B5.017 Hepatic and Gallbladder Physiology Flashcards
1
Q
hepatic vascular system
A
portal vein - 80% inflow
hepatic artery- 20% inflow
central vein system
hepatic vein
2
Q
biliary system
A
intrahepatic bile duct L/R hepatic duct common hepatic duct gallbladder cystic duct common bile duct
3
Q
portal triad
A
portal arteriole
portal venule
bile duct
4
Q
liver sinusoids
A
large capillary between plates of hepatocytes
drain blood into central vein
5
Q
central veins
A
at center of hepatic lobule
drains filtered blood to hepatic vein and IVC
6
Q
liver cell types
A
hepatocytes sinusoidal endothelial cells cholangiocytes Kupffer cells stellate cells
7
Q
discuss bile and blood flow in the liver
A
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
8
Q
function of gallbladder
A
store bile (50 ml) concentrates bile
9
Q
function of sphincter of Oddi
A
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
10
Q
functions of liver
A
production of bile regulation of cholesterol homeostasis regulation of blood sugar production of urea detoxification of blood production of blood proteins
11
Q
bile composition
A
water
organic solutes
inorganic electrolytes
proteins
12
Q
organic solute components of bile
A
cholesterol
bile salts
phospholipids
13
Q
protein components of bile
A
IgA, IgM, IgG
mucin (glycosylated protein)
albumin
apolipoproteins
14
Q
in what forms can cholesterol be found in the body?
A
membrane
intracellular lipid droplets
lipoproteins
esterified and non-esterified (free)
15
Q
hepatic cholesterol inputs
A
de novo synthesis (primary)
diet
both of these contribute to cholesterol pool in hepatocyte
16
Q
factors promoting biliary cholesterol secretion
A
increased uptake from blood
increased de novo cholesterol synthesis
decreased bile acid synthesis
90% of cholesterol secreted into bile
17
Q
how are bile acids made
A
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
18
Q
what are bile salts
A
conjugated bile acids
bile acid conjugated to amino acid
has a amphipathic structure and acts as a physiological detergent
19
Q
components of bile transported into bile duct from hepatocytes
A
bilirubin
phospholipids
bile acids
cholesterol
20
Q
bilirubin bile transporter
A
MRP2
21
Q
phospholipid bile transporter
A
MDR3
22
Q
cholesterol bile transporter
A
ABCG5/8
23
Q
bile acid bile transporter
A
BSEP
24
Q
discuss the enterohepatic circulation
A
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
25
what is farnesoid X receptor (FXR)
ligand activated transcriptional factor
| bile acids are the ligands
26
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
27
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
28
biliary cholesterol secretion amt
1-2 g/day
29
biliary bile acid secretion amt
10-20 g/day
30
human bile acid pool size
3-4 g
31
bile acid synthesis amt
0.2-0.4 g/day
32
what % of bile acids are recycled
95-98%
33
what % of cholesterol is recycled
50%
34
what is the main source of cholesterol in the body
de novo synthesis
35
how is cholesterol solubilized in bile
forms mixed micelles
bile salts and phospholipids form outer hydrophilic region
inner hydrophobic region filled with lipids
36
2 functions of mixed micelles
prevent cholesterol crystallization
| prevent interaction of bile salts with cholangiocytes, chronic interaction can cause damage and biliary injury
37
PFIC
progressive familial intrahepatic cholestasis
38
what is PFIC
progressive liver disease leading to liver failure
1/50,000-100,000
genetic defects in bile secretion
autosomal recessive
39
PFIC presentations
itching, jaundice, growth failure, cirrhosis, portal hypertension, hepatomegaly
40
PFIC type 1 characteristics
Byler disease
| ATP8B1 mutation- phospholipid flippase
41
mechanism of PFIC1
not well understood
| altered apical membrane structure that impairs biliary bile salt secretion with normal phospholipids in bile
42
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
43
PFIC type 2 characteristics
BSEP mutation
| biliary bile acid secretion defect, normal biliary phospholipids
44
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
```
45
outcomes of PFIC2
fast progression, cirrhosis in 1 year of life
| giant cell hepatitis, hepatocellular necrosis, portal fibrosis
46
importance of distinguishing between PFIC1 and PFIC2
generally PFIC2 more severe form, higher risk of HCC and cholangiocarcinoma
47
PFIC type 3 characteristics
MDR3 mutation
48
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
49
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
50
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
51
what is biliary atresia
progressive idiopathic disease of the extrahepatic biliary tree
52
biliary atresia epidemiology
1 in 15,000-20,000 most common cause of neonatal cholestasis
53
clinical/ lab findings of biliary atresia
elevated conjugated bilirubin causing jaundice in first 8 weeks of life
pale stool
elevated AST/ALT and GGT
54
treatment of biliary atresia
early surgical intervention (Kasai procedure)
| most common indication of liver transplant in children
55
what is Dubin-Johnson Syndrome
Mrp2 mutation
| substrates include bilirubin glucuronide, glutathione, etc
56
symptoms of Dubin-Johnson Syndrome
jaundice
normal liver enzymes
black liver due to impaired excretion of epi metabolites
