Diagnosis of iron deficiency and iron deficiency anemia in adults

INTRODUCTION — 

The diagnosis of iron deficiency (low iron stores, as measured by iron studies or other testing) 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.

Separate topics discuss causes of iron deficiency and treatment with oral and intravenous iron:

●Causes – (See "Determining the cause of iron deficiency in adolescents and adults".)

●Treatment – (See "Treatment of iron deficiency anemia in adults".)

Evaluation and management of iron deficiency in other populations are also presented separately:

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

●Adolescents – (See "Iron requirements and iron deficiency in adolescents".)

●Pregnancy – (See "Anemia in pregnancy" and "Nutrition in pregnancy: Dietary requirements and supplements", section on 'Iron'.)

EPIDEMIOLOGY — 

Iron deficiency, as identified by one of the tests listed below (see 'Diagnosis' below), affects a large proportion of the world's population, especially females of childbearing age, children, and individuals living in low- and middle-income countries (figure 1). The absolute prevalence of iron deficiency depends on the population studied.

Patients can have iron deficiency without anemia (also called non-anemic iron deficiency [NAID]) or iron deficiency anemia (IDA; low hemoglobin caused by iron deficiency). Untreated iron deficiency without anemia will often evolve to iron deficiency anemia over time, especially if the cause(s) of the deficiency are not addressed or treated. Anemia is a late finding. (See 'Stages of iron deficiency' below.)

In all of the studies evaluating the scope of the problem, iron deficiency without anemia is more prevalent than iron deficiency anemia, and females are affected more than males.

As examples:

●Iron deficiency with anemia, worldwide – A 2023 analysis of the global burden of anemia from 1990 to 2021 found iron deficiency to be the most common cause of anemia and of years lived with disability worldwide [1]. A previous global burden of anemia analysis found iron deficiency to affect approximately one in five females [2]. For virtually every population (males, females, different regions of the world), iron deficiency accounts for the largest proportion of cases of anemia. These findings are illustrated in the figure (figure 1).

●Iron deficiency with or without anemia, US – Data from the United States (US) general population have been collected periodically from various groups such as the National Health and Nutrition Examination Survey (NHANES) and the Centers for Disease Control (CDC) [3,4]. The prevalence of iron deficiency and iron deficiency anemia from one such survey from 2002 is summarized in the figure (figure 2). Subsequent surveys on selected populations suggest that the percentages of individuals with iron deficiency have not declined substantively over time [5].

●Iron deficiency without anemia, England – A 2020 study from England found higher rates of iron deficiency without anemia, using ferritin levels in 4451 non-anemic individuals over 50 years of age who were enrolled in the English Longitudinal Study of Ageing [6]. Of these, 389 (8.7 percent) were found to be iron-deficient, defined as a ferritin <30 ng/mL (<30 mcg/L). The prevalence of non-anemic iron deficiency was higher in females than males (10.9 versus 6.3 percent). Other features associated with a higher likelihood of non-anemic iron deficiency included alcohol consumption on more than one day per week and elevated C-reactive protein.

Prevalence is highest in menstruating and pregnant females, with data in various populations including the following:

●Menstruating individuals – It has been estimated that the proportion of menstruating females in the United States who have minimal or absent iron reserves is at least 20 percent and may be as high as 65 percent [7,8].

In a retrospective cohort of 644,066 non-pregnant, reproductive age females (ages 15 to 54) from Canada who had at least one ferritin measurement, 38 percent had iron deficiency (ferritin <30 ng/mL) [9]. Of all the iron-deficient patients, three-fourths had non-anemic iron deficiency. Of 708,337 who had a complete blood count, 19 percent had anemia on at least one occasion; 13 percent met criteria for iron deficiency anemia.

Case series in a number of countries dating back several decades continue to show that iron deficiency is a widespread phenomenon, with iron deficiency in 29 to 58 percent of healthy reproductive-age females and iron deficiency anemia ranging from 27 to 47 percent [8,10-12].

●Pregnant individuals – Iron deficiency is very common early in pregnancy (prevalence >50 percent in one series), suggesting that iron deficiency was present prior to the pregnancy [13]. Other studies show increasing prevalence as the pregnancy progresses, as discussed separately. (See "Anemia in pregnancy", section on 'Epidemiology and health care disparities'.)

●Athletes – A meta-analysis of studies evaluating the prevalence of iron deficiency in collegiate athletes and military recruits (17,519 participants from 122 studies) reported that 31 percent had ferritin <30 ng/mL (95% CI 27 to 35 percent) [14]. The prevalence of iron deficiency using different ferritin cutoffs and in different subgroups included:

•Ferritin <50 ng/mL – 54 percent (95% CI 45 to 63 percent)

•Ferritin <20 ng/mL

-All studies – 23 percent (95% CI 20 to 26 percent)

-Females – 31 percent (95% CI 26 to 36 percent)

-Males – 10 percent (95% CI 4 to 16 percent)

-Age <18 years – 26 percent (95% CI 21 to 31 percent)

-Age ≥18 years – 27 percent (95% CI 22 to 33 percent)

Mechanisms of iron deficiency in athletes are multifactorial. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'High-intensity athletics' and "Overtraining syndrome in athletes", section on 'Anemia and iron deficiency'.)

●Older adults – Iron deficiency anemia 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 [15].

●Racial and ethnic disparities – Racial and ethnic disparities in iron deficiency are also present. Analysis of over 60,000 females ≥25 years of age in the Hemochromatosis and Iron Overload Screening (HEIRS) study in the United States found the following prevalence of iron deficiency (defined as ferritin <15 ng/mL and transferrin saturation (TSAT) <10 percent) [16]:

•Hispanic Americans – 5.1 percent

•Black Americans – 4.3 percent

•Asian Americans – 2.1 percent

•White Americans – 2.0 percent

The prevalence of iron deficiency was 5.2 percent in Native Americans and 3.1 percent in Pacific Islanders, although fewer participants from these groups were included in the study [16]. Carrier status for a hereditary hemochromatosis variant in the HFE gene (C282Y or H63D) did not correlate with the prevalence of iron deficiency in any racial or age group in HEIRS participants.

