Correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis

AIM: To elucidate the correlation between hepatic blood flow and liver function in alcoholic liver cirrhosis (AL-LC).

Hepatic stellate cells and innate immunity in alcoholic liver disease

Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.

Inflammation and fibrosis in chronic liver diseases including nonalcoholic fatty liver disease and hepatitis C

At present chronic liver disease(CLD),the third commonest cause of premature death in the United Kingdom is detected late,when interventions are ineffective,resulting in considerable morbidity and mortality.Injury to the liver,the largest solid organ in the body,leads to a cascade of inflammatory events.Chronic inflammation leads to the activation of hepatic stellate cells that undergo transdifferentiation to become myofibroblasts,the main extra-cellular matrix producing cells in the liver;over time increased extra-cellular matrix production results in the formation of liver fibrosis.Although fibrogenesis may be viewed as having evolved as a“wound healing”process that preserves tissue integrity,sustained chronic fibrosis can become pathogenic culminating in CLD,cirrhosis and its associated complications.As the reference standard for detecting liver fibrosis,liver biopsy,is invasive and has an associated morbidity,the diagnostic assessment of CLD by non-invasive testing is attractive.Accordingly,in this review the mechanisms by which liver inflammation and fibrosis develop in chronic liver diseases are explored to identify appropriate and meaningful diagnostic targets for clinical practice.Due to differing disease prevalence and treatment efficacy,disease specific diagnostic targets are required to optimally manage individual CLDs such as non-alcoholic fatty liver disease and chronic hepatitis C infection.To facilitate this,a review of the pathogenesis of both conditions is also conducted.Finally,the evidence for hepatic fibrosis regression and the mechanisms by which this occurs are discussed,including the current use of antifibrotic therapy.

Risk factors for hepatic steatosis in adults with cystic fibrosis: Similarities to non-alcoholic fatty liver disease

AIM To investigate the clinical, biochemical and imaging characteristics of adult cystic fibrosis(CF) patients with hepatic steatosis as compared to normal CF controls.METHODS We performed a retrospective review of adult CF patients in an academic outpatient setting during 2016. Baseline characteristics, genetic mutation analysis as well as laboratory values were collected. Abdominal imaging(ultrasound, computed tomography, magnetic resonance) was used to determine presence of hepatic steatosis. We compare patients with hepatic steatosis to normal controls.RESULTS Data was collected on 114 patients meeting inclusion criteria. Seventeen patients(14.9%) were found to have hepatic steatosis on imaging. Being overweight(BMI > 25)(P = 0.019) and having a higher pp FEV1(75 vs 53, P = 0.037) were significantly associated with hepatic steatosis. Patients with hepatic steatosis had a significantly higher median alanine aminotransferase level(27 vs 19, P = 0.048). None of the hepatic steatosis patients had frank CF liver disease, cirrhosis or portal hypertension. We found no significant association with pancreatic insufficiency or CF related diabetes.CONCLUSION Hepatic steatosis appears to be a clinically and phenotypically distinct entity from CF liver disease. The lack of association with malnourishment and the significant association with higher BMI and higher pp FEV1 demonstrate similarities with non-alcoholic fatty liver disease. Long term prospective studies are needed to ascertain whether CF hepatic steatosis progresses to fibrosis and cirrhosis.

Hospitalizations for alcoholic liver disease during the COVID-19 pandemic increased more for women,especially young women,compared to men

BACKGROUND Alcoholic liver disease(ALD)remains one of the major indications for liver transplantation in the United States and continues to place a burden on the national healthcare system.There is evidence of increased alcohol consumption during the coronavirus disease 2019(COVID-19)pandemic,and the effect of this on the already burdened health systems remains unknown.AIM To assess the trends for ALD admissions during the COVID-19 pandemic,and compare it to a similar pre-pandemic period.METHODS This retrospective study analyzed all admissions at a tertiary health care system,which includes four regional hospitals.ALD admissions were identified by querying a multi-hospital health system’s electronic database using ICD-10 codes.ALD admissions were compared for two one-year periods;pre-COVID-19 from April 2019 to March 2020,and during-COVID-19 from April 2020 to March 2021.Data were analyzed using a Poisson regression model and admission rates were compared using the annual quarterly average for the two time periods,with stratification by age and gender.Percent increase or decrease in admissions from the Poisson regression model were reported as incident rate ratios.RESULTS One thousand three hundred and seventy-eight admissions for ALD were included.80.7%were Caucasian,and 34.3%were female.An increase in the number of admissions for ALD during the COVID-19 pandemic was detected.Among women,a sharp rise(33%)was noted in those below the age of 50 years,and an increase of 22%in those above 50 years.Among men,an increase of 24%was seen for those below 50 years,and a 24%decrease in those above 50 years.CONCLUSION The COVID-19 pandemic has had widespread implications,and an increase in ALD admissions is just one of them.However,given that women are often prone to rapid progression of ALD,this finding has important preventive health implications.

