Combined Iron and Vitamin B12 Deficiency (Mixed Anemia)
This patient has combined iron and vitamin B12 deficiency (mixed anemia), where the microcytic effect of iron deficiency masks the macrocytic effect of B12 deficiency, resulting in falsely normal or low MCV values. 1, 2
Diagnostic Interpretation
Understanding the Mixed Picture
The low MCV, MCH, MCHC, and low iron saturation clearly indicate iron deficiency anemia, which typically produces microcytic, hypochromic red blood cells 3
Concurrent vitamin B12 deficiency is masked by the iron deficiency, as B12 deficiency normally causes macrocytosis (elevated MCV), but when combined with iron deficiency, the two opposing effects neutralize each other, resulting in a normal or even low MCV 1, 2
Red cell distribution width (RDW) should be checked immediately, as an elevated RDW (>14%) is the key laboratory clue that reveals mixed deficiency states when microcytosis and macrocytosis coexist and mask each other 3, 4
The combination of low B12 with microcytic indices is pathognomonic for combined deficiency, and variations in MCV are determined by both iron status (ferritin, transferrin saturation) and vitamin B12 status (methylmalonic acid levels) 1, 2
Critical Management Priority
Treatment Sequence Matters
Vitamin B12 deficiency MUST be treated before initiating iron supplementation or folate therapy to prevent precipitating subacute combined degeneration of the spinal cord, which causes irreversible neurological damage 4, 5
Administer cyanocobalamin 1 mg intramuscularly three times weekly for 2 weeks, followed by 1 mg every 2-3 months for life if pernicious anemia or malabsorption is the underlying cause 4
If neurological symptoms are present (paresthesias, ataxia, cognitive changes), treat more aggressively with hydroxocobalamin 1 mg intramuscularly on alternate days until no further improvement, then 1 mg every 2 months 4
After B12 repletion is initiated, begin therapeutic iron supplementation to address the iron deficiency component 3
Essential Additional Workup
Confirm the Diagnosis
Measure serum methylmalonic acid (MMA) levels, as MMA >271 nmol/L confirms B12 deficiency even when serum B12 is borderline (150-200 pg/mL) 4
Check serum homocysteine levels, which are elevated in B12 deficiency (>12.7 μM) and provide additional confirmation 1, 6
Obtain reticulocyte count to assess bone marrow response and differentiate production versus destruction causes of anemia 4, 2
Measure serum ferritin and transferrin saturation to quantify iron deficiency severity, with transferrin saturation <16-20% confirming iron deficiency 3
Check inflammatory markers (CRP), as inflammation can falsely elevate ferritin up to 100 μg/L despite true iron deficiency 3, 4
Rule Out Underlying Causes
Investigate for malabsorption syndromes, including pernicious anemia (check gastric parietal cell antibodies), celiac disease, inflammatory bowel disease, or prior gastric/ileal surgery 3, 6
Assess for chronic blood loss as the source of iron deficiency, including gastrointestinal bleeding (especially given the 3-fold increased risk of gastric carcinoma in pernicious anemia patients) 5
Review dietary history for vegetarian/vegan diet, which predisposes to both B12 and iron deficiencies 1
Common Diagnostic Pitfalls
Avoid These Errors
Do not assume normal or low MCV excludes B12 deficiency - this is the most dangerous pitfall, as combined deficiencies produce misleading indices 1, 2
Do not rely on peripheral blood smear alone, as morphology may appear normal in mixed anemia despite severe deficiencies 2
Do not wait for macrocytosis to develop before checking B12, as neurological damage can occur with normal hematocrit and MCV 7
Do not give folate before excluding and treating B12 deficiency, as folic acid doses >0.1 mg daily may produce hematologic remission while allowing irreversible neurological progression 5
Do not interpret ferritin in isolation when inflammation is present, as ferritin up to 100 μg/L may still indicate iron deficiency in inflammatory states 3
Monitoring Response to Treatment
Track These Parameters
Repeat complete blood count daily from days 5-7 of B12 therapy, then frequently until hematocrit normalizes 5
Reticulocyte count should increase at least twice normal as long as hematocrit remains <35%, indicating adequate bone marrow response 5
Monitor serum potassium closely in the first 48 hours of B12 treatment, as rapid cell production can cause hypokalemia requiring replacement 5
Expect hemoglobin to increase by at least 2 g/dL within 4 weeks of appropriate treatment for both deficiencies 4
If reticulocytes fail to increase or hematocrit does not improve, reevaluate the diagnosis and check for complicating conditions (chronic disease, renal failure, hypothyroidism, myelodysplastic syndrome) 5