What is the differential diagnosis for a 6-year-old child presenting with fever, jaundice (icterus), hepatosplenomegaly, seizures (convulsions), mildly elevated transaminases, and increased direct bilirubin?

Differential Diagnosis for a 6-Year-Old with Fever, Jaundice, Hepatosplenomegaly, Seizures, and Conjugated Hyperbilirubinemia

The most critical diagnoses to consider urgently are hemophagocytic lymphohistiocytosis (HLH), severe systemic infections (particularly viral hepatitis, EBV, or bacterial sepsis), and less commonly, metabolic storage disorders like Gaucher disease or tyrosinemia type 1.

Immediate Life-Threatening Considerations

Hemophagocytic Lymphohistiocytosis (HLH)

• HLH should be at the top of your differential given the constellation of fever, hepatosplenomegaly, seizures (CNS involvement), and conjugated hyperbilirubinemia 1
• The classic triad of fever, jaundice, and hepatosplenomegaly is present in 50% of HLH patients 1
• Hepatic involvement shows median ALT elevation of 5× upper limit of normal and median total bilirubin of 136 µmol/L, consistent with "mildly raised transaminases" 1
• Seizures in this context suggest CNS involvement, which is a critical feature of HLH and indicates severe disease 1
• High serum bilirubin and elevated alkaline phosphatase are associated with poor prognosis 1
• Urgent workup needed: Complete blood count (looking for cytopenias), triglycerides, ferritin, fibrinogen, and bone marrow examination showing hemophagocytosis 1

Severe Systemic Infections

Viral Hepatitis and EBV

• Systemic infections affecting the liver commonly present with elevated transaminases, fever, and hepatomegaly 2
• EBV infectious mononucleosis can cause prolonged hepatitis with tender hepatomegaly, markedly deranged liver function, and conjugated hyperbilirubinemia 3
• EBV can produce ALT levels up to 1,795 µ/L and total bilirubin up to 154 µmol/L with hepatosplenomegaly 3
• Tender hepatomegaly and gallbladder wall thickening on ultrasound are important predictors of significant EBV liver involvement 3
• Seizures could represent CNS complications of severe EBV infection or metabolic derangements from hepatic dysfunction 3

Bacterial Sepsis

• Severe bacterial sepsis characteristically causes increases in serum bilirubin with hepatic involvement 2
• Fever with hepatosplenomegaly and neurological symptoms (seizures) suggests systemic inflammatory response 2
• Blood cultures and inflammatory markers (CRP, procalcitonin) are essential 2

Important Metabolic and Chronic Liver Diseases

Tyrosinemia Type 1

• Although typically presenting earlier in infancy, tyrosinemia can present with hepatomegaly, direct hyperbilirubinemia, and elevated transaminases 4
• Acute presentations include hepatic dysfunction with coagulopathy, hypoglycemia, and direct hyperbilirubinemia 4
• Neurological crises can occur, potentially manifesting as seizures 4
• Diagnosis requires elevated blood/urine succinylacetone levels 4
• This is less likely at age 6 without prior symptoms, but should be considered if other diagnoses are excluded 4

Gaucher Disease Type 1

• Presents with hepatosplenomegaly, which can be detected incidentally 5
• Typically associated with thrombocytopenia and bone involvement (Erlenmeyer flask deformities) 5
• However, Gaucher disease does NOT typically cause significant jaundice, fever, or seizures, making it less likely in this acute presentation 5
• Consider if chronic hepatosplenomegaly with thrombocytopenia is found 5

Alpha-1 Antitrypsin Deficiency

• Can present in childhood with hepatosplenomegaly, elevated conjugated bilirubin, and elevated transaminases 4
• However, fever and acute seizures are NOT typical features of AAT deficiency, making this less likely 4
• AAT deficiency typically presents with prolonged jaundice in infancy or chronic liver disease, not acute febrile illness with seizures 4

Less Likely but Consider

Kawasaki Disease

• Can cause mild jaundice and mild transaminase elevation as part of gastrointestinal manifestations 4
• However, Kawasaki disease requires fever ≥5 days plus 4 of 5 principal criteria (extremity changes, rash, conjunctival injection, oral changes, cervical lymphadenopathy) 4
• Seizures are not a typical feature of Kawasaki disease 4
• This diagnosis is unlikely without the characteristic mucocutaneous findings 4

Critical Diagnostic Algorithm

Immediate Laboratory Workup

1. Complete blood count with differential: Look for cytopenias (HLH), atypical lymphocytes (EBV), or leukocytosis (bacterial infection) 6, 1
2. Comprehensive metabolic panel: Assess severity of hepatic dysfunction 6
3. Coagulation studies (PT/INR): Evaluate synthetic liver function and bleeding risk 6, 7
4. Ferritin, triglycerides, fibrinogen: Markedly elevated ferritin suggests HLH 1
5. Blood cultures: Rule out bacterial sepsis 2
6. Viral serologies: EBV (VCA IgM/IgG, EBNA), hepatitis A/B/C, CMV 2, 3
7. Peripheral smear: Look for hemophagocytosis or hemolysis 6, 8

Imaging

• Abdominal ultrasound: Assess liver and spleen size, look for gallbladder wall thickening (suggests EBV), exclude biliary obstruction 6, 7, 3

Specialized Testing if Initial Workup Non-Diagnostic

• Bone marrow examination: If HLH suspected based on fever, cytopenias, hepatosplenomegaly, and elevated ferritin 1
• Urine succinylacetone: If metabolic disease suspected 4
• Leukocyte β-glucocerebrosidase activity: If chronic hepatosplenomegaly with thrombocytopenia 5

Critical Pitfalls to Avoid

• Do not dismiss seizures as simple febrile seizures—in the context of hepatosplenomegaly and jaundice, they suggest either CNS involvement from systemic disease (HLH) or severe metabolic derangement 1
• Do not delay bone marrow examination if HLH is suspected—this is a rapidly progressive, life-threatening condition requiring urgent diagnosis and treatment 1
• Do not assume mild transaminase elevation means mild disease—HLH and severe infections can present with relatively modest transaminase elevations but severe systemic illness 1
• Conjugated hyperbilirubinemia in a child always requires urgent evaluation—this is never physiologic and indicates significant hepatobiliary pathology 6