What is the diagnosis and treatment for a patient with macrocytic anemia, fatigue, mouth ulcers, and angular cheilosis, with a complete blood cell count showing low hemoglobin and macrocytic red blood cells?

Diagnosis: Vitamin B12 Deficiency (Megaloblastic Anemia)

This patient's presentation of macrocytic anemia (hemoglobin 11.5 g/dL with macrocytic red blood cells), fatigue, mouth ulcers, and angular cheilosis is most consistent with vitamin B12 deficiency, which requires immediate diagnostic confirmation and treatment initiation before considering folate supplementation to prevent irreversible neurological damage. 1, 2, 3

Diagnostic Workup

Initial Laboratory Testing

• Measure serum vitamin B12 level immediately (deficiency defined as <150 pmol/L or <203 ng/L), and if borderline, obtain methylmalonic acid level (>271 nmol/L confirms deficiency) 1
• Check serum folate and RBC folate levels (deficiency indicated by serum folate <10 nmol/L or RBC folate <305 nmol/L) 1
• Obtain reticulocyte count to differentiate megaloblastic (normal/low count) from non-megaloblastic causes (elevated count suggests hemolysis or hemorrhage) 1, 4
• Measure TSH and free T4 to exclude hypothyroidism as a cause of macrocytosis 1
• Check CRP and creatinine to assess for inflammatory conditions or renal failure 1

Blood Smear Examination

• Look for neutrophil hypersegmentation, which is one of the most sensitive and specific signs of megaloblastic anemia 5
• Evaluate for other dysplastic features that might suggest myelodysplastic syndrome, though this is less likely given the clinical presentation 6

Treatment Algorithm

Critical First Step: Treat B12 Before Folate

Never initiate folate supplementation before ruling out and treating vitamin B12 deficiency, as this can precipitate subacute combined degeneration of the spinal cord—an irreversible neurological complication. 1, 2, 3

Vitamin B12 Replacement Protocol

For confirmed B12 deficiency without neurological symptoms:

• Administer cyanocobalamin 1 mg (100 mcg) intramuscularly three times weekly for 2 weeks 1, 3
• Follow with 1 mg every 2-3 months for life 1
• Alternative FDA-approved regimen: 100 mcg daily for 6-7 days, then alternate days for seven doses, then every 3-4 days for 2-3 weeks, followed by 100 mcg monthly for life 3

For patients with neurological symptoms (if present):

• Administer hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement 1
• Then continue with 1 mg every 2 months 1

Folate Supplementation (If Deficient)

• Only after B12 deficiency is excluded or treatment initiated, give oral folic acid 5 mg daily for minimum of 4 months 6, 1
• Folic acid should be administered concomitantly with B12 if both deficiencies are present 3

Monitoring Response to Treatment

• Repeat complete blood counts to monitor response 1, 2
• Acceptable response is defined as hemoglobin increase of at least 2 g/dL within 4 weeks 1, 2
• Monitor reticulocyte count daily from days 5-7 of therapy, then frequently until hematocrit normalizes 3
• If reticulocytes have not increased or do not continue at least twice normal while hematocrit remains <35%, reevaluate diagnosis or treatment 3

Clinical Context and Oral Manifestations

The patient's angular cheilosis and mouth ulcers are classic mucocutaneous manifestations of vitamin B12 deficiency, reflecting the impaired DNA synthesis affecting rapidly dividing epithelial cells 1, 7. These symptoms, combined with fatigue and macrocytic anemia, strongly support megaloblastic anemia as the diagnosis.

Critical Pitfalls to Avoid

Folate Administration Without B12 Assessment

• Folic acid doses >0.1 mg daily can produce hematologic remission in B12-deficient patients while allowing neurological damage to progress 3
• This creates a false sense of improvement while irreversible spinal cord degeneration continues 3

Medication-Induced Macrocytosis

• Review current medications for azathioprine, methotrexate, or hydroxyurea, which can cause macrocytosis 1, 2
• However, these typically do not cause the oral manifestations seen in this patient 2

Concurrent Iron Deficiency

• In inflammatory conditions, ferritin may be falsely elevated despite true iron deficiency 1, 2
• Check transferrin saturation (<16% suggests iron deficiency) and RDW (elevated suggests coexisting iron deficiency) 1

Alcohol Use Assessment

• Chronic alcohol use is the most common cause of nonmegaloblastic macrocytic anemia and can impair B12 absorption 5, 8
• However, alcohol-related macrocytosis typically lacks the oral manifestations present in this case 5

Long-Term Management

Patients with pernicious anemia require monthly B12 injections for life—failure to maintain treatment will result in recurrence of anemia and potentially irreversible neurological damage 3. The patient must understand this is lifelong therapy, not a temporary intervention.