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									                         ANEMIA IN PRIMARY CARE
                           Jeanette M. Tetrault, M.D.
                                    Week 3
Learning Objectives:

   1. Generate the relevant differential diagnoses for microcytic, normocytic, and
      macrocytic anemias
   2. Evaluate a patient with microcytic anemia and know when further work-up is
   3. Understand the work-up for B12 and folate deficiencies
   4. Consider hemolytic anemia in the differential diagnosis of a patient with anemia


Ms. H. is a 28-year-old female with no past medical history who presents to your
office to establish care. On review of systems, she admits to feeling “a little tired all
the time” but attributes this to her life as a surgical resident. Her menstrual history
is described as having regular periods, once monthly, for seven days at a time, with
two to three days of “heavy” flow. Her physical exam is completely normal.


   1. What test(s), if any, would you order?                                                Formatted: Font: Bold, Not Italic
      Your major concern for a menstruating female who complains of mild fatigue is
      for anemia. More specifically, you should consider iron deficiency anemia. It
      would be reasonable to start with a CBC and specifically look at the MCV to look
      for a microcytic anemia. It would also be reasonable at this time to send a TSH
      and perform a depression screen, as these are other common treatable causes of
      non-specific fatigue. As the article points out, iron studies are often ambiguous
      and not often helpful. A ferritin level, however, may be helpful.


Ms. H. comes in for follow-up of her lab results two weeks later. You note that her
hemoglobin is 11 mg/dL and her MCV is 76.
2. What should you do next? What if she said her periods lasted 5 days with
   normal flow?
   This patient is uncomplicated, and it would be reasonable, as she was found to
   have a microcytic anemia in the setting of heavy periods, to treat her empirically
   with iron supplements and re-check a CBC in four to six weeks to confirm a
   response. Additionally, she should be scheduled for a Pap smear and pelvic exam
   to rule out any pathology given her heavy bleeding.

   In the U.S., most iron deficiency results from blood loss. Gastrointestinal losses
   should be considered in all patients, and fecal occult blood screening should be
   performed if no other sources of blood loss can be identified. The optimal
   approach to menstruating women with iron deficiency anemia is unclear. All
   premenopausal women with positive fecal occult blood loss, anemia out of
   proportion to menstrual blood loss, abdominal symptoms, family history of GI
   malignancy, or age greater than 50 should undergo endoscopic evaluation.(Bini,

   Other causes of iron deficiency anemia include decreased iron absorption (i.e.,
   celiac disease), intravascular hemolysis (which may be accompanied by
   hemoglobinuria or hemosideriuria), and gastric bypass surgery.

   One must also consider which iron formulation should be used. The most
   appropriate form of oral iron therapy is one containing iron salts such as ferrous
   fumerate, ferrous sulfate, or ferrous gluconate. The recommended daily dose is
   between 150-200mg of elemental iron daily. No evidence suggests that one
   preparation is more effective for the treatment of iron deficiency. Ferrous sulfate
   at 325 mg TID contains 195 mg of elemental iron. Absorption of iron is best when
   taken on an empty stomach. This regimen should increase hemoglobin 2 g/dL
   over the next three weeks.

   The most common complication of iron supplementation includes constipation,
   and patients should be counseled to increase water intake. Other side effects
   include nausea, epigastric tenderness, or vomiting.

   Other causes of microcytic anemia include anemia of chronic disease and
   thalassemia. Adults with previously undiagnosed thalassemia are most often
   heterozygous for alpha or beta thalassemia. Compared with iron deficiency
   anemia, the RBC count may be normal or increased, the MCV is usually markedly
   depressed (i.e., MCV <75fL), and the RDW is often normal (11.0-15%). Patients
   may have splenomegaly on examination. Peripheral smear shows abnormal RBC
   morphology, and a serum protein electrophoresis can be ordered for further
   evaluation of potential thalassemia trait.

Mr. A. is a 62-year-old black male with a history of diabetes and hypertension. At a
recent visit to the ER for hyperglycemia, he had a CBC that showed a normal white
count, a normal platelet count, hemoglobin of 11.0, MCV of 84, and RDW of 13%
(normal range, 11.0-15%). His chemistry panel at that time showed a creatinine of
1.6, which you note is his baseline, but was otherwise normal. On review of systems,
he denies fatigue, orthostasis, dizziness, melena, or hematochezia. Physical exam
shows a blood pressure of 148/90, A-V nicking, and a soft systolic murmur. The rest
of his exam is within normal limits.

   3. What is the differential diagnosis for his anemia?
      First, African-American males have lower normal hemoglobin values than white
      males, by 1-2 g/dl, therefore, this may not be “anemic” for him. However, he has
      multiple possible risk factors for anemia: erythropoietin deficiency (from chronic
      kidney disease, as a result of longstanding diabetes and hypertension), and
      anemia of chronic disease (ACD) (secondary to diabetes). His anemia is
      normocytic; all of the above can present as such. Also in the differential for
      normocytic anemia are vitamin B12 or folate deficiency, hemolytic anemia, and
      primary bone marrow disorder. Often times, anemia may be multi-factorial.

   4. What else would you do at this point?
      A repeat CBC with peripheral smear should be checked. Additionally, a ferritin
      level should be checked in this patient, to rule-out iron deficiency. A reticulocyte
      count may also be helpful—appropriately high with hemolysis and
      inappropriately low or normal in every other case. Suspicion for anemia of
      chronic kidney disease in this case is fairly high.(Weiss, 2005) Unless something
      further in his history suggested a greater possibility of hemolysis (e.g., jaundice,
      new onset pallor, splenomegaly, or gallstones) , it would be reasonable to defer
      the additional tests (including indirect bilirubin, LDH and haptoglobin) for now.


