L53 Heme Catabolism

Question 1

Draw out steps 1-4-4 of Heme Catabolism and know the enzymes involved

Answer 1

UDP glucouronyl trasferase

MRP2

Question 2

Know the details of the Diazo Reaction

Answer 2

traditional Bilirubin Measurement

• conjugated bilirubin acts FAST with Diazo (unfolded, soluble)
• UCB reacts slow with Diazo (folded, insoluble)
• methanot unfolds and solubilizes UCB so it can react with diazo

with methanol : TOTAL BILIRUBIN measured (100%CB+100%UCB)

without methanol: DIRECT Bilirubin measure
-100% CB+ 10-15% UCB)

IBR (indirect Bilirubin) is the other 85-90% of UCB
-calculation: IB=TB-DB

functioning”

Question 3

Neonatal Jaundice

Answer 3

50% of all neonates become clinically jaundiced in first 5 days of life

• low activity of hepatic UDP-glucuronyltransferase (UGT)
• inability to conjugate bilirubin leads to a rise in serum UCB

normal: serum bilirybin peaks at 72 hours (5-6mg/dL) and declines to normal levels (<1) in 7-10 days

when UCB levels exceed 20mg/dL there is an increased risk of kernicterus (life threatening accumulation of UCB in the brain)

phototherapy treatment to reduce neonatal Jaundice

Question 4

Factors creating Neonatal jaundice: 5

Answer 4

FACTORS:

1. Low UGT activity
   - only 1% of normal adult level of UGT in neonates at birth, reaches adult level at 14 weeks
   - breast milk jaundice when some womens breast milk contains UGT inhibitors (discontinue breast feeding)
2. Decreased Hepatic uptake of UB
   - decreased levels of GST result in UCB not being efficiently trapped
   - delayed closure of ductus vesosus (placental shunt) allows bilirubin rich portal blood to bypass the liver
3. increased production of UBL higher turnover in RBC in infants compared to adults.
   - RBC degratdation is accelerated dut to teh shorter life span of neonatal RBC’s producing larfer amounts of UCB (even in healthy)
   - additional paths: sickle cell, toxic or allergic reactions
4. decreased production of serum albuminL which carries UCB in blood (no escort to the liver, becuase undeveloped liver not producing albumin)
   - immaturity of liver
   - insufficient albumin to tarnsport UCB leading to free UCB
5. INcreased uptake of UCB in neonate intestine
   - no intestinal flora yet, so CB is not converted to urobilinogen by bacteria
   - brush border enzyme B GLUCURONIDASE can de conjugate CB back to UCB (goes back in blood)
   - bound by serum albumin again
   - enteroheparic recirculation of UCM is thought to be a major contributing factor in neonatal jaundice

Question 5

Kernicterus

Answer 5

when UCB level exceed 20mg/dL

• excess not albumin bound and enters brain and precepitates in basal ganglia
• a bilirubin encephalopathy can cause perm nerve damage, (hearing to mental retardation or death)
• “yellow kern”-part in the brain that is most affected by buildup of UCB
• Phototherapy and plasmapheresis the ONLY means of preventing kernicturus

Question 6

Blue Light Therapy

Answer 6

bilirubin sensitive to light

• blue light alters the conformation of UB and yeilds photoisomers that are more polar and water soluble than UCB in its native form
• photoisomers of UCB do NOT enter the brain, and can be excreted in urine of bile

NOT UV LIGHT

Question 7

Crigler Najjar Syndrome Type 1

Answer 7

Defet in UDP- Glucuronyltransferase (UGT)

• rare autosomal recessive MANY mutations
• 200 cases worldwide 20 in Amish and Mennonite

SEVER non hemolytic unconjugated hyperbulirubinemia
-without treatment most patients DIE of kernicterus

12 hours/day phototherapy, (SLEEP)
-intermitent plasmpapheresisoften used during crises
Heme oxygenase inhibitors can be used to decrease production of bilirubin

survival till puberty with treatment
and liver transplant

Question 8

Crigler Najjar Syndrome Type 2

Answer 8

Less sever than Type 1, generally have 10% normal function

Autosomal recessive: point mutations

serum bilirubin levels are lower than type 1

kernicterus is unusual

phenobarbital treatement reduces UB by 25% by increasing UGT production

Question 9

Gilbert Syndrome

Answer 9

Defect in UDP Gucuronyltransferase (UGT)
-cased by TATAA box defects leading to reduced expression of UGT or by missense mutations

-aka constitutional heparic dysfunction or familial non hemolytic jaundice (5% of population)

mild-chronic and unconjugated hyperbilirubinemia
-treated with phenybarbitol

syndrome oftern diagnosed in young adults, mild jaundice with exertion, stress, fasting, or asymptomatic

Individuals with this disorder suffer severe diarrhea and neutropenia when treated with anticancer drug Irinotecan which is also metabolized by UGT

Question 10

Dubin - Johnson Syndrome

Answer 10

MRP2 protein defective (10% of normal activity)

autosomal recessive

rare, a relatively benign condition causing mild jaundice

characterized by conjugated hyperbilirubinemia and black picgment of liver with normal function

-black from epinephrine buildup, (not cuase but hallmark sign)

Question 11

Rotor Syndrome

Answer 11

defect int eh hepatic bilirubin binding protein GST

• milder form of conjugated bilirubinemia than dubin johnson (very rare and benign)
• how is it conjugated that is in the blood????

rotor is clinically distinguished from DJ by lower serum bilirubin levels and absence of liver pigmentation