Genetics of GI Disorders Flashcards
What are examples of genetic disorders related to heme metabolism?
- Crigler Najjar Syndrome
- Gilbert’s Disease
- Dubin Johnson Syndrome
- Rotor Syndrome
What is Crigler Najjar Syndrome?
- AR
- affects metabolism of bilirubin
What does Crigler Najjar syndrome cause?
Non-hemolytic jaundice
higher than normal levels of unconjugated bilirubin
brain damage in infants
Vignette of Crigler Najjar syndrome
An INFANT is brought to the pediatrician by his parents
because they are concerned about the YELLOW COLOR of his
skin and general BEHAVIOR CHANGES. They report that he has
seemed more tired and weak with his ARMS just FLOPPING
down by his side instead of him reaching for his toys. The
parents are known to be first cousins.
What is absent or low in hereditary unconjugated hyperbilirubinemia?
bilirubin-glucose
Which type of Crigler Najjar syndrome is more severe?
1 –>kernicterus and severe jaundice
Mutation in what enzyme renders its activity totally absent or not expressed in type 1 Crigler Najjar syndrome?
UGT1A1
What is another name for type 2 Crigler Najjar syndrome?
Arias syndrome
Mutation of what enzyme renders it defective and less active than normal in type 2 Crigler Najjar syndrome?
UGT1A1
UGT1A1 is ____ in type 1 and ____ in type 2 Crigler Najjar syndrome
absent or not expressed, less active than normal
What does UGT1A1 convert in the heme pathway?
Bilirubin to Bilirubin glucuronides (conjugates)
What is a common presentation of Crigler Najjar syndrome?
hereditary unconjugated hyperbilirubinemia
—>type 1 and 2 Crigler Najjar syndrome
What are physical exam findings on a patient with Crigler Najjar syndrome?
jaundice
oculomotor palsy
What are the sx of Crigler Najjar syndrome?
neonatal jaundice sepsis hypotonia kernicterus --->deafness, poor mental progression/development
Describe kernicterus
bilirubin deposition in the brain–> poor mental fxn/development
if severe–>die within few years
What is another function of UGT1A1?
metabolizes anti-cancer drugs (SN-38) via adding glucose and excreting in bile and feces
What are treatments for Crigler Najjar syndrome?
- Plasmapheresis
- Phototherapy
- Phenobarbital-UGT1A1 inducer (only for type 2)
- Liver transplant
How does phenobarbital-UGT1A1 inducer affect type 2 Crigler Najjar syndrome?
results in increased UDP-glucuronyl transferase mRNA synthesis and UGT activity
–>why only tmt for type 2 (type 1 is not fxnl)
What does UGT1A1 gene code for?
UDP-glucuronosyl transferase
Gilber’s Syndrome typical vignette
A 24-year-old third-year medical student is two weeks into
her first surgery rotation when her senior resident tells her
that her EYES look a little YELLOW. She experienced her first
needle stick injury in the operating room just one week
earlier and begins to worry about hepatitis. Other than
rarely having the time to eat at work, she has no other
complaints or symptoms.
What is a common presentation of Gilbers syndrome?
hereditary unconjugated hyperbilirubinemia
How does hereditary unconjugated hyperbilirubinemia differ in Crigler Najjar and Gilbert’s syndromes?
CN: no UGT1A1 (type 1) or little (type 2)
G: defect in UGT1A1 gene promoter
Describe Gilbert’s Syndrome
Defect in gene promotor for UGT1A1—>
- mild decrease in UDP-glucuronyl transferase activity d/t lower expression of wild type enzyme
- mild decrease in bilirubin uptake
Is Gilbert’s syndrome AD or AR?
either, common in population
Is Crigler Najjar syndrome AD or AR?
AR
–>common first cousin parents
How does Gilbert’s syndrome present?
Largely asymptomatic
–>occasional mild jaundice
d/t ETOH, stress, fasting
What is the current hypothesis for why fasting causes mild jaundice in Gilbert’s syndrome?
increased hepatic uptake of non-esterified FA during fasting–> interferes with clearance of bilirubin from liver–> unconjugated hyperbilirubinemia
How do you dx Gilbert’s syndrome?
Isolated unconjugated hyperbilirubinemia
–>without hepatitis or hemolysis
Fasting test
Rifampin test
Describe fasting test to dx Gilbert’s disease
unconjugated bilirubin will rise day of fasting with low lipid diet (increases a lot c/t nml)
Describe Rifampin test to dx Gilbert’s disease
unconjugated bilirubin rises after dose of Rifampin (induces cytochrome P450)
Given a vignette, how can you distinguish CN from Gilbert’s syndromes?
infant vs adult
What is the tmt for Gilbert’s syndrome?
NONE
–>avoid irinotecan (cancer drug SN-38)
Dubin Johnson typical vignette
A 22-year-old motorcycle accident victim with unknown past medical history is brought
into the ED with severe head injuries. He is stabilized and brought to the surgical ICU
where he is deemed to be brain dead by both the intensivist and neurosurgery staff. The
organ transplant team is contacted and determine that he is an eligible kidney donor.
However, he is not eligible for liver donation. Upon entering the abdomen during harvest,
the team notices that his LIVER is BLACK.
What mutation causes Dubin Johnson syndrome?
mutations in MRP2 (ABC transporter from hepatocyte into bile)
What mutation causes Rotors Syndrome?
mutations in OATP1B1 AND OATP1B3 (uptake transporter from blood into hepatocyte)
What causes hereditary conjugated hyperbilirubinemia?
