Iron deficiency anemia (IDA) refers to anemia caused by the iron depletion (ID) and iron deficiency erythropoiesis (IDE). Iron deficiency can be divided into three stages: ID, IDE, and IDA. IDA typically manifests as microcytic hypochromic anemia induced by iron deficiency, along with other abnormalities.
Based on etiology, IDA can be classified into several types: insufficient iron intake (e.g., inadequate complementary food for infants or picky eating habits in adolescents), increased iron demand (e.g., in pregnancy), malabsorption (e.g., gastrointestinal disorders), impaired iron transport (e.g., atransferrinemia, liver disease, chronic inflammation), excessive iron loss (e.g., heavy menstrual bleeding, hemorrhoidal bleeding, or other forms of blood loss), and impaired iron utilization (e.g., sideroblastic anemia, lead poisoning, anemia of chronic disease).
Epidemiology
IDA is the most common type of anemia. The World Health Organization (WHO) estimates that roughly 1/4 of the global population is anemic, with a significant concentration among preschool-aged children and women, and the majority of cases are due to iron deficiency. In 2016, there were over 120 million patients with IDA worldwide. The prevalence of IDA is notably higher in developing countries, economically disadvantaged regions, children, and women of reproductive age.
Iron Metabolism
Iron in the human body is divided into two main categories:
- Functional iron, which includes hemoglobin iron (accounting for 67% of total body iron), myoglobin iron (15% of body iron), transferrin-bound iron (3–4 mg), lactoferrin, and iron integrated into enzymes and cofactors.
- Stored iron, with amounts of approximately 1,000 mg in males and 300–400 mg in females, including ferritin and hemosiderin. The total iron content in a healthy adult male is about 50–55 mg/kg body weight, while in females, it is 35–40 mg/kg.
Under normal conditions, about 20–25 mg of iron is required daily for erythropoiesis, primarily derived from the breakdown of senescent red blood cells. Iron balance in the body is maintained by absorbing 1–1.5 mg of iron daily from dietary sources, while pregnant and breastfeeding women require 2–4 mg per day. Animal-based foods have a higher iron absorption rate (up to 20%) compared to plant-based foods (1%–7%).
Iron absorption primarily occurs in the duodenum and upper jejunum. Several factors influence iron absorption, including the oxidation state of dietary iron (ferric or ferrous), gastrointestinal function (e.g., pH balance), iron stores in the body, the erythropoietic activity of the bone marrow, and certain medications (e.g., vitamin C). Once absorbed, ferrous iron in the bloodstream is oxidized to ferric iron by ceruloplasmin and then binds to transferrin for transport to tissues. Through the transferrin receptor on erythroblast membranes, transferrin-bound iron enters cells, releases from transferrin, and is reduced back to ferrous iron to participate in hemoglobin synthesis.
Recent research has identified hepcidin, a hormone secreted by the liver, as the key negative regulatory factor for dietary iron absorption in the intestine and the release of iron from macrophages. Hepcidin expression is regulated by systemic iron status, inflammatory factors, bacterial infections, endotoxins (lipopolysaccharides), and cytokines.
Excess iron is stored as ferritin and hemosiderin within the mononuclear phagocyte systems of the liver, spleen, and bone marrow. These reserves are mobilized for use when iron demand increases. Under normal circumstances, daily iron loss does not exceed 1 mg and primarily occurs through desquamated intestinal mucosal cells in feces, with minor amounts excreted in urine and sweat. In lactating women, some iron is also lost through breast milk.
Etiology
Increased Iron Demand with Insufficient Iron Intake
This condition is common in infants, adolescents, pregnant women, and lactating women. Infants have a high iron requirement, and lack of iron-rich complementary foods such as eggs and meat may lead to iron deficiency. Picky eating habits in adolescents can result in insufficient iron intake. Women with heavy menstrual bleeding, during pregnancy, or while breastfeeding experience increased iron demand, and inadequate intake of iron-rich foods can easily lead to iron deficiency anemia (IDA).
