Nadine Pannicke

Infliximab as a rescue treatment in difficult-to-treat autoimmune hepatitis

BACKGROUND & AIMS Autoimmune hepatitis is a chronic inflammatory liver disease that leads to liver cirrhosis and corresponding complications, if left untreated. Current standard treatment with azathioprine and prednisolone induces remission in the vast majority of patients. However, for those patients not responding to standard treatment or not tolerating these drugs, few alternatives can be used and their effectiveness might be limited. We sought to analyze the safety and efficacy of off-label treatment with infliximab in a cohort of eleven patients with difficult-to-treat autoimmune hepatitis. METHODS Patients with difficult-to-treat autoimmune hepatitis who could not be brought into remission with standard treatment, either due to drug intolerance or to insufficient drug impact, were treated off-label with infliximab for a minimum of six months. Patient files were reviewed retrospectively. RESULTS Treatment with infliximab led to reduction of inflammation, evidenced by a decrease in transaminases (mean AST prior treatment 475 U/L ± 466, mean AST during treatment 43 U/L ± 32) as well as in immunoglobulins (pretreatment mean IgG 24.8 mg/dl ± 10.1, mean IgG during treatment 17.38 mg/dl ± 6). Infectious complications occurred in seven out of eleven patients and close monitoring was necessary. CONCLUSIONS Infliximab may be considered as rescue therapy in patients with difficult-to-treat autoimmune hepatitis, albeit treatment may be associated with infectious complications.

Biliary Strictures and Recurrence After Liver Transplantation for Primary Sclerosing Cholangitis: A Retrospective Multicenter Analysis

Liver transplantation (LT) is the only definitive treatment for patients with end‐stage liver disease due to primary sclerosing cholangitis (PSC), but a high rate of biliary strictures (BSs) and of recurrent primary sclerosing cholangitis (recPSC) has been reported. In this multicenter study, we analyzed a large patient cohort with a long follow‐up in order to evaluate the incidence of BS and recPSC, to assess the impact on survival after LT, and to identify risk factors. We collected clinical, surgical, and laboratory data and records on inflammatory bowel disease (IBD), immunosuppression, recipient and graft outcome, and biliary complications (based on cholangiography and histology) of all patients who underwent LT for PSC in 10 German transplant centers between January 1990 and December 2006; 335 patients (68.4% men; mean age, 38.9 years; 73.5% with IBD) underwent transplantation 8.8 years after PSC diagnosis with follow‐up for 98.8 months. The 1‐, 5‐, and 10‐year recipient and graft survival was 90.7%, 84.8%, 79.4% and 79.1%, 69.0%, 62.4%, respectively. BS was diagnosed in 36.1% after a mean time of 3.9 years, and recPSC was diagnosed in 20.3% after 4.6 years. Both entities had a significant impact on longterm graft and recipient survival. Independent risk factors for BS were donor age, ulcerative colitis, chronic ductopenic rejection, bilirubin, and international normalized ratio (INR) at LT. Independent risk factors for recPSC were donor age, IBD, and INR at LT. These variables were able to categorize patients into risk groups for BS and recPSC. In conclusion, BS and recPSC affect longterm graft and patient survival after LT for PSC. Donor age, IBD, and INR at LT are independent risk factors for BS and recPSC and allow for risk estimation depending on the recipient‐donor constellation. Liver Transpl 22:42‐52, 2016.

Low Risk of Hepatocellular Carcinoma in Patients With Primary Sclerosing Cholangitis With Cirrhosis

