Part 9.2: RBC synthesis

Question 1

Stimulation of erythropoiesis

Rate of erythrocyte synthesis

Answer 1

1) Decrease O2 supply stimulates kidney (major) and liver (minor) to produce erythropoietin

2) Erythropoietin hormone stimulates proerythroblasts in bone marrow
- Synthetic erythropoietin (EPO) is a doping strategy in sports

3) Erythroblasts mature (early, intermediate, late) –> Reticulocytes which enter the blood

4) Reticulocytes mature –> erythrocytes and ↑ O2 supply

*2.4 million erythrocytes synthesized per second

Question 2

Disorders related to biosynthesis of heme

Answer 2

Acute intermittent porphyria:
- autosomal dominant defective porphobilinogen deaminase
- excessive production of ALA and porphobilinogen
- abdominal pain
- neurological and psychotic episodes (“Madness of King George”)

Porphyria Cutanea Tarda
- autosomal dominant defective uroporphryrinogen decarboxylase
- photosensitivity, vesicles and bullae (blisters) on exposed skin
- Red wine colored urine
- Must live in shade and be active at night (vampires!)

Question 3

Biosynthesis of heme pathway

Answer 3

1) Gly + succinyl coA –> ALA (aminolevulinic acid) by ALA synthase (+ B6) in mitochondria
- Inhibited by heme

2) 2 ALA –> Porphobilinogen (PBG) by ALA dehydratase

3) 4 PBG –> uroporphyrinogen III by PBG deaminase
- acute intermittent porphyria

4) Uroporphyrinogen III (UPG) –> coporphyrinogen III by UPG decarboxylase
- Porphyria Cutanea Tarda

5) Coporphyrinogen III –> protoporphyrin by protoporphyrinogen oxidase

6) Protoporphyrin –> heme by ferrochelase

Question 4

Heme degradation pathway: pre-hepatic

Answer 4

1) Fe3+ removed from heme and ring is broken Heme –> Biliverdin by heme oxidase

2) Biliverdin –> Bilirubin by bilirubin reductase

3) Bilirubin is bound by albumin and transported in blood stream
- Jaundice

Question 5

Heme degradation pathway: hepatic

Answer 5

4-5) 2x Bilirubin + UDP-GlcA –> bilirubin diglucuronide by UDP-glucuronyl transferase
- Conjugation increases solubility

6) excretion into bile in gallbladder

Question 6

Heme degradation pathway: post-hepatic

Answer 6

7) Bilirubin-diglucuronide –> bilirubin by microbiome

8) Bilirubin –> urobilinogen by microbial SI enzymes

Reabsorbed into kidneys:
9) Urobilinogen –> urobilin (yellow) and excreted in urine

Unreabsorbed:
10) Urobilinogen –> stercobilin (red-brown) excreted in feces

Question 7

Jaundice AKA

Causes of pre-hepatic, hepatic and post-hepatic jaundice and neonatal

Answer 7

hyperbilirubinemia or icterus (itchy) - build up for unconjugated bilirubin

Pre-hepatic:↑ RBC degradation which ↑ unconjugated bilirubin, hemolysis, G6PDH deficiency, malaria

Hepatic: liver disease, impaired conjugation of bilirubin

Post-hepatic: cholestasis, biliary atresia, blocked bile duct (pale feces and dark urine due to diversion to urinary excretion)

Neonatal - developmental immaturity of enzymes
- Light therapy (blue UV) to help break down excess bilirubin