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Autoimmune hepatitis is a chronic liver disease which, if untreated, can lead to cirrhosis of the liver and liver failure. The majority of patients respond well to standard immunosuppressive therapy, but some experience adverse effects, or lack of treatment efficacy. Diagnosis, assessment of therapeutic response and choice of second-line therapy may be challenging. This article provides a summary of updated knowledge concerning diagnosis and treatment of patients with complex autoimmune hepatitis.

Background & aims The prognostic role of gender in patients with liver cirrhosis is not fully understood. Our primary aim was to assess how gender affects cumulative incidence and risk of death without liver transplantation (LT) in cirrhotic patients with gastroesophageal varices. Secondary aims were to assess the relationship between gender and cause specific death, risk of variceal bleeding and incidence rates of gastroesophageal varices in patients with cirrhosis. Methods All new patients with gastroesophageal varices due to liver cirrhosis at Oslo University Hospital between 2006 and May 2016 were identified. Clinical data were retrieved retrospectively from hospital files. Causes of death were classified according to a specified protocol in cases of in-hospital-death, otherwise by data from the Norwegian Death Registry. Competing risk analyses were used to calculate cumulative incidences and risks of i) all-cause death, ii) cause-specific death and iii) variceal bleeding or re-bleeding. Results Cumulative one- and five years incidence of death without LT in 266 included patients were 28% and 51%, respectively. In univariate analysis, risk of death was positively associated with age, Child Pugh class, alcoholic liver disease and presentation with variceal bleeding, and negatively associated with female sex. In a multivariate model, risk of death without LT was associated with female sex (SHR 0.59 [0.40–0.86]), age (SHR 1.05 [1.04–1.07] per year), Child Pugh class B (SHR 1.54 [1.03–2.32]) and Child Pugh class C (SHR 4.29 [2.57–7.17]). Variceal bleeding caused 27% of deaths. Adjusting for age and Child Pugh score, a trend towards reduced risk of death due to variceal bleeding was seen in women (SHR 0.53; [0.26–1.06]). High alcohol consumption was associated with increased risk of first variceal bleeding, both at univariate analysis (SHR 7.73 [1.71–34.9]) and multivariate analysis (SHR 13.9 [2.51–77.0]). Conclusions Reduced mortality due to variceal bleeding may contribute to improved survival without LT in cirrhotic women with gastroesophageal varices.

Objective: The aim of this study was to non-invasively explore new methods of ultrasound attenuation measurements in livers of patients with Non-Alcoholic-Fatty-Liver-Disease (NAFLD) and to measure the liver tissue elasticity. Material and method: Sixteen patients with NAFLD, twelve patients with liver fibrosis and fifteen healthy subjects were included. Echo Levels (ELs) in dB were measured at 2 and 7cm depths in the right liver to calculate the attenuation. ELs were measured in liver and right kidney tissue to calculate the Hepato-Renal Index (HRI). This index was calculated both as a difference, HRIdiff; (EL Liver –EL Kidney) and HRI-ratio; (EL Liver / EL Kidney) using built-in software of the ultrasound scanner. Liver tissue elasticity was measured using transient elastography (TE, Fibroscan®). NAFLD and liver fibrosis were confirmed by liver biopsy. Results: We found that HRI- diff was significantly higher in the NAFLD group compared with healthy subjects, 6.2 dB (0.8-11.4) vs.1. 9 dB (0.0-6.1), p=0.012. HRI- ratio was significantly lower between the same two groups, 0.9 dB (0.81.02) vs.1.01 dB (0.9-1.12), and p

Objectives Recent studies suggest that activin A, a member of the transforming growth factor (TGF) superfamily, is involved in the pathogenesis of liver disorders. We sought to explore its possible role in non-alcoholic fatty liver disease (NAFLD). Methods Serum levels of activin A and its natural inhibitor, follistatin, were measured in patients with NAFLD (n=70) and in control subjects (n=30). Gene expression was quantified in liver biopsies obtained from patients with NAFLD (n=13) and controls (n=6). Effects of activin A were examined in Huh7 (human hepatoma cell line) hepatocytes. Results Patients with NAFLD had significantly elevated serum levels of activin A and follistatin compared with healthy controls. In patients with non-alcoholic steatohepatitis (NASH, n=38), there were particularly high levels of activin A that were significantly related to the degree of hepatic fibrosis. Liver biopsies from NAFLD patients showed a markedly increased activin A-follistatin mRNA ratio, indicating increased hepatic activin A activity. In hepatocytes, activin A enhanced the expression of collagen and TGF-beta(1), promoted matrix metalloproteinase activity, induced mitochondrial beta-oxidation, downregulated fatty acid (FA) synthase activity, promoted decreased weight percentage of saturated FAs, and altered the composition of polyunsaturated FAs. Conclusions Our findings support the complex role of activin A in the pathogenesis of NAFLD, involving effects on fibrosis and lipid accumulation.

