The Genetis of GI disorders Flashcards
what is Crigler Najjar syndrome?
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
what are the two types of Crigler najjar syndrome
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)
what other metabolites does UGT1A1 conjugate?
SN-38 which is a toxic anti-cancer drug
it adds a glucuronate on to SN-38 to make it soluble for elimination
what are patient presentations of Crigler Najjar syndrome:
Neonatal jaundice
sepsis
hypotonia
Kernicterus:
- bilirubin deposition in brain
- poor development/mental function
- if severe patients die within a few years
what is treatment of Crigler Najjar?
- Plasmapheresis
- Phototherapy
- Phenobarbital (UGT1A1 inducer) (this only works for Type II to increase the UDP-glucuronyl transferase mRNA synthesis and UGT activity
- Liver transplant
What is Gilberts syndrome?
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
how does Gilberts syndrome present?
Largely asymptomatic
Occasional recurrent mild jaundice
- associated with fasting
- stress or infection
- EtOH intake
How to diagnosis for Gilberts syndrome?
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
what is the treatment of gilberts syndrome and what is the prognosis, prevention, and complications?
treatment: no treatment needed
avoid certain medications (irinotecan)
-anti cancer drug that needs UGT1A1 to be conjugated
What is Dubin johnson syndrome and what is its presentation?
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
what is rotors syndrome? and how does it present?
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
how do lab results present for Dubin-johnson and Rotors syndrom
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
What is wilsons disease?
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
Wilson disease presentation
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
What do lab results show in Wilsons disease?
- 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
Treatment for Wilsons disease? and what are they at risk for?
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
Aldose B deficiency - Hereditary fructose intolerance
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
Fructokinase deficiency: essential fructosuria
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
Galactosemias
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
PEP production in Mitochondria
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
Glycogen Storage disease IB
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
PEPCK deficiency
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
Von Gierkes disease
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
Fasting vs starving
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
