Heme Synthesis And Breakdown

Question 1

What is structure of heme?

Answer 1

A porphyrin ring that contains 4 pyrrole rings and one ferrous (Fe2+) (there are four porphyrin rings per hemoglobin)

Question 2

What are the phases of heme synthesis?

Answer 2

Phase one- generation of ALA from glycine and succinyl CoA in mitochondria
Phase two- generation of Coproporphyrinogen III from ALA in the cytosol
Phase three- generation of heme from Coproporphyrinogen III in the mitochondria

Question 3

What are the enzymes used in phase one of heme synthesis?

Answer 3

ALA synthase

Question 4

What are the enzymes used in phase two of heme synthesis?

Answer 4

ALA dehydrogenase, PRB deaminase, uroporphyrinogen III synthase, uroporphyrinogen decarboxylase

Question 5

What are the enzymes used for phase three in heme synthesis?

Answer 5

Coproporphyrinogen oxidase, protoporphyrinogen oxidase and ferrochelatase

Question 6

What is the cofactor for ALA synthase and what occurs when the cofactor is not present?

Answer 6

The cofactor is Vitamin B6 and without this there is anemia

Question 7

What happens when lead is introduced into the body?

Answer 7

Lead will disrupt ALA dehydrogenase and ferrochelatase activity. This will result in the accumulation of ALA and protoporphyrin IX- ALA is a neurotoxin so have neuro sx, anemia since no heme production and weakness because no cytochromes developing

Question 8

What are the sx of lead poisoning and why?

Answer 8

Neurological sx from build up of ALA
Anemia since no heme production
Weakness since no cytochrome production

Question 9

What is acute intermittent porphyria?

Answer 9

An acute hepatic porphyria that results in a defect in the PRB deaminase. There will be a build up of ALA and PRB

Question 10

What is congenital erythropoietic porphyria?

Answer 10

An erythropoietic porphyria that results in a defect in uroporphyrinogen III synthase that results in red fluorescence to the tissues due to a build up of uroporphyrin I.

Question 11

What is porphyria cutaneous tarda?

Answer 11

An acute hepatic and erythropoietic porphyria that results in a defect in the enzyme uroporphyrinogen decarboxylase. This is the most common porphyria in the US.

Question 12

What is variegata porphyria?

Answer 12

An acute hepatic porphyria that is the result of a defect in the enzyme protoporphyrinogen oxidase. This is the “celebrity porphyria”.

Question 13

What is heme degraded into?

Answer 13

Heme will degrade into bilirubin

Question 14

What is the enzyme that will convert heme to biliverdin?

Answer 14

Heme oxygenase by cutting the bridge between the pyrrole rings- it requires oxygen and will create CO2. Fe2+ is also converted Fe3+

Question 15

What are the enzymes that convert heme to bilirubin?

Answer 15

Heme oxygenase then biliverdin reductase

Question 16

What happens when bilirubin is released into the blood?

Answer 16

BR is unconjugated/indirect and insoluble till taken to the liver by albumin

Question 17

What happens to bilirubin in the liver?

Answer 17

Bilirubin is converted from indirect/unconjugated to direct/conjugated via UDP- glucuronyl transferase. This makes bilirubin diglucuronide

Question 18

What is an important side reaction in the degradation of heme and why?

Answer 18

the conversion of glucose to UDP-glucose then UDP-glucuronic acid. This molecule is used to help convert indirect bilirubin to direct bilirubin. (Bilirubin to bilirubin diglucuronide)

Question 19

What happens to the conjugated version of bilirubin?

Answer 19

It is stored in the gall bladder till it is released in bile to be excreted through feces or urine.

Question 20

What happens to bilirubin once it leaves the gallbladder?

Answer 20

It is released into the stomach then will be converted back to bilirubin. This will be broken down further to urobilinogen by micros. From there is it secreted by the kidneys in the form of urobilin or by the intestines as stercobilin.

Question 21

What is jaundice?

Answer 21

Also known as hyperbilirubinemia. It is when there is excess bilirubin in the blood stream. There is an imbalance in the production and excretion of bilirubin.

Question 22

What are the three stages that can cause jaundice?

Answer 22

Pre hepatic, intrahepatic or post hepatic

Question 23

What are the causes of pre hepatic hyperbilirubinemia?

Answer 23

This occurs before the liver can pick up BR. This leads to excess levels of unconjugated BR levels which result from hemolytic anemia, hemorrhaging, or inability of the liver to pick up BR/conjugate it

Question 24

What will the findings be in a pre hepatic pt?

Answer 24

elevated levels of unconjugated/indirect BR- normal conjugated BR levels, normal liver enzymes (AST and ALT), normal urobilinogen levels in urine but no direct BR present.

Question 25

What are the causes of intrahepatic hyperbilirubinemia?

Answer 25

occurs in the liver. Impaired hepatic uptake, conjugation or secretion of conjugated BR. Can occur from general liver dysfunction or disorders of enzymes.

Question 26

What are the findings in a intra-hepatic pt?

Answer 26

Variable increases in unconjugated and conjugated BR depending on the issue. Will have increased AST and ALT levels. Urobilinogen is normal but there is conjugated BR in urine.

Question 27

What are the causes of post-hepatic hyperbilirubinemia?

Answer 27

Problems with BR excretion. Can be the result of complications with the gall bladder, tumors in liver or drugs.

Question 28

What are the findings with post hepatic pt?

Answer 28

Elevated levels of conjugated BR in the blood. Small increases in unconjugated BR levels. Normal AST and ALT levels. Conjugated BR in the urine but no urobilinogen. No stercobilin in the feces.

Question 29

What is the cause of neonatal jaundice?

Answer 29

Occurs for a few reasons- immature hepatic metabolic pathways, deficiency in UDP-GT enzyme, an increase in fetal hemoglobin

Question 30

What is phototherapy?

Answer 30

a treatment for jaundice that exposes them to a blue fluorescent light. It causes BR to undergo photoconversion to more soluble isomers.

Question 31

What is Criggler-Najjar Syndrome?

Answer 31

Deficiency in UDP-GT. There are two types- absence of the gene or mutation of the gene

Question 32

What happens in Criggler-Najjar syndrome type I?

Answer 32

Complete absence of UDP-GT. Get severe hyperbilirubinemia- babies will have BR accumulation in the brain which will cause encephalopathy and brain damage.

Question 33

What are some therapies involved in managing type one Criggler-Najjar syndrome?

Answer 33

Blood transfusions, phototherapy, heme oxygenase inhibitors, liver transplants

Question 34

What happens in Criggler-Najjar syndrome type II?

Answer 34

There is a mutation to UDP-GT but the enzyme is still about 10 percent active. Not as severe hyperbilirubinemia

Question 35

What is Gilbert syndrome?

Answer 35

Reduced activity in UDP-GT but still about 25 percent active. Relatively common (2-10%). Serum BR is relatively low but will increase with fasting, stress or alcohol.

Question 36

What is hepatitis?

Answer 36

inflammation of the liver. Leads to liver dysfunction. Can be caused by virus, cirrhosis or cancer. Will lead to elevated conjugated and unconjugated BR