KASL Clinical Practice Guidelines: Management of Alcoholic Liver Disease

 [bib_ref] GRADE: an emerging consensus on rating quality of evidence and strength of..., Guyatt [/bib_ref] 

## List of key questions
The committee identified the following key questions to be covered in these guidelines. Current evidence and recommendations are provided for each key question.
1. What is the burden of ALD in Korea? 2. How should moderate drinking, heavy drinking, binge drinking, hazardous drinking, harmful drinking, and alcohol use disorder be defined? 3. What diseases are included in the spectrum of ALD? 4. What is the natural history of ALD? 5. How do the quantity of alcohol consumed, drinking habit, and type of alcohol affect the development of ALD? 6. How do sex, ethnicity, and obesity affect ALD? 7. What is the relationship between viral hepatitis and ALD? 8. What are the characteristics of the pathophysiology of ALD? 9. What are the criteria for the clinical diagnosis of ALD? [bib_ref] Psychometric properties of the alcohol use disorders identification test: a Korean version, Kim [/bib_ref]. Is a liver biopsy necessary for the diagnosis of ALD? 11. What is the prognosis for alcoholic hepatitis? 12. What are useful prognostic factors for alcoholic hepatitis? 13. How is therapy for alcohol withdrawal syndrome (AWS) implemented? 14. What methods are available to promote alcohol abstinence? [bib_ref] Association between alcohol consumption and metabolic syndrome among Korean adults: nondrinker versus..., Park [/bib_ref]. Is enteral or parenteral nutritional support helpful for patients with ALD? [bib_ref] Prevalence of alcoholic liver disease among Korean adults: results from the fourth..., Park [/bib_ref]. What treatments increase the survival rate in alcoholic hepatitis? 17. Which patients should be given steroids or pentoxifylline treatment? 18. How should treatment outcomes for alcoholic hepatitis be evaluated? [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref]. What should be done for patients with alcoholic hepatitis who are nonresponsive to medical treatment? 20. What are the indications for liver transplantation in patients with ALD? 21. What pharmacologic agents are being tried for treatment of ALD? 22. What policies are needed to decrease harmful use of alcohol in Korea?

## Epidemiology
Alcohol consumption ranks third among the risk factors for disease and disability throughout the world, and causes 2.5 million deaths annually, constituting 4% of all deaths worldwide. [bib_ref] Alcohol and public health, Room [/bib_ref] ALD, including liver cirrhosis and hepatocellular carcinoma (HCC), is responsible for approximately 25% of deaths due to alcohol consumption,which demonstrates the importance of ALD in the gen-eral population. The number of alcohol-related deaths is directly proportional to the per-capita alcohol consumption. [bib_ref] Are the recent trends in liver cirrhosis mortality affected by the changes..., Corrao [/bib_ref] [bib_ref] Large decreases in alcohol-related problems following a slight reduction in alcohol consumption..., Smart [/bib_ref] According to a European study, every 1 L increase in per-capita alcohol consumption increases the incidence of liver cirrhosis by 14% in men and 8% in women. [bib_ref] Per capita alcohol consumption and liver cirrhosis mortality in 14 European countries, Ramstedt [/bib_ref] The Korean culture is lenient toward drinking and the inebriated state. Alcohol is considered a social lubricant, and drinking is thought to be an important component in business and various other social interactions. Alcohol consumption has increased over the past 40 years in Korea concomitantly with the country's rapid socioeconomic development. The per-capita alcohol consumption in Korea increased from 7 L in the 1980s to , and is now considered to be among the highest in the world [fig_ref] Figure 1: Adult alcohol consumption per capita in 2005 [/fig_ref].Economic loss due to alcohol has increased in line with the increase in alcohol consumption, from 2.6% of the gross domestic product (GDP) in 2000 to 2.9% of the GDP in 2004. [bib_ref] Socioeconomic costs of alcohol drinking in Korea, Chung [/bib_ref] [bib_ref] Socioeconomic costs of alcohol drinking in Korea, Lee [/bib_ref] The large absolute increase in alcohol consumption has led to a rapid increase in alcohol-related diseases and accidents. [bib_ref] Korean status of alcoholics and alcoholrelated health problems, Park [/bib_ref] According to recent data from the Korea National Health and Nutrition Examination Survey (KNHANES), the prevalence of alcohol use disorder, identified as a score of 12 or higher on the Korean version of the Alcohol Use Disorders Identification Test (AUDIT, AU-DIT-K), increased from 21.3% in 2005 to [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref].1% in 2009, which

## Hazardous drinking and alcohol use disorder
Excessive drinking is associated with an increased risk of disease, the most prominent of which is ALD. [bib_ref] Alcohol-related morbidity and mortality, Rehm [/bib_ref] [bib_ref] Meta-analysis of alcohol intake in relation to risk of liver cirrhosis, Corrao [/bib_ref] [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref] Therefore, it is of critical importance that hazardous drinkers are identified and treated in order to prevent or slow the progression of ALD. Hazardous drinkers are generally identified based on criteria developed by the US National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the World Health Organization (WHO), in which moderate drinking, heavy drinking, binge drinking, hazardous drinking (NIAAA: at-risk drinking), and harmful drinking are defined based on both the amount of alcohol consumed and drink-ing habit [fig_ref] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking,... [/fig_ref]. [bib_ref] Assessing alcohol problems : a guide for clinicians and researchers. NIAAA treatment..., Allen [/bib_ref] Although most patients with alcohol use disorder are hazardous drinkers, hazardous drinking is generally defined as the stage before alcohol use disorder, and is therefore only used when alcohol use disorder is not present.
Alcohol use disorder is diagnosed with a focus on psychological, social, and physical problems, and disability caused by alcohol consumption in the past 12 months, rather than on the amount of alcohol consumed or the drinking habit. Criteria from the WHO and the American Psychiatric Association (APA) are generally used. The APA's Diagnostic and Statistical Manuals of Mental Disorders, 4th Edition (DSM-IV) divides alcohol use disorder into two categories: alcohol abuse and alcohol dependence.Alcohol abuse, which generally refers to the stage prior to alcohol dependence, is defined as persistent drinking despite recurrent social, interpersonal, and legal problems as a result of the alcohol use, and it is known that around 10% of alcohol abusers progress to alcohol dependence. [bib_ref] Prospective evaluation of the four DSM-IV criteria for alcohol abuse in a..., Schuckit [/bib_ref] Alcohol dependence is a condition that results from the prolonged and (usually) high consumption of alcohol that has resulted in physiological dependence on this consumption. This dependence produces significant problems in the person's life. Due to the ambiguity in the definition of alcohol abuse, the WHO's International Classification of Diseases, 10th Revision (ICD 10) does not classify it,and alcohol use disorder is defined in the recently revised DSM-V as mild, moderate, or severe based on the severity rather than alcohol abuse versus dependence (Appendix 1). [bib_ref] The conceptual development of DSM-V, Regier [/bib_ref] [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref] Screening test for alcohol use disorder Given that a significant portion of patients who visit primary care facilities are hazardous drinkers, the risk for many diseases due to alcohol consumption may be decreased with proper recognition and interventions that lead to abstinence or decreased drinking. [bib_ref] Provider training for patient-centered alcohol counseling in a primary care setting, Ockene [/bib_ref] [bib_ref] Strategies to increase alcohol screening in health care settings, Fleming [/bib_ref] [bib_ref] Hazardous and harmful alcohol consumption in primary care, Reid [/bib_ref] [bib_ref] Screening for alcohol problems in primary care: a systematic review, Fiellin [/bib_ref] The best screening test for hazardous drinkers is a questionnaire, since this has been shown to have a higher sensitivity than blood-based tests. [bib_ref] Comparison of the CAGE questionnaire versus some biochemical markers in the diagnosis..., Girela [/bib_ref] While many questionnaires are available, the ones most frequently used are the CAGE (Cut down, Annoyed, Guilty, Eyeopener) questionnaire and the AUDIT questionnaire. The CAGE questionnaire is simple, being based on four yes/no questions, and while easily adoptable it has low sensitivity for hazardous drinking, the stage before alcohol use disorder (Appendix 2). [bib_ref] Hazardous and harmful alcohol consumption in primary care, Reid [/bib_ref] [bib_ref] The CAGE questionnaire: validation of a new alcoholism screening instrument, Mayfield [/bib_ref] [bib_ref] The CAGE questionnaire for alcohol misuse: a review of reliability and validity..., Dhalla [/bib_ref] [bib_ref] The value of the CAGE in screening for alcohol abuse and alcohol..., Aertgeerts [/bib_ref] [bib_ref] Joint use of clinical parameters, biological markers and CAGE questionnaire for the..., Bataille [/bib_ref] [bib_ref] Screening for problem drinking : Comparison of CAGE and AUDIT, Bradley [/bib_ref] AUDIT is a ten-item questionnaire developed by the WHO and is appropriate for most primary care settings (Appendix 3). [bib_ref] Screening for problem drinking : Comparison of CAGE and AUDIT, Bradley [/bib_ref] such as the quantity consumed and the drinking habit, the next three items gauge alcohol dependence, and the last four items measure the level of harmful drinking such as the psychological and social impacts. AUDIT is the most appropriate test for identifying both alcohol use disorder and hazardous drinking, 37-39 with AUDIT-K being used for a Korean cohort (Appendix 4). [bib_ref] Screening criteria of alcoholism by alcohol use disorders identification test (AUDIT) in..., Kim [/bib_ref] The disadvantages of AUDIT include the larger number of questions and the longer time required to grade each question. Therefore, a shorter version has been developed, called AUDIT-Consumption (AUDIT-C), which employs only the first three questions regarding alcohol consumption. This has the advantage of a shorter testing time while maintaining a relatively high sensitivity and specificity. [bib_ref] The AU-DIT alcohol consumption questions (AUDIT-C): an effective brief screening test for..., Bush [/bib_ref] [bib_ref] Audit-3 and audit-4: effectiveness of two short forms of the alcohol use..., Gual [/bib_ref] Given the limited amount of time available for outpatients in Korea, the third question of AUDIT (AUDIT-3) alone can also be used to reduce the response time, since in this version of AUDIT the third question of AUDIT regarding binge drinking is asked first, and if the answer is negative for the past 1 year, screening is ended early due to the low likelihood of that patient being a hazardous drinker; while for a positive answer, additional AUDIT questions are asked to complete the screening test. 41

## [recommendations]
2. If a patient appears to be at risk of alcohol-related medical problems, a structured questionnaire, such as AUDIT, should be administered to obtain more qualitative information about a patient's alcohol consumption and problems. (A1) 3. AUDIT-K is recommended as a screening test for outpatients with alcohol use disorder; alternatively, AUDIT-C or AU-DIT-3 may be used for convenient testing. (B1)

# Future research
1. There is a need to assess the prevalence of ALD in patients with alcohol use disorder.

## Natural history of alcoholic liver dis-ease
ALD encompasses a broad spectrum of diseases including fatty liver, hepatitis, liver cirrhosis, and HCC. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Multiple stages of liver injury may coexist in a given individual. [bib_ref] Morphology of alcoholic liver disease, Lefkowitch [/bib_ref] [bib_ref] Alcoholic liver disease. An update, Mendez-Sanchez [/bib_ref] [bib_ref] Alcoholic liver disease, O&apos;shea [/bib_ref] In ALD, the occurrence and severity of liver fibrosis is important in the progression of the disease to liver cirrhosis [fig_ref] Figure 2: Natural history, spectrum, and pathophysiology of alcoholic liver disease [/fig_ref]. A Korean study tracking 727 patients with ALD for an average period of 480 days found that the overall death rate was 14.6%, with the main causes of death being variceal bleeding (31.1%), liver failure (24.5%), and hepatorenal syndrome/sepsis (11.3%).However, the natural history of ALD remains unclear. Regardless of the spectrum of ALD, abstaining from alcohol prevents progression of the disease, improves the survival rate, and decreases the need for liver transplantation. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] Moreover, liver fibrosis and liver cirrhosis may occur in 5-15% of abstaining patients, and so abstinence per se does not guarantee a disappearance of ALD. [bib_ref] Fatty liver: a study of 270 patients with biopsy proven fatty liver..., Leevy [/bib_ref] [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcoholic steatohepatitis, Stickel [/bib_ref] Alcoholic fatty liver Alcoholic fatty liver, also known as alcoholic steatosis, is the ini-tial presentation of liver injury due to chronic alcohol consumption. Fatty liver is the most common disease associated with alcohol use, and is seen in 80-90% of heavy drinkers. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] While full recovery is possible with abstinence at this stage, one study found that continued alcohol use (400 g/week) increased the risk of progression to cirrhosis in 30% of cases, and to fibrosis or cirrhosis in 37%. [bib_ref] Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver, Teli [/bib_ref] However, significant liver injury may still occur in individuals who drink less. Once alcoholic fatty liver develops, it is not clear whether it will remain a fatty liver or progress to a more severe liver disease. Comorbidities due to environmental and genetic factors, viral hepatitis, obesity, and HIV infection may convert alcoholic fatty liver into steatohepatitis.