It is likely that this study underestimated the prevalence of iron deficiency because it used very stringent cutoffs for ferritin and TSAT. Higher values (ferritin of <30 ng/mL and/or TSAT of <20 percent) have a 98 percent sensitivity and 92 percent specificity for absent bone marrow iron. (See 'Diagnosis' below.)

The reason(s) for these disparities may include socioeconomic differences, differences in access to health care, or racism (overt or covert). (See "Use of race and ethnicity in medicine", section on 'Historical fallacies and racism'.)

●Blood donors – Blood donors in the general population typically have slightly lower iron stores than non-donors, although this rarely translates to iron deficiency anemia [17]. 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 49 percent across donors of different ages and both sexes, with highest rates in premenopausal female donors [18-20]. This has led some experts to consider screening for iron deficiency and/or recommending iron supplementation for blood donors, as discussed separately. (See "Blood donor screening: Overview of recipient and donor protections", section on 'Anemia'.)

Considerations regarding screening are discussed below and separately. (See 'Screening (asymptomatic individuals)' below and "Anemia in pregnancy", section on 'Screening for anemia and iron deficiency'.)

STAGES OF IRON DEFICIENCY — 

Iron deficiency can be caused by a time-limited or chronic condition. If the underlying cause is not addressed, iron deficiency is a progressive condition that eventually causes anemia, and anemia becomes progressively severe (table 1).

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 3). Typical amounts of iron in these sites is as follows (table 2):

●RBCs – Approximately 2000 mg, 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 800 to 1000 mg (adult males); approximately 400 to 500 mg (adult females)

Storage iron in males 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. Females have less storage iron, depending upon the extent of menses, pregnancies, deliveries, and iron intake. In one study, 93 percent of United States females 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 [21]. Diet, previous pregnancies, degree of menstrual blood loss, and socioeconomic circumstances may contribute to variation in iron stores. 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.

Progressive iron depletion — Iron deficiency occurs in several stages, as illustrated by progressive changes in laboratory findings (table 1) [22,23]. 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, production of iron-deficient RBCs and anemia occurs. Mild anemia may be followed by microcytosis [24,25].

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 serum ferritin, but without anemia, may have symptoms of fatigue or show decreased exercise tolerance at this stage. Iron deficiency without anemia also can cause pica and restless legs syndrome. (See 'Clinical manifestations' below.)

Further loss of iron results in anemia, which is initially normocytic with a normal absolute reticulocyte count (table 1). This stage of iron deficiency is common in the United States. As noted above, estimates have suggested that 20 to 65 percent of menstruating females in the United States have absent iron stores [7,8,26]. (See 'Epidemiology' above.)

Common laboratory findings at this stage include:

●Low ferritin and serum iron (Fe).

●Increased transferrin (Tf; total iron binding capacity [TIBC]). If only transferrin concentrations are available, they can be converted to the TIBC (in mcg/dL) by multiplying the transferrin concentration (in mg/dL) by 1.389.

●Low transferrin saturation (TSAT; Fe/TIBC or Fe/Tf).

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

More profound deficiency leads to classic findings of anemia with RBCs that are hypochromic (low mean corpuscular hemoglobin [MCH]) and microcytic (low mean corpuscular volume [MCV]). Reticulocyte production cannot be increased, and the reticulocyte count becomes inappropriately low (despite being in the "normal" range in many cases). 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 erythropoietin and reduced hepcidin, provided that kidney function is normal and that the individual does not have an inflammatory condition that increases hepcidin production. The mechanisms of these changes are discussed 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. Low ferritin (<30 ng/mL) reflects absolute iron deficiency. (See 'Sequence of testing' below.)

●Functional iron deficiency (also referred to as iron-restricted erythropoiesis) – In some individuals, iron is not available for RBC production [27,28]. There are two main categories/mechanisms:

•Anemia of chronic disease/anemia of inflammation – The predominant mechanism is a block in iron release from macrophages into the circulation, which occurs with inflammation and increased hepcidin production. Common causes include infections, malignancies, rheumatologic disorders (rheumatoid arthritis, systemic lupus erythematosus), or chronic medical conditions such as diabetes. Diagnosis and management are discussed in detail separately. (See "Anemia of chronic disease/anemia of inflammation".)

•Erythropoiesis-stimulating agents (ESAs) – Another mechanism of functional iron deficiency is treatment with an ESA (erythropoietin or darbepoetin) in an individual with chronic kidney disease or cancer and chemotherapy-induced anemia. 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. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Redistribution after EPO/erythropoiesis-stimulating agents (ESAs)'.)

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

CLINICAL MANIFESTATIONS

Symptoms overview — 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 [29]. Typical symptoms include [30,31]:

Iron deficiency can cause the following symptoms:

●Fatigue or exercise intolerance

●Pica (craving for non-food substances such as clay or paper), especially pagophagia (ice craving)

●Restless legs syndrome

●Hair loss

●Headache

●Beeturia (red urine following beet ingestion; not specific for iron deficiency)

Anemia can cause additional symptoms such as:

●More severe fatigue

●Irritability

●Dyspnea

●Tachycardia

●Hemodynamic compromise, if severe

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.

The classic presentation pattern in a patient without comorbidities is a multigravid female who presents with tiredness and fatigue and a complete blood count (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 1). Iron studies are likely to show low iron in the range of 10 mcg/dL, low ferritin (below 30 ng/mL), and increased transferrin (around 400 mcg/dL) or high TIBC, with a low calculated transferrin saturation (TSAT; below 20 percent). Such a patient is likely to have a brisk response to iron therapy.

