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Digestive Systems, Nutrition, and Metabolism > Heme Degredation and Bilirubin Metabolism > Flashcards

Heme Degredation and Bilirubin Metabolism Flashcards

1
Q

Describe the link between digestive systems and heme degradation.

A

Just so happens that the end product of heme breakdown is bilirubin, which is secreted in bile.

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2
Q

What happpens if heme degredation tanks?

A
  1. hyperrbilirubinemia
  2. jaundice (main symptom)
  3. Disterbance sin metabolic pathways in digestive system.
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3
Q

Describe the process of heme degradation.

A

RBC lasts 3 months. At the end of it, it gets to spleen and is degraded in spleen cells by a phagocyte…a macrophage of the reticuloendothelial system, especially in spleen and liver), creating heme. Heme is then converted to bilirubin. The bilirubin is then sent to hepatocytes, bound to albumin. When it gets to hepatocyte, it is conjugated with glucuronic acid to make it more soluble. It is then finally released from hepatocyte in the bile.

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4
Q

What is special about bilirubin in terms of physical properties?

A

Very insoluble. This is why it uses albumin to be transported to the liver hepatocytes.

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5
Q

job of heme?

A

transports O2 in both blood and muscle through hempoglobin and myoglobine. also a part oc cytochrome c (electron transport chain) among other things.

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6
Q

Where do you find the majority of heme? Where is the bulk of bilirubin obtained from?

A
  1. RBC.

2. RBC breakdown….accounts for 85% of bilirubin production

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7
Q

After the 60 to 120 days of life the RBC lives, where do they end up?

A
  1. Extravascularly speaking, they are filterd from blood in spleen (or bone marrow/liver). At this point, macrophages phagocytoce them through reticuloendothelial system (RES). This represents the majority (more than 90%) of the degradation of senescent RBCs.
  2. Intravascularly speaking, RBCs just happen to rupture while in circulation (while in the vasculature). This is the last 10% cause of their death.
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8
Q

List some pathologies associated with extravascualr hemolysis

A
  1. RBC membrane abnormalies which restrict RBC deformabilty such as sickle cell anemia, thalassemia, pyrubate kinase deficiency (was slanted…likely to be expanded later)
  2. Note that reduced deformability makes RBC passage difficult, leading to red cell sequestration and phagocytosis by macrophages located within the splenic cords.
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9
Q

List some pathologies associated with intravascular hemolysis

A

Enzyme defects such as glucose-6-phosphate dehydrogenase (G6PD) deficiency, mechanical trauma, complement fixation ,and other toxic damage to the RBC, Favism. May see fragmented RBDs (schistocytes) in the blood.

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10
Q

What is globin? What are the 3 components of RBC. What part of RBC becomes bilirubin?

A
  1. Protein part of RBC. Gets broken down into AA.
  2. Globin, Fe (gets recycled), Heme.
  3. Heme.
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11
Q

Describe the fate of intravascular hemoglobin

A
  1. Hemoglobin is bound to haptoglobin.
  2. Hemoglobin-haptoglobin complex binds to receptor on macrophage
  3. Macrophage endocytosis them. Lysosomes break it down into Fe, heme, and globin.
  4. heme is converted to bilirubin. the same way it would be if it were extravascularly found
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12
Q

How is stray heme handled?

A
  1. Heme without full hemoglobin setup is taken by hemopexin.
  2. hemopxin-heme complex binds to macrophage receptor
  3. Heme is uptaken and convered to bilirubin.
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13
Q

Describe the enzymes involved in degradation of heme to bilirubin in macrophages. What is significant about O2 use in this process? What is significant about the ultimate final product’s color?

A
  1. heme it converted to biliverdin using Heme Oxygenase (and O2, and NADPH). NOTE: O2 is used, and the product if CO. CO acts as a signal molecule and vasodilator. Also note that Fe that’s removed is recycled.
  2. Biliverdin is converted to bilirubin using Biliverdin Reductase (and more NADPH). It is yellowish/red/orange…this is where the jaundice is coming from. Bilirubin is ultimately sent to the liver.
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14
Q

List some properties about bilirubin.

