hepatic vascular system
portal vein - 80% inflow
hepatic artery- 20% inflow
central vein system
hepatic vein
biliary system
intrahepatic bile duct L/R hepatic duct common hepatic duct gallbladder cystic duct common bile duct
portal triad
portal arteriole
portal venule
bile duct
liver sinusoids
large capillary between plates of hepatocytes
drain blood into central vein
central veins
at center of hepatic lobule
drains filtered blood to hepatic vein and IVC
liver cell types
hepatocytes sinusoidal endothelial cells cholangiocytes Kupffer cells stellate cells
discuss bile and blood flow in the liver
blood flows from portal triad at edge of lobule to central vein
bile flows in opposite direction, from center of lobule toward bile duct in portal triad
function of gallbladder
store bile (50 ml) concentrates bile
function of sphincter of Oddi
high pressure zone of resistance to bile flow from the common bile duct into the duodenum
prevents reflux of duodenal contents into the pancreatic and bile ducts
promotes filling of the gallbladder
functions of liver
production of bile regulation of cholesterol homeostasis regulation of blood sugar production of urea detoxification of blood production of blood proteins
bile composition
water
organic solutes
inorganic electrolytes
proteins
organic solute components of bile
cholesterol
bile salts
phospholipids
protein components of bile
IgA, IgM, IgG
mucin (glycosylated protein)
albumin
apolipoproteins
in what forms can cholesterol be found in the body?
membrane
intracellular lipid droplets
lipoproteins
esterified and non-esterified (free)
hepatic cholesterol inputs
de novo synthesis (primary)
diet
both of these contribute to cholesterol pool in hepatocyte
factors promoting biliary cholesterol secretion
increased uptake from blood
increased de novo cholesterol synthesis
decreased bile acid synthesis
90% of cholesterol secreted into bile
how are bile acids made
from cholesterol
need 18-20 enzymes, full set only found in liver
can be further processed by bacterial 7a dehydroxylase to yield secondary bile acids
what are bile salts
conjugated bile acids
bile acid conjugated to amino acid
has a amphipathic structure and acts as a physiological detergent
components of bile transported into bile duct from hepatocytes
bilirubin
phospholipids
bile acids
cholesterol
bilirubin bile transporter
MRP2
phospholipid bile transporter
MDR3
cholesterol bile transporter
ABCG5/8
bile acid bile transporter
BSEP
discuss the enterohepatic circulation
bilirubin, cholesterol, bile acids, and phospholipids enter bile duct from hepatocytes
bile transported into gut lumen
bile acids reabsorbed by ASBT in enterocytes and transferred back to hepatocytes via portal circulation
cholesterol reabsorbed by NPC1L1 in enterocytes and released as a chylomicron in blood or back into gut lumen
what is farnesoid X receptor (FXR)
ligand activated transcriptional factor
bile acids are the ligands
how does FXR regulate bile acid homeostasis
bile acid activated FXR inhibits CYP7A1 to decrease bile acid synthesis
bile acid activated FXR induces BSEP increase biliary bile acid secretion
maintains bile acid pool size over time
role of bile acid sequestrants
bind negatively charged bile salts in the intestine and prevent their re-absorption
force excretion in feces
remove feedback inhibition of bile salts, so more cholesterol is converted into bile salts, thus lowering cholesterol
biliary cholesterol secretion amt
1-2 g/day
biliary bile acid secretion amt
10-20 g/day
human bile acid pool size
3-4 g
bile acid synthesis amt
0.2-0.4 g/day
what % of bile acids are recycled
95-98%
what % of cholesterol is recycled
50%
what is the main source of cholesterol in the body
de novo synthesis
how is cholesterol solubilized in bile
forms mixed micelles
bile salts and phospholipids form outer hydrophilic region
inner hydrophobic region filled with lipids
2 functions of mixed micelles
prevent cholesterol crystallization
prevent interaction of bile salts with cholangiocytes, chronic interaction can cause damage and biliary injury
PFIC
progressive familial intrahepatic cholestasis
what is PFIC
progressive liver disease leading to liver failure
1/50,000-100,000
genetic defects in bile secretion
autosomal recessive
PFIC presentations
itching, jaundice, growth failure, cirrhosis, portal hypertension, hepatomegaly