Alcoholic liver disease and hepatitis C virus infection

Alcohol consumption and hepatitis C virus(HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher(up to 50%) in alcoholic patients than in the general po pulation. However, the presence of advanc e d alcoholic liver disease(ALD) or intravenous drug use(IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefi t from addi tionalsupport during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.

CEUS and Fibroscan in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis

AIM: To determine intra-hepatic blood flow and liver stiffness in patients with non-alcoholic fatty liver disease(NAFLD) and non-alcoholic steatohepatitis (NASH) using contrast-enhanced ultrasound and fibroscan.METHODS: This prospective study included 15 patients with NAFLD, 17 patients with NASH and 16 healthy controls.In each patient, real-time ultrasound was used to locate the portal vein (PV) and the right liver lobe, and 5 mL of SonoVue? was then injected intravenous in a peripheral vein of the left arm over a 4-s span. Digital recording was performed for 3 min thereafter. The recording was subsequently retrieved to identify an area of interest in the PV area and in the right liver parenchyma(LP) to assess the blood flow by processing the data using dedicated software (Qontrast?, Bracco, Italy).The following parameters were evaluated: percentage of maximal contrast activity (Peak%), time to peak (TTP, s), regional blood volume (RBV, cm3), regional blood flow (RBF, cm3/s) and mean transit time (MTT, s).At 24-48 h post-injection, liver stiffness was evaluated using Fibroscan and measured in kPa. The statistical evaluation was performed using Student’s t test.RESULTS: In the PV, the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patientscompared with the controls (Peak%: NAFLD 26.3 ± 6.6,NASH 28.1 ± 7.3 vs controls 55.8 ± 9.9, P < 0.001;RBV: NAFLD 4202.3 ± 3519.7, NASH 3929.8 ± 1941.3vs controls 7473 ± 3281, P < 0.01; RBF: NAFLD 32.5± 10.8, NASH 32.7 ± 12.1 vs controls 73.1 ± 13.9, P< 0.001). The TTP in the PV was longer in both patient groups but reached statistical significance only in the NASH patients compared with the controls (NASH 79.5± 37.8 vs controls 43.2 ± 30, P < 0.01). In the LP,the Peak%, RBV and RBF were significantly reduced in the NAFLD and NASH patients compared with the controls (Peak%: NAFLD 43.2 ± 7.3, NASH 41.7 ± 7.7 vs controls 56.6 ± 6.3, P < 0.001; RBV: NAFLD 4851.5± 2009, NASH 5069.4 ± 2292.5 vs controls 6922.9 ±2461.5, P < 0.05; RBF: NAFLD 55.7 ± 10.1, NASH 54.5 ± 12.1 vs controls 75.9 ± 10.5, P < 0.001). The TTP was longer in both patient groups but did not reach statistical significance. The MTT in both the PV and LP in the NAFLD and NASH patients was not different from that in the controls. Liver stiffness was significantly increased relative to the controls only in the NASH patients(NASH: 6.4 ± 2.2 vs controls 4.6 ± 1.5, P < 0.05).CONCLUSION: Blood flow derangement within the liver present not only in NASH but also in NAFLD suggests that a vascular flow alteration precedes liver fibrosis development.

Alcoholic liver disease and hepatitis C:A frequently underestimated combination

Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epidemiology and combined impact of ALD and HCV on the progres sion of liver disease.ALD and HCV affect the progres sion of liver disease to liver cirrhosis and hepatocellular carcinoma(HCC) in a synergistic manner.Thus, the risk for HCC increases f ive times with a daily alcohol con sumption of 80 g;in the presence of HCV it is increased 20fold, and a combination of both risk factors leads to a more than 100fold risk for HCC development.Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication.Several molecu lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression.They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron.Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liversecreted systemic iron hormone hepcidin.A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future.For now, it can be generally concluded that HCVinfect ed patients should abstain from alcohol and alcoholicsshould be encouraged to participate in detoxification programs.

