Iron Deficiency and Microcytic Hypochromic Anemia

Etiology

Because most of the body's iron is in RBCs, bleeding from any site can cause iron deficiency. Bleeding from the GI tract or menstruation is the most common cause of iron deficiency in developed countries, as a Western diet typically provides enough iron. Overt causes of bleeding, such as hematemesis, menorrhagia, multiple pregnancies, and childbirth, can easily be recognized based on history alone. Other causes, such as occult GI bleeding, malabsorption, and frequent blood donations, can be overlooked.[5][6]

Inadequate dietary intake is rare in developed nations. Dietary iron exists in 2 forms: heme iron, derived from animal sources and more efficiently absorbed, and nonheme iron, found in plant-based food. Most dietary iron is consumed in the nonheme form. Individuals from lower socioeconomic backgrounds, vegetarians or vegans, and older patients who do not eat a balanced diet are prone to developing iron deficiency. In toddlers, excessive milk or juice intake, prolonged bottle-feeding, and frequent snacking contribute to iron deficiency. A typical American diet contains about 10 to 20 mg of iron, of which only 1 to 2 mg is absorbed.[7][8] About 25 mg of iron per day is required for erythropoiesis, indicating that the majority of this requirement is supplied by macrophages in the spleen and liver, which recycle iron from senescent blood cells.[9]

GI sources of iron deficiency are common in developed countries. Etiologies of blood loss include inflammatory bowel disease, gastric or duodenal ulcers, gastroduodenal erosions, Mallory-Weiss tears, arteriovenous malformations, GI cancers, esophagitis, gastritis, varices, diverticuli, polyps, and hemorrhoids. GI bleeding can be classified into upper and lower sources and can be life-threatening. Gastroenterologists must be involved, and rarely, surgical involvement is necessary.[10][11][12][13] Please see StatPearls' companion resource, "Gastrointestinal Bleeding," for further information.

Malabsorption of iron can occur in celiac disease, atrophic gastritis, Helicobacter pylori infection, and bariatric surgery. Up to 14% of patients with inflammatory bowel disease and 46% of patients with celiac disease have iron deficiency anemia. Reduced iron absorption can also occur in association with dietary elements such as tannins, phosphates, phytates, oxalates, and calcium. Certain medications can interfere with iron absorption. Examples include gastric acid-suppressing drugs, antibiotics, levodopa, levothyroxine, and ibandronate.[14] In some low-resource countries, parasitic infections, including Stronglyloides, Schistosoma, and helminths, are significant contributors to iron deficiency.[15]

Iron deficiency also occurs in conditions such as chronic kidney disease (CKD), chronic heart failure, inflammatory bowel disease, certain malignancies, and rheumatoid arthritis. Please see StatPearls' companion resources, "Anemia" and "Anemia of Chronic Kidney Disease," for further reference.

Genetic Conditions

Genetic disorders affecting iron metabolism can also cause iron deficiency; these conditions can be part of a syndrome or single-gene abnormalities. Syndromes associated with chronic iron deficiency include ATR-X syndrome.[16] SLC11A2 mutations and iron-refractory iron deficiency anemia due to TMPRSS6 mutations are rare inherited conditions characterized by elevated hepcidin levels and iron deficiency. These conditions often do not respond to oral iron supplements and require intravenous (IV) iron.[17][18][19] Mutations in any of the enzymes involved in iron metabolism, such as divalent metal transporter 1 (DMT1), transferrin, and ceruloplasmin, can also cause iron deficiency.[20] Hereditary sideroblastic anemias are caused by various genetic defects, resulting in a functional lack of iron with high or normal iron reserves. Please see StatPearls' companion resource, "Sideroblastic Anemia," for further information.[18]

Iron Deficiency in Pregnancy

Pregnant patients require 500 to 1100 mg of additional iron during their pregnancy. These patients experience dilutional anemia from increased intravascular volume, and a normal hemoglobin level in a pregnant patient is less than 11 g/dL in the first trimester and less than 10 g/dL in the second and third trimesters. Erythrocyte mass should increase by about 25% to accommodate the increased volume (mediated by increased erythropoietin); inadequate iron stores can impair this response. 

