Symptoms and Most Common Causes of Severe Vitamin B12 Deficiency
Are MDS, Leukemia, and Aplastic Anemia Major Causes?
No—myelodysplastic syndrome, acute leukemia, and aplastic anemia are not causes of vitamin B12 deficiency; rather, severe B12 deficiency can mimic these bone marrow disorders by producing pancytopenia and dysplastic changes that resemble MDS or acute leukemia on peripheral smear and bone marrow biopsy. 1, 2
Clinical Symptoms of Severe Vitamin B12 Deficiency
Severe B12 deficiency presents with a broad spectrum of hematologic, neurologic, and psychiatric manifestations that often appear before anemia develops:
Hematologic Manifestations
- Megaloblastic macrocytic anemia with elevated MCV (>98 fL), often the initial laboratory finding 3, 4
- Pancytopenia (anemia, leukopenia, thrombocytopenia) that can be profound enough to mimic bone marrow failure or MDS 1, 2, 5
- Hypersegmented neutrophils on peripheral smear, a hallmark dysplastic feature 1
- Hypercellular bone marrow with blastic differentiation, which can be mistaken for acute leukemia 1, 2
- Hemolysis with undetectable haptoglobin due to ineffective erythropoiesis 5
Neurologic Manifestations
- Subacute combined degeneration of the spinal cord (myelopathy), the most common neurologic complication 6, 4
- Peripheral neuropathy with paresthesias, numbness, and tingling 7, 4
- Ataxia and gait disturbances from posterior column involvement 5, 6
- Cognitive difficulties, memory problems, and "brain fog" 7, 4
- Visual disturbances including blurred vision and optic neuropathy 7
- Importantly, neurologic symptoms can occur without anemia, making diagnosis challenging 6, 4
Psychiatric Manifestations
- "Megaloblastic madness" with prominent psychiatric impairment 5
- Depression and mood disturbances 7
- Cognitive impairment that may be irreversible if untreated 7, 4
Most Common Causes of Severe Vitamin B12 Deficiency
The causes of severe B12 deficiency relate to impaired absorption or inadequate intake:
Malabsorption Disorders (Most Common)
- Pernicious anemia (autoimmune destruction of gastric parietal cells and intrinsic factor), the classic cause of severe deficiency 7, 5, 4
- Atrophic gastritis affecting the gastric body, impairing intrinsic factor production 7
- Ileal resection >20 cm or ileal Crohn's disease affecting the terminal ileum (site of B12 absorption) 7, 8
- Post-bariatric surgery (especially Roux-en-Y gastric bypass), causing permanent malabsorption 7, 8
Medication-Induced Deficiency
- Metformin use >4 months, particularly common in diabetic patients 7
- Proton pump inhibitors (PPIs) or H2 blockers >12 months, reducing gastric acid needed to release food-bound B12 7
- Colchicine, anticonvulsants, sulfasalazine, and methotrexate 7
Dietary Inadequacy
Age-Related Deficiency
- Age >75 years, with 18.1% of those >80 years having metabolic B12 deficiency 7
Critical Diagnostic Pitfall: B12 Deficiency Mimicking Bone Marrow Disorders
The most important clinical trap is that severe B12 deficiency can produce bone marrow findings indistinguishable from myelodysplastic syndrome or acute leukemia:
- Bone marrow biopsy may show hypercellularity with blastic differentiation and dysplastic changes so profound that induction chemotherapy is considered 1, 2
- Peripheral smear shows pancytopenia with dysplastic features (hypersegmented neutrophils, macrocytosis) 1, 2
- Always check serum B12, methylmalonic acid (MMA), and homocysteine before diagnosing MDS or initiating chemotherapy in patients with unexplained pancytopenia and dysplastic changes 1, 2
- These hematologic abnormalities completely reverse with parenteral B12 supplementation, confirming the diagnosis retrospectively 1, 2, 5
Diagnostic Algorithm for Suspected Severe B12 Deficiency
Step 1: Initial Testing
- Measure serum total B12 as first-line test (cost £2, rapid turnaround) 7
Step 2: Confirmatory Testing (if indeterminate)
- Methylmalonic acid (MMA): >271 nmol/L confirms functional B12 deficiency with 98.4% sensitivity 7
- Homocysteine: >15 μmol/L supports deficiency but less specific than MMA 7
- Complete blood count: Check for macrocytosis, pancytopenia, hypersegmented neutrophils 7, 1
Step 3: Identify Underlying Cause
- Intrinsic factor antibodies for pernicious anemia 7
- Gastrin levels if pernicious anemia suspected (markedly elevated >1000 pg/mL) 7
- Medication review: Metformin, PPIs, H2 blockers 7
- Dietary history: Vegetarian/vegan diet 7, 6
Treatment of Severe B12 Deficiency
With Neurologic Involvement
- Hydroxocobalamin 1 mg IM on alternate days until no further improvement, then maintenance 1 mg IM every 2 months for life 7, 8
Without Neurologic Involvement
- Hydroxocobalamin 1 mg IM three times weekly for 2 weeks, then maintenance 1 mg IM every 2–3 months for life 7, 8
Critical Warning
- Never administer folic acid before treating B12 deficiency, as it may mask anemia while allowing irreversible neurological damage to progress 7, 8
Key Takeaway
Severe vitamin B12 deficiency is not caused by MDS, leukemia, or aplastic anemia—but it can mimic these disorders so convincingly that patients are referred for chemotherapy. Always exclude B12 deficiency with serum B12 and MMA testing before diagnosing bone marrow malignancy in patients with unexplained pancytopenia and dysplastic changes. 1, 2 The most common causes are pernicious anemia, ileal disease, post-bariatric surgery, and medication-induced malabsorption (metformin, PPIs). 7, 4 Neurologic symptoms often precede or occur without anemia, and early treatment with parenteral B12 is essential to prevent irreversible damage. 6, 4