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Anemia – An Approach James Czarnecki, D.O. Internal Medicine Resident Lecture Series Background Definition Strictly defined as a decrease in red blood cell (RBC) mass. Usually discovered and quantified by measurement of the RBC count, hemoglobin concentration, and hematocrit. Frequency WHO chose 12.5 g/dL for both adult males and females. In the US, limits of 13.5 g/dL for men and 12.5 g/dL for women – these values are more realistic. Using these values, approximately 4% of men and 8% of women have lower values. A significantly greater prevalence is observed in patient populations. Mortality / Morbidity Varies greatly depending on etiology. Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approx. 1% with benign peptic ulcers). The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy. Mortality / Morbidity Many symptoms associated with anemia are not caused by diminished RBC mass. Patients with pernicious anemia are often asymptomatic when they are detected incidentally with an Hb of 6 g/dL. Patients with iron deficiency anemia develop symptoms at Hb of 10-11 g/dL because of depletion of iron-containing protein other than Hb. Mortality / Morbidity Tolerance of anemia is proportional to the anemia’s rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia. Race Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. For example: Hemoglobinopathies Thalassemia G6-PD deficiency Sex Anemia is twice as prevalent in females than in males. This difference is significantly greater during the childbearing years due to pregnancies and menses. Approximately 65% of body iron is incorporated into circulating Hb. Each gram of Hb contains 3.46 mg of iron. Each healthy pregnancy depletes a mother of approximately 500 mg of iron. Sex A male must absorb about 1 mg of iron to maintain equilibrium, a premenopausal female must absorb an average of 2 mg daily. Females have a markedly lower incidence of anemia from X-linked anemias such as G6PD deficiency and sex-linked sideroblastic anemia. Age Severe genetically acquired anemias (ie, sickle cell disease, thalassemia, Fanconi Syndrome) are more commonly found in children because they do not survive to adulthood. During the childbearing years, women are more likely to become iron deficient. Age Neoplasia increased the prevalence with each decade of life and can produce anemia from bleeding from the replacement of bone marrow with tumor from the development of anemia associated with chronic disorders Age Use of aspirin, NSAIDs, and coumadin increases with age and can produce gastrointestinal bleeding. Clinical Approach History Carefully obtain a history and perform a physical examination in every patient with anemia because the findings usually provide important clues to the etiology of the underlying disorder. Areas of inquiry found valuable are the following. History The duration can be established by obtaining a history of previous blood examination Obtain a careful family not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully document pregnancies, abortions, and menstrual loss. History Patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon. Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula. History Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia. A thorough dietary history is important in a patient who is anemic. It must include foods that the patient both eats and avoids, as well as an estimate of their quantity. Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history. History Obtain a history or presence of fever because infections, neoplasms, and collagen vascular disease can cause anemia. Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus. History Relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria, or paroxysmal nocturnal hemoglobinuria. Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection, or malignancy. Physical Physical Too often, the physical is rushed without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. Examine optic fundi carefully, but not at the expense of the conjunctivaie and the sclerae, which can show pallor, icterus, petechia, or telangiectasia. Physical Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Carefully search for both hepatomgaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or absence of nodules. Physical A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia. The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. Physical The heart should not be ignored because enlargement may provide evidence of the duration and severity of an underlying anemia, and murmurs may be the first evidence of a bacterial endocarditis, which could explain an etiology of an underlying anemia. Causes Causes