Diagnostic Workup and Management
This patient requires immediate measurement of serum vitamin B12, folate, and reticulocyte count to differentiate megaloblastic from non-megaloblastic causes of macrocytic anemia, with the elevated alkaline phosphatase prompting concurrent abdominal imaging to exclude biliary obstruction or infiltrative liver disease. 1
Initial Laboratory Evaluation
The macrocytic anemia (hemoglobin 131 g/L, which equals 13.1 g/dL—actually normal for males) with abdominal bloating and elevated alkaline phosphatase creates a diagnostic pattern requiring systematic evaluation:
Essential first-line tests:
- Serum vitamin B12 level (deficiency defined as <150 pmol/L or <203 ng/L; if borderline, obtain methylmalonic acid >271 nmol/L to confirm) 1, 2
- Serum folate and RBC folate levels (deficiency: serum folate <10 nmol/L or RBC folate <305 nmol/L) 1, 2
- Reticulocyte count to differentiate regenerative from non-regenerative causes—elevated count suggests hemolysis or hemorrhage, while normal/low count indicates megaloblastic anemia or bone marrow dysfunction 1, 3
- Peripheral blood smear to assess for neutrophil hypersegmentation (highly sensitive and specific for megaloblastic anemia) and red cell morphology 4, 5
Addressing the Elevated Alkaline Phosphatase
Given the elevated alkaline phosphatase with abdominal bloating, biliary obstruction must be excluded:
- Abdominal ultrasound as initial imaging to evaluate for biliary dilation or hepatic pathology 6
- Fractionation of alkaline phosphatase or GGT measurement to confirm hepatobiliary vs. bone origin 6
- If conjugated hyperbilirubinemia is present alongside elevated alkaline phosphatase, more urgent evaluation for biliary obstruction is warranted 6
Critical Treatment Principle
Never initiate folate supplementation before ruling out and treating vitamin B12 deficiency—this can precipitate subacute combined degeneration of the spinal cord, an irreversible neurological complication. 1, 2, 7
Treatment Algorithm Based on Results
If vitamin B12 deficiency is confirmed:
- Administer cyanocobalamin 1 mg (1000 mcg) intramuscularly three times weekly for 2 weeks, then 1 mg every 2-3 months for life 1, 2, 7
- If neurological symptoms develop, switch to hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months 1, 2
- Monitor with repeat CBC; acceptable response is hemoglobin increase ≥2 g/dL within 4 weeks 1, 2
If folate deficiency is identified (only after B12 excluded or treatment initiated):
If reticulocyte count is elevated with low haptoglobin:
- This combination is pathognomonic for hemolysis 3
- Obtain LDH, indirect bilirubin, and peripheral smear for red cell morphology 3
- Consider hereditary spherocytosis, pyruvate kinase deficiency, or hemoglobinopathies 3
Additional Considerations
Medication review: Hydroxyurea, methotrexate, and azathioprine can cause macrocytosis independent of vitamin deficiency 1, 2
Alcohol use assessment: Chronic alcohol consumption (>2 weeks of heavy intake) causes both macrocytosis and impairs B12 absorption 1, 4, 5
Inflammatory conditions: In the presence of inflammation, ferritin may be falsely elevated despite concurrent iron deficiency; check transferrin saturation and RDW if inflammatory markers are elevated 1, 2
Common Pitfalls to Avoid
- Do not assume normal hemoglobin excludes significant pathology—the patient may have compensated hemolysis or early deficiency 3
- Do not overlook combined deficiencies—microcytosis from iron deficiency can coexist with macrocytosis from B12/folate deficiency, resulting in falsely normal MCV with elevated RDW 1, 3
- Do not delay imaging for elevated alkaline phosphatase—biliary obstruction or infiltrative disease requires prompt identification 6
- Do not give folate empirically—always exclude B12 deficiency first to prevent irreversible neurological damage 2, 7
Referral Indications
Refer to hematology if: