Macrocytic and Megaloblastic Anemias PDF - Chapter 15

6/28/2024 MACROCYTIC AND MEGALOBLASTIC ANEMIAS Chapter 15 PREAMBLE  PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY....

6/28/2024 MACROCYTIC AND MEGALOBLASTIC ANEMIAS Chapter 15 PREAMBLE  PowerPoints are a general overview and are provided to help students take notes over the video lecture ONLY. o PowerPoints DO NOT cover the details needed for the Unit exam  Each student is responsible for READING the TEXTBOOK for details to answer the UNIT OBJECTIVES  Unit Objectives are your study guide (not this PowerPoint)  Test questions cover the details of UNIT OBJECTIVES found only in your Textbook! 1  6/28/2024 MACROCYTIC ANEMIAS Macrocytosis, an increased MCV (usually between 100 and 120 fL), can be observed in megaloblastic anemia but can be caused by nonmegaloblastic etiologies. Nonmegaloblastic macrocytic anemias lack a common pathophysiology. MEGALOBLASTIC ANEMIAS Characterized by: Hypercellular marrow with nuclear to cytoplasmic asynchrony Intramedullary cell death due to ineffective erythropoiesis Leukopenia and thrombocytopenia are present Two major categories based on etiology: Vitamin B12 (cobalamin, Cbl) deficiency Folic acid deficiency 2  6/28/2024 ETIOLOGY 1. Increased utilization of B12 due to parasitic infections such as Diphyllobothrium latum tapeworm 2. Pathogenic bacteria in disorders such as diverticulitis and small-bowel stricture 3. Malabsorption syndrome caused by gastric resection, carcinoma, and some forms of celiac disease or sprue 4. Inflammatory disorders of the terminal ileum 5. Nutritional deficiency or diminished supply of B12 PERNICIOUS ANEMIA (PA) ETIOLOGY PA may be associated with autoimmune endocrinopathies and antireceptor autoimmune disease. Chronic autoimmune thyroiditis (Hashimoto’s thyroiditis) Insulin-dependent diabetes mellitus Addison’s disease Primary ovarian failure Primary hypoparathyroidism, Graves’ disease Myasthenia gravis A genetic predisposition to pernicious anemia is suggested by the clustering of the disease and of gastric autoantibodies in families. The underlying gastritis that causes pernicious anemia is immunologically related to an autoantibody to intrinsic factor, a serum inhibitor of intrinsic factor, and autoantibodies to parietal cells. 3  6/28/2024 PERNICIOUS ANEMIA (PA): EPIDEMIOLOGY Research studies have recently documented that 1.9% of persons older than 60 years have undiagnosed pernicious anemia. Earlier studies suggested that pernicious anemia is restricted to Northern Europeans; however, newer studies report the disease in both Blacks and Latin Americans. The median age at diagnosis is 60 years. Slightly more women than men are affected. PHYSIOLOGY Folate: necessary for the production of thymidine nucleotides used in DNA production. Tetrahydrofolate (a form of folate) donates a methyl group to dUMP to form thymidine. Vitamin B12: the source of the folate is 5- methyltetrahydrofolate. The methyl group is removed to make tetrahydrofolate and donated to detoxify homocysteine into methionine. The substance that removes the methyl group is vitamin B12. 4  6/28/2024 PATHOPHYSIOLOGY Both folate and vitamin B12 have the same effect on DNA production, but folate has a direct implication, whereas vitamin B12 has an indirect application. The lack of thymidine leaves empty spaces in the DNA replicate that are temporarily filled by uracil, but eventually, the replicated DNA is nonfunctional, which causes cell division to stop. The result is a macrocytic cell; one that is large and incapable of dividing anymore. NUCLEAR TO CYTOPLASMIC ASYNCHRONY Precursors begin to divide. The lack of vitamin B12 or folate cause mitosis to lag behind in the nucleus. The result is a cell with a normal cytoplasmic appearance but a younger looking nuclear appearance. This is most prominent in the polychromatophilic normoblast stage of development. 