Iron deficiency is the most common cause of anemia during pregnancy, occurring in up to 26% of pregnant patients, depending on the parameters measured. Iron deficiency is associated with increased adverse events and poorer perinatal and neonatal outcomes. A large study found increased rates of autism spectrum disorder, attention deficit hyperactivity syndrome, and intellectual disability in patients whose mother had anemia before 30 weeks of gestation. Other possible associations include severe maternal morbidity, postpartum hemorrhage, preeclampsia, placenta previa, and need for hospital admission.[6][21]

Thalassemias

Thalassemias are caused by genetic defects in globin chain synthesis, which disrupt normal hemoglobin production. Deficient alpha- or beta-globin synthesis results in an excess of the corresponding globin chain, which precipitates in erythroid precursors, leading to apoptosis and ineffective erythropoiesis.[22] Chronic anemia and hypoxia stimulate marrow hyperplasia and extramedullary hematopoiesis. Iron overload occurs from both increased absorption (due to suppressed hepcidin via erythroid signals such as erythroferrone) and repeated transfusions.[23] In addition, thalassemias damage red cell precursors and shorten RBC lifespan.[24]

The combination of defective globin synthesis, ineffective erythropoiesis, peripheral hemolysis, and iron overload distinguishes thalassemia pathophysiologically from pure iron deficiency, but mild thalassemia trait may present with mild microcytosis and normal iron parameters.[24][25][26] Please see StatPearls' companion resources, "Alpha Thalassemia" and "Beta Thalassemia."

Lead Poisoning

Chronic lead poisoning, though less common, can cause microcytic anemia, particularly in children and individuals in developing countries. Common sources of exposure include environmental lead, such as paint in older homes and contaminated water; occupational exposure; and ingestion of lead-containing herbs. Signs of lead poisoning include weakness, abdominal pain, and neurologic symptoms. Chronic lead poisoning can also cause microcytic anemia by interfering with enzymes involved in hemoglobin production, such as erythrocyte pyrimidine-specific 5'-nucleotidase and erythrocyte nucleotidase, resulting in microcytic hypochromic anemia and hemolytic anemia. Basophilic stippling in erythrocytes on Wright stain, caused by RNA clumping, is considered pathognomonic for chronic lead poisoning. Please see StatPearls' companion resource, "Lead Toxicity," for further information.[27][28][29]

Epidemiology

According to the Global Burden of Disease Study 2021, the disease-adjusted life years for iron deficiency increased between 1990 and 2021, with the highest burden observed in low socioeconomic areas.[30] According to the National Health and Nutrition Examination Survey, approximately 14% of adults in the United States have iron deficiency anemia.[6] The prevalence of iron deficiency among nonpregnant adults in the United States varies by the ferritin threshold. This prevalence is estimated at 5.9 million using a threshold of 15 ng/mL, but increases by 3.3 million when the threshold is changed to 45 ng/mL.[31]

In the United States, iron deficiency is observed in 9% of children aged 1 to 2. Compared to White children, Hispanic children are twice as likely to have an iron deficiency. The prevalence in adolescent girls and women in the reproductive age group is between 9% and 11%. Iron deficiency is most common in multiparous women from low-income minority populations. In males, it is observed in around 1% of the population, with a slightly higher prevalence of 2% to 4% in middle-aged and older men.[7][32] A positive correlation has also been observed between obesity and the risk of developing iron deficiency, likely due to increased hepcidin production by adipocytes.[6][15]

Alpha thalassemia traits are believed to be protective against malaria; in regions with high malaria incidence, the trait can be found in up to 90% of the population. Hemoglobin H disease is similar and found mostly in warm climates. The regions with the highest incidence are Southeast Asia, the Mediterranean, and the Middle East. Hemoglobin Constant Spring is the most common form of non-deletion alpha thalassemia. About 1% to 2% of individuals living in northeastern Thailand, 5% to 8% of those in southern China, and one-quarter of women in an ethnic minority population in Vietnam have Hemoglobin Constant Spring.[33][34]

