Hematology - 09 Impaired or Defective Production Anemia

HEMATOLOGY CAUSES OF IRON-DEFICIENCY ANEMIA IMPAIRED OR DEFECTIVE PRODUCTION ANEMIA • OUTLINE • • • • Introduction o Factors associated with Anemia due to Impaired or Defective Production Disorders of Iron Metabolism and Heme Synthesis o Iron Deficiency Anemia o Sideroblastic Anemia o Iron Overload o Anemia of Chronic Disease o Iron Studies Bone Marrow Failure o Aplastic Anemia o Pure Red Cell Aplasia (PRCA) Defects of DNA Metabolism o Megaloblastic Anemia • INTRODUCTION FACTORS ASSOCIATED WITH ANEMIA DUE TO IMPAIRED OR DEFECTIVE PRODUCTION • • • Disorders of Iron Metabolism and Heme Synthesis o Iron Deficiency Anemia o Sideroblastic Anemia o Anemia of Chronic Disease o Iron overload Bone Marrow Failure o Aplastic Anemia Defects of DNA metabolism o Megaloblastic Anemia o Non-megaloblastic anemia o Macrocytic, Normochromic Anemias • DISORDERS OF IRON METABOLISM AND HEME SYNTHESIS IRON DEFICIENCY ANEMIA • • • • Most common anemia (US) Insufficient iron for high synthesis Inadequate intake, increases need, impaired absorption or chronic blood loss May arise from: o Pregnancy (requires higher iron to supply for the baby) o Normal growth (RBC increases as body mass increase; requiring more iron) o Menstruating women, Blood loss, Intravascular hemolysis (iron is excreted with blood loss) o GI disorders (tumors, ulcers, hemorrhoids, aspirin ingestion, alcoholism) ▪ Tumor, ulcers, hemorrhoid - blood loss from bleeding ▪ Aspirin & alcoholism - cause gastritis leading to chronic bleeding o Parasitic infections (T. trichiura, hookworms, S. haematobium, S. mansoni) o March hemoglobinuria (Marching/Runner’s anemia) ▪ Condition seen among runners, soldiers, athletes subjected to strenuous physical exercise ▪ Exercise-induced hemoglobinuria ▪ Occurs from foot-pounding trauma • • Inadequate Intake o Loss of iron (~1mg/day) ▪ Due to skin or intestinal lumen desquamation ▪ Iron - removed through desquamation/shedding of enterocytes where ferritin is located o Iron replacement: 1 mg/day ▪ Hgb are liberated from lysed RBC which are bound to transferrin for transfer to bone marrow or storage ▪ Can be acquired through diet o The body can conserve iron but it is not sustainable o Inadequate iron over time will lead to depleted iron stores → inability to produce Hb Increased Need o When iron intake becomes inadequate to meet the needs of expanding erythron o Rapid growth: infancy, childhood, adolescence ▪ Period of rapid growth ▪ As body grows, RBC mass expands which requires higher Hb needing iron for sythesis o Pregnancy (Supplies iron to mother and fetus) Impaired Absorption o Failure to absorb iron intake/absorption o Malabsorption (celiac disease) ▪ Celiac disease - autoimmune disease of the small intestines; Ab are against small intestine • Impairs the function of small intestine o Matriptase-2 protein mutation ▪ Cause increased hepcidin • Hepcidin - negative iron regulator which binds ferroportin and degrades it o Ferroportin - important in transporting/ exporting iron from enterocyte to circualtion • Increased binding to ferroportin which increases its degradation which decreases the release of iron o Decreased stomach acidity ▪ Acidity of stomach is an important factor for the conversion of ferric to ferrous iron ▪ Few ferric iron are converted to ferrous (only absorbable form of iron) o Drugs (stomach acid reducers) Chronic Blood Loss o Common cause of excessive iron loss o Bleeding in small-moderate amount for long periods o Excessive loss of Hb in the body: slow hemorrhage or hemolysis o Heavy menstrual bleeding, fibroid tumors, GI bleeding bec of ulcers and tumors, kidney stones, and PNH Clinical Symptoms: o Fatigue, dizziness, pallor ▪ Pallor in conjunctiva nailbed, o Pica ▪ Craving for non-food items (dirt, clay, laundry starch, ice) ▪ Pagophagia - craving for