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Diagnostic approach to anemia in adults

Diagnostic approach to anemia in adults
Authors:
Robert T Means, Jr, MD, MACP
Robert A Brodsky, MD
Section Editor:
Joann G Elmore, MD, MPH
Deputy Editors:
Jennifer S Tirnauer, MD
Jane Givens, MD, MSCE
Literature review current through: Dec 2022. | This topic last updated: Sep 09, 2022.

INTRODUCTION — Evaluation for anemia is one of the most common problems in clinical practice. The evaluation may be straightforward in an otherwise healthy individual with a single cause of anemia, but in many cases the cause is not readily apparent and multiple conditions may be contributing.

An approach to the evaluation of the adult with anemia is presented here. Diagnosis of specific conditions is discussed in separate topic reviews referenced below. Evaluation of anemia in children is discussed separately. (See "Approach to the child with anemia".)

BASIC PRINCIPLES

Anemia definitions — Anemia is defined for patient care as a reduction in one or more of the major red blood cell (RBC) measurements obtained as a part of the complete blood count (CBC): hemoglobin concentration, hematocrit, or RBC count. A low hemoglobin concentration and/or low hematocrit are the parameters most widely used to diagnose anemia, with the following cutoffs (table 1):

Females – Hemoglobin <11.9 g/dL (119 g/L) or hematocrit <35 percent

Males – Hemoglobin <13.6 g/dL (136 g/L) or hematocrit <40 percent

Additional information about how these values are determined and variation in cutoff values includes the following:

Hemoglobin – Hemoglobin is reported as the concentration of hemoglobin in whole blood. When measured by an electronic counter, hemoglobin concentration is directly determined, while hematocrit is calculated from other parameters. For this reason, many physicians prefer to use hemoglobin to define and describe anemia. Values may be expressed as grams of hemoglobin per 100 mL (g/dL) or per liter (g/L). To convert to mmol/L, the hemoglobin in g/dL can be multiplied by 0.62. Hemoglobin can be reported non-invasively by continuous monitoring [1-3].

Hematocrit – Hematocrit (HCT), also called packed cell volume (PCV), is the percentage of blood volume occupied by RBCs. It can be measured directly following centrifugation of a blood sample (picture 1 and picture 2).

When measured by an electronic cell counter, HCT is calculated from the RBC count (in millions/microL) and the mean corpuscular volume (MCV; in femtoliters [fL]): HCT = ([RBC x MCV]/10).

RBC count – RBC count is the number of RBCs contained in a specified volume of whole blood, usually expressed as millions of cells per microL of whole blood.

Other normal ranges have been proposed. World Health Organization (WHO) criteria for anemia in adult males is hemoglobin <13 and in adult females is hemoglobin <12 g/dL [4]. However, these criteria were intended for use within the context of international nutrition studies and were not initially designed to serve as "gold standards" for diagnosing anemia [5].

Normal ranges for laboratory tests are defined as the range of values centered at the median that includes 95 percent of an apparently healthy population. For that reason, normal values of hemoglobin, HCT, and RBC count may differ depending on the population tested. Since hemoglobin is measured and HCT calculated (HCT = MCV x RBC count/10), hemoglobin is likely to be more accurate. (See 'Caveats for normal ranges' below.)

Some reports have described lower values for hemoglobin in Black Americans than in White Americans (approximately 0.5 to 1 g/dL lower for Black Americans) [5-9]. It is not clear whether this difference is due to health disparities such as greater frequency of iron deficiency, to a higher presence of alpha thalassemia in individuals of African ancestry, or to other causes [10]. We use the same hemoglobin and HCT thresholds for evaluating anemia in all racial and ethnic groups (we do not assume that a slightly lower value in a Black American is normal).

The increased frequency of anemia seen with aging has led to suggestions that a different standard for the normal hemoglobin should be used in older adults [5]. Review of data from the National Health and Nutrition Examination Survey (NHANES) indicates that the mean hemoglobin values for adults >70 years are within the usual normal ranges (14.5 g/dL for males and 13.4 g/dL for females), while the 5th percentiles are below the normal ranges (11.7 g/dL for males and 10.9 g/dL for females) [11]. This lower boundary may reflect an increased prevalence of comorbidities, especially chronic kidney disease [12]. Another study that used survey data to try to identify a lower normal hemoglobin in older individuals concluded that the World Health Organization (WHO) definitions are applicable in older adults [13]. Thus, rather than seeking to define a lower limit for the reference range for older individuals as a population, we prefer to focus on determining the appropriate evaluation of a low hemoglobin in each person and to individualize the approach to each person's circumstances, with an informed discussion and shared decision-making. (See 'Older adults' below.)

In individuals with anemia, hemoglobin and HCT decrease in parallel, although the HCT/hemoglobin ratio (approximately 3 in most cases) may vary according to the volume (size) of the cells. The RBC count also usually parallels the hemoglobin and HCT, except in cases of extreme microcytosis such as thalassemia, in which the RBC count may be increased despite the presence of anemia. The RBC count is less commonly used to diagnose anemia for this reason. A finding of high RBC count in an individual with anemia suggests thalassemia. (See "Diagnosis of thalassemia (adults and children)", section on 'CBC and hemolysis testing'.)

For research, anemia can be defined as a reduced RBC mass, expressed in mL/kg, as determined via blood volume studies. However, blood volume studies are not used in clinical practice, and increasingly they are not used in research. These studies are impractical, costly, and rarely available.

Caveats for normal ranges — The "normal" ranges specified in the table (table 1) may not apply in certain settings:

Causes of lower values

Intense physical activity – Values in endurance athletes may vary significantly from those in other healthy individuals. Various causes may contribute, including dilutional anemia from increased plasma volume, iron deficiency, and/or "march" hemolysis. (See "Exercise-related gastrointestinal disorders", section on 'Gastrointestinal bleeding' and "Non-immune (Coombs-negative) hemolytic anemias in adults", section on 'Foot strike or hand strike'.)

Pregnancy – During a healthy pregnancy, maternal red cell mass increases, but plasma volume increases to a greater degree, causing a relative decrease in hemoglobin and HCT [14]. By the criterion of RBC mass, the individual is not anemic, but hemoglobin, HCT, and RBC count frequently decrease to anemic levels (figure 1). The terms "physiologic" or "dilutional" anemia have been applied to this setting, although these individuals are not actually anemic and do not require evaluation as long as their hemoglobin remains ≥11 g/dL in the first trimester, ≥10.5 g/dL in the second trimester, and ≥10.5 g/dL in the third trimester. (See "Anemia in pregnancy".)

Older age – Values for hemoglobin and HCT in apparently healthy older adults are generally lower than those in younger adults, and differences between males and females that are seen in younger adults are lessened with aging [15-17]. (See 'Older adults' below.)

Causes of higher values (may occasionally mask underlying anemia)

Smoking – Smoking causes an increase in hemoglobin, HCT, and RBC count due to increased levels of carbon monoxide, which reduces oxygen delivery. Thus, individuals who smoke or have significant exposure to secondary smoke or other sources of carbon monoxide may have HCT higher than normal [18]. A study of blood donors who smoke found a significant correlation between the patients' blood carboxyhemoglobin and hemoglobin values [19]. (See "Carbon monoxide poisoning", section on 'Pathophysiology'.)

