A polygenic risk score for alcohol-associated cirrhosis among heavy drinkers with European ancestry.

BACKGROUND: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis. METHODS: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239). RESULTS: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis. CONCLUSIONS: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC.

[Alcohol as a health risk: new recommendations for dealing with alcohol]. / Gesundheitsrisiko Alkohol ­ neue Empfehlungen zum Umgang mit Alkohol.

BACKGROUND: Chronic alcohol consumption is related to more than 200 disorders. Up until now, limits for low-risk use of alcohol were 24 g/ day for men and 12 g/ day for women. Recent epidemiologic studies have shown that any alcohol may be harmful. AIM: The aim of this review is to reassess the health risk of alcohol. RESULTS: There is a linear relationship between the amount of alcohol consumed and mortality risk. No risk-free dose of alcohol exists. However, health risk varies not only with the amount of alcohol consumed but also with target organs, as well as individual genetic and non-genetic factors such as smoking, medication use, exposure to environmental toxins, and pre-existing disease that deteriorates with alcohol use. High-risk groups for the damaging effect of alcohol include children and adolescents, old people, and women. Diseases that are affected by alcohol even at a low dose include arterial hypertension, cardiac arrhythmia (extrasystole, arterial fibrillation), some liver diseases (non-alcoholic fatty liver disease, hepatitis C, porphyria) as well as breast cancer. For these disorders, a threshold of low risk does not exist. Finally, in addition to breast cancer, alcohol is a risk factor for cancer of the oral cavity, the larynx, pharynx, oesophagus, liver, and colorectum. During pregnancy alcohol is completely forbidden. CONCLUSION: There is no such thing as a risk-free dose of alcohol.

Pathogenesis of Alcoholic Fatty Liver a Narrative Review.

Alcohol effect hepatic lipid metabolism through various mechanisms, leading synergistically to an accumulation of fatty acids (FA) and triglycerides. Obesity, as well as dietary fat (saturated fatty acids (FA) versus poly-unsaturated fatty acids (PUFA)) may modulate the hepatic fat. Alcohol inhibits adenosine monophosphate activated kinase (AMPK). AMPK activates peroxisome proliferator activated receptor a (PPARα) and leads to a decreased activation of sterol regulatory element binding protein 1c (SRABP1c). The inhibition of AMPK, and thus of PPARα, results in an inhibition of FA oxidation. This ß-oxidation is further reduced due to mitochondrial damage induced through cytochrome P4502E1 (CYP2E1)-driven oxidative stress. Furthermore, the synthesis of FAs is stimulated through an activation of SHREP1. In addition, alcohol consumption leads to a reduced production of adiponectin in adipocytes due to oxidative stress and to an increased mobilization of FAs from adipose tissue and from the gut as chylomicrons. On the other side, the secretion of FAs via very-low-density lipoproteins (VLDL) from the liver is inhibited by alcohol. Alcohol also affects signal pathways such as early growth response 1 (Egr-1) associated with the expression of tumour necrosis factor α (TNF α), and the mammalian target of rapamycin (mTOR) a key regulator of autophagy. Both have influence the pathogenesis of alcoholic fatty liver. Alcohol-induced gut dysbiosis contributes to the severity of ALD by increasing the metabolism of ethanol in the gut and promoting intestinal dysfunction. Moreover, pathogen-associated molecular patterns (PAMPS) via specific Toll-like receptor (TLR) bacterial overgrowth leads to the translocation of bacteria. Endotoxins and toxic ethanol metabolites enter the enterohepatic circulation, reaching the liver and inducing the activation of the nuclear factor kappa-B (NFκB) pathway. Pro-inflammatory cytokines released in the process contribute to inflammation and fibrosis. In addition, cellular apoptosis is inhibited in favour of necrosis.

Ashwagandha-induced acute liver injury: A case report.

Drug-induced liver injury became one of the most important liver disorders and diagnostic challenge for clinicians and pathologists. Here, we report a rare case of ashwagandha-induced acute liver injury. The patient developed jaundice 2 weeks after starting ashwagandha intake and recovered within 5 months after withdrawal without any specific treatment.

Effect of Clomethiazole Vs. Clorazepate on Hepatic Fat and Serum Transaminase Activities in Alcohol-Associated Liver Disease: Results from a Randomized, Controlled Phase II Clinical Trial.

