GRAPHICS View All

RELATED TOPICS




Causes and diagnosis of iron deficiency and iron deficiency anemia in adults
Author:
Stanley L Schrier, MD
Section Editor:
William C Mentzer, MD
Deputy Editor:
Jennifer S Tirnauer, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Feb 2018. | This topic last updated: Oct 25, 2017.

INTRODUCTION — The diagnosis of iron deficiency is a major public health goal and an important aspect of the care of many adults. This topic will review the causes of iron deficiency in adults and an approach to the diagnostic evaluation. Treatment of iron deficiency in adults is discussed separately. (See "Treatment of iron deficiency anemia in adults".)

Iron deficiency in other populations is presented in separate topic reviews:

Children, diagnosis and prevention of iron deficiency – (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis".)

Children, treatment of iron deficiency – (See "Iron deficiency in infants and children <12 years: Treatment".)

Adolescents, diagnosis and treatment of iron deficiency – (See "Iron requirements and iron deficiency in adolescents".)

Pregnancy, prevention of iron deficiency – (See "Nutrition in pregnancy", section on 'Iron'.)

EPIDEMIOLOGY — Iron deficiency affects over 12 percent of the world's population, especially women of childbearing age, children, and individuals living in low- and middle-income countries. The absolute prevalence of iron deficiency depends on the population studied.

In the United States, data on the general population have been collected periodically from the 1960s onward via the National Health and Nutrition Examination Survey (NHANES) [1]. The prevalence of iron deficiency and iron deficiency anemia from the NHANES III study (1988 to 1994) according to age and sex are listed in the table (table 1).

In the 1988 to 1994 NHANES III survey, iron deficiency was present in approximately 9 to 11 percent of females of adolescent and/or childbearing age [2]. Iron deficiency anemia was present in approximately 2 to 5 percent. In comparison, iron deficiency was present in <1 percent of males of the same age range.

Pregnant women have a considerably greater likelihood of iron deficiency (25 percent, verus 10 percent of non-pregnant women in another publication that used 1999 to 2006 NHANES data); another publication using approximately the same data set linked iron deficiency with food insecurity [3,4]. The prevalence of iron deficiency also correlates with a greater number of pregnancies [5].

Iron deficiency in older adults is also greater than that seen in the general population. In a series of 190 adults in the community >65 years of age with anemia, 12 percent were due to iron deficiency [6]. (See "Anemia in the older adult", section on 'Iron deficiency anemia'.)

Blood donors in the general population typically have slightly lower iron stores than non-donors, although this rarely translates to iron deficiency anemia [7]. Various blood donor series from a number of North American and European countries have estimated the rate of subclinical iron deficiency in the range of 5 to 15 percent [8,9].

Population series in other countries have reported the following prevalences of iron deficiency:

Iran – 41 percent (female medical students) [10]

Jordan – 35 to 39 percent (women and children) [11]

Korea – 2 percent (males) and 22 percent (females) [12]

Kuwait – 21 percent (children ages 5 to 11 years) to 4 percent (age ≥50 years) [13]

Mexico – 4 percent (males) and 18 percent (females) [14]

Portugal – 17 percent (adults) [15]

Sierra Leone – 8 percent (women and children) [16]

Rates of iron deficiency in children are presented separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents".)

CAUSES OF IRON DEFICIENCY — The major causes of iron deficiency are decreased dietary intake, reduced absorption, and blood loss. In adults in resource-rich countries, dietary intake is almost always adequate, and it is usually reasonable to assume that the cause is blood loss until proven otherwise, with the implied need to search for and identify the cause. (See 'Search for source of blood and iron loss' below.)

Blood loss — The major cause of iron deficiency in resource-rich countries is blood loss, either overt or occult [17-22].

Overt bleeding is obvious and not difficult for the clinician to recognize, often by history alone:

Traumatic hemorrhage

Hematemesis or melena

Hemoptysis

Menorrhagia

Pregnancy and delivery

Hematuria

Other causes of blood loss that may be overlooked include:

Frequent blood donation

Excessive diagnostic blood testing

Underestimation of the degree of menorrhagia

Lactation

Occult bleeding, typically gastrointestinal (eg, gastritis, malignancy, telangiectasia) but may also include hemolysis with urinary losses

Exercise-induced blood loss, often due to occult gastrointestinal bleeding (see "Exercise-related gastrointestinal disorders", section on 'Gastrointestinal bleeding' and "Approach to the adult with anemia", section on 'Athletes')

Gastrointestinal parasites (eg, hookworm, whipworm), especially in developing countries

Typical iron loss during pregnancy and lactation have been estimated at approximately 1000 mg each for pregnancy, delivery, and nursing. Menstrual blood losses account for approximately 1 mg of iron loss per day.

Typical iron loss during hemodialysis may be as much as 2 g per year, which is highly likely to produce iron deficiency without supplementation. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in hemodialysis patients".)

The likelihood that iron deficiency is due to an occult gastrointestinal lesion has been illustrated in several case series.

In a 2012 series of 621 patients with definite or probable iron deficiency anemia, cancer and high-risk adenomas were identified in 51 of 310 (16 percent) of the individuals who underwent endoscopy [23].

In a 2005 series of 148 adults (median age, 66 years) with chronic iron deficiency who underwent endoscopy, 18 (12 percent) were found to have a malignant tumor [24].

In a 2002 report from the first National Health and Nutrition Examination Survey and Epidemiologic Followup Study (NHANES I) that included 9024 adults, 18 new gastrointestinal malignancies were identified [25]. Iron deficiency was a strong predictor of gastrointestinal cancer in men and postmenopausal women but not in premenopausal women, with the following rates of gastrointestinal cancer detection over a two-year period:

Premenopausal women with iron deficiency – 0 of 442

Men and postmenopausal women with iron deficiency – 5 of 274 (2 percent)

Men and postmenopausal women without iron deficiency – 11 of 5733 (0.2 percent)

These findings reinforce the importance of identifying the cause of blood loss, especially in men and postmenopausal women. (See 'Search for source of blood and iron loss' below.)

Reduced iron absorption — Reduced absorption of iron is an uncommon cause of iron deficiency, especially in healthy individuals and in resource-rich countries. Iron is absorbed in the upper gastrointestinal tract; the duodenum is the site of maximal absorption [26]. However, a number of factors determine the efficiency of iron absorption, and a number of medical conditions may interfere with normal uptake of dietary iron. The most clinically important are disorders that affect the mucosal cells responsible for iron absorption, such as celiac disease, atrophic gastritis, Helicobacter pylori (H. pylori) infection, and bariatric surgery. Inherited disorders that interfere with iron absorption are very rare.

Dietary heme iron (iron from meat rather than plant sources) is better absorbed than non-heme iron, and an acidic environment (eg, normal gastric acid without acid-reducing medications) facilitates absorption. There are also a number of foods that may impair iron absorption such as tannates, phosphates, phytates (mineral-binding compounds found in whole grains and seeds), and foods high in calcium (table 2). It would be very difficult to develop iron deficiency solely due to these factors, but they may contribute to iron deficiency in the setting of blood loss, or, less commonly, extremely low intake [22].

Celiac disease/atrophic gastritis/H. pylori — Celiac disease (also called gluten-sensitive enteropathy or nontropical sprue) is a disorder of small bowel inflammation triggered by exposure to gluten in susceptible individuals. It predominantly affects whites of northern European ancestry, with a prevalence of approximately 1 in 70 to 1 in 300 (0.3 to 1 percent) in these populations. (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults".)

Celiac disease – Celiac disease can contribute to anemia by several mechanisms, including iron deficiency, reduced absorption of supplemental iron, and malabsorption of other nutrients required for red blood cell (RBC) production including vitamin B12, folic acid, and copper [27]. There may also be a component of anemia of chronic inflammation (anemia of chronic disease) as well as blood loss, although the contribution (if any) of gastrointestinal blood loss from celiac disease to iron deficiency is unclear [27]. Various reports have commented on the unexpected presence of celiac disease in individuals with iron deficiency and vice versa. As an example, in a series of 102 patients diagnosed with celiac disease in a northern European hospital, 70 had anemia as the presenting feature, and 34 of these 70 (approximately half) were premenopausal women, who might otherwise be thought to have iron deficiency on the basis of heavy menses [28]. In another series of 200 Scandinavian patients with anemia who underwent testing for celiac disease, 10 (5 percent) were found to be positive by serologic testing confirmed by intestinal biopsy [29].

Gastritis and H. pylori – Gastritis related to an autoimmune mechanism or H. pylori has also been implicated in causing iron deficiency [30,31]. In a series of 150 patients (mostly adults) with iron deficiency anemia, refractoriness to oral iron treatment was noted in 24 of 34 (71 percent) with antiparietal cell antibodies and autoimmune gastritis, and in 15 of 22 (68 percent) with H. pylori (as well as all eight with celiac disease) [32]. In another series of 71 patients with iron deficiency anemia who did not have an obvious source of blood loss and underwent upper and lower endoscopy, diagnoses related to reduced absorption included atrophic gastritis in 19 (27 percent) and H. pylori in 13 (18 percent), as well as celiac disease in four (6 percent) [20].

The possibility of these conditions should be reviewed in individuals with unexplained iron deficiency, especially those at increased risk based on demographic features and those for whom oral iron therapy is ineffective. (See "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)

Bariatric surgery — Bariatric surgery includes a number of procedures that promote weight loss by limiting gastric reservoir capacity and/or shortening the length of functional small intestine, which causes malabsorption. Procedures that bypass the duodenum such as roux-en-Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD-DS) have the greatest risk of causing iron deficiency because they reduce the site of maximal absorption and in some cases reduce gastric acid availability. (See "Bariatric procedures for the management of severe obesity: Descriptions" and "Regulation of iron balance", section on 'Intestinal iron absorption'.)

Routine iron supplementation and monitoring of iron status with repletion as needed is used after most bariatric surgeries. (See "Bariatric surgery: Postoperative nutritional management".)