The prevalence of beta thalassemia also parallels that of malaria as a proposed survival advantage for carriers of these genes. Gene drift and founder effects are other reasons why thalassemia is more frequent in certain areas.[35] The frequency of beta-thalassemia mutations varies across regions of the world, with the highest prevalence in the Mediterranean, the Middle East, and Southeast and Central Asia. Over 60,000 children are born with beta-thalassemia yearly; however, the true number is likely higher, given that many are born in countries with minimal health care. The prevalence of beta-thalassemia is estimated at 80 to 90 million carriers, representing approximately 1.5% of the global population.[36][37] In Cyprus, the reported carrier prevalence among Greek and Turkish populations is as high as 15%.[38]

Pathophysiology

Iron homeostasis is maintained by balancing absorption and iron losses. Dietary iron comes in 2 forms: heme iron, which is reduced (Fe²⁺) and is directly absorbed, and nonheme iron (Fe³⁺), which must be reduced before absorption. Absorption of both types occurs primarily in the proximal intestine, but through different receptors. Heme iron is absorbed through the heme carrier-1 protein, which is responsive to hypoxia.[9][39] The absorption of nonheme iron is more complex. The first nonheme iron is reduced in the duodenum by reductases such as cytochrome B (DCYTB). Nonheme iron is absorbed by enterocytes in the brush border as the divalent form via DMT1. Iron is then transported to the bloodstream by ferroportin-1 on the basolateral enterocytes. Ferroportin-1 works with the ferroxidase hephaestin, which oxidizes ferrous iron to facilitate its binding to transferrin. Hepcidin is an inhibitory protein synthesized by the liver that downregulates ferroportin and decreases iron absorption. Hepcidin levels are often increased in chronic disease and inflammatory states.[8][17][40][41]

Once absorbed, iron is sequestered in ferritin if body stores are adequate. Ferritin is a primarily intracellular protein—with small amounts circulating in the blood—located in the bone marrow, spleen, and liver, which is responsible for the storage and release of iron. Ferritin is also an acute-phase reactant, and its levels may be elevated in chronic disease, inflammatory states, and malignancy.[6][9][42] Iron is released through ferritin degradation, after which free iron is oxidized by ferroxidases such as ceruloplasmin. Iron then binds to the transferrin receptor and is transported to cells for metabolism.[9][41] Transferrin is also involved in iron recycling by transporting iron from reticuloendothelial cells and the liver to proliferating cells throughout the body. Transferrin is synthesized in the liver and, unlike ferritin, it is involved exclusively in iron metabolism. Transferrin synthesis is regulated by hypoxia and iron levels. Low iron levels upregulate iron-regulatory proteins 1 and 2, thereby optimizing cellular iron availability by increasing the expression of multiple genes.[43] Hypoxia induces hypoxia-inducible factor α and β, which increase transferrin expression.[9]

Iron deficiency occurs in 3 stages. In the prelatent stage, iron stores are low or absent, but serum iron concentration is normal. In the latent stage, transferrin saturation and serum iron are reduced, along with low ferritin. The last stage is marked by a drop in hemoglobin, depletion of iron stores, and reductions in serum iron and transferrin saturation.[44][45][44] Because hemoglobin levels decline only in the late stage, they are an insensitive marker of early iron deficiency and do not reliably reflect iron stores.[46]

Histopathology

On peripheral smear, hypochromia is evident as an enlarged central zone of pallor (>1/3 of the RBC diameter) and a thin hemoglobinized rim. Microcytosis is reflected by a reduced mean corpuscular volume (<80 fL in adults with iron deficiency). In iron deficiency anemia, anisopoikilocytosis is common; pencil cells (elongated elliptocytes) and target cells may be present, with elevated red cell distribution width supporting heterogeneous cell sizes. In iron deficiency anemia, bone marrow shows reduced to absent stainable iron on Perls (Prussian blue) staining of aspirate particles or macrophages; in severe deficiency, iron may be completely absent. These marrow iron assessments remain the gold standard for documenting depleted iron stores. However, they are invasive and are now often supplanted by ferritin-first algorithms (see Images Iron Deficiency Anemia and Normal Versus Iron Deficiency Anemia).[47][48]

