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anemia_06-07_mod.ppt anemia_06-07_mod.ppt Presentation Transcript

  • ANEMIA Masatoshi Kida, M.D. Dept. of Pathology University of Vermont
  • ANEMIA
    • any condition in which the number of red cells , the amount of hemoglobin or the volume of packed red blood cells per unit volume is less than normal.
    • a pathophysiological condition in which the body cannot meet its demands for oxygen.
  • Blood Reference Values WBC 4,800-10,800/mm 3 RBC M: 4.7-6.1 mil/mm 3 F: 4.2-5.4 mil/mm 3 ( or x 10 6 /  L) Plt 130,000-400,000/mm 3 Hgb M: 14.0-18.0 g/dL F: 12.0-16.0 g/dL Hct M: 42-52% F: 37-47% MCV [= Hct(%) / RBC count(x10 6 /  L)/10] 80-100  3 (or fL) MCH [= Hgb(g/dL) / RBC count(x10 6 /  L)/10] 27-33 pg MCHC [= Hgb(g/dL) / Hct(%)/100] 32-36 g/dL RDW 8.5-11.5 % reticulocyte (absolute number) 40,000-100,000 /  L
  • Erythrocyte Indices
    • Hemoglobin (Hgb)
    • Hematocrit (Hct)
    • Mean Corpuscular Volume (MCV)
    • Mean Corpuscular Hemoglobin (MCH)
    • Mean Corpuscular Hemoglobin Concentration (MCHC)
    • Red Cell Distribution Width (RDW)
    • [Packed Cell Volume (PCV)]
  • RBC “rule of 3’s”
    • For normal erythrocytes:
      • hemoglobin (g/dL)  3 x RBC count (millions)
      • hematocrit (%)  3 x hemoblobin (g/dL)  3%
    • Failure to obey this “rule of 3’s” suggests an abnormality in erythrocytes (sickle cells, etc)
  • classification of anemia by color
    • hypochromic (decreased color)
      • increased central pallor
    • normochromic (normal color)
      • central pallor ~1/3 of the RBC diameter
    • hyperchromic (increased color)
      • (~spherocytosis)
      • loss of central pallor
  • anemia
    • M: Hb <13.5 Hct <41
    • F: Hb <12 Hct <36
  •  
  • ANEMIA morphologic classification microcytic MCV <80 normocytic MCV 80-100 macrocytic MCV >100
  • ANEMIA classification by volume
    • microcytic anemia (MCV <80)
    • normocytic anemia (MCV 80-100)
    • macrocytic anemia (MCV >100)
  • ANEMIA classification by volume
    • microcytic anemia (MCV <80)
      • iron deficiency anemia
      • thalassemia syndromes
      • anemia of chronic disease
      • sideroblastic anemia
  • ANEMIA classification by volume
    • microcytic anemia (MCV <80)
    • normocytic anemia (MCV 80-100)
      • anemia of blood loss
      • hemolytic anemia
  • ANEMIA classification by volume
    • microcytic anemia (MCV <80)
    • normocytic anemia (MCV 80-100)
    • macrocytic anemia (MCV >100)
      • megaloblastic anemia
  • ANEMIA classification by volume
    • microcytic anemia (MCV <80)
      • iron deficiency anemia
      • thalassemia syndromes
      • anemia of chronic disease
      • sideroblastic anemia
    • normocytic anemia (MCV 80-100)
      • anemia of blood loss
      • hemolytic anemia
    • macrocytic anemia (MCV >100)
      • megaloblastic anemia
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • a. intrinsic abnormality
        • b. extrinsic abnormality
    • II ↓ RBC production
      • 1. stem cell abnormality
      • 2. erythroblast abnormality
      • 3. unknown/multiple mechanism
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • blood loss
        • a. acute : trauma, massive hemorrhage
        • b. chronic : GI lesion, GYN lesion
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
    hereditary spherocytosis hereditary elliptocytosis
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
            • hereditary spherocytosis
            • hereditary elliptocytosis
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
    pyruvate kinase def. G6PD def.
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
            • pyruvate kinase def.
            • G6PD def.