Genetic Hemoglobinopathies Thalassemias Defects of the RBC cytoskeleton Rh null disease Hereditary xerocytosis Fanconi anemia Causes Nutritional Iron deficiency Vitamin B-12 deficiency Folate deficiency Starvation and generalized malnutrition Hemorrhage Immunologic – Antibody-mediated abnormalities Causes Physical effects Trauma Burns Frostbite Prosthetic valves and surfaces Drugs and chemicals Aplastic anemia Megaloblastic anemia Causes Chronic diseases and malignancies Renal disease Hepatic disease Chronic infections Neoplasia Collagen vascular diseases Causes Infections Virals – Hepatitis, infectious mononucleosis, cytomegalovirus Bacterial – Clostridia, gram-negative sepsis Protozoal – Malaria, leishmaniasis, toxoplasmosis Differentials Differentials Aplastic Anemia Cooley Anemia Hemolytic Anemia Iron Deficiency Anemia Low LDL Cholesterol Megaloblastic Anemia Pernicious Anemia Differentials Sickle Cell Anemia Spur Cell Anemia Thalassemia, Alpha Thalassemia, Beta Work Up Work Up Detection of anemia involves the adoption of arbitrary criteria. In the US: Anemia is suggested in male with Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5 g/dL. Once the existence of anemia is established, investigate the pathogenesis. Work Up A rational approach is to begin by examining the peripheral smear and laboratory values obtained on the blood count. If the anemia is either microcytic (MCV < 84) or macrocytic (MCV > 96), the investigative approach can be then limited. Work Up A rapid method of determining whether cellular indices are normocytic and normocromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Work Up In microcytic hypochromic anemia, seek a source of bleeding. The appropriate lab tests are serum iron level and TIBC and serum ferritin level. If the serum iron level is decreased and TIBC is increase, a diagnosis of iron deficiency can be made. Work Up When a normocytic, normochromic anemia is encountered, classify the anemia into 3 possible etiologies (ie, blood loss, hemolysis, or decreased production). In most anemias, one of these causes is the dominant factor, however in some, more than a single cause may play an important role (ie, pernicious anemia). Microcytic Hypochromic Anemia (MCV < 83; MCHC < 31) Serum Iron TIBC Bone Marrow Iron Comment Iron Deficiency - + 0 Responsive to iron therapy Chronic inflammation - - ++ Unresponsive to iron therapy Thalassemia major + N ++++ Reticulocytosis and indirect bilirubinemia Thalassemia minor N N ++++ Target Cells Lead poisoning N N ++ Basophilic stippling of RBCs Sideroblastic + N ++++ Ring sideroblasts in marrow Hemoglobin N N ++ Hemoglobin electrophoresis Macrocytic Anemia (MCV > 95) Megaloblastic bone marrow Deficiency of vitamin B-12 Deficiency of folic acid Drugs affecting DNA synthesis Inherited disorders of DNA synthesis Macrocytic Anemia (MCV > 95) Nonmegaloblastic bone marrow Liver disease Hypothyroidism and hypopituitarism Accelerated erythropoiesis (reticulocytes) Hypoplastic and aplastic anemia Infiltrated bone marrow Various Forms of RBCs Macrocyte – Larger than normal Microcyte – Small than normal Hypochromic – less hemoglobin in cell Spherocyte – Loss of central pallor, stains more densely, often microcytic. Target cell – hypochromic with central “target” of hemoglobin (liver disease) Various Forms of RBCs Leptocyte – Hypochromic cell with a normal diameter and decreased MCV Elliptocyte – Oval to cigar shaped (B-12, folate) Schistocyte – Fragmented helmet-shaped RBC Stomatocyte – Slitlike area of central pallor in erythrocyte (liver disease, acute alcoholism) Various Forms of RBCs Tear-shaped RBCs – Drop-shaped erythrocyte, often microcytic. Acanthocyte – Five to 10 spicules of various lengths and at irregular intervals on the surface of RBCs. Echninocyte – Evenly distributed spicules on surface of RBCs, usually 10-30 (uremia, peptic ulcer, carcinoma) Sickle Cell – Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C. Imaging Studies Imaging Studies Useful in the workup for anemia when a neoplastic etiology is suggested. Permit discovery of the neoplasm or centrally located adenopathy. Occasionally, they are useful in detecting or confirming the existence of splenomegaly. Procedures Procedures Investigate gastrointestinal bleeding by endoscopy and radiographic studies to identify the bleeding site. May leave the source of GI bleeding undetected if the lesion is small. Bone marrow aspirates and biopsy finding are particularly useful in establishing the etiology of anemia in patients with decreased production of RBCs. Treatment Medical Care Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia Nutritional therapy is used to treat iron deficiency, vitamin B12, and folic acid. Corticosteroids