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Approach to anemia in adults Background • Anemia is reduction of red cell mass • Diagnosis and treatment is essential – Identify a potentially life threatening disorder – Identify a treatable systemic disease – Identify a disease for which primary treatment of anemia improves outcomes Objectives • • • • Definition of anemia Interpretation of important laboratory tests General approaches by classification Emerging concepts – Anemia of inflammation (chronic diseases) – Anemia in the elderly • Indications for referral Etiology of anemia • • • • • Iron deficiency 25% Anemia of inflammation 25% Hemoglobinopathy 25% Hemolytic anemia/marrow failure 15% Myelodysplasia 10% First Step in Evaluation Clinical Presentation Approach • Detailed History • Review of Systems • Physical Exam • Laboratory Evaluation – Prior documentation of CBC’s – CBC with RETICULOCYTE COUNT – Review peripheral blood smear 6 History Family history Spherocytosis Sickle cell anemia Thalassemia Diet Vegetarian Drugs/Toxins Infection Alcohol Abuse Folate deficiency Liver disease Malabsorption B12 Folate Iron Exposure Lead Chemotherapy Peptic Ulcer Disease Diverticulitis Colonic Polyps GI Malignancy colorectal esophageal Recent Surgery Travel 7 Microcytic Anemia Drug Associated Heme Synthesis Antagonists Pb – often normocytic Al – hemodialysis Antibiotics Isoniazid Chloramphenicol 8 Macrocytic Anemia and Macrocytosis Drug Associated Folate Antagonists Methotrexate Purine Antagonists Acyclovir Mercaptopurine Imuran Altered Folate Metabolism Cobalamin Malabsorption Oral Colchicine Contraceptives Neomycin Anticonvulsants Impaired Triamterene Cobalamin Sulfonamides Utilization Pentamidine Nitrous Oxide Alkylating Agents Cytoxan 9 Normochromic Normocytic Anemia Drug Associated Antibiotics Isoniazid chloramphenicol Anti-Inflammatory Au 10 Symptoms Weakness Fatigue Dizziness Headache Chest pain SOB / DOE Palpitations Cold intolerance Dysphagia Jaundice Hematemesis Diarrhea Constipation Melena Hematachezia Hematuria Menorrhagia Pica (clay, dirt, chalk, ice) Hematoma Physical Exam Physical Exam Ophtho exam Flame hemorrhage Papilledema Exudates Pallor Blue sclera Angular Cheilitis Iron Deficiency Glossitis B12 / Folate / Iron Tachycardia Jaundice Liver Disease Hemolysis Guiaic positive Splenomegaly Malignancy Infection Liver disease Chronic Hemolysis Adenopathy Skin Pallor Ulcerations Scars Thin/Brittle, Spoonshaped nails Edema Neurologic Headache, fatigue Lack of concentration Syncope Paresthesias Ataxia Dementia 13 Erythropoetic therapy for anemia • Chronic kidney disease – Improves survival – Improves quality of life – Decreases/increases vascular events • Congestive heart failure – Improves LV function – Decreased hospitalization • Cancer patients – Decrease fatigue – Improves quality of life – Increases mortality in solid tumors What is anemia? • • • • • Must be interpreted in context Acute vs. chronic Gender Race “Normal” 5% of healthy general population may be outside normal range Normal hemoglobin (g/dL) ranges White African Male Female Male Female 12.7-17.0 (12.8-17.7)* 11.6-15.6 (11.5-15.4)* 11.3-16.4 (12.8-17.7)* 10.5-14.7 (11.5-15.4)* Tefferri A Mayo Clin Proc 2005 from NHANES-II, Mayo Clinic *CHCS current values Essential laboratory tests in the evaluation of anemia • Hemoglobin – amount of lysed pigment in a volume of blood • Mean corpuscular volume – size of red blood cells • Red cell