Symptoms related to the underlying cause of iron deficiency may also be present, such as gastrointestinal upset or dark stools. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'History'.)

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 non-food objects [32].

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, fabric softener sheets, or raw rice or pasta (amylophagia)

●Ice (pagophagia)

Other reported substances have included:

●Chalk

●Ashes

●Charcoal

●Coffee grounds

●Baby powder

●Paint chips

The specific substances that are craved may depend on what is available and what is considered culturally acceptable [33,34].

The craving for these non-food substances may be intense. During pregnancy, pica may also be misinterpreted as food cravings unrelated to iron status. However, pica is a symptom of iron deficiency, which is very common in pregnancy. Testing for iron deficiency should include hemoglobin as well as iron studies (at a minimum, ferritin). Individuals may be symptomatic from iron deficiency before becoming anemic; hemoglobin alone is insufficient for testing. (See "Anemia in pregnancy", section on 'How to screen for iron deficiency'.)

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 iron deficiency [33,35-37]. It may be present in patients who are not anemic, and the symptoms resolve rapidly with treatment with iron (disappears during iron infusions), 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) [35]. Pica should not be attributed to cultural practices or a psychiatric disorder without first ruling out iron deficiency.

The mechanism of pica in individuals with iron deficiency is not well understood. Pica may also contribute to iron deficiency by reducing iron absorption, depending on the substance ingested. (see "Determining the cause of iron deficiency in adolescents and adults", section on 'Foods that affect iron absorption').

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 [38-40].

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, 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 White 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 examples:

●In a 2023 series of 987 medical records of individuals with laboratory-confirmed iron deficiency, 398 (40 percent) of the records mentioned RLS [37].

●In a 2013 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 [41].

While overall findings linking RLS to iron deficiency are not conclusive, they warrant the measurement of hemoglobin and iron parameters in individuals who present with this symptom, and administration of iron when stores are low. A 2018 guideline from the International Restless Legs Syndrome Study Group provides a consensus on intervention with oral or intravenous iron [42]. Some clinicians will give a trial of iron therapy even when iron parameters are normal as some will experience a reduction in symptoms. This subject is discussed in depth separately. (See "Management 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

●Mood changes – Depressed mood or irritability is often cited as a symptom of iron deficiency. In a series of 2516 nonpregnant females age 20 to 44 years, iron deficiency correlated with depressive symptoms even after adjusting for confounders, especially if they had a low-income (prevalence ratio 1.27, 95% CI 1.03-1.58) [43]. Other possible causes are discussed separately. (See "Approach to the adult patient with suspected depression".)

●Hearing loss – 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 [44]. 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 [24,30]:

●Pallor

●Dry or rough skin

●Atrophic glossitis with loss of tongue papillae, which may be accompanied by tongue pain or dry mouth (picture 2 and picture 3) [45]

●Cheilosis (also called angular cheilitis) (picture 4 and picture 5)

●Koilonychia (spoon nails) (picture 6 and picture 7)

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

●Alopecia (rare) in especially severe cases [46]

●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 [47,48]. Patients with more severe anemia may have tachycardia, a cardiac murmur, or (rarely) hemodynamic instability [30].

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. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Evaluation for the cause'.)

DIAGNOSTIC EVALUATION

Overview of evaluation — The possibility of iron deficiency should be addressed in the following adult populations (algorithm 1):

●Unexplained anemia – 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 "Diagnostic approach to anemia in adults".)

●Symptoms of iron deficiency – Individuals without anemia who have any of the typical clinical findings such as pica (especially pagophagia [ice-craving]) or restless legs syndrome (RLS). We specifically ask about these two symptoms due to their strong association with iron deficiency [37]. (See 'Clinical manifestations' above.)

●Pregnancy – (See "Anemia in pregnancy".)

●Kidney disease – Individuals with chronic kidney disease who have anemia or who are receiving hemodialysis or an erythropoiesis-stimulating agent (ESA) are routinely evaluated. (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 obtain a complete blood count (CBC) and review the hemoglobin and red blood cell (RBC) indices, especially mean corpuscular volume (MCV), and to take a history for possible causes of blood loss. (See "Diagnostic approach to anemia in adults", section on 'Evaluation based on CBC/retic count'.)

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. (See "Microcytosis/Microcytic anemia", section on 'Approach to the evaluation'.)

Review of the peripheral blood smear is likely to provide valuable information regarding the characteristic morphologies seen in iron deficiency anemia (picture 1) versus other causes of anemia. The history, CBC, RBC indices, and findings on the peripheral blood smear usually allow the clinician to make a presumptive diagnosis of iron deficiency anemia.

There are two complementary ways to confirm (or exclude) the diagnosis of iron deficiency:

●Iron studies (see 'Iron studies (list of available tests)' below)

●Assessing response to a trial of iron therapy (see 'Response to a therapeutic trial of iron' below)

Iron studies should be obtained in almost all individuals. 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. In otherwise healthy anemic individuals who are pregnant, a trial of iron may be a reasonable first step. This approach may also be used in resource-limited settings. (See "Anemia in pregnancy", section on 'Treatment of iron deficiency'.)

●Source of deficiency – Even before the diagnosis of iron deficiency is confirmed, patients with suspected iron deficiency should be evaluated for the source of the deficiency. Details of the evaluation are discussed separately. (See "Determining the cause of iron deficiency in adolescents and adults".)

●Bone marrow (usually not required) – 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. (See 'Sequence of testing' below.)

Findings on CBC — The complete blood count (CBC) can identify anemia but not iron deficiency or other causes.

Changes in the CBC occur in proportion to the severity of iron deficiency and tend to lag behind changes in iron studies; reduced storage iron precedes anemia. In turn, a slight decline in hemoglobin (usually 1 to 2 g/dL) precedes microcytosis (table 1). Thus, in early iron deficiency and in many individuals in high-resource settings, the CBC may be relatively normal.