The antidiabetic agent metformin is regularly discussed as a promising treatment for non-alcoholic fatty liver disease (NAFLD), which is characterized by insulin resistance. However, the evidence for its beneficial effects is limited, and conflicting reports have been published. The purpose of this study was to conduct a randomized, double-blind, placebo-controlled trial to test whether metformin improves liver histology in patients with non-alcoholic fatty liver disease.Forty-eight patients with biopsy-proven NAFLD were randomized to treatment with metformin (n=24) or placebo (n=24) for 6 months. A second liver biopsy was obtained in all subjects who completed the trial (n=44). Data analyses are restricted to this group (per-protocol analyses). The primary outcome was changes in histologically assessed liver steatosis. Secondary outcomes were changes in NAFLD activity (NAS)-score, liver steatosis assessed by computed tomography (CT), liver transaminases, body-weight, metabolic variables and inflammatory markers.No significant differences between treatment with metformin or placebo were observed for changes in liver steatosis, assessed either histologically or by CT, NAS-score, liver transaminases or on markers of insulin resistance or inflammation. In contrast, beneficial effects of metformin were observed on changes in body-weight (p0.001), serum levels of cholesterol (p=0.004), LDL-cholesterol (p0.001), glucose (p=0.032) and on HbA1c (p=0.020).Treatment with metformin for 6 months was no better than placebo in terms of improvement in liver histology in patients with NAFLD. Nevertheless, the use of metformin could still be beneficial in this group as it is associated with a reduction in serum levels of lipids and glucose. (ClinicalTrials.gov number, NCT00303537).

Background and Aims There is limited data on hepatitis C (HCV) treatment uptake among people who inject drugs including individuals receiving opioid substitution treatment (OST). We aimed to calculate cumulative HCV treatment uptake, estimate annual treatment rates, and identify factors associated with HCV treatment among individuals who have received OST in Norway. Methods This observational study was based on linked data from The Norwegian Prescription Database and The Norwegian Surveillance System for Communicable Diseases between 2004 and 2013. Both registries have national coverage. From a total of 9919 individuals who had been dispensed OST (methadone, buprenorphine or buprenorphine-naloxone), we included 3755 individuals who had been notified with HCV infection. In this population, dispensions of HCV treatment (pegylated interferon and ribavirin), benzodiazepines, selective serotonin reuptake inhibitors and antipsychotics were studied. Results Among 3755 OST patients notified with HCV infection, 539 (14%) had received HCV treatment during the study period. Annual HCV treatment rates during OST ranged between 1.3% (95% confidence interval [CI] 0.7–2.2) in 2005 and 2.6% (95% CI 1.9–3.5) in 2008 with no significant changes over time. HCV treatment uptake was not associated with age or gender, but associated with duration of active OST (adjusted odds ratio [aOR] 1.11 per year; 95% CI 1.07–1.15), high (> 80%) OST continuity (aOR 1.62; 95% CI 1.17–2.25), and heavy benzodiazepine use (aOR 0.65; 95% CI 0.49–0.87). Conclusions Cumulative HCV treatment uptake among OST patients notified with HCV infection in Norway between 2004 and 2013 was 14%. Annual treatment rates during OST remained unchanged below 3% per year. High continuity of OST over time and absence of heavy benzodiazepine use predicted HCV treatment uptake. Increased awareness for HCV among OST patients is needed as tolerable and efficient directly acting antiviral treatment is being introduced.

