Hepatobiliary Function Flashcards
Main Function of Liver
- absorbed nutrients and detoxify ingested and/or toxins
- detoxification of substances
- metabolism of CHO, proteins, lipids, and many hormones
- bile production and secretion
- bilirubin production, conjugation, & excretion
- filtration of storage of blood
- storage of vitamin A and iron
- formation of coagulation factors
Metabolic Functions of the Liver
- carbohydrate (3)
- protein (4)
- lipid (2)
Carbohydrate
1) Storage of glucose as glycogen
2) Gluconeogenesis and release of glucose
3) convert fructose and galactose to glucose
Protein
1) synthesis of nonessential AA
2) modification of AA for use in biosynthetic pathways for carbohydrates (deamination)
3) Synthesis of plasma proteins (albumin & clotting factors)
4) Conversion of ammonia to urea
Lipid
1) Synthesis of lipoproteins, cholesterol, and phospholipids
2) Fatty acid oxidation & de novo lipogenesis
Liver Failure
result in hypoalbuminemia
lead to edema
Hepatic portal system : two capillary beds
1) abdominal and pelvic parts of the gut from the abdominal part of the esophagus to lower anal canal ( together with pancreas, gallbladder, and spleen)
2) hepatic sinusoidal “capillary” bed
Cirrhosis
- describe
- cause
chronic liver disease in which normal liver cells are damaged and replaced by scar tissue (fibrosis)
- due to excessive alcohol intake/ alcohol abuse
- > accumulation of fat within hepatocytes -> steatohepatitis ( fatty liver accompanied by inflammation-> scarring of liver and cirrhosis)
Portal Hypertension
- describe
- location
- causes
- relationships
increased resistance to portal blood flow
occurs in liver
cirrhosis can cause portal HTN
More parallel=lower resistance
more series= greater resistance
Primary biliary Cirhosis
chronic disease that causes the bile ducts in the liver to become inflamed, damaged, and are eventually lost
Circulation of Liver
- inputs
- outputs
lots of blood 27% of Q
Inputs:
- hepatic portal vein- nutrient rich blood from GI, low O2
- hepatic artery- O2 rich from systemic circulation
Outputs:
- hepatic ducts for bile excretion
- hepatic vein- low O2 to vena cava
Consequences of Portal Hypertension (6)
increased hydrostatic pressure OR decreased oncotic pressure is culprit
1) ascites
2) esophageal varices
3) hepatic encephalopathy
4) malnutrition
5) skin spider angiomata, periumbilical caput medusa
6) Hemorrhoids
Esophageal varices
swollen connection betwen systemic and portal systems at inferior end of esophagus
Caput medusae
swollen connections between systemic and portal systems around umbilicus
how liver dysfunction can 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
Bile
- where it is produced and secreted
- composition (6)
- function
Liver
Composition
- Bile Salts (50%)
- Bile pigment (2%)
- bilirubin - cholesterol (4%)
- Phospholipids, such as lecithin (40%)
- Ions
- Water
Function
- Vehicle for elimination of substances from body
- Solubilizes lipids that are naturally insoluble
Bile Canaliculi (canalicular bile )
secreted by ductule cells in response to osmotic effects of anion transport
where newly synthesized and returning bile acids
Formation of bile salt
- pathway
- types of bile acid
cholic acid-> chenodeoxycholic acid-> deoxycholic acid-> lithocholic acid
primary bile acids synthesized in hepatocytes
secondary bile acids synthesized in lumen small intestine
Bile salts conjugated in liver
what do bile salts form?
micelles with products of lipid digestion
Biliary System’s Organs (5)
-function of overall organs
- Liver
- Gallbladder & bile duct
- Duodenum
- Ileum
- Portal Circulation
Mechanism of bile secretion & absorption of bile salts
- 5 steps
1) Synthesis and secretion of bile salts
2) Bile salts are stored & concentrated in gallbladder (absorption of ions & H2O)
3) CCK- induced gallbladder contraction & sphincter of Oddi relaxation
4) Absorption of bile salts into portal circulation
5) Delivery of bile salts to liver
Enterohepatic Circulation:
-steps
recycles bile acid/salts by returning bile salts to liver to be reused
1) Bile salts use portal circulation via transport in terminal ileum
2) Bile salts back to liver
3) some bile salts are lost in feces and replaced by synthesis of new bile
Where are bile salts secreted? are they secreted actively or passively?
