15.8 Flashcards
In the hepatocyte, bilirubin is carried by ___
Ligandin
Ligandin transports bilirubin to the ___ where ___ ___ ___ is located - for conjugation!
ER, location of UDP glucuronyl transferase for conjugation.
In neonates, there is a switch in Hb and so there is an excess of ___ for the levels of ___ and ___ ___ ___ - can get jaundice.
Haem
For levels of ligandin and UDP glucuronyl transferase - so excess bilirubin and jaundice!
Major causes of jaundice:
Pre-hepatic:
Classic unconjugated/INDIRECT hyperbilirubinaemia.
Haemolysis and ineffective erythropoiesis.
Post-hepatic:
Classic conjugated/DIRECT hyperbilirubinaemia.
Gall stones, biliary strictures, cancers, inflammation of bile duct.
Hepatic:
Before microsome (i.e. ER) - e.g. drugs that interfere with uptake of bilirubin to ER where UDPGT is.
At microsome e.g. in infants, immature enzymes, Gilbert’s syndrome, Crigler-Najjar syndrome (no UDPGT).
After microsome - e.g. impaired excretion, so it is conjugated by not pumped into canaliculi e.g. in Dubin-Johnson syndrome (cMOAT deficiency).
Findings in haemolytic jaundice:
High unconjugated bilirubin.
Plasma - AST and hydroxybutyrate dehydrogenase are slightly elevated
Plasma haptoglobin is decreased
Urine urobilinogen is increased
More retics by EPO, decreased Hb, evidence of haemolysis on blood film
Jaundice is common in neonates because:
Increased haem catabolism (due to switch from HbF to HbA)
Immaturity of liver in bilirubin conjugation and excretion (immature ligandin AND UDPGT)
Treatment by phototherapy
Crigler-Najjar syndrome types
Type 1 - serious lack
Type 2 - partial deficiency
Of UDP glucuronyl transferase
Can be life threatening!
Gilbert’s syndrome is similar to ___-___ syndrome, but not life threatening
Crigler-Najjar syndrome
There is decreased activity of UDP GT - only one copy of gene mutation, but in C-N both copies are mutated.
Quite common!
Dubin-Johnson is lack of ___
cMOAT - benign.
Rotor syndrome is similar to ___-___ syndrome
Dubin Johnson syndrome
G6PD deficiency is the most common enzyme deficiency in the world, and death can result from ____ anaemia
Haemolytic anaemia
Deficiency only, lack of G6PD is incompatible with life.
GSH protection?
GSH is an antioxidant
GSH reacts with H2O2 -> GSSH and water.
GSSH is converted to GSH using NADPH (and NADPH is converted to NADP).
G6PD converts NADP to NADPH
SO if G6PD deficiency -> less NADPH, less GSH, less antioxidant effects and more oxidative stress -> oxidative haemolysis.
The first metabolite of glucose is glucose-6-phosphate.
G6P can go via glycolysis to pyruvate OR shunt into ___ ___ ___
Pentose phosphate pathway
The first step and enzyme of PPP is G6PD - NADP to NADPH and production of reduced glutathione i.e. (GSH).
Chloroquine, an antimalarial drug is contraindicated in patients with ___ ___. Why?
G6PD deficiency.
Chloroquine interacts with haem to produce ROS.
ROS is normally removed by GSH system, but if G6PD deficiency -> no NADPH/GSH -> membrane destruction (haemolytic jaundice) and globin precipitation (Heinz bodies).
Galactosaemia?
Lactose -> glucose and galactose.
But to use galactose, need to epimerise to glucose.
Failure of enzymes to epimerise galactose to glucose -> galactosaemia!
There are three types due to failure of three different enzymes:
1. Galactokinase
Converts galactose to 1-phosphate form.
2. Galactose-1-phosphate uridyl transferase.
3. Epimerase
Number 2 is the most common to fail.
