Genetics of GI Disorders

Question 1

• What are the genetic disorders related to the metabolism of heme?

Answer 1

• Unconjugated:
  
  • Crigler Najjar
  • Gilbert’s
• Conjugated:
  
  • Dubin Johnson
  • Rotor

Question 2

• Crigler Najjar

Answer 2

• AR
• Non-hemolytic jaundice
• Increased levels of unconjugated bilirubin
• Type 1: NO function of UDP Glucouronyl Transferase; increased risk for kernicterus/presents at an earlier age
• Type 2 (Arias): DECREASED function of UDP Glucouronyl transferase (UGT1A1-coding region) (CAN TREAT WITH PHENOBARBITOL)
• Tx: Plasmapheresis, Phototherapy, Liver transplant

Question 3

• Gilbert’s Syndrome (AD or AR)

Answer 3

• Defect in gene promotor for UGT1A1
  
  • ​Mild decreased UDP glucouronyltransferase activity
• Asymptomatic:
  
  • Jaundice with fasting, stress, EtOH intake
• Can test via fasting test or rifampin test (fasting test is more specific)
• No treatment needed (avoid irinotecan)

Question 4

• Fasting test

Answer 4

• Unconjugated bilirubin will rise after a day of fasting with low lipid/400 kCal diet

Question 5

• Rifampin test

Answer 5

• Rifampin induces Cytochrome P450 and competes for excretory pathways in the liver; increase in uncojugated bilirubin
• Diagnose:
  
  • Gilbert’s
  • Chronic Liver Disease

Question 6

• Dubin Johnson (AR)

Answer 6

• Conjugated hyperbilirubinemia
• Mutation in MRP 2 (can’t excrete bile from liver)
• Grossly black liver (histologically normal)
• Normal urine coproporphyrin levels

Question 7

• Rotor’s Syndrome (AR)

Answer 7

• Mutation in OATP1B1 and OATP3B3 uptake transporter proteins on basolateral surface of hepatocytes
• Conjugated hyperbilirubinemia
• Patients generally asymptomatic
• Jaundice w/ fatigue/pregnancy, oral contraceptives
• Normal color liver
• ELEVATED URINE COPROPORPHYRIN LEVELS

Question 8

• When does breast feeding jaundice occur?
• When does breast milk jaundice occur?

Answer 8

• Breast feeding-first 2-4 days of life
• Breast milk-2nd week of life

Question 9

• Wilson’s Disease

Answer 9

• Mutation in ATP7B in hepatocytes
• Free Cu2+ accumulates and free radicals produced damage liver, brain, cornea and joints
• Labs
  
  • ​Decreased serum Cu2+ d/t decreased ceruloplasmin
  • Increase in serun non-ceruloplasmin bound Cu2+
  • Increase in urine/serum free Cu2+
  • Hemolytic anemia
• Symptoms:
  
  • Parkinsonian like symptoms
  • Hemiballismus-flailing, ballistic, undesired movements of the limbs
  • Dementia
• PE:
  
  • Cirrhosis
  • Kayer-Fleischer rings in cornea

Question 10

• Treatments for Wilson Disease

Answer 10

• MEDICAL
  
  • Ammonium tetrathiomolybdate-increases urinary excretion of Cu2+
  • Penicillamine-Cu2+ chelating agent
  • Trientine-Cu2+ chelating agent
  • Zinc-competes with Cu2+ for absorption in the gut via ATP7B

Question 11

• Patient’s with Wilson’s Disease are at risk for

Answer 11

• Hepatitis
• Cirrhosis
• HCC (Hepatocellular Carcinoma)
• Fanconi’s Disease of PTs

Question 12

• Galactosemia

Answer 12

Absence of GALT enzyme (can’t convert galactose 1 phosphate-UDP glucose)

Sx:

Poor feeding

Failure to thrive

Hepatocellular damage-Hepatomegally/Jaundice

Proteinuria

Tx:

Avoid lactose

Question 13

• Hereditary fructose intolerance

Answer 13

• Def in aldolase B (can’t convert Fructose 1 phosphate to glyceraldehyde or DHAP)
• Acoid fructose, sucrose, and sorbitol

Question 14

• PEPCK Deficiency

Answer 14

• Can’t convert OAA-PEP (mitochondria)
• Can’t use OAA from TCA cycle to make glucose

Question 15

• Von Gierke Disease

Answer 15

• Def in Glucose 6 Phosphate
• Can’t convert Glucose 6 phosphate to glucose and phosphate