Genetics of GI Disorders

Question 1

Cytochrome P450 enzymes

Answer 1

Detoxifies/activates the most drugs of any enzyme family
Determine intensity and duration of drug action
Biosynthesis of steroid hormones, bile acids, fatty acids and eicosanoids

Question 2

Crigler Najjar

Answer 2

Autosomal recessive
Unconjugated hyperbilirubinemia
Absent or very low levels of hepatic bilirubin-glucose
Causes brain damage in infants - kernicterus - caused by bilirubin deposition in brain
Type 1 - severe. UGT mutation renders enzyme absent
Type 2 mild. UGT mutation in coding region renders enzyme defective and less active
UDP glucuronyl transferase= UGT

Question 3

Crigler Najjar treatments

Answer 3

Plasmapheresis
Phototherapy
Phenobarbital- UGT1AI inducer - only for type II
Liver transplant

Question 4

Gilberts syndrome

Answer 4

Hereditary unconjugated hyperbilirubinemia due to defect in gene promotor for UGT
Mild decreased UGT activity due to lower expression
AD or AR inheritance
Largely asymptomatic, jaundice associated w/fasting

Question 5

Diagnosing gilberts syndrome

Answer 5

Isolated unconjugated hyperbilirubinemia WITHOUT evidence of hepatitis or hemolysis
Fasting test
Rifampin test- rifampin increases bilirubin levels in everybody. On fasting for 12-24hrs, an increase of bilirubin 2-6hr after administration of rifampin distinguishes those with gilberts from those without

Question 6

Dubin-Johnson

Answer 6

Black kidney due to impaired excretion of epinephrine metabolites
Increased TOTAL bilirubin levels
Hereditary conjugated hyperbilirubinemia - decreased hepatic excretion of conjugated bilirubin
Mutations in MRP2 (transports conj-bilirubin from liver to bile)

Question 7

Rotor syndrome

Answer 7

Mutation in both OATP1B1 and OATP1B3 (transports conj-bilirubin from blood to hepatocyte)
Milder than Dubin-Johnson
Increased direct/conjugated bilirubin levels
No black liver

Question 8

Distinguishing Rotor from DJS

Answer 8

Rotor has elevated coproporphyrin levels in urine

Question 9

Wilsons disease biochemical cause

Answer 9

Free copper accumulation in many tissues such as liver, brain, cornea, joints
Mutation in ATP7B (transporter that pumps copper from liver into bile) results in:
-Inadequate copper excretion by liver into bile
-Failure of copper to enter circulation bound to ceruloplasmin
Free copper generates free radicals
AR inheritance

Question 10

Wilsons disease presentation

Answer 10

Hepatomegaly
Jaundice
Acute hepatitis
Portal hypertension
Cirrhosis
Kayser Fleischer rings in eyes
Many central nervous system symptoms as well - cerebellar symptoms, dysphagia, behavior changes, dementia

Question 11

Wilsons disease labs

Answer 11

Increased serum non-ceruloplasmin bound copper
Decreased total serum copper due to dec. ceruloplasmin
Increased urine/serum free copper
Hemolytic anemia
Liver biopsy will show increased hepatic copper

Question 12

Wilsons disease treatments

Answer 12

Copper chelating agents
Ammonium tetrathiomolybdate- facilitates urinary exc of copper
Zinc- competes with copper for absorption in the gut via same transporter ATPB7

Question 13

Essential/benign fructosuria

Answer 13

Deficiency in fructokinase

Fructose accumulates in urine because it cannot be trapped in hepatocytes via phosphorylation

Question 14

Galactosemias classic and non classic form

Answer 14

Classic- galactose-1-phosphate uridyltransferase GALT is deficient
Causes cataracts, hepatomegaly, jaundice and failure to thrive in newborns
Non classic Mild form- deficiency in galactokinase or UDP-galactose epimerase
Galactose accumulates in blood/urine especially after high galactose meals are consumed such as milk

Question 15

Aldolase B deficiency

Answer 15

Hereditary fructose intolerance
Deficiency in hepatic aldolase B - cleaves F1P into GAP and DHAP
Fructose and F1P accumulate
F1P sequesters cellular phosphate - causes low blood phosphorus
Low blood glucose results too
Treat with low fructose/sucrose diet

Question 16

Von Gierke disease GSD Ia

Answer 16

Deficient G6P
Free glucose is unable to be released into blood stream by liver
Pts exhibit market fasting hypoglycemia
Also have lactic acidosis and hepatomegaly due to buildup of glycogen
Hyperlipidemia

Question 17

Fasting versus starving

Answer 17

Body adapts to fasting by depleting energy stores such as glycogen, then lipolysis
Starvation occurs when body energy stores are depleted, and the body resorts to utilizing essential tissues for energy
-results in reduction in organ volume w/gradual loss of function, loss of muscle mass, and many others

Question 18

PEPCK deficiency

Answer 18

PEPCK catalyzes conversion of oxaloacetate into PEP

Symptoms include increased acid in blood, hypoglycemia, loss of muscle tone, hepatomegaly and failure to thrive

Question 19

PEP production in mitochondria

Answer 19

When lactate levels are high, OAA is converted directly to PEP in the mitochondria- because lactate converts to pyruvate which produces NADH, therefore malate–>OAA conversion is not favorable so OAA is directly converted to PEP
PEP is then converted to glucose via gluconeogenesis

Question 20

Glycogen storage disease Ib

Answer 20

Defect of transport protein that moves G6P from cytosol into lumen of ER of hepatocytes
Very similar condition to GSD Ia because G6Phosphatase is still unable to do its job and create free glucose
Treatment with uncooked cornstarch at night because it is broken down to glucose slowly throughout fasting at night
Or surgical transposition of portal vein - redirects nutrient rich blood from intestine into peripheral circulation, reducing liver uptake of glucose and increasing glucose rich blood supply to tissues