Genetic Disorders affecting the GI system

Question 1

UDP Glucuronyl transferase-related disorders

Answer 1

Crigler-Najjar syndrome results from a deficiency of UDP-glucuronyl transferase. Type 1 results from a complete absence of the gene with sever hyperbilirubinemia that accumulates in the brain of affected newborns and that causes a form of encephalopahty called kernicterus. Therapy includes transfusinos in the immediate neonatal period, phototherapy, heme oxygenase inhibitors to reduce transient worsening of hyperbilirubinemia, oral calcium phosphate and carbonate to form complexes with bilirubin in the gut, and liver transplantation prior to the onset of brain damage and before phototherapy becomes ineffective. Type II is a benign form of this disorder resulting from a mutation that causes a partial deficiency o the gene. Gilbert syndrome is a relatively common, benign disorder resulting from the decreased activity of DUP-glucoronyl transferase.

Question 2

Dubin Johnson Syndrome

Answer 2

caused by a defect in the canalicular mutliple organic anion transporter (cMOAT, Mrp2, ABCC2) and leads to an accumulation of conjugated (direct) bilirubin, which can no logner e exported from the hepatocytes into the bile. This is a benign condition that usually does not require treatment. However, during pregnancy or after oral contraceptives, jaundice may occur. The latter are contraindicated in these patients.

Question 3

genetic disorders of heme metabolism

Answer 3

criglar-najjar syndrome 
dubin-johnson syndrome 
gilbert's disease 
porphyria cutanea tarda 
acute intermittent porphyria

Question 4

genetic disorders of copper and iron metabolism

Answer 4

wilson’s disease

hemochromatosis

Question 5

genetic disoders of carbohydrate metabolism

Answer 5

galactosemia
hereditary fructose intolerance
PEP carboxykinase deficiency
von Gierke’s disease

Question 6

enzyme that converts heme to biliverdin

Answer 6

heme oxygenase

Question 7

enzyme that converts biliverdin to bilirubin

Answer 7

bilirubin reductase

Question 8

the conversion of heme to bilirubin occurs in what cell

Answer 8

the macrophage of RES

Question 9

in the blood, bilirubin transiently binds what protein for transportation, failure of this binding resulting in what condition

Answer 9

albumin

jaundice

Question 10

in the liver, bilirubin is converted to bilirubin-monoglucuronide and then to bilirubin diglucucuronide by what enzyme

Answer 10

UDP-glucuronyl transferase handles both these steps

Question 11

insufficient or absent UDP-glucuronyl transferase is characteristic of what disease

Answer 11

crigler-najjar syndrome
Type 1: total absence, severe form –> brain damage kernicture
type 2: <25% UDP-Glucuronyl transferase function

Question 12

gilberts disease MoA

Answer 12

decrease in bilirubin with phenobarbital
liver doesnt properly process bilirubin - example of nonhemolytic jaundice
UGT1A1 gene results in decreased activity of bilirubin uridine diphosphate glucuronylosyltrasnferase

Question 13

dubin johnson syndrome and rotor syndrome are both a result of

Answer 13

impaired biliary excretion of conjugated organic anions and bilirubin

Question 14

porphoryia cutanea tarda results from a deficiency in what enzyme

Answer 14

uroporphyrinogen decarboxylase, an enzyme involved in the synthesis of heme

Question 15

acute intermittent porphyria is caused by a deficiency in what enzyme

Answer 15

pophobilinogen daminase

Question 16

wilsons disease gene deficiency

Answer 16

ATP7B codes for a copper transporting ATPase in the trans-golgi network of the liver and brain
balances copper level in the body by excreting excess copper into bile and plasma

Question 17

characteristics of wilsons disease

Answer 17

** borwn ring in the edge of cornea *** 
copper builds up in the body, esp brain and liver 
vomiting, weakness, fluid buildup in abdomen, swelling of legs, yellowish skin, itchiness 
tremors 
muscle stiffness 
trouble speaking 
personality changes 
anxiety 
seeing/hearing things others do not

Question 18

hemachromatosis

Answer 18

organ dysfuntion due to iron overload: cirrhosis, arthritis, endocrinopathy, skin pigmentation, cardiomyopathy; usually manifests in 6th decade

Question 19

iron is transported into enterocytes in what form

Answer 19

Fe2+

Question 20

what is the apical membrane iron transporter in enterocytes

Answer 20

DMT 1

Question 21

what is the BLM iron transporter of enterocytes

Answer 21

ferroportin (requires ferroxidase)

Question 22

regulates iron content in body by modulated absorption

Answer 22

hepcidin

Question 23

what molecule regulates hepcidin

Answer 23

HFE

Question 24

galactosemia enzyme deficiency

Answer 24

GALT (rate limiting step of Galactose breakdown)
infants are unable to utilize galactose found in milk
suffer from malnutrition, failure to thrive
accumulates in tissues –> damage to liver, brain, eyes
cataracts develop in the first few weeks

Question 25

hereditary fructose intolerance results from a deficiency in what enzyme

Answer 25

aldolase B in the liver | converts frutose 1-P to glyceraldehyde and DHAP

Question 26

Von gierke disease results from a deficiency in what enzyme and enzymatic pathway

Answer 26

glucose 6 phosphate (only in liver, kidney,s pancreatic beta cells) that cleaves the phosphate of glucose-6P gluconeogenesis/glycogen storage disease

Question 27

PEPCK deficiency results in an inability to form what from OAA

Answer 27

PEP | PEPCK == PEP carboxykinase, a key enzyme in gluconeogenesis

Question 28

ALT, AST will give you an idea of what cells of the liver

Answer 28

hepatocytes

Question 29

ALP gives you an idea of whats happening to whatt cells in the liver

Answer 29

canalicular system cells

Question 30

crigler najjar enzyme deficiency

Answer 30

bilirubin-UGT | UGT1A1

Question 31

treatment for crigler najjar

Answer 31

plasmapheresis phototherapy phenobarbitol (induces UGT1A1)

Question 32

gilberts syndrome enzyme

Answer 32

hereditary unconjugated hyperbilirubinemia UGT1A1 activity but mild

Question 33

gilbert's syndrome aggravating factors

Answer 33

fasting stress EtOH

Question 34

diseases of unconjugsted hyperbilirubinemia

Answer 34

crigler najjar | gilberts

Question 35

dubin-johnson/rotor syndrome share what MoA

Answer 35

hereditary conjugated hyperbilirubinemia | leads to decreased hepatic excretion of conjugated bilirubin

Question 36

black liver

Answer 36

dubin johnson (due to impaired excretion of epinephrine metabolites)

Question 37

rotor is a milder form of what disease

Answer 37

dubin johnson

Question 38

wilsons disease enzyme deficiency

Answer 38

ATP7B moves copper from inside the cell to outside the cell cant excrete it