Genetics Of GI Disorders

Question 1

Drug-Drug interactions

Answer 1

EX: St. John’s Worth Herbal Remedy for depression (Hyperforin + Hypericin ——> CYP3A4 drug metabolizing enzyme ——> chews up birth control
= miracle baby

Question 2

CYPs (cytochromes P450)

Answer 2

Catalyze many chemical reactions by hydroxylation of an aliphatic or aromatic carbon (oxidative metabolism)
Paired with a Reductase——> bring e- to HEME——> +O2 = H2O + OH- (which binds to BC)

Question 3

CYP3A4

Answer 3

Heme containing protein in LIVER and GI

Xenobiotics that detoxifies or activates = makes prodrug—> Drug

Question 4

Other drugs that work like St. John’s worth

Answer 4

Rifampicin

Phenobarbital

Question 5

Crigler Najjar

Answer 5

Autosomal Recessive effecting bilirubin metabolism
= Non-Hemolytic JAUNDICE
= high unconjugated bilirubin
=Brian damage
= low hepatic bilirubin-glucose (conjugated)
Other Sx: lethargy, high risk in babies of parents from same family

Question 6

2 types of Crigler Najjar

Answer 6

TYPE 1 : severe jaundice + Kernicterus : brain dysfunction due to unconjugated-bilirubin

Type 2 : Arias Syndrome, not as severe

Question 7

What enzyme is effected in Crigler Najjar

Answer 7

UGT Enzypes subfamily 1
UGT1A1——> TYPE 1 : mutation on this = no activity of enzyme
——> TYPE 2 : mutation in coding region = defective or less active enzyme activity

Question 8

What is the pathway from Bilirubin to get excreted into urine

Answer 8

Heme —HO—> Biliverdin—BVR—> Bilirubin—UGT1A1—> Conjugated Bilirubin (Bilirubin glucuronides) ——> Excreted

Question 9

Other effects of UGT1A1 besides the Criglers Najjar

Answer 9

Metabolizes Anti-cancer drugs by hepatic UGT1A1 adding Glucurinide to drug = excreted

Question 10

Criglers Najjar Sx:

Answer 10

Neonatal jaundice
Sepsis
Hypotonia
Kernicterus = bilirubin deposited in the brain (cant get excreted)
-brain dysfunction (oculomotor palsy CN3)
-deafness

Question 11

Criglers Najjar Tx:

Answer 11

Plasmapheresis
Phototherapy (Billy Lights) 
Phenobarbital (UGT1A1 inducer) = only type 2
Liver Transplant = last resort

Question 12

Gilbert’s Syndrome

Answer 12

Yellow eyes, no other complaints (older people, not neonatals), does not eat during work 
DEFECTED PROMOTER (regulator) for UGT1A1
= lower expression of UGT1A1, + lower bilirubin uptake = very common
*mild jaundice associated with FASTING

Question 13

Gilbert’s Syndrome how is it associated with fasting

Answer 13

During fasting : higher uptake of non-esterified FAs ——I clear bilirubin = unjonjugated hyperbilirubinemia during fasting
(STRESS, INFECTION, ALCOHOL) are other associated things

Question 14

How does the Gilbert’s Syndrome present in labs

Answer 14

NO Hepatitis, NO hemolysis
Unconjugated Hyperbilirubinemia , while fasting
RIFAMPIN TEST : test bilirubin level by administering this drug while fasting and if level increase to 1.9mg/dL = + test

Question 15

Gilbert’s Syndrome Tx:

Answer 15

Since you have low level of UTG1A1 = avoid drugs that are metabolized by it = Irinotecan
= NO Treatment needed
= prevent fasting

Question 16

Dubin -Johnson/Rotor’s Syndrome severe head injury form MVA
Brain dead in ICU
While looking at the liver in the ABD his liver is black

Answer 16

=Black liver
mutated MRP2 ——> transports bile acid form hepatocytes to bile (DUBIN JOHNSON)
= mutated OATP1B1 and OATP1B3 ——> hepatic uptake transporters (ROTOR’S)

Question 17

What are MRP2 s

Answer 17

Part of ABC transporters
Transport bile acid from hepatocytes to bile
Also moves things back into SI in the GI

Question 18

What are OATP s

Answer 18

Influx transporters on sinusoidal membrane P1B1, P1B3, P1B1 = help liver uptake of substrate drugs into hepatocytes

Question 19

Black liver is caused by

Answer 19

Pigment substance deposition , impaired Epinephrine metabolites excretion

Question 20

Dubin Johnson’s

Answer 20

Conjugated hyperbilirubinemia (cant get transported to excretion, since bile acids cant get out to bile) 
BLACK LIVER = impaired Epinephrine excretion

Question 21

Rotors Syndrome

Answer 21

Milder + NO black liver
Normal life expectancy
Mutates OATP1B3 and OATP1B1 = impaired secretion and storage of bilirubin in LIVER
Conjugated hyperbilirubinemia
Jaundice, no bilirubinuria
Sx: most are asymptomatic, fatigue, pregnancy, oral contraceptives = can cause jaundice and worse Sx (X hepatic excretion)

Question 22

Increased TOTAL bilirubin
Elevated Urine Coproporphyrin levels
BLACK liver

Answer 22

DJS
RS
DJS

Question 23

Wilson’s Disease

Answer 23

Unsteady gate, forgetfulness, Turret-like spells
Multicolored and concentric rings in iris,
CANT EAT Cu (chocolate, shellfish, some water)

Question 24

Where are Cu acculturation happening in Wilson’s Disease

Answer 24

LIVER, BRAIN, CORNEA, JOINTS = hepato-lenticular degeneration
MUTATION of ATP7B = Liver cant excrete Cu into bile since it is found in circulation without CERULOPLASMIN (transport protein for Cu)
- free Cu can also cause free radicals and damage tissues

Question 25

where is Cu put onto the ceruloplasmin before excreted into blood

Answer 25

In the Golgi of LIVER by ATP7B | DURING LOW Cu

Question 26

How is CU excreted into bile

Answer 26

Uses ATP7B to activate Cu pump to get Cu excreted into bile by liver cells DURING Cu EXCESS

Question 27

Wilson’s Disease Sx

Answer 27

CNS and Liver disorders Cardiac and renal and iris problems Parkinson’s sx (Cu deposited Putamen) Hemiballismus (Cu deposited in subthalamic nucleus) Dementia (C deposited in Cerebral Cortex)

Question 28

Wilson’s Disease on PE

Answer 28

Cirrhosis Corneal slit lamp examination = KAYSER FLEISHER RIGNS (not seen in primary biliary cirrhosis) LOW : Serum Cu HIGH : Serum non-ceruloplasmin bound Cu, Cu-free urine Hemolytic anemia Liver Biopsy : HIGH hepatic Cu

Question 29

Wilson’s Disease Tx:

Answer 29

Ammonium tetrathionolybdate = helps excrete Cu Penicillamine = agent chelating Cu Tridentine = agent Chelating Cu Zinc = competes Cu for absorption by ATP7B= less Cu absorption Liver Transplant - last resort

Question 30

Wilson’s Disease risks

Answer 30

Hepatitis Cirrhosis Hepatic Elul are Carcinoma (HCC) Fanconi’s Disease of proximal tubules