Alcoholic liver disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Alcohol has existed as early as the Neolithic period, there are many warnings against excessive alcohol consumption in greek literature as well. Alcoholic liver disease is one of the most common preventable causes of death in Western countries. The main cause of alcoholic liver disease is excessive alcohol consumption over a long period of time. The disease spectrum ranges from alcoholic steatosis to alcoholic hepatitis and alcoholic cirrhosis. The most feared complications are hepatic failure and hepatocellular carcinoma. Since the most important cause is alcohol abuse, physicians must have a low threshold to screen patients for abuse, as many alcohol dependent patients will not discuss the problem or may not see it as a problem. Alcoholic steatosis is mostly asymptomatic, and patients may present either with alcoholic hepatitis or fulminant hepatic failure or carcinoma. The cornerstone of therapy for alcoholic liver disease is abstinence, abstinence can reverse alcoholic steatosis, hepatitis as well as fibrosis in some cases.

Alcohol has existed as the most abused substance for many centuries. In 1960 alcohol was recognized as a hepatotoxin.

Alcoholic liver disease may be classified according to histology and symptoms into different subtypes: reversible and irreversible.

The pathogenesis of alcoholic liver disease is complex and still remains unclear, the metabolites of the oxidative metabolism in the liver; acetaldehyde and reactive oxygen species are thought to be involved in the toxic effects of ethanol on the liver.

The primary cause of alcoholic liver disease is excessive consumption of alcohol over a long period of time.

Alcoholic liver disease should be differentiated from other diseases that produce similar symptoms, and other types of liver diseases. It should also be differentiated from diseases of the gallbladder. Conditions that may present in a similar manner to alcoholic liver disease are; cholecystitis, cholelithiasis, drug toxicity, non-alcoholic fatty liver disease, and other forms of hepatitis (eg. viral, autoimmune).

The incidence of alcoholic liver disease is very high among alcoholics, and those who consume excessive amounts of alcohol. It does still depend on the amount and type of alcohol consumed. The mortality rate is high in those who present with alcoholic hepatitis and those individuals whose disease has progressed to cirrhosis. The average age of presentation is between 40 and 50 years. The disease tends to progress faster in individuals of hispanic ethnicity and women are at greater risk of developing alcoholic liver disease than men.

The most potent risk factor in the development of alcoholic liver disease is alcohol consumption. Other risk factors include female gender, hispanic ethnicity, and genetic factors.

All patients who present with elevated liver enzymes, signs of liver disease or increased frequency of accidental trauma should be screened for alcohol abuse. Most individuals who consume heavy amounts of alcohol tend to deny it, hence there must be a strong suspicion under these circumstances. Physicians must have a low threshold to screen for alcohol abuse.

Alcoholic liver disease progresses through three stages (steatosis, alcoholic hepatitis, and cirrhosis) with the continued use of alcohol. Serious complications begin to occur with the development of alcoholic hepatitis, when portal hypertension, coagulopathies, and intractable jaundice. Complications of cirrhosis include hepatic encephalopathy and hepatocellular carcinoma. Prognosis varies dependent on level of progression of illness, and whether treatment is given. Prognosis can be measured using laboratory values, and three prognostic scores: the MELD score, the Glasgow Alcoholic Hepatitis Score, and the ABIC score.

The diagnostic study of choice in developing countries for the diagnosis of cirrhosis in alcoholic liver disease is liver biopsy. In developed countries the diagnostic study of choice for cirrhosis is now the FibroScan or transient elastography.

History should focus on the history of alcohol use by the patient, and the history of symptoms that may have developed.

There are certain stigmata associated with alcoholic liver disease that one should look for on physical examination. These include; jaundice, gynecomastia, spider angiomata, bruising, hepatosplenomegaly, ascites, testicular atrophy, asterixis, and palmar erythema. A thorough neurologic and mental status exam should also be done to assess for signs of hepatic encephalopathy, or other neurologic deficits that may be caused by chronic alcohol use.

It is important to take a complete history and find out about the patient’s alcohol use and current signs and symptoms for alcoholic liver disease. As laboratory tests do not give the definitive diagnosis of alcoholic liver disease. It is also important to rule out other causes of liver disease such as, chronic viral hepatitis which could co-exist, autoimmune hepatitis, hemochromatosis and drug related hepatotoxicity. Initial assessment must include a complete blood count, hepatic panel (ALT, AST, bilirubin, GGT, alkaline phosphatase), INR and PT.

An ECG may be helpful in the diagnosis of alcoholic liver disease. Findings on an ECG suggestive of cirrhosis include prolonged QTc interval.

