Iron Deficiency Anemia

Etiology and Risk Factors

Iron deficiency is the most common form of anemia and the leading nutritional cause of anemia worldwide (Davoren & Hsu, 2019; Pereiras & Arnall, 2026). In developed countries, the main mechanism is iron loss through bleeding rather than inadequate intake (Davoren & Hsu, 2019).

Causes and contributors include (Davoren & Hsu, 2019; Norris, 2020; Shergill & McQuaid, 2012):

• Menstrual blood loss, especially heavy menses
• Pregnancy, as the fetus extracts maternal iron
• Gastrointestinal bleeding from peptic ulcer disease, arteriovenous malformations, angiodysplasia, inflammatory bowel disease, or colorectal malignancy
• Aspirin, nonsteroidal anti-inflammatory drug (NSAID), and other antiplatelet use, which can cause or worsen gastrointestinal bleeding
• Malabsorption from celiac disease, Helicobacter pylori infection, partial gastrectomy, or gastric bypass
• Low dietary iron, including some vegetarian diets
• Rapid growth in infancy, childhood, and adolescence
• Low iron stores at birth and diets dominated by cow’s milk in infants
• Chronic intravascular hemolysis with urinary iron loss, as with cardiac valvular disease
• Iron depletion during erythropoietin therapy

Epidemiology and Clinical Context

Premenopausal women have the highest incidence of iron deficiency because of recurrent menstrual losses, and pregnancy adds to the deficit. In men and postmenopausal women, gastrointestinal bleeding is the usual cause (Davoren & Hsu, 2019). Iron requirements are proportionally highest between 3 and 24 months of age, and iron deficiency in children is associated with impaired cognitive and physical development that can be reversed if treated early (Davoren & Hsu, 2019; Norris, 2020). Iron deficiency is also one of the most common causes of anemia in older adults (Norris, 2020).

Pathophysiology

The body conserves iron efficiently. Most iron used for new red cells is recycled from senescent cells by macrophages, and only 1 to 2 mg must be absorbed daily, mainly in the duodenum, to replace normal losses. Iron circulates bound to transferrin and is stored as ferritin and hemosiderin (Norris, 2020; Pereiras & Arnall, 2026).

Iron export into plasma is regulated by hepcidin, a liver peptide that binds the iron exporter ferroportin and causes its degradation. When stores are low, hepcidin falls and iron absorption and release increase. When stores are adequate or inflammation is present, hepcidin rises and iron remains trapped in enterocytes and macrophages (Davoren & Hsu, 2019). The same mechanism explains anemia of chronic disease, in which iron is present but unavailable for red cell production (Pereiras & Arnall, 2026).

Iron is inserted into protoporphyrin IX in the final step of heme synthesis. Without iron, heme production falls, and heme deficiency also suppresses globin synthesis, so each red cell precursor receives less hemoglobin (Davoren & Hsu, 2019).

The deficit develops in stages (Davoren & Hsu, 2019):

• Iron stores are depleted while the blood count remains normal.
• Hemoglobin falls, but individual red cells may still appear normal, so early iron deficiency can be normocytic.
• The erythropoietin-stimulated marrow often produces a reactive thrombocytosis.
• Red cells eventually become microcytic and hypochromic, with anisocytosis, poikilocytosis, and target cells.

Clinical Manifestations

Common manifestations include (Davoren & Hsu, 2019; Norris, 2020; Pereiras & Arnall, 2026):

• Fatigue
• Weakness
• Dyspnea on exertion
• Pallor of the skin, conjunctivae, and nail beds
• Tachycardia and palpitations
• Benign flow murmur
• Headache or lightheadedness

Findings more specific to iron deficiency include (Davoren & Hsu, 2019; Norris, 2020; Pereiras & Arnall, 2026):

• Glossitis
• Angular cheilitis
• Koilonychia (spoon-shaped nails)
• Dysphagia
• Pica, including cravings for ice, starch, or clay

Because the anemia usually develops slowly, patients compensate through increased cardiac output, redistribution of blood flow, and increased red cell 2,3-bisphosphoglycerate. A hemoglobin of 11 to 12 g/dL may be tolerated with few symptoms, and many cases are discovered on a complete blood count (CBC) drawn for another reason. Some patients present with signs of the bleeding source rather than the anemia (Davoren & Hsu, 2019).

