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    Hemoglobin

    Heme = Fe++ + Porphyrin Ring

    +

    Globin

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    Hemoglobin

    Function Conjugated protein

    for transport of O2 &

    CO2

    &

    Buffer (O2

    Dissociation Curve)

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    Basic Structure

    How many? subunits:

    How many? iron-containing tetrapyrroleheme rings

    How many? polypeptide

    globin chains ? identical alpha chains

    ? identical non-alphachains

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    Basic Structure

    Each chain arrangedin -helix w/ 8individual helicalsegments (labeled A -H)

    Each globin moleculehas both hydrophobic& hydrophilic areas

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    Basic Structure

    Fe-containing heme ring w/inhydrophobic region of globin -Heme Pocket

    Hydrophobic nature protectsFe residue from oxidation

    Each Fe at center of hemeresidue held in place & kept

    active (Fe++) by 2 histidineresidues

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    Hemoglobin Chemistry

    O2 binds to heme (Iron)

    97% carried this way

    CO2 binds to globin

    20% bound

    80% free in plasma

    CO2 causes acidity in

    plasma, effects the pH

    balance of the blood

    Blood can carry both at

    one time different

    binding

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    Basic Structure

    Each globin (141 aa)

    All non- chains (146

    aa) W/ considerable

    structural homology

    among non-alpha

    chains

    Full saturation: 1 gm

    Hgb holds 1.34 mL of

    O2

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    Normal Hgb:

    Hgb A1

    95 - 98% (adult)

    15 - 40% at birth

    predominates at 6 12mons

    Hgb F

    < 2% (adult)

    1 - 0.8% (3 y/o)

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    Hgb derivatives (Heme changes)

    Oxyhgb (bright red) vs Reduced hgb (purple red)

    Maintained by methemoglobin- cytochrom C

    reductase 575 nm

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    Hgb derivatives (Heme changes)

    Carboxyhgb (cherry

    pink)

    200 X affinity vs O2 Collect in citrate

    Test: ammonia + blood

    (25% COHgb)

    CO poisoning occur atlevels of 20-30%

    540 nm

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    Heavy smokers: Smokers: 1-10%

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    Hgb derivatives (Heme changes)

    Methgb (0.5% normal in

    blood)

    Fe++ Fe+++ brown

    No O2 binding cyanotic

    Induced by oxidizing

    agents (nitrates, nitrites,

    quinones, chlorates)

    G-6-PD deficiency

    525 nm

    Sulfhgb (0- 2.2% normal

    in blood)

    Sulfa drugs (sulfonamides);

    aromatic aminestrinitrotoluene

    Irreversible binding RES

    Myoglobins

    Porphyrins

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    Iron Metabolism

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    Body Iron Distribution and StorageDietary iron

    Utilization Utilization

    Duodenum

    (average, 1 - 2 mg

    per day)

    Muscle

    (myoglobin)

    (300 mg)

    Liver

    (1,000 mg)

    Bone

    marrow

    (300 mg)Circulating

    erythrocytes

    (hemoglobin)

    (1,800 mg)

    Reticuloendothelial

    macrophages

    (600 mg)

    Sloughed mucosal cellsDesquamation/Menstruation

    Other blood loss(average, 1 - 2 mg per day)

    Storage

    iron

    Plasma

    transferrin

    (3 mg)

    Iron loss

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    Major Iron Compartments

    Metabolic:

    Hgb 1800 - 2500 mg

    Myoglobin 300 - 500 mg

    Storage:

    Iron storage 0 - 1000 mg

    Transit:

    Serum iron 3 mg

    Total 3000 - 4000 mg

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    Red cell indices

    Hemoglobin (gm\dl): 13.5- 17 M

    12- 15 F

    Hematocrit (Vol%): Volume of RBCs /Total blood

    39- 49 % M

    33- 43% F

    RBCs ct (106/ul): 4.3- 5.9 M3.5- 5 F

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    Iron Deficiency

    Anemia (IDA)

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    Clinical

    Features: General features of

    Anemia

    Pallor, Weakness,Lethargy

    Breathlessness onexertion

    Palpitationsheart failurepedal edema

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    Clinical

    Features: Special features in

    IDA:

    Angular cheilitis,atrophic glossitis,

    Esophagealatrophy/web

    dysphagia,Koilonychia, brittle

    nails, gastricatrophy

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    PBS: Response to Iron Tx

    Dimorphic blood film

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    Other LAB Tests:

    DEC SERUM Fe

    DEC SERUM FERRITIN Most useful, cost effective test of Fe stores

    > 100 ng/ml r/o IDA Except in acute hepatitis or liver necrosis butnot chronic liver dse (elevated- release of Fe stores)

    Falsely elevated- disseminated TB & Hodgkin's disease

    INC TIBC (high specificity- near 100% but poorsensitivity- < 30%)

    BM: ASYNCHRONOUS RBC-POIESIS

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    Hemochromatosis: Overview

    Def: Xss accumulation of Fe w/ organ damage

    Iron arithmetic: Normal total body pool: 2-5 gm

    Hgb (2 gm)

    Storage: ferritin & hemosiderin (0.5 - 1 gm)

    Myoglobin (0.3 gm)

    Normal liver storage: 0.5 gm

    Hemochromatosis: Total body Fe > 50 gm

    At least 1/3 is stored in liver

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    Hemochromatosis: classification

    Genetic (hereditary) vs secondary (acquired)

    Secondary causes iron overload: Parenteral iron overload (transfusions, iron-dextran

    injections)

    Ineffective erythropoiesis hemolytic anemias (mostcommon secondary cause)

    Increased oral intake (Bantu siderosis)Congenital atransferrinemia

    Chronic liver disease (mostly alcoholic)

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    Genetic Hemochromatosis

    Homozygous recessive

    HFE gene on chr 6p (near HLA gene locus)

    MC mutation in HFE: tyrosine substituted forcysteine at aa 282 (C282Y)

    Gene frequency: 6% northern European whites;homozygosity 0.45% (1 in 220)

    M: F = 6:1

    Males show disease earlier (no menses)

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    Hereditary Hemochromatosis:

    pathogenesis

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    Genetic Hemochromatosis:

    Pathology Deposition hemosiderin

    in multiple organs (browngranules of aggregatedferritin):

    Liver & pancreas (mostsevere)

    Myocardium

    Pituitary, adrenal, thyroid,parathyroid glands

    Joints (synovitis) and skin

    Testes (atrophy)

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    Hemochromatosis

    Genetic dse

    Excess amounts of

    iron Arthritis, cirrhosis,

    DM, heart failure,

    HCC

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    Hemochromatosis: Clinical Dx

    Signs:Abdominal pain

    Hepatomegaly

    Skin pigmentation(brown-gray)

    DM

    Cardiac dysfunction

    Arthritis

    Hypogonadism

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    Hemochromatosis: Clinical Dx

    Diagnostic tools:

    Markedly elevated serum ferritin (best screening test)

    HFE gene molecular analysis Liver biopsy w/ quantitative Fe analysis

    Normal: < 1,000 ug Fe/gm

    Hemochromatosis: > 10,000 ug Fe/gm

    Evaluate for secondary causes (vs. genetic)

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    Anemia of Chronic

    Disease: ACD

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    ACD - ETIOLOGY: ANY

    CHRONIC DSE Inflammatory:

    Temporal arteritis

    (may be a presenting

    sign)

    Rheumatoid arthritis

    Cancer

    Non-inflammatory:

    CHF

    COPD DM

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    ACD

    Infections: TB, SBE, Osteomyelitis

    Chronic UTI or PN

    Fungal

    Malignancy: Mets

    Leukemia

    Lymphoma

    Myeloma

    Chronic inflammatorydisorders: RA

    SLE Sarcoid

    Collagen Vascular Dse

    Polymyalgia Rheumatica

    Chronic Hepatitis

    Decubitus ulcer

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    ACDDefect

    Storage Iron

    IL-1TNF IFN

    Erythroid Precursors

    (dec responsiveness to EPO)

    BM Storage

    Iron (Blue)

    Fe SEQUESTRATION IN BM HISTIOCYTES

    w/ defective Fe utilization & shorten RBC survival

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    ACD - LAB DX:

    INC. ESR

    INC. HAPTOGLOBIN

    Dec serum Fe

    Dec TIBC