“Pseudotumoral” hepatic pattern in acute alcoholic hepatitis:A case report

In acute alcoholic hepatitis (AAH), a "pseudotumoral" appearance of the liver parenchyma on computed tomography (CT) scan has been reported. The main findings are hypervascularized areas closely similar to those observed in large hepatocellular carcinomas. We report a case of a patient affected by AAH with an unusual appearance of these "pseudotumoral" areas on CT scan, close resembling a metastatic cancer rather than a primary hepatocellular carcinoma. In fact, in contrast with previous reports, the picture was characterized by the presence of many inhomogeneous, hypoattenuated areas highlighted during both pre- and post-contrast phases. Moreover, we report the first description of "pseudotumoral" lesions on ultrasound scan. This patient was successfully treated with corticosteroids, even if many controversies still exist regarding their efficacy in this setting.

Different effects of a CD14 gene polymorphism on disease outcome in patients with alcoholic liver disease and chronic hepatitis C infection

AIM： Clinical and experimental data suggest that gut-derived endotoxins are an important pathogenic factors for progression of chronic liver disease. Recently, a C-T （-159） polymorphism in the promoter region of the CD14 gene was detected and found to confer increased CD14 expression and to be associated with advanced alcoholic liver damage. Here, we investigated this polymorphism in patients with less advanced alcoholic liver disease （ALD） and chronic hepatitis C virus （HCV） infection. METHODS： CD14 genotyping was performed by PCR-RFLP analysis in （a） 121 HCV patients, （b） 62 patients with alcohol-associated cirrhosis （AIc-Ci）, （c） 118 individuals with heavy alcohol abuse without evidence of advanced liver damage （Alc-w/o Ci）, and （d） 247 healthy controls. Furthermore, serum levels of soluble CD14 （sCD14） and transaminases were determined. RESULTS： The TT genotype was significantly more frequent in Alc-Ci compared to Alc-w/o Ci or controls （40.3% vs 23.7% or 24.0%, respectively）. In Alc-w/o Ci, serum levels of transaminases did not differ significantly between patients with different CD14 genotypes. In HCV patients, TT-homozygotes had significantly higher sCD14 levels and sCD14 serum levels were significantly higher in patients with advanced fibrosis or cirrhosis. However, no association was found between CD14 genotypes and histological staging or grading. CONCLUSION： Considering serum transaminases as surrogate markers for alcoholic liver damage, the CD14 polymorphism seems to exhibit different effects during the course of ALD. Differences in genotype distribution between cirrhotic HCV patients and alcoholics and the known functional impact of this polymorphism on CD14 expression levels further indicate differences in the pathophysiological role of CD14 and CD14-mediated lipopolysaccharides signal transduction with regard to the stage as well as the type of the underlying liver disease.

Cost-effectiveness of enhanced liver fibrosis test to assess liver fibrosis in chronic hepatitis C virus and alcoholic liver disease patients

AIM To assess liver fibrosis(LF) in hepatitis C virus(HCV) and alcoholic liver disease(ALD), estimate health outcomes and costs of new noninvasive testing strategies METHODS A Markov model was developed to simulate LF progression in HCV and ALD for a cohort of 40-yearold men with abnormal levels of transaminases. Three different testing alternatives were studied: a single liver biopsy; annual Enhanced liver fibrosis(ELF?) followed by liver stiffness measurement(LSM) imaging as a confirmation test if the ELF test is positive; and annual ELF test without LSM. The analysis was performed from the perspective of a university hospital in Spain.Clinical data were obtained from published literature. Costs were sourced from administrative databases of the hospital. Deterministic and probabilistic sensitivity analyses were performed.RESULTS In HCV patients, annual sequential ELF test/LSM and annual ELF test alone prevented respectively 12.9 and 13.3 liver fibrosis-related deaths per 100 persons tested, compared to biopsy. The incremental costeffectiveness ratios(ICERs) were respectively €13400 and €11500 per quality-adjusted life year(QALY). In ALD, fibrosis-related deaths decreased by 11.7 and 22.1 per 100 persons tested respectively with sequential ELF test/LSM and annual ELF test alone. ICERs were €280 and €190 per QALY, respectively.CONCLUSION The use of the ELF test with or without a confirmation LSM are cost-effective options compared to a single liver biopsy for testing liver fibrosis in HCV and ALD patients in Spain.

Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis?

The liver involvement in alcoholic liver disease(ALD) classically ranges from alcoholic steatosis, alcoholic hepatitis or steatohepatitis, alcoholic cirrhosis and even hepatocellular carcinoma. The more commonly seen histologic features include macrovesicular steatosis, neutrophilic lobular inflammation, ballooning degeneration, Mallory-Denk bodies, portal and pericellular fibrosis. Nonalcoholic steatohepatitis(NASH) is a condition with similar histology in the absence of a history of alcohol intake. Although the distinction is essentially based on presence or absence of a history of significant alcohol intake, certain histologic features favour one or the other diagnosis. This review aims at describing the histologic spectrum of alcoholic liver disease and at highlighting the histologic differences between ALD and NASH.

The effect of NAFLD (non-alcoholic fatty liver disease) on long-term outcome of chronic hepatitis B in Iranian patients

Background: The influence of Non-Alcoholic Fatty Liver Disease on the outcome of chronic hepatitis B disease, including viral, biochemical and histologic characteristics, in Iranian patients is not yet fully un- derstood. Aim: To evaluate the effect of Non-Alcoholic Fatty Liver Disease (NAFLD) on long-term histology- cal, biochemical and viral outcome of chronic he- pa-tictis B in Iranian patients. Methods: We retro- spec-tively evaluated 94 “e Ag” negative chronic hepatitis B patients (with NAFLD: 44, without NAFLD: 50). Non-Alcoholic Fatty Liver Disease was diagnosed based on liver biopsy according to Kleiner classifica-tion. Liver biopsy was done for all patients. Serologi-cal and biochemical variables were evaluated with repeated measure analysis. Results: Non-Alcoholic Fat- ty Liver Disease (NAFLD) was present in 47% of the patients (44 out of 94 patients). In the NAFLD group, increase in AST, ALT, stage (P = 0.002), grade, and total score of liver biopsy were independently related to non-alcoholic fatty liver disease, while HBV-DNA viral load did not correlate with the presence of a fatty liver. Conclusion: Abnormalities of liver enzymes and liver histopathology are more prevalent in concurrent chronic hepatitis B and Non-Alcoholic Fatty Liver Disease (NAFLD).

Distinctive aspects of peptic ulcer disease,Dieulafoy'slesion,and Mallory-Weiss syndrome in patients withadvanced alcoholic liver disease or cirrhosis

AIM:To systematically review the data on distinctive aspects of peptic ulcer disease(PUD),Dieulafoy’s lesion(DL),and Mallory-Weiss syndrome(MWS)in patients with advanced alcoholic liver disease(a ALD),including alcoholic hepatitis or alcoholic cirrhosis.METHODS:Computerized literature search performed via Pub Med using the following medical subject heading terms and keywords:"alcoholic liver disease","alcoholic hepatitis","alcoholic cirrhosis","cirrhosis","liver disease","upper gastrointestinal bleeding","nonvariceal upper gastrointestinal bleeding","PUD",‘‘DL’’,‘‘Mallory-Weiss tear",and"MWS’’.RESULTS:While the majority of acute gastrointestinal(GI)bleeding with a ALD is related to portal hypertension,about 30%-40%of acute GI bleeding in patients with a ALD is unrelated to portal hypertension.Such bleeding constitutes an important complication of a ALD because of its frequency,severity,and associated mortality.Patients with cirrhosis have a markedly increased risk of PUD,which further increases with the progression of cirrhosis.Patients with cirrhosis or a ALD and peptic ulcer bleeding(PUB)have worse clinical outcomes than other patients with PUB,including uncontrolled bleeding,rebleeding,and mortality.Alcohol consumption,nonsteroidal anti-inflammatory drug use,and portal hypertension may have a pathogenic role in the development of PUD in patients with a ALD.Limited data suggest that Helicobacter pylori does not play a significant role in the pathogenesis of PUD in most cirrhotic patients.The frequency of bleeding from DL appears to be increased in patients with a ALD.DL may be associated with an especially high mortality in these patients.MWS is strongly associated with heavy alcohol consumption from binge drinking or chronic alcoholism,and is associated with a ALD.Patients with a ALD have more severe MWS bleeding and are more likely to rebleed when compared to non-cirrhotics.Preendoscopic management of acute GI bleeding in patients with a ALD unrelated to portal hypertension is similar to the management of a ALD patients with GI bleeding from portal hypertension,because clinical distinction before endoscopy is difficult.Most patients require intensive care unit admission and attention to avoid over-transfusion,to correct electrolyte abnormalities and coagulopathies,and to administer antibiotic prophylaxis.Alcoholics should receive thiamine and be closely monitored for symptoms of alcohol withdrawal.Prompt endoscopy,after initial resuscitation,is essential to diagnose and appropriately treat these patients.Generally,the same endoscopic hemostatic techniques are used in patients bleeding from PUD,DL,or MWS in patients with a ALD as in the general population.CONCLUSION:Nonvariceal upper GI bleeding in patients with a ALD has clinically important differences from that in the general population without a ALD,including:more frequent and more severe bleeding from PUD,DL,or MWS.