distribution width – measure of variation of cell size • Red blood cell count – absolute number of red blood cells per volume • Platelet count • White blood cell count • Peripheral blood smear Useful tests in selected cases • • • • • • • • • Ferritin Iron panel Soluble transferrin receptor Peripheral blood smear Creatinine Reticulocyte count B12/folate level TSH Chronic hepatitis panel • • • • • • Homocysteine Methylmalonic acid SPEP ANA CRP/ESR Bone marrow aspirate and biopsy • Haptoglobin • LDH Diagnostic approach to anemia 1. Review prior CBCs 2. Take comprehensive history and physical 3. Classify anemia by MCV – – – Microcytic (MCV <80 fL) Normocytic (MCV 80-100 fL) Macrocytic (MCV >100 fL) • • Mild macrocytosis MCV 100-110 fL Marked macrocytosis MCV >110 fL 4. Reticulocyte Count (classification of proliferation) 5. Order appropriate additional tests Case 1 • 52 year old male construction worker with chief complaint of fatigue for 2 months. He now reports getting dyspneic when climbing ladders or carrying heavy loads at work. He says, “I never go to doctors.” • PMH None, PSH appendectomy, FH adopted, SH tobacco 20 py, drinks 2 beers daily, Medications occasional motrin • Physical exam unremarkable • ROS occasional crampy abdominal pain Case 1 • Hgb 10.2 gm/dl, MCV 78 fL, RDW 19.5, Platelets 450,000/dL • How do you classify the anemia? Case 1 • Ferritin 5 • Fecal occult blood test is positive Schrier, S. ASH Image Bank 2002;2002:100325 Copyright ©2002 American Society of Hematology. Copyright restrictions may apply. Features of iron deficiency anemia • Clinical – Symptoms of anemia – Evidence of blood loss – Pica (very specific) • Laboratory – Microcytic anemia (occasionally normocytic) – Elevated RDW – Elevated platelet count – Low serum iron, ferritin and elevated TIBC Microcytic Anemias Fe Deficiency Anemia 26 Iron Serum Iron TIBC Ferritin Iron Deficiency* Sideroblastic NL Thalassemia NL Anemia of Chronic Disease *Iron Saturation: Serum Iron / TIBC <10% = Iron deficiency; most common cause of microcytosis Ferritin < 10 ng/ml 27 Iron Deficiency – Etiologies • History – GI (blood loss, diarrhea/constipation), menses, coagulopathy, urine color (coke-colored [bilirubin] OR red [hematuria, hemoglobinuria]) • Guaiac stools – Office DRE – Hemocult cards as outpatient • Colonoscopy / EGD • PT / APTT, UA 28 Iron • % of oral iron absorbed = 10% • Daily oral requirement for males and nonmenstruating non-pregnant females = 10mg (Daily loss = 1 mg) • Daily oral requirement for menstruating females = 20 mg (Daily loss = 1.5 – 2 mg) • Daily oral requirement for pregnant females = 30 mg: 150mg ferrous sulfate OR 250mg ferrous gluconate (Daily needs = 4 – 6 mg) 29 30 Chronology of Iron Loss 31 Stages of iron deficiency Normal Iron deficiency without anemia Iron deficiency with mild anemia Severe iron deficiency Marrow RE iron 2-3+ stores 0 0 0 Plasma iron level 75-150 Normal or reduced Normal or reduced Reduced Iron binding capacity 300-400 Normal or elevated Normal or elevated Elevated Hemoglobin 13-15 13-15 9-10 6-7 Hypochromia Not present Not present Slight or not present Profound Microcytosis Not present Not present Slight or not present Present Ferritin 12-300 <4 <4 <4 33 Iron Iron-Rich Foods Quantity Oysters Beef liver Prune juice Clams Walnuts Ground beef Chickpeas Bran flakes Pork roast Cashew nuts Shrimp Raisins Sardines Spinach 3 ounces 3 ounces 1/2 cup 2 ounces 1/2 cup 3 ounces 1/2 cup 1/2 cup 3 ounces 1/2 cup 