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EASL Clinical Practice Guidelines: Management of alcohol-related liver disease

Published:April 05, 2018DOI:https://doi.org/10.1016/j.jhep.2018.03.018

      Summary

      The harmful use of alcohol has been estimated to cause approximately 3.3 million deaths every year, corresponding to nearly 6% of all deaths globally. Therefore, the effective management and treatment of alcoholic liver disease is a pertinent public health issue. In the following Clinical Practice Guidelines, the latest data on the treatment and management of alcohol-related liver disease will be reviewed and up to date recommendations for clinical management will be provided.

      Guideline development process

      A panel of clinicians with an interest in liver disease and alcoholic liver disease (ALD), approved by the European Association for the Study of the Liver (EASL) Governing Board, wrote and discussed this Clinical Practice Guidelines (CPG) document between November 2016 and March 2017. The guidelines were independently peer reviewed, and all contributors to the CPG disclosed their conflicts of interest by means of a disclosure form provided by the EASL Office prior to work commencing. The EASL Ethics Committee reviewed the composition of the panel to eliminate the potential for real or perceived bias. The CPG panel conflict of interests are declared in this submission.

      Methods

      These guidelines have been produced using evidence published before 1 October, 2017. Where possible, the level of evidence and recommendation are cited (Table 1). The evidence and recommendations in these guidelines have been graded using methods adapted from the grading of recommendations assessment development and evaluation (GRADE system). The strength of recommendations thus reflects the quality of underlying evidence. The GRADE system offers two grades of recommendation: strong or weak (Table 1). The CPG thus consider the quality of evidence: the higher, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted. Where no clear evidence exists, guidance is based on the consensus of expert opinion in the literature and the writing committee. Recommendations must also be interpreted in a context specific manner.
      Table 1Level of Evidence and Grade of Recommendations (adapted from GRADE system).
      Level of evidence
      Level was graded down if there is a poor quality, strong bias or inconsistency between studies. Level was graded up if there is a large effect size.
      Confidence in the evidence
      Level 1Data derived from meta-analyses or systematic reviews or from (multiple) randomized trials with high quality.Further research is unlikely to change our confidence in the estimate of benefit and risk.
      Level 2Data derived from a single RCT or multiple non-randomized studiesFurther research (if performed) is likely to have an impact on our confidence in the estimate of benefit and risk and may change the estimate.
      Level 3Small studies, retrospective observational studies, registries.Any estimate of effect is uncertain.
      Recommendations
      GradeWording associated with the grade of recommendation
      A (strong)Strong recommendation: factors influencing the strength of the recommendation include the quality of the evidence, presumed patients-important outcomes and cost“must”, “should”, or “EASL recommends”
      B (weak)Weaker recommendation: variability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption“can”, “may”, or “EASL suggests”
      * Level was graded down if there is a poor quality, strong bias or inconsistency between studies. Level was graded up if there is a large effect size.

      Terminology

      Public health aspects

      Alcohol-related morbidity and mortality

      According to the World Health Organization’s (WHO) 2014 report on noncommunicable diseases, harmful use of alcohol causes approximately 3.3 million deaths every year, corresponding to 5.9% of all deaths. Furthermore, 139 million disability-adjusted life years, or 5.1% of the global burden of disease and injury, were attributable to alcohol consumption. The proportion of global deaths attributable to alcohol differs based on gender, with 7.6% of deaths among males and 4.0% of deaths among females attributable to alcohol.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      Alcohol-related morbidity and mortality has a wide geographical variation, with the highest alcohol-attributable fractions reported in the WHO European Region.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      Within each country there is an excellent correlation between the level of alcohol consumption and the prevalence of alcohol-related harm. In fact, although mean alcohol consumption in the World is 6.2 litres of pure alcohol per person per year, the consumption in Europe is 10.9 litres/year.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      According to data from the OECD report 2017, alcohol consumption in the OECD countries, averaged nine litres of pure alcohol per person per year. This number results from a significant percentage of heavy drinkers: 30% of men and 12% of women binge-drink at least once per month.

      OECD. Alcohol consumption among adults. In: Health at a Glance 2017.2017:72–73.

      Despite divergent trends at the national level, the WHO European Region is still the region with the highest adult per capita alcohol consumption. Between 1990 and 2014, there was a slight decrease in the overall level of consumption due to decreases in the richest countries in the central western European Union (EU) and Mediterranean parts of the Region, while drinking levels in central-eastern EU remained stable over the past 25 years, and increased in the eastern and the south-eastern parts of the WHO European Region.

      Shield KDR, M.M., Rehm, J. Public health successes and missed opportunities Trends in alcohol consumption and attributable mortality in the WHO European Region, 1990–2014. In. WHO. Copenhagen, Denmark: WHO Regional Office for Europe; 2016.

      Alcohol consumption over the last 20 years in the UK and Finland has increased significantly, while other countries such as France, Spain and Portugal were able to reduce the number of liver-related deaths.
      • Sheron N.
      Alcohol and liver disease in Europe-Simple measures have the potential to prevent tens of thousands of premature deaths.
      Alcohol has an impact on over 200 diseases and types of injuries. In most cases the impact is detrimental. The largest number of deaths attributable to alcohol consumption are from cardiovascular diseases, followed by injuries, gastrointestinal diseases (mainly liver cirrhosis) and cancers.

      OECD. Tackling Harmful Alcohol Use: Economics and Public Health Policy. Paris 2015.

      However, the alcohol-attributable fraction is highest for liver diseases, especially cirrhosis, and foetal alcohol syndrome.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      In the EU, based on the WHO mortality database, 41% of the liver deaths are attributed to alcohol, and 46% are of unknown aetiology. It is probable that a significant percentage of those classified as unknown are actually due to alcohol.
      • Sheron N.
      Alcohol and liver disease in Europe-Simple measures have the potential to prevent tens of thousands of premature deaths.
      In fact, reliability of death certificate codification varies among countries, and in an undetermined proportion of deaths in which alcohol is the key factor the certifying doctor may choose not to explicitly mention alcohol on the death certificate.
      • Bell G.
      • Cremona A.
      Alcohol and death certification: a survey of current practice and attitudes.
      Although alcohol consumption is higher in rich countries, in those with lower economic wealth, the morbidity and mortality risks are higher per litre of pure alcohol consumed than in the higher income countries.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      The economic contribution of the alcohol industry, in terms of employment and taxation, are often cited as reasons for not attempting to restrict alcohol consumption using pricing strategies or marketing restrictions. In the EU in 2003, it was calculated that harmful alcohol consumption resulted in estimated costs of €125 billion, equivalent to 1.3% of gross domestic product (GDP).

      SANCO D. Alcohol-related harm in Europe: Key Data, Factsheet. In: SANCO D, ed. Belgium 2006.

      This exceeds by an order of magnitude the reported contribution (about €9 billion) of the alcohol industry to the EU economy.

      Rabinovich L, Brutscher P-B, de Vries H, Tiessen J, Clift J, Reding A. The affordability of alcoholic beverages in the European Union Understanding the link between alcohol affordability, consumption and harms. Rand report 2009; http://ec.europa.eu/health/ph_determinants/life_style/alcohol/documents/alcohol_rand_en.pdf, 2018

      Consensus on the definition of a “drink” and of “heavy episodic drinking”

      The quantification of alcohol consumption is not easy in clinical practice. Although the quantification in grams of alcohol per/day or week is more precise, it is time-consuming and frequently difficult to obtain, since patients are not able to recall the different types of drinks and their amount. Consequently, it may be advantageous to quantify by number of drinks. However, there has been large discrepancy in the definition of a “drink”, regarding the grams of alcohol, varying from 8 to 16 g. According to the Dietary guidelines for Americans, one standard drink of “pure” alcohol is defined as 14 g.

      DHHS, DoA. 2015–2020 Dietary Guidelines for Americans. In: 8th ed. http://health.gov/dietaryguidelines/2015/guidelines/2015.

      We suggest standardising the measure to 10 g, to facilitate comparisons among studies, as has been used by the WHO.

      (WHO) WHO. Food based dietary guidelines. 2003.

      According to ICD-10, harmful drinking is considered when alcohol use is causing damage to health that may be either physical or mental: IC10-2016 online (http://apps.who.int/classifications/icd10/browse/2016/en#/F10.1)
      Heavy episodic drinking has been defined as consumption of more than 60 g of pure alcohol on one occasion.
      • Rehm J.
      • Gmel Sr., G.E.
      • Gmel G.
      • Hasan O.S.M.
      • Imtiaz S.
      • Popova S.
      • et al.
      The relationship between different dimensions of alcohol use and the burden of disease-an update.
      Binge drinking is the consumption within about two hours of four or more drinks for women and five or more drinks for men.

      DHHS, DoA. 2015–2020 Dietary Guidelines for Americans. In: 8th ed. http://health.gov/dietaryguidelines/2015/guidelines/2015.

      Levels of alcohol consumption and disease risk

      An important aspect of public health policy concerning alcohol has been the attempt to establish a safe threshold for consumption. This pertains mostly to what extent moderate alcohol consumption is cardio-protective, illustrated by the so called ‘J’ shaped curve in the relationship between alcohol consumption and overall mortality.
      • Corrao G.
      • Rubbiati L.
      • Bagnardi V.
      • Zambon A.
      • Poikolainen K.
      Alcohol and coronary heart disease: a meta-analysis.
      Although there is strong evidence that heavy alcohol intake associates with increased risk of cardiomyopathy, hypertension, atrial arrhythmias and haemorrhagic stroke, light–moderate drinkers seem to have a lower risk of coronary artery disease.
      • Klatsky A.L.
      Alcohol and cardiovascular diseases: where do we stand today?.
      This positive effect of alcohol may offset some of the large array of negative health consequences of even moderate alcohol consumption. However, alcohol is a recognised carcinogen, and no threshold level of consumption exists for the risk of cancer. Alcohol consumption has been associated with an increased risk of several cancers, and in at least four of them, including breast cancer, the risk begins at doses as low as 10 g/1 unit/day.
      • Bagnardi V.
      • Rota M.
      • Botteri E.
      • Tramacere I.
      • Islami F.
      • Fedirko V.
      • et al.
      Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis.
      While alcohol is undoubtedly a risk factor for cirrhosis it is still unclear whether there is a continuous dose-response relationship or a threshold of consumption at which the risk emerges. In a meta-analysis from 2010 the close dose-response relationships between the average amount of alcohol consumed and the risk of liver cirrhosis were confirmed. The authors’ found evidence for threshold effects, with increased risks of mortality from liver cirrhosis among men and women drinking 12–24 g of ethanol per day.
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • Irving H.
      • Baliunas D.
      • Patra J.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      Indeed, among women, a significant increase was also seen for those drinking up to 12 g/day. The evidence therefore suggests that if a threshold exists, it is very low, and may in fact be difficult to detect because of limitations in measuring consumption. However, for practical issues, it can be recommended that if alcohol is consumed, limit intake to no more than two drinks for females and three drinks for males (each containing 10 g of alcohol) per day, since this amount was not associated with a significant increase in risk of liver cirrhosis morbidity.

      (WHO) WHO. Food based dietary guidelines. 2003.

      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • Irving H.
      • Baliunas D.
      • Patra J.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      One important issue is the impact of alcohol drinking patterns, with controversy regarding the risks of binge drinking. In that respect, Askgaard found that daily drinking was associated with the highest risk of liver cirrhosis,
      • Askgaard G.
      • Gronbaek M.
      • Kjaer M.S.
      • Tjonneland A.
      • Tolstrup J.S.
      Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study.
      whereas Aberg et al. found that binge drinking was associated with an increased risk of liver disease independently of average alcohol intake and confounders.
      • Aberg F.
      • Helenius-Hietala J.
      • Puukka P.
      • Jula A.
      Binge drinking and the risk of liver events: A population-based cohort study.
      Further clinical and experimental studies are required to define the role of ALD and the underlying mechanisms.
      Importantly, there is good clinical evidence that cessation of drinking at any point in the natural history of the disease reduces the risks of disease progression and occurrence of complications from cirrhosis.
      • Masson S.
      • Emmerson I.
      • Henderson E.
      • Fletcher E.H.
      • Burt A.D.
      • Day C.P.
      • et al.
      Clinical but not histological factors predict long-term prognosis in patients with histologically advanced non-decompensated alcoholic liver disease.

      Public health policies to reduce population risk for ALD

      Several alcohol-related policies have been shown to be effective and cost-effective. Reducing morbidity and mortality associated with ALD, depends on policies that reduce alcohol consumption in general. Effective interventions include:
      • Price based policies
        • o
          Taxation
        • o
          Minimum unit pricing
      • Limitation of alcohol availability
      • Restriction of marketing and advertising
      Reducing the affordability of alcohol has been shown to have a significant effect on reducing ALD-related liver deaths.
      • Wagenaar A.C.
      • Salois M.J.
      • Komro K.A.
      Effects of beverage alcohol price and tax levels on drinking: a meta-analysis of 1003 estimates from 112 studies.
      • Wagenaar A.C.
      • Tobler A.L.
      • Komro K.A.
      Effects of alcohol tax and price policies on morbidity and mortality: a systematic review.
      Minimum unit pricing, setting a floor price for a unit of alcohol, has been shown to be very effective. In British Columbia, it reduced alcohol-related mortality by 32% one year after implementation.
      • Stockwell T.
      • Zhao J.
      • Martin G.
      • Macdonald S.
      • Vallance K.
      • Treno A.
      • et al.
      Minimum alcohol prices and outlet densities in British Columbia, Canada: estimated impacts on alcohol-attributable hospital admissions.
      This measure also has the advantage of being more effective for heavy consumers and for low-income groups.
      Other effective alcohol policies have been suggested by WHO, that are based on age-related vulnerability, including partial or total advertising bans, restrictions on access to alcohol through minimum ages at which it is legal to purchase alcohol, and laws aimed to prevent any alcohol consumption by young people when driving vehicles.

      WHO. GLOBAL STATUS REPORT on noncommunicable diseases 2014. WHO Library Cataloguing-in-Publication Data; 2014.

      Children and young adults are particularly sensitive to alcohol marketing. A series of longitudinal experimental studies have proven that marketing impacts on the drinking behaviour of children.

      Forum SGotEAaH. Does marketing communication impact on the volume and patterns of consumption of alcoholic beverages, especially by young people? – a review of longitudinal studies. In: DG SANCO EC, European Alcohol and Health Forum, ed2009.

