Vitamin B6 Deficiency Anemia
Vitamin B6 deficiency anemia is a microcytic, hypochromic anemia caused by impaired heme synthesis due to insufficient pyridoxal phosphate (vitamin B6), which serves as an essential cofactor for ALA synthase 2 (ALAS2), the rate-limiting enzyme in erythroid heme production. 1, 2
Pathophysiology
Vitamin B6 (pyridoxine) functions as a critical coenzyme in heme biosynthesis through its active form, pyridoxal phosphate (PLP). 1, 3
Key mechanistic features:
ALAS2 enzyme dependency: Vitamin B6 is required for ALA synthase 2 activity in mitochondria, which catalyzes the first step of heme synthesis by combining glycine and succinyl-CoA to form δ-aminolevulinic acid. 1
Impaired iron incorporation: When B6 is deficient, protoporphyrin synthesis decreases, leading to reduced iron incorporation into heme and subsequent mitochondrial iron accumulation in erythroblasts (ring sideroblasts). 1, 2
Ineffective erythropoiesis: The resulting heme deficiency causes ineffective red blood cell production, leading to increased intestinal iron uptake and systemic iron overload despite anemia. 1
Clinical Presentation
Hematologic features:
- Microcytic, hypochromic anemia with low mean corpuscular volume (MCV) 1, 4, 5
- Elevated serum ferritin and transferrin saturation (paradoxical iron overload) 1, 2
- Ring sideroblasts on bone marrow examination (iron-laden mitochondria surrounding the nucleus) 1, 4
- Hyperplastic but ineffective erythropoiesis 4
- Normal to elevated red cell distribution width 1
Clinical manifestations vary by etiology:
Genetic forms (X-linked sideroblastic anemia): Males typically present in the first two decades with mild anemia or later with iron overload complications; females can be affected through skewed X-inactivation. 1
Acquired deficiency: Presents with progressive anemia that may be therapy-resistant to standard iron supplementation. 4, 5
Causes of Vitamin B6 Deficiency Anemia
Genetic causes:
- X-linked sideroblastic anemia (XLSA): Most common genetic form, caused by ALAS2 gene mutations affecting either the catalytic domain or pyridoxine cofactor binding site. 1
Acquired causes:
Malabsorption: Post-gastrointestinal surgery (particularly pancreatectomy), inflammatory bowel disease. 5
Medication-induced: Isoniazid (tuberculosis treatment), penicillamine, anticonvulsants, corticosteroids, and certain anti-cancer drugs act as B6 antagonists. 6
Chronic kidney disease and dialysis: Increased losses through dialysis, altered metabolism, and increased requirements with erythropoietin therapy. 2, 7
Increased requirements: Erythropoietin-stimulating agent (ESA) therapy dramatically increases B6 consumption for hemoglobin synthesis. 2, 7
Dietary deficiency: Rare in developed countries but can occur in elderly populations. 3
Diagnosis
Laboratory findings:
- Low plasma pyridoxal phosphate (PLP) levels: normal range 5-50 mg/L (20-200 nmol/L) 6
- Microcytic, hypochromic anemia with low MCV 1, 2, 5
- Elevated serum ferritin (often >700 ng/mL) and transferrin saturation (>40%) 2
- Elevated corrected reticulocyte count indicating ineffective erythropoiesis 2
- Bone marrow: normocellular to hypercellular with erythroid hyperplasia, ring sideroblasts on Prussian blue staining, and increased iron stores 4, 2
Important diagnostic considerations:
- In inflammatory conditions or serious illness, measure red cell PLP instead of plasma levels, as inflammation can falsely lower plasma PLP. 6
- Consider B6 deficiency in any patient with microcytic anemia who fails to respond to iron supplementation, especially if ferritin is elevated. 5
Treatment
For acquired vitamin B6 deficiency anemia:
Initial therapy: Oral pyridoxine 50-200 mg daily is effective for improving anemia and correcting iron overload in responsive patients. 1
Maintenance therapy: Once response is achieved, reduce to lifelong maintenance dose of 10-100 mg daily to avoid neurotoxicity from excessive doses. 1
Critical principle: Do not label patients as pyridoxine-refractory until iron stores are normalized, as iron overload itself compromises mitochondrial function and heme biosynthesis. 1
Iron management: Most patients can be treated with phlebotomy for iron overload since the anemia is typically mild; hemoglobin typically increases rather than decreases after reversal of iron overload. 1
For dialysis patients:
Without EPO therapy: Pyridoxine 5-6 mg daily for prevention. 7
With EPO therapy: Pyridoxine 20 mg daily due to dramatically increased consumption during hemoglobin synthesis. 7
Higher doses (50 mg daily) may benefit cellular immunity parameters in hemodialysis patients. 7
For genetic X-linked sideroblastic anemia:
- Trial of pyridoxine 50-200 mg daily; approximately 40-60% of patients respond. 1
- Non-responders may require chronic transfusion support with iron chelation. 1
- Hematopoietic stem cell transplantation is curative but carries significant risks. 1
Monitoring and Follow-up
Response assessment:
- Check hemoglobin and vitamin B6 levels 3-6 months after starting supplementation. 6
- Once normalized, monitor annually in stable patients. 6
- For dialysis or CKD patients, monitor every 3 months until stabilization. 6
Expected outcomes:
- Hemoglobin improvement typically occurs within weeks to months of adequate B6 supplementation. 4, 2
- Case reports demonstrate sustained remission with long-term vitamin B6 therapy, with relapse upon discontinuation. 4
Critical Pitfalls to Avoid
Do not overlook B6 deficiency in ESA-resistant anemia: Any pediatric or adult dialysis patient not responding to standard ESA and iron therapy should be evaluated for B6 deficiency. 2
Avoid excessive B6 dosing: Doses exceeding 100 mg daily long-term can cause sensory neuropathy with numbness, paresthesias, ataxia, and loss of deep tendon reflexes. 1, 6
Do not assume iron deficiency: The combination of microcytic anemia with elevated ferritin and transferrin saturation should immediately raise suspicion for sideroblastic anemia, not iron deficiency. 2, 5
Check medication lists: Review all medications for B6 antagonists (isoniazid, penicillamine, anticonvulsants) that may precipitate deficiency. 6
Consider malabsorption: In patients with gastrointestinal surgery or disease, oral B6 may be inadequate; intravenous administration may be necessary. 5