CBC findings consistent with iron deficiency or iron deficiency anemia include:

●Low hemoglobin (females: <11.9 g/dL [<119 g/L]; males: <13.6 g/dL [<136 g/L])

●Low hematocrit (females <35 percent; males <40 percent)

●Low mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC)

●High red cell distribution width (RDW)

●Microcytosis, hypochromia, poikilocytosis, and target cells on the blood smear (picture 1)

●Low reticulocyte count and reticulocyte hemoglobin content (CHr, available on some autoanalyzers; not required for evaluation)

Any of these findings should raise suspicion for iron deficiency and prompt diagnostic testing.

The low RBC count is useful for distinguishing iron deficiency from thalassemia in an individual with markedly microcytic anemia and an abnormal blood smear. A typical RBC count for a patient with a hemoglobin of 9 g/dL is approximately 3 million/microL. (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", section on 'Causes of thrombocytosis'.)

The low MCV and MCH are reflected on the peripheral blood smear by microcytic, hypochromic RBCs (picture 1). 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 [49]. 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 [50]. In some studies, a reticulocyte hemoglobin content of <26 pg/cell has correlated well with the finding of iron deficiency and/or the need for iron [51,52]. (See "Automated complete blood count (CBC)", section on 'Reticulocytes'.)

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.

The tables summarize stages of iron deficiency (table 1) and typical findings on iron studies (table 3).

Ferritin is the most useful test, if low, since there is no other cause of low ferritin besides iron deficiency. Otherwise, patients require iron and total iron binding capacity (TIBC), from which one calculates transferrin saturation (TSAT) [23,24,30]. To avoid the inconvenience and cost of an additional office visit, our practice is to order all three tests (serum ferritin, iron, and TIBC) in many patients, especially older individuals and those who may have a concomitant inflammatory condition that may increase serum ferritin. 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 (table 3):

●Serum iron – Serum iron alone is not a test for iron deficiency; its utility is in calculating transferrin saturation (TSAT). 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 disease/anemia of inflammation (ACD/AI). 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 iron-containing supplements and dietary intake as well as normal diurnal variation.

By itself, low serum iron is not diagnostic of any condition. Since serum iron may be transiently affected by dietary iron or iron supplements, it is recommended that the sample be drawn after an overnight fast or several hours after ingestion of iron-containing foods or pills. (See 'Test interference' below.)

Iron can be measured in serum (preferred) or plasma.

●Serum transferrin – Transferrin is a circulating transport protein for iron. It is increased in iron deficiency but can be decreased in ACD/AI. 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 [24].

●Transferrin saturation – Transferrin saturation (TSAT) is the ratio of serum iron to TIBC:

If not provided directly it can be calculated; calculators are available using inputs for iron and TIBC in standard units (micrograms/dL) (calculator 1) or SI units (micromol/L) (calculator 2).

In iron deficiency, iron is reduced and TIBC is increased, resulting in a lower TSAT. Normal values are in the range of 25 to 45 percent [53,54]. Values below 10 percent are common in individuals with iron deficiency, and a cutoff of <20 percent is generally used to screen for iron deficiency, although other thresholds may be used in pregnancy. (See 'Pregnancy' below and "Anemia in pregnancy", section on 'Screening for anemia and iron deficiency'.)

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 increases in proportion to body iron stores. However, ferritin is also an acute phase reactant that can increase independently of iron status in disorders associated with inflammation, infection, liver disease, heart failure, and malignancy [55]. (See "Acute phase reactants".)

Thus, while a very low ferritin level is diagnostic of iron deficiency, the ferritin level may be "falsely normal" in individuals with comorbidities, and a ferritin within the normal range cannot be used to eliminate the possibility of iron deficiency in individuals with comorbidities (algorithm 1). (See 'Diagnosis' below.)

The ferritin concentration that identifies iron deficiency and the absence of marrow iron is debated. While many sources use a cutoff level of 12 to 15 ng/mL (99 percent specific but only 57 percent sensitive), our practice is to use a cutoff of 30 ng/mL, which is supported by bone marrow correlations and international guidelines [56,57]. The sensitivity and specificity for a cutoff at 30 ng/mL is estimated to be 92 percent and 98 percent, respectively [58]. A 2024 guideline from the American Gastroenterological Association uses a cutoff of <45 ng/mL to define iron deficiency in patients with anemia, recognizing that individuals with inflammatory conditions may have iron deficiency with ferritins up to 100 ng/mL [59].

There are several commercially available assays for ferritin measurement, and reported ferritin levels may vary due to differences in calibration technique [60]. Thus, ferritin levels near the boundaries of diagnostic cutoffs should be interpreted and managed within the context of other lab values and clinical factors.

●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 [61].

Individuals with iron deficiency generally have increased sTfR, with reference ranges determined by the individual laboratory performing the testing. Different laboratories may report sTfR as mg/L or as nmol/L.

sTfR is not used in routine practice but can be helpful in complex cases. The major advantage of sTfR is that it reflects overall erythropoiesis, which is increased in iron deficiency. (See 'Patients with inconclusive initial testing or comorbidities' below.)

Some studies have claimed that it is more useful than ferritin because it is unaffected by inflammation [62]. 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). 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/anemia of inflammation (ACD/AI) (see 'Differential diagnosis' below) because sTfR is increased in iron deficiency and normal in ACD/AI, whereas ferritin is decreased in iron deficiency and normal-to-increased in ACD [21,23,63-66]. Patients with ACD/AI are likely to have an sTfR-ferritin index <1, whereas those with isolated iron deficiency or iron deficiency plus ACD/AI 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 if the serum ferritin is low [67-69]. (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 "Lead exposure, toxicity, and poisoning in adults: Clinical manifestations and diagnosis" and "Erythropoietic protoporphyria and X-linked protoporphyria", section on 'Erythrocyte protoporphyrin'.)