## Alcoholic hepatitis
Alcoholic hepatitis (also known as alcoholic steatohepatitis), which is usually accompanied by fatty liver disease includes a broad spectrum of pathological processes. Symptomatic patients present with advanced liver disease, with concomitant cirrhosis in more than 50% of them. [bib_ref] Prognosis of alcoholic cirrhosis in the presence and absence of alcoholic hepatitis, Orrego [/bib_ref] The prognosis is even worse with severe alcoholic hepatitis, with a 1-month mortality of 40%. [bib_ref] Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial, Carithers [/bib_ref] Drink excessively, may induce recurrent episodes of alcoholic hepatitis in patients with ALD, and if this is severe or associated with liver cirrhosis, complications occur due to liver failure and portal hypertension, leading to a high short-term mortality. In addition, longterm follow-up of these patients has shown that they rarely improve, instead usually remaining with alcoholic hepatitis or progressing to liver cirrhosis. [bib_ref] Natural history of alcoholic hepatitis. IV. Glycosaminoglycuronans and collagen in the hepatic..., Galambos [/bib_ref] Liver fibrosis is common in alcoholic hepatitis and is accelerated in the presence of chronic alcoholic hepatitis. [bib_ref] Alcoholic hepatitis, Lucey [/bib_ref] Even in patients with fatty liver or steatohepatitis but without liver fibrosis, 38-56% will eventually progress to liver cirrhosis with continued alcohol consumption. [bib_ref] Nonalcoholic steatohepatitis--a long-term follow-up study: comparison with alcoholic hepatitis in ambulatory and..., Cortez-Pinto [/bib_ref] [bib_ref] Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of..., Pares [/bib_ref] [bib_ref] Incidence and mortality of alcoholic hepatitis in Denmark 1999-2008: a nationwide population..., Sandahl [/bib_ref] Alcoholic liver cirrhosis Long-term excessive drinking results in a 15-30% lifetime risk of alcoholic liver cirrhosis. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] [bib_ref] Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver, Teli [/bib_ref] [bib_ref] Prognosis and life expectancy in chronic liver disease, Propst [/bib_ref] At the time of diagnosis of alcoholic liver cirrhosis it is accompanied by no complications in 24% of patients, ascites alone in 55%, variceal bleeding alone in 6%, combined ascites and variceal bleeding in 4%, and hepatic encephalopathy in 11%. [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] In a patient initially presenting without complications, ascites (12%), variceal bleeding (6%), and hepatic encephalopathy (4%) may appear as a first complication within 1 year of diagnosis. [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] The rate of decompensation within 1 year of a diagnosis is 37.6% with alcoholic liver cirrhosis, compared to 25.2% in non-alcoholic liver cirrhosis. [bib_ref] The rate of decompensation and clinical progression of disease in people with..., Fleming [/bib_ref] As in other diseases, alcoholic liver cirrhosis may lead to decompensated liver cirrhosis and is associated with a risk of developing HCC. [bib_ref] A 20-year prospective study of cirrhosis, Saunders [/bib_ref] The incidence of HCC is 7.2-16.0% in alcoholic liver cirrhosis, with a 1% annual risk in patients with decompensated alcoholic liver cirrhosis. 61,66-69 Viral hepatitis plays a significant role in the development of HCC in chronic drinkers. [bib_ref] National survey of hepatocellular carcinoma in heavy drinkers in Japan, Horie [/bib_ref] The overall risk of death in patients with alcoholic liver cirrhosis is 5-30 times higher in alcoholics than in the general population. [bib_ref] All-cause mortality in people with cirrhosis compared with the general population: a..., Fleming [/bib_ref] For advanced alcoholic liver cirrhosis the median survival time is 1-2 years and the 5-year survival rate is 23-50%, which is worse than that for non-alcoholic liver cirrhosis. [bib_ref] Alcoholic liver disease, Bruha [/bib_ref] In compensated alcoholic liver cirrhosis, the 5-year survival rate approaches 90% with abstinence but decreases to less than 70% with continued drinking. [bib_ref] Alcoholic liver disease: natural history, Diehl [/bib_ref] In decompensated alcoholic liver cirrhosis the 5-year survival rate is 60% with abstinence and 30% with continued drinking. [bib_ref] Liver disease in alcohol abusers: clinical perspective, Diehl [/bib_ref] The median survival time for decompensated alcoholic liver cirrhosis is 61 months, [bib_ref] Long-term clinical course of decompensated alcoholic cirrhosis: a prospective study of 165..., Alvarez [/bib_ref] and 80% of patients who continue drinking even in the presence of ascites will die within 7 months. [bib_ref] Continued heavy drinking and survival in alcoholic cirrhotics, Borowsky [/bib_ref] The 1-year mortality rate is 17% among patients with liver cirrhosis but without any complications, while this increases to 20-64% if complications develop, in which case the 5-year mortality rate approaches 58-85%. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] [bib_ref] Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study, Jepsen [/bib_ref] Future research There is a need to elucidate the natural history of ALD.

## Risk factors for alcoholic liver disease

## Quantity of alcohol consumed
A standard drink is sometimes used as a unit measure to estimate the quantity of alcohol consumed, and it varies markedly between countries; in Korea it corresponds to 12 g of pure alcohol. The risk of ALD substantially increases in both sexes when alcohol consumption exceeds 30 g/day. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] An increased risk of liver injury with alcohol consumption exceeding 30 g/day was found in the large-scale Dionysos cohort study performed in northern Italy. [bib_ref] Prevalence of chronic liver disease in the general population of northern Italy:..., Bellentani [/bib_ref] [bib_ref] Alcohol and cirrhosis: dose--response or threshold effect?, Kamper-Jorgensen [/bib_ref] There are also other reports of a proportional relationship between the quantity of alcohol consumed and the risk of ALD. The minimum amount of alcohol required for liver cirrhosis is 20-40 g/ day in men and 10-20 g/day in women, and most retrospective studies also show that the risk of liver injury is increased when alcohol consumption exceeds 40-80 g/day. [bib_ref] Alcohol consumption and the risk of alcohol related cirrhosis in women, Norton [/bib_ref] [bib_ref] Ascitic cirrhosis in relation to alcohol consumption, Pequignot [/bib_ref] [bib_ref] Greater risk of ascitic cirrhosis in females in relation to alcohol consumption, Tuyns [/bib_ref] [bib_ref] Alcohol consumption and the risk of cirrhosis, Batey [/bib_ref] [bib_ref] Determinants of alcohol use and abuse: Impact of quantity and frequency patterns..., Zakhari [/bib_ref] [bib_ref] Alcoholic hepatitis 2010: a clinician's guide to diagnosis and therapy, Amini [/bib_ref] Many prospective studies have found a proportional relationship between the quantity of alcohol consumed and the presence of alcoholic liver injury. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcohol and mortality, Klatsky [/bib_ref] [bib_ref] A prospective study of alcoholic liver disease and mortality, Bouchier [/bib_ref] According to the USA guidelines for non-alcoholic fatty liver disease, significant alcohol consumption has been defined in the past 2 years as exceeding 21 standard drinks per week in men and 14 standard drinks per week in women. [bib_ref] Endpoints and clinical trial design for nonalcoholic steatohepatitis, Sanyal [/bib_ref] [bib_ref] The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by..., Chalasani [/bib_ref] In conclusion, there is a quantity dependent relationship between the amount of alcohol consumed and the risk of ALD. Although most prospective and retrospective studies demonstrate that the prevalence of liver injury increases in proportion to the daily alcohol intake, this relationship does not always hold, suggesting that other factors, such as genetic predisposition, can also be involved. [bib_ref] Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for..., Hrubec [/bib_ref] [bib_ref] Epidemiology of alcoholic liver disease, Grant [/bib_ref] Drinking habit ALD is seen more frequently in daily drinkers than in intermittent drinkers. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] [bib_ref] Alcohol and cirrhosis: dose--response or threshold effect?, Kamper-Jorgensen [/bib_ref] [bib_ref] Epidemiology of alcoholic cirrhosis, Wilkinson [/bib_ref] Binge drinking, a form of drinking habit that has recently surfaced as a social problem in many countries, is defined as consuming more than five drinks for men and four drinks for women over a time period of 2 hours [fig_ref] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking,... [/fig_ref]. [bib_ref] Determinants of alcohol use and abuse: Impact of quantity and frequency patterns..., Zakhari [/bib_ref] This consumption of a large amount of alcohol over a short period of time is associated with the development of ALD. [bib_ref] Diet and stroke, Renaud [/bib_ref] [bib_ref] Effect of binge drinking on the liver: an alarming public health issue?, Mathurin [/bib_ref] The risk of ALD is also increased with habits such as drinking without meals, drinking at multiple locations at a time, mixing drinks, and initiating alcohol drinking at a younger age. [bib_ref] Drinking habits as cofactors of risk for alcohol induced liver damage. The..., Bellentani [/bib_ref] [bib_ref] Drinking patterns, dependency and life-time drinking history in alcoholrelated liver disease, Hatton [/bib_ref] 

## Types of alcohol
While few studies have investigated the association between type of alcohol and liver injury, the available data suggest that liver injury is associated more strongly with the total quantity of alcohol consumed than with the type of alcohol. A notable finding is that small amounts of wine reportedly decrease mortality rates associated with both cardiovascular and non-cardiovascular disease, including liver disease. [bib_ref] Mortality associated with moderate intakes of wine, beer, or spirits, Gronbaek [/bib_ref] [bib_ref] Type of alcohol consumed and mortality from all causes, coronary heart disease,..., Gronbaek [/bib_ref] However, there is still controversy regarding the association between the type of alcohol consumed and the risk of liver injury, especially for liver cirrhosis.

## Sex
The frequency of liver injury is higher among women than men, even when the same quantity of alcohol is consumed. Many studies have found that the incidence of alcoholic liver injury is higher in women than in men with a daily alcohol consumption of 30-80 g. [bib_ref] Alcohol and mortality, Klatsky [/bib_ref] [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] High blood alcohol levels in women. The role of decreased gastric alcohol..., Frezza [/bib_ref] Liver injury occurs more easily in women, including over shorter time periods or involving smaller quantities of alcohol. [bib_ref] Sex-related differences among 100 patients with alcoholic liver disease, Morgan [/bib_ref] [bib_ref] Changing pattern of alcoholic liver disease in Great Britain: relation to sex..., Krasner [/bib_ref] The relatively safe level of alcohol consumption in women has been reported as less than 10-20 g. [bib_ref] Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of..., Pares [/bib_ref] [bib_ref] Greater risk of ascitic cirrhosis in females in relation to alcohol consumption, Tuyns [/bib_ref] [bib_ref] A prospective study of alcoholic liver disease and mortality, Bouchier [/bib_ref] [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] Morbidity in alcoholics. Evidence for accelerated development of physical disease in women, Ashley [/bib_ref] In a large prospective study, the risk of developing ALD with a weekly alcohol consumption of 336-492 g differed significantly between men (7.0) and women (17.0). [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] The risk of liver cirrhosis was dramatically increased in women with a daily alcohol intake exceeding 40 g. [bib_ref] Alcohol consumption and the risk of alcohol related cirrhosis in women, Norton [/bib_ref] [bib_ref] Sex-related differences among 100 patients with alcoholic liver disease, Morgan [/bib_ref] [bib_ref] Morbidity in alcoholics. Evidence for accelerated development of physical disease in women, Ashley [/bib_ref] The blood alcohol concentration is higher in women than in men after consuming the same amount of alcohol, resulting in a higher risk of ALD. [bib_ref] Ethanol elimination in males and females: relationship to menstrual cycle and body..., Marshall [/bib_ref] Women exhibit a decreased level of alcohol dehydrogenase (ADH) in the stomach, resulting in a slower first step of alcohol metabolism, increased bioavailability of alco-hol, and increased risk of liver injury. [bib_ref] High blood alcohol levels in women. The role of decreased gastric alcohol..., Frezza [/bib_ref] In addition, factors such as a lower body distribution of alcohol due to a higher body fat content and an estrogen-induced increase in oxidative stress and inflammation contribute to the increased risk of ALD in women. [bib_ref] Gender differences in pharmacokinetics of alcohol, Baraona [/bib_ref] 

## Ethnicity
There may be an association between ethnicity and the risk of alcoholic liver injury. [bib_ref] Racial and ethnic differences in alcohol-associated aspartate aminotransferase and gamma-glutamyltransferase elevation, Stewart [/bib_ref] The frequency of alcoholic liver cirrhosis is higher in African-American and Latin-American men than in white men, and the death rate for this condition is the highest among Latin-American men. [bib_ref] The critical dimension of ethnicity in liver cirrhosis mortality statistics, Stinson [/bib_ref] These differences seem to be independent of the quantity of alcohol consumed. 106

