Genetics of GI Disorders Flashcards
What initiates heme metabolism?
macrophages
What are the steps to heme metabolism?
RBC –> macrophage –> heme dissociates from globin –> iron dissociates from heme –> porphyrin ring –> porphyrin ring opens to become bilirubin (yellow and toxic) –> bilirubin + albumin to liver — UDP glucoronyl transferase —> conjugated bilirubin –> stercobilinogen in intestines — oxidation —> stercobilin (brown)
stercobilinogen –> urobilinogen –> urobilin
Is unconjugated bilirubin water soluble?
NO
must attach to albumin when traveling in the blood to the liver
Is conjugated bilirubin water soluble?
YES
Where does the bilirubin and albumin dissociate in the liver?
space of Disse
What are conjugated bilirubin?
soluble bilirubin that UDP glucuronyl tranferase has added glucuronic acid (1= mono, 2= di)
What transports conjugated bilirubin to the canuliculi?
MRP2 multidrug resistance associated protein 2
What is Crigler Najjar syndrome?
autosomal recessive
major deficiency in UDP glucuronyl transferase
build up of unconjugated bilirubin in blood
brain damage in infants
What is Gilbert’s syndrome?
autosomal dominant or autosomal recessive
deficiency of UDP glucuronyl transferase from a defect in the gene promotor of UGT1A1
usually asymptomatic
during periods of increased hemolysis mild jaundice can occur
5-10% of population
What is Dubin Johnson syndrome?
autosomal recessive
mutation in MRP2 protein
conjugated bilirubin is not excreted into bile in gut
build up of conjugated bilirubin
asymptomatic besides jaundice
grossly black liver due to impaired excretion of epi metabolites
What is Rotor’s syndrome?
autosomal recessive
similar to Dubin Johnson
causes increase in conjugated bilirubin in blood
Mutation in OATP1B1 and OATP1B3
What type of genetic condition is Gilbert’s syndrome?
autosomal recessive or autosomal dominant
What is a common cause of mild isolated hyperbilirubinemia with all other LFTs normal?
Gilbert’s syndrome
What can exacerbate periods of jaundice in Gilbert’s syndrome?
What can improve the periods of jaundice?
- fasting
- alcohol
- acute illness
- estrogen
- Nicotinic acid from IV
improved by low dose barbituates
What is the treatment for Gilbert’s syndrome?
none
avoid certain meds (irinotecan)
if severe jaundice, phenobarbitone can decrease the concentration of unconjugated bilirubin in serum
What is Wilson’s disease?
genetic disorder
excess copper kept in tissues
can form hydroxyl radical when exposed to hydrogen peroxide
What does ATP7B do?
- binds copper to apoceruloplasmin
2. package into vesicles for exocytosis to bile
What is the genetic defect in Wilson’s disease?
autosomal recessive defect in ATP7B
Wilson’s disease
-neural effects
- basal ganglia = movement disorder
- cerebral cortex = dementia
- deterioration in school performance
- behavioral changes
- inco-ordination (handwriting deteriorates)
- dystonia
- dysarthria
- excessive salvation
- mask-like facies
- dysphagia
What is a symptom of Wilson’s disease that is useful for diagnosis?
Kayser-Fleischer ring
copper deposit in Descemet’s membrane of the cornea
What are the first symptoms of Wilson’s disease?
When do they appear?
acute hepatitis –> cirrhosis
late childhood
What is significant about the blood and urine in Wilson’s disease?
blood
- decrease ceruloplasmin
- increased free copper
urine
1. increased free copper
What are complications of Wilson’s disease?
- hepatosplenomegaly
- renal disease
- hemolytic anemia
What is the genetic defect in classic galactosemia?
- autosomal recessive disorder with the abscence of -galactose 1 phosphate uridyltransferase
- normally catalyzes reaction galactose 1 phosphate to glucose 1 phosphate
- causes accumulation of galactose 1 phosphate
What are the symptoms of classic galactosemia?
infantile cataracts, failure to thrive, hepatomegaly, and jaundice
brain damage –> mental retardation
What is the treatment of classic galactosemia?
complete removal of lactose and galactose from the diet
What are symptoms of Crigler Najjar syndrome type I?
severe jaundice and kernicterus
What is more severe Crigler Najjar type I or II
type I
When does Crigler najjar present?
early in life
What is the gene for Crigler Najjar?