Redistribution after erythropoietin/erythropoiesis-stimulating agents — A response to treatment with erythropoietin (EPO) for the anemia of chronic renal failure often leads to the discovery of absolute or functional iron deficiency (see 'Absolute versus functional deficiency' below) since the iron requirements generated by this response in the short term can usually not be met by mobilization of the patient's iron stores alone [33]. This is a particular problem in patients on maintenance hemodialysis. These individuals may lose an average of 2 g of iron per year, mainly from repeated blood testing and blood losses within the hemodialysis circuit [34]. Thus, iron deficiency will develop in almost all patients undergoing dialysis who are treated with EPO, as well as some individuals with chronic renal failure not receiving dialysis, unless supplemental iron is administered. This subject is discussed in detail in separate topic reviews. (See "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients" and "Treatment of iron deficiency in hemodialysis patients" and "Hyporesponse to erythropoiesis-stimulating agents (ESAs) in chronic kidney disease".)

EPO or other erythropoiesis-stimulating agents (ESAs) are also used for patients with cancer-associated anemia. The anemia may be multifactorial and include a component of bleeding and iron deficiency. In addition, functional iron deficiency may limit the availability of iron and the response to ESA therapy in these patients, and those with borderline iron stores may rapidly develop more classic features of iron deficiency. Thus, iron status is routinely monitored, and supplementation provided in many cases. This subject is also discussed in detail separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer" and "Hematologic complications of malignancy: Anemia and bleeding".)

Urinary/pulmonary hemosiderosis — In some conditions, iron may be lost when there is shedding of iron-laden cells, especially over a prolonged period of time or multiple episodes.

Urinary – Chronic or intermittent intravascular hemolysis with hemosiderin accumulation in urinary epithelial cells may lead to iron loss through urinary shedding of these cells. Examples include individuals with intensive athletic training, prosthetic heart valve-associated hemolysis, or paroxysmal nocturnal hemoglobinuria (PNH). (See "Approach to the adult with anemia", section on 'Athletes' and "Overview of the management of patients with prosthetic heart valves", section on 'Hemolytic anemia' and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria", section on 'Hemolysis'.)

Pulmonary – Pulmonary hemosiderosis, such as in individuals with diffuse alveolar hemorrhage or idiopathic pulmonary hemosiderosis may lead to iron loss through swallowing of iron-laden alveolar or bronchial epithelial cells. These conditions also may cause a component of functional iron deficiency, in which iron is trapped in pulmonary macrophages. (See "Idiopathic pulmonary hemosiderosis" and "The diffuse alveolar hemorrhage syndromes".)

Inherited disorders/IRIDA

IRIDA due to TMPRSS6 mutation – Iron refractory iron deficiency anemia (IRIDA) is a rare inherited disorder in which absorption of oral iron is markedly impaired. IRIDA is caused by loss-of-function mutations of the TMPRSS6/matriptase 2 gene, which encodes a serine protease that cleaves membrane-bound hemojuvelin [35-44]. Membrane-bound hemojuvelin promotes hepcidin synthesis and impairs iron absorption in the gut; cleavage of membrane-bound hemojuvelin reduces hepcidin synthesis, increasing iron absorption. Loss of TMPRSS6 function thus causes iron deficiency due to inappropriately high hepcidin levels, with markedly reduced iron absorption and increased sequestration of iron in macrophages [41,45-50]. (See "Regulation of iron balance", section on 'Hemojuvelin'.)

In published case reports as well as our own experience, patients with IRIDA are not anemic at birth, and the clinical phenotype develops after the neonatal period (eg, after one month of age). Suspicion of IRIDA usually occurs during a pediatric routine evaluation. However, in some patients, the condition is recognized only in adulthood, either because the anemia is mild or because it has been misclassified. Patients present with mild hypochromic, microcytic anemia with very low serum iron levels and low transferrin saturation. Serum ferritin levels are mostly within the normal range or even slightly elevated following treatment with intravenous iron [41]. The diagnosis is pursued after elimination of causes of iron deficiency refractory to iron therapy such as celiac disease, H. pylori infection, autoimmune gastritis, or anemia of chronic disease/inflammation [36]. The diagnosis of IRIDA is confirmed by demonstrating biallelic mutation in TMPRSS6; testing laboratories are listed on the Genetic Testing Registry website.

SLC11A2 mutation – Iron deficiency anemia has also been described in individuals with mutations in the SLC11A2 gene, which encodes the divalent metal transporter DMT1 [51-55]. (See "Regulation of iron balance", section on 'Duodenal iron transporter'.)

STAGES OF IRON DEFICIENCY — The development of iron deficiency, and the rapidity with which it progresses, depend on the individual's baseline iron stores, which are correlated with age, sex, and the steady state iron balance; as well as the degree, duration, and rapidity of iron or blood loss. (See "Regulation of iron balance".)

Normal body iron content — The normal body iron content in an adult is approximately 3 to 4 grams. The majority of iron is present in circulating red blood cells (RBCs), with additional iron in myoglobin and certain enzymes, as well as iron in storage and transport forms (figure 1). Typical amounts of iron in these sites is as follows (table 3):

Hemoglobin in circulating RBCs – Approximately 2 g, corresponding to approximately 2000 mL (25 to 30 mL/kg) of RBCs

Iron-containing proteins (eg, myoglobin, cytochromes, catalase) – Approximately 400 mg

Plasma iron bound to transferrin – 3 to 7 mg

Storage iron in the form of ferritin or hemosiderin – Approximately 0.8 to 1 g (men); approximately 0.4 to 0.5 g (women)

Storage iron in adult men has been estimated as being approximately 10 mg/kg, and is found mostly in the monocyte-macrophage system in the liver, spleen, and bone marrow. Adult women have less storage iron, depending upon the extent of menses, pregnancies, deliveries, lactation, and iron intake. In one study, 93 percent of women in the United States 20 to 45 years of age had iron stores of 5.5 ± 3.4 mg/kg, while the other 7 percent had an iron deficit of 3.9 ± 3.2 mg/kg [56]. Other estimates have suggested that up to 20 percent of menstruating women in the United States have absent iron stores [57]. The storage pool can be looked upon as a reserve of iron that can be utilized when there is increased need for hemoglobin synthesis, as in acute blood loss, growth in children and adolescents, pregnancy, lactation, and response to treatment with erythropoietin.

Ferritin levels are used as a surrogate for iron stores and are generally a good measure of storage iron as long as the individual does not have an active inflammatory process or chronic disease (ferritin is an acute phase reactant). For ferritin levels in the range from 20 to 300 ng/mL, there appears to be a direct quantitative relationship between the ferritin concentration and iron stores [58] (see 'Iron studies (list of available tests)' below):

 Iron stores (mg)  ≈  (8 to 10)  x  ferritin (ng/mL)

Progressive iron depletion — Iron deficiency occurs in several stages, as illustrated by progressive changes in laboratory findings (table 4) [17,21]. These stages are defined by the extent of depletion, first of iron stores and then of iron available for hemoglobin synthesis. Eventually, if negative iron balance continues, the iron and hemoglobin deficiency are so severe that production of iron-deficient RBCs and anemia occurs.

In the first stage, iron stores can be totally depleted without causing anemia. Once these stores are depleted, there is still enough iron present in the body within the "labile" iron pool from the daily turnover of red cells for normal hemoglobin synthesis, but the individual becomes vulnerable to development of anemia should there be further iron losses. Some individuals with extremely low levels of serum ferritin, but without anemia, may have symptoms of fatigue or show decreased exercise tolerance at this stage.

Further loss of iron results in anemia, which is initially normocytic with a normal absolute reticulocyte count (table 4). This stage of iron deficiency is common in the United States. As noted above, it has been estimated that as much as 20 percent of menstruating women in the United States have no iron reserves and are in this stage [59]. Common laboratory findings at this stage include:

Low levels of ferritin and serum iron (Fe)

Increased levels of transferrin (Tf; total iron binding capacity [TIBC])

Low percent saturation of transferrin (ie, Fe/TIBC or Fe/Tf, stated as a percent)

Increased unsaturated iron binding capacity (UIBC = TIBC - Fe)

More profound deficiency results in the classical findings of anemia with RBCs that are hypochromic (low mean corpuscular hemoglobin concentration [MCHC]) and microcytic (low mean corpuscular volume [MCV]). Reticulocyte production cannot be increased in the setting of iron deficiency, and the reticulocyte count becomes inappropriately low (despite being in the "normal" range in many cases). It is worth noting, however, that other concomitant causes of anemia such as vitamin B12 deficiency may cause macrocytosis and obscure the microcytosis caused by iron deficiency. (See 'Diagnostic evaluation' below.)

The normal physiologic changes in response to iron deficiency produce a number of compensatory changes, including increased production of erythropoietin and reduced production of hepcidin, provided that renal function is normal and that the individual does not have an inflammatory condition that suppresses hepcidin production. The mechanisms of these changes are discussed in detail separately. (See "Regulation of iron balance".)

Absolute versus functional deficiency — We distinguish between absolute and functional iron deficiency.

Absolute iron deficiency – Absolute iron deficiency refers to the absence of (or severely reduced) storage iron in the monocyte-macrophage system, including bone marrow, liver, and spleen.

Functional iron deficiency – Some individuals have adequate iron stores for normal hematopoiesis, but the iron is not available for RBC production [60,61]. There are two main categories/mechanisms:

Anemia of chronic inflammation – The most common mechanism is a block in iron release from macrophages back into the circulation, which occurs in the setting of inflammation and increased hepcidin production (ie, anemia of chronic inflammation, also called anemia of chronic disease [ACD]). Common causes include infections, malignancies, or chronic medical conditions such as diabetes. The diagnosis and management of ACD is discussed in detail separately. (See "Anemia of chronic disease/inflammation".)

Erythropoiesis-stimulating agents – Another mechanism of functional iron deficiency is treatment with erythropoiesis-stimulating agents (ESA) such as erythropoietin (eg, in individuals with renal insufficiency or cancer). In these cases, iron stores may be available but their release into the circulation may not be rapid enough to support the increased erythropoietic rate; thus, these individuals have insufficient iron stores to respond to the ESA; this is also referred to as iron restricted erythropoiesis. (See 'Redistribution after erythropoietin/erythropoiesis-stimulating agents' above.)