## Malnutrition
Protein-calorie malnutrition is a common clinical manifestation of ALD.The degree of malnutrition is known to be strongly correlated with the development of complications such as ascites, hepatic encephalopathy, and hepatorenal syndrome, and a gradual increase in mortality.ALD is accompanied by deficiencies in micronutrients such as folate, thiamine, pyridoxine, vitamin A, vitamin E, zinc, and magnesium, and such deficiencies in folate, vitamin E, and zinc may accelerate liver disease. [bib_ref] Nutrition and alcoholic liver disease, Halsted [/bib_ref] [bib_ref] Alcoholic liver disease and malnutrition, Mcclain [/bib_ref] Obesity Obesity increases the severity of alcohol-induced liver injury. [bib_ref] Obesity and alcoholic liver disease, Diehl [/bib_ref] The relationship between obesity and alcohol consumption differs between men and women. [bib_ref] Beer consumption and the 'beer belly': scientific basis or common belief?, Schutze [/bib_ref] [bib_ref] The association of lifetime alcohol use with measures of abdominal and general..., Bergmann [/bib_ref] In obese persons, excessive drinking leads to increased risks of liver disease, [bib_ref] Co-occurrence of obesity and patterns of alcohol use associated with elevated serum..., Tsai [/bib_ref] [bib_ref] A cohort study of the effect of alcohol consumption and obesity on..., Shen [/bib_ref] liver cirrhosis, and mortality. [bib_ref] Body mass index and risk of liver cirrhosis in middle aged UK..., Liu [/bib_ref] [bib_ref] Effect of body mass index and alcohol consumption on liver disease: analysis..., Hart [/bib_ref] [bib_ref] Risk factors for alcoholic liver disease in China, Lu [/bib_ref] High body mass index and fasting glucose are independent risk factors for the progression of liver fibrosis even after correcting for the amount of alcohol consumed and the duration of alcohol abuse, [bib_ref] Risk factors of fibrosis in alcohol-induced liver disease, Raynard [/bib_ref] which is thought to be due to insulin resistance and hyperinsulinemia. [bib_ref] Alcohol and liver fibrosis, Cubero [/bib_ref] Therefore, obesity is an important risk factor for liver cirrhosis in the presence of excessive drinking. [bib_ref] Risk factors of fibrosis in alcohol-induced liver disease, Raynard [/bib_ref] [bib_ref] Excess weight risk factor for alcoholic liver disease, Naveau [/bib_ref] 

## Genetic factors
Concomitant alcoholic liver cirrhosis is seen three times as frequently in monozygotic twins than in dizygotic twins, suggesting a genetic susceptibility in ALD. [bib_ref] Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for..., Hrubec [/bib_ref] Several family studies have also suggested an association between alcohol dependence and genetic factors. [bib_ref] Alcohol problems in adoptees raised apart from alcoholic biological parents, Goodwin [/bib_ref] Genetic polymorphisms in enzymes involved in alcohol metabolism, such as ADH2, ADH3, and aldehyde dehyrogenase 2 (ALDH2), are related to alcohol dependence and ALD. [bib_ref] Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic..., Zintzaras [/bib_ref] The ALDH2*2 allele produces an ALDH2 variant with greatly reduced enzymatic activity and delayed aldehyde metabolism, and a lower risk of developing alcohol addiction; a meta-analysis of data related to Asian populations found that the presence of the ALDH2*2 allele was associated with a lower frequency of alcohol dependence and ALD. [bib_ref] Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele..., Li [/bib_ref] The frequency of the ALDH2*2 allele was significantly lower among Korean patients with alcoholic liver cirrhosis than among those without it. [bib_ref] Genetic polymorphisms of alcohol-metabolizing enzymes and cytokines in patients with alcohol induced..., Kim [/bib_ref] [bib_ref] Association between polymorphisms of ethanol-metabolizing enzymes and susceptibility to alcoholic cirrhosis in..., Lee [/bib_ref] Mutation of the gene encoding patatin-like phospholipase domain-containing protein 3 (PNPLA3) has been suggested as a genetic risk factor for ALD, with a higher frequency of PNPLA3 rs738409 GG found in a highrisk group for progression to ALD. [bib_ref] Meta-analysis of the influence of I148M variant of patatin-like phospholipase domain containing..., Sookoian [/bib_ref] Two recent meta-analyses have provided evidence of an association between genetic polymorphisms in the gene encoding interleukin (IL)-10 and alcoholism, [bib_ref] Interleukin-10 gene polymorphism is associated with alcoholism but not with alcoholic liver..., Marcos [/bib_ref] and an increased risk of ALD among alcoholics with allelic variants of the gene encoding glutathione-S -transferase. [bib_ref] Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease, Marcos [/bib_ref] However, these candidate genes have not been confirmed in Korean studies. Studies of ALD have thus far been limited to identifying specific genetic mutations, indicating a need for genome-wide association analyses.

## Viral factors
The prevalence of hepatitis C virus (HCV) is higher among alcoholics than non-alcoholics, and the combination of HCV and alcohol has a synergistic effect on liver injury. [bib_ref] Hepatitis C virus and alcohol, Siu [/bib_ref] Possible underlying mechanisms for this include immune suppression, stimulation of viral replication, increased oxidative stress, and hepatocyte cytoxicity. Alcohol intake by patients with HCV infection increases the risk of liver cirrhosis and HCC, [bib_ref] The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in..., Harris [/bib_ref] and reduces their responses to interferon treatment. [bib_ref] Alcohol use and treatment of hepatitis C virus: results of a national..., Anand [/bib_ref] Unlike for HCV, data is limited regarding the association between hepatitis B virus (HBV) and progression of liver disease due to alcohol consumption. Nevertheless, alcohol consumption does have an adverse effect on hepatitis patients. [bib_ref] Southern Europe as an example of interaction between various environmental factors: a..., Donato [/bib_ref] Specifically, alcohol directly affects host-cell metabolism and gene expression, which acts to increase the expression and replication of viral genes. [bib_ref] Ethanol and hepatocellular injury, French [/bib_ref] Therefore, patients with HBV should avoid consuming alcohol. 97

## Smoking
Smoking is a risk factor for ALD, causes oxidative stress, and accelerates fibrosis in patients with ALD.Abstaining from smoking is therefore recommended in patients with ALD.

## Coffee
Many studies have found that the risk of ALD reduces as coffee consumption increases, and that coffee may suppress the development of ALD. [bib_ref] Cof fee and liver diseases, Muriel [/bib_ref] [bib_ref] Coffee, cirrhosis, and transaminase enzymes, Klatsky [/bib_ref] [bib_ref] Coffee, caffeine, and the risk of liver cirrhosis, Corrao [/bib_ref] [bib_ref] Does coffee protect against liver cirrhosis?, Gallus [/bib_ref] A marked decrease in mortality due to liver disease was found among those who drink three or more cups of coffee per day compared to those who drink two or fewer cups per day. [bib_ref] Coffee intake and mortality from liver cirrhosis, Tverdal [/bib_ref] The consumption of caffeinated drinks other than coffee is not associated with a decreased incidence of liver cirrhosis, which suggests that substances other than caffein in coffee have an important role in ALD. 140

## [recommendations]

## Excessive drinking, defined as an average alcohol consumption exceeding 40 g/day in men and 20 g/day in women, increases the risk of alcoholic liver injury and should be avoided. (a1) 5. daily or binge drinking increases the risk of ald and should be avoided. (a1)
6. Alcohol abstinence is necessary for patients with chronic viral hepatitis. (B1) 7. Obesity and smoking increase ALD, and so weight control and smoking cessation are recommended. (B1)

# Future research
1. There is a need to characterize cases of ALD that are accompanied by other liver diseases such as viral hepatitis.
2. There is a need to assess the interactions between the risk factors for ALD.
3. There is a need for genome-wide association studies involving patients with ALD.

## Pathophysiology of alcoholic liver dis-ease
The pathophysiology of ALD varies according to the stage of the disease and the presence of genetic and non-genetic factors affect the onset and clinical progression of ALD.models, and because these experiments only cause moderate degrees of liver disease, fibrosis, and injury, the mechanism underlying the pathophysiology of ALD in humans has not yet been fully elucidated. 144

## Alcoholic fatty liver (steatosis)
Steatosis is the initial reaction to alcohol abuse and is characterized by the adiposis of hepatocytes. Alcoholic fatty liver occurs through many complex mechanisms, via the following four steps. [bib_ref] Alcoholic liver disease: pathogenesis and new therapeutic targets, Gao [/bib_ref] First, alcohol oxidation leads to increases in the synthesis of nicotinamide adenine dinucleotide (NADH), triglycerides, and fatty acids, and to the suppression of mitochondrial -oxidation. [bib_ref] Alcohol and lipids, Baraona [/bib_ref] Second, there is an increase in the influx of free fatty acids from the adipose tissue and chylomicrons from the visceral mucosa into the liver. [bib_ref] Alcohol and lipids, Baraona [/bib_ref] Third, ethanol mediates the suppression of adenosinemonophosphate-activated protein kinase (AMPK) activation, resulting in an increase in lipid biosynthesis, suppression of peroxisome proliferator-activated receptor  (PPAR), and decrease in lipolysis due to the activation of sterol regulatory element binding protein 1c (SREBP1c). [bib_ref] Role of adiponectin in the protective action of dietary saturated fat against..., You [/bib_ref] [bib_ref] Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in..., Ji [/bib_ref] [bib_ref] Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage, Nakajima [/bib_ref] Fourth, there is acetaldehyde-induced mitochondria and microtubule damage, resulting in decreased NADH oxidation and accumulation of very-low-density lipoprotein (VLDL). 145

## Alcoholic steatohepatitis
Steatohepatitis is defined as a condition with fatty liver, inflammatory cell infiltration comprising mainly polymorphonuclear leukocytes, and hepatocyte injury. In ALD, although alcoholic steatohepatitis is a necessary step in the progression to liver fibrosis and cirrhosis, liver fibrosis is not included in the definition of steatohepatitis. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Currently, there is no consensus on the pathologic classification of steatohepatitis, and the severity of this condition is determined by environmental factors such as the quantity of alcohol consumed, lifestyle, and dietary habits. [bib_ref] Alcoholic liver disease: pathogenesis and new targets for therapy, Altamirano [/bib_ref] Various factors affect the onset of alcoholic steatohepatitis. First, the toxic effect of acetaldehyde and the production of oxygen free radicals affect the development of this condition. Ethanol is metabolized into acetaldehyde by ADH within the cytosol, P450 within the microsomes, and catalase within the peroxisomes. Ethanol metabolism results in the production of oxygen free radicals, peroxidation of lipids, and a decrease in mitochondrial glutathione and S-adenosyl-L-methionine (SAMe) levels, and these metabolites sensitize the hepatocyte to injury. Acetaldehyde is then metabo-lized by mitochondrial ADH into acetate, which combines with protein and DNA to alter their function, ultimately affecting protein synthesis. [bib_ref] Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption, Niemela [/bib_ref] [bib_ref] Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde, Theruvathu [/bib_ref] These products then act as auto-antigens to activate the immune system, increasing the lymphocyte count and causing liver injury. Furthermore, acetaldehyde causes oxidative stress and apoptosis through mitochondrial damage and impairment of glutathione function. [bib_ref] Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and..., Seitz [/bib_ref] Second, there are pro-inflammatory cytokines. Alcohol metabolites and oxygen free radicals stimulate the signal-transduction pathways related to nuclear factor-B (NFB), signal transducer and activator of transcription-Janus kinase (STAT-JAK), and c-Jun N-terminal kinase (JNK), which induce the production of inflammation mediators such as tumor necrosis factor- (TNF-), IL-17, CXC chemokines, and osteopontin. [bib_ref] Intrahepatic gene expression in human alcoholic hepatitis, Seth [/bib_ref] Alcohol abuse disrupts the normal intestinal microbiota and increases the permeability of the endotoxins produced by intestinal bacteria, increasing serum lipopolysaccharide levels, [bib_ref] endotoxin-neutralizing-capacity, sCD14, sI-CAM-1, and cytokines in patients with various degrees of alcoholic..., Urbaschek [/bib_ref] and causing an inflammatory reaction in Kupffer cells via the CD14/toll-like receptor 4 (TLR 4) pathway. [bib_ref] Alcoholic liver injury involves activation of Kupffer cells by endotoxin, Thurman [/bib_ref] This inflammatory environment in ALD causes the infiltration of polymorphonuclear leukocytes, production of oxygen free radicals, and hepatocyte injury.

## Fibrosis in alcoholic liver disease
Liver fibrosis is a recovery response seen in every form of chronic liver injury, and is characterized by the excessive accumulation of extracellular matrix proteins such as collagen. [bib_ref] Liver fibrosis, Bataller [/bib_ref] [bib_ref] Mechanisms of hepatic fibrogenesis, Friedman [/bib_ref] Fibrosis can occur in alcoholic steatohepatitis, and occurs mainly where ADH is located, typically in pericentral and perisinusoidal regions. [bib_ref] Liver fibrosis, Bataller [/bib_ref] In the progression stage, collagen bands become apparent and bridging fibrosis develops. This stage precedes liver cirrhosis and the formation of regeneration nodules. The cytological and molecular biological mechanism of fibrosis in ALD is currently not well understood. [bib_ref] Alcohol and liver fibrosis, Cubero [/bib_ref] Metabolites of alcohol such as acetaldehyde directly activate hepatic stellate cells (HSCs), the main producers of collagen in the injured liver, and play a major role in the production of portal fibroblasts and bone-marrow-derived myofibroblasts. [bib_ref] Liver fibrosis, Bataller [/bib_ref] [bib_ref] Mechanisms of hepatic fibrogenesis, Friedman [/bib_ref] HSCs are also activated by injured hepatocytes, activated Kupffer cells, and infiltration of polymorphonuclear leukocytes. These cells secrete growth factors such as transforming growth factor-1 (TGF-1) and platelet-derived growth factor (PDGF), cytokines such as leptin, angiotensin II, IL-8, and TNF-, soluble mediators such as nitric oxide, and oxygen free radicals. Importantly, oxygen free radicals stimulate the signaling pathway within HSCs, which includes extracellular signal-regulated kinase, phosphoinositide 3 kinase (PI3K)/Akt, and JNK. [bib_ref] Cytokines and renin-angiotensin system signaling in hepatic fibrosis, Moreno [/bib_ref] These oxygen free radicals also enhance the activity of tissue inhibitor of metalloproteinase 1, reducing the activity of metalloproteinases and stimulating the accumulation of extracellular matrix proteins such as collagen.

