Macrocytic anemia Notes

NOTES NOTES MACROCYTIC ANEMIA GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Bone marrow produces larger than normal erythrocytes AKA red blood cells (RBCs) CAUSES ▪ Multifactorial: nutritional deficits, genetics, substance exposure (e.g. certain drugs, alcohol) SIGNS & SYMPTOMS ▪ Fatigue, dyspnea, weight loss, pallor, impaired concentration/memory, diarrhea, onychoschizia (brittle nails) DIAGNOSIS LAB RESULTS ▪ ▪ ▪ ▪ ▪ Complete blood count Peripheral blood smear analysis Blood chemistry Iron studies Genetic testing TREATMENT ▪ Address underlying causes MEGALOBLASTIC ANEMIA osms.it/megaloblastic-anemia PATHOLOGY & CAUSES ▪ Macrocytic, normochromic anemia characterized by formation of large RBCs CAUSES Cobalamin and/or folate deficiency ▪ Impaired DNA synthesis during erythropoiesis → uncoordinated maturation of cytoplasm and nuclei in erythroblasts (nuclear-cytoplasmic asynchrony) → abnormally large RBCs (macrocytosis) + defective cells with fragile membranes → RBCs die prematurely → anemia B12 deficiency ▪ Insufficient diet (e.g. vegan diet without B12 supplements, alcoholism, systemic/mental illness, food insecurity) ▪ Malabsorption ▫ Lack of intrinsic factor → pernicious anemia ▫ Surgical: gastrectomy, bariatric surgery → lack of absorptive surface → pernicious anemia ▫ Pancreatic insufficiency → impaired binding of B12 to intrinsic factor → pernicious anemia ▫ Medications that interfere with absorption: e.g. biguanides, H2 receptor blockers, proton-pump inhibitors, neomycin OSMOSIS.ORG 409

▫ Fish tapeworm (Diphyllobothrium latum) → competes with host for B12 Folate deficiency ▪ Insufficient diet ▪ Adequate diet but increased requirements (e.g. pregnancy, lactation, chronic hemolysis, exfoliative skin disease) ▪ Malabsorption (e.g. celiac disease, inflammatory bowel disease, gastric surgery) ▪ Metabolic interference from medications (e.g. methotrexate, phenytoin, trimethoprim) ▪ Alcoholism Less common causes of macrocytosis ▪ Thiamine-responsive megaloblastic anemia syndrome, congenital anemias (Fanconi anemia, Diamond–Blackfan anemia), myelodysplastic syndromes, pure RBC aplasia, lipid abnormalities (e.g. liver disease), thyroid disease, copper deficiency ▪ Impaired DNA synthesis also causes formation of giant metamyelocytes → neutrophils with hypersegmented nuclei SIGNS & SYMPTOMS ▪ From decreased number of functional RBCs in circulation → decreased RBC oxygencarrying capacity → tissue hypoxia ▫ Fatigue ▫ Activity intolerance ▫ Pallor ▫ Compensatory mechanisms: increased heart rate, bounding pulse ▪ From increased rate of hemolysis, destruction of defective cells ▫ Jaundice: hemolysis → increased serum bilirubin ▫ Splenomegaly: increased reticuloendothelial activity secondary to extravascular hemolysis ▪ From neuronal demyelination (if B12 decreased): numbness, tingling, weakness, possible neuropsychiatric symptomatology 410 OSMOSIS.ORG DIAGNOSIS LAB RESULTS ▪ Peripheral blood cell analysis ▫ Increased mean corpuscular volume (MCV) ▫ Increased mean corpuscular hemoglobin (MCH) ▫ Normal mean corpuscular hemoglobin concentration (MCHC) ▫ Hypersegmented neutrophils ▫ Anisocytosis (different sizes of RBCs) ▫ Poikilocytosis (abnormally-shaped RBCs) ▫ Macroovalocytes (large oval-shaped cells) ▪ Decreased RBC count secondary to increased hemolytic destruction of defective erythrocytes ▪ Decreased reticulocyte count → formation impaired in anemias caused by defective DNA synthesis ▪ Mild leukopenia and/or thrombocytopenia caused by defective DNA synthesis ▪ Decreased serum hemoglobin and hematocrit related to decreased number of circulating RBCs ▪ Markers of hemolysis ▫ Increased lactate dehydrogenase (LDH) ▫ Increased serum unconjugated bilirubin ▫ Decreased haptoglobin ▪ Decreased serum B12 and/or folate levels ▪ Increased homocysteine or methylmalonic acid are also evidence of B12 deficiency TREATMENT MEDICATIONS ▪ Supplementation: increased dietary vitamin B12 and/or folate when indicated ▫ Parenteral vitamin B12 if pernicious anemia ▫ Dietary vitamin B12 found in animal products ▫ Folate found in both plant, animal products, esp. dark green leafy vegetables

