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.     

Liver transplantation for autoimmune hepatitis in Peru: outcomes and recurrence

Background. Liver transplantation is the only therapy for end-stage liver disease. Cirrhosis secondary to autoimmune hepatitis (AIH) is an indication in 4-6% of adult transplants. Aims. To describe the outcomes and recurrence of AIH in liver transplant patients.Material and methods. Twenty patients were retrospectively studied. Results. The female/male ratio was 3:1, the median age was 36.7 years (range, 16 to 39 years), and the median MELD score was 18.5. According to serological analysis, 19 patients were AIH type 1 and one patient was AIH type 2. AIH was associated with human leukocyte antigen (HLA) DR13+ and DR4+. The overall 5-year patient and graft survival rates were 94 and 85%, respectively. Three (15.7%) cases of recurrent AIH were diagnosed based on histological evidence. Clinical and histological features of acute and chronic rejection were present in four (20%) and three (16.6%) patients, respectively. Conclusion. AIH frequently affected young women, was the most frequent indication for liver transplantation. Rejection and recurrence were commonly associated with AIH, but did not affect patient survival. No significant relationship between HLA-DR type and recurrence was found. Rapid progression to cirrhosis should be considered in severe recurrences.     

Impact of pretransplant antinuclear antibody and antismooth muscle antibody titers on disease recurrence and graft survival following liver transplantation in autoimmune hepatitis patients

Background and Aims: Disease recurrence following transplantation occurs in 20–45% of patients with autoimmune hepatitis (AIH). Factors associated with an increased risk of recurrence include human leukocyte antigen (HLA) DR3 and HLA DR4 positivity, inadequate immunosuppression, and severity of inflammation in the native liver. Titers of several autoantibodies can be elevated in patients with AIH, including antinuclear antibody (ANA) and antismooth muscle antibody (SMA); however, it is unclear whether or not the degree of elevation influences the risk of disease recurrence following transplantation. Methods: We conducted a retrospective study to evaluate the potential impact of pretransplant titers on post‐transplant outcomes for patients with AIH. Sixty‐three patients with AIH who underwent 72 liver transplants between 1 January 1989 and 1 January 2009 were included, with a median follow up of 10 months. Patients were divided into group A (ANA or SMA ≥ 1 : 160) and group B (titers ≤ 1 : 160). Results: There was no significant difference in the recurrence rates or death between patients in groups A and B, respectively. Only race appeared to impact outcomes, with African American patients having a higher incidence of death and recurrent disease post‐transplant compared to other ethnicities. Conclusions: Based on our findings, pretransplant ANA and SMA levels do not appear to impact recurrence rates or outcomes following liver transplantation for AIH.     

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.     

Risk factors and outcomes associated with alcohol relapse after liver transplantation

Alcoholic liver disease(ALD) is the second most common indication for liver transplantation(LT) in the United States and Europe. Unlike other indications for LT, transplantation for ALD may be controversial due to the concern for alcohol relapse and non-compliance after LT. However, the overall survival in patients transplanted for ALD is comparable or higher than in patients transplanted for other etiologies of liver disease. While the rate of alcohol use after liver transplantation does not differ among various etiologies of liver disease, alcohol relapse after transplantation for ALD has been associated with complications such as graft rejection, graft loss, recurrent alcoholic cirrhosis and reduced long-term patient survival. Given these potential complications, our review aimed to discuss risk factors associated with alcohol relapse and the efficacy of various interventions attempted to reduce the risk of alcohol relapse. We also describe the impact of alcohol relapse on post-transplant outcomes including graft and patient survival. Overall, alcohol liver disease remains an appropriate indication for liver transplantation, and long-term mortality in this group of patients is primarily attributed to cardiovascular disease or de novo malignancies rather than alcohol related hepatic complications, among those who relapse.     

Liver transplantation for autoimmune hepatitis: a long-term pathologic study

Autoimmune hepatitis (AIH) after liver transplantation (LT) may recur and is difficult to diagnose. Our aims were to define the histopathology of and factors related to AIH recurrence. Fourteen of 475 patients received LT for AIH; 2 died perioperatively. Liver specimens (native and post-LT biopsies) from 12 other patients were reviewed and correlated with pre- and post-LT clinical course and outcome. Recurrent AIH was seen in 5 of 12 patients, 35 to 280 days post-LT as lobular hepatitis with acidophil bodies and lymphoplasmacytic infiltrate. Portal/interface hepatitis was seen with disease progression and 2 of 5 patients developed cirrhosis. Of 7 nonrecurrent patients, 1 had acquired hepatitis C with lobular/portal hepatitis and none developed cirrhosis. Histology suggestive of overlap syndrome was seen in 3 of 12 native livers with no effect on post-LT course or pathology. High-grade necroinflammation was present in native livers at LT in 5 of 5 cases with recurrent AIH and in 1 of 7 without recurrence (P <.01). Pre-LT disease duration, donor/recipient gender distribution, HLA studies, and rejection episodes did not correlate with AIH recurrence. We conclude that (1) recurrent AIH is not uncommon and was seen in 42% of patients with lymphoplasmacytic lobular, portal, and interface hepatitis; (2) acidophil bodies with lymphoplasmacytic cells are seen in early recurrent AIH; (3) recurrent AIH appears at variable time periods post-LT, and the progression is slow; and (4) high-grade inflammation in native liver at LT is a strong predictor of recurrent AIH.     