# Future research
1. There is a need to study how genetic differences influence the progression of liver fibrosis.

## Clinical diagnosis of alcoholic liver disease
For the diagnosis of ALD, the presence of heavy drinking, which is a prerequisite, must be confirmed through history and questionnaires and may be supplemented by blood tests. Identifying liver disease might require methods such as a physical examination, blood tests, and radiologic studies, and a liver biopsy may also be performed under certain circumstances.

## History taking
The type of alcoholic beverage, quantity of alcohol consumed, weekly drinking frequency, and duration of drinking are all important data to obtain during history-taking. Since patients frequently deny or underreport the amount of drinking, it is helpful to obtain the drinking history through questionnaires or from family members. Although currently there is no consensus on the minimum amount of alcohol required for ALD, a cutoff that is often applied is an average alcohol intake exceeding 40 g/day in men and 20 g/ day in women. [bib_ref] Prediction of risk of liver disease by alcohol intake, sex, and age:..., Becker [/bib_ref] [bib_ref] Detecting symptoms of alcohol abuse in primary care settings, Mcquade [/bib_ref] [bib_ref] Biological correlates and detection of alcohol abuse and alcoholism, Eckardt [/bib_ref] [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] The average daily alcohol intake is calculated using the following equation: [amount consumed (mL)alcohol by volume (%)specific gravity of alcohol (0.785)number of drinking days per week]7. For example, if a person drinks one Soju bottle (360 mL, 19% alcohol by volume) three times a week, then the amount consumed would be (360 mL19%0.785)100 =53.7 g, and the average daily alcohol intake would be (53.7 g3) 7=23 g. The alcohol contents of various forms of alcoholic beverage are listed in [fig_ref] Table 3: Alcohol contents of different types of alcoholic beverage The Korean Association for... [/fig_ref].
A standard drink in Korea contains 12 g of alcohol (as defined by the Ministry of Health and Welfare), and so is approximately equal to 1.5 nips of Soju (90 mL), 1 can of beer (355 mL), 1 bowl of Makgeolli (230 mL), 1 glass of wine (120 mL), or 1 nip of whisky (40 mL).

## Symptoms and signs
The effects of ALD can range from being asymptomatic to liver failure and death. While symptoms and signs such as epigastric discomfort, fever, fatigue, anorexia, malaise, weight loss, tender hepatomegaly, jaundice, spider angiomata, cachexia, gynecogenic changes, and right upper-quadrant abdominal bruit may occur, they are nonspecific. [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] [bib_ref] The importance of a coexistent hepatic rub and bruit. A clue to..., Sherman [/bib_ref] [bib_ref] Enlarged, tortuous arteries and hepatic bruit, Goldstein [/bib_ref] In severe alcoholic hepatitis or liver cirrhosis, symptoms and signs such as ascites, lower extremity edema, hepatic encephalopathy, and esophageal variceal bleeding may be seen. [bib_ref] Alcoholic hepatitis, Mendenhall [/bib_ref] Damage to organs other than the liver may manifest as gastritis, peptic ulcer, pancreatitis, neuropathy, myopathy, Dupuytren's contracture, cardiomyopathy, arrhythmia, anemia, parotid gland hypertrophy, lacrimal gland hypertrophy, altered mental status due to delirium tremens, and sleep disorders. [bib_ref] Relationship between ethanol-related diseases and nutritional status in chronically alcoholic men, Estruch [/bib_ref] [bib_ref] The risk of alcohol, Anderson [/bib_ref] [bib_ref] Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to..., Lazarevic [/bib_ref] [bib_ref] H pylori infection and other risk factors associated with peptic ulcers in..., Salih [/bib_ref] [bib_ref] Alcohol drinking and risk of hospitalization for heart failure with and without..., Klatsky [/bib_ref] [bib_ref] Alcoholic skeletal muscle myopathy: definitions, features, contribution of neuropathy, impact and diagnosis, Preedy [/bib_ref] 

## Blood tests
Blood tests for detecting a history of chronic alcohol consumption include serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltranspeptidase (GGT), mean corpuscular volume (MCV), and carbohydrate deficient transferrin (CDT). [bib_ref] Screening for excessive alcohol drinking. Comparative value of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and..., Yersin [/bib_ref] [bib_ref] Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl..., Reynaud [/bib_ref] [bib_ref] CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative..., Conigrave [/bib_ref] Combining the results of several of these tests is superior to using any single test. [bib_ref] Combinations of carbohydrate-deficient transferrin, mean corpuscular erythrocyte volume, gamma-glutamyltransferase, homocysteine and folate..., Rinck [/bib_ref] In ALD, AST elevation is more prominent than that of ALT, but the levels of AST and ALT usually do not exceed 300 IU/L. Alcoholic hepatitis may be suspected when the AST/ALT ratio exceeds 2, 174,175 and has a very high probability when it exceeds 3. [bib_ref] High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy..., Nyblom [/bib_ref] Because GGT is elevated by alcohol consumption in about 75% of habitual drinkers, it is useful to determine whether a patient with ALD has indeed abstained from drinking. [bib_ref] Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase, Seitz [/bib_ref] However, care must be exercised since GGT may also be elevated due to non-alcoholic liver disease, obesity, diabetes, smoking, or drug use. [bib_ref] Additive effects of moderate drinking and obesity on serum gammaglutamyl transferase activity, Puukka [/bib_ref] [bib_ref] Alcohol biomarkers in applied settings: recent advances and future research opportunities, Litten [/bib_ref] In general, GGT levels recover slowly following abstinence from alcohol. MCV may also be elevated by heavy drinking, and is occasionally observed when the daily alcohol consumption exceeds 60 g. [bib_ref] Macrocytosis of chronic alcoholism, Wu [/bib_ref] [bib_ref] Biochemical and haematological markers of alcohol intake, Whitehead [/bib_ref] While MCV elevation alone has a low sensitivity, this is increased when accompanied by GGT elevation or when the levels decrease following treatment; [bib_ref] Biochemical detection and monitoring of alcohol abuse and abstinence, Sharpe [/bib_ref] MCV returns to normal after several months of abstinence. [bib_ref] Macrocytosis in alcohol-related liver disease: its value for screening, Morgan [/bib_ref] While CDT is known as a useful biochemical marker for heavy drinking, [bib_ref] Screening for excessive alcohol drinking. Comparative value of carbohydrate-deficient transferrin, gamma-glutamyltransferase, and..., Yersin [/bib_ref] [bib_ref] Objective diagnosis of alcohol abuse: compared values of carbohydrate-deficient transferrin (CDT), gamma-glutamyl..., Reynaud [/bib_ref] [bib_ref] Carbohydrate-deficient transferrin as a marker of chronic alcohol abuse: a critical review..., Arndt [/bib_ref] [bib_ref] Carbohydrate-deficient transferrin (CDT) as a marker of alcohol abuse: a critical review..., Bortolotti [/bib_ref] it is not a popular measure due to its high specificity but low sensitivity. [bib_ref] Carbohydrate-deficient transferrin as compared to other markers of alcoholism: a systematic review, Salaspuro [/bib_ref] Other findings seen with progression of liver disease include a decrease in serum albumin, increase in bilirubin, prolonged prothrombin time, and decrease in platelet count.

## Radiologic tests
Radiologic tests can be used to identify steatosis, evaluate the progression of liver disease and the presence of complications, and rule out diseases such as biliary tract disease and liver tumors. [bib_ref] Prognostic indicators in compensated cirrhosis, Zoli [/bib_ref] However, radiologic tests alone cannot be used for the definitive diagnosis of alcohol as the cause of liver disease. Ultrasonography is useful for identifying steatosis, and findings such as liver morphology and splenomegaly can be used to evaluate the progression of liver disease. [bib_ref] A position statement on NAFLD/NASH based on the EASL 2009 special conference, Ratziu [/bib_ref] Although abdominal computed tomography (CT) scans and magnetic resonance imaging (MRI) are more accurate than ultrasonography for evaluating steatosis, there currently are no standardized test protocols and these methods are costly. [bib_ref] Noninvasive quantitation of human liver steatosis using magnetic resonance and bioassay methods, Assignies [/bib_ref] [bib_ref] Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic..., Mancini [/bib_ref] Liver elastography may be used to indirectly evaluate the degree of fibrosis in ALD. This test is based on the correlation between liver stiffness due to fibrosis and liver elasticity, and employs ultrasonography or MRI. [bib_ref] Ultrasound-based Liver Elastography: Recent Advances, Lee [/bib_ref] [bib_ref] Clinical applications of transient elastography, Jung [/bib_ref] [bib_ref] Performance of magnetic resonance elastography and diffusion-weighted imaging for the staging of..., Wang [/bib_ref] While these tests have the advantage of being noninvasive, they are also non-standardized and care must be exercised when interpreting the results since the presence of steatosis and severe inflammation may interfere with correct interpretations.

## Histologic diagnosis

## Histologic findings
A liver biopsy is the standard test for making a definitive diagnosis of ALD and evaluating the inflammatory activity and fibrosis stage. Common histologic findings in ALD include steatosis, hepatocyte injury, lobular inflammation, Mallory-Denk bodies, megamitochondria, ductular proliferation, ductular bilirubinostasis, intraparenchymal cholestasis, fibrosis, and liver cirrhosis. [bib_ref] Morphology of alcoholic liver disease, Lefkowitch [/bib_ref] [bib_ref] Histologic spectrum of alcoholic liver disease, Macsween [/bib_ref] Although histologic findings are sometimes used to classify ALD into simple steatosis or fatty liver, steatohepatitis, hepatic fibrosis, or liver cirrhosis, it is possible for these conditions to coexist in a patient, and currently there is no definitive classification scheme for these findings.
Alcoholic fatty liver is the most common finding in ALD, wherein hepatocytes exhibit typical macrovesicular steatosis characteristics such as cell expansion due to large fat droplets, and displacement of the nucleus toward the cell membrane. [bib_ref] Pathology of alcoholic liver disease. VA Cooperative Study Group 119, French [/bib_ref] These changes first appear in the central zone of the lobule and progress over time to eventually encompass the entire lobule. [bib_ref] Pathology of alcoholic liver disease. VA Cooperative Study Group 119, French [/bib_ref] The ballooning degeneration of hepatocytes is occasionally accompanied by apoptotic bodies. Mallory-Denk bodies, the eosinophilic and crescentic aggregation of intermediate filaments and other proteins around the nucleus, may also be seen.
Specific histologic characteristics of alcoholic steatohepatitis include steatosis, ballooning degeneration of hepatocytes, and lobular infiltration by inflammatory cells, especially by polymorphonuclear neutrophils.Megamitochondria and Mallory-Denk bodies, although not specific for ALD, are nonetheless suggestive of active drinking. Periportal ductular proliferation, ductular bilirubinostasis, and intraparenchymal cholestasis may also be observed. Fibrous tissue may begin to accumulate around the terminal hepatic vein in the lobular central zone, and then progress to perisinusoidal and pericellular areas, resulting in the characteristic "chicken-wire fibrosis." Sclerosing hyaline necrosis refers to hepatocyte necrosis in zone 3 accompanied by perivenular and perisinusoidal fibrosis. The occurrence of terminal hepatic vein occlusion and sinusoid narrowing will increase the portal pressure and thicken the fibrous septum, ultimately resulting in the micronodular form of liver cirrhosis. [bib_ref] Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological..., Mathurin [/bib_ref] Clinical application of liver biopsy A liver biopsy is performed percutaneously with sonographic guidance or via the jugular vein; the latter approach is used when a percutaneous liver biopsy is contraindicated due to severe coagulopathy or moderate-to-severe ascites. [bib_ref] Transjugular liver biopsy--indications, adequacy, quality of specimens, and complications--a systematic review, Kalambokis [/bib_ref] A liver biopsy carries the risk of complications such as intraperitoneal hemorrhage and abdominal pain, and may be fatal in rare instances. Furthermore, the accuracy of a liver biopsy is limited by factors such as sampling error and interobserver variation. A liver biopsy, while not necessary for diagnosis or treatment, is useful for establishing an ALD diagnosis and for assessing the severity of disease to predict the prognosis in all patients with suspected ALD. [bib_ref] Appropriateness of liver biopsy, Poynard [/bib_ref] [bib_ref] Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with..., Naveau [/bib_ref] Around 20% of alcohol abusers with abnormal liver function tests were found to have etiologies other than alcohol, and only 70% of patients with suspected severe alcoholic hepatitis were definitively diagnosed with alcoholic hepatitis using a liver biopsy. [bib_ref] Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy..., Levin [/bib_ref] In patients with severe alcoholic hepatitis, the existence of severe inflammation was a useful marker for whether treatment with steroids would be effective. [bib_ref] Survival and prognostic factors in patients with severe alcoholic hepatitis treated with..., Mathurin [/bib_ref] In patients with a diagnosis of alcoholic steatohepatitis without sepsis, severe intraparenchymal cholestasis, along with Maddrey's discriminant function (DF) score, was an independent predictor for short-term mortality. [bib_ref] Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis, Spahr [/bib_ref] Also, in patients with acute exacerbation of alcoholic liver cirrhosis, early liver biopsy was useful for confirming the diagnosis of alcoholic hepatitis as well as estimating the prognosis. [bib_ref] The role of liver biopsy in the diagnosis and prognosis of patients..., Mookerjee [/bib_ref] A liver biopsy is rarely performed for the diagnosis and treatment of ALD in Korea. However, for patients with severe alcoholic hepatitis who may need specific medical treatment such as corticosteroids, a liver biopsy may be considered for a definitive diagnosis and for determining the prognosis.

