Jaundice

Question 1

What is heme?

Answer 1

• heme is the prosthetic group of hemoglobin, myoglobin, cytochromes, catalase, and peroxidase

Question 2

When does jaundice occur?

Answer 2

• when serum bilirubin levels exceed 2 mg/dL

- (hyperbilirubinemia is greater than 1 mg/dL)

Question 3

Normal Serum Bilirubin Levels

Answer 3

• between 0.1 and 1.0 mg/dL

- (majority is unconjugated bilirubin, only a small amount is conjugated)

Question 4

What are the two types of bilirubin? Which is water-insoluble?

Answer 4

• unconjugated bilirubin: water insoluble (AKA indirect bilirubin)
• conjugated bilirubin: water soluble (AKA direct bilirubin)

Question 5

What makes up conjugated bilirubin?

Answer 5

• bilirubin + 2 glucuronic acid

- (known as bilirubin diglucuronide)

Question 6

What are the 5 general causes of hyperbilirubinemia/jaundice? Which type of bilirubin is increased in each?

Answer 6

• increased unconjugated: increased bilirubin production, decreased hepatic bilirubin uptake, disrupted intracellular conjugation
• increased conjugated: disrupted secretion of bilirubin into bile canaliculi, bile duct obstruction

Question 7

T or F: all cells produce heme.

Answer 7

• true!

- however, major locations are in the liver and in the bone marrow (erythroid progenitor cells)

Question 8

What is the main enzyme involved in heme production?

Answer 8

• ALA synthase

Question 9

What do phenobarbitals do to heme synthesis? What about lead?

Answer 9

• phenobarbitals induce heme synthesis by activating ALA synthase
• lead inhibits several enzymes involved in heme production, so it prevents heme formation

Question 10

How long do RBCs circulate the body before being degraded by the liver and/or spleen?

Answer 10

• between 90 and 120 days

Question 11

____% of heme degradation is of old, worn-out RBCs; what is the remaining percentage of?

Answer 11

• 85% is old RBCs

- 15% is immature RBCs, myoglobin, and cytochromes

Question 12

Hemoglobin gets broken down into ______ and ______.

Answer 12

• heme and globin
• heme –> iron + bilirubin –> excretion and/or reabsorption
• globin –> amino acids –> recycled into hemoglobin synthesis

Question 13

Where does heme get broken down into bilirubin? List the steps involved.

Answer 13

• heme breakdown into bilirubin occurs in the MACROPHAGE (the bilirubin then leaves the cell and heads to the liver in the blood)
• heme oxygenase converts heme into biliverdin –> biliverdin reductase converts biliverdin into bilirubin

Question 14

Why do we convert biliverdin into bilirubin? (ie: why don’t we just stop at biliverdin?)

Answer 14

• because biliverdin is very insoluble!

- bilirubin is also insoluble, but less so than its precursor

Question 15

Bilirubin is pretty hydrophobic (water-insoluble), so how does it move around the blood and into the liver?

Answer 15

• it gets joined by albumin! this makes it more soluble, allowing it to travel in the blood

Question 16

What happens to bilirubin once it enters the liver?

Answer 16

• it gets acted on by UDP-glucoronosyl transferase and gets converted into bilirubin diglucuronide (conjugated bilirubin)
• this further increases the molecule’s solubility

Question 17

What happens to bilirubin diglucuronide once it is actively secreted into the duodenal lumen?

Answer 17

• it gets hydrolyzed by bacterial enzymes into urobilinogen
• some (20%) urobilinogen gets reabsorbed into the circulation where it is mainly returned via enterohepatic circulation to the liver (90%), or where it gets converted to urobilin and excreted by the kidneys (10%)
• most (80%) urobilinogen gets converted to stercobilin and is excreted with feces

Question 18

What color is urobilinogen? Urobilin? Stercobilin? What color is conjugated bilirubin?

