Liver transplantation for severe alcoholic hepatitis– The PRO view

Although liver transplantation has become accepted as a life‐saving treatment of last resort for most life‐threatening liver disorders, the use of liver transplantation to rescue patients with severe alcoholic hepatitis unresponsive to medical therapy remains controversial. I propose the concepts that alcohol use disorder is an illness, that on occasion results in alcoholic liver disease and that treatment of alcoholic liver disease, including treatment of patients with severe alcoholic hepatitis, combines treatment of the alcohol use disorder and of alcoholic liver disease. From this I derive the following principal to govern selection of patients for liver transplantation of patients with alcohol use disorder: that alcohol use disorder should impact suitability for liver transplantation as a co‐morbid disorder, in the same way as other common co‐morbid disorders such as diabetes mellitus or systemic hypertension, are factored in the selection process. We should relate the risk of drinking relapse to the prognosis of the patient after transplantation, rather than in a binary construct of likelihood of maintaining abstinence vs drinking.     

Alcoholic liver disease: Treatment

The excess consumption of alcohol is associated with alcoholic liver diseases(ALD). ALD is a major healthcare problem, personal and social burden, and significant reason for economic loss worldwide. The ALD spectrum includes alcoholic fatty liver, alcoholic hepatitis, cirrhosis, and the development of hepatocellular carcinoma. The diagnosis of ALD is based on a combination of clinical features, including a history of significant alcohol in-take, evidence of liver disease, and laboratory findings. Abstinence is the most important treatment for ALD and the treatment plan varies according to the stage of the disease. Various treatments including abstinence, nutritional therapy, pharmacological therapy, psycho-therapy, and surgery are currently available. For severe alcoholic hepatitis, corticosteroid or pentoxifylline are recommended based on the guidelines. In addition, new therapeutic targets are being under investigation.     

Alcoholic liver injury： Pathological features and models—Role of alcohol in the regulation of iron metabolism

Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis, an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.     

Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH)

Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.     

Pathogenesis and management of alcoholic hepatitis

Alcoholic hepatitis is a potentially life-threatening complication of alcoholic abuse, typically presenting with symptoms and signs of hepatitis in the presence of an alcohol use disorder. The definitive diagnosis requires liver biopsy, but this is not generally required. The pathogenesis is uncertain, but relevant factors include metabolism of alcohol to toxic products, oxidant stress, acetaldehyde adducts, the action of endotoxin on Kupffer cells, and impaired hepatic regeneration. Mild alcoholic hepatitis recovers with abstinence and the long-term prognosis is determined by the underlying disorder of alcohol use. Severe alcoholic hepatitis is recognized by a Maddrey discriminant function >32 and is associated with a short-term mortality rate of almost 50%. Primary therapy is abstinence from alcohol and supportive care. Corticosteroids have been shown to be beneficial in a subset of severely ill patients with concomitant hepatic encephalopathy, but their use remains controversial. Pentoxifylline has been shown in one study to improve short-term survival rates. Other pharmacological interventions, including colchicine, propylthiouracil, calcium channel antagonists, and insulin with glucagon infusions, have not been proven to be beneficial. Nutritional supplementation with available high-calorie, high-protein diets is beneficial, but does not improve mortality. Orthotopic liver transplantation is not indicated for patients presenting with alcoholic hepatitis who have been drinking until the time of admission, but may be considered in those who achieve stable abstinence if liver function fails to recover.     

酒精性肝病并酒精性戒断综合征32例临床分析

探讨酒精性肝病患者中酒精戒断综合征的临床特点,并分析酒精性肝病的严重程度是否影响戒断症状的轻重。回顾性分析了32例酒精性肝病合并酒精戒断综合征的患者,用SPSS统计软件进行统计分析表明酒精性肝病的严重程度并不影响戒断症状的轻重,酒精性肝病的严重程度与饮酒时间密切相关而与平均每天酒量关系不大,而戒断则反之。因此长期酗酒引起酒精性肝病者每天饮酒（精）量越大越容易出现戒断综合征,须提高警惕避免误诊。     

Alcoholic hepatitis and concomitant hepatitis C virus infection

Hepatitis C virus(HCV)infection and alcohol abuse are two most important causes of chronic liver disease in the United States.Alcoholic hepatitis is a unique clinical syndrome among patients with chronic and active alcohol abuse with a potential for high short-term mortality.About 20%of patients presenting with alcoholic hepatitis have concomitant HCV infection.Mortality from alcoholic hepatitis is increased in the presence of concomitant hepatitis C due to synergistic interaction between HCV and alcohol in causing hepatocellular damage.Large prospective randomized studies are needed to develop guidelines on the use of corticosteroids among patients with alcoholic hepatitis and concomitant HCV infection.The impact of antiviral therapy on mortality and outcome in the setting of alcoholic hepatitis remains a novel area for future research.     

