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The guidelines provide three key recommendations regarding public health aspects of alcohol-related liver disease (ALD): 1. Excess alcohol consumption should be addressed using pricing-based policies and regulation of availability to reduce population risk. 2. Advertising and marketing of alcohol should be banned to decrease consumption. 3. Primary care facilities for managing alcohol use disorder must be widely available and screening for harmful drinking and ALD should be performed in high-risk groups followed by brief intervention and multidisciplinary treatment.

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Alcohol-related liver disease Clinical Practice Guidelines
About these slides • These slides give a comprehensive overview of the EASL clinical practice guidelines on the management of alcohol-related liver disease • The guidelines were first presented at the International Liver Congress 2018 and are published in the Journal of Hepatology – A full copy of the publication can be downloaded from the Clinical Practice Guidelines section of the EASL website • Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source
About these slides • Definitions of all abbreviations shown in these slides are provided within the slide notes • When you see a home symbol like this one: , you can click on this to return to the outline or topics pages, depending on which section you are in • Please send any feedback to: slidedeck_feedback@easloffice.eu These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials
Guideline panel EASL CPG ALD. J Hepatol 2018;69:154–81 • Chair – Mark Thursz • Panel members – Antoni Gual, Caroline Lackner, Philippe Mathurin, Christophe Moreno, Laurent Spahr, Martina Sterneck, Helena Cortez-Pinto (EASL Governing Board representative) • Reviewers – Ewan Forrest, Fabio Caputo, Vijay Shah, EASL Governing Board
Outline EASL CPG ALD. J Hepatol 2018;69:154–81 • Grading evidence and recommendations Methods • Terminology Background • Key recommendations Guidelines • Suggestions for future studies Conclusions
Methods Grading evidence and recommendations
Grading evidence and recommendations *Level was downgraded if there was poor quality, strong bias or inconsistency between studies; level was upgraded if there was a large effect size 1. Guyatt GH, et al. BMJ 2008:336:924–6; 2. EASL CPG ALD. J Hepatol 2018;69:154–81 • Grading is adapted from the GRADE system1,2 Level of evidence* Confidence in the evidence 1 Data derived from meta-analyses or systematic reviews or from (multiple) randomized trials (RCTs) with high quality Further research is unlikely to change our confidence in the estimate of benefit and risk 2 Data derived from a single RCT or multiple non-randomized studies Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate 3 Small studies, retrospective observational studies, registries Any estimate of effect is uncertain Grade of recommendation (wording associated with the grade of recommendation) A Strong (“must”, “should”, or “EASL recommends”) B Weak (“can”, “may”, or “EASL suggests”)
Background Terminology
Terminology *Histologically-defined lesion; †At this point the term alcoholic hepatitis has become too standardized to change (may be reviewed in future guidelines) EASL CPG ALD. J Hepatol 2018;69:154–81 • The term ‘alcoholic’ is stigmatizing – Undermines patient dignity and self-esteem • These guidelines use the following terms Previous term Current term Abbreviation Alcoholic Alcohol use disorder AUD Alcoholic liver disease Alcohol-related liver disease ALD Alcoholic cirrhosis Cirrhosis due to alcohol-related liver disease ALD cirrhosis Alcoholic steatohepatitis* Steatohepatitis due to ALD ASH Alcoholic fibrosis Fibrosis due to ALD ALD fibrosis Alcoholic hepatitis Alcoholic hepatitis† AH
Guidelines Key recommendations
Topics EASL CPG ALD. J Hepatol 2018;69:154–81 1. Public health aspects 2. Alcohol use disorders 3. Diagnostic tests in the management of ALD 4. Management of alcoholic hepatitis 5. Alcohol-related fibrosis and cirrhosis 6. Liver transplantation Click on a topic to skip to that section
Public health aspects: Alcohol-related morbidity and mortality 1. WHO. Global status report on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Worldwide, harmful use of alcohol is associated with: – ~3.3 million deaths every year 1 • 5.9% of all deaths overall (7.6% in men, 4.0% in women)1 – ~139 million disability-adjusted life years • 5.1% of the global burden of disease and injury • Alcohol has an impact on over 200 diseases and types of injuries • Most deaths attributable to alcohol consumption from: – Cardiovascular diseases – Injuries – Gastrointestinal diseases • Mainly cirrhosis – Cancers • Alcohol-attributable fraction is highest for liver diseases and foetal alcohol syndrome
Public health aspects: Alcohol-related morbidity and mortality 1. WHO. Global status report on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018; 2. Sheron N. J Hepatol 2016;64:95767; EASL CPG ALD. J Hepatol 2018;69:154–81 • WHO European Region has the highest adult per capita alcohol consumption1 • In the EU, 41% of liver deaths are attributed to alcohol2 – Likely to be an under-representation due to inaccuracies in coding data – Attribution of alcohol is likely in around 60–80% of cases in larger EU member states2 Data from the WHO mortality database categorized into three groups (definite ALD, another defined diagnosis or unknown aetiology). The wide variation in % mortality from ALD is strongly related to inaccuracies in coding the data2 ALD Unknown liver disease Definitely not ALD 0 20 40 60 80 100 Percentage Liver disease aetiology in larger EU member states since 2000
Public health issues: Definitions of “drink” and “drinking” EASL CPG ALD. J Hepatol 2018;69:154–81 • Quantification of alcohol consumption is not easy in clinical practice • Grams of alcohol is more precise, but: – Time consuming and frequently difficult to obtain – Patients cannot recall the different amounts and types of drink Term Definition One standard drink 10 g of alcohol Harmful drinking Where alcohol use is causing damage to either physical or mental health Heavy episodic drinking Consumption of more than 60 g of pure alcohol on one occasion Binge drinking Consumption within about 2 hours of four or more drinks for women and five or more drinks for men
Public health aspects: Data are conflicting around a safe alcohol limit EASL CPG ALD. J Hepatol 2018;69:154–81 • Light–moderate intake: reduced risk of coronary artery disease • Heavy chronic alcohol intake: increased risk of cardiomyopathy, hypertension, atrial arrhythmias and haemorrhagic stroke • Alcohol is a recognized carcinogen – No threshold level of consumption known for cancer risk • Chronic use of alcohol is a risk factor for cirrhosis • Unclear whether there is a continuous dose–response relationship • Unclear whether there is a threshold at which the risk emerges • Risks of binge drinking vs. daily drinking remain controversial • Cessation of drinking at any point reduces risk of disease progression and occurrence of complications Recommendation Limit daily intake to ≤2 standard drinks for women and ≤3 for men. This amount is not associated with significant increase in cirrhosis mortality
Public health aspects: Policies to reduce population risk for ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Effective interventions include: – Price based policies • Taxation • Minimum unit pricing – Limitation of alcohol availability – Restriction of marketing and advertising • Policies based on age-related vulnerability – Partial or total advertising bans – Restrictions on access to alcohol through minimum ages at which it is legal to purchase alcohol – Laws to prevent any alcohol consumption by young people when driving vehicles
Public health aspects: Impact of minimum unit pricing in British Colombia Sheron N. J Hepatol 2016;64:95767; EASL CPG ALD. J Hepatol 2018;69:154–81 Rates of 100% alcohol-attributable deaths and CPI-adjusted minimum alcohol prices
Public health aspects: Screening to reduce ALD-related morbidity and mortality EASL CPG ALD. J Hepatol 2018;69:154–81 • Early recognition and intervention are required – Goal of abstinence or decreased alcohol consumption should be implemented to reduce the risk of liver disease in harmful drinkers • Screening for harmful drinking should be performed by GPs, and in patients admitted to emergency facilities, with screening for ALD in high-risk patients • Suggested screening methods include: – Blood markers – Transient elastography • Screening must be followed by an intervention with a multidisciplinary team – Specialist alcohol care teams are required to care for patients
Public health aspects *Either directly or indirectly EASL CPG ALD. J Hepatol 2018;69:154–81 • Harmful alcohol use is associated with considerable mortality and morbidity • Policies aimed at reducing harmful alcohol consumption and screening for AUD and for ALD should be implemented Recommendations Excess alcohol consumption should be addressed using pricing-based policies and regulation of availability A 1 Advertising and marketing of alcohol* should be banned A 2 Primary care facilities for managing AUD must be widely available A 2 Screening for harmful alcohol consumption should be performed by GPs and in emergency departments A 2 Screening for ALD should be performed in high-risk populations, such as those in alcohol rehabilitation clinics, or harmful drinkers identified by their GP A 2 Patients identified through screening should undergo brief intervention and referral to a multidisciplinary team A 1 Grade of recommendation Level of evidence
Alcohol use disorders: Terminology and definitions EASL CPG ALD. J Hepatol 2018;69:154–81 • The DSM-V defines AUD as a problematic pattern of alcohol use leading to clinically significant impairment or distress – Graded severity depending on the number of diagnostic criteria met – New concept that overcomes the arbitrary differentiation between alcohol abuse and dependence • Reduces stigmatization of alcoholism • WHO still uses the terms hazardous and harmful alcohol use and alcohol dependence • The term ‘risky drinker’ is commonly used to define people who drink excessively Recommendations The term alcohol use disorder (defined by DSM-V criteria) should be used in preference to alcoholic, alcohol abuse, alcohol dependence or risky drinker A Grade of recommendation
Alcohol use disorders: DSM-V criteria *Or a closely related substance, such as benzodiazepine EASL CPG ALD. J Hepatol 2018;69:154–81 Manifested by ≥2 of the following, occurring within a 12-month period: 1 Alcohol is often taken in larger amounts or over a longer period than was intended 2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use 3 A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects 4 Craving, or a strong desire or urge to use alcohol 5 Recurrent alcohol use resulting in a failure to fulfil major role obligations at work, school, or home 6 Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol 7 Important social, occupational, or recreational activities are given up or reduced because of alcohol use 8 Recurrent alcohol use in situations in which it is physically hazardous 9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol 10 Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of alcohol 11 Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol b. Alcohol* is taken to relieve or avoid withdrawal symptoms
Alcohol use disorders: DSM-V criteria *Or a closely related substance, such as benzodiazepine EASL CPG ALD. J Hepatol 2018;69:154–81 Manifested by ≥2 of the following, occurring within a 12-month period: 1 Alcohol is often taken in larger amounts or over a longer period than was intended 2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use 3 A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects 4 Craving, or a strong desire or urge to use alcohol 5 Recurrent alcohol use resulting in a failure to fulfil major role obligations at work, school, or home 6 Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol 7 Important social, occupational, or recreational activities are given up or reduced because of alcohol use 8 Recurrent alcohol use in situations in which it is physically hazardous 9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol 10 Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of alcohol 11 Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol b. Alcohol* is taken to relieve or avoid withdrawal symptoms Severity graded as: Mild: presence of 2 to 3 criteria Moderate: presence of 4 to 5 criteria Severe: presence of 6 or more criteria