liver usually functionally normal
57
crigler najjar syndrome
complete loss of UGT1A1 function
elevated unconjugated bilirubin
bilirubin encephalopathy
58
gilbert syndrome
partial loss of enzyme activity due to mutation or genetic variation
generally healthy with occasional episodes of jaundice often when under stress
59
PBC
primary biliary cholangitis
60
epidemiology of PBC
1 in 10,000
anti-mitochondrial antibody (AMA) in 95% PBC patients
female dominant (95%)
middle age (35-70)
61
clinical presentation of PBC
pruritis, dry mouth/eye, fatigue appear first
jaundice appears later
hypercholesterolemia, xanthomas
elevated ALP, GGT
62
definitive diagnosis of PBC
liver biopsy confirming bile duct pathology
63
Ursodeoxycholic acid (UDCA) mechanism
increases bile acid pool hydrophobicity
promotes biliary bicarb secretion
anti-apoptosis
decreases pruritis
64
treatments for PBC
UDCA
FXR agonist
bile acid sequestrant (pruritis)
65
FXR agonist mechanism
inhibits bile acid synthesis
inhibits inflammation
reduces liver enzymes in PBC pts
increases pruritis
66
PSC
primary sclerosing cholangitis
67
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%)
68
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
69
treatments for PSC
no approved pharm treatments
pruritis treated with cholestyramine
manage symptoms
70
ICP
intrahepatic cholestasis of pregnancy
71
what is ICP
common pregnancy related liver disease
| reversible, rapidly resolves after delivery
72
clinical presentation of ICP
pruritis in 3rd trimester, jaundice may follow
| elevation of AST, ALT, bile acids
73
etiology of ICP
unclear
| environmental, hormonal, genetic factors
74
treatment of ICP
UDCA, cholestyramine
| symptoms resolve quickly after delivery (35-38th week)
75
cholelithiasis epidemiology
95% of all biliary tract diseases
| 10-20% of adults in US, 1-3% symptomatic per year
76
cholelithiasis race risk factors
native americans > Hispanics > Caucasians > Africans > asians
77
cholelithiasis age risk factors
3rd decade
| increases with age
78
cholelithiasis gender risk factors
more common in females
| high during fertile years, contraceptives, estrogen replacement
79
cholelithiasis modifiable risk factors
obesity, dyslipidemia, DM2, metabolic syndrome, pregnancy, rapid weight loss, TPN
80
cholelithiasis drug risk factors
octreotide: inhibits CCK release
clofibrate: lipid lowering agent that increases biliary cholesterol and decreases bile acid secretion
81
cholesterol stones
>80% of gallstones
| cholesterol monohydrate crystals
82
pigment stones
<20% of gallstones
| black or brown pigment
83
black pigment gallstones
calcium bilirubinate polymer
formed in gallbladder
chronic hemolysis (sickle cell anemia)
Crohn's disease (ileal resection)
84
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
85
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)
86
biliary sludge
microscopic gallstones
suspension of cholesterol monohydrate crystal or calcium bilirubin particulates in mucin gel
can vanish or progress to gallstone
87
nucleation
pro nucleating agent: mucin gel, a scaffold that allows gallstones to grow
anti nucleating agents: apolipoprotein A, UDCA (increases vesicle stability)
88
clinical stages of gallstones
1. lithogenic: conditions favor formation
2. asymptomatic
3. symptomatic- episodes of biliary colic after a fatty meal
4. complicated- gallbladder attack
89
complications of gallstones
```
biliary colic
acute cholecysitis (empyema, gangrene, perforation)
choledocholitiasis
ascending cholangitis
pancreatitis
gallbladder cancer
```
90
what is acute cholescystitis and what are the primary types
inflammation of the gallbladder
calculous (90%)
acalculous (10%)
91
clinical pres calculous
RUQ pain, mild fever, murphys sign
92
lab testing calculous
```
mild elevation of liver enzymes
leukocytosis
mild elevation of ALP
bilirubin (jaundice)
amylase and lipase
tachycardia
```
93
diagnosis calculous
US: gallstone lodged in neck or cystic duct, GB wall thickening, distended GB, pericystic fluid
94
gallbladder empyema
accumulation of infected fluid
| risk of sepsis, perforation
95
gallbladder hydrops
prolonged cystic obstruction
| non inflammatory
96
treatment of calculous
supportive
IV fluid, antibiotics, pain meds
cholecystectomy
97
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
98
the bile is sterile because of:
constant bile flow
bacterioactivity of bile salts
IgA
barrier function of the sphincter of Oddi
99
predisposing factors to ascending cholangitis
biliary obstruction and stasis
| ERCP of stent placement disrupting sphincter of Oddi barrier function
100
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
101
clinical presentation of ascending cholangitis
charcots triad: fever, RUQ pain, jaundice
| Reynold pentad: fever, RUQ pain, jaundice, hypotension, altered mental status
102
treatment of ascending cholangitis
supportive care: IV fluid, antibiotics, pain med
| removal of stone (ERCP)
103
function of UDCA
decreases biliary cholesterol saturation
| promotes bile secretion and flow
104
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)
105
UDCA other uses
preventative
PFIC3, rapid weight loss, recurring choledocholithiasis
alternative to invasive procedure in pregnancy related sludge and gallstones
