Lecture 25: The Genetics of GI Disorders Flashcards
What is Crigler Najjar Type I vs. Type II?
- Hereditary unconjugated hyperbilirubinemia
Type I: severe due to absent levels of hepatic bilirubin-UGT activity (UGT1A1)
Type II: less severe (Arias syndrome), only partly deficient in gene
What function does UGT1A1 have on SN-38
- SN-38 is a toxic antineoplastic drug metabolized by UGTA1
Treatment for Crigler-Najjar?
- Plasmapheresis
- Phototherapy (blue lights)
- Phenobarbital-UGT1A1 inducer: only for Type II - results in increased UDP-glucuronyl transferase mRNA synthesis and UGT activity
- Liver transplant
What is Gilbert’s Syndrome; genetic issue; and what will be decreased?
- Hereditary unconjugated hyperbilirubinemia due to defect in promotor gene for UGT1A1
- Mild decrease in UDP-glucuronyl trasnferase activity
- Mild decrease in bilirubin uptake
- Autosomal dominant or recessive inheritance (very common)
Symptoms of Gilbert’s syndrome?
- Largely asymptomatic, but occasional recurrent mild jaundice
- Associated w/ fasting, stress, and EtOH intake
What testing is available to diagnose Gilbet’s Syndrome?
- Genetic testing
- Fasting test: unconjugated bilirubin will rise after a day of fasting w/ low lipid, 400kcal diet (more specific test for Gilbert’s)
- Rifampin test: unconjugated bilirubin rises after a dose of Rifampin, induces cytochrome P-450 and competes for excretory pathways in liver (less specific to Gilbert’s as levels can rise in those w/ chronic liver disease
Treatment for Gilbert’s syndrome; avoid what med?
- No treatment needed!
- Avoid certain medications (irinotecan)
What are the 2 types of hereditary conjugated hyperbilirubinemia?
1) Dubin-Johnson syndrome - benign and AR
2) Rotor’s syndrome - AR and milder than DJS
*Both associated w/ decreased hepatic excretion of conjugated bilirubin
What is one of the common gross pathologies of DJS that differentiates it from Rotors?
Grossly black liver due to impaired excretion of epinephrine metabolites in DJS
Patients w/ DJS or Rotor’s syndrome may present with jaundice or icteric when?
During pregnancy or w/ oral contraceptives
What is the molecular basis for DJS?
Defect in the canalicular multiple organic anion transporter (cMOAT, MRP2, ABCC2) and leads to the accumulation of conjugated (direct) bilirubin, which can no longer be excreted from hepatocytes into the bile
What labs are significant in DJS?
- Direct hyperbilirubinemia (usually 2-5 mg/dL) and resulting increased total bilirubin in DJS
- Coproporphyrin III:coproporphyrin I ratio is 1:3-4 (opposite of normal)
- Normal total urine coproporphyrin levels
What labs are significant in Rotor’s syndrome?
- Coproporphyrin III:coproporphyrin I ratio is 1:3-4 (opposite of normal)
- Elevated total urine coproporphyrin levels
Treatment for DJS and Rotor’s syndrome; what medication is contradindicated in these patients?
- No treatment is needed
- Oral contraceptives are contraindicated in these patients
What are intrahepatic causes of portal HTN?
Liver cirrhosis and fibrosis due to disorders such a hemochromatosis and Wilson disease
Explain the relationship between macrophages and iron?
Macrophages engulf and digest aged erythrocytes, which allows for the extraction of iron from degraded hemoglobin.
What is Wilson’s disease; caused by; genetic inheritance pattern?
- Free copper accumulation in many tissues (liver, brain, cornea, joints)
- Mutation in ATP7B results in: inadequate copper excretion by liver into bile and failure of copper to enter circulation bound to ceruloplasmin
- AR inheritance
What normally represents the largest fraction of copper in the body and why is free/unbound copper dangerous?
- Copper bound to ceruloplasmin
- Free copper generates free radicals that damage tissues
What type of protein is the one affected by Wilson disease?
Transmembrane P-type ATPase encoded by ATP7B that uses ATP–>ADP to pump copper into bile and plasma
What are some common presentations associated w/ Wilson’s disease?
- Proximal renal tubular dysfunction
- Kayser Fleischer rings
- Hepatomegaly, jaundice, acute hepatitis, portal HTN, cirrhosis
- Arthritis and Rickets
- Neuro defects
What are some of the neurological symptoms caused by Wilson’s disease and what causes them?
- Parkinson-like symptoms: copper deposits in putamen
- Hemiballismus: flailing, ballistic, undesired movements of the limbs caused by copper deposits in subthalamic nucleus
- Dementia: copper deposits in cerebral cortex
What are the relevant labs for Wilson’s disease?
- Decreased total serum copper due to decreased ceruloplasmin
- Increased serum non-ceruloplasmin bound copper
- Increased urine/serum free copper
- Hemolytic anemia
What are the treatment options for Wilson’s disease?
- Ammonia tetrathiomolybdate –> facilitates urinary excretionn of Cu
- Penicillamine –> Copper chelating agent
- Trientine –> Copper chelating agent
- Zinc –> competes w/ copper for absorption in the gut via ATPB7
People with Wilson’s disease are at risk for several liver disease, what are they?
- Hepatitis
- Cirrhosis
- Hepatocellular carcinoma (HCC)
*Also at risk for Fanconi’s disease of the proximal tubules