In thalassemias, peripheral smear also shows microcytosis and hypochromia, but typically with more uniform microcytosis (often normal red cell distribution width), numerous target cells, and sometimes basophilic stippling; overall RBC count is often normal or high relative to the degree of anemia. Alpha thalassemia (hemoglobin H disease) features hemoglobin H inclusion bodies (β4 tetramers) detectable on brilliant cresyl blue (supravital) staining.[49] Beta-thalassemia shows marrow erythroid hyperplasia with ineffective erythropoiesis—expansion of early erythroid precursors with apoptosis of late forms—driven by globin chain imbalance (excess unpaired alpha-chains), oxidative stress, and downstream hepcidin suppression; chronic cases develop extramedullary hematopoiesis and iron overload from increased absorption or transfusion.[50] Marrow iron stores in thalassemia are normal to increased, unless coexisting iron deficiency is present.[51] Ring sideroblasts are not a feature of thalassemia per se; they indicate sideroblastic processes or myelodysplastic syndromes. However, Perls staining is routinely used in marrow evaluation to document iron distribution and, when indicated, exclude sideroblastic change.[52]

Lead poisoning also causes microcytic, hypochromic anemia. Hematologically, lead causes anemia by interfering with the function of several enzymes involved in heme synthesis and in maintaining erythrocyte membrane integrity, such as δ-aminolevulinic acid dehydratase, leading to decreased erythrocyte production and increased erythrocyte destruction.[53] Lead toxicity can also cause bone marrow suppression by inhibiting Wnt3a/β-catenin signaling.[54] The classic appearance of basophilic stippling is thought to represent clumps of degraded RNA, which is normally cleared by the enzyme pyrimidine-5’-nucleotidase, which is inhibited by lead.[55] Basophilic stippling can be observed in disordered erythropoiesis and erythrocyte maturation. Basophilic stippling is considered a pathognomonic finding in lead poisoning in conjunction with hypochromic microcytic anemia—though normocytic anemia may occur—and deposition of lead in the gingiva and joints.[56][57] Occasionally, circulating nucleated RBCs and mild poikilocytosis may be noted (see Image. Basophilic Stippling).[58]

History and Physical

Patients with iron deficiency can exhibit symptoms both in the presence and absence of anemia. The symptoms of iron deficiency without anemia are similar to those with anemia, but less severe. The majority of symptoms are nonspecific and can include, but are not limited to, generalized weakness, fatigue, poor concentration, mood changes, irritability, headaches, shortness of breath on exertion, dry mouth, hair loss, dysphagia, brittle fingernails, restless leg syndrome, and decreased exercise capacity. These symptoms are attributable to low oxygen delivery to tissues and reduced activity of iron-containing enzymes. Pallor is typically a late sign of iron deficiency anemia. Restless leg syndrome is associated with decreased brain iron on magnetic resonance imaging, and up to 40% of patients with this condition may have iron deficiency, with or without anemia.[6] 

Pica, a symptom of craving and consumption of non-nutritious and non-food substances, occurs in approximately half of patients with absolute iron deficiency. Pagophagia (craving for ice) is quite specific to iron deficiency.[6][59] Patients may have a history of dry mouth, hair loss, dysphagia, brittle fingernails, and restless leg syndrome.

The physical examination can be normal or may reveal dry skin, hair loss, atrophic glossitis, cheilosis, pallor, brittle nails, and koilonychia (spoon-shaped nails). Cardiac auscultation may reveal a systolic flow murmur. Pallor and pale conjunctivae are later signs of iron deficiency anemia (see Images Atrophic Glossitis: Atrophy of Filiform Taste Bud and Iron Deficiency: Spoon-Shaped Nail).[6][60]

Beeturia is a finding that is not specific to iron deficiency but is more common in individuals with iron deficiency. This condition results from a change in GI function caused by severe iron deficiency and is characterized by red discoloration of the urine after eating beets.[61] Please see StatPearls' companion resource, "Beeturia," "Alpha Thalassemia," "Beta Thalassemia," and "Lead Poisoning," for further information.

