Topic 2&3: Heme Metabolism

Question 1

what is the structure of heme?

Answer 1

composed of an iron molecule surrounded by a protoporphyrin ring

Question 2

where does the iron component of heme come from?

Answer 2

it’s ingested through the food we eat and absorbed in the duodenum

Question 3

where does the protoporphyrin component of heme come from?

Answer 3

must be synthesized as part of the eight-step heme synthesis pathway

heme is created as the final step of the pathway after the enzyme ferrochelatase inserts iron into the protoporphyrin ring

Question 4

what does ALA synthase enzyme of the heme synthesis pathway require to remain functional?

Answer 4

vitamin B6 (pyridoxine)

without vitamin B6, this pathway does not form heme, leading to a condition known as sideroblastic anemia

Question 5

how can vitamin B6 deficiency occur?

Answer 5

one way vitamin B6 deficiency can occur is from using the anti-tuberculosis drug isoniazid

Question 6

what is isoniazid? what does it do?

Answer 6

INH is an anti-tuberculosis drug that can cause vitamin B6 deficiency

INH metabolites directly inhibit pyridoxine and also inhibit the conversion of pyridoxine to an active metabolite

this leads to a vitamin B6 deficiency that clinically manifests as peripheral neuropathy (numbness and paresthesias of the distal extremities)

vitamin B6 supplementation is important when administering INH

Question 7

A patient on Isoniazid (INH) therapy for tuberculosis may develop a deficiency of which vitamin?

Answer 7

Patients on INH may develop vitamin B6 deficiency leading to peripheral neuropathy

Question 8

what happens to hemoglobin after an RBC dies?

Answer 8

hemoglobin is broken down into heme + globin via heme catabolism pathway

Question 9

what is heme broken down into? how?

Answer 9

bilirubin!

heme is broken down by macrophages via intracellular heme oxygenase to yield bilirubin

bilirubin is an orange-yellow pigment that correspondingly causes the orange-yellow pigment skin discoloration called jaundice

Question 10

how is bilirubin transported through the blood?

Answer 10

Initially, bilirubin is unconjugated/lipid soluble (insoluble in aqueous solutions at physiologic pH) and is therefore carried through the blood while bound to albumin

If it’s not bound to albumin, it cannot be transported through the blood

Question 11

where is unconjugated bilirubin transported to?

Answer 11

liver

transported via albumin

Question 12

where can unconjugated bilirubin travel in the body?

Answer 12

unconjugated/lipid soluble bilirubin can travel anywhere in the body, even up to the skin

Question 13

what happens to unconjugated bilirubin once it gets to the liver?

Answer 13

unconjugated bilirubin is conjugated by the enzyme (UDP)-glucuronyl-transferase (UGT1A1) to become conjugated/water soluble bilirubin

in order for unconjugated bilirubin to enter the liver, it goes through the canalicular membrane transporter

Question 14

how does unconjugated bilirubin enter the liver?

Answer 14

in order for unconjugated bilirubin to enter the liver, it goes through the canalicular membrane transporter

Question 15

where can conjugated bilirubin travel in the body?

Answer 15

can be transported through the bile canalicular system or ureters without traveling to other parts of the body, such as the skin

does not need to be shuttled by albumin and can be transported in aqueous solutions without a carrier because it is water soluble

it can be dissolved in bodily fluids such as bile, urine, and blood

Question 16

where does conjugated bilirubin in the liver go? what happens to it?

Answer 16

conjugated bilirubin is excreted into the bile and travels via the bile ducts into the intestine

in the intestines, an enzyme produced by bacteria called beta-glucuronidase hydrolyzes the glucuronic acid, reforming unconjugated bilirubin

then, other bacterial-mediated processes convert unconjugated bilirubin into urobilinogen (colorless)

Question 17

what happens to urobilinogen?

Answer 17

urobilinogen can go in two directions
1. it is either converted into stercobilin (a brown pigment that gives stool its color)
OR
2. small amounts of urobilinogen are reabsorbed and sent back to the liver

a small amount of urobilinogen is ALWAYS reabsorbed (20%) = enterohepatic cirulation

Question 18

what is enterohepatic circulation?

Answer 18

the process in which a small amount of bile salts are continuously recycled

it’s when a small amount of urobilinogen is always reabsorbed

Question 19

what are the final steps of urobilinogen processing?