Answer 18

• urobilinogen: colorless
• urobilin: yellow (urine)
• stercobilin: brown (feces)
• conjugated bilirubin: dark brown

Question 19

4 Classifications of Jaundice

Answer 19

• pre-hepatic/hemolytic, hepatic/hepatocellular, post-hepatic/obstructive, and neonatal

Question 20

Pre-Hepatic Jaundice

Answer 20

• AKA hemolytic jaundice
• increased hemolysis results in overproduction of bilirubin beyond liver’s capacity to take it in
• main increase is in unconjugated bilirubin levels
• more bilirubin in blood = more in liver = more in bile, so patients will also have darker urine (b/c increased urobilin) and darker feces (b/c increased stercobilin)

Question 21

What are three examples of disorders that can cause pre-hapatic jaundice?

Answer 21

• incompatible blood transfusion, malaria, and sickle-cell anemia

Question 22

Post-Hepatic Jaundice

Answer 22

• AKA obstructive jaundice
• obstruction prevents bile secretion, leading to build-up of bilirubin
• main increase is in conjugated bilirubin levels
• lack of bilirubin in bile, so patients will have light colored, floating feces (no stercobilin and steatorrhea), but will have DARK urine
• conjugated bilirubin in serum also results in nausea and anorexia (loss of appetite)

Question 23

In post-hepatic jaundice, bilirubin isn’t entering the duodenal lumen, explaining why these patients have light colored, floating feces; why, then, do patients have dark urine? (ie: why isn’t their urine also colorless?)

Answer 23

• because the elevated conjugated bilirubin enters the blood and the kidneys, and this gives urine a very dark color

Question 24

Hepatic Jaundice

Answer 24

• AKA hepatocellular jaundice
• liver dysfunction and/or damage results in a loss of function, causing an increase in unconjugated AND conjugated bilirubin
• patients will have light, floating feces, dark urine, nausea, and anorexia

Question 25

Neonatal Jaundice

Answer 25

- jaundice is common in many neonates because it takes about 2 weeks for the hepatic machinery to mature and develop - mainly an increase in unconjugated bilirubin - worrying because excess bilirubin can cross the immature blood-brain barrier, resulting in toxic encephalopathy

Question 26

What are the most common causes of jaundice?

Answer 26

- hepatitis, biliary obstruction, and hemolytic anemia

Question 27

Gilbert Syndrome

Answer 27

- a benign (not associated with any increased morbidity), inherited condition resulting in mild, fluctuating increases in unconjugated bilirubin - a result of decreased levels of bilirubin UDP glucuronyl transferase and decreased bilirubin uptake

Question 28

Dubin-Johnson Syndrome

Answer 28

- an inherited defect in the transport protein needed for hepatocellular excretion of bilirubin, leading to large increases in conjugated bilirubin - patients have a VERY dark liver (but the color is NOT due to the conjugated bilirubin!)

Question 29

Unconjugated bilirubin is also known as ______ bilirubin; conjugated bilirubin is also known as _______ bilirubin.

Answer 29

- unconjugated = indirect | - conjugated = direct

Question 30

What is a major complication of physiologic jaundice of the newborn if left untreated? How do we treat this type of jaundice?

Answer 30

- kernicterus: a bilirubin induced brain dysfunction (can be fatal) - (unconjugated bilirubin is very fat soluble and can therefore deposit in the brain) - treat this jaundice with phototherapy, which makes unconjugated bilirubin water-soluble (note that it does NOT make it into conjugated bilirubin)

Question 31

Crigler-Najjar Syndrome (types I and II)

Answer 31

- absence of UDP-glucuronosyltransferase, resulting in early and rapid onset of elevated unconjugated bilirubin, jaundice, kernicterus and death within a few years if untreated - treat with plasmapheresis and phototherapy - type I is more severe than type II

Question 32

What is the difference between jaundice and cholestasis?

Answer 32

- jaundice = excess bilirubin that manifests as discoloration - cholestasis = retention of bile (excess bilirubin, bile salts, and cholesterol) that manifests as pruritis and xanthomas - (obstructive jaundice usually results in cholestasis as well)

Question 33

Rotor Syndrome

Answer 33

- a milder form of Dubin-Johnson syndrome (inability of liver to excrete the conjugated bilirubin. Into biliary tract) - unlike Dubin-Johnson, patient's liver is NOT black here