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
    Thalassemia sickle cell disease Hb C disease
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
            • Thalassemia
            • sickle cell disease
            • Hb C disease
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
    PNH
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
            • PNH
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
          • mechanical trauma
          • chemical injury
          • infection
          • immunologic injury
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
          • mechanical trauma (microangiopathic HA)
            • TTP/HUS, DIC
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
          • mechanical trauma
          • chemical injury
            • lead poisoning
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
          • mechanical trauma
          • chemical injury
          • infection
            • malaria
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
        • extrinsic abnormality
          • mechanical trauma
          • chemical injury
          • infection
          • immunologic injury
            • autoimmune hemolytic anemia
            • drug mediated injuries
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
          • acquired memb. defect
        • extrinsic abnormality
          • mechanical trauma
          • chemical injury
          • infection
          • immunologic injury
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
    • II ↓ RBC production
      • 1. stem cell abnormality
      • 2. erythroblast abnormality
      • 3. unknown/multiple mechanism
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
    • II ↓ RBC production
      • stem cell abnormality
        • aplastic anemia
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
    • II ↓ RBC production
      • 1. stem cell abnormality
      • 2. erythroblast abnormality
        • megaloblastic anemia
        • iron deficiency anemia (defective Hb synthesis)
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
    • II ↓ RBC production
      • 1. stem cell abnormality
      • 2. erythroblast abnormality
      • 3. unknown/multiple mechanism
        • sideroblastic anemia
  • Hereditary Spherocytosis
      • intrinsic defect in the membrane cytoskeleton
      • genetic: autosomal dominant
      • pathoetiology: spectrin deficiency -> decreased RBC surface memb. -> loss of biconcavity
      • anemia: moderate anemia
      • normocytic
      • hyperchromic
      • reticulocytosis
      • entrapment of spherocytes in the spleen ( splenomegaly ) ( extravascular hemolysis )
      • increased erythrocyte osmotic fragility
  • Hereditary Spherocytosis
  • Hereditary Spherocytosis
    • Sx: 1. mild to moderate hemolytic anemia
    • 2. splenomegaly
    • 3. marked compensatory erythroid hyperplasia in BM
    • 4. jaundice, pigment cholelithiasis ← ( ↑ bilirubin )
    • 5. increased risk for acute red-cell aplasia due to parvovirus B19 infection
    • Lab: 1. increased osmotic fragility
    • 2. normal MCV with increased MCHC
    • Tx: splenectomy
  • Hereditary Elliptocytosis
      • intrinsic defect in the membrane cytoskeleton
      • genetic: autosomal dominant
      • pathoetiology: impaired aggregation of spectrin
      • anemia: 90% of pt. are non-anemic
      • non-hypochromic elliptocytes >25% (nl=<15%)
      • Sx: splenomegaly
  • Embden-Meyerhof glycolytic pathway
  • Pyruvate Kinase Deficiency
      • autosomal recessive
      • most common red cell enzyme deficiency involving Embden-Meyerhof glycolytic pathway
      • inability to maintain normal ATP levels
      • mild to moderate hemolysis
      • splenomegaly
      • patients tolerate anemia rather well (  high levels of 2,3-DPG )
      • Dx: - fluorescent spot test
      • - enzyme assay
  • X
  • fluorescent spot test
    • Pyruvate kinase catalyzes the phosphorylation of ADP to ATP with the formation of pyruvate . Pyruvate then reduces any NADH present to NAD with formation of lactate. Loss of florescence of NADH under ultra-violet light is observed as evidence of the presence of pyruvate kinase.