●Reticulocyte hemoglobin content (CHr) – The reticulocyte hemoglobin content (CHr, also called Ret-He) is available on some autoanalyzers and has the potential of providing very rapid information about iron status (at same time as CBC), especially in the presence of iron-restricted erythropoiesis [70]. Unlike the serum ferritin, the CHr is not influenced by inflammation. This parameter is used more extensively in individuals with chronic kidney disease; there is less information regarding its role in managing anemia and iron therapy in other adults. A study in 556 unselected anemic individuals (Hb <13 g/dL) indicated that the combination of Hb <10.3 g/dL plus CHr <28.5 pg was 84 percent sensitive and 78 percent specific in predicting response to iron [71] (see "Diagnosis of iron deficiency in chronic kidney disease", section on 'Percent hypochromic HRCs and reticulocyte hemoglobin content'). One caveat to remember when considering the CHr is that individuals with thalassemia have reduced RBC hemoglobin content due to decreased globin chain synthesis; in these individuals, a low CHr is unreliable for diagnosing iron deficiency, although an elevated CHr can exclude iron deficiency.

●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'.)

Test interference — Recent intake of iron-rich foods or of oral iron supplements (even in multiple vitamins) may affect serum iron and therefore TSAT (table 3). For this reason, testing obtained in a fasting state are the most reliable. Ferritin concentration is not affected by food.

●Oral iron can transiently increase the serum iron concentration, with a dose-dependent peak at approximately four hours after the oral dose [72,73]. This could falsely increase the TSAT (which represents a ratio of serum iron to transferrin) and thus make an individual appear to have more normal iron stores than they actually have. Therefore, an iron studies panel that measures iron and calculates TSAT should be drawn after an overnight fast or at least five to nine hours after the last ingestion of iron-containing foods or pills [74].

●Intravenous iron also increases serum iron and TSAT, and as a result, may alter the results of iron studies testing, similar to oral iron [75]. After a dose of intravenous iron, we typically wait and retest iron studies at the time of repeat CBC (eg, after approximately four weeks).

The use of tumor necrosis factor (TNF) inhibitors in individuals with chronic inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease appears to reduce the ferritin level (perhaps to a more accurate representation of iron stores) and increase the TSAT [76-78]. This may reflect the reduction in hepcidin and improved iron availability that these agents produce. In such cases, the serum ferritin is likely to be most representative of the level of iron stores despite its acute phase reactivity. (See "Anemia of chronic disease/anemia of inflammation", section on 'Cytokine effects' and "Anemia of chronic disease/anemia of inflammation", section on 'Iron studies'.)

Data evaluating the effects of recent blood transfusion on iron studies are limited. One study showed transient elevation of the serum iron and resultant TSAT within the first 24 hours of a blood transfusion [79]. However, other studies have shown only small, subclinical changes in iron parameters. As an example, a study that measured iron parameters 48 to 72 hours after a transfusion noted that in the individuals with low ferritin and TSAT prior to transfusion, 97 percent remained low after transfusion, and concluded that testing could be performed after transfusion [80]. If there is any doubt about the results of testing, it may be prudent to wait a day after transfusion to order iron studies (if indicated) in a patient who received a transfusion, based on a theoretical concern for test interference from hemolyzed cells [81-83].

In contrast to transient changes in iron studies related to the effects of a dose of iron on serum iron levels, true improvements in iron stores are expected if an iron-deficient individual receives supplemental iron and/or a blood transfusion. These improvements will be reflected in the iron studies (eg, serum ferritin and TSAT will increase, reflecting increased iron stores).

Sequence of testing

Individuals without comorbidities — Testing can be done using an iron studies panel, which includes serum iron, transferrin or total iron binding capacity (TIBC), calculated transferrin saturation (TSAT), and ferritin (algorithm 1). If one or more of the results is consistent with iron deficiency, this is typically sufficient to make the diagnosis. (See 'Diagnosis' below.)

Some clinicians prefer to order a single test rather than the entire iron studies panel. This is especially useful in individuals with a classic presentation, such as new onset microcytic anemia in a young female with heavy menstrual bleeding or a multiparous female, and/or when there is a desire to limit testing, provided it would not be overly burdensome to return for additional testing if needed (if the first testing is inconclusive), or if additional testing can be ordered as an "add-on" if needed. In such cases, either the ferritin or the TSAT can be used as the initial test.

As noted above, the normal ferritin concentration ranges from 30 to 200 ng/mL (mcg/L) in otherwise healthy, iron-replete individuals (see 'Iron studies (list of available tests)' above). A ferritin level below 30 ng/mL is considered diagnostic of iron deficiency regardless of the patient's underlying condition or hemoglobin concentration. In individuals with anemia, a ferritin <30 ng/mL is sufficient to diagnose iron deficiency. However, a ferritin in the normal range does not exclude iron deficiency in an individual for whom there is a strong suspicion for iron deficiency. A TSAT <20 percent can also be used, as discussed below. (See 'Diagnosis' below.)

In contrast to a low ferritin, a low serum iron cannot be used to diagnose or exclude iron deficiency. Serum iron may be low in anemia of chronic disease/anemia of inflammation (ACD/AI) or increased by recent ingestion of an iron tablet. (See "Anemia of chronic disease/anemia of inflammation".)

Evidence to support the use of serum ferritin alone in appropriate patients includes a several observational studies in anemic adults comparing serum ferritin with the gold standard test (bone marrow stainable iron), as well as a 1992 systematic review [84]. In this review, serum ferritin radioimmunoassay had the greatest predictive value for iron deficiency (figure 4):

●A ferritin level ≤15 ng/mL had a 99 percent specificity for iron deficiency. Ferritin ≤15 ng/mL was highly specific in individuals with inflammatory states.

●A ferritin ≤15 ng/mL had a sensitivity of only 59 percent, meaning that a large proportion of individuals with iron deficiency would be missed.