Alcohol use disorders: Screening tools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year
Alcohol use disorders: Screening tools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption
Alcohol use disorders: Screening tools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption Questions 46 explore dependence
Alcohol use disorders: Screening tools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption Questions 46 explore dependence Questions 710 explore alcohol-related problems
Alcohol use disorders: Screening tools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Total scores of ≥8 indicate hazardous and harmful alcohol use Scores of ≥20 or above clearly warrant evaluation for alcohol dependence Scores ≥1 on Q2 or Q3: hazardous level of alcohol consumption Scores >0 on Q4–6: alcohol dependence Points scored on Q7–10: alcohol-related harm
Alcohol use disorders: Screening EASL CPG ALD. J Hepatol 2018;69:154–81 • Patients with AUD have a high prevalence of psychiatric co-morbidity – Anxiety disorders – Affective disorders – Schizophrenia • At higher risk of developing other addictions – Special attention should be paid to coordination between hepatologists and addiction specialists (psychiatrists, psychologists, and social workers) Recommendations • AUDIT or AUDIT-C should be used to screen patients for AUD and dependence A 1 • Patients with AUD should be screened for concurrent psychiatric disorders and other addictions A 1 Grade of recommendation Level of evidence
Alcohol use disorders: Management of alcohol withdrawal syndrome EASL CPG ALD. J Hepatol 2018;69:154–81 • AWS is a severe medical condition affecting alcohol-dependent patients who suddenly discontinue or decrease alcohol consumption • Light or moderate AWS usually develops 6–24 hours after the last drink • Symptoms may include: – Increased blood pressure and pulse rate – Tremors – Hyperreflexia – Irritability – Anxiety – Headache – Nausea and vomiting • Symptoms may progress to more severe forms of AWS – Characterized by delirium tremens, seizures, coma, cardiac arrest, and death
Alcohol use disorders: Management of alcohol withdrawal syndrome EASL CPG ALD. J Hepatol 2018;69:154–81 • Pharmacological treatment is recommended for both moderate and severe AWS – Symptom-triggered regimen rather than fixed-dose schedule in order to prevent accumulation • Benzodiazepines are considered the ‘gold standard’ treatment for AWS – Efficacy for reducing both withdrawal symptoms and the risk of seizures and/or delirium tremens Recommendations • Benzodiazepines should be used to treat AWS but should not be prescribed beyond 10–14 days because of the potential for abuse and/or encephalopathy A 1 Grade of recommendation Level of evidence
Alcohol use disorders: Medical management of AUD in patients with ALD 1. Lackner C, et al. J Hepatol. 2017;66:6108; EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol abstinence is a critical goal in patients with ALD – Abstinence improves clinical outcomes at all stages of ALD • Naltrexone, nalmefene, disulfiram and acamprosate are approved to treat AUD – Disulfiram should be avoided in patients with severe ALD • Disulfiram, naltrexone and acamprosate are approved for abstinence Effect of abstinence during follow-up on survival probability1 0 0.0 0.2 2 0.4 0.6 0.8 1.0 4 6 8 9 10 Time (years) Survival probability 1 3 5 7 Abstinence No Yes P=0.017 0 0.0 0.2 2 0.4 0.6 0.8 1.0 4 6 8 9 10 Time (years) Survival probability 1 3 5 7 Abstinence No Yes P=0.013 Early/compensated ALD Decompensated ALD
Alcohol use disorders: Medical management of AUD in patients with ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Pharmacological treatments for AUD show modest results • Non-pharmacological/psychosocial management of the addictive process is recognized as the most relevant aspect of treatment Recommendations • Gastroenterology/hepatology centres should have access to services to provide effective psychosocial therapies A • Pharmacotherapy should be considered in patients with AUD and ALD A 1 Grade of recommendation Level of evidence
Diagnostic tests in the management of ALD: Screening and clinical diagnosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Diagnosis of ALD is usually suspected with: – Documentation of regular alcohol consumption of >20 g/d in females and >30 g/d in males AND – Presence of clinical and/or biological abnormalities suggestive of liver injury • A high proportion of patients with histological features of ALD do not show any clinical symptoms or laboratory abnormalities – Asymptomatic patients consuming a critical amount of alcohol should undergo appropriate screening investigations • Consider ALD in patients presenting with extrahepatic manifestations of AUD – E.g. symmetric peripheral neuropathy, pancreatitis, cardiomyopathy
Diagnostic tests in the management of ALD: Screening investigations *Platelets >150,000 and Fibroscan® <20 EASL CPG ALD. J Hepatol 2018;69:154–81 Rule out alternative or additional causes of liver injury • HBV and HCV serology • Autoimmune markers • Transferrin and transferrin saturation • α1-antitrypsin Suspected advanced fibrosis or cirrhosis Evaluate liver function and evidence of portal hypertension: • Serum albumin, prothrombin time or INR • Serum bilirubin levels • Platelet and WBC counts Upper GI endoscopy for oesophageal varices unless low risk based on Baveno criteria* Abnormalities on initial screening Liver function tests (including GGT, ALT, AST) + Liver fibrosis (e.g. TE) Ultrasound
Diagnostic tests in the management of ALD: Liver biopsy: Indication and performance EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver biopsy may be used to: – Establish the definite diagnosis of ALD – Assess the exact stage and prognosis of liver disease – Exclude alternative or additional causes of liver injury • Liver biopsy is recommended: – Within Phase 2 clinical trials, and should be considered in larger scale Phase 3 clinical trials – In case of inconclusive non-invasive test results – In case of any suspicion of a competing liver disease • Liver biopsy is not generally recommended for all patients with suspected ALD – Risks should be carefully weighed against the clinical benefits and therapeutic consequences
Diagnostic tests in the management of ALD: Histological features and diagnosis of ALD types Images provided courtesy of Lackner C. EASL CPG ALD. J Hepatol 2018;69:154–81 • Lesions predominate in centrilobular regions (in pre-cirrhotic stages) – Alcoholic steatosis o Macro and eventually variable blend of macro- and microvesicles – Alcoholic steatohepatitis (ASH) o Variable degree of macrovesicular steatosis o Hepatocellular injury with ballooning, potentially necrosis o Lobular inflammation – Alcoholic fibrosis/cirhosis o Pericellular fibrosis (PCF) and/or septal F in precirrhotic stage o Micronodular cirrhosis ± PCF • A single lesion or any combination may be found in a given individual Main histological diagnoses: Steatosis Steatohepatitis Cirrhosis
Diagnostic tests in the management of ALD: Histological features and diagnosis of ALD types EASL CPG ALD. J Hepatol 2018;69:154–81 • Types of ALD differ with respect to prognosis • About 90% of heavy drinkers have hepatocellular steatosis – Prognosis is debated; may be associated with progression to cirrhosis (particularly mixed steatosis pattern) • ASH is considered a progressive lesion – Increases the risk of cirrhosis and HCC • Morphological lesions of ALD and metabolic syndrome-associated NAFLD show broad overlap: – Hepatocellular injury and fibrosis are often more severe in ALD – Some lesions of ALD are very rare or have not been described in patients with pure NAFLD: • Sclerosing hyaline necrosis, alcoholic foamy degeneration (i.e., large portions of the parenchyma affected by microvesicular steatosis), fibro-obliterative changes in hepatic veins, portal acute inflammation, cholestasis
Diagnostic tests in the management of ALD: Non-invasive tests to estimate liver fibrosis *PGAA index: combines α2alpha-2-macroglobulin, prothrombin time, serum GGT, serum apolipoprotein A1; †ELF combines hyaluronic acid (HA), the N-terminal pro-peptide of collagen type III (PIIINP) and tissue inhibitor of metalloproteinase-1 (TIMP-1). The test is validated for diagnosis of >F3 fibrosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Tests can distinguish mild from severe fibrosis – Less well suited to classify intermediate fibrosis stages • Not helpful in the early diagnosis of ALD Test Cut-off F4 prevalence (%) AUROC (95% CI) PPV (%) NPV (%) Hyaluronic acid 250 μg/L 0.78 35 98 PGAA index* 10 27 0.87 (0.79–0.92) 72 92 FibroTest ≥0.70 31 0.94 (0.90–0.96) 73.4 93.5 ≥0.75 15 0.88 (0.79–0.93) 43.9 92.8 ELF test† ≥10.5 23 0.92 (0.89–0.96) 71 94 Fibrometer ≥0.5 31 0.94 (0.90–0.97) 53.7 98.9 FIB-4 <1.45 31 0.80 (0.72–0.86) NA NA <1.45 15 0.80 (0.71–0.87) NA NA Diagnostic performance of some non-invasive serum fibrosis tests for cirrhosis diagnosis:
Diagnostic tests in the management of ALD: Non-invasive tests to estimate liver fibrosis Figure reproduced with permission from Mueller S, et al. World J Gastroenterol 2014;20:14626–41 (see notes). Liver stiffness scale with cut-off values for various fibrosis stages in patients with ALD without pronounced inflammation, congestion, tumours or mechanic cholestasis. EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver stiffness measurement (TE) – Correlates with degree of fibrosis <6 kPa 68 kPa 812.5 kPa >12.5 kPa Soft Stiff Normal Grey zone F3 fibrosis F4 cirrhosis 6 8 12.5 75 Liver stiffness (kPa) • ALD is associated with greater liver stiffness compared with viral hepatitis/cirrhosis • AH also markedly increases LSM in patients with ALD independent of fibrosis stage – Inflammation, cholestasis or liver congestion and alcohol consumption may interfere with LSM, independently of fibrosis • Elevated LSM in patients with ALD and AST serum levels >100 U/L should therefore be interpreted with caution
Diagnostic tests in the management of ALD: Non-invasive tests to estimate liver fibrosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Hepatic imaging (ultrasonography, MRI, CT) – No role in establishing alcohol as the specific aetiology of liver disease – May be useful for: • Quantification of steatosis • Exclusion of other causes of chronic liver disease such as primary sclerosing cholangitis • Assessment of advanced liver disease and its complications
Diagnostic tests in the management of ALD: Tests for alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 INDIRECT MARKERS (GGT, ALT, AST, MCV) Easy and inexpensive Most frequently used markers for early detection of ALD Low sensitivity and specificity No single marker or combination of markers can differentiate between different causes of liver disease DIRECT MARKERS (EtG, EtS, PEth, FAEEs) Higher specificity (direct products of ethanol metabolism) Longer detection window vs. direct determination of ethanol in blood or exhaled air Various confounding factors may have an impact on results
Diagnostic tests in the management of ALD: Indirect markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors GGT Serum Chronic excessive 42–86% 40–84% Liver disease, BMI, sex, drugs AST Serum Chronic excessive 43–68% 56–95% Liver and muscle diseases, BMI, drugs ALT Serum Chronic excessive 30–50% 51–92% Liver disease, BMI, drugs MCV Serum Chronic excessive 24–75% 56–96% Vitamin B12, folic acid deficiency, haematological diseases % CDT Serum 1–2 weeks 50–80 g/d for >1–2 weeks 25–84% 70–98% Liver cirrhosis/disease, nicotine, transferrin level, weight, sex, pregnancy, rare genetic variations Diagnostic performance of indirect markers is not adequate
Diagnostic tests in the management of ALD: Direct markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 • Direct markers have higher specificity than indirect markers Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors Breath alcohol Exhaled air 4–12 hours 97% 93% Alcohol-containing mouth wash EtOH Serum 4–12 hours EtG Urine Up to 80 hours >5 g 89% 99% Increases results Accidental contamination of food, mouth wash, alcohol-free beer, etc. with alcohol. UTI Decreases results: Urine dilution deliberately or by diuretics. UTI EtG Hair ≤6 months >20–40 g/d for >3 months 85–92% 87–97% Increases results Seriously impaired renal function EtG containing hair treatment Decreases results Hair treatment: dying, perming, bleaching
