Iron deficiency anemia

Principles of IDA management

• Confirm the diagnosis.
• Identify its cause.
• Correct or manage the primary cause.
• Provide iron therapy, orally or parenterally.
• Confirm therapy success.

Iron physiology

• Daily iron balance: intake ~10 to 20 mg, absorbed ~1 to 2 mg (regulated by hepcidin), losses ~1 mg/day (women lose more with menstruation). Total body iron ~3 to 4 g (~70% in Hb, ~25% storage in ferritin/hemosiderin).
• Hepcidin: master regulator. ↑ hepcidin → degrades ferroportin (iron exporter on enterocytes and macrophages) → ↓ iron absorption + ↓ iron release. ↑ in inflammation (IL-6 driver) → anemia of inflammation; ↓ in iron deficiency (allows ↑ absorption).
• Heme iron (animal sources) is more bioavailable than non-heme (plant). Vitamin C enhances; tannins, phytates, calcium impair absorption.
• Transferrin saturation (TSAT) = serum iron / TIBC × 100. Normal 20 to 45%.
• Ferritin: intracellular iron storage protein; serum level reflects body iron stores. <30 ng/mL diagnostic of iron deficiency. <100 in inflammation may still indicate iron deficiency.

Causes of iron deficiency

• Blood loss (most common in adults): GI bleeding (occult: peptic ulcer, NSAID gastropathy, colon cancer, polyps, AVMs, esophagitis, hookworm in endemic areas); menstrual loss (menorrhagia, fibroids); urinary (rare but consider hematuria); chronic hemolysis (PNH); frequent blood draws (hospitalized).
• ↓ Intake: vegetarian/vegan, infants weaning to cow milk, restrictive diets, food insecurity. Iron-rich foods: meat, liver, beans (black beans, lentils).
• ↑ Demand: pregnancy (especially 2nd/3rd trimester), lactation, growth spurts, athletes (foot-strike hemolysis, GI losses).
• Malabsorption: celiac disease (screen with anti-tTG IgA + total IgA), atrophic gastritis (autoimmune or H. pylori), bariatric surgery (gastric bypass, duodenum bypassed), achlorhydria, IBD, gastric/duodenal resection, chronic PPI use (mild).
• Iron-refractory iron deficiency anemia (IRIDA): TMPRSS6 mutations → ↑ hepcidin → oral iron unresponsive; blunted IV iron response (may be overcome by high doses). Autosomal recessive, rare, often presents in childhood.
• Hookworm (Necator, Ancylostoma): major cause of IDA in endemic regions (leading infectious/GI blood-loss cause globally); check stool O and P plus eosinophilia in immigrants/travelers.
• Always evaluate cause: men and post-menopausal women → GI workup (EGD + colonoscopy). Premenopausal women with menorrhagia → gyn evaluation if history suggests.
• Celiac screening (anti-tTG IgA + total IgA): unexplained iron deficiency, especially with diarrhea or other malabsorption clues.

Clinical features

• Classic anemia symptoms: fatigue, dyspnea, palpitations, pallor.
• Iron-specific signs: pica (eating ice, pagophagia is most specific; clay, dirt), restless legs syndrome (often resolves with iron correction), koilonychia (spoon nails), angular cheilitis, glossitis, dysphagia (Plummer-Vinson syndrome: esophageal web + iron deficiency + glossitis; ↑ esophageal SCC risk).