- type I vs type II
- also metabolizes
UGT1A1
type I - totally absent or not expressed
type II - (Arias syndrome) - defective, less active than normal
-also metabolizes anti-cancer drugs and other molecules
What are symptoms and PE findings for Crigler Najjar?
- neonatal jaundice
- sepsis
- hypotonia
- kernicterus: deafness, poor mental progression/development caused by bilirubin deposition in brain
PE findings
- jaundice
- oculomotor palsy
What is the treatment for Crigler Najjar?
- plasmapheresis
- phototherapy
- phenobarbital - UGT1A1 inducer for type II
- liver transplant??
What are the tests for Gilbert’s syndrome?
- unconjugated hyperbilirubinemia without evidence of hepatitis or hemolysis
- genetic testing
- fasting test: unconjugated bilirubin will rise after a day of fasting with low lipid 400 kcal diet
- rifampin test: unconjugated bilirubin rises after a dose of Rifampin (less specific b/c can also rise with chronic liver disease)
More than ___ of the serum bilirubin is conjugated in Rotor’s syndrome
50%
What is a black liver indicative of?
Dubin-Johnson syndrome
What is found in the urine in Rotor’s syndrome?
bilirubinuria
When may someone with Rotor’s syndrome become jaundice or icteric?
during fatigue, pregnancy, or with oral contraceptives
What are lab findings for Dubin-Johnson?
- direct hyperbilirubinemia and resulting increased in total bilirubin
- coproporphyrin III:corproporphyrin I ratio 1:3-4 opposite of normal
- total urine corproporphyrin levels normal
What are the lab findings for Rotor’s syndrome?
- coproporphyrin III:corproporphyrin I ratio 1:3-4 opposite of normal
- total urine corproporphyrin levels elevated
What tissues does copper accumulate in with Wilson’s disease?
- liver
- brain
- cornea
- joints
What is the other name for Wilson’s disease?
What is the gene mutation?
hepatolenticular degeneration
ATP7B
What is wrong in Wilson’s disease?
- inadequate copper excretion by liver into bile
- failure of copper to enter circulation bound to ceruloplasmin
What is ceruloplasmin?
transport protein for copper
-usually represents the largest fraction of copper in the body
What does free copper generate?
free radicals that damage tissue
What is the inheritance pattern for Wilson’s disease?
autosomal recessive
What are symptoms of Wilson’s disease?
- parkinson-like symptoms secondary to copper deposits in putamen
- hemiballismus- flailing, ballistic, undesired movements of the limbs secondary to copper deposits in subthalamic nucleus
- dementia secondary to copper deposits in cerebral cortex
What are PE findings for Wilson’s disease?
- cirrhosis
- corneal deposits on slip lamp examination
- Kayser-Fleischer rings RARELY seen in other conditions that may result in increased copper such as primary biliary cirrhosis.
What are lab results for Wilson’s disease?
- low total serum copper (due to decreased ceruloplasmin)
- elevated serum non-ceruloplasmin bound copper
- elevated urine/serum free copper
- heemolytic anemia
What will a liver biopsy show for Wilson’s Disease?
increased hepatic copper
What are the treatment options for Wilson’s Disease?
Medical
-ammonium tetrathiomolybdate –> facilitates urinary excretion of copper
-penicillamine –> copper chelating agent
-trientine –> copper chelating agent
-zinc –> competes with copper for absorption in the gut via the same transporter (ATPB7)
Surgical
-consider liver transplantation as clinical condition deteriorates
What is Wilson’s disease a risk factor for?
- hepatitis
- cirrhosis
- hepatocellular carcinoma
- Fanconi’s disease of the proximal tubules
A 10 week old boy was presented to the metabolic unit of a pediatric hospital for irregularities in brain development. He was born by vaginal delivery after 38 week gestation with a birth weight of 2.7 kg (5.95 lb) to a 33 yo woman of hispanic descent. From week 10 of gestation ultrasonography had shown progressive enlargement of ventricles, absence of corpora collosa, and hypoplasia of the brainstem and cerebellum. After birth he had been in respiratory distress, showed hypotonia, was feeding poorly, and had frequent seizures. Labs: blood pH 7.2, serum pyruvate, lactate, and Alanine elevated, citrate reduced. Imaging: H-MRI at 1.5 T cconfirmed the US findings, 2D chemical shift at 2.37 ppm-attributed to lactate and pyruvate respectively - in the cerebrospinal fluid. What should the pt be treated with?