Medications/drugs – Certain medications can increase the hemoglobin concentration; examples include androgens and sodium-glucose co-transporter 2 (SGLT2) inhibitors [20,21]. (See "Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)

Hemoconcentration – Individuals with dehydration or hypovolemia related to vomiting or diarrhea will have a relative increase in hemoglobin and HCT due to hemoconcentration. Anemia will become apparent after volume replacement. This is particularly a problem in patients with severe burns, in whom substantial RBC loss may be masked by exudative loss of plasma volume until fluid resuscitation has occurred [22].

High altitude – Persons living at high altitude have higher values than those living at sea level due to relative hypoxia [23]. (See "High altitude, air travel, and heart disease", section on 'Long-term altitude exposure'.)

RBC indices — The red blood cell (RBC) indices describe RBC size, hemoglobin content, and uniformity of the RBC population. These values can be very helpful in determining the cause of anemia. The mean corpuscular volume (MCV) and red cell distribution width (RDW) are generally the most useful.

MCV – Mean corpuscular volume (MCV) is the average volume (size) of the RBCs. It can be measured, as it is in automated cell counters, or calculated (MCV in femtoliters [fL] = 10 x HCT [in percent] ÷ RBC [in millions/microL]). RBCs with MCV in the normal range are roughly the same diameter as the nucleus of a normal lymphocyte on the peripheral blood smear. Anemia can be classified based on whether the MCV is low, normal, or elevated. (See 'Evaluation based on MCV' below.)

MCH – Mean corpuscular hemoglobin (MCH) is the average hemoglobin content in a RBC. It is calculated (MCH in picograms [pg]/cell = hemoglobin [in g/dL] x 10 ÷ RBC [in millions/microL]). A low MCH is typically reflected in an enlarged area of central pallor in RBCs on the peripheral blood smear (greater than one-third of the RBC diameter), which defines "hypochromia" on the blood smear. This may be seen in iron deficiency and thalassemia.

MCHC – Mean corpuscular hemoglobin concentration (MCHC) is the average hemoglobin concentration per RBC. It is calculated as (MCHC in grams [g]/dL = hemoglobin [in g/dL] x 100 ÷ HCT [in percent]). Very low MCHC values are typical of iron deficiency anemia, and very high MCHC values typically reflect spherocytosis or RBC agglutination. Examination of the peripheral blood smear is helpful in distinguishing these findings. (See "Evaluation of the peripheral blood smear", section on 'Red blood cells'.)

RDW – Red cell distribution width (RDW) is a measure of the variation in RBC size, which is reflected in the degree of anisocytosis on the peripheral blood smear. RDW is calculated as the coefficient of variation (CV) of the red cell volume distribution (RDW = [standard deviation/MCV] x 100).

A high RDW implies a large variation in RBC sizes, and a low RDW implies a more homogeneous population of RBCs. A high RDW can be seen in a number of anemias, including iron deficiency, vitamin B12 or folate deficiency, myelodysplastic syndrome (MDS), and hemoglobinopathies, as well as in patients with anemia who have received transfusions. Review of the peripheral blood smear often is helpful in identifying the cause. (See "Evaluation of the peripheral blood smear".)

Details of how these indices are determined and potential causes of spurious results are presented separately. (See "Automated hematology instrumentation".)

Reticulocyte production — The reticulocyte is a stage in RBC development directly before the mature RBC. Reticulocytes are continually produced to replace RBCs that are cleared from the circulation (approximately 1 percent of RBCs are cleared per day). The reticulocyte count reflects the rate of RBC production.

Measurement – Reticulocytes can be reported as a percentage of total RBCs or as an absolute count (table 2). Reticulocytes can be appreciated on a standard blood smear stained with Wright-Giemsa as RBCs with a blue tint (polychromatophilia) that are larger than mature RBCs, with irregular borders and a lack of central pallor (picture 3).

Manual count (percentage) – Reticulocytes can be enumerated manually after supravital staining of a blood sample with dyes such as new methylene blue (picture 4). The manual reticulocyte count is reported as a percentage of RBCs, with a normal range of 0.5 to 2 percent in the absence of anemia.

Automated count (million cells/microL) – Automated blood counters measure the absolute reticulocyte count directly after staining with a fluorescent dye such as thiazole orange, which binds to the RNA of reticulocytes; the reticulocyte percentage from those devices is a calculated value [24]. (See "Automated hematology instrumentation", section on 'Automated counting of reticulocytes'.)

Interpretation – The appropriate count depends on the hemoglobin level. The "normal" reticulocyte count refers to the count in a non-anemic individual at steady state.

Steady state – At steady state, approximately 1 to 2 percent of circulating RBCs are reticulocytes, corresponding to an absolute reticulocyte count of approximately 25,000 to 100,000/microL (0.25 to 1 x 1011/L).

Anemia – In anemia, the reticulocyte count rises. A normal bone marrow can increase the rate of RBC production approximately fivefold in adults (seven- to eightfold in children). Thus, under optimal conditions, reticulocyte percentages of at least 4 to 5 percent (often considerably higher) and absolute reticulocyte counts as high as 350,000/microL (3.5 x 1011/L) are possible.

An increased reticulocyte count represents a normal bone marrow response to anemia. Incorporation of the reticulocyte count into the anemia evaluation can be especially helpful in diagnosing certain disorders including hemolytic anemias and multifactorial anemias. (See 'Reticulocyte count' below.)

Correction factors for the manual count – The usefulness of reticulocyte counting can be improved in some settings by adjusting for the degree of anemia and its effects on reticulocyte production; examples include the corrected reticulocyte count and/or the reticulocyte production index. Alternatively, the absolute reticulocyte count can be used.

The reticulocyte stage of RBC development lasts for approximately four days. In the steady state, reticulocytes generally spend three days in the bone marrow and one day in the circulation. In severe anemia, reticulocytes can leave the bone marrow earlier and can circulate for two to three days, as illustrated in the figure (figure 2). This is the basis for the calculation of the reticulocyte production index [25]. (See "Regulation of erythropoiesis".)

If a laboratory does not report an absolute reticulocyte count or one of the corrected reticulocyte count parameters, calculators and other tools are available online (calculator 1).

Correlation with symptoms — The function of RBCs is to deliver oxygen to tissues, and with the exception of symptoms like pica in iron deficiency, the cardinal signs and symptoms of anemia result from impaired oxygen delivery.

Oxygen delivery, in turn, reflects a complex interplay of factors including the degree of anemia.

Blood oxygen content and release – The oxygen content of blood reflects the quantity of RBC hemoglobin present. The amount of hemoglobin is assessed by the hemoglobin concentration and indirectly by the HCT and RBC counts. Each gram of RBC hemoglobin can bind 1.34 to 1.39 mL of oxygen [26].

While blood oxygen content is a function of hemoglobin, oxygen delivery to the tissues can also be affected by changes in the affinity of hemoglobin for oxygen, expressed as the partial pressure of oxygen at which hemoglobin is 50 percent saturated (p50), as well as blood volume and tissue perfusion. (See "Oxygen delivery and consumption" and "Hemoglobin variants that alter hemoglobin-oxygen affinity", section on 'Hemoglobin variants that can affect oxygen affinity'.)

