Biliary secretion: Hepatobiliary function Flashcards
what is the livers Main functions in its role with the GI function?
- Bile production and secretion
- Metabolism of carbohydrates, proteins, and lipids
- Bilirubin production and excretion
- Detoxification of substances
What two capillary beds do the hepatic portal system connects?
1) That of the abdominal and pelvic parts of the gut from the abddominal part of the esophagus to the lower anal canal together with the pancreas, gallbladder and spleen
2) Hepatic sinusoidal capillary bed
What are the three main Metabolic functions of the liver?
Carbohydrate metabolism:
- gluconeogenesis
- storage of glucose as glycogen
- release of glucose
Protein Metabolism:
- synthesis of nonessential amino acids
- Modifications of amino acids for use
- synthesis of almost all plasma proteins
- conversion of ammonia to urea
Lipid metabolism:
- Fatty acid oxidation
- synthesis of lipoproteins, cholesterol, and phospholipids
in liver failure: what might arise based on the plasma proteins?
since liver is important for synthesis of all plasma proteins
-liver failure can result in hypoalbuminemia which may lead to edema
what are clinical manifestations of liver function failure?
- Hepatic enecphalopathy
- Ascites
- Caput medusae
- Esophageal varices
- Bruising
what is cirrhosis? main cause? what is steatohepatitis?
Chronic liver disease in which normal liver cells are damaged and replaced by scar tissue
- Excessive alcohol is the most common cause
- alcohol abuse leads to accumulation of fat within the hepatocytes
Fatty liver leads to steatohepatitis
-fatty liver accompanied by inflammation which leads to scarring of liver and cirrhosis
what can cirrhosis lead to in the liver?
Portal hypertension
Develops when there is resistance to portal blood flow, which most often occurs in the liver
What are the changes to the venous circulation assocated with portal hypertension?
Esophageal varices:
-swollen connection between systemic and portal systems at inferior end of esophagus
Caput Medusae:
-swollen connections between systemic and portal systems around umbilicus
How does liver dysfunction lead to hepatic encephalopathy?
Decreased hepatic urea cycle metabolism in the context of liver cirrhosis or portosystemic shunting leads to accumulation of ammonia in the systemic circulation
Ammonia readily crosses the blood brain barrier and alters brain function
what is the composition of bile and what is biles function?
Bile composition:
- Bile salts 50%
- Bile pigments (bilirubin) 2%
- Cholesterol (4%)
- Phospholipids (40%) (lecithin)
- Ions
- H2O
Bile function:
- Vehicle for the elimination of substances from the body
- solves the insolubility problem of lipids
where does formation of the bile acids and salts occur and what are their names?
Primary bile acids: location of synthesis is the liver hepatocytes
- Cholic acid
- chenodeoxycholic acid
Secondary bile acids: Location lumen of small intestine
- Deoxycholic acid
- Lithocholic acid
Bile salts: location of conjugation is the liver
-all the previous acids with either a glycine or taurine
How do bile salts help with digestion?
they form a micelle with the products of lipid digestion to help with the access of the lipid to make them more soluble
what is the route of the bile in the biliary system?
Created in the liver where they then travel to the gall bladder where they are stored and concentrated between meals
Bile released into the duodenum where they emulsify and digest the fats
in the jejunum the form their micelles and allow for fat absorption
in the ileum there is active absorption of bile acids
5 step mechanism of bile secretion and absorption of bile salts?
1) synthesis and secretion of bile salts from the liver
2) bile salts are strored and concentrated in the gallbladder due to absorption of ions and H20 (secretin important in this)
3) CCK induced gallbladder contraction and sphincter of oddi relaxation
4) Absorption of bile salts into the portal circulation
5) delivery of bile salts to the liver
How are bile salts secreted across the canalicular membrane?
Together with newly synthesized bile acids, and the returning bile acids are secreted into the bile canaliculi by ductule cells in response to the osmotic effects of anion transport
Secretion of bile acids is accompanied by the passive movement of cations into the canaliculus (H20, Ca, K, Cl, Na)
Canalicular bile is primarly an ultrafiltrate of plasma
What does Secretin stimulate in the ductule cells of the biliary system?