Dubin Johnson and Rotor syndromes
What causes hereditary unconjugated hyperbilirubinemia?
Crigler Najjar and Gilbert’s syndromes
What causes black liver?
Dubin Johnson syndrome
–>d/t impaired excretion of epinephrine metabolites
Is Dubin Johnson syndrome AD or AR?
AR
Does Rotor’s syndrome cause black liver?
No
–Milder than Dubin Johnson
What is hereditary conjugated hyperbilirubinemia?
decreased hepatic excretion of conjugated bilirubin
Is tmt required for Rotor’s syndrome?
no
–>typically asymptomatic
What are physical exam findings of Rotor’s syndrome?
may have jaundice or icterus during fatigue, pregnancy or with oral contraceptives
–>reduced hepatic excretory fxn
What is the MRP2 transporter?
transports material from hepatocyte into bile
–>dubin johnson syndrome
What are the OATP transporters?
uptake transporters from blood to hepatocyte
–>rotor syndrome
What syndrome has elevated total urine coproporphyrin levels?
rotor’s syndrome
What syndrome has normal total urine coproporphyrin levels?
dubin johnson syndrome
What syndrome has increased total bilirubin?
dubin johnson syndrome
What is the relation of UGT1A1 and UDP-glucuronosyl transferase?
UGT1A1 is the gene that makes the enzyme UDP-glucuronosyl transferase
–>conjugates bilirubin in the liver
What genetic disorders are related to iron and copper metabolism?
Hemochromatosis
Wilson’s Disease
Wilson’s Disease typical vignette
• A 33-year-old female is referred to a neurologist by her primary care
physician for unsteady gate, forgetfulness, and recent episodes of
Turret-like spells where she will fling one arm out and above her
head seemingly unprovoked.
• One physical exam, the neurologist notices that her irises appear
multicolored with concentric rings around the periphery. He is
concerned for a metabolic disease and orders several laboratory and
radiologic studies.
• In the interim he has advised her to avoid eating chocolate and
shellfish.
Foods that are usually high in copper, especially organ meats, shellfish, dried
beans, peas, whole wheat, and chocolate that is high in cocoa such as
dark chocolate.
• Drinking water should be analyzed because it may contain too
much copper
Mutation of what leads to Wilson’s Disease?
ATP78
–>transports copper from one side of cell to the other
What is another name for hepatolenticular degeneration?
Wilson’s Disease
In Wilson’s Disease, free copper accumulates in
liver, brain, cornea, joints
What does mutation fo ATP7B result in?
- inadequate copper excretion by liver into bile
- failure of copper to enter circulation bound to ceruloplasmin (normally bound is largest fraction of copper in body)
- free copper generates free radicals that damage tissues
Is Wilson’s disease AD or AR?
AR
What does free copper generate?
free radiacals that damage tissues
What is the largest fraction of copper in the body?
copper bound to transport protein ceruloplasmin
What are sx of Wilson’s Disease?
Dementia
–>secondary to copper deposits in cerebral corte
Hemiballismus
–> secondary to copper deposits in subthalamic nucleus
Parkinson-like sx
–>secondary to copper deposits in putamen
What shows on physical exam of pt with Wilson’s Disease?
Cirrhosis
Corneal deposits
–>Kayser-Fleischer rings
What would a liver biopsy show in pt with Wilson’s Disease?
increased hepatic copper
What would labs show in Wilson’s Disease?
- decreased total serum copper d/t decrease in ceruloplasmin
- increased serum non-ceruloplasmin bound copper
- increased urine/serum free copper
- hemolytic anemia
What are treatments for Wilson’s disease?
- Liver transplant
- Copper chelating agents (penicillamine, trientine)
- Zinc (competes with copper for absorption so it will be excreted)
- Ammonium tetrathiomolybdate (helps urinary excretion of copper)
What is Wilson’s Disease risk factor for?
- hepatitis
- cirrhosis
- hepatocellular carcinoma
- Fanconi’s disease of proximal tubules
Define hemochromatosis
AR
accumulation of iron in liver, heart, pancreas, skin
–>d/t unregulated duodenal reabsorption of iron
What can hemochromatosis cause?
cirrhosis heart failure DM bronzed skin malabsorption
Define acute intermittent porphyria (heme synthesis)
AD
–>PBG deaminase deficiency in liver leads to excessive production of ALA and PBG
–>periodic abd pain, neuro dysfxn
Define porphyria cutanea tarda (heme synthesis)
Deficiency in uroporphyrinogen decarb
AD, both blood and liver
MOST COMMON PORPHYRIA
–>wine colored urine, photosensitivity leads to vesicles on skin
Define galactosemia
- galactose to glucose 1-phosphate prevented
- failure to thrive, liver failure, sepsis bleeding
Secondary d/t defect in galactokinase
—>cataracts
Define hereditary fructose intolerance
AKA Aldolase B deficiency
–>AR d/t deficiency in enzyme that allows fructose to accumulate
–>damage liver and kidney, low glucose level, low tolerance for high frustose foods
Describe PEPCK deficiency
rate AR
increased acid in bood, hypoglycemia, loss of muscle tone, liver enlargement, failure to thrive
no conversion of oxaloacetate to PEP (TCA cycle impaired)
Describe von Gierke disease
glycogen storage disease
AR
can’t release free glucose into blood by liver
–>fasting hypoglycemia, lactic acidosis, hepatomegaly, hyperlipidemia
What is the time difference between breast milk and breast feeding jaundice?
breast milk within 2 weeks of life
breast feeding within 2-4 days of life