## Classification and clinical features of alcoholic liver disease
The diagnosis of ALD may be made in patients with a daily alcohol consumption exceeding 40 g in men and 20 g in women, with clinical, laboratory, radiological, or histological evidence of liver disease, and in whom other etiologies for liver injury can be excluded. Although excluding other etiologies of liver disease such as viral hepatitis, non-alcoholic fatty liver disease, and drug-induced liver injury is helpful for diagnosing ALD, because it is possible that more than one etiology is present, it is important to identify which is the main lesion. ALD is categorized based on the underlying pathology into alcoholic fatty liver, alcoholic hepatitis, and alcoholic liver cirrhosis [fig_ref] Table 4: Clinical features of alcoholic liver disease PMNL, polymorphonuclear leukocyte [/fig_ref].While exclusive forms do exist, overlapping clinical features are seen in most cases.
Alcoholic fatty liver is usually asymptomatic. In blood tests, AST, ALT, or bilirubin levels may be normal or mildly elevated. [bib_ref] Diagnosis and therapy of alcoholic liver disease, Levitsky [/bib_ref] While these values typically return to normal following several weeks of alcohol abstinence, [bib_ref] Histologic spectrum of alcoholic liver disease, Macsween [/bib_ref] in some cases the disease may progress to liver fibrosis or cirrhosis. [bib_ref] Prospective evaluation of alcohol abuse and alcoholic liver injury in men as..., Sorensen [/bib_ref] Alcoholic hepatitis presents with various clinical features. In mild cases it is difficult to distinguish alcoholic hepatitis from alcoholic fatty liver, while in severe cases alcoholic hepatitis carries a high risk of death due to liver failure. Liver fibrosis may lead to portal hypertension, making it difficult to distinguish it from liver cirrhosis. [bib_ref] Alcoholic hepatitis, Mendenhall [/bib_ref] Blood tests may reveal anemia, leukocytosis, and thrombocytopenia, and the AST/ALT ratio typically exceeds 2. [bib_ref] The SGOT/SGPT ratio--an indicator of alcoholic liver disease, Cohen [/bib_ref] [bib_ref] High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy..., Nyblom [/bib_ref] [bib_ref] Serum activity of mitochondrial aspartate aminotransferase: a sensitive marker of alcoholism with..., Nalpas [/bib_ref] While these clinical features usually resolve following abstinence, they may last more than 6 months in severe alcoholic hepatitis.
Alcoholic liver cirrhosis and liver cirrhosis due to other etiologies share similar clinical features. [bib_ref] A systematic review of the diagnostic accuracy of physical examination for the..., De Bruyn [/bib_ref] While it is not uncommon to be asymptomatic, anorexia and malnutrition due to habitual drinking can result in weight loss and skeletal muscle atrophy. Progression of liver cirrhosis may cause spider angioma, gynecomastia, and jaundice, and portal hypertension may result in variceal bleeding, ascites, and hepatic encephalopathy. Even in alcoholic liver cirrhosis, alcohol abstinence and proper nutrition can result in improved clinical features. 48

## [recommendations]
8. Thorough history-taking for details such as the amount, frequency, duration, and type of drinking is necessary to make a diagnosis of ALD. (A1) 9. With adequate history of excessive drinking and clinical evidence for liver disease, the diagnosis of ALD can be made. In patients with severe alcoholic hepatitis requiring corticosteroid treatment, a liver biopsy should be considered for both a definitive diagnosis and estimation of prognosis. (B1)

# Future research
1. There is a need to evaluate the usefulness of a liver biopsy in ALD. 2. There is a need for standardized histological criteria for the classification and evaluation of the severity of ALD.
3. There is a need to develop noninvasive diagnostic methods for ALD.

## Prognosis evaluation for alcoholic liver disease
Evaluation of the prognosis for ALD focuses mainly on alcoholic hepatitis. Severe alcoholic hepatitis is traditionally defined as having a DF score of 32 or as having the evidence of hepatic encephalopathy. Severe alcoholic hepatitis has a poor prognosis without treatment, with a 28-day mortality rate of 30-50%. [bib_ref] Survival and prognostic factors in patients with severe alcoholic hepatitis treated with..., Mathurin [/bib_ref] In patients with alcoholic hepatitis of all severities, early prognosis stratification and treatment decisions are important for improving the prognosis. Various prognostic models in patients with alcoholic hepatitis have been developed over the past decades, such as the DF score, Model for End-Stage Liver Disease (MELD) score, Glasgow Alcoholic Hepatitis Score (GAHS), and the ABIC (Age, Bilirubin, International Normalized Ratio, Creatinine) score [fig_ref] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/fig_ref].
The DF score was first introduced in 1978 in a clinical trial assessing the treatment response to corticosteroids in patients with alcoholic hepatitis, and was modified slightly in 1989. The modified DF (mDF) score has been widely used for stratifying the severity of alcoholic hepatitis in practice. [bib_ref] Corticosteroid therapy of alcoholic hepatitis, Maddrey [/bib_ref] Patients with alcoholic hepatitis and an mDF score of <32 had a survival rate of 90%, while those with an mDF score of 32 had a survival of rate of 50-65%. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] The MELD score was initially developed to estimate the prognosis in patients who had undergone the transjugular intrahepatic portosystemic shunt (TIPS) procedure, and was later adopted as a model for selecting candidates for liver transplantation.Several studies have investigated the utility of the MELD score for assessing the prognosis of patients with ALD, albeit with different cutoff values. [bib_ref] MELD accurately predicts mortality in patients with alcoholic hepatitis, Dunn [/bib_ref] [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] [bib_ref] Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis..., Sheth [/bib_ref] [bib_ref] Influence of serum sodium on MELD-based survival prediction in alcoholic hepatitis, Vaa [/bib_ref] One study proposed that a MELD score of 21 provided high sensitivity and specificity in detecting patients with a poor prognosis. The MELD score was found to be a more useful predictor of prognosis in patients with accompanying ascites or hepatic encephalopathy. [bib_ref] MELD accurately predicts mortality in patients with alcoholic hepatitis, Dunn [/bib_ref] [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] The GAHS was developed to overcome the limitations of other models in assessing the prognosis of patients with alcoholic hepatitis, such as the low specificity of the mDF score and the unclear cutoff value for the MELD score. [bib_ref] Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and..., Forrest [/bib_ref] In patients with an mDF score of 32, those with a GAHS of <9 gained no survival benefit with steroid treatment, while those with a GAHS of 9 had a poor prognosis without steroid treatment. Therefore, the GAHS may be useful for identifying a subgroup of patients who may derive benefit from corticosteroids among patients with an mDF score of 32. [bib_ref] The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids, Forrest [/bib_ref] The ABIC model was constructed using four components: age, serum bilirubin, prothrombin time, and serum creatinine. Using cutoff values of 6.71 and 9.0, the ABIC model divided patients with alcoholic hepatitis into those with a low, intermediate, and high risk of death at 90 days, which was also useful in predicting mortality at 1 year. [bib_ref] A new scoring system for prognostic stratification of patients with alcoholic hepatitis, Dominguez [/bib_ref] Patients with an intermediate risk of death may benefit from corticosteroid or pentoxifylline therapy. [bib_ref] A new scoring system for prognostic stratification of patients with alcoholic hepatitis, Dominguez [/bib_ref] One study found the hepatic venous pressure gradient (HVPG) to be higher in patients who died due to alcoholic hepatitis than in those who survived, while another study found no association between HVPG and the short-or long-term prognosis of patients with alcoholic hepatitis. [bib_ref] Prognostic value of hepatic venous pressure gradient for in-hospital mortality of patients..., Rincon [/bib_ref] [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] Further research on this subject is needed.
Some studies have found that the prognosis in patients with alcoholic hepatitis can be estimated more accurately from the Child-Turcotte-Pugh (CTP) score and the mDF score than from the MELD score, [bib_ref] Comparison of model for end-stage liver disease score with discriminant function and..., Jeong [/bib_ref] but most studies show that the mDF and MELD scores are more predictive than the CTP score. Hence, the CTP score is not usually used for estimating prognosis in alcoholic hepatitis. [bib_ref] MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant..., Srikureja [/bib_ref] [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] [bib_ref] Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score..., Ali [/bib_ref] Korean studies have found the mDF score to be an independent prognostic factor for alcoholic hepatitis, with the MELD score yielding comparable results.Based on recent studies, the mDF, MELD, ABIC scores, and GAHS appear to be better prognostic models than the CTP score. All of the models were found to be good predictors of short-term mortality but poor predictors of long-term mortality. [bib_ref] The utility of scoring systems in predicting early and late mortality in..., Palaniyappan [/bib_ref] Based on these studies, the mDF and MELD scores are useful for predicting short-term mortality and guiding treatment decisions in patients with severe alcoholic hepatitis. The GAHS and the ABIC score also show potential as prognostic models for alcoholic hepatitis. [bib_ref] Comparison of Maddrey Discriminant Function, Child-Pugh Score and Glasgow Alcoholic Hepatitis Score..., Ali [/bib_ref] [bib_ref] Treatment of severe forms of alcoholic hepatitis: Where are we going?, Mathurin [/bib_ref] With respect to predicting survival in patients treated with corticosteroids, early change in bilirubin level (ECBL; defined as a change in bilirubin levels after 1 week of treatment) and the Lille model based on ECBL are notable and are described in the following section. [bib_ref] Bilirubin response to corticosteroids in severe alcoholic hepatitis, Morris [/bib_ref] [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] [Recommendation] [bib_ref] Psychometric properties of the alcohol use disorders identification test: a Korean version, Kim [/bib_ref]. The mDF score and the MELD score are useful for determining the prognosis and guiding treatment in patients with alcoholic hepatitis. (A1)

# Future research
1. There is a need for clinical models that predict poor prognosis among patients with an mDF score of <32.

## Treatment for alcoholic liver disease
The treatment for ALD varies depending on the stage of the disease. For alcoholic fatty liver, abstinence or controlled drinking is the most important treatment. The various treatment approaches for alcoholic hepatitis are described in separate section. For alcoholic liver cirrhosis, treatment involves abstinence and following the KASL Clinical Practice Guidelines for Liver Cirrhosis.

## Therapy for alcohol withdrawal syndrome
AWS refers to the group of symptoms and signs that occur 6-24 hours following the abrupt cessation of alcohol consumption among those who habitually drink excessively. Symptoms and signs include those of autonomic nervous system activation such as tachycardia, sweating, and hand tremor, gastrointestinal symptoms such as nausea and vomiting, and if severe, deficits in cognitive function such as hallucinations, seizures, and withdrawal delirium that may lead to death. Alcohol withdrawal seizure is a rebound phenomenon that can occur following the abrupt cessation of alcohol consumption that is due to a lowered seizure threshold. Because there is no need for anticonvulsants in patients with alcohol withdrawal seizure, it is necessary to distinguish it from genuine seizure. Delirium tremens is a serious complication of AWS, typical symptoms of which include altered mental status, disorientation to person, place, or time, and intra-and inter-daily variations of symptoms. [bib_ref] Management of alcohol withdrawal delirium. An evidence-based practice guideline, Mayo-Smith [/bib_ref] The symptoms are typically worst at 3-5 days following the abrupt cessation of alcohol consumption. Signs of autonomic nervous system activation such as high fever, tachycardia, hypertension, and sweating, as well as comorbidities such as dehydration, electrolyte imbalance, renal failure, head trauma, infection, gastrointestinal bleeding, pancreatitis, and liver failure should be carefully and strictly evaluated, and frequent monitoring of vital signs is necessary. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] The Clinical Institute Withdrawal Assessment for Alcohol (CIWA) is known to be helpful for evaluating the severity of AWS, treatment planning, and facilitating objective communication between healthcare providers. However, high scores may be seen in psychiatric conditions that are similar to AWS, such as anxiolytic withdrawal, anxiety disorder, and physical conditions such as sepsis, hepatic encephalopathy, and severe pain. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] For this reason, the CIWA protocol is not recommended for a diagnosis of AWS. [bib_ref] Korean addiction treatment guidelines series (II): Pharmacological treatment of alcohol withdrawal, Kim [/bib_ref] A comparison of inpatient versus outpatient treatment revealed that outpatient treatment was more cost-effective, but there was no difference in the alcohol abstinence rate at 6 months. [bib_ref] Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with..., Hayashida [/bib_ref] If there are serious complications of AWS such as delirium, seizures, or physical and/or psychological comorbidities, admission and inpatient treatment is recommended, with treatment goals of symptomatic relief without complications and maintenance of abstinence as a long-term treatment. Therefore, psychiatric consultation is recommended for the evaluation and acute management of AWS and long-term abstinence planning.
For pharmacological treatment, long-acting benzodiazepines (e.g., chlordiazepoxide and diazepam) are recommended for the prevention of seizures, with effects such as anxiety relief, sedation, and somnolence via activation of gamma-aminobutyric acid (GABA). [bib_ref] Pharmacotherapies for alcohol abuse. Withdrawal and treatment, Saitz [/bib_ref] Lorazepam, which is an intermediate-acting benzodiazepine, is recommended for patients with severe AWS, advanced age, recent head trauma, liver failure, respiratory failure, other serious medical comorbidities, or obesity. Lorazepam is started at a dosage of 6-12 mg/day and tapered off following resolution of the withdrawal symptoms [fig_ref] Table 6: Treatment of alcohol withdrawal syndrome [/fig_ref]. [bib_ref] Alcohol abuse and depence, O&apos;coner [/bib_ref] Diminished cognitive function due to thiamine deficiency is common in patients with alcohol use disorder; thiamine should thus be given to all patients with AWS (100-300 mg/day) and maintained for 2-3 months following resolution of their withdrawal symptoms. 233

