Lecture 22: Genetics of GI Disorders

Question 1

What does St. John’s Wort do?

Answer 1

has hyperforin and Hypericin which induces CYP3A4 which chews up steroid meds and a lot of different drugs

Question 2

What does biotransformation mean?

Answer 2

fat soluble drugs converted to water soluble

Question 3

What are the phases of drug biotransformation?

Answer 3

Phase 1: Oxidative metabolism (ROHH)
Phase 2: Conjugative metabolism (CSMG)
Phase 3: Drug transport/effux/excretion

Question 4

How does Rifampicin, Phenobarbital and St. John’s Wort activate the xenobiotic response?
What genes do they upregulate?

Answer 4

they bind to PXR-RXR > upregulate genes that make enzymes for detoxification processes
Phase 1: Cyp3A
Phase 2: UGT1A1
Phase 3: Oatp2, Mrp2

Question 5

What are the major transporters that absorb the drug in these types of cells?
enterocyte
hepatocyte
kidneys

Answer 5

• OATP
• OATPB1/B3 (hepatocyte membrane), MRP2 (canalicular membrane)
• MRP2/4 (to urine)

Question 6

Crigler Najjar/Hereditary Unconjugated Hyperbilirubinemia

Answer 6

• autosomal recessive disease, usually presents in infant
• non-hemolytic jaundice due to defective UDPGT enzyme which conjugates bilirubin in the liver, lots of unconjugated bilirubin, brain damage if untreated

Question 7

Type 1 Crigler Najjar vs Type 2 Crigler Najjar

Answer 7

Type 1: UGT1A1 mutation, absent activity, more severe version

Type 2: UGT1A1 mutation, less activity compared to normal

Question 8

Other than bilirubin conjugation, what other roles does UGT1A1 do?

Answer 8

metabolizes anti-cancer drugs like Ironotecan. conjugates its toxic metabolite SN38 by adding glucose = SN38 glucuronide

Question 9

Kernicterus

Answer 9

bilirubin buildup and deposit on brain > impairs brain fxn, lead to death if severe

Question 10

How do you treat Crigler Najjar syndrome?

Answer 10

plasmapheresis
phototherapy
Phenobarbitol (induces UGT1A1, only works on Type 2)
Liver transplant

Question 11

What is the pathophysiology of Gilbert’s syndrome?

Answer 11

• hereditary unconjugated hyperbili w/o evidence of hemolysis or hepatitis
• UGT1A1 promoter defect = 30% UDPGT activity compared to normal

Question 12

What are the symptoms of Gilbert syndrome?

Treatment?

Answer 12

• usually asymptomatic, mild jaundice occasionally, associated with fasting
• usually doesn’t need treatment, but avoid Irinotecan

Question 13

Causes of Dubin Johnson syndrome vs. Rotor’s syndrome

Answer 13

DJS: MRP2 mutation (transports stuff from hepatocyte to bile)
Rotor’s: OATP1B1/B3 mutation (impairs bilirubin storage in liver)

*both conjugated hyperbilirubinemia

Question 14

Symptoms of Dubin Johnson vs Rotor’s

Answer 14

DJS: conjugated bili + black liver due to impaired excretion of metabolites, pigment deposition
RS: conjugated bili + liver not black, usually benign

Question 15

Labs in Dubin Johnson vs Rotor’s

Answer 15

DJS: elevated bilirubin, normal urine coproporphyrin
RS: normal total bili, elevated urine coproporphyrin

Question 16

Hemochromatosis

Answer 16

increased iron absorption due to decreased hepcidin (which dissolves the iron transporter)

Question 17

Wilson Disease
cause
symptoms

Answer 17

• copper accumulation in brain, liver and tissues due to ATP7B mutation
• multiple colored rings in iris/Keyser Fleischer rings, parkinson’s like symptoms, ballistic limb movements, CNS stuff

Question 18

Why is ATP7B important in Wilson Disease?

Answer 18

transports copper into bile, if mutated copper is not excreted out of liver
-it also helps bind copper to ceruloplasmin in liver, so without it copper accumulates in the blood and becomes free radicals

Question 19

What are the lab findings for Wilson disease?

Answer 19

• low total serum copper (due to lack of ceruloplasmin)

- high free serum copper and urine copper

Question 20

How do you treat Wilson Disease?

Answer 20

• chelation therapy (penicillamine, trientine)
• Zn (competitive inhibitor of Cu for absorption in gut, prevents Cu from being absorbed)
• Ammonium tetrathiomolybdate (induces Cu urine excretion)
• Liver transplant

Question 21

Galactosemia
Classic vs type 2
Clinical

Answer 21

Deficiency in GALT enzyme (classic) or Galactokinase (type 2)
Classic symptoms:
-Vomiting/Diarrhea after consuming milk
-Enlargement of liver
-Cataracts

Type 2 symptoms:
-build of galactitol (cataracts)

Question 22

What is Von Gierke Disease?

Answer 22

Deficiency in Glucose-6 phosphatase