The effects of laparoscopic Roux-en-Y gastric bypass and one-anastomosis gastric bypass on glycemic control and remission of type 2 diabetes mellitus: study protocol for a multi-center randomized controlled trial (the DIABAR-trial).

BACKGROUND: Metabolic surgery induces rapid remission of type 2 diabetes mellitus (T2DM). There is a paucity of high level evidence comparing the efficacy of the laparoscopic Roux-en-Y gastric bypass (RYGB) and the laparoscopic one-anastomosis gastric bypass (OAGB) in glycemic control. Also, the mechanisms that drive the conversion of T2DM in severe obese subjects to euglycemia are poorly understood. METHODS: The DIABAR-trial is an open, multi-center, randomized controlled clinical trial with 10 years follow-up which will be performed in 220 severely obese patients, diagnosed with T2DM and treated with glucose-lowering agents. Patients will be randomized in a 1:1 ratio to undergo RYGB or OAGB. The primary outcome is glycemic control at 12 months follow-up. Secondary outcome measures are diverse and include weight loss, surgical complications, psychologic status and quality of life, dietary behavior, gastrointestinal symptoms, repetitive bloodwork to identify changes over time, glucose tolerance and insulin sensitivity as measured by mixed meal tests, remission of T2DM, presence of non-alcoholic fatty liver disease/non-alcoholic steatohepatitis in liver biopsy, oral and fecal microbiome, cardiovascular performance, composition of bile acids, and the tendency to develop gallstones. DISCUSSION: The DIABAR-trial is one of the few randomized controlled trials primarily aimed to evaluate the glycemic response after the RYGB and OAGB in severe obese patients diagnosed with T2DM. Secondary aims of the trial are to contribute to a deeper understanding of the mechanisms that drive the remission of T2DM in severe obese patients by identification of microbial, immunological, and metabolic markers for metabolic response and to compare complications and side effects of RYGB and OAGB. TRIAL REGISTRATION: ClinicalTrials.gov NCT03330756 ; date first registered: October 13, 2017.

Doppler follow-up after TIPS placement is not routinely indicated. A 16-years single centre experience.

BACKGROUND AND AIMS: Transjugular intrahepatic portosystemic shunt (TIPS) is an effective intervention to treat complications of portal hypertension. Since the introduction of polytetrafluoroethylene (PTFE)-covered stents, TIPS patency rates have improved, and the need for routine TIPS surveillance has become questionable. Aims of this study were to assess the indications, clinical outcome and survival, and yield of Doppler ultrasound follow-up in patients who received a TIPS in an academic centre. METHODS: A retrospective cohort study of all adult consecutive patients who underwent PTFE-covered TIPS placement between 2001 and 2016. Clinical, biochemical, and imaging findings were reviewed and analysed. RESULTS: A total of 103 patients were included for analysis. At one-year follow-up, control of bleeding was successful in 91% (41/45), and control of refractory ascites in 80% (8/10). In patients with variceal bleeding, a higher MELD score was a risk factor for 90-day mortality (HR 1.28 per point, p < 0.001) and one-year mortality (HR 1.24 per point, p < 0.001). In patients with refractory ascites, a higher MELD score was only a risk factor for 90-day mortality (HR 1.13 per point, p = 0.03). Doppler ultrasound investigations during follow-up revealed abnormalities in 4% (6/166), all of which were associated with clinical deterioration, while abnormalities were detected in 11.4% (19/166) of patients who presented with clinical symptoms of TIPS dysfunction. CONCLUSION: The use of routine Doppler ultrasound follow-up after PTFE-covered TIPS placement seems unnecessary as it had a very low yield and abnormal Doppler findings were almost always associated with clinical symptoms of TIPS dysfunction.

Prevention of hepatic encephalopathy by administration of rifaximin and lactulose in patients with liver cirrhosis undergoing placement of a transjugular intrahepatic portosystemic shunt (TIPS): a multicentre randomised, double blind, placebo controlled trial (PEARL trial).

