1、Anemia,Robb Friedman, MD Updated by Eyal Oren, MD,What is Anemia?,ANEMIA IS NEVER NORMAL Reduction below normal in the mass of red blood cells in the circulation Hemoglobin concentration, hematocrit, RBC count Men: HGB 13.5 or HCT 41% Women: HGB 12.0 or HCT 36%,Anemia and Volume Status,HGB and HCT a
2、re CONCENTRATIONS Therefore dependent upon plasma volume Acute bleeds not reflected for 24-36 hrs Due to volume deficit being slowly repaired via movement of fluid from extravascular space to intravascular Anemic patients who are dehydrated will not appear anemic Pregnant women expand RBCs 25% but p
3、lasma volume increases 50%, producing “physiologic anemia”,Anemia: Special Cases,People who live at high altitude have greater RBC volume Smokers have increased HCT African-American HGBs are 0.5 to 1.0g/dL lower than Caucasians Athletes (increased plasma volume, Fe deficiency, hemolysis, polycythemi
4、a, use of performance enhancing agents),Anemia and the Elderly,Multiple studies support that the elderly do not have a “lower normal range” Anemia, while common in the elderly, is still abnormal HGB 13 in males and 12 in females associated with an increased relative risk of mortality (1.6 and 2.3 re
5、spectively),Anemia: History,Is the patient bleeding? NSAIDs, ASA Past medical history of anemia? Family history? Alcohol, nutritional questions Liver, renal diseases Menstrual history if applicable Ethnicity Environmental/work toxins (ie lead),Symptoms of Anemia,Decreased O2 delivery Hypovolemia if
6、acute loss Exertional dyspnea, fatigue, palpitations, “bounding pulses” Severe: heart failure, angina, MI “Pica” craving for clay or paper products Pagophagia craving for ice,Signs of Anemia,Tachycardia, tachypnea, orthostasis Pallor Jaundice Koilonychia or “Spoon nails” Splenomegaly, lymphadenopath
7、y Petechiae, ecchymoses Atrophy of tongue papillae Guaiac,The Three Causes of Anemia,Decreased red blood cell production Increased red blood cell destruction Red blood cell loss,Decreased RBC production,Lack of iron, B12, folate Marrow is dysfunctional from myelodysplasia, tumor infiltration, aplast
8、ic anemia, etc. Bone marrow is suppressed by chemotherapy or radiation Low levels of erythropoeitin, thyroid hormone, or androgens,Increased RBC destruction,RBCs live about 100 days Acquired: autoimmune hemolytic anemia, TTP-HUS, DIC, malaria Inherited: spherocytosis, sickle cell, thalassemia,RBC Lo
9、ss,Bleeding! Obvious vs occult Iatrogenic: venesection e.g. daily CBC, surgical, hemodialysis Retroperitoneal,Approach to Anemia,LOOK AT THE SMEAR! Convenient to separate into three classes based on the size of the RBC MCV and RDW Microcytosis: 100 fL CBC, reticulocyte count, Fe, Ferritin, TIBC, fol
10、ate, B12, LDH, CMP, ESR,Reticulocytes,Nucleated RBCs form in marrow where they mature for 3 days and then spend 1 day in circulation (before maturing to RBC) Given avg life span of RBC of 100 days, 1% of RBCs are destroyed each day Retics form 1% of circulating RBCs qd Nl RBC count is 5million/uL so
11、 marrow makes 50,000 reticulocytes/uL blood qd With epo, can increase to 250,000 retics/uL blood qd (given nl marrow and replete iron, folate, b12),Reticulocyte Count,Anemia with high retic # = appropriate response Anemia with normal to low retic # = reduced marrow response Must adjust for anemia, u
12、se reticulocyte production index Retic % x HCT/45 or x , nml is 1.0, less = inadeq. Retic Or RI = retics x (Hct/45) / Correction Factor CF: Hct 41-50 (1), 30-40 (1.5), 20-29 (2), 10-19 (2.5) Reflects increased circulating time for retics as Epo pushes them out of the marrow earlier,Microcytic Anemia
13、,Iron Deficiency Anemia Thalassemia Anemia of chronic disease (esp. RA and lymphoma) Sideroblastic anemia (myelodysplastic syndromes),Iron Deficiency Anemia,The definitive test is serum ferritin Low serum ferritin is diagnostic of iron deficiency Although ferritin is an acute phase reactant, it will
14、 still be low in iron deficiency Also, high TIBC Low serum Fe is not in itself diagnostic, neither is marrow staining Anisocytosis and poikilocytosis Reactive thrombocytosis,Microcytic Anemia,Thalassemia,Decreased production of either -globin or -globin chains Abnormal hemoglobin electrophoresis Pol