Diagnostic tests in the management of ALD: Direct markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 • Direct markers have higher specificity than indirect markers Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors Breath alcohol Exhaled air 4–12 hours 97% 93% Alcohol-containing mouth wash EtOH Serum 4–12 hours EtG Urine Up to 80 hours >5 g 89% 99% Increases results Accidental contamination of food, mouth wash, alcohol-free beer, etc. with alcohol. UTI Decreases results: Urine dilution deliberately or by diuretics. UTI EtG Hair ≤6 months >20–40 g/d for >3 months 85–92% 87–97% Increases results Seriously impaired renal function EtG containing hair treatment Decreases results Hair treatment: dying, perming, bleaching To confirm recent alcohol abstinence in forensic settings or to regularly monitor patients in alcohol addiction programmes and prior to listing for LT To evaluate alcohol abuse in forensic settings, such as child custody cases, or to confirm 6-month alcohol abstinence in LT recipients
Diagnostic tests in the management of ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Many patients with ALD are asymptomatic – Detection is only possible with appropriate screening • Liver biopsy is associated with recognized risks and should be used in selected patients only Recommendations Liver biopsy is required where there is diagnostic uncertainty, precise staging is required, or in clinical trials A 1 Screening of patients with AUD should include determination of LFTs and a measure of liver fibrosis A 1 Abstinence can be accurately monitored by measurement of EtG in urine or hair A 2 Grade of recommendation Level of evidence
Management of alcoholic hepatitis: Definition and diagnosis *Ascites and/or encephalopathy; †Defined histologically by steatosis, hepatocyte ballooning, and an inflammatory infiltrate with polymorphonuclear neutrophils EASL CPG ALD. J Hepatol 2018;69:154–81 • Clinical – Recent jaundice ± other signs of liver decompensation* in patients with ongoing alcohol abuse • Cardinal sign is a progressive jaundice, often associated with fever, malaise, weight loss and malnutrition • Histological – Steatohepatitis† • Laboratory – Neutrophilia – Hyperbilirubinaemia (>50 μMol/L) – AST >2 x ULN and AST/ALT ratio typically greater than 1.5–2.0 – Severe: prolonged PT, hypoalbuminaemia, and decreased platelet count Recommendations A recent onset of jaundice in patients with excessive alcohol consumption should prompt clinicians to suspect AH A 1 Grade of recommendation Level of evidence
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + +
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + First score and still most widely used
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score >20: high risk of 90-day mortality
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score ≥9 + mDF ≥32: poor prognosis and survival benefit with corticosteroids
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Classification according to low, medium, and high risk of death at 90 days
Management of alcoholic hepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy; †In a subsequent analysis <0.16, 0.16<0.56 and ≥0.56 indicated complete, partial, and null response, respectively EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score is 01; a score of ≥0.45 indicates non-response to corticosteroids†
Management of alcoholic hepatitis: General measures EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol abstinence is the cornerstone of therapy – Early management of AUD is recommended in all patients with AH • Considering the potential risk of Wernicke’s encephalopathy, supplementation with B-complex vitamins is recommended • Other general approaches include: – Treatment of hepatic encephalopathy (lactulose, rifaximin) – Treatment of ascites (salt restriction) – Prevention of renal failure in patients with severe AH • Avoidance of diuretics and nephrotoxic drugs • Volume expansion if needed • Use of beta-blockers may increase the risk of AKI
Management of alcoholic hepatitis: Nutrition EASL CPG ALD. J Hepatol 2018;69:154–81 • Protein energy malnutrition is present in almost every patient with severe AH, and is associated with poor prognosis • Use of tube feeding is strongly recommended if patients are not able to maintain adequate oral intake • Insufficient evidence to support a recommendation for parenteral nutrition, particularly given the high risk of line sepsis Recommendations A careful evaluation of nutritional status should be performed; patients should aim to achieve a daily energy intake ≥35–40 kcal/kg BW and 1.2–1.5 g/kg protein, and to adopt oral route as first-line intervention A 2 Grade of recommendation Level of evidence
Management of alcoholic hepatitis: Corticosteroids *Prednisolone 40 mg/day or methylprednisolone 32 mg/day EASL CPG ALD. J Hepatol 2018;69:154–81 • Use of corticosteroids is limited by concerns about heightened risks of sepsis and gastrointestinal bleeding • Early identification of non-responders to corticosteroids is important to define stopping rules and limit unnecessary exposure • At the end of the course of treatment corticosteroids can be stopped immediately or the dose tapered over a period of 3 weeks Recommendations In the absence of active infection, corticosteroids* should be considered in patients with severe AH to reduce short-term mortality A 1 N-acetylcysteine (for 5 days, intravenously) may be combined with corticosteroids in patients with severe AH B 2 Early non-response (at Day 7) to corticosteroids should be identified and strict rules for the cessation of therapy should be applied A 1 In case of non-response to corticosteroids, highly selected patients should be considered for early liver transplantation A 1 Grade of recommendation Level of evidence
Management of alcoholic hepatitis: Infection EASL CPG ALD. J Hepatol 2018;69:154–81 • Infection is a frequent and severe complication in patients with severe AH, and is one of the major causes of death – Bacterial infections are responsible for 90% of infectious episodes – Invasive aspergillosis has been reported as a complication associated with poor outcome – Sporadic cases of pneumocystis pneumonia have been described in patients with severe AH and concomitant corticosteroid treatment, with a very high mortality rate • Corticosteroids do not appear to increase the risk of infection or mortality from infection, but may exacerbate infection Recommendations Systematic screening for infection should be performed before initiating therapy, during corticosteroid treatment, and during follow-up period A 1 Grade of recommendation Level of evidence
Management of suspected alcoholic hepatitis: Treatment algorithm *Particularly in null responders (Lille score ≥0.56). EASL CPG ALD. J Hepatol 2018;69:154–81 Stop treatment* and assessment for early liver transplantation in highly selected patients Continue treatment for 28 days Lille score ≥0.45 Lille score <0.45 mDF <32 and GAHS <9 Assess treatment response at Day 7 (Lille score) Prednisolone 40 mg/day ± NAC No specific therapy mDF ≥32 or GAHS ≥9 Assessment of disease severity (prognostic scores) • Systematic evaluation of nutritional status and energy intake • Daily target 35–40 kcal/kg BW • Prefer oral route as first-line intervention • Supplementation with B-complex vitamins Consider liver biopsy if diagnosis is uncertain Perform systematic extensive screening for infection Treatment of alcohol dependence Clinical diagnosis of AH
Alcohol-related fibrosis and cirrhosis *Ascites, jaundice, variceal bleeding, infections, hepatorenal syndrome, hepatic encephalopathy, cachexia EASL CPG ALD. J Hepatol 2018;69:154–81 • A range of environmental and host factors have been linked with risk of progression to advanced ALD (extensive liver fibrosis and cirrhosis) – Cigarette smoking, gender, ethnicity, comorbid conditions (e.g. diabetes and obesity), microbial dysbiosis, chronic infection with HBV and HCV and/or HIV, α-antitrypsin deficiency, iron overload – Genetic risk factors • Polymorphisms in the PNPLA3 gene • Genetic variants on TM6SF2 and MBOAT7 – Type and pattern of alcohol use • ALD cirrhosis may present as compensated or decompensated* – May also be associated with extrahepatic alcohol-related organ damage • Alcohol-related cardiomyopathy, acute and chronic pancreatitis, central and peripheral nerve involvement, hepatic encephalopathy
Alcohol-related fibrosis and cirrhosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Treating comorbid conditions must be encouraged together with interventions targeting alcohol misuse – Obesity and other components of the metabolic syndrome • Management of patients with ALD cirrhosis focuses on: – Alcohol abstinence – Nutritional support including calories, vitamins and micronutrients – Primary and secondary prophylaxis of cirrhotic complications Recommendations Advise complete abstinence from alcohol in patients with alcohol-related cirrhosis to reduce the risk of liver-related complications and mortality A 1 Identify and manage cofactors, including obesity and IR, malnutrition, smoking, iron overload and viral hepatitis A 1 Apply general recommendations for screening and management of complications of cirrhosis to ALD cirrhosis A 1 Grade of recommendation Level of evidence
Liver transplantation: Trends in liver transplantation of ALD 1. Data from European Liver Transplant Registry; EASL CPG ALD. J Hepatol 2018;69:154–81 • LT is the most effective therapeutic option for patients with ESLD – 1-year post-transplant patient and graft survival is ~80–85% • Liver outcomes after LT in patients with AUD have improved – Graft and patient survival now similar to after LT for other aetiologies • Alcohol-related cirrhosis represents an increasing proportion of LTs in Europe1 ALD cirrhosis (24,452) Autoimmune cirrhosis (2,992) Cryptogenic (unknown) cirrhosis (5,750) Other cirrhosis (2,880) Primary biliary cirrhosis (8,130) Secondary biliary cirrhosis (998) Viral + cirrhosis due to alcohol (2,792) Virus-related cirrhosis (28,043) 0 20 40 60 80 100 Percentage Aetiology of cirrhosis leading to LT in Europe
Liver transplantation: Selection of patients for LT *Particularly URT and GI EASL CPG ALD. J Hepatol 2018;69:154–81 Psychological assessments • Psychosocial to establish likelihood of long-term abstinence post-LT – Limited evidence to support use of the 6-month abstinence rule alone • Psychiatric evaluation in cases of personality disorder, depression, anxiety, poly-substance abuse or other psychiatric disorders • Laboratory tests for abstinence may be used in patients on the transplant waiting list Medical assessments • Pancreatic function • Renal function • Nutritional status • Central and peripheral neuropathy • Myopathy and cardiomyopathy • Encephalopathy/alcohol-related dementia • Atherosclerosis and ischaemic heart disease • Neoplastic or pre-neoplastic disease* A multidisciplinary approach evaluating medical and psychological suitability for LT is essential
Liver transplantation: Selection of patients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS
Liver transplantation: Selection of patients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS
Liver transplantation: Selection of patients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS • MELD accurately estimates the survival benefit following LT – Generally recommended to prioritize organ allocation • Clinical manifestations of liver decompensation are not independent predictors of survival over and above MELD – Onset in an abstinent patient should prompt consideration of referral to a transplant centre • Increasing evidence of the benefit of early LT in for patients with severe AH not responding to medical therapy – Selection criteria for such patients need to be more clearly defined