A. low galactose diet
B. coenzyme Q and carnitine
C. uncooked corn starch meals in the evening
D. allopurinol
E. dichloroacetate, thiamine, and citrate
E. dichloroacetate, thiamine, and citrate
What is classic galactosemia?
-symptoms
- galactose in the blood
- occurs when the conversion of galactose to glucose 1 phosphate is prevented due to galactose 1-P uridyltransferase deficiency
Symptoms in neonates
- failure to thrive
- liver failure, jaundice
- sepsis
- bleeding
- hepatomegaly
Treatment: restrict galactose intake
What is Duarte varient of galactosemia?
milder form
-5-25% residual GALT activity in erythrocytes
Treatment: restrict galactose intake
What is nonclassic galactosemia?
- conversion of galactose to galactose 1 phosphate is prevented due to a defect in galactokinase
- galactose and galactitol accumulate in the blood and urine (galactosuria)
- galactitol deposition in the eye leads to cataracts in early infancy
Treatment: restrict galactose intake
What is essential fructosuria?
- fructosuria = presence of high concentrations of fructose in the urine
- caused by genetic mutations that cause deficiencies in enzymes involved in fructose metabolism
- autosomal recessive disorder marked by hepatic deficiency in fructokinase (phosphorylates fructose to fructose 1 phosphate
- asymptomatic
What is hereditary fructose intolerance?
- autosomal recessive disorder caused by a deficiency in hepatic aldolase B, an enzyme that cleaves fructose 1 phosphate into glyceraldehyde and dihydroxyacetone phosphate (DHAP)
- fructose and fructose 1 phosphate accumulate
- fructose 1 phosphate sequesters cellular phosphorus (needed for generation of ATP)
- damages liver and leads to kidney disease/failure
- low blood levels of phosphorus (hypophosphatemia)
- hypoglycemia
- low tolerance for foods high in fructose and sucrose
What is fasting?
voluntary not eating for various lengths of time
- body adapts to this by depleting energy stores
- days 1-2: glycogen stores in liver
- followed by lipolysis
What is starvation?
- body energy stores are depleted and the body resorts to using essential tissues for energy
- result is reduction in organ volume with gradual loss of function, loss of muscle mass, weakness, anemia, diarrhea, reduction in mental capacity, immune deficiency, and death
What is Von Gierke disease?
type Ia glycogen storage disease
- autosomal recessive disorder
- 1/100,000 live births
- deficiency in glucose 6 phosphatase activity (mutation in catalytic unit) (releases free glucose into blood by liver) –> no glycogenoloysis and gluconeogenesis
Symptoms
- marked fasting hypoglycemia
- lactic acidosis
- hepatomegaly
- hyperlipidemia and lactic acidemia in patients with retarded growth
What is glycogen storage disease Ib (GSD Ib)?
-caused by defect of transport protein that moves glucose-6-phosphate from the cytosol into the lumen of the ER of hepatocytes (GLUT7)
Treatment: liver transplant, surgical transposition of teh portal vein (redirects nutrient-rich blood from the intestine to the peripheral circulation, improves tissue supply with glucose, reduces glucose uptake in the liver)
-uncooked cornstarch before bedtime to keep blood glucose up during the night
What is PEPCK deficiency?
rare autosomal recessive disorder of carbohydrate metabolism
- normally catalyzes the conversion of oxaloacetate into phosphoenolpyruvate
- increased acid in the blood (acidemia)
- hypoglycemia
- loss of muscle tone
- liver enlargement and impairment of function
- failure to thrive
How is PEP produced in mitochondria?
- mitochondrial PEP carboxykinase converts OAA to PEP in the mitochondria
- PEP is transported into cytosol where it is converted to glucose via gluconeogenesis when lactate levels are elevated
- conversion of lactate to pyruvate by lactate dehydrogenase generates NADH, which does not favor coversion of malate to OAA in cytosol, so OAA is directly converted to PAP by mitochondrial PEP carboxykinase
