Haem metabolism and bilirubin Flashcards
What are the constituents of the hemoglobin?
- Hb has two parts:
1) Protein part (globin)
2) Non-protein part (Haem “porphyrin + iron)
- Bilirubin is the degradation product of heme
- Porphyrin is a cyclic molecule formed by the linkage of four pyrrole rings via a methenyl bridge
When and where is the RBC degraded?
- After about 120 days
- RBCs are degraded by the reticuloendothelial system (liver and spleen)
How many steps are there for haem degradation?
2
What is the first step in the degradation of haem?
1) The porphyrin ring is opened by the OXIDATION RXN catalyzed by the MICROSOMAL HAEM OXYGENASE (using NADPH & O2)
- This rxn will produce:
1) Biliverdin
2) Carbon monoxide
3) Release of iron
What is the second step of the degradation of haem?
1) Reduction of biliverdin forming a red-orange bilirubin
- Unconjugated-Bilirubin is insoluble and thus it binds to albumin to be transported to the liver (to become conjugated)
- FYI: Some drugs like sulphonamides displace bilirubin from the albumin which has the potential to cause neurological damage
How is bilirubin conjugated?
- In the hepatocytes
1) Bilirubin is dissociated from the albumin
2) Bilirubin then binds to the intracellular protein ligandin
3) Microsomal Bilirubin UDP-Glucuronosyltransferase (bilirubin UGT) then conjugates bilirubin to two molecules of glucuronic acid
- Bilirubin will then get transferred to the bile
What is the function of the Bilirubin UGT?
It transfers 2 glucuronic acid from UDP-Glucuronic acid and links it to the bilirubin on both sides (making the bilirubin conjugated and thus water-soluble)
What are the syndromes that result from the deficiency of bilirubin UGT?
1) Crigler-Najjar 1 & 2
2) Gilbert syndrome
How is UDP-Glucuronic acid formed?
By the conversion of the UDP-glucose via an oxidation reaction catalyzed by UDP-Glucose dehydrogenase
Who is the donor of glucuronic acid?
UDP-Glucuronic acid
What are the various ways by which glucuronic acid is obtained?
1) Lysosomal degradation of glycosaminoglycans (GAGs)
2) Diet
3) From glucose-6-phosphate via the uronic acid pathway
How is bilirubin transferred to bile?
Conjugated bilirubin is Actively Transported against its concentration gradient into the Bile Canaliculi and then into the bile
- In a disease of the liver this energy-dependent step is disturbed
- FYI: Unconjugated bilirubin is not secreted into the bile
What is Dubin Jhonson Syndrome?
It is when there is a deficiency in the transporter of the conjugated bilirubin
How is bilirubin secreted?
1) Conjugated bilirubin is hydrolyzed and reduced by the bacteria in the gut, yielding UROBILINOGEN (colorless compound)
2) In the intestine, urobilinogen is further oxidized by the intestinal bacteria into STERCOBILIN (giving the brown color of the feces)
- Some urobilinogen is reabsorbed from the gut and enters the portal blood
What is the fate of the bilirubin that gets reabsorbed from the gut and enters the portal blood?
1) Re-secreted into the bile
2) Urobilinogen reaches the kidney and gets converted to a yellow urobilin
What is jaundice?
- Yellowish discoloration of the sclera, skin, and nail beds, due to the deposition of bilirubin (hyperbilirubinemia)
- It is a symptom of an underlying disease
- 2-3mg/dl level of bilirubin is considered jaundice
What are the different types of jaundice?
1) Prehepatic (hemolytic jaundice): due to the hemolysis of the RBC
2) Hepatocellular jaundice (hepatic): due to a problem in the liver
3) Obstructive jaundice (post-hepatic jaundice): due to an obstruction of the biliary tract
4) Neonatal jaundice
What is the hemolytic jaundice (prehepatic jaundice)?
- Due to the excessive destruction of RBC where normally the liver can conjugate up to 3000 mg of bilirubin/day, but in cases of hemolytic anemia like sickle cell anemia, pyruvate kinase or glucose-6-phosphate dehydrogenase deficiency the rate of bilirubin production exceed the rate of bilirubin conjugation and thus:
1) Increased UCB
2) Normal/Increased CB
3) Urine and blood urobilinogen will be increased
4) There is no bilirubin urea (as UCB is hydrophobic)
5) Dark stool because of urobilin, urobilinogen, and stercobilin
What is meant by hepatocellular (intrahepatic) jaundice?
- It is the reduction in the ability to conjugate bilirubin due to damaged hepatocytes (liver cirrhosis and hepatitis), which will result in:
1) Increased UCB
2) Increased urobilinogen in the urine and in the blood
3) Dark urine and pale stool (Let’s simplify this rule:- bilirubin (Urobilinogen) increases in blood = darker urine / Bilirubin (Conjugated-bilirubin) increases in intestine = darker stool, if lesser bilirubin reaches the intestine = paler stool. So if any process in either 1- conjugation or 2- release of Conjugated bilirubin to the intestine is DISTURBED then the stool will be PALER)
4) Increased in AST (Aspartate transaminase) and ALT (Alanine transaminase)
5) Increased conjugated bilirubin due to inefficient bile secretion which might lead to cholelithiasis
- Other liver functions might be damaged like low albumin levels and increasing the tendency of bleeding due to low synthesis of clotting factors
What is the conjugated jaundice (post-hepatic jaundice)?
- Obstruction in the secretion of bile which might be because of a tumor or gallstones
- It is associated with GI pain, Nausea, and pale stool
- Due to the extra-hepatic cholelithiasis, CB increases in blood giving urine a dark color and the feces a pale one
- Bilirubinuria is always pathological
What is meant by neonatal jaundice?
- Could be physiological or pathological
1) Physiological is due to a rise in UCB due to immature bilirubin- UGT at birth
2) Pathological jaundice could be inherited, rhesus incompatibility, etc
- If the concentration of UCB increases and exceeds the binding capacity of albumin, it can then diffuse into the basal ganglia leading to toxic encephalopathy/Kernicterus
How is neonatal jaundice treated?
Phototherapy which converts the UCB to a water-soluble isomer (lumirubin)
How to calculate the concentration of bilirubin?
- Measured by the Van Den Berg Reaction
1) This reaction is dependent on the solubility of bilirubin, where when using water CB is more soluble than UCB yielding the concentration of CB (Direct bilirubin)
2) We then use methanol as a solvent which will interact with both the UCB and CB yielding the (total bilirubin)
3) We then calculate the concentration of the UCB by misusing the Total bilirubin concentration from the direct bilirubin concentration (CB)
What are some of the features of cholelithiasis?
Hypercholesteremia and itching
In which types of jaundice is UCB high?
1) Prehepatic
2) Intrahepatic
In which type of jaundice is the CB high?
1) Intrahepatic
2) Obstructive
In which type of jaundice is the ALP high?
Obstructive jaundice (used to detect biliary duct cholestasis)
