Malte H. Wehmeyer

Acute Hepatitis E: Two Sides of the Same Coin

The relevance of acute hepatitis E virus (HEV) infections has been underestimated for a long time. In the past, HEV infection had been interpreted falsely as a disease limited to the tropics until the relevance of autochthonous HEV infections in the Western world became overt. Due to increased awareness, the incidence of diagnosed autochthonous HEV infections (predominantly genotype 3) in industrialized countries has risen within the last decade. The main source of infections in industrialized countries seems to be infected swine meat, while infections with the tropical HEV genotypes 1 and 2 usually are mainly transmitted fecal-orally by contaminated drinking water. In the vast majority of healthy individuals, acute HEV infection is either clinically silent or takes a benign self-limited course. In patients who develop a symptomatic HEV infection, a short prodromal phase with unspecific symptoms is followed by liver specific symptoms like jaundice, itching, uncoloured stool and darkened urine. Importantly, tropical HEV infections may lead to acute liver failure, especially in pregnant women, while autochthonous HEV infections may lead to acute-on-chronic liver failure in patients with underlying liver diseases. Immunosuppressed individuals, such as transplant recipients or human immunodeficiency virus (HIV)-infected patients, are at risk for developing chronic hepatitis E, which may lead to liver fibrosis and cirrhosis in the long term. Importantly, specific treatment options for hepatitis E are not approved by the regulation authorities, but off-label ribavirin treatment seems to be effective in the treatment of chronic HEV-infection and may reduce the disease severity in patients suffering from acute liver failure.

Nonalcoholic fatty liver disease is associated with excessive calorie intake rather than a distinctive dietary pattern

AbstractWe aimed to assess the dietary patterns associated with nonalcoholic fatty liver disease (NAFLD) and the efficacy of dietary interventions in a real-life setting at a tertiary medical center in Northern Germany.Clinical and laboratory data as well as data obtained by a semiquantitative food frequency questionnaire of 55 consecutive patients diagnosed with NAFLD were compared to an age and gender-matched cohort of 88 healthy individuals by univariate analysis. The efficacy of the dietary intervention was assessed in a subgroup of 24 NAFLD patients 6 months after receiving dietary advice. Macronutritional components of the diet were normalized for absolute daily energy intake.NAFLD patients consumed more calories per day as compared with healthy controls (P <0.001). The absolute amounts of most nutritional components ingested by NAFLD patients were higher than those of the controls. However, there were no significant differences with regards to the relative consumption of carbohydrates (P = 0.359), fat (P = 0.416), and fructose (P = 0.353) per 1000 kcal energy intake. NAFLD patients displayed a higher intake of glucose/1000 kcal (P = 0.041) and protein/1000 kcal (P = 0.009) but a lower intake of fibers/1000 kcal (P < 0.001) and mineral nutrients/1000 kcal (P = 0.001) than healthy controls. In the longitudinal analysis patients significantly reduced their caloric intake and their ALT levels improved 6 months after the dietary counselling (P < 0.001).Our data from a German real-life cohort demonstrate that dietary patterns of patients with NAFLD display great variability and little disease specificity, while the most distinctive feature compared with healthy controls was higher energy intake in NAFLD patients.

Real-world effectiveness of sofosbuvir-based treatment regimens for chronic hepatitis C genotype 3 infection: Results from the multicenter German hepatitis C cohort (GECCO-03)

