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EVALUATION OF THE ANEMIC PATIENT. Is the patient really anemic? Hemoglobin declines with advanced ageHemoglobin declines with advanced age African heritage.

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Presentation on theme: "EVALUATION OF THE ANEMIC PATIENT. Is the patient really anemic? Hemoglobin declines with advanced ageHemoglobin declines with advanced age African heritage."— Presentation transcript:

1 EVALUATION OF THE ANEMIC PATIENT

2 Is the patient really anemic? Hemoglobin declines with advanced ageHemoglobin declines with advanced age African heritage - 0.5 g/dl lower hgbAfrican 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 recumbenceEdematous 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

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7 Clinical Clues 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 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 differentialCBC performed by machine, including differential Quality of “flagging” abnormal values variesQuality of “flagging” abnormal values varies All “flagged” results should be reviewed when diagnosis is not known.All “flagged” results should be reviewed when diagnosis is not known. Blood smear from abnormal CBC should be reviewed by a humanBlood 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 * False positive - Howell-Jolly, Heinz, & Pappenheimer bodies, Malaria, Babesia, porphyria High fluorescenceLow fluorescence

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

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

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

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

20 BLOOD SMEAR RBC size, shapeRBC size, shape Polychromasia (young retics)Polychromasia (young retics) RBC inclusions (nucleated rbc, Howell-Jolly bodies, etc)RBC inclusions (nucleated rbc, Howell-Jolly bodies, etc) RouleauxRouleaux Abnormal/immature leukocytesAbnormal/immature leukocytes Platelet number/morphologyPlatelet number/morphology

21 NormalPolychromasia

22 Normal rbc Microcytosis, hypochromia

23 NormalMacrocytic/megaloblastic

24 Microangiopathic hemolytic anemia Spur cell anemia (liver disease)

25 Hereditary spherocytosis

26 Rouleaux (myeloma, Waldenstroms)

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

28 DIFFERENTIAL DIAGNOSIS GUIDED BY RETIC INDEX, MCV HyporegenerativeHyporegenerative  Microcytic  Macrocytic  Normocytic HyperregenerativeHyperregenerative

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

30 Laboratory assessment of microcytic anemia TestFe Defic Anemia of inflammation Thal FerritinLow*NL/highNL Serum FeLow NL TIBCHighNL/low*NL % SatLow NL Retic index NL/low NL/high *best discriminators of Fe defic vs anemia of inflammation

31 TESTS OF IRON STATUS TESTS OF IRON STATUS Practical 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 AlcoholHypothyroidismReticulocytosis

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: TESTDEFICIENCY MethymalonateB-12 HomocysteineB-12 or folate

35 Megaloblastic Anemia - Drugs Folate antagonistsFolate antagonists  methotrexate  trimethoprim Most cancer chemotherapyMost cancer chemotherapy Anti-retroviral agentsAnti-retroviral agents  zidovudine  delavirdine  lamivudine  zalcitabine Nitrous oxideNitrous oxide ArsenicArsenic ChlordaneChlordane AnticonvulsantsAnticonvulsants  Dilantin  Valproate  Lamotrigine

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 Hematocrit → Serum EPO →

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

39 ANEMIA WITH IMPAIRED ERYTHROPOIETIN RESPONSE IN DIABETIC PATIENTS 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 Arch Intern Med. 2005;165:466-469

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 HemolysisImmuneMechanical/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)Blood smear (fragments, spherocytes, sickle cells, malaria, etc) Nonspecific indicators of hemolysis: LDH, bilirubinNonspecific indicators of hemolysis: LDH, bilirubin Direct Coombs testDirect Coombs test  Warm antibody = IgG  C3  Cold antibody = C3 only (cold agglutinin) Indicators of intravascular hemolysis: haptoglobin, urine hemosiderin, plasma or urine hemoglobinIndicators of intravascular hemolysis: haptoglobin, urine hemosiderin, plasma or urine hemoglobin Other: Hgb electrophoresis, rbc enzyme levels, G6PD, osmotic fragility, PNH testing etcOther: Hgb electrophoresis, rbc enzyme levels, G6PD, osmotic fragility, PNH testing etc

43 INDICATIONS FOR BONE MARROW BIOPSY Retic index not appropriately increasedRetic index not appropriately increased No evidence of iron/B-12/folate deficiency, renal failure, endocrinopathy, inflammation or other low EPO stateNo evidence of iron/B-12/folate deficiency, renal failure, endocrinopathy, inflammation or other low EPO state Poor response to EPO, iron or vitamin replacementPoor response to EPO, iron or vitamin replacement WBC/plts/diff abnormal, monoclonal gammopathy, or other peripheral blood evidence of marrow disorderWBC/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 Hyper-regenerative Evaluate for hemolysis and bleeding Hypo-regenerative Rule out treatable nutritional deficiency, endocrinopathy, etc Low-EPOHigh-EPO Trial of EPO Consider BMBxContinue EPO Retic index Epo level Response No response


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