Topic 2&3: Heme Metabolism Flashcards
what is the structure of heme?
composed of an iron molecule surrounded by a protoporphyrin ring
where does the iron component of heme come from?
it’s ingested through the food we eat and absorbed in the duodenum
where does the protoporphyrin component of heme come from?
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
what does ALA synthase enzyme of the heme synthesis pathway require to remain functional?
vitamin B6 (pyridoxine)
without vitamin B6, this pathway does not form heme, leading to a condition known as sideroblastic anemia
how can vitamin B6 deficiency occur?
one way vitamin B6 deficiency can occur is from using the anti-tuberculosis drug isoniazid
what is isoniazid? what does it do?
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
A patient on Isoniazid (INH) therapy for tuberculosis may develop a deficiency of which vitamin?
Patients on INH may develop vitamin B6 deficiency leading to peripheral neuropathy
what happens to hemoglobin after an RBC dies?
hemoglobin is broken down into heme + globin via heme catabolism pathway
what is heme broken down into? how?
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
how is bilirubin transported through the blood?
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
where is unconjugated bilirubin transported to?
liver
transported via albumin
where can unconjugated bilirubin travel in the body?
unconjugated/lipid soluble bilirubin can travel anywhere in the body, even up to the skin
what happens to unconjugated bilirubin once it gets to the liver?
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
how does unconjugated bilirubin enter the liver?
in order for unconjugated bilirubin to enter the liver, it goes through the canalicular membrane transporter
where can conjugated bilirubin travel in the body?
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
where does conjugated bilirubin in the liver go? what happens to it?
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)
what happens to urobilinogen?
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
what is enterohepatic circulation?
the process in which a small amount of bile salts are continuously recycled
it’s when a small amount of urobilinogen is always reabsorbed
what are the final steps of urobilinogen processing?
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)
what are the steps of the heme breakdown pathway?
- heme is broken down into bilirubin
- Unconjugated bilirubin is transported to the liver
- Bilirubin is conjugated in the liver
- Bilirubin is converted into urobilinogen
- Urobilinogen is reabsorbed or excreted as stercobilin
- Urobilinogen is excreted into the bile and urine
Which enzyme is responsible for the conjugation of bilirubin?
The enzyme that conjugates bilirubin is UDP-glucuronyl-transferase
what are the two types of hyperbilirubinemia?
conjugated and unconjugated
what is unconjugated hyperbilirubinemia?
aka indirect hyperbilirubinemia
the buildup of unconjugated/lipid soluble bilirubin in the blood
think of unconjugated hyperbilirubinemia as a symptom of a certain condition
what causes unconjugated hyperbilirubinemia?
- increased breakdown of RBCs releasing free, unconjugated bilirubin into the bloodstream
- decreased conjugation of bilirubin causing an accumulation of unconjugated bilirubin
what conditions cause increased breakdown of RBCs?
various types of hemolytic anemias
G6PD deficiency, hereditary spherocytosis, hemolytic disease of the newborn, etc.
what diseases are examples of decreased conjugation of bilirubin?
- Gilbert’s syndrome: decreased activity of UDP-glucuronyl transferase on exertion
- Crigler-Najjar syndrome type I and II
- Gray baby syndrome: due to chloramphenicol toxicity which displaces unconjugated bilirubin from albumin
what is gilbert’s syndrome?
decreased activity of UDP-glucuronyl transferase on exertion
causes decreased conjugation of bilirubin
what is gray baby syndrome?
due to chloramphenicol toxicity which displaces unconjugated bilirubin from albumin
causes decreased conjugation of bilirubin
what is the clinical presentation of unconjugated hyperbilirubinemia?
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
what is conjugated hyperbilirubinemia?
the buildup of conjugated/water soluble bilirubin in the blood
should also be thought of as a symptom of a certain condition
what causes conjugated hyperbilirubinemia?
- a deficiency of the canalicular membrane transporter which allows the excretion of conjugated bilirubin from the liver into the bile
- impaired bile flow = blockage of the bile ducts
what are Dubin-Johnson syndrome and Rotor syndrome?
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
what can impair bile flow?
- choledocolithiasis (gallstones blocking the common bile duct)
- tumors pressing on and obstructing the biliary tree
- biliary strictures
- even the parasite Clonerchis sinensis
what is the clinical presentation of conjugated hyperbilirubinemia?
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!
what is scleral icterus?
yellow sclera of the eyes
if conjugated hyperbilirubinemia is due to blockage of the bile ducts, what other symptoms besides dark urine will occur?
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)
