Bile + Bilirubin B&B

Question 1

which 2 molecules are conjugated to bile acids to create a hydrophilic end?

Answer 1

1. taurine (organic acid) —> taurocholic acid
2. glycine (amino acid) —> glycocholic acid

makes the bile a better surfactant

Question 2

what enzyme is required to synthesize bile acids in the liver (via classic pathway)? what 2 cofactors are required?

Answer 2

cholesterol 7-alpha hydroxylase - requires NADPH + O2

notably, it is a cytochrome P450 enzyme

Question 3

where does most lipid (TGs) absorption occur? where does bile acid reabsorption occur?

Answer 3

lipid absorption = jejunum

conjugated bile acids stay behind and are absorbed by active transporters in the terminal ileum

Question 4

name 3 bile acid resins and state their function

Answer 4

1. cholestyramine
2. colestipol
3. colesevelam

retain bile acids and prevent reabsorption so more are excreted in the stool

Question 5

how are bile salts antimicrobial?

Answer 5

disrupt bacterial cell membranes

loss of bile salts = bacterial overgrowth (seen in liver disease)

Question 6

what are the lab findings of cholestasis? (2)

Answer 6

cholestasis = disrupted bile flow to intestines

lab findings show:
1. direct (conjugated) hyperbilirubinemia
2. elevated alkaline phosphatase (produced by bile duct epithelial cells)

Question 7

what are the short-term (4) and long-term (2) symptoms of cholestasis?

Answer 7

cholestasis = disrupted bile flow to intestines

short-term:
1. jaundice
2. pruritis (bile salts in skin)
3. dark urine (conjugated bilirubin)
4. clay colored stool (loss of sterocobilin, metabolic product of bilirubin)

long term: fat malabsorption + decreased fat soluble vitamin levels

Question 8

how can lab values help differentiate between damage to the liver vs bile ducts?

Answer 8

when rise in alkaline phosphatase is&raquo_space;> rise in AST/ALT = “cholestatic pattern”, primary abnormality in bile ducts

when rise in AST/ALT&raquo_space;> rise in alk phos = ”hepatocellular pattern”, primary abnormality in liver

Question 9

what is the best first test to differentiate extrahepatic vs intrahepatic causes of cholestasis?

Answer 9

RUQ ultrasound - will show whether there is dilation of bile ducts [dilation = bile duct obstruction]

workup of extrahepatic cause = additional imaging
workup of intrahepatic cause = lab tests, biopsy

Question 10

name 4 intrahepatic causes of cholestasis

Answer 10

cholestasis = disrupted bile flow to intestines

intrahepatic causes:
1. primary biliary cirrhosis
2. cholestasis of pregnancy
3. contraceptives
4. erythromycin

[extrahepatic causes = gallstones, pancreatic mass, biliary strictures]

Question 11

which 2 enzymes are required for the degradation of heme?

Answer 11

1. heme —> biliverdin (green) via heme oxygenase
2. bilverdin —> bilirubin (yellow/brown) via biliverdin reductase

Question 12

what enzyme is required for bilirubin conjugation?

Answer 12

UDP glucuronyltransferase (UGT)

conjugated to glucuronic acid —> increased water solubility for excretion with bile

Question 13

what happens to bilirubin once it reaches the intestines (2 steps)? what are its 2 fates?

Answer 13

in intestines, converted twice by bacteria:
1. back to unconjugated form via bacterial beta-glucuronidase
2. unconjugated bilirubin —> urobilinogen via bacterial enzymes

then, either #1 excreted in feces (90%) via conversion to stercobilin (makes stool brown) or #2 reabsorbed by intestines (10%) to be taken up by liver (most) or excreted in urine as urobilin (makes urine yellow)

Question 14

what type of bilirubin (un/conjugated) can be detected in the urine in some pathologies, and why?

Answer 14

conjugated only because this is the form that is water soluble

bilirubin is normally absent from urine samples

same thing with dark urine - only caused by high levels of conjugated bilirubin

Question 15

what are the bilirubin lab findings in hemolysis? (2)

Answer 15

1. elevated serum unconjugated bilirubin
2. increased urine urobilinogen (reabsorbed following bacterial conversion in intestines, some will end up in urine due to liver being overwhelmed)

NO urine bilirubin (unconjugated = insoluble, cannot cross glomerulus)

Question 16

what are the bilirubin lab findings in biliary obstruction (cholestasis)? (4)

Answer 16

conjugation occurs normally, but excretion is repaired

1. elevated serum and urine direct (conjugated) bilirubin —> dark urine
2. cholestatic LFT pattern (high alkaline phosphatase&raquo_space; high ALT/AST)
3. clay colored stools due to lack of stercobilin (gives brown color)
4. absent urobilinogen (no bilirubin to intestine = lack of conversion)

Question 17

what are the bilirubin lab findings in primary liver disease?

Answer 17

elevated total bilirubin - fractionation of direct/indirect is unreliable (mix of both usually)

dx of primary liver disease will be made my LFTs, Abs, imaging, biopsy anyway

Question 18

how do urine levels of urobilinogen change early vs late in primary liver disease?

