B5.017 - Hepatic and Gallbladder Physiology Flashcards
1
Q
what makes up the portal triad
A
bile duct portal venule portal arteriole
2
Q
what are liver sinusoids
A
large capillaries between plates of hepatocytes that drain blood into central vein
3
Q
what is the central vein
A
drains filtered blood to hepatic vein and IVC
4
Q
liver cell types
A
hepatocytes sinusodal endothelial cells kupffer cells stellate cells
5
Q
what are kupffer cells
A
Kupffer cells are the monocyte/macrophage cells of the liver. They are the first line against infection or toxins in the liver.
6
Q
what are stellate cells
A
Stellate (Ito) cells store lipid soluble vitamins (most notably Vitamin A) and fat. They secrete extracellular matrix components and contract, causing hepatic fibrosis in cirrhosis.
7
Q
describe flow of bile compared to central vein
A
they flow in opposite directions
8
Q
what are chonlangiocytes
A
cells lining the bile dictule
9
Q
what does the gall bladder do
A
stores bile and concentrates bile
10
Q
what is the sphincter of oddi
A
high pressure zone of resistance to bile flow from the common bile duct into duodenum. Prevents reflux of duodenal contents into the pancreatic and bile ducts and promote sifting of the gallbladder
11
Q
functions of the liver
A
production of bile regulation of cholesterol synthesis regulation of blood sugar production of urea detox of blood production of blood proteins
12
Q
composition of bile
A
water proteins Na Bile salts bilirubinfatty acids lecithin K Ca Cl HCO3
13
Q
what cells produce water to go into bile
A
hepatocytes cholangiocytes
14
Q
what proteins are there in bile
A
IgA, IgM, IgG Mucin Albumin Apolipoproteins
15
Q
what is mucin
A
glycosylated protein, forming gel, lubrication, barrier
16
Q
how does bile become more concentrated
A
the longer bile sits in the gall bladder the more concentrated it gets. It continuously pumps Na out of the gall bladder lumen and water follows
17
Q
factors promoting biliary cholesterol secretion
A
increased uptake from blood increased de novo cholesterol synthesis decreased bile acid synthesis
18
Q
where does majority of our cholesterol come from
A
de novo synthesis
19
Q
describe de novo synthesis of cholesterol
A
HMGCoA Reductase is the major enzyme creating cholesterol pool. CYP7A1 then converts cholesterol to bile acids
20
Q
what are the types of bile in the bile acid pool and what are their %
A
CA - 50% - CYP7A1, CYP8B1 CDCA - 30% - CYP7A1 DCA - 15% - bacterial 7alpha dehydroxylase LCA - <5% - bacterial 7alpha dehydroxylase
21
Q
why is bile made by the liver
A
the liver is the only organ with all the enzymes necessary to make bile
22
Q
what does conjugation of bile acids do
A
makes the bile acids into bile salts that then are water soluble and can transport fats to the cells lining the duodenum to take up the nutrients
23
Q
what amino acids are bile acids combined with
A
glycine and taurine
24
Q
what is MRP2
A
transports bilirubin into bile from hepatocyte
25
what is CYP7A1
converts cholesterol into bile acid
26
what is MDR3
transports phospholipids into bile
27
what is ABCG5 and ABCG8
transports cholesterol into bile
28
what is BSEP
transports bile acids into bile
29
what is NTCP
transports bile acids from the enterocyte --\> portal circulation back to the hepatocyte
30
what is Ostalpha and beta
transport bile acids into portal circulation
31
what is ASBT
bile acid transporter into the enterocyte
32
what is ABCG5 and 8
pumps cholseterol out of the enterocyte back into the lumen to be excreted
33
what percentage of bile do you lose in feces
5%
34
what is FXR
farsenoid x receptor a nuclear receptor that is a ligand activated transcriptional factor, bile acid binds to it and it inhibits CYP7A1 to decrease bile acid synthesis Key in feedback inhibition of bile acid
35
what does bile acid activated FXR do
inhibits CYP7A1 to decrease bile acid synthesis induces BSEP to increase biliary acid secretion
36
what do bile acid sequestrants do
bind negatively charged bile salts in the intestine and prevent their reabsorption
37
what are bile acid sequestrants
cholestyramine colesevelam
38
how much ingested cholesterol is kept
50%
39
what is CCK
peptide hormone secreted by enteroendocrine cells (I cells)
40
what stimulates CCK secretion
dietary fat and amino acids
41
what does CCK do
stimulates gallbadder contraction causes relaxation of the sphincter of Oddi stimulates pancreatic acinar cells to secretive digestive juice inhibits gastric emptying and promotes digestion
42
what are micelles
formed from bile salts formed in the gut containing dietary lipids and bile salts