Diagnostic Evaluation

History

Assess:

• Menstrual pattern and volume
• Pregnancy and postpartum status
• Melena, hematochezia, hematemesis, or hematuria
• Aspirin, NSAID, antiplatelet, and anticoagulant use
• Change in bowel habits, abdominal pain, or weight loss
• Diet, including vegetarian or restricted diets
• Prior gastric or bariatric surgery
• Symptoms of celiac disease or inflammatory bowel disease
• Blood donation
• Family history of colorectal cancer

Melena usually indicates bleeding proximal to the ligament of Treitz, although slow bleeding from the small bowel or right colon can also produce it. Hematochezia usually indicates lower gastrointestinal bleeding but can result from brisk upper gastrointestinal bleeding (Shergill & McQuaid, 2012).

Laboratory Testing

• CBC: Low hemoglobin with low mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) in established deficiency, often with an elevated red cell distribution width (RDW) (Norris, 2020; Pereiras & Arnall, 2026).
• Reticulocyte count: Inappropriately low for the degree of anemia because the marrow lacks substrate (Davoren & Hsu, 2019).
• Serum ferritin: The most sensitive and specific single test; a low value is diagnostic. Ferritin rises with acute or chronic inflammation, so a normal value does not exclude iron deficiency in a patient with infection, inflammatory disease, or malignancy (Davoren & Hsu, 2019).
• Total iron-binding capacity: Typically high in iron deficiency and low in anemia of chronic disease (Pereiras & Arnall, 2026).
• Serum iron and transferrin saturation: Low, but also low in many chronic illnesses (Davoren & Hsu, 2019; Pereiras & Arnall, 2026).
• Soluble transferrin receptor-to-ferritin ratio: A high ratio supports iron deficiency when ferritin is not diagnostic (Davoren & Hsu, 2019).

Additional Testing

Depending on the presentation, evaluation may include:

• Endoscopic evaluation of the gastrointestinal tract
• Celiac disease testing
• H. pylori testing
• Urinalysis for hematuria
• Gynecologic evaluation for heavy menstrual bleeding

In men and postmenopausal women without a known cause of iron deficiency, endoscopic evaluation to exclude malignancy is mandatory. A hematologic response to iron supports the diagnosis, and bone marrow examination is rarely required (Davoren & Hsu, 2019).

Expected Findings

The characteristic pattern is (Davoren & Hsu, 2019; Norris, 2020; Pereiras & Arnall, 2026):

• Microcytic, hypochromic anemia with elevated RDW and variable cell size and shape
• Low ferritin and transferrin saturation with high total iron-binding capacity
• Inappropriately low reticulocyte response; reactive thrombocytosis may occur

Differential Diagnosis

Anemia of Chronic Disease

Chronic infection, autoimmune disease, chronic kidney disease, and malignancy can produce a normocytic or mildly microcytic anemia with low serum iron. Ferritin is normal or high and total iron-binding capacity is low, reflecting hepcidin-mediated iron sequestration. The two conditions can coexist (Pereiras & Arnall, 2026).

Thalassemia

Thalassemia produces microcytosis through defective globin chain synthesis rather than iron deficiency (Davoren & Hsu, 2019). When iron studies are normal in a microcytic anemia, hemoglobin electrophoresis can identify thalassemia (Pereiras & Arnall, 2026).

Anemia of Chronic Kidney Disease

Reduced erythropoietin production causes a normocytic anemia that becomes more common and more severe as kidney function declines. Treatment includes erythropoietin therapy and iron supplementation (Norris, 2020).

Acute Blood Loss

Acute hemorrhage produces a normocytic anemia with an early reticulocyte response. Iron deficiency develops only after stores are depleted by ongoing or repeated loss (Norris, 2020).

Findings That Reduce Diagnostic Probability

Few laboratory findings exclude iron deficiency by themselves. The following findings should lower its position in the differential or prompt evaluation for an alternative:

• A high MCV suggests B12 or folate deficiency, medication effect, or another macrocytic process (Davoren & Hsu, 2019).
• An elevated reticulocyte count with rising bilirubin and lactate dehydrogenase suggests hemolysis or acute blood loss rather than a production defect (Norris, 2020).
• Normal or elevated ferritin with low total iron-binding capacity favors anemia of chronic disease, although inflammation can mask coexisting iron deficiency (Davoren & Hsu, 2019; Pereiras & Arnall, 2026).
• Microcytosis with normal iron studies suggests thalassemia and warrants hemoglobin electrophoresis (Pereiras & Arnall, 2026).
• Leukopenia or thrombocytopenia with the anemia suggests marrow disease or another nutritional deficiency, such as copper deficiency after bariatric surgery (Pereiras & Arnall, 2026).