Oxygen delivery is increased by:

Decreases in pH

Increases in RBC 2,3 bisphosphoglycerate (2,3 BPG) concentration

Increased body temperature

Blood volume and tissue perfusion – Studies in animal models demonstrate that at any given HCT, systemic oxygen transport is lower with lower blood volume [27]. This is primarily a consequence of decreased tissue perfusion.

Other conditions besides hypovolemia that can impair tissue perfusion include:

Hypotension

Peripheral vasoconstriction

Decreased cardiac output

Bradycardia

Coronary artery obstruction

Any or all of these can worsen symptoms at a given degree of anemia.

Rate of decline in red cell mass – Symptoms of anemia also reflect the rate with which RBC mass declines, which determines the extent of compensatory changes. Following acute blood loss, an individual will initially have normal values for hemoglobin and HCT, but these values will decline over the ensuing 36 to 48 hours as most of the total blood volume deficit will be replaced by the movement of fluid from the extravascular into the intravascular space or with fluid resuscitation. Only then will the hemoglobin and HCT reflect blood loss. Thus, until the total blood volume deficit is fully repleted, the hemoglobin and HCT will underestimate the degree of blood loss [28]. The rapid onset of symptoms in these cases primarily reflects initial hypovolemia and hypotension and their effects on tissue oxygenation.

Conversely, when anemia develops gradually over time (as with iron deficiency, vitamin B12 deficiency, or a myelodysplastic syndrome [MDS]), compensatory increases in blood volume and tissue adaptation to hypoxia may prevent symptoms from developing until the hemoglobin is very low.

In general, clinical scenarios associated with a rapid decline in red cell mass that do not permit compensatory mechanisms to mitigate reduced tissue perfusion (large volume acute blood loss, acute hemolysis) will be more symptomatic for any given level of hemoglobin or HCT than low-level chronic blood loss, hemolysis, or anemias due to underproduction of RBCs.

WAYS TO APPROACH THE DIAGNOSIS

Categories to consider — All approaches to the diagnosis of anemia divide patients into categories; they are then informed by the probability of particular diagnoses in each category. An example is provided in the flowchart (algorithm 1).

There are several conceptual frameworks in which to categorize anemia. Most clinicians with experience in evaluating anemia use a combination of these conceptual frameworks tailored to the specific patient and the urgency with which diagnostic confirmation is required. Typically, this starts with the clinical features (patient sex, age, and underlying conditions), with review of the complete blood count (CBC) and red blood cell (RBC) indices, and reticulocyte count with other testing (especially useful if the mean corpuscular volume [MCV] is in the normal range).

Some of the more common ways to categorize anemia are based on:

Obvious clinical features such as acute blood loss or known cause for malabsorption of nutrients needed for RBC production. (See 'Evaluation based on clinical presentation' below.)

Medications and underlying conditions known to be associated with anemia, such as chronic inflammatory disorders, myelodysplastic syndromes, or thalassemia. Selected medicines that can cause anemia and their mechanisms are summarized in the table (table 3).

"Flags" on the initial CBC and chemistry panel, including other cytopenias, an abnormal differential, abnormalities of RBC shape, or evidence of kidney or liver dysfunction. (See 'Evaluation based on CBC/retic count' below.)

Whether the RBCs are small (microcytic) or large (macrocytic). (See 'Evaluation based on MCV' below.)

Whether the bone marrow is functioning appropriately (based on whether the reticulocyte count appropriately increased). (See 'Reticulocyte count' below.)

An experienced clinician will consider all of these frameworks simultaneously.

The clinical scenarios and certain findings on the CBC are most likely to point to serious, "can't-miss" diagnoses that require immediate interventions. (See 'Pancytopenia' below.)

Information to gather

General clinical information — A history and physical examination may identify features that increase the likelihood of specific diagnoses.

Known underlying medical conditions and medications (table 3) that cause anemia

Family history of a specific type of anemia such as sickle cell disease or thalassemia

Causes of acquired anemia

Dietary practices (eg, vegan diet lacks vitamin B12)

Travel (eg, acquired parasitic infections)

Infections

Bleeding (heavy menses, melena)

Chronicity of the anemia

Symptoms or conditions that would suggest hemolysis

Dark urine

Jaundice

History of gallstones

Anemia with certain food or drug exposures (fava beans, oxidant drugs)

Symptoms or findings that suggest kidney or liver disease or hypersplenism

Rapidity with which symptoms developed (if present) (see 'Correlation with symptoms' above)

Laboratory test results — Laboratory parameters may be especially useful for constructing a list of likely diagnoses before the clinical history can be elicited (eg, if the patient is not present or not able to provide relevant history) and when the clinical context does not point to an obvious cause.

It is assumed that the individual has already had a CBC with RBC indices and white blood cell (WBC) differential.

With some caveats, the following testing is appropriate in the initial evaluation of unexplained anemia:

Reticulocyte count – Reflects the ability of the bone marrow to produce RBCs and can be used to categorize possible causes of anemia. (See 'Reticulocyte count' below.)

Chemistry panel – Should include assessments of kidney and liver function, with creatinine, alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

Hemolysis labs – Lactate dehydrogenase (LDH), bilirubin, and haptoglobin (table 4), if the clinical history suggests hemolytic anemia and/or the reticulocyte count is increased. (See 'Hemolysis' below.)

Blood smear – A review of the peripheral blood smear is always desirable in the initial evaluation of anemia. However, it is not always possible to obtain this immediately, and some workflows will direct the blood smear to an off-site reviewer who is unfamiliar with the patient. These practices may make blood smear review during the initial evaluation an unrealistic expectation in many primary care practices. In contrast, review of the blood smear is a routine component of the anemia evaluation by a hematologist.

In some settings, review of a blood smear by an experienced professional is critical to the evaluation and treatment; these settings are indicated in the following sections. Interpretation of specific findings is discussed separately. (See "Evaluation of the peripheral blood smear".)

More extensive initial testing may be needed in an individual who is critically ill. Conversely, certain tests may be omitted in an individual with an obvious clinical presentation that suggests a specific diagnosis. As an example, a young woman with new onset microcytic anemia can be evaluated for iron deficiency by iron studies, without the need for reticulocyte count, LDH, liver function tests, or review of the peripheral blood smear. (See 'Evaluation based on clinical presentation' below.)

Ideally, laboratory results are incorporated with clinical information as soon as possible to help narrow and/or expand the diagnostic possibilities, as illustrated in the flowchart (algorithm 1). Further information can be gathered simultaneously or sequentially, depending on the clinical scenario.

EVALUATION BASED ON CLINICAL PRESENTATION — Certain patterns (features of the clinical history or obvious abnormalities in the initial laboratory results) can be very helpful in suggesting specific diagnoses if present.

Acute blood loss — Diagnosis of the underlying etiology of anemia is generally not a challenge in an individual with obvious gastrointestinal bleeding or trauma.

Typically, the major challenge is identifying and managing the specific site of bleeding. If an obvious anatomic site of bleeding cannot be identified, further evaluations for occult bleeding are appropriate. (See "Evaluation of occult gastrointestinal bleeding".)

Other assessments such as coagulation studies or assessment for a bleeding disorder may also be appropriate. (See "Approach to the adult with a suspected bleeding disorder".)