Secreted actively across canalicular membrane
Bile salt + newly synthesized bile acid=>
returning bile acids are secreted into bile canaliculi
when are canalicular bile secreted?
by ductule cell in response to osmotic effects of anion transport
Bile Salt Transporters
- Uptake into hepatocytes (2)
- Uptake into caniculi (2)
- into enterocytes
- exit enterocytes
Uptake into heptaocytes
- NTCP- Na dependent transport protein
- sodium taurocholate cotransporting polypeptide - OATPS *- organic anion transport protein
Uptake into caniculi
- BSEP- bile salt excretory pump
- MRP2- multidrug resistance protein 2
Into Enterocytes
- ASBT- apical sodium dependent bile acid transporter
Exit Enterocytes
- OST alpha/beta : organic solute tranporter alpha beta
Where is bile salt recycling mostly in?
- Ileal transport process (90%)
- bile acids to portal blood
- feces (5-10%)
Effects of increased bile secretion
- which hormone
increase rate of return
negative feedback on synthesis
Cholesterol 7a- hydroxylase is inhibited by bile salts
Bile formation is driven by..?
bile acids
Secretin on bile
- effects
secretin stimulates HCO3 & H2O secretion from ductile cell
- increase bile volume, HCO3 conc, pH
- decrease bile salt con
Bile flow during period of digestion:
1) interdigestive period
2) On eating
Interdigestive period
- gallbladder fills with bile
- gallbladder is relax
- sphincter of Oddi is closed
On eating
CCK mediated
- contraction of bladder
- relaxation of sphincter of Oddi
Bilirubin Production & Excretion
- very important!
- pathway
in RBC
Hemoglobin-> Biliverdin -> Bilirubin-> Bilirubin-albumin (transport to liver)
Liver uncojugated Bilirubin (UDP glucuronyl transferase)-> conjugated bilirubin -> conjugated bilirubin+ bile
SI/ Colon
Conjugated bilirubin -> Urobilinogen-> Urobilin , stercobilin-> excreted feces
If bilirubin is not excreted in feces, what happens?
will return to liver via enterohepatic circulation
Liver Function Test
NOT AN ACTUAL TEST OF FUNCTIONALITY
- biochemical and function test
- pretty imprecise bc it does not reflect health of liver
Liver Enzymes measured in serum
- if enzymes are elevated, what do they suggest?
- Aminotransferases:
- alanine aminotransferase (ALT)
- aspartate aminotransferase (AST)
- – if elevated=> hepatocyte injury - Alkaline phosphatase (Alk Phos)
- – if elevated => cholestasis (gallstones)
Jaundice
- nickname
- causes (5)
- hereditary defects (5)
aka Icterus
Hyperbilirubenemia
- excess bilirubin (hemolytic anemia
- unconjugated - decreased bilirubin uptake bilirubin into hepatocytes
- uncojugated - disturbed intracellular protein binding or conjugation
- uncojugated or conjugated - disturbed secretion of conjugated bilirubin into bile canaliculi
- conjugated - intrahepatic or extrahepatitic bile duct obstruction
- conjugated
Defects 1. Gilbert's Syndrome 2. Dubin-Johnson Syndrome 3. Rotor Syndrom 4. Crigler- Najjar syndrome Type 1 5. Crigler- Najjar syndrome Type 2
Bilirubin pathway
- RBC breakdown-> 2. unconjugated bilirubin delivery to liver-> 3. uptake to liver-> 4. conjugated bilirubin -> 5. secretion into bile -> 6. passage of bile
Hemolytic Anemia
- which pathways is defected
- effects on bilirubin
- RBC breakdown
form of anemia due to hemolysis ( too much RBC)
increased unconjugated bilirubin
no change in conjugated bilirubin
Neonatal Jaundice
- which pathways is defected
- effects on bilirubin
- causes
- treatment
- RBC breakdown
- uptake to liver
increased unconjugated bilirubin in blood suring 1st week
Infants are tired and feed poorly
Causes:
