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ANEMIA An Outpatient Diagnostic Approach Matthew Crowe PGY-2 5/4/2015 DISCLAIMER Anemia is broad SOME COMMON CAUSES Microcytic Sickle cell Autoimmune Iron deficiency Thalassemia Drug induced Chronic disease Virus Sideroblastic Lymphoid d/o Idiopathic Macrocytic Alloimmune Drug induced Immediate transfusion rxn B12 deficiency Delayed transfusion reaction Folate deficiency Neonatal hemolytic Myelodysplasia Mircoangiopathic (TTP/HUS) Aplastic anemia Infection (malaria) Large granular lymphocyte d/o Chemical agent Excess alcohol use Chronic disease Liver disease Primary bone marrow d/o Hemolytic anemia Aplastic anemia Spurious Pure red cell aplasia Ineffective erythemropoiesis Normocytic anemia Drugs, toxins, radiation Iron deficiency Immune mediated Renal insufficiency Infiltrating process Spherocytosis G6PD deficiency OVERVIEW Introduction Definitions Classification Physiology Diagnostic approach History and physical Diagnostic tools Classification & workup Review Questions ANEMIA Pathologic state of insufficient erythrocytes to carry oxygen to peripheral tissues Clinically, a reduction of one of the major RBC components Not a disease, but a sign of underlying illness or pathology ANEMIA Blood loss Production defect Destruction PHYSIOLOGY Lifespan Production Erythropoietin Components Nutrition PHYSIOLOGY PHYSIOLOGY PHYSIOLOGY DIAGNOSTIC APPROACH Symptoms Exam CBC? Other labs? DIAGNOSTIC APPROACH History Duration Medical history Procedures Family history Medications Diet Exam DIAGNOSTIC APPROACH Different approaches, categorizations MCV Underutilized Reticulocyte count Peripheral smear DIAGNOSTIC APPROACH LABORATORY Reticulocyte count Measure of new cells being produced 1% is normal (daily cell turnover) Absolute count or corrected/index Most helpful if extremely low, or >3% Production vs blood loss or hemolysis LABORATORY Peripheral smear MICROCYTIC Rule out iron deficiency Low ferritin diagnostic of iron-depletion Iron, TIBC, % saturation RDW, anisocytosis (vs ACD) Reactive thrombocytosis Severe: cigar-shaped cells, elliptocytes MICROCYTIC Normal ferritin? Pre-existing microcytosis? Smear: polychromasia, basophilic stippling, target cells (not IDA) Thalassemic syndrome Decreased production of globin chain Structural abnormality of globin chain Hemoglobin electrophoresis MICROCYTIC Sideroblastic anemia Not IDA or thalassemia Increased RDW Dimorphic RBCs Marrow with ringed sideroblasts MICROCYTIC Anemia of chronic disease Usually normocytic Rheumatoid, PM, DM, CTD, HL, RCC, chronic infection Normal RDW Unremarkable smear Diagnosed on clinical grounds NORMOCYTIC Rule out treatable causes Nutritional Renal disease Hemolysis Chronic disease? Bone marrow disorder? NORMOCYTIC Nutritional anemia Iron deficiency B12 / cobalamin deficiency Folate deficiency NORMOCYTIC Anemia in renal disease Unremarkable smear Normal erythropoietin level Inappropriate May not be noticeable until more advanced disease NORMOCYTIC Hemolytic anemia Cell destruction (LDH) Hemoglobin catabolism (indirect bili) Clearing hemoglobin (hapto) Bone marrow regeneration (retic) None of these are specific LDH + hapto 90% specific Normal LDH + hapto >25 92% sensitive r/o NORMOCYTIC Hemolytic anemia Process inherent to RBC vs extrinsic Mebranopathies, enzymopathies, hemoglobinopathies Immune, micoangiopathic, infection, chemical Intravascular vs extravascular NORMOCYTIC Intravascular vs extravascular NORMOCYTIC Ruled out the above? History, history, history Meds, alcohol, radiation, chemical exposure, recent trauma or surgery? Anemia of chronic disease Primary bone marrow disorder NORMOCYTIC Anemia of chronic disease Cytokine mediated process Inhibition RBC production or function Support Comorbid conditions Unremarkable smear Maybe ESR elevation Often mistaken for IDA given iron studies Ferritin NORMOCYTIC NORMOCYTIC Primary bone marrow disorder Smear is most helpful CBC for other cell lines May need bone marrow Myelodysplastic syndrome Pure red cell dysplasia Aplastic anemia Marrow infiltration MACROCYTIC Rule out drug-induced causes Review medications, alcohol, treatments Hydroxyurea, MTX, TMP, zidovudine 