AIMS: Alcohol-associated liver disease (ALD) is a global health problem caused, among other factors, by oxidative stress from the formation of reactive oxygen species (ROS). One important source of ROS is microsomal ethanol metabolism catalyzed by cytochrome P450 2E1 (CYP2E1), which is induced by chronic ethanol consumption. Inhibition of CYP2E1 by clomethiazole (CMZ) decreases oxidative stress in cell cultures and improves ALD in animal studies. Our study aimed to assess the benefits of a CYP2E1 inhibitor (clomethiazole) in detoxification of patients with ALD. METHODS: Open label, randomized controlled clinical trial to study whether CYP2E1 inhibition improves ALD in the patients with alcohol use disorders admitted for alcohol detoxification therapy (ADT). Patients had to have a serum aspartate aminotransferase (AST) activity exceeding twice the upper normal limit at time of admission and be non-cirrhotic defined by fibroscan value <12 kPa. Sixty patients were randomly assigned to ADT with either CMZ or clorazepate (CZP) for 7-10 days in a 1:1 ratio. The chlorzoxazone test of CYP2E1 activity was performed at enrolment and at 2 points during the study. RESULTS: ADT improved hepatic steatosis (controlled attenuation parameter) in both groups significantly. A trend towards a greater improvement in hepatic fat content during ADT (-21.5%) was observed in the CMZ group (252 ± 48 dB/m vs. 321 ± 38 dB/m; P < 0.0001) compared with the CZP group (-13.9%; 273 ± 38 dB/m vs. 317 ± 39 dB/m; P < 0.0001). As already reported, serum AST (P < 0.004) and alanine aminotransferase (ALT) activities (P < 0.0006) significantly decreased in CMZ patients as compared with patients on CZP by the end of hospitalization. A significant correlation was found between AST (P = 0.023), ALT (P = 0.009), GGT (P = 0.039) and CAP. CONCLUSION: This study demonstrates that CMZ improves clinical biomarkers for ALD in humans most likely due to its inhibitory effect on CYP2E1. Because of its addictive potential, CMZ can only be given for a short period of time and therefore other CYP2E1 inhibitors to treat ALD are needed.

Molecular, Viral and Clinical Features of Alcohol- and Non-Alcohol-Induced Liver Injury.

Hepatic cells are sensitive to internal and external signals. Ethanol is one of the oldest and most widely used drugs in the world. The focus on the mechanistic engine of the alcohol-induced injury has been in the liver, which is responsible for the pathways of alcohol metabolism. Ethanol undergoes a phase I type of reaction, mainly catalyzed by the cytoplasmic enzyme, alcohol dehydrogenase (ADH), and by the microsomal ethanol-oxidizing system (MEOS). Reactive oxygen species (ROS) generated by cytochrome (CYP) 2E1 activity and MEOS contribute to ethanol-induced toxicity. We aimed to: (1) Describe the cellular, pathophysiological and clinical effects of alcohol misuse on the liver; (2) Select the biomarkers and analytical methods utilized by the clinical laboratory to assess alcohol exposure; (3) Provide therapeutic ideas to prevent/reduce alcohol-induced liver injury; (4) Provide up-to-date knowledge regarding the Corona virus and its affect on the liver; (5) Link rare diseases with alcohol consumption. The current review contributes to risk identification of patients with alcoholic, as well as non-alcoholic, liver disease and metabolic syndrome. Additional prevalence of ethnic, genetic, and viral vulnerabilities are presented.

Hepatic Steatosis and Fibrosis in Chronic Inflammatory Bowel Disease.

Background and Purpose: Chronic inflammatory bowel diseases (IBD) frequently affect extraintestinal organs including the liver. Since limited evidence suggests the presence of liver disease in IBD patients, we studied the frequency of hepatic steatosis and fibrosis in these patients and characterized disease-related factors. Methods: In this retrospective, cross-sectional, hospital-based, single-center study, consecutive patients with Crohn's disease (CD) and ulcerative colitis (UC) were included who had undergone routine abdominal ultrasound including transhepatic elastography. Hepatic steatosis was diagnosed by hyperechogenicity on B-mode ultrasound and by measuring controlled attenuation parameter (CAP). Hepatic fibrosis was assumed if transhepatic elastography yielded a stiffness > 7 kPa. Results: 132 patients (60% CD) with a median disease duration of 10 years were included. Steatosis assessed by B-mode ultrasound and CAP correlated well. Of the IBD patients, 30.3% had non-alcoholic fatty liver (NAFL). Factors associated with NAFL were age, BMI, duration of disease, as well as serum activities of aspartate-aminotransferase (AST) and gamma-glutamyl-transpeptidase (GGT). In multivariate analysis, only disease duration was independently associated with hepatic steatosis. Hepatic fibrosis was found in 10 (8%) of all IBD patients, predominantly in patients with CD (10/11). Conclusions: Pure hepatic steatosis is common in both CD and UC, whereas hepatic fibrosis occurs predominantly in CD patients. Association of disease duration with NAFLD suggests a contribution of IBD-related pathogenetic factors. Longitudinal studies are needed to better understand the impact of IBD on hepatic disorders.

