Hepatocellular carcinoma shows a rising incidence worldwide, and the largest burden of disease in Western countries derives from patients with alcoholic liver disease (ALD) and cirrhosis, the latter ...being the premier premalignant factor for HCC. The present chapter addresses key issues including the epidemiology of alcohol-associated HCC, and its link to other coexisting non-alcoholic liver diseases, and additional host and environmental risk factors including the underlying genetics. Also discussed are molecular mechanisms of alcohol-associated liver cancer evolution involving the mediators of alcohol toxicity and carcinogenicity, acetaldehyde and reactive oxygen species, as well as the recently described mutagenic adducts which these mediators form with DNA. Specifically, interference of alcohol with retinoids and cofactors of transmethylation processes are outlined. Information presented in this chapter illustrates that the development of HCC in the context of ALD is multifaceted and suggests several molecular targets for prevention and markers for the screening of risk groups.
Herbal and dietary supplements (HDS) have been used for health-related purposes since more than 5000 years, and their application is firmly anchored in all societies worldwide. Over last decades, a ...remarkable renaissance in the use of HDS can be noticed in affluent societies for manifold reasons. HDS are forms of complementary and alternative medicines commonly used to prevent or treat diseases, or simply as a health tonic. Another growing indication for HDS is their alleged benefit for weight loss or to increase physical fitness. Access is easy via internet and mail-order pharmacies, and their turnover reaches billions of dollars in the USA and Europe alone. However, HDS are generally not categorized as drugs and thus less strictly regulated in most countries. As a result, scientific evidence proving their beneficial effects is mostly lacking, although some HDS may have purported benefits. However, the majority lacks such proof of value, and their use is predominantly based on belief and hope. In addition to missing scientific evidence supporting their use, HDS are typically prone to batch-to-batch variability in composition and concentration, contamination, and purposeful adulteration. Moreover, numerous examples of preparations emerged which have been linked to significant liver injury. These include single ingredients, such as kava, germander, and several Chinese herbals. Other HDS products associated with liver toxicity consist of multiple, often ill-defined ingredients, such as Hydroxycut and Herbalife. Affirmative diagnostic tests are not available, and the assessment of liver injury ascribed to HDS depends on a thorough and proactive medical history, careful exclusion of other causes, and a search for available reports on similar events linked to the intake of the suspected preparation or ingredients contained therein.
Alcoholic liver disease (ALD) is a leading cause of cirrhosis, liver cancer, and acute and chronic liver failure and as such causes significant morbidity and mortality. While alcohol consumption is ...slightly decreasing in several European countries, it is rising in others and remains high in many countries around the world. The pathophysiology of ALD is still incompletely understood but relates largely to the direct toxic effects of alcohol and its main intermediate, acetaldehyde. Recently, novel putative mechanisms have been identified in systematic scans covering the entire human genome and raise new hypotheses on previously unknown pathways. The latter also identify host genetic risk factors for significant liver injury, which may help design prognostic risk scores. The diagnosis of ALD is relatively easy with a panel of well-evaluated tests and only rarely requires a liver biopsy. Treatment of ALD is difficult and grounded in abstinence as the pivotal therapeutic goal; once cirrhosis is established, treatment largely resembles that of other etiologies of advanced liver damage. Liver transplantation is a sound option for carefully selected patients with cirrhosis and alcoholic hepatitis because relapse rates are low and prognosis is comparable to other etiologies. Still, many countries are restrictive in allocating donor livers for ALD patients. Overall, few therapeutic options exist for severe ALD. However, there is good evidence of benefit for only corticosteroids in severe alcoholic hepatitis, while most other efforts are of limited efficacy. Considering the immense burden of ALD worldwide, efforts of medical professionals and industry partners to develop targeted therapies in ALF has been disappointingly low.
Approximately 3.6% of cancers worldwide derive from chronic alcohol drinking, including those of the upper aerodigestive tract, the liver, the colorectum and the breast. Although the mechanisms for ...alcohol-associated carcinogenesis are not completely understood, most recent research has focused on acetaldehyde, the first and most toxic ethanol metabolite, as a cancer-causing agent. Ethanol may also stimulate carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. Alcohol-related carcinogenesis may interact with other factors such as smoking, diet and comorbidities, and depends on genetic susceptibility.