INTRODUCTION: Cirrhotic patients with portal hypertension can suffer from variceal bleeding or refractory ascites and can benefit from a transjugular intrahepatic portosystemic shunt (TIPS). Post-TIPS hepatic encephalopathy (HE) is a common (20%-54%) and often severe complication. A prophylactic strategy is lacking. METHODS AND ANALYSIS: The Prevention of hepatic Encephalopathy by Administration of Rifaximin and Lactulose in patients with liver cirrhosis undergoing placement of a TIPS (PEARL) trial, is a multicentre randomised, double blind, placebo controlled trial. Patients undergoing covered TIPS placement are prescribed either rifaximin 550 mg two times per day and lactulose 25 mL two times per day (starting dose) or placebo 550 mg two times per day and lactulose 25 mL two times per day from 72 hours before and until 3 months after TIPS placement. Primary endpoint is the development of overt HE (OHE) within 3 months (according to West Haven criteria). Secondary endpoints include 90-day mortality; development of a second episode of OHE; time to development of episode(s) of OHE; development of minimal HE; molecular changes in peripheral and portal blood samples; quality of life and cost-effectiveness. The total sample size is 238 patients and recruitment period is 3 years in six hospitals in the Netherlands and one in Belgium. ETHICS AND DISSEMINATION: This study protocol was approved in the Netherlands by the Medical Research Ethics Committee of the Academic Medical Centre, Amsterdam (2018-332), in Belgium by the Ethics Committee Research UZ/KU Leuven (S62577) and competent authorities. This study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. Study results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov (NCT04073290) and EudraCT database (2018-004323-37).

[Immune-mediated cholangiopathies : Diagnostic and therapeutic challenges]. / Autoimmunassoziierte Gallenwegserkrankungen : Diagnostische und therapeutische Herausforderungen.

BACKGROUND: Immune-mediated cholangiopathies comprise primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC) and IgG4-associated cholangitis (IAC). A common feature is the progressive destruction of bile ducts leading to cholestasis with fibrosis and cirrhosis of the liver over time. The diseases are mostly identified during routine laboratory testing. Clinical signs and symptoms such as pruritus, fatigue or jaundice are infrequent in the early stage. DIAGNOSIS: The diagnostic work-up involves the patient's history, physical examination, serological tests, abdominal ultrasonography, magnetic resonance cholangiopancreatography (MRCP) and, where necessary, liver biopsy and genetic testing. THERAPY: Ursodeoxycholic acid (UDCA) is an effective treatment of PBC. Second-line therapies in addition to UDCA for incomplete UDCA responders are obeticholic acid (OCA) and bezafibrate, whereby only OCA has received approval for this indication from American (Federal Drug Administration) and European (European Medicines Agency) authorities. In PSC, UDCA improves prognostic markers; dominant bile duct strictures are treated with endoscopic balloon dilatation. Despite therapy, liver transplantation is frequently necessary for PSC. The risk of developing cholangiocarcinoma, colon cancer, and gallbladder cancer is increased for patients with PSC. In contrast to PBC and PSC, IAC responds well to corticosteroids. Disease relapse, however, is common, making long-term treatment with low-dose prednisolone or azathioprine necessary.

[IgG4-associated cholangitis - clinical presentation of an overlooked disease entity]. / IgG4-assoziierte Cholangitis ­ klinische Präsentation eines lange übersehenen Krankheitsbildes.

IgG4-associated cholangitis (IAC) is the hepatobiliary manifestation of immunoglobulin G4-related disease, which is an immune-mediated fibroinflammatory systemic disorder characterised by often elevated IgG4 serum levels and typical histopathological findings in affected tissues. IAC is frequently (>90%) accompanied by autoimmune pancreatitis type 1 (AIP), which is the pancreatic manifestation of immunoglobulin G4-related disease. In 80-85% of the cases patients with IAC are male, above 50 years of age and present with jaundice and weight loss. A remarkable percentage of patients with IAC has a history of long-term exposure to solvents, oil products and other organic agents representing so-called "blue-collar workers". Clinical features and imaging (i. e. strictures or mass-forming lesions in the biliary tract) may mimic other biliary diseases, such as primary or secondary sclerosing cholangitis and cholangiocarinoma. The HISORt criteria are used for diagnosing IAC and comprise histologic and imaging findings, serum IgG4, organ manifestation pattern and response to immunosuppressive therapy. Serum IgG4 levels are of diagnostic value when it is above 4 times the upper limit of normal. Determination of the blood IgG4/IgG mRNA ratio using quantitative polymerase chain reaction (qPCR) is an accurate diagnostic tool currently under clinical validation. The majority of patients show an excellent response to corticosteroid therapy. Symptom recurrence, however, is common making long-term treatment with low-dose prednisolone and/or azathioprine frequently necessary.