Alcohol: basic and translational research; 15th annual Charles Lieber &1st Samuel French satellite symposium.

The present review is based on the research presented at the symposium dedicated to the legacy of the two scientists that made important discoveries in the field of alcohol-induced liver damage: Professors C.S. Lieber and S.W. French. The invited speakers described pharmacological, toxicological and patho-physiological effects of alcohol misuse. Moreover, genetic biomarkers determining adverse drug reactions due to interactions between therapeutics used for chronic or infectious diseases and alcohol exposure were discussed. The researchers presented their work in areas of alcohol-induced impairment in lipid protein trafficking and endocytosis, as well as the role of lipids in the development of fatty liver. The researchers showed that alcohol leads to covalent modifications that promote hepatic dysfunction and injury. We concluded that using new advanced techniques and research ideas leads to important discoveries in science.

A genetic risk score and diabetes predict development of alcohol-related cirrhosis in drinkers.

BACKGROUND & AIMS: Only a minority of excess alcohol drinkers develop cirrhosis. We developed and evaluated risk stratification scores to identify those at highest risk. METHODS: Three cohorts (GenomALC-1: n = 1,690, GenomALC-2: n = 3,037, UK Biobank: relevant n = 6,898) with a history of heavy alcohol consumption (≥80 g/day (men), ≥50 g/day (women), for ≥10 years) were included. Cases were participants with alcohol-related cirrhosis. Controls had a history of similar alcohol consumption but no evidence of liver disease. Risk scores were computed from up to 8 genetic loci identified previously as associated with alcohol-related cirrhosis and 3 clinical risk factors. Score performance for the stratification of alcohol-related cirrhosis risk was assessed and compared across the alcohol-related liver disease spectrum, including hepatocellular carcinoma (HCC). RESULTS: A combination of 3 single nucleotide polymorphisms (SNPs) (PNPLA3:rs738409, SUGP1-TM6SF2:rs10401969, HSD17B13:rs6834314) and diabetes status best discriminated cirrhosis risk. The odds ratios (ORs) and (95% CIs) between the lowest (Q1) and highest (Q5) score quintiles of the 3-SNP score, based on independent allelic effect size estimates, were 5.99 (4.18-8.60) (GenomALC-1), 2.81 (2.03-3.89) (GenomALC-2), and 3.10 (2.32-4.14) (UK Biobank). Patients with diabetes and high risk scores had ORs of 14.7 (7.69-28.1) (GenomALC-1) and 17.1 (11.3-25.7) (UK Biobank) compared to those without diabetes and with low risk scores. Patients with cirrhosis and HCC had significantly higher mean risk scores than patients with cirrhosis alone (0.76 ± 0.06 vs. 0.61 ± 0.02, p = 0.007). Score performance was not significantly enhanced by information on additional genetic risk variants, body mass index or coffee consumption. CONCLUSIONS: A risk score based on 3 genetic risk variants and diabetes status enables the stratification of heavy drinkers based on their risk of cirrhosis, allowing for the provision of earlier preventative interventions. LAY SUMMARY: Excessive chronic drinking leads to cirrhosis in some people, but so far there is no way to identify those at high risk of developing this debilitating disease. We developed a genetic risk score that can identify patients at high risk. The risk of cirrhosis is increased >10-fold with just two risk factors - diabetes and a high genetic risk score. Risk assessment using this test could enable the early and personalised management of this disease in high-risk patients.

The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology.

This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.

Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers.

INTRODUCTION: Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS: We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS: The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION: If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.

Genome-wide Association Study and Meta-analysis on Alcohol-Associated Liver Cirrhosis Identifies Genetic Risk Factors.

