What is the optimal management for a patient with thalassemia trait who has low iron stores (serum ferritin <45 µg/L)?

Management of Thalassemia Trait with Low Iron Stores

In patients with thalassemia trait and ferritin <45 µg/L, iron supplementation is indicated to correct true iron deficiency, which can coexist with thalassemia trait and cause additional symptoms beyond the baseline microcytosis.

Understanding the Clinical Scenario

Thalassemia trait (particularly β-thalassemia minor) causes lifelong microcytic hypochromic red cells with normal or elevated ferritin levels 1, 2. However, when ferritin falls below 45 µg/L in a patient with known thalassemia trait, this indicates superimposed iron deficiency that requires treatment 3, 4.

• The combination of low MCV and normal ferritin is the classic pattern for thalassemia trait alone 1, 2
• When ferritin drops to <45 µg/L, true iron deficiency has developed on top of the baseline thalassemia 3, 4
• Ferritin <30 µg/L generally indicates depleted iron stores requiring intervention 3, 4
• Ferritin <15 µg/L has 99% specificity for absolute iron deficiency 3, 4

Diagnostic Confirmation

Before initiating iron therapy, confirm the diagnosis with:

• Calculate transferrin saturation (TSAT): Values <16–20% confirm iron deficiency even when ferritin is borderline 3, 4
• Check inflammatory markers (CRP, ESR): Ferritin is an acute-phase reactant; inflammation can mask true iron deficiency by falsely elevating ferritin 3, 4
• Review complete blood count: Look for worsening microcytosis beyond the patient's baseline thalassemia pattern, elevated RDW, or development of anemia 3, 5

The key distinction: thalassemia trait patients typically maintain ferritin >30 µg/L unless they develop concurrent iron deficiency from blood loss, malabsorption, or inadequate dietary intake 1, 2.

Investigation for Iron Loss

All adults with confirmed iron deficiency require evaluation for the source of iron loss, even when thalassemia trait is present 3, 5:

For Adult Men and Postmenopausal Women

• Bidirectional endoscopy (upper endoscopy + colonoscopy) is mandatory because gastrointestinal malignancy is the most common serious cause 3, 5
• Screen for celiac disease with tissue transglutaminase antibodies (present in 3–5% of iron deficiency cases) 3, 4
• Test for Helicobacter pylori non-invasively (stool antigen or urea breath test) 3, 4

For Premenopausal Women

• GI evaluation is conditional rather than mandatory if the patient is young with heavy menses and no GI symptoms 3, 4
• Screen for celiac disease and H. pylori first 3, 4
• Reserve bidirectional endoscopy for: age ≥50 years, GI symptoms (abdominal pain, altered bowel habits, visible blood), positive celiac/H. pylori testing, failure to respond to oral iron after 8–10 weeks, or strong family history of colorectal cancer 3, 4

Iron Supplementation Protocol

Initiate oral iron immediately; do not delay treatment while awaiting diagnostic workup 3, 4:

• Ferrous sulfate 65 mg elemental iron daily (or ferrous bisglycinate if better tolerated) 3, 4
• Alternate-day dosing (60 mg every other day) improves absorption by 30–50% and reduces GI side effects compared to daily dosing 3, 4
• Take on an empty stomach for optimal absorption; if GI symptoms occur, take with meals 3
• Expected side effects include constipation, nausea, or diarrhea 3

Expected Response

• Hemoglobin should rise by ≥10 g/L within 2 weeks of starting therapy 3, 4
• Repeat CBC and ferritin at 8–10 weeks to assess response 3, 4
• Target ferritin >100 ng/mL to fully restore iron stores and prevent recurrence 3, 4

When to Switch to Intravenous Iron

Consider IV ferric carboxymaltose (15 mg/kg, maximum 1000 mg per dose) when 3, 4:

• Oral iron intolerance (severe nausea, constipation, diarrhea)
• Confirmed malabsorption (celiac disease, inflammatory bowel disease, post-bariatric surgery)
• Ongoing blood loss exceeding oral replacement capacity
• Failure to respond to adequate oral iron after 8–10 weeks
• Chronic inflammatory conditions (CKD, heart failure, cancer)

Critical Pitfalls to Avoid

• Do not assume microcytosis in thalassemia trait excludes the need for iron workup: When ferritin is <45 µg/L, true iron deficiency is present and requires investigation and treatment 3, 4, 1, 2
• Do not diagnose thalassemia trait without first correcting iron deficiency: The two conditions frequently coexist, and iron deficiency can mask or exaggerate the microcytosis 1, 2
• Do not discontinue iron once hemoglobin normalizes: Continue supplementation for 3 months after hemoglobin correction to achieve ferritin >100 ng/mL 3, 4
• Do not attribute iron deficiency solely to thalassemia trait: Thalassemia trait does not cause iron deficiency; a source of iron loss must be identified 1, 5, 2
• Do not overlook celiac disease: Present in 3–5% of iron deficiency cases and easily missed without serologic screening 3, 4

Long-Term Monitoring

• For patients with recurrent low ferritin (menstruating females, vegetarians, athletes, blood donors), screen ferritin every 6–12 months 3, 4
• Do not continue daily iron supplementation once ferritin normalizes, as this is potentially harmful 3
• If iron deficiency recurs despite adequate supplementation, escalate GI investigation for occult bleeding or malabsorption 3, 4