What are the primary causes of cirrhosis?

Primary Causes of Cirrhosis

The most common causes of cirrhosis globally are chronic viral hepatitis (hepatitis B and C), alcohol-related liver disease, and metabolic dysfunction-associated steatotic liver disease (MASLD), with the relative prevalence varying by geographic region. 1, 2

Major Etiologies

Viral Hepatitis

• Hepatitis B and C viruses account for approximately 78% of hepatocellular carcinoma cases and 57% of cirrhosis cases worldwide, making them the leading global causes. 2
• Hepatitis C is the most common underlying liver disease among patients with cirrhosis in North America, Europe, and Japan. 2
• Hepatitis B is the major cause of cirrhosis in Asia and Africa and approximately 20% of cases in Western countries. 2
• HBV-related risk factors for progression to cirrhosis include HBeAg seropositivity, high viral load, and genotype C. 1
• HCV genotype 1b has been associated with increased risk of progression to cirrhosis and hepatocellular carcinoma. 1

Alcohol-Related Liver Disease (ARLD)

• Alcohol excess causes approximately 36% of liver cancers and is a leading cause of cirrhosis in Western countries. 2
• In England and Scotland, alcohol is the predominant cause, with ARLD accounting for nearly 70% of cirrhosis cases in northern England. 2
• In some European countries, alcohol accounts for 40-50% of cirrhosis cases. 1
• In the United States, alcohol use disorder accounts for approximately 45% of all cases of cirrhosis. 3

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/NAFLD)

• MASLD affects up to one in five people (approximately 19% of adults) in the United Kingdom and Western nations. 2
• MASLD-associated cirrhosis contributes 10-14% of cirrhosis cases in Western countries. 2
• The risk of developing cirrhosis in MASLD-related chronic liver disease is between 18-27%, which exceeds the risk in HCV-related disease. 2
• In the United States, nonalcoholic fatty liver disease accounts for approximately 26% of cirrhosis cases. 3
• Obesity, diabetes, and metabolic syndrome are risk factors for NAFLD progression to cirrhosis. 1

Less Common but Important Causes

Autoimmune and Cholestatic Diseases

• Autoimmune hepatitis causes cirrhosis in approximately one-third of adult patients and about half of children at presentation. 2
• Primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis all increase cirrhosis risk. 2

Genetic/Hereditary Conditions

• Hemochromatosis carries a 200-fold increased relative risk of cirrhosis compared to the normal population and can lead to cirrhosis in up to 45% of cases. 1, 2
• Alpha-1-antitrypsin deficiency is a well-documented cause of cirrhosis. 1
• Wilson disease can progress to cirrhosis if untreated. 4

Cryptogenic Cirrhosis

• Cryptogenic cirrhosis or cirrhosis of unknown etiology is found in 3%-30% of patients with cirrhosis. 4
• NASH is considered one of the leading causes of cryptogenic cirrhosis in many western countries, based on serial biopsy reports demonstrating progression of prior histological NASH to cirrhosis without continuing definitive evidence of NASH. 4
• Other putative causes include silent or "burnt out" autoimmune hepatitis, occult viral infection, and covert alcoholism. 4

Geographic Variations

The relative prevalence of cirrhosis causes varies significantly by region:

• In Asia and Africa, hepatitis B predominates. 2
• In North America and Europe, alcohol-related liver disease and MASLD are increasingly common, with ARLD and MASLD combined accounting for nearly 70% of cases in northern England. 2
• In the United States, causes often overlap, with hepatitis C accounting for 41% of cases. 3

Clinical Implications

• Approximately one-third of cirrhotic patients will develop liver cancer during their lifetime. 2
• Chronic HBV infection carries a 15-25% risk of premature death from liver cancer or end-stage liver disease. 2
• The incidence of cirrhosis in the United States tripled from 1975 through 2005, largely due to HCV-related disease. 2