Answer 19

1) transportation via the blood to the liver and re- excretion into the bile or
2) transportation to the kidney, where it is further broken down into urobilin (yellow pigment that gives urine its color)

Question 20

what are the steps of the heme breakdown pathway?

Answer 20

1. heme is broken down into bilirubin
2. Unconjugated bilirubin is transported to the liver
3. Bilirubin is conjugated in the liver
4. Bilirubin is converted into urobilinogen
5. Urobilinogen is reabsorbed or excreted as stercobilin
6. Urobilinogen is excreted into the bile and urine

Question 21

Which enzyme is responsible for the conjugation of bilirubin?

Answer 21

The enzyme that conjugates bilirubin is UDP-glucuronyl-transferase

Question 22

what are the two types of hyperbilirubinemia?

Answer 22

conjugated and unconjugated

Question 23

what is unconjugated hyperbilirubinemia?

Answer 23

aka indirect hyperbilirubinemia

the buildup of unconjugated/lipid soluble bilirubin in the blood

think of unconjugated hyperbilirubinemia as a symptom of a certain condition

Question 24

what causes unconjugated hyperbilirubinemia?

Answer 24

1. increased breakdown of RBCs releasing free, unconjugated bilirubin into the bloodstream
2. decreased conjugation of bilirubin causing an accumulation of unconjugated bilirubin

Question 25

what conditions cause increased breakdown of RBCs?

Answer 25

various types of hemolytic anemias

G6PD deficiency, hereditary spherocytosis, hemolytic disease of the newborn, etc.

Question 26

what diseases are examples of decreased conjugation of bilirubin?

Answer 26

1. Gilbert’s syndrome: decreased activity of UDP-glucuronyl transferase on exertion
2. Crigler-Najjar syndrome type I and II
3. Gray baby syndrome: due to chloramphenicol toxicity which displaces unconjugated bilirubin from albumin

Question 27

what is gilbert’s syndrome?

Answer 27

decreased activity of UDP-glucuronyl transferase on exertion

causes decreased conjugation of bilirubin

Question 28

what is gray baby syndrome?

Answer 28

due to chloramphenicol toxicity which displaces unconjugated bilirubin from albumin

causes decreased conjugation of bilirubin

Question 29

what is the clinical presentation of unconjugated hyperbilirubinemia?

Answer 29

jaundice!!!!

unconjugated hyperbilirubinemia is a lipid soluble molecule that is insoluble in aqueous solutions at physiologic pH

so if it accumulates, it will not stay in the blood, bile, or urine. It will diffuse into tissues, particularly the skin and the brain

Question 30

what is conjugated hyperbilirubinemia?

Answer 30

the buildup of conjugated/water soluble bilirubin in the blood

should also be thought of as a symptom of a certain condition

Question 31

what causes conjugated hyperbilirubinemia?

Answer 31

1. a deficiency of the canalicular membrane transporter which allows the excretion of conjugated bilirubin from the liver into the bile
2. impaired bile flow = blockage of the bile ducts

Question 32

what are Dubin-Johnson syndrome and Rotor syndrome?

Answer 32

there is a deficiency of the canalicular membrane transporter, and consequently conjugated bilirubin cannot be excreted into the bile

conjugated bilirubin then diffuses into the bloodstream instead

Question 33

what can impair bile flow?

Answer 33

1. choledocolithiasis (gallstones blocking the common bile duct)
2. tumors pressing on and obstructing the biliary tree
3. biliary strictures
4. even the parasite Clonerchis sinensis

Question 34

what is the clinical presentation of conjugated hyperbilirubinemia?

Answer 34

usually first manifests as dark brown urine because the water-soluble bilirubin in the blood is filtered via the glomerulus into the urine

conjugated bilirubin is a water-soluble molecule that is soluble in aqueous solutions at physiologic pH so if it accumulates, it will stay in the blood, bile, and urine

won’t diffuse into the skin or brain because it’s water soluble!

Question 35

what is scleral icterus?

Answer 35

yellow sclera of the eyes

Question 36

if conjugated hyperbilirubinemia is due to blockage of the bile ducts, what other symptoms besides dark urine will occur?

Answer 36

pale stools

since conjugated bilirubin is not released into the intestines (where it normally undergoes breakdown into stercobilin, the pigment that gives stool its brown color)