Should I, as a primary care physician, refer a 29-year-old African-American male with severe glucose‑6‑phosphate dehydrogenase deficiency (quantitative activity 3.9 U/g Hb, ~19% of normal) to hematology?

Hematology Referral for Severe G6PD Deficiency

No, you do not need to refer this patient to hematology solely based on the diagnosis of severe G6PD deficiency (19% activity). G6PD deficiency, even when severe, is primarily managed in primary care through patient education, avoidance of triggers, and monitoring for hemolytic episodes 1, 2.

When Hematology Referral IS Indicated

Refer to hematology only if any of the following complications develop 3:

• Grade 3 or higher hemolytic anemia (hemoglobin drop requiring transfusion, evidence of severe hemolysis with LDH >2x normal, undetectable haptoglobin, or hemodynamic instability) 3
• Chronic nonspherocytic hemolytic anemia (persistent hemolysis without identifiable triggers, which occurs in approximately half of G6PD mutations—typically the rare sporadic variants rather than the common polymorphic variants) 1, 2
• Unexplained pancytopenia or other cytopenias beyond isolated anemia 3
• Recurrent severe hemolytic episodes despite trigger avoidance 1
• Neonatal jaundice requiring exchange transfusion (not applicable to this 29-year-old patient) 2

Primary Care Management Strategy

Immediate Actions

Patient education is the cornerstone of management 4, 1:

• Absolutely contraindicated medications that must be avoided 4:

  • Dapsone (potent oxidant causing methemoglobinemia and hemolysis)
  • Methylene blue (can cause severe hemolytic anemia)
  • Primaquine (contraindicated in severe deficiency; may be used at reduced dosing only in mild-to-moderate deficiency >30% activity with close monitoring)
  • Tafenoquine (contraindicated regardless of severity)
  • Rasburicase

• Common medications requiring caution 4:

  • NSAIDs, cephalosporins, penicillins, fluoroquinolones (ciprofloxacin)
  • Rifampin, ribavirin
  • Quinine/quinidine
  • Lorazepam, diclofenac
  • Chloroquine/hydroxychloroquine are relatively safe in standard doses despite older teaching 4

• Fava bean avoidance (critical trigger for acute hemolysis) 1, 2

• Infection awareness: Any acute infection can trigger hemolysis and requires close monitoring 1, 2

Monitoring Protocol

Baseline assessment 3:

• Complete blood count with reticulocyte count
• Peripheral blood smear
• LDH, haptoglobin, indirect bilirubin (establish baseline for comparison during suspected hemolytic episodes)

Routine follow-up 1:

• Most G6PD-deficient individuals remain asymptomatic throughout their lifetime with proper trigger avoidance
• Annual CBC is reasonable to document stable baseline hemoglobin
• No routine hematology follow-up is needed for asymptomatic patients

Recognition of Hemolytic Crisis

Instruct the patient to seek immediate care for 1, 2:

• Dark urine (hemoglobinuria)
• Jaundice
• Severe fatigue or dyspnea
• Pallor
• Abdominal or back pain

If hemolytic crisis occurs, obtain 3:

• CBC with reticulocyte count
• Peripheral smear (look for bite cells, blister cells, Heinz bodies)
• LDH, haptoglobin, indirect bilirubin
• Direct antiglobulin test (Coombs)
• Assess for triggering medications or infection

Key Clinical Pitfalls

Do not assume all normocytic anemia in this patient is due to G6PD deficiency 5. With a quantitative activity of 19%, this patient has severe deficiency, but G6PD deficiency causes hemolysis only when triggered—it does not cause chronic baseline anemia in most cases 1, 2. If this patient presents with anemia:

• Low reticulocyte count suggests a production problem unrelated to G6PD (iron deficiency, B12/folate deficiency, chronic disease, renal insufficiency) 5
• High reticulocyte count with evidence of hemolysis (elevated LDH, low haptoglobin, elevated indirect bilirubin) suggests G6PD-related hemolysis and requires identification of the trigger 5

Screen for G6PD deficiency before prescribing oxidant drugs 4. This patient's African-American ethnicity places him at risk for the GdA- variant, which typically causes milder, self-limited hemolysis compared to the Mediterranean variant 4. However, with only 19% activity, he is at the severe end of the spectrum and requires strict avoidance of all high-risk medications 4.

Pregnancy considerations: If this patient has daughters, they may be carriers or affected (if they inherit the deficient X chromosome). Female carriers with intermediate activity (30-70%) can still experience hemolysis with oxidant stress 4, 6.

Documentation and Care Coordination

• Document G6PD deficiency prominently in the problem list and allergy section of the electronic health record 4
• Provide the patient with a written list of contraindicated medications to carry 4
• Alert pharmacy systems to flag high-risk medications 4
• Educate the patient that over-the-counter medications and herbal supplements may also trigger hemolysis 1

In summary, primary care management through education and trigger avoidance is appropriate for this asymptomatic patient with severe G6PD deficiency. Hematology referral is reserved for patients who develop complications such as severe hemolytic anemia, chronic hemolysis, or unexplained cytopenias 3, 1.