43
describe the structure of micelles
bile salts form the edge whereas lipids exist in a bilayer on the inside of the micelle providing a large surface area for action of pancreatic lipase
44
what do micelles do
facilitate the absorption of digested lipid by gut enterocytes and provide a large surface area for the action of pancreatic lipase
45
what is progressive familial intrahepatic cholestasis (PFIC)
progressive liver disease leading to liver failure genetic defects in bile secretion autosomal recessive
46
presentation of PFIC
itching, jaundice, growth failure, cirrhosis, portal hypertension, hepatomegaly
47
progressive familial intrahepatic cholestasis type 1 genetic disorder
byler disease ATP8B1 mutation - phospholipid flippase
48
PFIC1 mechanism
not well understood, but may be associated with altered apical membrane structure that impairs biliary bile salt secretion with normal phospholipids in bile
49
labs for PFIC1
mildly elevated AST/ALT Normal GGT not associated with gallstone risk
50
symptoms of PFIC1
early infancy onset, cirrhosis in first decade of life, elevated serum bile acids, severe pruritis diarrhea, pancreatitis, short stature
51
PFIC2 mutation
BSEP - BSEP is integral in bile acid movement out of hepatocyte to move to enterocyte biliary acid secretion deficit, normal biliary phospholipids
52
PFIC2 progression
fast, cirrhosis in 1 year of life giant cell hepatitis, hepatocellular necrosis, portal fibrosis
53
PFIC2 labs
higher AST/ALT than PFIC1
Generally **normal GGT**
serum bile acid elevation,
severe pruritis
**1/3 develop gallstones**
portal hypertension
more severe than hepatobiliary disease than PFIC1 and higher risk than HCC and cholangiocarcinoma
54
PFIC3 mutation
MDR3 mutation
ABCB4 transporter
55
describe PFIC3
exposure of cholangiocytes to normal levels of detergent bile acids causes chilangiopathy
decreased phospholipid secretion resulting in **unstable micelles**, crystallization of cholesterol and **small bile duct obstruction**
late infancy onset, slow progression, cirrhosis in young adult life
56
labs for PFIC3
**more severe elevation of AST/ALT than PFIC1 and 2**
higher GGT distinguishes PFIC3 from PFIC1 and PFIC2
pruritis
57
treatment for PFIC
UDCA - more effective in PFIC3
bile acid sequestrants for pruritis
srugical before cirrhosis in PIFC1 and PFIC2
liver transplant only effective treatment for PFIC3
58
biliary atresia
progressive idiopathic disease of extrahepatic biliary tree
most common cause of neonatal cholestasis
59
labs of biliary atresia
**elevated conjugated bilirubin** causing jaundice in first 8 weeks of life and **pale stool**
**elevated AST/ALT and GGT**
60
treatment for biliary atresia
early surgical intervention (Kasai procedure)
improves transplant free outcome
most common indication of liver transplantation in children
61
what is dubin johnson syndrome
**Mrp2 (ABCC2 mutation**) which transports bilirubin into bile
jaundice usually only symptom
normal liver enzymes
**black liver** due to impaire excretion of epinephrine metabolites
liver usually functionally normal
good prognosis
62
what is crigler najjar syndrome
complete loss of enzyme activity (elevated unconjugated bilirubin, bilirubin encephalopathy)
63
gilbert syndrome
partial loss of enzyme activity due to mutation or genetic variation. Generally healthy. get a little yellow under stress
64
PBC
primary biliary cholangitis
autoimmune destruction of small bile ducts in portal triad
65
what causes PBC
anti mitochondrial antibody AMA in ~95% PBC
female dominant
middle aged
66
clinical presentation of PBC
pruritis, dry mouth/eye and fatigue appear first, jaundice usually appears later
hypercholesterolemia, xanthomas
elevated ALP, GGT
liver biopsy to confirm
67
what is UDCA
increases bile acid pool hydrophilicity
promotes biliary bicarbonate secretion
anti apoptosis
decreases pruritis
60% responders have normal life span
40% do not have adequate response
68
what deo FXR agonists do
inhibit bile acid synthesis
inhibit inflammation
reduces liver enzymes in PBC patients
increases pruritis
69
what is treatment for pruritis
bile acid sequestrant
cholestyramine
70
what are FXR agonists
obeticholic acid
OCA
ocaliva
71
what is PSC
affects both intra and extrahepatic duct (fibrosis around bile duct)
male dominant
autoimmune mediated destruction of bile duct (most patients have elevated **IgM and pANCA)**
up to 80% have IBD
72
labs for PSC and symptoms
pruritis, elevated ALP, GGT, hyperbilirubinemia
narrowing of bile duct
portal hypertension, cirrhosis, hepatosplenomegaly