    phosphoenol pyruvate pyruvate lactate PK ADP ATP *NADH NAD
  •  
  • G6PD Deficiency
      • Pathophysiology: decreased half life of G6PD
      • increased vulnerability to oxidative denaturation due to limited
      • generation of NADPH (older RBCs are preferentially destroyed)
      • Genetics:
      • high genetic heterogeneity
      • x-linked recessive (  full expression in male hemizygote)
      • Sx:
      • hemolysis after exposure to oxidant stress
      • - drugs: primaquine, chloroquine, sulfonamides, nitrofurantoins
      • - infections: viral hepatitis, pneumonia, typhoid fever
      • “ favism” : hemolysis after ingestion of fava beans (Mediterranean type)
      • Lab:
      • - poikilocytes, some spherocytes
      • - Heinz bodies : precipitates of denatured hemoglobin material
      • - “bite cells”
  • G6PD Deficiency bite cell Heinz bodies
  • ANEMIA pathophysiologic classification
    • I RBC loss
      • 1. blood loss
      • 2. ↑ RBC destruction
        • intrinsic abnormality
          • membrane disorder
          • enzyme disorder
          • Hgb synthesis disorder
            • Thalassemia
            • sickle cell disease
            • Hb C disease
  • hemoglobin molecule two  chains two  chains four  -globin genes two  -globin genes
  • globin genes CH16 CH11
  • Thalassemia Syndromes
      • heterogeneous hemolytic disorders characterized by quantitative abnormalities of hemoglobin synthesis
      • genetic defect in globin production
      • selective depression or absence of a- or b- chain of hemoglobin
      • broad spectrum of presentation
      • predominantly seen in persons of Mediterranean , African and Asian ancestry
      • α -thalassemia : α -chain deficiency due to gene deletion
      • β -thalassemia : β -chain deficiency due to point mutation (Cooley’s anemia)
  • Thalassemia Syndromes pathophysiology
      • Two (2) pathological mechanisms to contribute to develop anemia
      • 1. inadequate Hgb formation  low MCHC, hypochromasia
      • 2. relative excess of unaffected Hgb chain
      •  aggregation and precipitation of excess chain
      •  damage to the cell membrane
      •  loss of K+ and impaired DNA synthesis
      •  apoptosis of RBCs in BM (“ ineffective erythropoiesis ”)
  • Thalassemia Syndromes pathophysiology
      • ineffective erythropoiesis
      • +  severe erythroid hyperplasia
      • hemolysis excess absorption of iron
      • severe iron overload
  • α -thalassemia  1  2  /  normal  1  2  /   + -thal heterozygote (mild)  1  2  /   0 -thal heterozygote (moderate)
  • α -thalassemia  1  2  /   + -thal homozygote (moderate)  1  2  /   0 -thal x  + -thal (severe)  1  2  /   0 -thal homozygote (lethal)
  • β -thalassemia
    • clinical classification of β thal is based on the severity of the anemia (based on the type of genetic defect and gene dosage )
    • β + -> some β chain production
    • β 0 -> no β chain production
    • clinical manifestation
    • homozygous ( β + / β + or β 0 / β 0 ) severe
    • heterozygous ( β + / β or β 0 / β ) mild
  • β -thalassemia promoter gene mutation: 75-80% reduction of transcription rate (  + thal) chain termination mutation: premature termination of mRNA translation (  0 thal) splicing mutation: aberrant splicing (  0 &  + thal) most common cause of thal
  • “ Thalassemia Major”
      • homozygous β + / β + or β 0 / β 0
      • severe anemia at 6 to 9 months of age requiring blood transfusion
          • death at early age, if not transfused
      • severe erythrophagocytosis and extramedullary hematopoiesis
      •  hepatosplenomegaly
      • marked red marrow expansion  “Crew-Cut” sign
      • hemosiderosis
      • heart disease 2º to hemochromatosis is the major cause of death in older patients
  • “ Thalassemia Major”
  • “ Thalassemia Major”
      • Dx:
      • anemia work up
      • hemoglobin electrophoresis  no or very low HbA
      • markedly elevated HbF
      • DNA analysis
      • Rx:
      • blood transfusion with iron chelators
        • improvement of anemia
        • suppression of secondary features related to excessive erythropoiesis
      • BM transplantation
  • “ Thalassemia Minor”
      • much more common than Thalassemia major
      • heterozygous b + /b or b 0 /b
      • peripheral smear: hypochromia, microcytosis, basophilic stippling, target cells
      • may be resistant against falciparum malaria
      • usually asymptomatic or mild anemia (microcytic anemia)
      • DDx: iron deficiency anemia
            • serum iron
            • total iron binding capacity
            • serum ferritin
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  • Sickle Cell Disease
      • prototype of hereditary hemoglobinopathies
      • structurally abnormal hemoglobin from a point mutation
  • Sickle Cell Disease
      • - severe anemia  generalized growth and developmental impairment
      • - vaso-occlusive complications
      • - painful crisis: bones, lungs, liver, brain, spleen, penis
      • - acute chest syndrome
      • - aplastic crisis
      • - sequestration crisis (splenic hyperplasia  pooling of blood)
      • - chronic hyperbilirubinemia
      • - increased susceptibility to infection  septicemia, meningitis
      • (encapsulated bacteria)
      • Dx: clinical findings
      • peripheral blood smear
      • hemoglobin analysis
  • Sickle Cell Trait
      • - heterozygous (Ss) Hb S -- 30-40%
      • - approx. 10% of American blacks
      • - normal peripheral blood count and RBC life span
      • - rare sickling with low oxygen tension, low pH
      • (local ischemia, high altitude, pneumonia, etc.)