There are no x-ray findings associated with alcoholic liver disease. However, a chest x-ray may be helpful in the diagnosis of complications of cirrhosis, which include hydrothorax and pneumonia.

Abdominal CT scan may be helpful in the diagnosis of alcoholic liver disease. Findings on CT scan suggestive of hepatic steatosis and cirrhosis may be seen.

An abdominal MRI may be helpful in the diagnosis of alcoholic liver disease. Findings on MRI can not confirm the cause of the liver disease but they are suggestive of underlying liver disease. An MRI can be expensive as an initial choice of diagnostic study and does not yield any advantages when compared to an ultrasound in the setting of alcoholic steatosis.

Echocardiography/ultrasound may be helpful in the diagnosis of alcoholic liver disease.Since ultrasound is a non invasive technique it is used for initial evaluation of the liver. Findings on an ultrasound are suggestive of underlying liver disease but they can not confirm the etiology. However ultrasound can be used to exclude other causes of abnormal liver tests in patients who abuse alcohol; infiltrative disease, neoplastic disease, obstructive biliary pathology, cirrhosis or screen for hepatocellular carcinoma. Echocardiography can be used to detect hepatic cardiomyopathy and the severity of volume overload in cirrhotic patients.

There have been recent advances towards newer imaging modalities to help detect and quantify hepatic fibrosis and cirrhosis. These investigations are comparable to the gold standard that is liver biopsy to confirm the diagnosis of liver cirrhosis.

Liver biopsy is used to confirm the diagnosis when alcoholic hepatitis is suspected, and to help in guiding medical treatment. Microscopic findings on biopsy that indicate alcoholic hepatitis are: polymorphonuclear infiltration of cells, hepatic necrosis, ballooning hepatocytes, Mallory bodies within cells, and perivenular and perisinusoidal fibrosis.

The most important part of treatment is to stop using alcohol completely. If liver cirrhosis has not yet occurred, the liver can heal if you stop drinking alcohol. An alcohol rehabilitation program or counseling may be necessary to break the alcohol addiction. Vitamins, especially B-complex and folic acid, can help reverse malnutrition. If cirrhosis develops, there is a need to manage the complications of cirrhosis. It may need a liver transplant.

The most important part of treatment is to stop using alcohol completely. If liver cirrhosis has not yet occurred, the liver can heal if you stop drinking alcohol. An alcohol rehabilitation program or counseling may be necessary to break the alcohol addiction. Vitamins, especially B-complex and folic acid, can help reverse malnutrition.

Effective measures for the primary prevention of alcoholic liver disease include screening and counseling for alcohol abuse disorder. Physicians must have a low threshold for screening as many patients would not be comfortable about discussing their alcohol dependence.

Effective measures for the secondary prevention of alcoholic liver disease include abstinence. Abstinence can be achieved through drug therapies in an inpatient as well as an out patient setting.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Alcohol has existed as the most abused substance for many centuries. In 1960 alcohol was recognized as a hepatotoxin.

• Alcohol has existed as the most abused substance for many centuries.^[1]
• In 1960 alcohol was recognized as a hepatotoxin.
• The earliest lesion reported for alcoholic liver disease is alcoholic steatosis (fatty liver).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Alcoholic liver disease may be classified according to histology and symptoms into different subtypes: reversible and irreversible.

• Alcoholic liver disease may be classified according to progression of disease into different categories:^[1]
  • Alcoholic steatosis – reversible; active alcohol abuse / metabolic syndrome
  • Alcoholic steatohepatitis – reversible; active alcohol abuse / metabolic syndrome
  • Cirrhosis – irreversible; inflammation absent when abstinence from alcohol is observed

Alcoholic Liver Disease

Reversible

Irreversible

Alcoholic Steatosis

Alcoholic Steatohepatitis

Cirrhosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

The pathogenesis of alcoholic liver disease is complex and still remains unclear, the metabolites of the oxidative metabolism in the liver; acetaldehyde and reactive oxygen species are thought to be involved in the toxic effects of ethanol on the liver.