Evaluation

Evaluation for Iron Deficiency

The diagnosis of iron deficiency is based mainly on history, examination, and laboratory tests. In uncomplicated cases, serum iron, transferrin, serum ferritin, total iron-binding capacity, and transferrin saturation should be used for evaluation. Serum iron levels vary throughout the day and are influenced by diet. Iron indices should not be measured within 9 hours of consuming iron-containing foods.[6][44] Absolute iron deficiency is diagnosed when serum ferritin is less than 30 ng/mL or transferrin saturation is less than 20%. A ferritin level less than 30 ng/mL is 92% sensitive and 98% specific for absent bone marrow stores of iron. Transferrin saturation is calculated as (iron/total iron-binding capacity) × 100.[6][62][63] Healthy individuals generally have transferrin saturations of 25% to 35%. Hemoglobin does not drop until a significant percentage of body iron is depleted. Hence, normal hemoglobin does not exclude iron deficiency. Microcytosis is also not considered a sensitive indicator of iron deficiency.[6][46]

Other iron studies available for evaluating iron deficiency include the following.

• Soluble transferrin receptor and soluble transferrin receptor-ferritin index: Soluble transferrin receptor is elevated in iron deficiency because of the upregulation of transferrin receptors. Measurement of soluble transferrin receptor can help differentiate between absolute (increased soluble transferrin receptor) and functional iron deficiency (normal soluble transferrin receptor).[41][63][64]

• Zinc protoporphyrin/heme ratio: Decreased iron supply for the formation of hemoglobin leads to increased utilization of zinc and an increase in the zinc protoporphyrin/heme ratio; this test is preferable to the invasive bone marrow aspiration.[64]

• Reticulocyte hemoglobin content: This parameter provides an estimate of iron availability for RBC production over a few days before the test. Thus, it is a useful indicator of early iron deficiency, and sequential measurements can also help to guide response to parenteral iron therapy. Reticulocytosis (>2.5% reticulocytes) after iron repletion also suggests iron deficiency. Inflammation does not influence this parameter and is useful in determining iron status in patients with CKD.[64][65] 

Screening

The European Hematology Association recommends screening individuals at high risk for iron deficiency, including athletes, vegetarians, frequent blood donors, reproductive-aged women, adults older than 65, individuals with malabsorptive syndromes or bleeding disorders, socioeconomically disadvantaged populations, individuals with chronic parasitic infections, and those with chronic diseases. The International Federation of Gynecology and Obstetrics and the European Hematology Association recommend screening all pregnant and reproductive-aged women for iron deficiency. In contrast, the American College of Obstetricians and Gynecologists recommends screening only anemic patients for iron deficiency. The American Gastroenterology Association recommends screening all iron-deficient patients with upper GI symptoms, such as dyspepsia, epigastric pain, and nausea, for Helicobacter pylori infection and celiac disease. Some guidelines recommend screening all patients without a clear cause of iron deficiency with esophagogastroduodenoscopy and colonoscopy.[6] 

Evaluation for Thalassemias

When iron studies are normal or increased, thalassemia syndromes should be suspected.

• Complete blood count patterns: Thalassemia often shows a normal or elevated RBC count despite anemia, markedly reduced mean corpuscular volume (<70 fL), and normal red cell distribution width (in contrast to iron deficiency anemia).
• Peripheral smear: Shows target cells, basophilic stippling, and uniform microcytosis.
• Hemoglobin electrophoresis or high-performance liquid chromatography:
  • In beta-thalassemia trait, HbA2 is greater than 3.5%, and sometimes HbF elevation is diagnostic.
  • In alpha-thalassemia, electrophoresis may be normal; DNA analysis for alpha-globin gene deletions is required for confirmation.

• Ancillary markers: Reticulocyte hemoglobin content or zinc protoporphyrin can differentiate iron deficiency from thalassemia.[22][23]

If both conditions coexist, iron studies and hemoglobin electrophoresis results should be interpreted together.

Evaluation for Lead

Evaluation is primarily based on measurement of blood lead levels. Basophilic stippling on microscopy, along with symptoms of lead poisoning or microcytic hypochromic anemia, is pathognomonic for lead toxicity. 

Please see StatPearls' companion resources, "Alpha Thalassemia," "Beta Thalassemia," "Laboratory Evaluation of Alpha Thalassemia," "Evaluation of Beta Thalassemia," and "Lead Poisoning," for further information.