  • Paroxysmal Nocturnal Hemoglobinuria (PNH)
      • an acquired clonal disorder of stem cells, and results from a somatic mutation in phosphatidylinositol glycan A (PIGA) gene that is essential for the synthesis of the glycosylphosphatidylinositol (GPI) anchor protein of the membrane, and makes RBCs very sensitive to complement-mediated cell lysis due to the deficiency of proteins that regulate complement activity
    GPI-linked complement reg. Proteins CD55 (DAF) CD59 CD8 binding protein
  • Paroxysmal Nocturnal Hemoglobinuria (PNH)
      • clinical:
      • - chronic hemolysis without dramatic hemoglobinuria (75%)
      • - paroxysmal and nocturnal intravascular hemolysis (25%)
      • - venous thromboses in hepatic, portal or cerebral veins
  • TTP / HUS
      • Thrombotic Thrombocytopenic Purpura (TTP)
      • Hemolytic Uremic Syndrome (HUS)
      • - widespread formation of hyaline thrombi in microcirculation
      • - endothelial injury and activation of intravascular thrombosis seem to be the initiating mechanisms
      • - may have diverse causes
      • - verotoxins ( E.coli O157:H7)
      • - viral infection
  • TTP / HUS
      • TTP (Thrombotic Thrombocytopenic Purpura)
      • adult female with pentad
      • 1. Fever
      • 2. Thrombocytopenia
      • 3. Microangiopathic hemolytic anemia
      • 4. Transient neurologic deficits
      • 5. Renal failure
      • HUS (Hemolytic Uremic Syndrome)
      • child with acute renal failure
      • microangiopathic hemolytic anemia
      • thrombocytopenia
      • no neurologic symptoms
  • Disseminated Intravascular Coagulation (DIC)
      • - an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases
      • - activation of clotting system resulting in wide spread formation of microthrombi throughout the microcirculation
      • - as a consequence, causing consumption of platelets, fibrin and coagulation factors, and activation of thrombolytic mechanism
      • Two major triggering mechanisms
      • 1. release of tissue factor or thromboplastic substance
      • 2. widespread endothelial injury
  • Disseminated Intravascular Coagulation (DIC)
      • Pathology:- wide spread thrombi
      • (brain, heart, lungs, kidneys, adrenals, spleen , liver)
      • - microinfarcts
      • Clinical: - ~50% associated with obstetric complications
      • - ~30% with carcinomatosis
      • - microangiopathic anemia
      • - dyspnea, cyanosis
      • - convulsions, coma
      • - oliguria, acute renal failure
      • - shock, circulatory failure
  • Lead Poisoning
      • - inhibition of 5’-nucleotidase and sodium-potassium pump
      •  decreased RBC survival
      • - intestinal absorption of Pb is enhanced by def. of calcium, iron or zinc
      • - blood accumulates 5-10% of absorbed Pb
      • - Pb clearance:
      • from blood  rapidly cleared
      • from bone  slow (half-life = 30 yrs)
      • Lab: basophilic stippling
  • Malaria
      • - intracellular protozoan parasite ( Plasmodium )
      • P.falciparum : worldwide infection affecting 100 million people
      • 1 to 1.5 million deaths each year
      • other malaria parasites:
      • P.vivax
      • P.ovale
      • P.malariae
  • Immunohemolytic Anemia
      • several subtypes
      • (1) warm antibody type
      • (2) cold agglutinin type
      • (3) cold hemolysin
  • Immunohemolytic Anemia
      • (1) warm antibody type
      • - 80 to 90% of autoimmune hemolytic anemia
      • - lg G antibody
      • - coating RBC with anti-Rh Ab and complement
      • - RBCs are ultimately destroyed by splenic macrophages
      • clinical: - intermittent hemolysis
      • - moderate splenomegaly
      • - unpredictable clinical course
      • etiology:
      • a. idiopathic disease
      • b. secondary disorder
      • - lymphoma (lymphocytic lymphoma)
      • - leukemia (chronic lymphocytic leukemia)
      • - autoimmune disorders (SLE, collagen vascular diseases)
      • - viral infections
      • - drugs: penicillin, cephalosporin (hapten)
      • α -methyldopa (autoantibody)
  • Immunohemolytic Anemia
      • (2) cold agglutinin type
      • - 10 to 20% of autoimmune hemolytic anemia
      • - Ig M type antibody
      • - complement-coated RBC will be removed by liver Kupffer cells
      • etiology:
      • a. acute: - mycoplasma
      • - infectious mononucleosis
      • b. chronic: - idiopathic
      • - lymphoma
  • Immunohemolytic Anemia
      • (3) cold hemolysis
      • paroxysmal cold hemoglobinuria
      • - caused by IgG bind to RBCs at low temp and fix complement
      • - acute intermittent massive hemolysis after exposure to cold
      • - complement dependent hemolysis
      • - caused by IgG against P blood group antigen
      • - IgG-Ab (Donath-Landsteiner Ab) binds to RBC and fix complement at cold temp and then complement activation when temp is elevated.