• Ethanol metabolism in the liver is carried out mainly by two enzymes:^[1]
  • Alcohol dehydrogenase
  • Aldehyde dehydrogenase
• Both of these enzymes use NAD+ as a cofactor. Alcohol is converted to acetaldehyde and acetaldehyde is then further oxidized to acetate. Acetaldehyde is the toxic metabolite in this process.
• The metabolism of alcohol in the liver ends up producing an excess of reduced nicotinamide adenine dinucleotide (NADH). This changes the reduction–oxidation potential in the liver and inhibits key metabolic processes in the liver such as, the tricarboxylic acid cycle and the oxidation of fatty acids and thereby ends up promoting lipogenesis.^[2]
• Since acetaldehyde has an electrophilic nature it can form covalent chemical bonds with proteins, lipids and DNA. These covalent bonds that are formed are extremely pathogenic, as they have the ability to alter cell environments, protein structures and they can enable DNA damage and mutation.^{[3][4][5][6][7][8][9][10]}

• The cytochrome P450 enzymes (CYP) are a part of the microsomal ethanol oxidizing system. These are a large group of enzymes involved in numerous oxidizing reactions on different substrates. They catalyze many different reactions in order to make them in to more polar metabolites that are easier to excrete.^[11]

• There is an ethanol inducible form of CYP enzymes that is working in a small amount under normal physiological conditions. This enzyme CYP2E1 is converting ethanol to acetaldehyde and then to acetate. When there is chronic alcohol abuse, there is induction of the microsomal system and there is an increase in the expression of CYP2E1. This increase in CYP2E1 expression under chronic ethanol consumption can be hazardous, as this oxidation reaction can produces many different ROS; O₂^–, H₂O₂, OH^– and hydroxyethyl radical (HER).^{[12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]}

• Ethanol metabolism additionally promotes lipogenesis through the inhibition of peroxisome proliferator activated receptor α (PPAR-α) and AMP kinase, as well as the stimulation of sterol regulatory element binding protein 1, which is a membrane bound transcription factor. The sequence of all these events results in a fat storing metabolic remodeling of the liver.^[28][29][30]

• Two key factors that play an important role in the inflammatory process that leads to the alcohol mediated liver injury are:^[31][32]
  • Endotoxin
  • Gut permeability
• Endotoxin is associated to the lipopolysaccharide (LPS) component of the outer wall of gram-negative bacteria and is thought to be the key trigger in this inflammatory process.^[33][34]
• Gut permeability is the factor that is either enabling or preventing the transfer of the LPS-endotoxin from the intestinal lumen into the portal circulation.^[35][36]
• The fact that long term exposure to alcohol increases gut permeability has been observed in humans as LPS-endotoxin levels have been found to be elevated in patients with alcoholic liver injury.^[37]

• After the entry of LPS-endotoxin in to the portal circulation it binds to the LPS-binding protein, this is a key step in the inflammatory and histopathological response to alcohol ingestion.^[38]
• The LPS-LPS binding protein complex binds to the CD14 receptor on the cell surface membrane of the Kupffer cells in the liver.
• Activation of these Kupffer cells requires 3 main cellular proteins:^[39]
  • CD14 (monocyte differentiation antigen)^[40]
  • Toll-like receptor 4 (TLR4)^[41]
  • MD2, a protein, binds TLR4 with LPS-LPS binding protein
• The TLR4 then signals activation of early growth response 1 (EGR1), which is an early gene-zinc-finger transcription factor.^[42]
• The nuclear factor-kB (NF-kB) and the TLR4 adapter also play an important role in the activation of the kupffer cells.^[43]
• EGR1 plays the pivotal role in lipopolysaccharide-stimulated TNF-α production.
• In mice the absence of EGR1 prevents alcohol induced liver injury.^[44]

• Ethanol administration stimulates the release of mitochondrial cytochrome c and the expression of the Fas ligand, this leads to hepatic cell apoptosis mediated by the cascade-3 activation pathway.^[45]
• The cumulative effect of TNF-α and Fas-mediated apoptotic signals make the hepatocytes more susceptible to injury by stimulating an increase in natural killer T cells in the liver.^[46]

• Susceptibility to alcoholic liver disease could be determined by functional polymorphisms in the ADH2 gene.^[47][48]

• Polymorphism at position -238 of the TNF-α promoter region.^[49][50]

Conditions associated with alcoholic liver disease include:^[1][51]

• Obesity
• Chronic viral hepatitis
• Iron overload
• Cirrhosis
• Hepatocellular carcinoma

• On gross pathology, characteristic findings of alcoholic liver disease include:^[52]
  • Hepatomegaly
  • Nodules
    • Macronodules
    • Micronodules
  • Firm in consistency
  • Portal vein dilation

On microscopic histopathological analysis characteristic findings of alcoholic liver disease include:^{[53][54][55][56][57][58][59][60]}

• Non-cirrhotic liver
  • Steatosis
    • Macrovesicular steatosis – the cytoplasm of hepatocytes is occupied by large lipid droplets that end up displacing the nucleus and other organelles peripherally
  • Proliferation of the smooth endoplasmic reticulum
  • Distortion of the mitochondria (giant mitochondria)
  • Hepatocyte balooning (Mallory-Denk bodies)

• Cirrhotic liver:
  • Fibrous septae that are made up of collagen surrounding the hepatocytes which results in pseudo lobule formation.
  • This produces a nodular appearance of the liver and then progresses from micro nodular to macro nodular cirrhosis with time.
  • Proliferation of the bile ducts may also be seen.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

The primary cause of alcoholic liver disease is excessive consumption of alcohol over a long period of time.