73
ICP - intrahepatic cholestasis of pregnancy
common pregnancy related liver disease
reversible, rapidly resolves after pregnancy
usually presents in 3rd trimester, jaundice may follow
74
labs and treatment for ICP
elevated AST/ALT, bile acids, mild jaundice
UDCA, cholestyramine, symptoms resolve quickly after delivery
75
cholelithiasis epidemiology
~95% of all biliary tract diseases
Native americans \> hispanics \> caucasians \> africans \> asians
more common after 3rd decade, increases with age
F\>M
76
modifiablie risk factors for cholelithiasis
obesity, dyslipidemia, T2DM, metabolic syndrome, pregnancy, rapid weight loss, TPN
77
drugs that may lead to cholelithiasis
octreotide - long lasting analogue of somatostatin that inhibits CCK release
clofibrate - lipid lowering drug that increases biliary cholesterol and decreased bile acid secretion
78
what are the types of gallstones and their risk factors
cholesterol stones - \>80%
risk factors: obesity, gender, race, estrogen, age
pigment stones - \<20%
79
what are the types of pigment stones
1. black pigment stones - calcium bilirubinate polymer, formed in gallbladder,
1. chronic hemolysis (sickle cell), chrons disease
2. brown pigment stone - various amounts of cholestrol/fatty soap/ calcium bilirubinate
1. formed in bile duct, chronic biliary tract infection, bacterial beta glucuronidase deconjugates bilirubin, biliary stasis
80
pathogenesis of cholelithiasis
supersaturation of cholesterol or bilirubin salt in bile
81
what are pathogenic factors of cholelithiasis
hypersecretion of cholesterol or bilirubin
decreased secretion of bile salts and phospholipids
imbalance of nucleation/antinucleation proteins
decreased gallbladder motility
biliary stasis
82
what is biliary sludge
microscopic gallstones
suspension of cholesterol monohydrate crystal or calcium bilirubin particulates in mucin gel, can vanish or progress to gallstone
83
what is nucleation
altered balance of pronucleating vs antinucleating agnents in the bile
pronucleating agents: mucin gel, a hydrophobic molecule that promotes nucleation of crystals, a scaffold that allows gallstone to grow
anti nucleating agents - apolipoprotein A, UDCA
84
clinical stages of cholelithiasis
1. lithogenic state - conditions favor gallstone formation
2. asymptomatic gallstones
3. symptomatic - episodes of biliary colic after a fatty meal
4. complicated, gallbladder attack
85
complications of gallstones
asymptomatic stones do not requrie treatment
biliary colic
acute cholecystitis
empyema
gangrene
perforation
choledocholithiasis
ascendign cholangitis
pancreatitis
gallladder cancer
86
acute cholecystitis
what is it and presentation
inflammation of the gall bladder
acute calculous cholecystitis - 90%
acute acalculous cholecystitis - 10%
RUQ paint, mild fever, murphys sign
87
labs and dx for cholecystitis
mild elevation of liver enzymes, leukocytosis, mild elevation of ALP, bilirubin, amylase and lipase, tachycardia
dx is with US, gallstone lodged in neck or cystic duct, GB wall thickening, distene GB
88
what is gallbladder empyema
accumulation of infected fluid, mostly associated iwht acute cholecystitis and infected bile, Risk of sepsis, perforation
89
what is gallbladder hydrops
prolonged cystic duct obstruction
90
treatment of acute cholecystitis
IV fluid, antibiotics, pain meds
91
what is
92
acute acalculous cholecystitis causes and symptoms, treatment
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
treatment is supportive care, cholecystectomy, cholecystostomy
93
how does bile stay sterile
bile is sterile bc of constant bile flow, bacteriostatic activity of bile salts, IgA, Oddi,
94
predisposing factors of ascending cholangitis
biliary obstruction and stasis
Oddi disrupted
95
mechanism of ascending cholangitis
bacteria migrate into biliary system from the intestine
usually E coli, Klebsiella, enterobacter
high biliary pressure reduces antibacterial defense, increased bile ductular permeability permitting bacteria to enter the systemic circulation
presence of stomes promotes bacterial colonization
96
clinical presentation of ascending cholangitis
charcots triat: rever, RUQ, jaundice
reynolds pentad - fever, RUQ pain, jaundice, hypotension, altered mental status
97
treatment of ascending cholangitis
supportive care, antibiotics, pain medicine
removal of stone (ERCP)
98
what does UDCA in gallstone treatment
decreases biliary cholesterol saturation
promotes bile secretion and flow
gallstone dissolution
doesnt treat pigment stones
preventative use: PFIC3, rapid weight loss, recurring choledocholithiases