Thresholds for ferritin and transferrin saturation in absolute and functional iron deficiency are discussed below. (See 'Diagnosis' below.)

CLINICAL MANIFESTATIONS

Symptoms of anemia — The usual presenting symptoms in adults with iron deficiency are primarily due to anemia. The same symptoms may also be present in those with severely reduced iron stores and extremely low serum ferritin who are not anemic. Typical symptoms include [22]:

Fatigue

Weakness

Headache

Irritability

Exercise intolerance

Exertional dyspnea

Vertigo

Angina pectoris

These may be present in varying degrees and may not be appreciated at all until after iron deficiency is identified and treated. Many patients recognize in retrospect that they had fatigue, weakness, exercise intolerance, and/or pica (see 'Pica and ice craving' below) only after successful iron repletion.

Pica and ice craving — Pica refers to a desire for or compulsion to eat substances not fit as food; the term is derived from the Latin word for magpie (Pica pica), a bird that gathers a variety of non-food objects [62]. These substances may include earth substances such as clay or dirt (geophagia); paper products including wallpaper or toilet paper; starches including corn starch, laundry starch, or raw rice (amylophagia); or ice (pagophagia). Other reported substances have included chalk, ashes, charcoal, coffee grounds, baby powder, and paint chips. The specific substances that are craved may depend on what is available and what is considered culturally acceptable [63,64]. The craving for these non-food substances may be intense. In pregnant women, pica may also be misinterpreted as food cravings unrelated to iron status.

Overall, pica may be seen in many clinical settings and is not considered specific for iron deficiency. However, pagophagia (pica for ice) is considered quite specific for the iron deficiency state [63,65,66]. It may be present in patients who are not anemic and responds rapidly to treatment with iron, often before any increase is noted in the hemoglobin concentration. In one study of 55 unselected patients with iron deficiency anemia secondary to gastrointestinal blood loss, pica was present in 32 (58 percent), which manifested as pagophagia in 28 (51 percent of the total; 88 percent of those with pica) [65].

Pica may also contribute to iron deficiency by reducing iron absorption, depending on the substance ingested (see 'Reduced iron absorption' above). Its mechanism in individuals with iron deficiency is not well understood.

Beeturia — Beeturia is a phenomenon in which the urine turns red following ingestion of beets. Beeturia is increased in individuals with iron deficiency but the finding is not specific for iron deficiency. It has been noted in approximately 10 to 14 percent of healthy individuals following ingestion of beets and in as much as 49 to 80 percent of individuals with iron deficiency [67-69].

Beeturia is caused by increased intestinal absorption and subsequent excretion of the reddish pigment betalaine (betanin) present in beets. Betalaine, a redox indicator, is decolorized by ferric ions, which presumably explains the predisposition to beeturia when adequate amounts of iron are not available for decolorization of this pigment. (See "Urinalysis in the diagnosis of kidney disease", section on 'Red to brown urine'.)

Restless legs syndrome — Restless legs syndrome (RLS), also called Willis-Ekbom disease (WED), is a disorder in which there is an unpleasant or uncomfortable urge to move the legs during periods of inactivity. The discomfort is relieved by movement, often instantaneously. A number of changes in the central nervous system have been correlated with RLS. Of these, reduced iron in the central nervous system has been a consistent finding, regardless of total body iron stores. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults", section on 'Pathophysiology'.)

RLS is common in the general population, in some series affecting 5 to 15 percent of adults, especially in Caucasian populations. Iron deficiency may be one of the more common causes of RLS, and RLS may be one of the more common clinical manifestations of iron deficiency. As an example, in a series of 251 patients with iron deficiency anemia referred to a community-based hematology practice, the prevalence of clinically significant RLS was 24 percent, approximately nine times higher than that seen in the control population [70].

While overall findings linking RLS to iron deficiency are not conclusive, they warrant the measurement of hemoglobin and serum ferritin levels in individuals who present with this symptom, and administration of iron when ferritin is low. Some clinicians will give a trial of iron therapy even when ferritin levels are normal as some patients will experience a reduction in symptoms. This subject is discussed in depth separately. (See "Treatment of restless legs syndrome and periodic limb movement disorder in adults", section on 'Iron replacement' and "Treatment of iron deficiency anemia in adults", section on 'Iron deficiency without anemia'.)

Other findings — An association between iron deficiency and hearing loss in adults has been reported; the observation was based on a retrospective cohort study involving over 300,000 adults, in which the prevalence of combined hearing loss was 1.6 percent and the prevalence of iron deficiency was 0.7 percent [71]. Compared with controls, iron-deficient individuals had an adjusted odds ratio (OR) for combined hearing loss of 2.4 (95% CI 1.9-3.0). The mechanism of the association is not known, and we do not perform a formal audiologic evaluation unless the patient reports difficulty with hearing.

Findings on examination — The physical examination in individuals with iron deficiency (with or without anemia) may be normal or it may reveal one or more of the following findings [22,72]:

Pallor

Dry or rough skin

Blue sclerae

Atrophic glossitis with loss of tongue papillae, which may be accompanied by tongue pain or dry mouth (picture 1 and picture 2) [73]

Cheilosis (also called angular cheilitis) (picture 3 and picture 4)

Koilonychia (spoon nails) (picture 5 and picture 6)

Esophageal web, which may be accompanied by dysphagia (eg, Plummer-Vinson or Patterson-Kelly syndrome; rare)

Alopecia (rare) in especially severe cases [74]

Chlorosis (pale, faintly green complexion; extremely rare)

The more severe of these findings, including chlorosis and Plummer-Vinson syndrome, which were more common during the early 1900s, have virtually disappeared [75,76]. Patients with more severe anemia may have tachycardia, a cardiac murmur, or (rarely) hemodynamic instability [22].

For individuals with gastrointestinal blood loss, the stool may show overt or occult blood. However, absence of blood in the stool does not eliminate the possibilities of gastrointestinal bleeding or iron deficiency (or the need to evaluate for a source of gastrointestinal bleeding when appropriate), because bleeding may be intermittent.

Findings on CBC — Changes in the complete blood count (CBC) occur in proportion to the severity of iron deficiency, and tend to lag behind changes in iron studies (ie, reduced storage iron precedes anemia and microcytosis) (table 4). Thus, in early iron deficiency and in many individuals in high-resource settings, the CBC may be relatively normal.

As iron deficiency progresses and the individual becomes anemic, the following findings may be seen on the CBC:

Low red blood cell (RBC) count (typical RBC count for a patient with a hemoglobin of 9 g/dL would be approximately 3 million cells per microL)

Low hemoglobin and hematocrit

Low absolute reticulocyte count

Low mean corpuscular volume (MCV) and low mean corpuscular hemoglobin (MCH)

The low RBC count is useful for distinguishing iron deficiency from thalassemia in an individual with markedly microcytic anemia and an abnormal blood smear. (See 'Differential diagnosis' below.)

The platelet count may be increased in iron deficiency anemia. This is thought to result from stimulation of platelet precursors by erythropoietin. (See "Approach to the patient with thrombocytosis".)

The low MCV and MCH are reflected on the peripheral blood smear by microcytic, hypochromic RBCs (picture 7). As anemia progresses, increasingly abnormal forms (poikilocytosis) may be seen.

Automated counting of reticulocytes has also allowed measurement of reticulocyte indices (similar to RBC indices) that include reticulocyte volume, reticulocyte hemoglobin content, and reticulocyte hemoglobin concentration [77]. These are not used in routine practice, but some of the newer electronic counters can provide the result, which may be helpful as supporting information or for research [78]. In some studies, a reticulocyte hemoglobin content of <26 pg/cell has correlated well with the finding of iron deficiency [79,80]. (See "Automated hematology instrumentation", section on 'Automated counting of reticulocytes'.)

ROUTINE POPULATION SCREENING — The Centers for Disease Control and Prevention (CDC) in the United States has developed guidelines for screening various patient groups for iron deficiency, to detect deficiency at earlier stages and prevent serious complications of iron deficiency anemia in at-risk populations, as well as dietary recommendations to reduce the risk of iron deficiency [81]. Screening recommendations include the following:

Screening of adolescent and adult females of childbearing age every 5 to 10 years with a hemoglobin or hematocrit, with more frequent screening (eg, yearly) if there is extensive menstrual blood loss, low iron intake, or a history of iron deficiency. An abnormal result is repeated, and if anemia persists, a course of iron therapy is given. Further evaluation using RBC indices and serum ferritin is done if the trial of iron is ineffective. Notation is also made of the possibility of sickle cell disease or thalassemia, especially in the most frequently affected ethnic groups.

Screening of pregnant women at the first prenatal visit, with criteria for anemia stratified by the stage of pregnancy, with a therapeutic trial of iron if the anemia is below certain thresholds. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Dilutional anemia'.)

These recommendations diverge slightly from our suggestion that iron studies should be ordered to confirm the diagnosis of iron deficiency prior to beginning iron therapy in most individuals. Evaluation of the RBC indices, RBC count, and family history are also important so as not to miss a case of thalassemia, sickle cell disease, or other inherited condition, as stated in the guidelines.

These guidelines also diverge from a 2015 US Preventive Services Task Force (USPSTF) conclusion that there is insufficient evidence to support screening for iron deficiency anemia in pregnant women [82]. This 2015 document replaced a 2013 document that did advocate screening pregnant women [83].

Routine population screening of men or postmenopausal women for iron deficiency has not been demonstrated to be useful.

DIAGNOSTIC EVALUATION

Overview of evaluation — The possibility of iron deficiency should be addressed in the following adult populations:

Virtually all adults with unexplained anemia, especially those with new-onset anemia or microcytic anemia without reticulocytosis. (See "Approach to the child with anemia" and "Approach to the adult with anemia".)

Individuals without anemia who have any of the typical clinical findings such as pica (especially for ice) or restless legs syndrome (RLS). (See 'Clinical manifestations' above.)

Pregnant women. (See "Nutrition in pregnancy", section on 'Iron'.)

Individuals with chronic kidney disease who have anemia or who are receiving hemodialysis or an erythropoiesis-stimulating agent (ESA). (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of anemia in nondialysis chronic kidney disease".)

For these patients, it is reasonable to evaluate the complete blood count (CBC) and red blood cell (RBC) indices, especially mean corpuscular volume (MCV), and take a history for possible causes of blood loss. For those with microcytic or normocytic anemia, a reticulocyte count should be used to determine whether there is decreased RBC production, which is consistent with iron deficiency; increased RBC destruction (hemolysis); or blood loss. Review of the peripheral blood smear is likely to provide valuable information regarding the characteristic morphologies seen in iron deficiency anemia (picture 7) versus other causes of anemia. The patient's history, CBC, RBC indices, and findings on the peripheral blood smear usually allow the clinician to make a presumptive diagnosis of iron deficiency anemia. (See "Approach to the adult with anemia", section on 'Morphologic approach'.)

There are two complementary ways to confirm (or exclude) the diagnosis of iron deficiency: iron studies (see 'Iron studies (list of available tests)' below) and assessment of the response to a trial of iron therapy (see 'Response to a therapeutic trial of iron' below). In the vast majority of individuals, iron studies should be obtained. The results help to distinguish iron deficiency from other conditions, document the severity of the deficiency (if present), and provide a baseline prior to initiating iron administration. Exceptions may include individuals who do not have access to this testing (eg, in low-resource settings) or in routine obstetric practice. (See "Nutrition in pregnancy", section on 'Iron'.)

Even before the diagnosis of iron deficiency is confirmed, patients with suspected iron deficiency should be evaluated for the source of the deficiency, which is more likely to be dietary in individuals in resource-poor settings and more likely to be due to blood loss in menstruating or pregnant females and adults of either sex. The evaluation may include a thorough history and physical examination. Additional testing is discussed below, including colonoscopy if iron deficiency is confirmed. (See 'Search for source of blood and iron loss' below.)

The gold standard for documenting iron deficiency is an iron stain (Prussian blue stain) of a bone marrow aspirate smear to assess iron stores in bone marrow macrophages and erythroid precursors (sideroblasts) on marrow spicules. Lack of stainable iron in erythroid precursors as well as bone marrow macrophages is consistent with iron deficiency, whereas in anemia of chronic disease, increased stainable iron is seen in marrow macrophages but stainable iron is absent or reduced in erythroid precursors (picture 8). However, as noted in the following sections, other less-invasive and less-expensive methods are available and effective for confirming or excluding iron deficiency in the vast majority of cases. In some cases where there is an obvious other explanation for anemia and the patient is undergoing bone marrow testing, iron deficiency may be a surprise finding. In these cases, it is important to ensure that proper controls and confirmatory testing is performed.

Iron studies (list of available tests) — Iron deficiency anemia is characterized by reduced or absent iron stores and increased levels of transferrin proteins that facilitate iron uptake and transport to RBC precursors in the bone marrow (table 4). Of these iron studies, ferritin remains the most useful test, and most patients require only a ferritin level or testing of ferritin, iron, and total iron binding capacity (TIBC), from which one calculates transferrin saturation [21,22,72]. It is important to consider the entire clinical picture when deciding which tests to order and when evaluating test results.

Expected results of these and other tests in adults with iron deficiency are as follows:

Serum iron – Iron can be measured in serum (preferred) or plasma. The test measures circulating iron, most of which is bound to the transport protein transferrin. Serum iron is low in iron deficiency as well as in anemia of chronic inflammation (anemia of chronic disease [ACD]). This is because levels of serum iron depend on the efficiency of iron recycling by bone marrow and reticuloendothelial macrophages, which is reduced in both conditions. Serum iron can also fluctuate with dietary intake and normal diurnal variation. By itself, low serum iron is not diagnostic of any condition but must be evaluated in light of other tests such as transferrin saturation and ferritin. (See 'Differential diagnosis' below.)

Serum transferrin – Transferrin is a circulating transport protein for iron. It is increased in iron deficiency but can be decreased in ACD. Transferrin can also be reported as TIBC. The transferrin concentration (in mg/dL) can be converted to the TIBC (in mcg/dL) by multiplying by 1.389 [72].

Transferrin saturation – Transferrin saturation (TSAT) is the ratio of serum iron to TIBC: (serum iron  ÷  TIBC  x  100). In iron deficiency, iron is reduced and TIBC is increased, resulting in a lower transferrin saturation. Normal values are in the range of 25 to 45 percent [58,84]. Values below 10 percent are common in individuals with iron deficiency, and a cutoff of below 16 percent is generally used to screen for iron deficiency, although other thresholds may be used in some settings such as pregnancy (see 'Pregnant women' below). Because the TSAT is a ratio, in principle, an increase in the serum iron (eg, due to hemolysis or recent ingestion of an iron tablet) can raise the value, even in an individual who has iron deficiency and an increased TIBC.

Serum ferritin – Ferritin is a circulating iron storage protein that is increased in proportion to body iron stores. However, ferritin is also an acute phase reactant (see "Acute phase reactants") that can increase independently of iron status in disorders associated with inflammation, infection, liver disease, heart failure, and malignancy [85]. Thus, a very low ferritin level (eg, <15 ng/mL [<15 mcg/L]) is highly specific for iron deficiency, but a higher ferritin level may be "falsely normal" and cannot be used to eliminate the possibility of iron deficiency in individuals with comorbidities. The sensitivity for iron deficiency increases as the cutoff is raised, but specificity decreases; the ideal value is not clear and different values have been suggested for different populations, as discussed below. (See 'Diagnosis' below.)

Soluble transferrin receptor (sTfR) and sTfR-ferritin index – Soluble transferrin receptor (sTfR), also called circulating transferrin receptor or serum transferrin receptor, is a circulating protein derived from cleavage of the membrane transferrin receptor on bone marrow erythroid precursor cells. Its concentration in serum is directly proportional to erythropoietic rate and inversely proportional to tissue iron availability, similar to serum transferrin [86]. Thus, iron-deficient patients generally have increased levels of sTfR, with reference ranges determined by the individual laboratory performing the testing. sTfR is not used in routine practice but can be helpful in complex cases (see 'Patients with inconclusive initial testing or comorbidities' below). The major advantage of sTfR is that it reflects overall erythropoiesis, which is increased in iron deficiency. However, sTfR can be elevated in patients with hemolysis or with administration of erythropoiesis-stimulating agents (ESAs).

sTfR-ferritin index is calculated as the ratio of the sTfR (in mg/L) to the logarithm of the serum ferritin (in mcg/L): (sTfR  ÷  log[ferritin]). The sTfR reflects erythropoiesis, while the ferritin reflects the tissue iron stores; thus, a high sTfR-ferritin index (eg, above 2 to 3) is very likely to be a sign of iron deficiency due to increased erythropoietic drive and low iron stores. This index may be especially useful for population-based studies and for distinguishing between iron deficiency anemia and anemia of chronic disease (ACD) (see 'Differential diagnosis' below) because sTfR is increased in iron deficiency and normal in ACD, whereas ferritin is decreased in iron deficiency and normal to increased in ACD [21,56,87-90]. Patients with ACD are likely to have an sTfR-ferritin index <1, whereas those with isolated iron deficiency or iron deficiency plus ACD are likely to have an sTfR-ferritin index >2.

Some studies have shown the serum ferritin to be equally useful as the sTfR or the sTfR-ferritin index whereas others have found low serum ferritin to be a better predictor of iron deficiency than sTfR [91-93]. (See 'Patients with inconclusive initial testing or comorbidities' below.)

RBC protoporphyrin and RBC zinc protoporphyrin – In iron deficiency, intestinal zinc absorption increases, and zinc is incorporated into protoporphyrin in developing RBCs. Thus, elevated erythrocyte (RBC) zinc protoporphyrin (eg, >80 mcg/dL) is consistent with iron deficiency. However, zinc protoporphyrin is not specific for iron deficiency as it may be elevated in inflammatory states, hemodialysis, and lead poisoning. These assays are not widely available or routinely used for diagnosing iron deficiency. Their role in the diagnosis of other disorders (eg, lead poisoning, porphyria) is discussed separately. (See "Childhood lead poisoning: Clinical manifestations and diagnosis" and "Adult occupational lead poisoning" and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Erythrocyte protoporphyrin'.)

Bone marrow iron stain – Staining of the bone marrow aspirate smear for iron provides a qualitative assessment of iron in bone marrow cells (eg, macrophages, red blood cell precursors). Stainable bone marrow iron is considered the gold standard for assessing iron stores but is rarely required for diagnosis.

Appropriate use of these tests is described in the following sections. Additional information about the function of these proteins is presented separately. (See "Regulation of iron balance", section on 'Role of specific proteins'.)

Sequence of testing

Individuals without comorbidities — The serum or plasma ferritin concentration is an excellent indicator of iron stores in otherwise healthy adults and has replaced assessment of bone marrow iron stores as the gold standard for the diagnosis of iron deficiency in the healthy population (figure 2) [21,94-97]. By contrast, a low serum iron cannot be used to diagnose iron deficiency because iron may also be low in anemia of chronic disease.

The classic presentation of a patient without comorbidities is a multigravid woman who presents with tiredness and fatigue and a CBC that shows anemia with low MCV (eg, hemoglobin 8 g/dL, MCV 75 fL) and a peripheral blood smear that shows microcytic, hypochromic RBCs (picture 7). Iron studies are likely to show low iron (eg, 10 mcg/dL), low ferritin (eg, 10 ng/mL), and increased transferrin (eg, 400 mcg/dL; may also be reported as TIBC) with a low calculated transferrin saturation (2.5 percent). Such a patient is likely to have a brisk response to iron therapy. It is also important to consider the possibility of gastrointestinal blood loss, even in a menstruating woman.