Long-term management of alcoholic liver disease

Despite the epidemics of viral hepatitis C and nonalcoholic fatty liver disease, alcohol remains one of the major causes of liver disease. Commonly, hepatitis C and other liver diseases are found in association with alcohol consumption. This association in many instances is noted to accelerate the progression of liver disease. In many respects, the long-term management of alcoholic liver disease is not dissimilar from the long-term management of patients with cirrhosis from other etiologies. One major element is the abstinence of alcohol use. The ability to maintain sobriety has a major impact on the outcome of patients with alcoholic cirrhosis because maintaining abstinence can lead to significant regression of fibrosis and possibly early cirrhosis. Similarities in managing patients with cirrhosis due to alcohol or cirrhosis from other causes include vaccination to prevent superimposed viral hepatitis and screening for esophageal varices and hepatocellular carcinoma with subsequent appropriate therapy.     

Role of the ghrelin system in alcohol use disorder and alcohol-associated liver disease: A narrative review

Unhealthy alcohol consumption is a global health problem. Adverse individual, public health, and socioeconomic consequences are attributable to harmful alcohol use. Epidemiological studies have shown that alcohol use disorder (AUD) and alcohol-associated liver disease (ALD) are the top two pathologies among alcohol-related diseases. Consistent with the major role that the liver plays in alcohol metabolism, uncontrolled drinking may cause significant damage to the liver. This damage is initiated by excessive fat accumulation in the liver, which can further progress to advanced liver disease. The only effective therapeutic strategies currently available for ALD are alcohol abstinence or liver transplantation. Any molecule with dual-pronged effects at the central and peripheral organs controlling addictive behaviors and associated metabolic pathways are a potentially important therapeutic target for treating AUD and ALD. Ghrelin, a hormone primarily derived from the stomach, has such properties, and regulates both behavioral and metabolic functions. In this review, we highlight recent advances in understanding the peripheral and central functions of the ghrelin system and its role in AUD and ALD pathogenesis. We first discuss the correlation between blood ghrelin concentrations and alcohol use or abstinence. Next, we discuss the role of ghrelin in alcohol-seeking behaviors and finally its role in the development of fatty liver by metabolic regulations and organ crosstalk. We propose that a better understanding of the ghrelin system could open an innovative avenue for improved treatments for AUD and associated medical consequences, including ALD.     

Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption.

Alcoholic subjects with abnormal liver chemistry studies are often assumed to have alcoholic liver disease, even though the diagnosis is not established by liver biopsy. To determine the magnitude of nonalcoholic liver disease in patients with heavy alcohol consumption, the data on 145 consecutive patients judged to consume at least 80 g of alcohol daily for prolonged periods, and who underwent liver biopsy at the University of Chicago, were reviewed. Nonalcoholic liver disease was suspected clinically and confirmed by liver biopsy in 40 (28 per cent), whereas alcoholic liver disease was suspected in 105 but confirmed in only 83 (80 per cent). The remaining 22 patients had liver disorders, including cholangitis or pericholangitis, acute hepatitis or some form of chronic hepatitis, for which they required appropriate therapy. Neither clinical features, hepatitis B surface antigen (HBsAg), anti-HBsAg nor serum glutamic oxaloacetic transaminase to serum glutamic pyruvic transaminase (SGOT:SGPT) ratios distinguished these 22 patients from those with alcoholic liver disease. Thus, liver biopsy is necessary for the identification of nonalcoholic liver disease in patients suspected of harboring alcoholic liver disease, since other clinical features do not allow identification of these patients.     

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.     

New treatment options for alcoholic hepatitis

The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using “Omics” platforms, newer options for patients with alcoholic hepatitis are expected soon.     

Therapy for alcoholic liver disease

Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function ≥ 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and portopulmonary hypertension. Alcoholic cirrhotics have increased risk of developing hepatomas. Liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 mo of proven abstinence for eligibility. Alcoholic cirrhotics who maintain abstinence generally have a relatively favorable prognosis after liver transplantation.     

New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

Alcoholic liver disease is a major health problem in theUnited States and worldwide. Chronic alcohol consump-tion can cause steatosis, inflammation, fibrosis, cirrho-sis and even liver cancer. Significant progress has beenmade to understand key events and molecular playersfor the onset and progression of alcoholic liver diseasefrom both experimental and clinical alcohol studies. Nosuccessful treatments are currently available for treat-ing alcoholic liver disease; therefore, development ofnovel pathophysiological-targeted therapies is urgentlyneeded. This review summarizes the recent progresson animal models used to study alcoholic liver diseaseand the detrimental factors that contribute to alcoholicliver disease pathogenesis including miRNAs, S-ad-enosylmethionine, Zinc deficiency, cytosolic lipin-1β,IRF3-mediated apoptosis, RIP3-mediated necrosis andhepcidin. In addition, we summarize emerging adaptiveprotective effects induced by alcohol to attenuate alco-hol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.     

