Billiary Secretion Flashcards
What are the main functions of the liver?
bile production and secretion
Carb, protein, and lipid metabolism
Bilirubin production and excretion
Detoxification
What is the composition of bile?
bile salts - 50% Bile pigments (billirubin) - 2% Cholesterol - 4% Phospholipids (lecithin) - 40% ions H2O
What is Cirrhosis?
Chronic liver disease in which normal liver cells are damaged and replaced by scar tissue
What is the most common cause of cirrhosis? How does it lead to cirrhosis?
Excessive alcohol intake
leads to accumulation of fat within hepatocytes
fatty liver leads to steatohepatitis (fatty liver with inflammation) ->scarring
Cholesterol-> ________->primary bile acids
7alpha-hydroxycholesterol
Where are primary bile acids formed? name the 2 primary bile acids.
Location of synthesis: hepatocytes (liver)
Cholic acid
Chenodeoxycholic acid
Where are secondary bile acids formed? Name the secondary bile acids
Location: lumen of small intestine
Deoxycholic acid
Lithocholic acid
Where are bile salts conjugated? What are examples of conjugated bile salts?
Location: liver
Taurodeoxycholic acid
glycolithocholic acid
What are the properties and functions of bile salts?
Amphipathic molecules
Role: emulsify lipids and form micelles
What form of bile salts are more effective at solubilizing lipids?
Primary bile salts more than secondary bile salts
What are the relative amounts of the four bile acids from greatest to least?
Cholic acid > chenodeoxycholic acid > Deoxycholic acid > lithocholic acid
What are the properties and functions of phospholipids?
Amphipathic molecules, but are not soluble in H2O
Bile salts solubilize phospholipids forming micelles
What are the properties and functions of cholesterol?
It is solubilized as part of the micelle
Weakly polar molecule, that is in the interior of the micelle
What are the properties and functions of bile pigments?
bilirubin is most important
does not take part in micellar formation
What are the properties and functions of ions and H20 in bile?
Major cation: Na
Major anions: Cl and bicarb
Secretion of bile acids carries H20 and ions into bile by osmotic filtration
Additional ions and H20 are supplied by cells lining ducts and stimulated by secretin
At ____ concentrations of bile acids, there is no aggregation among bile acid molecules
low
At ____ concentration, bile acids aggregate to form ____.
high
micelles
What is the point of micelle formation called?
critical micellar concentration
What interacts with the interior of the micelle?
hydrophobic portions of the bile salts, phospholipids, monoglycerides, and fatty acids
Within the liver, ducts, and gallbladder, what is bile normally present as?
micellar solution
What are the components of the biliary system?
liver gallbladder and bile duct duodenum ileum: active absorption of bile acids portal circulation: bile acids returned to liver
Describe the steps of bile secretion and absorption of bile salts
- synthesis and secretion of bile salts from the liver
- bile salts stored and concentrated in gallbladder (absorption of ions and H2O)
- CCK and ACh induce gallbladder contraction
- CCK induce sphincter of Oddi relaxation
- Duodenum: emulsification and digestion of fats
- Micelle formation and fat absorption
(enterohepatic circulation)
- Active absorption of bile acids in ileum into portal circulation
- delivery of bile salts to liver
Together with newly synthesized bile acids, the returning bile acids are secreted into what?
bile canaliculi
What is canalicular bile secreted by?
ductule cells in response to osmotic effects of anion transport
How much of the bile acids is transported to the portal blood vs excreted?
ileal transport: more than 90%
3-5% excreted into feces
What exerts a negative feedback on the synthesis of bile acids in the liver?
Increase of bile secretion increases rate of return of bile acids to liver which exerts a negative feedback by..cholesterol 7alpha-hydroxylase is inhibited by bile salts
What can ileal resection do the the synthesis rate of bile acids?
Interrupts the enterohepatic circulation and increases synthesis 10-fold
What is canalicular bile primarily?
an ultrafiltrate of plasma
Almost all bile formation is driven by what?
bile acids (bile acid-dependent) Secretion of bile acids is accompanied by the passive movement of cations into the canaliculus
A small portion of bile secretion is stimulated by what?
Secretin - stimulates the secretion of bicarb, H20 and Na from ductile cells
results in significant increase in bile volume, bicarb concentration and pH
and a decrease concentration of bile salts
bile acid-independent from the ducts
Describe bile flow during interdigestive period
Gallbladder fills with bile
Gallbladder relaxed
Sphincter of Oddi closed
Describe bile flow during feeding
CCK-mediated contraction of the gallbladder
relaxation of the sphincter of oddi
Describe how bilirubin reaches the liver
Red blood cells broken down and hemoglobin enters RES
Hemoglobin->biliverdin->bilirubin in RES
Bilirubin carried by albumin in bloodstream to liver
Describe how bilirubin is processed in the liver
Unconjugated bilirubin ->conjugated bilirubin (bilirubin glucuronide: yellow) by UDP glucuronyl transferase + glucuronic acid
Makes bilirubin water soluble (conjugation)
Where does Conjugated bilirubin go under normal conditions?
