Genetics of GI disorders

Question 1

Breast Milk Jaundice?

Answer 1

super rare

linked to a substance in milk that might gum up UGT, but it’s not clear that it’s preventing it.

Question 2

In Dubin-Johnson syndrome, what’s the mutant?

Answer 2

the liver does not have the conjugated bilirubin transporter MRP2.. so you see a lot of conjugated bilirubin.

Question 3

Crigler Najjar is what kind of disorder?

what does it affect?

Answer 3

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

Question 4

What are the two types of crippler najjir?

which one will not present in adults?

Answer 4

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)

Question 5

What is UGT1A1?

Answer 5

UDP is shoved on it. glycosylating it “activates it”.

Question 6

what does UGT1A1 does other than with bilirubin?

Answer 6

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

Question 7

What happens when you stick a sugar group on a

Answer 7

started lipophilic.

when you stick a sugar group it becomes less soluble because of its polarity.

Question 8

if UGT1A1 is dead, does that mean no bilirubin will be glucoronydated?

Answer 8

there will still be bilirubin but it won’t be done as efficiently because UGT1A1 is the best at its job

Question 9

how do patients with Crigler Najjar present?

Answer 9

jaundice
sepsis
hypotonia
Kernicterus –> deafness, poor mental progression/development.

CNS problems, droopy arms.

Question 10

why is Kernicterus a bad problem?

Answer 10

bilirubin deposition in the brain leads to poor brain development/mental functions

if it’s severe enough, patients die within a few years

Question 11

what’s an option for treatment for Crigler Najjar-Treatment?

Answer 11

Plamapheresis

Phototherapy

Phenobarbital (only for type 2)

Question 12

how does phenobarbital work?

Answer 12

it induces the expression of UGT1A1, it’ll help increase its activity.. that’s why it only works for type 2.

Question 13

parents are known to be first cousins… flopping arms… jaundice… what are you thinking?

Answer 13

Crigler Najjar

Question 14

Gilbert’s Syndrome?

what is it caused by?

what’s built up?

what is the genetics of it?

Answer 14

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

Question 15

how do Gilbert patients present

how can the symptoms be exacerbated?

Answer 15

largely asymptomatic but people get occasional recurrent mild jaundice.

Fasting, Stress, Ethanol intake

Question 16

what evidence is not present for Gilbert’s syndrome individuals?

what tests do they do for testing?

which is more specific for Gilberts?

Answer 16

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)..

Question 17

what is the treatment for Gilbert’s syndrome?

Answer 17

no treatment needed!!

no consequences, but you need to avoid irenotecan drugs.

Question 18

Dubin-Johnson/Rotor’s syndrome?

Answer 18

Dubin johnson - mutations in MRP2

Rotor’s Syndrome = mutations in OATP1B1 and OATP1B3

Question 19

why would you have conjugated bilirubin for rotors/dubins?

Answer 19

MRP2 and OATP are downstream of UGTP acid so they should be conjugated by the point.. it should backup to the blood and spillover.

Question 20

Dubin Johnson Syndrome causes what?

Rotor syndrome causes what?

Answer 20

black liver

no black liver

Question 21

What is required for Rotor’s syndrome to happen?

what are the genetics of Rotor’s syndrome?

what kind of bilirubin?

Answer 21

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.

Question 22

What are the coproporphyrin levels in the urine for rotors and DJS?

Answer 22

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

Question 23

Congenital biliary atresia?

Answer 23

jaundice 2-6 weeks of age, high CONJUGATED bilirubin, dark urine and echoic stools

Question 24

Isoimmune hemolytic anemia?

what tests are confirmed?

Answer 24

indirect Coombs test is positive in mother and Coombs test is weakly positive in infant

Anemia is usually present!

Question 25

Breast milk jaundice?

Answer 25

presents jaundice in 2nd week of life.

Question 26

Breast Feeding jaundice?

Answer 26

appears first 2-4 days of life..

Question 27

Wilson’s disease:

genetics?

hallmark?

what is it caused by?

Answer 27

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

Question 28

what does ATP7B do?

Answer 28

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.

Question 29

how do you delineate Wilson’s disease from other choices?

Answer 29

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

Question 30

What would you see on a physical exam for Wilson’s disease?

Answer 30

Cirrhosis

Corneal deposits on slit lamp examination (Kayser-Fleischer rings)

Question 31

What’s the treatment of Wilson disease? (4)

what surgical thing do you do?

Answer 31

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

Question 32

risk factors of Wilson’s disease?

Answer 32

hepatitis
cirrhosis
Hepatocellular carcinoma

Question 33

what is biliary atresia?

Answer 33

presents 2-8 weeks after birth.

bile flow from the liver to the gallbladder is blocked..