15、ychromasia, basophilic stippling, target cells Normal/increased RBC mass,-Thalassemia,-Thalassemia: 4 genes : silent carrier 2/4: -Thalassemia trait, microcytosis and mild anemia : excess -chains form tetramers, results in severe anemia and microcytosis 4/4: hydrops fetalis Most common in SE Asian p
16、opulations,Basophilic stippling,-Thalassemia,2 genes mutation: -Thal trait, increased Hgb A2, rarely anemic, mild microcytosis 2/2 mutation: -Thalassemia disease, Hgb F, microcytosis, anemia Usually found in people of African or Mediterranean descent but has world-wide distribution,-Thalassemia,Macr
17、ocytic Anemia (MCV100),Drug Induced (hydroxyurea, AZT, MTX, chemotherapy) B12 / folate deficiency Myelodysplastic syndrome Liver disease, alcohol abuse Reticulocytes in the setting of hemolytic anemia Spurious (i.e. cold agglutinins, etc),Folate and B12,Serum folate usually sufficient, but if folate
18、 level is normal but folate deficiency is suspected, check serum homocysteine (elevated because of impaired folate dependent conversion of homocysteine to methionine) B12 can be spuriously low a more sensitive and specific test is serum methylmalonic acid level, will be increased if B12 is low. Schi
19、lling Test,B12 and Folate Deficiency,Myelodysplastic Syndrome,Primary bone marrow disorder, often found in elderly Macrocytosis, anemia Pseudo-Pelger-Huet abnormality the bilobed nucleus,Normocytic Anemia,Large and complicated group of disorders! Hemolytic Anemias Anemia of chronic disease Bone marr
20、ow disorder Nutritional (Fe deficiency) Anemia of Renal Insufficiency,Nutritional Anemias,Iron deficiency and B12/folate deficiency can present with normocytic anemia esp. if both deficiencies are concurrent. Check iron studies and B12, folate levels.,Anemia of Renal Insufficiency,Unremarkable perip
21、heral blood smear Inappropriately normal erythropoietin level Anemia usually severe and symptomatic when Cr 3.0 Mild to moderate anemia found in Cr 1.5-3.0 Tx: Epogen or similar, Fe (oral, IV),Hemolytic Anemias,Hemolytic Anemia: Intrinsic causes Spherocytosis, Sickle Cell,Evaluation of Hemolysis,LDH
22、: increases Indirect bilirubin increases (increased Hgb catabolism) Haptoglobin decreases Reticulocyte count increases Urine hemosiderin test = present for intravascular, absent for extravascular hemolysis! Coombs test + = autoimmune hemolytic anemia, - consider PNH (abnormal GPI protein, send flow
23、for CD55 and CD59),More hemolytic anemias,Anemia of Chronic Disease,Thought to be a cytokine mediated process which inhibits red blood cell production or interferes with action of erythropoietin Seen with diabetes, rheumatologic diseases, chronic infections, malignancy Indices: Low Fe, Low TIBC, Nl/
24、increased Ferritin,Anemia due to Primary Bone Marrow Disorder,Myelodysplastic syndrome Bone marrow infiltration: nucleated red blood cells found in circulation Might see “rouleaux” formation in multiple myeloma WBC, plts often abnormal Bone marrow biopsy,Anemia: Treatments,“Transfusion triggers” CAD
25、: Hgb 10 All pts: Hgb 7.0 Everyone else: usually Hgb 8.5 Iron supplementation Erythropoietin analogs B12, folate,What the hell is a Howell-Jolly Body?,Acanthocytes vs Echinocytes,Acanthocytes: “spur cells” found in liver disease Echinocytes: “burr cells” found in renal disease,Helmet vs. Teardrop Ce
26、lls,Anemia: Summary,ANEMIA IS NEVER NORMAL CONSIDER THE THREE CAUSES LOOK AT THE SMEAR CONSIDER THE ETIOLOGY BASED ON RBC MORPHOLOGY AND LABORATORY STUDIES TREAT APPROPRIATELY,MKSAP Questions,An 80-year-old man who had a hemicolectomy for colon cancer is evaluated because of a 4-month history of dia
27、rrhea, anorexia, and fatigue. He had a remote history of alcoholism. On physical examination, he is cachectic and mildly confused. His pulse rate is 70/min, and blood pressure is 140/85 mm Hg. His tongue is smooth. The abdomen is soft; there are no palpable masses or hepatosplenomegaly. A stool spec
28、imen is negative for occult blood. Neurologic examination shows loss of position sense in the feet. He has a wide-based gait. The Romberg test is positive. His hemoglobin is 9.4 g/dL, reticulocyte count is 2.5%, mean corpuscular volume is 125 fL, and serum lactate dehydrogenase is 400 U/L. Which of
29、the following is the most likely cause for his symptoms? ( A ) Alcoholic cerebellar degeneration ( B ) Vitamin B12 deficiency ( C ) Brain metastases ( D ) Folate deficiency ( E ) Liver metastases,Critique (Correct Answer = B) The patient most likely has vitamin B12 deficiency, based on the degree of