A
  1. It’s hydrophobic (not soluble in plasma)
  2. When released into plasma, it must be bound to albumin. High binding affinity
  3. Its color (yellow/orange/red) is what gives jaundice its color
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15
Q

Explain the reason for the color changes seen in bruises.

A

It’s all caused by hemoglobin to biliverdin to bilirubin conversion. They have their own associated colors. Starts from blue/red to purple to green to yellow. This shows you the pathway of heme degradation.

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16
Q

What happens to bilirubin when it enters the liver?

A

Bilirubin needs to stay in hepatocyte, so it links to Ligandin (new transporter) aka GST-B (glutathione-S-transferase B). Now the bilirubin is bound to intracellular transport of hepatocyte. This brings it to the Smooth ER where it will be processed.

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17
Q

What happens to bilirubin upon entering hepatocytes and being bound to ligandin?

A

It is conjugated to increase its solubility. It goes through 2 conjugations:
1. Bilirubin uses UDP-glucoronyl transferase (UDP-GT, also called
UGT1A1) enzyme to add UDP-glucuronic acid, turning the it into bilirubin monoglucuronide (BMG)
2. BMG gets a second UDP-glucuronic acid addition, turning it into Bilirubin diglucuronide (BDG) (dominant, more prominant form). Goal in adding these sugars is to make it more soluble. Same enzyme is used.

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18
Q

What are the 3 names for UDP-glucoronyl transferase

A
  1. UDP-glucoronyl transferase
  2. UDP-GT
  3. UGT1A1
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19
Q

What disease are related to screw up in UDP-GT

A
  1. Gilbert syndrome

2. Crigler-najjar syndrome (I and II)

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20
Q

Where does bilirubin conjugation occur? What happens after conjugation?

A
  1. Liver
  2. Post-conjugation, the molecule is ready to be put in bile. Stays in gallbladder till stimulated by CCK (just like bile) and then it is released.
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21
Q

What happens when bilirubin makes it to the intestine?

A

It is converted to fecal and urine pigments.

  1. Urobilinogen is the conjugated form of bilirubin, as a result of gut bacteria. IT IS COLORLESS.
  2. 90% of Urobilinogen is further converted to sterocobilin (red-brown color) and then excreted in feces. Both conversion occur in colon.
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22
Q

What happens to the last 10% of Urobilinogen that is not converted to sterocobilin?

A

It’s reabsorbed into portal circulation. Sent back to liver. If that Urobilinogen is recycled back into bile, it went through the enterhepatic Urobilinogen cycle. If not, the Urobilinogen is transported by blood to kidney, where it’s converted to urobilin and excreted as urine, which is why urine is yellow!

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23
Q

Emphasize difference between fate of BA/BS and fate of Urobilinogen

A

With BA/BS, the major pathway was through enterohepatic pathway. This is the direct opposite for that of Urobilinogen, as it is excreted 90% of the time. Note that conjugated CANNOT be taken up by intestine, like BA/BS can, which is why enterohepatic pathway is usually not the case.

24
Q

What happens if you orally ingest broad-spectrum antibiotics?

A

Greatly diminishes formation of urobilinogen

25
Q

A feature of the process of heme degradation is the lack of solubility of the degradation product bilirubin in aqueous solutions. Which one of the following statements CORRECTLY describes one of the means by which the system of organs, cells and enzymes that is responsible for heme degradation and excretion manages this low solubility in a healthy individual?

A

Acidic derivatives of glucose are covalently attached to bilirubin prior to its export in the bile. there are multiple answers tho, such as the use of albumin to get biliruben to the macrophage.

26
Q

Describe bilirubin transport across the sinusoidal and cannalicular membrane of hepatocytes.

A

From sinosoidal space, UNCONJUGATED bilirubin (as in, it’s bound to albumin) is transported by unknown transporter into hepatocyte. Once in, it’s bi-converted with UDP-GT to conjugated state. Final step entails conjugated form exiting through MRP2 = ABCC2 transporter into canalicular space.

27
Q

What happens if conjugated bilirubin is sent to MRP3 on sinosoidal side instead of MRP2 on canalicular side (the normal side)?

A

It is uptaken by fellow heptocyte OATP1B1/3 transporter on sinosoidal side and then sent out normal MRP2 transporter of that hepatocyte. This is called hepatocyte hopping. Goal is tot reduce upstream flow load of hepatocytes. Jean Gibney talked about this…zone 1 is where most of the action happens, and zone 3 is not. Zone 1 gets all the blood, while zone 3 is more likely to die.

