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Anemia Jenny Wright, MD Acting Instructor, Dept of Medicine Lecture Outline Casebased presentation highlighting common causes of anemia, including evaluation and treatment Case 1 26 year old female presents to clinic for evaluation after attempting to donate blood and being was told that she was anemic. What labs would you order at this visit? A) Hematocrit B) CBC, iron, TIBC, and ferritin C) CBC, reticulocyte count D) CBC, reticulocyte count, peripheral blood smear, iron, TIBC and ferritin Anemia Definition: Low oxygen carrying capacity in the blood due to low erythrocyte mass. We use the hematocrit or hemoglobin as surrogate markers for the erythrocyte mass because that it too difficult to measure. Hemoglobin of < 12 g/dL in women or a Hemoglobin of <13 g/dL in men is considered abnormal (WHO criteria). The hematocrit is approximately 3 x the hemoglobin. Overview of Causes Bloodloss Decreased production of RBCs: decreased erythropoetin (epo) Normal production of epo but decreased ability to respond to epo Destruction of RBCs: intravascular extravascular Anemia History: Patient reported symptoms will vary greatly based on the rapidity of the change in Hct, medical co-morbidities and the cause of the anemia. Physical exam findings: conjunctival rim pallor is the physical exam finding with the highest positive likelihood ratio (16.7) Conjunctival rim pallor Initial laboratory evaluation Reticulocyte count: this may be reported as the absolute count (determined by flow cytometry) or the reticulocyte count as a percentage of the total erythrocytes – in this case you want to calculate the reticulocyte index (RI=reticulocyte% x pt’s Hct/45 x 0.5). If low (RI<2), bone marrow hypoproliferation: production problems If normal (RI>2), bone marrow hyperproliferation: hemolytic anemia, acute blood loss Reticulocytes http://www.uptodate.com.offcampus.lib.washington.edu/online/content/images/ HEME/9131/Polychromatophilia.jpg Initial laboratory evaluation Peripheral blood smear: Offers important additional information regarding the morphology of the cells that cannot be obtained from other laboratory data. Examples include differentiation between types of hemolytic anemia, different types of macrocytic anemias. Example normal smear From UpToDate, http://www.uptodate.com/online/content/image.do;jsessionid=B 8AAB868DBB1B8B6463E3749C695F04E.1004?imageKey=HE ME%2F9057 Red blood cell indices Microcytic (MCV<81): iron deficiency, thalassemia, sideroblastic anemia, anemia of chronic disease Normocytic (MCV 81-98): anemia of chronic disease, aplastic anemia, bone marrow infiltration, kidney disease, acute blood loss Macrocytic (MCV >98): alcohol, B12 deficiency, folate deficiency, myelodysplasia, drug toxicity, reticulocytosis, liver disease Our patient’s smear 26 year old female presenting for evaluation after attempting to donate blood and being was told that she was anemic. Case 1, cont. Her labs reveal: low reticulocyte count, Hct 33%, MCV 74, iron 35 (low), TIBC 540 (high), ferritin 14 (low). What do you do next? A) treat with oral iron B) order a colonoscopy C) order a transfusion D) start oral contraceptive pills Dx of Fe deficiency anemia Ferritin can be the most useful single test, though due to the fact that this is an acute phase reactant, only in patients without infection/inflammation All pt’s with ferritin <15 are iron deficient (highly specific but not sensitive), values >100 essentially rule out iron deficiency. Other characteristic iron study results are: elevated TIBC, low transferrin saturation and low serum iron level Fe Def. Smear Progression of change: hypochromia, microcytosis, anisocytosis (increased RDW) Fe Def Anemia In severe cases may have additional physical exam findings: Management of Fe deficiency Evaluate for cause: In post-menopausal females and males you have to evaluate for GI blood loss. In menstruating females, menses is a common cause; the most common cause of anemia overall in females. Treat: Iron replacement can typically be given orally, ferrous sulfate or gluconate 325 mg, 1-3 times a day. Ideally pts are treated with TID medication though this is rarely tolerated Sulfate salt is cheaper but generally less well tolerated Case 1, cont. Three months later pt returns, still being told she can’t give blood! Her Hct is 34% and ferritin 15. What do you do now? A) review how she’s taking her medications B) transfusion C) give it more time D) start vitamin C Iron therapy Side effects of oral iron replacement lead to low compliance. Constipation, stomach upset May have less symptoms