Mr. A. returns the next week to follow-up. His tests reveal an unchanged CBC, a
ferritin of 120 and a reticulocyte count of 5%. He tells you at this visit that he
forgot to mention that he had an earache the week prior to his ER visit and went to
a walk in clinic and was given ampicillin.
   5. How does this information change your differential diagnosis, if at all?
      Infection- or drug-related hemolysis becomes a possibility. Ampicillin can be a
      cause of hapten-associated, immune-mediated hemolytic anemia.(Dhaliwal, 2003)
      The history is consistent, there is nothing to support iron-deficiency, and the
      reticulocyte count is above normal. The indirect bilirubin, LDH, and haptoglobin
      should be sent. Drug-related hemolysis is typically autoimmune, so a Coombs
      test would also be reasonable.

       The first step in the treatment of drug-related hemolysis is to remove the offending
       agent and monitor the patient for ongoing hemolytic anemia. Exchange
       transfusion is reserved only for severe cases.


Mr. B. is an 18-year-old college student who came to see you for a school physical.
His medical history is unremarkable. He takes no medications or herbal
supplements, but occasionally takes a multivitamin. Social history is notable for
occasional marijuana smoking and maintaining a vegan diet. Physical exam is
normal. His lab values are notable for a hemoglobin of 10.5, hematocrit of 31.5,
MCV of 107.

   6. What is your differential diagnosis for this patient, and what tests would you
      He has a macrocytic anemia, which is commonly caused by nutritional
      deficiencies (vitamin B12, folate), drugs (alcohol, hydroxyurea, methotrexate,
      trimethoprim, zidovudine, and 5-FU), and primary bone marrow disorders. It
      would be important to take a good history from this patient regarding alcohol use.
      As a vegan, he is at high risk for vitamin B12 deficiency.

       A vitamin B12 level and folate level should be sent first. Serum folate is a
       reflection of short-term folate balance and, therefore, may have wide fluctuation
       over time. RBC folate may be a more adequate indicator of tissue folate stores
       since it reflects an average folate concentration over time. In this patient, very
       recent use of multivitamins could artificially normalize the serum folate level
       (e.g., he knew he was coming to the doctor so he restarted his multivitamin
       routine yesterday). It would also be reasonable to send a homocysteine level in
       addition to evaluate folate stores. Folate is required to convert homocysteine to
       methionine. If the homocysteine level is normal, then folate deficiency is not
       present. If it is elevated, folate may or may not be deficient, as other factors may
       interfere with this conversion or otherwise raise homocysteine levels.
       In certain instances (e.g., elderly patients, pregnancy, and in patients with low
       WBC counts) vitamin B12 may be spuriously low. If the B12 is low or borderline
       in patients with these characteristics, a more sensitive and highly specific test
       would be to check a methylmalonic acid (MMA) level. Vitamin B12 is a co-factor
       for the conversion of mehylmalonyl coenzyme A to succinyl coenzyme A. A normal
       MMA level makes the diagnosis of B12 deficiency extremely unlikely.


Mr. B’s labs results are remarkable for a vitamin B12 level of 170 (lower limit of
normal is 180). The other studies sent are normal.

   7. Are there any other tests that should be sent now? How should this patient
      be treated?
      Vitamin B12 deficiency occurs because of inadequate intake, malabsorption, or in
      the setting of pernicious anemia (autoantibodies to intrinsic factor blocking
      absorption). Antibodies to intrinsic factor should be sent now. The sensitivity of
      testing for antibodies to intrinsic factor ranges between 50 and 85%, with a
      specificity approaching 100%. Anti-parietal cell antibody testing has much less
      favorable operating characteristics with a sensitivity below 50%.

       If anti-intrinsic factor antibodies are present, the patient has pernicious anemia
       and will require vitamin B12 therapy. If negative, then he most likely has
       deficiency secondary to inadequate intake, as a vegan. Although the Schilling test
       has historical value, it is rarely used for the diagnosis of pernicious anemia.

       Pernicious anemia is generally treated with 1000 micrograms of vitamin B12
       injected intramuscularly daily for one week followed by life-long monthly IM
       injections if the underlying disorder persists. There are no hypervitaminosis
       syndromes associated with vitamin B12 treatment, and the injections are
       inexpensive. Non-parenteral formulations are available and appear as effective as
       B12 injections, however, require greater patient compliance. High concentration
       oral B12 may be an option in some patients, and the dose ranges from 1-2
       milligrams daily. The effectiveness of this treatment should be followed with
       measurement of vitamin B12 and MMA levels. Sublingual and intranasal
       preparations are also available but have variable levels of absorption.

This chapter was adapted from prior chapter written by Dr. Meeta Prasad, M.D. in 2005,
Fifth Edition, Yale Office-based Medicine Curriculum.
Primary Reference:

   1. Tefferi, A. Anemia in adults: A contemporary approach to diagnosis. Mayo
      Clinic Proceedings. 2003; 78: 1274-1280.

Additional References:

   2. Weiss, G. et al. Anemia of chronic disease. New England Journal of Medicine.
      2005; 352: 1011-1023.
   3. Dhaliwal, G. et al. Hemolytic anemia. American Family Physician. 2003; 69 (11):
   4. Bini, EJ, Micale, PL, Weinshel, EH. Evaluation of the gastrointestinal tract in
      premenopausal women with iron deficiency anemia. Am J Med 1998; 105:281-6.

Jeanette Tetrault completed both residency and chief residency with the Yale Primary
Care Internal Medicine Residency program. She subsequently completed a clinical
epidemiology fellowship in the Ambulatory Care Fellowship at the West Haven VA
hospital. She is currently an instructor of medicine in the Department of General
Internal Medicine at Yale University School of Medicine. Her clinical and research
interests include HIV, Hepatitis C, and substance use disorders.

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