## [recommendations]
11. For AWS, psychiatric consultation is recommended for the evaluation, treatment, and long-term planning of alcohol abstinence. (A1) [bib_ref] Burden of liver disease in the United States: summary of a workshop, Kim [/bib_ref] 

## Alcohol abstinence
Alcohol abstinence is the most important treatment for patients with ALD, [bib_ref] Continued heavy drinking and survival in alcoholic cirrhotics, Borowsky [/bib_ref] [bib_ref] Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis...., Pessione [/bib_ref] since it improves their survival and prognosis and prevents the progression to liver cirrhosis through histologic improvements and a reduction in portal pressure. [bib_ref] Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and..., Veldt [/bib_ref] [bib_ref] Effects of ethanol consumption on hepatic hemodynamics in patients with alcoholic cirrhosis, Luca [/bib_ref] [bib_ref] The prognosis and outcome of alcoholic liver disease, Morgan [/bib_ref] Many treatment methods are currently being used to help maintain abstinence. 237

## Pharmacologic treatment
While many drugs have been used to promote alcohol abstinence among patients with alcohol use disorder, the use of these agents is limited to those with liver-function abnormalities (liverfunction tests: >3normal increase in bilirubin) or renal failure. There are few studies that target ALD patients with the exception of baclofen. More studies are required to obtain evidence of their efficacy and safety in patients with ALD.
Baclofen is a GABAB receptor agonist that is used as a muscle relaxant. [bib_ref] Antispasticity drugs: mechanisms of action, Davidoff [/bib_ref] A study involving patients with liver cirrhosis found that a 12-week course of baclofen effectively maintained abstinence by reducing the craving for alcohol. [bib_ref] Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent..., Addolorato [/bib_ref] Further studies should investigate the use of baclofen for abstinence in patients with ALD. [bib_ref] Baclofen for alcohol withdrawal, Liu [/bib_ref] [bib_ref] Baclofen effect related to liver damage, Heydtmann [/bib_ref] Acamprosate reduces the withdrawal effects of and the craving for alcohol. The desired concentration for acamprosate is reached within 1-2 weeks of initiating treatment and it is effective at maintaining abstinence in alcohol-dependent patients following withdrawal. [bib_ref] The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals:..., Mann [/bib_ref] [bib_ref] Acamprosate for alcohol dependence: a sexspecific meta-analysis based on individual patient data, Mason [/bib_ref] Treatment is initiated 3-7 days following the last episode of alcohol consumption and started after withdrawal symptoms have resolved. With respect to dosage, 1,998 mg/day is given to patients with a body weight of 60 kg and decreased by a one-third for those with a body weight of <60 kg, for a total treatment period of 3-6 months. [bib_ref] Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol..., Bouza [/bib_ref] [bib_ref] Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a..., Anton [/bib_ref] [bib_ref] Combined pharmacotherapies and behavioral interventions for alcohol dependence (The COMBINE Study): examination..., Donovan [/bib_ref] Naltrexone decreases the concentration of dopamine in the brain and dampens activation of the reward pathway by alcohol, thereby decreasing excessive drinking and recurrence rates and increasing abstinence duration in patients with alcohol dependence. [bib_ref] Opioid antagonists for alcohol dependence, Rosner [/bib_ref] [bib_ref] Opioid antagonists for pharmacological treatment of alcohol dependence-a critical review, Soyka [/bib_ref] With respect to dosage, 25 mg is given during the first 1-3 days and increased to 50 mg thereafter, with a typical total treatment period of 3-6 months, but this can also last for up to 12 months.Because there is risk of toxic liver injury, naltrexone is not recommended in patients with ALD.
Disulfiram is an inhibitor of ALDH that causes a buildup of acetaldehyde in the body following alcohol consumption. [bib_ref] Disulfiram: an old therapeutic with new applications, Barth [/bib_ref] Since the buildup of acetaldehyde results in unpleasant symptoms such as flushing, dizziness, nausea, vomiting, arrhythmia, dyspnea, and headache, it is known as an aversive therapy and is currently not commonly used.

## Psychosocial treatment
The goal of psychosocial treatment is to allow the patient to understand and obtain insight into his or her pathological pattern of drinking. Active psychological support should be provided with focus on the environment, reasons, and expected consequences of drinking, and should be accompanied by family and group therapy as well. [bib_ref] Mesa Grande: a methodological analysis of clinical trials of treatments for alcohol..., Miller [/bib_ref] [bib_ref] Behavioral therapies for drug abuse, Carroll [/bib_ref] The aim of individual psychotherapy for a patient with alcohol dependence is to establish a therapeutic plan by careful psychiatric evaluation and select treatment modalities such as individual interview, psychoeducation, group therapy, and cognitive behavioral therapy. The treatment principles of alcohol dependence involve (1) allowing the patient to accept his or her lack of control over alcohol, (2) providing education regarding alcohol dependence, and (3) helping the patient to achieve control over him-or herself in order to maintain abstinence. This sort of treatment should not end as part of inpatient treatment, but instead should be continued after discharge to prevent recurrence. It is therefore important that patients with alcohol dependence actively get involved in group therapy such as Alcoholics Anonymous. This group meets on a nationwide basis and makes it possible to reduce the craving for alcohol and maintain healthy abstinence through peer support.
Social support from family and friends is also necessary for successful therapy. Alcohol dependence is a dysfunctional family disorder, in that in many cases it is not only the patient who needs treatment but also family members who are subject to abuse from the patient. Both the patient and his or her family may benefit from active involvement in family education and therapy. Community alcohol counseling centers provide regular abstinence meetings, family meetings, and psychoeducation; coordination with these facilities may prove very helpful.
Other methods of psychosocial treatment include motivational enhancement, 12-step facilitation therapy, cognitive behavioral therapy, social skills training, and coping skills training. Behavioral therapy involves training the patient to use methods other than alcohol to alleviate anxiety, and includes interventions such as relaxation therapy and assertive training. Psychiatric consultation is recommended for psychosocial treatment.
Brief interventions are effective methods that involve providing pertinent evaluation, information, and advice to reduce risky drinking behavior and risk of ALD. [bib_ref] Brief interventions for alcohol problems: a review, Bien [/bib_ref] Commonly used brief interventions include motivational interviewing and counseling over a short time span. A brief intervention is delivered in a structured fashion, among which the FRAMES (Feedback, Responsibility, Ad-vice, Menu, Empathy, Self-efficacy) model is representative. The FRAMES method involves feedback about the dangers of continued drinking, emphasizes the drinker's responsibility in assuming the choices and consequences of drinking, advises abstinence, provides a menu of alternatives, empathizes with the drinker's perspective, and encourages self-motivation for abstinence. [bib_ref] A randomized controlled trial of Moderation-Oriented Cue Exposure, Heather [/bib_ref] [bib_ref] The efficacy of motivational interviewing as a brief intervention for excessive drinking:..., Vasilaki [/bib_ref] Brief interventions have been reported to lower morbidity and mortality related to drinking, and to be an effective non-pharmacologic approach for abstinence. [bib_ref] The efficacy of motivational interviewing as a brief intervention for excessive drinking:..., Vasilaki [/bib_ref] [bib_ref] The effectiveness of brief alcohol interventions in primary care settings: a systematic..., Kaner [/bib_ref] Brief interventions may be implemented in various healthcare settings, such as the inpatient or outpatient setting, private clinic, or public healthcare settings such as community counseling centers, or even healthcare services in the workplace and universities. It is a cost-effective method at a primary medical institution and is effective in patients with mild ALD. [bib_ref] Brief interventions for alcohol problems: a review, Bien [/bib_ref] [bib_ref] Can methodological features account for patient-treatment matching findings in the alcohol field?, Moyer [/bib_ref] [Recommendations]

## In patients with ald, alcohol abstinence is the most important treatment. (a1)
15. In patients with ALD, pharmacologic and psychosocial treatment can be implemented to achieve alcohol abstinence. (B2) [bib_ref] Prevalence of alcoholic liver disease among Korean adults: results from the fourth..., Park [/bib_ref]. In patients with ALD, baclofen and acamprosate can be used to achieve alcohol abstinence. (B2) 17. In hazardous drinkers and patients with alcohol use disorder, brief interventions should be implemented to encourage abstinence or controlled drinking. (A1)

# Future research
1. There is a need to evaluate the efficacy of combined therapy of baclofen and psychosocial therapy for alcohol abstinence in ALD.
2. There is a need to identify effective brief intervention methods.
3. There is a need to evaluate the efficacy and safety of naltrexone and acamprosate in ALD.
4. There is a need to evaluate new pharmacologic treatments for abstinence in ALD.

## Nutritional therapy
Many patients with ALD are malnourished, and the complications of ALD are significantly associated with the nutritional status.nutritional support in ALD patients. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] [bib_ref] Nutritional support in patients with chronic liver disease, Henkel [/bib_ref] While active nutritional support is known to improve biochemical markers and the nutritional status of ALD patients, it is not clear whether it also improves their survival rate. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] [bib_ref] Nutritional support for liver disease, Koretz [/bib_ref] Patients with severe alcoholic hepatitis who received parenteral nutrition had higher early mortality rates but lower late mortality rates than those receiving steroid treatment, with the net result being no difference in their overall mortality rates. [bib_ref] Short-and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral..., Cabre [/bib_ref] Long-term supplementation with branched-chain amino acids is known to improve nitrogen balance and yield improvements in hepatic encephalopathy and liver function tests. [bib_ref] Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized..., Marchesini [/bib_ref] Branched-chain amino acid supplementation at 34 g/day reduces the number of hospitalizations due to the complications of alcoholic liver cirrhosis such as infection, gastrointestinal bleeding, ascites, and hepatic encephalopathy. [bib_ref] Controlled trial on nutrition supplementation in outpatients with symptomatic alcoholic cirrhosis, Hirsch [/bib_ref] Depending on the state of the patient, protein and calorific intakes of 1.2-1.5 g/kg/day protein and 35-40 kcal/ kg/day, respectively, are recommended. [bib_ref] ESPEN Guidelines on Enteral Nutrition: Liver disease, Plauth [/bib_ref] If three meals per day does not provide an adequate nutritional intake, a greater number of smaller meals is recommended. [bib_ref] Liver cirrhosis: rationale and modalities for nutritional support--the European Society of Parenteral..., Lochs [/bib_ref] [bib_ref] Effect of a late evening meal on nitrogen balance in patients with..., Swart [/bib_ref] [bib_ref] Nocturnal oral glucose supplementation. The effects on protein metabolism in cirrhotic patients..., Zillikens [/bib_ref] If the patient is actively ill or in a critical state, higher protein (1.5 g/kg/day) and calorific (40 kcal/kg/day) intakes should be considered in conjunction with medical treatment.
While long term oral or parenteral nutrition is thought to be helpful for patients with alcoholic liver cirrhosis, definite conclusions cannot be drawn at present due to limitations in previous studies such as small sample size or insufficient treatment periods. [bib_ref] Review article: Nutritional therapy in alcoholic liver disease, Stickel [/bib_ref] Sufficient nutritional support can reduce the complications of ALD without imposing any additional risk.Currently there are no clear guidelines regarding the supplementation of vitamins or minerals in patients with ALD. However, it is recommended that patients with nutritional deficiency should be given adequate amounts of vitamin A, thiamine, vitamin B12, folic acid, pyridoxine, vitamin D, and zinc along with nutritional therapy. [bib_ref] Nutrition in alcoholic liver disease, Dicecco [/bib_ref] [Recommendations] [bib_ref] Meta-analysis of alcohol intake in relation to risk of liver cirrhosis, Corrao [/bib_ref]. Active and sufficient nutritional support should be provided to patients with ALD. If three meals per day do not provide adequate nutrition, additional meals in the early morning and late at night can help restore nutritional balance. (B1) [bib_ref] Average volume of alcohol consumption, patterns of drinking, and all-cause mortality: results..., Rehm [/bib_ref]. Vitamin and mineral supplementation should be provided along with nutritional therapy to patients with ALD. (B1)

## Treatment of alcoholic hepatitis

## Alcohol abstinence
Alcohol abstinence is the most important treatment for alcoholic hepatitis, [bib_ref] Alcoholic hepatitis, Lucey [/bib_ref] and should be administered as described above.