      • mostly seen after infection: mycoplasmal pneumonia
      • measles
      • mumps
  • Drug-Mediated Injury
      • (1) autoantibody induction
      • α -methyldopa  Ig G antibody
      • (2) immune complex formation (drug-Ab complex)
      • quinidine  Ig M complex
      •  complement-mediated lysis
      • (3) hapten formation (drug-RBC membrane protein complex)
      • penicillin
  • Aplastic Anemia
      • - pancytopenia characterized by
      • (1) anemia
      • (2) neutropenia
      • (3) thrombocytopenia
      • - failure or suppression of multipotent myeloid stem cells causes inadequate production or release of the differentiated cell lines
      • Etiology:
      • - 65% idiopathic
      • - chemicals/drugs
      • (benzene, chloramphenicol, alkylating agents, antimetabolite)
      • - whole body irradiation
      • - viral hepatitis
  • Aplastic Anemia
      • Pathology: markedly hypoplastic bone marrow
      • Clinical: - may occur at any age
      • - variable initial manifestations
      • (depending on the affected cell line)
      • - no splenomegaly
      • - normocytic and normochromic RBCs
      • - no reticulocytosis
      • Dx: bone marrow biopsy
      • hypocellular due to stem cell failure
  • Megaloblastic Anemia
      • A group of disorders characterized by a reduced rate of DNA synthesis
      • The dyssynchrony in nuclear (DNA) and cytoplasmic (RNA) development is the morphologic hallmark of this type of disorder, since RNA synthesis, RNA processing and protein synthesis are unaffected.
  • Vitamin B12 / Folate Deficiency
    • Vitamin B12 (cobalamin) -- a vital ingredient for DNA synthesis and Krebs cycle
    Methylcobalamin a coenzyme for tetrahydrofolate (FH 4 )
  • Vitamin B12 Absorption Vit B12: absorbed in ileum (with intrinsic factor) Intrinsic factor
  • Vitamin B12 / Folate Deficiency
      • Lab:
      • Blood: - macro-ovalocytes, giant hypersegmented PMNs (no giant platelets)
      • - pancytopenia
      • - elevated MCV
      • - anisocytosis
      • - poikilocytosis
      • BM: - hyperplastic
      • -  myeloid : erythroid ratio
      • - megaloblasts
      • - giant metamyelocytes
      • - autohemolysis ( -> ↑ serum bilirubin, ↑ LDH)
  • Vitamin B12 Deficiency
    • etiology:
    • dietary deficiency ---- rare
        • strict vegetarians)
    • decreased absorption
      • decreased intrinsic factor
        • gastrectomy
        • pernicious anemia
      • pancreatic insufficiency
      • intestinal malabsorption
        • parasites (fish tapeworm [ Diphyllobothrium latum ])
        • bacteria (blind-loop syndrome)
        • ileal Crohn’s disease
  • Vitamin B12 Deficiency
    • Sx:
    • weakness ← anemia (megaloblastic anemia)
    • sore (“beefy”) tongue ← generalized epithelial atrophy
    • demyelination of spinal cord (posterior and lateral portions) (subacute combined spinal degeneration)
      • loss of vibration and position senses ← posterior tracts loss
      • arm and leg dystaxia ← dorsal spinocerebellar tracts loss
      • spastic paralysis ← corticospinal tracts loss
  • Vitamin B12 Deficiency
    • Lab:
    • low serum B12 level
    • increased serum homocysteine
    • increased methylmalonic acid in urine
    • Dx: Schilling test
    • oral radioactive B12 -> 2 hrs later -> parenteral large flushing dose of non-labeled B12 -> measure urine for radioactive B12
    • nl: >7% of radio-labeled B12 excreted in 24-hr urine
    • abnormal (lacking IF): less than 7% of B12 excreted
    • Tx: intramuscular vitamin B12
    • -> increase in reticulocytes in 5 days
  • folate deficiency
    • etiology:
    • dietary deficiency (folate def. takes only months to develop)
      • “ tea and toast” diet (elderly individuals)
      • chronic alcoholics
    • decreased absorption
      • intestinal malabsorption (folate is absorbed in upper intestine)
    • increased requirement
      • pregnancy (folate def in pregnancy -> neural tube defects)
