The Genetics of GI Disorders

Question 1

what are the genetic disorders related to heme-metabolism?

Answer 1

crigler-Najjar Syndrome, gilbert’s disease, dubin-johnson syndrome, rotor syndrome

Question 2

what is crigler najjar syndrome?

Answer 2

rare autosomal recessive disorder that affects the metabolism of bilirubin; hereditary unconjugated hyperbilirubinemia

Question 3

what does crigler najjar syndrome cause?

Answer 3

non-hemolytic jaundice, higher than normal levels of unconjugated bilirubin, and brain damage in infants

Question 4

what would you expect to find in an infant with crigler najjar syndrome?

Answer 4

absent or very low levels of hepatic bilirubin-glucose

Question 5

what are the two types of crigler najjar syndrome?

Answer 5

type I: severe jaundice and kernicterus and Type II: less severe

Question 6

type I crigler najjar syndrome is caused by a mutation in what?

Answer 6

UGT1A1- it renders the enzyme activity totally absent or not expressed

Question 7

type II crigler najjar syndrome is caused by a mutation where?

Answer 7

in UGT1A1 coding region- renders the enzyme defective and less active than normal

Question 8

how does crigler najjar patient present?

Answer 8

neonatal jaundice, sepsis, hypotonia, kernicterus, occulomotor palsy

Question 9

what is kernicterus caused by?

Answer 9

bilirubin deposition in the brain

Question 10

what can you use to treat type II crigler najjar?

Answer 10

phenobarbital-UGT1A1 inducer

Question 11

what is gilbert’s syndrome?

Answer 11

hereditary unconjugated hyperbilirubinemia due to a defect in the gene promoter for UGT1A1

Question 12

what happens in gilbert’s syndrome?

Answer 12

there is a mild decrease in UDP-glucuronyl transferase activity due to lower expression of wild type enzyme; mild decrease in bilirubin uptake

Question 13

how does a patient with gilbert’s syndrome present?

Answer 13

mild jaundice, associated with fasting; stress; EtOH

Question 14

how would you diagnose gilbert’s syndrome?

Answer 14

if there was isolated unconjugated hyperbilirubinemia without evidence of hepatitis or hemolysis

Question 15

what is the treatment for gilbert’s syndrome?

Answer 15

no treatment needed; avoid certain medications though- like irinotecan

Question 16

what is Dubin-Johnson Syndrome caused by?

Answer 16

a mutation in MRP2

Question 17

what is rotor’s syndrome caused by?

Answer 17

mutations in OATP1B1 and OATP1B3

Question 18

what is Dubin-Johnson syndrome?

Answer 18

hereditary conjugated hyperbilirubinemia (decreased hepatic excretion of conjugated bilirubin)

Question 19

what causes the grossly black liver in Dubin Johnson Syndrome?

Answer 19

it is due to impaired excretion of epinephrine metabolites

Question 20

what is the milder form of Dubin Johnson syndrome that does not cause the grossly black liver?

Answer 20

Rotor’s syndrome

Question 21

In a patient with rotor’s syndrome, what do their total urine coproporphyrin levels look like?

Answer 21

they are elevated

Question 22

in a patient with Dubin-Johnson syndrome, what do their total urine coproporphyrin levels look like?

Answer 22

they are normal

Question 23

what is wilson’s disease caused by?

Answer 23

a mutation in the ATP7B gene

Question 24

what does the mutation in the ATP7B gene cause?

Answer 24

inadequate copper excretion by the liver into bile; failure of copper to enter circulation bound to ceruloplasmin

Question 25

what does a patient with wilson’s disease typically present with?

Answer 25

parkinson-like symptoms (secondary to the copper deposits in putamen) like hemiballisumus and dementia

Question 26

what are the physical exam findings of a patient with wilson’s disease?

Answer 26

cirrhosis and kayser-fleischer rings (corneal deposits)

Question 27

what do the labs look like in a patient with wilson’s disease?

Answer 27

decrease total serum copper due to decrease ceruloplasmin, increased serum non-cerulopasmin bound copper, increased urine/serum free copper, and hemolytic anemia

Question 28

what is a patient with wilson’s disease at risk of?

Answer 28

hepatitis, cirrhosis, and hepatocellular carcinoma

Question 29

what is a specific test used for Gilbert’s syndrome?

Answer 29

Rifampin test