What are the causes of hepatomegaly (enlarged liver) in adults?

Causes of Enlarged Liver (Hepatomegaly)

Hepatomegaly in adults results from a diverse spectrum of conditions, with the most common causes in Western populations being metabolic dysfunction-associated liver disease (MASLD), alcohol-related liver disease (ARLD), and chronic viral hepatitis, while less common but critical causes include malignant infiltration, Budd-Chiari syndrome, and lysosomal storage diseases.

Major Categories of Hepatomegaly

Chronic Liver Disease and Cirrhosis

MASLD and ARLD account for nearly 70% of chronic liver disease cases in Western populations, representing the dominant causes of hepatomegaly 1. MASLD affects up to one in five people in the United Kingdom and has similar prevalence in other Western nations 1. The condition is strongly associated with obesity, type 2 diabetes, and metabolic syndrome 1.

• MASLD is prevalent in >70% of people with type 2 diabetes, with between 12-20% having clinically significant fibrosis 1
• Alcohol-related liver disease causes approximately 36% of liver cancers and results in hepatomegaly through hepatocyte enlargement from intracellular water accumulation 1, 2
• Chronic HCV infection is the most common underlying liver disease in North America, Europe and Japan, affecting 0.5-1% of the UK population 1
• Chronic HBV infection affects 0.1-0.5% of the UK population and can cause hepatomegaly even without cirrhosis 1

Metabolic and Storage Disorders

Glycogenic hepatopathy occurs in poorly controlled diabetes when intermittent hyperglycemia and excessive insulin drive glycogen accumulation in hepatocytes 3. This condition is readily reversible with sustained euglycemic control, unlike steatosis which may progress to cirrhosis 3.

• Lysosomal storage diseases should be considered in patients with hepatosplenomegaly, particularly when other metabolic conditions are excluded 4
• Glycogen storage disease type I requires dietary therapy with frequent feedings to maintain blood glucose ≥70 mg/dL 5
• Hemochromatosis increases risk of cirrhosis and hepatocellular carcinoma 1

Vascular Causes

Budd-Chiari syndrome (acute hepatic vein thrombosis) presents with the classic triad of abdominal pain, ascites, and striking hepatomegaly 1, 5. This condition requires immediate anticoagulation and consideration for liver transplantation if significant liver failure is present 1, 5.

• Ischemic hepatic injury ("shock liver") occurs after cardiac arrest, hypotension, or severe congestive heart failure, with markedly elevated aminotransferases 1
• Congestive hepatomegaly results from right-sided heart failure or severe cardiac dysfunction 1

Malignant Infiltration

Massive hepatic enlargement with a history of cancer should prompt immediate evaluation for malignant infiltration through imaging and biopsy 1, 6. Common primary cancers causing hepatic infiltration include breast cancer, small cell lung cancer, lymphoma, and melanoma 1.

• Hepatocellular carcinoma develops in approximately one-third of cirrhotic patients during their lifetime 1
• In 20% of HCC cases, cancer occurs in non-cirrhotic liver, particularly with HBV and MASLD 1

Autoimmune and Inflammatory Conditions

• Autoimmune hepatitis causes chronic inflammation and hepatomegaly, increasing risk of cirrhosis and HCC 1
• Primary biliary cholangitis leads to progressive liver disease with hepatomegaly 1

Acute Conditions

Acute fatty liver of pregnancy and HELLP syndrome require expeditious delivery in consultation with obstetrical services 1, 5.

Diagnostic Approach

Initial evaluation must include detailed history of alcohol consumption, medications, supplements, toxic exposures, and assessment of metabolic risk factors 6. The standard workup includes:

• Laboratory tests: AST, ALT, alkaline phosphatase, GGT, total bilirubin, platelet count, albumin, and PT/INR 5, 6
• Abdominal ultrasound as the primary imaging modality to assess liver size, texture, and focal lesions 5, 6
• Liver elastography when physical exam is abnormal, enzymes persistently elevated, or ultrasound shows abnormalities 5, 6
• Fibrosis indices (APRI, FIB-4, GPR) to detect advanced fibrosis non-invasively 5, 6

Critical Pitfalls to Avoid

Failure to identify the underlying cause before initiating treatment leads to poor outcomes 5. Specific pitfalls include:

• Delaying treatment for Budd-Chiari syndrome or acute liver failure can be fatal 5
• Distinguishing glycogenosis from steatosis is essential, as glycogenosis is reversible with glycemic control while steatosis may progress to cirrhosis 3
• Missing malignant infiltration in patients with massive hepatomegaly and cancer history 1, 6
• Assuming normal liver enzymes exclude significant disease, as glycogenosis and other conditions can present with minimal enzyme elevation 3