Modern work-up and extended resection in perihilar cholangiocarcinoma: the AMC experience.

AIM: Perihilar cholangiocarcinoma (PHC) is a challenging disease and requires aggressive surgical treatment in order to achieve curation. The assessment and work-up of patients with presumed PHC is multidisciplinary, complex and requires extensive experience. The aim of this paper is to review current aspects of diagnosis, preoperative work-up and extended resection in patients with PHC from the perspective of our own institutional experience with this complex tumor. METHODS: We provided a review of applied modalities in the diagnosis and work-up of PHC according to current literature. All patients with presumed PHC in our center between 2000 and 2016 were identified and described. The types of resection, surgical techniques and outcomes were analyzed. RESULTS AND CONCLUSION: Upcoming diagnostic modalities such as Spyglass and combinations of serum biomarkers and molecular markers have potential to decrease the rate of misdiagnosis of benign, inflammatory disease. Assessment of liver function with hepatobiliary scintigraphy provides better information on the future remnant liver (FRL) than volume alone. The selective use of staging laparoscopy is advisable to avoid futile laparotomies. In patients requiring extended resection, selective preoperative biliary drainage is mandatory in cholangitis and when FRL is small (< 50%). Preoperative portal vein embolization (PVE) is used when FRL volume is less than 40% and optionally includes the left portal vein branches to segment 4. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) as alternative to PVE is not recommended in PHC. N2 positive lymph nodes preclude long-term survival. The benefit of unconditional en bloc resection of the portal vein bifurcation is uncertain. Along these lines, an aggressive surgical approach encompassing extended liver resection including segment 1, regional lymphadenectomy and conditional portal venous resection translates into favorable long-term survival.

[Chronic cholestatic liver diseases : Differential diagnosis, pathogenesis and current treatment in adults]. / Chronische cholestatische Leberkrankheiten : Differenzialdiagnose, Pathogenese und aktuelle Therapie beim Erwachsenen.

In the long-term course chronic cholestasis regularly leads to fibrotic restructuring and ultimately to functional failure of the liver, independent of the cause. Cholestatic diseases are often clinically asymptomatic. In order to avoid progression, early diagnosis of the underlying disease and a targeted therapy are therefore decisive. The differential diagnoses of chronic cholestasis are broad; therefore, algorithms are of assistance in the diagnostic work-up. A better understanding of the pathogenesis is now leading to the development of new therapeutic agents in addition to ursodeoxycholic acid, which has long been known for its anticholestatic effects. Obeticholic acid and, in the near future, bezafibrate are therapeutic options. The possibilities for genetic diagnostics of unclear cholestasis syndromes improve the understanding of the pathogenesis of many diseases and are being introduced increasingly earlier into the clinical routine.

[A 22-year-old mother with severe pruritus and increasing jaundice two weeks after starting hormonal contraception]. / Eine 22-jährige Mutter mit starkem Juckreiz und zunehmendem Ikterus zwei Wochen nach Beginn der hormonalen Kontrazeption.

Intermittent cholestatic liver disease may indicate an inherited deficiency of bile salt transport proteins. Episodes of cholestasis may start during pregnancy or during use of oral contraceptives or other medication. We describe the case of a 22-year-old mother with increasing jaundice and severe pruritus two weeks after starting hormonal contraception. A few months before she was suffering from intrahepatic cholestasis of pregnancy (ICP). Liver biopsy showed bland cholestasis with canalicular bile plugs. Treatment with ursodeoxycholic acid was not effective. Finally, rifampicin induced a complete remission of the cholestasis. Genetic testing showed a heterozygous mutation in the ABCB11 gene encoding the bile salt export pump (BSEP). Rifampicin activates nuclear receptors and may induce alternative pathways for the excretion of bile salts in patients with ABCB11 deficiency.

A lethal case of the dapsone hypersensitivity syndrome involving the myocardium.

In the Netherlands dapsone is used for the treatment of dermatitis herpetiformis, leprosy and Pneumocystis jiroveci pneumonia and prophylaxis in case of cotrimoxazole allergy. An idiosyncratic drug reaction, known as the dapsone hypersensitivity syndrome (DHS), appears in about 0.5-3.6% of persons treated with dapsone. DHS can be associated with fever, rash and systemic involvement. We present a 35-year-old woman who developed severe DHS seven weeks after starting dapsone. Six weeks after being discharged in a good clinical condition she died from fulminant myocarditis, 11 weeks after the first DHS symptoms and the discontinuation of dapsone.

