Practical Approach Approaching the Anemias Leslie N. Zypchen, FRCPC nemia is a common problem. One study Ryan’s case Ashowed that 13% of community-dwelling 1 individuals > 65 years of age were anemic. Ryan, 58, has long-standing rheumatoid arthritis Without performing bone marrow testing, one- (RA), for which he takes periodic nonsteroidal third of anemia cases in the elderly remain unex- anti-inflammatory drugs (NSAIDs). His RA has flared over the past several months and he 2 plained. presents to you with fatigue. His usual back pain The best approach to determining the cause of has also worsened. He states that his stools are anemia is dividing anemia into groups depending dark and he takes an iron supplement. on the mean corpuscular volume (MCV). Lab results © A workutp is performed and the followingtision Microcytic anemia ignoted:h ribu yr • Hemoglobin is 100 g/L,iswitht a mean, p l D nload Co corpusculariavolume ofd82owfl The differential diagnosis for microcytic ane- erc s can m• White bloodusercell and plateletl uscountse are m rised rsona mia includes only five items C(Tabloe 1). uthonormal r pe or ed. A py fo Furthermore, sideroblaslticeanemia ihnibadults,it is •leNocrmalo blood cell morphology on the Sa e pro sing r d us int a peripheral smear usuallyt frelatedo tooarimsyeelodysplasticnd spyndromer o auth iew a • A “normal” reticulocyte count of 45 x109 N Un lay, v and is not microcyticdisp . Lead poisoning in this • Ferritin 450 ug/L case is extremely rare. • Normal serum protein electrophoresis • Normal liver enzymes IDA vs. ACD • Normal lactate dehydrogenase • Normal creatinine The distinction between iron deficiency anemia (IDA) and anemia of chronic disease (ACD) is Questions difficult to make and patients often do not have 1. What is the cause of Ryan’s anemia? “classic” iron studies. Classically, IDA is asso- 2. Is further testing needed? ciated with: • low ferritin, Go to page 62 for Ryan’s follow-up. • low transferrin saturation, • low serum iron and • high total iron binding capacity (TIBC). The Canadian Journal of Diagnosis / December 2006 61 ractical PApproach Ryan’s follow-up Ferritin is the most useful test in diagnosing IDA.3 There is a perception that ferritin testing Ryan’s presentation is very consistent with is not as useful in patients with inflammatory anemia of chronic disease. Despite his NSAID illnesses. However, several studies have demon- use and report of dark stools, a ferritin of 450 ug/L essentially excludes iron deficiency and strated that ferritin remains a useful test in these investigations for a source of blood loss are not patients. For example, Guyatt, et al showed that warranted. in hospitalized elderly patients, a ferritin of Because of his worsening back pain, one could < 18 ug/L confirms iron deficiency, while a fer- be cautious and investigate further for myeloma with ritin of > 100 ug/L excludes iron deficiency in spine x-rays and a urine protein electrophoresis. most patients.4 With iron deficiency, one must Ryan follows up with his rheumatologist and a look for a source of blood loss. disease modifying antirheumatic drug is started. His RA flare settles over several months and, at IDA vs. thalassemia trait that time, a repeat complete blood count shows The clinical setting is useful in distinguishing that his hemoglobin has improved to 125 g/L. IDA from thalassemia trait, in that a bleeding history is often present with IDA and certain Table 1 ethnic groups are affected by thalassemia. With Causes of microcytic anemia IDA, the ferritin level is low. With thalassemia • Iron deficiency anemia traits, the ferritin level is normal or slightly • Anemia of chronic disease high. The pathologist may comment on helpful • Thalassemia and thalassemic features on the blood smear (e.g., target cells hemoglobinopathies with thalassemia). The hemoglobin elec- • Sideroblastic anemia • Lead poisoning trophoresis is normal in iron deficiency, but an increased hemoglobin A2 is seen with ß-tha- Classic iron studies in ACD include: lassemia trait. Of the α-thalassemias, only three • high ferritin, α−chain deletions (i.e., hemoglobin H disease) • normal transferrin saturation, can be detected on hemoglobin electrophoresis. • low serum iron and Α-thalassemia traits associated with one or two • low TIBC. α−chain deletions can only be diagnosed by The gold standard for distinguishing these ane- specialized testing. Other abnormal hemoglo- mias is bone marrow testing, but this is often bins may also be associated with microcytosis not indicated. (e.g., hemoglobin E). Dr. Zypchen is a Clinical Instructor, Department of Medicine, Normocytic anemia Division of Hematology, University of British Columbia and a Hematologist,Vancouver General Hospital,Vancouver, There are many causes of normocytic anemia British Columbia. and the first test should always be a reticulocyte 62 The Canadian Journal of Diagnosis / December 2006 Anemias count. (Though not comprehensive, the list of Table 2 bone marrow disorders in