Anemia, Iron Deficiency

Essentials of Diagnosis

• Iron deficiency is present if serum ferritin is < 12 ng/mL or < 30 ng/mL if also anemic

• In adults, caused by bleeding unless proved otherwise

• Responds to iron therapy

General Considerations

• Most common cause of anemia worldwide

• Causes

  • Blood loss (gastrointestinal [GI], menstrual, repeated blood donation)

  • Deficient diet

  • Decreased absorption of iron

  • Increased requirements (pregnancy, lactation)

  • Celiac disease (gluten enteropathy)

  • Hemoglobinuria

  • Iron sequestration (pulmonary hemosiderosis)

• Women with heavy menstrual losses may require more iron than can reasonably be absorbed; thus, they often become iron deficient

• Pregnancy and lactation also increase requirement for iron, necessitating medicinal iron supplementation

• Long-term aspirin use may cause blood loss even without documented structural lesion

• Search for a source of GI bleeding if other sites of blood loss (menorrhagia, other uterine bleeding, and repeated blood donations) are excluded

• Hereditary iron-refractory iron deficiency anemia

  • Rare autosomal recessive disorder

  • Defined as hemoglobin increment of < 1 g/dL (10 g/L) after 4–6 weeks of 100 mg/day of elemental oral iron

Demographics

• More common in women as a result of menstrual losses

Symptoms and Signs

• Easy fatigability

• Dyspnea

• Palpitations and tachypnea on exertion

• In severe iron deficiency

  • Skin and mucosal changes (eg, smooth tongue, brittle nails, spooning of nails [koilonychia], and cheilosis) may develop

  • Dysphagia may occur from esophageal webs (Plummer-Vinson syndrome)

• Pica (ie, craving for specific foods [eg, ice chips, lettuce] often not rich in iron) is common

Differential Diagnosis

• Microcytic anemia resulting from other causes

  • Thalassemia

  • Anemia of chronic disease

  • Sideroblastic anemia

  • Lead poisoning

Laboratory Tests

• Diagnosis can be made by

  • Laboratory confirmation of an iron-deficient state

  • Evaluation of response to a therapeutic trial of iron replacement

• The reticulocyte count is low or inappropriately normal

• A serum ferritin value < 12 mcg/L is a highly reliable indicator of reduced iron stores

• However, because serum ferritin levels may rise in response to inflammation or other stimuli, a normal ferritin level does not exclude a diagnosis of iron deficiency

• A ferritin level of < 30 ng/mL almost always indicates iron deficiency in anyone who is anemic

• As iron deficiency progresses, serum iron values decline to < 30 mcg/dL and transferrin levels rise to compensate, leading to transferrin saturations of < 15%

• As deficiency progresses, anisocytosis (variation in red blood cell [RBC] size) and poikilocytosis (variation in RBC shape) develop

• Abnormal peripheral blood smear: severely hypochromic RBCs, target cells, pencil-shaped or cigar-shaped cells in severe iron deficiency; platelet count is commonly increased, but it usually remains < 800,000/mcL

• Bone marrow biopsy for evaluation of iron stores

  • Rarely performed

  • If done, Prussian blue staining shows the absence of iron in erythroid progenitor cells

• As the MCV falls (ie, microcytosis), the blood smear shows hypochromic microcytic RBCs

• Low hepcidin level is found in isolated iron deficiency anemia; however, this test is not yet clinically available

Medications

• Ferrous sulfate, 325 mg orally once daily or every other day

  • Taken on an empty stomach is standard approach

  • Nausea and constipation limit patient compliance

  • Extended-release ferrous sulfate with mucoprotease is a well-tolerated oral preparation

• Taking ferrous sulfate with food reduces side effects but also its absorption

• Continue iron therapy for 3–6 months after restoration of normal hematologic values to replenish marrow iron stores

• Ferric pyrophosphate citrate (Triferic)

  • An additive to the dialysate designed to replace the 5–7 mg of iron that patients with chronic kidney disease tend to lose during each hemodialysis

  • Delivers sufficient iron to the marrow to maintain hemoglobin and not increase iron stores

  • May obviate the need for intravenous iron in hemodialysis patients

• Failure of response to iron therapy

  • Usually due to noncompliance

  • Occasional patients absorb iron poorly

  • Other reasons include incorrect diagnosis (anemia of chronic disease, thalassemia), celiac disease, and ongoing blood loss

• Indications for parenteral iron

  • Intolerance of oral iron

  • Refractoriness to oral iron, including hereditary iron-refractory iron deficiency anemia

  • GI disease (usually inflammatory bowel disease) precluding use of oral iron

  • Continued blood loss that cannot be corrected

• Parenteral iron preparations coat the iron in protective carbohydrate shells or contain low-molecular weight iron dextran, are safe, and can be administered over 15–60 minutes

• The iron deficit is calculated by determining the decrement in RBC mass from normal recognizing there is 1 mg of iron in each milliliter of RBCs

  • Total body iron ranges between 2 g and 4 g: ~50 mg/kg in men and 35 mg/kg in women

Therapeutic Procedures

• Treat underlying cause (eg, source of GI bleeding)

• Treat Helicobacter pylori infection in appropriate cases (can improve oral iron absorption)

Follow-Up

• Recheck complete blood count to observe for response to iron replacement by return of hematocrit to halfway toward normal within 3 weeks and fully to baseline after 2 months

• Iron supplementation during pregnancy and lactation: iron is included in prenatal vitamins

When to Refer

• No response to oral iron therapy

• If suspected diagnosis is not confirmed