Anemia of Chronic Disease & Sideroblastic Anemia PDF

Anemia of Chronic Disease & Sideroblastic Anemia Salah Eldin Khairallah, MD, PhD University of Tobruk, School of Medicine 2021-07-26 Interpretation of Iron related investigations Serum Iron Total Iron-Binding Capacity Iron that...

Anemia of Chronic Disease & Sideroblastic Anemia Salah Eldin Khairallah, MD, PhD University of Tobruk, School of Medicine 2021-07-26 Interpretation of Iron related investigations Serum Iron Total Iron-Binding Capacity Iron that is bound to transferrin. Normal (TIBC) serum iron level is ~100 μg/dL. Transferrin is the binding protein of iron and is synthesized in the liver TIBC correlates with transferrin. Amount of iron coming into the Normal TIBC is ~300 μg/dL macrophage is equal to the amount of iron leaving the macrophage to bind with Decreased ferritin stores leads transferrin to increased liver synthesis of Decreased serum iron occurs in iron transferrin deficiency (IDA) Increased serum iron occurs in iron In iron deficiency there is an overload diseases sideroblastic anemia Increase in transferrin and TIBC and hemochromatosis Interpretation of Iron related investigations Ferritin Ferritin is a soluble iron-binding storage protein. Hemosiderin Synthesized by bone marrow macrophages and hepatocytes Is an insoluble product of ferritin degradation in Keeps iron in a non-toxic form and macrophages are the lysosomes primary storage site for ferritin (from senescent RBCs) in the bone marrow Decreased and increased 1 μg/L of serum ferritin correlates with 8 mg of storage levels of hemosiderin iron correlate with changes in the Synthesis of ferritin in macrophages and hepatocytes ferritin stores in the bone increases in inflammation due to the release of marrow macrophages interleukin-6 Decrease in serum ferritin is diagnostic of iron deficiency Hemosiderin stains blue with Increase serum ferritin happens in Anemia of Chronic Prussian blue stain Diseases (ACD) and iron overload disease such as hemosiderosis, hemochromatosis 3. Red blood cell distribution Mean Corpuscular width (RDW) Hemoglobin Concentration Is an index which reflects any significant variation in size of the peripheral blood (MCHC) RBCs. Size variation is called Is the average Hb concentration in RBCs anisocytosis. 1. Decreased MCHC correlates with The value is only significant if it is decreased synthesis of Hb, such as increased. microcytic anemias (e.g., iron Example: Increased if RBCs which are deficiency), typically there is less Hb not uniformly the same size in RBC (hypochromasia) 2. Increased MCHC hereditary Example: such as mixture of microcytic spherocytosis. Spherocytes lack the and normocytic cells like what happens central area of pallor, which is called in iron deficiency anemia hyperchromasia or Hyperchromia Hematological Cluster of Differentiation Markers “CDs”  Example: PBS in Microcytic Hypochromic in Iron Deficiency  Pathophysiology of Microcytic Anemias Including Sideroblastic Anemia Decrease in hemoglobin synthesis is the hallmark of all microcytic anemias This is usually due to decrease synthesis of: a) Heme b) Globin chains  Anemia of Chronic Disease (ACD) Is the second commonest anemia after iron deficiency anemia Most common anemia in hospitalized patients Etiology of Anemia of chronic disease (ACD) 1. Chronic inflammation/Infections. Examples rheumatoid arthritis, tuberculosis (TB), and Crohn disease and chronic renal disease 2. Alcoholism. ACD is the most common anemia in alcoholics 3. Malignancy. ACD is the most common anemia in malignancy patients Regulation of iron absorption Pathogenesis of ACD A. Decreased heme synthesis B. Decreased renal production and/or response to Erythropoietin “EPO” C. Increased liver synthesis and release of hepcidin Comparison Between IDA and ACD Side of Comparison Fe+2 (Iron) Deficiency ACD Anemia (IDA) Serum Fe+3 Low Low TIBC High Low Transferrin Saturation Low Low/Normal Serum Ferritin Low Normal/High  Anemia of Chronic Disease (ACD) Laboratory findings and Peripheral Blood Morphology Treatment of ACD I. ACD is rarely < 9 g/dL II. Decreased serum iron, TIBC, and percent iron saturation 1. Treat the underlying disease III. Normochromic and normocytic (NCNC) with causing the inflammation normal MCV” 2. EPO (Injectable IV. When associated with renal disease, it may be Erythropoietin) in chronic moderately macrocytic (MCV is mildly high) renal impairment to V. When associated with chronic inflammatory states (e.g.,rheumatoid arthritis and Crohn increases Hb concentration disease), and accompanied by decreased serum 3. Hepcidin antagonists (recent iron and hypochromia and microcytosis, treatment modality) mimicking IDA; however, in contrast to IDA, TIBC is characteristically low  Laboratory Studies Used to Differentiate Microcytic Anemias “Hemoglobin Electrophoresis NEEDED HERE” TIBC: Total Iron Binding Capacity, ACD: Anemia Of Chronic Disease Salah Eldin Khairallah, MD, PhD Muir's Textbook of Pathology, Fifteenth Edition – Herrington, 2014 2016 Lecture Note, Tobruk Medical School  Pathophysiology of Microcytic Anemias Including Sideroblastic Anemia Decrease in hemoglobin synthesis is the hallmark of all microcytic anemias This is usually due to decrease synthesis of: a) Heme b) Globin chains  Sideroblastic Anemia Sideroblasttic Anemia is an iron-overload type of anemia. A defect in heme synthesis within the mitochondria of developing RBCs in the bone marrow leading to (microcytic anemia with ringed sideroblasts Causes 1. Chronic alcoholism (most common cause) Ringed sideroblasts 2. Pyridoxine (vitamin B6) deficiency 3. Lead (Pb) poisoning 4. X-linked recessive (XR) inheritance sideroblastic anemia Pathogenesis Heme which is the end product of porphyrin synthesis has a negative feedback relationship with δ-aminolevulinic acid synthase (ALA) Iron accumulates in mitochondria, which produces ringed sideroblasts  Sideroblastic Anemia, Pathogenesis Iron stores increase markedly in the bone marrow macrophages Sideroblasts die in the marrow (ineffective erythropoiesis) and phagocytosed by macrophages, which leads to excess iron stores 1. Chronic alcoholism related Sideroblastic Anemia Sideroblastic anemia is present in ~ 30% of hospitalized chronic alcoholics Alcohol is a mitochondrial toxin (poison) damaging mitochondrial heme biosynthetic pathways 2. Pyridoxine deficiency related Sideroblastic Anemia Vitamin B6 is a cofactor for δ-AminoLevulinic Acid (ALA) synthase, the rate-limiting reaction of heme synthesis Most common cause of deficiency is isoniazid (INH) therapy for TB. INH inactivates pyridoxine  Sideroblastic Anemia, Morphology Ringed sideroblasts in a bone marrow aspirate Note the dark blue iron granules around the nucleus of developing normoblasts (arrows) represent iron trapped within mitochondria Sideroblastic Anemia is due to a defect in mitochondrial heme synthesis  Lead (Pb) Poisoning and Sideroblastic Anemia Affects more children ages 1-5 years old. Lead can crosses placenta and insults baby Causes of lead poisoning 1. Pica (abnormal craving) for eating lead-based paint. Apartments built before 1950, when lead-based paints were primarily used 2. Homemade pottery glazes (hand crafts) used commercially Peripheral blood with coarse basophilic stippling of RBC in lead poisoning. These RBC with numerous dots represent ribosomes (arrow). Lead denatures ribonuclease; Lead poisoning produces a blue hence the ribosomes persist in the cytoplasm line at the gum margin of the teeth Laboratory Findings in the Common Types of Microcytic Anemias Megaloblastic And Aplastic Anemias Salah Eldin Khairallah, MD, PhD University of Tobruk, School of Medicine 2021-07-26  Megaloblastic Anemia Megaloblastic anemias are defined by large, abnormal-appearing erythroid precursor cells (megaloblasts) in the bone marrow typically due to deficiency of vitamin B12 or folate Pathogenesis: Decreased DNA synthesis, with a consequent delay in DNA replication and nuclear division, BUT with normal cytoplasmic maturation Morphologically: Nuclear-Cytoplasmic Asynchrony of large erythroid precursor cells with an open, loose-appearing chromatin pattern The final result is impaired red cell production; to a lesser degree, red cell destruction occurs within the bone marrow prior to release of mature erythrocytes into the peripheral blood (ineffective erythropoiesis) The Roles of Vitamin B12 and Folate in DNA Synthesis  Megaloblastic Anemia, Laboratory Abnormalities 1. Peripheral blood and bone marrow findings are identical in all forms of megaloblastic anemias 2. Vitamin B12 and folate levels are necessary to define the specific disease entity of megaloblastic anemia 3. Peripheral blood i. Pancytopenia (decreased red cells, white cells, and platelets) ii. Oval macrocytosis: Mean corpuscular volume (MCV) is often greater than 110 (normal about 80-100) iii. Hypersegmented neutrophils (more than five lobes) 4. Bone marrow: megaloblastic hyperplasia  Pernicious Anemia Very Common cause of vitamin B12 deficiency in older individual Autoimmune gastritis leading to lack of gastric intrinsic factor and failure of vitamin B12 absorption; and delayed DNA replication Autoimmune gastritis (type I gastritis) with destruction of gastric fundus parietal cells associated with lack of intrinsic factor (IF) Investigations 1. Peripheral Blood Smear: pancytopenia, oval macrocytes, hypersegmented neutrophils and megaloblastic hyperplasia 2. Stomach: Achlorhydria; anti-intrinsic factor antibodies Clinically: A. Subacute combined degeneration of spinal cord B. Peripheral neuropathy C. Hyperreflexia, absent position and