The primary cause of alcoholic liver disease is excessive consumption of alcohol over a long period of time.^[1][2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Alcoholic liver disease should be differentiated from other diseases that produce similar symptoms, and other types of liver diseases. It should also be differentiated from diseases of the gallbladder. Conditions that may present in a similar manner to alcoholic liver disease are; cholecystitis, cholelithiasis, drug toxicity, non-alcoholic fatty liver disease, and other forms of hepatitis (eg. viral, autoimmune).

Alcoholic liver disease can be differentiated from other diseases on the basis of clinical manifestations including fever, abdominal pain and jaundice. The diseases are:^{[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]}

• Hemochromatosis
• Wilson’s disease
• Viral hepatitis
• Alcoholic hepatitis
• Drug induced hepatitis
• Autoimmune hepatitis
• Cirrhosis
• Cholestatic jaundice

Abbreviations: RUQ= Right upper quadrant of the abdomen, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CT= Computed tomography

Classification of jaundice based on etiology Disease History and clinical manifestations Diagnosis Lab Findings Other blood tests Other diagnostic Family history Fever RUQ Pain Pruritis AST ALT ALK BLR Indirect BLR Direct Viral serology Hepatocellular Jaundice Alcoholic liver disease Alcoholic hepatitis – -/+ -/+ – ↑↑ ↑ N ↑/N N – – – Cirrhosis -/+ -/+ -/+ – ↑ ↑ ↑/N ↑/N ↑/N -/+ Low platelet Small liver on ultrasound Jaundice Hemochromatosis + – -/+ – ↑ ↑ ↑/N ↑/N N – Ferritin ↑ Liver biopsy Wilson’s disease + – -/+ – ↑ ↑ N ↑/N N – Serum cerulloplasmin ↑ Liver biopsy Viral hepatitis – -/+ – – ↑ ↑ N ↑/N N + Specific viral antibody for each type – Drug induced hepatitis – -/+ – – ↑ ↑ N ↑/N N – – – Autoimmune hepatitis -/+ – – -/+ ↑ ↑ N ↑/N N – Anti-LKM antibody Liver biopsy Cholestatic Jaundice Common bile duct stone -/+ – + + N N ↑ N ↑ – Dilated ducts on ultrasound CT/ERCP Hepatitis A cholestatic type – -/+ + + N N ↑ N ↑ + HAV– AB Abdominal ultrasound EBV / CMV hepatitis – -/+ + + N N ↑ N ↑ + Positive serology – Primary biliary cirrhosis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – AMA positive Liver biopsy Primary sclerosing cholangitis -/+ – -/+ + N/↑ N/↑ ↑ N ↑ – Beading on MRCP Liver biopsy Pancreatic carcinoma + – -/+ – N/↑ N/↑ ↑ N ↑ – Mass on ultrasound CT scan for diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

The incidence of alcoholic liver disease is very high among alcoholics, and those who consume excessive amounts of alcohol. It does still depend on the amount and type of alcohol consumed. The mortality rate is high in those who present with alcoholic hepatitis and those individuals whose disease has progressed to cirrhosis. The average age of presentation is between 40 and 50 years. The disease tends to progress faster in individuals of hispanic ethnicity and women are at greater risk of developing alcoholic liver disease than men.

• According to National Institute of Alcohol Abuse and Alcoholism the incidence of alcoholic steatosis is approximately 20,000 per 100,000 alcoholics and heavy drinkers.^[1]

• The prevalence of alcoholic liver disease is estimated to be 604 per 100,000 individuals within the age group of 25 to 44 years.^[2][3]
• The prevalence of alcoholic liver disease is estimated to be 948 per 100,000 individuals within the age group of 45 to 64 years.^[2][4][5]

• The 5-year mortality rate in patients suffering from well compensated alcoholic cirrhosis is approximately 58000 per 100,000 individuals.^[6]
• The 28-day mortality rate of patients suffering from alcoholic hepatitis ranges from a low of 20000 per 100,000 individuals to a high of 30000 per 100,000 individuals.^[7]

• Alcoholic hepatitis commonly affects individuals between 40 and 50 years.^[8][9]

• Alcoholic liver disease usually progresses faster in individuals of the hispanic ethnicity. Caucasian individuals are likely to develop disease later.^[10][11][12]

• Women are at a higher risk to be affected by alcoholic liver disease than men.^[13][14]

• Alcohol abuse is responsible for five percent (100,000 per year in 1996) of deaths occurring annually in the United States.^[15]

• In western countries alcoholic liver disease is the second most common indication for liver transplantation in patients with chronic liver disease.^[16]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

The most potent risk factor in the development of alcoholic liver disease is alcohol consumption. Other risk factors include female gender, hispanic ethnicity, and genetic factors.