HLA-DRB1*03:01 and HLA-DRB1*04:01 modify the presentation and outcome in autoimmune hepatitis type-1.

The classical human leukocyte antigen (HLA)-DRB1*03:01 and HLA-DRB1*04:01 alleles are established autoimmune hepatitis (AIH) risk alleles. To study the immune-modifying effect of these alleles, we imputed the genotypes from genome-wide association data in 649 Dutch AIH type-1 patients. We therefore compared the international AIH group (IAIHG) diagnostic scores as well as the underlying clinical characteristics between patients positive and negative for these HLA alleles. Seventy-five percent of the AIH patients were HLA-DRB1*03:01/HLA-DRB1*04:01 positive. HLA-DRB1*03:01/HLA-DRB1*04:01-positive patients had a higher median IAIHG score than HLA-DRB1*03:01/HLA-DRB1*04:01-negative patients (P<0.001). We did not observe associations between HLA alleles and alanine transaminase levels (HLA-DRB1*03:01: P=0.2; HLA-DRB1*04:01; P=0.5); however, HLA-DRB1*03:01 was independently associated with higher immunoglobulin G levels (P=0.04). The HLA-DRB1*04:01 allele was independently associated with presentation at older age (P=0.03) and a female predominance (P=0.04). HLA-DRB1*03:01-positive patients received immunosuppressive medication and liver transplantation. In conclusion, the HLA-DRB1*03:01 and HLA-DRB1*04:01 alleles are both independently associated with the aggregate diagnostic IAIHG score in type-1 AIH patients, but are not essential for AIH development. HLA-DRB1*03:01 is the strongest genetic modifier of disease severity in AIH.

Dutch guidance for the treatment of chronic hepatitis C virus infection in a new therapeutic era.

BACKGROUND: A new era for the treatment of chronic hepatitis C is about to transpire. With the introduction of the first-generation protease inhibitors the efficacy of hepatitis C treatment improved significantly. Since then, the therapeutic agenda has moved further forward with the recent approval of sofosbuvir and the expected approval of agents such as simeprevir and daclatasvir. This paper, developed parallel to the approval of sofosbuvir, is to serve as a guidance for the therapeutic management of chronic hepatitis C. METHODS: We performed a formal search through PubMed, Web of Science and ClinicalTrials.gov to identify all clinical trials that have been conducted with EMA-approved new agents in hepatitis C; for this version (April 2014) we focused on sofosbuvir. For each disease category, the evidence was reviewed and recommendations are based on GRADE. RESULTS: We identified 11 clinical trials with sofosbuvir and for each disease category recommendations for treatment are made. Not all disease categories were studied extensively and therefore in some cases we were unable to provide recommendations. CONCLUSION: The recent approval of sofosbuvir will most likely change the therapeutic landscape of chronic hepatitis C. The use of sofosbuvir-containing regimens can shorten the duration of therapy, increase efficacy and result in less side effects, compared with standard of care. The efficacy relative to standard of care needs to be weighed against the increased costs of sofosbuvir. With future approval of the other direct-acting antivirals, the outcome of hepatitis C treatment will likely improve further and this guidance will be updated.

Sarcoidosis of the liver: to treat or not to treat?

INTRODUCTION: Sarcoidosis is a non-caseating, granulomatous disease of incompletely understood aetiology that can affect nearly all organs including the liver. Hepatic involvement is thought to occur in 50-90% of patients but may remain undiagnosed in many cases. Evidence-based guidelines for the treatment of sarcoidosis of the liver are lacking. Patients usually receive no treatment or are treated pragmatically with corticosteroids. However, treatment with systemic corticosteroids has had mixed results. The use of ursodeoxycholic acid (UDCA) in the treatment of sarcoidosis-associated cholestasis has been reported by several groups, and is empirically prescribed to sarcoidosis patients with hepatic involvement. METHODS: The effect of UDCA on symptoms and serum liver tests was investigated in a retrospective cohort study in which hepatic sarcoidosis patients had received either no treatment, prednisolone treatment or UDCA treatment. For all patients, laboratory results on ASAT, ALAT, AP and GGT were collected. Patients described the severity of their symptoms before and after treatment on a numerical scale. RESULTS: A total of 17 patients participated in the study. Serum liver tests in the group treated with UDCA had improved as compared with the other groups. Also, symptomatic improvement of pruritus and fatigue was reported in the group treated with UDCA. CONCLUSION: This retrospective cohort study supports the empirical first-line use of UDCA in the treatment of sarcoidosis of the liver, especially in symptomatic patients. Prospective randomised trials are needed to adequately support this concept.