30、 macrocytosis and neurologic findings. An elevated serum lactate dehydrogenase level, due to intramarrow cell death from ineffective erythropoiesis, is consistent with this diagnosis. Severe macrocytosis (mean corpuscular volume 120 fL) is often associated with vitamin B12 deficiency or folate defic
31、iency (megaloblastic anemia), usually seen in conjunction with “oval” macrocytes. The presence of frequent hypersegmented neutrophils ( 5 segments) is strongly suggestive of vitamin B12 or folate deficiency. Bone marrow morphology in patients with vitamin B12 or folate deficiency is referred to as “
32、megaloblastic” and is characterized by the presence of large cells with immature nuclear chromatin but maturing erythrocyte cytoplasm (nuclear-cytoplasmic dissociation). Anemia accompanies this process; hence the term “ineffective erythropoiesis.” The intramarrow death of megaloblastic cells causes
33、the serum lactate dehydrogenase level to rise. If a patient has a low serum vitamin B12 or folate level, a bone marrow examination is probably unnecessary. However, the physician should determine the cause of the deficiency. If a patient has a normal serum vitamin B12 or folate level, a bone marrow
34、examination is frequently helpful to exclude myelodysplastic syndromes or other infiltrative marrow disorders. Folate deficiency can induce megaloblastosis within weeks to months, whereas vitamin B12 deficiency requires years to cause megaloblastosis since stores of vitamin B12 persist for years in
35、the liver and other tissues. In patients with vitamin B12 or folate deficiency, parenteral or oral repletion of vitamin B12 or folate reverses some morphologic abnormalities within hours. Serum folate levels fluctuate quickly with changes in dietary consumption. Low erythrocyte folate levels often r
36、eflect prior nutritional depletion. In patients who are hospitalized and are begun on regular diets, the erythrocyte folate test may provide a better assessment of tissue folate levels than determination of the serum folate level. The erythrocyte folate test often requires a special laboratory, and
37、results often are not quickly available. In patients with megaloblastic anemias, erythrocyte production is diminished and a “corrected” reticulocyte count is inappropriately low for the degree of anemia. This patient had a corrected reticulocyte count of 1% (inappropriately low for a hemoglobin leve
38、l of 9.4 g/dL). In addition to changes in the blood, the epithelial cells in patients with megaloblastic anemias may become atrophic and cause a smooth tongue and cheilosis. Posterior column dysfunction, particularly in patients with vitamin B12 deficiency, may lead to changes in vibratory or positi
39、on sense, causing ataxia. Signs of dementia may appear. However, neurologic dysfunction is very uncommon in adults with folate deficiency. Alcoholic cerebellar degeneration results in ataxia but not position loss. Although liver metastases are possible in a patient with a history of colon cancer, th
40、eir presence would not account for the neurological findings in this patient. Brain metastases would most likely produce focal neurological findings and also would not account for the blood findings.,A 26-year-old man is evaluated because of progressive fatigue, dyspnea on exertion, and orthostatic
41、dizziness for the past 2 to 3 weeks. He takes no medications. Physical examination is normal except for pallor. Laboratory StudiesHematocrit 13%Leukocyte count 8300/L; normal differentialReticulocyte count 0Platelet count 320,000/LA routine biochemical profile, including liver function tests, is nor
42、mal. A chest radiograph shows normal lung fields and a widened mediastinum, suggestive of an anterior mediastinal mass. Bone marrow biopsy shows absent erythrocyte precursors, normal megakaryocytes, and normal leukocyte numbers and maturation. Which of the following is the most likely cause of the m
43、ediastinal mass and anemia? ( A ) Hodgkins disease ( B ) Non-Hodgkins lymphoma ( C ) Thyroid carcinoma ( D ) Thymoma ( E ) Germ cell carcinoma,Critique (Correct Answer = D) Each of the listed neoplasms may present as an anterior mediastinal mass and may be associated with anemia of chronic disease.