There are limited data regarding the real world effectiveness of direct acting antivirals (DAA) for the therapy of chronic genotype 3 hepatitis C virus (HCV) infection. All HCV genotype 3 infected patients from the German hepatitis C cohort (GECCO), which is a prospective database of nine German hepatitis C treatment centers, were included in the study. Three hundred forty‐two chronically infected HCV genotype 3 patients were analyzed (253 males [74.0%], mean age 47.3 years, 127 cirrhotic patients [37.1%] mostly with Child A cirrhosis, 113 treatment experienced patients [37.1%], 38 HCV/HIV co‐infected patients [11.1%]). SVR12 rates in the “intention‐to‐treat” analysis were as follows: sofosbuvir/ribavirin 69.4% (75/108), sofosbuvir/peginterferon/ribavirin 80.6% (58/72), sofosbuvir/daclatasvir ± ribavirin for 12 weeks 88.3% (53/63), sofosbuvir/daclatasvir ± ribavirin for 24 weeks 79.3% (23/29), sofosbuvir/ledipasvir ± ribavirin for 12 weeks 71.4% (10/14), and sofosbuvir/ledipasvir ± ribavirin for 24 weeks 86.7% (26/30). Forty patients were lost to follow‐up, 23 patients had a relapse, 4 patients stopped treatment prematurely and 1 patient died. Female sex (P = 0.038) and treatment with two different DAAs (P = 0.05) were predictors for SVR12 in the multivariate analysis. In conclusion, sofosbuvir/daclatasvir ± ribavirin for 12 weeks and sofosbuvir/ledipasvir ± ribavirin for 24 weeks are effective for the treatment of HCV genotype 3 infected patients including cirrhotic, treatment‐experienced or HIV/HCV co‐infected patients.

Effect of antiviral therapy for HCV on lipid levels.

BACKGROUND HCV has complex interactions with human lipid metabolism leading to down regulation of cholesterol levels. Interferon (IFN) therapy has been shown to decrease cholesterol even further. With the availability of second-generation direct-acting antiviral agents (DAA) the effect of suppressing and eliminating HCV on lipid metabolism warrants reevaluation. METHODS Prospective German multicentre cohort on HCV- and HIV-HCV-infected patients treated with direct-antiviral agents (GECCO). Lipids were assessed at baseline, during and after therapy. Wilcoxon test corrected for multiple testing was used. RESULTS For the analysis, 520 patients with chronic hepatitis C were available. Patients with chronic hepatitis C were treated as follows: sofosbuvir (SOF)/pegylated IFN (PEG-IFN)/ribavirin (RBV; HCV=34, HIV-HCV=36), SOF/RBV (HCV=47, HIV-HCV=16), SOF/simeprevir (HCV=9, HCV-HIV=2), SOF/daclatasvir +/- RBV (HCV=27, HIV-HCV=47), SOF/ledipasvir +/- RBV (HCV=147, HCV-HIV=100) and ombitasvir/paritaprevir/ritonavir +/- dasabuvir +/- RBV (2D, HCV=2, HCV-HIV=6; 3D, HCV=39, HCV-HIV=8). On treatment there was a statistically significant increase in total cholesterol for any IFN-free DAA regimen, which was maintained after end of therapy. Changes of total cholesterol were driven by changes in low-density lipoprotein cholesterol, whereas high-density lipoprotein cholesterol remained unchanged. In contrast, total cholesterol decreased on SOF/PEG-IFN/RBV and increased after end of therapy above baseline levels. Triglycerides increased during treatment with SOF/PEG-IFN/RBV, but not on DAA-only regimens. CONCLUSIONS Suppressing and eliminating HCV with IFN-free DAA regimens increased cholesterol levels, but had no effect on triglycerides. In contrast IFN-based therapy decreased cholesterol and increased triglycerides during treatment and led to increases in cholesterol after achieving sustained virological response.

Efficacy and safety of sofosbuvir-based triple therapy in hepatitis C genotype 4 infection

BACKGROUND There are only limited data on sofosbuvir-based treatment regimens in hepatitis C virus (HCV) genotype 4-infected patients. AIMS To evaluate safety and efficacy of sofosbuvir-based triple-therapy in HCV genotype 4 infection. METHODS All HCV genotype 4-infected patients who started sofosbuvir-based triple-therapy at our two centres between January and June 2014 were prospectively included (N=24) and compared to genotype 4 patients treated with peginterferon/ribavirin between January 2001 and December 2012 (N=63). RESULTS The demographics in the sofosbuvir group and the controls were comparable (males 87.5% and 82.5%; mean age 46.7±9.0 years and 42.0±9.8 years, respectively). Sustained virological response was achieved in 83.3% in the sofosbuvir group and in 47.6% of controls (P=0.003). Fatigue (P=0.007), flu-like (P=0.015), gastrointestinal (P<0.001), dermatologic (P<0.001) and psychiatric symptoms (P=0.022) were more common in the control group. CONCLUSIONS In our real-life cohort, sofosbuvir-based triple therapy confirmed its high efficacy and safety for chronic genotype 4 hepatitis C.