Ferritin may be ordered as part of an "iron studies panel" or as an isolated test (algorithm 1). The diagnosis of iron deficiency can usually be made from the serum ferritin alone or the ferritin, iron, transferrin, and transferrin saturation without scheduling another visit [94-96,98,99]. However, in patients with a strong suspicion for iron deficiency, a normal ferritin value should not be used to exclude the possibility of iron deficiency; these individuals may require additional evaluations. (See 'Patients with inconclusive initial testing or comorbidities' below.)

As noted above, the normal ferritin concentration ranges from 40 to 200 ng/mL (mcg/L) in otherwise healthy, iron-replete individuals. (See 'Iron studies (list of available tests)' above.)

A ferritin level below 15 ng/mL is considered diagnostic of iron deficiency regardless of the patient's underlying condition. (See 'Diagnosis' below.)

Evidence to support the use of serum ferritin includes a 1992 systematic review that evaluated the performance of various iron studies compared with bone marrow stainable iron (the gold standard) in adults with anemia [100]. In this review, serum ferritin radioimmunoassay had the greatest predictive value for iron deficiency (figure 2):

A ferritin level ≤15 ng/mL had a likelihood ratio of 52-fold for iron deficiency

Ferritin levels in the range of 15 to 25 and 25 to 35 ng/mL remained predictive, but the likelihood decreased progressively the higher the ferritin cutoff was set (to 9 and 3, respectively)

By contrast, the lowest transferrin saturation and MCV had likelihood ratios of 10 and 12, respectively [100]. A ferritin below 15 ng/mL had a 99 percent specificity for iron deficiency. The analysis also demonstrated that ferritin levels ≤15 ng/mL were highly specific in individuals with inflammatory states.

However, the ferritin cutoff of 15 ng/mL will miss a large proportion of patients with iron deficiency. The sensitivity of this cutoff was only 59 percent in the systematic review, and in another study of 209 premenopausal women with absent iron stores on bone marrow testing, ferritin <16 ng/mL had a sensitivity of only 75 percent [100,101]. Thus, we also diagnose iron deficiency in individuals with a ferritin between 15 and 41 ng/mL who have anemia, especially if the history suggests iron deficiency and if the patient has a response to iron therapy. In a series of 62 anemic adults, a cutoff ferritin level of 30 ng/mL had a sensitivity and specificity of 92 and 98 percent, respectively [102], and in another series of 129 anemic adults, a cutoff ferritin level of 41 ng/mL had a sensitivity and specificity of 98 and 98 percent, respectively [88].

As noted above, ferritin is an acute phase reactant, and a normal or elevated ferritin level cannot be used to exclude iron deficiency in patients with comorbidities that cause acute phase reactants to be elevated. Additional testing may be helpful for those with values >41 ng/mL for whom the suspicion of iron deficiency is high.

Patients with inconclusive initial testing or comorbidities — Many individuals with iron deficiency or iron deficiency anemia in resource-rich countries do not have the classic presentation of anemia with a markedly decreased ferritin, either because they come to medical attention before severe deficiency develops or because they have multifactorial anemia (eg, iron deficiency and anemia of chronic disease). These patients may require additional assessment with other laboratory tests, a therapeutic trial of iron, or (very rarely) bone marrow evaluation (algorithm 1).

For patients with comorbidities and a serum ferritin <41 ng/mL, we consider the diagnosis of iron deficiency very likely, similar to patients without comorbidities. Other thresholds (eg, <30 ng/mL) may also be used [21].

For those with a chronic inflammatory condition and higher ferritin levels, a useful rule of thumb is to divide the patient's serum ferritin level by three, as inflammation can elevate the ferritin level approximately threefold [58]. As an example, in a study of 67 anemic adults with rheumatoid arthritis, a serum ferritin concentration <60 ng/mL had 83 percent accuracy for predicting a response to oral iron therapy [103]. However, changes in ferritin in inflammatory states can be highly variable, and other methods of determining iron deficiency in the setting of inflammation may be more helpful (eg, trial of iron administration; sTfR-ferritin index). (See 'Iron studies (list of available tests)' above and 'Response to a therapeutic trial of iron' below.)

If the serum ferritin is considered inconclusive, the transferrin saturation (TSAT) may be helpful. Confidence in the diagnosis of iron deficiency is greater with lower TSAT values, although the optimal threshold for TSAT to use for iron deficiency has not been established. The likelihood of iron deficiency is very high with a TSAT of <10 percent (<20 percent if concomitant inflammation); a TSAT value <16 percent is indicative of a need to address possible iron deficiency [21,22,100,104]. Transferrin saturation is challenging to interpret in inflammatory states. It is usually low, with both serum iron and transferrin reduced.

If the ferritin is above 41 ng/mL and the transferrin saturation is above 20 percent but the suspicion for iron deficiency remains, available testing includes the sTfR or sTfR-ferritin index, bone marrow aspirate with iron stain, or therapeutic trial of iron. The choice among these tests is individualized according to available resources, patient preference, and other diagnostic considerations. Involvement of the consulting hematologist may be helpful. (See 'Iron studies (list of available tests)' above and 'Response to a therapeutic trial of iron' below.)

In some patients the clinical situation is more complex, and additional evaluations and/or management considerations may predominate. Individuals with poorly controlled heart failure or diabetes may require a more thorough assessment of the reasons for poor control; individuals with other unexplained findings (eg, weight loss, adenopathy) may require further diagnostic testing for the cause of their symptoms. In such cases, it may be reasonable to defer a more extensive evaluation for iron deficiency and/or a therapeutic trial of iron until after these other issues are resolved.

The increase in ferritin level conferred by a chronic inflammatory state was demonstrated in a study that retrospectively reviewed records for several thousand patients who had measurements of ferritin as well as C-reactive protein (CRP) and albumin [105]. Median ferritin levels for increasing CRP were as follows:

CRP <10 mg/L (least inflammation) – ferritin 85 mcg/L

CRP 10 to 80 mg/L – ferritin 193 mcg/L

CRP >80 mg/L (greatest inflammation) – ferritin 342 mcg/L

Lower serum albumin levels were also associated with higher serum ferritin levels.

Pregnant women — Pregnancy is associated with increased iron requirements, and iron deficiency is common, especially in individuals who are not iron replete before the pregnancy (eg, due to heavy menses, prior pregnancies, or lactation) and possibly in those who do not receive prenatal vitamins with iron. This subject is discussed separately. (See "Nutrition in pregnancy", section on 'Iron'.)

For pregnant women with anemia greater than that expected by normal pregnancy physiology (see "Maternal adaptations to pregnancy: Hematologic changes", section on 'Dilutional anemia'), it is appropriate to test for iron deficiency. Serum ferritin is a good initial screening test. In one study of pregnant women, a serum ferritin concentration <30 ng/mL was the best single indicator of reduced storage iron [106]. When used as a screening test for iron deficiency, it had a sensitivity of 90 percent and specificity of 85 percent. Measurement of serum iron, transferrin/TIBC, and percent saturation of TIBC had significantly lower diagnostic accuracy; this may be because pregnancy increases the transferrin concentration (and thus decreases the percent saturation) independent of iron stores [99]. If iron studies are borderline for iron deficiency, they can be repeated in two to three weeks, and if they continue to fall, with transferrin saturation 15 percent or lower, iron can be administered. (See "Treatment of iron deficiency anemia in adults", section on 'Pregnancy'.)

Response to a therapeutic trial of iron — A presumptive diagnosis of iron deficiency anemia may be made using a therapeutic trial of iron in a patient with anemia who has an obvious cause of iron deficiency such as individuals in resource-limited settings where it is not possible to obtain iron studies routinely, or in young women with heavy menstrual periods or pregnancy. In such cases, patients with iron deficiency anemia are expected to have a rapid and complete response to iron administration that includes resolution of symptoms, reticulocytosis, and normalization of hemoglobin level. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)

However, as noted above, this approach should be reserved for individuals for whom other causes of anemia are unlikely (eg, it should be reserved for young, otherwise healthy individuals who do not have thalassemia) because it does not address other causes of anemia or the source of blood/iron loss, which is a crucial component of management. Further, it may be difficult to determine the reason(s) for a lack of response to iron if iron studies are not available. Additionally, administration of iron to an individual with thalassemia will worsen the existing iron overload commonly seen in this condition. Thus, it may be prudent to obtain iron studies to confirm the diagnosis even in cases where iron deficiency is considered extremely likely. For patients who wish to avoid a return appointment, we find it cost-effective to order iron studies and prescribe iron therapy at the same encounter, with plans to obtain additional testing only if the initial testing was inconclusive. (See 'Iron studies (list of available tests)' above.)

For those who do not respond to a therapeutic trial of iron, it is appropriate to obtain iron studies (eg, serum iron, transferrin/TIBC, and ferritin) as well as to investigate the reasons for a lack of response (table 5). (See 'Diagnostic evaluation' above and "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)

Diagnosis — We consider the diagnosis of iron deficiency to be confirmed by any one of the following findings in the appropriate clinical setting:

Serum ferritin <15 ng/mL (or <30 ng/mL in a pregnant woman)

Serum ferritin <41 ng/mL in a patient with anemia and comorbidities (see 'Patients with inconclusive initial testing or comorbidities' above)

Transferrin saturation <16 percent (<20 percent in individuals with inflammatory conditions); mostly used in patients for whom the ferritin is thought to be unreliable due to an inflammatory state

Anemia that resolves upon iron administration

Absence of stainable iron in the bone marrow (providing that adequate staining controls are performed)

Diagnosis should be accompanied by identification for the cause of iron deficiency and a strategy to treat the deficiency, if clinically indicated, as well as management of the underlying cause of the deficiency. For individuals with uncomplicated symptomatic iron deficiency or other comorbidities likely to benefit from iron repletion, the decision to treat with iron is straightforward. By contrast, there may be some individuals with significant comorbidities or other findings for whom it may be prudent to defer the correction of iron deficiency and avoid the gastrointestinal side effects of oral iron while addressing the patient's dominant findings. (See 'Search for source of blood and iron loss' below and "Treatment of iron deficiency anemia in adults".)