28
Q

Rotor syndrome

A

Issue/difficiency with OAT1b1/3 transporter on sinosoidal side, inhibiting hepatocyte hopping of conjugated bilirubin.

29
Q

Dubin-Johnson syndrome

A

Mutation of MRP2 aka ABCC2 transporter on canalicular side

30
Q

How do you measure plasma levels of conjugated? What is Direct Bilirubin?

A

Note that most of the bilirubin found in plasma is conjugated and bound to albumin, it’s coming from the spleen and headed to the liver. Some in the plasma may already be conjugated. YOU CAN ONLY MEASURE CONJUGATED BILIRUBIN. This is because you CANNOT measure bilirubin bound to albumin. This is called Direct Bilirubin.

31
Q

How do you unbind bilirubin from albumin so that you can measure all the bilirubin in the blood?

A

Treat with OH. End result is Total BIlirubin.

32
Q

What is the math behind calculating indirect (unconjugate) bilirubin?

A

Indirect (= unconjugated) bilirubin = Total bilirubin – Direct (= conjugated) bilirubin. Note that the unconjugated form is the majority.

33
Q

Color of conjugated bilirubin. Describe its properties.

A

Yellow. Incredibly insoluble, so it is tightly bound to albumin, and thus CANNOT be excreted in urine. All bilirubin in the urine is conjugated.

34
Q

Color of conjugated bilirubin in urine

A

Dark colored urine

35
Q

Color of urobilinogen

A

NO COLOR

36
Q

Color of urobilin

A

Yellow

37
Q

Color of stercobilin

A

Dark brown

38
Q

What are the properties of yellow gallstones?

A

Note: comprises 80% of gallstone cases. Made of cholesterol. associated with excess cholesterol in bile.

39
Q

Properties of black pigment stones

A

Made of Ca bilirubinate…in other words, bilirubin was precipitating out, not cholesterol. This is usually associated with excess hemolysis, causes too much bilirubin to be in circulation, leading to this issue.

40
Q

Properties of brown pigment gallbladder stones

A

Associated with BOUND, unconjugated bilirubin, composed of calcium salts. Usually caused by infection of gallbladder/bile duct, where bacterial enzymes convert bilirubin to insoluble derivatives that precipitate. south east asia issue.

41
Q

Explain pathology of hyperbilirubinemia. How is it detected?

A

Increased plasma concentrations of bilirubin, resulting from imbalance between its production and its excretion. Seen as jaundice, may have yellow sclera of eyes (ictirus), itchy skin (pruritus) which indicates bile accumulation as well, and it is usually just a symptom to a disease (the main issue)

42
Q

What is another name for jaundice?

A

Icterus

43
Q

Why do jaundice patients appear yellow?

A

Elastin in the sclera has a high affinity for bilirubin. Elastin does NOT bind carotene, so hypercerotenemia would not lead to yellowing of the eyes.

44
Q

What is kernicterus?

A

Bilirubin being found in the brain, evident in yellow pigmentation of the brain. It just so happens that bilirubin crosses the BBB. Bilirubin in the brain is neurotoxic in neonates, but is benign in adults. Kernicterus = yellow staining of deep nuclei of the brain. You will see jaundice.

45
Q

If you block UDP-GT, what form of bilirubin will be elevated?

A

Unconjugated form (you need to know that yell blob pic).

46
Q

What happens if you lose MRP2 or OATP1B13? Explain Dubin-Johnson and Rotor Syndrom.

A

Expect an increase in conjugated bilirubin (conjugated hyperbilirubinemia). This is Dubin-Johnson (MRP2) or Rotor Syndrom (OATP1B13). Expect urine to be dark colored because of the conjugation. Rotor syndrome is super rare. Dubin-Johnson is not as rare. Signal for the disease is a black liver due to impaired biliary secretion of conjugated bilirubin, keeping it trapped in the hepatocytes.