The 2012 revised Dutch national guidelines for the treatment of chronic hepatitis B virus infection.

In 2008, the Netherlands Association of Gastroenterologists and Hepatologists (Nederlands Vereniging van Maag-Darm-Leverartsen) published the Dutch national guidelines for the treatment of chronic hepatitis B virus infection. New insights into the treatment of chronic hepatitis B with relevance for clinical practice have been adopted in these concise, revised guidelines. The most important changes include the choice of initial antiviral therapy, licensing of tenofovir for the treatment of chronic hepatitis B and the management of antiviral resistance.

Chronic hepatitis E after solid organ transplantation.

Large outbreaks of acute hepatitis E, caused by hepatitis E virus (HEV) genotypes 1 and 2, are known from developing countries with suboptimal sanitation infrastructure. An increasing incidence of HEV infections is being reported in industrialised countries, caused mainly by HEV genotypes 3 and 4, which are often found among pigs. Recent evidence suggests that in immunocompromised patients about 50% of the cases of acute hepatitis E evolve to chronic hepatitis with rapid progression to cirrhosis. Thus, HEV should be considered a cause of chronic hepatitis in immunocompromised patients, such as solid organ transplant recipients. Because an antibody response to HEV may be absent in these patients, an HEV RNA test should be carried out when serum liver tests are elevated over months. In small case series, ribavirin has been shown to represent a promising treatment option for chronic HEV infection. To increase the awareness for HEV infection in immunocompromised patients, a representative case report of an HEV-infected renal transplant recipient with chronic hepatitis E, successfully treated with ribavirin, is presented. Studies are required to determine the optimal duration of ribavirin therapy and to assess outcome for solid organ transplant recipients with chronic HEV infection.

Molecular targets for the treatment of fibrosing cholangiopathies.

Emerging pathophysiologic insights are leading to novel approaches to treating fibrosing cholangiopathies. The current treatment, using ursodeoxycholic acid (UDCA), may slow the progression of some chronic cholangiopathies but cannot heal them. Apart from immunosuppressive interventions aimed at minimizing immune-mediated damage, the use of specific modifiers of hepatobiliary secretory and cytoprotective mechanisms may eventually give rise to a new class of disease-modifying anti-cholangiofibrotic drugs.

[Cholestatic pruritus : new insights into pathophysiology and current treatment]. / Cholestatischer Pruritus : Neues zur Pathophysiologie und aktuelle Therapie.

Pruritus is a common symptom of hepatobiliary disorders and may considerably diminish quality of life. Cholestatic pruritus exerts a circadian rhythm and is typically most severe in the evening hours and early at night. Itching is reported often to be most intense at the palms and the soles, but may also be generalized. The pathophysiological mechanisms of cholestatic pruritus have not been completely clarified. In the past, bile salts, histamine, progesterone metabolites and opioids have been discussed as potential causal substances; a correlation with itch intensity could never be proven. The enzyme autotaxin, which releases lysophosphatidic acid, has recently been identified as potential cholestatic pruritogen. Treatment aims to bind pruritogens in the gut lumen by resins such as cholestyramine, to modulate pruritogen metabolism by rifampicin and to influence central itch signaling by µ-opioid antagonists and selective serotonin re-uptake inhibitors. In cases of refractory pruritus experimental treatment options such as UV-therapy, extracorporeal albumin dialysis and nasobiliary drainage may be considered.

The challenge of cholestatic pruritus.