Infections complicating severe alcoholic hepatitis: Enterococcus species represent the most frequently identified pathogen.

Abstract Background: Patients with acute alcoholic steatohepatitis are at a high risk for infections. To date, neither disease-specific pathogen patterns, nor typical sites of infection, nor antibiotic treatment strategies have been established for AH. Aims: To characterize incidence of infections, pathogen spectrum, sites of infection, and related mortality of patients with AH under steroid therapy. Methods: We retrospectively analyzed clinical data of 73 patients with severe alcoholic hepatitis (MELD ≥ 20). Results: Infections were detected in 45 patients (73%). Patients who developed an infection after initiation of corticosteroid therapy had a higher 6-month mortality than patients without onset of infection after initiation of corticosteroid treatment (44% versus 24%, p = 0.116). The pathogen identified most frequently was Enterococcus species. Discussion: Infections frequently complicate severe alcoholic hepatitis and affect survival. The high rate of Enterococcus infections suggests that commonly used antibiotics, such as cephalosporins and quinolones, may represent an ineffective choice of empiric antibiotic treatment for complicated AH.

High Rate of Cardiac Abnormalities in a Postmortem Analysis of Patients Suffering From Liver Cirrhosis.

Background: Cirrhotic cardiomyopathy is a recently defined cardiac disorder in patients with end-stage liver disease. The frequency and exact manifestations of cardiac changes in liver cirrhosis is unknown. Goals: We aim to describe cardiac changes in a large autopsy study of patients with liver cirrhosis. Study: Postmortem data from 895 individuals with liver cirrhosis of different origin autopsied from 1995 to 2010 were analyzed. A total of 236 patients were excluded, mostly due to an advanced age above 70 years. The remaining 659 patients were assigned to 4 subgroups according to the etiology of cirrhosis: alcoholic cirrhosis (57.4%), nonalcoholic steatohepatitis (4.2%), viral hepatitis (9.3%), and cryptogenic cirrhosis (29.1%). Predefined clinical and cardiac parameters were assessed in these groups and compared by univariate and multivariate analyses to an age-matched and sex-matched control group including 40 deceased patients without evidence of chronic liver disease. Results: A critical heart weight (24%, P=0.024), hypertrophy of the right ventricle (24%, P<0.001), and dilatation of the right ventricle (36%, P=0.040) were significantly more frequent in the cirrhosis group compared with noncirrhotic controls. Cirrhosis patients had a greater risk for high-grade coronary sclerosis (30%, P=0.019). The etiology of cirrhosis was independently associated with hypertrophy and dilatation of the right ventricle, with nonalcoholic steatohepatitis patients being at the highest risk. Conclusion: Our results demonstrate a high rate of right-ventricular abnormalities and coronary sclerosis in individuals suffering from liver cirrhosis regardless of the etiology of cirrhosis.

Prediction of spontaneous bacterial peritonitis in cirrhotic ascites by a simple scoring system.

Abstract Background and aims. Spontaneous bacterial peritonitis (SBP) is a life-threatening complication in patients with liver cirrhosis. The aim of this prospective study was to identify predictors of SBP in order to develop a noninvasive method to identify or exclude an episode of SBP. Patients and methods. Three hundred and ninety-two consecutive patients, who underwent paracentesis from March 2008 through January 2012 in our department due to cirrhotic ascites, were screened. Ninety-six patients were excluded, mostly due to prior application of antibiotics. SBP was defined by an absolute neutrophil count ≥250 cells/µL ascites. We evaluated various clinical and laboratory parameters as potential predictors of SBP. A scoring system was developed in a training set of 220 and validated in a second set of 76 patients. Results. Fifty-eight patients (26%) in the training set and 17 patients in the validation set (22%) suffered from SBP. Thrombocytopenia ≤100,000 cells/µL, age >60 years and CRP >60 mg/L were identified as independent predictors of SBP. A scoring system combining these three parameters (weighting thrombocytopenia and age with 1 point each, but CRP with 2 points) reaches a positive predictive value for the diagnosis of SBP of 81.8% with a specificity of 98.8% (score ≥3). The negative predictive value at a threshold of 1 point is 93.5% with a sensitivity of 87.9%. Notably, a high MELD score is not associated with SBP (p = 0.3344). Conclusions. Combination of age, CRP and platelet count in a simple scoring system helps in the rapid diagnosis or exclusion of SBP.