Experimental models of metabolic and alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a multi-systemic disease that is considered the hepatic manifestation of metabolic syndrome (MetS). Because alcohol consumption in NAFLD patients is common, there is a significant overlap in the pathogenesis of NAFLD and alcoholic liver disease (ALD). Indeed, MetS also significantly contributes to liver injury in ALD patients. This “syndrome of metabolic and alcoholic steatohepatitis” (SMASH) is thus expected to be a more prevalent presentation in liver patients, as the obesity epidemic continues. Several pre-clinical experimental models that couple alcohol consumption with NAFLD-inducing diet or genetic obesity have been developed to better understand the pathogenic mechanisms of SMASH. These models indicate that concomitant MetS and alcohol contribute to lipid dysregulation, oxidative stress, and the induction of innate immune response. There are significant limitations in the applicability of these models to human disease, such as the ability to induce advanced liver injury or replicate patterns in human food/alcohol consumption. Thus, there remains a need to develop models that accurately replicate patterns of obesogenic diet and alcohol consumption in SMASH patients.     

Enfermedad hepática por alcohol. Guías de práctica clínica. Documento de consenso auspiciado por la AEEH

Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.     

Management of alcoholic hepatitis:Current concepts

Alcoholic hepatitis is a devastating form of acute liver injury seen in chronic alcohol abusers with significant morbidity and mortality.It is a multisystem disease that is precipitated by ingesting large quantities of alcohol with genetic and environmental factors playing a role.Prognostic criteria have been developed to predict disease severity and these criteria can serve as indicators to initiate medical therapy.Primary therapy remains abstinence and supportive care,as continued alcohol abuse is the most important risk factor for disease progression.The cornerstone of supportive care remains aggressive nutritional support,and although acute alcoholic hepatitis has been extensively studied,few specific medical therapies have been successful.Corticosteroids remain the most effective medical therapy available in improving short term survival in a select group of patients with alcoholic hepatitis;however,the long-term outcome of drug therapies is still not entirely clear and further clinical investigation is necessary.While liver transplantation for acute alcoholic hepatitis have demonstrated promising results,this practice remains controversial and has not been advocated universally,with most transplant centers requiring a prolonged period of abstinence before considering transplantation.Extracorporeal liver support devices,although still experimental,have been developed as a form of liver support to give additional time for liver regeneration.These have the potential for a significant therapeutic option in the future for this unfortunately dreadful disease.     

A Randomized, Double-Blind, Placebo-Controlled Pilot Study of Naltrexone in Outpatients With Bipolar Disorder and Alcohol Dependence

Background:  Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence.
Methods:  Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed.
Results:  The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends ( p  < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence.
Conclusions:  Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.     

Chronic liver inflammation: Clinical implications beyond alcoholic liver disease

Chronic alcohol exposure can lead to alcoholic liver disease, including hepatitis, cirrhosis and hepatocellular carcinoma, and chronic inflammation can simultaneously cause systemic medical illness. Recent evidence suggests that alcoholic liver disease is a predictor for liver-related diseases, cardiovascular disease, immunologic disease, and bone disease. Chronic inflammation in alcoholic liver disease is mediated by a direct inflammatory cascade from the alcohol detoxification process and an indirect inflammatory cascade in response to gut microflora-derived lipopolysaccharides (LPS). The pathophysiology of alcoholic liver disease and its related systemic illness is characterized by oxidative stress, activation of the immune cascade, and gut-liver interactions. Integrative therapeutic strategies for alcoholic liver disease include abstaining from alcohol consumption; general anti-inflammatories such as glucocorticoid, pentoxifylline, and tumour necrosis factor-α antagonist; antioxidants such as N- acetylcysteine; gut microflora and LPS modulators such as rifaximin and/or probiotics. This review focuses on the impact of chronic liver inflammation on systemic health problems and several potential therapeutic targets.     

Hépatite alcoolique aiguë

Alcoholic hepatitis is one of the most severe presentations of alcoholic liver disease. It is usually revealed by the recent onset of jaundice in a patient with alcoholic cirrhosis. Maddrey's discriminant function can help to recognize patients with poor prognosis (the 6-month mortality is above 50% when it exceeds 32). Corticosteroids increase survival in those patients with high risk of death. Other treatments (pentoxifylline, N-acetyl-cysteine or enteral nutrition) need to be investigated further before to recommend their routine use instead of, or in association with, corticoids. Liver transplantation can be proposed to highly selected patients who do not respond to medical therapy. In any case, long-term prognosis will primarily depend on the maintenance of alcohol abstinence.