Iron deficiency

What every physician needs to know about iron deficiency:

Iron deficiency is a decrease in total body iron that can be considered to have three successive stages of severity. On average, an iron-replete adult has storage iron reserves that correspond to the amount of iron in a single unit of red blood cells (about 200 to 250mg) in a woman and to the amount of iron in three to four units in a man (about 750 to 1,000mg).

This storage iron is mobilized when iron requirements exceed iron supply. Storage iron depletion describes a decrease in storage iron without effects on hemoglobin or on functional iron compounds in other tissues. An additional decrease in body iron produces iron deficiency without anemia, the stage where lack of iron limits the production of hemoglobin and other iron-requiring metabolites, but before the standards used to distinguish normal from anemic states detect the effect on red-cell production. Finally, further decreases in body iron produce frank iron-deficiency anemia.

Iron deficiency is the most common cause of anemia in the United States and worldwide. Anemia is often the first sign of iron deficiency, but is neither a sensitive or specific indicator, especially in patients with coexisting infectious, inflammatory, or malignant disorders and in those treated with erythropoiesis stimulating agents. Additional laboratory studies are almost always required to establish the diagnosis of iron deficiency.

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In the evaluation of patients with iron deficiency, the most important tasks are to identify and to treat the underlying cause of the decrease in body iron. In the majority of patients, the history, physical examination, screening laboratory studies, and review of the peripheral blood smear will suggest the basis for the decrease in body iron.

In men and post-menopausal women, pathological blood loss is by far the most common cause of iron deficiency. In women of child-bearing age, menstrual blood loss adds to iron requirements and each pregnancy occasions iron donation to the fetus. In committed blood donors, iron losses with repeated donation may produce iron deficiency. In infants, children, and adolescents, iron deficiency develops when iron requirements for growth surpass the supply from stores and diet. Iron deficiency is infrequently caused by impaired absorption of iron alone and is rarely the result of genetic disorders.

Correction of iron deficiency is seldom urgent and almost always best begun after the underlying cause has been identified. Iron should be administered only with great caution in the presence of active infection or inflammation, and preferably after their resolution. Oral iron remains the preferred treatment with parenteral preparations reserved for special subsets of patients.

What features of the presentation will guide me toward possible causes and next treatment steps:

The presentation of patients with iron deficiency may have no signs or symptoms or may have features common to all anemias, such as pallor, palpitations, tinnitus, headache, irritability, weakness, dizziness, easy fatigability, and other vague and nonspecific complaints. Both the degree and rate of development of iron deficiency anemia influence the presentation. Because iron deficiency often develops slowly, circulatory and respiratory adaptations may minimize the signs and symptoms, occasionally with remarkable tolerance of severe anemia. Nonetheless, severe iron deficiency anemia can produce cardiorespiratory failure and may need urgent management.

Manifestations of the underlying cause of iron deficiency, such as a source of blood loss, may be evident and help guide further evaluation.

Uncommonly, signs and symptoms thought to be relatively specific for iron deficiency, such as pagophagia, koilonychia, and blue sclerae are present.

Iron deficiency may also produce signs and symptoms independent of anemia, especially in epithelial tissues that have a high iron requirement because of rapid turnover. Glossitis, angular stomatitis, postcricoid esophageal web or stricture (which may become malignant), and gastric atrophy may develop. The combination of glossitis, a sore or burning mouth, dysphagia, and iron deficiency is called the Plummer-Vinson or Paterson-Kelly syndrome.

Other non-hematologic manifestations of iron deficiency include diminished immunity and resistance to infection, decreased physical endurance and work capacity, and impairments in attention, concentration, and other cognitive functions, along with a variety of behavioral and neuropsychological abnormalities, especially in infants and children.

What laboratory studies should you order to diagnosis iron deficiency and how should you interpret the results?

Uncomplicated iron deficiency produces a characteristic sequence of changes in readily available laboratory studies. After iron stores are exhausted, the plasma iron level falls, the total iron-binding capacity (a measure of the plasma transferrin concentration) rises, and the transferrin saturation (the ratio of the plasma iron to total iron-binding capacity) decreases to less than 16%. The supply of iron to developing erythroid cells becomes insufficient, resulting in iron-restricted erythropoiesis.

