The document summarizes heme catabolism and bilirubin metabolism. Heme is broken down, with iron entering the iron pool, globin being reutilized, and the porphyrin ring being converted to bile pigments. Bilirubin is formed from heme in red blood cells and transported to the liver bound to albumin. In the liver, bilirubin is conjugated and excreted into bile. Clinical issues can arise if bilirubin conjugation or transport is impaired, leading to jaundice.
2. Fate of Hb:
• Globin is reutilised or constituent amino acids are reutilised after
proteolysis
• Fe++ of haem enters “iron pool” for reutilisation or stored as “ferritin”
• Fe-free porphyrin portion of haem is degraded to bile pigments
Biliverdin and bilirubin, in RE cells
4. SOURCES OF BILIRUBIN
Mainly two –
(a) From ‘Haem’ of erythrocytes:
- 85% of bilirubin
Site: bone marrow, spleen and liver
(b) Other Sources of Bilirubin:
- 15% of newly synthesised bilirubin
• Haem formed from Hb - synthesis
• Destruction of immature erythrocytes
• Degradation of Hb, within erythrocyte precursors
• Breakdown of other haem pigments
5.
6. Formation of Bilirubin from Biliverdin:
• Occurs in RE cells
• Requires a specific enzyme bilirubin reductase
• NADH or NADPH act as hydrogen donor
Shunt Hyperbilirubinemia:
- Rare form of clinical jaundice
- Associated with ineffective erythropoiesis, hyperplastic bone marrow
- Unconjugated hyperbilirubinemia
7. Transport of Bilirubin
• Bilirubin formed in RE cells is in unconjugated form
• Highly lipid soluble
• Binding with albumin increases plasma solubility
• Normally in 100 ml of plasma, approx. 25 mg of bilirubin can be
tightly bound to albumin
8. Alterations of Albumin-Bilirubin Binding and its Biomedical
Significance
- Administration of anionic drugs like sulphonamides
- Increase in free fatty acids
- Asphyxia, hypoxia
All these promote Bilirubin encephalopathy
- Unconjugated bilirubin enters the neurons of the basal ganglia,
hippocampus, cerebellum, and medulla, causing necrosis of nerve cells
9. Transfer of Bilirubin from Plasma to Liver Cells
• Liver selectively remove unconjugated bilirubin
• Hepatic sinusoids have specific receptor
• Two non-albumin proteins help in intracellular binding of bilirubin
• They have been named as ligandins
11. Conjugated bilirubin:
• Water soluble and
• Smaller in molecular size
• Not bound to albumin
Glucuronyl Transferase Activity in Extrahepatic Tissues
• Skin, kidneys, adrenal glands, ovary, testes, intestinal mucosa and
synovial membrane.
• Probably monoglucuronide is formed
12. SECRETION OF BILIRUBIN IN THE BILE
• Active transport process
• Require MRP-2 (multi drug resistance protein 2) also called
“multispecific organic anion transporter” (MOAT)
• Located in the plasma membrane of the bile canalicular
membrane
14. Clinical aspect:
A. Inhibition of Glucuronyl Transferase Activity:
- Drugs and steroidal derivative inhibits the exzyme
- Basis of breast milk jaundice
- Pregnane –3 α-20β-diol is present in breast milk
- It inhibits the enzyme
- Unconjugated hyperbilirubinemia
- Stopping breast milk feeding, jaundice disappears
15. B. Transient Neonatal “Physiological” Jaundice
- Accelerated haemolysis, immature hepatic system for uptake,
conjugation and secretion of bilirubin
- Also reduced synthesis of substrate
- Kernicterus
Treatment:
- Administration of phenobarbital
- Exposure to visible light (phototherapy)