## Nutritional therapy
Most patients with severe alcoholic hepatitis are malnourished.
Although several studies have shown that enteral nutrition improves the survival rate irrespective of steroid treatment, it is still not clear whether nutritional therapy is effective in treating severe alcoholic hepatitis. [bib_ref] Short-and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral..., Cabre [/bib_ref] [bib_ref] Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic..., Alvarez [/bib_ref] Steroids Corticosteroids (prednisolone 40 mg/day for 28 days) are the most commonly recommended treatment for severe alcoholic hepatitis. They are thought to act by reducing the transcription of proinflammatory cytokines such as TNF-. In patients with histologically confirmed severe alcoholic hepatitis, serum levels of TNF- and intercellular adhesion molecule-1 (ICAM-1) were shown to decrease with steroid treatment, and the degree of change in the soluble form of ICAM-1 was found to be correlated with the degree of histological improvement. [bib_ref] Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular..., Spahr [/bib_ref] Indications for treatment with steroids are the presence of severe alcoholic hepatitis with a poor prognosis. Various prognosis prediction models such as mDF, MELD, and GAHS can be used to determine which patients should take steroids. Scores of mDF score 32, MELD >21, or GAHS 9, or hepatic encephalopathy are commonly used indications. Steroids are usually contraindicated in those with gastrointestinal bleeding, renal failure, pancreatitis, or uncontrolled infection.
Steroid treatment for alcoholic hepatitis has been investigated in many randomized controlled trials, and conflicting results were obtained in early clinical studies and meta-analyses. [bib_ref] Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial, Carithers [/bib_ref] [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] [bib_ref] Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables, Christensen [/bib_ref] [bib_ref] A randomized trial of prednisolone in patients with severe alcoholic hepatitis, Ramond [/bib_ref] [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual..., Mathurin [/bib_ref] [bib_ref] Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with..., Rambaldi [/bib_ref] While a Cochrane review of 15 studies found no survival benefit from steroids, 278 a subgroup analysis involving only "low-bias risk" studies revealed a survival benefit from steroids in patients with an mDF score of 32 or with hepatic encephalopathy. [bib_ref] Systematic review: glucocorticosteroids for alcoholic hepatitis--a Cochrane Hepato-Biliary Group systematic review with..., Rambaldi [/bib_ref] An analysis involving pooled data found that the 28-day survival rate was higher in the steroid group (84.6%) than in the placebo group (65.1%; P =0.001). [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual..., Mathurin [/bib_ref] That finding was recently confirmed in a study using data from the five recent randomized controlled trials [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] Therefore, steroids should be useful in patients with an mDF score of 32.
ECBL and the Lille model were recently introduced to predict prognosis based on the response to steroid treatment [fig_ref] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/fig_ref]. ECBL is defined when the bilirubin level at 7 days of treatment is lower than that on the first day of treatment. One study found that the 6-month survival rate was 82% in severe alcoholic hepatitis patients with confirmed ECBL but only 23% in those without ECBL.The Lille model is an improved model that includes ECBL as well as several additional variables. The probability of death is scored from 0 to 1 in the Lille model, and the 6-month survival rate was 25% in those patients with a score of >0.45, which is significantly lower than that of 85% for those with a Lille score of <0.45. [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] In a more recent study, patients were subdivided according to the percentile distribution of the Lille scores (35th, 35th-70th, and 70th percentiles), and classified as complete responders (0.16), partial responders (0.16-0.56), and null responders (0.56); the 28-day survival rate differed significantly between these groups, at 91.1%, 79.4%, and 53.3%, respectively. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] Given that infection occurs more frequently in patients who do not re-spond to steroid treatment than in those who do respond, it would be reasonable to discontinue steroids if the patient is thought to be a null responder based on ECBL or the Lille model. [bib_ref] Infection in patients with severe alcoholic hepatitis treated with steroids: early response..., Louvet [/bib_ref] The survival rate in these patients may be significantly higher after liver transplantation than when continuing with medical treatment only. [bib_ref] Early liver transplantation for severe alcoholic hepatitis, Mathurin [/bib_ref] However, a social consensus is needed on this issue.
In conclusion, treatment with steroids is effective in patients with mDF scores of 32. However, if ECBL is not observed or the Lille score is 0.56, steroids should be discontinued and other rescue therapies such as liver transplantation should be considered [fig_ref] Figure 3: Treatment algorithm for severe alcoholic hepatitis [/fig_ref]. [bib_ref] Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of..., Mathurin [/bib_ref] [bib_ref] The Lille model: a new tool for therapeutic strategy in patients with..., Louvet [/bib_ref] Pentoxifylline Pentoxifylline, given at a dose of 400 mg three times daily for 28 days, may be tried as an alternative to steroids for treating severe alcoholic hepatitis. [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] Pentoxifylline is a selective phosphodiesterase inhibitor that increases intracellular cAMP levels, which in turn decrease the expression of cytokines such as TNF-, IL-8, and macrophage inflammatory protein-1a.Pentoxifylline may be used in patients with infection or renal failure. A study involving 101 patients with severe alcoholic hepatitis found that the 28-day mortality rate was significantly lower in the pentoxifylline group (24.5%) than in the placebo group (46.1%). [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] Given that the percentage of deaths due to hepatorenal syndrome was 50% (6 of 12 patients) in the pentoxifylline group and 92% (22 of 24 patients) in the placebo group, it appears that the increase in survival rate may be due to a decrease in the incidence of hepatorenal syndrome. [bib_ref] Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled..., Akriviadis [/bib_ref] A randomized comparative study of pentoxifylline and steroids found that the death rate was lower in the pentoxifylline group. [bib_ref] Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial, De [/bib_ref] However, that study involved only a small group of patients, and the survival rate in the steroid group was far lower than that reported previously, thereby questioning the validity and acceptability of the conclusion. Another randomized controlled trial comparing the efficacies of pentoxifylline and corticosteroids in treating severe alcoholic hepatitis was recently performed in Korea. The 1-month survival rate of patients receiving pentoxifylline was 74.5%, compared to 87.0% in those receiving prednisolone. Although the trial was intended to assess the non-inferiority of pentoxifylline compared to corticosteroids, the observed efficacy of pentoxifylline was not statistically equivalent to that of corticosteroids, supporting corticosteroids as a preferred option for severe alcoholic hepatitis.It is currently unclear whether combination therapy of steroids and pentoxifylline is superior to monotherapy with either agent. A recent study found no survival benefit at 4 weeks or 6 months with combination therapy of steroids and pentoxifylline. [bib_ref] Corticosteroid plus pentoxifylline is not better than corticosteroid alone for improving survival..., Sidhu [/bib_ref] Therefore, combination therapy is not recommended at present.
The efficacy of early switching to pentoxifylline in steroid nonresponders has been investigated by either switching patients without ECBL to pentoxifylline or continuing them on steroids; 286 the 2-month survival rates did not differ between the two groups, at 35.5% and 31.0%, respectively. Pentoxifylline is therefore not recommended as a rescue therapy since steroid non-responders do not seem to obtain any benefit from an early switch to this drug.
In spite of these limitations, pentoxifylline is considered an effective alternative agent to steroids in the treatment of severe alcoholic hepatitis and improves survival rate. 287

## Anti-tnf- agents
Several anti-TNF- agents have been tested as treatments for alcoholic hepatitis under the assumption that clinical improvement may be seen by blocking TNF-, a major cytokine involved in alco-holic hepatitis. A pilot study demonstrated the efficacy of combination therapy of infliximab and steroids. [bib_ref] Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a..., Spahr [/bib_ref] However, the mortality rate was found to be higher with combination therapy in a follow-up study, and therefore infliximab is currently not recommended for the treatment of severe alcoholic hepatitis. [bib_ref] A double-blind randomized controlled trial of infliximab associated with prednisolone in acute..., Naveau [/bib_ref] Treatment with etanercept was also associated with a higher 6-month mortality rate, mainly due to higher rates of serious infections compared to the placebo group. [bib_ref] A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of..., Boetticher [/bib_ref] Therefore, anti-TNF- agents are currently not recommended for the treatment of alcoholic hepatitis.

## Antioxidants
N -acetylcysteine has not yet been found to be effective as a treatment for alcoholic hepatitis. [bib_ref] Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute..., Moreno [/bib_ref] A recent trial of combination therapy with N -acetylcysteine and steroids found an increase in the short-term survival rate but no improvement in the long-term survival rate. [bib_ref] Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis, Nguyen-Khac [/bib_ref] Specifically, the 1-month mortality rate was lower in the combination therapy group (8%) than in the steroid-only group (24%), but the 3-month and 6-month survival rates did not differ significantly between the two groups. Interestingly, the number of deaths due to hepatorenal syndrome was lower in the combination therapy group (9%) than in the steroid-only group (22%). [bib_ref] Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis, Nguyen-Khac [/bib_ref] Further research is needed to evaluate the efficacy of Nacetylcysteine.

# Future research
1. There is a need for new drugs that may be combined with steroids or pentoxifylline to increase the therapeutic efficacy in the treatment of severe alcoholic hepatitis.
2. There is a need to identify clinical factors that respond to ste-

## Liver transplantation
ALD is one of the most common indications for liver transplantation in North America and Europe. [bib_ref] Liver transplantation for alcoholic liver disease in Europe: a study from the..., Burra [/bib_ref] [bib_ref] An analysis of the OPTN/UNOS Liver Transplant Registry, Waki [/bib_ref] There is a tendency to avoid liver transplantation in chronic drinkers due to concerns about their continued drinking damaging the transplanted liver. The survival rate of livers transplanted due to ALD is similar to [bib_ref] Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival,..., Mackie [/bib_ref] [bib_ref] Histological features after liver transplantation in alcoholic cirrhotics, Burra [/bib_ref] [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] or higher than 293 that of liver transplantation due to other causes. Indications for transplantation in ALD are identical to those in other end-stage liver diseases. It is also known that the presence of ALD has no impact on the survival rate following liver transplantation in those with end-stage liver disease. [bib_ref] Effect of alcoholic liver disease and hepatitis C infection on waiting list..., Lucey [/bib_ref] The increase in survival rate following liver transplantation is limited to CTP class C patients with decompensated liver cirrhosis. [bib_ref] Immediate listing for liver transplantation versus standard care for Child-Pugh stage B..., Vanlemmens [/bib_ref] The 1-year and 5-year survival rates were found to be increased in CTP class C patients after liver transplantation than in the control group, but no such statistically significant increase in survival rate was seen in CTP class A or B patients.Six months of alcohol abstinence may result in improvement of liver disease and avoid unnecessary liver transplantation; therefore, an abstinence period of 6 months prior to liver transplantation is thought to be necessary. [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] Minimal criteria for placement of adults on the liver transplant waiting list:..., Lucey [/bib_ref] [bib_ref] Liver transplantation for alcoholic liver disease: a survey of transplantation programs in..., Everhart [/bib_ref] [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation..., Perney [/bib_ref] [bib_ref] A simple score for predicting alcohol relapse after liver transplantation: results from..., De Gottardi [/bib_ref] However, many recent studies have questioned whether 6 months of abstinence is a reliable predictor for resumption of drinking following transplantation, and have found poor predictability. [bib_ref] Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection..., Mccallum [/bib_ref] [bib_ref] Predictors of relapse to harmful alcohol after orthotopic liver transplantation, Kelly [/bib_ref] Recidivism following liver transplantation is common, with estimated rates of 10-52%. [bib_ref] Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival,..., Mackie [/bib_ref] [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Are preoperative patterns of alcohol consumption predictive of relapse after liver transplantation..., Perney [/bib_ref] [bib_ref] A simple score for predicting alcohol relapse after liver transplantation: results from..., De Gottardi [/bib_ref] [bib_ref] Predictors of relapse to harmful alcohol after orthotopic liver transplantation, Kelly [/bib_ref] [bib_ref] Liver transplantation for alcohol-related cirrhosis: a single centre long-term clinical and histological..., Schmeding [/bib_ref] [bib_ref] Analysis of factors that predict alcohol relapse following liver transplantation, Jauhar [/bib_ref] [bib_ref] Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic..., Dimartini [/bib_ref] [bib_ref] Long-term follow-up of patients with alcoholic liver disease after liver transplantation in..., Bjornsson [/bib_ref] [bib_ref] Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the..., Faure [/bib_ref] [bib_ref] Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?, Pageaux [/bib_ref] [bib_ref] Long term follow-up and outcome of liver transplantation for alcoholic liver disease:..., Biselli [/bib_ref] Alcohol consumption following liver transplantation causes histologic damage in the liver, including liver fibrosis. [bib_ref] Histological features after liver transplantation in alcoholic cirrhotics, Burra [/bib_ref] [bib_ref] Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?, Pageaux [/bib_ref] [bib_ref] Patterns of alcohol consumption after liver transplantation, Tang [/bib_ref] Heavy drinking following liver transplantation adversely affects the survival rate regardless of the reason for liver transplantation. [bib_ref] Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic..., Pfitzmann [/bib_ref] [bib_ref] Liver transplantation for alcohol-related cirrhosis: a single centre long-term clinical and histological..., Schmeding [/bib_ref] [bib_ref] Excessive alcohol consumption after liver transplantation impacts on long-term survival, whatever the..., Faure [/bib_ref] Various physical and psychological factors should be carefully evaluated prior to liver transplantation and such factors should also be followed up and monitored following liver transplantation. [bib_ref] Liver transplantation for alcoholic liver disease, Zetterman [/bib_ref] For liver transplantation performed in a patient with alcoholic hepatitis alone or alcoholic hepatitis superimposed on alcoholic cirrhosis, the survival rates of the transplanted liver and the patient did not differ significantly from those for patients with alcoholic cirrhosis alone. [bib_ref] Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for..., Tome [/bib_ref] [bib_ref] The impact of acute alcoholic hepatitis in the explanted recipient liver on..., Wells [/bib_ref] [bib_ref] Outcomes after liver transplantation for alcoholic hepatitis are similar to alcoholic cirrhosis:..., Singal [/bib_ref] Most European and North American liver transplantation centers do not consider patients with severe alcoholic hepatitis as candidates for liver transplantation, based on them not fulfilling the criterion of alcoholic abstinence for 6 months prior to liver transplantation. [bib_ref] Alcoholic liver disease, O&apos;shea [/bib_ref] [bib_ref] Minimal criteria for placement of adults on the liver transplant waiting list:..., Lucey [/bib_ref] However, a prospective, multicenter study found an increase in survival rate with liver transplantation in patients with severe alcoholic hepatitis who are not responsive to medical treatment. [bib_ref] Early liver transplantation for severe alcoholic hepatitis, Mathurin [/bib_ref] Therefore, liver transplantation may be considered in patients whose severe alcoholic hepatitis has not responded to medical treatment. However, improvement in long term survival must be verified in future studies.
Similar to those who have received liver transplantation for other causes, patients who have received liver transplantation due to ALD exhibit a high incidence of de novo cancer in other areas of the body. [bib_ref] Liver transplantation for alcoholic liver disease in Europe: a study from the..., Burra [/bib_ref] [bib_ref] Immediate listing for liver transplantation versus standard care for Child-Pugh stage B..., Vanlemmens [/bib_ref] [bib_ref] Alcohol abuse and de novo tumors in liver transplantation, Zanus [/bib_ref] [bib_ref] Increased cancer risk after liver transplantation: a population-based study, Haagsma [/bib_ref] [bib_ref] De novo malignancies after liver transplantation: incidence comparison with the Korean cancer..., Park [/bib_ref] Such de novo cancers are associated with an increased mortality following transplantation. It is thought that the immunosuppressive drugs that are used post-transplantation are related to the onset of new cancers. It is also known that liver transplantation due to ALD, compared to other causes, is associated with a strikingly high rate of cardiovascular complications. 293

