Iron Deficiency Without Anemia and Leukopenia/Lymphocytopenia
Iron deficiency without anemia does not typically cause leukopenia or lymphocytopenia; however, when these cytopenias occur in the setting of iron deficiency, they are reversible with iron replacement therapy and appear to represent a rare but recognized manifestation of severe iron depletion.
Evidence from Clinical Studies
Prevalence and Characteristics
In a large cohort of 1,567 females with iron deficiency anemia, 5.1% developed leukopenia, 4.0% developed neutropenia, and 1.2% developed lymphocytopenia, demonstrating that white blood cell abnormalities can occur in iron-deficient states 1.
Among iron-deficient patients who had normal white blood cell counts before treatment, 1.91% developed leukopenia after intravenous iron therapy, suggesting that the relationship between iron status and white cell counts is complex and bidirectional 2.
Neutropenia and lymphocytopenia associated with iron deficiency are reversible: 67% of neutropenic women with iron deficiency anemia showed increased absolute neutrophil count in response to iron therapy, and 100% had correction of their anemia 1.
Clinical Significance and Mechanism
The clinical significance of iron deficiency-associated leukopenia appears limited, with only 6.66% of affected patients developing infections (upper respiratory tract infection or urinary tract infection), and no serious infectious complications were reported 2.
Case reports document complete resolution of lymphocytopenia in iron-deficient patients after intravenous iron therapy, confirming the causal relationship 3.
A patient with chronic idiopathic neutropenia lasting 16 years experienced complete correction of both iron deficiency anemia and unexplained neutropenia after two and a half months of compliant oral iron supplementation, suggesting that some cases of "chronic benign neutropenia" may actually represent unrecognized iron deficiency-induced neutropenia 4.
Guideline Context: Iron Deficiency Manifestations
Recognized Manifestations of Iron Deficiency
CDC guidelines describe a spectrum of iron deficiency ranging from iron depletion (which causes no physiological impairments) to iron-deficiency anemia (which affects multiple organ systems), but do not specifically list leukopenia or lymphocytopenia among the recognized manifestations 5.
In infants and children, iron-deficiency anemia results in developmental delays and behavioral disturbances; in adults, it impairs work capacity; and in pregnant women, it increases risk for preterm delivery and low birthweight—but hematologic effects are described primarily in terms of red blood cell changes 5.
Iron Deficiency in Energy-Deficient Athletes
Among female athletes with energy deficiency, 24–47% experience iron deficiency without anemia at baseline, and iron deficiency can worsen the hypometabolic state by impairing thyroid hormone synthesis and shifting ATP production to less efficient pathways 5.
Recent survey data and controlled studies in athletes have questioned whether immunologic dysfunction is truly an effect of low energy availability, with observational data in athletes and controlled data from anorexia nervosa studies showing conflicting results regarding immune function 5.
Clinical Approach
When to Suspect Iron Deficiency as the Cause
If a patient presents with unexplained leukopenia, neutropenia, or lymphocytopenia, measure serum ferritin and transferrin saturation to assess iron status 1, 4.
In the absence of inflammation (normal CRP), a serum ferritin < 30 µg/L confirms iron deficiency; transferrin saturation < 20% is the primary confirmatory marker when ferritin is equivocal 6.
When inflammation is present (elevated CRP/ESR), ferritin values up to 100 µg/L may still represent iron deficiency, and transferrin saturation < 20% confirms the diagnosis 5, 6.
Treatment and Monitoring
Initiate iron replacement therapy (oral or intravenous depending on severity, tolerance, and absorption) and monitor complete blood count with differential at regular intervals 1, 4.
Expect improvement in white blood cell counts within weeks to months of iron repletion; if neutropenia or lymphocytopenia persists after documented correction of iron stores (ferritin > 50 µg/L), pursue alternative diagnoses 1, 4.
Continue iron therapy for at least 3–6 months after hemoglobin normalization to fully replenish iron stores 6.
Critical Caveats
Do not assume that all cases of leukopenia or lymphocytopenia in iron-deficient patients are caused by iron deficiency; other etiologies (autoimmune disorders, viral infections, medications, bone marrow disorders) must be excluded through appropriate clinical evaluation 1, 4.
The absence of anemia does not exclude clinically significant iron deficiency; iron depletion can cause metabolic, thyroid, and potentially hematologic effects even when hemoglobin remains normal 5.
Leukopenia developing after intravenous iron therapy (as opposed to pre-existing leukopenia in iron-deficient patients) represents a distinct phenomenon—likely a transient side effect of iron infusion—and should not be confused with iron deficiency-induced cytopenias 2.
In patients with chronic unexplained neutropenia and documented iron deficiency, a trial of iron replacement is warranted before pursuing more invasive investigations or immunosuppressive therapies, as the neutropenia may resolve with iron repletion alone 4.