16. c. Crigler-Najar Syndrome
- Type -1: autosomal recessive disorder
- Inherited absence of glucuronyl transferase activity
- Mutations in the gene encoding bilirubin-UGT in Ch 2
- Nonhaemolytic unconjugated hyperbilirubinaemia,
kernicterus
- T/t – Phototherapy
- Type – 2: Milder defect with benign course
- Some activity of the enzyme is retained
- No risk of kernicterus
17. d. Gilbert’s syndrome:
- Multifactorial
- low grade chronic unconjugated hyperbilirubinaemia and jaundice
- Bilirubin level <3 mg/dl
- Mild icterus of sclera of eye
- Patient usually complaints of fatigue, weakness, and abdominal pain
- Symptomatic management
18. e. Dubin johnson syndrome
- Autosomal recessive
- Mutations in the gene encoding MRP-2
- Conjugated hyperbilirubinaemia
f. Rotor syndrome
- Autosomal recessive
- Mutations in the gene encoding MOAT
- Conjugated hyperbilirubinaemia
19. Jaundice
- Yellowish discolouration of scle, skin and mucosa due to increased
deposition of bilirubin
- Clinical jaundice – bilirubin > 2mg/dL
Etiological classification of Jaundice
1. Hemolytic (Prehepatic)
2. Hepatocellular
3. Obstructive (Post hepatic)
20. Causes –
Hemolytic:
• Excessive RBC breakdown
a. Live failure
b. Renal disorder
c. Hypersplenism
d. Burns
e. Infections
f. Hemoglobinopathies
g. Drug induced hemolysis
h. Autoimmune diseases
21. Hepatocellular
• Infective or toxic damage to liver
a. Infective hepatitis
b. Alcoholic hepatitis
c. Cirrhosis of liver
d. Toxic chemicals
Obstructive
• Obstruction to bile overflow
a. Gall stones
b. Cancer of biliary system or pancreas
22. a. Intrahepatic cholestasis:
i. Chronic active hepatitis
ii. Biliary cirrhosis
iii. Lymphomas
iv. Primary hepatoma
v. Obstructive stage of viral hepatitis.
b. Extrahepatic obstruction:
i. Stones in the gallbladder or biliary tract
ii. Carcinoma of head of pancreas
iii. Enlarged lymph glands in the porta hepatis
23. FEATURES HEMOLYTIC
HEPATO
CELLULAR
OBSTRUCTIVE
TOTAL SEUM
BILIRUBIN
RAISED RAISED RAISED
CONJUGATED NORMAL ELEVATED ELEVETED
UNCONJUGATED ELEVETED ELEVETED NORMAL
UROBILINOGEN INCREASED DECREASED ABSENT
URINE NORMAL DEEP YELLOW DEEP YELLOW
STOOL DARK BROWN PALE
CLAY
COLOURED
STERCOLIBINOGEN INCREASED REDUCED ABSENT
Editor's Notes
One gram of Hb yields approx. 35 mg bilirubin
Each molecule of albumin appears to have:
• One “high-affinity” site
• One “low-affinity” site for bilirubin.
designated as ‘Y’ and ‘Z’
isolated from liver cytoplasm and account for most
of
The enzyme catalyses the transfer of Glucuronic acid from UDP-GA to various phenolic, carboxylic and amine receptors. The process is called conjugation reaction and it is carried out in the smooth endoplasmic reticulum of liver cells.
Glucuronic acid is attached through“ester-linkage” to the propionic acid carboxyl group of bilirubin
conjugated bilirubin can pass through glomerular filter and can appear in urine (bilirubinuria).
Unconjugated bilirubin cannot pass through glomerular filter and does not appear in urine.
Maleimide fragments, and Geometric isomers, which are excreted in bile
compensated haemolysis associated with unconjugated hyperbilirubinaemia
Due to a defect in hepatic clearance of bilirubin, possibly due to defect in uptake of bilirubin by liver cells
Due to reduced glucuronyl transferase activity
Due to mutations in the gene encoding bilirubin UGT
Hemolytic disease of newborns
Hemolytic disease of adults - G6PD deficiency