What are the different types of cirrhosis classified by etiology?

Types of Cirrhosis by Etiology

Cirrhosis can be classified into several major etiologic categories: viral hepatitis (hepatitis B and C), alcohol-related liver disease, metabolic dysfunction-associated steatotic liver disease (MASLD/NAFLD), autoimmune and cholestatic diseases, genetic/hereditary conditions, and cryptogenic cirrhosis. 1, 2

Major Etiologic Categories

Viral Hepatitis

• Hepatitis B and C viruses account for approximately 78% of cirrhosis cases worldwide and represent the leading global cause. 2
• Hepatitis C is the most common underlying liver disease among cirrhotic patients in North America, Europe, and Japan, with cirrhotic patients having a 3-5% annual risk of hepatocellular carcinoma development. 3
• Hepatitis B is the major cause of cirrhosis in Asia and Africa and accounts for approximately 20% of cases in Western countries. 2
• HBV can cause cirrhosis through direct viral integration into host DNA, even in non-cirrhotic livers. 3

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, ARLD accounts for nearly 70% of cirrhosis cases. 2
• Alcoholic cirrhosis carries a 1-4% annual risk of hepatocellular carcinoma development in male patients, similar to viral hepatitis. 3
• The rate of HCC development in women with alcohol-related cirrhosis is significantly lower than in men. 3

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

• MASLD affects approximately 19% of adults in the United Kingdom and Western nations and contributes 10-14% of cirrhosis cases. 2
• The spectrum includes nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and NASH cirrhosis. 3
• NASH cirrhosis is defined as the presence of cirrhosis with current or previous histological evidence of steatosis or steatohepatitis. 3
• The risk of developing cirrhosis in MASLD-related chronic liver disease is 18-27%, which exceeds the risk in HCV-related disease. 2
• Metabolic risk factors include obesity, type 2 diabetes mellitus, dyslipidemia, and metabolic syndrome. 3

Autoimmune and Cholestatic Liver Diseases

• Autoimmune hepatitis has a very low risk of HCC development, with rare descriptions in the literature unless HCV coinfection is present. 3
• Approximately one-third of adult patients and about half of children with autoimmune hepatitis have cirrhosis at presentation. 2
• Primary biliary cirrhosis (PBC) carries a risk of HCC development, with women having a low risk but males having a similar risk to patients with alcohol-related cirrhosis. 3
• Primary sclerosing cholangitis can progress to cirrhosis and is associated with biliary complications. 3

Genetic and Hereditary Conditions

• Genetic hemochromatosis in patients who were iron-loaded at presentation carries a very high risk of HCC development (7-9% per year), which falls with venesection but not to baseline levels (1-3% per year). 3
• Hemochromatosis carries a 200-fold increased relative risk of cirrhosis compared to the normal population. 2
• Wilson's disease can progress to cirrhosis if untreated, and HCC is well described despite adequate copper chelating therapy. 3, 2
• Alpha-1-antitrypsin deficiency is a well-documented cause of cirrhosis. 1, 4

Cryptogenic Cirrhosis

• Cryptogenic cirrhosis is defined as cirrhosis with no obvious etiology and constitutes approximately 3-30% of all cirrhosis cases. 4
• Patients with cryptogenic cirrhosis are heavily enriched with metabolic risk factors such as obesity and metabolic syndrome, suggesting "burnt-out" NAFLD. 3, 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. 2, 4
• Other putative causes include silent or "burnt-out" autoimmune hepatitis, occult viral infection, and covert alcoholism. 2, 4

Risk Stratification by Etiology

High-Risk Etiologies for HCC Development

• Viral hepatitis (HBV/HCV): 3-5% annual risk, up to 12% in some HBV cohorts. 3
• Genetic hemochromatosis: 7-9% annual risk when iron-loaded. 3
• Alcohol-related cirrhosis: 1-4% annual risk in males. 3

Lower-Risk Etiologies for HCC Development

• Autoimmune hepatitis: Very low risk unless HCV coinfection present. 3
• Primary biliary cirrhosis: Low risk in women, higher in men. 3

Clinical Pitfalls

• Do not overlook cryptogenic cirrhosis as a potential manifestation of NASH, particularly in patients with metabolic risk factors, as the histological features of NASH may disappear in advanced cirrhosis. 3, 4
• Alcohol consumption must be carefully quantified using validated questionnaires, as significant consumption is defined as >21 drinks per week in men and >14 drinks per week in women over a 2-year period. 3
• Non-cirrhotic HCC can occur in patients with viral liver disease, particularly HBV, where direct viral integration into host DNA may play a role. 3
• Fibrolamellar HCC occurs in young patients (average age 30 years) without cirrhosis and has an equal sex incidence. 3