      • Anderson P.
      • de Bruijn A.
      • Angus K.
      • Gordon R.
      • Hastings G.
      Impact of alcohol advertising and media exposure on adolescent alcohol use: a systematic review of longitudinal studies.
      In fact, reducing advertising in media, mostly publicity targeting young people is important, since they have been shown to be particularly susceptible.
      • Anderson P.
      • de Bruijn A.
      • Angus K.
      • Gordon R.
      • Hastings G.
      Impact of alcohol advertising and media exposure on adolescent alcohol use: a systematic review of longitudinal studies.

      Screening to reduce ALD-related morbidity and mortality

      A high proportion of patients admitted with decompensated ALD cirrhosis report having recent consultations in primary care or emergency units.
      • Verrill C.
      • Smith S.
      • Sheron N.
      Are the opportunities to prevent alcohol related liver deaths in the UK in primary or secondary care? A retrospective clinical review and prospective interview study.
      Since the risk of developing liver disease in harmful drinkers decreases with abstinence or decreased consumption, early recognition and interventions with that goal should be implemented.
      Screening for harmful alcohol consumption should be done systematically in patients, by their general practitioner (GP), and in patients admitted to emergency facilities. In fact, the feasibility of screening followed by an intervention in an emergency department was recently demonstrated in the UK.
      • Westwood G.
      • Meredith P.
      • Atkins S.
      • Greengross P.
      • Schmidt P.E.
      • Aspinall R.J.
      Universal screening for alcohol misuse in acute medical admissions is feasible and identifies patients at high risk of liver disease.
      In addition, screening for ALD should be undertaken in patients with clinical signs suggestive of harmful alcohol consumption or liver cirrhosis, i.e. patients presenting with bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren’s contracture, gynecomastia or extensive spider naevi.
      Screening for ALD should be performed in high-risk populations, such as those in alcohol rehabilitations clinics, or harmful drinkers identified by their GP. Screening in the workplace would be extremely helpful, although difficult to implement.
      • Cook P.A.
      • Morleo M.
      • Billington D.
      • Sanderson-Shortt K.
      • Jones C.
      • Gabbay M.
      • et al.
      Evaluation of work-based screening for early signs of alcohol-related liver disease in hazardous and harmful drinkers: the PrevAIL study.
      The best way to do such screening is still debatable. The Southampton traffic-light test is an algorithm, based on hyaluronic acid (HA), procollagen-3 N-terminal peptide (PIIINP), and platelet count, that expresses the results as red, amber or green, corresponding respectively to high, intermediate or low risk, and was suggested as a simple screening test.
      • Sheron N.
      • Moore M.
      • O'Brien W.
      • Harris S.
      • Roderick P.
      Feasibility of detection and intervention for alcohol-related liver disease in the community: the Alcohol and Liver Disease Detection study (ALDDeS).
      Another possibility is the use of transient elastography (TE) techniques that could be used in portable devices to increase availability for large groups. In fact, it was recently shown that TE has excellent diagnostic value for liver fibrosis in ALD.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      Whatever form of screening is used, it must be followed by an intervention with a multidisciplinary team. In fact, there is a need to create alcohol care teams to take care of these patients.
      • Hazeldine S.
      • Hydes T.
      • Sheron N.
      Alcoholic liver disease - the extent of the problem and what you can do about it.

      Suggestions for future studies

      • Priority to be given to further studies on screening in different populations, to diagnose patients prior to the development of end-stage liver disease
      • Excess alcohol consumption should be addressed using pricing-based policies and regulation of availability. (Grade A1)
      • Advertising and marketing of alcohol either directly or indirectly should be banned. (Grade A2)
      • Primary care facilities for managing AUD need to be made widely available. (Grade A2)
      • Screening for harmful alcohol consumption should be done by GPs and in Emergency Departments. (Grade A2)
      • Screening for ALD should be done in high-risk populations, such as those in alcohol rehabilitations clinics, or the harmful drinkers identified by their GP. (Grade A2)
      • Patients identified through screening should undergo brief intervention and referral to a multidisciplinary team. (Grade A1)

      Alcohol use disorders

      Terminology and definitions

      The publication of the DSM-V has been an important step forward to overcome the arbitrary differentiation between alcohol abuse and dependence, through the creation of the overarching concept of alcohol use disorder (AUD).

      Association“ AP. American Psychiatric Association Substance use and addiction-related disorders. In: Diagnostic and Statistical Manual of Mental Disorders, 5th edition. American Psychiatric Association 2013:481–589.

      This new concept is not only useful because it unifies the disorder, but also because it introduces a partially dimensional perspective into what has been traditionally called alcoholism. The categorical distinction between who is and who is not an alcoholic is not clinically useful and may be damaging because of stigmatisation.
      • Rehm J.
      • Anderson P.
      • Manthey J.
      • Shield K.D.
      • Struzzo P.
      • Wojnar M.
      • et al.
      Alcohol use disorders in primary health care: what do we know and where do we go?.
      Instead, the DSM-V defines AUD as a problematic pattern of alcohol use leading to clinically significant impairment or distress, with graded levels of severity depending on the number of diagnostic criteria met. As shown there are 11 diagnostic criteria and anyone meeting at least two of them during the last year qualifies for a diagnosis of AUD (Table 2). Severity is established based on the number of criteria met, ranging from mild (2–3 criteria), to moderate (4–5 criteria) and severe (6 or more criteria).
      Table 2DSM-V criteria for alcohol use disorder.
      Definition: A problematic pattern of alcohol use leading to clinically significant impairment or distress, as manifested by at least two 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 (or a closely related substance, such as a benzodiazepine) is taken to relieve or avoid withdrawal symptoms.
      The presence of at least 2 of these criteria indicates an AUD. The severity of the AUD is defined as:
      • Mild: The presence of 2 to 3 criteria
      • Moderate: The presence of 4 to 5 criteria
      • Severe: The presence of 6 or more criteria
      AUD, alcohol use disorder.
      It is still unclear what option will be taken in ICD-11, but for the moment, the WHO continues to use the terms hazardous and harmful alcohol use and alcohol dependence [5]. Even though it is not officially accepted, the term ‘risky drinker’ is commonly used to define people who drink excessively and can benefit from brief interventions provided by health practitioners in medical settings.
      The drinking habits of patients with liver diseases need to be routinely assessed, using tools with proven reliability.
      • Zakhari S.
      • Li T.K.
      Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease.

      Screening tools to identify alcohol use disorders

      Quantity frequency questionnaires and diaries (Timeline Followback) can be used to calculate patients’ drinking habits. The former tools are usually preferred for their simplicity, but in the last few years a relevant number of Apps (e.g. Drinkaware) have been developed for this monitoring purpose,
      • Barrio P.
      • Ortega L.
      • Lopez H.
      • Gual A.
      Self-management and shared decision-making in alcohol dependence via a mobile app: a pilot study.
      making prospective measurement of drinking much easier for motivated patients. A good alternative to quantity frequency questionnaires is the use of screening instruments. There are many tools that have been validated and translated into many languages, but the AUDIT (Alcohol Use Disorders Inventory Test) remains the ‘gold standard’ (Table 3). Developed by the WHO in 1982, it has proven to have good sensitivity and specificity in clinical settings across different countries.
      • Saunders J.B.
      • Aasland O.G.
      • Babor T.F.
      • de la Fuente J.R.
      • Grant M.
      Development of the alcohol use disorders identification test (AUDIT): WHO collaborative project on early detection of persons with harmful alcohol consumption–II.
      Table 3AUDIT questionnaire.
      Questions01234
      1. How often do you have a drink containing alcohol?NeverMonthly or less2 to 4 times a month2 to 3 times a week4 or more times a week
      2. How many drinks containing alcohol do you have on a typical day when you are drinking?1 or 23 or 45 or 67 to 910 or more
      3. How often do you have 5 or more drinks on one occasion?NeverLess than monthlyMonthlyWeeklyDaily or almost daily
      4. How often during the last year you found that you were not able to stop drinking once you had started?NeverLess than monthlyMonthlyWeeklyDaily or almost daily
      5. How often during the last year have you failed to do what was normally expected of you because of drinking?NeverLess than monthlyMonthlyWeeklyDaily 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 sessionNeverLess than monthlyMonthlyWeeklyDaily or almost daily
      7. How often during the last year have you had a feeling of guilt or remorse after drinkingNeverLess than monthlyMonthlyWeeklyDaily 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?NeverLess than monthlyMonthlyWeeklyDaily or almost daily
      9. Have you or someone else been injured because of your drinking?NoYes, but not in the last yearYes, during the last year
      10. Has a relative, friend, doctor or other healthcare worker been concerned about your drinking or suggested you cut down?NoYes, but not in the last yearYes, during the last year
      The AUDIT has 10 questions that explore consumption (1–3), dependence (4–6), and alcohol-related problems (7–10) (Table 3). There are two cut-off points, one for dependence and one for risky drinking. Shorter versions have been developed. The AUDIT-C includes just the first three questions of the AUDIT and is reliable for the screening of ‘risky drinking’.
      • Bush K.
      • Kivlahan D.R.
      • McDonell M.B.
      • Fihn S.D.
      • Bradley K.A.
      The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.
      • Gual A.
      • Segura L.
      • Contel M.
      • Heather N.
      • Colom J.
      Audit-3 and audit-4: effectiveness of two short forms of the alcohol use disorders identification test.
      In fact, it is a standardised way to quickly apply a quantity frequency questionnaire that includes ‘binge drinking’ occasions. The NIAAA (National Institute of Alcohol Abuse and Alcoholism) recommends using the third question of the AUDIT (How often do you have six or more drinks on one occasion?) as a single screening question, which should be followed by the whole AUDIT in case the answer is rated positive.
      • Zakhari S.
      • Li T.K.
      Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease.

      Screening of patients with psychiatric disorders

      Patients with AUD have a high prevalence of psychiatric co-morbidity. In general, population surveys of patients with AUD show a high prevalence of anxiety disorders, affective disorders, and schizophrenia.
      • Bourdon K.H.
      • Rae D.S.
      • Locke B.Z.
      • Narrow W.E.
      • Regier D.A.
      Estimating the prevalence of mental disorders in U.S. adults from the Epidemiologic Catchment Area Survey.
      • Grant B.F.
      • Goldstein R.B.
      • Saha T.D.
      • Chou S.P.
      • Jung J.
      • Zhang H.
      • et al.
      Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III.
      • Glass J.E.
      • Williams E.C.
      • Bucholz K.K.
      Psychiatric comorbidity and perceived alcohol stigma in a nationally representative sample of individuals with DSM-5 alcohol use disorder.
      Anxiety and affective disorders may be independent or concurrent with alcohol dependence. Independent disorders will need referral for specialised treatment, while concurrent disorders may disappear once the patient is weaned off alcohol.
      Patients with AUD have a higher risk of developing other addictions, including nicotine. Because cigarette smoking and alcohol abuse are synergistic in causing cardiovascular diseases and cancer, including hepatocellular carcinoma (HCC), hepatologists are encouraged to promote and assist smoking cessation in patients with ALD.
      • Altamirano J.
      • Bataller R.
      Cigarette smoking and chronic liver diseases.
      Since patients with AUD tend to be heavier smokers, the treatment of their nicotine dependence may require more intensive support or referral to specialised professionals.
      • Grant B.F.
      • Hasin D.S.
      • Chou S.P.
      • Stinson F.S.
      • Dawson D.A.
      Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions.
      Also, patients with AUD who are polydrug users are difficult to manage and should be systematically referred to specialised treatment units. Data suggest that AUD appears more than 10 years before the patient is referred for specialist treatment. Special attention should be paid to the coordination between hepatologists and addiction specialists (psychiatrists, psychologists, and social workers) in order to reduce the gap between the signs of AUD appearing and referral.
      • Addolorato G.M.A.
      • Leggio L.
      • Ferrulli A.
      • D’Angelo C.
      • Vassallo G.
      • Cossari A.
      • et al.
      Liver transplantation in alcoholic patients: impact of an alcohol addiction unit within a liver transplant center.

      Management of alcohol withdrawal syndrome

      Alcohol withdrawal syndrome (AWS) is a severe medical condition affecting alcohol-dependent patients who suddenly discontinue or decrease alcohol consumption. Light or moderate AWS usually develops within 6–24 h after the last drink. Symptoms may include increased blood pressure and pulse rate, tremors, hyperreflexia, irritability, anxiety, headache, nausea, and vomiting. These symptoms may progress to more severe forms of AWS, characterised by delirium tremens, seizures, coma, cardiac arrest, and death.
      • Fiellin D.A.
      • Kleber H.
      • Trumble-Hejduk J.G.
      • McLellan A.T.
      • Kosten T.R.
      Consensus statement on office-based treatment of opioid dependence using buprenorphine.
      Severity scores for AWS are potentially useful in the management of patients. While these scores are insufficiently validated in patients. with ALD, the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar) is useful in clinical practice.
      • Sullivan J.T.
      • Sykora K.
      • Schneiderman J.
      • Naranjo C.A.
      • Sellers E.M.
      Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar).
      A CIWA-Ar score >8 indicates a moderate AWS and a score ≥15 indicates severe AWS. Pharmacological treatment is recommended for both moderate and severe AWS using a symptom-triggered regimen rather than fixed dose schedule in order to prevent the accumulation of the drug.
      • Mirijello A.
      • D'Angelo C.
      • Ferrulli A.
      • Vassallo G.
      • Antonelli M.
      • Caputo F.
      • et al.
      Identification and management of alcohol withdrawal syndrome.
      Benzodiazepines are considered the ‘gold standard’ treatment for AWS, given their efficacy for reducing both withdrawal symptoms and the risk of seizures and/or delirium tremens.
      • Amato L.
      • Minozzi S.
      • Vecchi S.
      • Davoli M.
      Benzodiazepines for alcohol withdrawal.
      • Mayo-Smith M.F.
      • Beecher L.H.
      • Fischer T.L.
      • Gorelick D.A.
      • Guillaume J.L.
      • Hill A.
      • et al.
      Management of alcohol withdrawal delirium. An evidence-based practice guideline.
      Long-acting benzodiazepines (e.g. diazepam, chlordiazepoxide) provide more protection against seizures and delirium, but short and intermediate-acting benzodiazepines (e.g. lorazepam, oxazepam) are safer in elderly patients and those with hepatic dysfunction.
      • McKeon A.
      • Frye M.A.
      • Delanty N.
      The alcohol withdrawal syndrome.
      In Europe, clomethiazole is also used to treat AWS.
      • Jesse S.
      • Brathen G.
      • Ferrara M.
      • Keindl M.
      • Ben-Menachem E.
      • Tanasescu R.
      • et al.
      Alcohol withdrawal syndrome: mechanisms, manifestations, and management.
      It should be noted that both benzodiazepines and clomethiazole carry a potential risk of abuse, and it has been documented that patients with AUD are at higher risk. Hence clinicians should avoid the use of those drugs beyond the 10–14 initial days of treatment. Other drugs, such as baclofen and sodium oxybate, have been tested in the treatment of AWS. The additional value of these drugs is that they are also indicated for relapse prevention.
      • Caputo F.
      • Bernardi M.
      Medications acting on the GABA system in the treatment of alcoholic patients.
      Their strengths and limitations are discussed below.