Alcoholic liver disease (ALD) accounts for the majority of chronic liver disease in Western countries. The spectrum of ALD includes steatosis with or without fibrosis in virtually all individuals ...with an alcohol consumption of >80 g/day, alcoholic steatohepatitis of variable severity in 10-35% and liver cirrhosis in approximately 15% of patients. Once cirrhosis is established, there is an annual risk for hepatocellular carcinoma of 1-2%. Environmental factors such as drinking patterns, coexisting liver disease, obesity, diet composition and comedication may modify the natural course of ALD. Twin studies have revealed a substantial contribution of genetic factors to the evolution of ALD, as demonstrated by a threefold higher disease concordance between monozygotic twins and dizygotic twins. With genotyping becoming widely available, a large number of genetic case-control studies evaluating candidate gene variants coding for proteins involved in the degradation of alcohol, mediating antioxidant defence, the evolution and counteraction of necroinflammation and formation and degradation of extracellular matrix have been published with largely unconfirmed, impeached or even disproved associations. Recently, whole genome analyses of large numbers of genetic variants in several chronic liver diseases including gallstone disease, primary sclerosing cholangitis and non-alcoholic fatty liver disease (NAFLD) have identified novel yet unconsidered candidate genes. Regarding the latter, a sequence variation within the gene coding for patatin-like phospholipase encoding 3 (PNPLA3, rs738409) was found to modulate steatosis, necroinflammation and fibrosis in NAFLD. Subsequently, the same variant was repeatedly confirmed as the first robust genetic risk factor for progressive ALD.
Summary The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the ...nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3 , TM6SF2 and MBOAT7 , have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed ...to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification.
We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank UKBB cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5).
In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05).
Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings.
By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.
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•Genetic predisposition to liver fat accumulation predisposes to cirrhosis and HCC.•Hepatic fat promotes carcinogenesis, partly via fibrosis.•Polygenic risk scores may improve HCC risk stratification during dysmetabolism.
Role of integrins in fibrosing liver diseases Patsenker, Eleonora; Stickel, Felix
American journal of physiology: Gastrointestinal and liver physiology
301, Številka:
3
Journal Article
Recenzirano
Integrins and other cell adhesion molecules regulate numerous physiological and pathological mechanisms by mediating the interaction between cells and their extracellular environment. Although the ...significance of integrins in the evolution and progression of certain cancers is well recognized, their involvement in nonmalignant processes, such as organ fibrosis or inflammation, is only beginning to emerge. However, accumulating evidence points to an instrumental role of integrin-mediated signaling in a variety of chronic and acute noncancerous diseases, particularly of the liver.
Background & Aims Interleukin (IL)-17 signaling has been implicated in lung and skin fibrosis. We examined the role of IL-17 signaling in the pathogenesis of liver fibrosis in mice. Methods Using ...cholestatic and hepatotoxic models of liver injury, we compared the development of liver fibrosis in wild-type mice with that of IL-17RA −/− mice and of bone marrow chimeric mice devoid of IL-17 signaling in immune and Kupffer cells ( IL-17RA −/− to wild-type and IL-17A −/− to wild-type mice) or liver resident cells (wild-type to IL-17RA −/− mice). Results In response to liver injury, levels of Il-17A and its receptor increased. IL-17A increased appeared to promote fibrosis by activating inflammatory and liver resident cells. IL-17 signaling facilitated production of IL-6, IL-1, and tumor necrosis factor-α by inflammatory cells and increased the expression of transforming growth factor-1, a fibrogenic cytokine. IL-17 directly induced production of collagen type I in hepatic stellate cells by activating the signal transducer and activator of transcription 3 (Stat3) signaling pathway. Mice devoid of Stat3 signaling in hepatic stellate cells ( GFAPStat3 −/− mice) were less susceptible to fibrosis. Furthermore, deletion of IL-23 from immune cells attenuated liver fibrosis, whereas deletion of IL-22 exacerbated fibrosis. Administration of IL-22 and IL-17E (IL-25, a negative regulator of IL-23) protected mice from bile duct ligation-induced liver fibrosis. Conclusions IL-17 induces liver fibrosis through multiple mechanisms in mice. Reagents that block these pathways might be developed as therapeutics for patients with cirrhosis.
Alcohol misuse is the leading cause of cirrhosis and the second most common indication for liver transplantation in the Western world. We performed a genome-wide association study for alcohol-related ...cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls). We identified variants in the MBOAT7 (P = 1.03 × 10(-9)) and TM6SF2 (P = 7.89 × 10(-10)) genes as new risk loci and confirmed rs738409 in PNPLA3 as an important risk locus for alcohol-related cirrhosis (P = 1.54 × 10(-48)) at a genome-wide level of significance. These three loci have a role in lipid processing, suggesting that lipid turnover is important in the pathogenesis of alcohol-related cirrhosis.
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