Genetics of GI disorders Flashcards
Breast Milk Jaundice?
super rare
linked to a substance in milk that might gum up UGT, but it’s not clear that it’s preventing it.
In Dubin-Johnson syndrome, what’s the mutant?
the liver does not have the conjugated bilirubin transporter MRP2.. so you see a lot of conjugated bilirubin.
Crigler Najjar is what kind of disorder?
what does it affect?
autosomal recessive.. so need two copies of the allele.
metabolism of bilirubin –> causes non-hemolytic jaundice, higher than normal levels of unconjugated, brain damage in infants
What are the two types of crippler najjir?
which one will not present in adults?
type 1 -> UGT1A1 activity is absent. enzyme is dead
type 1 won’t present in adults because they won’t make it. type 1 is lethal.
type 2 –> mutation makes it less active (Arias syndrome)
What is UGT1A1?
UDP is shoved on it. glycosylating it “activates it”.
what does UGT1A1 does other than with bilirubin?
UGT1A1 has broad substrate specificity
(Ironotecan) is an anticancer agent. it’s a prodrug that needs to be converted by carboxyl esterase.. ironotecan is converted to SN-38… and in order to get rid of it we take UDP-Glucornate and strip the glucose off and strap it to SN-38.
this form SN-38-Gluronide is excreted.
all of this is made possible through UGT1A1
What happens when you stick a sugar group on a
started lipophilic.
when you stick a sugar group it becomes less soluble because of its polarity.
if UGT1A1 is dead, does that mean no bilirubin will be glucoronydated?
there will still be bilirubin but it won’t be done as efficiently because UGT1A1 is the best at its job
how do patients with Crigler Najjar present?
jaundice
sepsis
hypotonia
Kernicterus –> deafness, poor mental progression/development.
CNS problems, droopy arms.
why is Kernicterus a bad problem?
bilirubin deposition in the brain leads to poor brain development/mental functions
if it’s severe enough, patients die within a few years
what’s an option for treatment for Crigler Najjar-Treatment?
Plamapheresis
Phototherapy
Phenobarbital (only for type 2)
how does phenobarbital work?
it induces the expression of UGT1A1, it’ll help increase its activity.. that’s why it only works for type 2.
parents are known to be first cousins… flopping arms… jaundice… what are you thinking?
Crigler Najjar
Gilbert’s Syndrome?
what is it caused by?
what’s built up?
what is the genetics of it?
Hereditary increases in unconjugated hyperbilirubinemia due to DEFECT IN THE GENE PROMOTOR FOR UGT1A1
So the enzyme itself is wild type.
you get mild UDP-glucoronyl transferase activity due to lower expression of the wild type enzyme
you also get lower bilirubin uptake
AD or AR inheritance
how do Gilbert patients present
how can the symptoms be exacerbated?
largely asymptomatic but people get occasional recurrent mild jaundice.
Fasting, Stress, Ethanol intake
what evidence is not present for Gilbert’s syndrome individuals?
what tests do they do for testing?
which is more specific for Gilberts?
hyperbilirubinemia without the evidence of hepatitis or hemolysis
fasting test –> fasting will rise unconjugated bilirubin after a day of fasting with low lipid, 400kcal diet. ** more specific **
rifampicin test –> Rifampicin dose rises the uncongugated bilirubin by inducing cytochrome p-450 and competing for excretory pathways in the liver)..
what is the treatment for Gilbert’s syndrome?
no treatment needed!!
no consequences, but you need to avoid irenotecan drugs.
Dubin-Johnson/Rotor’s syndrome?
Dubin johnson - mutations in MRP2
Rotor’s Syndrome = mutations in OATP1B1 and OATP1B3
why would you have conjugated bilirubin for rotors/dubins?
MRP2 and OATP are downstream of UGTP acid so they should be conjugated by the point.. it should backup to the blood and spillover.
Dubin Johnson Syndrome causes what?
Rotor syndrome causes what?
black liver
no black liver
What is required for Rotor’s syndrome to happen?
what are the genetics of Rotor’s syndrome?
what kind of bilirubin?
you need to have mutations in both OATP1B1 AND OATP1B3!
Autosomal Recessive
so you can’t store bilirubin in the liver.. which is why you don’t have a black liver.
both but conjugated is more predominant.
What are the coproporphyrin levels in the urine for rotors and DJS?
elevated in rotors (because you can’t get it to the liver so its stuck in the blood with only one way out.. the urine)
DJS is normal
Congenital biliary atresia?
jaundice 2-6 weeks of age, high CONJUGATED bilirubin, dark urine and echoic stools
Isoimmune hemolytic anemia?
what tests are confirmed?
indirect Coombs test is positive in mother and Coombs test is weakly positive in infant
Anemia is usually present!
Breast milk jaundice?
presents jaundice in 2nd week of life.
Breast Feeding jaundice?
appears first 2-4 days of life..
Wilson’s disease:
genetics?
hallmark?
what is it caused by?
Autosomal recessive
irises appear multicolored with concentric rings
copper needs to be bound.. without it being bound it’s toxic and can accumulate in the liver, brain, cornea, joints.
there’s a mutation in ATP7B that results in inadequate copper excretion by liver into bile…. also failure of copper to enter circulation bound by ceruloplasmin
(so essentially copper trafficking within hepatocytes is nil, leading to accumulation of it in hepatocytes since the main route is impaired. eventually this causes tissue damage.0
what does ATP7B do?
functions to move copper through the transgolgi network in the liver and get it into the bile.
if ATP7B is mutant, copper accumulates in the liver. (essentially found on the basolateral membrane side, but just helps shove stuff outside.
how do you delineate Wilson’s disease from other choices?
presentation of CNS systems because copper accumulates through the liver –> then in the blood –> then in the brain
Parkinson-like symptoms
undesired movements of the limbs (Hemiballismus)
Dementia
What would you see on a physical exam for Wilson’s disease?
Cirrhosis
Corneal deposits on slit lamp examination (Kayser-Fleischer rings)
What’s the treatment of Wilson disease? (4)
what surgical thing do you do?
ammonium tetrathiomolybdate –> helps facilitate urinary excretion of copper
penicillamine –> copper chelating agent (bind copper and sequesters it away from doing away and secretes it)
Trientine –> same as above
Zinc –> competes with copper for absorption via the same ATPB7 transporter
liver transplant
risk factors of Wilson’s disease?
hepatitis
cirrhosis
Hepatocellular carcinoma
what is biliary atresia?
presents 2-8 weeks after birth.
bile flow from the liver to the gallbladder is blocked..