Liver transplantation: Selection of patients for LT EASL CPG ALD. J Hepatol 2018;69:154–81 • Selection of patients with ALD for LT – Based on presence of decompensated cirrhosis AND – Comprehensive psychosocial and medical assessment Recommendations LT should be considered in patients with ALD (classified as Child–Pugh C and/or MELD ≥15), as it confers a survival benefit A 1 Selection of patients with AUD should not be based on the 6-month criterion alone A 2 Duration of abstinence before listing should depend on the degree of liver insufficiency in selected patients with a favourable addiction and psychological profile and supportive relatives A 1 Abstinence in patients with AUD on the LT waiting list should be confirmed with regular clinical interviews and laboratory tests A 1 A multidisciplinary approach evaluating medical and psychological suitability for transplantation is mandatory before and after LT A 1 Early LT should be proposed to a minority of patients with severe AH not responding to medical therapy after a careful selection process A 1 Grade of recommendation Level of evidence
Liver transplantation: Post-LT follow-up and management: Relapse 1. Faure S, et al. J Hepatol 2012;57:30612; 2. Pfitzmann R, et al. Liver Transpl 2007;13:197205; 3. Bravata DM, et al. Liver Transpl 2001;7:191203; 4. Addolorato G, et al. Alcohol Clin Exp Res 2013;37:16018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Excessive alcohol consumption has a negative impact on long-term post-LT survival1,2 • Recipients with ALD are more likely to drink excessively3 • Multidisciplinary support pre- and post-LT has been shown to help prevent recidivism4 Comparison of Kaplan–Meier survival curves between excessive alcohol relapsers and other patients1 0 0.0 0.2 24 0.4 0.6 0.8 1.0 48 72 96 108 120 Time to event (months) Survival probability 12 36 60 84 No alcohol (abstinent patients, occasional relapsers, slip relapsers) Excess alcohol (excessive relapsers [women >20 g/day; men >30 g/day]) 368 345 102 293 56 56 11 49 No alcohol Excess alcohol Patients at risk:
Liver transplantation: Post-LT follow-up and management EASL CPG ALD. J Hepatol 2018;69:154–81 • Excessive alcohol consumption is associated with decreased survival post-LT • Patients transplanted for ALD are at increased risk of a range of extrahepatic complications – Cardiovascular events, metabolic syndrome and de novo malignancies Recommendations Integration of an addiction specialist may decrease the risk of relapse in heavy drinking individuals B 2 Patients should be screened regularly for cardiovascular and neurological disease, psychiatric disorders and neoplasms before and after LT A 1 Risk factors for cardiovascular disease and neoplasms, particularly cigarette smoking, should be controlled A 1 Early reduction in calcineurin inhibitor therapy may be considered to decrease the risk of de novo cancer after LT B 2 Grade of recommendation Level of evidence
Conclusions Suggestions for future studies
Conclusions: Suggestions for future studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Public health aspects – Priority to be given to further studies on screening in different populations, to diagnose patients prior to the development of end-stage liver disease • Alcohol use disorders – Further trials of pharmacotherapy in patients with advanced ALD are urgently required – Studies to demonstrate the efficacy of a multidisciplinary team intervention • Diagnostic tests in the management of ALD – Investigations focused on the mechanisms and prognostic significance of histological cholestasis – Investigation of the clinical utility of monitoring tests for alcohol consumption – Investigations to determine the optimal screening tool for liver fibrosis • Management of alcoholic hepatitis – Further studies are required to validate the use of the Lille score at Day 4 – New strategies need to be developed to reduce the risk of infection
Conclusions: Suggestions for future studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol-related fibrosis and cirrhosis – Large genome-wide analysis should confirm PNPLA3 rs738409 as an important susceptibility polymorphism in ALD and possibly identify other genetic polymorphisms for better screening – The interaction between environmental and genetic factors should be investigated – The mechanisms underlying the additive effects of components of the metabolic syndrome and alcohol on ALD progression should be explored – Additional studies are required to identify the factors influencing fibrosis regression after drinking cessation and long-term outcome in abstinent patients – Further evaluation of endpoints (clinical, anthropometrical) and re-nutritional strategies are needed in advanced ALD cirrhosis – Further randomized controlled studies are needed on pro-regenerative strategies in advanced ALD cirrhosis using clinically relevant endpoints – Further work is needed to select patients with ALD cirrhosis at high risk of extrahepatic malignancy to implement cancer surveillance – Additional work may determine if PNPLA3 variants can be a marker for the development of HCC in ALD cirrhosis
Conclusions: Suggestions for future studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver transplantation – Studies evaluating the effects of new immunosuppressive regimens on the risk of cardiovascular disease and de novo neoplasms are warranted – In patients with severe ASH not responding to medical therapy, early LT needs to be further evaluated in carefully selected patients

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ALD_EASL-CPG.PPTX

  • 1.
  • 2.
    About these slides •These slides give a comprehensive overview of the EASL clinical practice guidelines on the management of alcohol-related liver disease • The guidelines were first presented at the International Liver Congress 2018 and are published in the Journal of Hepatology – A full copy of the publication can be downloaded from the Clinical Practice Guidelines section of the EASL website • Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source
  • 3.
    About these slides •Definitions of all abbreviations shown in these slides are provided within the slide notes • When you see a home symbol like this one: , you can click on this to return to the outline or topics pages, depending on which section you are in • Please send any feedback to: slidedeck_feedback@easloffice.eu These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials
  • 4.
    Guideline panel EASL CPGALD. J Hepatol 2018;69:154–81 • Chair – Mark Thursz • Panel members – Antoni Gual, Caroline Lackner, Philippe Mathurin, Christophe Moreno, Laurent Spahr, Martina Sterneck, Helena Cortez-Pinto (EASL Governing Board representative) • Reviewers – Ewan Forrest, Fabio Caputo, Vijay Shah, EASL Governing Board
  • 5.
    Outline EASL CPG ALD.J Hepatol 2018;69:154–81 • Grading evidence and recommendations Methods • Terminology Background • Key recommendations Guidelines • Suggestions for future studies Conclusions
  • 6.
  • 7.
    Grading evidence andrecommendations *Level was downgraded if there was poor quality, strong bias or inconsistency between studies; level was upgraded if there was a large effect size 1. Guyatt GH, et al. BMJ 2008:336:924–6; 2. EASL CPG ALD. J Hepatol 2018;69:154–81 • Grading is adapted from the GRADE system1,2 Level of evidence* Confidence in the evidence 1 Data derived from meta-analyses or systematic reviews or from (multiple) randomized trials (RCTs) with high quality Further research is unlikely to change our confidence in the estimate of benefit and risk 2 Data derived from a single RCT or multiple non-randomized studies Further research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate 3 Small studies, retrospective observational studies, registries Any estimate of effect is uncertain Grade of recommendation (wording associated with the grade of recommendation) A Strong (“must”, “should”, or “EASL recommends”) B Weak (“can”, “may”, or “EASL suggests”)
  • 8.
  • 9.
    Terminology *Histologically-defined lesion; †At thispoint the term alcoholic hepatitis has become too standardized to change (may be reviewed in future guidelines) EASL CPG ALD. J Hepatol 2018;69:154–81 • The term ‘alcoholic’ is stigmatizing – Undermines patient dignity and self-esteem • These guidelines use the following terms Previous term Current term Abbreviation Alcoholic Alcohol use disorder AUD Alcoholic liver disease Alcohol-related liver disease ALD Alcoholic cirrhosis Cirrhosis due to alcohol-related liver disease ALD cirrhosis Alcoholic steatohepatitis* Steatohepatitis due to ALD ASH Alcoholic fibrosis Fibrosis due to ALD ALD fibrosis Alcoholic hepatitis Alcoholic hepatitis† AH
  • 10.
  • 11.
    Topics EASL CPG ALD.J Hepatol 2018;69:154–81 1. Public health aspects 2. Alcohol use disorders 3. Diagnostic tests in the management of ALD 4. Management of alcoholic hepatitis 5. Alcohol-related fibrosis and cirrhosis 6. Liver transplantation Click on a topic to skip to that section
  • 12.
    Public health aspects: Alcohol-relatedmorbidity and mortality 1. WHO. Global status report on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Worldwide, harmful use of alcohol is associated with: – ~3.3 million deaths every year 1 • 5.9% of all deaths overall (7.6% in men, 4.0% in women)1 – ~139 million disability-adjusted life years • 5.1% of the global burden of disease and injury • Alcohol has an impact on over 200 diseases and types of injuries • Most deaths attributable to alcohol consumption from: – Cardiovascular diseases – Injuries – Gastrointestinal diseases • Mainly cirrhosis – Cancers • Alcohol-attributable fraction is highest for liver diseases and foetal alcohol syndrome
  • 13.
    Public health aspects: Alcohol-relatedmorbidity and mortality 1. WHO. Global status report on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018; 2. Sheron N. J Hepatol 2016;64:95767; EASL CPG ALD. J Hepatol 2018;69:154–81 • WHO European Region has the highest adult per capita alcohol consumption1 • In the EU, 41% of liver deaths are attributed to alcohol2 – Likely to be an under-representation due to inaccuracies in coding data – Attribution of alcohol is likely in around 60–80% of cases in larger EU member states2 Data from the WHO mortality database categorized into three groups (definite ALD, another defined diagnosis or unknown aetiology). The wide variation in % mortality from ALD is strongly related to inaccuracies in coding the data2 ALD Unknown liver disease Definitely not ALD 0 20 40 60 80 100 Percentage Liver disease aetiology in larger EU member states since 2000
  • 14.
    Public health issues: Definitionsof “drink” and “drinking” EASL CPG ALD. J Hepatol 2018;69:154–81 • Quantification of alcohol consumption is not easy in clinical practice • Grams of alcohol is more precise, but: – Time consuming and frequently difficult to obtain – Patients cannot recall the different amounts and types of drink Term Definition One standard drink 10 g of alcohol Harmful drinking Where alcohol use is causing damage to either physical or mental health Heavy episodic drinking Consumption of more than 60 g of pure alcohol on one occasion Binge drinking Consumption within about 2 hours of four or more drinks for women and five or more drinks for men
  • 15.
    Public health aspects: Dataare conflicting around a safe alcohol limit EASL CPG ALD. J Hepatol 2018;69:154–81 • Light–moderate intake: reduced risk of coronary artery disease • Heavy chronic alcohol intake: increased risk of cardiomyopathy, hypertension, atrial arrhythmias and haemorrhagic stroke • Alcohol is a recognized carcinogen – No threshold level of consumption known for cancer risk • Chronic use of alcohol is a risk factor for cirrhosis • Unclear whether there is a continuous dose–response relationship • Unclear whether there is a threshold at which the risk emerges • Risks of binge drinking vs. daily drinking remain controversial • Cessation of drinking at any point reduces risk of disease progression and occurrence of complications Recommendation Limit daily intake to ≤2 standard drinks for women and ≤3 for men. This amount is not associated with significant increase in cirrhosis mortality
  • 16.
    Public health aspects: Policiesto reduce population risk for ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Effective interventions include: – Price based policies • Taxation • Minimum unit pricing – Limitation of alcohol availability – Restriction of marketing and advertising • Policies based on age-related vulnerability – Partial or total advertising bans – Restrictions on access to alcohol through minimum ages at which it is legal to purchase alcohol – Laws to prevent any alcohol consumption by young people when driving vehicles
  • 17.
