The Genetis of GI disorders

Question 1

what is Crigler Najjar syndrome?

Answer 1

Autosomal recessive disorder that affects the metabolism of bilirubin that leads to:

• Non-hemolytic jaundice
• higher than normal levels of unconjugated bilirubin
• brain damage in infants

Question 2

what are the two types of Crigler najjar syndrome

Answer 2

Type 1: mutation in UGT1A1 that renders the enzyme activity totally absent or not expressed

Type 2: mutation in UGT1A1 coding region that renders the enzyme defective and less active than normal
(arias syndrome)

Question 3

what other metabolites does UGT1A1 conjugate?

Answer 3

SN-38 which is a toxic anti-cancer drug

it adds a glucuronate on to SN-38 to make it soluble for elimination

Question 4

what are patient presentations of Crigler Najjar syndrome:

Answer 4

Neonatal jaundice
sepsis
hypotonia

Kernicterus:

• bilirubin deposition in brain
• poor development/mental function
• if severe patients die within a few years

Question 5

what is treatment of Crigler Najjar?

Answer 5

• Plasmapheresis
• Phototherapy
• Phenobarbital (UGT1A1 inducer) (this only works for Type II to increase the UDP-glucuronyl transferase mRNA synthesis and UGT activity
• Liver transplant

Question 6

What is Gilberts syndrome?

Answer 6

Hereditary unconjugated hyperbilirubinemia due to a defect in the gene promotor for UGT1A1

mild decrease in UDP-glucuronyl transferase activity due to lower expression of wild type enzyme

decrease in bilirubin uptake

can be an AD or AR inheritance

Question 7

how does Gilberts syndrome present?

Answer 7

Largely asymptomatic

Occasional recurrent mild jaundice

• associated with fasting
• stress or infection
• EtOH intake

Question 8

How to diagnosis for Gilberts syndrome?

Answer 8

Isolated unconjugated hyperbilirubinemia without evidence of hepatitis or hemolysis

Genetic testing

Fasting test:
-unconjugated bilirubin will rise after a day of fasting

Rifampin test:
-after fasting, administration of rifampin test can lead to an increase of bilirubin

Question 9

what is the treatment of gilberts syndrome and what is the prognosis, prevention, and complications?

Answer 9

treatment: no treatment needed

avoid certain medications (irinotecan)
-anti cancer drug that needs UGT1A1 to be conjugated

Question 10

What is Dubin johnson syndrome and what is its presentation?

Answer 10

Hereditary conjugated hyperbilirubinemia

• decrease hepatic excretion of conjugated bilirubinemia
• mutation in the MRP2 protein

patients present with a grossly black liver due to impaired excretion of epinephrine metabolites

• benign
• autosomal recessive

Question 11

what is rotors syndrome? and how does it present?

Answer 11

Hereditary hyperbilirubinemia

• decrease hepatic excretion of conjugated bilirubin
• mutation in both OATP1B1 and OATP1B3 uptake tranport proteins

patients are generally asymptomatic

• do not have a black liver
• bilirubinuria is typically present
• may have jaundice or icterus during fatigue, pregnancy, or oral contraceptives due to reduction in hepatic function

Question 12

how do lab results present for Dubin-johnson and Rotors syndrom

Answer 12

May show direct (conjugated) hyperbilirubinemia)

increased total bilirubin in DJS

Coproporphyrin III: coproporphyrin I ratio is 1:3 (opposite of normal)

Total urine coproporphyrin levels:

• elevated in rotors
• normal in DJS

Question 13

What is wilsons disease?

