Münevver Demir

Nonalcoholic fatty liver disease - current status and future directions.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common chronic liver disease worldwide with a reported prevalence ranging 6–33%, depending on the studied populations. It encompasses a spectrum of liver manifestations ranging from simple steatosis (also known as nonalcoholic fatty liver, NAFL) to nonalcoholic steatohepatitis (NASH), fibrosis and cirrhosis, which may ultimately progress to hepatocellular carcinoma. NAFLD is strongly associated with the components of metabolic syndrome, mainly obesity and type 2 diabetes mellitus. NAFLD patients are at increased risk of liver‐related as well as cardiovascular mortality. Current paradigm suggests a benign course for NAFL whereas NASH is considered to be the progressive phenotype. Although previously under‐recognized accumulating evidence suggests that NAFL may also progress, suggesting a higher number of patients at risk than previously appreciated. Liver biopsy remains the gold standard for definitive diagnosis, but the majority of patients can be diagnosed accurately by noninvasive methods. Approved therapies for NAFLD are still lacking and lifestyle modifications aiming at weight loss remain the mainstay of NAFLD treatment. Intensive research could identify insulin resistance, lipotoxicity and dysbiosis of the gut microbiota as major pathophysiological mechanisms, leading to the development of promising targeted therapies which are currently investigated in clinical trials. In this review we summarized the current knowledge of NAFLD epidemiology, natural history, diagnosis, pathogenesis and treatment and considered future directions.

NIKEI: a new inexpensive and non-invasive scoring system to exclude advanced fibrosis in patients with NAFLD.

Aims To develop, validate and compare a non-invasive fibrosis scoring system for non-alcoholic fatty liver disease (NAFLD) derived from routinely obtained clinical and biochemical parameters. Methods 267 consecutive patients with biopsy proven fatty liver or non-alcoholic steatohepatitis were randomly assigned to the estimation (2/3) or validation (1/3) group to develop a model for the prediction of advanced fibrosis. Univariate statistics were performed to compare patients with and without advanced fibrosis, and following a multivariate logistic regression analysis a new scoring system was constructed. This non-invasive Koeln-Essen-index (NIKEI) was validated and compared to the FIB-4 index by calculating the area under the receiver operating characteristic curve (AUC). We evaluated a stepwise combination of both scoring systems for the precise prediction of advanced fibrosis. To set in contrast, we additionally tested the diagnostic accuracy of the AST/ALT ratio, BARD score and the NAFLD fibrosis score in our cohort. Results Age, AST, AST/ALT ratio, and total bilirubin were identified as significant predictors of advanced fibrosis and used to construct the NIKEI with an AUC of 0.968 [0.937; 0.998] compared to 0.929 [0.869; 0.989] for the FIB-4 index. The absence of advanced fibrosis could be confirmed with excellent accuracy (99–100%). The positive predictive value of the FIB-4 index was higher (100% vs. 60%), however, the false negative rate was also high (33%). With a stepwise combination of both indices 82%–84% of biopsies would have been avoidable without a single misclassification. The AUROC for AST/ALT ratio, the NAFLD fibrosis score, and the BARD score were 0.81 (95% CI, 0.72–0.90), 0.96 (95% CI 0.92–0.99), and 0.67 (95% CI 0.55–0.78), respectively. Conclusion The NIKEI can reliably exclude advanced fibrosis in subjects with NAFLD. In combination with the FIB-4 index misclassification with inadequate clinical management can be avoided while the need for liver biopsies can be reduced.

Stepwise combination of simple noninvasive fibrosis scoring systems increases diagnostic accuracy in nonalcoholic fatty liver disease.

Objective: Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease ranging from simple fatty liver to steatohepatitis, fibrosis, and cirrhosis. We aimed to analyze the diagnostic performance and clinical utility of simple noninvasive tests alone or in combination for the detection of advanced fibrosis in patients with NAFLD. Design and Subjects: Data from 323 patients with biopsy-proven NAFLD/NASH who presented to the Clinic for Gastroenterology and Hepatology, University Hospital of Cologne between July 1998 and November 2009, were analyzed retrospectively. Sensitivity, specificity, positive predictive values, and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas for NAFLD, FIB-4, and BARD fibrosis scores. Results: The area under receiver operating characteristic curves were as follows: NAFLD fibrosis score 0.96 [95% confidence interval (CI), 0.92-0.99], FIB-4 0.95 (95% CI, 0.91-1.00), BARD 0.82 (95% CI, 0.71-0.92) with negative predictive values for advanced fibrosis of 96%, 98%, and 96%, respectively. When applying the NAFLD, FIB-4, or BARD scoring systems 25%, 15%, or 26% of cases with advanced fibrosis would have been missed. Combining FIB-4 and BARD in a stepwise fashion, patients would have been correctly classified without biopsy in 67% of cases without missing a single case of advanced fibrosis. Conclusions: The FIB-4 and NAFLD fibrosis scores perform better than the BARD scoring system. Liver biopsy can securely be replaced only with a stepwise combination of simple noninvasive tests, otherwise the assessment of risk due to advanced fibrosis may be misleading in a clinically meaningful proportion of patients.

