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Iron deficiency anemia

Last updated: October 27, 2021

Summary

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.

Epidemiology

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.

Etiology

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

Pathophysiology

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.”

Clinical features

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.

Esophageal web Angular cheilitis Koilonychia

References:^[2]^[11]

Diagnostics

Approach

Evaluation of suspected iron deficiency anemia

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]

Iron deficiency anemia

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]

Evaluation for underlying causes of iron deficiency ^[12]^[18]
Suspected etiology	Indications	Studies
Gastrointestinal pathologies	All men Nonmenstruating women Menstruating women without: Symptoms Identifiable gynecological etiology History or signs of bleeding (e.g., melena, epigastric pain, hematochezia) Signs of malabsorption Risk of GI malignancy ^[18] Age > 50 years History of polyps or inflammatory bowel disease	All patients: colonoscopy with EGD Consider celiac serology. Normal endoscopy or endoscopy declined Helicobacter pylori (urea breath test) Select patients Video capsule endoscopy Fecal occult blood/fecal immunochemical test
Gastrointestinal pathologies	Origin from or recent travel to resource-limited subtropical or tropical area Eosinophilia on CBC	Examination of stool for ova and parasites (see “Hookworm infections”) ^[20]
Gynecological pathologies	Menstruating women with abnormal uterine bleeding	Gynecologic workup for menorrhagia See “Diagnostics” in “Abnormal uterine bleeding” for more information.
Renal pathologies	Hematuria Clinical features of nephrotic syndrome	Urinalysis Renal and urinary tract ultrasound See “Diagnostics” in “Nephrotic syndrome” for more information.
Pulmonary pathologies	Hemoptysis Ongoing productive cough	Iron-staining of sputum sample Chest imaging as appropriate

Treatment

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.

Iron therapy for iron deficiency anemia
	Oral iron therapy	Parenteral iron therapy ^[1]^[13]
Indications	Indicated in all patients with IDA (if tolerated)	Oral iron therapy intolerance, nonadherence, or contraindications ^[4] Intestinal malabsorption Patients who decline indicated blood transfusions Chronic bleeding refractory to oral therapy Renal anemia, together with EPO treatment ^[1]^[21]
Agents	Ferrous sulfate Ferrous fumarate Ferrous gluconate	Ferric preparations Iron dextran Iron sucrose Others: ferrous gluconate, ferumoxytol
Dosage ^[13]	Adults: typically the equivalent of 100–200 mg elemental iron daily ^[13]^[18] Children: 3–6 mg/kg per day in a liquid preparation ^[1]^[4] Available forms (ferrous preparations) Ferrous sulfate ^[13] Ferrous fumarate ^[13] Ferrous gluconate ^[13] Absorption may be enhanced by simultaneous consumption of vitamin C (e.g., in orange juice).	Determine iron deficit using the Ganzoni formula. ^[13] Choose a replacement preparation. Administer in one or several sittings until calculated iron deficit is replaced. ^[13] Iron dextran Iron sucrose Ferrous gluconate Ferumoxytol
Adverse effects ^[1]^[22]	Gastrointestinal discomfort, nausea, constipation, black discoloration of stool	Thrombophlebitis Myalgia, arthralgia, and headaches within 1–2 days of infusion Rare: anaphylaxis (typically from iron dextran)
Duration	Should initially be administered for 3–6 months or three months after correction of anemia in order to build iron stores ^[1]^[4]	Depends on the iron deficit and chosen IV preparation
Monitoring ^[1]	Check CBC monthly until in normal range, then every three months for one year, then once again after another year. Adequate response: After one month, hemoglobin should have increased by ≥ 1 g/dL.

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.

Differential diagnoses

Diagnosis of anemia

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.

	Iron deficiency anemia	Anemia of chronic disease
Ferritin	↓	Normal to ↑
Iron	↓	normal to ↓
Transferrin/TIBC	↑	Slightly ↓
Transferrin saturation	↓	Normal to slightly ↓
RDW	↑	normal
Soluble transferrin receptor (sTfR)	↑	normal

References:^[2]^[25]

The differential diagnoses listed here are not exhaustive.

Prevention

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.

Special patient groups