      Medical management of alcohol use disorder in patients with ALD

      Alcohol abstinence represents a critical goal in patients with ALD since abstinence improves clinical outcomes at all stages of ALD. In the past, disulfiram was the only drug available for AUD. Disulfiram represents an effective alcohol pharmacotherapy;
      • Krampe H.
      • Ehrenreich H.
      Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment.
      however, disulfiram should be avoided in patients with severe ALD because of possible hepatotoxicity.
      • Forns X.
      • Caballeria J.
      • Bruguera M.
      • Salmeron J.M.
      • Vilella A.
      • Mas A.
      • et al.
      Disulfiram-induced hepatitis. Report of four cases and review of the literature.
      More recently, the growing understanding of the neurobiology of AUD has led to the development of effective pharmacologic agents that can complement psychosocial treatments, in particular naltrexone,
      • Anton R.F.
      Naltrexone for the management of alcohol dependence.
      nalmefene
      • van den Brink W.
      • Aubin H.J.
      • Bladstrom A.
      • Torup L.
      • Gual A.
      • Mann K.
      Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies.
      and acamprosate.
      • Kiefer F.
      • Mann K.
      Acamprosate: how, where, and for whom does it work? Mechanism of action, treatment targets, and individualized therapy.
      All those drugs are approved to treat AUD, however, disulfiram, naltrexone and acamprosate are approved for abstinence, while nalmefene is approved for the reduction of heavy drinking. It should be noted that these drugs have not been tested in patients with ALD cirrhosis. The opioid antagonist naltrexone has been intensively evaluated, especially the oral formulation.
      • Anton R.F.
      • O'Malley S.S.
      • Ciraulo D.A.
      • Cisler R.A.
      • Couper D.
      • Donovan D.M.
      • et al.
      Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial.
      A large trial also showed the efficacy of an intramuscular formulation of naltrexone in alcoholism,
      • Garbutt J.C.
      • Kranzler H.R.
      • O'Malley S.S.
      • Gastfriend D.R.
      • Pettinati H.M.
      • Silverman B.L.
      • et al.
      Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial.
      but has not been replicated. Given the potential for hepatotoxicity, naltrexone has not been tested in patients with ALD, and its use in this population is not currently recommended. Nalmefene, a different opioid modulator has been approved in Europe for the treatment of AUD with an aim of reducing the amounts drunk. While patients with ALD should not primarily have a reduction goal, nalmefene could be considered in those patients with early stages of liver disease where abstinence proves not to be feasible. Acamprosate is a modulator of the glutamatergic receptor system and a meta-analysis of 24 randomised controlled trials confirmed its efficacy as an alcohol pharmacotherapy.
      • Rosner S.
      • Hackl-Herrwerth A.
      • Leucht S.
      • Lehert P.
      • Vecchi S.
      • Soyka M.
      Acamprosate for alcohol dependence.
      Sodium Oxibate (gamma-hydroxybutyric acid) is approved in some European countries (Italy and Austria) to treat AUD,
      • Addolorato G.
      • Leggio L.
      • Ferrulli A.
      • Caputo F.
      • Gasbarrini A.
      The therapeutic potential of gamma-hydroxybutyric acid for alcohol dependence: balancing the risks and benefits. A focus on clinical data.
      and at the moment we write this guideline the EMA is about to take a final decision on the approval of this controversial drug at a European level. Among other compounds, topiramate, and baclofen seem the most promising pharmacotherapies for alcoholism.
      • Heilig M.
      • Egli M.
      Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms.
      Topiramate is an anticonvulsant medication, which has demonstrated safety and efficacy in reducing heavy drinking.
      • Johnson B.A.
      • Rosenthal N.
      • Capece J.A.
      • Wiegand F.
      • Mao L.
      • Beyers K.
      • et al.
      Topiramate for treating alcohol dependence: a randomized controlled trial.
      There was also a decrease in liver enzyme levels in patients treated with topiramate;
      • Johnson B.A.
      • Rosenthal N.
      • Capece J.A.
      • Wiegand F.
      • Mao L.
      • Beyers K.
      • et al.
      Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial.
      however, topiramate has not been tested in patients with ALD. Some studies suggest that baclofen, a GABA-B receptor agonist, increases abstinence rate and prevents relapse in alcohol-dependent patients.
      • Addolorato G.
      • Leggio L.
      Safety and efficacy of baclofen in the treatment of alcohol-dependent patients.
      Moreover, to date, baclofen represents the only alcohol pharmacotherapy tested in patients with AUD, with significant liver disease. A clinical trial demonstrated the safety and efficacy of baclofen in promoting alcohol abstinence in patients with ALD and cirrhosis,
      • Addolorato G.
      • Leggio L.
      • Ferrulli A.
      • Cardone S.
      • Vonghia L.
      • Mirijello A.
      • et al.
      Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study.
      but confirmatory studies in cirrhotic patients are warranted, since a recent trial in patients with hepatitis C virus (HCV) did not show any superiority of 30 mg of baclofen over placebo.
      • Hauser P.
      • Fuller B.
      • Ho S.B.
      • Thuras P.
      • Kern S.
      • Dieperink E.
      The safety and efficacy of baclofen to reduce alcohol use in veterans with chronic hepatitis C: a randomized controlled trial.
      Studies with high doses of baclofen have provided controversial results
      • Muller C.A.
      • Geisel O.
      • Pelz P.
      • Higl V.
      • Kruger J.
      • Stickel A.
      • et al.
      High-dose baclofen for the treatment of alcohol dependence (BACLAD study): a randomized, placebo-controlled trial.
      • Beraha E.M.
      • Salemink E.
      • Goudriaan A.E.
      • Bakker A.
      • de Jong D.
      • Smits N.
      • et al.
      Efficacy and safety of high-dose baclofen for the treatment of alcohol dependence: A multicentre, randomised, double-blind controlled trial.
      and the largest study to date
      • Reynaud M.
      • Aubin H.J.
      • Trinquet F.
      • Zakine B.
      • Dano C.
      • Dematteis M.
      • et al.
      A randomized, placebo-controlled study of high-dose baclofen in alcohol-dependent patients-the ALPADIR study.
      did not show any superiority of baclofen against placebo. The French ANSM (Agence nationale de sécurité du medicament) has issued a temporary recommendation for the use of baclofen (not exceeding 80 mg/day) for the treatment of AUD.

      ANSM. Réduction de la dose maximale de baclofène à 80mg par jour dans le cadre de la Recommandation Temporaire d’Utilisation (RTU) - Communiqué. 2017; http://ansm.sante.fr/S-informer/Communiques-Communiques-Points-presse/Reduction-de-la-dose-maximale-de-baclofene-a-80mg-par-jour-dans-le-cadre-de-la-Recommandation-Temporaire-d-Utilisation-RTU-Communique, 2018.

      Even though many other compounds have been tested for relapse prevention (i.e., gabapentin, ondansetron, etc.), no consistent results in large samples have been reported. In summary, all pharmacological treatments for AUD show modest results, and they cannot replace the non-pharmacological management of the addictive process, which is recognised by health authorities as the most relevant element of treatment.

      EMA. Guideline on the development of medicinal products for the treatment of alcohol dependence. European Medicines Agency 2010. 2010.

      FDA. Alcoholism: Developing drugs for treatment, Guidance for industry, draft guidance. European Medicines Agency 2015. 2015.

      In fact, this simply implies to add brief intervention techniques to the usual clinical management of patients with ALD.

      The effect of brief interventions

      There is a large body of evidence on the efficacy
      • Jonas D.E.
      • Garbutt J.C.
      • Amick H.R.
      • Brown J.M.
      • Brownley K.A.
      • Council C.L.
      • et al.
      Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.
      and effectiveness
      • O'Donnell A.
      • Anderson P.
      • Newbury-Birch D.
      • Schulte B.
      • Schmidt C.
      • Reimer J.
      • et al.
      The impact of brief alcohol interventions in primary healthcare: a systematic review of reviews.
      of brief interventions to reduce alcohol consumption in primary health care settings. A Cochrane review showed that brief interventions can reduce drinking by an average of 57 g per week in men.
      • Kaner E.F.
      • Dickinson H.O.
      • Beyer F.
      • Pienaar E.
      • Schlesinger C.
      • Campbell F.
      • et al.
      The effectiveness of brief alcohol interventions in primary care settings: a systematic review.
      Evidence is less conclusive in women and populations under 16 years of age. Its success depends largely on the presentation of objective feedback based on information provided by the physician and customised to the patients’ readiness to change (awareness of the risks linked to the existing drinking pattern and willingness to change that pattern). The technique attempts to increase a patient’s awareness of the problems caused, consequences experienced, and risks faced as a result of patterns of alcohol consumption. A brief intervention should at least have the components defined in the five As’ model:
      • Ask about use,
      • Advice to quit or reduce,
      • Assess willingness,
      • Assist to quit or reduce,
      • Arrange follow-up.
      When a motivational component is added to brief interventions its efficacy improves.
      • Vasilaki E.I.
      • Hosier S.G.
      • Cox W.M.
      The efficacy of motivational interviewing as a brief intervention for excessive drinking: a meta-analytic review.
      Motivational interviewing is a technique which aims to be both non-judgmental and non-confrontational.

      Miller W RS. Motivational Interviewing: Helping People Change. 3rd edition ed: Guilford Press; 2012.

      Essential components of a motivational approach are an empathic attitude and a collaborative approach that respects the patients’ autonomy and encourages them to find ways to reach the goals agreed. An example of brief intervention can be found at https://www.youtube.com/watch?v=KRu5uMwSkQg.

      Suggestions for future research

      • Further trials of pharmacotherapy in patients with advanced ALD are urgently required
      • Studies to demonstrate the efficacy of a multidisciplinary team intervention
      • The term alcohol use disorder (defined by DSM-V criteria) should be used in preference to alcoholic, alcohol abuse, alcohol dependence or risky drinker (Grade A)
      • AUDIT or AUDIT-C should be used to screen patients for AUD and dependence (Grade A1)
      • Patients with AUD should be screened for concurrent psychiatric disorders and other addictions. (Grade A1)
      • 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 (Grade A1)
      • Gastroenterology/Hepatology centres should have access to services to provide effective psychosocial therapies (Grade A)
      • Pharmacotherapy should be considered in patients with AUD and ALD (Grade A1)

      Diagnostic tests in the management of ALD

      Screening and clinical diagnosis of ALD

      Diagnosis of ALD is usually suspected upon documentation of regular alcohol consumption of >20 g/d in females and >30 g/d in males together with the presence of clinical and/or biological abnormalities suggestive of liver injury. As a high proportion of patients with histological features of ALD do not express any clinical symptoms or laboratory abnormalities, asymptomatic patients consuming a critical amount of alcohol should undergo appropriate screening investigations.
      • Askgaard G.
      • Leon D.A.
      • Kjaer M.S.
      • Deleuran T.
      • Gerds T.A.
      • Tolstrup J.S.
      Risk for alcoholic liver cirrhosis after an initial hospital contact with alcohol problems: A nationwide prospective cohort study.
      As previously mentioned, screening should be done in high-risk populations, such as those in alcohol rehabilitations clinics, or the harmful drinkers identified by their GP. Furthermore, ALD should be considered in patients presenting with extrahepatic manifestations of AUD, such as symmetric peripheral neuropathy, pancreatitis, cardiomyopathy and others.
      • Torruellas C.
      • French S.W.
      • Medici V.
      Diagnosis of alcoholic liver disease.
      A non-invasive model, the ALD/non-alcoholic fatty liver disease (NAFLD) index based on four parameters, mean corpuscular volume (MCV), aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio, body mass index, and gender was proposed for the differential diagnosis of ALD with NAFLD.
      • Dunn W.
      • Angulo P.
      • Sanderson S.
      • Jamil L.H.
      • Stadheim L.
      • Rosen C.
      • et al.
      Utility of a new model to diagnose an alcohol basis for steatohepatitis.
      Screening investigations should not only include liver function tests (LFTs), i.e. gamma glutamyl transpeptidase (GGT), serum ALT and serum AST, but also performance of a test to detect liver fibrosis (e.g. TE) since advanced liver fibrosis may present with normal LFTs. In case of any abnormalities an ultrasound should follow. To exclude alternative or additional causes of liver injury further laboratory work-up, including hepatitis B virus (HBV) and HCV serology, autoimmune markers, transferrin and transferrin saturation, α1-antitrypsin and in some cases also caeruloplasmin may be considered
      Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation from the NIAAA alcoholic hepatitis consortia.
      In case of suspected advanced fibrosis or cirrhosis, serum albumin, prothrombin time or international normalized ratio (INR), serum bilirubin levels, as well as platelet and white blood cell counts should be determined in order to evaluate liver function and evidence of portal hypertension. Whenever there is evidence of cirrhosis, upper gastrointestinal endoscopy should be performed to screen for oesophageal varices, unless there is a low risk of having varices requiring treatment based on Baveno criteria (platelets >150,000) and Fibroscan <20.
      • de Franchis R.
      • Baveno V.I.F.
      Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension.
      During follow-up clinical, laboratory and ultrasound surveillance is indicated for all patients with cirrhosis.