BACKGROUND AND AIMS: Only a minority of heavy drinkers progress to alcohol-associated cirrhosis (ALC). The aim of this study was to identify common genetic variants that underlie risk for ALC. APPROACH AND RESULTS: We analyzed data from 1,128 subjects of European ancestry with ALC and 614 heavy-drinking subjects without known liver disease from Australia, the United States, the United Kingdom, and three countries in Europe. A genome-wide association study (GWAS) was performed, adjusting for principal components and clinical covariates (alcohol use, age, sex, body mass index, and diabetes). We validated our GWAS findings using UK Biobank. We then performed a meta-analysis combining data from our study, the UK Biobank, and a previously published GWAS. Our GWAS found genome-wide significant risk association of rs738409 in patatin-like phospholipase domain containing 3 (PNPLA3) (odds ratio [OR] = 2.19 [G allele], P = 4.93 × 10-17 ) and rs4607179 near HSD17B13 (OR = 0.57 [C allele], P = 1.09 × 10-10 ) with ALC. Conditional analysis accounting for the PNPLA3 and HSD17B13 loci identified a protective association at rs374702773 in Fas-associated factor family member 2 (FAF2) (OR = 0.61 [del(T) allele], P = 2.56 × 10-8 ) for ALC. This association was replicated in the UK Biobank using conditional analysis (OR = 0.79, P = 0.001). Meta-analysis (without conditioning) confirmed genome-wide significance for the identified FAF2 locus as well as PNPLA3 and HSD17B13. Two other previously known loci (SERPINA1 and SUGP1/TM6SF2) were also genome-wide significant in the meta-analysis. GeneOntology pathway analysis identified lipid droplets as the target for several identified genes. In conclusion, our GWAS identified a locus at FAF2 associated with reduced risk of ALC among heavy drinkers. Like the PNPLA3 and HSD17B13 gene products, the FAF2 product has been localized to fat droplets in hepatocytes. CONCLUSIONS: Our genetic findings implicate lipid droplets in the biological pathway(s) underlying ALC.

Propofol-Induced Hepatitis.

OBJECTIVES: To present a rare case of propofol-induced hepatitis. MATERIALS AND METHODS: A 59-year old man was referred to our department because of suspicion of toxic hepatitis after propofol anaesthesia for endoscopic colonoscopy. RESULTS: The patient had jaundice, increased transaminases demonstrating liver necrosis, and liver stiffness of 18 kPa. Liver biopsy revealed bridging necrosis and initial post-collapse fibrosis. Following therapy with steroids and N-acetyl cysteine, the patient was discharged on the seventh day after admission in good general condition. CONCLUSION: Although propofol is considered safe, it can cause acute hepatitis, the seventh published case of which is reported here. Importantly, treatment with N-acetyl cysteine, a radical scavenger, but especially with steroids resulted in hepatic improvement. LEARNING POINTS: Drug-induced hepatitis is a severe illness caused by a large variety of agents, including many considered safe.It can occur in the absence of predisposing liver abnormality or disease.If the condition is correctly identified, clinical and laboratory abnormalities can be reversed with appropriate treatment.

Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research.

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10-20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.

[The role of Cytochrom P4502E1 in Alcoholic Liver Disease and alcohol mediated carcinogenesis]. / Die Bedeutung von Cytochrom P4502E1 bei der alkoholischen Lebererkrankung und bei der alkoholmediierten Karzinogenese.

Various factors are involved in the pathogenesis of alcoholic liver disease (ALD) and ethanol-mediated carcinogenesis. In addition to genetic, epigenetic and immunologic mechanisms, acetaldehyde-associated toxicity, oxidative stress as well as cytokine-mediated inflammation are of major importance. Oxidative stress, with the generation of reactive oxygen species (ROS), develops either in inflammation (alcoholic hepatitis) or during oxidation of ethanol via cytochrome P4502E1 (CYP2E1). CYP2E1 is induced by ethanol, oxidizes ethanol to acetaldehyde, and generates ROS during this process. ROS results in protein damage, enhanced fibrogenesis and DNA lesions. Furthermore, CYP2E1 induction results in an enhanced activation of various procarcinogens and an increased degradation of retinol and retinoic acid (RA), a compound responsible for cell differentiation and proliferation. An inhibition of CYP2E1 results in an improvement of ALD and chemically induced carcinogenesis in animal experiments. In humans, CYP2E1 is induced following the consumption of 40 grams of ethanol per day after one week. However, the induction varies inter-individually. The mechanism for this is still unclear. Patients with ALD show a significant correlation between CYP2E1, the occurrence of highly carcinogenic etheno DNA adducts and the severity of fibrosis. First results on the effect of CYP2E1 inhibition by chlormethiazole, a specific CYP2E1 inhibitor on ALD, can be expected soon.