ice o Angular cheilosis (Perleche, angular stomatitis) ▪ Presence of cracks at the corner of mouth o Glossitis ▪ Sore tongue o Koilonychia ▪ Spooning of fingernails • • Laboratory Findings (Screening): o RBC count, hemoglobin, hematocrit: Decreased o RBC indices: decreased o RDW: >15% o RBC: Microcytic, hypochromic o Reticulocyte count: decreased o Poikilocytosis (target cells, elliptocytes) o Thrombocytosis (chronic bleeding) Peripheral Smear: o Ring/Ringed Sideroblast ▪ Erythroblasts w/ iron deposits surrounding nucleus ▪ Observed in bone marrow ▪ Hallmark of sideroblastic anemia when present in bone marrow smear ▪ Stain: Prussian blue o Siderocyte/Pappenheimer Body ▪ Iron accumulation in mature RBCs ▪ Stain: • Perl’s Prussian Blue (siderocyte) • Wright Stain (Pappenheimer body) o RBC: Microcytic, Hypochromic SIDEROBLASTIC ANEMIA • • • • • Blocks in protoporphyrin pathway (heme synthesis pathway) - Impairs production of heme Iron overload in bone marrow o Iron only binds to protoporphyrin IX to form heme o Iron accumulation due to lack of binding Is a group of disorders Hereditary (X-linked, autosomal) o Porphyrias Acquired o Primary Sideroblastic Anemia (RARS) ▪ Refractory Anemia with Ringed Sideroblast o Secondary Sideroblastic Anemia ▪ Lead ▪ Antitubercular drugs ▪ Chloramphenicol ▪ Alcohol ▪ Chemotherapeutic drugs LEAD POISONING (PLUMBISM) • • • • • Acquired sideroblastic anemia Lead: o Interferes with conversion of aminolevulinic acid (ALA) to porphobilinogen ▪ Affects the action of ALA dehydratase o Interferes with incorporation of iron and protoporphyrin ▪ Affects the action of ferrochelatase o Inhibits pyrimidine 5’-nucleotidase ▪ Accumulation of substrate which precipitates causing coarse basophilic stippling o Can cause multiple blocks in heme synthesis pathway Mostly in children o Exposure to lead-based paint/materials Clinical symptoms: abdominal pain, muscle weakness, and gum lead line that forms from blue/black deposit of lead sulfate Laboratory Findings: o RBC: ▪ Initially: normocytic; normochromic ▪ Chronic exposure: microcytic, hypochromic ▪ Basophilic stippling o Urine ALA: Increased (due to interference in conversion) o RBC Protoporphyrin: Increased ▪ Measured using FEP (Free Erythrocyte Protopophyrin) ▪ Zinc protoporphyrin (may cause fluorescence) ▪ Utilize hemato fluorometer PORPHYRIA • • • Porphyra - purple o Due to wine-red color of urine of patients Group of inherited disorders characterized by impaired protoporphyrin production Clinical Symptoms: o Photosensitivity - deposition of porphyrins (substrates) that produce fluorescence ▪ Can cause serve burns upon sunlight exposure o Fluorescence in teeth and bone o Psychosis ▪ Generally associated with vampire legends o Wine-red color of urine ANEMIA OF CHRONIC DISEASE • • • • Enzyme affected Congenital Erythropoietic Porphyria (CEP) – Gunther’s Disease Uroporphyrinogen III synthase deficiency Inheritance Autosomal recessive Erythropoietic Protoporphyria (EPP) Ferrochelatase deficiency • Autosomal recessive Photosensitivity, Photosensitivity, mild mild anemia anemia (microcytic, hypochromic) Clinical Skin redness, hemolytic Symptoms anemia, skin photosensitivity, splenomegaly Porphyrins ↑↑↑ Uroporphyrinogen I ↑↑↑ Free (RBC) ↑↑ Coproporphyrinogen I Protoporphyrin • X-linked Erythropoietic Protoporphyria (XLEPP) ALA-synthase (gainof- Function; more rapid function) X-linked IRON OVERLOAD • • • • • HEREDITARY HEMOCHROMATOSIS • • • • • Most common form of iron overload disease Caused by mutation in HFE gene o Regulates the amount of iron absorbed from food o Mutation increases absorption of iron (can be toxic to pancreas which can lead to diabetes) Aka Bronze diabetes Clinical Symptoms: arthritis, liver cirrhosis, congestive heart failure, impotence, bronze skin, diabetes, thyroid deficiency Treatment: Phlebotomy o Extract blood to reduce iron