PFIC type 1 characteristics
Byler disease
ATP8B1 mutation- phospholipid flippase
mechanism of PFIC1
not well understood
altered apical membrane structure that impairs biliary bile salt secretion with normal phospholipids in bile
clinical/ lab findings of PFIC1
mildly elevated AST/ALT
generally normal GGT
not associated with gallstone risk
early infancy onset, cirrhosis in first decade
elevated serum bile acids, severe pruritis
diarrhea, pancreatitis, short stature
PFIC type 2 characteristics
BSEP mutation
biliary bile acid secretion defect, normal biliary phospholipids
clinical/ lab findings of PFIC2
higher AST/ALT elevation than PFIC2 generally normal GGT serum bile acid elevation, severe pruritis 1/3 patients get gallstones portal hypertension
outcomes of PFIC2
fast progression, cirrhosis in 1 year of life
giant cell hepatitis, hepatocellular necrosis, portal fibrosis
importance of distinguishing between PFIC1 and PFIC2
generally PFIC2 more severe form, higher risk of HCC and cholangiocarcinoma
PFIC type 3 characteristics
MDR3 mutation
mechanisms PFIC3
exposures of cholangiocytes to normal levels of detergent bile acids causes cholangiopathy
decreased phospholipid secretion resulting in unstable micelles, crystallization of cholesterol and small bile duct obstruction
clinical/ lab findings of PFIC2
late infancy onset, slow progression, cirrhosis in young adult life
more severe AST/ALT elevation than PFIC1 or PFIC2
higher GGT than PFIC1 and PFIC2
pruritis
treatments for PFIC
UDCA- more effective in PFIC3
bile acid sequestrants- pruritis
surgical therapy- done before cirrhosis in PFIC 1 and PFIC2 (biliary diversion)
liver transplant- only effective ttx in PFIC3
what is biliary atresia
progressive idiopathic disease of the extrahepatic biliary tree
biliary atresia epidemiology
1 in 15,000-20,000 most common cause of neonatal cholestasis
clinical/ lab findings of biliary atresia
elevated conjugated bilirubin causing jaundice in first 8 weeks of life
pale stool
elevated AST/ALT and GGT
treatment of biliary atresia
early surgical intervention (Kasai procedure)
most common indication of liver transplant in children
what is Dubin-Johnson Syndrome
Mrp2 mutation
substrates include bilirubin glucuronide, glutathione, etc
symptoms of Dubin-Johnson Syndrome
jaundice
normal liver enzymes
black liver due to impaired excretion of epi metabolites
liver usually functionally normal
crigler najjar syndrome
complete loss of UGT1A1 function
elevated unconjugated bilirubin
bilirubin encephalopathy
gilbert syndrome
partial loss of enzyme activity due to mutation or genetic variation
generally healthy with occasional episodes of jaundice often when under stress
PBC
primary biliary cholangitis
epidemiology of PBC
1 in 10,000
anti-mitochondrial antibody (AMA) in 95% PBC patients
female dominant (95%)
middle age (35-70)
clinical presentation of PBC
pruritis, dry mouth/eye, fatigue appear first
jaundice appears later
hypercholesterolemia, xanthomas
elevated ALP, GGT
definitive diagnosis of PBC
liver biopsy confirming bile duct pathology
Ursodeoxycholic acid (UDCA) mechanism
increases bile acid pool hydrophobicity
promotes biliary bicarb secretion
anti-apoptosis
decreases pruritis
treatments for PBC
UDCA
FXR agonist
bile acid sequestrant (pruritis)
FXR agonist mechanism
inhibits bile acid synthesis
inhibits inflammation
reduces liver enzymes in PBC pts
increases pruritis
PSC
primary sclerosing cholangitis
what is PSC
affects both intra and extrahepatic ducts (fibrosis around bile duct)
possible autoimmune mediated destruction of bile duct (most patients have elevated IgM and p-ANCA in 80%)
symptoms of PSC
up to 80% have IBD (ulcerative colitis, crohns)
pruritis, elevated ALP and GGT, hyperbilirubinemia
narrowing of bile duct (beaded)
portal hypertension, cirrhosis, hepatosplenomegaly
treatments for PSC
no approved pharm treatments
pruritis treated with cholestyramine
manage symptoms
ICP
intrahepatic cholestasis of pregnancy
what is ICP
common pregnancy related liver disease
reversible, rapidly resolves after delivery
clinical presentation of ICP
pruritis in 3rd trimester, jaundice may follow
elevation of AST, ALT, bile acids
etiology of ICP
unclear
environmental, hormonal, genetic factors
treatment of ICP
UDCA, cholestyramine
symptoms resolve quickly after delivery (35-38th week)
cholelithiasis epidemiology
