Anemia: A Strategy for the Workup

June 1, 2006

Anemia is usually detected as an incidentalfinding on a screening completeblood cell (CBC) count. Occasionally,a patient presents with symptoms andsigns that strongly suggest anemia,and a CBC count is ordered. In eithersetting, the next step is to determinethe cause of the anemia.

Anemia is usually detected as an incidentalfinding on a screening completeblood cell (CBC) count. Occasionally,a patient presents with symptoms andsigns that strongly suggest anemia,and a CBC count is ordered. In eithersetting, the next step is to determinethe cause of the anemia.

The usual approach is to measureserum iron, total iron-binding capacity,serum folate, and serum vitamin B12 inthe hope of finding a treatable condition.However, this battery of tests issomewhat costly, and the likelihood ofarriving at a diagnosis is only about 35%,since about 25% of anemias are causedby iron deficiency and about 10% by vitaminB12 or folate deficiency (Table).

 Table - Causes of anemia
Cause Frequency*

Iron deficiency 25% - 35%

Chronic disease 25% - 35%

Hemolytic anemia and marrow failure 15%

Myelodysplasia Approximately 10%

Thalassemia 5% - 10%

Other diseases 5% - 10%

*The frequency depends on the geographic region, ethnic background, socioeconomic status, mean age, and incidence of chronic disease of a given population.

In this article, I present a logical,cost-effective approach to the evaluationof anemia. This approach can enableyou to arrive at a diagnosis in approximately90% of patients. The remaining10% can be referred to ahematologist.

Include the following tests in theworkup in this sequence:

  • Red cell indices.
  • Red blood cell volume distributionwidth (RDW).
  • Blood smear.
  • Reticulocyte count.

Mean corpuscular volume. Startthe evaluation with an analysis of thered cell indices--particularly the meancorpuscular volume (MCV). The patient'sMCV guides the selection of additionallaboratory tests.

Low MCV. The MCV is usuallylow in patients with established irondeficiency and in those with thalassemia.The volume can also be low in patientswith anemia of chronic disease,although it is more likely to be lownormalor slightly low.

When the MCV is low, measurethe serum ferritin level to help distinguishbetween the possible causes ofmicrocytic anemia. A result of less than20 μg/L is diagnostic of iron deficiency.Results of 20 μg/L and greaterrequire measurement of the serum transferrin receptor level for clarification.This test has been available formany years but has not gained thewidespread use it deserves.

Normal MCV. The MCV is usuallynormal in patients with anemia ofchronic disease, hemorrhage, renaldisease, liver disease, endocrine failure,or hypoplasia (drug-related or autoimmune).In the early stages of vitaminB12 or folate deficiency and ofhemolytic disease, the abnormallysized red cell population is not largeenough to affect the MCV and thus itremains normal. In addition, if eitherB12 or folate deficiency is accompaniedby iron deficiency, the MCV mayalso remain normal. Similarly, thalassemiacomplicated by B12 deficiencycan result in a normal MCV.

To distinguish between the variouspossible causes of normocytic anemia,measure the serum ferritin leveland then the serum transferrin receptorlevel.

High MCV. An elevated MCVusually points to established hemolyticanemia or myelodysplasia,which can be either a preleukemiccondition (primary myelodysplasia)or a maturation defect associatedwith vitamin B12 or folate deficiency(secondary myelodysplasia). Drugtherapy and excessive alcohol consumptionalso produce macrocytosis.Although patients with liver diseaseoften have a normal MCV, hepaticdysfunction can result in macrocytosis.The absolute reticulocyte countcan help distinguish between the differentcauses of macrocytic anemia(see below).

Hypothyroidism and MCV. Becausehypothyroidism is common, especiallyin elderly patients, it is importantto understand its effect on theMCV. The MCV is usually normal inpatients who have endocrine failurebut may be elevated when vitamin B12or folate deficiency is also present. Onthe other hand, the MCV may be elevatedin hypothyroid patients without B12 or folate deficiency and returnto normal with thyroid hormonereplacement.

Mean corpuscular hemoglobinconcentration. The mean corpuscularhemoglobin (MCH) is of little valuein the initial workup because changesin the MCH usually parallel changesin the MCV. However, the mean corpuscularhemoglobin concentration(MCHC) deserves a brief mention.Apart from artifact, an elevatedMCHC can be a sign of spherocytosis,and a low MCHC suggests irondeficiency.

Red blood cell volume distributionwidth. This measure of redblood cell heterogeneity plays a minorrole in the evaluation of anemia.The RDW is not useful in distinguishingbetween diseases or in theidentification of early deficiencystates. The RDW is usually normal inmildly anemic patients with thalassemiaand in those who have anemia ofchronic disease (unless inflammationis the cause, in which case it increases).However, the RDW is substantiallyelevated in iron deficiency accompaniedby vitamin B12 or folatedeficiency, and in thalassemia with anadded myelodysplasia.

Reticulocyte count. The reticulocytecount is particularly importantwhen hemolytic disease is suspected.To determine the absolute reticulocytecount, multiply the uncorrectedvalue by the red blood cell count inmillions. For example, a healthy manwith a reticulocyte count of 1% and ared blood cell count of 5 million/μLwould have an absolute reticulocytecount of 50,000/μL.

If the result is over 100,000/μL,hemolytic anemia is likely. The responseto specific deficiency replacementand bone marrow invasion bytumor cells can also produce countsover 100,000/μL. In a patient withanemia, a count under 50,000/μLshows that red blood cell productionis insufficient.

If the absolute reticulocyte countis less than 100,000/μL and the MCVis elevated, myelodysplasia is themost likely diagnosis. To distinguishbetween primary and secondarymyelodysplasia, measure serum vitaminB12 and folate levels. A low resulton either test points to deficiency(secondary myelodysplasia) as thecause of the anemia. If both levelsare normal, consider a bone marrowexamination with cytogenetic studiesto confirm primary myelodysplasia(preleukemia).