    Public health aspects: Impactof minimum unit pricing in British Colombia Sheron N. J Hepatol 2016;64:95767; EASL CPG ALD. J Hepatol 2018;69:154–81 Rates of 100% alcohol-attributable deaths and CPI-adjusted minimum alcohol prices
  • 18.
    Public health aspects: Screeningto reduce ALD-related morbidity and mortality EASL CPG ALD. J Hepatol 2018;69:154–81 • Early recognition and intervention are required – Goal of abstinence or decreased alcohol consumption should be implemented to reduce the risk of liver disease in harmful drinkers • Screening for harmful drinking should be performed by GPs, and in patients admitted to emergency facilities, with screening for ALD in high-risk patients • Suggested screening methods include: – Blood markers – Transient elastography • Screening must be followed by an intervention with a multidisciplinary team – Specialist alcohol care teams are required to care for patients
  • 19.
    Public health aspects *Eitherdirectly or indirectly EASL CPG ALD. J Hepatol 2018;69:154–81 • Harmful alcohol use is associated with considerable mortality and morbidity • Policies aimed at reducing harmful alcohol consumption and screening for AUD and for ALD should be implemented Recommendations Excess alcohol consumption should be addressed using pricing-based policies and regulation of availability A 1 Advertising and marketing of alcohol* should be banned A 2 Primary care facilities for managing AUD must be widely available A 2 Screening for harmful alcohol consumption should be performed by GPs and in emergency departments A 2 Screening for ALD should be performed in high-risk populations, such as those in alcohol rehabilitation clinics, or harmful drinkers identified by their GP A 2 Patients identified through screening should undergo brief intervention and referral to a multidisciplinary team A 1 Grade of recommendation Level of evidence
  • 20.
    Alcohol use disorders: Terminologyand definitions EASL CPG ALD. J Hepatol 2018;69:154–81 • The DSM-V defines AUD as a problematic pattern of alcohol use leading to clinically significant impairment or distress – Graded severity depending on the number of diagnostic criteria met – New concept that overcomes the arbitrary differentiation between alcohol abuse and dependence • Reduces stigmatization of alcoholism • WHO still uses the terms hazardous and harmful alcohol use and alcohol dependence • The term ‘risky drinker’ is commonly used to define people who drink excessively Recommendations The term alcohol use disorder (defined by DSM-V criteria) should be used in preference to alcoholic, alcohol abuse, alcohol dependence or risky drinker A Grade of recommendation
  • 21.
    Alcohol use disorders: DSM-Vcriteria *Or a closely related substance, such as benzodiazepine EASL CPG ALD. J Hepatol 2018;69:154–81 Manifested by ≥2 of the following, occurring within a 12-month period: 1 Alcohol is often taken in larger amounts or over a longer period than was intended 2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use 3 A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects 4 Craving, or a strong desire or urge to use alcohol 5 Recurrent alcohol use resulting in a failure to fulfil major role obligations at work, school, or home 6 Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol 7 Important social, occupational, or recreational activities are given up or reduced because of alcohol use 8 Recurrent alcohol use in situations in which it is physically hazardous 9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol 10 Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of alcohol 11 Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol b. Alcohol* is taken to relieve or avoid withdrawal symptoms
  • 22.
    Alcohol use disorders: DSM-Vcriteria *Or a closely related substance, such as benzodiazepine EASL CPG ALD. J Hepatol 2018;69:154–81 Manifested by ≥2 of the following, occurring within a 12-month period: 1 Alcohol is often taken in larger amounts or over a longer period than was intended 2 There is a persistent desire or unsuccessful efforts to cut down or control alcohol use 3 A great deal of time is spent in activities necessary to obtain alcohol, use alcohol, or recover from its effects 4 Craving, or a strong desire or urge to use alcohol 5 Recurrent alcohol use resulting in a failure to fulfil major role obligations at work, school, or home 6 Continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol 7 Important social, occupational, or recreational activities are given up or reduced because of alcohol use 8 Recurrent alcohol use in situations in which it is physically hazardous 9 Alcohol use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by alcohol 10 Tolerance, as defined by either of the following: a. A need for markedly increased amounts of alcohol to achieve intoxication or desired effect b. A markedly diminished effect with continued use of the same amount of alcohol 11 Withdrawal, as manifested by either of the following: a. The characteristic withdrawal syndrome for alcohol b. Alcohol* is taken to relieve or avoid withdrawal symptoms Severity graded as: Mild: presence of 2 to 3 criteria Moderate: presence of 4 to 5 criteria Severe: presence of 6 or more criteria
  • 23.
    Alcohol use disorders: Screeningtools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year
  • 24.
    Alcohol use disorders: Screeningtools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption
  • 25.
    Alcohol use disorders: Screeningtools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption Questions 46 explore dependence
  • 26.
    Alcohol use disorders: Screeningtools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Questions 13 explore consumption Questions 46 explore dependence Questions 710 explore alcohol-related problems
  • 27.
    Alcohol use disorders: Screeningtools: AUDIT WHO. AUDIT. Available at: http://apps.who.int/iris/handle/10665/67205. Accessed August 2018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Developed by the WHO in 1982 and remains the gold standard • Good sensitivity and specificity in clinical settings across countries Question Score 0 1 2 3 4 1. How often do you have a drink containing alcohol? Never Monthly or less 2 to 4 times a month 2 to 3 times a week 4 or more times a week 2. How many drinks containing alcohol do you have on a typical day when you are drinking? 1 or 2 3 or 4 5 or 6 7 to 9 10 or more 3. How often do you have five or more drinks on one occasion? Never Less than monthly Monthly Weekly Daily or almost daily 4. How often during the last year have you found that you were not able to stop drinking once you had started? Never Less than monthly Monthly Weekly Daily or almost daily 5. How often during the last year have you failed to do what was normally expected of you because of drinking? Never Less than monthly Monthly Weekly Daily or almost daily 6. How often during the last year have you needed a first drink in the morning to get yourself going after a heavy drinking session? Never Less than monthly Monthly Weekly Daily or almost daily 7. How often during the last year have you had a feeling of guilt or remorse after drinking? Never Less than monthly Monthly Weekly Daily or almost daily 8. How often during the last year have you been unable to remember what happened the night before because of your drinking? Never Less than monthly Monthly Weekly Daily or almost daily 9. Have you or someone else been injured because of your drinking? No – Yes, but not in the last year – Yes, during the last year 10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down? No – Yes, but not in the last year – Yes, during the last year Total scores of ≥8 indicate hazardous and harmful alcohol use Scores of ≥20 or above clearly warrant evaluation for alcohol dependence Scores ≥1 on Q2 or Q3: hazardous level of alcohol consumption Scores >0 on Q4–6: alcohol dependence Points scored on Q7–10: alcohol-related harm
  • 28.
    Alcohol use disorders: Screening EASLCPG ALD. J Hepatol 2018;69:154–81 • Patients with AUD have a high prevalence of psychiatric co-morbidity – Anxiety disorders – Affective disorders – Schizophrenia • At higher risk of developing other addictions – Special attention should be paid to coordination between hepatologists and addiction specialists (psychiatrists, psychologists, and social workers) Recommendations • AUDIT or AUDIT-C should be used to screen patients for AUD and dependence A 1 • Patients with AUD should be screened for concurrent psychiatric disorders and other addictions A 1 Grade of recommendation Level of evidence
  • 29.
    Alcohol use disorders: Managementof alcohol withdrawal syndrome EASL CPG ALD. J Hepatol 2018;69:154–81 • AWS is a severe medical condition affecting alcohol-dependent patients who suddenly discontinue or decrease alcohol consumption • Light or moderate AWS usually develops 6–24 hours after the last drink • Symptoms may include: – Increased blood pressure and pulse rate – Tremors – Hyperreflexia – Irritability – Anxiety – Headache – Nausea and vomiting • Symptoms may progress to more severe forms of AWS – Characterized by delirium tremens, seizures, coma, cardiac arrest, and death
  • 30.
    Alcohol use disorders: Managementof alcohol withdrawal syndrome EASL CPG ALD. J Hepatol 2018;69:154–81 • Pharmacological treatment is recommended for both moderate and severe AWS – Symptom-triggered regimen rather than fixed-dose schedule in order to prevent accumulation • Benzodiazepines are considered the ‘gold standard’ treatment for AWS – Efficacy for reducing both withdrawal symptoms and the risk of seizures and/or delirium tremens Recommendations • Benzodiazepines should be used to treat AWS but should not be prescribed beyond 10–14 days because of the potential for abuse and/or encephalopathy A 1 Grade of recommendation Level of evidence
  • 31.
    Alcohol use disorders: Medicalmanagement of AUD in patients with ALD 1. Lackner C, et al. J Hepatol. 2017;66:6108; EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol abstinence is a critical goal in patients with ALD – Abstinence improves clinical outcomes at all stages of ALD • Naltrexone, nalmefene, disulfiram and acamprosate are approved to treat AUD – Disulfiram should be avoided in patients with severe ALD • Disulfiram, naltrexone and acamprosate are approved for abstinence Effect of abstinence during follow-up on survival probability1 0 0.0 0.2 2 0.4 0.6 0.8 1.0 4 6 8 9 10 Time (years) Survival probability 1 3 5 7 Abstinence No Yes P=0.017 0 0.0 0.2 2 0.4 0.6 0.8 1.0 4 6 8 9 10 Time (years) Survival probability 1 3 5 7 Abstinence No Yes P=0.013 Early/compensated ALD Decompensated ALD
  • 32.
    Alcohol use disorders: Medicalmanagement of AUD in patients with ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Pharmacological treatments for AUD show modest results • Non-pharmacological/psychosocial management of the addictive process is recognized as the most relevant aspect of treatment Recommendations • Gastroenterology/hepatology centres should have access to services to provide effective psychosocial therapies A • Pharmacotherapy should be considered in patients with AUD and ALD A 1 Grade of recommendation Level of evidence
  • 33.
    Diagnostic tests inthe management of ALD: Screening and clinical diagnosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Diagnosis of ALD is usually suspected with: – Documentation of regular alcohol consumption of >20 g/d in females and >30 g/d in males AND – Presence of clinical and/or biological abnormalities suggestive of liver injury • A high proportion of patients with histological features of ALD do not show any clinical symptoms or laboratory abnormalities – Asymptomatic patients consuming a critical amount of alcohol should undergo appropriate screening investigations • Consider ALD in patients presenting with extrahepatic manifestations of AUD – E.g. symmetric peripheral neuropathy, pancreatitis, cardiomyopathy
  • 34.
    Diagnostic tests inthe management of ALD: Screening investigations *Platelets >150,000 and Fibroscan® <20 EASL CPG ALD. J Hepatol 2018;69:154–81 Rule out alternative or additional causes of liver injury • HBV and HCV serology • Autoimmune markers • Transferrin and transferrin saturation • α1-antitrypsin Suspected advanced fibrosis or cirrhosis Evaluate liver function and evidence of portal hypertension: • Serum albumin, prothrombin time or INR • Serum bilirubin levels • Platelet and WBC counts Upper GI endoscopy for oesophageal varices unless low risk based on Baveno criteria* Abnormalities on initial screening Liver function tests (including GGT, ALT, AST) + Liver fibrosis (e.g. TE) Ultrasound
  • 35.