The immediate goal of management is to maintain or restore tissue perfusion and oxygen delivery by supporting intravascular volume and red blood cell (RBC) mass. This may require transfusions, including use of a massive transfusion protocol in some cases. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Thresholds for specific patient populations' and "Massive blood transfusion".)

After the patient is stabilized, iron stores should be assessed and iron replaced if low. Serum ferritin, if low, is a reliable indicator of iron stores. Serum iron concentration is not a reliable indicator of iron stores because it can be increased acutely by recent transfusion (due to iron release from damaged RBCs in the transfused product). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Sequence of testing'.)

Congenital anemia or a family history of anemia — A history of lifelong anemia or a family history of anemia can be helpful in reaching a diagnosis of a heritable/genetic syndrome.

Family history – If there is a family history of anemia, it is important to identify the specific relatives who were anemic, since not all positive family histories imply a familial syndrome. As an example, females with iron deficiency anemia due to menses and/or pregnancies will often report a family history of anemia, when in fact the affected family members are all females with iron deficiency anemia.

Patient history – Individuals with lifelong anemia due to chronic hemolytic disorders may describe episodes of jaundice during acute illnesses or episodes of anemia that is exacerbated during acute illnesses or with exposures to medications. Pigment gallstones may also be seen in chronic hemolytic anemias.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common cause of episodic hemolysis associated with febrile illnesses and certain medications (table 5). (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Diagnostic evaluation'.)

Laboratory findings – Many of the heritable anemias cause hemolysis. Laboratory findings obtained around the time of the event may show anemia, high reticulocyte count, high lactate dehydrogenase (LDH) and indirect bilirubin, and low haptoglobin (table 4). The most common types of heritable hemolytic anemias and specific causes of each type are summarized in the figure (figure 3).

The direct antiglobulin test (DAT) distinguishes immune causes (DAT-positive) from non-immune causes (DAT-negative). Heritable syndromes are typically DAT-negative. DAT-positivity can sometimes occur following transfusion (due to an immunologic transfusion reaction).

Blood smear – Evaluation of the peripheral blood smear is especially useful in individuals with lifelong anemia because many of the heritable syndromes have characteristic and easily visible abnormalities of RBC shape and appearance. (See "Evaluation of the peripheral blood smear", section on 'Red cell abnormalities'.)

The blood smear findings can in turn direct the subsequent laboratory tests needed to confirm or exclude a specific diagnosis.

As examples:

Bite or blister cells (picture 5) – G6PD deficiency, evaluated by measuring the G6PD level.

Microcytosis, target cells, teardrop cells (picture 6) – Thalassemia, evaluated by hemoglobin analysis or molecular (DNA) testing.

Spherocytes (picture 7), elliptocytes (picture 8), or stomatocytes (picture 9) – Hereditary spherocytosis (HS), elliptocytosis (HE), or stomatocytosis (HSt).

Details of testing are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency" and "Methods for hemoglobin analysis and hemoglobinopathy testing" and "Hereditary spherocytosis" and "Hereditary elliptocytosis and related disorders" and "Hereditary stomatocytosis (HSt) and hereditary xerocytosis (HX)".)

Premenopausal females — Iron deficiency is common in premenopausal reproductive age females due to menses and/or pregnancies. RBCs are microcytic in some individuals but may be normocytic in people with early or mild iron deficiency [29]. Other conditions contributing to anemia can also be present.

If the clinical history and examination are otherwise negative, we obtain iron studies (serum iron, serum transferrin or total iron binding capacity (TIBC), serum ferritin, and calculated transferrin saturation [TSAT]). A low ferritin is highly specific for iron deficiency. Obtaining the studies after an overnight fast may be useful as it avoids interference by dietary iron or iron-containing vitamins, which can increase the serum iron and calculated TSAT. (See "Iron requirements and iron deficiency in adolescents", section on 'Evaluation and presumptive diagnosis' and "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Diagnostic evaluation'.)

Findings that suggest another cause of anemia should also be pursued. This may include anemia during childhood, symptoms related to hemolysis, and other findings on the complete blood count (CBC) and blood smear.

Older adults — The prevalence of anemia increases substantially in patients over the age of 60 [30,31]. As noted above, we evaluate the underlying cause rather than attributing anemia to aging. (See 'Anemia definitions' above.)

Major causes – Major causes of anemia in older adults include [32]:

Nutritional deficiencies in approximately one third.

Kidney disease or anemia of chronic disease/inflammation (ACD/AI) in approximately one third.

Unexplained in the remaining third. Clonal disorders such as myelodysplastic syndrome may account for a significant proportion of unexplained anemias in older adults.

Routine testing – All individuals over the age of 60 should have testing for the following:

Kidney function – Estimation of glomerular filtration rate (GFR). eGFR <45 mL/min/1.73 m2 in the absence of another diagnosis implicates chronic kidney disease (CKD) as a cause.

Iron stores – Iron studies (serum iron, serum transferrin or TIBC, serum ferritin, and TSAT).

Vitamin B12 – Vitamin B12 level, with methylmalonic acid level if vitamin B12 deficiency is suspected and vitamin B12 level is equivocal.

Folate – Folate level if at risk for malnutrition.

Additional testing – Further testing may be appropriate in certain settings:

Monoclonal gammopathy – Testing is indicated if the mean corpuscular volume (MCV) is increased and/or if there is reduced eGFR or hypercalcemia. Serum free light chains and serum protein electrophoresis (SPEP) with immunofixation are obtained.

Androgen deficiency – Testing with serum testosterone level is indicated in older males with an isolated normocytic anemia in whom the testing above did not provide a diagnosis [33].

Myelodysplastic syndrome (MDS) and clonal cytopenias – Testing for a clonal bone marrow disorder is indicated if the MCV is slightly elevated and/or if there are other cytopenias or morphologic abnormalities on the blood smear. Molecular testing can be performed on peripheral blood using a gene panel for myeloid disorders (MDS panel) or clonal hematopoiesis (CH) panel. Bone marrow can be examined for signs of dysplasia for possible diagnosis of MDS.

Unexplained anemia of aging is a poorly defined syndrome often seen in older individuals. The mechanism is unclear and appears to be cytokine-mediated [34]. This is a diagnosis of exclusion in older individuals with normocytic anemia and an unrevealing workup. The diagnosis should be reassessed periodically to avoid missing a correctable disorder.

Malabsorption/malnutrition — A number of specific causes of anemia diagnoses occur at increased frequency in individuals with malnutrition and/or malabsorption. These may include deficiencies of iron, vitamin B12, folate, and copper, which may occur in isolation or simultaneously. In individuals with severely reduced intake due to anorexia nervosa or starvation, the bone marrow is often affected.

Gastric surgery – Gastric surgery, particularly bariatric surgery, is associated with malabsorption of vitamins and trace elements. This is particularly the case following Roux-en-Y procedures [35]. Gastric acid, proteins, and sugars protect iron from alkaline secretions of the duodenum. Rates of deficiencies with different procedures and details of routine supplementation are discussed separately. (See "Bariatric surgery: Postoperative nutritional management".)

Zinc supplements – Zinc ingestion, as a dietary supplement or in zinc-containing denture adhesives, can cause copper deficiency by inhibiting copper absorption. (See "Causes and pathophysiology of the sideroblastic anemias", section on 'Copper deficiency'.)