Response to steroids in de novo autoimmune hepatitis after liver transplantation

Graft dysfunction associated with autoimmune phenomena has been recently described in liver transplant recipients without previous autoimmune disease. However, the natural history, diagnostic criteria, and definitive therapeutic approach of de novo autoimmune hepatitis (de novo AIH) are poorly understood. We report 12 cases of de novo AIH 27.9 +/- 24.5 months after liver transplantation: the outcome of 7 patients treated with steroids is compared with a group of 5 nontreated patients. Nontreated patients lost the graft after 5.8 +/- 2.6 months from de novo AIH onset. All treated patients were alive after 48.4 +/- 14 (29-65) months from de novo AIH onset, and none of them lost the graft. However, 5 patients relapsed in relation to steroid tapering. All patients presented an atypical antiliver/kidney cytosolic autoantibody, associated to classical autoantibodies in 10 cases. Histological study showed several degrees of lobular necrosis and inflammatory infiltrate. HLA antigen frequencies and matching were compared with 2 control groups (16 orthotopic liver transplantation [LTX] patients without de novo AIH and 929 healthy blood donors); de novo AIH patients showed a higher prevalence of HLA-DR3 (54.5% vs. 25.9%, P =.04) than healthy controls, which was not observed in LTX patients without de novo AIH. In conclusion, this new disease should be included in the differential diagnosis of unexplained graft dysfunction. In addition, treatment with steroids results in a dramatically improved outcome. However, maintenance therapy is usually required.     

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.     

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

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

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.     

Spontaneous clearance of hepatitis C after liver and renal transplantation

Spontaneous clearance of hepatitis C virus (HCV) is rare in immunocompromised patients, such as those who have undergone organ transplantation. It has been recognized that patients receiving liver transplantation for HCV-related disease have decreased graft and patient survival compared with those transplanted for other etiologies. There is a growing trend toward treating HCV recurrence aggressively after liver transplantation. For other organ transplant recipients with concurrent HCV, treatment is not often an option, given the high rates of graft rejection and loss secondary to interferon and its immunomodulatory effects. Although spontaneous clearance of HCV has been reported in recipients of solitary liver and renal transplants, a common factor arising in these cases has been previous exposure to interferon. To date, no reports of spontaneous clearance of HCV RNA have been reported in a multiorgan transplant recipient. A case of spontaneous clearance of HCV RNA in an immunocompromised patient, within five months of simultaneous liver and kidney retransplantation is described. Importantly, this patient had no previous exposure to interferon.     

Recurrence of primary biliary cirrhosis after orthotopic liver transplantation

BACKGROUND/AIMS: The incidence of graft failure due to recurrence of primary biliary cirrhosis after liver transplantation and the clinical value of histological and serological parameters indicating a recurrence are still discussed controversially in the literature. METHODOLOGY: In a retrospective study 18 patients who had received orthotopic liver grafts for primary biliary cirrhosis were investigated for recurrence of disease. Histological findings, the appearance of primary biliary cirrhosis associated autoimmune diseases, the course of antimitochondrial antibodies, serological parameters of liver function and HLA status were evaluated. RESULTS: During a median follow-up period of 114 months, 6 of 18 patients developed a recurrence of primary biliary cirrhosis as indicated by liver biopsies, one patient developed clinical graft failure together with histological recurrence. Twelve patients developed autoimmune diseases. Antimitochondrial antibodies were present in all patients within a period of 12 months after transplantation. Serological parameters were elevated in 16 of 18 patients. Histological findings, serological parameters and associated diseases did not correlate with each other and with clinical symptoms of primary biliary cirrhosis recurrence. CONCLUSIONS: Graft failure due to recurrent disease can occur, but, despite a follow-up period of nearly 10 years, it is not possible to define predictive factors on the basis of histology or serology.     

Liver transplantation in autoimmune liver disease--selection of patients

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are autoimmune liver diseases, which are good indications for orthotopic liver transplantation (OLT). While there is effective treatment for AIH (steroids with or without azathioprine) and PBC (Ursodesoxycholic acid) no such treatment is currently established for PSC. The need for 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 through the risk of developing cholangiocellular carcinoma (CCC). Long-term (5-year) outcome after liver transplantation approaches 80-90% for autoimmune liver diseases unless CC complicates PSC at the time of OLT. The risk of disease recurrence has been recognized for each of these entities although its clinical relevance is controversial. This gets more important as long-term survival can be achieved for most of these patients today. In this review the natural course of autoimmune liver disease will be discussed and prognostic models will be presented, which are helpful for finding the optimal time point for liver transplantation.     

