What is the likely diagnosis in a patient with elevated total bilirubin (predominantly indirect), low haptoglobin, normal hemoglobin, and normal liver enzymes?

Hemolytic Anemia

This patient has hemolytic anemia. The combination of predominantly indirect hyperbilirubinemia (indirect 3.5 mg/dL, representing 83% of total bilirubin), undetectable haptoglobin (<10 mg/dL), and normal hemoglobin strongly indicates active hemolysis with compensated red cell production. 1

Diagnostic Reasoning

Bilirubin Pattern Analysis

• The indirect (unconjugated) bilirubin comprises >80% of the total bilirubin (3.5 of 4.2 mg/dL), which definitively points to either hemolysis or a defect in bilirubin conjugation. 1
• Gilbert syndrome—the most common cause of isolated unconjugated hyperbilirubinemia—is effectively ruled out because total bilirubin rarely exceeds 4-5 mg/dL in Gilbert syndrome, and haptoglobin remains normal. 1
• The direct bilirubin of 0.7 mg/dL represents only 17% of total bilirubin, excluding hepatocellular or cholestatic disease as the primary etiology. 1

Haptoglobin as the Key Diagnostic Marker

• Haptoglobin <10 mg/dL is pathognomonic for intravascular hemolysis, as haptoglobin binds free hemoglobin released from lysed red cells and the haptoglobin-hemoglobin complex is rapidly cleared by the liver. 2
• Undetectable haptoglobin combined with elevated indirect bilirubin establishes hemolysis with near certainty. 2
• Critical nuance: While elevated LDH is traditionally taught as a hemolysis marker, 25% of autoimmune hemolytic anemia cases present with normal LDH levels, so the absence of LDH elevation does not exclude hemolysis. 3

Hemoglobin Interpretation

• The hemoglobin of 13 g/dL indicates compensated hemolysis—the bone marrow is producing red cells rapidly enough to maintain near-normal hemoglobin despite ongoing destruction. 2
• This compensation is mediated by reticulocytosis, which should be confirmed on the next laboratory draw. 1, 2

Immediate Next Steps

Complete the Hemolysis Workup

• Order immediately: complete blood count with peripheral smear, reticulocyte count, and LDH. 1
• The peripheral smear will reveal spherocytes (hereditary spherocytosis or autoimmune hemolytic anemia), schistocytes (microangiopathic hemolytic anemia), or bite cells/blister cells (G6PD deficiency). 2
• Reticulocyte count >2% confirms active bone marrow compensation for hemolysis. 2

Determine the Hemolysis Etiology

• Obtain direct antiglobulin test (Coombs test) to evaluate for autoimmune hemolytic anemia, the most common acquired cause of hemolysis in adults. 2
• Test for G6PD deficiency, particularly if the patient is African American (11-13% prevalence), Mediterranean, or Asian descent. 1
• Critical pitfall: G6PD enzyme levels can be falsely elevated during active hemolysis—if the initial test is normal but clinical suspicion remains high, repeat testing at 3 months after the hemolytic episode resolves. 1
• Review medication history for oxidative drugs (antimalarials, sulfonamides, dapsone) that trigger hemolysis in G6PD deficiency. 2

Assess for Underlying Systemic Disease

• Check for lymphoproliferative disorders, autoimmune conditions (SLE, rheumatoid arthritis), or recent infections that can trigger secondary hemolysis. 2
• If spherocytes are present and Coombs test is negative, consider hereditary spherocytosis and obtain family history. 2

What NOT to Do

• Do not order abdominal ultrasound or pursue hepatobiliary imaging—isolated unconjugated hyperbilirubinemia with undetectable haptoglobin does not require imaging. 1
• Do not attribute the findings to Gilbert syndrome—the haptoglobin <10 mg/dL excludes this diagnosis. 1
• Do not delay the hemolysis workup to obtain additional liver function tests—the normal liver enzymes already exclude hepatocellular disease. 1
• Do not assume normal LDH rules out hemolysis—proceed with the full hemolysis evaluation regardless of LDH level. 3

Clinical Context and Prognosis

• The normal hemoglobin despite active hemolysis suggests this is either a chronic compensated process or an acute hemolytic episode caught early before anemia develops. 2
• If autoimmune hemolytic anemia is confirmed, first-line treatment is prednisone 1 mg/kg/day, with expected response within 1-2 weeks. 3
• If G6PD deficiency is identified, management consists of avoiding oxidative triggers—no specific treatment is required for the hemolysis itself. 2
• Hematology consultation is warranted if the hemolysis workup reveals autoimmune hemolytic anemia, microangiopathic hemolytic anemia, or if the etiology remains unclear after initial testing. 1