Week 4 (Bile Disease and Pancreatic/Biliary Malignancy Flashcards
How is bilirubin formed?
Heme -> Biliverdin-> Bilirubin (unconjugated/indirect)
Heme oxygenate is the rate limiting step of this process and act in the liver, spleen, and kidneys (spleen is most important site)
Why is bilirubin bound to albumin?
Helps with solubility before bilirubin-albumin bond is broken and bilirubin is taken into hepatocytes via carrier-membrane transport
How is bilirubin conjugated?
Unconjugated bilirubin (water insoluble) is conjugated with glucuronic acid by bilirubin UDP-glucuronosyltransferase (BUGT/UGT1A1). Once conjugated, bilirubin is water soluble.
How is bilirubin excreted after conjugation?
Excreted via canalicular membranes into bile; carrier mediated, stimulated by HCO3- and ATP-dependent transporters (canalicular multi specific organic anion transporter -cMOAT)
If bilirubin not excreted fast enough, refluxes back into circulation, forms covalent bond with albumin = delta bilirubin (will stay elevated because of ½ life of albumin)
Enterohepatic circulation: excreted into intestine; normal bacterial flora breaks down bilirubin (bacterial protease) into urobilinogen (then oxidized in the large intestines into stercobilin and excreted via feces)
Some urobilinogen can be excreted in urine (gives urine yellow pigment)
Which diseases affect canalicular multi specific organic anion transporters (cMOAT)?
CF, hyperinsulinemia, adrenoleukodystrophy, Dubin-Johnson syndrome
What happens when unconjugated and/or conjugated bilirubin refluxed into the plasma?
Can be reabsorbed into the hepatocyte or, in the case of conjugated bilirubin, excreted via the urine.
What does Dubin-Johnson syndrome do to bilirubin clearance?
*Dark liver on autopsy (possible due to epinephrine metabolites)
*Defect in ABCCA/MRP2 (issue with excretion)
*Mild Conjugated bilirubinemia (levels can rise due to illness, OCPs, and pregnancy
*Presence of bilirubinuria
Hard to distinguish from Rotor syndrome
What does rotor syndrome do to bilirubin clearance?
*No Liver pigment
*Defect in OATP (issues with hepatic uptake of bilirubin)
*Mild Conjugated bilirubinemia (levels can rise due to illness, OCPs, and pregnancy
*Presence of bilirubinuria
Hard to distinguish from Dubin-Johnson syndrome
What is intrahepatic cholestasis of pregnancy?
*Exacerbated by estrogen (known to cause cholestasis)
*Usually peaks in 2nd trimester when estrogen levels peak
*16% of patients carry a mutated ABCB4 gene
*Mutation in MDR3 protein (PFIC3) results in lack of canalicular transporters
*Results in phosphatidyl choline poor bile that damages the canalicular membrane
*Condition can be miserable for mom (intense pruritus)
*Associated with fetal loss (poorly understood pathophysiology)
*Ursodiol may decrease symptoms.
What defects are associated with a loss of bilirubin UDP-glucuronyltransferase activity/function?
Crigler-Najjar syndrome, type 1
Crigler-Najjar syndrome, type 2
Gilbert’s Syndrome
Physiologic neonatal jaundice
What is Gilbert’s Syndrome?
*Autosomal recessive inheritance pattern (Common, ~9% of Caucasians are homozygous; 4-5% have hyperbilirubinemia)
*Reduced bilirubin UDP-glucuronyltransferase activity (Usually 10-33% of normal)
*Hallmark is asymptomatic, mild, isolated hyperbilirubinemia (Generally <4mg/dL in absence of fasting or hemolysis)
What is Crigler-najjar Syndrome Type 1?
*Absent bilirubin glucuronyltransferase
*Presents in early infancy
*No bilirubin decrease with phenobarbital
*Severe
*Liver transplant is definitive therapy
*Kernicterus Common
What is Crigler-najjar Syndrome Type 2?
*Deficient bilirubin glucuronyl transferase
*Presents in early infancy
*Bilirubin (unconjugated) level decreases with Phenobarbital
*Mild
*Kernicterus Occasional
What is physiologic jaundice of a newborn?
*“Benign” self-limited process
*Bilirubin level peaks at 4-10 mg/dl at day 4-5 lasts 1-2 wks (All unconjugated)
*Bilirubin may increase to dangerous levels in:
Sepsis
Hypoxia
Dehydration
Hemolysis
Metabolic disease (eg, hypothyroidism)
Prematurity
*Can result in kernicterus if untreated
What can treat jaundice of a newborn?
UV therapy (unconjugated bilirubin undergoes a conformational change that can be excreted in the bile without conjugation)
What are the functions and contents of Bile?
*Bile is a substance produced in the liver, stored in the gallbladder, and secreted into the duodenum. 600-800ml/day in adults
It is comprised of mostly water with Bile acids, phospholipids and electrolytes. Also has smaller amounts of cholesterol and proteins. Conjugated bilirubin in smallest component.
It serves several purposes including removing xenobiotics (foreign compounds, the most important example include many drugs, which are hepatically cleared) and metabolic waste as well as aiding in fat absorption.
Bile has an important role in immunity and carries large amounts of IgA that are produced in the kupfer cells.
What does cholesterol metabolized by the liver form?
Primary bile acids (amphipathic and form micelles to help absorb fats)
Rate limiting step: cholesterol 7-alpha-hydroxylase (90% of alll bile acids); occurs in only hepatic peroxisomes
What further modifications occur as the bile flows down ductules?
*Remember bile flow opposes blood flow
IgA is added, glucose is actively reabsorbed, and the bile is alkalinized further.
What is the function of the Gallbladder
Fills during interdigestive periods
(due to the close of Sphincter of Oddi; allowing bile to reflux into gallbladder)
Concentrates bile
(Bile remains in the gallbladder where epithelial cells reabsorb ions and water isoosmotically, allowing a greater proportion of bile to have a greater proportion of organic components)
Ejects bile as needed in response to CCK elevations
(Bile is ejected from the gallbladder within 30 minutes of a meal. CCK is a hormone secreted by I cells of the duodenum and jejunum, and acts to relax the sphincter of oddi and contract the gallbladder)
What does pancreatic lipase do?
Takes triacylglycerol and breaks it into monoglyceride and 2 free fatty acids
Lipids primary absorbed in jejunum
What is the most commonly preformed abdominal surgeries and why?
Cholecystectomy
Due to gallstones being common (~6% of men and ~9% of women have gallstones in the US (~20,000,000 people))
How are Gallstones developed?
*Cholesterol exists in dynamic equilibrium in bile as cholesterol monohydrate crystals, micells, and liquid crystals
*Cholesterol, phospholipids, and bile salts are the 3 major lipids in bile.
*Increases in factors that favor crystallization (eg, low solubility, poor gallbladder motility) predispose to gallstone formation.
*Cholesterol monohydrate crystals are ~75% of all stones
What are the 3 important types of gallstones?
1) Cholesterol monohydrate stones, ~75%
2) Pigment stones, ~25% (mostly black)
*Black stones related to chronic hemolytic anemia, ileal disease, and ineffective erythropoiesis.
Situations in which the solubilization of unconjugated bilirubin is increased, thereby increasing concentration in bile.
Unconjugated bilirubin precipitates with calcium in bile to form stones
*Brown stones
3) “Rare” stones, ~0.5%
Caused by other things crystallizing to each other
Calcium carbonate
Fatty acid-calcium precipitants
Define Cholelithiasis
Gallstones