      Liver biopsy

      Indication and performance of a liver biopsy

      A liver biopsy may be used to establish the definite diagnosis of ALD, to assess the exact stage and prognosis of liver disease and to exclude alternative or additional causes of liver injury.
      • Crabb D.W.
      • Bataller R.
      • Chalasani N.P.
      • Kamath P.S.
      • Lucey M.
      • Mathurin P.
      • et al.
      Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation From the NIAAA alcoholic hepatitis consortia.
      • Altamirano J.
      • Miquel R.
      • Katoonizadeh A.
      • Abraldes J.G.
      • Duarte-Rojo A.
      • Louvet A.
      • et al.
      A histologic scoring system for prognosis of patients with alcoholic hepatitis.
      Approximately 20% of patients with a history of AUD and abnormal LFTs were found to have a co-existing aetiology of their liver disease.
      • Levin D.M.
      • Baker A.L.
      • Riddell R.H.
      • Rochman H.
      • Boyer J.L.
      Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Boursier J.
      • Kim D.J.
      • O'Grady J.
      • et al.
      Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis.
      For this reason, performance of a liver biopsy is recommended within phase II clinical trials, and should be considered in larger scale phase III clinical trials, in case of inconclusive non-invasive test results or in case of any suspicion of a competing liver disease.
      Usually the liver biopsy is done percutaneously under ultrasound guidance. Alternatively, it can be performed laparascopically or via a transjugular approach. The latter is specifically recommended in patients with a low platelet count and/or a prolonged prothrombin time. However, a liver biopsy is an invasive procedure with significant morbidity. Severe complications, such as intrahepatic bleeding, pneumothorax and others occur in approximately 2% of patients.
      • Filingeri V.
      • Francioso S.
      • Sforza D.
      • Santopaolo F.
      • Oddi F.M.
      • Tisone G.
      A retrospective analysis of 1.011 percutaneous liver biopsies performed in patients with liver transplantation or liver disease: ultrasonography can reduce complications?.
      Therefore, a biopsy is not generally recommended for all patients with suspected ALD, but the risks should be carefully weighed against the clinical benefits and therapeutic consequences.

      Histological features and diagnosis of ALD types

      The morphological spectrum of ALD encompasses four groups of elementary lesions which in the pre-cirrhotic stage predominate in the central regions of the hepatic lobuli: (a) macrovesicular steatosis, eventually a variable blend of macro and micro-vesicles (mixed type steatosis); (b) hepatocellular injury with ballooning, potentially necrosis; (c) lobular inflammation; (d) fibrosis or cirrhosis.
      • MacSween R.N.
      • Burt A.D.
      Histologic spectrum of alcoholic liver disease.
      In a given individual, a single lesion or any combination thereof may be found.
      • Lefkowitch J.H.
      Morphology of alcoholic liver disease.
      The main histological diagnoses in ALD include steatosis, alcoholic steatohepatitis (ASH), fibrosis/cirrhosis, and HCC.
      Alcoholic liver disease: morphological manifestations. Review by an international group.
      The prevalence of histological lesions among drinkers is not well known.
      • Naveau S.
      • Gaude G.
      • Asnacios A.
      • Agostini H.
      • Abella A.
      • Barri-Ova N.
      • et al.
      Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease.
      The types of ALD differ with respect to prognosis. About 90% of heavy drinkers have hepatocellular steatosis.
      • Bataller R.
      • Gao B.
      Liver fibrosis in alcoholic liver disease.
      Whether alcoholic steatosis is a benign condition or can progress is a matter of debate. Some studies suggest cirrhosis may occur after a median of 10.5 years in 10% of patients with histological steatosis without ASH or fibrosis. The mixed steatosis pattern has also been found associated with higher risk of progression.
      • Teli M.R.
      • Day C.P.
      • Burt A.D.
      • Bennett M.K.
      • James O.F.
      Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.
      Alcoholic steatohepatitis is considered a progressive lesion, which increases the risk of cirrhosis and HCC. The principal morphological features of ASH include steatosis, hepatocellular ballooning, necrosis, and lobular inflammation often predominated by neutrophil polymorphs. However, steatosis may be present in less than 5% of the parenchyma, or even absent in cases with severe ASH, after periods of abstinence, or in cirrhosis despite ongoing alcohol abuse.
      Alcoholic liver disease: morphological manifestations. Review by an international group.
      • Yip W.W.
      • Burt A.D.
      Alcoholic liver disease.

      Brunt EM N-TB, Burt AD. Fatty liver disease: alcoholic and non-alcoholic. In: Burt AD PB, Ferrel L, ed. MacSween’s Pathology of the Liver. Edinbourgh: Churchill Livingstone 2012:293–359.

      • Sakhuja P.
      Pathology of alcoholic liver disease, can it be differentiated from nonalcoholic steatohepatitis?.
      Ballooning is an ill-defined morphological term designating swelling, rounding and pale staining of the cytoplasm. Ballooned hepatocytes are characterised by a loss of cytoplasmic staining of keratin 8 and 18 (K8/18, constituents of the intermediate filament cytoskeleton)
      • Lackner C.
      • Gogg-Kamerer M.
      • Zatloukal K.
      • Stumptner C.
      • Brunt E.M.
      • Denk H.
      Ballooned hepatocytes in steatohepatitis: the value of keratin immunohistochemistry for diagnosis.
      and expression of sonic hedgehog
      • Rangwala F.
      • Guy C.D.
      • Lu J.
      • Suzuki A.
      • Burchette J.L.
      • Abdelmalek M.F.
      • et al.
      Increased production of sonic hedgehog by ballooned hepatocytes.
      on immunohistochemistry. Ballooned cells often contain large Mallory-Denk bodies (MDBs) composed mainly of K8/18 and few other proteins.
      • Zatloukal K.
      • French S.W.
      • Stumptner C.
      • Strnad P.
      • Harada M.
      • Toivola D.M.
      • et al.
      From Mallory to Mallory-Denk bodies: what, how and why?.
      Cholestasis can be observed in severe ASH in pre-cirrhotic or cirrhotic stage.
      Alcoholic liver disease: morphological manifestations. Review by an international group.
      In most patients, fibrosis is a central-based parenchymal feature. However, a portal-based fibrosis pattern has also been reported.
      • Colombat M.
      • Charlotte F.
      • Ratziu V.
      • Poynard T.
      Portal lymphocytic infiltrate in alcoholic liver disease.
      Inflammatory and fibrotic changes can involve hepatic veins (phlebosclerosis), and terminal hepatic venules and adjacent parenchyma (perivenular fibrosis), a severe form of which is referred to as sclerosing hyaline necrosis.
      • Edmondson H.A.
      • Peters R.L.
      • Reynolds T.B.
      • Kuzma O.T.
      Sclerosing hyaline necrosis of the liver in the chronic alcoholic. A recognizable clinical syndrome.
      With disease progression pericellular fibrosis extends, often in a septal fashion and paves the way for cirrhosis
      • Galambos J.T.
      Natural history of alcoholic hepatitis. 3. Histological changes.
      • Sorensen T.I.
      • Orholm M.
      • Bentsen K.D.
      • Hoybye G.
      • Eghoje K.
      • Christoffersen P.
      Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis.
      • Marbet U.A.
      • Bianchi L.
      • Meury U.
      • Stalder G.A.
      Long-term histological evaluation of the natural history and prognostic factors of alcoholic liver disease.
      • Pares A.
      • Caballeria J.
      • Bruguera M.
      • Torres M.
      • Rodes J.
      Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage.
      • Mathurin P.
      • Beuzin F.
      • Louvet A.
      • Carrie-Ganne N.
      • Balian A.
      • Trinchet J.C.
      • et al.
      Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features.
      which is typically micrododular, but is occasionally mixed micro- and macronodular. Particularly in cases of ongoing drinking, the parenchyma is dissected by severe pericellular fibrosis and nodules may be poorly defined.
      • Yip W.W.
      • Burt A.D.
      Alcoholic liver disease.

      Can ASH be distinguished histologically from non-alcoholic steatohepatitis?

      The morphological lesions of ALD and metabolic syndrome-associated NAFLD show broad overlap. Hepatocellular injury and fibrosis are often more severe in ALD. In an individual patient it may be impossible to decide on morphological grounds alone if liver disease is alcohol-related or not.
      • Lefkowitch J.H.
      Morphology of alcoholic liver disease.
      • Tiniakos D.G.
      Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients.
      • Popper H.
      • Thung S.N.
      • Gerber M.A.
      Pathology of alcoholic liver diseases.
      However, some of the lesions of ALD, e.g., 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, and cholestasis are very rare or have not been described in patients with pure NAFLD.
      • Dunn W.
      • Angulo P.
      • Sanderson S.
      • Jamil L.H.
      • Stadheim L.
      • Rosen C.
      • et al.
      Utility of a new model to diagnose an alcohol basis for steatohepatitis.
      • Tiniakos D.G.
      Liver biopsy in alcoholic and non-alcoholic steatohepatitis patients.
      • Brunt E.M.
      Nonalcoholic steatohepatitis: pathologic features and differential diagnosis.

      Histology in alcoholic hepatitis

      The concordance of clinical alcoholic hepatitis (AH) and ASH is not optimal. In 10–20% of patients liver biopsy does not confirm the clinically suspected diagnosis of AH.
      • Kryger P.
      • Schlichting P.
      • Dietrichson O.
      • Juhl E.
      The accuracy of the clinical diagnosis in acute hepatitis and alcoholic liver disease. Clinical versus morphological diagnosis.
      • Ramond M.J.
      • Poynard T.
      • Rueff B.
      • Mathurin P.
      • Theodore C.
      • Chaput J.C.
      • et al.
      A randomized trial of prednisolone in patients with severe alcoholic hepatitis.
      Furthermore, liver disease not related to alcohol, but requiring appropriate therapy, can be present in 10–20% of cases.
      • Levin D.M.
      • Baker A.L.
      • Riddell R.H.
      • Rochman H.
      • Boyer J.L.
      Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption.
      • Bissonnette J.
      • Altamirano J.
      • Devue C.
      • Roux O.
      • Payance A.
      • Lebrec D.
      • et al.
      A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis.
      Histological evaluation also aids in the diagnosis and assessment of liver injury in comorbid conditions.
      • Graziadei I.W.
      • Joseph J.J.
      • Wiesner R.H.
      • Therneau T.M.
      • Batts K.P.
      • Porayko M.K.
      Increased risk of chronic liver failure in adults with heterozygous alpha1-antitrypsin deficiency.
      • Mueller S.
      • Rausch V.
      The role of iron in alcohol-mediated hepatocarcinogenesis.
      • Neuman M.G.
      • Malnick S.
      • Maor Y.
      • Nanau R.M.
      • Melzer E.
      • Ferenci P.
      • et al.
      Alcoholic liver disease: Clinical and translational research.
      • Iida-Ueno A.
      • Enomoto M.
      • Tamori A.
      • Kawada N.
      Hepatitis B virus infection and alcohol consumption.
      • Novo-Veleiro I.
      • Alvela-Suarez L.
      • Chamorro A.J.
      • Gonzalez-Sarmiento R.
      • Laso F.J.
      • Marcos M.
      Alcoholic liver disease and hepatitis C virus infection.

      Prognostic utility of histology

      Ballooning, MDBs, lobular polymorphs, canalicular and/or ductular cholestasis, fibrosis and megamitochondria have been described as independent predictors of short-term outcome in patients with AH. In addition, visible bile in canaliculi and/or ductular reaction also predicted bacterial infection and sepsis.
      • Altamirano J.
      • Miquel R.
      • Katoonizadeh A.
      • Abraldes J.G.
      • Duarte-Rojo A.
      • Louvet A.
      • et al.
      A histologic scoring system for prognosis of patients with alcoholic hepatitis.
      • Katoonizadeh A.
      • Laleman W.
      • Verslype C.
      • Wilmer A.
      • Maleux G.
      • Roskams T.
      • et al.
      Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study.
      • Spahr L.
      • Rubbia-Brandt L.
      • Genevay M.
      • Hadengue A.
      • Giostra E.
      Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis.
      • Mookerjee R.P.
      • Lackner C.
      • Stauber R.
      • Stadlbauer V.
      • Deheragoda M.
      • Aigelsreiter A.
      • et al.
      The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
      Lobular neutrophils,
      • Mathurin P.
      • Duchatelle V.
      • Ramond M.J.
      • Degott C.
      • Bedossa P.
      • Erlinger S.
      • et al.
      Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone.
      low grade steatosis
      • Duvoux C.
      • Radier C.
      • Roudot-Thoraval F.
      • Maille F.
      • Anglade M.C.
      • Van Nhieu J.T.
      • et al.
      Low-grade steatosis and major changes in portal flow as new prognostic factors in steroid-treated alcoholic hepatitis.
      and ductular reaction
      • Dubuquoy L.
      • Louvet A.
      • Lassailly G.
      • Truant S.
      • Boleslawski E.
      • Artru F.
      • et al.
      Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis.
      may be useful to predict treatment response to corticosteroids. ASH, MDBs and cirrhosis
      • Pessione F.
      • Ramond M.J.
      • Peters L.
      • Pham B.N.
      • Batel P.
      • Rueff B.
      • et al.
      Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.
      • Cortez-Pinto H.
      • Baptista A.
      • Camilo M.E.
      • De Moura M.C.
      Nonalcoholic steatohepatitis–a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and hospitalized patients.
      have been identified as predictors of long-term survival. Recently, advanced fibrosis, but not clinical or biochemical factors, was found as the only independent predictor of long-term outcome in patients with compensated ALD.
      • Lackner C.
      • Spindelboeck W.
      • Haybaeck J.
      • Douschan P.
      • Rainer F.
      • Terracciano L.
      • et al.
      Histological parameters and alcohol abstinence determine long-term prognosis in patients with alcoholic liver disease.

      Grading and staging of ALD

      Formal grading and staging systems for ALD are few.
      • Yip W.W.
      • Burt A.D.
      Alcoholic liver disease.
      Based on the wide morphological overlap, some authors proposed that NAFLD grading systems may also be used for ALD,
      • Lefkowitch J.H.
      Morphology of alcoholic liver disease.
      • Tannapfel A.
      • Denk H.
      • Dienes H.P.
      • Langner C.
      • Schirmacher P.
      • Trauner M.
      • et al.
      Histopathological diagnosis of non-alcoholic and alcoholic fatty liver disease. Grade 2 consensus-based guidelines.
      but this concept can be challenged by the fact that several prognostic factors, like histological cholestasis, MDBs and megamitochondria are not considered in NAFLD grading. Recently the Alcoholic Hepatitis Histologic Score based on prognostic histological features of ASH was developed for prediction of 90-day mortality for patients with AH and ASH.
      • Altamirano J.
      • Miquel R.
      • Katoonizadeh A.
      • Abraldes J.G.
      • Duarte-Rojo A.
      • Louvet A.
      • et al.
      A histologic scoring system for prognosis of patients with alcoholic hepatitis.