Pruritus can be the dominant symptom of cholestatic liver disease but is difficult to treat since unraveling its pathophysiology is a great challenge. Serum autotaxin activity correlates with pruritus intensity, but its causal relationship, expression pattern and exact mode of action during cholestasis remain to be established. The anion exchange resin cholestyramine, the PXR agonist rifampicin, the opioid antagonist naltrexone and the serotonine reuptake inhibitor sertraline are recommended by evidence-based guidelines as stepwise therapeutic approaches to treat itch in cholestasis. Rifampicin, the most effective antipruritic agent in cholestatic itch, has been shown to reduce autotaxin transcription in vitro. Experimental approaches include UVB phototherapy, extracorporeal albumin dialysis, nasobiliary drainage and in desperate cases even liver transplantation. Relevant clinical observations along with the different metabolic, neurologic and endocrine targets of available therapies in cholestatic pruritus are reviewed here.

What an endoscopist should know about immunoglobulin-G4-associated disease of the pancreas and biliary tree.

Autoimmune pancreatitis (AIP) and IgG4-associated cholangitis (IAC) are the recently recognized pancreatobiliary manifestations of IgG4-associated systemic disease (ISD). Clinically, ISD of the pancreas and/or biliary tree may mimic pancreatic cancer, sclerosing cholangitis, or cholangiocarcinoma. Patients often present with abdominal pain, weight loss, jaundice, itch, and biochemical signs of pancreatitis and cholestasis. Tomography may reveal enlargement of the pancreas or may mimic malignant pancreatic lesions, and cholangiopancreatography may disclose irregularities of the pancreatic duct and stenoses of the distal and/or proximal common bile duct and intrahepatic bile ductules. Serum immunoglobulin G4 (IgG4) is elevated in most patients but, unlike tissue IgG4-loaded plasma cell infiltrates, is not diagnostic of the disease. The application of consensus diagnostic criteria for laboratory investigations, imaging, and histologic findings can identify patients who qualify for corticosteroid treatment. The excellent response to immunosuppressive therapy suggests an immune-mediated etiology of the disease, but the exact pathophysiological mechanisms are still under investigation. Relapse may occur after tapering down of corticosteroids, which supports the rationale of maintenance immunosuppression after remission has been induced.

Malignancies associated with chronic hepatitis C: case report and review of the literature.

Hepatocellular carcinoma (HCC) is a well-known consequence of hepatitis C virus (HCV) infection mainly in cirrhotic patients. Associations of other malignancies such as cholangiocellular carcinoma and B-cell malignancies with HCV are less well known. Here we review pathophysiological aspects of malignancies associated with HCV infection. A case report of HCV-related HCC and B-cell lymphoma illustrates the increased risk for HCV-infected patients to develop other malignancies besides HCC.

The role of mycophenolate mofetil in the management of autoimmune hepatitis and overlap syndromes.

BACKGROUND: Treatment failure occurs in 20% of autoimmune hepatitis patients on prednisolone and azathioprine (AZA). There is no established second line treatment. AIM: To assess the efficacy of mycophenolate mofetil as second line treatment after AZA-intolerance or AZA-nonresponse in autoimmune hepatitis and overlap syndromes. METHODS: Consecutive patients from the Dutch Autoimmune Hepatitis Group cohort, consisting of 661 patients, with autoimmune hepatitis or overlap syndromes, AZA-intolerance or AZA-nonresponse and past or present use of mycophenolate mofetil were included. Primary endpoint of mycophenolate mofetil treatment was biochemical remission. Secondary endpoints were biochemical response (without remission), treatment failure and prevention of disease progression. RESULTS: Forty-five patients treated with mycophenolate mofetil were included. In autoimmune hepatitis remission or response was achieved in 13% and 27% in the AZA-nonresponse group compared to 67% and 0% in the AZA-intolerance group (P = 0.008). In overlap-syndromes remission or response was reached in 57% and 14% in the AZA-nonresponse group and 63% and 25% of the AZA-intolerance group (N.S.); 33% had side effects and 13% discontinued mycophenolate mofetil. Overall 38% had treatment failure; this was 60% in the autoimmune hepatitis AZA-nonresponse group. Decompensated liver cirrhosis, liver transplantations and death were only seen in the autoimmune hepatitis AZA-nonresponse group (P < 0.001). CONCLUSIONS: Mycophenolate mofetil induced response or remission in a majority of patients with autoimmune hepatitis and azathioprine-intolerance and with overlap syndromes, irrespective of intolerance or nonresponse for azathioprine. In autoimmune hepatitis with azathioprine nonresponse mycophenolate mofetil is less often effective.