Alcoholic Liver Disease

Overview

Definition

Alcoholic liver disease encompasses alcoholic steatosis (fatty liver, reversible), steatohepatitis (can be reversible), and cirrhosis (irreversible). All are secondary to alcohol abuse.

Epidemiology

• 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

Etiology

• 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
  • Smoking
  • Diabetes

Pathophysiology

Ethanol metabolism

• 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.

Histopathological changes

• 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.

Clinical Presentation

Alcoholic steatosis (fatty liver)

• Asymptomatic
• May have vague abdominal discomfort
• Hepatomegaly on examination

Alcoholic hepatitis

• Low-grade fever
• Loss of appetite, nausea
• RUQ discomfort
• Jaundice
• Hepatomegaly
• Portal hypertension → ascites
• Lethargy, confusion (from hepatic encephalopathy)

Alcoholic cirrhosis

• Fatigue, malaise
• Weight loss
• Jaundice and scleral icterus (from hyperbilirubinemia)
• Pruritus (bile salt deposition in the skin)
• Hepatic encephalopathy:
  • Asterixis
  • Lethargy
  • Confusion
  • Coma
• Ascites (due to portal hypertension and decreased albumin)
• Upper GI bleeding (esophageal varices from portal hypertension)
• Skin changes:
  • Telangiectasias 
  • 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)
• Hyperestrogenism:
  • Gynecomastia
  • Hypogonadism (testicular atrophy)
  • Reduced libido 
  • Erectile dysfunction 
  • Infertility 
  • Amenorrhea
• Alopecia
• Smooth tongue due to 1 or more nutritional deficiencies (iron, folate, vitamin B₁₂)

Diagnosis and Severity Scores

History

• 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
  • Anorexia
• GI symptoms:
  • RUQ pain
  • Nausea/vomiting
  • Diarrhea

Physical exam

• General:
  • Jaundice, scleral icterus
  • Characteristic cirrhotic skin changes
• Abdominal:
  • Hepato- or splenomegaly
  • Abdominal distention (from ascites)
  • RUQ tenderness

Laboratory studies

• 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
  • Anemia
  • Hyponatremia

Imaging

• Ultrasound:
  • Steatosis:
    • Hepatomegaly
    • ↑ Liver echogenicity
  • Hepatitis:
    • Diffuse echogenicity due to increased fat deposition
    • Hepatomegaly
    • Edema near the portal triad
  • Cirrhosis:
    • Echogenicity with irregular areas
    • Atrophy of right lobe
    • Hypertrophy of left and caudate lobes
    • Shrunken nodular liver in advanced cirrhosis
    • Ascites
• 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)

Liver biopsy

• 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

Management

Hepatic stenosis

• Alcohol cessation
• Healthy diet

Alcoholic hepatitis

Mild-to-moderate hepatitis:

• 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.

Severe hepatitis:

• Model for End-Stage Liver Disease score > 21
• Measures used for mild-to-moderate hepatitis + pharmacological therapy:
  • Glucocorticoids:
    • Prednisolone
    • Aim is to reduce inflammatory changes in hepatocytes.
  • Pentoxifylline (for patients with contraindications to steroids):
    • Active GI bleed
    • Severe pancreatitis 
    • Active infection
    • Renal failure

Cirrhosis

• Supportive management similar to alcoholic hepatitis
• Esophageal varices:
  • Patients should get screened with upper endoscopy.
  • Prophylaxis of bleeding is aimed at reducing portal hypertension:
    • Beta-blockers
    • Transjugular intrahepatic shunts
• Symptomatic management of ascites:
  • Salt restriction, water restriction
  • Diuretics
  • 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

Prognosis

• 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.

Differential Diagnosis

• 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.