Starvation or anorexia nervosa – Anemia is seen in approximately one-third of individuals with severe malnutrition or anorexia nervosa, either alone or in combination with neutropenia or leukopenia [36]. The bone marrow may show gelatinous necrosis. Anemia will improve with restored food intake. (See "Anorexia nervosa in adults and adolescents: Medical complications and their management", section on 'Hematologic'.)

Iron deficiency causes microcytosis, while vitamin B12, folate, and copper deficiency cause macrocytosis. If both iron deficiency and one of the other deficiencies are present, the MCV may be in the normal range, often with an increased red cell distribution width (RDW).

Vitamin B12 and copper deficiency can cause other cytopenias; neutropenia commonly accompanies the anemia in copper deficiency. Vitamin B12 and copper deficiency both can produce posterior column neurologic abnormalities.

The evaluation in all cases should include serum iron, transferrin or TIBC, ferritin, vitamin B12, and folate levels. Copper level should be measured in malnourished individuals with anemia accompanied by neutropenia and/or neuropathy, as well as those with anemia in the setting of gastric/bariatric surgery or a history of zinc ingestion. Individuals with any of these deficiencies should be evaluated for the underlying cause.

Underlying systemic illness — Chronic anemia in patients with systemic illnesses may reflect anemia of chronic disease/inflammation (ACD/AI), particularly in disorders associated with inflammatory processes such as rheumatoid arthritis or systemic lupus erythematosus (SLE).

The reduction in hemoglobin is often mild to moderate. The red cells are typically normocytic, although there may occasionally be a moderate degree of microcytosis due to iron-restricted erythropoiesis. Iron studies show decreased serum iron and TSAT and normal or elevated ferritin concentrations. Serum erythropoietin is typically increased above the level seen in patients who are not anemic but to a lesser degree than would be observed in uncomplicated iron deficiency (figure 4). Serum hepcidin is not routinely available but would be expected to be elevated.

Underlying conditions commonly associated with ACD/AI include:

Cancer

Chronic kidney disease (may be associated with concomitant erythropoietin deficiency)

Rheumatologic conditions

Hypothyroidism

Infections

There is debate about whether diabetes mellitus per se causes ACD/AI, or whether ACD/AI can only be caused by complications of diabetes. Studies attempting to distinguish between the two are lacking, and many individuals with diabetes have other comorbidities such as infection that could contribute to ACD/AI [37]. Anemia in an individual with diabetes should not be attributed to diabetes without a thorough evaluation for other causes.

The evaluation focuses on eliminating other reversible contributing factors (eg, concomitant nutrient deficiencies), and management focuses on treating the underlying condition. (See "Anemia of chronic disease/anemia of inflammation".)

EVALUATION BASED ON CBC/RETIC COUNT — The complete blood count (CBC) provides other information on white blood cell (WBC) and platelet counts and in some cases a reticulocyte count, WBC differential, or information about abnormal cells.

This information should be assessed and may help to direct subsequent testing, especially if there are indications of potentially serious, can't miss diagnoses such as those associated with pancytopenia (see 'Pancytopenia' below), or if there are schistocytes (indicative of microangiopathic hemolysis) on the blood smear. (See 'Hemolysis' below.)

Pancytopenia — Pancytopenia is the combination of anemia, thrombocytopenia, and neutropenia (or leukopenia).

Findings from peripheral blood smear examination are critical in the assessment of pancytopenia. Other testing is directed by the findings, as discussed separately. (See "Approach to the adult with pancytopenia".)

Findings of particular concern that warrant hematologist involvement and bone marrow examination include:

Severe pancytopenia.

Blasts or immature myeloid/lymphoid forms, which suggest acute leukemia.

Abnormal lymphocytes (hairy cells, large granular lymphocytes, prolymphocytes).

Leukoerythroblastosis (picture 10) with or without teardrop cells (dacrocytes; (picture 11)).

Pancytopenia with hemolysis or thrombosis.

Pancytopenia or bicytopenia (anemia with leukopenia or anemia with thrombocytopenia) in an older individual with normal vitamin B12, folate, and copper levels.

Potential diagnoses are numerous (table 6). They include drug-induced pancytopenia (cytotoxic drugs, anti-infective drugs, anticonvulsants (table 7)), certain infections (viral [hepatitis, cytomegalovirus, Epstein Barr virus] and severe non-viral [clostridial sepsis, malaria, leishmaniasis, leptospirosis, babesiosis]), bone marrow failure (aplastic anemia), myelodysplasia, myelofibrosis, clonal disorders such as paroxysmal nocturnal hemoglobinuria (PNH), and hematologic malignancies. (See "Approach to the adult with pancytopenia" and "Aplastic anemia: Pathogenesis, clinical manifestations, and diagnosis", section on 'Differential diagnosis'.)

These disorders can also present with isolated anemia or bicytopenia. In most cases, reticulocyte parameters are decreased (see 'Reticulocyte count' below). PNH is associated with bone marrow failure and hemolytic anemia, and reticulocyte values may be normal or increased [38]. (See "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)

While a bone marrow disorder is always a consideration in individuals with pancytopenia, in some individuals, pancytopenia may be due to other causes:

Hypersplenism – Cirrhosis can cause pancytopenia due to sequestration of cells in the spleen (hypersplenism). Macrocytosis and target cells are often seen on the peripheral blood smear. The mean corpuscular volume (MCV) will typically be elevated to a moderate degree, usually no higher than 105 fL. Splenic imaging is appropriate if splenomegaly has not been previously documented. (See "Evaluation of splenomegaly and other splenic disorders in adults", section on 'Hypersplenism'.)

Nutrient deficiency – Deficiency of vitamin B12, copper, and/or folate may also cause pancytopenia and should be evaluated, especially if the peripheral blood smear shows macroovalocytes (picture 12), hypersegmented neutrophils (picture 13), and/or if the MCV is >110 fL. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency".)

Autoimmune – Autoimmune cytopenias typically affect a single cell line but can affect more than one cell line simultaneously, especially if there is an underlying rheumatologic disorder such as systemic lupus erythematosus (SLE) or a lymphoid disorder such as chronic lymphocytic leukemia (CLL). (See "Hematologic manifestations of systemic lupus erythematosus" and "Overview of the complications of chronic lymphocytic leukemia".)

HLH – Hemophagocytic lymphohistiocytosis (HLH) may be primary (typically in children) or secondary to an infection, malignancy, or rheumatologic condition. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)

TMAs – Thrombotic microangiopathies (TMAs) such as thrombotic thrombocytopenic purpura (TTP) typically cause thrombocytopenia and microangiopathic hemolytic anemia, with a very low platelet count and schistocytes on the blood smear. Some types of drug-induced TMAs such as due to quinine can cause pancytopenia. Disseminated intravascular coagulation (DIC) can cause pancytopenia due to TMA plus bone marrow suppression, with coagulation abnormalities often prominent. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)" and "Drug-induced thrombotic microangiopathy (DITMA)", section on 'Quinine' and "Evaluation and management of disseminated intravascular coagulation (DIC) in adults".)