Iron Malabsorption
Iron malabsorption is frequently observed after partial gastrectomy. Reduced gastric acid secretion and rapid food transit into the jejunum bypass the primary absorption site for iron (the duodenum), leading to reduced iron absorption. Additionally, gastrointestinal disorders of varying causes, such as chronic unexplained diarrhea, chronic enteritis, and Crohn's disease, can lead to IDA due to impaired iron absorption.
Excessive Iron Loss
Prolonged chronic iron loss that is not corrected can result in IDA. Common causes include chronic gastrointestinal bleeding (e.g., hemorrhoids, gastric and duodenal ulcers, hiatal hernia, gastrointestinal polyps, gastrointestinal tumors, parasitic infections, or ruptured esophageal and gastric varices), heavy menstrual bleeding (associated with intrauterine devices, uterine fibroids, or menstrual irregularities), hemoptysis, and alveolar hemorrhage (as seen in pulmonary hemosiderosis, Goodpasture syndrome, tuberculosis, bronchiectasis, or lung cancer). Other causes include hemoglobinuria (e.g., paroxysmal nocturnal hemoglobinuria, cold antibody-mediated autoimmune hemolysis, mechanical heart valves, or exercise-induced hemoglobinuria) and conditions such as hereditary hemorrhagic telangiectasia, chronic kidney disease with hemodialysis, or frequent blood donations.
Pathogenesis
Effects of Iron Deficiency on Iron Metabolism
When stored iron levels decrease to the point where they are insufficient to support functional iron needs, abnormal iron metabolism indices are observed. These include reductions in storage iron markers (e.g., ferritin and hemosiderin), decreases in serum iron levels and transferrin saturation, and increases in total iron-binding capacity and unsaturated transferrin levels. Transferrin receptors are expressed on the surfaces of erythroid precursor cells in the bone marrow, and their expression is closely related to the metabolism of iron required for hemoglobin synthesis. When intracellular iron is deficient, transferrin receptors are shed into the bloodstream, forming soluble transferrin receptors (sTfR).
Effects of Iron Deficiency on the Hematopoietic System
Iron deficiency within erythrocytes impairs heme synthesis. Protoporphyrin, unable to bind with iron to form heme, accumulates in red blood cells as free erythrocyte protoporphyrin (FEP) or binds to zinc to form zinc protoporphyrin (ZPP). This leads to reduced hemoglobin production, resulting in red blood cells with less cytoplasm and smaller volumes, characteristic of microcytic hypochromic anemia. In severe cases, granulocyte and platelet production may also be affected.
Effects of Iron Deficiency on Tissue and Cell Metabolism
Tissue iron deficiency reduces the activity of iron-containing and iron-dependent enzymes, affecting patients' mental health, behavior, physical endurance, immune function, and, in children, growth and intellectual development. Iron deficiency can also lead to mucosal tissue pathology and ectodermal tissue nutritional disorders.
Clinical Manifestations
Symptoms of the Underlying Cause of Iron Deficiency
Manifestations include melena, hematochezia, or abdominal discomfort caused by peptic ulcers, tumors, or hemorrhoids; abdominal pain or altered stool characteristics resulting from intestinal parasitic infections; heavy menstrual bleeding; weight loss caused by neoplastic diseases; and hemoglobinuria in cases of intravascular hemolysis.
Symptoms of Anemia
Common symptoms include fatigue, easy fatigability, dizziness, headache, blurred vision, tinnitus, palpitations, shortness of breath, and anorexia. Physical findings include pale skin and mucosa, along with an increased heart rate.
Symptoms of Iron Deficiency in Tissues
Patients may exhibit abnormal mental and behavioral states, such as irritability, anxiety, poor concentration, and pica (craving non-food items). Physical endurance and energy levels may decline, and susceptibility to infections may increase. Children may experience delayed growth and development, as well as intellectual impairment. Other manifestations include stomatitis, glossitis, atrophy of lingual papillae, angular cheilitis, dysphagia, brittle or thinning hair, dry and wrinkled skin, and dry, fragile, or cracked nails. Severe cases may present with flattened or concave nails, referred to as koilonychia (spoon nails).