Using a higher ferritin cutoff may improve sensitivity while maintaining a reasonable specificity. Various observational studies comparing ferritin levels with bone marrow stainable iron have found that a ferritin cutoff of <30 ng/mL provides a sensitivity in the range of 90 to 92 percent and a specificity in the range of 75 to 98 percent [56,85-87].

The relative performance of these iron studies tests in diagnosing iron deficiency compared with bone marrow iron staining is illustrated in the figure (figure 4) [23,88-91]. This demonstrates that ferritin has the best performance in individuals without comorbidities; however, ferritin is an acute phase reactant and can increase in the setting of an infection or obesity [88-90,92,93]. In such cases, TSAT may be more useful if low, or additional testing may be required. TSAT is a ratio of iron to TIBC, and it is most reliable when decreased due to an increase in TIBC. TSAT can be falsely elevated by recent intake of iron-containing foods or an iron tablet. (See 'Iron studies (list of available tests)' above.)

Patients with inconclusive initial testing or comorbidities — Many individuals with iron deficiency or iron deficiency anemia in resource-abundant 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 a TSAT or other laboratory tests listed above (see 'Iron studies (list of available tests)' above), a therapeutic trial of iron, or (very rarely) bone marrow evaluation.

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 [94]. 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. However, attempts to "correct" ferritin values for other markers have not shown good accuracy [95].

Pregnancy — 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, as well as our approach to screening for iron deficiency and evaluating anemia in pregnancy, is discussed in detail separately. (See "Anemia in pregnancy", section on 'Iron deficiency'.)

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 with a history of heavy menstrual periods or pregnancy, particularly in resource-limited settings where it is not possible to obtain iron studies routinely, as long as thalassemia is not a concern.

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 (typically by three weeks). A trial of iron in pregnant individuals with anemia was recommended in a 2020 United Kingdom Guideline on iron deficiency in pregnancy [57]. (See "Treatment of iron deficiency anemia in adults", section on 'Response to iron supplementation' and "Anemia in pregnancy", section on 'Management'.)

However, 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 4). (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 (algorithm 1):

●Serum ferritin <30 ng/mL

●Transferrin saturation <20 percent, 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 (table 5). (See "Determining the cause of iron deficiency in adolescents and adults" and "Treatment of iron deficiency anemia in adults".)

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.

We diagnose functional iron deficiency 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 less than 20 percent (see 'Absolute versus functional deficiency' above). 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 patients with nondialysis chronic kidney disease (CKD)" and "Treatment of iron deficiency in patients on dialysis" and "Role of ESAs in adults with non-hematologic cancers".)

By contrast, patients with anemia of chronic disease/anemia of inflammation (ACD/AI) 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/anemia of 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. A history of antithrombotic medication (aspirin, anticoagulation) cannot be used as a rationale to forgo this evaluation. Details are presented separately. (See "Determining the cause of iron deficiency in adolescents and adults".)

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 6). 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/anemia of inflammation (ACD/AI) may also cause microcytic or normocytic anemia. Additional causes of anemia are listed in the table (table 6). (See "Microcytosis/Microcytic anemia", section on 'Causes of microcytosis/hypochromia'.)

•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 "Diagnosis of thalassemia (adults and children)".)

•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 congenital sideroblastic anemias are described as microcytic. However, while cells derived from the sideroblastic clone are microcytic, the overall mean corpuscular volume (MCV) is typically normal or elevated in acquired sideroblastic anemia. Unlike iron deficiency, sideroblastic anemias are often associated with increased iron stores; bone marrow iron is required for the formation of ring sideroblasts. (See "Sideroblastic anemias: Diagnosis and management".)

•Anemia of chronic disease/anemia of inflammation (ACD/AI) – ACD/AI 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/AI may have microcytic or normocytic anemia with a low serum iron and low transferrin (or TIBC). Unlike those with iron deficiency, individuals with ACD/AI have a chronic inflammatory state, often with increased storage iron (picture 8) and high levels of ferritin and other acute phase reactants.

Inflammation can increase the ferritin, making it challenging to determine whether an individual with a borderline ferritin level has iron deficiency, ACD/AI, or both (table 7). Both conditions may decrease the TSAT. 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/anemia of inflammation".)

•Other anemias – Other causes of anemia include kidney 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 "Diagnostic approach to anemia in adults" and "Microcytosis/Microcytic anemia".)

Indications for referral (hematologist or gastroenterologist)

●Hematologist – 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. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Inherited disorders/IRIDA' and "Treatment of iron deficiency anemia in adults", section on 'Oral versus IV iron'.)

●Gastroenterologist – Referral to a gastroenterologist is appropriate in individuals for whom a source of gastrointestinal blood loss or malabsorption is suspected or if there is suspicion for autoimmune gastritis or celiac disease. These individuals may require endoscopic confirmation and/or surveillance, and gastroenterology teams may have additional resources to help with required lifestyle changes. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Indications for endoscopic evaluation'.)

SCREENING (ASYMPTOMATIC INDIVIDUALS)

Overview of screening considerations — In clinical research and guideline panels, a clear distinction is made between evaluation of symptoms by obtaining a complete blood count (CBC) or CBC plus iron studies (eg, in a female with heavy menstrual periods and fatigue), versus screening, by obtaining a CBC or iron studies in a truly asymptomatic individual, such as a menstruating female without fatigue.

In practice, these distinctions can blur. Symptoms can be subtle, and some patients may only become aware of symptoms in retrospect (eg, noting that they are no longer fatigued or irritable after iron deficiency or iron deficiency anemia has been recognized and treated, even though they did not identify these symptoms at the time the diagnosis was made).

For those who are asymptomatic, physicians often need to consider many risk factors for iron deficiency including age, sex, menstrual and pregnancy history, gastrointestinal conditions that could affect absorption of iron, patient concerns, and family history, in determining whether it is appropriate to screen for iron deficiency or iron deficiency anemia.

