Part 9.1: RBCs Flashcards
Adult hemoglobin structure (including heme structure)
Fetal hemoglobin structure
2 alpha, 2 beta globin chains
- 4 heme groups
Each heme group has 4 pyrrole N structures with iron in the center
- Iron binds O2
- Histidine binds iron from heme to the globin
- heme is a special product not a protein
Fetal hemoglobin has 2 alpha, 2 gamma globin chains
- greater affinity for oxygen than adult
- on sO2 (saturation) vs. pO2 (partial pressure), at 50% saturation fetal hemoglobin has a lower O2 partial pressure
Different forms of hemoglobin
Oxy-Hb: oxygen bound to heme
- 95% or higher should be oxy-Hb, below 90% is respiratory distress
Deoxy-Hb: no oxygen bound to heme
- darker maroon red
Carboxy-Hb: CO binds to heme more strongly than O2
- bright cherry red color when bound
Carbamino-Hb: CO2 bound to globin for transport out
NO bound globin: binds globin for transport
Met-Hb: oxidized (Fe3+) hemoglobin
- brown color, requires NADPH to reduced
Fetal Hb: 2 alpha, 2 gamma globin chains
- greater affinity for oxygen than adult
Glucose metabolism in RBC (7 steps)
1) Oxy-Hb drops off oxygen at tissues
2) Glucose enters via GLUT1 and glycosylates deoxy-Hb –> HbA1c
3) Glucose –> G6P by hexokinase: >90% of glucose goes towards glycolysis, < 10% to PPP to regeneration NADPH
- NADH produced to reduce Met-Hb
- GSSG –> 2 GSH
4) Pyruvate from glycolysis must be converted to lactate to cross membrane and undergoes Cori cycle and then gluconeogenesis
5) Deoxy-Hb –> Met-Hb by oxidation, Met-Hb –> Deoxy-Hb by NADH
6) 1,3-diphosphoglycerate –> 2,3 diphosphoglycerate influences rate of O2 release from Hb
7) ATP from glycolysis is used to power cell function such as maintaining electrolyte balance
G6PDH Deficiency
Normal function of G6PDH: conversion of G6P –> 6-phosphoglucono-lactone, produces NADPH
- Deficiency results in NADPH deficiency
Most common genetic disorder - cross-linked recessive with many possible SNPs
400 million people –> 4000 deaths
Vulnerability: infection/fava beans oxidative stress, Advanced glycation end-products (AGEs), hemolytic anemia, increased bilirubin and jaundice
Heterozygotes are protected against malaria
Iron metabolism cycle
1) Fe2+ consumed
2) Converted to Fe3+ in enterocytes and bound by transferrin
- 6 Fe binding sites, normally 1/3 are bound
3) Converted to Fe2+ in bone marrow and added to protoporphyrin to form heme
4) heme is added to Hb and circulated in RBCs
5) RBC are broken up into heme (insoluble), Fe and porphyrin ring
6) Liver and spleen excretes heme as bilirubin (bile), iron is recycled
Stages of development of iron deficiency
1) ↓ iron stores and plasma ferritin levels
2) Changes in iron transport:
↑ absorption efficiency, transferrin iron binding capacity and receptors in bone marrow
↓ transferrin saturation %
3) Defective erythropoiesis: ↓ plasma iron and ↑ erythrocyte protoporphyrin
4) Iron deficiency anemia: microcytic hypochromic erythrocytes and ↓ erythrocyte production
- neural and behavior signs
Causes of iron deficiency
Decreased dietary iron: ↓ intake (vegan), ↓ absorption
Absorption inhibition: Ca/Zn mineral interactions, absorption inhibitors
Increased red cell mass/demand: pregnancy, childhood growth
Increased losses: occult losses (GI bleeding), hemolysis, vitamin E deficiency, G6PDH deficiency, heavy menstruation
Clinical iron deficiency anemia
Hb < 140 mg/L in men, Hb < 120 mg/L women
Free erythrocyte protoporphyrin = defective erythropoiesis
↓ transferrin saturation = ↓ transport
↓ ferritin = ↓ iron stores
Iron RDA and daily losses
Male RDA = 8 mg/day, 1mg losses per day
Female RDA = 18 mg/day, 1.4 mg losses per day
Losses due to: GI blood, mucosal, bile, desquamated skin cells and sweat, urinary losses, menstrual losses (.5 mg)
Iron absorption for heme and non-heme
Overall absorption
25% absorption for heme iron, absorbed as heme and bioavailable
- Fe released in enterocytes
~10% absorption of non-heme iron/elemental (between 1-50% absorption)
- Released from ligands by HCL and absorbed as Fe2+
Overall average rate of absorption = 10-15%
- RDA is set to take variable absorption into account
Regulation of iron stores during deficiency
During deficiency:
↑ synthesis of intestinal reductase divalent metal transporter 1 (DMT1) which absorbs Fe2+
- apical side
↑ ferroportin synthesis transports Fe2+ to basolateral side for transfer to transferrin
↓ Hepcidin peptide hormone levels from liver
Hepcidin function
Function during deficiency
Hepcidin normal function: ↓ ferroportin function
- makes it harder to release Fe stores
During iron deficiency: ↓ hepcidin released to ↑ Fe absorption
Anemia during chronic disease and infections: IL-6 ↑ hepcidin (prevents absorption) and ↓ transferrin
Reticuloendothelial cells are
Macrophages which have ferroportin
Hemochromatosis dysfunction
Genetic basis and public policy implications
Build up symptoms
Decreased hepcidin synthesis causing chronic Fe absorption (↑ ferroportin) and overload leading to tissue damage
5+ types autosomal recessive
More common than iron deficiency in men
- Public policy - can’t fortify with more iron because of people with hemochromatosis
Iron is deposited as hemosiderin –> cirrhosis of the liver