Reticulocyte count — Anemia can also be classified on the basis of reticulocyte production. This approach is most informative when the reticulocyte count is either very decreased or very elevated. Attention must be paid to the particular reticulocyte parameter reported (absolute count versus percentage) and is most helpful using a reticulocyte parameter that is corrected for the degree of anemia (table 2). (See 'Reticulocyte production' above.)

Reticulocytosis requires a normally functioning bone marrow replete with iron, folate, cobalamin (vitamin B12), and copper, and a normally functioning kidney that can sense a decrease in oxygen delivery and produce a compensatory increase in erythropoietin (EPO). Thus, a decreased reticulocyte count suggests underproduction of red blood cells (RBCs; bone marrow suppression), and an increased reticulocyte count usually suggests hemolysis or blood loss. If both bone marrow suppression and hemolysis or blood loss are present, the reticulocyte count will be inappropriately low.

Causes

Decreased – Anemia with a decreased (or inappropriately low) reticulocyte count may be due to:

-Deficiency of iron, vitamin B12, folate, or copper

-Medications that suppress the bone marrow (table 3)

-Primary bone marrow disorders including myelodysplastic syndrome (MDS), myelofibrosis, or leukemia

-Very recent bleeding (within five to seven days, before bone marrow compensation has occurred)

Increased – Anemia with an increased reticulocyte count may be due to:

-Hemolysis

-Repletion of deficient iron, vitamin B12, folate, or copper (early phase of recovery)

-Recovery from bleeding

Regardless of other causes of anemia, an insufficient increase in the reticulocyte count suggests that the function of the bone marrow and/or the kidney are impaired.

Evaluation – If the reticulocyte count is increased and the cause of anemia is not readily apparent, additional laboratory testing for hemolysis is appropriate (table 4). (See 'Hemolysis' below.)

Response to treatment – An increase in reticulocyte count following treatment can also be very helpful in determining if the cause of anemia was determined accurately and completely. As examples:

If anemia was attributed to a deficiency (iron, vitamin B12, folate), brisk reticulocytosis is expected to occur within one to two weeks of repletion.

If the reticulocyte count does not increase with correction of a deficiency, this suggests an additional cause of anemia is interfering with bone marrow function. As an example, vitamin B12 or folate deficiency may occur concurrently with iron deficiency, causing a normocytic anemia (see 'Normocytic (normal MCV)' below). This combination of findings is often seen in malabsorption syndromes such as for celiac disease, autoimmune gastritis, or bariatric surgery. (See 'Malabsorption/malnutrition' above.)

Hemolysis — Hemolytic anemia should be considered when there is a rapid fall in hemoglobin concentration with an increased reticulocyte count in the absence of blood loss (table 2). Other abnormal laboratory findings indicative of hemolysis are summarized in the table (table 4).

Schistocytes on the blood smear indicate likely hemolysis due to mechanical RBC destruction. Schistocytes plus thrombocytopenia indicate possible thrombotic microangiopathy (TMA), which may be life-threatening. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Chronic hemolysis may present with a stable hemoglobin, a high reticulocyte count, and a normal lactate dehydrogenase (LDH) and bilirubin. The combination of an increased LDH and reduced haptoglobin is 90 percent specific for acute hemolysis, while the combination of a normal LDH and a serum haptoglobin greater than 25 mg/dL is 92 percent sensitive for ruling out hemolysis [39,40].

Intramedullary hemolysis (within the bone marrow) due to ineffective erythropoiesis, as may be seen in thalassemia or vitamin B12 deficiency, may produce elevations of bilirubin and LDH without reticulocytosis.

Causes of hemolysis are numerous and can be categorized in several ways, as summarized in the table (table 8) and discussed in more detail separately. (See "Diagnosis of hemolytic anemia in adults".)

These include:

Hereditary, non-immune:

Hemoglobinopathies (sickle cell disease, thalassemias, unstable hemoglobins)

Hereditary red cell enzyme deficiencies (glucose-6-phosphate dehydrogenase [G6PD], pyruvate kinase [PK], glucose phosphate isomerase, 5’ nucleotidase)

Hereditary RBC membrane defects (hereditary spherocytosis [HS], elliptocytosis [HE], stomatocytosis [HSt])

Acquired, non-immune

Membrane defects (liver disease, acquired acanthocytosis)

Infections (malaria, babesiosis, clostridial sepsis, Bartonellosis, trypanosomiasis, visceral leishmaniasis)

Drug-induced (oxidant stress)

Severe burns

Thrombotic microangiopathies (thrombotic thrombocytopenic purpura [TTP], hemolytic uremic syndrome [HUS], drug-induced TMA)

Mechanical (intravascular devices, artificial heart valve, giant hemangioma, footstrike hemolysis)

Hypersplenism (may have a component of phagocytosis but is not antibody mediated)

Vasculitis

Severe hypertension

Heavy metals (Wilson disease, copper toxicity, arsine toxicity)

Envenomation (snake, brown recluse spider, hobo spider)

Hypophosphatemia

Acquired, immune-mediated

Autoimmune (warm autoimmune hemolytic anemia [AIHA], cold agglutinin disease, paroxysmal cold hemoglobinuria)

Hemolytic transfusion reactions

Drug-induced

Once hemolysis is confirmed, the specific cause must be identified to ensure appropriate management. Details of the evaluation are discussed in a separate topic review. (See "Diagnosis of hemolytic anemia in adults", section on 'Diagnostic approach'.)

EVALUATION BASED ON MCV — Many individuals with anemia will be otherwise well, and the clinical history and other initial findings on the complete blood count (CBC) may not be helpful for suggesting specific diagnoses leading to anemia. A diagnostic approach based on the mean corpuscular volume (MCV) is most useful in these cases, as illustrated in the flowchart (algorithm 1).

Evaluation of anemia using the MCV is especially useful for microcytic and macrocytic anemia. (See 'Microcytosis (low MCV)' below and 'Normocytic (normal MCV)' below.)

Microcytosis (low MCV) — A decreased MCV (usually <80 fL) reflects a defect in cellular hemoglobin synthesis. These anemias are summarized in the table (table 9) and discussed in detail separately and briefly below. (See "Microcytosis/Microcytic anemia".)

Causes

Iron deficiency – Restricted iron availability (iron deficiency and some cases of anemia of chronic disease/anemia of inflammation [ACD/AI], which can cause functional iron deficiency). (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Anemia of chronic disease/anemia of inflammation".)

Decreased globin chains – Qualitative abnormalities in globin proteins such as thalassemia, hemoglobin (Hb) C, and Hb E (but not Hb S). (See "Pathophysiology of thalassemia" and "Diagnosis of thalassemia (adults and children)" and "Overview of compound sickle cell syndromes".)

Decreased heme – Abnormalities of the heme porphyrin ring, including congenital sideroblastic anemias and lead poisoning. (See "Causes and pathophysiology of the sideroblastic anemias" and "Lead exposure, toxicity, and poisoning in adults".)

Very low MCV – Iron deficiency and thalassemia are the most likely causes of a very low MCV (<80 fL). The ratio of the MCV to the red blood cell (RBC) count (Mentzer index) is useful in predicting the likelihood of thalassemia trait versus iron deficiency. If the ratio of MCV (in fL) to RBC count (in millions of cells/microL) is less than 13, thalassemia is more likely than iron deficiency [41].

In practice, all individuals with a low MCV should have iron studies to evaluate iron status (and should have deficiency corrected if present), because the results of hemoglobin analysis can be altered by concomitant iron deficiency. (See "Methods for hemoglobin analysis and hemoglobinopathy testing", section on 'Patient with suspected thalassemia'.)

Evaluation

All patients – All patients with microcytic anemia should have serum iron, total iron binding capacity (TIBC)/transferrin, and serum ferritin concentrations measured, with calculated transferrin saturation (TSAT). Iron studies will identify iron deficiency (the most likely diagnosis for microcytic anemia) and ACD/AI in most cases. Mild microcytosis with iron studies showing low iron, low TIBC, and high-normal to high ferritin in the appropriate clinical context (eg, chronic inflammatory condition with normal MCV prior to its development) is consistent with ACD/AI. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults", section on 'Iron studies (list of available tests)'.)

Individuals with normal iron studies – Thalassemia testing should be ordered in individuals with microcytic anemia who do not have iron deficiency or ACD/AI to identify beta thalassemia or other hemoglobinopathies. Globin gene studies may be needed to diagnose alpha thalassemia; the family history may be helpful in determining likelihood of these disorders. Minimal to mild anemia and microcytosis may indicate non-transfusion-dependent thalassemia (thalassemia trait). Basophilic stippling may also be seen with beta thalassemia [42]. (See "Methods for hemoglobin analysis and hemoglobinopathy testing".)

Individuals with normal hemoglobin – Basophilic stippling (picture 14) suggests possible lead poisoning, and whole blood lead levels should be measured. The diagnosis of sideroblastic anemia requires a bone marrow examination. (See "Bone marrow aspiration and biopsy: Indications and technique", section on 'Indications' and "Evaluation of bone marrow aspirate smears".)

Macrocytosis (high MCV) — An increased MCV (>100 fL) is typically attributed to asynchronous maturation of nuclear chromatin, although other causes may also be present. These anemias are summarized in the table (table 10) and discussed in detail separately and briefly below. (See "Macrocytosis/Macrocytic anemia".)

Causes

Megaloblastic anemia – Asynchronous nuclear maturation (megaloblastosis), in which the rate of cell division is reduced relative to cytoplasmic expansion. (See "Macrocytosis/Macrocytic anemia", section on 'Megaloblastic anemia'.)

Megaloblastic maturation can be due to:

-Vitamin B12 deficiency

-Folate deficiency

-Copper deficiency

-Myelodysplastic syndrome (MDS)

-Aplastic anemia

-Diamond Blackfan anemia

-Drugs that interfere with DNA synthesis

Membrane changes – In some cases, conditions that increase RBC membrane (such as liver disease or excess alcohol [even without liver disease]) and other underlying disorders such as hypothyroidism can cause increases in MCV. Stomatocytosis (hereditary or acquired) can also cause macrocytic anemia. (See "Macrocytosis/Macrocytic anemia", section on 'Causes of macrocytosis/macrocytic anemia'.)

Reticulocytosis – Reticulocytes are larger than mature RBCs (picture 3), and a high level of reticulocytosis will increase the MCV. This will be associated with an increased red cell distribution width (RDW) and can often be suspected from examination of the peripheral blood smear. (See 'Reticulocyte production' above.)

Reticulocytes may be increased in:

-Hemolytic anemias (acute or chronic)

-Recovery from bleeding

-Repletion of iron or other deficient nutrient

-Recovery from bone marrow suppression such as binge drinking alcohol

Spurious – Increased concentrations of immunoglobulin or acute phase proteins such as occurs with inflammation or a polyclonal or monoclonal gammopathy may cause small rouleaux (picture 15) that are counted by electronic counters as single large cells. This is a laboratory artifact that can be assessed by viewing the peripheral blood smear.

Evaluation

All individuals – Serum vitamin B12 level should be measured in all patients with unevaluated macrocytosis. All individuals who are nutritionally compromised or who have had gastric surgery should also have serum folate measured. In patients without known nutritional/gastric issues who have MCV >110 fL and a normal vitamin B12 level, serum methylmalonic acid (MMA) and serum folate should be measured. (See "Clinical manifestations and diagnosis of vitamin B12 and folate deficiency", section on 'Diagnostic evaluation'.)

Individuals with normal vitamin B12 and folate

-Thyroid stimulating hormone (TSH) should be checked. (See "Macrocytosis/Macrocytic anemia", section on 'Hypothyroidism'.)

-Alcohol use should be assessed. The MCV typically is not >105 fL in alcohol-induced macrocytosis. (See "Hematologic complications of alcohol use", section on 'Anemia'.)

-Serum copper level should be checked, especially if neutropenia and/or neuropathy are present or if the history reveals zinc ingestion or other risk factors. (See "Copper deficiency myeloneuropathy", section on 'Causes of acquired copper deficiency'.)

-The peripheral blood smear (or report) should be reviewed. If the blood smear shows target cells, liver synthetic tests should be measured. The MCV in liver disease typically is not >105 fL. Other morphologic abnormalities such as stomatocytosis should be evaluated, if present. If the copper level is normal and the blood smear shows evidence of dysplasia such as bilobed or immature neutrophils or binucleate RBCs, or other cytopenias, refer to a hematologist for bone marrow and/or molecular (DNA) studies on bone marrow or peripheral blood. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)".)

Normocytic (normal MCV) — A normal MCV (80 to 100 fL) is the most common finding in anemic adult males and postmenopausal females. Normocytic anemias can be more challenging to evaluate than anemias with an MCV that is obviously low or high. Causes are more numerous and may be multifactorial, an underlying condition may not be apparent, and other findings may be nonspecific.

Often normocytic anemia is associated with a slightly elevated RDW, and the reticulocyte count is not substantially increased (and may be decreased). An increased RDW may indicate a population of microcytic or macrocytic RBCs that is too small to shift the MCV out of the normal range, or combined microcytic and macrocytic processes, such as iron deficiency plus vitamin B12 or folate deficiency [43].

Causes

Nutrient deficiency – Any of the causes of acquired microcytic or macrocytic anemia, especially early stages of deficiency of iron, vitamin B12, folate, or copper. (See 'Microcytosis (low MCV)' above and 'Macrocytosis (high MCV)' above.)

Multiple causes – Combined microcytic plus macrocytic anemia [43]. The most characteristic situation is simultaneous deficiency of vitamin B12 and iron in an individual with celiac disease or autoimmune gastritis. (See "Epidemiology, pathogenesis, and clinical manifestations of celiac disease in adults" and "Metaplastic (chronic) atrophic gastritis".)

Hemolytic anemia without marked reticulocytosis (due to concomitant bone marrow suppression from another cause). (See "Diagnosis of hemolytic anemia in adults", section on 'Hemolysis without reticulocytosis'.)

ACD/AI – Anemia of chronic disease/anemia of inflammation (ACD/AI). (See "Anemia of chronic disease/anemia of inflammation".)

CKD – Anemia of chronic kidney disease (CKD). (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

HF – Anemia of heart failure (HF), including cardio-renal syndrome [44]. (See "Evaluation and management of anemia and iron deficiency in adults with heart failure" and "Cardiorenal syndrome: Definition, prevalence, diagnosis, and pathophysiology".)