Table 2 focuses on Causes of normocytic anemia those disorders that may be present with an Hyperproliferative isolated anemia). This allows distinction of the • Bleeding anemia into a hyperproliferative anemia • Hemolysis associated with a reticulocytosis, or a hypoproliferative anemia associated with a Hypoproliferative • Bone marrow: normal low or inappropriately normal reticulocyte - Anemia of chronic disease count. There are only two causes of a hyper- - Early iron deficiency proliferative anemia: bleeding and hemolysis. - Systemic illness More commonly, the reticulocyte count is > Liver disease low or inappropriately normal. In this circum- > Renal disease - Endocrine stance, there is a broad differential diagnosis > Hypogonadism and it is useful to divide such anemias into > Hypothyroidism those associated with a normal bone marrow > Hypoadrenalism vs. those associated with an abnormal bone > Hypopituitarism marrow. Other tests that might be helpful • Bone marrow: abnormal include blood workup, such as: - Bone marrow failure > Myelodysplastic syndrome • iron studies, > Pure red cell aplasia • creatinine, - Bone marrow infiltration • liver enzymes and > Myeloma • hormone levels. > Indolent lymphoma It is difficult to diagnose a bone marrow Table 3 disorder without a bone marrow examination, Causes of macrocytic anemia but bloodwork, such as a serum protein elec- trophoresis, looking for myeloma, may pro- Megaloblastic vide some hints. • B12 or folate deficiency Unfortunately, the straightforward distinc- • Drugs interfering with B12, folate metabolism or DNA synthesis tion into hyperproliferative anemia vs. hypoproliferative anemia is not always easy, as Non-megaloblastic it is not uncommon that multiple mechanisms • Bone marrow: normal - Alcohol abuse coexist (e.g., a patient may have both hemoly- - Liver disease sis and marrow infiltration with lymphoma). - Hypothyroidism Lastly, when considering normocytic and • Bone marrow: abnormal macrocytic anemias, some of the items on the - Myelodysplastic syndrome differential diagnosis are common to both cat- - Pure red cell aplasia - Myeloma egories of anemia. The Canadian Journal of Diagnosis / December 2006 63 ractical PApproach Take-home message Macrocytic anemia • Dividing anemias into categories, based on When considering macrocytic anemia, reticulo- the mean corpuscular volume, remains the cytosis, causing a slight macrocytosis, should most effective way to differentiate between first be excluded. The next question is whether the anemias or not the anemia is megaloblastic (Table 3 pres- • There are only three common causes of ents bone marrow disorders that might be pres- microcytic anemia. These are: - iron deficiency, ent with an isolated anemia). This term refers to - anemia of chronic disease and the morphologic changes associated with - thalassemia impairment in DNA synthesis in the bone mar- • The reticulocyte count is the first test to row. In megaloblastic anemias, the pathologist order when trying to distinguish the cause will see hypersegmented neutrophils and oval of normocytic anemia macrocytes. However, this information is often • For normocytic and macrocytic anemias, consider whether the patient might have a not available. Measurement of the following may bone marrow disorder be helpful: • the reticulocyte count, Frequently • B12 and folate levels, • liver enzymes and Asked Questions • thyroid stimulating hormone. 1. Are full iron studies needed to diagnose However, if this testing is normal and the patient iron deficiency? is unwell or has a severe anemia, bone marrow In most circumstances, a ferritin test alone testing may be needed. is sufficient, but higher cut-off values may be appropriate in patients with inflammatory In all circumstances and with any anemia, diseases. when patients present with multiple cytopenias, 2. What is the best way to start sorting out one should consider a bone marrow disorder. the many causes of normocytic anemia? Dx Measuring a reticulocyte count allows differentiation of the anemia into a hyperproliferative vs. a hypoproliferative anemia. References 3. When should hematological consultation 1. Culleton BF, Manns BJ, Zhang J, et al: Impact of anemia on hospital- and bone marrow examination be ization and mortality in older adults. Blood 2006; 107(10):3841-6. considered? 2. Guralnik JM, Eisenstaedt RS, Ferrucci L, et al: Prevalence of anemia in persons 65 years and older in the United States: Evidence for a high When the patient is constitutionally unwell or rate of unexplained anemia. Blood 2004; 104(8):2263-8. has concerning symptoms such as back pain, 3. Guyatt GH, Oxman AD, Ali M, et al: Laboratory diagnosis of iron-defi- when the anemia is severe and unexplained ciency anemia: An overview. J Gen Intern Med 1992; 7(2):145-53. or when there are additional cytopenias. 4. Guyatt GH, Patterson C, Ali M, et al: Diagnosis of iron-deficiency in the elderly. Am J Med 1990; 88(3):205-9. 64 The Canadian Journal of Diagnosis / December 2006.