Bilirubin Metabolism

Question 1

What is bilirubin? What are some consequences of defects in its metabolism?

Answer 1

Bilirubin is a product of heme breakdown. Defects in heme degradation or excretion of bilirubin through bile can result in Hyperbilirubinemia, juandice and other disturbances in metabolic pathways.

Question 2

Briefly describe the process of heme degradation in 5 steps.

Answer 2

1. Phagocytes eat up old RBCs to breakdown into globin, iron and heme.
2. Heme is metabolized into bilirubin in phagocytes.
3. Albumin binds to bilirubin to transport it to hepacytes by circulation.
4. Hepatocytes free bilirubin and combine it with glucuronic acid to make conjugated bilirubin.
5. Conjugated bilirubin is excreted into bile to head out into intestines.

Question 3

Up to ___% of daily production of bilirubin comes from breakdown of ___. The remainder of other heme-like proteins is turned over in the ____ ____.

Answer 3

85% of daily bilirubin from metabolism of old RBCs.

Remainder of hemoproteins is converted in bone marrow.

Question 4

The lifespan of a RBC is from __ to __ days. Old RBCs are either filtered in the ____ to be swallowed up by macrophages of the ______ system. This process represents ___% of degradation.

Answer 4

Life of RBC = 60-120 days

90% of old RBCs are filtered in spleen to be phagocytosed as part of the reticuloendothelial system (RES).

Question 5

About ___% of RBCs undergo intravascular ______. This is the ____ of RBCs within circulation.

Answer 5

~10% of old RBCs undergo hemolysis where they rupture in circulation.

Question 6

Abnormalities in the RBC membrane restricts ______. This leads to RBC _____ and _____ by macrophages in the splenic cords.

Answer 6

Extravascular hemolysis pathologies restrict RBC “deformability”. Leads to RBC sequestration and phagocytosis by splenic macrophages.

Question 7

Pathologies in intravascular hemolysis include (but are not limited to)… This results in fragmented RBCs called ____.

Answer 7

Intravascular hemolysis pathologies include G6PD deficiency, mechanical trauma and Favism (toxic damage). This results in Schistocytes.

Question 8

What RBC membrane abnormalities can result in an upregulation of extravascular hemolysis?

Answer 8

Sickle cell anemia, thalassemia and Pyruvate Kinase Deficiency.

Question 9

What are the 2 ways that heme can be taken into the macrophages of the liver in intravascular hemolysis?

Answer 9

1. Extracellular heme is incorporated into hemopexin-heme that enter macrophage.
2. Hb binds haptoglobin to undergo receptor-mediated endocytosis in liver macrophages.

Question 10

What enzyme is involved with the 1st step in degradation of heme? What are the requirements and side-products?

Answer 10

Heme Oxygenase converts Heme into (green) Biiverdin. This step requires NADPH and O2 but releases Iron, NADP and Carbon monoxide (vasodilator). This is the only reaction in the body that produces CO

Question 11

What enzyme is involved in the 2nd step of heme degradation? What are the requirements and product?

Answer 11

Biliverdin Reductase converts Biliverdin into (yellow) Bilirubin. This step requires NADPH to make the hydrophobic bilirubin that has a high affinity for albumin if unconjugated.

Question 12

In the blood, bilirubin is bound to _____;whereas, in the liver cell, it is bound to _____.

Answer 12

Albumin;

Ligandin (cytoplasmic transport protein in hepatocytes)

Question 13

What is the function of ligandin as it relates to bilirubin metabolism?

Answer 13

Ligandin, which is an intra-cellular transport protein in the liver cell, has a higher affinity for bilirubin than albumin does. It transports bilirubin to the liver cell’s SER to be processed.

Question 14

What happens to bilirubin within the SER of Hepatocytes? What are the effects?

Answer 14

Bilirubin becomes more SOLUBLE from the addition of glucoronic acid moieties by UDP-glucoronyl transferase (UDP-GT) enzyme. Conjugated bilirubin (BDG 85% and BMG 15%) is more POLAR and thus more soluble.

Question 15

What is the enzyme responsible for conjugating Bilirubin?

Answer 15

UDP-GT or UGT1A1 in the smooth ER of hepatocytes adds glucoronic acid (sugar) moeities to bilirubin. This makes it more soluble in blood.

Question 16

Bilirubin is converted into pigments that color the wastes that leave the body. Feces are brown because most urobilinogen is converted to ______. Meanwhile, urine is yellow because the remaining urobilinogen is turned into ______.

Answer 16

90% of urobilinogen is converted to red-brown “Stercobilin” by microbial enzymes. 10% of reabsorbed urobilinogen is turned into yellow “Urobilin” in the kidney.

Question 17

Unlike bile salts/acids, most of the bilirubin is ______, so it does not circulate ______.

Answer 17

Most bilirubin is EXCRETED in the feces, so it does not circulate enterohepatically.

Question 18

Oral administration of _______ antibiotics greatly reduces the formation of ________.

Answer 18

Broad-spectrum antibiotics reduces the formation of Urobilinogen. This is due to the changes in gut microbiota that impacts its formation.

Question 19

Heme degradation produces the insoluble bilirubin by-product. How does the body manage the low solubility in a healthy individual?

Answer 19

Acidic derivative of glucose are covalently attached to bilirubin prior to its export in the bile.

Question 20

Bilirubin _______ is made in the liver and sent into bile. Bilirubin that is ______ is bound to albumin in the blood stream.

Answer 20

Bilirubin Diglucuronide;

Unconjugated Bilirubin

Question 21

Explain the purpose of bilirubin “Hepatocyte Hopping”. What are the transporters involved in this process?