Laboratory diagnosis

• Making the diagnosis: positive clinical history + microcytic anemia → IDA; iron studies confirm. Serum ferritin reflects total body iron and is the first parameter to fall; low ferritin is always consistent with iron deficiency.
• Ferritin <15 to 30 ng/mL = diagnostic of iron deficiency; <100 with inflammation may still indicate iron deficiency. Acute-phase reactant: rises with infection, malignancy, inflammation; can be falsely normal/elevated.
• Serum iron: ↓ but diurnal variation; not standalone (best fasting).
• TIBC: ↑ in IDA (transferrin upregulated); ↓ in ACD/inflammation; ↓↓ in malnutrition/liver disease.
• Transferrin saturation (TSAT) = serum Fe/TIBC × 100; <15 to 20% supports IDA. ↓ in both IDA and ACD.
• CBC: microcytic, hypochromic; ↑ RDW (key point: thal trait has normal RDW); reactive thrombocytosis common.
• Smear: pencil cells, target cells (some), anisopoikilocytosis.
• Other markers:
  • Soluble transferrin receptor (sTfR): not affected by inflammation. ↑ in iron deficiency, hemolysis, ineffective erythropoiesis. Ratio sTfR/log ferritin (ferritin index) helpful if ACD overlap.
  • Reticulocyte hemoglobin content (CHr or RET-He): ↓ in iron-restricted erythropoiesis; useful in pediatrics and CKD.
  • % hypochromic RBCs: used in dialysis to monitor iron status.

Treatment: oral iron

• First-line: oral ferrous salts (sulfate, fumarate, gluconate). Each 325 mg ferrous sulfate = ~65 mg elemental iron.
• Dosing strategy: be more aggressive early when the patient is more anemic (daily dosing); once Hb has normalized but ferritin/iron stores remain low, switch to every-other-day dosing. Every-other-day dosing (~60 to 120 mg elemental iron) improves fractional absorption and reduces GI side effects. Specific optimal dose is not well established (studies lacking).
• Take on empty stomach with vitamin C (orange juice) for maximal absorption. Avoid with calcium, dairy, coffee/tea, antacids, PPIs.
• Side effects: nausea, constipation, dark stools (not melena), epigastric discomfort, metallic taste. Reduce dose or change formulation if intolerant. Liquid formulation may stain teeth.
• Newer oral options: ferric maltol (Accrufer/Feraccru), heme iron polypeptide (Proferrin), better tolerated.
• Expected response: retic ↑ at ~1 week, Hb ↑ by ~1 to 2 g/dL by 2 to 4 weeks. Continue a minimum of 3 months (often 3 to 6 months) after Hb normalizes to replenish stores (target ferritin >50 to 100).

Iron therapy follow-up

• Minimum 3 months of therapy after Hb normalizes.
• Baseline: at diagnosis/initiation.
• 1 to 2 weeks (severe patients only): assess initial response with CBC/retic.
• 1 month: anemia improving, Hb ↑ by at least 1 to 2 g/dL, ↑ retic count.
• 3 months: if anemia resolved, continue iron about 3 months after Hb normalization to replete stores (check ferritin, target >50 to 100); stop only once stores are replete and losses controlled.
• Avoid frequent iron panels during oral repletion, since stores (ferritin) lag behind Hb; serum iron and TSAT rise within days and are falsely high for ~48 h after IV iron. Monitoring interval depends on setting (monthly in HD patients).
• Reasons for persistent IDA: incorrect diagnosis; persistent etiology (ongoing blood loss); insufficient iron dose or too-short duration; non-adherence; malabsorption (inflammation/GI condition, or rare IRIDA).

IV iron: indications

• Not standard of care for the majority of patients. Approved/appropriate uses: CKD; intolerance to oral iron; persistent IDA despite oral iron; IRIDA and concomitant IDA with anemia of inflammation. Also used for ongoing loss exceeding oral repletion, pregnancy 2nd to 3rd trimester (if oral intolerant/severe), active IBD, heart failure with iron deficiency, gastric bypass, and severe deficiency needing rapid correction.
• Dosing is by product labeling or calculated with the Ganzoni formula (target Hgb, weight). Distinguishing properties among agents: strength of the carbohydrate shell binding the iron, and immunogenic properties.