Laboratory Tests
Peripheral Blood Examination
Findings often indicate microcytic hypochromic anemia. Mean corpuscular volume (MCV) is below 80 fl, mean corpuscular hemoglobin (MCH) is less than 27 pg, and mean corpuscular hemoglobin concentration (MCHC) is less than 320 g/L. Peripheral blood smear shows small red blood cells with an enlarged central pallor area. Reticulocyte counts are typically normal or slightly elevated. White blood cell and platelet counts may be normal or decreased, although platelet count can also be elevated in some patients.
Bone Marrow Examination
Bone marrow typically shows active or markedly active proliferation, predominantly involving the erythroid lineage. No significant abnormalities are usually found in granulocyte or megakaryocyte lineages. Erythroid precursors mainly consist of intermediate and late-stage normoblasts that appear small, with dense nuclear chromatin, scant cytoplasm, irregular cell borders, and features of defective hemoglobin production, known as the "nuclear maturity lagging behind cytoplasmic immaturity" phenomenon.
Iron Metabolism Tests
Serum iron falls below 8.95 μmol/L, total iron-binding capacity (TIBC) is elevated above 64.44 μmol/L, and transferrin saturation is reduced to below 15%. The concentration of soluble transferrin receptor (sTfR) exceeds 8 mg/L. Serum ferritin levels are reduced, typically below 12 μg/L. Bone marrow aspirates stained with potassium ferrocyanide (Prussian blue stain) reveal the absence of hemosiderin-containing particles in marrow macrophages and iron-depleted erythroblasts, with sideroblasts comprising less than 15%.
Erythrocyte Porphyrin Metabolism Tests
Free erythrocyte protoporphyrin (FEP) exceeds 0.9 μmol/L (whole blood), zinc protoporphyrin (ZPP) exceeds 0.96 μmol/L (whole blood), and the FEP/Hb ratio exceeds 4.5 μg/g Hb.
Serum Transferrin Receptor Testing
Measurement of soluble transferrin receptor (sTfR) in serum is considered the best indicator of iron-deficient erythropoiesis. An sTfR concentration greater than 26.5 nmol/L (2.25 μg/ml) generally supports the diagnosis of iron deficiency.
Diagnosis
The diagnostic criteria of ID include:
- Serum ferritin <12 μg/L
- Bone marrow iron staining shows the absence of stainable iron in macrophages and a reduction of sideroblasts to less than 15%
- Hemoglobin levels and serum iron remain within normal ranges
The diagnostic criteria of IDE include:
- Serum ferritin <12 μg/L
- Bone marrow iron staining shows the absence of stainable iron in macrophages and a reduction of sideroblasts to less than 15%
- Transferrin saturation <15%
- FEP/Hb >4.5 μg/g Hb
- Hemoglobin levels remain normal
The diagnostic criteria of IDA include:
- Serum ferritin <12 μg/L
- Bone marrow iron staining shows the absence of stainable iron in macrophages and a reduction of sideroblasts to less than 15%
- Transferrin saturation <15%
- FEP/Hb >4.5 μg/g Hb
- Microcytic hypochromic anemia: Hemoglobin levels <120 g/L in men, <110 g/L in women, <100 g/L in pregnant women; MCV <80 fl, MCH <27 pg, MCHC <320 g/L
Etiological Diagnosis
Identifying the underlying cause is crucial for curative treatment of IDA. In some cases, the etiology of iron deficiency may be more severe than the anemia itself. For example, chronic blood loss associated with gastrointestinal malignancies or IDA resulting from gastric cancer recurrence after gastrectomy may require repeated fecal occult blood testing and, if necessary, gastrointestinal X-ray or endoscopic examinations. Women with heavy menstrual bleeding should undergo evaluation for potential gynecological conditions.
Differential Diagnosis
Differentiation is necessary to exclude the following microcytic anemias:
Sideroblastic Anemia
This condition involves impaired utilization of iron in red blood cells, either due to genetic causes or unknown mechanisms. Laboratory findings include microcytic anemia, elevated serum ferritin concentrations, increased hemosiderin-laden macrophages in the bone marrow, increased sideroblasts, and ringed sideroblasts. Serum iron and transferrin saturation are elevated, while total iron-binding capacity is not reduced.
