Causes of Hepatosplenomegaly
Primary Disease Categories
Hepatosplenomegaly results from three major disease categories: chronic liver disease with portal hypertension, hematologic/malignant disorders, and metabolic storage diseases, with the specific etiology determined through systematic evaluation. 1
Chronic Liver Disease with Portal Hypertension
Portal hypertension from chronic liver disease is one of the most common causes, typically presenting with splenomegaly accompanied by thrombocytopenia and other signs of portal hypertension. 1 Specific cirrhotic causes include:
- Chronic viral hepatitis B or C 1
- Non-alcoholic steatohepatitis (NASH) and alcoholic steatohepatitis 1
- Autoimmune hepatitis 1
- Hereditary hemochromatosis 1
- Wilson disease - can present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension, often with Kayser-Fleischer rings and neurological/psychiatric symptoms 2, 3
- Primary biliary cirrhosis 1
Infectious Causes
Infectious etiologies represent a critical category, particularly in endemic regions:
- Schistosomiasis (S. mansoni, S. japonicum, S. intercalatum, S. guineensis, S. mekongi) - hepatosplenic schistosomiasis can result in hepatosplenomegaly, hepatic 'pipestem' fibrosis, and portal hypertension with esophageal varices 4
- Chronic malaria exposure - associated with hepatosplenomegaly even in the absence of schistosomiasis, with synergistic exacerbation when both infections coexist 5, 6, 7
- Cytomegalovirus (CMV) infection - particularly in transplant recipients 4
- Parvovirus B19 infection - can cause anemia and hepatosplenomegaly in transplant recipients 4
- Endocarditis - can lead to splenic abscess and splenomegaly 2, 3
- Tuberculosis, toxoplasmosis, Pneumocystis pneumonia - associated with hemophagocytic syndrome 4
- Parasitic infections - including fascioliasis, toxocariasis, toxoplasmosis, hydatid disease, and leishmaniasis 8
Hematologic and Malignant Disorders
- Myeloproliferative disorders, particularly myelofibrosis - associated with massive splenomegaly (>10cm below costal margin) 2, 3
- Hemophagocytic syndrome (HPS) - rare cause presenting with fever in all patients and hepatosplenomegaly in 9 of 17 patients, often related to viral infections (CMV, Epstein-Barr virus, human herpes virus 6 and 8), with poor prognosis (8 of 17 patients died) 4
- Posttransplantation lymphoproliferative disease 4
- Autoimmune disorders - including rheumatoid arthritis with Felty syndrome 2
Metabolic Storage Diseases
Lysosomal storage diseases commonly present with both hepatomegaly and splenomegaly:
- Acid sphingomyelinase deficiency (ASMD/Niemann-Pick disease) - presents with massive splenomegaly (>10x normal size), growth failure, hyperlipidemia, and characteristic storage cells 2, 3, 9
- Lysosomal acid lipase deficiency (LALD) - presents with hepatosplenomegaly and dyslipidemia 2
- Gaucher disease 3
- Niemann-Pick disease type C 3
- Glycogen storage diseases (GSDs) - frequently present with hepatomegaly, with some types also causing splenomegaly 2
Other Important Causes
- Cystic fibrosis - hepatobiliary involvement can present with hepatosplenomegaly 2
- Griscelli syndrome type 2 - characterized by oculocutaneous hypopigmentation, silvery grey hair, recurrent pyogenic infections, and hepatosplenomegaly, with most patients eventually developing an "accelerated phase" of hemolymphatic histiocytosis (HLH) that is often fatal 4
- Chédiak-Higashi syndrome (CHS) - presents with partial oculocutaneous albinism, recurrent pyogenic infections, and progressive neurological dysfunction, with hepatosplenomegaly during the accelerated phase 4
- Hermansky-Pudlak syndrome type 2 - presents with hypopigmentation, thrombocytopenia, neutropenia, and recurrent infections 4
Clinical Pitfalls to Avoid
A critical pitfall is delaying hepatology referral when hepatosplenomegaly is identified, as this can prevent progression of liver fibrosis. 1 Another common error is misclassifying idiopathic non-cirrhotic portal hypertension (INCPH) patients as cirrhotic on ultrasound. 1
In pediatric populations, up to 12% of healthy children aged 1-3 years have palpable spleens, so palpability alone does not confirm pathologic splenomegaly—ultrasound with age-appropriate reference values is required for definitive diagnosis. 2