We diagnose functional iron deficiency (see 'Absolute versus functional deficiency' above) in patients with chronic kidney disease or a malignancy who are candidates for treatment with an erythropoiesis-stimulating agent (ESA) if the serum ferritin is in the range of 100 to 500 ng/mL and the transferrin saturation is in the range of 20 to 30 percent. The implication is that these individuals would benefit from iron administration (typically, intravenous iron). (See "Diagnosis of iron deficiency in chronic kidney disease" and "Treatment of iron deficiency in nondialysis chronic kidney disease (CKD) patients" and "Treatment of iron deficiency in hemodialysis patients" and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer".)

By contrast, patients with anemia of chronic disease generally are not diagnosed with functional iron deficiency because the major management intervention for these individuals is treatment of the underlying chronic condition. (See "Anemia of chronic disease/inflammation".)

Search for source of blood and iron loss — Iron deficiency almost always requires treatment, which includes iron administration and identification of the underlying cause, regardless of the severity of the deficiency and/or the presence of anemia [107]. Even before the diagnosis of iron deficiency is confirmed, individuals with suspected iron deficiency should be asked to provide information that might identify the source of the deficiency, which is more likely to be dietary in individuals in resource-poor settings and more likely to be due to blood loss in menstruating or pregnant females and adults of either sex.

This initial evaluation may involve the following:

Dietary history for infants (eg, use of cow's milk rather than iron-supplemented formula or breastfeeding)

Menstrual/pregnancy/lactation history for females (table 6)

History of gastrointestinal blood loss, melena, hematemesis, and hematuria

History of multiple blood donations

Marathon running [96]

Use of non-steroidal anti-inflammatory drugs (NSAIDS) or anticoagulants

Personal or family history of bleeding diathesis, including platelet disorders, von Willebrand disease, hereditary hemorrhagic telangiectasia

Personal or family history of celiac disease, colon cancer, or other gastrointestinal disorders

Review of the results of prior gastrointestinal evaluations (eg, routine colon cancer screening)

Testing the stool for occult blood in adults 50 years of age or older

If iron deficiency is diagnosed, additional testing for possible occult gastrointestinal blood loss (eg, with endoscopy) is indicated for adults of all ages for whom a source of bleeding would be treated [108]. Several of the common causes, such as colonic and uterine cancer, have ominous prognoses unless discovered and treated promptly. An exception might be a very elderly individual who would prefer not to be treated or evaluated for malignancy. Evaluation for occult gastrointestinal bleeding and an approach to testing for gastrointestinal lesions is presented in detail separately. (See "Evaluation of occult gastrointestinal bleeding" and "Approach to acute lower gastrointestinal bleeding in adults" and "Evaluation of suspected small bowel bleeding (formerly obscure gastrointestinal bleeding)".)

The use of an anticoagulant or the presence of thrombocytopenia are important to note as they may contribute to bleeding. However, anticoagulation or thrombocytopenia do not diminish the importance of searching for the site(s) of bleeding such as a gastrointestinal or colonic lesion, as these hemostatic changes are often more likely to unmask a bleeding source (and potentially result in earlier diagnosis) than to cause bleeding from a normal mucosa [109].

Celiac disease is important to identify if present; this can present at any age and symptoms may be absent (or may only be appreciated in retrospect). Celiac disease is also a common cause of a lack of response to iron therapy in patients with known iron deficiency because it interferes with iron absorption. (See 'Celiac disease/atrophic gastritis/H. pylori' above and "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation'.)

Differential diagnosis — The differential diagnosis of iron deficiency (without anemia) includes other causes of fatigue, pica, and restless legs syndrome (RLS). The differential diagnosis of iron deficiency anemia includes other causes of microcytic or hypoproliferative anemia (table 7). It is important to keep in mind that anemia may be multifactorial, and some individuals with other causes of anemia may also have iron deficiency.

Other causes of fatigue – Other causes of fatigue are numerous and include a number of endocrine, cardiac, pulmonary, and other medical and psychiatric conditions. Like iron deficiency, symptoms may be vague and nonspecific, and in some cases, these individuals may have anemia of chronic inflammation (anemia of chronic disease). Unlike iron deficiency, individuals with these other conditions do not have laboratory evidence of low iron stores or a response to iron therapy. An approach to evaluating unexplained fatigue in adults is presented separately. (See "Approach to the adult patient with fatigue".)

Other causes of pica – Other causes of pica include a primary eating disorder, which may be associated with developmental disabilities, and possibly micronutrient deficiencies (eg, zinc) and lead poisoning. As in patients with iron deficiency, patients with these conditions often are unaware of the source of the urge to eat non-food substances. Unlike iron deficiency, individuals with these other disorders do not have laboratory evidence of low iron stores or a response to iron therapy. (See "Eating disorders: Overview of epidemiology, clinical features, and diagnosis", section on 'Pica'.)

Other causes of restless legs syndrome – Other causes of RLS include a number of neurologic conditions, pregnancy, leg cramps, and sleep disturbances. Like iron deficiency, these can cause a strong urge to move the legs. Unlike iron deficiency, these other conditions are not associated with globally decreased iron stores or evidence of iron deficiency in the peripheral blood. (See "Clinical features and diagnosis of restless legs syndrome and periodic limb movement disorder in adults".)

Other causes of anemia and/or microcytosis – The other major causes of microcytic anemia are thalassemia and sideroblastic anemia; anemia of chronic disease may also cause microcytic or normocytic anemia. Additional causes of anemia are listed in the table (table 7). (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis'.)

Thalassemia – Thalassemias are inherited hemoglobin disorders associated with reduced production of alpha globin (alpha thalassemia), and beta globin (beta thalassemia). Like iron deficiency, thalassemia can cause microcytic anemia with hypochromic RBCs and target cells on the peripheral blood smear, the extent of which depends on the thalassemia phenotype (picture 9 and picture 10 and picture 11). Unlike iron deficiency anemia, individuals with thalassemia have normal to increased RBC production and a normal to high RBC count on the CBC, characteristic findings on hemoglobin analysis, and often increased iron stores due to ineffective erythropoiesis and/or transfusions. (See "Clinical manifestations and diagnosis of the thalassemias".)

Sideroblastic anemia – Sideroblastic anemias are characterized by the presence of ring sideroblasts on an iron stain of a bone marrow aspirate (picture 12). Causes are varied and include a number of rare inherited and acquired disorders, copper deficiency, and myelodysplastic/myeloproliferative neoplasms. Like iron deficiency, some of the inherited sideroblastic anemias can be microcytic. Unlike iron deficiency, these disorders are often associated with increased iron stores. By definition, individuals with sideroblastic anemia have iron present in the bone marrow aspirate because stainable iron is required to produce the ring sideroblast phenotype. (See "Sideroblastic anemias: Diagnosis and management".)

Anemia of chronic disease – Anemia of chronic inflammation (anemia of chronic disease [ACD]) is characterized by reduced production of RBCs due to an inflammatory block; iron is present in the reticuloendothelial system and bone marrow macrophages but cannot be supplied to developing RBCs due to high levels of hepcidin, which traps iron in storage cells. Like those with iron deficiency, patients with ACD may have microcytic or normocytic anemia with a low serum iron and low transferrin (or TIBC). Unlike those with iron deficiency, individuals with ACD have a chronic inflammatory state, often with increased storage iron (picture 8) and high levels of ferritin and other acute phase reactants. Distinction between iron deficiency anemia and ACD may be difficult, and in especially challenging cases may require calculation of the sTfR-ferritin index (see 'Iron studies (list of available tests)' above), bone marrow evaluation, therapeutic trial of iron, and/or repeat testing after additional treatment for an underlying inflammatory state. (See "Anemia of chronic disease/inflammation".)

Other anemias – Other causes of anemia include renal failure, hypo- or hyperthyroidism, excessive alcohol use, and bone marrow disorders such as myelodysplastic syndromes (MDS). Lead poisoning rarely causes anemia unless it is severe. Like iron deficiency, these may develop gradually with nonspecific symptoms. Unlike iron deficiency, these anemias are associated with other laboratory findings rather than (or in addition to) evidence of decreased iron stores; in many cases the anemia is normocytic or macrocytic. MDS can be associated with microcytic or macrocytic anemia. Excess alcohol generally causes macrocytic anemia. (See "Approach to the adult with anemia" and "Microcytosis/Microcytic anemia" and "Anemia in adults due to decreased red blood cell production".)

Indications for referral (hematologist or gastroenterologist) — Referral to a hematologist is not indicated in the majority of patients with straightforward iron deficiency. However, referral is appropriate for those in whom iron studies are inconclusive, the diagnosis is unclear, or the administration of intravenous iron is under consideration. Referral to a gastroenterologist is appropriate in individuals for whom an occult source of gastrointestinal blood loss or malabsorption is suspected.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Anemia caused by low iron (The Basics)")

Beyond the Basics topics (see "Patient education: Anemia caused by low iron in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Iron deficiency affects over 12 percent of the world's population, especially women of childbearing age, children, and individuals living in low- and middle-income countries. The absolute prevalence depends on the population studied. (See 'Epidemiology' above.)

Major causes of iron deficiency include blood loss and reduced absorption (eg, due to celiac disease, Helicobacter pylori [H. pylori], gastritis, or bariatric surgery). Less common causes include use of erythropoiesis-stimulating agents (ESAs), urinary or pulmonary hemosiderosis, or rare inherited disorders. (See 'Causes of iron deficiency' above.)

Iron deficiency occurs in several stages, as illustrated by progressive changes in laboratory findings (table 4). (See 'Stages of iron deficiency' above.)

Clinical manifestations of iron deficiency depend on severity and may include symptoms of anemia, pica, and restless legs syndrome. The examination may be normal or show pallor, alopecia, dry skin, atrophic glossitis (picture 1), angular cheilitis (picture 3), or koilonychia (spoon nails) (picture 5). The complete blood count (CBC) may be normal or show microcytic, hypochromic anemia (picture 7) with low red blood cell (RBC) and reticulocyte counts and an elevated platelet count. (See 'Clinical manifestations' above.)

