Bile + Bilirubin B&B Flashcards
which 2 molecules are conjugated to bile acids to create a hydrophilic end?
- taurine (organic acid) —> taurocholic acid
- glycine (amino acid) —> glycocholic acid
makes the bile a better surfactant
what enzyme is required to synthesize bile acids in the liver (via classic pathway)? what 2 cofactors are required?
cholesterol 7-alpha hydroxylase - requires NADPH + O2
notably, it is a cytochrome P450 enzyme
where does most lipid (TGs) absorption occur? where does bile acid reabsorption occur?
lipid absorption = jejunum
conjugated bile acids stay behind and are absorbed by active transporters in the terminal ileum
name 3 bile acid resins and state their function
- cholestyramine
- colestipol
- colesevelam
retain bile acids and prevent reabsorption so more are excreted in the stool
how are bile salts antimicrobial?
disrupt bacterial cell membranes
loss of bile salts = bacterial overgrowth (seen in liver disease)
what are the lab findings of cholestasis? (2)
cholestasis = disrupted bile flow to intestines
lab findings show:
1. direct (conjugated) hyperbilirubinemia
2. elevated alkaline phosphatase (produced by bile duct epithelial cells)
what are the short-term (4) and long-term (2) symptoms of cholestasis?
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
how can lab values help differentiate between damage to the liver vs bile ducts?
when rise in alkaline phosphatase is»_space;> rise in AST/ALT = “cholestatic pattern”, primary abnormality in bile ducts
when rise in AST/ALT»_space;> rise in alk phos = ”hepatocellular pattern”, primary abnormality in liver
what is the best first test to differentiate extrahepatic vs intrahepatic causes of cholestasis?
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
name 4 intrahepatic causes of cholestasis
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]
which 2 enzymes are required for the degradation of heme?
- heme —> biliverdin (green) via heme oxygenase
- bilverdin —> bilirubin (yellow/brown) via biliverdin reductase
what enzyme is required for bilirubin conjugation?
UDP glucuronyltransferase (UGT)
conjugated to glucuronic acid —> increased water solubility for excretion with bile
what happens to bilirubin once it reaches the intestines (2 steps)? what are its 2 fates?
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)
what type of bilirubin (un/conjugated) can be detected in the urine in some pathologies, and why?
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
what are the bilirubin lab findings in hemolysis? (2)
- elevated serum unconjugated bilirubin
- 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)
what are the bilirubin lab findings in biliary obstruction (cholestasis)? (4)
conjugation occurs normally, but excretion is repaired
- elevated serum and urine direct (conjugated) bilirubin —> dark urine
- cholestatic LFT pattern (high alkaline phosphatase»_space; high ALT/AST)
- clay colored stools due to lack of stercobilin (gives brown color)
- absent urobilinogen (no bilirubin to intestine = lack of conversion)
what are the bilirubin lab findings in primary liver disease?
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
how do urine levels of urobilinogen change early vs late in primary liver disease?
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
How do rifampin and probenecid affect bilirubin levels?
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]
describe the pathology of Gilbert’s Syndrome
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]
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?
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
describe the pathology of 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]
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?
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]
contrast Gilbert’s Syndrome vs Crigler-Najjar Syndrome
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)
describe the pathology of kernicterus
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
name two drugs used to treat Crigler Najjar syndrome Type II
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
describe the pathology of 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
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.
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
explain why preterm infants are at a greater risk for neonatal jaundice
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
what is the treatment for neonatal jaundice and why does this work?
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]