Ideally, the recommendation for individuals who are truly asymptomatic would be based on high-quality evidence from randomized trials that answered the question of whether screening improved patient-important outcomes. However, trials that compare screening versus not screening in otherwise healthy individuals have not been conducted, and trials in which some individuals are not screened may be challenging to conduct.

Practice is evolving towards increased use of screening for iron deficiency in the absence of anemia, since anemia is a late finding, and iron deficiency is likely to progress to anemia if not diagnosed and treated.

A 2024 guideline from the European Hematology Association (EHA) recommends screening for iron deficiency in any adult at risk (table 8); this includes all of the following, regardless of symptoms or the presence or absence of anemia [96]:

●All people who menstruate

●Anyone who is pregnant

●Athletes

●Vegetarians

●Regular blood donors

●Individuals with bleeding disorders or receiving an anticoagulant

●Individuals with a history of gastric surgery

●Patients with chronic infections

●Any patients undergoing major surgery

●Patients at risk for reduced access to medical care (socioeconomically disadvantaged)

●Older adults, especially those with chronic conditions

●Adolescents, due to increased iron requirements during growth spurts

These recommendations are also addressed in several guidelines on screening in pregnancy or in premenopausal females who may become pregnant. They are consistent with a 2023 International Federation of Gynecology and Obstetrics (FIGO) statement [97]. They contrast with recommendations from the United States Preventive Services Task Force (USPSTF) and the American College of Obstetricians and Gynecologists (ACOG), which do not recommend screening asymptomatic, non-anemic individuals for iron deficiency [98-101]. The USPSTF relied primarily on data from randomized trials and reached the conclusion that there was insufficient evidence for or against screening to make a recommendation. Editorials mentioned that these recommendations could possibly lead to worsening in health disparities and the need for more studies of this subject [102,103]. (See "Anemia in pregnancy", section on 'Screening during pregnancy'.)

The EHA guideline also recommends screening in pediatric populations, which is discussed separately. (See "Iron deficiency in infants and children <12 years: Screening, prevention, clinical manifestations, and diagnosis" and "Iron requirements and iron deficiency in adolescents", section on 'Screening'.)

In the absence of randomized trials, clinicians may benefit from reviewing the prevalence of iron deficiency, availability of resources for screening, and competing needs in their specific patient population.

The following may be helpful:

●Symptoms or findings on examination – All experts agree that an individual with any symptoms or physical findings suggestive of iron deficiency should be tested, as outlined above. (See 'Diagnostic evaluation' above.)

●Truly asymptomatic individuals – Experts vary in their decision-making and practice regarding screening asymptomatic individuals for iron deficiency, and these decisions can be individualized according to local guidance, the patient population, individual patient factors (including other aspects of medical care that may take priority), and patient preference.

•Individuals at high risk – We are most likely to screen for iron deficiency in those at highest risk of iron deficiency and its complications, including individuals with prior pregnancies, heavy menstrual periods, and/or conditions that might cause blood loss or iron malabsorption. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Causes (organized by mechanism)'.)

Screening during pregnancy is discussed separately. (See "Anemia in pregnancy".)

•Individuals taking aspirin – Screening of individuals who are taking antithrombotic medications has not been extensively evaluated. Analysis of a trial that randomly assigned 19,114 older individuals (≥65 years for those identified as Black or Hispanic; ≥70 years for White) to receive daily aspirin (100 mg) or placebo for primary prevention of death or disability (the ASPREE trial) found that those assigned to aspirin had statistically significant increases in prevalence of anemia and iron deficiency [104]. The risk of anemia, assessed by annual hemoglobin testing, was 51 events per 1000 person-years with aspirin versus 43 events per 1000 person-years with placebo (hazard ratio 1.2, 95% CI 1.1-1.3). The risk of iron deficiency, defined as ferritin <45 ng/mL and assessed in 7139 participants who underwent ferritin testing at baseline and after three years, was 13 percent with aspirin versus 9.8 percent with placebo. Most of the participants did not have clinically obvious bleeding; major bleeding occurred in 3 percent in the aspirin group and 2.1 percent in the placebo group, and this did not account for the effects on hemoglobin or ferritin.

For individuals taking aspirin, the decision to perform surveillance for anemia and/or iron deficiency is individualized. We are more likely to screen older individuals and those who place a value on identifying and treating iron deficiency. If anemia or iron deficiency anemia is diagnosed, the source of blood loss must be investigated. (See "Determining the cause of iron deficiency in adolescents and adults", section on 'Blood loss'.)

•Individuals at low risk or those who prefer not to be screened – In some populations, not screening for iron deficiency is reasonable. This is especially true for males and postmenopausal females who are not in any at-risk category, individuals for whom other aspects of medical care are more pressing, and individuals who are not concerned or distressed by the possibility of not being screened. These individuals may still have a CBC for other reasons, and if a CBC is done, the results, including the hemoglobin and mean corpuscular volume (MCV), should be reviewed. (See 'Stages of iron deficiency' above.)

The method of screening and frequency are also individualized according to the risk profile and findings on prior testing, as discussed below. (See 'Method of screening and frequency' below.)

Practices may also shift as new information emerges regarding the prevalence and complications of iron deficiency. (See 'Epidemiology' above and "Anemia in pregnancy", section on 'Screening for anemia and iron deficiency'.)

Method of screening and frequency — If a decision is made to screen for iron deficiency, the following approaches can be used:

●CBC alone (sequential testing) – One option is to start with a CBC (screen for anemia), including review of the mean corpuscular volume (MCV), which decreases as iron deficiency advances, and obtain iron studies only if anemia or microcytosis is found. This may be most reasonable for individuals with a lower risk of iron deficiency and those for whom returning for a second test would not be overly burdensome.

Screening with a CBC alone will miss most individuals with iron deficiency because anemia is a late-stage finding. (See 'Stages of iron deficiency' above.)

