What causes hepatosplenomegaly (enlarged liver and spleen) in a patient?

Causes of Hepatosplenomegaly (Enlarged Liver and Spleen)

Hepatosplenomegaly results from three primary disease categories: liver disease with portal hypertension (most common in the United States), hematologic/malignant disorders, and metabolic storage diseases, with the specific etiology determined through systematic evaluation of risk factors, laboratory findings, and imaging studies. 1, 2

Primary Disease Categories

Liver Disease and Portal Hypertension

Portal hypertension from chronic liver disease is the most common cause of hepatosplenomegaly in the United States and typically presents with splenomegaly accompanied by thrombocytopenia and other signs of portal hypertension. 3, 2

Cirrhotic causes include: 4

• Chronic viral hepatitis B or C
• Non-alcoholic steatohepatitis/alcoholic steatohepatitis
• Autoimmune hepatitis
• Hereditary hemochromatosis
• Wilson's disease (can present with isolated splenomegaly from clinically inapparent cirrhosis)
• Primary biliary cirrhosis

Non-cirrhotic portal hypertension causes include: 4

• Idiopathic non-cirrhotic portal hypertension (INCPH), which commonly presents with large spleen and normal liver function initially, caused by portal venous obliteration from thrombophilia (40% prevalence), immunological disorders, specific medications (azathioprine, didanosine), or HIV infection
• Congenital liver fibrosis
• Sarcoidosis
• Schistosomiasis (common in tropical regions where up to 80% may have splenomegaly)

Hematologic and Malignant Disorders

Myeloproliferative disorders, particularly myelofibrosis, cause massive splenomegaly (>10cm below costal margin) and should be suspected when platelet counts exceed 200,000/mm³ despite splenomegaly. 4, 5, 6

Other hematologic causes include: 1, 5

• Leukemia and lymphoma
• Autoimmune disorders (rheumatoid arthritis with Felty syndrome)

Metabolic Storage Diseases

Lysosomal storage diseases should be considered in young adults with unexplained hepatosplenomegaly and normal liver function tests, as these conditions often have a 4+ year diagnostic delay due to their rarity. 1, 7

Key storage disorders include: 1, 5, 6

• Acid sphingomyelinase deficiency (ASMD): presents with massive splenomegaly (>10x normal size), mixed dyslipidemia with decreased HDL, and may have pulmonary involvement
• Gaucher disease
• Niemann-Pick disease type C: shows significant hepatosplenomegaly, growth failure, hyperlipidemia, and characteristic storage cells
• Lysosomal acid lipase deficiency (LALD): presents with hepatosplenomegaly and dyslipidemia
• Glycogen storage diseases

Infectious Causes

Common infectious etiologies include: 6, 2, 8

• Infectious mononucleosis (all patients have enlarged spleen, half have liver enlargement)
• Endocarditis (can lead to splenic abscess)
• Malaria (common in tropical regions)

Other Causes

Additional considerations: 4, 5

• Cystic fibrosis hepatobiliary involvement
• Abdominal malignancies
• Focal inflammatory lesions (pancreatitis, diverticulitis, appendicitis, Crohn's disease, ulcerative colitis)
• Portal/splenic vein thrombosis from local or systemic prothrombotic conditions

Diagnostic Algorithm

Initial Laboratory Evaluation

Order complete blood count to assess for cytopenias (particularly thrombocytopenia suggesting portal hypertension) and leukocytosis (suggesting myeloproliferative disorders). 1, 5

Additional first-line tests: 1, 5

• Liver function tests (transaminases, alkaline phosphatase, gamma-glutamyl transferase, bilirubin)
• Lipid profile (mixed dyslipidemia with decreased HDL suggests storage disorders)
• Blood glucose, lactate, and uric acid levels

Imaging Studies

Abdominal ultrasound with Doppler is the initial imaging modality to confirm hepatosplenomegaly, assess liver morphology, detect focal lesions, and identify signs of portal hypertension (reduced portal flow velocity, loss of respiratory changes, or flow reversal). 1

Advanced imaging when indicated: 1

• CT or MRI for detailed morphology assessment and portosystemic shunting detection
• Vibration-controlled transient elastography (VCTE) for liver stiffness assessment (excellent diagnostic performance with AUC 0.90 for portal hypertension; values <12 kPa suggest INCPH rather than cirrhosis)
• Chest X-ray or CT if ASMD suspected (to evaluate pulmonary involvement)

Specialized Testing Based on Initial Findings

If portal hypertension suspected: 1

• Calculate liver fibrosis indices (APRI, FIB-4, GGT-to-Platelet Ratio)
• LSPS score (combining liver stiffness, spleen size, platelet count) improves diagnostic accuracy
• Hepatic venous pressure gradient (HVPG) measurement is gold standard but limited to specialized centers

If storage disease suspected (young adult, normal LFTs, dyslipidemia): 1, 5

• Genetic testing for SMPD1 gene (ASMD)
• Enzymatic analysis on liver biopsy samples when feasible
• Bone marrow biopsy to identify storage cells

If myeloproliferative disorder suspected: 4

• V617F JAK2 mutation testing in granulocytes (100% specific)
• Bone marrow biopsy showing dystrophic megakaryocyte clusters

If thrombotic etiology suspected: 4

• Prothrombotic workup including Factor V Leiden, Factor II mutation, antithrombin/protein C/protein S levels, antiphospholipid antibodies
• Flow cytometry for paroxysmal nocturnal hemoglobinuria (CD55/CD59 deficient clones)

Liver Biopsy Considerations

Liver histology remains essential to exclude severe fibrosis or cirrhosis when diagnosing INCPH, but avoid biopsy in suspected hereditary hemorrhagic telangiectasia due to bleeding risk. 4, 1

Critical Clinical Pearls

Common pitfalls to avoid: 1, 5

• Do not delay hepatology referral when hepatosplenomegaly is identified, as this prevents progression of liver fibrosis
• In children aged 1-3 years, up to 12% have palpable spleens normally—do not rely solely on palpability; use ultrasound with age-appropriate reference values
• INCPH patients are often radiologically misclassified as cirrhotic on ultrasound due to liver surface nodularity and portal vein wall thickening
• Serum markers alone (APRI, FIB-4) have limitations and should be combined with imaging findings

Red flags requiring urgent evaluation: 6

• Sudden left upper quadrant pain (splenic infarction)
• Persistent fever with left upper quadrant pain (splenic abscess)
• Guarding and rebound tenderness (bowel infarction from mesenteric vein thrombosis)