Alcoholic hepatitis 2010:A clinician's guide to diagnosis and therapy

Alcoholic hepatitis(AH)remains a common and life threatening cause of liver failure,especially when it is severe.Although the adjective"acute"is frequently used to describe this form of liver injury,it is usually subacute and has been developing for weeks to months before it becomes clinically apparent.Patients with this form of alcoholic liver disease usually have a history of drinking heavily for many years.While certain aspects of therapy,mainly nutritional support and abstinence are well established,significant debate has surrounded the pharmacologic treatment of AH,and many institutions practice widely varying treatment protocols. In recent years a significant amount of literature has helped focus on the details of treatment,and more data have accumulated regarding risks and benefits of pharmacologic treatment.In particular,the efficacy of pentoxifylline has become increasingly apparent,and when compared with the risks associated with prednisolone,has brought this drug to the forefront of therapy for severe AH.This review will focus on the clinical and laboratory diagnosis and pharmacologic therapies that should be applied during hospitalization and continued into outpatient management.We conclude that the routine use of glucocorticoids for severe AH poses significant risk with equivocal benefit,and that pentoxifylline is a better,safer and cheaper alternative.While the full details of nutritional support lie beyond the scope of this article,nutrition is a cornerstone of therapy and must be addressed in every patient diagnosed with AH. Finally,while traditional psychosocial techniques play a major role in post-hospitalization care of alcoholics, we hope to make the medical clinician realize his or her role in reducing recidivism rates with early and frequent outpatient visits and with the use of baclofen to reduce alcohol craving.

Optimal management for alcoholic liver disease: Conventional medications, natural therapy or combination?

Alcohol consumption is the principal factor in thepathogenesis of chronic liver diseases.Alcoholic liver disease(ALD)is defined by histological lesions on the liver that can range from simple hepatic steatosis to more advanced stages such as alcoholic steatohepatitis,cirrhosis,hepatocellular carcinoma and liver failure.As one of the oldest forms of liver injury known to humans,ALD is still a leading cause of liver-related morbidity and mortality and the burden is exerting on medical systems with hospitalization and management costs rising constantly worldwide.Although the biological mechanisms,including increasing of acetaldehyde,oxidative stress with induction of cytochrome p4502E1,inflammatory cytokine release,abnormal lipid metabolism and induction of hepatocyte apoptosis,by which chronic alcohol consumption triggers serious complex progression of ALD is well established,there is no universally accepted therapy to prevent or reverse.In this article,we have briefly reviewed the pathogenesis of ALD and the molecular targets for development of novel therapies.This review is focused on current therapeutic strategies for ALD,including lifestyle modification with nutrition supplements,available pharmacological drugs and new agents that are under development,liver transplantation,application of complementary medicines,and their combination.The relevant molecular mechanisms of each conventional medication and natural agent have been reviewed according to current available knowledge in the literature.We also summarized efficacy vs safety on conventional and herbal medicines which are specifically used for the prevention and treatment of ALD.Through a system review,this article highlighted that the combination of pharmaceutical drugs with naturally occurring agents may offer an optimal management for ALD and its complications.It is worthwhile to conduct large-scale,multiple centre clinical trials to further prove the safety and benefits for the integrative therapy on ALD.