Answer 18

in intestines, conjugated bilirubin is unconjugated, then converted to urobilinogen by bacterial enzymes

elevated early in disease: urobilinogen reabsorbed from intestines, but can’t be excreted in bile —> spills into urine

lacking late in disease: lack of unconjugated bilirubin to intestines = lack of urobilinogen formation

Question 19

How do rifampin and probenecid affect bilirubin levels?

Answer 19

rifampin = antibiotic
probenecid = gout drug

both compete with bilirubin for uptake by the liver —> blunt hepatic uptake of unconjugated bilirubin —> cause a mild increase in unconjugated bilirubin and total bilirubin

[all other LFTs are normal]

Question 20

describe the pathology of Gilbert’s Syndrome

Answer 20

defective gene promoter of the UDP-glucuronyltransferase, which conjugates bilirubin to glucuronic acid so it is water soluble

causes mild increase in unconjugated bilirubin, but jaundice can occur with increased bilirubin production - fasting, fever, physical exertion, stress, menses

[but no serious clinical consequences]

Question 21

Pt presents with jaundice. They report they have been very stressed at work and eating less. Pt reports this has occurred in the past following febrile illnesses or heavy physical exertion. Labs show a mild increase in total and unconjugated bilirubin. All other LFTs are normal. Which enzyme is most likely affected?

Answer 21

dx = Gilbert’s Syndrome: defective gene promoter of UDP-glucuronyltransferase, which conjugates bilirubin to glucuronic acid so it is water soluble

—> mild increase in unconjugated bilirubin (usually <3mg/dl)

no serious clinical consequences

Question 22

describe the pathology of Crigler-Najjar Syndrome

Answer 22

severely reduced/absent UDP-glucuronyltransferase, which conjugates bilirubin to glucuronic acid so it is water soluble

Type I presents in infancy with very high unconjugated bilirubin (>20mg/dl) —> jaundice, kernicterus (bilirubin-induced brain damage), often fatal

[Type II is less severe]

Question 23

Infant is being examined for jaundice. Labs show unconjugated bilirubin is 28mg/dl (very high). Which enzyme is affected, and what is the feared consequence?

Answer 23

dx = Crigler-Najjar Syndrome: severely reduced/absent UDP-glucuronyltransferase, which conjugates bilirubin to glucuronic acid so it is water soluble

Type I presents in infancy with very high unconjugated bilirubin (>20mg/dl) —> jaundice, kernicterus (bilirubin-induced brain damage, often fatal)

[Type II is less severe]

Question 24

contrast Gilbert’s Syndrome vs Crigler-Najjar Syndrome

Answer 24

both affect UDP-glucuronyltransferase (UGT), which conjugates bilirubin

Gilbert’s Syndrome: defective gene promoter of UGT —> mild increase in unconjugated bilirubin (<3mg/dl), jaundice can occur with increased bilirubin production (stress, fever, etc) but no serious consequences

Crigler-Najjar Syndrome (Type I): severely reduced/absent UGT, presents in infancy with very high unconjugated bilirubin (>20mg/dl) —> jaundice, kernicterus (bilirubin-induced brain damage, often fatal)

Question 25

describe the pathology of kernicterus

Answer 25

Unconjugated bilirubin is soluble in fat —> easily crosses the blood brain barrier or placenta

acts as a neurotoxin to the basal ganglia and brainstem nuclei

Usually need bilirubin level >25mg/dl for connectors to occur - newborns (esp. preterm) are particularly vulnerable

Question 26

name two drugs used to treat Crigler Najjar syndrome Type II

Answer 26

reduced levels of UDP-glucuronyltransferase, which conjugates bilirubin (Type II less severe than Type I)

Type II can be treated with:
1. phenobarbital (anti seizure/sedative)
2. clofibrate (lipid-lowering agent)

both induce liver glucuronidation —> lower bilirubin levels

Question 27

describe the pathology of Dubin-Johnson Syndrome

Answer 27

defective liver excretion of conjugated bilirubin due to abnormal genes that code for multi drug resistant proteins (MRPs, necessary for bilirubin excretion to bile)

—> conjugated hyperbilirubinemia, may see bilirubin in urine
—> liver turns black (idk, just go with it)

benign condition, no tx required

Question 28

During a patient’s gallbladder surgery, the surgeon notes that the liver appears black. The patient has no symptoms related to this finding. After surgery, labs are taken, which show a mild elevation in conjugated bilirubin at 4mg/dL. It is decided that no treatment is required. Explain this finding.

Answer 28

Dubin-Johnson Syndrome: defective liver excretion of conjugated bilirubin due to abnormal genes that code for multi drug resistant proteins (MRPs, necessary for bilirubin excretion to bile)

—> conjugated hyperbilirubinemia, may see bilirubin in urine
—> liver turns black (idk, just go with it)

benign condition, no tx required

Question 29

explain why preterm infants are at a greater risk for neonatal jaundice

Answer 29

Infants have high bilirubin levels due to more RBCs + “immature” UDP-glucuronyltransferase (conjugates bilirubin)

—> increased unconjugated bilirubin, can lead to kernicterus (brain damage due to unconjugated bilirubin)

preterm infants have most immature enzyme and are most at risk

Question 30

what is the treatment for neonatal jaundice and why does this work?

Answer 30

Phototherapy – exposes skin to specific wavelength of light that converts bilirubin to lumirubin (isomer), which is more water soluble and allows excretion without conjugation

[infants, have immature UDP-glucuronyltransferase]