Long-term outcome of Japanese patients with type 1 autoimmune hepatitis

The long-term outcome of patients with autoimmune hepatitis (AIH) in Japan has not been well-defined. The aim of this study was to clarify the outcome of this disease over a long follow-up period compared with that of the general Japanese population as well as that among patients. A total of 203 AIH patients were enrolled for a mean follow-up period of 131 months. All patients were treated with corticosteroids with or without azathioprine. The overall survival of AIH patients was similar to that of the general population in Japan. The prognosis of AIH subgroups divided according to disease severity, sex, incidence of relapse, liver histology, presence of cirrhosis, probable or definite AIH score, antibody to hepatitis B core antigen antibody positivity, or human leukocyte antigen DR4-positivity did not differ greatly among patients. However, the prognosis of patients experiencing two or more relapses was significantly poorer than that of patients with remission or a single relapse both in univariate (P < 0.001) and multivariate (P = 0.020) analyses. The development of liver malignancy was also a possibility among AIH patients with multiple relapses. Severe adverse effects of corticosteroids were rare, even in patients who underwent long-term treatment. CONCLUSION: Repeated relapses of AIH are significantly associated with a poorer long-term prognosis in Japan. AIH patients can expect a similar prognosis to that of the general population, provided they are adequately managed with continuous low doses of immunosuppressive therapy, especially after the first relapse.     

Living-donor liver transplantation for autoimmune hepatitis and autoimmune hepatitis-primary biliary cirrhosis overlap syndrome

Aim: Recurrent autoimmune hepatitis (AIH) following liver transplantation has been reported in 20–30% of cases, mainly of Western populations. The aim of this study was to review our experience of living‐donor liver transplantation (LDLT) in Japanese patients with AIH. Methods: Among 375 adult (age ≥18 years) LDLT performed at our center between 1996 and 2010, 16 (4.2%) were for patients with AIH (n = 12) or AIH–primary biliary cirrhosis overlap syndrome (n = 4). The patient and donor characteristics and post‐transplantation course were reviewed. Results: All recipients were female with a median age of 48 years (range, 21–58). Low‐dose methylprednisolone and calcineurin inhibitors were continued in all patients. Acute cellular rejection occurred in 10 (63%), which was more frequent than in our overall series of 28.5% (107/375 cases). Overall survival rate was 81.2% at 5 years. At the end of the follow up (median, 6.0 years [range, 0.1–9.6]), 13 patients were alive with normal liver function tests (aspartate transaminase, 18 ± 5 IU/mL; alanine transaminase, 16 ± 8 IU/mL). None of the survivors exhibited liver function test results suspicious for recurrent AIH, which might indicate liver biopsy. Conclusion: Survival after LDLT for AIH and overlap syndrome was excellent and there was no evidence of clinical recurrence. The recurrence rate of AIH after liver transplantation may differ among countries, and requires further investigation.     

Recurrence of diseases following orthotopic liver transplantation

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disese recurrence.     

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.     

Long-term results of patients undergoing liver transplantation for primary sclerosing cholangitis.

Liver transplantation is the only effective therapeutic option for patients with end-stage liver disease due to primary sclerosing cholangitis (PSC). In this study, we analyzed a single center's experience with 150 consecutive PSC patients who received 174 liver allografts. Mean follow-up was 55 months. Actuarial patient survival at 1, 2, 5, and 10 years was 93.7%, 92.2%, 86.4%, and 69.8%, respectively, whereas graft survival was 83.4%, 83.4%, 79.0%, and 60. 5%, respectively. The main indication for retransplantation was hepatic artery thrombosis, and the major cause of death was severe infection. Patients with PSC had a higher incidence of acute cellular and chronic ductopenic rejection compared to a non-PSC control group. Chronic ductopenic rejection adversely affected patient and graft survival. Biliary strictures, both anastomotic and nonanastomotic, were frequent and occurred in 16.2% and 27.2% of patients, respectively. The incidence of recurrent PSC was 20%. A negative impact on patient survival was not seen in patients with either postoperative biliary strictures or recurrence of PSC. Six patients (4%) had cholangiocarcinoma and 1 patient died related to recurrence of malignant disease. Seventy-eight percent of PSC patients had associated inflammatory bowel disease, most commonly chronic ulcerative colitis, which did not adversely impact patient outcome posttransplantation. Nine patients required proctocolectomy after liver transplantation; 5 because of intractable symptoms related to inflammatory bowel disease and 4 due to the development of colorectal carcinoma/high-grade dysplasia. Our data show that liver transplantation provides excellent long-term patient and graft survival for patients with end-stage PSC.     

Transplantation for autoimmune hepatitis

Autoimmune hepatitis (AIH) is a good indication for liver transplantation, with 5- and 10-year survival rates approaching 75%. Determining the timing for transplantation remains difficult because progression to end-stage disease may be difficult to predict. After transplantation, the patients are at risk of recurrent AIH. This syndrome is not well-characterized and requires clearer definition. Introduction of corticosteroids is not always associated with arrest of disease. De novo AIH may also develop in the allograft. Although there is usually a good response to the reintroduction of corticosteroids or greater immunosuppression, some patients develop graft failure. Patients grafted for AIH tend to be at higher risk for both acute and chronic rejection. Withdrawal of immunosuppression is unlikely to be achieved.