What are the non‑alcoholic etiologies of liver cirrhosis?

Non-Alcoholic Causes of Liver Cirrhosis

The primary non-alcoholic causes of liver cirrhosis include non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), chronic viral hepatitis (B and C), autoimmune liver diseases, cholestatic diseases, and metabolic disorders including iron and copper overload. 1

Major Non-Alcoholic Etiologies

Non-Alcoholic Fatty Liver Disease (NAFLD) and NASH

• NAFLD affects approximately 30% of adults in developed countries, with rates as high as 90% in obese individuals and 50% in those with diabetes. 2
• Approximately 30% of patients with NAFLD progress to NASH, which significantly increases cirrhosis risk. 2
• NASH cirrhosis has become the second most common indication for liver transplantation and the third most common cause of hepatocellular carcinoma in the United States. 2
• Between 12-20% of people with type 2 diabetes have clinically significant fibrosis (≥F2 stage). 3
• The degree of liver fibrosis is the strongest predictor of mortality in NAFLD/NASH patients. 2

Chronic Viral Hepatitis

• Chronic hepatitis C (HCV) infection is a major cause of cirrhosis, with coexistent hepatic steatosis being common and strongly associated with more advanced liver disease. 3
• Chronic hepatitis B infection leads to cirrhosis through long-term inflammation and fibrosis. 1

Autoimmune and Cholestatic Diseases

• Primary biliary cirrhosis (PBC) shows high prevalence of steatosis (40.5%) and steatohepatitis (15%) in affected patients. 3
• Autoimmune hepatitis causes progressive fibrosis leading to cirrhosis. 1
• Cholestatic diseases result in chronic bile duct injury and subsequent cirrhosis. 1

Metabolic Disorders

• Hemochromatosis (iron overload) has a curious association with alcohol intake but is fundamentally a genetic disorder causing cirrhosis. 4
• Wilson's disease (copper overload) leads to hepatic copper accumulation and cirrhosis. 1
• Porphyria cutanea tarda, while associated with alcohol, has genetic origins. 4

Key Clinical Distinctions

Metabolic Syndrome as a Driver

• Diabetes is a major risk factor for developing NASH, disease progression, and worse liver outcomes. 3
• Components of metabolic syndrome (obesity, type 2 diabetes, dyslipidemia) can convert stable cirrhosis into progressive disease by causing superimposed NAFLD. 5
• NAFLD is prevalent in >70% of people with type 2 diabetes in the United States. 3

Prognostic Differences

• Non-alcoholic cirrhosis generally has better prognosis than alcoholic cirrhosis, with alcoholic cirrhosis showing 5-year survival of 23-50% compared to better outcomes in non-alcoholic etiologies. 2
• The rate of decompensation within 1 year of diagnosis is 25.2% in non-alcoholic liver cirrhosis versus 37.6% in alcoholic liver cirrhosis. 2

Critical Screening Considerations

High-Risk Populations Requiring Evaluation

• Adults with type 2 diabetes or prediabetes, particularly those with obesity or cardiometabolic risk factors, should be screened for NAFLD with clinically significant fibrosis using fibrosis-4 index, even with normal liver enzymes. 3
• Patients with persistently elevated aminotransferases for >6 months and low fibrosis-4 index should be evaluated for other causes of liver disease. 3
• Those with indeterminate or high fibrosis-4 index require additional risk stratification by liver stiffness measurement with transient elastography or enhanced liver fibrosis biomarker. 3

Mortality Patterns

• Cardiovascular disease represents the most common cause of death in patients with NAFLD/NASH, surpassing liver-related mortality in many cases. 2
• Liver-related mortality increases progressively with advancing fibrosis. 2
• Hepatocellular carcinoma has an annual incidence of approximately 2.6% in cirrhotic patients, though this can occur even without cirrhosis in NASH patients. 2

Common Pitfalls to Avoid

• Do not assume normal liver enzymes exclude significant liver disease—NAFLD with significant fibrosis can present with normal aminotransferases. 3
• Recognize that multiple etiologies can coexist—obese diabetic patients with autoimmune liver disease commonly exhibit steatosis and steatohepatitis on biopsy. 3
• NAFLD increases risk of chronic kidney disease, particularly when liver fibrosis is present, requiring comprehensive screening. 3