Causes of Hepatosplenomegaly with Lymphadenopathy in Children
The most common causes of hepatosplenomegaly with lymphadenopathy in children are infections (particularly viral infections like EBV and CMV), followed by hematologic malignancies (acute lymphoblastic leukemia and lymphomas), hemophagocytic lymphohistiocytosis, and metabolic storage disorders. 1, 2, 3
Malignant Causes
Acute lymphoblastic leukemia (ALL) is a critical diagnosis to exclude, as approximately 20% of pediatric ALL patients present with lymphadenopathy, splenomegaly, and/or hepatomegaly on physical examination. 1 The clinical presentation typically includes:
- Fatigue, constitutional symptoms (fevers, night sweats, weight loss), and easy bruising or bleeding 1
- In children specifically, extremity or joint pain may be the only presenting symptoms 1
- Diagnosis requires demonstration of ≥20% bone marrow lymphoblasts 1
Non-Hodgkin lymphoma and Hodgkin lymphoma are the most frequently diagnosed malignancies in children presenting with lymphadenopathy, with non-Hodgkin lymphoma being more common. 4 Lymphoblastic lymphoma presents similarly to ALL but with disease primarily in nodal or extranodal sites and <20% bone marrow involvement. 1
Chronic myeloid leukemia (CML) in children more often presents with splenomegaly and larger spleen size at diagnosis than in adults, and 20% present with bleeding manifestations despite normal platelet counts. 1
Infectious Causes
Viral infections represent the most widely encountered cause of lymphadenopathy with hepatosplenomegaly in children, with most being nonspecific viral and bacterial infections. 2, 4 Specific pathogens include:
- Epstein-Barr virus (EBV) and cytomegalovirus (CMV) are the most frequently diagnosed viral infections causing this triad. 4
- Hepatitis A was found in 7% of children with hepatosplenomegaly in one series 2
- Urinary tract infections were present in 10% of cases 2
- Toxoplasmosis was identified in 17 cases in one lymphadenopathy series 4
- Cat scratch disease was diagnosed in 4 cases 4
Hemophagocytic lymphohistiocytosis (HLH), often triggered by EBV infection, presents with fever, lymphadenopathy, hepatosplenomegaly, lymphocytosis, anemia, thrombocytopenia, and increased liver enzymes. 3, 5 On ultrasound within 1 week of presentation, findings include splenomegaly (89% of cases), hepatomegaly (78%), ascites (67%), gallbladder wall thickening (67%), increased periportal echogenicity (33%), and lymphadenopathy (33%). 3
Metabolic Storage Disorders
Lysosomal storage diseases commonly present with hepatomegaly, splenomegaly, and lymphadenopathy, with Niemann-Pick disease type A showing massive hepatosplenomegaly, lymphadenopathy, growth failure, and hyperlipidemia. 6, 7 Key features include:
- Acid sphingomyelinase deficiency (ASMD) can present with massive splenomegaly (>10x normal size). 6, 8
- Lysosomal acid lipase deficiency (LALD) presents with hepatosplenomegaly and dyslipidemia 6
- Gaucher disease and Niemann-Pick disease type C frequently present with splenomegaly 8
- Glycogen storage diseases frequently present with hepatomegaly, with some types also causing splenomegaly 6
Autoimmune and Lymphoproliferative Disorders
Autoimmune lymphoproliferative syndrome (ALPS) should be considered in children with unexplained chronic lymphadenopathy and splenomegaly, particularly when accompanied by multilineage cytopenias and increased risk of B-cell lymphoma. 1 The syndrome results from:
- Mutations in FAS (most common), FAS ligand, caspase 10, caspase 8, or NRAS genes 1
- Failure of lymphocyte apoptosis leading to accumulation of proliferating lymphocytes 1
- Childhood onset chronic lymphadenopathy, splenomegaly, and autoimmune cytopenias 1
Autoimmune disorders including rheumatoid arthritis with Felty syndrome can cause splenomegaly with lymphadenopathy. 6, 9
Hepatic Causes
Wilson disease can present with isolated splenomegaly due to clinically inapparent cirrhosis with portal hypertension, and may show Kayser-Fleischer rings or neurological symptoms. 6, 8
Cirrhosis with portal hypertension is a common cause of splenomegaly, often associated with thrombocytopenia and other signs of portal hypertension. 6, 9
Cystic fibrosis hepatobiliary involvement can present with hepatosplenomegaly. 6
Other Causes
- Sarcoidosis was detected in 22 cases in one pediatric lymphadenopathy series 4
- Kawasaki syndrome was diagnosed in 3 cases 4
- Langerhans cell histiocytosis was found in 2 cases 4
Diagnostic Approach
Initial laboratory evaluation should include complete blood count (to assess for cytopenias, anemia, thrombocytopenia, leukopenia, or lymphocytosis), liver function tests (transaminases, gamma-glutamyl transferase, alkaline phosphatase), lipid profile, blood glucose, lactate, and uric acid levels. 6, 9
Abdominal ultrasound should be performed to confirm hepatosplenomegaly and assess for other abdominal pathology, as up to 12% of healthy children aged 1-3 years have palpable spleens, making imaging essential for definitive diagnosis. 6, 9
Bone marrow examination is indicated when malignancy is suspected, particularly in patients with systemic symptoms or those older than 60 years. 9
Excisional lymph node biopsy remains the gold standard diagnostic method when the etiology remains unclear after initial workup. 4
Critical Red Flags Requiring Urgent Evaluation
Persistence of unexplained hepatosplenomegaly with lymphadenopathy for more than 2 months, especially with substantial volume enlargement or alteration in organ consistency, mandates referral to specialists. 2
Constitutional symptoms (fever, night sweats, weight loss), pallor, jaundice, easy bruising, or bone/joint pain require immediate evaluation for malignancy. 1, 2
Sudden left upper quadrant pain may indicate splenic infarction or rupture and requires urgent evaluation. 8, 9
Referral Algorithm
Patients with hepatosplenomegaly and lymphadenopathy should be initially referred to a pediatric gastroenterologist/hepatologist, as the liver is often the primary affected organ. 6
Concurrent hematology referral is indicated when malignancy is suspected based on cytopenias, constitutional symptoms, or abnormal blood counts. 9
Referral to a medical geneticist is indicated if storage disorders are suspected based on dyslipidemia, growth failure, or characteristic clinical features. 6, 9
Infectious disease consultation is warranted when fever and splenomegaly suggest infectious etiology. 9
Common Pitfalls to Avoid
Do not assume immune thrombocytopenic purpura (ITP) is the cause of splenomegaly, as less than 3% of ITP patients have splenomegaly; moderate to massive splenomegaly suggests an alternative diagnosis. 9
Do not delay referral when hepatosplenomegaly with lymphadenopathy is identified, as this can prevent progression of liver fibrosis in metabolic disorders or delay diagnosis of malignancy. 6
Most children with hepatosplenomegaly and lymphadenopathy have deficiency anemia associated with infections that general pediatricians can diagnose, but persistent unexplained cases require specialist evaluation. 2