Diagnosing and Classifying Anemia in Adult Primary Care

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Chronic disease

If the patient has microcytic anemia and is not iron deficient or does not have thalassemia, then anemia related to a chronic disease should be considered.5 In such cases, the provider should order a reticulocyte count, which reveals how the bone marrow is responding to the anemia.5 Reticulocytes are immature red cells that have just been released from the bone marrow into the blood stream. The bone marrow increases the release of these cells in response to anemia.6

Any condition that stimulates reticulocyte production or prevents the bone marrow from producing reticulocytes will result in abnormal values (see Table 3). A normal reticulocyte count, expressed as the reticulocyte production index, is between 0.5% and 1.5%.5 The reticulocyte count is low in iron deficiency anemia and diseases that lead to decreased bone marrow production.5,6 Bone marrow suppression can occur in the context of chronic disease, infection, or inflammation. Malignancies are a less common cause for chronic disease microcytic anemia.6

Causes of Abnormal Reticulocyte Count image

If the cause of the decreased reticulocyte count is iron deficiency anemia, then treatment with iron supplementation should result in an increased reticulocyte count within one week.13 The primary care provider works in conjunction with the specialist to monitor the patient’s anemia when it is due to chronic disease or malignancy.


In macrocytic anemia, the RBCs are larger than normal (MCV > 100 fL). This form of anemia is usually caused by vitamin B12 and folate deficiency, but it can also result from alcoholism, certain medications (eg, chemotherapy, antivirals), bone marrow disorders (eg, leukemia), and liver disease (eg, cirrhosis; see Figure).5,14 Common medications that can cause macrocytosis include the antiseizure drug phenytoin, the antibiotics trimethoprim/sulfamethoxazole and nitrofurantoin, the disease-modifying antirheumatic drug sulfasalazine, and immunosuppressants such as azathioprine.14,15 Antiviral agents, such as reverse transcriptase inhibitors (eg, zidovudine) used to treat HIV infection, can also cause macrocytosis with or without anemia.6,14

Macrocytic anemias caused by low serum levels of B12 and folate usually reflect problems with gastrointestinal malabsorption. For example, gastric bypass or Crohn disease can lead to malabsorption of vitamin B12 and increase a patient’s risk for macrocytic anemia.13

Vitamin B12 deficiency occurs in patients with pernicious anemia because they are missing intrinsic factor, which is necessary to facilitate B12 absorption in the ileum.10 Low vitamin B12 and folate levels also can result from inadequate dietary intake, although this is rare in the United States due to mandatory fortification of certain foods. A diet low in fresh vegetables is the leading cause of folate deficiency. While folate deficiency related to poor nutritional intake can be seen in all age groups, vitamin B12 deficiency more frequently affects the elderly or persons following a strict vegan diet.14

In addition to the fatigue and pallor associated with macrocytic anemia, patients with vitamin B12 deficiency may also have a smooth tongue, peripheral neuropathy, and edema.5,14 Severe vitamin B12 deficiency can lead to subacute combined degeneration of the spinal cord, with demyelination of the dorsal and lateral columns most often occurring in the cervical and thoracic regions.16,17 This spinal cord degeneration can cause paresthesia, muscle spasticity, and ataxia.16

When there is a macrocytic anemia, but the B12 or folate level is only borderline low, additional tests should be performed to help distinguish between B12 and folate deficiency. Both B12 and folate deficiencies can cause elevated homocysteine levels.13 Clinically significant B12 deficiency causes elevation of methylmalonic acid (MMA), whereas folate deficiency does not.13,14 Elevation of MMA can be very sensitive for B12 deficiency but lacks specificity in certain situations, such as pregnancy, renal insufficiency, and advanced age.13,14

Treatment of vitamin B12 and folate deficiencies with supplementation prevents progression of the disease, and has the potential to relieve most of the symptoms. Oral, sublingual, or parenteral vitamin B12 or oral folate supplements can be started in the primary care setting once the provider has identified whether the patient is B12 deficient, folate deficient, or both.

The vitamin B12 dose used for deficiency-induced macrocytic anemia depends on the cause—for example, a temporary condition such as pregnancy versus a lifelong disorder such as pernicious anemia.13 The usual oral dosing regimen is 2 mg/d; if intramuscular injections are used, 50 to 100 mcg are given daily for a week, followed by weekly injections for a month, and then monthly injections of 1 mg for life, if necessary.13 Bone marrow response to supplemental B12 is very rapid, with increased reticulocyte counts seen within four or five days.13

The usual dose for oral folic acid is 1 mg/d as needed.13 Folic acid can be given for folate deficiency only if the vitamin B12 level is normal. Giving folate to a patient with untreated vitamin B12 deficiency can potentially worsen subacute combined degeneration of the spinal cord.13,16


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