Treatment / Management

Iron Deficiency

Patients with uncomplicated iron deficiency without comorbidities should receive treatment with oral iron therapy. Oral iron is readily available, inexpensive, effective, safe, and convenient. Common ferric salts include ferrous sulfate (35 mg elemental iron), ferrous fumarate (100 mg elemental iron), and ferrous gluconate (35 mg elemental iron). These salts typically come in 325 mg tablets, of which only a small percentage (5%-20%) is absorbed.[6][41][66] Vitamin C (200-500 mg) is often recommended in combination with oral iron to enhance its absorption, as it reduces Fe³⁺ to Fe²⁺.[67] GI adverse effects often limit patient compliance. These adverse effects occur in up to 70% of patients taking oral iron, leading to treatment nonadherence. GI symptoms can be reduced with chelated iron.[62][64][68] Ferric complexes, including ferric polysaccharide, ferric polymaltose, and ferric polydextrose, are better tolerated than ferric salts. (B3)

Iron protein succinylate is comprised of iron bound to milk proteins; it is fairly well tolerated and highly effective, but is expensive. Ferric citrate is often used in patients with CKD or those undergoing dialysis because it also reduces phosphorus levels. Ferric maltol delivers iron to enterocytes while keeping the unabsorbed fraction chelated, therefore increasing tolerability in patients with irritable bowel disease. Sucrosomial iron and liposomal iron can be absorbed independently of DMT1 and may also be better tolerated than ferric salts in patients with irritable bowel disease. Carbonyl iron and heme iron polypeptides are also available as oral supplements, although data regarding their efficacy and safety remain limited.[66]

No meaningful clinical difference in hemoglobin has been found between daily and alternate-day oral iron dosing, but alternate-day dosing may improve tolerability and compliance. Enteric-coated and time-release formulations decrease iron absorption. The most robust response was observed with multiple daily doses, so therapy selection should be individualized based on the desired response and patient preference regarding adverse effects.[69] Treatment should continue until the ferritin, transferrin saturation, and hemoglobin are within normal ranges. Hemoglobin should increase by at least 1 g/dL within 2 to 4 weeks of starting oral iron. Expert guidelines recommend a 12-week course of oral iron/vitamin C supplementation in patients with restless leg syndrome who have transferrin saturation less than 45% or a ferritin level less than 75 ng/mL. In patients diagnosed with iron deficiency, hemoglobin should be monitored every 3 months for the first year, and then twice annually for the subsequent 2 years.[6][66](A1)

The recommended dietary allowance of iron for women of reproductive age is 18 mg/d, of which approximately 10% is absorbed. Notably, the average iron intake for women is 13 mg/d.[6] Red meat, liver, organ meats, sardines, and anchovies all contain high levels of bioavailable heme iron. However, most dietary iron comes from nonheme sources, including fortified grains and cereals, chickpeas, lentils, spinach, broccoli, and kale. As noted earlier, vitamin C and acidic environments facilitate iron absorption. Fiber, calcium, coffee, and tea decrease iron absorption. Please refer to the "Deterrence and Patient Education" section for more information on requirements by age/gender and dietary content of food.

Many patients cannot replete their iron stores with oral iron alone and require parenteral iron. This group includes patients with malabsorption, ongoing iron loss, irritable bowel syndrome, nonresponsiveness to oral iron, chronic disease, or those who are unable to tolerate oral supplementation. These patients should be treated with IV iron. IV iron is available in several forms, such as ferric carboxymaltose, ferric gluconate, ferric/iron sucrose, ferumoxytol, ferric derisomaltose, and low-molecular-weight iron dextran. No significant difference has been observed among the formulations; however, low-molecular-weight iron dextran, ferric carboxymaltose, ferric derisomaltose, and ferumoxytol allow single-infusion administration.[6][41]

