https://www.journal-of-hepatology.eu/article/S0168-8278(12)00288-7/pdf

EASL Clinical Practical Guidelines: Management of Alcoholic Liver Disease

https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jhep.2003.50127

Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.

https://aasldpubs.onlinelibrary.wiley.com/doi/pdf/10.1002/hep.22010

Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease.

F TWIN, AND adoption studies have convincingly demonstrated that genes play an important role in the development of alcohol dependence, accounting for approximately 50–60% of the population variance (McGue, 1999). Additionally, patterns of alcohol use seem to be under genetic influence. Twin studies have demonstrated that dimensions of alcohol use, such as quantity of alcohol consumed on a typical drinking occasion, frequency of use, and frequency of intoxication, and alcohol metabolism measures, such as time to peak blood alcohol concentration and rate of elimination, are under substantial genetic influence (Heath, 1995). Furthermore, there is evidence of genetic effects on patterns of alcohol use as early as adolescence, and these effects seem to increase over time (Rose et al., 2001). It is unclear to what extent the genes that influence patterns of alcohol use overlap with those that influence alcohol dependence. Despite strong evidence for genetic effects contributing to alcoholism susceptibility, detecting the specific genes that increase or decrease the risk for alcoholism has proven difficult. Many factors contribute to the slow progress in isolating the genes involved in drinking behavior. Many genes are thought to contribute to alcoholism susceptibility, and different genes are likely contributing to alcohol dependence in different individuals. Additionally, the environment plays a substantial role in drinking patterns, with nearly half of the variance in drinking patterns and alcohol dependence attributed to environmental factors. Furthermore, these genes and environments probably interact. Data from a Finnish twin study of alcohol use among adolescents demonstrated that the magnitude of genetic influences can vary dramatically between environments, with up to 5-fold differences demonstrated in different environments (Dick et al., 2001). This suggests that some environments may exacerbate the expression of genetic predispositions, whereas others may be protective. Finally, there is substantial phenotypic heterogeneity in the manifestation of alcohol dependence, with alcoholics differing on dimensions such as age of onset of problems, alcohol symptoms, drinking history, and comorbid disorders. Some evidence suggests that genes may be more important in certain subtypes of alcoholics (Cloninger et al., 1981). Other investigators have studied endophenotypes as a means to deal with the substantial heterogeneity involved in alcohol dependence. Endophenotypes are phenotypes that are thought to be intermediaries between a particular disorder and the biological processes that lead to the manifestation of this disorder. For example, brain wave activity, as measured by electroencephalogram (EEG) and eventrelated potential (ERP), has been studied as an endophenotype for both alcohol dependence and schizophrenia. It is possible that genes act more directly on an endophenotype, as compared with a diagnostic classification, and, therefore, the study of endophenotypes may more efficiently lead to the identification of genes. All of these factors considerably complicate efforts to identify the genes involved in alcohol dependence and to understand the contribution of any specific gene that is identified. A number of genetic strategies have been used in the study of alcohol dependence. These include both linkage and association studies. Linkage studies involve the ascertainment of families with multiple affected individuals; genotyping of segments of DNA that exhibit variation, called polymorphic markers, is often used to detect chromosomal regions in which affected individuals within a family demonstrate increased sharing of a particular marker allele, suggesting that there may be a gene nearby involved in the disorder. Association studies can use either families or unrelated controls; they test the association between a particular allele at a candidate gene and a specific outcome across families. Association methods typically can detect significant effects over much smaller physical distances as compared with linkage studies. For a more extensive review of the methods used in genetic studies, see Dick and Foroud (2003). Here we review the evidence for candidate genes that have been implicated in genetic studies of alcohol dependence and related phenotypes, such as quantitative indices of alcohol use, and endophenotypes, such as EEG. This review is not meant to be exhaustive in reporting all candidate genes, but, rather, covers in detail many of the candidate genes currently thought to be most promising. From the Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana. Received for publication September 30, 2002; accepted February 12, 2003. Supported by NIH Grants AA13358, AA00285, and AA07611. Reprint requests: Tatiana Foroud, PhD, Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 W. Walnut St., IB-130, Indianapolis, IN 46202-525; Fax: 317-274-2387; E-mail: tforoud@iupui.edu. Copyright © 2003 by the Research Society on Alcoholism.

Candidate Genes for Alcohol Dependence: A Review of Genetic Evidence From Human Studies

The field of genetics holds great promise for furthering our understanding of the etiology of drug dependence and for identifying novel targets for treatment. Genetic studies utilizing twins and families have demonstrated a considerable role for genetics in nicotine and/or alcohol dependence. Risk for alcoholism or nicotine dependence is likely to be the result of a large number of genes, each contributing a small fraction of the overall risk. While this review will focus on studies in humans, many of the candidate genes for human nicotine and alcohol dependence listed here were originally postulated to be important, based on data from animal studies. The review will briefly summarize the results from twin and adoption studies that provide estimations of heritability, the results from chromosomal linkage studies that identify regions of chromosomes that may contain relevant genes, and the results of candidate gene studies. For each topic the data will be presented for nicotine dependence, alcohol dependence, and for nicotine and alcohol dependence together. In addition, each section will review briefly some of the confounding issues in the specific type of approach utilized.