47
Q

Gilbert’s disease

A

Benign, inherited disorder caused by mutation of PROMOTER REGION of UDP-GT gene, resulting in reduced expression in this enzyme. Expect INCREASED unconjugated bilirubin. Jaundince triggered by fasting or illness or stress. Expect in teens all the way to 30s. Treat with phenobarbital, which induces UDP glucuonyl transferase expression. Note that even though the disease reduces expression of the enzyme, the products created are fine.

48
Q

Crigler-Najjar syndrome I

A

Not benign. autosomal recessive (rare). Common in Amish, Caucasian group of philly. Nearly presence of UDP-GT. Result is incredibly reduced presence of conjugated bilirubin. Result: unconjugated hyperbilirubinemia, leading to high risk of kericterus if found in baby. Fatal. Treat with phototherapy for 8-16 hrs daily, or with plasmapheresis. Will need liver transplant by age 5.

49
Q

What is phototherapy?

A

Breaks unconjugated bilirubin to soluble form so that it can be excreted in urine.

50
Q

Crigler-Najjar syndrome II

A

Milder form. 10% normal UDP-GT activity. Cause is point mutation in UDP-GT gene, resulting in substitution of single AA, which reduces but does not wreck enzyme activity. Expect unconjugated hyperbilirubinemia. Difference between I and II is that II has lower levels of hyperbilirubinemia and later onset age. Treat with phenobarbital, which induces UDP glucuonyl transferase expression.

51
Q

Explain neonatal jaundice/physiologic jaundice of newborn

A

Babies happen to be born with low levels of hepatic enzyme UDP-GT at birth. Full expression not expected till week 4. Issue more common in premature babies. Result: indirect (non-conjugated) bilirubin levels go up. Fail to treat = kernicterus…neurotoxi to brain (encephalopathy). Treat with fluorescent light, which converts bilirubin to more polar compound (through isomerization and oxidation), making it easier to be excreted without conjugation. Expect this issue to appear on day 3. if on day one, likely a worse issue.

52
Q

Explain hemolytic jaundice

A

Pre-hepatic jaundice. The disruption happens before bilirubin has been transported from the blood to the liver; it’s caused by conditions such as sickle cell anemia and hemolytic anemia. Expect increase in nonconjugated bilirubin. Thalasemia is example (rbcs lysing faster than body can keep up). Essentially, amount of bilirubin beeing brought into hepatocytes is sky high. can’t keep up.

53
Q

Explain hepatic or intra-hepatic jaundice

A

The disruption happens inside the liver; causes can be due to liver damage/cirrhosis (or genetic such as Gilbert’s syndrome). Also called hepatocellular jaundice. May or may not result in creases in unconjugated bilirubin. Depends on enzymes affected. Essentially, the flow of indirect bilirubin entry is normal, but the liver is not doing it’s job. Decreased bilirubin uptake and impaired bilirubin conjugation. Both conjugated and unconjugated bilirubin can increase because of this.

54
Q

Explain obstructive jaundice

A

Post hepatic jaundice. The disruption prevents the bile (and the bilirubin inside it) from draining out of the gallbladder and into the digestive system; caused by conditions such as gallstones or tumors. Could also be pancreatic cancer, blocking the bile from getting into the duodenum. Conjugated form is the once coming into bile duct, so expect urine to be darker. However, because bilirubin is not getting into feces, as in, there is no stercobilin since the bilirubin is never unconjugated in the colon, feces has a pale clay color.

55
Q 
An otherwise healthy medical student notices that his skin and eyes develop episodic mild yellow discoloration around the time of exams. His urine remains normal in color. He does not drink alcohol. The most likely diagnosis is which of the following?
A. Excessive hemolysis
B. Gilbert syndrome
C. Crigler-Najjar syndrome Type I
D. Cirrhosis of the liver
E. Dubin-Johnson syndrome
A

Gilbert syndrome. it is the most benign one, and it can be stress induced. Step worthy

56
Q 
A newborn infant is noted to be suffering from mild jaundice, but no bilirubin is found in the urine. The child's symptoms are most likely attributable to a developmental delay in the expression or establishment of which of the following?
A. Colonic bacterial colonization
B. Haptoglobin
C. UDP glucuronyl transferase
D. Heme oxygenase
E. Biliverdin reductase
A

UDP glucuronyl transferase

Digestive Systems, Nutrition, and Metabolism (20 decks)

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