are useful in the treatment of autoimmune hemolytic anemia. Medical Care Treatment of aplastic disorders includes removal of the offending agent whenever it can be identified, supportive therapy for the anemia, and prompt treatment of infection. Surgical Care Surgical Care Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the GI tract, the uterus, or the bladder. Patients should be hemodynamically stable before and during surgery. Splenectomy has been advantageous in hereditary spherocytosis and hereditary elliptocysosis. Surgical Care Bone marrow and stem cell transplantation have been used in patients with: Leukemia Lymphoma Multiple myeloma Myelofibrosis Aplastic disease Consultations Consultations Surgical consultation is indicated to control bleeding, for splenectomy when necessary, and for biopsies to establish the presence of neoplasia Consultation with gastroenterologists is frequently sought to identify a bleeding site in the gut. Urologic consultation may be needed to investigate hematuria. Diet Diet Iron deficiency anemia is prevalent in geographic locations where little meat is in the diet. A strict vegetarian diet requires iron and vitamin B-12 supplementation. Folic acid deficiency occurs among people who consume few leafy vegetables. Coexistence of iron and folic acid deficiency is common among Third World nations. Activity Activity The activity of patients with severe anemia should be curtailed until the anemia is partially corrected. Transfusion can often be avoided by ordering bed rest. March hemoglobinuria is a rare hemolytic disorder usually observed in young males. Individuals develop hemoglobinuria after marching or running on hard surfaces. Can be treated by curtailing the precipitating exercise. Follow Up Follow Up Patients with chronic anemia can usually be cared for on an outpatient basis. Follow-up care is necessary to ensure that therapy is being continued and to assess the efficacy of treatment. The most serious complications of severe anemia arise from tissue hypoxia. Follow Up Shock, hypotension, or coronary and pulmonary insufficiency can occur. This is more common in older individuals with underlying pulmonary and cardiovascular disease. Hemolytic transfusion reactions and transmission of infectious disease are risks of blood product transfusions. Medical / Legal Pitfalls Medical / Legal Pitfalls Negligence in transfusion of either incompatible blood or blood containing a potentially identifiable infectious agent Failure to recognize a hemolytic transfusion reaction and to initiate prompt and appropriate therapy Delayed diagnosis, investigation, and treatment of a neoplastic disorder because the etiology of an anemia was not pursued in a timely manner Medical / Legal Pitfalls Failure to provide appropriate therapy and to ensure that the patient has adequate follow-up care Underestimating the potential severity of an anemia. Histopathology Decreased Production of RBCs Microcytic Anemia Peripheral Smear Peripheral Smear Peripheral Smear Bone Marrow Aspirate Bone Marrow Aspirate Competency Exam Question #1 All of the following are matched correctly, except: (A) Macrocyte – Larger than normal (B) Microcyte – Smaller than normal (C) Spherocyte – Loss of central pallor (D) Schistocyte – Hypochromic cell with a normal diameter (E) Stomatocyte – Slitlike area of central pallor in an erythrocyte. Question #1 All of the following are matched correctly, except: (A) Macrocyte – Larger than normal (B) Microcyte – Smaller than normal (C) Spherocyte – Loss of central pallor (D) Schistocyte – Hypochromic cell with a normal diameter (E) Stomatocyte – Slitlike area of central pallor in an erythrocyte. Question #2 Which of the following deficiencies would most likely lead to megaloblastic anemia? A) vitamin E deficiency B) vitamin B6 deficiency C) iron deficiency D) folic acid deficiency E) Vitamin B12 deficiency Question #2 Which of the following deficiencies would most likely lead to megaloblastic anemia? A) vitamin E deficiency B) vitamin B6 deficiency C) iron deficiency D) folic acid deficiency E) Vitamin B12 deficiency Question #3 The peripheral blood of a patient with iron deficiency anemia will most likely show what picture? a) microcytic, hypochromic red cells b) microcytic, normochromic red cells c) macrocytic, hypochromic red cells d) normocytic, hypochromic red cells e) normocytic, normochromic red cells Question #3 The peripheral blood of a patient with iron deficiency anemia will most likely show what picture? a) microcytic, hypochromic red cells b) microcytic, normochromic red cells c) macrocytic, hypochromic red cells d) normocytic, hypochromic red cells e) normocytic, normochromic red cells End of Lecture http://im.official.ws