IV iron preparations: comparison

• Ferric carboxymaltose (Injectafer): high single dose repletion but ↑ hypophosphatemia (~40% any-grade), which can be severe and prolonged with repeat dosing (monitor phosphate; consider an alternative formulation if multiple doses anticipated; osteomalacia with chronic use).
• Ferric derisomaltose (Monoferric): full repletion in a single 1000 mg infusion; lower hypophosphatemia rate than FCM (PHOSPHARE-IDA).
• Ferumoxytol (Feraheme): iron oxide nanoparticle that can interfere with MRI for ~3 months.
• Hypersensitivity: rare with newer formulations; do not routinely premedicate (premedication may increase reactions per Auerbach et al.).

Anemia of inflammation (overlap)

• A form of iron-restricted erythropoiesis: IL-6 → ↑ hepcidin → blocks ferroportin → ↓ iron release into circulation (an immunoprotective response that limits iron availability to pathogens). Iron is present but sequestered in hemosiderin-laden macrophages.
• Initially normocytic; prolonged course becomes microcytic. Concomitant iron deficiency and anemia of inflammation may coexist (e.g., IBD with blood loss).
• Treat the underlying inflammation; if severe/prolonged, assess for concomitant iron deficiency and treat with IV iron if needed. sTfR (elevated in iron deficiency, unaffected by inflammation) helps distinguish overlap but is unreliable in hemolytic anemias.

Special situations

• Pregnancy: Hb <11 in 1st/3rd or <10.5 in 2nd trimester. PO iron first-line; IV iron in 2nd to 3rd trimester if PO intolerant or severe deficiency.
• CKD on dialysis: IV iron preferred. CKD on dialysis: give IV iron when ferritin ≤500 ng/mL and TSAT ≤30%; withhold when ferritin >500 to 700 or TSAT ≥40% (initiation/withholding thresholds, not fixed targets). ESAs (epoetin, darbepoetin) often combined.
• Heart failure with iron deficiency: IV ferric carboxymaltose improves NYHA class, exercise tolerance, and hospitalization in HFrEF (FAIR-HF, CONFIRM-HF, AFFIRM-AHF).
• HEART-FID (Mentz, NEJM 2023) and IRONMAN (Kalra, Lancet 2022): in HFrEF + iron deficiency, IV ferric carboxymaltose (HEART-FID) or ferric derisomaltose (IRONMAN): HEART-FID (hierarchical endpoint of death and HF hospitalizations through 12 mo plus 6MWD at 6 mo) missed its prespecified threshold (p=0.019 vs 0.01); IRONMAN (recurrent HF hospitalization + CV death over median 2.7 yr) was not significant (RR 0.82, 95% CI 0.66 to 1.02, p=0.070) (HEART-FID hierarchical p=0.019 but not meeting the pre-specified threshold). Pooled effect modest: use IV iron for symptom/QoL benefit, not mortality. 2022 AHA/ACC/HFSA HF guideline: IV iron is Class 2a for symptomatic HFrEF with iron deficiency to improve functional status.
• IBD: IV iron preferred (oral worsens GI symptoms and is poorly absorbed in active disease).
• Gastric bypass: IV iron often required long-term.
• Plummer-Vinson syndrome: iron deficiency + dysphagia + esophageal web + glossitis + cheilitis; ↑ SCC risk of the post-cricoid hypopharynx and upper esophagus.

High yield

• Ferritin <30 is diagnostic and falls first; ferritin <100 with inflammation may still be iron deficiency. sTfR helps in ACD overlap.
• Dosing: daily when actively anemic, then every-other-day to top off stores (better absorption, fewer side effects).
• Always evaluate the cause in adults: exclude GI bleed and malabsorption.
• IV iron: preferred in CKD/dialysis, IBD, HF, gastric bypass, and pregnancy 2nd/3rd trimester when oral is not tolerated.
• Test dose / black box: LMW iron dextran (both); ferumoxytol (black box, no test dose). Newer FCM/derisomaltose neither.
• FCM hypophosphatemia: monitor; consider derisomaltose for repeat dosing.
• Pica (especially pagophagia) and restless legs are suggestive and often improve with iron repletion.