BACKGROUND & AIMS Primary sclerosing cholangitis (PSC) is associated with an increased risk of hepatobiliary malignancies. However, little is known about the incidence of hepatocellular carcinoma (HCC) among patients with PSC; current recommendations on screening these patients for HCC are conflicting. We investigated the risk of HCC in patients with PSC with cirrhosis. METHODS We performed a retrospective study of patients with well-defined PSC from 2 large-volume tertiary care centers in Germany; data were collected from periods of up to 33 years. Liver cirrhosis was based on histology results or the presence of ascites, esophageal varices, or transient elastography values greater than 14 kPa. Statistical analysis was performed using the Kaplan-Meier method and the Cox proportional hazard model. Data from 509 patients (67% male), with a total of 4202 patients-years, were included in the final analysis. RESULTS We identified 119 patients with cirrhosis. During 292 patient-years, none of these patients developed HCC. Most HCCs were identified incidentally at the time of liver transplantation. We therefore reviewed data on liver explants from 140 patients who underwent transplantation; none were found to contain HCC. In contrast to the low numbers of HCCs among patients with PSC, 35 patients developed cholangiocarcinoma, 3 patients developed gallbladder cancer, and 9 patients developed colorectal cancer. CONCLUSIONS Based on a retrospective analysis of more than 500 patients with PSC, we confirm their high risk for hepatobiliary malignancies. However, the risk of HCC, even among patients with cirrhosis, seems to be low--regular HCC surveillance may not be warranted.

Transient elastography in autoimmune hepatitis: Timing determines the impact of inflammation and fibrosis.

BACKGROUND & AIMS There is an unmet need for the non-invasive monitoring of fibrosis progression in patients with autoimmune hepatitis (AIH). The aim of this study was to assess the diagnostic performance of transient elastography in patients with AIH and to investigate the impact of disease activity on its diagnostic accuracy. METHODS Optimal cut-offs were defined in a prospective pilot study (n=34) and the diagnostic performance of transient elastography validated in an independent second cohort (n=60). To explore the impact of disease activity on liver stiffness, patients were stratified according to biochemical response and the time interval between start of immunosuppression and transient elastography. RESULTS Liver stiffness strongly correlated with histological fibrosis stage (pilot study: ρ=0.611, p<0.001; validation cohort: ρ=0.777, p<0.0001). ROC curves defined an area under the receiver operating curve of 0.95 for diagnosing cirrhosis at the optimal cut-off of 16kPa. The performance of transient elastography was impaired when patients were analysed in whom transient elastography was performed within 3months from start of treatment. In this setting, liver stiffness correlated with histological grading (ρ=0.558, p=0.001), but not with staging. In contrast, using the cut-off of 16kPa, the accuracy for diagnosing cirrhosis was excellent in patients treated for 6months or longer (area under the receiver operating curve 1.0). CONCLUSIONS Liver inflammation has a major impact on liver stiffness in the first months of AIH treatment. However, transient elastography has an excellent diagnostic accuracy for separating severe from non-severe fibrosis after 6months of immunosuppressive treatment. LAY SUMMARY Transient elastography is a special ultrasound scan, which assesses liver stiffness as a surrogate marker for liver fibrosis/scarring. Transient elastography has been shown to be a reliable non-invasive method to assess liver fibrosis in various chronic liver diseases, it takes less than 5min and has a high patient acceptance. The current study validated for the first time this technique in a large cohort of patients with autoimmune hepatitis (AIH) and demonstrates that it is a reliable tool to detect liver fibrosis in treated AIH. For the monitoring of potential disease progression under treatment, the validation of liver stiffness as non-invasive marker of liver fibrosis will greatly improve patient care in autoimmune hepatitis.

Efficacy and Limitations of Budesonide as a Second-Line Treatment for Patients With Autoimmune Hepatitis

BACKGROUND & AIMS: Many patients with autoimmune hepatitis (AIH) develop steroid‐specific side effects or require doses of steroids that are unacceptable for long‐term treatment. We investigated the efficacy of budesonide as an alternative steroid for patients previously treated with prednisolone who developed side effects or were unable to reduce their dose of prednisolone below acceptable levels. We also report the effects of more than 12 months of budesonide treatment in a large cohort of patients with AIH. METHODS: We performed a retrospective analysis of data from 60 patients (51 female) with AIH who were treated initially with prednisolone (mean time, 47 mo) but then switched to budesonide, managed at a single center in Germany from 2001 through June 2016. Patients were evaluated after 6 months, 12 months, 24 months, 36 months, and at the last follow‐up evaluation; response to treatment with budesonide was assessed based on normal serum levels of aminotransferases and IgG (biochemical response). RESULTS: Thirty patients were switched to budesonide therapy because of prednisolone‐induced side effects and 30 patients switched because of prednisolone dependency. Overall, a biochemical response was detected in 55% of patients after 6 months of budesonide treatment, in 70% after 12 months, and in 67% after 24 months. At the last follow‐up evaluation (mean time, 63 mo) 23 patients (38%) still were receiving budesonide treatment. Fifteen patients (25%) had switched back to prednisolone therapy because of insufficient response to budesonide or its side effects. Fifteen patients with osteopenia at the beginning of budesonide treatment were followed up and evaluated by dual‐energy X‐ray absorptiometry. After a median of 24 months of budesonide treatment, bone mineral density had improved in 6 patients, remained stable in 8 patients, and worsened in 1 patient. CONCLUSIONS: We performed a retrospective analysis of patients with AIH that confirmed the therapeutic value of budesonide beyond 12 months of treatment in patients who are intolerant to or dependent on prednisolone. Although budesonide‐induced side effects appear to be mild in real life, effectiveness was limited in a considerable proportion of patients; close monitoring is advised.