There is a low risk of allergic reactions with all IV iron formulations. Anaphylaxis with IV iron is extremely rare, occurring with fewer than 1 in 200,000 administrations. High-molecular-weight dextran has been withdrawn due to a high frequency of serious anaphylactic reactions.[41] Complement activation–related pseudoallergy is the most common infusion reaction with IV iron. This reaction can occur at any time without prior sensitization and is not life-threatening. Most infusion reactions can be managed by stopping the infusion, hydration, and monitoring. Medications to consider if symptoms do not improve include IV steroids, 5-HT3 antagonists, and second-generation antihistamines.[70] Hypophosphatemia occurs with certain IV iron formulations and is observed within 2 weeks of administration. The highest incidence is observed with ferric carboxymaltose, and this agent should be avoided in patients prone to hypophosphatemia.[71](B3)

During pregnancy, oral iron supplementation is given in the first trimester, as the safety of IV iron in this period remains unestablished. According to the Centers for Disease Control and the American College of Obstetricians and Gynecologists, oral iron is given to all pregnant women who can tolerate it. One recommendation is to provide women with at least 27 mg of elemental iron during pregnancy and 9 mg during lactation. Exceptions include women with severe anemia, women with inflammatory bowel disease, and those who have undergone bariatric surgery. In these patients, IV iron is preferable. All IV forms have equal efficacy and safety except for some formulations of ferric gluconate, which utilize benzyl alcohol as a preservative and should be avoided because of the possibility of harm to the fetus.[72]

Testing should not be repeated within 4 weeks of IV Iron administration, as results can be misleading before then. Ferritin and transferrin saturation should be measured after 4 weeks, and iron supplementation should be given till both return to the normal range.[70] (B3)

Thalassemia Syndromes

Management of thalassemia requires a tailored approach based on transfusion dependence, iron overload, and ineffective erythropoiesis.

1. Transfusion support

• Transfusion-dependent thalassemia requires regular packed RBC transfusions to maintain pretransfusion hemoglobin levels around 9 to 10.5 g/dL, suppressing marrow expansion and improving growth and organ function.[22]

2. Iron chelation Therapy

• Chronic transfusion can cause secondary iron overload and warrant chelation when serum ferritin is greater than 1000 ng/mL or liver iron is greater than 3 mg/g dry weight.

• Chelating agents include:

  • Deferoxamine (parenteral)—gold standard for decades

  • Deferiprone (oral)—effective for cardiac iron

  • Deferasirox (oral)—convenient once-daily dosing

• Combination therapy (deferiprone + deferoxamine) offers superior cardiac protection.[73]

(B3)

 3. Stem cell transplant 

• Stem cell transplant (bone marrow transplant) is a potential option in selected cases, such as children born with severe thalassemia, potentially eliminating the need for lifelong blood transfusions.[74] 
(B2)

• However, this procedure has complications, and the clinician must weigh them against the benefits. Risks include graft-versus-host disease, chronic immunosuppressive therapy, graft failure, and transplantation-related mortality.[75]

4. Gene therapy

• Gene therapy is a recent advance in the management of severe thalassemia. The procedure involves harvesting the patient's autologous hematopoietic stem cells and genetically modifying them with vectors that express the normal genes. The cells are reinfused into patients after they have undergone the required conditioning to eliminate existing hematopoietic stem cells. The modified stem cells then produce normal hemoglobin chains, restoring effective erythropoiesis.

• Genome editing techniques: Another recent approach is the editing of genomic libraries using zinc-finger nucleases, transcription activator-like effectors, and clustered regularly interspaced short palindromic repeats (CRISPR) with the Cas9 nuclease system. These techniques target specific mutation sites and replace them with the normal sequence. The limitation of this technique is its inability to produce a sufficient number of corrected genes to cure the disease.[76]

5. Splenectomy

• Patients with thalassemia major often undergo splenectomy to limit the number of required transfusions. Splenectomy is the usual recommendation when the annual transfusion requirement exceeds 200 to 220 mL RBCs/kg/year, with a hematocrit of 70%.

• Splenectomy not only limits the number of required transfusions but also controls the spread of extramedullary hematopoiesis.

• Postsplenectomy immunizations are necessary to prevent bacterial infections, including Pneumococcus, Meningococcus, and Haemophilus influenzae. Postsplenectomy sepsis is possible in children, so this procedure is deferred until 6 to 7 years of age, and then penicillin is given for prophylaxis until they reach a certain age. 

