What are the causes of hepatomegaly?

Causes of Hepatomegaly

Life-Threatening Causes Requiring Immediate Recognition

In neonates with hepatomegaly and shock, congenital heart disease (particularly ductal-dependent lesions) must be ruled out immediately with echocardiography while starting prostaglandin infusion. 1

• Neonatal sepsis presents with hepatomegaly alongside tachycardia, respiratory distress, poor feeding, and reduced perfusion, particularly with maternal chorioamnionitis or prolonged rupture of membranes 1
• Inborn errors of metabolism causing hyperammonemia or hypoglycemia can simulate septic shock and present with hepatomegaly 1
• Diffuse hepatic infantile hemangiomas cause severe hepatomegaly before 4 months of age and can lead to abdominal compartment syndrome, compromised ventilation, renal failure, or high-output cardiac failure 1
• Budd-Chiari syndrome presents with abdominal pain, ascites, and striking hepatomegaly, requiring immediate anticoagulation 2
• Acute liver failure with hepatomegaly requires intensive cardiovascular support and close monitoring for malignant infiltration, especially in patients with massive hepatomegaly or cancer history 2

Metabolic and Storage Disorders

Glycogen storage diseases are a major metabolic cause of hepatomegaly, with distinct patterns based on subtype.

Glycogen Storage Disease Type I

• Presents with hypoglycemia, pronounced hepatomegaly, lactic acidosis, hyperlipidemia, and nephromegaly 3
• Blood glucose may decrease to <40 mg/dl within 3-4 hours of feeding during infancy 3
• Hepatomegaly typically decreases with age, but liver adenomas develop commonly and hepatocellular carcinoma can occur 3
• Beta-hydroxybutyrate levels are only mildly elevated relative to free fatty acids, distinguishing it from fatty acid oxidation disorders 1

Glycogen Storage Disease Type III

• Dominant features during infancy and childhood include hepatomegaly, hypoglycemia, hyperlipidemia, and growth retardation 3
• Elevated transaminases and creatine kinase levels indicate muscle involvement (Type IIIa) 3, 1
• Hepatomegaly and hepatic symptoms improve with age and usually resolve after puberty, though progressive liver cirrhosis can occur 3
• Hepatic adenomas occur with prevalence ranging from 4% to 25%, with rare reports of hepatocellular carcinoma 3

Lysosomal Storage Diseases

• Gaucher disease and Niemann-Pick disease present with hepatomegaly but are distinguished by massive splenomegaly and absence of hypoglycemia 1, 4
• Pompe disease (GSD Type II) can rarely cause severe infantile cardiomyopathy with hepatomegaly from cardiac failure, distinguished by absence of hypoglycemia 1
• Mucopolysaccharidosis Type VI shows reduction in liver size with enzyme replacement therapy (Naglazyme) 2

Fatty Liver Diseases

Nonalcoholic fatty liver disease (NAFLD) affects 20-30% of the general population, increasing to 70% in obesity and 90% in diabetes mellitus. 5

• The disease spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) with inflammation, which can progress to fibrosis and cirrhosis 5
• Most patients are asymptomatic, with the condition often discovered incidentally through abnormal liver enzymes or imaging 5
• Hepatic glycogenosis in diabetic patients occurs during periods of hyperglycemia when glucose freely enters hepatocytes driving glycogen synthesis, augmented by supraphysiologic insulin levels 6
• In diabetic patients, glycogenosis causes mildly to moderately elevated aminotransferases and is readily reversible with sustained euglycemic control, unlike steatosis which may progress to cirrhosis 6

Alcohol-Related Hepatomegaly

• Alcohol-induced hepatomegaly results from an increase in hepatocyte size, not cell number, with 50-60% of increased liver weight accounted for by intracellular water 7
• Hepatocyte enlargement compresses vascular-sinusoidal pathways, resulting in increased intrahepatic and portal pressure once a threshold in cell size (1600-1700 μm²) is exceeded 7
• Portal hypertension correlates strongly with hepatocyte size regardless of cirrhosis presence, suggesting cell size is a major determinant of portal hypertension 7

Infectious Causes

• Viral hepatitis can cause hepatomegaly with neuropsychiatric symptoms independent of disease severity 3
• HIV-infected patients receiving nucleoside analog antiretroviral therapy can develop hepatomegaly with severe steatosis, though this syndrome is rare (1.3 per 1000 person-years) 8
• Meningitis and encephalitis must be ruled out with lumbar puncture in patients with hepatomegaly and altered consciousness 3

Congestive and Vascular Causes

• Congestive heart failure from structural heart disease causes hepatomegaly, particularly in ductal-dependent lesions 1
• Budd-Chiari syndrome requires treatment of underlying prothrombotic causes (e.g., myeloproliferative disorders) concomitantly with anticoagulation 2

Biliary and Cholestatic Causes

• Cystic fibrosis-associated liver disease presents with hepatomegaly and requires UDCA at 20-30 mg/kg/day to improve serum liver tests and histological parameters 2
• Biliary atresia must be distinguished from intrahepatic cholestasis using hepatobiliary scintigraphy, with acholic stools and conjugated hyperbilirubinemia as key features 1

Neoplastic and Infiltrative Causes

• Malignant infiltration should be suspected in patients with massive hepatomegaly or cancer history, requiring imaging and liver biopsy 2
• Hepatocellular adenomas and carcinoma develop in glycogen storage diseases with increasing age 3

Common Diagnostic Pitfalls

• Failure to distinguish cardiac from metabolic causes delays life-saving prostaglandin therapy in ductal-dependent lesions 1
• Assuming all hepatomegaly with hypoglycemia is GSD without checking beta-hydroxybutyrate can miss fatty acid oxidation disorders requiring completely different management 1
• Missing biliary atresia by not recognizing acholic stools and conjugated hyperbilirubinemia delays surgical intervention 1
• Overlooking hepatic hemangiomas in infants with multiple cutaneous hemangiomas misses opportunity for early treatment before cardiac decompensation 1
• In diabetic patients, distinguishing glycogenosis from steatosis is critical since glycogenosis is reversible with glycemic control and does not progress to cirrhosis, unlike steatosis 6