      Non-invasive test in ALD

      Non-invasive markers of AH

      The risk of obtaining a liver biopsy in patients with clinically suspected AH is well recognised and has fostered efforts to develop non-invasive tests. Recently serum levels of caspase-cleaved keratin 18 (K18) epitopes M30 and M65 assessed by ELISA in a large cohort of patients with ALD were found to predict the histological diagnosis of AH with modest diagnostic accuracy (AUROCs 0.776 and 0.784, respectively). Furthermore high serum levels of these markers were also predictive of non-HCC liver-related mortality in patients with alcoholic cirrhosis.
      • Mueller S.
      • Nahon P.
      • Rausch V.
      • Peccerella T.
      • Silva I.
      • Yagmur E.
      • et al.
      Caspase-cleaved keratin-18 fragments increase during alcohol withdrawal and predict liver-related death in patients with alcoholic liver disease.
      A comparable result was reported by an independent group [2].
      • Bissonnette J.
      • Altamirano J.
      • Devue C.
      • Roux O.
      • Payance A.
      • Lebrec D.
      • et al.
      A prospective study of the utility of plasma biomarkers to diagnose alcoholic hepatitis.
      In this study, with the definition of two cut-offs, classification of approximately two-thirds of patients with clinically suspected AH was achieved. However, the interpretation of K18 fragment serum levels has to consider the clinical setting, since M30 and M65 levels may also increase during phases of abstinence.
      • Mueller S.
      • Nahon P.
      • Rausch V.
      • Peccerella T.
      • Silva I.
      • Yagmur E.
      • et al.
      Caspase-cleaved keratin-18 fragments increase during alcohol withdrawal and predict liver-related death in patients with alcoholic liver disease.
      At present K18 fragments cannot be recommended in clinical practice.

      Non-invasive tests to estimate liver fibrosis

      Serum markers that have been evaluated for non-invasive assessment of stage in ALD may be classified as indirect or direct fibrosis tests.
      • Lombardi R.
      • Buzzetti E.
      • Roccarina D.
      • Tsochatzis E.A.
      Non-invasive assessment of liver fibrosis in patients with alcoholic liver disease.
      In contrast to direct tests, indirect fibrosis tests are routine clinical and biochemical parameters not regarded as surrogate markers of extracellular matrix turn over. Both types of tests, either singly or in combination, have been shown to exhibit good accuracy for distinguishing mild from severe fibrosis, but are less well suited to classify intermediate fibrosis stages and are not helpful in the early diagnosis of ALD.
      • Stickel F.
      • Datz C.
      • Hampe J.
      • Bataller R.
      Pathophysiology and management of alcoholic liver disease: update 2016.
      (Table 4).
      Table 4Diagnostic performance of some non-invasive serum fibrosis tests for diagnosis of cirrhosis in patients with ALD in studies.
      TestCut-offPrevalence of F4 (%)AUROC (95% CI)PPV (%)NPV (%)Reference
      Hyaluronic acid250 μg/L0.783598
      • Stickel F.
      • Poeschl G.
      • Schuppan D.
      • Conradt C.
      • Strenge-Hesse A.
      • Fuchs F.S.
      • et al.
      Serum hyaluronate correlates with histological progression in alcoholic liver disease.
      PGAA index
      PGAA index: combines α2alpha-2-macroglobulin, prothrombin time, serum GGT, serum apolipoprotein A1.
      10270.87 (0.79–0.92)7292
      • Naveau S.
      • Essoh B.M.
      • Ghinoiu M.
      • Marthey L.
      • Njike-Nakseu M.
      • Balian A.
      • et al.
      Comparison of Fibrotest and PGAA for the diagnosis of fibrosis stage in patients with alcoholic liver disease.
      FibroTest≥0.70310.94 (0.90–0.96)73.493.5
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Naveau S.
      • Gaude G.
      • Asnacios A.
      • Agostini H.
      • Abella A.
      • Barri-Ova N.
      • et al.
      Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease.
      ≥0.75150.88 (0.79–0.93)43.992.8
      Enhanced liver fibrosis (ELF) test
      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.
      ≥10.5230.92 (0.89–0.96)7194
      • Thiele M.
      • Madsen B.S.
      • Hansen J.F.
      • Detlefsen S.
      • Antonsen S.
      • Krag A.
      • et al.
      Accuracy of the enhanced liver fibrosis test vs fibrotest, elastography and indirect markers in detection of advanced fibrosis in patients with alcoholic liver disease.
      Fibrometer≥0.5310.94 (0.90–0.97)53.798.9
      • Naveau S.
      • Gaude G.
      • Asnacios A.
      • Agostini H.
      • Abella A.
      • Barri-Ova N.
      • et al.
      Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease.
      FIB-4<1.45310.80 (0.72–0.86)n.a.n.a.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Naveau S.
      • Gaude G.
      • Asnacios A.
      • Agostini H.
      • Abella A.
      • Barri-Ova N.
      • et al.
      Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease.
      <1.45150.80 (0.71–0.87)n.a.n.a.
      ALD, alcoholic liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operating characteristic curve; CDT, carbohydrate deficient transferrin; EtG, ethyl glucuronide EtOH, ethanol; GGT, γ-glutamyl transpeptidase; n.a., not available; NPV, negative predictive value; PPV, positive predictive value; UTI, urinary tract infection.
      * 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.
      Liver stiffness measurement (LSM) by TE has been demonstrated to be a useful tool for assessing hepatic fibrosis in patients with ALD.
      • Mueller S.
      • Millonig G.
      • Sarovska L.
      • Friedrich S.
      • Reimann F.M.
      • Pritsch M.
      • et al.
      Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
      • Nahon P.
      • Kettaneh A.
      • Tengher-Barna I.
      • Ziol M.
      • de Ledinghen V.
      • Douvin C.
      • et al.
      Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease.
      • Nguyen-Khac E.
      • Chatelain D.
      • Tramier B.
      • Decrombecque C.
      • Robert B.
      • Joly J.P.
      • et al.
      Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests.
      • Nguyen-Khac E.
      • Saint-Leger P.
      • Tramier B.
      • Coevoet H.
      • Capron D.
      • Dupas J.L.
      Noninvasive diagnosis of large esophageal varices by Fibroscan: strong influence of the cirrhosis etiology.
      • Janssens F.
      • de Suray N.
      • Piessevaux H.
      • Horsmans Y.
      • de Timary P.
      • Starkel P.
      Can transient elastography replace liver histology for determination of advanced fibrosis in alcoholic patients: a real-life study.
      • Foucher J.R.
      • Otzenberger H.
      • Gounot D.
      The BOLD response and the gamma oscillations respond differently than evoked potentials: an interleaved EEG-fMRI study.
      In patients with ALD, liver stiffness correlates with the degree of fibrosis. In the studies that did not consider the presence of AH as a potential confounding factor, the cut-off values for F3 and F4 fibrosis were considerably higher than in patients with viral hepatitis. Several studies have shown that patients with alcoholic cirrhosis had significantly higher values of liver stiffness than patients with viral cirrhosis, presumably because of the higher degree of fibrosis in ALD.
      • Michalak S.
      • Rousselet M.C.
      • Bedossa P.
      • Pilette C.
      • Chappard D.
      • Oberti F.
      • et al.
      Respective roles of porto-septal fibrosis and centrilobular fibrosis in alcoholic liver disease.
      A recent study indicated that AH markedly increases LSM in patients with ALD independent of fibrosis stage.
      • Mueller S.
      • Millonig G.
      • Sarovska L.
      • Friedrich S.
      • Reimann F.M.
      • Pritsch M.
      • et al.
      Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
      • Mueller S.
      • Sandrin L.
      Liver stiffness: a novel parameter for the diagnosis of liver disease.
      Therefore, elevated liver stiffness values in patients with ALD and AST serum levels >100 U/L should be interpreted with caution, because of the possibility of falsely elevated liver stiffness as a result of superimposed AH.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Mueller S.
      • Millonig G.
      • Sarovska L.
      • Friedrich S.
      • Reimann F.M.
      • Pritsch M.
      • et al.
      Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
      Furthermore, inflammation, cholestasis or liver congestion may interfere with LSM, independently of fibrosis.
      • Castera L.
      • Pinzani M.
      Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango?.
      In addition, alcohol consumption may also be a modifying factor as shown by the decrease of liver stiffness in abstainers and the increase in relapsers.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Mueller S.
      • Millonig G.
      • Sarovska L.
      • Friedrich S.
      • Reimann F.M.
      • Pritsch M.
      • et al.
      Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis.
      • Gelsi E.
      • Dainese R.
      • Truchi R.
      • Marine-Barjoan E.
      • Anty R.
      • Autuori M.
      • et al.
      Effect of detoxification on liver stiffness assessed by Fibroscan(R) in alcoholic patients.
      In a recent prospective, cross sectional, biopsy-controlled, single centre study featuring 199 patients with ALD, LSM by TE and 2-dimensional shear wave elastography were shown to be equally suited to rule out rather than rule in advanced fibrosis and cirrhosis. At the defined cut-offs, negative predictive values were above 90% for both techniques.
      • Thiele M.
      • Detlefsen S.
      • Sevelsted Moller L.
      • Madsen B.S.
      • Fuglsang Hansen J.
      • Fialla A.D.
      • et al.
      Transient and 2-dimensional shear-wave elastography provide comparable assessment of alcoholic liver fibrosis and cirrhosis.
      In another prospective multicentre study, the diagnostic utility of serum markers, FibroTest, PGAA index, APRI (AST to platelet ratio index), FIB-4 (Fibrosis-4) and FORNS index or combinations thereof (i.e., TE-FibroTest and TE-PGAA) were compared with TE for the prediction of advanced fibrosis and cirrhosis. The AUROC for the prediction of cirrhosis by TE was slightly better than for prediction of advanced fibrosis, 0.93 and 0.90, respectively, and did not differ significantly from the diagnostic accuracy of any of the serum markers alone or the combinations of serum markers with TE. Based on TE values, an algorithm for management of patients with ALD was proposed that may help to reduce the need for biopsy.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      In a recent large prospective study performed in Danish primary and secondary healthcare centres the enhanced liver fibrosis test (ELF) determining the three direct markers HA, PIIINP and tissue inhibitor of metalloproteinase-1 (TIMP-1) was found to have the same high diagnostic accuracy (Table 4) for detecting advance fibrosis ≥F3 as the FibroTest. For patients in primary care, ELF values below 10.5 and FibroTest values below 0.58 had negative predictive values for advanced liver fibrosis of 98% and 94%, respectively.
      • Thiele M.
      • Madsen B.S.
      • Hansen J.F.
      • Detlefsen S.
      • Antonsen S.
      • Krag A.
      • et al.
      Accuracy of the enhanced liver fibrosis test vs fibrotest, elastography and indirect markers in detection of advanced fibrosis in patients with alcoholic liver disease.
      • Stickel F.
      • Poeschl G.
      • Schuppan D.
      • Conradt C.
      • Strenge-Hesse A.
      • Fuchs F.S.
      • et al.
      Serum hyaluronate correlates with histological progression in alcoholic liver disease.
      • Naveau S.
      • Essoh B.M.
      • Ghinoiu M.
      • Marthey L.
      • Njike-Nakseu M.
      • Balian A.
      • et al.
      Comparison of Fibrotest and PGAA for the diagnosis of fibrosis stage in patients with alcoholic liver disease.
      Another test based on radiological techniques is transient MR elastography (MRE). In NAFLD, MRE may have higher accuracy in the detection of advanced fibrosis than TE.
      • Younossi Z.M.
      • Loomba R.
      • Anstee Q.M.
      • Rinella M.E.
      • Bugianesi E.
      • Marchesini G.
      • et al.
      Diagnostic modalities for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) and associated fibrosis.
      Although the utility of this method has not been extensively evaluated in patients with ALD, it may also emerge as a useful tool for the non-invasive assessment of fibrosis in this setting, as these diseases share many parallels.
      • Singh S.
      • Muir A.J.
      • Dieterich D.T.
      • Falck-Ytter Y.T.
      American gastroenterological association institute technical review on the role of elastography in chronic liver diseases.

      Hepatic imaging techniques

      Imaging techniques such as ultrasonography, MRI, and CT may allow quantification of steatosis, help exclude other causes of chronic liver disease such as primary sclerosing cholangitis, and contribute to the assessment of advanced liver disease and its complications independently of the aetiology. However, imaging studies do not have a role in establishing alcohol as the specific aetiology of liver disease.
      Steatosis can be screened using ultrasonography, CT, and MRI.
      • Kramer H.
      • Pickhardt P.J.
      • Kliewer M.A.
      • Hernando D.
      • Chen G.H.
      • Zagzebski J.A.
      • et al.
      Accuracy of LIVER fat quantification with advanced CT, MRI, and ultrasound techniques: prospective comparison with MR spectroscopy.
      Among those methods, ultrasound probably has the lowest sensitivity and specificity, especially when steatosis is below a threshold of 20–30%. MRI and MR spectroscopy are reliable tools for assessing the amount of steatosis and can detect 5–10% of steatosis.
      • Maruzzelli L.
      • Parr A.J.
      • Miraglia R.
      • Tuzzolino F.
      • Luca A.
      Quantification of hepatic steatosis: a comparison of computed tomography and magnetic resonance indices in candidates for living liver donation.
      However, the standardisation of sequence characteristics isare not well established yet and most importantly their cost and availability are limiting. Controlled attenuation parameter (CAP), a novel, inexpensive ultrasound based elastography method was recently shown to represent a useful measure of hepatic steatosis. However, prevalence, aetiology of liver disease, diabetes, and BMI have to be considered in the correct interpretation of CAP results.
      • Karlas T.
      • Petroff D.
      • Sasso M.
      • Fan J.G.
      • Mi Y.Q.
      • de Ledinghen V.
      • et al.
      Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis.