Secretin stimulates the secretion of HCO3- and H20 from the ductile cells resulting in a significant increase in bile volume, HCO3- concentration and pH
-decrease in the concentration of bile salts
what occurs in the gallbladder to make the bile more concentrated?
absorption of Na+, Cl-, HCO3-, and H20
-ACh plays a role in this
when does bile flow occur and when is it secreted into the duodenum
during interdigestive periods, Gallbladder fills with bile
- gallbladder is relaxed
- sphincter of oddi is closed
on eating:
-CCK mediated contraction of the bladder as well as relaxation of the sphincter of Oddi that allows for the release of BIle into the duodenum
How is Bile salts recirculated to the liver?
Enterohepatic circulation:
- Bile salts are transported from the ileum to the portal blood
- bile salts back to liver
- synthesis of bile salts to replace the amount that was lost
what are the two types of systems that allow for the uptake of bile across the basolateral membrane of the hepatocytes
- Na+ dependent transport protein, sodium taurocholate cotransporting polypeptide (NTCP)
- Na+ independent transport protein, organic anion transport protein (OATPs)
what are all the transporters associated with the movement of bile: into the enterocyte into the portal circulation into the hepatocyte into the bile canaliculi
into the enterocyte:
-Apical sodium dependent bile acid transporter (ASBT)
into the portal circulation:
-Organic solute transporter alpha-beta (OSTa-OSTb)
into the hepatocyte:
-Sodium taurocholate cotransporting polypeptide (NTCP)
into the bile canaliculi:
- Bile salt exretory pump (bsep)
- multidrug resistant protein 2 (mrp2)
what percentage of Bile salts is reused and what percentage is lost?
more than 90 percent recycled back for use via the portal blood
3-5 percent of Bile excreted into the feces
how does an ileal resection affect the rates of bile acid synthesis
less reabosrption of bile therefore greater need for bile synthesis and less secretion
how does an increase in bile secretion rate affect the bile synthesis rate?
increase in bile secretion will increase the rate of return of bile acids to the liver via portal blood which leads to a negative feedback on synthesis
-inhibition of cholesterol 7a hydroxylase is inhibited by bile salts
where is bilirubin conjugated and what is excreted out of the urine and feces?
bilirubin conjugated in the liver via UDP glucuronyl transferase
urobilin and sterocobilin give feces its color
urobilinogen give urine its color
Characteristics, Factors increasing and decreasing secretion: Saliva
Characteristics:
- high HCO3- concentration
- high potassium concentration
- hypotonic
- a-amylase, lingual lipase
factors increasing secretion:
- PNS
- SNS
Factors decreasing secretion:
- Sleep
- dehydration
- atropine
Characteristics, Factors increasing and decreasing secretion: Gastric
Characteristics:
- HCl
- pepsinogen
- intrinsic factor
Factors increasing secretion:
- Gastrin
- ACh
- Histamine
- PNS
Factors decreasing secretion:
- H+ in the stomach
- CHyme in the duodenum
- somatostatin
- atropine
- cimetidine
- omeprazole
Characteristics, Factors increasing and decreasing secretion: Pancreatic
Characteristics:
- High HCO3- concentration
- Isotonic
- pancreatic lipase, amylase, proteases
Factors increasing secretion:
- secretin
- CCK
- PNS
- CCK
Factors decreasing secretion:
-None
Characteristics, Factors increasing and decreasing secretion: Bile
Characteristics:
- Bile salts
- bilirubin
- phospholipids
- cholesterol
Factors increasing secretion:
- CCK
- PNS
Factors decreasing secretion:
-Ileal resection
Types of Unconjugated jaundice
- Hemolytic anemia
- some cases of heart failure so a decrease in delivery of bilirubin
- Gilberts syndrome
- Crigler-najjar syndrome
Types of conjugated jaundice
- Dublin johnson syndrome
- rotor syndrome
- Biliary tree obstruction
Hemolytic anemia
Form of anemia due to hmolysis
Any cause of hemolytic anemia could lead to increased production of bilirubin
Increased bilirubin level overwhelms livers capacity to produce conjugated bilirubin
-increase in unconjugated bilirubin leading to jaundice
Physiological neonatal jaundice
increase in unconjugated bilirubin in blood during 1st week postnatal age
causes:
- bilirubin production elevated because of increased breakdown of fatal erythrocytes (shortened lifespan of fetal erythrocytes)
- low activity of UDP glicironyl erythrocytes
sometimes infants with jaundice may be very tired and feed poorly
Gilbert syndrome
Increased levels of unconjugated bilirubin in the blood
- mild
- usually recognized during adolescence
- cases of hyperbilirubinemia are mild under physiological stress/fasting
Mutation in gene that code for uridine diphosphate glucuronosyltransferase
-UGT1A1 activity level is 30 percent of normal
(important for movement of bilirubin into the liver)
Criger-Najjar syndrome and the two types?
