EVALUATION OF THE ANEMIC PATIENT

1. EVALUATION OF THE ANEMIC PATIENT

2. Is the patient really anemic? • Hemoglobin declines with advanced age • African heritage - 0.5 g/dl lower hgb • Hematocrit lower by a mean of 4 points in recumbent vs standing position • Edematous pts have 12% drop in Hct/Hgb after one hour of recumbence

3. Blood 2004;104:2263-2268 • Data from the Third National Health and Nutrition Examination Survey (1988-1994) • Prevalence of anemia rises rapidly after age 50, prevalence 20% over age 85 • 11% of men, 10.2% of women over 65 anemic • 1/3 due to nutritional deficiency, 1/3 to chronic inflammation or renal disease, 1/3 unexplained • Most cases mild; only 2.8% of women and 1.6% of men had Hgb < 11 g • Unexplained mild “anemia” in elderly people may simply be an effect of aging in some cases

7. History Family history Timing of symptoms Medications Occupation/Hobbies Diet Mouth problems GI symptoms Bruising/bleeding GU symptoms Exam Mouth Sternal tenderness Lymph nodes Cardiac murmurs Liver/Spleen size Skin exam Pelvic/rectal Clinical Clues • Always consider/rule out blood loss!

8. Look hardest for readily treatable causes of anemia • Nutritional deficiency (iron, B-12, folate) • Endocrinopathy (esp thyroid) • Low-EPO state (more common than you think) • GI blood loss • Most treatable causes of anemia can be diagnosed without marrow biopsy

9. Confirm laboratory data • CBC performed by machine, including differential • Quality of “flagging” abnormal values varies • All “flagged” results should be reviewed when diagnosis is not known. • Blood smear from abnormal CBC should be reviewed by a human

10. KINETICS OF ERYTHROPOIESIS Hyporegenerative (marrow not working well) Hyperregenerative (marrow working) Calculating the reticulocyte index will usually tell you which category your patient is in

11. Reticulocytes • “Reticulin” - insoluble ribosomal RNA • Present after extrusion of nucleus until degradation of rRNA. • Retics normally spend 3.5 days in marrow, 1 day in blood • Normal 28 -115 thousand per microliter Reticulocytes demonstrated by Crystal Violet stain of blood smear (most labs now use flourescent dye and automated cell counter)

12. Measuring Reticulocytes Maturation Mature RBC High fluorescence Low fluorescence * False positive - Howell-Jolly, Heinz, & Pappenheimer bodies , Malaria, Babesia, porphyria

13. Reticulocyte Response • Reticulocyte count = % retics • Reticulocyte Index correlates best with RBC production • Correct for low RBC count (absolute retic count) • Correct for immature retics if present (factor of 2) • “Normal” RI = 1 but should go up in anemia if marrow function normal • Normal or low RI in anemia implies hyporegenerative state • Very high RI (>4) suggests hemolysis • Misleading results possible if not in steady state

14. Retic Index When Hct 25 or less, use 1/2 for maturation time term

15. Example • 75 yo with osteomyelitis • receiving extended antibiotic therapy • poor appetite, weight loss • Labs: • Hct 25, WBC 12.0, Platelets 545, MCV 92, • Retic 5.8% (normal 0.5 to 2.2%) RI = 1.6 too low

16. Hyporegenerative anemia Retic index not appropriately increased • Nutritional deficiency (iron, B-12, folate) • Marrow dyscrasia (leukemia, myelodysplasia, aplastic anemia etc) • Thalassemia • Low EPO state (renal disease, inflammation, endocrinopathy, ? old age)

17. Hyperregenerative anemia Retic index increased • Hemolysis • Blood loss • Retic count increase generally less striking than in hemolysis

18. Interpreting the MCV • The MCV reflects the average size of RBC • Macrocytic (MCV >95) • Microcytic (MCV <82) • Normocytic

19. Pernicious anemia Aplastic anemia Myelodysplasia Hemolysis Normal inflammation Thal trait Iron deficiency

20. BLOOD SMEAR • RBC size, shape • Polychromasia (young retics) • RBC inclusions (nucleated rbc, Howell-Jolly bodies, etc) • Rouleaux • Abnormal/immature leukocytes • Platelet number/morphology

21. Normal Polychromasia

22. Microcytosis, hypochromia Normal rbc

23. Normal Macrocytic/megaloblastic

24. Spur cell anemia (liver disease) Microangiopathic hemolytic anemia

25. Hereditary spherocytosis

26. Rouleaux (myeloma, Waldenstroms)

27. Neutrophil hyposegmentation (myelodysplastic syndrome) Leukoerythroblastic (marrow infiltration)

28. DIFFERENTIAL DIAGNOSIS GUIDED BY RETIC INDEX, MCV • Hyporegenerative • Microcytic • Macrocytic • Normocytic • Hyperregenerative

29. Microcytic, hyporegenerative anemia • Iron deficiency (R/O GI bleeding!) • Thalassemia • Inflammation • Sideroblastic anemia (myelodysplasia, lead poisoning etc) Microcytosis implies defective hemoglobin production