      Tests for alcohol consumption

      Indirect marker for alcohol consumption

      As the measurement of GGT, ALT, AST and MCV is easy and inexpensive, they remain the most frequently used markers for early detection of ALD.
      • Seitz H.K.
      Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase.
      However, all these laboratory values are only indirect markers for ALD, with low sensitivity and specificity (Table 5).
      • Gough G.
      • Heathers L.
      • Puckett D.
      • Westerhold C.
      • Ren X.
      • Yu Z.
      • et al.
      The utility of commonly used laboratory tests to screen for excessive alcohol use in clinical practice.
      • Hock B.
      • Schwarz M.
      • Domke I.
      • Grunert V.P.
      • Wuertemberger M.
      • Schiemann U.
      • et al.
      Validity of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin.
      • Reynaud M.
      • Schellenberg F.
      • Loisequx-Meunier M.N.
      • Schwan R.
      • Maradeix B.
      • Planche F.
      • et al.
      Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV).
      • Staufer K.
      • Andresen H.
      • Vettorazzi E.
      • Tobias N.
      • Nashan B.
      • Sterneck M.
      Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.
      No single marker or combination of markers can differentiate between different causes of liver disease. GGT is usually higher in patients with ALD compared to those who have other liver diseases. However, serum GGT activity loses its specificity for alcohol in more advanced liver disease because its activity is elevated in patients with extensive fibrosis regardless of the cause.
      • Poynard T.
      • Aubert A.
      • Bedossa P.
      • Abella A.
      • Naveau S.
      • Paraf F.
      • et al.
      A simple biological index for detection of alcoholic liver disease in drinkers.
      Likewise, elevation of AST may be observed in all forms of ALD with a sensitivity of 50% and a specificity of around 80% (Table 5). AST levels are rarely above 300 U/ml, while serum ALT levels are commonly lower. Also the AST/ALT ratio which is typically greater than 1, is neither specific, nor sensitive, particularly in the cirrhotic stage of disease.
      • Hock B.
      • Schwarz M.
      • Domke I.
      • Grunert V.P.
      • Wuertemberger M.
      • Schiemann U.
      • et al.
      Validity of carbohydrate-deficient transferrin (%CDT), gamma-glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin.
      • Nyblom H.
      • Berggren U.
      • Balldin J.
      • Olsson R.
      High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking.
      Table 5Direct and indirect markers of alcohol consumption.
      BiomarkerBiological materialDetection windowEtOH amountSensitivitySpecificityConfounding factorsRef.
      Indirect alcohol markers
      GGTSerumChronic excessive42–86%40–84%Liver disease, BMI, sex, drugs
      • Torruellas C.
      • French S.W.
      • Medici V.
      Diagnosis of alcoholic liver disease.
      • Gough G.
      • Heathers L.
      • Puckett D.
      • Westerhold C.
      • Ren X.
      • Yu Z.
      • et al.
      The utility of commonly used laboratory tests to screen for excessive alcohol use in clinical practice.
      • Reynaud M.
      • Schellenberg F.
      • Loisequx-Meunier M.N.
      • Schwan R.
      • Maradeix B.
      • Planche F.
      • et al.
      Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl transferase (GGT), and mean corpuscular volume (MCV).
      • Staufer K.
      • Andresen H.
      • Vettorazzi E.
      • Tobias N.
      • Nashan B.
      • Sterneck M.
      Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.
      • Wuyts B.
      • Delanghe J.R.
      • Kasvosve I.
      • Gordeuk V.R.
      • Gangaidzo I.T.
      • Gomo Z.A.
      Carbohydrate-deficient transferrin and chronic alcohol ingestion in subjects with transferrin CD-variants.
      ASTSerumChronic excessive43–68%56–95%Liver and muscle diseases, BMI, drugs
      ALTSerumChronic excessive30–50%51–92%Liver disease, BMI, drugs
      MCVSerumChronic excessive24–75%56–96%Vitamin B12, folic acid deficiency, haematological diseases
      %CDTSerum1–2 weeks50–80 g/d for >1–2 weeks25%–84%70%–98%Liver cirrhosis/disease, nicotin, transferrin level, weight, sex, pregnancy, rare genetic variations
      Direct alcohol markers
      Breath alcoholExhaled air4–12 h97%93%Alcohol-containing mouth wash
      • Jaffe D.H.
      • Siman-Tov M.
      • Gopher A.
      • Peleg K.
      Variability in the blood/breath alcohol ratio and implications for evidentiary purposes.
      EtOHSerum4–12 h
      EtGUrineUp to 80 h>5 g89%99%Increases results:
      • -
        Accidental contamination of food, mouth wash, alcohol free beer, etc. with alcohol
      • -
        UTI
      Incresed results:
      • -
        Urine dilution deliberately or by diuretics
      • -
        UTI
      • Staufer K.
      • Andresen H.
      • Vettorazzi E.
      • Tobias N.
      • Nashan B.
      • Sterneck M.
      Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.
      • Wurst F.M.
      • Wiesbeck G.A.
      • Metzger J.W.
      • Weinmann W.
      On sensitivity, specificity, and the influence of various parameters on ethyl glucuronide levels in urine–results from the WHO/ISBRA study.
      EtGHair≤6 mo>20–40 g/d for >3 months85–92%87–97%Increases results:
      • -
        Seriously impaired renal function
      • -
        EtG containing hair treatment
      Decreases results:
      • -
        Hair treatment: dying, perming, bleaching
      • Sterneck M.
      • Yegles M.
      • Rothkirch von G.
      • Staufer K.
      • Vettorazzi E.
      • Schulz K.H.
      • et al.
      Determination of ethyl glucuronide in hair improves evaluation of long-term alcohol abstention in liver transplant candidates.
      • Crunelle C.L.
      • Yegles M.
      • De Doncker M.
      • Dom G.
      • Cappelle D.
      • Maudens K.E.
      • et al.
      Influence of repeated permanent coloring and bleaching on ethyl glucuronide concentrations in hair from alcohol-dependent patients.
      • Fosen J.T.
      • Morini L.
      • Sempio C.
      • Ganss R.
      • Morland J.
      • Hoiseth G.
      Levels of hair ethyl glucuronide in patients with decreased kidney function: possibility of misclassification of social drinkers.
      • Stewart S.H.
      • Koch D.G.
      • Willner I.R.
      • Randall P.K.
      • Reuben A.
      Hair ethyl glucuronide is highly sensitive and specific for detecting moderate-to-heavy drinking in patients with liver disease.
      • Pragst F.
      Interpretation problems in a forensic case of abstinence determination using alcohol markers in hair.
      In addition, the indirect alcohol marker carbohydrate deficient transferrin (CDT) may be measured to confirm critical alcohol consumption in patients who are suspected to deny or underreport intake. However, CDT can only indicate heavy alcohol consumption, since a daily intake of 50–80 g of ethanol over a period of at least one to two weeks is required for a positive CDT test result. After alcohol cessation, CDT normalises after two to three weeks.
      • Helander A.
      • Wielders J.
      • Anton R.
      • Arndt T.
      • Bianchi V.
      • Deenmamode J.
      • et al.
      Reprint of Standardisation and use of the alcohol biomarker carbohydrate-deficient transferrin (CDT).
      There are many confounding factors for the measurement of CDT (Table 5) among which the stage of liver disease is probably most critical.
      • Anton R.F.
      • Lieber C.
      • Tabakoff B.
      CDTect Study Group
      Carbohydrate-deficient transferrin and gamma-glutamyltransferase for the detection and monitoring of alcohol use: results from a multisite study.
      • Niemela O.
      Biomarker-based approaches for assessing alcohol use disorders.
      So, patients with cirrhosis more commonly have a false negative result. To increase reliability CDT should be expressed as percent of total transferrin, thereby accounting for individual variations in transferrin levels. Furthermore, only one of the isoforms, the disialotransferrin glycoform of CDT, should be measured by high-performance liquid chromatography. So, depending on the assay used and the patient population tested, the sensitivity and specificity of CDT testing varies considerably (Table 5).
      • Helander A.
      • Wielders J.
      • Anton R.
      • Arndt T.
      • Bianchi V.
      • Deenmamode J.
      • et al.
      Reprint of Standardisation and use of the alcohol biomarker carbohydrate-deficient transferrin (CDT).
      • Anttila P.
      • Jarvi K.
      • Latvala J.
      • Blake J.E.
      • Niemela O.
      A new modified gamma-%CDT method improves the detection of problem drinking: studies in alcoholics with or without liver disease.
      • DiMartini A.
      • Day N.
      • Lane T.
      • Beisler A.T.
      • Dew M.A.
      • Anton R.
      Carbohydrate deficient transferrin in abstaining patients with end-stage liver disease.

      Direct markers for alcohol consumption

      In comparison to all these indirect alcohol markers, the direct alcohol markers, i.e. ethyl glucuronide (EtG), ethyl sulfate (EtS), phosphatidylethanol (PEth) and fatty acid ethyl esters (FAEEs) have a much higher specificity, since they are all direct products of the non-oxidative metabolism of ethanol. Furthermore, in comparison to direct determination of ethanol in blood or exhaled air, they have a much longer detection window, which is often critical in order to uncover alcohol intake.
      • Cabarcos P.
      • Alvarez I.
      • Tabernero M.J.
      • Bermejo A.M.
      Determination of direct alcohol markers: a review.
      To date, determination of the ethanol conjugate EtG in urine (uEtG) is widely applied in many European countries for proving recent alcohol abstinence in forensic settings or for regular monitoring of patients in alcohol addiction programmes and prior to listing for liver transplantation. Depending on the level of alcohol intake, EtG remains in the urine for up to 80 hours. For screening purposes an inexpensive immunoassay is recommended with the possibility of confirmation of positive results via the more expensive liquid chromatography tandem spectrometry.
      • Wurst F.M.
      • Wiesbeck G.A.
      • Metzger J.W.
      • Weinmann W.
      On sensitivity, specificity, and the influence of various parameters on ethyl glucuronide levels in urine–results from the WHO/ISBRA study.
      If a cut-off of 0.1 mg/L is used, consumption of very small amounts of alcohol (<5 g) can be detected, so that accidental alcohol intake via, for example, sweets, sauces, alcohol-containing mouth solution etc., may cause a positive test result. Therefore, a higher cut-off is often used resulting in a slightly lower, but still very high sensitivity.
      • Staufer K.
      • Andresen H.
      • Vettorazzi E.
      • Tobias N.
      • Nashan B.
      • Sterneck M.
      Urinary ethyl glucuronide as a novel screening tool in patients pre- and post-liver transplantation improves detection of alcohol consumption.
      Notably, uEtG is not influenced by the presence of compensated or decompensated cirrhosis. So, in a cohort of 141 liver transplant candidates and recipients the sensitivity and specificity of uEtG of 89% and 99%, respectively, outperformed all other indirect alcohol markers, including GGT, AST, ALT, MCV and CDT, in predicting alcohol consumption.
      In contrast to urinary EtG, determination of EtG in the scalp hair (hEtG) of patients is a powerful tool for monitoring not only short-term, but long-term abstinence from alcohol over a period of up to six months. Thereby each hair segment of 1 cm length reflects alcohol consumption over approximately one month. However, if samples less than 3 cm or greater than 6 cm are used, the results should be interpreted with caution (www.soht.org). In individuals with short hair, incorporation of EtG from sweat into hair after recent alcohol consumption is a concern.
      • Agius R.
      • Ferreira L.M.
      • Yegles M.
      Can ethyl glucuronide in hair be determined only in 3 cm hair strands?.
      In individuals with long-hair, treatments, such as dying, perming or bleaching, may play an increasing role in reducing EtG concentration in the hair. Also, slower hair growth in sick, cirrhotic patients should be considered when assessing results. Nevertheless, several studies show a high correlation between daily alcohol intake and hEtG concentrations in 3–6 cm long hair segments
      • Appenzeller B.M.
      • Agirman R.
      • Neuberg P.
      • Yegles M.
      • Wennig R.
      Segmental determination of ethyl glucuronide in hair: a pilot study.
      • Morini L.
      • Politi L.
      • Groppi A.
      • Stramesi C.
      • Polettini A.
      Determination of ethyl glucuronide in hair samples by liquid chromatography/electrospray tandem mass spectrometry.
      and internationally accepted cut-off values for abstinence (<7 pg/mg), “social drinking” (hEtG 7–30 pg/mg) and chronic excessive alcohol consumption with more than 60 g ethanol intake per day (hEtG >30 pg/mg) have been defined (www.soht.org). Due to its high specificity and sensitivity (Table 5), interest in hEtG testing has grown over the past few years, especially for evaluating alcohol abuse in forensic settings,
      • Suesse S.
      • Pragst F.
      • Mieczkowski T.
      • Selavka C.M.
      • Elian A.
      • Sachs H.
      • et al.
      Practical experiences in application of hair fatty acid ethyl esters and ethyl glucuronide for detection of chronic alcohol abuse in forensic cases.
      for example child custody cases, or in confirmation of six-month alcohol abstinence in liver transplant recipients.
      • Sterneck M.
      • Yegles M.
      • Rothkirch von G.
      • Staufer K.
      • Vettorazzi E.
      • Schulz K.H.
      • et al.
      Determination of ethyl glucuronide in hair improves evaluation of long-term alcohol abstention in liver transplant candidates.
      To get a comprehensive picture of the true alcohol consumption of a patient, it is best to combine different available methods, i.e. questionnaires with uETG and hETG testing. In addition to these already well established direct alcohol markers with high reliability, determination of other direct markers, such as EtS in urine, FAEES in hair and PEth in serum or in dried blood spots may gain increasing recognition in the future, as additional methods for confirming suspected alcohol intake.
      • Voican C.S.
      • Louvet A.
      • Trabut J.B.
      • Njike-Nakseu M.
      • Dharancy S.
      • Sanchez A.
      • et al.
      Transient elastography alone and in combination with FibroTest((R)) for the diagnosis of hepatic fibrosis in alcoholic liver disease.
      • Andresen-Streichert H.
      • Beres Y.
      • Weinmann W.
      • Schrock A.
      • Muller A.
      • Skopp G.
      • et al.
      Improved detection of alcohol consumption using the novel marker phosphatidylethanol in the transplant setting: results of a prospective study.
      • Wuyts B.
      • Delanghe J.R.
      • Kasvosve I.
      • Gordeuk V.R.
      • Gangaidzo I.T.
      • Gomo Z.A.
      Carbohydrate-deficient transferrin and chronic alcohol ingestion in subjects with transferrin CD-variants.
      • Jaffe D.H.
      • Siman-Tov M.
      • Gopher A.
      • Peleg K.
      Variability in the blood/breath alcohol ratio and implications for evidentiary purposes.
      • Crunelle C.L.
      • Yegles M.
      • De Doncker M.
      • Dom G.
      • Cappelle D.
      • Maudens K.E.
      • et al.
      Influence of repeated permanent coloring and bleaching on ethyl glucuronide concentrations in hair from alcohol-dependent patients.
      • Fosen J.T.
      • Morini L.
      • Sempio C.
      • Ganss R.
      • Morland J.
      • Hoiseth G.
      Levels of hair ethyl glucuronide in patients with decreased kidney function: possibility of misclassification of social drinkers.
      • Stewart S.H.
      • Koch D.G.
      • Willner I.R.
      • Randall P.K.
      • Reuben A.
      Hair ethyl glucuronide is highly sensitive and specific for detecting moderate-to-heavy drinking in patients with liver disease.
      • Pragst F.
      Interpretation problems in a forensic case of abstinence determination using alcohol markers in hair.

