What are the causes, symptoms, and treatment options for a patient with low normal vitamin B12 levels and low ferritin (iron storage) levels, indicating iron deficiency anemia?

Low Normal B12 and Low Ferritin (16 µg/L): Causes and Symptoms

A ferritin of 16 µg/L indicates absolute iron deficiency requiring treatment, while low-normal B12 warrants further evaluation with methylmalonic acid (MMA) to confirm true deficiency before initiating therapy. 1

Causes of Low Ferritin (16 µg/L)

Iron Deficiency Etiology

• Chronic blood loss is the most common cause, particularly from gastrointestinal sources (ulcers, malignancy, angiodysplasia) or menstrual bleeding in premenopausal women 1
• Reduced dietary intake from inadequate consumption of heme iron (meat, fish) and non-heme iron sources 1
• Malabsorption disorders including celiac disease, inflammatory bowel disease, atrophic gastritis, or post-surgical states (gastric/small bowel resection) 1
• Medication-induced malabsorption from chronic proton pump inhibitor or H2-blocker use (>12 months) 2
• Increased physiologic demands during pregnancy and lactation 1

Interaction with Riboflavin Status

• Poor riboflavin (vitamin B2) status interferes with iron handling, affecting both iron absorption and mobilization of ferritin from tissues, contributing to anemia when iron intakes are low 1

Causes of Low-Normal B12

Primary Etiologies

• Malabsorption from pernicious anemia (autoimmune gastritis with intrinsic factor deficiency), atrophic gastritis, or Helicobacter pylori infection 2, 3
• Dietary insufficiency in vegans, strict vegetarians, or elderly with reduced dairy product intake 2, 4
• Medication-induced from metformin use (>4 months) or chronic acid suppression therapy (>12 months) 2, 3
• Post-surgical following gastric or ileal resection, or bariatric surgery 2
• Age-related decline in absorption, particularly in adults >75 years 2

Clinical Symptoms

Iron Deficiency Manifestations

• Systemic symptoms: Fatigue, weakness, lethargy, reduced exercise tolerance, headache, and shortness of breath from tissue hypoxia 5
• Specific iron-related symptoms (even without anemia): Reduced physical performance, cognitive dysfunction, restless legs syndrome, loss of libido, and sleeping disorders 1
• Mucocutaneous findings: Angular stomatitis, glossitis, nail changes, and impaired mucosal regeneration 1

Vitamin B12 Deficiency Manifestations

• Hematologic: Megaloblastic anemia with macrocytosis (though may be masked by concurrent iron deficiency creating normocytic picture) 2, 4
• Neurologic: Peripheral neuropathy, ataxia, subacute combined degeneration of the spinal cord (potentially irreversible if untreated) 2, 3
• Neuropsychiatric: Fatigue, brain fog, depression, cognitive impairment, and memory problems 2, 3

Combined Deficiency Considerations

When both deficiencies coexist, the MCV may be normal (microcytosis from iron deficiency masked by macrocytosis from B12 deficiency), making diagnosis more challenging 1, 4

Diagnostic Approach

Confirming Iron Deficiency

• Ferritin <30 µg/L without inflammation confirms absolute iron deficiency 1
• Your ferritin of 16 µg/L is diagnostic regardless of inflammation status 1
• Check transferrin saturation (<16% supports iron deficiency) and inflammatory markers (CRP, ESR) to assess for anemia of chronic disease 1

Confirming B12 Deficiency

• If serum B12 <180 pg/mL: Diagnostic for deficiency 3
• If serum B12 180-350 pg/mL (low-normal): Measure methylmalonic acid (MMA); elevated MMA confirms tissue B12 deficiency 2, 3
• Do not rely on B12 level alone in borderline cases, as normal serum levels can miss tissue deficiency 2, 4

Identifying Underlying Causes

• For iron deficiency: Bidirectional endoscopy (upper endoscopy and colonoscopy) to evaluate for GI blood loss, particularly in patients >45 years or with alarm symptoms 1
• For B12 deficiency: Test for Helicobacter pylori, anti-intrinsic factor antibodies, and anti-parietal cell antibodies to diagnose autoimmune gastritis 3
• Review medication list for metformin, PPIs, H2-blockers 2, 3

Treatment Recommendations

Iron Replacement

• Oral iron: Ferrous sulfate 200 mg three times daily (or equivalent ferrous gluconate/fumarate) is first-line 1
• Alternative dosing: Recent evidence suggests alternate-day dosing may improve absorption with fewer adverse effects 1
• Duration: Continue for 3 months after hemoglobin normalization to replenish stores 1
• Intravenous iron: Reserved for oral intolerance (after trying ≥2 preparations), malabsorption, or need for rapid repletion 1
• Ferric carboxymaltose allows single large doses (up to 1000 mg) with low adverse event rates 1

B12 Replacement (if deficiency confirmed by MMA)

• Oral supplementation: High-dose oral B12 (1-2 mg daily) is as effective as intramuscular for most patients 2, 6
• Intramuscular therapy: Preferred for severe deficiency, neurologic symptoms, or malabsorption 2, 6
  • Loading: 1000 µg hydroxocobalamin intramuscularly
  • Maintenance: 1000 µg every 2 months (though up to 50% may require more frequent dosing based on symptom response) 6
• Lifelong supplementation required for malabsorption causes (pernicious anemia, post-bariatric surgery) 2, 6

Monitoring

• Iron: Recheck hemoglobin and MCV at 3-4 weeks (expect 2 g/dL rise); then monitor every 3 months for 1 year, then annually 1
• B12: Do not use serum B12 or MMA levels to titrate injection frequency; base adjustments on clinical symptom response 6
• Re-treatment threshold: Reinitiate iron when ferritin drops <100 µg/L or hemoglobin falls below normal 1

Critical Pitfall

Do not supplement B12 based solely on low-normal levels without confirming tissue deficiency with MMA, as unnecessary supplementation provides no benefit and may delay diagnosis of other conditions 2, 3. However, always treat confirmed iron deficiency (ferritin 16 µg/L) regardless of B12 status 1.