Anemia (microcytic, normocytic, and macrocytic) will be something that as students you will run into regularly in rotations, and in the future as clinicians is something that you must be familiar and comfortable with.  Today we will start off our series with microcytosis.

You can learn more about the other types of anemia below:

The finding of microcytic anemia is often incidental and will be found on routine screening blood work.  By definition microcytic anemia is present when the red blood cell level, hemoglobin, and hematocrit are all below the threshold of normal, and then the mean corpuscular volume (MCV) additionally is less than 80 μm3.  The normal values for a patient’s hemoglobin, hematocrit, RBCs, and MCV all vary with age as below.

Variations in hemoglobin levels
Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.


In the U.S. the most common cause of microcytosis is iron deficiency anemia (IDA).  However, other etiologies include anemia of chronic disease, sideroblastic anemia, thalassemia, or lead toxicity.

Differential diagnosis of microcytosis
Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.


Etiologies of Microcytosis

Once iron deficiency is found on lab results, our job is to find out why it is occurring.  It is not good enough to find the anemia and proverbially wash your hands clean of the situation.  Based on the age and sex of the patient presenting with iron deficiency anemia depends on the most likely underlying etiology.

Etiologies of iron deficiency anemia
Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.


In children, the most common cause of IDA is decreased oral intake of iron-fortified foods.  In menstruating females, the most common etiology is menstrual bleeding.  If iron deficiency anemia is present in men or non-menstruating females, you must complete a gastrointestinal evaluation to rule out any occult blood loss from gastrointestinal malignancy.1

Once diagnosed, often the history encounter can point us toward the underlying etiology of a patient’s IDA.  Important history findings such as nutritional intake focused on whole milk intake in children, pica, cravings for ice can be signs of iron deficiency.

Exposure to toxins such as lead, a patient’s ethnicity or family history of anemia, joint pain or other symptoms of underlying chronic infection or inflammatory illness are essential topics to ask about as well.

Lastly, in non-menstruating females and males, you must assess for GI symptoms including abdominal pain, change in stool frequency or caliber, hematochezia, bright red blood per rectum (BRBPR), or dark, tarry stools.

Most patients with microcytic anemia are asymptomatic, but findings that may be present on examination include a systolic heart murmur, pallor of the nail beds, mucosa, and palmar creases.1

Laboratory Testing for Microcytic Anemia

Once microcytic anemia is seen on a CBC further lab work may help determine the underlying etiology including red cell distribution width (RDW), and serum iron studies (serum iron, ferritin, and TIBC).  Other tests that may be indicated include hemoglobin electrophoresis, reticulocyte count, and peripheral blood smear.

Laboratory tests in microcytosis
Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.


RDW measures the variation in width/size of RBCs and often can be increased in patients with iron deficiency anemia but is often normal in patients with anemia of chronic disease (AOCD).  However, this test cannot aid in differentiating IDA and beta-thalassemia trait.  The RBC count can help in this instance because it is often normal to high in beta-thalassemia trait and low in iron deficiency anemia.1

Serum iron levels are often low in IDA and AOCD.  If serum iron is low, it is important to look at the ferritin, transferrin saturation, and TIBC next which help to differentiate between IDA and AOCD.  TIBC will be increased in IDA but decreased in AOCD, and normal in thalassemias.

Transferrin saturation is the percentage calculated by taking the serum iron/TIBC multiplied by 100.  A value of less than 16% is often consistent with iron deficiency anemia.1

Ferritin reflects the true iron stores and does not fluctuate with acute serum iron changes.  However, ferritin is an acute phase reactant and can be elevated with inflammation, arthritis, malignancy, CKD, and liver disease.  Iron deficiency anemia is likely if the ferritin level is below 15 mcg/L in a healthy individual or less than 50 mcg/L in a person with an underlying cause of chronic inflammation.  If ferritin is over 100 mcg/L, then IDA can usually be ruled out.

Diagnosing the cause of microcytosis
Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.


Now that we know what tests to run and how to differentiate between multiple etiologies of microcytic anemia based on lab results, we will put it all together.