1) increased bilirubin production due to breakdown of fetal erythrocytes (unconjugated bilirubin)
2) low activity of UDP glucuronyl transferase
Treatment
- Phototherapy
- if bilirubin >21 mg/dl
- works to change trans-bilirubin into water-soluble cis-bilirubin isomer
Gilbert’s Syndrome
- which pathways is defected
- effects on bilirubin
- Conjugated bilirubin
30% of ppl asymptomatic
-seen during adolescence
mutation in gene that encodes UDP-glucoronyl transferase
- hyperbilirubinemia
INCREASE unconjugated bilirubin
- no change in conjugated bilirubin
Crigler- Najjar Syndrome
- which pathways is defected
- effects on bilirubin
- Conjugated bilirubin
mutation in gene that encodes for UDP-glucuronyl transferase
-nonhemolytic jaundice
- increased levels of unconjugated bilirubin
- no changes in conjugated bilirubin
Type 1- more severe
Type 2- less severe
Criggler Najjar Syndrome Type 1
- which pathways is defected
- effects on bilirubin
- treatment
- Conjugated bilirubin
starts earlier in life
- Jaundice apparent at birth or in infancy
KERNICTERUS- form of brain damage caused by accumulation of unconjugated bilirubin in regions of brain
Treatment:
- Phototherapy- can be up to 12 hr/d
- heme oxygenase inhibitors, oral calcium phosphate anda carbonate, liver transplantation
Criggler Najjar Syndrome Type 2
- which pathways is defected
- effects on bilirubin
- treatment
- conjugated bilirubine
later in life-> survival into adult hood
less than 20% function of UDP- glucoronyl transferase
less likely to develop kernicterus
Therapy
- PHENOBARBITOL
- treat type 2 to aid in conjugation of bilirubin ( no response in patients with Type 1)
Kernicterus
- describe
- clinical features
permanent neurologic sequelae of bilirubin induced neurologic dysfunction
develops during 1st year PN
Clinical PResentation
- cerebral palsy
- sensory neural hearing loss
- gaze abnormalities
Dubin-Johnson Syndrome
- which pathways is defected
- causes
- secretion into bile
mild jaundice throughout life
- may not appear until puberty or adulthood
- may be worsened with alcohol, birth control pills, infection, pregnancy
defect in ability of hepatocytes to secrete conjugated bilirubin into bile
- MUTATIONS in MRP2
liver has black pigmentation - result of an intracellular melanin-like substance
Rotor Syndrome
- which pathways is defected
- causes
- bilirubin effect
- liver uptake
- conjugated bilirubin
- secretion into bile
similar to Dubin-Johnson syndrome
liver cells not pigmented
increased conjugated bilirubin in blood
- can have increase in BOTH conjugated and unconjugated bilirubin
Gene mutation OATP1B1 and OATP1B3
Enterohepatic recycling of bilirubin is compromised
Gallstones
- nickname
- causes (4)
- storage of gallstone
aka cholelithiasis
Causes:
- too much absorption of water from bile
- too much absorption of bile acids from bile
- too much cholesterol in bile
- inflammation f epithelium
Storage:
75%- gallstones stay in gallbladder
20%- cystic duct ( biliary pain)
LFT: abnormal bilirubin
tests liver’s ability to detoxify metabolites and transport organic anions into bile
exm. hyperbilirubinemia
- figure out whether predominantly conjugated or unconjugated
LFT: abnormal albumin
severe impairment in liver function reduces albumin
- can occur in heart failrue, nephrotic syndrome, protein losing enteropathy, and/or malnutrition
LFT: abnormal prothrombin time
reflects degree of liver failure
- PT increase as ability of liver failure/hepatic dysfunction diminishes
- correlates with liver failure/hepatic dysfunction
INR- international normalized ratio