6. Cholecystectomy 

• Patients may develop cholelithiasis due to increased hemoglobin (Hb) breakdown and bilirubin deposition in the gallbladder. If it becomes symptomatic, patients should undergo cholecystectomy at the same time as they undergo splenectomy.

7. Diet and exercise

• Reports indicate that drinking tea reduces iron absorption from the GI tract.

• Vitamin C helps in iron excretion from the gut, especially when used with deferoxamine. But using vitamin C in large quantities and without concomitant deferoxamine use, there is a higher risk for fatal arrhythmias. Therefore, the recommendation is to use low doses of vitamin C in combination with iron chelators (eg, deferoxamine).[76]

8. Emerging and adjunctive therapies

• Luspatercept, an erythroid maturation agent, reduces transfusion burden by improving late-stage erythropoiesis by decreasing transforming growth factor-beta activity. Luspatercept is Food and Drug Administration-approved for the treatment of anemia in patients with ß-thalassemia.[73]
(B3)

• Gene-editing therapies, such as CRISPR-Cas9–mediated correction of the beta-globin gene, are under evaluation to normalize erythropoiesis and minimize iron loading.[77]

Lead Toxicity

• Pediatric screening guidelines for lead vary by state because the prevalence of lead toxicity tends to be higher in older urban areas. However, the Early Periodic Screening, Diagnosis, and Treatment (EPSDT) component of Medicaid requires that all children enrolled in Medicaid receive screening at 12 and 24 months. Children aged 3 to 5 who have not previously been screened are also required to undergo testing.[78]
(A1)

• The Occupational Safety and Health Administration requires employers to implement medical surveillance, including lead screening, for any employee who may be exposed to airborne lead at concentrations exceeding 30 mg/min averaged over 8 hours for more than 30 days/year.[79] Screening is typically performed using capillary blood due to its convenience and speed; however, any elevated capillary result (over 5 mcg/dL) should be confirmed with a venous whole blood sample.
(B3)

• In patients with confirmed elevated whole blood venous lead levels, additional laboratory tests to assess iron status and anemia are recommended.

• An abdominal x-ray should be considered if the patient may have ingested a lead-containing foreign body, such as paint chips, a bullet, or a fishing weight.

• As with all patients in whom the toxin-mediated disease is suspected, the evaluation should include a detailed history and a thorough physical examination.

• In cases of lead exposure, a detailed exposure history should be obtained, focusing on occupation and hobbies (for adults, the patient; for children, parents or caregivers), home environment (e.g., age of the home, recent renovations or repairs), and food and water sources.[79][80]
(B3)

Differential Diagnosis

The differential diagnosis for iron deficiency without anemia is broad, as most symptoms are nonspecific and overlap with many other conditions. Potential causes include fatigue-related disorders such as fibromyalgia, chronic fatigue syndrome, depression or mood disorders, chronic medical conditions, and hypothyroidism. Other considerations include causes of pica, eating disorders, psychiatric conditions, malnutrition, causes of restless legs syndrome-like neurological conditions, and pregnancy. Causes of microcytosis in the absence of iron deficiency anemia include thalassemia; sideroblastic anemia; lead poisoning; copper deficiency; certain medications, such as isoniazid; and chloramphenicol.

Complications

Complications of iron deficiency and microcytic hypochromic anemia include the following:

• If untreated, iron deficiency is associated with significant cognitive impairment and poor quality of life.
• During pregnancy, untreated iron deficiency can affect fetal brain maturation, lead to low birth weight, and predispose the baby to iron deficiency. Maternal adverse outcomes include depression, increased risk of sepsis, and maternal mortality.[81][82]
• In patients undergoing cardiac or abdominal surgery, preoperative iron deficiency correlates with poor outcomes.[62] 
• In patients with heart failure, chronic iron deficiency shows an association with an increase in mortality. 
• Initially, iron repletion can transiently increase the risk of malaria or other infections in children in endemic areas.[66]
• If malignancy is the underlying cause of GI, uterine, or urinary bleeding, a diagnosis delay can lead to advanced disease and higher morbidity and mortality.