The most potent risk factor in the development of alcoholic liver disease is the quantity and frequency of alcohol consumption. Other risk factors include gender, age, and genetic factors.^{[1][2][3][4][5][6][7][8]}

• Common risk factors in the development of alcoholic liver disease include:^{[9][10][11][12][13]}
  • Female gender
  • Hispanic ethnicity
  • Obesity
  • Genetic factors

• Less common risk factors in the development of alcoholic liver disease include:
  • Age
  • Co-existing chronic viral hepatitis
  • Iron overload
  • Smoking

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

All patients who present with elevated liver enzymes, signs of liver disease or increased frequency of accidental trauma should be screened for alcohol abuse. Most individuals who consume heavy amounts of alcohol tend to deny it, hence there must be a strong suspicion under these circumstances. Physicians must have a low threshold to screen for alcohol abuse.

• Patient should be asked about daily or weekly alcohol consumption.^[1]
• Patient should be asked about the CAGE questions (sensitivity ≥ 70% and Specificity > 90%):^[1]
  • Have you ever felt the need to cut down on your drinking?
  • Are you easily annoyed by criticism of your drinking?
  • Have you ever felt guilty about you drinking?
  • Have you ever needed an eye opener?
• Two positive CAGE answers indicate dependence on alcohol.
• Alcohol use disorders identification test (AUDIT-C) should also be implemented to detect alcohol abuse:^[2]
  • Men should score ≥ four points (Sensitivity = 86% and Specificity = 89%).
  • Women should score ≥ three points (Sensitivity = 73% and Specificity = 91%).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: M. Khurram Afzal, MD [2]

Alcoholic liver disease progresses through three stages (steatosis, alcoholic hepatitis, and cirrhosis) with the continued use of alcohol. Serious complications begin to occur with the development of alcoholic hepatitis, when portal hypertension, coagulopathies, and intractable jaundice. Complications of cirrhosis include hepatic encephalopathy and hepatocellular carcinoma. Prognosis varies dependent on level of progression of illness, and whether treatment is given. Prognosis can be measured using laboratory values, and three prognostic scores: The MELD score, the Glasgow Alcoholic Hepatitis Score, and the ABIC score.

Significant aspects regarding natural history of alcoholic liver disease include:^[1][2][3]

• Alcoholic liver disease is thought to progress through three main histological stages with the continued use of alcohol.
• Steatosis is the first stage occuring when triglycerides accumulate in hepatocytes.
• This is reversible with abstinence.
• Steatohepatitis or alcoholic hepatitis is the next stage characterized by:
  • Fatty change
  • Inflammation
  • Hepatocellular injury
  • Necrosis
• The last stage is cirrhosis which is characterized by:
  • Dense and diffuse micronodular fibrosis.
  • This stage is irreversible, and is a risk factor for the development of hepatocellular carcinoma.

Complications of alcoholic hepatitis include:^{[2][3][4][5][6][7]}

• Portal hypertension (ascites, variceal bleeding, hepatorenal syndrome)
• Coagulopathy
• Intractable jaundice

Complications of cirrhosis include:^{[2][3][4][5][6][7]}

• Hepatocellular carcinoma
• Hepatic encephalopathy

Poor prognostic factors of alcoholic liver disease include:^[4][5][8]

• Prolonged prothrombin time
• Serum Bilirubin >10 mg/dL
• Hepatic encephalopathy
• Azotemia
• Leukocytosis
• Unresponsive to steroid treatment
• Reverse portal flow on doppler ultrasound

Prognostic scores used to assess the prognosis of patients with alcoholic liver disease include:^[4][5][8]

• MELD score for cirrhosis
• Glasgow alcoholic hepatitis score (age, white blood cell, blood urea nitrogen, prothrombin time ratio, and bilirubin level)
• ABIC score – age, serum bilirubin, serum creatinine

Class I

1. ” Patients presenting with a high clinical suspicion of alcoholic hepatitis should have their risk for poor outcome stratified using the Maddrey Discriminant Function (MDF), as well as other available clinical data. Evaluating a patient’s condition over time with serial calculation of the Model for End-Stage Liver Disease (MELD) score is also justified. (Level of evidence: B) ”

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