With reduction of the amount of iron available for heme synthesis, the erythrocyte zinc protoporphyrin level progressively increases. The reticulocyte hemoglobin content (CHr, measured by some automated hematology analyzers) decreases, and the reticulocyte count falls. In the peripheral blood smear, experienced observers can detect the appearance of hypochromic, microcytic erythrocytes whose proportion increases with the duration and severity of iron-restricted erythropoiesis. Automated hematology analyzers detect decreases in the mean corpuscular volume and, in some instruments, increases in the proportion of hypochromic cells. Eventually, the hemoglobin concentration and hematocrit fall.

The rate and degree of change in erythrocyte morphology and red cell indices is governed by the time needed to replace the normal population of normocytic, normochromic cells, and the degree of disparity between erythroid iron requirements and iron supply.

None of these laboratory measures is diagnostic of iron deficiency. The characteristic sequence of laboratory changes in iron-restricted erythropoiesis can result not only from iron deficiency but also from many other disorders that impair iron delivery to the erythroid marrow. Infectious, inflammatory, malignant and, rarely, genetic disorders can produce hypoferremia and constrain the provision of iron to the developing red cell (see below). Moreover, many of the conditions producing iron-restricted erythropoiesis also can coexist with iron deficiency.

Two further laboratory studies may provide more specific diagnostic information. To detect the absence of storage iron, the defining feature of iron deficiency, measurement of the serum (or plasma) ferritin may be helpful. Ferritin is the principal storage protein for intracellular iron but small amounts of ferritin are also secreted into plasma. Although the function is still uncertain, the amount of ferritin synthesized and secreted into the plasma seems to be proportional to the magnitude of body iron stores. Plasma ferritin concentrations decline with storage iron depletion.

Diagnostic interpretation of serum ferritin concentrations is often complicated by conditions that increase serum ferritin independently of body iron stores. Serum ferritin is an acute-phase reactant that is increased in infectious, inflammatory, and malignant disorders. Liver disease may also release tissue ferritins from damaged hepatocytes. Thus, while a low serum ferritin (less than 12 microg/L) is virtually diagnostic of absent iron stores, a serum ferritin within, or above, the reference range does not exclude iron deficiency.

For evidence of tissue iron deficiency, measurement of the serum transferrin receptor concentration may be helpful. The soluble transferrin receptor is a truncated form of the tissue transferrin receptor. Normally, about 80% of plasma transferrin receptors are derived from the erythroid marrow, and their concentration is determined primarily by erythroid marrow activity. Decreased levels of circulating soluble transferrin receptor are found in patients with erythroid hypoplasia (aplastic anemia, chronic renal failure), while increased levels are present in patients with erythroid hyperplasia (thalassemia major, sickle cell anemia, anemia with ineffective erythropoiesis, chronic hemolytic anemia). Iron deficiency increases soluble transferrin receptor concentrations. The plasma transferrin receptor concentration reflects the total body mass of tissue receptor; thus, in the absence of other conditions causing erythroid hyperplasia, an increase in plasma transferrin receptor concentration provides a sensitive, quantitative measure of tissue iron deficiency.

In particular, measurement of plasma transferrin receptor concentration may help differentiate between the anemia of iron deficiency and the anemia associated with chronic inflammatory disorders. Although the plasma ferritin concentration may be disproportionately elevated in relation to iron stores in patients with inflammation or liver disease, the plasma transferrin receptor concentration seems to be less affected by these disorders.

The serum transferrin receptor/serum ferritin ratio seems to improve the identification of iron deficiency in the presence of chronic infection or inflammation and, at present, provides the best available means for noninvasive diagnosis of iron deficiency. Nonetheless, at present no single noninvasive laboratory measurement or combination of measurements can provide a certain diagnosis of iron deficiency in all circumstances. If uncertainty remains, bone marrow examination can be definitive (see below).

