Iron deficiency anemia

Iron deficiency anemia (IDA) is the most common form of anemia worldwide and can be due to inadequate intake, decreased absorption (e.g., atrophic gastritis, inflammatory bowel disease), increased demand (e.g., during pregnancy), or increased loss (e.g., gastrointestinal bleeding, menorrhagia) of iron. Prolonged deficiency depletes the iron stores in the body, resulting in decreased erythropoiesis and anemia. Symptoms are nonspecific and include fatigue, pallor, lethargy, hair loss, brittle nails, and pica. Diagnostic lab values include low hemoglobin, microcytic, hypochromic red blood cells on peripheral smear, and low ferritin and iron levels. Once diagnosed, the underlying cause should be determined. Patients at risk for underlying gastrointestinal malignancy should also undergo a colonoscopy. Iron deficiency anemia is treated with oral (most common) or parenteral iron supplementation. Severe anemia or those with concomitant cardiac conditions may also require blood transfusions. The underlying cause of IDA should also be corrected.

• Most common form of anemia worldwide ^[1]
• ∼ 3% of the general population in the United States is affected ^[2]
• Ethnic variations: African-American and Mexican-American populations in the US are at increased risk.
• Prevalence highest in: ^[3]
  • Children up to 5 years of age
  • Young women of child-bearing age (due to menstrual blood loss)
  • Pregnant women

Epidemiological data refers to the US, unless otherwise specified.

The most common causes of IDA can be divided by age groups and pathophysiologic mechanisms.

Based on age ^[1][4]

• Infants
  • Exclusive intake of nonfortified cow's milk; (cow's milk has a very low concentration of iron and also disrupts iron absorption)
  • Exclusive breastfeeding after 6 months of age ^[5]
• Children
  • Malnutrition (mainly resource-limited countries)
  • Excessive intake of cow's milk (> 24 ounces/700 mL per day)
  • Meckel diverticulum
• Adolescence: menarche/menstruation
• Adults (20–50 years)
  • Menorrhagia or pregnancy (females)
  • Peptic ulcer disease (males)
• Adults > 50 years
  • Colon polyps/carcinoma in high-income countries
  • Hookworm (Ancylostoma duodenale, Necator americanus) in resource-limited countries

In resource-limited countries, adults > 50 years that present with IDA should have colon polyps/carcinoma ruled out as a potential underlying etiology.

Based on underlying mechanism ^[4][6][7]

• Iron losses
  • Bleeding
    • Gastrointestinal bleeding
      • Occult gastrointestinal malignancy (e.g., colon cancer)
      • Hookworm infestation (e.g., Ancylostoma spp., Necator americanus)
      • Peptic ulcer disease
      • Increased risk with NSAID use ^[8]
    • Menorrhagia
    • Hemorrhagic diathesis (e.g., hemophilia, von Willebrand disease)
  • Meckel diverticulum
  • Dialysis-dependent renal failure
  • Frequent blood donation
• Decreased iron intake
  • Chronic undernutrition
  • Cereal-based diet
  • Strict vegan diet ^[1]
• Decreased iron absorption
  • Achlorhydria/hypochlorhydria (e.g., due to autoimmune or H. pylori infection-induced atrophic gastritis)
  • Inflammatory bowel disease, celiac disease
  • Surgical resection of the duodenum
  • Bariatric surgery
• Increased demand
  • Pregnancy
  • Lactation
  • Growth spurt
  • Erythropoietin (EPO) therapy

• Iron deficiency → ↓ binding of iron to protoporphyrin (last reaction in heme synthesis) → ↓ production of hemoglobin
• For more information about the different physiological roles of iron and associated laboratory parameters, see “Iron metabolism” in “Laboratory medicine” and “Iron” in “Trace elements.”

• Signs and symptoms of anemia
  • Fatigue, lethargy
  • Pallor (primarily seen in highly vascularized mucosa, e.g., the conjunctiva)
  • Cardiac: tachycardia, angina, dyspnea on exertion, pedal edema, and cardiomyopathy in severe cases
• Brittle nails, koilonychia (spoon-like nail deformity); , hair loss
• Pica, dysphagia
• Angular cheilitis: inflammation and fissuring of the corners of the mouth ^[9]
• Atrophic glossitis: erythematous, edematous, painful tongue with loss of tongue papillae (smooth, bald appearance)
• IDA can be associated with Plummer-Vinson syndrome (PVS) ^[10]
  • Triad of iron deficiency anemia, postcricoid dysphagia, and upper esophageal webs
  • Associated with an increased risk of esophageal squamous cell carcinoma and glossitis
  • Etiopathogenesis unknown

DICEd Plumm - Dysphagia, Iron deficiency anemia, Carcinoma of the esophagus, Esophageal webs in Plummer-Vinson syndrome.

References:^[2][11]

Approach

• Diagnosis of IDA requires the presence of anemia (low hemoglobin or hematocrit) and evidence of low iron stores (usually determined by serum ferritin and iron levels).
• IDA typically manifests as microcytic, hypochromic anemia with anisocytosis, low serum ferritin, and low serum iron levels.

