What is the appropriate workup for a patient presenting with hepatosplenomegaly (enlargement of the liver and spleen)?

Hepatosplenomegaly Workup

Initial Laboratory Evaluation

Begin with a complete blood count (CBC) with differential to assess for cytopenias, particularly thrombocytopenia which may indicate portal hypertension or hematologic malignancy, along with comprehensive metabolic panel and liver function tests. 1

• CBC with differential is essential to identify thrombocytopenia, granulocytosis, or other cytopenias that suggest portal hypertension, hypersplenism, or hematologic disorders 1
• Liver function tests including transaminases (AST, ALT), gamma-glutamyl transferase, alkaline phosphatase, and bilirubin to assess hepatocellular injury and cholestasis 2
• Lipid profile to identify mixed dyslipidemia with decreased HDL, which is characteristic of storage disorders like acid sphingomyelinase deficiency (ASMD) 1, 3
• Blood glucose, lactate, and uric acid levels when hypoglycemia is present or suspected, as this combination with hepatomegaly suggests glycogen storage disease 4
• Inflammatory markers including ESR, CRP, and SAA (where available) to assess systemic inflammation in autoinflammatory conditions 4

Initial Imaging Studies

Abdominal ultrasound with Doppler is the first-line imaging modality to confirm hepatosplenomegaly, assess organ morphology, detect focal lesions, and evaluate for portal hypertension. 1

• Doppler ultrasonography provides information about portal blood flow velocity, respiratory flow changes, and can detect portal hypertension by identifying reduced flow velocity or flow reversal 1
• Measure and document the exact size of liver and spleen, noting centimeters below costal margins 2
• Assess for signs of cirrhosis, portal hypertension, and portosystemic shunting 1

Key Differential Diagnoses to Prioritize

Lysosomal Storage Diseases

• Acid sphingomyelinase deficiency (ASMD) should be strongly considered in young adults with unexplained hepatosplenomegaly, normal liver function tests, and mixed dyslipidemia, as diagnosis is often delayed 4+ years due to rarity 1, 3
• Gaucher disease and Niemann-Pick disease typically present with massive splenomegaly (often >10x normal size) that helps differentiate from glycogen storage diseases 4, 2
• Lysosomal acid lipase deficiency (LALD) presents with hepatosplenomegaly and dyslipidemia 2

Liver Disease

• Cirrhosis with portal hypertension is one of the most common causes in the United States and typically presents with thrombocytopenia and other signs of portal hypertension 2, 5
• Wilson disease can present with isolated splenomegaly from clinically inapparent cirrhosis; look for Kayser-Fleischer rings and neuropsychiatric symptoms 2
• Cystic fibrosis hepatobiliary involvement should be considered, particularly in younger patients 2

Hematologic Malignancies

• Leukemia and lymphoma are important considerations, particularly when accompanied by B-symptoms and cytopenias 1
• Myeloproliferative disorders, especially myelofibrosis, are associated with massive splenomegaly 2

Glycogen Storage Diseases

• GSD Type III presents with hepatomegaly and hypoglycemia; glucagon stimulation 2 hours post-meal produces normal glucose rise, but no response after overnight fast 4

Infectious Causes

• Infectious mononucleosis is a common cause in the United States 5
• Malaria and schistosomiasis should be considered with appropriate travel history 5

Advanced Diagnostic Testing Based on Initial Findings

When Storage Disorders Are Suspected

• Genetic testing for SMPD1 gene if ASMD is suspected based on clinical presentation and lipid abnormalities 1, 3
• Plasma total and free carnitine, acylcarnitine profile, plasma amino acids, and urine organic acids when metabolic disorders are suspected 4
• Chest X-ray or CT to evaluate for interstitial lung disease, which commonly accompanies ASMD 1, 3

When Portal Hypertension Is Suspected

• Vibration-controlled transient elastography (VCTE) to assess liver stiffness, with excellent diagnostic performance (AUC 0.90) for clinically significant portal hypertension 1
• LSPS score (combining liver stiffness, spleen size, and platelet count) improves diagnostic accuracy for portal hypertension 1
• Calculate liver fibrosis indices including APRI, FIB-4, and GGT-to-Platelet Ratio, though these should be combined with imaging findings rather than used alone 1
• CT or MRI for detailed assessment when ultrasound is inadequate or to detect portosystemic shunting 1

When Hematologic Disorders Are Suspected

• Bone marrow biopsy if hematologic malignancy is suspected or to identify storage cells in lysosomal storage diseases 1
• Flow cytometry on bone marrow samples when lymphoproliferative disorders are considered 6

When Glycogen Storage Disease Is Suspected

• Critical blood samples during hypoglycemia including insulin, growth hormone, cortisol, free fatty acids, beta-hydroxybutyrate, and acetoacetate 4
• Glucagon stimulation test (2 hours post-meal vs. after overnight fast) to differentiate GSD types 4
• CK levels which are often elevated in GSD Type III with muscle involvement 4

Tissue Biopsy Considerations

• Liver biopsy should be reserved for cases where non-invasive tests are inconclusive, but avoided in suspected hereditary hemorrhagic telangiectasia due to bleeding risk 1
• Muscle biopsy may be indicated when myopathy is present; requires proper processing with snap freezing in liquid nitrogen for enzymatic analysis (15 mg minimum) 4
• Molecular testing is now preferred over biopsy for confirming lysosomal storage diseases when enzymatic testing is available 7

Critical Clinical Pearls and Pitfalls

• Do not dismiss palpable spleen in children as normal without ultrasound confirmation, though up to 12% of healthy children aged 1-3 years have palpable spleens 2
• Massive splenomegaly with hepatomegaly strongly suggests storage disorders (Gaucher, Niemann-Pick) rather than glycogen storage diseases, which typically have less prominent splenomegaly 4
• Normal liver function tests do not exclude serious pathology; ASMD commonly presents with hepatosplenomegaly and normal LFTs 1
• Hepatic venous pressure gradient (HVPG) is the gold standard for portal hypertension assessment but is invasive and limited to specialized centers 1
• Urinalysis every 6-12 months to monitor for proteinuria from AA amyloidosis in chronic inflammatory conditions 4
• Patients with splenomegaly should avoid contact sports due to rupture risk 5

Referral Algorithm

Refer initially to hepatology/gastroenterology as the liver is the primary affected organ in most cases, with concurrent hematology consultation if massive splenomegaly or cytopenias predominate. 2

• Hepatology referral is appropriate for most cases since liver involvement with fibrosis and cirrhosis represents major morbidity 2
• Metabolic disease specialist referral when storage disorders are confirmed or highly suspected 3
• Concurrent hepatology and hematology evaluation when bleeding disorders coexist with hepatosplenomegaly 2
• Pediatric gastroenterology/hepatology for children, with subsequent metabolic specialist referral if storage disorders suspected 2