30. Laboratory assessment of microcytic anemia *best discriminators of Fe defic vs anemia of inflammation

31. TESTS OF IRON STATUSPractical aspects • Low serum ferritin almost always indicates iron deficiency • Low serum iron and high TIBC almost always indicate iron deficiency • Ferritin > 100 rarely found in iron deficiency • Exception - liver inflammation/necrosis • Normal serum iron rarely found in iron deficiency • Exception - iron deficiency recently treated with oral iron • When TIBC is low or normal, low serum iron not a reliable indicator of iron deficiency! • Iron deficiency may be hard to diagnose via blood tests in setting of inflammation (eg, low iron, low TIBC, intermediate ferritin level) • Therapeutic trial of iron +/- EPO a reasonable alternative to marrow biopsy

32. Macrocytic, hyporegenerative anemia Megaloblastic: B12/folate deficiency Myelodysplastic syndrome Drug-induced Non-megaloblastic: Liver disease Alcohol Hypothyroidism Reticulocytosis

33. Macrocytic Anemia - Causes Colon-Othero; Med Clin North Am: 581, 1992

34. B-12/Folate deficiency • Therapeutic trial reasonable if blood level of vitamin borderline • In equivocal cases consider confirmatory tests:

35. Folate antagonists methotrexate trimethoprim Most cancer chemotherapy Anti-retroviral agents zidovudine delavirdine lamivudine zalcitabine Nitrous oxide Arsenic Chlordane Anticonvulsants Dilantin Valproate Lamotrigine Megaloblastic Anemia - Drugs

36. Normocytic, hyporegenerative anemia Marrow disorders Aplastic anemia Pure red cell aplasia Inherited anemia (Diamond-Blackfan) Myelophthisic state Myelodysplasia Leukemia and other heme malignancy Low EPO state Uremia, inflammation, endocrinopathy, HIV infection, etc Relatively common in elderly

37. Expected EPO Levels in Uncomplicated Anemia Serum EPO→ Hematocrit→

38. Anemia of Renal Insufficiency • Due to low EPO, shortened RBC survival, and altered iron kinetics. • Anemia begins to develop when CrCl is below 40ml/min/1.73M2 • Common problem in elderly, can be improved with EPO, often given with po or iv iron • Example: 70yo woman, 5’2”, 110 lbs, Cr 1.6 CrCl = 22ml/min/1.73M2

39. ANEMIA WITH IMPAIRED ERYTHROPOIETIN RESPONSE IN DIABETIC PATIENTS Arch Intern Med. 2005;165:466-469 • Subjects: 722 patients with diabetes mellitus • Measurements/data collection: Clinical data, lab measurements including CBC, iron studies, EPO • Findings: 23.3% of patients were anemic. 77.4% of these had inappropriately low (ie, normal) EPO levels • EPO levels inappropriately low in 69% of anemic diabetic patients with apparently normal renal function. Most of these patients had albuminuria and only mild anemia. • CONCLUSIONS: Diabetic renal disease can cause mild anemia in the absence of renal impairment. Most diabetics with anemia could benefit from EPO treatment

40. ERYTHROPOIETIN AND AGING In 143 initially healthy subjects followed for 8-30 years, serum erythropoietin levels rose steadily with age, while hemoglobin levels remained constant or declined slightly. This suggests that older individuals are more dependent on EPO to maintain the Hgb, and are at greater risk for anemia if there is even slight impairment in EPO production. Ershler et al, J Am Geriatr Soc 2005;53:1360

41. Hyperregenerative anemia Blood loss Hemolysis Immune Mechanical/microangiopathic Hereditary (hemoglobinopathy, membrane defect, enzyme deficiency) Acquired membrane defect (PNH, spur cells) Infection (malaria, Clostridia, babesiosis)

42. Hemolytic anemia – laboratory evaluation • Blood smear (fragments, spherocytes, sickle cells, malaria, etc) • Nonspecific indicators of hemolysis: LDH, bilirubin • Direct Coombs test • Warm antibody = IgG  C3 • Cold antibody = C3 only (cold agglutinin) • Indicators of intravascular hemolysis: haptoglobin, urine hemosiderin, plasma or urine hemoglobin • Other: Hgb electrophoresis, rbc enzyme levels, G6PD, osmotic fragility, PNH testing etc

43. INDICATIONS FOR BONE MARROW BIOPSY • Retic index not appropriately increased • No evidence of iron/B-12/folate deficiency, renal failure, endocrinopathy, inflammation or other low EPO state • Poor response to EPO, iron or vitamin replacement • WBC/plts/diff abnormal, monoclonal gammopathy, or other peripheral blood evidence of marrow disorder • Would you treat leukemia/MDS or other neoplastic disorder if you found it?

44. ALGORITHM FOR EVALUATION OF ANEMIA ANEMIC PATIENT Retic index Hyper-regenerative Hypo-regenerative Evaluate for hemolysis and bleeding Rule out treatable nutritional deficiency, endocrinopathy, etc Epo level Low-EPO High-EPO Continue EPO Trial of EPO Consider BMBx Response No response