Answer 13

Free copper accumulation in many tissues like the liver, cornea, brain, and joints
-also known as hepatolenticular degeneration

Mutation in ATP7B which causes inadquate copper excretion by liber into bile
-failure of copper to enter circulation bound to ceruplasmin

Free copper generates free radicals that damage tissues

AR inheritance

Question 14

Wilson disease presentation

Answer 14

Kayser Fleischer rings in cornea

Parkinson like symptoms
-secondary to copper dposits in putamen

Hemiballismus: flailing, ballistic undesired movements of the limbs
-secondary to copper desposits in subthalamic nucleus

Dementia:
-secondary to copper desposits in cerebral cortex

Cirrhosis

Question 15

What do lab results show in Wilsons disease?

Answer 15

• decrease in serum copper due to decrease ceruloplasmin
• increase serum non-ceruloplasmin bound copper
• increase urine/serum free copper
• hemolytic anemia

Liver biopsy: if performed will show increased hepatic copper

Question 16

Treatment for Wilsons disease? and what are they at risk for?

Answer 16

Medical:

• ammonium tetrathiomolybdate which facilitates urinary excretion of copper
• penicillamine which increases copper chelating agent
• Trientine: copper chelating agent
• zinc: competes with copper for absorption in the gut viat the same ATP7B7 transporter

Surgical:
-liver transplant

risk factors:

• Hepatitis
• cirrhosis
• hepatocellular carcinoma (HCC)
• Fanconis disease

Question 17

Aldose B deficiency - Hereditary fructose intolerance

Answer 17

destructive autosomal recessive disorder caused by deficiency in hepatic aldose B
-cleaves fructose 1 phosphate into glyceraldehyde and dihydroxyacetone phasphate (DHP)

without this enzyme Fructose 1 phosphate accumulates

damage to the liver, kidney disease/failure,

patients present with low blood levels pf phosphorus and glucose

• hypophospatemia
• hypoglycemia

also have low tolerance for foods high in fructose and sucrose

Question 18

Fructokinase deficiency: essential fructosuria

Answer 18

presence of high concentrations of fructose in the urine
due to problems with fructose metabolism

essential fructosuria:
-hepatic deficiency in fructokinase that phosphorylates fructose to fructose 1 phosphate

Question 19

Galactosemias

Answer 19

Classic glactosemia:

• GALT is deficient
• leads to infants with cataracts, hepatomegaly, and jaundice and failure to thrive

milder form of glactosemia Non classic:

• deficiency in galactokinase or uridine diphosphate galactose epimerase
• galactose accumulates in the blood of these patients
• can get accumulation of galactiol in the lens

Question 20

PEP production in Mitochondria

Answer 20

Mitochondrial PEP carboxylase converts OAA to PEP in the mitochondria

PEP is then transported to cytosol to be turned to glucose via gluconeogenesis

this process occurs when there is elevated lactate levels because the body does not favor the conversion of Malate to OAA therefore it converts to PEP

Question 21

Glycogen Storage disease IB

Answer 21

defect in the transport protein that moves glucose 6 phosphate from the cytosol to the lumen of the ER of hepatocytes

the defect is int eh glucose 6 phosphatse

treatment is liver transplant or surgical transposition of the portal vein

Question 22

PEPCK deficiency

Answer 22

Phosphoenolpyruvate carboxylase (PEPCK) autosomal recessive disorder 
-normally converts OAA to PEP but cant

leads to increae acid in blood, hypoglycemia, and loss of muscle tone

liver enlargement and failure to thrive

Question 23

Von Gierkes disease

Answer 23

type 1a glycogen storage disease is an autosomal recessive disease
-deficiency in glucose 6 phosphate which removes the phosphate from glucose to allow for it to be a free glucose to enter the blood

marked hypoglycemia due to inabillity to perform glycogenolysis and gluconeogenesis

present with lactic acidosis and hepatomegaly due to build up of glycogen, hyperlipidemia, show signs of retarded growth

Question 24

Fasting vs starving

Answer 24

Fasting: body depletes energy stores of glycogen for the first few days and then follow by lipolysis

starvation: body energy stores are already depleted and utilizes essential tissue for energy
- loss of organs, muscle mass, weakness, anemia, reduction of mental capacity, eventually death