In some clinical circumstances, a therapeutic trial of iron is an alternative means of confirming the diagnosis of iron deficiency. Unequivocal proof that iron deficiency is the cause of an anemia can be provided by a specific characteristic response to, and exclusively to, treatment with iron. The definitive diagnostic response consists of both of the following:

  • A reticulocytosis, starting about 3 to 5 days after adequate iron therapy is begun, attaining a maximum on days 8 to 10, and then gradually declining
  • An increase in hemoglobin concentration, beginning just after the maximum reticulocytosis, and no later than 3 weeks after iron therapy is begun, and then persisting until the hemoglobin concentration is returned to normal.

A number of confounding factors may complicate interpretation of the results of a therapeutic trial of iron, including poor compliance with iron therapy, malabsorption of therapeutic iron, continuing blood loss, and the effects of coexisting conditions, especially infectious, inflammatory, or malignant disorders. Despite a positive result with therapeutic iron, the underlying cause of the iron deficiency must be determined.

What conditions can underlie iron deficiency?

In uncomplicated iron deficiency, the characteristic sequence of changes in laboratory studies summarized above is virtually pathognomonic. By contrast, coexisting disorders can produce changes in iron-related measurements that both mimic and obscure those resulting from iron deficiency. Infection, inflammation, malignancy, renal and liver disease principally affect indicators of iron status through their effects on a common pathway that modulates the expression of hepcidin, the chief controller of body iron supply and storage.

With iron deficiency, hepcidin synthesis is suppressed. Plasma iron levels fall because the amounts of iron available from macrophage recycling of senescent erythrocytes, from intestinal absorption, and from mobilization of storage iron in hepatocytes are unable to meet the demands for red cell production, resulting in iron-restricted erythropoiesis. By contrast, infection, inflammation, liver disease, and malignancy typically stimulate hepcidin production via cytokine-mediated pathways. Plasma iron levels fall and iron-restricted erythropoiesis develops because release of iron from macrophages, enterocytes, and hepatocytes is impeded, increasing the amounts of iron in stores.

Consequently, infectious, inflammatory, and malignant disorders can produce changes in the plasma iron, transferrin saturation, erythrocyte zinc protoporphyrin, reticulocyte hemoglobin content, the proportions of hypochromic, microcytic erythrocytes, and in hemoglobin and hematocrit that resemble those resulting from iron deficiency.

Serum ferritin concentrations are decreased with uncomplicated iron deficiency, but increased with infection, inflammation, and malignancy. When occurring together, the effect of infection, inflammation, and malignancy on increasing serum ferritin often predominates over the decrease with lack of iron, concealing the presence of iron deficiency. By contrast, the increase in serum transferrin receptor with iron deficiency is less affected by infection, inflammation, and malignancy. Thalassemia trait can also produce microcytosis, but has little effect on other indicators of iron status.

In patients treated with erythropoiesis stimulating agents for the anemia of chronic renal disease or other disorders, the increased iron requirements of the erythroid marrow can not be met by iron mobilization from replete stores, resulting in iron-restricted erythropoiesis. This state, sometimes labeled “functional iron deficiency” despite the presence of storage iron, is a form of iron-restricted erythropoiesis resulting from stimulated erythropoietic demand for iron.

Uncommonly, a similar pattern can result from endogenous increases in erythropoietin owing to anemia, hypoxemia, and other conditions. Laboratory evaluation shows the pattern of iron-restricted erythropoiesis with a serum ferritin in the reference range, or elevated, and an increased serum transferrin receptor concentration. The CHr may be the earliest indicator that stimulated erythropoietic demand for iron exceeds the available supply.

Rarely, laboratory indicators of iron status are altered by a variety of inherited disorders of iron metabolism. The need for further consideration of a genetic basis for iron deficiency is suggested by a lifelong history of abnormal iron studies coupled with anemia refractory to iron therapy.

When do you need to get more aggressive tests:

If uncertainty about the diagnosis of iron deficiency remains after careful laboratory assessment of the indicators of iron status, bone marrow examination can be definitive. Bone marrow aspiration and biopsy provides information about all of the following:

  • Macrophage storage iron, by semiquantitative grading of marrow hemosiderin stained with Prussian Blue or, if needed, by chemical measurement of nonheme iron
  • Iron supply to erythroid precursors, by determining the proportion and morphology of marrow sideroblasts (that is, normoblasts with visible aggregates of iron in the cytoplasm)
  • General morphologic features of hematopoiesis. If iron deficiency is present, iron stores are absent; if the anemia of chronic disease alone is responsible, iron stores are present and typically increased.