95% of all biliary tract diseases
10-20% of adults in US, 1-3% symptomatic per year
cholelithiasis race risk factors
native americans > Hispanics > Caucasians > Africans > asians
cholelithiasis age risk factors
3rd decade
increases with age
cholelithiasis gender risk factors
more common in females
high during fertile years, contraceptives, estrogen replacement
cholelithiasis modifiable risk factors
obesity, dyslipidemia, DM2, metabolic syndrome, pregnancy, rapid weight loss, TPN
cholelithiasis drug risk factors
octreotide: inhibits CCK release
clofibrate: lipid lowering agent that increases biliary cholesterol and decreases bile acid secretion
cholesterol stones
> 80% of gallstones
cholesterol monohydrate crystals
pigment stones
<20% of gallstones
black or brown pigment
black pigment gallstones
calcium bilirubinate polymer
formed in gallbladder
chronic hemolysis (sickle cell anemia)
Crohn’s disease (ileal resection)
brown pigment stone
various amounts of cholesterol/fatty soap/ calcium bilirubinate
formed in bile duct
chronic biliary tract infection
bacterial B glucuronidase deconjugates bilirubin
biliary stasis
pathogenic factors of cholelithiasis
supersaturation of cholesterol or bilirubin salt in bile
- hypersecretion of cholesterol or bilirubin
- decreased secretion of bile salt and phospholipids
- imbalance of nucleation/anti-nucleation proteins
- decreased gallbladder motility
- biliary stasis (obstruction)
biliary sludge
microscopic gallstones
suspension of cholesterol monohydrate crystal or calcium bilirubin particulates in mucin gel
can vanish or progress to gallstone
nucleation
pro nucleating agent: mucin gel, a scaffold that allows gallstones to grow
anti nucleating agents: apolipoprotein A, UDCA (increases vesicle stability)
clinical stages of gallstones
- lithogenic: conditions favor formation
- asymptomatic
- symptomatic- episodes of biliary colic after a fatty meal
- complicated- gallbladder attack
complications of gallstones
biliary colic acute cholecysitis (empyema, gangrene, perforation) choledocholitiasis ascending cholangitis pancreatitis gallbladder cancer
what is acute cholescystitis and what are the primary types
inflammation of the gallbladder
calculous (90%)
acalculous (10%)
clinical pres calculous
RUQ pain, mild fever, murphys sign
lab testing calculous
mild elevation of liver enzymes leukocytosis mild elevation of ALP bilirubin (jaundice) amylase and lipase tachycardia
diagnosis calculous
US: gallstone lodged in neck or cystic duct, GB wall thickening, distended GB, pericystic fluid
gallbladder empyema
accumulation of infected fluid
risk of sepsis, perforation
gallbladder hydrops
prolonged cystic obstruction
non inflammatory
treatment of calculous
supportive
IV fluid, antibiotics, pain meds
cholecystectomy
describe acute acalculous cholecystitis
distended gallbladder without stone
critically ill patients
major cause: bile stasis resulted from fever, dehydration, lithogenic bile, absence of feeding
higher risk of gangrene and perforation
ttx: supportive care, emergency cholecystectomy, cholecystostomy
the bile is sterile because of:
constant bile flow
bacterioactivity of bile salts
IgA
barrier function of the sphincter of Oddi
predisposing factors to ascending cholangitis
biliary obstruction and stasis
ERCP of stent placement disrupting sphincter of Oddi barrier function
mechanisms of ascending cholangitis
bacteria migrates into biliary system from intestine
high biliary pressure reduces antibacterial defense
increased bile ductular permeability permitting bacteria to enter the systemic circulation
presence of stones promotes bacterial colonization
clinical presentation of ascending cholangitis
charcots triad: fever, RUQ pain, jaundice
Reynold pentad: fever, RUQ pain, jaundice, hypotension, altered mental status
treatment of ascending cholangitis
supportive care: IV fluid, antibiotics, pain med
removal of stone (ERCP)
function of UDCA
decreases biliary cholesterol saturation
promotes bile secretion and flow
UDCA in gallstone dissolution
can be achieved in 50% of pts within 6 mo to 2 years
gallstone size determinant of outcome
ineffective in pigment stones
high recurring rate (50% in 3-5 years)
UDCA other uses
preventative
PFIC3, rapid weight loss, recurring choledocholithiasis
alternative to invasive procedure in pregnancy related sludge and gallstones