    Diagnostic tests inthe management of ALD: Liver biopsy: Indication and performance EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver biopsy may be used to: – Establish the definite diagnosis of ALD – Assess the exact stage and prognosis of liver disease – Exclude alternative or additional causes of liver injury • Liver biopsy is recommended: – Within Phase 2 clinical trials, and should be considered in larger scale Phase 3 clinical trials – In case of inconclusive non-invasive test results – In case of any suspicion of a competing liver disease • Liver biopsy is not generally recommended for all patients with suspected ALD – Risks should be carefully weighed against the clinical benefits and therapeutic consequences
  • 36.
    Diagnostic tests inthe management of ALD: Histological features and diagnosis of ALD types Images provided courtesy of Lackner C. EASL CPG ALD. J Hepatol 2018;69:154–81 • Lesions predominate in centrilobular regions (in pre-cirrhotic stages) – Alcoholic steatosis o Macro and eventually variable blend of macro- and microvesicles – Alcoholic steatohepatitis (ASH) o Variable degree of macrovesicular steatosis o Hepatocellular injury with ballooning, potentially necrosis o Lobular inflammation – Alcoholic fibrosis/cirhosis o Pericellular fibrosis (PCF) and/or septal F in precirrhotic stage o Micronodular cirrhosis ± PCF • A single lesion or any combination may be found in a given individual Main histological diagnoses: Steatosis Steatohepatitis Cirrhosis
  • 37.
    Diagnostic tests inthe management of ALD: Histological features and diagnosis of ALD types EASL CPG ALD. J Hepatol 2018;69:154–81 • Types of ALD differ with respect to prognosis • About 90% of heavy drinkers have hepatocellular steatosis – Prognosis is debated; may be associated with progression to cirrhosis (particularly mixed steatosis pattern) • ASH is considered a progressive lesion – Increases the risk of cirrhosis and HCC • Morphological lesions of ALD and metabolic syndrome-associated NAFLD show broad overlap: – Hepatocellular injury and fibrosis are often more severe in ALD – Some lesions of ALD are very rare or have not been described in patients with pure NAFLD: • Sclerosing hyaline necrosis, alcoholic foamy degeneration (i.e., large portions of the parenchyma affected by microvesicular steatosis), fibro-obliterative changes in hepatic veins, portal acute inflammation, cholestasis
  • 38.
    Diagnostic tests inthe management of ALD: Non-invasive tests to estimate liver fibrosis *PGAA index: combines α2alpha-2-macroglobulin, prothrombin time, serum GGT, serum apolipoprotein A1; †ELF combines hyaluronic acid (HA), the N-terminal pro-peptide of collagen type III (PIIINP) and tissue inhibitor of metalloproteinase-1 (TIMP-1). The test is validated for diagnosis of >F3 fibrosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Tests can distinguish mild from severe fibrosis – Less well suited to classify intermediate fibrosis stages • Not helpful in the early diagnosis of ALD Test Cut-off F4 prevalence (%) AUROC (95% CI) PPV (%) NPV (%) Hyaluronic acid 250 μg/L 0.78 35 98 PGAA index* 10 27 0.87 (0.79–0.92) 72 92 FibroTest ≥0.70 31 0.94 (0.90–0.96) 73.4 93.5 ≥0.75 15 0.88 (0.79–0.93) 43.9 92.8 ELF test† ≥10.5 23 0.92 (0.89–0.96) 71 94 Fibrometer ≥0.5 31 0.94 (0.90–0.97) 53.7 98.9 FIB-4 <1.45 31 0.80 (0.72–0.86) NA NA <1.45 15 0.80 (0.71–0.87) NA NA Diagnostic performance of some non-invasive serum fibrosis tests for cirrhosis diagnosis:
  • 39.
    Diagnostic tests inthe management of ALD: Non-invasive tests to estimate liver fibrosis Figure reproduced with permission from Mueller S, et al. World J Gastroenterol 2014;20:14626–41 (see notes). Liver stiffness scale with cut-off values for various fibrosis stages in patients with ALD without pronounced inflammation, congestion, tumours or mechanic cholestasis. EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver stiffness measurement (TE) – Correlates with degree of fibrosis <6 kPa 68 kPa 812.5 kPa >12.5 kPa Soft Stiff Normal Grey zone F3 fibrosis F4 cirrhosis 6 8 12.5 75 Liver stiffness (kPa) • ALD is associated with greater liver stiffness compared with viral hepatitis/cirrhosis • AH also markedly increases LSM in patients with ALD independent of fibrosis stage – Inflammation, cholestasis or liver congestion and alcohol consumption may interfere with LSM, independently of fibrosis • Elevated LSM in patients with ALD and AST serum levels >100 U/L should therefore be interpreted with caution
  • 40.
    Diagnostic tests inthe management of ALD: Non-invasive tests to estimate liver fibrosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Hepatic imaging (ultrasonography, MRI, CT) – No role in establishing alcohol as the specific aetiology of liver disease – May be useful for: • Quantification of steatosis • Exclusion of other causes of chronic liver disease such as primary sclerosing cholangitis • Assessment of advanced liver disease and its complications
  • 41.
    Diagnostic tests inthe management of ALD: Tests for alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 INDIRECT MARKERS (GGT, ALT, AST, MCV) Easy and inexpensive Most frequently used markers for early detection of ALD Low sensitivity and specificity No single marker or combination of markers can differentiate between different causes of liver disease DIRECT MARKERS (EtG, EtS, PEth, FAEEs) Higher specificity (direct products of ethanol metabolism) Longer detection window vs. direct determination of ethanol in blood or exhaled air Various confounding factors may have an impact on results
  • 42.
    Diagnostic tests inthe management of ALD: Indirect markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors GGT Serum Chronic excessive 42–86% 40–84% Liver disease, BMI, sex, drugs AST Serum Chronic excessive 43–68% 56–95% Liver and muscle diseases, BMI, drugs ALT Serum Chronic excessive 30–50% 51–92% Liver disease, BMI, drugs MCV Serum Chronic excessive 24–75% 56–96% Vitamin B12, folic acid deficiency, haematological diseases % CDT Serum 1–2 weeks 50–80 g/d for >1–2 weeks 25–84% 70–98% Liver cirrhosis/disease, nicotine, transferrin level, weight, sex, pregnancy, rare genetic variations Diagnostic performance of indirect markers is not adequate
  • 43.
    Diagnostic tests inthe management of ALD: Direct markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 • Direct markers have higher specificity than indirect markers Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors Breath alcohol Exhaled air 4–12 hours 97% 93% Alcohol-containing mouth wash EtOH Serum 4–12 hours EtG Urine Up to 80 hours >5 g 89% 99% Increases results Accidental contamination of food, mouth wash, alcohol-free beer, etc. with alcohol. UTI Decreases results: Urine dilution deliberately or by diuretics. UTI EtG Hair ≤6 months >20–40 g/d for >3 months 85–92% 87–97% Increases results Seriously impaired renal function EtG containing hair treatment Decreases results Hair treatment: dying, perming, bleaching
  • 44.
    Diagnostic tests inthe management of ALD: Direct markers of alcohol consumption EASL CPG ALD. J Hepatol 2018;69:154–81 • Direct markers have higher specificity than indirect markers Biomarker Biological material Detection window EtOH amount Sens. Spec. Confounding factors Breath alcohol Exhaled air 4–12 hours 97% 93% Alcohol-containing mouth wash EtOH Serum 4–12 hours EtG Urine Up to 80 hours >5 g 89% 99% Increases results Accidental contamination of food, mouth wash, alcohol-free beer, etc. with alcohol. UTI Decreases results: Urine dilution deliberately or by diuretics. UTI EtG Hair ≤6 months >20–40 g/d for >3 months 85–92% 87–97% Increases results Seriously impaired renal function EtG containing hair treatment Decreases results Hair treatment: dying, perming, bleaching To confirm recent alcohol abstinence in forensic settings or to regularly monitor patients in alcohol addiction programmes and prior to listing for LT To evaluate alcohol abuse in forensic settings, such as child custody cases, or to confirm 6-month alcohol abstinence in LT recipients
  • 45.
    Diagnostic tests inthe management of ALD EASL CPG ALD. J Hepatol 2018;69:154–81 • Many patients with ALD are asymptomatic – Detection is only possible with appropriate screening • Liver biopsy is associated with recognized risks and should be used in selected patients only Recommendations Liver biopsy is required where there is diagnostic uncertainty, precise staging is required, or in clinical trials A 1 Screening of patients with AUD should include determination of LFTs and a measure of liver fibrosis A 1 Abstinence can be accurately monitored by measurement of EtG in urine or hair A 2 Grade of recommendation Level of evidence
  • 46.
    Management of alcoholichepatitis: Definition and diagnosis *Ascites and/or encephalopathy; †Defined histologically by steatosis, hepatocyte ballooning, and an inflammatory infiltrate with polymorphonuclear neutrophils EASL CPG ALD. J Hepatol 2018;69:154–81 • Clinical – Recent jaundice ± other signs of liver decompensation* in patients with ongoing alcohol abuse • Cardinal sign is a progressive jaundice, often associated with fever, malaise, weight loss and malnutrition • Histological – Steatohepatitis† • Laboratory – Neutrophilia – Hyperbilirubinaemia (>50 μMol/L) – AST >2 x ULN and AST/ALT ratio typically greater than 1.5–2.0 – Severe: prolonged PT, hypoalbuminaemia, and decreased platelet count Recommendations A recent onset of jaundice in patients with excessive alcohol consumption should prompt clinicians to suspect AH A 1 Grade of recommendation Level of evidence
  • 47.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + +
  • 48.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + First score and still most widely used
  • 49.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score >20: high risk of 90-day mortality
  • 50.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score ≥9 + mDF ≥32: poor prognosis and survival benefit with corticosteroids
  • 51.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Classification according to low, medium, and high risk of death at 90 days
  • 52.
    Management of alcoholichepatitis: Evaluation of severity *Modified version (mDF) cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy; †In a subsequent analysis <0.16, 0.16<0.56 and ≥0.56 indicated complete, partial, and null response, respectively EASL CPG ALD. J Hepatol 2018;69:154–81 • Different prognostic models aim to identify patients at high risk of early death – Often incorporate the same variables and have similar efficacy in predicting short-term survival • Lille model can predict pattern of response to corticosteroid treatment – Based on pre-treatment data plus the response of serum bilirubin Score Bilirubin PT/INR Creatinine/ urea Leucocytes Age Albumin Change in bilirubin (Day 0 to 7) Maddrey DF* + + – – – – – MELD + + + – – – – GAHS + + + + + – – ABIC + + + – + + – Lille + + + – + + + Score is 01; a score of ≥0.45 indicates non-response to corticosteroids†
  • 53.
    Management of alcoholichepatitis: General measures EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol abstinence is the cornerstone of therapy – Early management of AUD is recommended in all patients with AH • Considering the potential risk of Wernicke’s encephalopathy, supplementation with B-complex vitamins is recommended • Other general approaches include: – Treatment of hepatic encephalopathy (lactulose, rifaximin) – Treatment of ascites (salt restriction) – Prevention of renal failure in patients with severe AH • Avoidance of diuretics and nephrotoxic drugs • Volume expansion if needed • Use of beta-blockers may increase the risk of AKI
  • 54.
