Anemia Searching for clues beyond iron deficiency an interview with Pierre Laneuville, MD and Chantal Cassis, MD

1 2 3

What are the causes of anemia?
Anemia can result from deficient hemoglobin production, increased red blood cell (RBC) destruction, or from blood loss. Impaired hemoglobin production leads to hypoproliferative anemias with low or inappropriately normal reticulocyte counts. Increased RBC destruction or hemolysis and/or blood loss cause hyperproliferative anemias with elevated reticulocyte counts. In adults, the most common variants are iron deficiency anemia, megaloblastic anemias due to folate or vitamin B12 deficiency, anemia of chronic disease, anemia due to renal failure, and myelodysplastic syndrome (MDS). Since iron deficiency anemia has been discussed in depth in the April 2007 issue of Parkhurst Exchange, we will focus this discourse on anemias with other causes.

How are anemias classified?
Mechanistically, anemias are hypoproliferative, i.e. reticulocyte counts are low due to an inability to synthesize proper amounts of RBCs, or hyper-proliferative. In the hyperproliferative case, reticulocyte counts are high but can't compensate for increased blood loss or destruction of RBCs. The reticulocyte count is used to differentiate between these two variants.

Anemias can be further subdivided according to the mean corpuscular volume (MCV) of the RBCs. The cells can be microcytic (MCV < 80 fL), macrocytic (MCV > 100 fL) or normocytic (80 fL < MCV < 100 fL). This classification aids in identifying the source of the anemia (see Table). It's important to rule out sources of pseudo-macrocytosis when interpreting the MCV. RBC agglutination and very elevated reticulocyte numbers can give a falsely high MCV, as the machine may count them as large RBCs.

How does classification help pinpoint the cause of anemia?
Hypoproliferative anemias often manifest as microcytic and megaloblastic macrocytic anemias. Iron deficiency, acquired and congenital sidero-blastic anemias, vitamin B12 or folate deficiencies, MDS or other primary marrow failure processes, and drugs such as antiretrovirals, methotrexate and alcohol all give rise to hypoproliferative anemias. Other important causes that present with normal MCVs include anemia of chronic disease, renal failure with decreased erythropoietin production, multiple myeloma and endocrinopathies such as hypothyroidism.

Hyperproliferative anemias include all causes of normocytic anemia secondary to RBC destruction. Hemolysis can be immune-mediated -- as is the case in auto-immune hemolytic anemia -- or nonimmune-mediated. Nonimmune hemolytic anemias may be caused by factors intrinsic to the RBCs such as cell membrane disorders (hereditary spherocy-tosis), hemoglobinopathies (sickle cell anemia) or enzymopathies (glucose-6-phosphate dehydrogenase deficiency [G6PD]). They can also be the result of factors extrinsic to the RBC such as infectious agents (malaria), prosthetic valves or fibrin clots like those formed in disseminated intravascular coagulation. Nonmegaloblastic macrocytic anemias due to alcohol abuse, liver disease or hypothyroidism also present with elevated reticulocyte counts. Finally, thalassemia syndromes are the sole microcytic anemias that can present with increased reticulocyte counts. Usually, these counts are normal or slightly elevated in thalassemia.

What information should we get from the history?
Often, you can clarify the etiology of anemia solely based on laboratory investigations, but the history and physical exam focus the laboratory workup and avoid unnecessary tests which may be costly, invasive and time-consuming to the patient.

You first need to assess the impact of anemia on the person's health. Is the individual so fatigued that he or she is unable to participate in the activities of daily life? Is the anemia worsening cardiopulmonary function in a patient at risk? If so, you should treat more aggressively and consider temporary measures such as blood transfusions.

The history should also provide clues as to the etiology of the anemia. Based on the mechanisms mentioned above, look out for a history of overt or occult blood loss. In men, this includes asking about bloody stools, melena, bloody vomit and blood in the urine. The same questions apply to women, but also take a detailed history of menses including regularity, length of cycle in days, number of days with heavy bleeding, number of pads or tampons used per day or hour, waking at night to change, and the presence of clots. There are no official abnormal values for these parameters, so use clinical judgement in interpreting the numbers. Menses should usually last no longer than 7 days -- with heavy bleeding for 3 days or less.

What risk factors should we look out for?
For hypoproliferative anemias, inquire about the ethnic background, longstanding anemia and family history, as they're common factors in thalassemia. Gastrointestinal (GI) symptoms, known GI pathology or GI surgeries, as well as symptoms of autoimmune disease -- e.g. joint pain, synovitis, vitiligo, skin rash, photosensitivity and aphthous ulcers -- suggest deficiencies in folate, vitamin B12 or iron. Prolonged use of proton pump inhibitors or histamine receptor blockers may also lead to vitamin B12 malabsorption. Excessive alcohol consumption can be directly toxic to the bone marrow, resulting in macrocytic anemia. The presence of inflammatory illnesses, malignancy or chronic renal failure would support a diagnosis of anemia of chronic disease.