3 ounces 1/2 cup 3 ounces 1/2 cup Approximate Iron Content (mg) 13.2 7.5 5.2 4.2 3.75 3.0 3.0 2.8 2.7 2.65 2.6 2.55 2.5 2.4 34 Iron homeostasis Andrews N. N Engl J Med 1999;341:1986-1995 Interpreting iron and ferritin Ferritin Falsely low Falsely high Iron Falsely low Falsely high Hypothyroidism Fever Circadian variation Circadian variation Ascorbate deficiency Inflammation Infection Iron ingestion Infection Inflammation Sideroblastic and aplastic anemia Liver disease Maligancy Ineffective erythropoeisis Ascorbate deficiency Liver disease Case 2 • 48-year-old white man is referred for a new anemia. He is an executive in a software company and reports fatigue and dyspnea while backpacking • ROS negative. • Physical examination: He is a normal, healthy-looking man, perhaps pale, with a clean tongue. The results of his chest, abdomen, and neurologic exams are all normal. Case 2 • • • • Hemoglobin 9.2 gm/dl Mean corpuscular volume (MCV) 112 fL White blood cells 3,400/ul normal differential Platelets 132,000/ul Spurious macrocytosis • Red blood cell clumping – Cold agglutinins – Paraproteinemia • Intracellular hyperosmolality – Hyperglycemia • Leukemic cells counted as RBCs – Marked leukocytosis as in CLL Common drugs associated with macrocytosis • Marrow toxin and interference with folate metabolism – Alcohol • Marrow toxin – Chemotherapy: methotrexate, hydroxyurea, cyclophosphamide… – Zidovudine • Altered folate metabolism – – – – Anti-epileptic drugs Triamterene Sulfmethoxazole Trimethoprim • B12 malabsorption – Colchicine – Neomycin Evaluation of B12 levels • • • • • • • Falsely low Folate deficiency Multiple myeloma Waldenstrom’s macroglobulinemia Recent nuclear scan First trimester Transcobalamin I def Advanced age Falsely normal • Increase in transcobalamin I and III • Myeloproliferative disorders • Severe liver disease Indications for testing of metabolites of B12 and folate • Borderline B12 and folate levels • Existing conditions that perturb B12/folate levels • When both B12/folate are low to confirm B12 deficiency • In pts with clearly low levels, for which there is an alternative explanation (eg. an alcoholic with a high MCV, low B12 but no anemia) Interpretation of MMA/Hcy MMA Hcy Diagnosis Increased Increased B12 deficiency confirmed, folate deficiency possible Normal Increased Folate deficiency likely; B12 deficiency <5% Normal Normal B12 deficiency very unlikely** From Hoffman R et al, Hematology: Basic Principles and Practice, 3rd Edition Case 2 laboratory results • B12 level 100 pg/mL, folate >20 ng/mL Schrier, S. ASH Image Bank 2001;2001:100231 Copyright ©2001 American Society of Hematology. Copyright restrictions may apply. B12 supplementation • B12 load – B12 1000 mcg IM/SC qd x 7 then qwk x 4 then q month – B12 1000 mcg IM/SC tiw x 2 weeks, qwk x 8 – B12 2000 mcg po x 2 months • B12 maintenance – B12 1000 mcg IM/SC q month life – B12 1000 mcg po qd for life • Folate 1 mg po qd x 30 days Case 3 • 45 year old African-American female presents with fatigue for 6 months. She now only works 6 hours a day at her secretarial job and is now dyspneic climbing 2 flights of stairs at home. • PMH: Hypertension, depression, G6P6 • PSH: C-section x 2, breast biopsy – benign • FH: Father – multiple myeloma, Mother – DM2 on hemodialysis, 2 younger siblings are well • SH: No tobacco or alcohol • ROS: Joint pains for about 6 months, intermittent chest pain worse with deep breathing • Medications: Lisinopril, aspirin, venlafaxine Case 3 • • • • Hemoglobin 8.0 gm/dL MCV 81 fL WBC 3,200/uL Platelets 450,000/uL Lab results • Ferritin 25 ng/mL • Fe 20 mcg/dL Iron Sat 10% TIBC 200 mcg/dL • LDH WNL Hcy WNL Management of iron deficiency • Rule out blood loss, reason for negative iron balance – Gastrointestinal – Genitourinary – Poor iron absorption – Pregnancy – Pulmonary hemosiderosis – Intravascular hemolysis – Erythropoeitin Oral iron supplementation • Goal: 150-200 mg elemental iron daily • Administration – DO NOT give with food – Give 2 hrs from antacids – May give with ascorbic acid 250 mg • Gastrointestinal intolerance (~20%) – Decrease daily elemental iron dose • Switch from sulfate to gluconate or elixir – Give with food (will decrease absorption) Oral iron supplementation • Measuring response – Expect Hgb increase of 2 gm/dL in 2 weeks – Assess compliance/drug interactions • Duration – 4-6 months after iron “replete” to allow for restoration of storage iron – At least until ferritin>50 • NB: all anemia does not respond to iron!!! Case 3 continued • Pt returns after 3 months of oral iron therapy • She remains fatigued, but improved, and has increasing complaints of joint pain • Hgb 10.0 gm/dL, MCV 88 fL, RBC Count 4 million, Reticulocyte 1.0%, Iron saturation 30%, Ferritin 80 Soluble transferrin receptor • Truncated portion of membrane receptor is released when ligand (diferric transferrin) is not bound (i.e. iron deficient states) • sTfR is normal in anemia of chronic diseases – Transferrin-receptor expression is negatively affected by inflammatory cytokines • Useful in clarifying anemia of chronic disease and iron status AoCD versus iron deficiency Punnonen K Blood 1997; Goodnough L N Engl J Med 2005 Interpreting reticulocyte counts • Reticulocytes are erythrocytes new to peripheral circulation • Need to correct for degree of anemia – Reticulocyte index = Retic % x [Pt Hct/NlHct] – Absolute reticulocyte count = Retic % x RBC number • Appropriate reticulocytosis – Reticulocyte index >2% – Absolute reticuocyte count >100,000/mcl Differential diagnosis based on degree of reticulocytosis Retic index <2% or ARC <100,000 mcg/L AoCD Anemia sec to CKD Drugs/toxins Endocrinopathies Iron deficiency Marrow infiltration Nutritional (B12/folate deficiency) Sideroblastic anemia Retic index >2% or ARC >100,000 mcg/L Appropriate response to blood loss or nutritional supplementation Hemolytic anemias Pathophysiological Mechanisms Underlying Anemia of Chronic Disease Pathophysiology of AoCD • Inflammatory cytokines (IL6, TNF-a, IFN-g) – – – – Increase storage iron Inhibit EPO production Blunted EPO response Impair BM erythropoiesis • Production of hepcidin – Inhibits GI iron absorption – Inhibits release of iron from macrophages and hepatocytes Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023 Algorithm for the Differential Diagnosis among Iron-Deficiency Anemia, Anemia of Chronic Disease, and Anemia of Chronic Disease with Iron Deficiency Weiss G and Goodnough L. N Engl J Med 2005;352:1011-1023 Anemia in the elderly 10-30% of elderly are anemic • Consequences – Decreased physical performance – Increased mortality in CHF patients – EPO improved LV function in elderly CKD patients treated with EPO • About 30% have “unexplained anemia” Guralnik J Hematology: ASH Education Book 2005 Unique etiologies of anemia in the elderly • • • • • • • Dysregulated inflammatory response Age-related decline in renal function Blunted