      Suggestions for future studies

      • Investigations focussed 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
      • Liver biopsy is required where there is diagnostic uncertainty, where precise staging is required or in clinical trials (Grade A1)
      • Screening of patients with AUD should include determination of LFTs and a measure of liver fibrosis. (Grade A1)
      • Abstinence can be accurately monitored by measurement of EtG in urine or hair (Grade A2)

      Management of alcoholic hepatitis

      Definition and diagnosis

      Alcoholic hepatitis is a distinct clinical syndrome characterised by the recent onset of jaundice with or without other signs of liver decompensation (i.e. ascites and/or encephalopathy) in patients with ongoing alcohol abuse.
      • Morgan T.R.
      • Ghany M.G.
      • Kim H.Y.
      • Snow K.K.
      • Shiffman M.L.
      • De Santo J.L.
      • et al.
      Outcome of sustained virological responders with histologically advanced chronic hepatitis C.
      It is not uncommon for patients to have ceased alcohol consumption days or weeks before the onset of symptoms. Underlying this clinical syndrome is steatohepatitis, a disease defined histologically by steatosis, hepatocyte ballooning, and an inflammatory infiltrate with polymorphonuclear neutrophils.
      • MacSween R.N.
      • Burt A.D.
      Histologic spectrum of alcoholic liver disease.
      However, the clinical features of this syndrome can also result from sepsis, drug-induced liver injury, gallstone migration, etc.
      The cardinal sign of AH is a progressive jaundice, that is often associated with fever (even in the absence of infection), malaise, weight loss and malnutrition. The laboratory profile of AH reveals neutrophilia, hyperbilirubinemia (>50 μMol/L), serum levels of AST greater than twice the upper limit of normal range, AST >50 IU/ml, although rarely above 300 IU/ml, with an AST/ALT ratio typically greater than 1.5–2.0. In severe forms, prolonged prothrombin time, hypoalbuminemia, and decreased platelet count are frequently observed.
      Diagnosis of AH is based on clinical (i.e. recent onset of jaundice) and typical laboratory findings mentioned earlier in a patient with a history of heavy alcohol use. Liver biopsy (performed by transjugular route to reduce the risk of bleeding) can be useful to confirm the diagnosis, rule out other diagnoses found in 10–20% of cases,
      • Jonas D.E.
      • Garbutt J.C.
      • Amick H.R.
      • Brown J.M.
      • Brownley K.A.
      • Council C.L.
      • et al.
      Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.
      • Zatloukal K.
      • French S.W.
      • Stumptner C.
      • Strnad P.
      • Harada M.
      • Toivola D.M.
      • et al.
      From Mallory to Mallory-Denk bodies: what, how and why?.
      and for prognostication.
      • Altamirano J.
      • Miquel R.
      • Katoonizadeh A.
      • Abraldes J.G.
      • Duarte-Rojo A.
      • Louvet A.
      • et al.
      A histologic scoring system for prognosis of patients with alcoholic hepatitis.
      • Kryger P.
      • Schlichting P.
      • Dietrichson O.
      • Juhl E.
      The accuracy of the clinical diagnosis in acute hepatitis and alcoholic liver disease. Clinical versus morphological diagnosis.
      • Ramond M.J.
      • Poynard T.
      • Rueff B.
      • Mathurin P.
      • Theodore C.
      • Chaput J.C.
      • et al.
      A randomized trial of prednisolone in patients with severe alcoholic hepatitis.
      The main restrictions on the use of liver biopsy in routine clinical practice are access to transjugular liver biopsy, risks and the costs of the procedure. Therefore, the decision to perform biopsy has to take into account the availability of the procedure and experience of the team. Biopsy must only be performed in cases where there is diagnostic uncertainty. In the absence of a liver biopsy more stringent clinical and laboratory criteria should be applied to avoid the misdiagnosis of alcoholic hepatitis, particularly amongst patients with cirrhosis.
      • Crabb D.W.
      • Bataller R.
      • Chalasani N.P.
      • Kamath P.S.
      • Lucey M.
      • Mathurin P.
      • et al.
      Standard definitions and common data elements for clinical trials in patients with alcoholic hepatitis: recommendation From the NIAAA alcoholic hepatitis consortia.
      The incidence of AH remains largely unknown. A retrospective Danish study based on diagnosis codes revealed an increasing incidence, from 37 cases/million in 1999 to 46 cases/million in 2008 in men and 24 cases/million rising to 34 cases/million in women.
      • Sandahl T.D.
      • Jepsen P.
      • Thomsen K.L.
      • Vilstrup H.
      Incidence and mortality of alcoholic hepatitis in Denmark 1999–2008: a nationwide population based cohort study.
      Although female sex is an independent risk factor for AH, it is more frequent in men. Excess weight is another risk factor for AH.
      • Naveau S.
      • Giraud V.
      • Borotto E.
      • Aubert A.
      • Capron F.
      • Chaput J.C.
      Excess weight risk factor for alcoholic liver disease.
      Although no clear threshold for the amount of alcohol consumption has been identified, AH generally occurs after decades of heavy alcohol use (>80 g/day).

      Evaluation of severity

      Different prognostic models have been developed which aim to identify patients at high risk of early death using baseline and dynamic variables (Table 6). The Maddrey discriminant function (DF) was the first score that reliably defined individuals at the highest risk of death in the short-term, and remains the most widely used in clinical practice and clinical trials. DF was originally developed in 1978,
      • Maddrey W.C.
      • Boitnott J.K.
      • Bedine M.S.
      • Weber Jr., F.L.
      • Mezey E.
      • White Jr., R.I.
      Corticosteroid therapy of alcoholic hepatitis.
      and then modified (mDF) in 1989.
      • Carithers Jr., R.L.
      • Herlong H.F.
      • Diehl A.M.
      • Shaw E.W.
      • Combes B.
      • Fallon H.J.
      • et al.
      Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial.
      In its modified version, a cut-off value of 32 identifies patients with severe AH and is usually the threshold used for initiating specific therapy. In the absence of treatment, the one-month survival of patients with mDF ≥32 has improved from 50% in early publication to 85% in recent trials.
      • Thursz M.R.
      • Richardson P.
      • Allison M.
      • Austin A.
      • Bowers M.
      • Day C.P.
      • et al.
      Prednisolone or pentoxifylline for alcoholic hepatitis.
      • Phillips M.
      • Curtis H.
      • Portmann B.
      • Donaldson N.
      • Bomford A.
      • O'Grady J.
      Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis–a randomised clinical trial.
      Patients with a non-severe AH (i.e. mDF <32) had a less than 10% risk of one-month mortality.
      • Mathurin P.
      • Mendenhall C.L.
      • Carithers Jr., R.L.
      • Ramond M.J.
      • Maddrey W.C.
      • Garstide P.
      • et al.
      Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.
      However, the long-term prognosis of those patients remains largely unknown.
      Table 6Variables incorporated in the five prognostic scores most commonly used in alcoholic hepatitis.
      ScoreBilirubinPT/INRCreatinine/ureaLeucocytesAgeAlbuminChange in bilirubin from day 0 to day 7
      Maddrey++
      MELD+++
      GAHS+++++
      ABIC+++++
      Lille++++++
      Maddrey, Maddrey discriminant function; MELD, model for end-stage liver disease; GAHS, Glasgow alcoholic hepatitis score; ABIC, age, serum bilirubin, INR, and serum creatinine score.
      More recently, several prognostic scores such as the model for end-stage liver disease (MELD), the Glasgow alcoholic hepatitis score (GAHS), and the ABIC (age, serum bilirubin, INR, and serum creatinine) score have been developed in the setting of AH. The MELD score is already a well-validated prognostic score in cirrhosis (www.mayoclinic.org/meld/mayomodel7.html). Its usefulness in assessing the short-term prognosis of AH has been studied in retrospective studies, which suggest that patients with an MELD score above 20 are at a high risk of 90-day mortality.
      • Dunn W.
      • Jamil L.H.
      • Brown L.S.
      • Wiesner R.H.
      • Kim W.R.
      • Menon K.V.
      • et al.
      MELD accurately predicts mortality in patients with alcoholic hepatitis.
      GAHS was derived from five variables independently associated with outcome (age, serum bilirubin, blood urea, prothrombin time, and peripheral blood white blood cell count) and identifies patients at greatest risk of death in the absence of treatment.
      • Forrest E.H.
      • Evans C.D.
      • Stewart S.
      • Phillips M.
      • Oo Y.H.
      • McAvoy N.C.
      • et al.
      Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score.
      The GAHS ranges from 5 to 12 and patients with an mDF ≥32 and a GAHS ≥9 have a poor prognosis and an 84-day survival benefit when treated with corticosteroid.
      • Forrest E.H.
      • Morris A.J.
      • Stewart S.
      • Phillips M.
      • Oo Y.H.
      • Fisher N.C.
      • et al.
      The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids.
      The ABIC score classified patients with AH according to low, intermediate and high risk of death at 90 days.
      • Dominguez M.
      • Rincon D.
      • Abraldes J.G.
      • Miquel R.
      • Colmenero J.
      • Bellot P.
      • et al.
      A new scoring system for prognostic stratification of patients with alcoholic hepatitis.
      These different scoring systems often incorporate the same variables and appear to have similar efficacy in predicting short-term survival.
      • Sandahl T.D.
      • Jepsen P.
      • Ott P.
      • Vilstrup H.
      Validation of prognostic scores for clinical use in patients with alcoholic hepatitis.
      • Vergis N.
      • Atkinson S.R.
      • Knapp S.
      • Maurice J.
      • Allison M.
      • Austin A.
      • et al.
      In patients with severe alcoholic hepatitis, prednisolone increases susceptibility to infection and infection-related mortality, and is associated with high circulating levels of bacterial DNA.
      Early improvements in liver function have a major impact on short-term mortality. An early change in bilirubin levels, evaluated at day seven of therapy, was initially proposed to easily identify corticosteroid-treated patients at high risk of six-month mortality.
      • Mathurin P.
      • Abdelnour M.
      • Ramond M.J.
      • Carbonell N.
      • Fartoux L.
      • Serfaty L.
      • et al.
      Early change in bilirubin levels is an important prognostic factor in severe alcoholic hepatitis treated with prednisolone.
      Similarly, an early change in the MELD score in the first week has been shown to predict in-hospital mortality.
      • Srikureja W.
      • Kyulo N.L.
      • Runyon B.A.
      • Hu K.-Q.
      MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant Function score in patients with alcoholic hepatitis.
      Subsequently, the Lille model, which is based on pretreatment data plus the response of serum levels of bilirubin to a seven-day course of corticosteroid therapy was developed.
      • Louvet A.
      • Naveau S.
      • Abdelnour M.
      • Ramond M.J.
      • Diaz E.
      • Fartoux L.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      This score ranges from 0 to 1; a score ≥0.45 indicates non-response to corticosteroids. A subsequent analysis that re-evaluated the Lille score identified three patterns of response to corticosteroid therapy: complete responders (Lille score ≤0.16), partial responders (Lille score 0.16–0.56) and null responders (Lille score ≥0.56), and strongly suggested that corticosteroids should be discontinued in null responders at day seven of therapy.
      • Mathurin P.
      • O'Grady J.
      • Carithers R.L.
      • Phillips M.
      • Louvet A.
      • Mendenhall C.L.
      • et al.
      Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
      Recently, the combination of MELD and the Lille model was suggested as an effective predictive algorithm of short-term mortality.
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Boursier J.
      • Kim D.J.
      • O'Grady J.
      • et al.
      Combining data from liver disease scoring systems better predicts outcomes of patients with alcoholic hepatitis.

      Treatment of alcoholic hepatitis

      General measures

      Regardless of the severity, alcohol abstinence is the cornerstone of therapy and early management of AUD is recommended in all patients with AH (Fig. 1). In severe AH, a recent paper demonstrated that severity of liver injury determines short-term survival while alcohol abstinence is the main determinant of long-term prognosis.
      • Louvet A.
      • Labreuche J.
      • Artru F.
      • Bouthors A.
      • Rolland B.
      • Saffers P.
      • et al.
      Main drivers of outcome differ between short term and long term in severe alcoholic hepatitis: A prospective study.
      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) and treatment of ascites (salt restriction). Patients with severe AH are at risk of developing acute kidney injury (AKI) which negatively impacts survival.
      • Altamirano J.
      • Fagundes C.
      • Dominguez M.
      • Garcia E.
      • Michelena J.
      • Cardenas A.
      • et al.
      Acute kidney injury is an early predictor of mortality for patients with alcoholic hepatitis.
      Measures aimed at preventing the development of renal failure are therefore recommended. They include avoidance of diuretics and nephrotoxic drugs and volume expansion if needed. Considering prevention of variceal bleeding, it was suggested that the use of beta-blockers increases the risk of AKI.
      • Serste T.
      • Njimi H.
      • Degre D.
      • Deltenre P.
      • Schreiber J.
      • Lepida A.
      • et al.
      The use of beta-blockers is associated with the occurrence of acute kidney injury in severe alcoholic hepatitis.
      Figure thumbnail gr1
      Fig. 1Treatment algorithm in patients with suspected alcoholic hepatitis. *Particularly in null responders (Lille score ≥0.56). AH, alcoholic hepatitis; BW, bodyweight; DILI, drug-induced liver injury; GAHS, Glasgow alcoholic hepatitis score; mDF, maddrey discriminant function.

