Path Chapter 18: Liver and Biliary Tract (pages 882-889)
Over 95% of biliary tract disease is due to cholelithiasis (gallstones)
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Cholelithiasis – stones in the gallbladder
The gallbladder stores bile made in the liver, until it needs released for a meal
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The gallbladder isn’t needed for the bile system to work though
o Liver can hold a L of bile, gallbladder can hold 50 mL
o People don’t have digestion or absorption problems after a cholecystectomy
The most common gallbladder congenital anomaly is where the fundus folds inwards, which creates a
Phrygian cap
Gallstones affect 10-20% of people in developed countries
Over 80% of gallstones are “silent,” and don’t cause any problems for decades
Two main types of gallstones – page 884
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Cholesterol stones – made mostly of cholesterol, more common in the western world
o Most common risk factors for developing cholesterol stones:
 Benedum: “fertile, fat, female, forty…”
 Age – risk increases as you age
 Sex – women are more at risk
 Both age and sex are due to hypersecretion of biliary cholesterol
 Also, as you age, you’re more likely to get metabolic syndrome and
obesity, which are both risk factors
 Estrogen – estrogen increases cholesterol uptake and making
 Estrogen, including oral contraceptives and pregnancy, increases
expression of liver lipoprotein receptors (to take up cholesterol)
 Also stimulates liver HMG-CoA reductase activity (enzyme to make
cholesterol)
 Obesity or rapid weight loss – both cause increased biliary cholesterol secretion
 Clofibrate – drug to lower blood cholsesterol by increasing liver HMG CoA
reductase, and decreasing conversion of cholesterol to bile acids by decreasing
cholesterol-7-α-hydroxylase activity
 All of that leads to excess biliary secretion of cholesterol
 Gallbladder stasis – if the gallbladder isn’t working for any reason, it creates an
environment for any kind of gallstone to form
 Genetics
 ATP-binding cassette (ABC) proteins – liver proteins that transport bile
lipids
 ABCG5 and ABG2 genes work in biliary cholesterol secretion
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The mutant form is called D19H, and can cause cholesterol
gallstones to form
 D19H causes you to absorb less, but make more
cholesterol
o Cholesterol is made soluble in bile by aggregating it with water-soluble bile salts, and
water-insoluble lecithins (they both act as detergents)
o When cholesterol concentrations are supersaturated, the cholesterol starts to clump
into solid cholesterol monohydrate crystals
o For cholesterol gallstones to form, you need 4 simultaneous conditions:
 The bile is supersaturated with cholesterol
 There is less movement than normal in or by the gallbladder
 Cholesterol nucleation (clumping) is accelerated
 Hypersecretion of mucus in the gallbladder traps the clumped cholesterol,
leading to their consolidation into stones
o Morphology of cholesterol stones:
 Cholesterol stones are only found in the gallbladder
 Cholesterol stones appear pale yellow, round, and have granular, hard surfaces
 The more calcium carbonate, phosphates, and bilirubin there is though,
the more the stone is discolored to gray or black
 Cholesterol stones are radiolucent
Pigment stones – made mostly of unconjugated bilirubin mixed with calcium salts, more
common in Asians
o Unconjugated bilirubin is usually a minor part of the bile
o Anything that causes increased amounts of unconjugated bilirubin in bile will increase
the risk of developing pigment stones
 Includes hemolytic syndromes, severe ileal dysfunction or bypass, and bacterial
infection of the bile tree
 Hemolytic syndromes increase the secretion of conjugated bilirubin into the bile
 1% of conjugated bilirubin gets unconjugated while in the bile tree, so if
there’s more conj. Bilirubin secretion, more unconjugated bilirubin piles
up, which can exceed its solubility
o Pigment stones are most often caused by bacterial infections of the bile tree, or
parasites
 Infection of the bile tree causes the microbe to release β-glucuronidases to
unconjugated the bilirubin
o Pigment stones can be classified as “black” or “brown”
 Black pigment stones – usually found when there is no infection
 Black pigment stones have oxidized calcium salts of unconjugated
bilirubin, and a little calcium carbonate, calcium phosphate, mucin, and
cholesterol
 Calcium carbonate makes 50-75% of black stones radiopaque
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Brown pigment stones – usually found when there is an infection present
 Brown pigment stones have pure calcium salts of unconjugated
bilirubin, mucin, a decent amount of cholesterol, and fats
 Brown stones have calcium soaps, making them radiolucent
Mucin acts as the cement holding gallstones together