Chapter 50 Macrocytic Anemia Figure 50.1 A hyperlobated neutrophile in a peripheral blood smear; a characteristic feature of megaloblastic anemia. Figure 50.2 An erythrocyte displaying a Cabot ring and basophilic stippling. These features represent disordered erythropoiesis and are seen in many conditions, including megaloblastic anemias. SIDEROBLASTIC ANEMIA osms.it/sideroblastic-anemia PATHOLOGY & CAUSES ▪ Anemias caused by altered mitochondrial function and defects in heme synthesis within erythroid cells TYPES Congenital forms ▪ Involve inheritance patterns affecting nuclear/mitochondrial genes encoding for erythrocyte synthesis—X-linked/autosomal recessive/mitochondrial inheritance patterns ▫ Syndromic: presents with clinical manifestations of anemia along with effects on other organ systems (e.g. exocrine pancreatic insufficiency, sensorineural deafness, hepatic/renal failure, myopathy) ▫ Non-syndromic: main features associated with anemia, iron overload Acquired forms ▪ Clonal: myelodysplastic syndromes/ myeloproliferative neoplasms alter erythrocytes, granulocytes, platelets ▪ Reversible (metabolic): caused by exposure to a substance (e.g. excessive alcohol/drugs such as isoniazid, chloramphenicol; copper deficiency/zinc overload) Both congenital & acquired ▪ Impaired erythropoiesis, hemoglobin synthesis → reduced iron in RBCs + defective RBCs undergo apoptosis within bone marrow + fewer functional RBCs in circulation → anemia ▪ Circulating RBC morphology: microcytic/ dimorphic (normocytic-to-macrocytic) COMPLICATIONS ▪ Systemic effects of heme synthesis defects include impaired utilization of iron → accumulation in mitochondria → systemic iron overload → complications from hemochromatosis (e.g. diabetes, cardiac OSMOSIS.ORG 411

▪ ▪ ▪ ▪ pathology) ▫ Repeated blood transfusions add to iron overload Anemia-induced acceleration of erythropoiesis → erythroid hyperplasia of bone marrow Increased risk of infection Acute leukemia develops in some cases Infection possibly fatal Complete blood count ▪ Decreased serum hemoglobin ▪ Decreased RBC count ▪ Decreased/low reticulocyte count—related to ineffective erythropoiesis Iron studies ▪ Hemochromatosis Genetic testing SIGNS & SYMPTOMS ▪ Presentation variable depending on cause ▪ Clinical manifestations of decreased oxygen-carrying capacity of RBCs and hypoxia (e.g. fatigue, dyspnea, palpitations, pallor; mild jaundice if hemolysis significant) ▪ Erythropoietic hemochromatosis will manifest as varying degrees of iron overload (e.g. hepatosplenomegaly, cardiac arrhythmias, heart failure) DIAGNOSIS LAB RESULTS Bone marrow aspirate smear ▪ Presence of sideroblasts confirms diagnosis ▫ Prussian blue stain reveals iron ring around nucleus TREATMENT ▪ If sideroblastic anemia acquired, cause is reversible with treatment MEDICATIONS ▪ X-linked sideroblastic anemia: vitamin B6 (pyridoxine) SURGERY ▪ Reduce organ damage secondary to iron overload ▫ Mild anemia: therapeutic phlebotomy OTHER INTERVENTIONS ▪ Reduce organ damage secondary to iron overload ▫ Mild anemia: therapeutic phlebotomy ▫ Chelation therapy (e.g. deferoxamine) RBC indices ▪ Low MCH ▪ MCV may be low/normal/high ▫ Acquired sideroblastic anemias often produce macrocytic erythrocytes ▫ Hereditary sideroblastic anemias produce microcytic erythrocytes Blood smear analysis ▪ Anisocytosis ▪ Poikilocytosis ▪ Micro/macrocytosis ▪ Hypochromic erythrocytes ▪ Iron-containing inclusions (Pappenheimer bodies) may be present 412 OSMOSIS.ORG Figure 50.3 An erythrocyte displaying a Cabot ring and basophilic stippling. These features represent disordered erythropoiesis and are seen in many conditions, including megaloblastic anemias.