    Management of alcoholichepatitis: Nutrition EASL CPG ALD. J Hepatol 2018;69:154–81 • Protein energy malnutrition is present in almost every patient with severe AH, and is associated with poor prognosis • Use of tube feeding is strongly recommended if patients are not able to maintain adequate oral intake • Insufficient evidence to support a recommendation for parenteral nutrition, particularly given the high risk of line sepsis Recommendations A careful evaluation of nutritional status should be performed; patients should aim to achieve a daily energy intake ≥35–40 kcal/kg BW and 1.2–1.5 g/kg protein, and to adopt oral route as first-line intervention A 2 Grade of recommendation Level of evidence
  • 55.
    Management of alcoholichepatitis: Corticosteroids *Prednisolone 40 mg/day or methylprednisolone 32 mg/day EASL CPG ALD. J Hepatol 2018;69:154–81 • Use of corticosteroids is limited by concerns about heightened risks of sepsis and gastrointestinal bleeding • Early identification of non-responders to corticosteroids is important to define stopping rules and limit unnecessary exposure • At the end of the course of treatment corticosteroids can be stopped immediately or the dose tapered over a period of 3 weeks Recommendations In the absence of active infection, corticosteroids* should be considered in patients with severe AH to reduce short-term mortality A 1 N-acetylcysteine (for 5 days, intravenously) may be combined with corticosteroids in patients with severe AH B 2 Early non-response (at Day 7) to corticosteroids should be identified and strict rules for the cessation of therapy should be applied A 1 In case of non-response to corticosteroids, highly selected patients should be considered for early liver transplantation A 1 Grade of recommendation Level of evidence
  • 56.
    Management of alcoholichepatitis: Infection EASL CPG ALD. J Hepatol 2018;69:154–81 • Infection is a frequent and severe complication in patients with severe AH, and is one of the major causes of death – Bacterial infections are responsible for 90% of infectious episodes – Invasive aspergillosis has been reported as a complication associated with poor outcome – Sporadic cases of pneumocystis pneumonia have been described in patients with severe AH and concomitant corticosteroid treatment, with a very high mortality rate • Corticosteroids do not appear to increase the risk of infection or mortality from infection, but may exacerbate infection Recommendations Systematic screening for infection should be performed before initiating therapy, during corticosteroid treatment, and during follow-up period A 1 Grade of recommendation Level of evidence
  • 57.
    Management of suspectedalcoholic hepatitis: Treatment algorithm *Particularly in null responders (Lille score ≥0.56). EASL CPG ALD. J Hepatol 2018;69:154–81 Stop treatment* and assessment for early liver transplantation in highly selected patients Continue treatment for 28 days Lille score ≥0.45 Lille score <0.45 mDF <32 and GAHS <9 Assess treatment response at Day 7 (Lille score) Prednisolone 40 mg/day ± NAC No specific therapy mDF ≥32 or GAHS ≥9 Assessment of disease severity (prognostic scores) • Systematic evaluation of nutritional status and energy intake • Daily target 35–40 kcal/kg BW • Prefer oral route as first-line intervention • Supplementation with B-complex vitamins Consider liver biopsy if diagnosis is uncertain Perform systematic extensive screening for infection Treatment of alcohol dependence Clinical diagnosis of AH
  • 58.
    Alcohol-related fibrosis andcirrhosis *Ascites, jaundice, variceal bleeding, infections, hepatorenal syndrome, hepatic encephalopathy, cachexia EASL CPG ALD. J Hepatol 2018;69:154–81 • A range of environmental and host factors have been linked with risk of progression to advanced ALD (extensive liver fibrosis and cirrhosis) – Cigarette smoking, gender, ethnicity, comorbid conditions (e.g. diabetes and obesity), microbial dysbiosis, chronic infection with HBV and HCV and/or HIV, α-antitrypsin deficiency, iron overload – Genetic risk factors • Polymorphisms in the PNPLA3 gene • Genetic variants on TM6SF2 and MBOAT7 – Type and pattern of alcohol use • ALD cirrhosis may present as compensated or decompensated* – May also be associated with extrahepatic alcohol-related organ damage • Alcohol-related cardiomyopathy, acute and chronic pancreatitis, central and peripheral nerve involvement, hepatic encephalopathy
  • 59.
    Alcohol-related fibrosis andcirrhosis EASL CPG ALD. J Hepatol 2018;69:154–81 • Treating comorbid conditions must be encouraged together with interventions targeting alcohol misuse – Obesity and other components of the metabolic syndrome • Management of patients with ALD cirrhosis focuses on: – Alcohol abstinence – Nutritional support including calories, vitamins and micronutrients – Primary and secondary prophylaxis of cirrhotic complications Recommendations Advise complete abstinence from alcohol in patients with alcohol-related cirrhosis to reduce the risk of liver-related complications and mortality A 1 Identify and manage cofactors, including obesity and IR, malnutrition, smoking, iron overload and viral hepatitis A 1 Apply general recommendations for screening and management of complications of cirrhosis to ALD cirrhosis A 1 Grade of recommendation Level of evidence
  • 60.
    Liver transplantation: Trends inliver transplantation of ALD 1. Data from European Liver Transplant Registry; EASL CPG ALD. J Hepatol 2018;69:154–81 • LT is the most effective therapeutic option for patients with ESLD – 1-year post-transplant patient and graft survival is ~80–85% • Liver outcomes after LT in patients with AUD have improved – Graft and patient survival now similar to after LT for other aetiologies • Alcohol-related cirrhosis represents an increasing proportion of LTs in Europe1 ALD cirrhosis (24,452) Autoimmune cirrhosis (2,992) Cryptogenic (unknown) cirrhosis (5,750) Other cirrhosis (2,880) Primary biliary cirrhosis (8,130) Secondary biliary cirrhosis (998) Viral + cirrhosis due to alcohol (2,792) Virus-related cirrhosis (28,043) 0 20 40 60 80 100 Percentage Aetiology of cirrhosis leading to LT in Europe
  • 61.
    Liver transplantation: Selection ofpatients for LT *Particularly URT and GI EASL CPG ALD. J Hepatol 2018;69:154–81 Psychological assessments • Psychosocial to establish likelihood of long-term abstinence post-LT – Limited evidence to support use of the 6-month abstinence rule alone • Psychiatric evaluation in cases of personality disorder, depression, anxiety, poly-substance abuse or other psychiatric disorders • Laboratory tests for abstinence may be used in patients on the transplant waiting list Medical assessments • Pancreatic function • Renal function • Nutritional status • Central and peripheral neuropathy • Myopathy and cardiomyopathy • Encephalopathy/alcohol-related dementia • Atherosclerosis and ischaemic heart disease • Neoplastic or pre-neoplastic disease* A multidisciplinary approach evaluating medical and psychological suitability for LT is essential
  • 62.
    Liver transplantation: Selection ofpatients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS
  • 63.
    Liver transplantation: Selection ofpatients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS
  • 64.
    Liver transplantation: Selection ofpatients for LT 1. Poynard T, et al. J Hepatol 1999;30:11307; EASL CPG ALD. J Hepatol 2018;69:154–81 • Survival benefit related to LT is restricted to patients with advanced decompensation 5-year survival in patients with ALD cirrhosis: LT vs. non-transplanted1 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 58% (44–72%) Matched: 31% (17–45%) Simulated: 35% (30–40%) Child–Pugh C; p=0.008 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Transplanted: 66% (54–78%) Matched: 54% (40–68%) Simulated: 56% (52–60%) Child–Pugh B; p=NS 0 0.00 0.25 500 0.50 0.75 1.00 1,000 1,500 2,000 Time (days) Survival probability Transplanted: 71% (58–84%) Matched: 70% (54–84%) Simulated: 70% (65–75%) Child–Pugh A; p=NS • MELD accurately estimates the survival benefit following LT – Generally recommended to prioritize organ allocation • Clinical manifestations of liver decompensation are not independent predictors of survival over and above MELD – Onset in an abstinent patient should prompt consideration of referral to a transplant centre • Increasing evidence of the benefit of early LT in for patients with severe AH not responding to medical therapy – Selection criteria for such patients need to be more clearly defined
  • 65.
    Liver transplantation: Selection ofpatients for LT EASL CPG ALD. J Hepatol 2018;69:154–81 • Selection of patients with ALD for LT – Based on presence of decompensated cirrhosis AND – Comprehensive psychosocial and medical assessment Recommendations LT should be considered in patients with ALD (classified as Child–Pugh C and/or MELD ≥15), as it confers a survival benefit A 1 Selection of patients with AUD should not be based on the 6-month criterion alone A 2 Duration of abstinence before listing should depend on the degree of liver insufficiency in selected patients with a favourable addiction and psychological profile and supportive relatives A 1 Abstinence in patients with AUD on the LT waiting list should be confirmed with regular clinical interviews and laboratory tests A 1 A multidisciplinary approach evaluating medical and psychological suitability for transplantation is mandatory before and after LT A 1 Early LT should be proposed to a minority of patients with severe AH not responding to medical therapy after a careful selection process A 1 Grade of recommendation Level of evidence
  • 66.
    Liver transplantation: Post-LT follow-upand management: Relapse 1. Faure S, et al. J Hepatol 2012;57:30612; 2. Pfitzmann R, et al. Liver Transpl 2007;13:197205; 3. Bravata DM, et al. Liver Transpl 2001;7:191203; 4. Addolorato G, et al. Alcohol Clin Exp Res 2013;37:16018; EASL CPG ALD. J Hepatol 2018;69:154–81 • Excessive alcohol consumption has a negative impact on long-term post-LT survival1,2 • Recipients with ALD are more likely to drink excessively3 • Multidisciplinary support pre- and post-LT has been shown to help prevent recidivism4 Comparison of Kaplan–Meier survival curves between excessive alcohol relapsers and other patients1 0 0.0 0.2 24 0.4 0.6 0.8 1.0 48 72 96 108 120 Time to event (months) Survival probability 12 36 60 84 No alcohol (abstinent patients, occasional relapsers, slip relapsers) Excess alcohol (excessive relapsers [women >20 g/day; men >30 g/day]) 368 345 102 293 56 56 11 49 No alcohol Excess alcohol Patients at risk:
  • 67.
    Liver transplantation: Post-LT follow-upand management EASL CPG ALD. J Hepatol 2018;69:154–81 • Excessive alcohol consumption is associated with decreased survival post-LT • Patients transplanted for ALD are at increased risk of a range of extrahepatic complications – Cardiovascular events, metabolic syndrome and de novo malignancies Recommendations Integration of an addiction specialist may decrease the risk of relapse in heavy drinking individuals B 2 Patients should be screened regularly for cardiovascular and neurological disease, psychiatric disorders and neoplasms before and after LT A 1 Risk factors for cardiovascular disease and neoplasms, particularly cigarette smoking, should be controlled A 1 Early reduction in calcineurin inhibitor therapy may be considered to decrease the risk of de novo cancer after LT B 2 Grade of recommendation Level of evidence
  • 68.