●CBC plus iron studies (simultaneous testing) – Obtain a CBC and iron studies concurrently. This may be most reasonable in those with a higher risk of iron deficiency and in those for whom returning for a second test would be especially burdensome or would reduce adherence to testing.

The frequency of screening is also individualized:

●Annual – Annual screening may be reasonable for those at the highest risk, such as menstruating females with heavy periods.

●Less frequent – Less frequent, or even one-time screening, may be reasonable for other individuals, especially males and postmenopausal females.

Screening recommendations of others — The variation in practice alluded to above is reflected in available guidelines, which vary in screening approaches for different populations and often remain silent on the role of screening in older adults. Many of the available recommendations focus on populations discussed separately, as discussed in the linked topic reviews.

●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 [105]. Screening recommendations include the following:

•Screening of adolescent and adult females of childbearing age every 5 years with a hemoglobin or hematocrit, with more frequent screening (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 red blood cell (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. (See "Iron requirements and iron deficiency in adolescents".)

•Evaluation of the RBC indices, RBC count, and family history, so as not to miss a case of thalassemia, sickle cell disease, or other inherited condition.

●A 2019 guideline from the United Kingdom recommends iron deficiency screening of all high-risk individuals who are pregnant, using serum ferritin as the preferred test [57]. Recommendations for adolescents and during pregnancy are discussed separately. (See "Iron requirements and iron deficiency in adolescents", section on 'Screening' and "Anemia in pregnancy", section on 'Screening during pregnancy'.)

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 5^th to 6^th 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 10^th to 12^th 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: Low iron (The Basics)")

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

PATIENT PERSPECTIVE TOPIC — 

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Iron deficiency anemia".)

SUMMARY AND RECOMMENDATIONS

●Prevalence – Iron deficiency affects >12 percent of the world's population, especially females, children, and individuals living in under-resourced areas. It is the most common cause of anemia in virtually every region of the world (figure 1). (See 'Epidemiology' above.)

●Progression – Iron deficiency occurs in several stages, with progressive changes in laboratory findings (table 1). Anemia is a late finding. (See 'Stages of iron deficiency' above.)

●Clinical findings – Clinical manifestations may include symptoms of anemia, pica, and restless legs syndrome. The examination may be normal or show pallor, alopecia, rough or dry skin, atrophic glossitis (picture 2), angular cheilitis (picture 4), or koilonychia (spoon nails) (picture 6). The complete blood count (CBC) may be normal or it may show microcytic, hypochromic anemia (picture 1), low red blood cell (RBC) count, low reticulocyte count, and elevated platelet count (table 1). (See 'Clinical manifestations' above.)

●Diagnosis – Any individual with suggestive symptoms should be tested, with a CBC and iron studies done simultaneously (algorithm 1). Iron studies can be ordered as a panel (iron, transferrin or total iron binding capacity [TIBC], transferrin saturation [TSAT], and ferritin), or a single test (typically, ferritin) can be ordered, with additional testing if needed (table 3). (See 'Overview of evaluation' above.)

•Serum ferritin level <30 ng/mL or TSAT <20 percent is confirmatory. (See 'Diagnosis' above.)

•Complex patients may require TSAT, soluble transferrin receptor (sTfR), sTfR-ferritin index, reticulocyte hemoglobin content (CHr), or bone marrow iron stain. (See 'Patients with inconclusive initial testing or comorbidities' above.)

•Response to iron administration may help confirm the diagnosis. Lack of response may be due to an additional or alternative cause of anemia or to conditions that interfere with absorption. (See 'Response to a therapeutic trial of iron' above and "Treatment of iron deficiency anemia in adults", section on 'Approaches to lack of response'.)

●Causes – Causes of absolute and functional iron deficiency are discussed separately. Determining the cause is a key aspect of management. (See "Determining the cause of iron deficiency in adolescents and adults" and "Anemia of chronic disease/anemia of inflammation".)

●Differential diagnosis – The differential diagnosis includes other causes of fatigue, pica, and restless legs syndrome, anemia of chronic disease/anemia of inflammation (ACD/AI), thalassemia (table 9), other microcytic anemias (table 10), anemias with a low reticulocyte count (table 6), and others. Some individuals may have multiple causes of anemia. (See 'Differential diagnosis' above and "Diagnosis of thalassemia (adults and children)" and "Anemia of chronic disease/anemia of inflammation".)

●Screening – Screening can be done using a complete blood count (CBC) plus ferritin or a CBC alone, reserving iron studies for individuals with microcytosis and/or anemia. Screening with a CBC alone will miss most individuals with iron deficiency because anemia is a late-stage finding.

Our approach to screening is as follows (see 'Screening (asymptomatic individuals)' above):

•For premenopausal females (particularly with prior pregnancies or heavy menstrual periods), pregnant people, and other individuals at increased risk (table 8), we suggest screening (Grade 2C).

Screening is appropriate for all at-risk individuals regardless of symptoms or the presence or absence of anemia. Not screening is reasonable, especially if other medical care is more pressing. Risk categories are discussed above. (See 'Overview of screening considerations' above.)

•For males and postmenopausal females who are not in any at-risk category, we do not screen. Screening may be reasonable, and we have a low threshold for evaluating suggestive symptoms or findings. (See 'Clinical manifestations' above.)

•Screening in pregnancy is discussed separately. (See "Anemia in pregnancy", section on 'Screening during pregnancy'.)

●Treatment – (See "Treatment of iron deficiency anemia in adults".)

●Related topics – Diagnosis of iron deficiency in children, during pregnancy, and in chronic kidney disease, and the general evaluation of anemia are discussed separately. (See "Approach to the child with anemia" and "Anemia in pregnancy" and "Diagnosis of iron deficiency in chronic kidney disease" and "Diagnostic approach to anemia in adults".)

ACKNOWLEDGMENTS — 

UpToDate gratefully acknowledges Stanley L Schrier, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.