      • infancy
    • folate antagonists
      • chemotherapy (i.e. methotrexate)
  • folate deficiency
    • Sx:
    • megaloblastic anemia
    • no neurologic degeneration
    • Lab:
    • low serum folate level
    • increased serum homocysteine
    • Tx: folate
  • Iron Deficiency Anemia
    • Iron: absorbed in duodenum
    • When iron loss exceeds its intake for a long time, iron storage decreases and insufficient amount of iron is available for hemoglobin production
    • Iron deficiency anemia develops in sequence of stages:
    • 1. Iron Depletion
    • 2. Iron Deficient Erythropoiesis
    • 3. Iron Deficiency Anemia
  • Iron Deficiency Anemia
    • Clinical:
    • - general fatigue
    • - SOB
    • - spoon nails (koilonychia)
    • - smooth, sore tongue
    • - epithelial atrophy
    • - pica (eating unusual things [e.g., dirt])
  • Iron Deficiency Anemia
      • Lab:
      • Blood: - normochromic-normocytic
      •  microcytosis, anisocytosis, poikilocytosis, hypochromia
      • - decreased reticulocytes
      • - low MCV
      • - relatively low Hgb, Hct
      • Marrow: no iron storage
      • normoblastic hyperplasia
      •  smaller normoblast with deficient Hgb
  • Iron Deficiency Anemia
      • Serum iron (nl = 50-160 mg/dL) : low
      • Serum iron-binding capacity (nl = 250-400 mg/L) : increased
      • % saturation of TIBC (nl = 20-55%) : <15%
      • Serum ferritin (nl = 12-300 mg/L) : low
  • sideroblastic anemia
    • due to altered production of heme (defect in protoporphyrin production)
    • associated with ring sideroblasts in bone marrow
    • peripheral blood: may show dismorphic RBCs
    • lab: increased serum iron ferritin free erythrocyte protoporphyrin (FEP) % saturation of TIBC decreased TIBC
  • Sideroblastic Anemia
      • a heterogeneous group of disorders associated with various defects in the porphyrin biosynthetic pathway
          • porphyrn biosynthesis defects
          • diminished heme synthesis
          • increased cellular iron uptake
      • characterized by the association of anemia with presence of ringed sideroblast (a normoblast containing excessive deposits of iron within mitochondria) in bone marrow
  • Sideroblastic Anemia
      • Sub-types:
      • Hereditary Sideroblastic Anemias
      • hereditary sex-linked
      • inheritance undetermined
      • Acquired Sideroblastic Anemias
      • primary (idiopathic) sideroblastic anemia
      • secondary (drug- or toxin-induced) sideroblastic anemia
      • anti TB drugs (isoniazid, cycloserine, pyrazinamide)
      • lead poisoning
      • chloramphenicol
      • ethanol
  • Sideroblastic Anemia
  • Sideroblastic Anemia
      • clinical: characterized by hypochromic, often microcytic, red cells in the blood usually mixed with normochromic cells
        • hypochromic anemia
        • hyperferremia
        • increased transferrin saturation
      • Lab: serum iron: increased
      • TIBC: decreased
      • % saturation: greatly elevated
      • bone marrow: - markedly increased iron storage
      • - erythroid hyperplasia
      • - increased sideroblasts
  • anemia work-up
    • M: Hb <13.5 Hct <41
    • F: Hb <12 Hct <36
    • [check MCV]
    • MCV <80 = microcytic
      • Fe deficiency
      • thalassemia
      • anemia of chronic disease
      • sideroblastic anemia
  • anemia work-up
    • MCV >100 = macrocytic
      • megaloblastic anemia
        • VitB12 deficiency
        • folate deficiency
      • alcoholic liver disease
    • MCV 80-100 = normocytic
    • [chech reticulocyte count]
  • anemia work-up
    • low reticulocyte:
      • - marrow failure - leukemia/metastasis
      • - aplastic anemia - renal failure
      • myelofibrosis - anemia of chronic disease
    • high reticulocyte:
      • sickle cell anemia - autoimmune hemolytic anemia
      • G6PD deficiency - hereditary sphelocytosis
      • paroxysmal nocturnal hemoglobiuria
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