if they take it with food (though this decreases absorption) Consider other causes of poor absorption: celiac sprue, IBD, taking with an antacid, PPI, calcium. If not a compliance issue consider w/u for celiac disease Vitamin C enhances absorption Expect Hct to improve within a few weeks of therapy though pts should continue treatment for 6 mo -1 yr, would like to see ferritin level normalized Case 2 A 52 year-old woman with lupus is admitted to the hospital for pneumonitis. During her evaluation she is found to have a Hct of 30 and MCV of 80. What is the differential diagnosis of her anemia? Case 2, continued What additional labs would you order to work up her anemia? A. reticulocyte count, iron, vitamin B12, and folate B. reticulocyte count, epo level C. reticulocyte count, smear, ferritin, iron and TIBC D. reticulocyte count, smear and ferritin Anemia of Chronic Disease Lab findings: Hypoproliferative anemia (low reticulocyte count) Typically a normocytic anemia, though 25% of cases are microcytic Classically labs will reveal an normal - elevated ferritin, and low serum iron and TIBC. Bone marrow stores of iron are normal (though testing for this is not indicated) Etiology: multiple contributing factors including decreased transfer of iron to red blood cells, decreased response to Epo, decreased Epo release Treatment: Treat underlying cause ACD +/- Fe def. ACD +/- Fe def. Anemia over half You’re way there! Fe def is most common anemia in pre-menopausal females Anemia of chronic disease is the most common anemia in men Case 3 48 year old female is admitted to the hospital for severe alcohol withdrawal. She is experiencing alcoholic hallucinosis and you are unable to obtain a reliable history. Admission labs are remarkable for: Hct 34%, MCV 105, RI <2 . Her PMHx is remarkable for rheumatoid arthritis. Case 3, cont. The most likely diagnosis is: A. chronic GI blood loss due to gastritis B. dietary B12 deficiency C. folate deficiency D. anemia of chronic disease Macrocytic anemia Other causes include: Alcohol Drug toxicity: zidovudine (AZT), hydroxyurea Hypothyroidism Liver disease Myelodysplasia Besure to assess reticulocyte count to eval for stress erythropoiesis Megaloblastic macrocytosis The smear in a patient with macrocytic anemia is helpful in identification of megaloblastic changes – macro-ovalocytes and hypersegmented neutrophils (>5 lobes) Etiologies include: B12 deficiency, folate deficiency, drugs that cause abnl DNA synthesis or folate metabolism, and myelodysplastic syndromes Non-megaloblastic macrocytosis is typical of liver disease and hyposplenism, on smear patients may have large target cells, acanthocytes, and Howell-Jolly bodies. Megaloblastic Macrocytic Anemia Non-megaloblastic macrocytosis Folate deficiency Found in: Fruits (e.g. citrus, melon, bananas), leafy green vegetables, and fortified grain products Causes include: alcohol due to both a decreased ability to absorb folate and, frequently, decreased intake of folate rich foods Malabsorption (celiac disease, IBD) Diseases/conditions associated with rapid cell turnover such as sickle cell disease, psoriasis, pregnancy Medications: trimethoprim, phenytoin, methotrexate Vitamin B12 deficiency The body stores large amounts of B12 therefore decreased dietary intake rarely lead to deficiency, typically due to decreased absorption due to pernicious anemia and intrinsic factor deficiency, atrophic gastritis or IBD. Medications to decrease stomach acid can also contribute to B12 deficiency (PPIs, antacids) In addition to causing anemia, B12 deficiency can lead to a metabolic peripheral neuropathy and neuropsychiatric disease (not the case for folate deficiency) Case 3, cont. Labs reveal a low folate level and a normal B12 level (450). You initiate folic acid supplementation with 1 mg po q day. As was done here, you always want to assure that pts don’t also have B12 deficiency prior to treating for folate deficiency, you may be able to improve a patients anemia but the neurologic symptoms will progress Vitamin B12 Iflevels are at the lower limits of normal (200-300), then consider checking methylmalonic acid and homocysteine levels, these will be elevated in the case of B12 deficiency Should be given orally, IM in rare situations Oral dosing is 1000 – 2000 mcg po q day IM dosing is 1000 mcg IM q day x 7 days, then q wk x 4 wks then q month Case 4 A 28 year African American old female presents to clinic with fatigue. She has a history of cellulitis and just finishing a 14 day course of therapy with Bactrim. TSH is normal, Hct is 25%, MCV 98. What do you think is the most likely cause