5-FU, chemotherapy agents Alcohol Rule out nutritional causes B12 / cobalamin Folate MACROCYTIC Folate deficiency Folate level usually low RBC-folate level (chronicity) Homocysteine level Increased Conversion to methionine Must also check B12 MACROCYTIC B12 deficiency B12 level usually low Pregnancy, elderly, leukopenia, borderline level? Methylmalonic acid level Cofactor in conversion to succinyl CoA Specific? Renal insufficiency, metabolic disorders Homocysteine also elevated MACROCYTIC B12 deficiency Confirmed? Screen for intrinsic factor antibodies Pernicious anemia? Schilling test can differentiate pernicious anemia from malabsorptive disorders Sprue, IBD, amyloidosis, intestinal lymphoma MACROCYTIC No drug or nutrition related etiology? Bone marrow disease? May need biopsy Other clues on smear? Substantial polychromasia (retic) Hemolysis Round RBC morphology Liver disease (target cells) Hypothyroidism REVIEW What is anemia Physiology How is it classified Diagnostic approach History and physical Diagnostic tools REVIEW Anemia is not a disease, but a sign of underlying pathology Do not rely on any one data piece Anemia is dynamic Beware of multiple causes TEST YOUR KNOWLEDGE A 22-year-old woman undergoes a new patient evaluation. She was recently diagnosed with systemic lupus erythematosus manifesting as painful joints, malar photosensitive rash, oral aphthous ulcers, and a positive antinuclear antibody and anti-Smith antibody titer. Her menstrual pattern is normal, and her medical history is otherwise noncontributory. Her only medications are hydroxychloroquine and a multivitamin. On physical examination, temperature is 37.2 °C (99.0 °F), blood pressure is 126/78 mm Hg, pulse rate is 88/min, and respiration rate is 17/min. BMI is 20. The patient has a malar rash and thinning hair, but no joint abnormalities, oral lesions, pericardial or pleural rubs, or heart murmurs. Laboratory studies: Hemoglobin Leukocyte count Ferritin Iron Reticulocyte count Total iron-binding capacity Transferrin saturation Creatinine 8.2 g/dL (82 g/L) 3900/µL (3.9 × 109/L) 556 ng/mL (556 µg/L) 18 µg/dL (3.2 µmol/L) 2% 180 µg/dL (32 µmol/L) 10% 1.0 mg/dL (88.4 µmol/L) Which of the following is the most likely diagnosis? A Inflammatory anemia B Iron deficiency C Microangiopathic hemolytic anemia D Warm antibody-associated hemolysis TEST YOUR KNOWLEDGE A 32-year-old man is evaluated for fatigue, dyspnea, lethargy, and yellowing of the eyes of 1 week's duration. Medical history is significant for a recent communityacquired methicillin-resistant Staphylococcus aureus skin infection of the right forearm treated with a 14-day course of trimethoprim-sulfamethoxazole. Treatment concluded yesterday, and his infection has resolved. On physical examination, temperature is 36.8 °C (98.4 °F), blood pressure is 103/53 mm Hg, pulse rate is 112/min, and respiration rate is 16/min. He has scleral icterus. On cardiopulmonary examination, he is tachycardic. The remainder of the physical examination is normal. Laboratory studies: Hemoglobin Leukocyte count Mean corpuscular volume 9.6 g/dL (96 g/L) 8900/µL (8.9 × 109/L) with a normal differential 104 fL (compared with a value of 85 fL 3 years ago) Platelet count 259,000/µL (259 × 109/L) Reticulocyte count 6.4% Three years ago, the routine complete blood count was normal. Which of the following is the most likely diagnosis? A Cold agglutinin disease B Glucose-6-phosphate dehydrogenase deficiency C Hereditary spherocytosis D Sickle cell disease E Thalassemia REFERENCES Tefferi, Ayalew. "Anemia in Adults: A Contemporary Approach to Diagnosis." Mayo Clinic Proceedings 78.10 (2003): 1274-280. Web. 3 May 2015. DeLoughery, Tom. Anemia: An Approach To Diagnosis. Rep. N.p.: Oregon Health & Science U, 2010. Print. MKSAP 16, ACP UpToDate: “Approach to the adult patient with anemia” Armando Hasudungan, Armando. "Haematology - Red Blood Cell Life Cycle." YouTube. YouTube, 29 Sept. 2014. Web. 03 May 2015. <https://www.youtube.com/watch?v=cATQFej6oAc>. Image of RBC & components. Digital image. Air We Breathe: Air Composition. Chemistryland, n.d. Web. 3 May 2015. http://www.chemistryland.com/CHM107/AirWeBreathe/Comp/AirComposition.html.