  • 69.
    Conclusions: Suggestions forfuture studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Public health aspects – Priority to be given to further studies on screening in different populations, to diagnose patients prior to the development of end-stage liver disease • Alcohol use disorders – Further trials of pharmacotherapy in patients with advanced ALD are urgently required – Studies to demonstrate the efficacy of a multidisciplinary team intervention • Diagnostic tests in the management of ALD – Investigations focused on the mechanisms and prognostic significance of histological cholestasis – Investigation of the clinical utility of monitoring tests for alcohol consumption – Investigations to determine the optimal screening tool for liver fibrosis • Management of alcoholic hepatitis – Further studies are required to validate the use of the Lille score at Day 4 – New strategies need to be developed to reduce the risk of infection
  • 70.
    Conclusions: Suggestions forfuture studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Alcohol-related fibrosis and cirrhosis – Large genome-wide analysis should confirm PNPLA3 rs738409 as an important susceptibility polymorphism in ALD and possibly identify other genetic polymorphisms for better screening – The interaction between environmental and genetic factors should be investigated – The mechanisms underlying the additive effects of components of the metabolic syndrome and alcohol on ALD progression should be explored – Additional studies are required to identify the factors influencing fibrosis regression after drinking cessation and long-term outcome in abstinent patients – Further evaluation of endpoints (clinical, anthropometrical) and re-nutritional strategies are needed in advanced ALD cirrhosis – Further randomized controlled studies are needed on pro-regenerative strategies in advanced ALD cirrhosis using clinically relevant endpoints – Further work is needed to select patients with ALD cirrhosis at high risk of extrahepatic malignancy to implement cancer surveillance – Additional work may determine if PNPLA3 variants can be a marker for the development of HCC in ALD cirrhosis
  • 71.
    Conclusions: Suggestions forfuture studies EASL CPG ALD. J Hepatol 2018;69:154–81 • Liver transplantation – Studies evaluating the effects of new immunosuppressive regimens on the risk of cardiovascular disease and de novo neoplasms are warranted – In patients with severe ASH not responding to medical therapy, early LT needs to be further evaluated in carefully selected patients

Editor's Notes

  • #8 GRADE, Grading of Recommendations Assessment, Development and Evaluation; RCT, randomized controlled trial
  • #12 ALD, alcohol-related liver disease
  • #13 World Health Organization. GLOBAL STATUS REPORT on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018
  • #14 ALD, alcohol-related liver disease; WHO, World Health Organization World Health Organization. GLOBAL STATUS REPORT on noncommunicable diseases 2014. Available at: http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed August 2018 Sheron N. Alcohol and liver disease in Europe--Simple measures have the potential to prevent tens of thousands of premature deaths. J Hepatol 2016;64:957–67
  • #17 ALD, alcohol-related liver disease
  • #18 CPI, consumer price index Sheron N. Alcohol and liver disease in Europe--Simple measures have the potential to prevent tens of thousands of premature deaths. J Hepatol 2016;64:957–67
  • #19 ALD, alcohol-related liver disease; GP, general practitioner
  • #20 ALD, alcohol-related liver disease; AUD, alcohol use disorder; GP, general practitioner
  • #21 AUD, alcohol use disorder; DSM-V, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition; WHO, World Health Organization
  • #22 DSM-V, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • #23 DSM-V, Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
  • #24 AUDIT, Alcohol Use Disorders Identification Test; WHO, World Health Organization World Health Organization. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Care. Second Edition. http://apps.who.int/iris/handle/10665/67205. Accessed August 2018
  • #25 AUDIT, Alcohol Use Disorders Identification Test; WHO, World Health Organization World Health Organization. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Care. Second Edition. http://apps.who.int/iris/handle/10665/67205. Accessed August 2018
  • #26 AUDIT, Alcohol Use Disorders Identification Test; WHO, World Health Organization World Health Organization. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Care. Second Edition. http://apps.who.int/iris/handle/10665/67205. Accessed August 2018
  • #27 AUDIT, Alcohol Use Disorders Identification Test; WHO, World Health Organization World Health Organization. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Care. Second Edition. http://apps.who.int/iris/handle/10665/67205. Accessed August 2018
  • #28 AUDIT, Alcohol Use Disorders Identification Test; WHO, World Health Organization World Health Organization. AUDIT: The Alcohol Use Disorders Identification Test. Guidelines for Use in Primary Care. Second Edition. http://apps.who.int/iris/handle/10665/67205. Accessed August 2018
  • #29 AUD, alcohol use disorder; AUDIT, Alcohol Use Disorders Identification Test;
  • #30 AWS, alcohol withdrawal syndrome
  • #31 AWS, alcohol withdrawal syndrome
  • #32 ALD, alcohol-related liver disease; AUD, alcohol use disorder 1. Lackner C, Spindelboeck W, Haybaeck J, Douschan P, Rainer F, Terracciano L, Haas J, Berghold A, Bataller R, Stauber RE. Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease. J Hepatol 2017;66:610–8.
  • #33 ALD, alcohol-related liver disease; AUD, alcohol use disorder
  • #34 ALD, alcohol-related liver disease; AUD, alcohol use disorder
  • #35 ALD, alcohol-related liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GGT, gamma glutamyl transferase; GI, gastrointestinal; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio; TE, transient elastography; WBC, white blood cell
  • #36 ALD, alcohol-related liver disease
  • #37 ALD, alcohol-related liver disease; ASH, steatohepatitis due to alcohol-related liver disease
  • #38 ALD, alcohol-related liver disease; ASH, steatohepatitis due to alcohol-related liver disease; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease
  • #39 ALD, alcohol-related liver disease; AUROC, area under receiver operating characteristic; ELF, enhanced liver fibrosis; GGT, gamma glutamyl transferase; NA, not available; NPV, negative predictive value; PPV, positive predictive value
  • #40 AH, alcoholic hepatitis; ALD, alcohol-related liver disease; AST, aspartate aminotransferase; kPa, kilopascals; LSM, liver stiffness measurement; TE, transient elastography Figure reproduced from Mueller S, et al. World J Gastroenterol 2014;20:14626–41. Copyright © The author(s) 1995-2018. Published by Baishideng Publishing Group Inc. All rights reserved. Articles published by this open-access journal are distributed under the terms of the Creative Commons Attribution-Noncommercial (CC BY-NC 4.0) License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license.
  • #41 ALD, alcohol-related liver disease; CT, computed tomography; MRI, magnetic resonance imaging
  • #42 ALD, alcohol-related liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; EtG, ethyl glucuronide; EtS, ethyl sulfate; FAEE, fatty acid ethyl ester; GGT, gamma glutamyl transferase; MCV, mean corpuscular volume; PEth, phosphatidylethanol
  • #43 ALD, alcohol-related liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; CDT, carbohydrate deficient transferrin; EtG, ethyl glucuronide; EtOH, ethanol; GGT, gamma glutamyl transferase; MCV, mean corpuscular volume
  • #44 ALD, alcohol-related liver disease; EtG, ethyl glucuronide; EtOH, ethanol; UTI, urinary tract infection.
  • #45 ALD, alcohol-related liver disease; EtG, ethyl glucuronide; EtOH, ethanol; LT, liver transplantation; UTI, urinary tract infection.
  • #46 ALD, alcohol-related liver disease; AUD, alcohol use disorder; EtG, ethyl glucuronide; LFT, liver function test
  • #47 AH, alcoholic hepatitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PT, prothrombin time; ULN, upper limit of normal
  • #48 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #49 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #50 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #51 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #52 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #53 ABIC, age, serum bilirubin, INR, and serum creatinine score; AH, alcoholic hepatitis; GAHS, Glasgow Alcoholic Hepatitis Score; INR, international normalized ratio; Maddrey DF, Maddrey discriminant function; MELD, Model for End-Stage Liver Disease; PT, prothrombin time
  • #54 AH, alcoholic hepatitis; AKI, acute kidney injury; AUD, alcohol use disorder
  • #55 AH, alcoholic hepatitis; BW, body weight
  • #56 AH, alcoholic hepatitis
  • #57 AH, alcoholic hepatitis
  • #58 AH, alcoholic hepatitis; BW, body weight; GAHS, Glasgow alcoholic hepatitis score; mDF, modified Maddrey discriminant function; NAC, N-acetylcysteine
  • #59 ALD, alcohol-related liver disease; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus
  • #60 ALD, alcohol-related liver disease; IR, insulin resistance
  • #61 ALD cirrhosis, cirrhosis due to alcohol-related liver disease; AUD, alcohol use disorder; ESLD, end-stage liver disease; LT, liver transplantation
  • #62 GI, gastrointestinal; LT, liver transplantation; URT, upper respiratory tract
  • #63 ALD cirrhosis, cirrhosis due to alcohol-related liver disease; LT, liver transplantation; NS, non-significant 1. Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, Messner M, Launois B, Samuel D, Cherqui D, Pageaux G, Bernard PH, Calmus Y, Zarski JP, Miguet JP, Chaput JC. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130–7
  • #64 ALD cirrhosis, cirrhosis due to alcohol-related liver disease; LT, liver transplantation; NS, non-significant 1. Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, Messner M, Launois B, Samuel D, Cherqui D, Pageaux G, Bernard PH, Calmus Y, Zarski JP, Miguet JP, Chaput JC. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130–7
  • #65 AH, alcoholic hepatitis; ALD cirrhosis, cirrhosis due to alcohol-related liver disease; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NS, non-significant 1. Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, Messner M, Launois B, Samuel D, Cherqui D, Pageaux G, Bernard PH, Calmus Y, Zarski JP, Miguet JP, Chaput JC. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130–7
  • #66 AH, alcoholic hepatitis; ALD, alcohol-related liver disease; AUD, alcohol use disorder; LT, liver transplantation; MELD; Model for End-Stage Liver Disease
  • #67 ALD, alcohol-related liver disease; LT, liver transplantation 1. Faure S, Herrero A, Jung B, Duny Y, Daures JP, Mura T, Assenat E, Bismuth M, Bouyabrine H, Donnadieu-Rigole H, Navarro F, Jaber S, Larrey D, Pageaux GP. Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the primary indication. J Hepatol 2012;57:306–12 2. Pfitzmann R, Schwenzer J, Rayes N, Seehofer D, Neuhaus R, Nüssler NC. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2007;13:197–205 3. Bravata DM, Olkin I, Barnato AE, Keeffe EB, Owens DK. Employment and alcohol use after liver transplantation for alcoholic and nonalcoholic liver disease: a systematic review. Liver Transpl 2001;7:191–203 4. Addolorato G, Mirijello A, Leggio L, Ferrulli A, D'Angelo C, Vassallo G, Cossari A, Gasbarrini G, Landolfi R, Agnes S, Gasbarrini A; Gemelli OLT Group. Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center. Alcohol Clin Exp Res 2013;37:1601–8
  • #68 ALD, alcohol-related liver disease; LT, liver transplantation
  • #70 ALD, alcohol-related liver disease
  • #71 ALD, alcohol-related liver disease; HCC, hepatocellular carcinoma
  • #72 ASH, steatohepatitis due to alcohol-related liver disease; LT, liver transplantation