Factors associated with long-term survival after liver transplantation: A retrospective cohort study

AIM To identify predictive factors associated with long-term patient and graft survival (> 15 years) in liver transplant recipients. METHODS Medical charts of all de novo adult liver transplant recipients (n = 140) who were transplanted in Hamburg between 1997 and 1999 were retrospectively reviewed. In total, 155 transplantations were identified in this time period (15 re-transplantations). Twenty-six orthotopic liver transplant (OLT) recipients were early lost to follow-up due to moving to other places within 1 year after transplantation. All remaining 114 patients were included in the analysis. The following recipient factors were analysed: Age, sex, underlying liver disease, pre-OLT body mass index (BMI), and levels of alanine aminotransferase (ALT), bilirubin, creatinine and gamma-glutamyltransferase (gamma-GT), as well as warm and cold ischemia times. Furthermore, the following donor factors were assessed: Age, BMI, cold ischemia time and warm ischemia time. All surviving patients were followed until December 2014. We divided patients into groups according to their underlying diagnosis: (1) hepatocellular carcinoma (n = 5, 4%); (2) alcohol toxic liver disease (n = 25, 22.0%); (3) primary sclerosing cholangitis (n = 6, 5%); (4) autoimmune liver diseases (n = 7, 6%); (5) hepatitis C virus cirrhosis (n = 15, 13%); (6) hepatitis B virus cirrhosis (n = 21, 19%); and (7) other (n = 35, 31%). The group “other” included rare diagnoses, such as acute liver failure, unknown liver failure, stenosis and thrombosis of the arteria hepatica, polycystic liver disease, Morbus Osler and Caroli disease. RESULTS The majority of patients were male (n = 70, 61%). Age and BMI at the time point of transplantation ranged from 16 years to 69 years (median: 53 years) and from 15 kg/m2 to 33 kg/m2 (median: 24), respectively. Sixty-six OLT recipients (58%) experienced a follow-up of 15 years after transplantation. Recipient’s age (P = 0.009) and BMI (P = 0.029) were identified as risk factors for death by χ2-test. Kaplan-Meier analysis confirmed BMI or age above the median as predictors of decreased long-term survival (P = 0.008 and P = 0.020). Hepatitis B as underlying disease showed a trend for improved long-term survival (P = 0.049, χ2-test, P = 0.055; Kaplan-Meier analysis, Log rank). Pre-transplant bilirubin, creatinine, ALT and gamma-GT levels were not associated with survival in these patients of the pre-era of the model of end stage liver disease. CONCLUSION The recipients’ age and BMI were predictors of long-term survival after OLT, as well as hepatitis B as underlying disease. In contrast, donors’ age and BMI were not associated with decreased survival. These findings indicate that recipient factors especially have a high impact on long-term outcome after liver transplantation.

The Impact of Individual Patient Data in a Network Meta Analysis: An investigation into parameter estimation and model selection

The use of individual patient data (IPD) in network meta-analysis (NMA) is becoming increasingly popular. However, as most studies do not report IPD, most NMAs are performed using aggregate data for at least some, if not all, of the studies. We investigate the benefits of including varying proportions of IPD studies in an NMA. Several models have previously been developed for including both aggregate data and IPD in the same NMA. We performed a simulation study based on these models to examine the impact of additional IPD studies on the accuracy and precision of the estimates of both the treatment effect and the covariate effect. We also compared the deviance information criterion (DIC) between models to assess model fit. An increased proportion of IPD resulted in more accurate and precise estimates for most models and datasets. However, the coverage probability sometimes decreased when the model was misspecified. The use of IPD leads to greater differences in DIC, which allows us choose the correct model more often. We analysed a Hepatitis C network consisting of 3 IPD observational studies. The ranking of treatments remained the same for all models and datasets. We observed similar results to the simulation study: The use of IPD leads to differences in DIC and more precise estimates for the covariate effect. However, IPD sometimes increased the posterior SD of the treatment effect estimate, which may indicate between study heterogeneity. We recommend that IPD should be used where possible, especially for assessing model fit.