hypoxia-erythropoeitin sensing Loss of hematopoeitic stem cell reserve Decreased sex steroids Frequent co-morbidities Polypharmacy Guralnik J Hematology: ASH Education Book 2005 Indications for hematology referral • Diagnosis – – – – – Unexplained anemia Anemia with additional cytopenias Suspected hemoglobinopathy Hemolytic anemias Bone marrow aspiration and biopsy • Treatment – Non-response to therapy – Hemolytic anemias – Myelodysplasia How Do I Distinguish Intravascular From Extravascular Hemolysis? • Intravascular – RBC fragments: incompatible PRBC transfusion; MAHA Haptoglobin – low Hemopexin – low Hemoglobinuria Urine hemosiderin – elevated; evidence of recent (up to 3 months) intravascular hemolysis • Extravascular – microspherocytes: AIHA Haptoglobin – normal; unless hemolysis is severe Direct Coomb’s test – positive 65 -Thalassemia Trait 66 -Thalassemia Major 67 Warm-Antibody Hemolytic Anemia 68 Is It Possible to Have a Hemolytic Anemia with a Normal or Low Reticulocyte Count? • You bet! Can happen: coexisting bone marrow hypoproduction Ab mediated destruction of RBC precursors in marrow Folate deficiency with chronic hemolysis Renal failure – decreased EPO B19 Parvovirus infection 69 Questions? www.ashimagebank.org Maslak, P. ASH Image Bank 2002;2002:100375 Figure 1. Peripheral blood smear of a patient with plasma cell leukemia contains lymphoplasmcytoid lymphocytes and circulating plasma cell Copyright ©2002 American Society of Hematology. Copyright restrictions may apply. Target Cells Fe deficiency – microcytic Hemoglobinopathies (thalassemias, Hb C,S and E) - microcytic Liver disease – normocytic / macrocytic Abetalipoproteinemia – normocytic / macrocytic 71 Hyposplenism – normocytic Tear Drop Cells (Dacryocytes) Thalassemias – especially Myelodysplastic syndromes Bone marrow replacement – fibrosis, malignancy 72 Schistocytes Vasculitis Also: -thalassemia Malignant HTN ARF DIC TTP/HUS Mechanical valve Microangiopathic Hemolytic Anemias (MAHAs) 73 Nucleated Red Blood Cells Acute blood loss Severe hemolytic anemia Marrow infiltration Myeloproliferative syndrome 74 Spherocytes Transfusion – most common in clinical practice Alloimmune hemolytic anemia (e.g. ABO incompatibility) Autoimmune hemolytic anemia G6PD deficiency Hereditary spherocytosis Hypophosphatemia Burns C perfringens sepsis 75 Bite Cell (Degmacyte) G6PD deficiency MAHA - sometimes 76 Heinz-Body Anemia G6PD deficiency supravital stain – crystal violet 77 Sickle Cells 78 Howell-Jolly Bodies Hyposplenism Splenectomy Hemolytic anemias – sometimes DNA fragments 79 Basophilic Stippling Pb poisoning thalassemias hemoglobinopathies ribosomal RNA fragments 80 Pappenheimer Bodies in Siderocytes MDS – esp sideroblastic anemias Post splenectomy Pb poisoning Hemolytic anemias ribosomal RNA + Fe 81 Rouleaux Multiple myeloma Waldenström’s macroglobulinemia Pregnancy Inflammation Erythrocytosis 82 RBC Agglutination Cold-agglutinin (IgM) hemolytic anemia (EBV, Mycoplasma pneumoniae) Waldenström’s macroglobulinemia Warm antibody (IgG) hemolytic anemia 83 Polychromatophilia (Polychromasia) Hyperproduction Hyposplenism are reticulocytes 84 Elliptocytes Hereditary Macrocytic anemias Fe deficiency anemia 85 Burr Cells (Echinocytes) Renal failure Liver disease – sometimes Storage artifact 86 Spur Cells (Acanthocytes) Liver disease – most commonly EtOH related Abetalipoproteinemia Neuroancanthocytosis 87 Stomatocytes Normal Liver disease Hereditary Malignancy 88