What imaging studies (if any) will be helpful?

No imaging studies are indicated for the diagnosis of iron deficiency, although they may be useful in establishing the underlying cause for the lack of iron.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Rarely, severe iron deficiency anemia may need immediate red cell transfusion to prevent cardiac or cerebral ischemia. Red cell transfusion may also be required to support patients whose chronic rate of iron loss exceeds the rate of replacement possible with parenteral therapy.

In patients with heart failure and iron deficiency, clinical trials have provided evidence that treatment with intravenous iron improves outcomes.

What therapy is indicated for iron deficiency?

Generally, iron therapy for iron deficiency can be deferred until the underlying cause for the lack of iron has been identified. If coexistent infection or inflammation is present, iron should be withheld until these disorders are resolved or well controlled.

For most patients, oral iron is the treatment of choice because of its effectiveness, safety, and, economy. Oral iron therapy should begin with a ferrous iron salt, taken separately from meals in three or four divided doses and supplying a daily total of 150 to 200mg of elemental iron in adults or 3mg of iron per kilogram of body weight in children. Simple ferrous preparations are the best absorbed and least expensive. Ferrous sulfate is the most widely used, either as tablets containing 60 to 70mg of iron for adults or as a liquid preparation for children.

Administration between meals maximizes absorption. In patients with a hemoglobin concentration less than 10g/dL, this regimen initially will provide approximately 40 to 60mg of iron daily for erythropoiesis, permitting red cell production to increase to two to four times normal and the hemoglobin concentration to rise by approximately 0.2g/dL/day. An increase in the hemoglobin concentration of at least 2g/dL after 3 weeks of therapy generally is used as the criterion for an adequate therapeutic response.

For milder anemia, a single daily dose of approximately 60mg of iron per day may be adequate. After the anemia has been fully corrected, oral iron should be continued to replace storage iron, either empirically for an additional 4 to 6 months, or until the plasma ferritin concentration exceeds approximately 50microg/L. Most patients are able to tolerate oral iron therapy without difficulty, but 10 to 20% may have symptoms that are attributable to iron. The most common side effects are gastrointestinal and can usually be managed by administering iron with food and decreasing the dose. These measures will diminish the amount of iron absorbed daily, and thereby prolong the period of treatment, but haste in the correction of iron deficiency is rarely needed.

Parenteral iron therapy, despite the reductions in the risk of adverse reactions with newer preparations, should be reserved for the exceptional patient who either remains intolerant of oral iron despite repeated modifications in dosage regimen, malabsorbs iron, or has iron needs that cannot be met by oral therapy because of either chronic uncontrollable bleeding or other sources of blood loss, such as hemodialysis, or a coexisting chronic inflammatory state, such as inflammatory bowel disease. For renal dialysis patients who are managed with erythropoiesis stimulating agents, intravenous iron therapy is recommended.

What other therapies are helpful for reducing complications?


What should you tell the patient and the family about prognosis?

The patient and family should be told that the prognosis for iron deficiency itself is excellent, and that an excellent response to either oral or parenteral iron can be expected. The overall prognosis is determined by the underlying cause of the iron deficiency.

Both a subjective and a clinical response to treatment can be expected in the first few days after treatment is begun. An enhanced sense of well being may precede the hematologic response. In the absence of complicating factors, reticulocytosis is expected within 3 to 5 days, reaches a peak by days 8 to 10, and then gradually decreases. An increase in hemoglobin follows the reticulocytosis and should be within the reference range by 6 weeks.

“What if” scenarios.

If the expected full response to iron therapy does not occur, then a complete re-evaluation of the patient should be undertaken. Most often, the difficulty is the result of an error in diagnosis, with the anemia resulting from iron-restricted erythropoiesis due to infection, inflammation, or malignancy being mistaken for iron deficiency anemia. Ongoing occult blood loss may cause an incomplete response. Other nutritional deficiencies, hepatic or renal disease, or infectious, inflammatory, or malignant disorders may delay recovery. A genetic basis for iron deficiency should be considered if these possibilities can be excluded and the anemia is does not respond fully to parenteral therapy, especially in the presence of a lifelong history.

