What are the causes and initial management of hepatosplenomegaly with severe anemia in children?

Causes of Hepatosplenomegaly with Severe Anemia in Children

In children presenting with hepatosplenomegaly and severe anemia, the most critical diagnoses to consider are lysosomal storage disorders (particularly acid sphingomyelinase deficiency and Gaucher disease), chronic myeloid leukemia, hemophagocytic lymphohistiocytosis, and congenital infections, with the diagnostic approach prioritizing complete blood count with differential, peripheral blood smear examination, and abdominal ultrasound as initial steps. 1

Primary Diagnostic Categories

Lysosomal Storage Disorders

Acid sphingomyelinase deficiency (ASMD) is a critical consideration when hepatosplenomegaly presents with severe anemia in infancy or early childhood. 1

• Infantile neurovisceral ASMD presents with marked hepatosplenomegaly, failure to thrive, and severe anemia with thrombocytopenia and leukopenia, typically before 6 months of age 1
• Chronic visceral ASMD commonly presents with isolated splenomegaly at routine pediatric visits between ages 2-6 years, with subsequent development of thrombocytopenia and anemia 1
• Diagnosis requires enzyme assay for acid sphingomyelinase activity and genetic testing of the SMPD1 gene 1
• A diagnostic delay of 4+ years is common with ASMD due to its rarity, making early recognition critical 2

Gaucher disease Type 1 presents with hepatosplenomegaly, thrombocytopenia, and anemia, often detected incidentally. 3

• Diagnosis is confirmed by very low leukocyte β-glucocerebrosidase activity and elevated plasma chitotriosidase 3
• Erlenmeyer flask deformities of long bones may be present on imaging 3

Hematologic Malignancies

Chronic myeloid leukemia (CML) in children presents with marked hepatosplenomegaly and severe anemia, with median white blood cell count of 240,000/µL. 1

• Twenty percent of children with CML-CP present with bleeding manifestations despite normal or elevated platelet counts 1
• Splenic complications include infarction and rupture, requiring urgent imaging if left upper quadrant pain develops 1
• Diagnosis requires detection of Philadelphia chromosome or BCR::ABL1 fusion gene 1
• Children with hyperleukocytosis (WBC >100 × 10⁹/L) require immediate intravenous hyperhydration and hydroxyurea 1

Immune Dysregulation Syndromes

Hemophagocytic lymphohistiocytosis (HLH) presents with high fever, lymphadenopathy, hepatosplenomegaly, pancytopenia including severe anemia, and markedly elevated ferritin levels. 1

• HLH occurs as the "accelerated phase" in Chediak-Higashi syndrome, Griscelli syndrome type 2, and Hermansky-Pudlak syndrome type 2 1
• These syndromes present with oculocutaneous hypopigmentation, silvery-grey hair, recurrent pyogenic infections, and hepatosplenomegaly from infancy 1
• Giant azurophilic lysosomal granules on peripheral blood smear are pathognomonic for Chediak-Higashi syndrome 1
• Without aggressive chemotherapy and immunosuppression, HLH is usually fatal 1

Congenital Infections

Congenital toxoplasmosis in HIV-exposed infants presents with hepatosplenomegaly, maculopapular rash, generalized lymphadenopathy, jaundice, and hematologic abnormalities including severe anemia, thrombocytopenia, and neutropenia. 1

• All infants whose mothers are both HIV-infected and seropositive for Toxoplasma should be evaluated for congenital toxoplasmosis 1
• Diagnosis uses enzyme immunoassay to detect Toxoplasma-specific IgM, IgA, or IgE in neonatal serum within the first 6 months 1

Initial Diagnostic Workup Algorithm

First-Line Laboratory Studies

• Complete blood count with differential and reticulocyte count to assess severity of anemia, presence of cytopenias, and bone marrow response 2, 4
• Peripheral blood smear examination to identify giant granules (Chediak-Higashi), atypical cells (leukemia), or evidence of hemolysis 1
• Liver function tests including transaminases to evaluate hepatic involvement 1, 2
• Abdominal ultrasound to confirm splenomegaly, assess splenic volume, and evaluate for portal hypertension 2

Second-Line Investigations Based on Initial Findings

• If white blood cell count is markedly elevated (>100 × 10⁹/L), obtain BCR::ABL1 testing or cytogenetics for Philadelphia chromosome to rule out CML 1
• If ferritin is markedly elevated with fever and cytopenias, evaluate for HLH with triglycerides, fibrinogen, and soluble IL-2 receptor 1
• If hypopigmentation is present with recurrent infections, examine peripheral smear for giant granules and consider genetic testing for Chediak-Higashi, Griscelli, or Hermansky-Pudlak syndromes 1
• If hepatosplenomegaly persists unexplained for >2 months with substantial organ enlargement, refer for lysosomal enzyme assays (acid sphingomyelinase, glucocerebrosidase) 1, 2, 4

Critical Diagnostic Pitfalls

Do not assume immune thrombocytopenia (ITP) is the diagnosis when splenomegaly is present, as less than 3% of ITP patients have splenomegaly, and moderate to massive splenomegaly indicates an alternative diagnosis. 2

• Bone marrow examination is unnecessary in children with typical ITP features and should not delay evaluation for alternative diagnoses 1

Do not overlook metabolic causes such as severe rickets with secondary myelofibrosis, which can present with anemia and hepatosplenomegaly. 5

Do not miss Wilson's disease in preschool-aged children presenting with hemolytic anemia, hepatosplenomegaly, and decompensated liver disease, as severe mutations can cause very early liver disease. 6

Specialist Referral Indications

• Hematology referral is indicated for unexplained cytopenias, suspected leukemia, or consideration of bone marrow examination in children >60 months with systemic symptoms 2
• Medical genetics/metabolic specialist referral is essential when storage disorders (ASMD, Gaucher disease) are suspected based on persistent unexplained hepatosplenomegaly 1, 2
• Hepatology/gastroenterology referral is indicated if liver disease, portal hypertension, or ascites is present 2
• Infectious disease referral is appropriate for children with fever, hepatosplenomegaly, and suspected congenital or chronic infections 1, 2

Initial Management Considerations

For children with severe anemia and hepatosplenomegaly pending definitive diagnosis:

• Avoid transfusion to hemoglobin >10 g/dL in splenic sequestration, as sequestered red cells may be acutely released causing overtransfusion 1
• In CML with hyperleukocytosis, initiate hydroxyurea (25-50 mg/kg/day) and intravenous hyperhydration (2.5-3 liters/m²/day) immediately 1
• Monitor closely for acute complications including splenic rupture, leukostasis, or progression to HLH 1