Alcoholic Liver Disease

Alcoholic liver disease is a spectrum of disorders ranging from fatty liver to

cirrhosis secondary to chronic alcohol use disorder. Excessive and prolonged
consumption of alcohol results in impairment of the lipolysis pathway, causing
inflammatory changes within the hepatocytes. Patients typically present during
the hepatitis stage with jaundice, fever, and abdominal pain. Diagnosis is based
on a history of alcohol use disorder and confirmed by laboratory derangement
with an AST/ALT ratio > 2. Alcoholic liver disease carries a high mortality rate if
patients present with severe hepatitis. Management aims at alcohol abstinence
for reversal (at certain stages) and addressing contributing factors (such as viral
infections or drugs) to minimize damage to the hepatocytes. Approximately 10% of
patients regress with alcohol abstinence during the hepatitis stage. Cirrhosis is
frequently irreversible.

Last updated: January 19, 2024

CONTENTS

Overview
Pathophysiology
Clinical Presentation
Diagnosis and Severity Scores
Management
Differential Diagnosis
References

Overview
Definition
Alcoholic liver disease encompasses alcoholic steatosis (fatty liver,
reversible), steatohepatitis (can be reversible), and cirrhosis (irreversible). All
are secondary to alcohol use disorder.
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).
Image by Lecturio.

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.
Pathophysiology of alcoholic liver disease:
FA: fatty acid; TNF: tumor necrosis factor
Image by Lecturio.
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)
Image by Lecturio.

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 cirrhosis with concomitant empyema (asterisk and arrows):
Liver appears nodular, irregular, and shrunken (notice abdominal ascites).
Image: “Subacute bacterial empyema” by Department of Pulmonary Medicine, Institute of Liver and Biliary
Sciences, New Delhi, India. License: CC BY 4.0

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 steatosis
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
Management algorithm of alcoholic hepatitis

Image by Lecturio.

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

1. 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

2. 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
3. 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

4. Patel R, Mueller M. (2020). Alcoholic Liver Disease. StatPearls Publishing.

https://www.ncbi.nlm.nih.gov/books/NBK546632/

5. Woodley M, Whelan A. (1992). Manual of Medical Therapeutics. 27th Edition; p. 309–322.