Treatment and Management

Management has two goals: correct the cause of iron loss and replace the deficit (Norris, 2020).

Oral Iron

Oral iron therapy includes (Pereiras & Arnall, 2026):

• Ferrous sulfate is the most commonly used product.
• The preferred regimen is 50 to 65 mg of elemental iron two to three times daily on an empty stomach, 1 hour before or 2 hours after meals.
• Every-other-day dosing can produce results similar to daily dosing with fewer adverse effects in some populations and may improve tolerability (Pereiras & Arnall, 2026).
• Nausea, heartburn, abdominal pain, constipation, and dark stools are common. Taking iron with food or switching to a salt with less elemental iron, such as ferrous gluconate, can improve tolerance.
• Iron reduces absorption of fluoroquinolones, tetracyclines, eltrombopag, and mycophenolate, so doses should be separated by several hours (Pereiras & Arnall, 2026).

Monitoring Response

Reticulocytosis should occur within 7 to 10 days, and hemoglobin should rise by about 1 g/dL per week. A patient whose hemoglobin has not increased by 2 g/dL within 3 weeks should be reassessed for nonadherence, malabsorption, ongoing blood loss, or an incorrect diagnosis (Pereiras & Arnall, 2026). Hemoglobin often normalizes before stores are replenished, and oral replacement of stores takes several months (Norris, 2020).

Parenteral Iron

Parenteral iron is indicated for intolerance of oral iron, impaired absorption, or inability to adhere to oral therapy. Available products include iron sucrose, sodium ferric gluconate, ferumoxytol, ferric carboxymaltose, ferric derisomaltose, and low-molecular-weight iron dextran. Serious reactions are rare, but iron dextran requires a test dose and observation because of its anaphylaxis risk (Pereiras & Arnall, 2026).

Transfusion

Red cell transfusion is generally reserved for patients with acute symptoms such as chest pain or dyspnea. A restrictive threshold of 7 g/dL is reasonable in patients without significant cardiovascular disease (Pereiras & Arnall, 2026).

Complications and Red Flags

Urgent evaluation is required for:

• Hemodynamic instability, syncope, or orthostatic changes
• Melena, hematochezia, or hematemesis
• Chest pain, dyspnea at rest, or signs of heart failure
• Severe anemia in an older adult or a patient with coronary disease
• Weight loss, change in bowel habits, or other features of gastrointestinal malignancy
• Failure to respond to adequate iron replacement

Orthostatic hypotension or tachycardia with gastrointestinal bleeding indicates significant intravascular volume loss (Shergill & McQuaid, 2012).

Clinical Reasoning Priorities

Once iron deficiency is established, determine why it occurred. Unexplained deficiency in men and postmenopausal women requires gastrointestinal evaluation, and failure to respond to replacement should prompt reassessment for nonadherence, malabsorption, ongoing blood loss, or an alternate diagnosis (Davoren & Hsu, 2019; Pereiras & Arnall, 2026).

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References

Davoren, J. B., & Hsu, G. (2019). Blood disorders. In G. D. Hammer & S. J. McPhee (Eds.), Pathophysiology of disease: An introduction to clinical medicine (8th ed.). McGraw-Hill Education.

Norris, T. L. (2020). Porth’s essentials of pathophysiology (5th ed.). Wolters Kluwer.

Pereiras, M. A., & Arnall, J. R. (2026). Anemia. In M. A. Chisholm-Burns, P. M. Malone, J. M. Kolesar, K. C. Lee, P. B. Bookstaver, & K. R. Matthias (Eds.), Pharmacotherapy principles & practice (7th ed.). McGraw Hill.

Shergill, A., & McQuaid, K. R. (2012). Acute gastrointestinal bleeding. In M. C. Henderson, L. M. Tierney, Jr., & G. W. Smetana (Eds.), The patient history: An evidence-based approach to differential diagnosis (2nd ed., pp. 426–439). McGraw-Hill Medical.