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Hemoglobin Function
&
Basic Structure
Basic Structure
Basic Structure
Hemoglobin Chemistry
CO2 causes acidity in plasma, effects the pH balance of the blood Blood can carry both at one time different binding
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
Hgb F
Normal Hgb:
Hgb A1
< 2% (adult) 1 - 0.8% (3 y/o) <2% present at 1 year of age 10% still present at 4 mons 65-90% of total HgB at birth 90 - 95% - fetal life
Hgb A2
by methemoglobin- cytochrom C
reductase 575 nm
X affinity vs O2 Collect in citrate Test: ammonia + blood (25% COHgb) CO poisoning occur at levels of 20-30% 540 nm
Fe++ Fe+++ brown No O2 binding cyanotic Induced by oxidizing agents (nitrates, nitrites, quinones, chlorates) G-6-PD deficiency 525 nm
Myoglobins Porphyrins
Iron Metabolism
Plasma transferrin (3 mg) Muscle (myoglobin) (300 mg) Circulating erythrocytes (hemoglobin) (1,800 mg)
Storage iron
Sloughed mucosal cells Desquamation/Menstruation Other blood loss (average, 1 - 2 mg per day) Iron loss
Storage: Iron storage 0 - 1000 mg Transit: Serum iron 3 mg Total 3000 - 4000 mg
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 M 3.5- 5 F
IDA - Pathogenesis:
Decreased Iron stores Decreased Hb Synthesis Delayed maturation of erythroblasts (cytoplasmic) Decreased cytoplasm, more division (microcytes) Decreased hb content (hypochromia) Anemia.
Clinical Features:
Clinical Features:
cheilitis, atrophic glossitis, Esophageal atrophy/web dysphagia, Koilonychia, brittle nails, gastric atrophy
DEC Hb, HCT, RBC MCV < 70 (IDA & THALASSEMIA) Low Retic count High RDW PBS: Microcytic Hypochromic RBCs
Most useful, cost effective test of Fe stores > 100 ng/ml r/o IDA Except in acute hepatitis or liver necrosis but not chronic liver dse (elevated- release of Fe stores) Falsely elevated- disseminated TB & Hodgkin's disease
INC TIBC (high specificity- near 100% but poor sensitivity- < 30%) BM: ASYNCHRONOUS RBC-POIESIS
Hemochromatosis: Overview
Hemochromatosis: classification
injections) Ineffective erythropoiesis hemolytic anemias (most common secondary cause) Increased oral intake (Bantu siderosis) Congenital atransferrinemia Chronic liver disease (mostly alcoholic)
Genetic Hemochromatosis
Homozygous recessive HFE gene on chr 6p (near HLA gene locus) MC mutation in HFE: tyrosine substituted for cysteine 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)
Deposition hemosiderin in multiple organs (brown granules of aggregated ferritin): Liver & pancreas (most severe) Myocardium Pituitary, adrenal, thyroid, parathyroid glands Joints (synovitis) and skin Testes (atrophy)
Hemochromatosis
Genetic dse Excess amounts of iron Arthritis, cirrhosis, DM, heart failure, HCC
Hemochromatosis: Clinical Dx
Signs:
Abdominal
Hemochromatosis: Clinical Dx
Diagnostic tools:
Markedly
elevated serum ferritin (best screening test) HFE gene molecular analysis Liver biopsy w/ quantitative Fe analysis
Inflammatory:
Temporal
Non-inflammatory:
CHF COPD DM
ACD
Malignancy:
RA SLE Sarcoid Collagen Vascular Dse Polymyalgia Rheumatica Chronic Hepatitis Decubitus ulcer
ACD
Fe SEQUESTRATION IN BM HISTIOCYTES Defect w/ defective Fe utilization & shorten RBC survival
ACD
Normal
IDA
Sample question #1
ACD is due to inadequate production of, or poor response to, which one of the following?
A. B. C. D. E. Iron Folate Erythropoietin Ferritin Hemosiderin AFP, Nov. 15, 2000
Heme Synthesis
Heme Synthesis
Heme Synthesis
PBG (monopyrrole) Protoporphyrin IX (biologically active tetrapyrrole) Fe inserted into tetrapyrrole ring in mitochondria
Heme synthesis:
Stimulated
Sideroblastic Anemia
SIDEROBLASTIC A. MECHANISM:
Defective prdn of heme under- hgb erythroid precursors w/ microcytosis REFRACTORY A. (RESISTANT TO TX) INEFFECTIVE ERYTHROPOIESIS (ANEMIA W/ HYPERPLASTIC BM)
NEUTROPENIA
MALNUtrition
CHLORAMPHENICOL-
MITOCHONDRIAL
PBS: Papenheimer Bodies; Basophilic stippling in Pb poisoning; Dimorphic (macrocytic + intensely microcytic RBCs) in patient w/ acquired sideroblastic a; anisopoikilocytosis; Target cells
Serum Fe: Inc Stigmata of a myelodysplastic syndrome BM: Ringed sideroblasts on BM Fe stain; inc hemosiderin
Porphyria
Etiology:
Uroporphyrinogen Anti
decarboxylase def
HC Ab photosensitivity
S/S:
Cutaneous
Features:
Portal
Lab tests:
Inc
Variegate porphyria
AD disorder Features: Cutaneous fragility & photosensitivity Acute neurological attacks common
Hereditary coproporphyria
AR Uroporphyrinogen synthetase defect expressed in RBCs w/ inc porphyrin levels in stool Acute neurological attacks + cutaneous manifestations
Globin Synthesis
22
2b2 e G A b
A2
Adult A
1.5-3.5%
>95%
b cluster - chromosome 11
Hemoglobin Catabolism
Ferritin
Reduced
Normal
Increased
Iron deficiency
HB electrophoresis
Hypochromia
Microcytic Note: Anisocyosis: RDW poikilocytes
WAKAS!!!