If the expected full response is not obtained with oral iron therapy, the adequacy of the form and dose of iron used should be reconsidered, compliance with the treatment regimen reviewed, and, finally, the possibility of malabsorption considered. A screening test for iron malabsorption is the administration to the fasting patient of 100mg of elemental iron as ferrous sulfate in a liquid preparation, followed by measurements of plasma iron concentrations 1 and then 2 hours later.

In an iron-deficient patient with an initial plasma iron concentration less than 50mg/dL, an increase in plasma iron concentration of 200 to 300mg/dL is expected. An increase in plasma iron concentration less than 100mg/dL suggests malabsorption, and may be an indication for a small-bowel biopsy.


Iron deficiency results from a sustained increase in iron requirements over iron supply. The iron requirement is the sum of physiologic needs (for the small daily losses in body cells and fluids, for losses during menstruation and pregnancy in women, and for growth in infants, children and adolescents) and any additional amounts for replacement of pathological losses (most often, some form of blood loss). In normal men, the daily basal iron loss is slightly less than 1.0mg/day. In healthy menstruating women, the daily basal iron loss is approximately 1.5mg/day. In iron balance, these physiologic losses are matched with the iron supply derived from controlled absorption of corresponding amounts of iron from the diet.

Iron balance is maintained by hepcidin, the chief controller of body iron supply and storage, through interaction with ferroportin, a transmembrane protein that is the only known cellular iron exporter in humans. Hepcidin binds to ferroportin, inducing its internalization and degradation, thereby inhibiting iron efflux from the principal sources of plasma iron: macrophages, duodenal enterocytes, and hepatocytes.

Under physiologic conditions, hepatic hepcidin production is the mechanism whereby body iron supply is coordinated with iron need. If body iron stores expand, hepcidin production increases. Increments in plasma hepcidin reduce the amount of ferroportin in cell membranes, causing a prompt fall in plasma iron concentration by decreasing macrophage release of iron derived from senescent red blood cells, diminishing delivery of iron from enterocytes absorbing dietary iron, and inhibiting release of iron stored in hepatocytes. Conversely, if body iron stores contract, hepcidin production decreases. Decrements in plasma hepcidin concentration increase the amount of ferroportin, producing a rise in plasma iron concentration as a consequence of enhanced delivery from macrophages, increased dietary iron absorption from enterocytes, and mobilization of storage iron from hepatocytes.

In addition to these effects of body iron stores, hepcidin production is stimulated by inflammation and inhibited by increased erythropoiesis. Depending on clinical circumstances, the effects of inflammation or increased erythropoiesis on hepatic hepcidin synthesis may predominate over the effects of body iron stores.

The most common pathologic cause of increased iron requirements leading to iron deficiency is blood loss, usually gastrointestinal in origin from any hemorrhagic lesion, including malignancy, ulcer, gastritis, drug-induced lesions (alcohol, salicylates, steroids, and nonsteroidal antiinflammatory agents) and parasitic infections (hookworm infection, Schistosoma mansoni, Schistosoma japonicum, and severe Trichuris trichiura). Less commonly, genitourinary blood loss (including chronic hemoglobinuria and hemosiderinuria resulting from paroxysmal nocturnal hemoglobinuria or from chronic intravascular hemolysis) can be responsible. Repeated blood donation also may lead to iron deficiency. In infants, children, and adolescents, the need for iron for growth may exceed the supply available from diet and stores.

Impaired absorption of iron in itself can restrict iron supply but is uncommonly the sole source of iron deficiency. Nonetheless, in those patients in whom gastrointestinal evaluation fails to identify a source of blood loss, as well as in those unresponsive to oral iron therapy, coeliac disease, autoimmune, atrophic, or Helicobacter pylorigastritis may be responsible.

What other clinical manifestations may help me to diagnose iron deficiency?