A number of tests are available for evaluating iron status (algorithm 1). Serum ferritin is the most useful, especially in uncomplicated patients (eg, those without a chronic inflammatory state or multifactorial anemia). Ferritin is often measured together with the serum iron and transferrin (TIBC) and the percent transferrin saturation (TSAT) is calculated. (See 'Overview of evaluation' above and 'Iron studies (list of available tests)' above.)

A serum ferritin level <15 ng/mL is considered confirmatory for iron deficiency at any hemoglobin concentration, and a serum ferritin level <41 ng/mL is considered confirmatory for iron deficiency anemia in an individual with a low hemoglobin concentration. (See 'Individuals without comorbidities' above.)

More complex patients may require additional testing including TSAT, soluble transferrin receptor (sTfR) or sTfR-ferritin index, or bone marrow iron stain. (See 'Patients with inconclusive initial testing or comorbidities' above.)

A response to a therapeutic trial of iron administration may be helpful in confirming the diagnosis of iron deficiency anemia. Lack of a response may be due to an alternative diagnosis or to conditions such as celiac disease or H. pylori infection. (See 'Response to a therapeutic trial of iron' above and "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)

Patients with iron deficiency or iron deficiency anemia should have a thorough history and examination for possible causes of the deficiency, which may precede the final diagnosis. Those with confirmed iron deficiency for whom a cause is not obvious should have additional evaluations that may include endoscopy or testing for H. pylori or celiac disease, especially individuals age 50 or older and those who do not have a response to iron repletion. (See 'Search for source of blood and iron loss' above.)

The differential diagnosis of iron deficiency includes a number of other causes of fatigue, pica, and restless legs syndrome. The major conditions in the differential diagnosis of iron deficiency anemia include thalassemias, sideroblastic anemias, and the anemia of chronic inflammation/anemia of chronic disease. (See 'Differential diagnosis' above and "Clinical manifestations and diagnosis of the thalassemias" and "Anemia of chronic disease/inflammation".)

Treatment of iron deficiency and iron deficiency anemia in adults is presented in detail separately. (See "Treatment of iron deficiency anemia in adults".)

Related topics, including an overall approach to anemia in adults and the diagnosis of iron deficiency in children, pregnant women, and individuals with chronic renal failure, are also discussed separately. (See "Approach to the adult with anemia" and "Approach to the child with anemia" and "Maternal adaptations to pregnancy: Hematologic changes" and "Diagnosis of iron deficiency in chronic kidney disease".)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