44、However, pure red cell aplasia (which this patient has) is often associated with a benign or invasive thymoma. Approximately 5% to 15% of thymomas occur in patients with pure red cell aplasia. Other thymoma-associated autoimmune disorders include myasthenia gravis, systemic lupus erythematosus, thro
45、mbocytopenia, and, rarely, malabsorption states. A careful search by CT or MRI is always warranted in patients with newly diagnosed or relapsing red cell aplasia or myasthenia. The other listed entities are also included in the differential diagnosis for an anterior mediastinal mass. Germ cell tumor
46、s have not been associated with pure red cell aplasia, and Hodgkins disease, non-Hodgkins lymphoma, and thyroid carcinoma are rarely associated with this disorder. Chronic lymphocytic leukemia is also commonly associated with red cell aplasia and may present with variable degrees of lymphadenopathy
47、but not with an isolated anterior mediastinal mass, as in the patient discussed here.,A 36-year-old black man with known sickle cell anemia is evaluated because of a 2-week history of fever, a macular rash on his trunk, and arthralgias. Subsequently, he developed weakness and dyspnea on exertion. Se
48、veral of his children had febrile illnesses with associated rashes and fatigue over the past month. These illnesses resolved spontaneously without sequelae. On physical examination, his temperature is 38.8 C (101.8 F), pulse rate is 100/min, and blood pressure is 160/70 mm Hg. A maculopapular, trunc
49、al rash is noted. There is conjunctival pallor. The remainder of his examination is unremarkable. Laboratory StudiesHemoglobin 5.2 g/dLLeukocyte count 5000/LReticulocyte count 0%Platelet count 130,000/LSerum lactate dehydrogenase 622 U/LWhich of the following is the most likely diagnosis? ( A ) Paro
50、xysmal nocturnal hemoglobinuria ( B ) Parvovirus infection ( C ) Glucose-6-phosphate dehydrogenase deficiency ( D ) Aplastic anemia,Critique (Correct Answer = B) Patients with hemolytic disorders may occasionally present with reticulocytopenia and an “aplastic crisis.” This patient has sickle cell a
51、nemia with parvovirus infection, which is causing an aplastic crisis. Parvovirus may infect patients with hemolytic anemias (for example, patients with hereditary spherocytosis, sickle cell disease, or thalassemia). In children with sickle cell anemia, over 80% of aplastic crises may be attributed t
52、o parvovirus infections. In adults, the usual presenting features are rash, arthritis, and anemia. The “slapped cheek” syndrome is rarely a presenting feature. There is usually a complete suppression of erythropoiesis to a reticulocyte level of 0%. The bone marrow shows giant dysplastic (megaloblast
53、oid) erythroblasts, occasionally with viral inclusions. The diagnosis is usually made by demonstrating IgM antibodies to the virus. IgG antibodies appear later during the course of the infection and persist. Parvovirus in the blood may be detected by the polymerase chain reaction, which is the defin
54、itive diagnostic method. Occasionally, other blood components such as leukocytes and platelets are affected and result in mild to moderate pancytopenia. The diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) should be considered in patients with bone marrow failure or aplasia, unusual location o
55、f thromboses, and unexplained hemolysis. The anemia may be severe, and patients with PNH typically have reticulocytopenia. There is no characteristic finding on bone marrow examination, although the bone marrow of patients with PNH may demonstrate myelodysplastic changes. The diagnosis is based on d
56、emonstration of exquisite sensitivity to complement-mediated lysis by the sucrose lysis test or the acidified serum lysis test (Hams test). Glucose-6-phosphate dehydrogenase (G6PD) deficiency is another cause of hemolysis that occasionally is associated with reticulocytopenia. In patients with G6PD
57、deficiency, erythrocytes are subject to oxidative stresses. Hemoglobin becomes oxidized and precipitates within the erythrocytes, which then undergo destruction by the reticuloendothelial system. G6PD deficiency is an autosomal recessive disorder that predominantly affects males. After a hemolytic e
58、pisode, qualitative assays may be normal because only erythrocytes that are resistant to G6PD remain. The African variant of G6PD is associated with a mild form of hemolysis, whereas the Mediterranean variant is usually severe. Causes include infectious stresses, drugs such as quinidine and sulfonam
59、ides, or, in the Mediterranean variant, favism (consumption of fava beans). Therapy requires avoiding certain medications and supportive care in crisis situations. In contrast to this patients presentation, patients with aplastic anemia have pancytopenia with severe anemia, reticulocytopenia, thrombocytopenia, and granulocytopenia. In patients with severe aplastic anemia, the bone marrow examination shows less than 5% cellularity with only residual lymphocytes and plasma cells. The abnormal cells described above that are attributable to parvovirus infection are not seen.,