Genetics of alcohol and tobacco use in humans

Alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P-4502E1 (CYP2E1), and then to acetate by aldehyde dehydrogenase (ALDH). Polymorphisms of these ethanol-metabolizing enzymes may be associated with inter-individual difference in alcohol metabolism and susceptibility to alcoholic liver disease. We determined genotype and allele frequencies of ALDH2, CYP2E1, ADH2, and ADH3 in male Korean patients with alcoholic cirrhosis (n=56), alcoholics without evidence of liver disease (n=52), and nondrinkers (n=64) by using PCR or PCR-directed mutagenesis followed by restriction enzyme digestion. The prevalences of heterozygous ALDH2*1/*2 plus homozygous ALDH2*2/*2 in patients with alcoholic cirrhosis (7.1%) and alcoholics without evidence of liver disease (3.8%) were significantly lower than that in nondrinkers (45.3%). The c2 allele frequencies of the CYP2E1 in alcoholic cirrhosis, alcoholics without evidence of liver disease, and nondrinkers were 0.21, 0.20, and 0.20, respectively. Allele frequencies of ADH2*2 in the three groups were 0.78, 0.74, and 0.77 and those of ADH3*1 were 0.94, 0.98, and 0.95. Therefore, we confirmed the observation that the ALDH2*2 gene protects against the development of alcoholism. However, the development of cirrhosis in Korean alcoholic patients was not associated with polymorphisms of ethanol-metabolizing enzymes.

/pdf/association-between-polymorphisms-of-ethanol-metabolizing-2ze88o28zi.pdf

Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.

Simple Summary It is still controversial whether tenofovir disoproxil fumarate (TDF) has a lower risk of hepatocellular carcinoma (HCC) development than entecavir (ETV) in patients with chronic hepatitis B (CHB). Furthermore, other antiviral treatment-related outcomes need to be evaluated between the two antivirals to provide essential information for clinical practice. Using a multicenter cohort of 4210 CHB patients, we demonstrated that ETV and TDF are comparable in terms of HCC development as well as mortality, incidence of liver-related outcome, extrahepatic malignancy or new decompensation events, and seroconversion rates. Patients treated with TDF experienced more side effects than those treated with ETV. The results of this study can be applied to the development of a personalized antiviral treatment strategy for CHB patients. Abstract Tenofovir disoproxil fumarate (TDF) is reportedly superior or at least comparable to entecavir (ETV) in preventing hepatocellular carcinoma (HCC) among chronic hepatitis B (CHB) patients; however, it remains controversial. This study aimed to conduct comprehensive comparisons between the two antivirals. CHB patients initially treated with ETV or TDF between 2012 and 2015 at 20 referral centers in Korea were included. The primary outcome was the cumulative incidence of HCC. The secondary outcomes included death or liver transplantation, liver-related outcome, extrahepatic malignancy, development of cirrhosis, decompensation events, complete virologic response (CVR), seroconversion rate, and safety. Baseline characteristics were balanced using the inverse probability of treatment weighting (IPTW). Overall, 4210 patients were enrolled: 1019 received ETV and 3191 received TDF. During the median follow-ups of 5.6 and 5.5 years, 86 and 232 cases of HCC were confirmed in the ETV and TDF groups, respectively. There was no difference in HCC incidence between the groups both before (p = 0.36) and after IPTW was applied (p = 0.81). Although the incidence of extrahepatic malignancy was significantly higher in the ETV group than in the TDF group before weighting (p = 0.02), no difference was confirmed after IPTW (p = 0.29). The cumulative incidence rates of death or liver transplantation, liver-related outcome, new cirrhosis development, and decompensation events were also comparable in the crude population (p = 0.24–0.91) and in the IPTW-adjusted population (p = 0.39–0.80). Both groups exhibited similar rates of CVR (ETV vs. TDF: 95.1% vs. 95.8%, p = 0.38), and negative conversion of hepatitis B e antigen (41.6% vs. 37.2%, p = 0.09) or surface antigen (2.8% vs. 1.9%, p = 0.10). Compared to the ETV group, more patients in the TDF group changed initial antivirals due to side effects, including decreased kidney function (n = 17), hypophosphatemia (n = 20), and osteoporosis (n = 18). In this large-scale multicenter study, ETV and TDF demonstrated comparable effectiveness across a broad range of outcomes in patients with treatment-naïve CHB during similar follow-up periods.

/pdf/inverse-propensity-score-weighted-analysis-of-entecavir-and-31c3ev05.pdf

Inverse Propensity Score-Weighted Analysis of Entecavir and Tenofovir Disoproxil Fumarate in Patients with Chronic Hepatitis B: A Large-Scale Multicenter Study

Han Chu Lee

Papers

Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in a Korean male population.

Inverse Propensity Score-Weighted Analysis of Entecavir and Tenofovir Disoproxil Fumarate in Patients with Chronic Hepatitis B: A Large-Scale Multicenter Study