Laboratory tests ^[12]

• Complete blood count with differential
  • ↓ Hemoglobin: anemia is typically defined as a hemoglobin level less than 2 SD below normal (for age and sex) ^[1]
    • ♂: < 13.5 g/dL
    • ♀: < 12 g/dL
  • ↓ Hematocrit
  • RBC: initially normal (decreased with prolonged deficiency)
  • ↓ Mean corpuscular volume: microcytic
  • ↓ Mean corpuscular hemoglobin: hypochromic
  • Normal or ↓ reticulocyte count
  • ↑ Red cell distribution width (RDW) : differentiates IDA from anemia of chronic disease and thalassemia trait (where the RDW is usually normal)
  • ↑ Platelet count (reactive thrombocytosis) ^[13][14]
• Iron studies
  • ↓ Serum ferritin
    • ♂: 15–200 ng/mL
    • ♀: 12–150 ng/mL
  • ↓ Serum iron (50–170 μg/dL)
  • ↑ Serum transferrin and total iron binding capacity (TIBC)
  • ↓ Transferrin saturation (< 20%)
  • ↑ Serum free erythrocyte protoporphyrin
  • Normal or ↑ EPO ^[15]
• Peripheral blood smear: anisocytosis and hypochromasia (increased zone of central pallor)
• Bone marrow biopsy: (rarely indicated): In patients with suspected IDA and nondiagnostic iron studies, low bone marrow iron is diagnostic of IDA.

Low ferritin and iron levels in combination with an elevated TIBC are diagnostic of iron deficiency anemia.

Increased ferritin does not rule out iron deficiency anemia. It can be increased in response to simultaneous inflammation.

Evaluation for underlying cause ^[1][12]

• Occult gastrointestinal bleeding
  • Recommended for:
    • Patients at risk for GI malignancy
      • All men (especially if > 50 years old)
      • Nonmenstruating women
    • Patients with a history or signs of bleeding (e.g., melena, epigastric pain, hematochezia)
  • Initial workup
    • Stool guaiac test (screening only)
    • Colonoscopy with or without EGD: to evaluate for GI malignancy, polyps, inflammatory bowel disease, celiac disease, etc.
• Other causes
  • If no risk factors (e.g., advanced age) for occult GI bleeding, consider treating empirically with oral iron and monitor for response
  • Evaluation for menorrhagia, celiac disease, Crohn disease, ulcerative colitis, etc.
  • See “Heavy menstrual bleeding.”
  • Examination of stool for ova and parasites if concern for Ancylostoma duodenale, Necator americanus (e.g., patient from a resource-limited country, eosinophilia on CBC ) ^[16]
    • Repeat stool tests may be necessary since egg-laying may be delayed.
    • Note that hookworms can also cause a positive stool occult blood test.

• Dietary modifications
  • Infants and young children: restrict cow's milk intake, use iron-fortified formula, introduce iron-rich foods (pureed form)
  • Adults: increase consumption of iron-rich diet (meats, iron-fortified food, fresh green leafy vegetables)
• Oral iron therapy
  • Indicated in all patients with IDA (if tolerated)
  • Should initially be administered for 3–6 months ^[4]
  • Adverse effects: gastrointestinal discomfort, nausea, constipation, black discoloration of stool
  • Absorption may be enhanced by simultaneous consumption of vitamin C (e.g., with lime juice).
  • Foods (e.g., tea, cereals) and drugs (e.g., calcium, antacids, PPIs) that decrease intestinal absorption of iron should be avoided.
• Parenteral iron therapy
  • Indicated in
    • Nonadherence/intolerance to oral iron therapy
    • Intestinal malabsorption
    • Patients with Hb < 6 g/dL who decline blood transfusions
  • Available forms (ferric preparations): iron dextran, iron sucrose, and sodium ferric gluconate
  • Adverse effects
    • Thrombophlebitis
    • Iron dextran can cause anaphylactic shock (rarely), myalgia, arthralgia, and headaches within 1–2 days of infusion.
• Blood transfusion
  • See “Transfusion.”
  • Recommended for severe anemia (Hb < 7 g/dL)
• Treat the underlying disease (e.g., antihelminthics for hookworm, OCPs for menorrhagia)

References:^[2][17]

See "Diagnostics" in “Anemia.”

• Normocytic anemia
  • Acute blood loss anemia
  • Occult bleeding
  • Anemia of chronic disease
  • Hemolytic anemia
  • Chronic kidney disease
  • Aplastic anemia
• Microcytic anemia
  • Thalassemia
    • Laboratory studies reveal hemolysis: ↓ haptoglobin, ↑ indirect bilirubin, ↑ reticulocytes
    • Confirmed on Hb-electrophoresis
  • Sideroblastic anemia: Serum ferritin levels and transferrin saturation levels are normal or increased.
  • Lead poisoning (esp. in children)
    • Erythrocytes show characteristic basophilic stippling on peripheral smear.
    • High levels of lead in blood
  • Anemia of chronic disease (may co-exist with IDA): Serum ferritin levels and transferrin saturation levels are usually normal.

References:^[2][12]

The differential diagnoses listed here are not exhaustive.

Iron deficiency anemia in pregnancy

• Epidemiology
  • > 40% of pregnant women are iron deficient ^[18]
  • Second most common cause of anemia in pregnant women (after physiologic anemia)
• Etiology: increased iron requirements
• Treatment: oral or IV iron supplementation (see “Treatment” above) ^[19][20]
• Complications
  • Increased risk of adverse pregnancy outcomes
  • Impaired fetal neurodevelopment