of her anemia? A. hemolysis B. iron deficiency C. folate deficiency D. anemia of chronic disease Hemolytic anemia to order: reticulotye count, peripheral Labs smear, haptoglobin, indirect bilirubin and LDH The peripheral smear will help you differentiate between causes of hemolysis Extravascular Hemolytic Anemia Etiologies of extravascular hemolysis include: Congenital hemoglobin abnormalities: hemoglobinopathies Erythrocyte membrane abnormalities: hereditary spherocytosis Erythrocyte metabolic abnormalities: G6PD deficiency Auto-immune process: idiopathic, underlying malignancy, CVD, lymphoproliferative disorders, medications (PCN, cephalosporins, NSIADs) Extravascular Hemolysis What’s going on here? http://www.uptodate.com/online/content/image.do;jsessionid=49B7B6DD5EECE1FD7800F AECB4D78805.1102?imageKey=HEME%2F8853 Glucose 6-phospate dehydrogenase deficiency X-linked enzyme deficiency that results in decreased glutathione levels Most common form results in severe hemolysis with medications (primaquine, sulfa, dapsone), fava beans and some infxn. Dx: enzyme activity testing, may have false negative test in the setting of acute hemolysis, re-test at 2-3 months Intravascular hemolytic anemia Etiologies include: Microangiopathic hemolytic anemia – TTP, HUS, DIC, HELLP Shearing due to malfunctioning mechanical heart valves Intravascular Hemolysis Case 4, cont. She has labs consistent with hemolytic anemia, and the following smear. What do you think is going on and what test can you send to confirm this? From UpToDate, http://www.uptodate.com/online/c ontent/image.do;jsessionid=B8A AB868DBB1B8B6463E3749C69 5F04E.1004?imageKey=HEME% 2F9278 Case 4, cont. You send a direct antiglobulin test (Coombs test) and it is positive, confirming the diagnosis of auto-immune hemolytic anemia. She is treated with steroids and does well. Transfusions When to transfuse? General rule: Hct <21%, consider at <25% in pt’s with multiple medical problems Other times to consider: on-going rapid blood loss, highly symptomatic patients, patient with low Hct and severe cardiovascular disease You expect the Hct to increase 3% for each unit of blood transfused Case 5 63 year old female with DM and CKD presents for evaluation of fatigue. Labs reveal Hct 31%, MCV 87, iron 43 (40-155), TIBC 241 (270-535), ferritin 95 (10-180), transferrin sat. 18% (10- 45%). How can you treat her anemia? Transfusion Epo Epo and iron Iron replacement Anemia of Chronic Kidney Disease Burr cells Anemia of Chronic Kidney Disease Hypoproliferative (low reticulocyte count), normocytic anemia For erythropoietin therapy to be effective need adequate iron stores – ferritin >100 and transferrin saturation >20% Treatment goal is hemoglobin of 11-12 (Hct 33-36%), higher levels are associated with increased morbidity and mortality – carries a Black Box warning Can use darbopoetin or epoetin Case 6 A 27 yr old man of SE Asian descent comes in for a routine exam required for employment. He is in good health, without weight loss, fatigue or bleeding sx. FH negative for anemia. Exam is unremarkable and pt has no HSM. Neg stool guaiac. Labs: WBC 5.3, HCT 35%, MCV 65, plts 330K, Retic index 0.8. Case 6, cont. What is the best test to confirm the most likely cause of this patient’s anemia? Obtain CBC on siblings Perform ultrasound for spleen size Measure serum ferritin and iron studies Check glucose-6-phosphate dehydrogenase screen Perform hemoglobin electrophoresis Thalassemia Thalassemia trait: mild anemia with pronounced microcytosis (MCV <70) Ethnicity: Mediterranean, Asian, African Pt are asymptomatic FamHx is often negative Dx thal trait: Hemoglobin electrophoresis Thalassemia intermedia: • Ineffective erythropoiesis, more severe anemia, often require frequent transfusions, at risk of development of iron overload Iron deficiency anemia: usually more pronounced microcytic anemia than thal trait Thalassemia Microcytic, hypochromic RBC, target and teardrop cells Anemia Summary Evaluation: CBC – eval. RBC data alongside WBC and Plt counts, RBC indices Reticulocyte count – if bone marrow is responding appropriately Smear – morphologic clues to etiology Anemia Summary Most common etiologies: Females – Iron deficiency Men – Anemia of chronic disease Hx and labs, possibly including soluble transferrin receptor will help you differentiate Anemia by size Microcytic:iron def., thalassemia trait, thalassemia intermedia Normocytic: anemia of chronic disease (25% microcytic), chronic renal failure, hemolytic anemia, acute blood loss Macrocytic anemia: Folate def., B12 def.
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