What is the appropriate work‑up and differential diagnosis for a 45‑year‑old man presenting with hepatomegaly and splenomegaly?

Hepatosplenomegaly in a 45-Year-Old Male: Work-Up and Differential Diagnosis

Begin with abdominal ultrasound with Doppler and complete blood count with differential, as these are the essential first-line tests to confirm hepatosplenomegaly, assess liver morphology, detect portal hypertension, and identify cytopenias that guide subsequent evaluation. 1, 2

Initial Laboratory Evaluation

Obtain the following blood tests immediately:

• Complete blood count with differential to assess for thrombocytopenia (suggesting portal hypertension), leukocytosis (suggesting infection or myeloproliferative disorder), or cytopenias (suggesting hematologic malignancy) 1, 2
• Comprehensive metabolic panel including liver function tests (ALT, AST, alkaline phosphatase, GGT, bilirubin, albumin) to evaluate for hepatocellular injury versus cholestasis 3, 2
• Lipid profile specifically noting HDL cholesterol, as profoundly low HDL (<30 mg/dL) in a lean patient strongly suggests lysosomal storage disease, particularly acid sphingomyelinase deficiency (ASMD) or Gaucher disease 1, 3, 4
• Serum LDH, beta-2 microglobulin, and calcium to assess for hematologic malignancies 5

Initial Imaging

• Abdominal ultrasound with Doppler is the mandatory first imaging study to confirm hepatosplenomegaly, measure organ volumes, assess liver morphology, detect focal lesions, evaluate portal blood flow velocity, and identify signs of portal hypertension 1, 2
• Document liver and spleen measurements in centimeters below the costal margin and calculate volumes in multiples of normal if possible 1, 3

Key Differential Diagnoses by Category

Portal Hypertension/Chronic Liver Disease (Most Common in This Age Group)

Consider these cirrhotic causes when splenomegaly accompanies thrombocytopenia:

• Chronic viral hepatitis B or C 2
• Non-alcoholic steatohepatitis or alcoholic liver disease 2
• Autoimmune hepatitis 2
• Wilson disease (look for Kayser-Fleischer rings, neuropsychiatric symptoms) 3
• Hereditary hemochromatosis 2
• Primary biliary cholangitis 2

Lysosomal Storage Diseases (Critical Not to Miss)

These conditions have a 4+ year diagnostic delay and are often treatable, making early recognition essential:

• Acid sphingomyelinase deficiency (ASMD) presents with massive splenomegaly (>10x normal), hepatomegaly, profoundly low HDL cholesterol (mean 22 mg/dL), elevated LDL cholesterol, normal or mildly elevated liver enzymes, and mixed dyslipidemia in lean patients 1, 3, 4
• Gaucher disease type 1 presents with massive splenomegaly (mean 13x normal), hepatomegaly, profoundly low HDL cholesterol (mean 26 mg/dL), LOW LDL cholesterol (distinguishing it from ASMD), and normal liver enzymes 3, 4
• Niemann-Pick disease type C presents with hepatosplenomegaly, growth failure, hyperlipidemia, and characteristic storage cells 3
• Lysosomal acid lipase deficiency (LALD) presents with hepatosplenomegaly and dyslipidemia 3

Hematologic/Malignant Disorders

• Myeloproliferative disorders, particularly myelofibrosis (associated with massive splenomegaly) 3, 2
• Leukemia and lymphoma 1
• Mastocytosis (requires bone marrow biopsy with CD117/tryptase staining and KIT D816V mutation testing) 5

Infectious Causes

• Schistosomiasis (S. mansoni, S. japonicum) causing hepatosplenic disease with pipestem fibrosis 2, 6
• Liver abscess, particularly in immunocompromised patients 7
• Cytomegalovirus, parvovirus B19, tuberculosis, toxoplasmosis (especially in transplant recipients) 2

Algorithmic Approach to Further Testing

If Thrombocytopenia and Signs of Chronic Liver Disease Present:

• Calculate liver fibrosis indices (APRI, FIB-4, GGT-to-Platelet Ratio) 1, 2
• Perform vibration-controlled transient elastography (VCTE) to assess liver stiffness; values <12 kPa suggest idiopathic non-cirrhotic portal hypertension rather than cirrhosis 2
• Consider hepatic venous pressure gradient (HVPG) measurement at specialized centers as the gold standard for portal hypertension assessment 1, 2
• Order viral hepatitis serologies, autoimmune markers (ANA, ASMA, anti-LKM), ceruloplasmin (Wilson disease), ferritin and transferrin saturation (hemochromatosis) 2

If Normal Liver Enzymes with Massive Splenomegaly and Low HDL in Lean Patient:

• Measure plasma chitotriosidase as an elevated level alerts to lysosomal storage disease 8
• Order genetic testing for SMPD1 gene (ASMD) and GBA gene (Gaucher disease) 1, 3
• Measure disease-specific biomarkers: lyso-sphingomyelin for ASMD and glucosylsphingosine for Gaucher disease 4
• Consider liver elastography to assess for fibrosis 1
• Obtain chest X-ray or CT to evaluate for interstitial lung disease, which commonly accompanies ASMD 1

If Cytopenias or Concern for Hematologic Malignancy:

• Perform bone marrow biopsy with immunohistochemistry for CD117, tryptase, CD2, CD25, and CD30 5
• Order V617F JAK2 mutation testing if myeloproliferative disorder suspected 2
• Measure serum tryptase if mastocytosis suspected 5
• Consider allele-specific quantitative PCR for KIT D816V mutation in peripheral blood 5

If Infectious Etiology Suspected:

• Obtain travel history and exposure to endemic areas for schistosomiasis 6
• Order stool examination for ova and parasites with specific schistosomiasis testing 6
• Consider CT abdomen/pelvis to evaluate for abscess or lymphadenopathy 2

Critical Clinical Pearls and Pitfalls

• Do not delay hepatology referral when hepatosplenomegaly is identified, as this prevents progression of liver fibrosis 3, 2
• Splenomegaly can be massive (>10x normal) in ASMD and may precede hepatomegaly 1, 3
• HDL cholesterol inversely correlates with liver and spleen volume in lysosomal storage diseases, making it a potential biomarker of disease activity 4
• Up to 73% of patients with chronic granulomatous disease have liver enzyme elevations during follow-up, with persistent alkaline phosphatase elevations in 25% 7
• Avoid misclassifying idiopathic non-cirrhotic portal hypertension (INCPH) as cirrhosis on ultrasound; VCTE values <12 kPa suggest INCPH 2
• Liver biopsy should be avoided in suspected hereditary hemorrhagic telangiectasia due to bleeding risk 1
• Serum markers alone (APRI, FIB-4) have limitations and should be combined with imaging findings 1

Red Flags Requiring Urgent Evaluation

• Sudden left upper quadrant pain (consider splenic infarction or rupture) 2
• Persistent fever with left upper quadrant pain (consider splenic abscess) 2
• Guarding and rebound tenderness (consider peritonitis) 2

Specialized Testing Based on Initial Findings

• Genetic testing and enzymatic analysis are now preferred over liver biopsy for confirming lysosomal storage diseases 9
• Molecular testing for additional genetic lesions using next-generation sequencing or myeloid gene panels if aggressive systemic mastocytosis or associated hematologic disorder suspected 5
• Liver biopsy may be considered if non-invasive tests are inconclusive, looking for granulomata, lobular hepatitis, venopathy, nodular regenerative hyperplasia, or storage cells 1, 9, 7