5  6/28/2024 CLINICAL SIGNS AND SYMPTOMS Possible changes in skin color to a lemon-yellow appearance. The nail beds, skin creases, and periorbital areas may become hyperpigmented owing to melanin deposition. Angular cheilitis (cracking at the corners of the mouth), dyspepsia, and diarrhea can occur. Glossitis and a painful tongue are frequently observed. Early graying of the hair. Tiredness, dyspnea on exertion, vertigo, or tinnitus secondary to anemia. Congestive heart failure, angina, or palpitations may be noted. Neurological and cognitive abnormalities. LABORATORY FINDINGS #1 Hemoglobin, microhematocrit, and RBC count are low. Mean corpuscular volume (MCV) may be as high as 130 fL. Mean corpuscular hemoglobin (MCH) varies but is usually increased in 90% of cases. 6  6/28/2024 LABORATORY FINDINGS #2 Moderate to significant anisocytosis and poikilocytosis Many macrocytic, ovalocytic red cells precursors, notably metarubricytes LABORATORY FINDINGS #3 Red cell inclusions Basophilic stippling Howell-Jolly bodies Cabot rings may be observed Abnormalities in leukocytes Hypersegmented (more than four lobes) neutrophils An increase in the percentage of eosinophils (eosinophilia) Platelets are also typically decreased in number. 7  6/28/2024 LABORATORY FINDINGS #4 Usually, hypercellular with megaloblastic changes in either the erythroid line or all lines, but it can be hypocellular and mimic aplastic anemia. Erythrocyte precursors are enlarged with a decreased nuclear-cytoplasmic ratio. Nuclear-cytoplasmic asynchrony, with relative immaturity of the nucleoplasm, is typical. Granulocytic precursors may also display nuclear-cytoplasmic dissociation and enlargement. Characteristically, giant metamyelocytes with large, incompletely segmented nuclei are seen. Number of mitoses are increased and the myeloid-erythroid ratio (M:E ratio) is diminished to 1:1 or less. Iron stores are increased, unless iron deficiency is coincidentally present. LABORATORY FINDINGS #5 8  6/28/2024 CLINICAL CHEMISTRY Serum haptoglobin-binding capacity—decreased. Serum vitamin B12—decreased. Folate—normal. Serum iron—increased. Total iron-binding capacity—normal or decreased. Percent transferrin—increased. Serum lactic dehydrogenase isoenzymes 1 and 2—significantly increased. Unconjugated bilirubin—increased. Urinary methylmalonic acid and homocysteine levels—elevated. An extremely elevated LDH, isoenzymes 1 and 2, is an important diagnostic finding. Uric acid levels are low secondary to decreased DNA synthesis. TREATMENT Standard treatment for vitamin B12 deficiency is regular monthly intramuscular injections of at least 100 mg of vitamin B12 to correct the vitamin deficiency. Reticulocyte count begins to increase 2 to 3 days after treatment and peaks in 5 to 8 days; higher and later peaks occur in more severe anemia. Hematocrit begins to increase in approximately 1 week and will normalize within 4 to 8 weeks. MCV typically increases for the first 3 to 4 days, presumably because of reticulocytosis and then begins to decrease. The normal reference range is expected to be reached in 25 to 78 days. 9  6/28/2024 FOLIC ACID DEFICIENCY: ETIOLOGY 1. Drugs can interfere with the absorption or proper distribution of folic acid 2. Increased utilization caused by pregnancy or acute leukemia 3. Treatment with antimetabolites that are folate antagonists FOLATES Sources: Yeast, green leafy vegetables, and organ meats such as liver and kidneys Human body does not store much—usually 3 to 4 month supply. Chronically inadequate diet can produce folic acid deficiency leading to megaloblastic anemia. Alcohol is the most common pharmacological cause of folic acid deficiency. 10  6/28/2024 FA DEFICIENCY: EPIDEMIOLOGY Lack of dietary folic acid from green leafy vegetables Increased demands, such as during pregnancy and infancy Malabsorption disorders such as sprue or gluten sensitivity Biologic competition for dietary folate due to bacterial overgrowth in the intestine Medications Alcoholism LABORATORY FINDINGS 11  6/28/2024 POSTAMBLE  READ the TEXTBOOK for the details to answer the UNIT OBJECTIVES.  USE THE UNIT OBJECTIVES AS A STUDY GUIDE  All test questions come from detailed material found in the TEXTBOOK (Not this PowerPoint) and relate back to the Unit Objectives 12