vibration sensations D. Abnormal Schilling test Impaired vitamin B12 absorption corrected by intrinsic factor Tractology Of The Spinal Cord  Vitamin B12 Deficiency SubAcute Combined Degeneration (demyelination) (SACD) of spinal cord A. Posterior column dysfunction decreases vibratory sensation and proprioception (joint sense) B. Lateral corticospinal tract dysfunction produces spasticity C. Dorsal spinocerebellar tract dysfunction causes ataxia Subacute Combined Degeneration (SACD) of the spinal cord Note the pale areas of demyelination in the posterior columns and the lateral corticospinal tracts  Folic Acid (Folate Deficiency) Anemia Similar to vitamin B12 deficiency folate deficiency, predisposes to megaloblastic anemia but no neurologic abnormalities (in contrast to vitamin B12 deficiency) Mechanisms of Folate deficiency leading to megaloblastic anemia 1. Severe dietary deprivation: in chronic alcoholics or fad dieters 2. Pregnancy: an additional fetal demands and borderline maternal diet 3. Phenytoin: interferes with the absorption of folate 4. Oral contraceptive pills 5. Folic acid antagonist chemotherapy such as methotrexate 6. Relative folate deficiency increased demand because of compensatory accelerated erythropoiesis in hemolytic anemia 7. Intestinal malabsorption syndromes caused by: - Sprue - Giardia lamblia infection  Clinical Feature of B12 Deficiency 1. Symptoms and signs of anemia 2. Glossitis associated with a smooth, sore tongue and atrophy of the papillae 3. Neurologic disease associated with demyelination a) Peripheral neuropathy with sensorimotor dysfunction b) Subacute combined degeneration (SACD) (demyelination) of spinal cord B, Glossitis in vitamin B12 c) Dementia from cerebral involvement deficiency d) 20% of patients have neurologic disease This patient with untreated pernicious without anemia anemia developed the so typically described as (Beefy tongue)  Laboratory Findings in Vitamin B12 Deficiency 1. Decreased serum vitamin B12 2. Increased serum homocysteine and methylmalonic acid 3. Peripheral blood smear include: i. Pancytopenia ii. Oval (egg-shaped) macrocytes iii. Hypersegmented neutrophils: neutrophils have more than five nuclear lobes Pernicious Anemia Lemon Tinge Pallor 4. Bone marrow Typical lemon-yellow skin color of a woman Megaloblastic nucleated cells are present with with pernicious anemia and severe a primitive open (lacy) chromatin pattern megaloblastic anemia. The color is from the combination of pallor (from anemia) and jaundice (from ineffective erythropoiesis) 5. Schilling test: to localize the reason of B12 deficiency due to intrinsic factor deficiency Megaloblasts, Bone Marrow Aspirate Hypersegmented “Polymorphonuclear Note the open chromatin pattern and enlarged nuclei Leukocytes”, Megaloblastic Anemia of red blood cell and white blood cell precursors Normal neutrophils have three to five lobes. In indicating a lack of nuclear maturation megaloblastic anemias the number is often increased Clinical and Laboratory Findings in Vitamin B12 and Folic Acid Deficiencies Peripheral Blood Smear in Different Subtypes Of Anemia  Where is the M A R R O W? VERY EARLY EMBRYO: Yolk Sac NEWBORN: Liver, Spleen: NEWBORN BONE CHILDHOOD: AXIAL SKELETON & APPENDICULAR SKELETON BOTH HAVE RED (active) MARROW ADULT: AXIAL SKELETON RED MARROW, APPENDICULAR SKELETON YELLOW MARROW Aplastic Anemia To Diagnose Aplastic Anemia, there should be: 1. Characteristically there is markedly hypocellular bone marrow with almost total loss of hematopoietic cells, including the three (3) hematopoietic series: erythroid myeloid precursor cells and megakaryocytes Aplastic Anemia The marrow is “empty” Spicules of bone 2. Peripheral blood showed pancytopenia and substitution of numerous fat cells for (anemia, leukopenia, and the normal cellular bone marrow thrombocytopenia) and reticulocytopenia  Aplastic Anemia, Etiology 1. Immunologic alterations in myeloid stem (progenitor) cells, causing T- cell activation and release of cytokines that suppress or destroy the myeloid stem cells 2. Mutations in TERT, the gene for the RNA component of telomerase, cause short telomerases in congenital aplastic anemia and some acquired causes Normal bone marrow Bone Marrow in patient with Aplastic Anemia. See normal reference bone marrow, left Aplastic Anemia, Etiology  Aplastic Anemia, Clinical Features Clinical findings in aplastic anemia Fever, due to infection associated with neutropenia Bleeding, due to thrombocytopenia Fatigue, breathlessness due to anemia Laboratory in Aplastic Anemia PBS: Pancytopenia, reticulocytopenia Bone marrow hypocellular bone marrow Lymphocytes are present in the marrow and peripheral blood, because the pluripotential stem cell is proximal to the myeloid progenitor stem cell Prognosis: complete recovery occurs in