Alcoholic liver disease encompasses alcoholic steatosis (fatty liver, reversible), steatohepatitis (can be reversible), and cirrhosis (irreversible). All are secondary to alcohol abuse.
- Prevalence of alcohol use disorder in the United States is 18%.
- The disease is the 2nd most common cause of cirrhosis in the United States.
- Prevalence of alcoholic fatty liver disease is 4% in the United States.
- Alcoholic hepatitis develops in about 35% of alcoholics.
- About 15%–20% of heavy drinkers will develop cirrhosis.
- Age of presentation is usually before 60 years old.
- High mortality rate in severe alcoholic liver disease: if left untreated → 45% in 1 month
- Main causative factor is heavy alcohol consumption:
- Men: > 40 g/day
- Women: > 20 g/day
- Risk factors for the development of alcoholic liver disease include:
- Women with increased susceptibility
- Hepatitis C virus (HCV) infection
- Obesity and non-alcoholic fatty liver disease
- High-fat diet
- There are multiple pathways, but the major one is the acetaldehyde pathway:
- Acetaldehyde and reduced nicotinamide adenine dinucleotide (NAD+) are generated.
- Acetaldehyde is metabolized to acetate by acetaldehyde dehydrogenase.
- Acetaldehyde dehydrogenase has multiple isoforms with different levels of activity.
- Accumulation of acetaldehyde is 1 factor responsible for liver injury.
- With excessive alcohol consumption, microsomal cytochrome P450 plays a role in metabolism:
- Reactive oxygen species are formed in this pathway.
- Contribute to oxidative damage in alcoholic liver disease
- Alcohol metabolism causes:
- Relative hypoxia in liver zone III (near central veins; poorly oxygenated) > zone I (around the portal tracts where oxygenated blood enters)
- Necrosis and hepatic vein sclerosis
- Alcohol increases intestinal permeability:
- Bacterial translocation
- Elevated levels of endotoxin in blood
- Endotoxin causes inflammatory cytokine activation and contributes to inflammation of liver parenchyma.
- Steatosis stage:
- Increased NAD+ decreases ATP supply to the liver impairing lipolysis.
- Fatty acids and triglycerides accumulate in the liver.
- Swollen hepatocytes (macrovesicules)
- Fat infiltration in hepatocytes close to the venules
- Can develop within 2 days of excess ethanol consumption
- Resolves within 2 weeks of discontinuation of alcohol
- Hepatitis stage:
- Generation of inflammatory cytokines
- Lobular infiltration of PMN
- Ballooning degeneration of hepatocytes
- Mallory bodies (intracellular eosinophilic aggregates representing hyaline deposits)
- Hepatocellular necrosis
- Inflammation leads to activation of stellate cells and pericellular fibrosis.
- Cirrhosis stage:
- Perivenular fibrosis (collagen deposition near the hepatic vein and sinusoid)
- Continuous injury and regeneration lead to regenerative nodule formation.
- Damage is usually irreversible.
- Progressive fibrosis leads to obstruction of normal portal blood flow and development of portal hypertension.
Alcoholic steatosis (fatty liver)
- May have vague abdominal discomfort
- Hepatomegaly on examination
- Low-grade fever
- Loss of appetite, nausea
- RUQ discomfort
- Portal hypertension → ascites
- Lethargy, confusion (from hepatic encephalopathy)
- Fatigue, malaise
- Weight loss
- Jaundice and scleral icterus (from hyperbilirubinemia)
- Pruritus (bile salt deposition in the skin)
- Hepatic encephalopathy:
- Ascites (due to portal hypertension and decreased albumin)
- Upper GI bleeding (esophageal varices from portal hypertension)
- Skin changes:
- Caput medusae (dilation of periumbilical veins)
- Peripheral palmar erythema
- Clubbed nails
- Dupuytren’s contracture (flexion deformities of fingers from thickening and shortening of palmar fascia)
- Hypogonadism (testicular atrophy)
- Reduced libido
- Erectile dysfunction
- Smooth tongue due to 1 or more nutritional deficiencies (iron, folate, vitamin B12)
Diagnosis and Severity Scores
- Alcohol consumption (duration, quantity, and frequency)
- Inquire about other potential causes:
- Hereditary disorders (hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency)
- Viral hepatitis (IV drug use)
- Medications (e.g., acetaminophen overuse)
- Constitutional symptoms:
- Fever, malaise
- Weight loss
- GI symptoms:
- RUQ pain
- Jaundice, scleral icterus
- Characteristic cirrhotic skin changes
- Hepato- or splenomegaly
- Abdominal distention (from ascites)
- RUQ tenderness
- Alcoholic fatty liver disease:
- ↑ AST > ↑ ALT
- ↑ GGT (gamma glutamyl transferase)
- Alcoholic hepatitis:
- AST/ALT ratio > 2: a very specific marker of alcoholic liver disease
- AST or ALT < 500
- ↑ Alkaline phosphatase (ALP) and GGT
- ↑ Bilirubin
- ↓ Albumin
- ↑ PT, INR, and PTT
- Macrocytic anemia
- Neutrophilic leukocytosis
- Alcoholic cirrhosis:
- ↑ AST > ALT: usually modest elevation
- ↑ Bilirubin
- ↑ GGT
- ↑ ALP (< 2–3x the normal value)
- ↑ Ammonia
- ↓ Total protein (↓ albumin)
- ↑ PT
- ↓ Platelets
- ↑ Liver echogenicity
- Diffuse echogenicity due to increased fat deposition
- Edema near the portal triad
- Echogenicity with irregular areas
- Atrophy of right lobe
- Hypertrophy of left and caudate lobes
- Shrunken nodular liver in advanced cirrhosis
- CT scan:
- Provides the same information as ultrasound
- May show nodular liver, right-lobe atrophy, left-lobe hypertrophy, ascites
- Good for ruling out hepatocellular carcinoma (HCC)
- Gold standard for cirrhosis
- Not necessary if convincing clinical picture and laboratory studies
- Can be done with a percutaneous, transjugular, or laparoscopic approach
Disease severity scores
Maddrey discriminant function:
- Estimates disease severity and mortality risk for alcoholic hepatitis
- Calculated from serum bilirubin and PT
- Discriminant function ≥ 32:
- High short-term mortality
- May benefit from glucocorticoids
Glasgow alcoholic hepatitis score:
- Based on age, serum bilirubin, BUN, PT, and WBC count
- Glasgow alcoholic hepatitis score ≥ 9 is predictive of mortality.