To evaluate the predictive value of transient elastography (TE), easy available biochemical scores and a combination of these to detect advanced liver fibrosis (i.e. fibrosis stage ≥F3) in patients with chronic liver disease of different etiologies.A valid TE was obtained in 418 patients with chronic liver disease of mixed etiologies during the period of 2007-2010. Reliable fibrosis staging and biochemical data for calculation of APRI, FIB4, and AST/ALT-ratio (AAR) were available in 187 cases of which 50 had clinical obvious cirrhosis. Logistic regression analyses were performed to investigate if biochemical scores were significant predictors of advanced fibrosis independent of TE.In the whole group, TE correlated significantly with APRI and FIB4 but not with AAR. In patients with TE ≥7 kPa, a new formula combining TE and FIB4 improved the accuracy for detecting advanced fibrosis. Area under the receiver operating characteristic curve (AUROC) and sensitivity for the combined formula was 0.94 and 0.92, respectively, as opposed to 0.90 and 0.87 for TE alone. After exclusion of cases with clinical obvious cirrhosis, only FIB4 was a significant predictor of advanced liver fibrosis independent of TE. A combined formula gave a marginally improved AUROC in this group.Our findings suggest that the combination of TE and FIB4 is useful in the prediction of advanced fibrosis. The effect of this combination was marginal when only asymptomatic patients were included. Larger studies are needed to see if this effect is statistically significant and to detect possible differences according to etiology.

The aspartate amino transferase/alanine amino transferase (ASAT/ALAT) ratio is increased in cirrhosis. Some studies indicate that the ratio may provide prognostic information as well. The purpose of this study was to further elucidate the role of the ASAT/ALAT ratio as a predictor of survival by assessing it together with classical risk factors such as age, gender and Child-Pugh (CP) class in a mixed cohort of patients with cirrhosis.Eighty-nine patients with alcoholic cirrhosis and 81 patients with non-alcoholic cirrhosis treated at Aker University Hospital between 1999 and 2004 were identified retrospectively. Survival data from these patients per August 2006 were retrieved from the Norwegian Death Registry. Clinical and biochemical data at time of diagnosis were assessed as predictors of survival using the Kaplan-Meier method and Cox regression models.Median ASAT/ALAT ratio was significantly higher in alcoholic cirrhosis (2.42) as compared with non-alcoholic cirrhosis (1.42). In both groups, a ratio above the median was predictive of poor outcome, p=0.024 and p=0.032, respectively. Other significant predictors of death were CP class (p0.001), clinical decompensation (p0.001) and age (p=0.001). Cox regression analyses showed that the ASAT/ALAT ratio was a predictor of death independently of CP class, gender and age in non-alcoholic, but not in alcoholic cirrhosis. The estimated increased hazard (risk of dying) in non-alcoholic cirrhosis was 5% (CI: 1-8%) per 0.10 increase in ASAT/ALAT ratio.A high ASAT/ALAT ratio is associated with increased mortality in cirrhosis. In non-alcoholic patients the ratio may provide prognostic information independently of classical risk factors.

To investigate the incidence rate and causes of cirrhosis in a Norwegian population. We also sought to assess the degree of underreporting of cirrhosis to the Norwegian Death Registry.All 1264 patients treated at Aker University Hospital in the period January 1999 to March 2004 who were given a diagnosis indicating cirrhosis, chronic liver disease or symptoms possibly attributable to cirrhosis were screened retrospectively. A search in the registry of histological diagnoses at Department of Pathology was also carried out. Based on the results of histological examinations and non-histological criteria, cirrhosis was confirmed in 194 patients. Calculations of the incidence rate of cirrhosis and frequencies of the various etiologies were based on 93 patients living in the catchment area of the hospital. Causes of death were retrieved from the Norwegian Death Registry.The incidence rate of cirrhosis was 134 per million per year. The majority of cases were due to alcoholic liver disease (53%), followed by viral liver disease (12%), various autoimmune liver diseases (12%), hemochromatosis (4%) and non-alcoholic steatohepatitis (NASH) (3%). No etiology was established in 16%, a group with a high prevalence of diabetes mellitus, indicating that some of these cases were possibly caused by NASH. Among 105 deaths in this cohort of 194 cirrhotic patients, the diagnosis of cirrhosis was absent in the Norwegian Death Registry in 30% of cases.The incidence of cirrhosis in Norway is relatively low, with alcohol as the most important etiologic factor. Significant underreporting to the Norwegian Death Registry was observed.

