What are the appropriate diagnostic tests and management for a 22-year-old female with sudden onset fatigue, jaundice (yellowing of the eyes), pallor, scleral icterus, and tachycardia, with no history of travel?

Diagnostic Workup and Management for Acute Hemolytic Anemia with Jaundice

This 22-year-old female with sudden onset fatigue, jaundice, pallor, and tachycardia most likely has acute hemolytic anemia, and you should immediately order a complete blood count with peripheral smear, reticulocyte count, total and fractionated bilirubin, liver enzymes, lactate dehydrogenase, haptoglobin, direct Coombs test, and abdominal ultrasound to differentiate hemolysis from hepatobiliary causes. 1, 2

Initial Laboratory Testing

The clinical presentation of sudden onset fatigue, pallor (indicating anemia), jaundice, and tachycardia (compensatory response to anemia) in a young female without travel history strongly suggests hemolytic anemia rather than hepatobiliary disease. 3, 2

Essential first-line tests include:

• Complete blood count (CBC) with differential and peripheral blood smear - to confirm anemia, assess for other cytopenias, and visualize RBC morphology for evidence of hemolysis (spherocytes, schistocytes, bite cells) 3, 1
• Reticulocyte count with reticulocyte index (RI) - elevated RI (>2.0) indicates increased RBC production consistent with hemolysis or blood loss, while low RI suggests bone marrow dysfunction 3
• Total and fractionated bilirubin - unconjugated (indirect) hyperbilirubinemia predominates in hemolysis, while conjugated (direct) hyperbilirubinemia suggests hepatobiliary obstruction 1, 4, 5
• Lactate dehydrogenase (LDH) - markedly elevated in hemolysis 3
• Haptoglobin - decreased or absent in hemolysis as it binds free hemoglobin 3
• Direct Coombs test (direct antiglobulin test) - positive in autoimmune hemolytic anemia, negative in other causes 2, 6
• Liver enzymes (AST, ALT, alkaline phosphatase) - to differentiate hepatocellular from cholestatic patterns 1, 4

Imaging Studies

Abdominal ultrasound is the recommended initial imaging study to exclude biliary obstruction, assess liver parenchyma, and evaluate for splenomegaly (which may indicate hemolysis or portal hypertension). 1, 2 Ultrasound has 65-95% sensitivity for detecting cirrhosis and 32-100% sensitivity for biliary obstruction. 2

Diagnostic Algorithm Based on Laboratory Results

If unconjugated hyperbilirubinemia with elevated reticulocyte count:

• This confirms hemolytic anemia 3, 2
• Proceed with direct Coombs test to differentiate autoimmune from non-autoimmune causes 2, 6
• Consider infectious workup including Epstein-Barr virus (EBV), which can cause secondary cold agglutinin syndrome and life-threatening hemolysis in young adults 6
• Evaluate for glucose-6-phosphate dehydrogenase (G6PD) deficiency, hereditary spherocytosis, and other hemoglobinopathies 2

If conjugated hyperbilirubinemia with elevated alkaline phosphatase:

• This suggests cholestatic/obstructive causes 4
• Ultrasound findings of biliary dilation indicate need for advanced imaging (MRCP or ERCP) 1
• Consider choledocholithiasis (13-14% of jaundice cases), malignancy (6.2% of cases), or drug-induced cholestasis 2

If mixed pattern with elevated transaminases:

• Consider hepatocellular causes: viral hepatitis, autoimmune hepatitis, drug-induced liver injury, or alcoholic hepatitis 3, 2, 4
• Sepsis can cause both hemolysis and hepatic dysfunction, creating mixed hyperbilirubinemia 2, 4

Immediate Management Priorities

Assess hemodynamic stability and transfusion needs:

• Tachycardia suggests compensatory response to anemia; evaluate for signs of hemodynamic compromise 3
• Transfuse packed red blood cells if hemoglobin <7 g/dL or if symptomatic with chest pain, dyspnea, or hemodynamic instability 3
• In suspected autoimmune hemolytic anemia, use blood bank protocols for crossmatching as antibodies may complicate typing 6

If autoimmune hemolytic anemia is confirmed (positive Coombs test):

• Initiate corticosteroids (prednisone 1 mg/kg/day) as first-line therapy 6
• In life-threatening cases with severe hemolysis, consider rituximab as salvage therapy 6
• Avoid cold exposure if cold agglutinin disease is suspected 6

If infectious hepatitis is suspected:

• Order hepatitis A, B, C serologies, EBV panel, and cytomegalovirus testing 3, 6
• EBV can cause both hepatitis and secondary hemolytic anemia in young adults 6

Critical Pitfalls to Avoid

• Do not assume hepatobiliary disease without checking reticulocyte count - the combination of sudden onset, pallor, and tachycardia in a young patient strongly favors hemolysis over primary liver disease 3, 2
• Do not delay transfusion in symptomatic patients - fatigue with tachycardia indicates significant anemia requiring urgent intervention 3
• Do not miss drug-induced causes - obtain detailed medication history including over-the-counter drugs and herbal supplements, as drug reactions account for 0.5-7% of jaundice cases 2
• Do not overlook sepsis - it is the most common cause of jaundice in U.S. studies (22-27%) and can cause both hemolysis and hepatic dysfunction 2, 4

Additional Considerations

Hemolysis accounts for only 2.5% of jaundice cases overall, but in a young female with acute presentation, pallor, and tachycardia, it becomes the leading differential diagnosis. 2 The absence of travel history makes endemic infections less likely but does not exclude viral causes such as EBV, which can present with life-threatening hemolysis and hepatic failure. 6