increased levels of unconjugated bilirubin in the blood
-mutations in the gene that codes for UDP glucuronyl transferase
Type 1 is very severe
- no function of UDP glucuronyl transferase
- Kernicterus: permanent brain damage via blirubin crossing BBB (cerebral palsy, sensoryneural hearing loss, gaze abnormalities)
Type 2 is less severe
- less than 20% function of UDP glucuronyltransferase
- less likely to develop kernicterus
- will survive into adulthood
what are the treatments of Crigler-Najjar syndrome?
Phototherapy
-does not work well after 4 years of age due to thickening of skin
Blood transfusions:
-decrease bilirubin amounts
Oral caclium phosphate and carbonate
-help form complexes with bilirubin in gut
Liver transplant
Phenobarbitol:
- aids in the conjugation of bilirubin
- works with type 2 not with type 1
Dubin Johnson syndrome
Increased conjugated bilirubin without elevation of liver enzymes
- defect in ability for hepatocytes to secrete conjugated bilirubin into the bile
- mutation in MRP2 gene (multidrug resistant associated protein 2) this transports bilirubin out of liver into bile
Mild jaundice
Liver has black pigmentation
-result of intracellular melanin like substance but is otherwise histologically normal
Rotor syndrome
Build up of both unconjugated and conjugated bilirubin, however majority is conjugated bilirubin
Gene mutation that leads to an abnormally short nonfunctional OATP1B1 and OATP1B3 proteins or an absence of these proteins
-normally transport bilirubin and other compounds from the blood into the liver so they can be cleared from the body
liver is NOT pigemented
what is the primary treatment for neonates with unconjugated hyperbilirubinemia
Phototherapy
-for total serum bilirubin over 21mg/dL
helps isomerize the bilirubin making it more water soluble cis bilirubin isomer
Causes of Cholelithiasis
1) too much absorption of water from bile
2) too much absorption of bile acids from bile
3) too much cholesterol in bile
4) inflammation of epithelium
Gallstones occur when there is excess in either pigment of bilirubin breakdown or cholesterol
- pigment
- cholesterol
difference between: Cholecystitis Cholelithiasis Choledocholithiasis cholangitis
Cholecystitis: inflammation of the gallbladder, mos commonly due to obstruction of the cystic duct
Cholelithiasis: gallstone
Choledocholithiasis: gallstones occluding the common bile duct
- patients may have jaundice and conjugated hyperbilirubinemia
- potentially can block pancreatic duct and cause pancreatitis
Cholangitis: infection of the bile duct
what are common Liver enzymes that are tested and what does elevation of these mena?
Serum aminotransferases:
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)
- if elevated, primarily result of hepatocyte injury
Alkaline Phosphatase
-if elevated primarily result of bile duct injury
What are the three various function test/proteins to look for in the liver?
BIlirubin: in part measures the livers ability to detoxify metabolites and transport organic anions into the bile
-important to determine hyperbilirubinemia is from conjugated or unconjugated overproduction
Albumin: severe impairment of hepatocyte function is likely to reduce level of albumin in the plasma
- albumin levels fall as the synthetic function of the liver declines with worsening Cirrrhosis
- hypoalbuminemia can be seen in kidney glomerular disease as well
PT: prothrombin time reflects the degreeof hepatic synthetic dyfunction
- increases as the ability of a cirrhotic liver synthesize clotting factor diminishes
- worsening coagulopathy correlates with the severity of hepatic dysfunction