Combined glucocorticoid and antiviral therapy of hepatitis B virus-related liver failure

Acute hepatic failure due to hepatitis B virus (HBV) can occur both during primary infection as well as after reactivation of chronic infection. Guidelines recommend considering antiviral therapy in both situations, although evidence supporting this recommendation is weak. Since HBV is not directly cytopathic, the mechanism leading to fulminant hepatitis B is thought to be primarily immune-mediated. Therefore, immunosuppression combined with antiviral therapy might be a preferred therapeutic intervention in acute liver failure in hepatitis B. Here we report our favourable experience in three hepatitis B patients with fulminant hepatic failure who were treated by combining high-dose steroid therapy with standard antiviral treatment, which resulted in a rapid improvement of clinical and liver parameters.

Heparin-induced thrombocytopenia associated with acute liver graft failure

An orthotopic liver transplantation (OLT) is of a proven benefit in an acute liver failure (ALF). Heparin-induced thrombocytopenia (HIT) is strongly associated with thromboembolic complications. We present the case of a 56-year-old patient who underwent an OLT owing to an ALF of unknown aetiology. HIT type II with consecutive hepatic and portal vein thrombosis caused progressive graft failure. Total hepatectomy and porto-caval shunt were performed to reduce the toxic effects of liver cell necrosis such as multiorgan failure involving the respiratory, renal and cardiovascular systems. A suitable liver graft was allocated after an anhepatic bridging period of 56 h. Specific complications due to end-stage liver failure—such as acidosis, coagulopathy, decrease of vascular resistance, cerebral oedema, myocardial infarction and right heart failure—were treated. Following a re-OLT, the patient made a complete recovery. We present a rare case of HIT-associated early liver graft failure followed by a prolonged anhepatic phase and finally a successful re-OLT.

Elevated γ-Glutamyltransferase

Question: A 50-yearold man was referred to our department for further investigation of suspected chronic liver disease. He had known elevated gamma-glutamyltransferase (GGT) serum levels for the past 10 –15 years. A diagnostic procedure was initiated by his general practitioner because of abdominal discomfort and heartburn. This inluded abdominal magnetic resonance imaging (MRI). After intravenous administration of gadolinium an inhomogeneous and nodular ppearing liver tissue raised the suspicion of chronic liver disease and potential liver cirrhosis (Figure A). There were no cystic lesions. The gallbladder and bile ducts seemed normal. The patients presented to our department without any signs of chronic liver disease and he was not obese. His regular prescription included a calcium antagonist, statin, and beta-blocker for arterial hypertension and hyperlipidemia. For his abdominal complaints, he was taking omeprazole on demand. Regular alcohol consumption and drug abuse were denied. The laboratory workup showed an elevated serum GGT level of 157 U/L (normal, 66) with the other liver enzymes and complete blood count within the normal range. There was no evidence of autoimmune liver disease, viral hepatitis, or metabolic liver disease. Ultrasonography revealed a diffusely inhomogeneous liver parenchyma, but no clear signs of liver cirrhosis or mass lesions. There was no evidence of splenomegaly suggestive of portal hypertension. Because the etiology of his liver disease remained unclear, mini-laparoscopy with liver biopsy was performed. Macroscopically, both liver lobes were interspersed with whitish, indented lesions giving the liver surface an irregular and nodular appearance (Figure B; Video Clip). What is the diagnosis? See the GASTROENTEROLOGY web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI.