Alcohol consumption leads to loss of healthy life, but the ADH1B*2 allele may still protect from NASH

Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease worldwide, affecting almost a quarter of the world population (1,2), and is a main cause of severe hepatic complications such as cirrhosis and liver cancer. In histological assessment NAFLD and alcoholic liver disease (ALD) are difficult to distinguish; NAFLD diagnosis thus requires a limit of alcohol intake. However, NAFLD and ALD very frequently coexist in the same patient, making it difficult to identify the exact cause of liver complications. Almost 5?6% of all worldwide deaths (~3 million) are caused by the harmful use of alcohol (https://www.who.int/publications/i/item/9789241565639), therefore alcohol represents a major health problem at a global scale. There is an association between the amount of alcohol consumption and ALD, however, only 30% of chronic drinkers develop alcoholic hepatitis, and 10?20% progress to advanced fibrosis or cirrhosis (3), underscoring the role of genetic factors involved in disease severity and progression. Any level of alcohol consumption, regardless of the amount, leads to loss of healthy life. The recommendation in clinical practice should be to avoid alcohol intake, particularly in the presence of any liver disease. Moderate alcohol consumption has been reported by many studies to be associated with less severe NAFLD, although some of these cross-sectional studies may be affected by selection bias (4-6). In contrast a longitudinal analysis of liver biopsies from patients with NAFLD showed that modest alcohol consumption was associated with lower NASH resolution in comparison with nondrinkers (7). Recently, Chang et al. showed that the risk of liver steatosis in low and moderate alcohol consumers (MACs) was lower in comparison with nondrinkers (8); however, the proportion of hepatic steatosis plus fibrosis was higher in drinkers. The exact mechanism of the deleterious effect of alcohol consumption on NAFLD in obese patients is still unclear. When combined with free fatty acids the polyphenol resveratrol resulted in the stimulation of profibrogenic effects in hepatic stellate cells (key cells for induction and propagation of hepatic fibrosis) instead of any protective role (9). Therefore, it is important to shed light on the exact role of alcohol intake in addition to NAFLD to solve the currently rather conflicting data on this issue. The work published by Vilar-Gomez et al. in Gastroenterology (10) clarifies some knowledge gaps about alcohol metabolism and consumption, and the severity of NAFLD by studying the role of alcohol dehydrogenase (ADH)-1B, in particular ADH1B*2, in this context. The authors started from a finding generated in a previous work by Sookoian et al., where they observed that patients with low alcohol intake and the ADH1B*2 allele showed a less severe NAFLD by histology compared to other patients studied (11). Vilar-Gomez et al. studied 1,697 patients enrolled into various studies conducted by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) over a period of 10 years [2009?2019]; the NASH CRN Pathology committee reviewed all liver biopsies, and comprehensive alcohol consumption was obtained by AUDIT and LDH questionnaire, binge and heavy drinkers were excluded (170 patients). Remarkably, the frequency of ADH1B*2 carriage varied across race being high in Asians/Pacific Islanders/Hawaiians (86%) and low in non-Hispanic whites (8%), Hispanics (14%), and Blacks (4%), but the study was focused on the 1,153 non-Hispanic whites, which were mainly female, obese, and hypertensive. Among the 1,153 patients, 30% had advanced fibrosis, and 60% had definite NASH. The cohort included 720 non-drinkers and 433 moderate drinkers, but no heavy alcohol consumers. ADH1B*2 carriers were more likely to be male, and moderate alcohol consumption was similar between ADH1B*1 and ADH1B*2 carriersFil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Canbay, Ali. Ruhr Universität Bochum; Alemani

RESPONSE OF SOME FORAGE PEA GENOTYPES TO SALT STRESS DURING THE SEEDLING STAGE

Salinity stress is a common problem under dry climatic condition all over the world. The determination of salt tolerant genotypes has a crucial importance to alleviate this problem. Pea known as the most salt tolerant plant among legumes and seedling stage is the most sensitive to salt stress than the other growth stages. The experiment was carried out in the growth chamber to observe tolerance of the examined genotypes to different salt doses. Therefore germination rates, mean germination time (mgt), root/shoot lengths and fresh/dry seedling weights of some forage pea genotypes (Local population, Crackerjack, Golyazi, Ozkaynak, Rose, Taskent, Tore, Ulubatlı) under different salt concentrations (Control, 5, 10, 15 and 20 dS m-1) were determined. The results showed that salinity x genotype interaction was significant among genotypes with respect to all investigated parameters. Crackerjack had the highest germination rate and root length with the increasing salt levels and it was followed by Ozkaynak, Rose, Taskent and Tore. Ozkaynak was the fastest germinated genotype with respect to mgt with 1,92 days and the genotype had the longest shoot length. Fresh seedling weight of Crackerjack was the higher than all other genotypes but there was not a significant difference between Rose and Crackerjack. Results indicated that Taskent, Tore, Ozkaynak, cultivars could be recommended upto moderate saline areas while Crackerjack and Rose could be recommended for slightly saline area

A Review of the Epidemiology, Pathophysiology, and Efficacy of Anti-diabetic Drugs Used in the Treatment of Nonalcoholic Fatty Liver Disease

In recent years, epidemiological studies have consistently demonstrated that the coexistence of nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) is strongly associated with increased mortality and morbidity related to hepatic- and extrahepatic causes. Indeed, compared with the general population, patients with T2DM are more likely to be diagnosed with more severe forms of NAFLD (i.e., nonalcoholic steatohepatitis (NASH) with liver fibrosis). There is an ongoing debate whether NALFD is a consequence of diabetes or whether NAFLD is simply a component and manifestation of the metabolic syndrome, since liver fat (steatosis) and even more advanced stages of liver fibrosis can occur in the absence of diabetes. Nevertheless, insulin resistance is a key component of the mechanism of NAFLD development; furthermore, therapies that lower blood glucose concentrations also appear to be effective in the treatment of NAFLD. Here, we will discuss the pathophysiological and epidemiological associations between NAFLD and T2DM. We will also review currently available anti-diabetic agents with their regard to their efficacy of NAFLD/NASH treatment.Open Access funding enabled and organized by Projekt DEA

Hepatokines and adipokines in NASH-related hepatocellular carcinoma

Summary The incidence of hepatocellular carcinoma (HCC) is increasing in industrialised societies; this is likely secondary to the increasing burden of non-alcoholic fatty liver disease (NAFLD), its progressive form non- alcoholic steatohepatitis (NASH), and the metabolic syndrome. Cumulative studies suggest that NAFLD- related HCC may also develop in non-cirrhotic livers. However, prognosis and survival do not differ between NAFLD- or virus-associated HCC. Thus, research has increasingly focused on NAFLD-related risk factors to better understand the biology of hepatocarcinogenesis and to develop new diagnostic, pre- ventive, and therapeutic strategies. One important aspect thereof is the role of hepatokines and adipo- kines in NAFLD/NASH-related HCC. In this review, we compile current data supporting the use of hepatokines and adipokines as potential markers of disease progression in NAFLD or as early markers of NAFLD-related HCC. While much work must be done to elucidate the mechanisms and interactions underlying alterations to hepatokines and adipokines, current data support the possible utility of these factors – in particular, angiopoietin-like proteins, fi broblast growth factors, and apelin – for detection or even as therapeutic targets in NAFLD-related HCC.Supported by the German Research Foundation (DFG CA267/13-3; CA267/14-1) and the Wilhelm Laupitz Foundation (A.C. and O.K.)

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.This research was funded by the German Research Foundation (DFG CA267/13-3; CA267/14-1 to A.C.) and by the Wilhelm Laupitz Foundation (A.C. and O.K.)

Circulating microRNAs: promising candidates serving as novel biomarkers of acute hepatitis

Acute liver failure as life threatening condition comprises a difficult diagnostic situation to evaluate potential outcomes and therapeutic options. Thus, prognostic indicators are urgently needed for evaluation of progression of liver injury, clinical outcome, prognosis, and for therapeutic response. Recently, circulating microRNA, in particular miR-122, was described as a potential biomarker of acute liver injury after intoxication of mice. Circulating microRNA (miRNA) molecules are very stable and RNase-resistant due to protein aggregation and vesicle enclosure. Since miRNA species are known to be associated with chronic liver damage or with liver cancer, circulating miRNA patterns are suggested to serve also as reporters for progression of acute liver failure. miRNA profiling analyses using PCR arrays or next generation sequencing, may achieve identification of miRNA species that are linked to the rapid progression of acute liver injury, to the outcome of liver failure, or to the therapeutic response. Therefore, circulating miRNAs are promising, non-invasive biomarkers of future diagnostic approaches. However, normalisation of circulating miRNA levels is essential and further standardisation of miRNA quantification assays is needed

Significance of Simple Steatosis: An Update on the Clinical and Molecular Evidence

Non-alcoholic fatty liver disease (NAFLD) is defined clinicopathologically by the accumulation of lipids in >5% of hepatocytes and the exclusion of secondary causes of fat accumulation. NAFLD encompasses a wide spectrum of liver damage, extending from simple steatosis or non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH)-the latter is characterized by inflammation and hepatocyte ballooning degeneration, in addition to the steatosis, with or without fibrosis. NAFLD is now the most common cause of chronic liver disease in Western countries and affects around one quarter of the general population. It is a multisystem disorder, which is associated with an increased risk of type 2 diabetes mellitus as well as liver- and cardiovascular-related mortality. Although earlier studies had suggested that NAFL is benign (i.e., non-progressive), cumulative evidence challenges this dogma, and recent data suggest that nearly 25% of those with NAFL may develop fibrosis. Importantly, NAFLD patients are more susceptible to the toxic effects of alcohol, drugs, and other insults to the liver. This is likely due to the functional impairment of steatotic hepatocytes, which is virtually undetectable by current clinical tests. This review provides an overview of the current evidence on the clinical significance of NAFL and discusses the molecular basis for NAFL development and progression.Fil: Mazzolini Rizzo, Guillermo Daniel. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sowa, Jan Peter. Ruhr Universität Bochum; AlemaniaFil: Atorrasagasti, María Catalina. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Kücükoglu, Özlem. Otto-von-Guericke-Universität Magdeburg; AlemaniaFil: Syn, Wing Kin. Universidad del País Vasco; España. Medical University of South Carolina; Estados Unidos. University of the Basque Country; EspañaFil: Canbay, Ali. Ruhr Universität Bochum; Alemani

Bioelectrical impedance analysis in clinical practice: implications for hepatitis C therapy BIA and hepatitis C

<p>Abstract</p> <p>Background</p> <p>Body composition analysis using phase angle (PA), determined by bioelectrical impedance analysis (BIA), reflects tissue electrical properties and has prognostic value in liver cirrhosis. Objective of this prospective study was to investigate clinical use and prognostic value of BIA-derived phase angle and alterations in body composition for hepatitis C infection (HCV) following antiviral therapy.</p> <p>Methods</p> <p>37 consecutive patients with HCV infection were enrolled, BIA was performed, and PA was calculated from each pair of measurements. 22 HCV genotype 3 patients treated for 24 weeks and 15 genotype 1 patients treated for 48 weeks, were examined before and after antiviral treatment and compared to 10 untreated HCV patients at 0, 24, and 48 weeks. Basic laboratory data were correlated to body composition alterations.</p> <p>Results</p> <p>Significant reduction in body fat (BF: 24.2 ± 6.7 kg vs. 19.9 ± 6.6 kg, genotype1; 15.4 ± 10.9 kg vs. 13.2 ± 12.1 kg, genotype 3) and body cell mass (BCM: 27.3 ± 6.8 kg vs. 24.3 ± 7.2 kg, genotype1; 27.7 ± 8.8 kg vs. 24.6 ± 7.6 kg, genotype 3) was found following treatment. PA in genotype 3 patients was significantly lowered after antiviral treatment compared to initial measurements (5.9 ± 0.7° vs. 5.4 ± 0.8°). Total body water (TBW) was significantly decreased in treated patients with genotype 1 (41.4 ± 7.9 l vs. 40.8 ± 9.5 l). PA reduction was accompanied by flu-like syndromes, whereas TBW decline was more frequently associated with fatigue and cephalgia.</p> <p>Discussion</p> <p>BIA offers a sophisticated analysis of body composition including BF, BCM, and TBW for HCV patients following antiviral regimens. PA reduction was associated with increased adverse effects of the antiviral therapy allowing a more dynamic therapy application.</p

Sarcoidosis of the Intra- and Extrahepatic Bile Ducts with Concomitant Cholangitis in a Patient with Ulcerative Colitis

Cholangitis in patients with ulcerative colitis (UC) can lead to misdiagnosis of primary sclerosing cholangitis (PSC). Furthermore, it can mimic cholangiocellular carcinoma, which also can lead to inappropriate and potentially harmful treatment of the patient. An 18-year-old male patient with known UC presented with pain in his right upper abdomen and elevation of the cholestatic liver enzymes (alkaline phosphatase: 197 U/L, γ-glutamyltransferase: 229 U/L) and increased inflammatory parameters (leukocytosis and CrP of 13.6 mg/L). Magnetic resonance cholangiopancreatography revealed unclear stenosis in the bifurcation of the main hepatic bile duct as well as in the prepapillary bile duct. Ultrasound (US) examination and endoscopic retrograde cholangiopancreatography showed dilatation of the intra -and extrahepatic bile ducts, which raised the suspicion of PSC. US image with dilated intra- and extrahepatic dilatation of the bile duct was also suggestive for autoimmune cholangitis. However, serum analysis revealed an elevated soluble interleukin-II receptor (1,305 U/mL), while immunoglobulin G4 was within normal ranges. Liver biopsy demonstrated hepatic inflammation and presence of granulomatous cells within the portal fields – convenient to sarcoidosis. After starting treatment with steroids, we observed a rapid clinical response with improvement of the dilated bile ducts and decrease of the initially elevated cholestatic liver enzymes. Sarcoidosis within the bile duct is a rare condition. Steroids are the treatment of choice and – along with the histology – are furthermore helpful to differentiate between several potential differential diagnoses like IgG4 cholangitis, primary biliary cholangitis, or PSC