Overview
Definition
Alcoholic liver disease encompasses alcoholic steatosis (fatty liver, reversible), steatohepatitis (can be reversible), and cirrhosis (irreversible). All are secondary to alcohol abuse.
The 3 stages of alcoholic liver disease:
These 3 stages of alcoholic liver disease may overlap and do not necessarily occur in sequence: alcoholic fatty liver (reversible), alcoholic hepatitis (reversible if alcohol stopped), and alcohol-related cirrhosis (irreversible). They are also risk factors for developing hepatocellular carcinoma (HCC).
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.
Progression of liver damage in alcoholic liver disease (left to right):
1. Healthy hepatocytes (no liver damage)
2. Bloated hepatocytes with steatosis (distended by fat droplets), no inflammation: steatosis (liver damage still reversible)
3. Inflamed and dying hepatocytes, possible fibrosis: hepatitis (liver damage still reversible)
4. Dead cells: cirrhosis (irreversible liver damage)
Steatohepatitis with established cirrhosis; thick bands of fibrosis (arrows) encircling a hepatocyte nodule
Image: “Hematoxylin and Van Gieson’s stain” by Alexander Boyd et al. License: CC BY 4.0Alcohol-induced steatosis (histological features of liver sections):
Image: “Representative histological feature of liver sections” by College of Veterinary Medicine, South China Agricultural University, Guangzhou, Guangdong Province, PR China. License: CC BY 4.0
(A): normal control group
(B): 10% alcohol-induced fatty liver with macrovesicles (indicated by arrowhead) of hepatocytes
(C): 20% alcohol-induced fatty liver with macrovesicles (indicated by red arrow) of hepatocytes graded as high in the alcoholic fatty liver disease group. The green arrow represents the formation of Mallory bodies.Liver biopsy showing Mallory bodies, large-droplet steatosis, and neutrophils
Image: “Liver biopsy” by Institute of Infectious and Tropical Diseases, University of Brescia, Italy. License: CC BY 2.0Gross pathology of alcoholic liver cirrhosis: The cut surface shows areas with diffuse pallor due to a dense network of scar tissue.
Image: “Gross pathology of alcoholic liver cirrhosis” by Centers for Disease Control and Prevention/Dr. Edwin P. Ewing, Jr. License: CC0 1.0
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
- Steatosis:
- 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 cirrhosis with concomitant empyema (asterisk and arrows):
Liver appears nodular, irregular, and shrunken (notice abdominal ascites).
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
- Glucocorticoids:
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.
References
- 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.