Heme synthesis, Degradation and Porphyrias - Part 3

Question 1

Does heme degradation start in macrophages or in hepatocytes?

Answer 1

RBC that have reached their life-span are phagocytosed by cells of the reticulendothelial system (RES) . Heme degradation starts in macrophages, whereas bilirubin conjugation to bilirubin-diglucuronate takes place in hepatocytes

Question 2

What is the name of the enzyme that starts heme degradation?

Answer 2

Heme oxygenase

Question 3

Does Heme oxygenase form carbon monoxide or carbon dioxide?

Answer 3

forms one carbon monoxide per heme

Question 4

In heme degradation, what is formed by Heme oxygenase?

Answer 4

green biliverdin

Question 5

Once biliverdin is made by Heme Oxygenase, what comes next?

Answer 5

Biliverdin is then reduced to the red-orange bilirubin

Question 6

Regarding heme degradation, what is released into bile?

Answer 6

Bilirubin is conjugated in the liver and released into the bile.

Question 7

What is defective in Dubin-Johnson syndrome?

Answer 7

Dubin-Johnson syndrome is due to a hereditary deficiency of the ABC transporter that transports conjugated bilirubin from the hepatocyte into the biliary canaliculus.

Question 8

What are bile pigments?

Answer 8

Bile has a yellowish green color. Bilirubin and its derivatives are known as bile pigments.

Question 9

Can bilirubin be changed to biliverdin and vice versa?

Answer 9

It is possible to oxidize bilirubin to biliverdin. This is a special antioxidant function of bilirubin. The formed biliverdin can then again be reduced to bilirubin

Question 10

Why are the feces of newborns of a clayish-grey color?

Answer 10

Due to lack of urobilinogen in the gut of fetuses.

-Urobilinogen in the intestines of adults leads to the brown stercobilin in the large intestine.

Question 11

Is bilirubin complexed with albumin or is it covalently bound?

Answer 11

Bilirubin is not covalently bound to albumin, it is noncovalently bound in hydrophobic pockets of albumin, which is described as complexed to albumin (fatty acids acids are transported the same way).

Question 12

Which protein binds bilirubin in liver cytosol?

Answer 12

Bilirubin-albumin reaches the liver, where albumin stays in the blood and only bilirubin enters the hepatocyte, where it is bound in liver cytosol to the protein LIGANDIN.

Question 13

Which compound is used for formation of conjugated bilirubin and how was it formed?

Answer 13

• Bilirubin is transported to the ER and is conjugated with UDP-glucuronic acid, mostly using two, leading to diglucuronyl-bilirubin
• UDP-glucuronic acid is formed in one step from UDP-glucose by UDP-glucose dehydrogenase

Question 14

What is the normal fate of conjugated bilirubin in the liver?

Answer 14

Conjugated bilirubin is normally released from the liver into the bile by active transport performed by a specific ABC transporter against a concentration gradient

Question 15

Is the conjugation of bilirubin or is the release of conjugated bilirubin from the
liver the rate-limiting step of bilirubin metabolism?

Answer 15

The rate limiting step of bilirubin metabolism is the energy-dependent release of conjugated bilirubin into the bile

Question 16

What is kernicterus?

Answer 16

Kernicterus is a special form of jaundice

-In the neonate this can lead to accumulation of bilirubin in basal nuclei of the brain.

Question 17

Which enzyme activity, in regards to heme degredation, is low after birth but then increases in the following days and weeks to adult levels, as the fetal bilirubin was transferred to the mother and this enzyme is not needed until after birth.

Answer 17

Bilirubin UDP-glucuronyl transferase

Question 18

Why is phototherapy used to immediately treat jaundice in babies?

Answer 18

Bilirubin is dangerous and can lead not only to general jaundice in infants which can be detected in the sclerae, but also to the often deadly kernicterus which can progress hidden

Question 19

How does the blue florescent light treat babies with jaundice?

Answer 19

Blue fluorescent light changes bilirubin to more water-soluble isomers that can be released in urine without being conjugated with glucuronic acid.

Question 20

Describe Crigler-Najjar syndromes Type I and Type II.

Answer 20

Crigler-Najjar syndromes are devastating hereditary enzyme deficiencies of bilirubin UDP-glucuronyl transferase . They lead to severe jaundice, which can be found as early onset (Type I, almost no enzyme activity) or onset later on during childhood (Type II, 10-20% of normal enzyme activity left).

Question 21

What is Crigler-Najjar Type II also known as? What are patients treated with?

Answer 21

Crigler-Najjar Type II is also known as Arias syndrome. Patients need in severe cases life-long treatment with blue light or with drugs like phenobarbital (to stimulate synthesis of UDP-glururonyl transferase).

Question 22

What is Gilberts’syndrome? Enzyme deficient? How is it triggered?

Answer 22

Gilberts’ syndrome is a genetic defect that leads to mild jaundice.

-Bilirubin UDP-glucuronyl transferase is about to 50% deficient in this common genetic defect which can be triggered by fasting or infections.

Question 23

In Gilberts’ syndrome, there is what in the blood?

Answer 23

-leads to temporarily elevated levels of unconjugated bilirubin in the blood