Genetics of GI Disorders Flashcards
What are the genetic disorders related to heme metabolism?
- Crigler - Najjar syndrome
- Gilbert’s Syndrome
- Dubin - Johnson Syndrome
- Rotor Syndrome
How is Crigler - Najjar syndrome inherited?
Autosomal Recessive
Crigler - Najjar syndrome affects metabolism of _____
Bilirubin
When in life does Crigler - Najjar syndrome present?
Very early in life
Describe the 2 types of Crigler - Najjar syndromes
Type 1: mutation that causes absent UGT1A1 enzyme
Type 2: mutation that causes defective or less active UGT1A1 enzyme
Crigler - Najjar syndrome is detected because the infants have high levels of what?
Unconjugated hyperbilirubinemia
How is heme supposed to break down?
Heme Biliverdin Bilirubin Bilirubin glucuronides = Excreted
Where in the pathway for heme metabolism is the enzyme UGT1A1 important?
Taking bilirubin to bilirubin glucuronides so they can be excreted - thus a mutation in that enzyme causes crazy high levels of bilirubin
What are the symptoms/signs of Crigler - Najjar syndrome?
Severe Jaundice and brain dysfunction
Kernicterus - deafness and poor mental progession
Hypotonia
Arias Syndrome
Type 2 Crigler - Najjar syndrome (less severe than Type 1)
How does one get Gilbert’s syndrome?
Hereditary
Gilbert’s syndrome is characterized by what?
Unconjugated hyperbilirubinemia
- Decrease in bilirubin uptake (mild)
Gilbert’s syndrome is associated with a defect in?
UGT1A1 gene promotor
What are the symptoms of Gilbert’s Syndrome?
LARGELY ASYMPTOMATIC
- occasional recurrent mild jaundice that can be associated with fasting, stress and alcohol
How do you test for Gilbert’s syndrome?
Rifampin test:
- Fast 12-24 hours
- Administer Rifampin
- Bilirubin levels greater than 1.9
What is the treatment for Gilbert’s syndrome?
NONE needed
What 2 syndromes are characterized by increased levels of CONJUGATED bilirubin?
Dubin - Johnson syndrome
Rotor’s Syndrome
Dubin-Johnson syndrome has mutations in what and what does it normally do?
MRP2 - transports molecules across extra/intracellular membranes
What is the main physical exam finding with Dubin-Johnson syndrome?
BLACK LIVER
Why is the liver black in Dubin-johnson syndrome?
Impaired excretion of epinephrine metabolites
How is Dubin-Johnson syndrome inherited?
Autosomal recessive
What are the urine coproporphyrin levels with Dubin-Johnson syndrome?
Normal
Dubin-Johnson syndrome has increased _______ levels due to impaired hepatic secretion of _____
Conjugated bilirubin
Bilirubin
Rotor’s syndrome has mutations in what and what does it normally do?
OATP1B1 and OATP1B3 - facilitate liver uptake of drugs
What are the main symptoms of Rotor’s syndrome?
ASYMPTOMATIC - NO black liver
What are the urine coproporphyrin levels with Rotor’s syndrome?
Elevated
Rotor’s Syndrome has increased ______ levels due to impaired secretion/storage of _____
Conjugated bilirubin
Bilirubin
Which is more severe, Dubin-Johnson syndrome or Rotor’s syndrome?
Dubin-Johnson syndrome
What gene is mutated for Wilson’s Disease?
ATP7B
Overall sign of Wilson’s Disease?
Increased free copper accumulation in many tissues
Why is there an increase in free copper due to Wilson’s Disease?
ATP7B gene for wilson disease protein does not pump copper into bile or bind it to ceruloplasmin to go into blood
How is Wilson’s Disease inherited?
Autosomal recessive
Free copper generates _____ that will ____ tissues
Free radicals
Damage tissues
What type of protein is wilson’s disease protein?
Transmembrane P-type ATPase that uses ATP -> ADP to pump copper into bile and plasma
What are the symptoms for Wilson’s Disease?
Parkinson-like symptoms
Hemiballismus - flailing undesired movement of limbs
Dementia
Cirrhosis
Kayser-Fleischer rings around iris of eye
Lab signs of Wilson’s Disease?
- Decreased total serum copper due to decreased ceruloplasmin
- Increased urine copper
- Increased non-bound copper
- Liver biopsy shows increased hepatic copper
Wilson’s disease is a risk factor for many liver diseases. List some.
Cirrhosis
Hepatitis
Hepatocellular carcinoma
Fanconi’s disease of proximal tubules
What disease characterizes too much iron in the body?
Hemochromatosis