## [recommendations]
24. Liver transplantation should be considered in patients with decompensated liver cirrhosis. (A1) [bib_ref] Differences in the profiles of DSM-IV and DSM-5 alcohol use disorders: implications..., Dawson [/bib_ref]. Early liver transplantation may be considered in patients with severe alcoholic hepatitis who do not respond to medical treatment. (A2)

# Future research
1. There is a need to determine the appropriate timeline for liver transplantation with regard to abstinence from alcohol in patients with ALD.

## Miscellaneous therapies

## Propylthiouracil
Histologic findings of central hypoxia due to thyroid hormone can occur in ALD, raising the question of whether propylthiouracil (PTU) would be effective in reducing pericentral hypoxia and cellular damage by suppressing metabolic activation due to ethanol. Some studies have found that PTU improves the mortality rate by suppressing hypermetabolic activation. [bib_ref] Commentary on the hypermetabolic state and the role of oxygen in alcohol-induced..., Mezey [/bib_ref] [bib_ref] Long-term treatment of alcoholic liver disease with propylthiouracil, Orrego [/bib_ref] However, a Cochrane meta-analysis of 6 studies involving 710 ALD patients that compared PTU versus placebo found no clear improvement in liver histology or in the liver-related or overall mortality rate. [bib_ref] Propylthiouracil for alcoholic liver disease, Rambaldi [/bib_ref] 

## Colchicine
Colchicine affects liver fibrosis by suppressing collagen production, activating collagenase activity, and suppressing collagen transcellular trafficking. It has also been found to contribute to the production of cytokines that stimulate fibroblast proliferation. As such, colchicine has been investigated as a treatment agent for ALD. Clinical studies involving patients with alcoholic liver cirrhosis found that colchicine exhibited anti-inflammatory and anti-fibrotic effects, [bib_ref] Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient..., Morgan [/bib_ref] [bib_ref] Treatment of cirrhosis with colchicine. A double-blind randomized trial, Kershenobich [/bib_ref] and had a positive effect on survival. [bib_ref] Colchicine in the treatment of cirrhosis of the liver, Kershenobich [/bib_ref] However, subsequent controlled trials produced conflicting results, and a meta-analysis of 15 randomized trials involving 1,714 patients with ALD found no clear association between colchicine and liver function or histologic improvement, or liver-related or overall mortality. [bib_ref] Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis, Rambaldi [/bib_ref] Therefore, considering its side effects, colchicine is not recommended for treatment of ALD.

## Polyunsaturated lecithin
Polyunsaturated lecithin (PUL) is a cell membrane component found in soybean extract. While its mechanism of action is unclear, it is thought to act by modulating collagenase activity. [bib_ref] Polyunsaturated lecithin prevents acetaldehyde-mediated hepatic collagen accumulation by stimulating collagenase activity in..., Li [/bib_ref] A study involving baboons with alcoholic liver damage found that PUL caused histologic improvement in the liver and decreased the activation of hepatic stellate cells. [bib_ref] Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon, Lieber [/bib_ref] However, there was no clear association between polyenylphosphatidylcholine and progression of liver fibrosis in a follow-up randomized controlled study. [bib_ref] Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease, Lieber [/bib_ref] Since PUL is a component of normal cells with a favorable side effect profile, this agent should be investigated further.

## S-adenosyl-l-methionine
SAMe is a methyl-group donor that is involved in the biosynthesis of glutathione, a major intracellular antioxidant. A clinical study found that SAMe improved survival in both CTP class A and B patients compared to the placebo group. Although some studies have found that SAMe has treatment value in ALD, a meta-analysis found SAMe to exert no statistically significant effects on overall mortality, 334,335 liver-related mortality, complications, or liver transplantation results. [bib_ref] S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial, Mato [/bib_ref] Metadoxine Metadoxine antioxidant therapy has been approved for the treatment of ALD in several countries. A large randomized controlled trial involving 136 patients with fatty liver that compared a 3-month course of metadoxine (1,500 mg/day) with placebo found meaningful improvements in liver function in both groups but with a faster recovery course in the metadoxine group. [bib_ref] Metadoxine accelerates fatty liver recovery in alcoholic patients: results of a randomized..., Caballeria [/bib_ref] The persistence of fatty liver as visualized by ultrasonography was significantly decreased in the metadoxine group relative to the placebo group (28% vs. 70%). These positive effects were more noticeable in patients who had abstained from alcohol than in those who had continued to drink. However, the clinical implications remain unclear, and metadoxine is therefore not recommended for the treatment of ALD. Further research is needed to investigate the effects of metadoxine.

## Angiotensin ii receptor blocker
One randomized controlled trial has found that combination therapy with the angiotensin II receptor antagonist candesartan and ursodeoxycholic acid effects a greater histologic improvement than monotherapy with ursodeoxycholic acid. 339

## Anti-cytokine agents
Anti-cytokine treatment has been proposed based on the effect of cytokines on liver fibrosis and cirrhosis. [bib_ref] Cytokine gene expression in cirrhotic and non-cirrhotic human liver, Llorent [/bib_ref] Although there are reports of anti-inflammatory effects of thalidomide, misoprostol, adiponectin, and probiotic agents, more evidence is needed before these agents should be used as treatments for ALD. [bib_ref] Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty..., Li [/bib_ref] [bib_ref] Adiponectin, a new member of the family of soluble defense collagens, negatively..., Yokota [/bib_ref] Silymarin Silymarin, a milk thistle extract with activating and anti-oxidative properties, has been evaluated in many studies as a potential treatment agent for ALD. [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases, Rambaldi [/bib_ref] [bib_ref] Randomized controlled trial of silymarin treatment in patients with cirrhosis of the..., Ferenci [/bib_ref] Although one study found that silymarin contributes to improved survival, this result has not been confirmed for ALD patients in meta-analyses such as the Cochrane review. [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases, Rambaldi [/bib_ref] [bib_ref] Milk thistle for alcoholic and/or hepatitis B or C liver diseases--a systematic..., Rambaldi [/bib_ref] Future research There are isolated reports that PTU, colchicine, PUL, SAMe, metadoxine, and silymarin affect the prognosis of ALD patients, but these have not been confirmed. There is a need to investigate new pharmacologic agents.

## Strategies for the reduction and pre-vention of harmful use of alcohol
Chronic, excessive alcohol consumption and binge drinking are risk factors for various physical and psychological diseases; there should thus be consistent and nationwide efforts to address this issue. Strategies for decreasing the harmful use of alcohol should be implemented through various public, private, and government organizations.In 2010 the WHO implemented the "Global Strategy to Reduce Harmful Use of Alcohol" campaign and proposed areas for national action. [bib_ref] The WHO global strategy to reduce the harmful use of alcohol, Chick [/bib_ref] However, the lenient culture toward drinking, cheap pricing of distilled beverages, and easy accessibility to alcohol in Korea have all contributed to the physical, psychological, social, and economical damage caused by alcohol use. [bib_ref] Socioeconomic costs if alcohol drinking in Korea, Chung [/bib_ref] Strategies to reduce the harmful use of alcohol include reducing its accessibility by limiting sales or increasing prices, restricting alcohol-related advertising, promoting preventive education and public campaigns, and implementing early identification and intervention programs. Verified strategies such as increasing prices and limiting accessibility are currently not in place in Korea, and the adolescent-related policies that are present are not strictly enforced. Furthermore, preventive education and public campaigns are grossly insufficient due to issues such as budgetary constraints, and early identification and intervention programs for hazardous or harmful drinking are not being implemented appropriately at present. There is a need for a change in the public perception toward harmful use of alcohol and specific and realistic strategies for alcohol control such as enforcing the legal drinking age, restricting alcohol-related advertisements, modifying liquor taxes, setting minimum prices for alcohol, limiting public drinking, and starting early intervention and mandatory treatment programs for intoxicated individuals.[Recommendation] [bib_ref] Provider training for patient-centered alcohol counseling in a primary care setting, Ockene [/bib_ref]. There is a need to increase public attention towards the harmful use of alcohol, and specific strategies such as limiting the accessibility of alcohol, price controls, and banning alcohol-related advertisements should be implemented. (A1)
[fig] Figure 1: Adult alcohol consumption per capita in 2005 (World Health Organization Global Status Report on Alcohol and Health, 2011). [/fig]
[fig] Figure 2: Natural history, spectrum, and pathophysiology of alcoholic liver disease. [/fig]
[fig] Figure 3: Treatment algorithm for severe alcoholic hepatitis. http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/fig]
[fig] [: Recommendations] 20. Alcohol abstinence is the single most important treatment for improving survival in alcoholic hepatitis. (A1) 21. Treatment with steroids is needed for patients with severe alcoholic hepatitis who have an mDF score of 32. (A1) 22. During steroid treatment it is important to identify patients with a high mortality risk based on ECBL or the Lille score, where rescue therapy such as liver transplantation may be considered. (B1) 23. Pentoxifylline is an alternative treatment agent to steroids that can improve the survival rate in patients with severe alcoholic hepatitis. (B1) [/fig]
[table] Table 1: The grading of recommendations, assessment, development, and evaluation (GRADE) system [/table]
[table] Table 2: Definitions of moderate drinking, heavy drinking, binge drinking, at-risk drinking, hazardous drinking, harmful drinking, alcohol abuse, and alcohol dependence 20-22 http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table]
[table] Table 3: Alcohol contents of different types of alcoholic beverage The Korean Association for the Study of the Liver (KASL) KASL clinical practice guidelines: management of alcoholic liver disease http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table]
[table] Table 4: Clinical features of alcoholic liver disease PMNL, polymorphonuclear leukocyte; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time. *Usually <300 IU/L.  Ultrasonography, computed tomography, and magnetic resonance imaging. http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table]
[table] Table 5: Prognostic models in patients with alcoholic hepatitis203,212,217,218,226 [/table]
[table] Table 6: Treatment of alcohol withdrawal syndrome (AWS)227,228,[230][231][232] Indications for admission Significant AWS, high levels of recent drinking, history of withdrawal seizures or delirium tremens, co-occurrence of a serious medical or psychiatric illness, or failure of outpatient treatment Dosage and routes given for a standard fixed-dose regimen, which includes dose tapers over time.  Alternative to benzodiazepine that is effective in seizure prevention.  To be used carefully as adjunctive therapy only in cases of agitation or psychotic symptoms such as hallucinations that are not controlled by benzodiazepine. [/table]
[table] , 326: http://www.e-cmh.org http://dx.doi.org/10.3350/cmh.2013.19.3.216 [/table]