      Nutrition

      Malnutrition is commonly associated with cirrhosis and its severity.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • Assis-Camilo M.
      • Pirlich M.
      • Kondrup J.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      Several studies have highlighted that protein energy malnutrition is present in almost every patient with severe AH, and is associated with poor prognosis.
      • Mendenhall C.L.
      • Moritz T.E.
      • Roselle G.A.
      • Morgan T.R.
      • Nemchausky B.A.
      • Tamburro C.H.
      • et al.
      Protein energy malnutrition in severe alcoholic hepatitis: diagnosis and response to treatment. The VA Cooperative Study Group #275.
      The European Society for Clinical Nutrition and Metabolism (ESPEN) recommend a daily energy intake of 35–40 kcal/kg of body weight (BW) and a daily protein intake of 1.2–1.5 g/kg of BW in patients with AH.
      • Plauth M.
      • Cabre E.
      • Riggio O.
      • Assis-Camilo M.
      • Pirlich M.
      • Kondrup J.
      • et al.
      ESPEN guidelines on enteral nutrition: liver disease.
      However, these objectives are often difficult to achieve in clinical practice. Therefore, the use of tube feeding is strongly recommended if patients are not able to maintain adequate oral intake. A randomised controlled trial comparing 28 days of total enteral nutrition to corticosteroid treatment in 71 patients with severe AH suggested that these approaches resulted in comparable one- and six-month survival rates.
      • Cabre E.
      • Rodriguez-Iglesias P.
      • Caballeria J.
      • Quer J.C.
      • Sanchez-Lombrana J.L.
      • Pares A.
      • et al.
      Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.
      More recently, a multicentre randomised controlled trial compared the combination of 14 days of intensive enteral nutrition using a feeding tube plus corticosteroids for 28 days to corticosteroid therapy alone, and showed that combination therapy did not improve survival.
      • Moreno C.
      • Deltenre P.
      • Senterre C.
      • Louvet A.
      • Gustot T.
      • Bastens B.
      • et al.
      Intensive enteral nutrition is ineffective for patients with severe alcoholic hepatitis treated with corticosteroids.
      Tolerance of the feeding tube was an important issue, since nearly half of the patients prematurely withdrew the feeding tube. Interestingly, a post hoc analysis of this study demonstrated that, regardless of the allocated therapy, patients with a daily calorie intake below 21.5 kcal/kg of BW had a significantly higher risk of one- and six-month mortality and infections. Thus, it appears reasonable to recommend a careful evaluation of nutritional status and energy intake, to target 35–40 kcal/kg of BW and a daily protein intake of 1.2–1.5 g/kg of BW and to adopt the oral route as first-line intervention in patients with severe AH.
      While parenteral nutrition might circumvent the complications of naso-gastric feeding there is not currently sufficient evidence to support a recommendation, particularly given that parenteral feeding is associated with a high risk of line sepsis.

      Corticosteroids

      The use of corticosteroids to treat AH has been controversial, owing to the divergent findings of individual studies and meta-analyses.
      • Imperiale T.F.
      • McCullough A.J.
      Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials.
      • Imperiale T.F.
      • O'Connor J.B.
      • McCullough A.J.
      Corticosteroids are effective in patients with severe alcoholic hepatitis.
      • Christensen E.
      • Gluud C.
      Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables.
      A large multicentre randomised trial (STOPAH) was conducted in the United Kingdom between 2011 and 2014, in patients with a clinical diagnosis of severe AH, in order to resolve the controversy over the use of corticosteroids or pentoxifylline (PTX).
      • Thursz M.R.
      • Richardson P.
      • Allison M.
      • Austin A.
      • Bowers M.
      • Day C.P.
      • et al.
      Prednisolone or pentoxifylline for alcoholic hepatitis.
      This study reported a borderline reduction in mortality at 28 days for patients treated with prednisolone 40 mg/day compared with control patients. Importantly, prednisolone therapy provided no benefit to patients after one month, which was subsequently confirmed in a network meta-analysis.
      • Singh S.
      • Murad M.H.
      • Chandar A.K.
      • Bongiorno C.M.
      • Singal A.K.
      • Atkinson S.R.
      • et al.
      Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systematic review and network meta-analysis.
      The applicability of corticosteroid therapy is limited by concerns about heightened risks of sepsis and gastrointestinal bleeding. Therefore, early identification of non-responders to corticosteroids is important to define stopping rules and limit unnecessary exposure. The Lille score allows clinicians to predict poor response to corticosteroids at seven days of therapy
      • Louvet A.
      • Naveau S.
      • Abdelnour M.
      • Ramond M.J.
      • Diaz E.
      • Fartoux L.
      • et al.
      The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids.
      (see section “evaluation of severity”). In case of poor response, it is recommended that corticosteroids be interrupted, particularly in “null responders” (defined by Lille score ≥0.56).
      • Mathurin P.
      • O'Grady J.
      • Carithers R.L.
      • Phillips M.
      • Louvet A.
      • Mendenhall C.L.
      • et al.
      Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data.
      Practically, prednisolone at a dose of 40 mg per day or methylprednisolone at a dose of 32 mg per day is prescribed for 28 days. At the end of the course of treatment, the prednisolone or methylprednisolone can be stopped all at once, or the dose can be gradually tapered over a period of three weeks.

      N-acetylcysteine

      Antioxidant therapy is of theoretical interest in the treatment of AH because of increasing evidence that oxidative stress is a key mechanism in alcohol-mediated hepatotoxicity.
      Alcohol and oxidative liver injury.
      Ethanol consumption results in depletion of endogenous antioxidant capacities, and patients with AH show evidence of antioxidant deficiencies.
      • Fernandez-Checa J.C.
      • Ookhtens M.
      • Kaplowitz N.
      Effect of chronic ethanol feeding on rat hepatocytic glutathione. Compartmentation, efflux, and response to incubation with ethanol.
      Because N-acetylcysteine (NAC) restores the glutathione store and consequently limits oxidative stress, it has been studied, either alone or in combination with other antioxidants, in several trials of severe AH. In those different trials, NAC did not increase survival compared to standard medical therapy.
      • Phillips M.
      • Curtis H.
      • Portmann B.
      • Donaldson N.
      • Bomford A.
      • O'Grady J.
      Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis–a randomised clinical trial.
      • Moreno C.
      • Langlet P.
      • Hittelet A.
      • Lasser L.
      • Degre D.
      • Evrard S.
      • et al.
      Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial.
      • Stewart S.
      • Prince M.
      • Bassendine M.
      • Hudson M.
      • James O.
      • Jones D.
      • et al.
      A randomized trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis.
      A multicentre French trial compared the effects of the combination of NAC and prednisolone to prednisolone and placebo.
      • Nguyen-Khac E.
      • Thevenot T.
      • Piquet M.A.
      • Benferhat S.
      • Goria O.
      • Chatelain D.
      • et al.
      Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis.
      In this study, NAC was administered intravenously for five days. Mortality at one month was significantly lower in the NAC plus prednisolone group compared to the prednisolone plus placebo arm. Importantly, NAC combined with prednisolone, also significantly reduced the incidence of hepatorenal syndrome and infections. Therefore, the combination of NAC and prednisolone appear to improve prognosis of patients with severe AH, and this combination should be tested in a future large clinical trial to confirm its efficacy.

      Granulocyte colony stimulating factor

      Granulocyte colony stimulating factor (GCSF) is a glycoprotein that stimulates the bone marrow to produce and release neutrophils and stem cells (CD34+) into the bloodstream. Ineffective liver regeneration has been postulated as one of the key factor leading to progressive liver failure and non-recovery in patients with AH.
      • Dubuquoy L.
      • Louvet A.
      • Lassailly G.
      • Truant S.
      • Boleslawski E.
      • Artru F.
      • et al.
      Progenitor cell expansion and impaired hepatocyte regeneration in explanted livers from alcoholic hepatitis.
      In animal models, the administration of GCSF was able to mobilise the hematopoietic stem cells, induce liver regeneration, and improve survival.
      • Yannaki E.
      • Athanasiou E.
      • Xagorari A.
      • Constantinou V.
      • Batsis I.
      • Kaloyannidis P.
      • et al.
      G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs.
      Spahr et al. demonstrated that GCSF administered subcutaneously for five days in patients with AH, mobilised CD34+ stem cells, increased circulating hepatocyte growth factor and induced proliferation of hepatic progenitor cells.
      • Spahr L.
      • Lambert J.F.
      • Rubbia-Brandt L.
      • Chalandon Y.
      • Frossard J.L.
      • Giostra E.
      • et al.
      Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial.
      A randomised placebo-controlled trial from India using GCSF for one month in patients with ACLF (>50% had AH) showed significantly improved short-term survival, and decreased risk of infection and kidney injury in the GCSF group.
      • Garg V.
      • Garg H.
      • Khan A.
      • Trehanpati N.
      • Kumar A.
      • Sharma B.C.
      • et al.
      Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.
      Another randomised controlled trial from India assessed the effects of PTX vs. a combination of PTX and GCSF.
      • Singh V.
      • Sharma A.K.
      • Narasimhan R.L.
      • Bhalla A.
      • Sharma N.
      • Sharma R.
      Granulocyte colony-stimulating factor in severe alcoholic hepatitis: a randomized pilot study.
      A significantly larger proportion of patients who received PTX plus GCSF survived for 90 days than those who received only PTX. Although the sample size was limited, these findings indicate that GCSF might improve the prognosis of patients with severe AH. Moreover, GCSF is easy to administer and is well tolerated. However, a European study of GCSF in decompensated cirrhosis (mostly caused by AH) reported negative results so further trials are required before it can be recommended as a treatment in severe AH.
      • Spahr L.
      • Chalandon Y.
      • Terraz S.
      • Kindler V.
      • Rubbia-Brandt L.
      • Frossard J.L.
      • et al.
      Autologous bone marrow mononuclear cell transplantation in patients with decompensated alcoholic liver disease: a randomized controlled trial.

      Pentoxifylline

      Pentoxifylline, a phosphodiesterase inhibitor, has been evaluated in patients with AH for its ability to inhibit production of tumour necrosis factor (TNF). In the initial randomised study comparing PTX to placebo in patients with severe AH, patients treated with PTX had an improved six-month survival.
      • Akriviadis E.
      • Botla R.
      • Briggs W.
      • Han S.
      • Reynolds T.
      • Shakil O.
      Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.
      This survival benefit was not accompanied by significant changes in liver function, but it was related to a marked reduction in the incidence of hepatorenal syndrome. A large French multicentre trial, which evaluated PTX vs. placebo in 335 Child-Pugh C cirrhotic patients (mainly ALD origin, 133 with AH) reported no significant difference in short-term mortality between both arms, in the overall study and in subjects with AH.
      • Lebrec D.
      • Thabut D.
      • Oberti F.
      • Perarnau J.M.
      • Condat B.
      • Barraud H.
      • et al.
      Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis.
      The combination of corticosteroids with PTX was also evaluated in different trials. In the Corpentox study,
      • Mathurin P.
      • Louvet A.
      • Duhamel A.
      • Nahon P.
      • Carbonell N.
      • Boursier J.
      • et al.
      Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis: a randomized clinical trial.
      28-day treatment with PTX (1,200 mg/day) plus prednisolone, compared with prednisolone plus placebo in patients with severe AH, did not result in improved short-term survival. Although not significant, incidence of hepatorenal syndrome was lower in patients receiving the combination of PTX and prednisolone. In the STOPAH trial
      • Thursz M.R.
      • Richardson P.
      • Allison M.
      • Austin A.
      • Bowers M.
      • Day C.P.
      • et al.
      Prednisolone or pentoxifylline for alcoholic hepatitis.
      survival (at one month, three months, and one year) was not better in patients receiving PTX compared to those not receiving PTX. Finally, an early switch to PTX in non-responders to corticosteroids did not improve two-month survival compared to matched non-responders treated with corticosteroids only.
      • Louvet A.
      • Diaz E.
      • Dharancy S.
      • Coevoet H.
      • Texier F.
      • Thevenot T.
      • et al.
      Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids.
      In summary, evidence for a survival benefit of PTX therapy in patients with severe AH is very weak, and the drug can no longer be recommended.

      Anti-TNF agents

      Based on animal models suggesting a key role of TNF-α in the pathogenesis of ALD,
      • Iimuro Y.
      • Gallucci R.M.
      • Luster M.I.
      • Kono H.
      • Thurman R.G.
      Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.
      and increased liver and serum levels of TNF-α in human ALD,
      • McClain C.J.
      • Barve S.
      • Barve S.
      • Deaciuc I.
      • Hill D.B.
      Tumor necrosis factor and alcoholic liver disease.
      both infliximab and etanercept were evaluated in AH in randomised controlled trials.
      • Naveau S.
      • Chollet-Martin S.
      • Dharancy S.
      • Mathurin P.
      • Jouet P.
      • Piquet M.A.
      • et al.
      A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.
      • Boetticher N.C.
      • Peine C.J.
      • Kwo P.
      • Abrams G.A.
      • Patel T.
      • Aqel B.
      • et al.
      A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.
      Those studies showed a higher risk of death and of severe infections in AH patients treated with anti-TNF agents. Therefore, those agents are not considered as a treatment option in AH.

      Extracorporeal liver support

      Extracorporeal liver support procedures can remove some potentially damaging circulating molecules, and are therefore, of potential interest in patients with severe AH. Some encouraging preliminary data with albumin dialysis were reported in patients with severe AH.
      • Pares A.
      • Mas A.
      Extracorporeal liver support in severe alcoholic hepatitis.
      • Jalan R.
      • Sen S.
      • Steiner C.
      • Kapoor D.
      • Alisa A.
      • Williams R.
      Extracorporeal liver support with molecular adsorbents recirculating system in patients with severe acute alcoholic hepatitis.
      However, to date, no clear benefit has been demonstrated using these extracorporeal liver support devices.
      • Banares R.
      • Nevens F.
      • Larsen F.S.
      • Jalan R.
      • Albillos A.
      • Dollinger M.
      • et al.
      Extracorporeal albumin dialysis with the molecular adsorbent recirculating system in acute-on-chronic liver failure: the RELIEF trial.

      Infection in alcoholic hepatitis

      Infection is a frequent and severe complication in patients with severe AH, and is one of the major causes of death. A recent meta-analysis found a 28-day cumulative incidence of infection of approximately 20%.
      • Hmoud B.S.
      • Patel K.
      • Bataller R.
      • Singal A.K.
      Corticosteroids and occurrence of and mortality from infections in severe alcoholic hepatitis: a meta-analysis of randomized trials.
      Other trials reported higher incidence of infection in up to 65% during a three-month follow-up.
      • Moreno C.
      • Deltenre P.
      • Senterre C.
      • Louvet A.
      • Gustot T.
      • Bastens B.
      • et al.
      Intensive enteral nutrition is ineffective for patients with severe alcoholic hepatitis treated with corticosteroids.