Endocrine – Anemia with endocrine deficiency, including hypothyroidism (most cases), androgen deficiency, or adrenal insufficiency (in adrenal insufficiency, anemia may be masked by volume contraction). (See 'Caveats for normal ranges' above and "Clinical manifestations of adrenal insufficiency in adults", section on 'Hematologic findings'.)

Cancer – Cancer-associated anemia, including monoclonal gammopathies. (See "Causes of anemia in patients with cancer".)

Clonal hematopoietic stem cell disorders – Anemia due to a clonal disorder of erythropoiesis (myelodysplastic syndrome, aplastic anemia, or clonal cytopenias of uncertain significance [CCUS]) [45]. The strict definition of clonal hematopoiesis of indeterminate potential (CHIP) includes normal hemoglobin and other blood counts. (See "Clinical manifestations and diagnosis of myelodysplastic syndromes (MDS)" and "Idiopathic and clonal cytopenias of uncertain significance (ICUS and CCUS)".)  

Early blood loss – Blood loss that has not yet caused iron deficiency. (See "Evaluation of occult gastrointestinal bleeding".)

PRCA – Pure red cell aplasia. (See "Acquired pure red cell aplasia in adults".)

Partially treated anemia – Anemia in process of correction or following transfusion. A "dimorphic RBC population" (presence of two distinct populations of RBCs of different sizes) may be suspected when an increased RDW is present; it can be confirmed by examination of the peripheral blood smear, although the distinct populations may not always be recognized. This finding is traditionally taught as a clue to sideroblastic anemia [46]. However, it is more commonly seen during early treatment of iron deficiency or megaloblastic anemia, or following transfusion of a patient with microcytic or macrocytic anemia.

Evaluation

Reticulocyte count and chemistry panel – All individuals with normocytic anemia of unknown cause should have a reticulocyte count and chemistry panel (or review of results of this testing) during the initial evaluation, and abnormalities of this testing should be pursued (algorithm 1). (See 'Laboratory test results' above.)

Iron studies and hemolysis labs – If the reticulocyte count and chemistry panel are unrevealing, determine serum iron concentration, serum TIBC/transferrin, and serum ferritin concentration measured and transferrin saturation (TSAT) calculated, to diagnose iron deficiency or ACD/AI. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults".)

If iron stores are normal, evaluate for hemolysis. (See 'Hemolysis' above.)

Additional tests – If hemolysis is absent and there are no other obvious diagnoses, consider conditions listed above including cancer, endocrine disorders, blood loss, and nutrient deficiencies.

-Normocytic anemia with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 sq m and no other identified cause is most probably the anemia of chronic kidney disease. (See "Overview of the management of chronic kidney disease in adults", section on 'Anemia'.)

-Evaluation for disorders common in older adults is generally reasonable, including testing for monoclonal gammopathies, clonal cytopenias, androgen deficiency (in men), and bone marrow evaluation for myelodysplasia and pure red cell aplasia. (See 'Older adults' above.)

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: Complete blood count (CBC) (The Basics)" and "Patient education: Anemia caused by low iron (The Basics)" and "Patient education: Anemia of inflammation (anemia of chronic disease) (The Basics)" and "Patient education: Autoimmune hemolytic anemia (The Basics)" and "Patient education: Pernicious anemia (The Basics)" and "Patient education: Vitamin B12 deficiency and folate deficiency (The Basics)".)

Beyond the Basics topics (See "Patient education: Anemia caused by low iron in adults (Beyond the Basics)" and "Patient education: Heavy or prolonged menstrual bleeding (menorrhagia) (Beyond the Basics)".)

SUMMARY AND RECOMMENDATIONS

Definitions – Criteria for diagnosing anemia and caveats for defining normal ranges are summarized in the table (table 1) and discussed above. (See 'Anemia definitions' above and 'Caveats for normal ranges' above.)

Generally accepted cutoffs include:

Females – Hemoglobin <11.9 g/dL or hematocrit <35 percent

Males – Hemoglobin <13.6 g/dL or hematocrit <40 percent

Conceptual framework – Anemia can be categorized in several ways, including pattern recognition for typical clinical presentations and laboratory findings; according to red blood cell (RBC) size; or according to whether the bone marrow is able or unable to increase RBC production, typically based on the reticulocyte count. Most experienced clinicians will consider these frameworks simultaneously. (See 'Categories to consider' above.)

Initial assessment – A history and physical examination may identify features that suggest specific diagnoses or medications that might be implicated (table 3). In addition to a complete blood count (CBC) with RBC indices and white blood cell (WBC) differential, most patients with anemia should have a reticulocyte count and chemistry panel with creatinine and hepatic transaminases. Tests for hemolysis and review of the peripheral blood smear are appropriate in some clinical situations. (See 'Information to gather' above.)

Common clinical scenarios – Common presentations that can help narrow the diagnosis include acute bleeding, hereditary anemias, iron deficiency in premenopausal reproductive age females, bone marrow and nutritional disorders in older adults, combined nutrient defects due to malabsorption, and inflammatory conditions that produce anemia of chronic disease/chronic inflammation (ACD/AI). (See 'Evaluation based on clinical presentation' above.)

Initial laboratory abnormalities – Pancytopenia raises concern for an underlying bone marrow disorder (table 6), which may be life-threatening in some cases. A high reticulocyte count suggests hemolysis or blood loss. Clinical and laboratory findings of hemolysis (table 4) warrant testing to determine whether RBC destruction is hereditary versus acquired and immune versus non-immune (table 8). (See 'Evaluation based on CBC/retic count' above.)

RBC size – For most individuals who lack an obvious clinical pattern that can be used to narrow the diagnosis, the evaluation can focus on RBC size, as determined by the mean corpuscular volume (MCV). MCV is also useful for expanding or narrowing diagnostic possibilities in individuals with various clinical presentations. Causes of anemia categorized by MCV are listed in the table (table 11); an approach summarizing the evaluation is provided in the flowchart (algorithm 1).

Low MCV – Common causes of microcytic anemia (MCV <80 fL) include iron deficiency, thalassemia, and some cases of ACD/AI (table 9). (See 'Microcytosis (low MCV)' above and "Microcytosis/Microcytic anemia".)

High MCV – Common causes of macrocytic anemia (MCV >100 fL) include megaloblastic anemias (vitamin B12, folate, or copper deficiency; certain drugs; and myelodysplastic syndrome [MDS]), liver disease, alcohol, hypothyroidism, and hemolysis with a high reticulocyte count (table 10). (See 'Macrocytosis (high MCV)' above and "Macrocytosis/Macrocytic anemia".)

Normal MCV – Normocytic anemia (MCV between 80 and 100 fL) can be challenging to evaluate. Causes include early or combined nutrient deficiencies, multifactorial causes, a number of chronic medical conditions, clonal bone marrow disorders, and other causes of bone marrow dysfunction. Testing for iron deficiency, hemolysis, endocrine disorders, and other disorders may be appropriate, guided by the patient's age and other medical conditions. (See 'Normocytic (normal MCV)' above.)

ACKNOWLEDGMENT — We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The editors at UpToDate gratefully acknowledge Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

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

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Topic 7133 Version 70.0

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