  1. http://www.cdc.gov/nchs/data/nhanes/survey_content_99_16.pdf (Accessed on June 07, 2016).
  2. Looker AC, Dallman PR, Carroll MD, et al. Prevalence of iron deficiency in the United States. JAMA 1997; 277:973.
  3. Miller EM. Iron status and reproduction in US women: National Health and Nutrition Examination Survey, 1999-2006. PLoS One 2014; 9:e112216.
  4. Park CY, Eicher-Miller HA. Iron deficiency is associated with food insecurity in pregnant females in the United States: National Health and Nutrition Examination Survey 1999-2010. J Acad Nutr Diet 2014; 114:1967.
  5. Mei Z, Cogswell ME, Looker AC, et al. Assessment of iron status in US pregnant women from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Am J Clin Nutr 2011; 93:1312.
  6. Price EA, Mehra R, Holmes TH, Schrier SL. Anemia in older persons: etiology and evaluation. Blood Cells Mol Dis 2011; 46:159.
  7. Mast AE, Bialkowski W, Bryant BJ, et al. A randomized, blinded, placebo-controlled trial of education and iron supplementation for mitigation of iron deficiency in regular blood donors. Transfusion 2016; 56:1588.
  8. Baart AM, van Noord PA, Vergouwe Y, et al. High prevalence of subclinical iron deficiency in whole blood donors not deferred for low hemoglobin. Transfusion 2013; 53:1670.
  9. Mantilla-Gutiérrez CY, Cardona-Arias JA. [Iron deficiency prevalence in blood donors: a systematic review, 2001-2011]. Rev Esp Salud Publica 2012; 86:357.
  10. Shams S, Asheri H, Kianmehr A, et al. The prevalence of iron deficiency anaemia in female medical students in Tehran. Singapore Med J 2010; 51:116.
  11. Serdula MK, Nichols EK, Aburto NJ, et al. Micronutrient status in Jordan: 2002 and 2010. Eur J Clin Nutr 2014; 68:1124.
  12. Lee JO, Lee JH, Ahn S, et al. Prevalence and risk factors for iron deficiency anemia in the korean population: results of the fifth KoreaNational Health and Nutrition Examination Survey. J Korean Med Sci 2014; 29:224.
  13. Al Zenki S, Alomirah H, Al Hooti S, et al. Prevalence and Determinants of Anemia and Iron Deficiency in Kuwait. Int J Environ Res Public Health 2015; 12:9036.
  14. Mejía-Rodríguez F, Shamah-Levy T, Villalpando S, et al. Iron, zinc, copper and magnesium deficiencies in Mexican adults from the National Health and Nutrition Survey 2006. Salud Publica Mex 2013; 55:275.
  15. Fonseca C, Marques F, Robalo Nunes A, et al. Prevalence of anaemia and iron deficiency in Portugal: the EMPIRE study. Intern Med J 2016; 46:470.
  16. Wirth JP, Rohner F, Woodruff BA, et al. Anemia, Micronutrient Deficiencies, and Malaria in Children and Women in Sierra Leone Prior to the Ebola Outbreak - Findings of a Cross-Sectional Study. PLoS One 2016; 11:e0155031.
  17. Cook JD, Skikne BS. Iron deficiency: definition and diagnosis. J Intern Med 1989; 226:349.
  18. Bryant BJ, Yau YY, Arceo SM, et al. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion 2013; 53:1637.
  19. Spencer B. Blood donor iron status: are we bleeding them dry? Curr Opin Hematol 2013; 20:533.
  20. Annibale B, Capurso G, Chistolini A, et al. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med 2001; 111:439.
  21. Camaschella C. Iron-deficiency anemia. N Engl J Med 2015; 372:1832.
  22. Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet 2016; 387:907.
  23. Khadem G, Scott IA, Klein K. Evaluation of iron deficiency anaemia in tertiary hospital settings: room for improvement? Intern Med J 2012; 42:658.
  24. Ho CH, Chau WK, Hsu HC, et al. Predictive risk factors and prevalence of malignancy in patients with iron deficiency anemia in Taiwan. Am J Hematol 2005; 78:108.
  25. Ioannou GN, Rockey DC, Bryson CL, Weiss NS. Iron deficiency and gastrointestinal malignancy: a population-based cohort study. Am J Med 2002; 113:276.
  26. Camaschella C. Iron deficiency: new insights into diagnosis and treatment. Hematology Am Soc Hematol Educ Program 2015; 2015:8.
  27. Harper JW, Holleran SF, Ramakrishnan R, et al. Anemia in celiac disease is multifactorial in etiology. Am J Hematol 2007; 82:996.
  28. Unsworth DJ, Lock FJ, Harvey RF. Iron-deficiency anaemia in premenopausal women. Lancet 1999; 353:1100.
  29. Corazza GR, Valentini RA, Andreani ML, et al. Subclinical coeliac disease is a frequent cause of iron-deficiency anaemia. Scand J Gastroenterol 1995; 30:153.
  30. Unsworth DJ, Lock RJ, Harvey RF. Improving the diagnosis of coeliac disease in anaemic women. Br J Haematol 2000; 111:898.
  31. Hershko C, Lahad A, Kereth D. Gastropathic sideropenia. Best Pract Res Clin Haematol 2005; 18:363.
  32. Hershko C, Hoffbrand AV, Keret D, et al. Role of autoimmune gastritis, Helicobacter pylori and celiac disease in refractory or unexplained iron deficiency anemia. Haematologica 2005; 90:585.
  33. Kalantar-Zadeh K, Höffken B, Wünsch H, et al. Diagnosis of iron deficiency anemia in renal failure patients during the post-erythropoietin era. Am J Kidney Dis 1995; 26:292.
  34. Eschbach JW, Cook JD, Scribner BH, Finch CA. Iron balance in hemodialysis patients. Ann Intern Med 1977; 87:710.
  35. Delbini P, Vaja V, Graziadei G, et al. Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. Br J Haematol 2010; 151:281–4.
  36. Hershko C, Camaschella C. How I treat unexplained refractory iron deficiency anemia. Blood 2014; 123:326.
  37. Finberg KE, Heeney MM, Campagna DR, et al. Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA). Nat Genet 2008; 40:569.
  38. Guillem F, Lawson S, Kannengiesser C, et al. Two nonsense mutations in the TMPRSS6 gene in a patient with microcytic anemia and iron deficiency. Blood 2008; 112:2089.
  39. Melis MA, Cau M, Congiu R, et al. A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica 2008; 93:1473.
  40. Edison ES, Athiyarath R, Rajasekar T, et al. A novel splice site mutation c.2278 (-1) G>C in the TMPRSS6 gene causes deletion of the substrate binding site of the serine protease resulting in refractory iron deficiency anaemia. Br J Haematol 2009; 147:766.
  41. De Falco L, Sanchez M, Silvestri L, et al. Iron refractory iron deficiency anemia. Haematologica 2013; 98:845.
  42. Jaspers A, Caers J, Le Gac G, et al. A novel mutation in the CUB sequence of matriptase-2 (TMPRSS6) is implicated in iron-resistant iron deficiency anaemia (IRIDA). Br J Haematol 2013; 160:564.
  43. Khuong-Quang DA, Schwartzentruber J, Westerman M, et al. Iron refractory iron deficiency anemia: presentation with hyperferritinemia and response to oral iron therapy. Pediatrics 2013; 131:e620.
  44. Poggiali E, Andreozzi F, Nava I, et al. The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment. Am J Hematol 2015; 90:306.
  45. Silvestri L, Guillem F, Pagani A, et al. Molecular mechanisms of the defective hepcidin inhibition in TMPRSS6 mutations associated with iron-refractory iron deficiency anemia. Blood 2009; 113:5605.
  46. Heeney MM, Finberg KE. Iron-refractory iron deficiency anemia (IRIDA). Hematol Oncol Clin North Am 2014; 28:637.
  47. Nai A, Pagani A, Silvestri L, Camaschella C. Increased susceptibility to iron deficiency of Tmprss6-haploinsufficient mice. Blood 2010; 116:851.
  48. Finberg KE, Whittlesey RL, Fleming MD, Andrews NC. Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 2010; 115:3817.
  49. Casu C, Rivella S. Iron age: novel targets for iron overload. Hematology Am Soc Hematol Educ Program 2014; 2014:216.
  50. Stirnberg M, Gütschow M. Matriptase-2, a regulatory protease of iron homeostasis: possible substrates, cleavage sites and inhibitors. Curr Pharm Des 2013; 19:1052.
  51. Mims MP, Guan Y, Pospisilova D, et al. Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload. Blood 2005; 105:1337.
  52. Iolascon A, d'Apolito M, Servedio V, et al. Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2). Blood 2006; 107:349.
  53. Beaumont C, Delaunay J, Hetet G, et al. Two new human DMT1 gene mutations in a patient with microcytic anemia, low ferritinemia, and liver iron overload. Blood 2006; 107:4168.
  54. Iolascon A, De Falco L. Mutations in the gene encoding DMT1: clinical presentation and treatment. Semin Hematol 2009; 46:358.
  55. Barrios M, Moreno-Carralero MI, Cuadrado-Grande N, et al. The homozygous mutation G75R in the human SLC11A2 gene leads to microcytic anaemia and iron overload. Br J Haematol 2012; 157:514.
  56. Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003; 101:3359.
  57. Cook JD, Finch CA, Smith NJ. Evaluation of the iron status of a population. Blood 1976; 48:449.
  58. Cook JD. Clinical evaluation of iron deficiency. Semin Hematol 1982; 19:6.
  59. Cook JD, Skikne BS, Lynch SR, Reusser ME. Estimates of iron sufficiency in the US population. Blood 1986; 68:726.
  60. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood 2010; 116:4754.
  61. Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2013; 161:639.
  62. Johnson BE. Pica. In: Clinical Methods: The History, Physical, and Laboratory Examinations, 3rd edition, Walker HK, Hall WD, Hurst JW (Eds), Butterworths, Boston 1990.
  63. Simpson E, Mull JD, Longley E, East J. Pica during pregnancy in low-income women born in Mexico. West J Med 2000; 173:20.
  64. Kettaneh A, Eclache V, Fain O, et al. Pica and food craving in patients with iron-deficiency anemia: a case-control study in France. Am J Med 2005; 118:185.
  65. Rector WG Jr. Pica: its frequency and significance in patients with iron-deficiency anemia due to chronic gastrointestinal blood loss. J Gen Intern Med 1989; 4:512.
  66. Reynolds RD, Binder HJ, Miller MB, et al. Pagophagia and iron deficiency anemia. Ann Intern Med 1968; 69:435.
  67. Tunnessen WW, Smith C, Oski FA. Beeturia. A sign of iron deficiency. Am J Dis Child 1969; 117:424.
  68. Sotos JG. Beeturia and iron absorption. Lancet 1999; 354:1032.
  69. WATSON WC, LUKE RG, INALL JA. BEETURIA: ITS INCIDENCE AND A CLUE TO ITS MECHANISM. Br Med J 1963; 2:971.
  70. Allen RP, Auerbach S, Bahrain H, et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013; 88:261.
  71. Schieffer KM, Chuang CH, Connor J, et al. Association of Iron Deficiency Anemia With Hearing Loss in US Adults. JAMA Otolaryngol Head Neck Surg 2017; 143:350.
  72. Auerbach M, Adamson JW. How we diagnose and treat iron deficiency anemia. Am J Hematol 2016; 91:31.
  73. Osaki T, Ueta E, Arisawa K, et al. The pathophysiology of glossal pain in patients with iron deficiency and anemia. Am J Med Sci 1999; 318:324.
  74. Trost LB, Bergfeld WF, Calogeras E. The diagnosis and treatment of iron deficiency and its potential relationship to hair loss. J Am Acad Dermatol 2006; 54:824.
  75. HOWELL JT, MONTO RW. Syndrome of anemia, dysphagia and glossitis (Plummer Vinson syndrome). N Engl J Med 1953; 249:1009.
  76. Crosby WH. Whatever became of chlorosis? JAMA 1987; 257:2799.
  77. Brugnara C. Use of reticulocyte cellular indices in the diagnosis and treatment of hematological disorders. Int J Clin Lab Res 1998; 28:1.
  78. Mast AE, Blinder MA, Dietzen DJ. Reticulocyte hemoglobin content. Am J Hematol 2008; 83:307.
  79. Brugnara C, Zurakowski D, DiCanzio J, et al. Reticulocyte hemoglobin content to diagnose iron deficiency in children. JAMA 1999; 281:2225.
  80. Fishbane S, Galgano C, Langley RC Jr, et al. Reticulocyte hemoglobin content in the evaluation of iron status of hemodialysis patients. Kidney Int 1997; 52:217.
  81. Recommendations to prevent and control iron deficiency in the United States. Centers for Disease Control and Prevention. MMWR Morb Mortal Wkly Rep 1998; 47(RR-3):1.
  82. Siu AL, U.S. Preventive Services Task Force. Screening for Iron Deficiency Anemia and Iron Supplementation in Pregnant Women to Improve Maternal Health and Birth Outcomes: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med 2015; 163:529.
  83. https://www.uspreventiveservicestaskforce.org/Page/Document/RecommendationStatementFinal/iron-deficiency-anemia-screening (Accessed on November 29, 2016).
  84. Finch CA, Huebers H. Perspectives in iron metabolism. N Engl J Med 1982; 306:1520.
  85. Tran TN, Eubanks SK, Schaffer KJ, et al. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood 1997; 90:4979.
  86. Lok CN, Loh TT. Regulation of transferrin function and expression: review and update. Biol Signals Recept 1998; 7:157.
  87. Radtke H, Meyer T, Kalus U, et al. Rapid identification of iron deficiency in blood donors with red cell indexes provided by Advia 120. Transfusion 2005; 45:5.
  88. Punnonen K, Irjala K, Rajamäki A. Serum transferrin receptor and its ratio to serum ferritin in the diagnosis of iron deficiency. Blood 1997; 89:1052.
  89. Brugnara C. Iron deficiency and erythropoiesis: new diagnostic approaches. Clin Chem 2003; 49:1573.
  90. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med 2005; 352:1011.
  91. Suominen P, Punnonen K, Rajamäki A, Irjala K. Serum transferrin receptor and transferrin receptor-ferritin index identify healthy subjects with subclinical iron deficits. Blood 1998; 92:2934.
  92. Malope BI, MacPhail AP, Alberts M, Hiss DC. The ratio of serum transferrin receptor and serum ferritin in the diagnosis of iron status. Br J Haematol 2001; 115:84.
  93. Cazzola M, Beguin Y, Bergamaschi G, et al. Soluble transferrin receptor as a potential determinant of iron loading in congenital anaemias due to ineffective erythropoiesis. Br J Haematol 1999; 106:752.
  94. Fairbanks VF. Laboratory testing for iron status. Hosp Pract 1990; 26:17.
  95. Zanella A, Gridelli L, Berzuini A, et al. Sensitivity and predictive value of serum ferritin and free erythrocyte protoporphyrin for iron deficiency. J Lab Clin Med 1989; 113:73.
  96. McMahon LF Jr, Ryan MJ, Larson D, Fisher RL. Occult gastrointestinal blood loss in marathon runners. Ann Intern Med 1984; 100:846.
  97. Finch CA, Bellotti V, Stray S, et al. Plasma ferritin determination as a diagnostic tool. West J Med 1986; 145:657.
  98. Brittenham GM. Disorders of iron metabolism: Iron deficiency and overload. In: Hematology Basic Principles and Practice, 2nd ed, Hoffman R, Benz EJ Jr, Shattil SJ, et al. (Eds), Churchill Livingstone, New York 1995.
  99. Bridges KR, Seligman PA. Disorders of iron metabolism. In: Blood: Principles & Practice of Hematology, Handin RI, Lux SE, Stossel TP (Eds), 1995. p.ch.49.
  100. Guyatt GH, Oxman AD, Ali M, et al. Laboratory diagnosis of iron-deficiency anemia: an overview. J Gen Intern Med 1992; 7:145.
  101. Hallberg L, Bengtsson C, Lapidus L, et al. Screening for iron deficiency: an analysis based on bone-marrow examinations and serum ferritin determinations in a population sample of women. Br J Haematol 1993; 85:787.
  102. Mast AE, Blinder MA, Gronowski AM, et al. Clinical utility of the soluble transferrin receptor and comparison with serum ferritin in several populations. Clin Chem 1998; 44:45.
  103. Hansen TM, Hansen NE. Serum ferritin as indicator of iron responsive anaemia in patients with rheumatoid arthritis. Ann Rheum Dis 1986; 45:596.
  104. Beutler E, Waalen J. The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration? Blood 2006; 107:1747.
  105. McSorley ST, Jones I, McMillan DC, Talwar D. Quantitative data on the magnitude of the systemic inflammatory response and its relationship with serum measures of iron status. Transl Res 2016; 176:119.
  106. van den Broek NR, Letsky EA, White SA, Shenkin A. Iron status in pregnant women: which measurements are valid? Br J Haematol 1998; 103:817.
  107. Goddard AF, James MW, McIntyre AS, et al. Guidelines for the management of iron deficiency anaemia. Gut 2011; 60:1309.
  108. Rockey DC, Cello JP. Evaluation of the gastrointestinal tract in patients with iron-deficiency anemia. N Engl J Med 1993; 329:1691.
  109. Hreinsson JP, Jonasson JG, Bjornsson ES. Bleeding-related symptoms in colorectal cancer: a 4-year nationwide population-based study. Aliment Pharmacol Ther 2014; 39:77.
Topic 7150 Version 55.0