapy. It is important to identify and distinguish autoimmune hepatitis and variant syndromes from other forms of liver disease because of response to corticosteroid therapy.     

Application of nucleoside analogues to liver transplant recipients with hepatitis B

Hepatitis B is a common yet serious infectious disease of the liver, affecting millions of people worldwide. Liver transplantation is the only possible treatment for those who advance to end-stage liver disease. Donors positive for hepatitis B virus(HBV) core antibody(HBc Ab) have previously been considered unsuitable for transplants. However, those who test negative for the more serious hepatitis B surface antigen can now be used as liver donors, thereby reducing organ shortages. Remarkable improvements have been made in the treatment against HBV, most notably with the development of nucleoside analogues(NAs), which markedly lessen cirrhosis and reduce post-transplantation HBV recurrence. However, HBV recurrence still occurs in many patients following liver transplantation due to the development of drug resistance and poor compliance with therapy. Optimized prophylactic treatment with appropriate NA usage is crucial prior to liver transplantation, and undetectable HBV DNA at the time of transplantation should be achieved. NA-based and hepatitis B immune globulin-based treatment regimens can differ between patients depending on the patients' condition, virus status, and presence of drug resistance. This review focuses on the current progress in applying NAs during the perioperative period of liver transplantation and the prophylactic strategies using NAs to prevent de novo HBV infection in recipients of HBc Ab-positive liver grafts.     

Lupus Hepatitis and Autoimmune Hepatitis (Lupoid Hepatitis)

Liver dysfunction occurs in approximately 50% of patients with systemic lupus erythematosus (SLE), and patients with SLE and elevated liver enzymes can present a complicated and difficult differential diagnosis. Lupus hepatitis and autoimmune hepatitis are 2 immunologic conditions involving the liver, which can have similar clinical, laboratory and systemic presentations, leading to difficulties in diagnosis. Physicians need to be aware of these 2 hepatic diseases as diagnosis and appropriate therapy need to occur early in the disease course to prevent progression to advanced liver disease. We review the liver diseases associated with SLE and discuss the approach to the diagnostic evaluation of these patients. In particular, differentiation between lupus hepatitis and autoimmune hepatitis requires careful clinical and often histologic evaluation.     

Five cases of de novo inflammatory bowel disease after orthotopic liver transplantation

Immunosuppression is currently the treatment of choice for severe inflammatory bowel disease (IBD). Thus, it was anticipated that the course of preexisting IBD should improve after orthotopic liver transplantation (OLT). Despite sufficient allograft immunosuppressive therapy, however, exacerbation of IBD or the development of de novo IBD after OLT were described in some cases, primarily in patients transplanted for end-stage primary sclerosing cholangitis (PSC). In addition, the development of de novo IBD in patients undergoing OLT for indications other than PSC was described. Evaluating our collective of 314 liver transplanted patients we found five patients transplanted for various indications other than PSC (autoimmune hepatitis [AIH], acute-on-chronic hepatitis B, Wilson's disease, and cryptogenic cirrhosis) who developed de novo IBD after OLT despite sufficient immunosuppressive therapy with tacrolimus or cyclosporine. PSC was widely excluded in these patients by clinical and histological examinations and there was no sign of an enteric infection. It was remarkable that all patients were suspected to have an autoimmune background. Four of our patients were women and almost all patients showed histologically typical signs of an ulcerative colitis (UC). To prevent allograft rejection, three of five patients were treated with cyclosporine and the other two with tacrolimus. After diagnosis, treatment with aminosalicylates and corticosteroids led to complete clinical and histological remission. However, relapses occurred frequently after termination of specific therapy. In combination with previous reports, our cases indicate an immune dysregulation leading to the development of de novo IBD after OLT under immunosuppressive therapy. Reviewing the literature, it should be considered that apart from the autoimmune background, immunosuppressive therapy may itself play a major role in the development of de novo IBD. From the clinical point of view, it is of critical importance to detect this phenomenon, since diarrhea is an important cause of morbidity and mortality in transplanted patients and therapy for this disorder completely differs from the treatment for other causes of diarrhea. Aminosalicylates and courses of corticosteroids offer an effective treatment.     

自身免疫性肝炎的鉴别与诊断

自身免疫性肝炎(AIH)是一种与自身免疫反应相关的慢性持续性肝脏炎症性疾病。该病女性多发,未经干预者有进展为肝硬化、肝癌的可能。组织学特征性表现为中重度界面性肝炎伴淋巴-浆细胞浸润。AIH临床表现具有明显的异质性,与具有相似临床、生化、血清学和组织学特征的其他肝脏疾病存在鉴别难点,误诊者可严重影响预后。综述了AIH鉴别和诊断的要点,希望有利于临床诊疗工作。     

自身免疫性肝炎的诊断—附一例报告

为加强对自身免疫性肝炎的认识，报道一例除外其它肝损害病因，经血清生化学（肝功能、免疫球蛋白，等）、血身抗体和肝组织病理学证实的儿童自身免疫性肝炎，不明原因的肝脏损害，自身免疫性肝炎应作为鉴别诊断之一，及时检测血清生化学、自身抗体、肝组织病理并除外其它肝损害病因将有助于诊断。