Excreted in urine
transferred to small intestine
Describe the breakdown of bilirubin glucuronide in the intestine
Bacteria in the small intestine breaks conjugated bilirubin to bilirubin
In terminal ileum: H2 added to form urobilinogen
Urobilinogen can go back to liver via enterohepatic circulation or go to cecum
cecum: urobilin and stercobilin (dark color)
feces
Why do infants have elevated levels of unconjugated bilirubin in the blood during the first week of life?
Bilirubin production is elevated because of increased breakdown of fetal erythrocytes
Low activity of UDP glucuronyl transferase
What is physiological neonatal jaundice?
What is the treatment?
Elevated levels of unconjugated bilirubin causes a yellow color of the skin on the face and then moves down to chest, belly, legs, and soles of feet Tired and feed poorly Needs phototherapy (459 nm)if serum bilirubin is greater than 21 mg/dL to change trans-bilirubin into water-soluble Cis-bilirubin isomer(excreted via urine or stool)
What are the five known hereditary defects in bilirubin metabolism?
Crigler-Najjar syndromes 1 and 2
Gilbert’s syndrome
Dubin-Johnson syndrome
Rotor syndrome
What is hemolytic anemia?
too much breakdown of red blood cells causing anemia
Leads to jaundice due to increase production of bilirubin and overwhelmed liver’s capacity to make conjugated bilirubin
What is Gilbert’s syndrome?
*also called constitutional hepatic dysfunction and familial nonhemolytic jaundice
Increase levels of unconjugated bilirubin in blood due to problems with uptake into liver
Mild
adolescence
hyperbilirubinemia: episodic, mild, due to stress
also Mutation in UDP glucuronyltransferase enzyme gene or factors interfering with glucuronidation (move bilirubin into liver issues)
30% have no signs or symptoms
Uptake of bile salts across the basolateral membrane of the hepatocytes is mediated by two types of systems. Describe them
NTCP: Na-dependent transport protein (sodium taurocholate cotransporting polypeptide)
OATPs: Na-independent transport protein
(organic anion transport proteins)
What is Crigler-Najjar Syndrome?
Increased levels of unconjugated bilirubin in the blood
Nonhemolytic jaundice
mutations with gene that code for UDP glucuronyltransferase
What is type 1 crigler-Najjar syndrome?
Very severe starts earlier in life apparent at birth/infancy no function of UDP glucuronyltransferase Kernicterus: brain damage, died of this or survived til early adulthood with brain damage
What is kernicterus?
in infants with crigler-Najjar syndrome type 1, unconjugated bilirubin can accumulate in the brain and nerve tissue
cause lethargy and weak muscle tone (hypotonia)
Neurological problems
What is type 2 Crigler-najjar syndrome? CN2
Starts later in life
less than 20% function of UDP glucuronyltransferase
Less likely to develop kernicterus
most affected individuals survive into adulthood
What are the treatments for Crigler-Najjar syndrome?
light treatment (phototherapy) needed throughout persons’ life (issues after 4 bc of thick skin)
Blood transfusions
Oral calcium phosphate and carbonate to form complexes with bilirubin in gut
Liver transplant in type 1
Phenobarbitol drug for type 2
What is dubin-johnson?
Increase conjugated bilirubin in the serum without elevation of liver enzymes
Hepatocytes cant secrete conjugated bilirubin into bile
MRP2 mutation: transports bilirubin out of liver cells into bile normally
What are the clinical presentations of dubin-johnson?
Mild jaundice throughout life after puberty
Only symptom and worse with alcohol, birth control, infection, pregnancy
Liver is black but otherwise histologically normal: intracellular melanin-like substance
More common Iranian and Moroccan Jews living in Israel
What is Rotor syndrome?
buildup of both unconjugated and conjugated bilirubin; majority conjugated
Abnormally short, nonfunctional or absent OATP1B1 and OATP1B3 proteins: Normally transport bilirubin from blood into liver
Liver cells not pigmented
What transporters take Bile acids out of enterocytes into portal circulation?
OSTa and OSTb
What transporters take bile acids from hepatocyte to bile duct?
BSEP and MRP2
What transporters take bile acids from biliary excretion into the enterocyte?
ASBT
Small or large gallstones are usually asymptomatic? why?
Large gallstones stay in gallbladder while small stones can pass to biliary duct and get stuck there leading to choledocholithiasis
What can choledocholithiasis lead to?
inflammation of the gallbladder: cholecystitis
Causes intermittent crampy pain, usually in right upper quadrant
When does a cholelithiasis cause jaundice?
If the stone passes to the common bile duct and obstruct it, that outflow of both the gallbladder and liver is affected
When does a cholelithiasis cause pancreatitis ?
When the stone passes all the way to the entrance of the duct at the duodenum and obstruct the pancreatic duct
What is gallstone ileus?
Stone passes into the duodenum and obstructs it
Gallstones predispose the development of _____
cancer
What is the role of the liver in the detoxification of substances and toxins?
liver enzymes can modify endogenous and exogenous toxins
render them water soluble
allows them to be excreted through bile or urine
What is the process of Phase I of drug metabolism
it is the First pass metabolism
Drugs are processed via cytochrome P450 enzymes
What is the process of Phase II of drug metabolism?
Conjugation step
Further detoxification of the drug
Conjugated with glucoronide, sulfate, a.a., or glutathione
Why is it important to consider first pass metabolism in drug design?
because with oral administration, the drug goes through the liver first before it reaches systemic system