Glutathione peroxidase 4 is reversibly induced by HCV to control lipid peroxidation and to increase virion infectivity

Objective Inflammation and oxidative stress drive disease progression in chronic hepatitis C (CHC) towards hepatocellular carcinoma. HCV is known to increase intracellular levels of reactive oxygen species (ROS), but how it eliminates ROS is less well known. The role of the ROS scavenger glutathione peroxidase 4 (GPx4), induced by HCV, in the viral life cycle was analysed. Design The study was performed using a replicative in vitro HCV infection model and liver biopsies derived from two different CHC patient cohorts. Results A screen for HCV-induced peroxide scavengers identified GPx4 as a host factor required for HCV infection. The physiological role of GPx4 is the elimination of lipid peroxides from membranes or lipoproteins. GPx4-silencing reduced the specific infectivity of HCV by up to 10-fold. Loss of infectivity correlated with 70% reduced fusogenic activity of virions in liposome fusion assays. NS5A was identified as the protein that mediates GPx4 induction in a phosphatidylinositol-3-kinase-dependent manner. Levels of GPx4 mRNA were found increased in vitro and in CHC compared with control liver biopsies. Upon successful viral eradication, GPx4 transcript levels returned to baseline in vitro and also in the liver of patients. Conclusions HCV induces oxidative stress but controls it tightly by inducing ROS scavengers. Among these, GPx4 plays an essential role in the HCV life cycle. Modulating oxidative stress in CHC by specifically targeting GPx4 may lower specific infectivity of virions and prevent hepatocarcinogenesis, especially in patients who remain difficult to be treated in the new era of interferon-free regimens.

Circadian Variation in Arterial Blood Pressure and Glaucomatous Optic Neuropathy—A Systematic Review and Meta-Analysis

BACKGROUND Epidemiological studies have led to equivocal results concerning the role of arterial blood pressure as a risk factor for the development of glaucomatous damage and progressive visual field loss in glaucoma has been attributed to low nighttime blood pressure, especially when oral antihypertensives have been combined with beta-blocking eyedrops. In order to answer the question whether nocturnal blood pressure or blood pressure dip during ambulatory blood pressure monitoring are associated with progressive visual field loss we performed a systematic review and meta-analysis of studies in patients with primary open-angle glaucoma and normal tension glaucoma. METHODS After searching MEDLINE, the Cochrane Library, and EMBASE, only 5 studies could be found reporting information on the method of ambulatory blood pressure measurements, separate data for daytime and nighttime blood pressure, definition of nocturnal blood pressure dip, and assessment of visual fields over a period of at least 2 years. RESULTS There was no difference in mean systolic or diastolic diurnal and nocturnal blood pressure between patients with or without progressive visual field loss. The odds ratio for deteriorating visual fields over 2 years with nocturnal dips >10% in systolic or diastolic blood pressure was 3.32 (1.84-6.00) and 2.09 (1.20-3.64), respectively. Data allowing a separate analysis of over-dipping were not available. CONCLUSIONS Nocturnal blood pressure fall is a risk factor for progressive visual field loss in glaucoma. However, prospective studies are needed to define a tolerable degree of dipping. Antihypertensive therapy in glaucomatous patients should be controlled with ambulatory blood pressure monitoring.

Hepatocyte expression of angiotensin II type 1 receptor is downregulated in advanced human liver fibrosis.

Background: The renin–angiotensin system plays an important role in fibrosis. Angiotensin II regulates key steps in tissue remodelling processes through angiotensin II type 1 receptor (AT1R). In bile duct‐occluded rats, AT1R expression is significantly decreased in advanced liver fibrosis. Therefore, we studied the AT1R expression in human liver tissue during different stages of fibrosis caused by chronic hepatitis C.

Neighbor of Punc E 11: expression pattern of the new hepatic stem/progenitor cell marker during murine liver development.

We have previously identified Neighbor of Punc E 11 (Nope) as a specific cell surface marker of stem/progenitor cells in the murine fetal liver that is also expressed in hepatocellular carcinoma. Here, we focus on the differential expression pattern of Nope during murine fetal and postnatal liver development as well as in a normal and regenerating adult liver including oval cell activation. In the fetal liver, Nope shows a constantly high expression level and is a useful surface marker for the identification of Dlk, E-cadherin, and CD133-positive hepatoblasts by flow cytometry. Postnatally, Nope expression declines rapidly and remains barely detectable in the adult liver as shown by quantitative real-time reverse-transcriptase polymerase chain reaction and western blot analyses. Immunohistochemically, costainings for Nope- and epithelial-specific markers (E-cadherin), markers of early hepatoblasts (alpha-fetoprotein), and biliary marker proteins (CK19) demonstrate that Nope is initially expressed on bipotent hepatoblasts and persists thereafter on commited hepatocytic as well as cholangiocytic progenitor cells during late fetal liver development. Postnatally, Nope loses its circular expression pattern and is specifically directed to the sinusoidal membrane of early hepatocytes. While Nope is only weakly expressed on cholangiocytes in the normal adult liver, activated stem/progenitor (oval) cells clearly coexpress Nope together with the common markers A6, EpCAM, and CD24 in the 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse model. In conclusion, Nope should be most useful in future research to define the differentiation stage of hepatic-specified cells of various sources and is a promising candidate to identify and isolate hepatic stem cells from the adult liver.

HIV/Hepatitis C Virus Co-infection among Adults Beginning Antiretroviral Therapy, Malawi

To the Editor: Throughout the world, ≈115 million persons have hepatitis C virus (HCV) antibodies, ≈37 million are infected with HIV type 1, and an estimated 2.3 million persons are infected with both viruses (1). The estimated prevalence of HIV infection among adults in Malawi is 9.1% (2). Data concerning HCV seroprevalence in Malawi are conflicting and range from 0.0% to 18.0%, depending on the studied population and the chosen methods for HCV infection diagnosis (3–6). In a recent study, researchers used stored blood samples (without HCV confirmatory assays) from studies in rural and urban Malawian populations (1989–2008); an HCV seroprevalence of 6.8% was found in HIV-positive patients (7). In contrast, in a cohort of HIV-negative mothers (2006–2010), only 0.5% were found to be HCV positive with confirmatory HCV testing by immunoblot (8). These studies were not included in a 2015 metaanalysis that estimated the seroprevalence of HCV infection and HIV/HCV co-infection in Malawi to be 7.7% and 2.0%, respectively (9). Liver disease progresses more rapidly in HIV/HCV co-infected patients than in HCV monoinfected patients (10), and the highly effective second-generation direct-acting antiviral therapies are less toxic than interferon-based treatment regimens. It is crucial to gather accurate epidemiologic information on the burden of HIV/HCV co-infection to support the design and implementation of HCV treatment initiatives in resource-limited settings such as sub-Saharan Africa.

Real-world risk score for hepatocellular carcinoma risk prediction in CHBV: a validation outside of Asia

With great interest we have read the recent paper by Poh et al 1 suggesting the use of a routine parameter-based risk score for the development of hepatocellular carcinoma (HCC) in Asian patients with chronic HBV infection (CHBV). With an estimated 240 million people being chronically infected by HBV worldwide, CHBV is a major global health burden, putting these people at risk for the development of liver cirrhosis and HCC.2–4 It remains challenging to identify those patients with CHBV carrying a high risk for HCC development applying an easy to use, readily available and cost effective test system. Therefore risk predicting …

Performance of simple noninvasive scoring systems for the prediction of advanced fibrosis in patients with chronic hepatitis B

Background and aim The aim of the study was to analyze the diagnostic performance and clinical utility of simple noninvasive tests for the detection of advanced fibrosis in patients with chronic hepatitis B (CHB) infection seen at a tertiary referral center in Germany. Patients and methods We retrospectively analyzed 239 adult CHB patients with available liver biopsies. Patient demographics, hepatitis B markers, antiviral treatment, laboratory parameters, results from liver imaging, and histology were recorded. The sensitivity, specificity, and positive and negative predictive values were determined along with the area under receiver operating characteristic curves (AUROC) using published formulas and cut-off values for fibrosis index based on the four factors, aspartate aminotransferase–alanine aminotransferase ratio index (AAR), aspartate aminotransferase-to-platelet ratio index (APRI), and age–platelet index. Results The median documented duration of CHB infection was 31 months (range: 6–340 months); 86% of the patients were Caucasian and 71% were men. The AUROCs for the detection of advanced fibrosis were 0.75 [95% confidence interval (CI): 0.67–0.82], 0.72 (95% CI: 0.64–0.80), 0.48 (95% CI: 0.39–0.56), and 0.73 (95% CI: 0.66–0.81) for fibrosis index the four factors, APRI, AAR, and age–platelet index, respectively. Patients with advanced fibrosis on biopsy were misclassified as having mild fibrosis in 35% (APRI) to 82% (AAR) of cases. Conclusion Because of their moderate test performance (AUROCs: 0.48–0.75) and their high misclassification rate, we could not confirm a reliable clinical utility for the analyzed noninvasive fibrosis scoring systems for the prediction of advanced fibrosis in mostly Caucasian CHB patients.