Model for End-Stage Liver Disease score:
- Predicts survival in cirrhosis, but can also be used for alcoholic hepatitis.
- Based on serum bilirubin, creatinine, INR, and serum Na
- Scale range: 6–40
- Alcohol cessation
- Healthy diet
- Alcohol cessation:
- Disulfiram, naltrexone, acamprosate
- Referral to Alcoholics Anonymous
- Hydration and electrolyte correction
- Nutritional supplementation (especially thiamine)
- Treat any concomitant hepatitis B (HBV) or HCV infection.
- Model for End-Stage Liver Disease score > 21
- Measures used for mild-to-moderate hepatitis + pharmacological therapy:
- Aim is to reduce inflammatory changes in hepatocytes.
- Pentoxifylline (for patients with contraindications to steroids):
- Active GI bleed
- Severe pancreatitis
- Active infection
- Renal failure
- Supportive management similar to alcoholic hepatitis
- Esophageal varices:
- Patients should get screened with upper endoscopy.
- Prophylaxis of bleeding is aimed at reducing portal hypertension:
- Transjugular intrahepatic shunts
- Symptomatic management of ascites:
- Salt restriction, water restriction
- Therapeutic paracentesis
- Hepatic encephalopathy:
- Restrict protein intake.
- Oral lactulose
- Oral neomycin
- Surveillance for HCC
- Liver transplant is indicated for:
- Failure of medical management
- Model for End-Stage Liver Disease score > 20
- Only for patients who have been abstinent
- 10%–20% of patients with alcoholic hepatitis progress to cirrhosis every year.
- 10% of individuals with alcoholic hepatitis regress with abstinence.
- Median survival for compensated cirrhosis (without complications) is > 12 years.
- Median survival in cirrhosis with Model for End-Stage Liver Disease score ≥ 21 is ≤ 6 months.
- Non-alcoholic fatty liver disease: presents with findings similar to steatohepatitis (the same lab results and clinical presentation). A distinction between alcoholic and non-alcoholic fatty liver disease can only be drawn based on patient history. Diagnosis is established based on clinical presentation and laboratory studies. Treatment is focused on lifestyle modifications.
- Viral hepatitis: infection from a virus causing acute liver disease. Presentation includes jaundice, fever with hepatomegaly, and transaminase elevation often > 500. Further differentiation can be established by detecting viral antigens and antibodies in the serum. Treatment is based on the cause; certain types can be prevented by vaccination.
- Autoimmune hepatitis: acute liver failure presenting with fatigue, jaundice, hepatomegaly, and RUQ tenderness. Drug-induced hepatitis must be ruled out by history and laboratory evaluation. The presence of an anti-smooth muscle antibody is a strong indicator of autoimmune hepatitis. The patient is treated with immunosuppressants.
- Other causes of hepatitis (drug-induced): jaundice, hepatomegaly, and RUQ discomfort present after ingestion of a hepatotoxic drug. Injury can be hepatocellular (elevated transaminases) and/or cholestatic (elevated ALP). Treatment is the removal of the offending drug.
- Goldberg E., Chopra S. (2021). Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis. Retrieved February 23, 2021, from https://www.uptodate.com/contents/cirrhosis-in-adults-etiologies-clinical-manifestations-and-diagnosis
- Scott L Freidman. (2020). Alcoholic hepatitis: Clinical manifestations and diagnosis. UpToDate. Retrieved February 19, 2021, from https://www.uptodate.com/contents/alcoholic-hepatitis-clinical-manifestations-and-diagnosis
- Scott L Freidman. (2020). Management and prognosis of alcoholic hepatitis. UpToDate. Retrieved February 10, 2021, from https://www.uptodate.com/contents/management-and-prognosis-of-alcoholic-hepatitis
- Patel R, Mueller M. (2020). Alcoholic Liver Disease. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK546632/
- Woodley M, Whelan A. (1992). Manual of Medical Therapeutics. 27th Edition; p. 309–322.