Iron deficiency anemia

Iron deficiency anemia (IDA) is the most common form of anemia worldwide and can be caused by 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 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. While IDA typically manifests as a hypochromic and microcytic anemia, it may also be normocytic. A low ferritin level is diagnostic for iron deficiency, but further iron studies may be necessary, especially in patients with chronic inflammation. Once IDA is diagnosed, the underlying cause must be determined. This typically involves a gastroscopy and colonoscopy or a gynecologic workup in women with abnormal uterine bleeding. Iron deficiency anemia is treated with oral or parenteral iron supplementation. Patients with anemia severe enough to cause cardiopulmonary instability require blood transfusions.

See also “Anemia.”

• Most common form of anemia worldwide ^[1]
• ∼ 3% of the general population in the United States is affected. ^[2]
• 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 group and pathophysiologic mechanism.

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-rich 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
    • Thin membranes of normal esophageal tissue protrude into the esophagus causing symptoms such as dysphagia, odynophagia, and food impaction.
    • Acquired esophageal webs are much more common than congenital webs and are mainly observed in Plummer–Vinson syndrome.
  • 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

• Initial investigations
  • Routine studies: CBC (± blood smear) to check Hb and Hct
  • Iron studies: to confirm the diagnosis of iron deficiency
  • Evaluation for underlying causes of iron deficiency: recommended in the majority of patients
• Empiric iron therapy can be initiated if:
  • The patient's history points to a clear explanation for IDA (e.g., history of multiple blood donations or inadequate nutritional iron intake)
  • No pathology is found in a young, otherwise healthy patient after the initial investigations
• Advanced studies (e.g., capsule endoscopy, angiographic or scintigraphic studies): Consider in older symptomatic patients with negative initial workup and no response to empiric iron therapy. ^[12]

Routine studies ^[1][12][13]

• CBC
  • ↓ Hemoglobin: Anemia is typically defined as a hemoglobin level less than two standard deviations below the mean (adjusted for age and sex). ^[1][13]
    • Women: nonpregnant < 12 g/dL; pregnant < 11 g/dL
    • Men: < 13 g/dL
    • Children: See “Definition" section in “Anemia” for details.
  • ↓ Hematocrit
  • ↑ Platelet count (reactive thrombocytosis) ^[14][15]
• Red blood cell indices ^[12]
  • RBC: initially normal (decreased with prolonged deficiency)
  • Mean corpuscular volume
    • Typically ↓ (microcytic)
    • May be normal (normocytic)
    • Children: age-specific lower limit of normal for MCV values is (70 + age in years)
  • Mean corpuscular hemoglobin
    • Typically ↓ (hypochromic)
    • May be normal (normochromic)
  • Normal or ↓ reticulocyte count
  • Red cell distribution width (RDW)
    • Increases in established IDA
    • Can help distinguish IDA from anemia of chronic disease and certain types of thalassemia (in which the RDW is usually normal). ^[16]
• Peripheral blood smear: : anisocytosis and hypochromasia (increased zone of central pallor) ^[17]

Diagnosis of iron deficiency ^{[1][4][13][18]}

• Iron studies
  • Best initial test: ↓ serum ferritin ^[1]
    • < 45 ng/mL: IDA highly likely ^[18]
    • 45–100 ng/mL: Consider further evaluation (e.g., transferrin, TSAT).
    • Comorbid chronic inflammatory conditions, CKD, CHF: further evaluation even if ferritin is normal
  • Further evaluation
    • ↓ Serum iron ^[1]
    • ↑ Serum transferrin and total iron binding capacity (TIBC)
    • ↓ Transferrin saturation (TSAT) ^[4][13]
    • ↑ Serum soluble transferrin receptor (sTfR) ^[17]
  • Additional tests to consider
    • Serum free erythrocyte protoporphyrin: elevated
    • EPO: normal or elevated ^[19]
• Bone marrow biopsy ^[1][17]
  • Gold standard, but only indicated in patients with suspected IDA and equivocal iron studies.
  • Findings: decreased or absent stainable iron stores ^[12]

In combination with an elevated TIBC, low ferritin and iron levels 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][18]

Treatment of the underlying condition

Examples include:

• Abnormal uterine bleeding: e.g., hormonal therapy (OCPs), tranexamic acid, gynecological surgery
• GI pathology
  • H. pylori eradication therapy
  • GI bleeding: e.g., polypectomy, treatment of GI malignancy (e.g., colon cancer)
  • See also “Treatment” in “PUD”, “IBD”, “Celiac disease”.
• Hookworm infection: antihelminthics
• Malnutrition or malabsorption: Identification and treatment of underlying causes (e.g., eating disorders) and nutritional supplementation

Dietary modifications

• All patients
  • Encourage consumption of iron-rich foods.
  • Counsel patients taking iron supplements to avoid the following substances that reduce iron absorption: ^[1][13]
    • Food: e.g., tea, cereals, dairy products
    • Drugs: e.g., calcium, antacids, PPIs
• Infants < 1 year old: : Avoid cow's milk. ^[12]

Iron therapy

Oral supplementation is effective and inexpensive, however, adherence is often poor due to side effects. Parenteral iron therapy is beneficial in select cases.

Ganzoni formula

• Definition: a formula used to calculate the total iron deficit in patients with iron deficiency anemia
• Formula: total iron deficit in mg = subject weight in kg x (target hemoglobin in g/dL - current hemoglobin in g/dL) x 2.4 + iron stores in mg

Blood transfusion ^[23][24]

See “Transfusion” for further information.

• Consider pRBCs in:
  • Hemodynamically unstable patients with anemia
  • Severe anemia (Hb ≤ 7 g/dL)
  • Select patients with Hb ≤ 8 g/dL
• Avoid pRBCs in: hemodynamically stable patients with mild or moderate IDA.

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][25]

The differential diagnoses listed here are not exhaustive.

Screening ^[26][27][28]

• Universal screening is generally not recommended in adults
• The American Academy of Pediatrics (AAP) recommends one-time laboratory screening (Hb level) in all infants at the age of 9–12 months
• All infants and children between 4–36 months should be clinically assessed for risk factors of iron deficiency at every well child examination, followed by annual assessments thereafter.
• Selective screening (Hb level) in individuals who are at increased risk of iron deficiency
  • Children with at least one of the following risk factors:
    • History of prematurity and/or low birth weight
    • Exclusive breastfeeding > 4–6 months of age
    • A diet of nonfortified formula or cow milk in infants < 12 months
    • Consumption of > 24 oz milk per day or insufficient intake of iron-fortified cereal or meat in infants > 12 months
    • Low socioeconomic status
  • Adolescent girls and nonpregnant women with heavy menstrual bleeding
  • Pregnant women

Recommendations for breastfed infants ^[26]

• Preterm breastfed infants should receive 2mg/kg per day supplemental iron for the first 12 months of life.
• Term breastfed children > 6 months should receive dietary iron (e.g., fortified cereal) or oral iron 1mg/kg per day.

Iron deficiency anemia in pregnancy

• Definition ^[29]
  • First trimester: hemoglobin level < 11 g/dL
  • Second trimester: hemoglobin level < 10.5 g/dL
  • Third trimester: hemoglobin level < 11 g/dL
• Epidemiology
  • > 40% of pregnant women have an iron deficiency. ^[30]
  • Second most common type of anemia in pregnant women (after physiologic anemia)
• Etiology
  • Increased fetal iron requirements for RBC production and fetoplacental growth
  • Increased maternal total blood volume
• Diagnostics
  • CBC (± blood smear) to assess Hb and Hct
  • If anemia is present: iron studies (ferritin level and transferrin saturation)
  • Testing should be repeated at 24–28 weeks
    • Initial iron studies normal: CBC, reticulocyte count
    • Initial iron studies abnormal: CBC, reticulocyte count, and ferritin levels
• Treatment
  • Oral or IV iron supplementation (see “Treatment” above) ^[31][32]
    • Assess response to iron supplementation after 2–3 weeks.
    • If anemia persists: assess for lack of response to iron, inability to properly absorb iron, or decreased adherence to treatment due to side effects
  • Transfusion: in severe anemia or severe symptoms
• Complications
  • Increased risk of adverse maternal/fetal outcomes (e.g., low birth weight, neonatal anemia, premature labor)
  • Impaired fetal neurodevelopment
• Prevention: Supplementation of iron with prenatal vitamins and folic acid is recommended in all pregnant women. ^[33]