Answer 21

A fraction of conjugated bilirubin is off-loaded to downstream hepatocytes to prevent the saturation of biliary transport in upsteam hepatocytes. MRP2 normally shuttles the product into canalicular space, but MRP3 on the sinusoidal side reroutes some to the blood for downstream liver cells to pick up.

Question 22

What deficiency results in Rotor Syndrome? What are the effects?

Answer 22

Deficiency in the transporters that take in unconjugated bilirubin from blood into liver cells (OATP1B1/3). This can present as juandice since too much bilirubin would be in circulation.

Question 23

What deficiency results in Dubin-Johnson Syndrome? What are some possible effects?

Answer 23

Deficiency in MRCP2 transporters from mutations in ABCC2 gene can result in less conjugated bilirubin being taken into the canalicular space.

Question 24

Only the ____ bilirubin can be measured DIRECTLY. Concentrations of ______ bilirubin can be calculated indirectly.

Answer 24

Conjugated measured directly; unconjugated measured indirectly. “Un is In-direct!”
Indirect unconjugates = Total bilirubin - direct conjugates

Question 25

How would a scientist find total bilirubin in order to calculate the unconjugated bilirubin of a patient?

Answer 25

The scientist would treat the bilirubin with Alcohol to acquire TOTAL concentration. From there he can subtract direct conjugates from Total to estimate the indirect unconjugated bilirubin.

Question 26

Conjugated bilirubin can present as ____ urine.

Answer 26

Dark-colored urine

Question 27

Describe the difference between black pigment and brown pigment gallstones.

Answer 27

Black-pigment stones are made of Calcium bilirubinate that form from HEMOLYSIS leading to XS bilirubin. Whereas, Brown-pigment stones are composed of calcium salts of unconjugated bilirubin that are associated with gallbladder infections (common in East Asian countries).

Question 28

What are the signs associated with Hyperbilirubinemia?

Answer 28

Hyperbilirubinemia can present clinically as jaundice. This features yellow sclera and itchy yellow skin as symptoms.

Question 29

How can a physician differentiate hyperbilirubinemia from hypercarotenemia?

Answer 29

The doc will not see yellow sclera in a patient who has too much carotene as compared to the patient with too much bilirubin. This is because elastin in sclera does not bind to carotene; but it has a high affinity for bilirubin.

Question 30

What is Kernicterus and in what patient population might it occur?

Answer 30

Kernicterus is a yellow staining of the deep nuclei of the brain that might occur in newborns. Bilirubin (which can cross the BBB) is neurotoxic and is very debilitating.

Question 31

What causes Criggler-Najjar Syndrome type I? What are the effects and how can it be treated?

Answer 31

Criggler-Najjar is associated with a defective UDP-GT enzyme that conjugates bilirubin. This results in high levels of UNCONJUGATED bilirubin. This puts individuals at a high risk of KERNICTERUS and a SEVERE case of jaundice; treatment with phototherapy, plasmapheresis or liver transplant

Question 32

How can a doc differentiate Criggler-Najjar Syndrome from either Rotor or Dubin-Johnson Syndromes?

Answer 32

Checking plasma levels of the type of bilirubin that is high can indicate the type of hereditary hyperbilirubinemia. High indirect measures = Criggler; High direct measures = Rotor/Dubin’s

Question 33

What is the cause of Gilbert’s syndrome? What are the effects and how is it treated?

Answer 33

Gilbert’s = mutation in promoter region of UDP-GT gene; relatively BENIGN liver disorder + unconjugated bilirubin + jaundice from fasting or stress; treated with small amounts of phenobarbital that induces UDP-GT expression.

Question 34

What is the cause of Dubin-Johnson Syndrome? What is the effect and key feature?

Answer 34

A mutation in MRP2 transporter results in higher levels of CONJUGATED bilirubin. A common feature of this is “Black liver” from impaired biliary secretion of conjugates.

Question 35

What is the treatment for neonatal jaundice and how does it work?

Answer 35

Blue fluorescent light is a treatment for jaundice seen in more often in premature babies than full-terms. It works by converting bilirubin to a more POLAR compound that can be excreted WITHOUT CONJUGATION.

Question 36

What are common causes of pre-hepatic, intra-hepatic and post-hepatic jaundice disorders, respectively?

Answer 36

1. Pre-hepatic jaundice = Sickle cell or hemolytic anemia (high unconjugated bilirubin)
2. Intra-hepatic jaundice = Cirrhosis, Gilbert’s Syndrome (elevated both)
3. Post-hepatic jaundice = obstructive from gallstones or tumors (elevated conjugated bilirubin)

Question 37

What 2 key features in waste are seen in a patient with post-hepatic (obstructive) jaundice?

Answer 37

1. Darker urine from elevated levels of conjugated bilirubin.
2. Clay-colored feces from absence of brown-colored stercobilin (urobilinogen product)

Question 38

A chronic alcoholic comes in for a physical checkup and the doc orders him to pee in a cup. Aside from the high BAC, what should be expected in plasma and in urine?

Answer 38

Chronic alcohol use may damage the liver, leading to high levels of BOTH conjugated and unconjugated bilirubin in plasma. This can also present as darker urine.

Question 39

A newborn infant is suffering from a mild case of jaundice. No bilirubin is found in the urine. The symptoms presented may be due to a developmental delay in what enzyme?

Answer 39

UDP glucouronyl transferase (UDP-GT) delay is common in physiological neonatal jaundice common in premature babies. This should resolve with blue flourescent light.