Liver transplantation in alcoholic liver disease current status and controversies

Alcoholic cirrhosis remains the second most common indication for liver transplantation.A comprehensive medical and psychosocial evaluation is needed when making a decision to place such patients on the transplant list.Most transplant centers worldwide need a minimum of 6 mo of alcohol abstinence for listing these patients.Patients with alcohol dependence are at high risk for relapse to alcohol use after transplantation(recidivism).These patients need to be identified and require alcohol rehabilitation treatment before transplantation.Recidivism to the level of harmful drinking is reported in about 15%-20%cases.Although,recurrent cirrhosis and graft loss from recidivism is rare,occurring in less than 5%of all alcoholic cirrhosis-related transplants,harmful drinking in the post-transplant pe-riod does impact the long-term outcome.The development of metabolic syndrome with cardiovascular events and de novo malignancy are important contributors to non liver-related mortality amongst transplants for alcoholic liver disease.Surveillance protocols for earlier detection of de novo malignancy are needed to improve the long-term outcome.The need for a minimum of 6 mo of abstinence before listing makes transplant a nonviable option for patients with severe alcoholic hepatitis who do not respond to corticosteroids.Emerging data from retrospective and prospective studies has challenged the 6 mo rule,and beneficial effects of liver transplantation have been reported in select patients with a first episode of severe alcoholic hepatitis who are unresponsive to steroids.

Liver transplantation and alcoholic liver disease:History,controversies,and considerations

Alcohol consumption accounts for 3.8% of annual global mortality worldwide, and the majority of these deaths are due to alcoholic liver disease(ALD), mainly alcoholic cirrhosis. ALD is one of the most common indications for liver transplantation(LT). However, it remains a complicated topic on both medical and ethical grounds, as it is seen by many as a "self-inflicted disease". One of the strongest ethical arguments against LT for ALD is the probability of relapse. However, ALD remains a common indication for LT worldwide. For a patient to be placed on an LT waiting list, 6 mo of abstinence must have been achieved for most LT centers. However, this "6-mo rule" is an arbitrary threshold and has never been shown to affect survival, sobriety, or other outcomes. Recent studies have shown similar survival rates among individuals who undergo LT for ALD and those who undergo LT for other chronic causes of end-stage liver disease. There are specific factors that should be addressed when evaluating LT patients with ALD because these patients commonly have a high prevalence of multisystem alcohol-related changes. Risk factors for relapse include the presence of anxiety or depressive disorders, short pre-LT duration of sobriety, and lack of social support. Identification of risk factors and strengthening of the social support system may decrease relapse among these patients. Family counseling for LT candidates is highly encouraged to prevent alcohol consumption relapse. Relapse has been associated with unique histopathological changes, graft damage, graft loss, and even decreased survival in some studies. Research has demonstrated the importance of a multidisciplinary evaluation of LT candidates. Complete abstinence should be attempted to overcome addiction issues and to allow spontaneous liver recovery. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including 12-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Nutritional therapy helps to reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. For muscular recovery, supervised physical activity has been shown to lead to a gain in muscle mass and improvement of functional activity. Early LT for acute alcoholic hepatitis has been the subject of recent clinical studies, with encouraging results in highly selected patients. The survival rates after LT for ALD are comparable to those of patients who underwent LT for other indications. Patients that undergo LT for ALD and survive over 5 years have a higher risk of cardiorespiratory disease, cerebrovascular events, and de novo malignancy.

Definition,epidemiology and magnitude of alcoholic hepatitis

Alcoholic liver disease(ALD) is a major cause of alcoholrelated morbidity and mortality.Its presentation ranges from fatty liver to alcoholic hepatitis(AH),cirrhosis,and hepatocellular carcinoma.Although the amount and pattern of alcohol consumption is a well recognized predisposing factor for the development of serious liver pathology,environmental factors and the host's genetic makeup may also play significant roles that have not yet been entirely explored.Continuing alcohol consumption is a major factor that influences the survival of patients with AH.The presence of cirrhosis at presentation or its development on follow up is a major factor determining the outcome in the long run.This chapter deals with the epidemiology and magnitude of ALD in general and AH in particular.

Pathogenesis of alcoholic liver disease:Role of oxidative metabolism

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-&#x003b2;-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.