A relatively specific symptom of iron deficiency is pagophagia, a variant of pica characterized by the obsessive consumption of ice. The clinical history also should elicit symptoms associated with disorders that have a high prevalence of iron deficiency, including heart failure, pulmonary arterial hypertension, and restless legs syndrome (Ekbom syndrome), a neurologic disorder characterized by a distressing need or urge to move the legs (akathisia). Distinctive physical findings occur in only a small proportion of patients with iron deficiency but include koilonychia (thin, brittle fingernails with the distal half of the nail in a concave or “spoon” shape) and blue sclerae (a bluish hue of the sclerae thought to result from thinning of the sclerae, making the choroid visible). Glossitis and angular stomatitis are other, much less specific, physical manifestations.

What other additional laboratory studies may be ordered?

Gene sequencing is needed for definitive identification of a variety of rare genetic disorders that either cause iron deficiency or simulate some of the laboratory features of iron deficiency, including iron-refractory iron deficiency anemia (mutations in TMPRSS6, encoding matriptase-2), atransferrinemia (mutations in TF, encoding transferrin), aceruloplasminemia (mutations in CP, encoding ceruloplasmin), divalent metal transporter 1 (DMT1) deficiency (mutations in SLC11A2, encoding DMT1 {divalent metal transporter 1]), some forms of ferroportin disease (mutations in SLC40A1, encoding ferroportin), heme oxygenase 1 deficiency (mutations in HMOX1, encoding heme oxygenase 1), and several inherited sideroblastic anemias.

What’s the evidence?

Auerbach, M, Ballard, H. “Clinical use of intravenous iron: administration, efficacy, and safety”. Hematology Am Soc Hematol Educ Program. vol. 2010. 2010. pp. 338-347. [This paper provides recommendations for the use of intravenous iron preparations for the treatment of iron deficiency.]

Baker, RD, Greer, FR. “Diagnosis and prevention of iron deficiency and iron-deficiency anemia in infants and young children (0-3 years of age)”. Pediatrics. vol. 126. 2010. pp. 1040-1050. [This paper summarizes the current guidance of the American Academy of Pediatrics for the diagnosis and management of iron deficiency in infants and young children.]

Camaschella, C, Poggiali, E. “Inherited disorders of iron metabolism”. Curr Opin Pediatr. vol. 23. 2011. pp. 14-20. [This paper describes the pathophysiology and clinical features of the rare genetic disorders that either cause iron deficiency or mimic some of the laboratory features of iron deficiency.]

Carson, JL, Adamson, JW. “Iron deficiency and heart disease: ironclad evidence?”. Hematology Am Soc Hematol Educ Program. vol. 2010. 2010. pp. 348-350. [This review describes the present state of evidence about the clinical role for treatment of iron deficiency in the management of patients with heart failure.]

Ganz, T, Nemeth, E. “Hepcidin and disorders of iron metabolism”. Annu Rev Med. vol. 62. 2011. pp. 347-360. [This review describes the role of the hepcidin-ferroportin axis in iron homeostasis.]

Goodnough, LT, Nemeth, E, Ganz, T. “Detection, evaluation, and management of iron-restricted erythropoiesis”. Blood. vol. 116. 2010. pp. 4754-4761. [This review discusses differentiating iron deficiency from other causes of iron-restricted erythropoiesis.]

Hershko, C, Skikne, B. “Pathogenesis and management of iron deficiency anemia: Emerging role of celiac disease, Helicobacter pylori, and autoimmune gastritis”. Semin Hematol. vol. 46. 2009. pp. 339-350. [This review suggests screening for sometimes overlooked gastrointestinal disorders in patients in whom no source of blood loss is identified by conventional screening and in those unresponsive to oral iron therapy.]

Madore, F, White, CT, Foley, RN. “Clinical practice guidelines for assessment and management of iron deficiency”. Kidney Int Suppl. vol. 110. 2008. pp. S7-S11. [This paper presents the guidelines of the Canadian Society for Nephrology for the diagnosis and management of iron deficiency in patients with chronic renal disease.]

Munoz, M, Garcia-Erce, JA, Remacha, AF. “Disorders of iron metabolism. Part 1: molecular basis of iron homoeostasis”. J Clin Pathol. vol. 64. 2011. pp. 281-286. [These reviews provide an overall summary of current understanding of the genes and proteins involved in the regulation of iron metabolism, with an emphasis on the clinical implications for the diagnosis and management of iron deficiency.]