After you confirm microcytosis the next step is to order a ferritin level.  If this is low, this diagnosis of iron deficiency is made.  Remember it is crucial to rule out gastrointestinal malignancy contributing to IDA in males and non-menstruating females.  Gastrointestinal malignancy should also be considered in menstruating females if the iron deficiency anemia persists with appropriate iron replacement therapy, or if GI symptoms are present.1

If the ferritin level is normal or high, the next step is to look at the serum iron, TIBC, and transferrin saturation levels.  If the serum iron and transferrin saturation are low with an elevated TIBC, this is consistent with IDA.

If the serum iron level is low and the TIBC and transferrin saturation are decreased or normal the most likely etiology is anemia of chronic disease.

If iron, TIBC and transferrin saturation are all normal, then you should next complete a hemoglobin electrophoresis and peripheral blood smear.  This can help identify cases of alpha and beta thalassemia, sideroblastic anemia, or other hemoglobinopathies.

As mentioned earlier if there are history findings concerning for toxic exposure, a serum lead level can be completed.  Bone marrow biopsy can be helpful for diagnosis of sideroblastic anemia as well.1

Diagnosing the Cause of Microcytosis 

Iron deficiency anemia primarily occurs when the intake of dietary iron does not match the need of the body.1  The simple mismatch typically will only cause mild anemia; however, blood loss or malabsorption can lead to more severe and significant anemia.

Women of childbearing age, pregnant women, and children are most likely to be affected by IDA.  Heavy menstrual blood loss that leads to severe anemia should warrant further investigation for clotting disorders, such as von Willebrand disease.1

Beta-thalassemia is an autosomal recessive condition where normal beta globin chains in hemoglobin structures are underproduced.  Beta-thalassemia trait is the heterozygous form, and beta-thalassemia major is the homozygous form of disease.  Beta thalassemia is more common in those of African American, Southeast Asian, Greek, Italian, or Mediterranean descent.

Patients with beta-thalassemia trait typically have mild anemia with their hemoglobin rarely less than 9.3 g/dL.  Also, the MCV can sometimes be much lower than instances where a patient would have IDA solely.  However, even though there can be subtle differences on the CBC between beta-thalassemia and IDA, the way to confirm the diagnosis is with a hemoglobin electrophoresis.

Alpha thalassemia is caused by the underproduction of alpha globin chains.  It is most prevalent in persons of African or Southeast Asian descent.  Alpha globin chain production is based upon four genes on two separate chromosomes.  If one gene is deleted, the patient is a silent carrier with normal blood results findings on testing.

If two genes are deleted, this causes alpha thalassemia trait which causes microcytosis without anemia.  Hemoglobin electrophoresis testing is often normal in patients with alpha thalassemia trait.  Diagnosis is usually one of exclusion.1

Anemia of chronic disease can be caused by inflammatory diseases or chronic infections.  In this disease, increased levels of cytokines cause a decrease in erythropoietin production, interference with iron metabolism, and decreased erythropoietin effectiveness.1

Most cases of AOCD is normocytic, but 25 to 30 percent of cases are microcytic on lab findings.  The anemia is usually mild but can progress with severe autoimmune conditions.  Although in AOCD patients iron will be low, the ferritin, however, will often be elevated due to this being an acute phase reactant, responding to chronic inflammation.

I hope this article serves as a review for practicing clinicians on the evaluation, diagnosis, and work up of microcytic anemia, and for current students as a tool to learn how to evaluate, diagnose, and work up this disease.  

For students, anemia will be a commonly tested topic on school exams as well as on the PANCE, and hopefully, this article will serve as a tool in your arsenal.

You can learn more about the other types of anemia below:

Resources

  1. Am Fam Physician. Evaluation of Microcytosis. 2010;82(9):1117-1122. Copyright © 2010 American Academy of Family Physicians.
  2. UpToDate. Microcytosis/Microcytic Anemia. Accessed: April 23, 2018.

This article, blog, or podcast should not be used in any legal capacity whatsoever, including but not limited to establishing standard of care in a legal sense or as a basis of expert witness testimony.  No guarantee is given regarding the accuracy of any statements or opinions made on the podcast or blog.