Objectives: The tumor necrosis factor superfamily member 14, LIGHT (homologous to lymphotoxin, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes), has been involved in various autoimmune disorders and has been shown to influence hepatic lipid metabolism. We hypothesized that LIGHT could also have a pathogenic role in nonalcoholic fatty liver disease (NAFLD). Methods: Serum levels of LIGHT in NAFLD patients and control subjects, as well as LIGHT and interleukin (IL)-8 released from Huh7 (human hepatoma cell line) hepatocytes, were determined by enzyme-linked immunosorbent assay. The mRNA expression of LIGHT in the liver tissue and mRNA levels of LIGHT and IL-8 in Huh7 hepatocytes were assessed by real-time quantitative reverse transcription-PCR. Results: (i) Serum levels of LIGHT were significantly elevated in NAFLD patients (n=66) as compared with healthy controls (n=16), with no differences between simple steatosis (n=34) and nonalcoholic steatohepatitis (NASH) (n=32). (ii) Within the liver, NAFLD patients (n=14) had significantly increased mRNA levels of the two LIGHT receptors, herpes virus entry mediator and lymphotoxin β receptor (LTβR), as compared with controls (n=7), with no difference between simple steatosis (n=8) and NASH (n=6). (iii) LIGHT markedly increased the release of IL-8 in Huh7 hepatocytes in a time- and dose-dependent manner. (iv) The reactive oxygen species (ROS) H2O2 (hydrogen peroxide) enhanced the LIGHT-mediated release of IL-8 in Huh7 hepatocytes. Conclusion: We show increased levels of LIGHT and its two membrane-bound receptors in NAFLD, potentially promoting hepatic inflammation through ROS interaction. Our findings should encourage further studies on the role of LIGHT in NAFLD development and progression. © 2015 the American College of Gastroenterology All rights reserved. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License.

The majority of patients with non-alcoholic fatty liver disease (NAFLD) have simple steatosis. A minority, however, present with non-alcoholic steatohepatitis (NASH), a condition that can lead to advanced fibrosis and cirrhosis. The frequencies of NASH and fibrosis among patients with NAFLD and sustained elevation of liver function tests (LFT) are uncertain. Our aim was to estimate these frequencies. We characterize a population with NAFLD, with special emphasis on insulin resistance and the metabolic syndrome, and study possible predictors for different stages of the disease.All referred patients with sustained elevation of LFT, radiological evidence or clinical suspicion of fatty liver, and absence of other liver disease, were invited to participate in our study in the period June 2002 to December 2004.Of 129 patients who met the inclusion criteria, 88 underwent liver biopsy. NAFLD was verified in 83 of them. Among these patients, 59 (71%) had the metabolic syndrome, 41 (49%) had NASH and 36 (43%) had fibrosis. Abnormal glucose tolerance (T2DM or impaired glucose tolerance) was the only independent risk factor for NASH (OR: 3.14; 95% CI: 1.20-8.23). Independent predictors for fibrosis were abnormal glucose tolerance (OR: 3.83; 95% CI: 1.29-11.40) and body mass index (OR: 1.20; 95% CI: 1.06-1.36) per kg/m2.Both NASH and fibrosis are frequently present among patients with NAFLD and sustained elevation of LFT. The probability of these potentially progressive stages of NAFLD increases with the presence of abnormal glucose tolerance.

Background/Aims To elucidate the role of systemic inflammation in nonalcoholic fatty liver disease (NAFLD). Methods Serum samples in 47 patients with histologically verified NAFLD (22 with simple steatosis and 25 with nonalcoholic steatohepatitis [NASH]), and in 30 age-, sex- and ethnicity-matched healthy controls, were assessed for (i) general markers of inflammation (C-reactive protein [CRP], tumor necrosis factor [TNF]-α, and interleukin [IL]-6), (ii) chemokines (CC-chemokine ligand [CCL] 2/monocyte chemoattractant protein [MCP]-1, CCL19 and CCL21), (iii) adipocytokines related to insulin resistance and inflammation (adiponectin and leptin) and (iv) a marker of oxidative stress (8-isoprostane-F2α). Results Serum levels of several inflammatory cytokines were increased in NAFLD as compared to controls, and IL-6 ( P =0.017), CCL2/MCP-1 ( P =0.008) and CCL19 ( P =0.001), but not CRP ( P =0.199), remained elevated also after correction for sex, body mass index (BMI) and age. Comparing NASH with simple steatosis, levels of TNF-α ( P =0.024) and CCL2/MCP-1 ( P =0.012) were elevated and adiponectin (in women) ( P =0.001) were decreased also after adjustment for sex, BMI and presence of the metabolic syndrome. Conclusions Our results indicate that patients with NAFLD are characterized by a low-grade systemic inflammation. The high CCL2/MCP-1 levels in NASH might be of importance for the conversion from simple steatosis to NASH.