Laboratory Findings: o RBC: normocytic, normochromic or slightly microcytic, hypochromic anemia o Hemoglobin: Decreased o ESR: Increased o Ferritin: Normal to increase o Serum Iron and TIBC: low IRON STUDIES ↑ Free protoporphyrin CEP, EPP, XLEPP - hematologic porphyria o Cutaneous porphyria due to photosensitivities New term: Anemia of Chronic inflammation Inability to use iron (stored) o Due to inflammation Increased level of Hepcidin o Negative iron regulator that regulates iron absorption by degrading ferroportin o Positive acute phase reactant (↑ in inflammation) o Increased levels do not release iron Associated with: o Infections (HIV, TB) o Inflammation (RA, SLE) o Malignancies (Cancer, Hodgkin Lymphoma) • • • Backbone of iron metabolism defects Used for diagnosing defects in iron metabolism Helpful in differentiating microcytic, hypochromic anemia Serum Iron – measure of iron bound to transferrin Total Iron Binding Capacity (TIBC) – indirectly measures transferrin concentration by measuring its ability to bind iron o inc. bound iron/serum iron = dec. TIBC o measures unbound iron Transferrin Saturation (% Saturation) – percentage of iron binding sites occupied by iron Serum Ferritin – reflection of body’s tissue iron stores o Main storage form of iron o Generally, the first laboratory test that declines after iron deficiency Free Erythrocyte Protoporphyrin (FEP) – measurement of protoporphyrin without iron. o Measures as zinc protoporphyrin (ZPP) using hematofluorometer o Zinc binds to free protoporphyrin Serum Serum Transferrin TIBC FEP/ZPP Iron Ferritin Saturation IDA Low Low High Low High Sideroblastic High High Normal/ High High Anemia Low Lead Variable Normal Normal Normal High Poisoning ACD/ACI Low Normal/ High Low Low High Thalassemia Normal/ Normal/ High Normal High/ Normal High Normal Normal Hypocellular (patchy, lacking) BONE MARROW FAILURE APLASTIC ANEMIA • • • • • • Fatal bone marrow failure syndrome No response in erythropoietin Features: o Pancytopenia ▪ Decrease of all blood cells (RBC, WBC, plt) o Reticulocytopenia ▪ Decreased reticulocyte due to shortage of reticulocyte synthesis in bone marrow o Bone Marrow Hypocellularity ▪ Decrease in components of bone marrow that can produce blood cells (red marrow) ▪ May lead to pancytopenia o Depletion of hematopoietic stem cells Etiology: o Acquired (80-85%) o Inherited (15-20%) Etiologic Classification of Aplastic Anemia o Acquired (80-85%) ▪ Idiopathic (70% of acquired cases) ▪ Secondary (10-15% of acquired cases) • Dose dependent/predictable (cytotoxic drugs, benzene, radiation) • Idiosyncratic o Drugs o Chemicals (insecticides, cutting/lubricating oils) • Viruses o Epstein-Barr virus o Hepatitis virus (non-A, non-B, non-C, non-G) o Human Immunodeficiency virus (HIV) • Miscellaneous conditions o Paroxysmal nocturnal hemoglobinuria o Autoimmune diseases o Pregnancy o Inherited (15-20%) ▪ Fanconi anemia ▪ Dyskeratosis congenita ▪ Shwachman-Diamond syndrome Laboratory Findings: o RBC: normocytic, normochromic o Hgb: decreased (<10 g/dL) o Retics: decreased o WBC: decreased o Platelets: decreased o Bone Marrow: ▪ Severely Hypocellular ▪ Decreased to absent erythroid, granulocytic and megakaryocytic cells, precursor & progenitor cells INHERITED APLASTIC ANEMIAS • • • Fanconi Anemia – characterized by aplastic anemia, physical abnormalities and cancer susceptibility o Clinical features: Low birth weight, skin hyperpigmentation (café-au-lait spots), and short stature o Can be associated w/ dwarfism Dyskeratosis congenita – characterized by pancytopenia, mucocutaneous abnormalities, and bone marrow failure Shwachman-Bodian-Diamond Syndrome – characterized by pancreatic insufficiency, cytopenia, skeletal abnormalities, and hematologic malignancies o Peripheral Smear: Neutropenia, pancytopenia (25%) ▪ Rare occurrence of pancytopenia (25% of cases) ▪ Neutropenia - decreased neutrophil; most common manifestation PURE RED CELL APLASIA (PRCA) • • • Erythropoietic disorder o Decreased RBC (normal WBC & plt) May be acquired or inherited o Acquired – transient erythroblastopenia of childhood o Inherited – Diamond-blackfan anemia (congenital PRCA) Laboratory Findings: o RBC: Normocytic, normochromic (macrocytic) o Reticulocytes: decreased o WBC and platelets: Normal o Bone Marrow: Erythroid hypoplasia ▪ Higher myeloid to erythroid ratio (↑ myeloid) DEFECTS OF DNA METABOLISM • • Macrocytic, normochromic anemias Can be megaloblastic & non-megaloblastic MEGALOBLASTIC ANEMIA • • • Defective DNA synthesis (RNA synthesis unaffected) Caused by Vitamin B12 (cobalamin) and folate deficiency Presence of nuclear-cytoplasmic asynchrony o Found in bone marrow o Nuclear-cytoplasmic asynchrony - growth of nucleus & cytoplasm is asynchronous o Growth of nucleus of diminished (lower rate of maturation) ▪ Cause faster cytoplasm maturation o Normal maturation of cytoplasm o Due to defect in DNA synthesis • • • Peripheral Smear: o RBC: macrocytic; normochromic with o Oval macrocytes, teardrops/dacryocytes o Howell-Jolly Bodies o nucleated RBC o basophilic stippling o Pappenheimer bodies o Cabot Rings o Hypersegmented neutrophils (5-10 lobes) • Laboratory Findings: o Hemoglobin, Hematocrit: Decreased o Retics count: Decreased o Lactate dehydrogenase: Increased o Total and Indirect Bilirubin: Increased o Iron: Increased o Chemistry tests similar with hemolytic anemia ▪ Due to RBC enzyme lactate dehydrogenase mostly found in RBC ▪ RBC liberates content and degradation during hemolysis Can be similar with hemolytic anemia o Due to release of defective cells from defective DNA synthesis o Defective cells undergo apoptosis which liberates their content FOLIC ACID DEFICIENCY VITAMIN B12 (COBALAMIN) DEFICIENCY • • • aka Pernicious anemia, Addison’s anemia Causes: o Intrinsic factor deficiency ▪ Intrinsic factor - produced are gastric parietal cells which binds B12 from diet before absorption • Deficiency cause inability to absorb vit. B12 ▪ Autoimmune deficiency (pernicious anemia) • Body produce antibody against intrinsic factor or against gastric parietal cells that produce IF ▪ H. pylori infection - Cause peptic ulcer o Malabsorption, Diphyllobotrium latum infection, total gastrectomy, total vegetarian diet ▪ Malabsorption - ineffective absorption of vit B12 ▪ D. latum - competes w/ intestine on vit B12 absorption ▪ Diet - vit. B12 is only acquired from animal products Clinical findings: o Pernicious anemia o Achlorhydria ▪ Absence of gastric acid (HCl) ▪ Due to gastric parietal cells’ inability to produce gastric acids o Weakness and numbness o Sore tongue (glossitis) o GI disorders o CNS problems • • • • Laboratory Findings: o Hgb, Hct, RBC: decreased o RBC indices: decreased Peripheral Smear: o Macrocytosis, Anisocytosis, Poikilocytosis o Basophilic stipplings o nRBC o Hypersegmented neutrophils o Bone Marrow: dominated with megaloblastic cells (due to nuclear cytoplasmic asynchrony) Causes: o Poor dietary intake o Malabsorption syndrome o Pregnancy o Drugs: Methotrexate (chemotherapeutic drug that antagonizes folic acid) ▪ Destroys cancer cells by decreasing DNA synthesis rate of cancer cells ▪ Also affect normal cells causing megaloblastic anemia Clinical Findings: o Similar to pernicious anemia (without CNS involvement) Laboratory Findings and Blood picture: o Similar to pernicious anemia (Vit. B12 deficiency) o Decreased Folic Acid MEGALOBLASTIC VS NON-MEGALOBLASTIC MEGALOBLASTIC NON-MEGALOBLASTIC Vitamin B12 deficiency Liver disease Folic acid deficiency Alcoholism Pernicious anemia Bone marrow failure Hypersegmented Present Absent Neutrophils Shape of Oval Round Macrocytes MCV ≥120 fL 100-110 fL • Non-megaloblastic - not from DNA metabolism defect o Rarely exceed 120fL MCV Causes