Thalassemia
This inherited hemoglobinopathy is associated with abnormal globin chain synthesis and often presents with a family history and hemolytic features. Peripheral blood smear typically shows a significant number of target cells. Laboratory evidence includes abnormal globin chain synthesis, such as elevated fetal hemoglobin or hemoglobin A2, and the presence of hemoglobin H inclusions. Serum ferritin, bone marrow iron stores, serum iron, and transferrin saturation are usually not decreased and are often elevated.
Anemia of Chronic Disease (ACD)
This condition arises from disordered iron metabolism due to chronic inflammation, infection, or malignancies. The anemia is typically microcytic. Iron stores (serum ferritin and hemosiderin in marrow macrophages) are increased, while serum iron, transferrin saturation, and total iron-binding capacity are reduced.
Atransferrinemia
This autosomal recessive disorder (congenital) or acquired condition secondary to severe liver disease or malignancy is characterized by microcytic hypochromic anemia. Markedly reduced levels of serum iron, total iron-binding capacity, serum ferritin, and bone marrow hemosiderin are observed. Congenital cases manifest in infancy with growth retardation and multi-organ involvement, while acquired cases exhibit symptoms related to the primary disease.
Treatment
The principles for treating iron deficiency anemia (IDA) involve addressing the underlying cause and replenishing iron stores.
Treatment of the Underlying Cause
It is essential to identify the causes of ID/IDA. For adolescents, women of reproductive age, pregnant women, and lactating women with IDA caused by insufficient iron intake, dietary improvements may be needed, with the addition of iron-rich and easily absorbed foods such as lean meat and animal liver. Women of reproductive age may benefit from prophylactic iron supplementation with elemental iron on a daily or alternate-day basis. IDA resulting from menorrhagia requires investigation into the underlying cause of the excessive menstrual bleeding. Patients with parasitic infections may require antiparasitic treatment. Patients with malignant tumors may be treated with surgery, radiotherapy, or chemotherapy. Peptic ulcer patients may benefit from treatments to reduce stomach acid and protect the gastric lining.
Iron Supplementation Therapy
Therapeutic iron compounds are classified into two types: inorganic and organic iron. Inorganic iron, such as ferrous sulfate, is commonly used, while organic iron includes compounds like iron dextran, ferrous gluconate, ferric sorbitol, ferrous fumarate, ferrous succinate, and polysaccharide-iron complexes. Adverse effects associated with inorganic iron tend to be more pronounced than those with organic iron. Oral iron formulations are the preferred option. For example, ferrous sulfate may be administered at 0.3 g three times daily, or iron dextran at 50 mg two to three times daily. Administering iron supplements after meals can reduce gastrointestinal side effects and improve tolerability.
Dietary factors can influence the absorption of iron supplements. Iron absorption may be inhibited by foods like cereals, dairy products, and tea, while it can be enhanced by fish, meat, and vitamin C. Indicators of effective oral iron supplementation include an initial increase in reticulocyte count, peaking 5–10 days after starting the medication, followed by a rise in hemoglobin concentration within 2 weeks, with hemoglobin levels typically returning to normal within approximately 2 months. Iron supplementation should continue for at least 4–6 months after hemoglobin normalization, until ferritin levels normalize. If oral iron is not tolerated or gastrointestinal anatomy alterations interfere with iron absorption, intramuscular or intravenous iron administration may be considered. Iron dextran is one of the most commonly used injectable iron formulations. It is recommended to administer a test dose of 0.5 ml initially. If no allergic reactions occur within one hour, the full therapeutic dose may be given. The total required dose of injectable iron can be calculated using the following formula: (Target hemoglobin concentration - Patient's hemoglobin concentration) (g/L) × 0.33 × Patient's weight (kg).
Prognosis
Patients with IDA primarily caused by nutritional deficiencies typically achieve recovery. Prognosis for those with secondary IDA depends on the treatability of the underlying condition.
Prevention
Preventative efforts focus on nutrition and health care for infants, adolescents, and women. Infants may benefit from the early introduction of iron-rich foods such as eggs and liver. For adolescents, correcting unhealthy eating habits and regularly screening for and treating parasitic infections may be important. Pregnant and lactating women may require iron supplementation. Preventing and managing menorrhagia is crucial for women of menstrual age. Preventive strategies can also extend to managing populations at risk for neoplastic diseases and chronic hemorrhagic conditions.