Gallstones can be present for decades before symptoms show up, and most never develop
symptoms – we all most likely have some stones
Gallstones cause a pain called “biliary pain,” which is excruciating and constant or “colicky”
(spasmodic) – biliary colic
Gallstones can cause inflammation of the bile tree (cholangitis) or gallbladder (cholecystitis),
obstructive cholestasis, and pancreatitis
The bigger the gallstone, the less likely it will enter the bile ducts and obstruct
o The small stones fit into the ducts easily, and are more dangerous
Gallstone ileus (aka Bouveret’s syndrome) – when the gallstone erodes into adjacent parts of
the GI
Gallstones increase the risk for cancer (carcinoma) of the gallbladder
Cholecystitis – inflammation of the gallbladder
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Cholecystitis almost always happens in association with gallstones (90% of the time)
Cholecystitis can be acute, chronic, or both
Acute cholecystitis – acute inflammation and irritation of an obstructed gallbladder
o 90% of the time it’s caused by an obstruction of the cystic duct or neck of the
gallbladder
o Acute cholecystitis is the main complication of gallstones, and the most common reason
for an emergency cholecystectomy (gallbladder removal)
o The irritation disrupts the glycoprotein mucus layer that normally protects
 This exposes the mucosal epithelium to the detergent action of bile salts
 Prostaglandins are released from the gallbladder wall and add to the
inflammation
o This leads to gallbladder dysmotility – distention and increased intraluminal pressure
block blood flow to the mucosa
o At this point, infection can take place and lead to more and worse symptoms
o Acute acalculous (no stones) cholecystitis is thought to result from ischemia
 Rare, happens only 10% of the time
 The cystic artery is an end artery with no collateral circulation
 Inflammation and edema can compromise blood flow
 Cholesterol, bile, and mucus can accumulate and block flow as well
 Risk factors for acute acalculous cholecystitis are sepsis with hypotension and
multisystem organ failure, immunosuppression, trauma, burns, diabetes, and
infections
o Morphology of acute cholecystitis:
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The gallbladder is usually enlarged
The gallbladder may look bright red, or blotchy purple to green-black
A fibrin layer usually coats the serosa, and severe cases include a suppurative
coagulated exudate
 Only difference between calculous and acalculous is whether a stone is there or
not
 Empyema of the gallbladder – when the exudate in the gallbladder is pretty
much pure pus, as opposed to a mix of bile, pus, fibrin, and blood like usual
 In mild acute cholecystitis, the gallbladder wall is thickened, edematous, and
hyperemic (blood engorged)
 In severe acute cholecystitis, the gallbladder becomes a green-black necrotic
organ – called gangrenous cholecystitis
o An attack of acute cholecystitis starts with right upper quadrant or epigastric pain
 Usually includes mild fever, lack of appetite, tachycardia, nausea, vomiting, and
sweating (red – benedum asked us about)
 If there is also hyperbilirubinemia (seen as jaundice), it means the common bile
duct is obstructed
 Acute cholecystitis may also show leukocytosis (increased WBCs) and mildly
increased alkaline phosphatase
 Acute cholecystitis can show up as sudden intense pain and be an emergency
for treatment, or with mild symptoms that don’t need any medical help
 For those who recover without medical help, most have recurrences,
and ¼ have symptoms get worse in future attacks
 The longer you wait to treat, the greater the chances of gangrene or
perforation, leading to death
 Acalculous has a higher risk for these two
 Rarely, infections or atherosclerosis can cause acalculous cholecystitis
Chronic cholecystitis
o Can either be a product of repeated bouts of acute cholecystitis, or can develop with no
previous attacks
o 90% of the time, chronic cholecystitis involves gallstones (cholelithiasis)
o Supersaturation of bile causes both the inflammation, and creates the environment for
stones to form
 So supersaturation of bile is the cause of the cholecystitis
o 1/3 the time, chronic cholecystitis includes infections by E. coli or enterococci
o Unlike acute calculous cholecystitis, obstruction of gallbladder outflow isn’t required
o Symptoms of chronic cholecystitis are similar to acute
 Includes anywhere from biliary colic pain, to right upper or epigastric pain
o Morphology of chronic cholecystitis:
 May show signs of remaining fibrin from preexisting acute inflammation
 The gallbladder wall is thickened and opaque gray-white
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Outpouchings of the mucosal epithelium through the gallbladder wall are called
Rokitansky-Aschoff sinuses, and may be seen
 If you see dystrophic calcification, it’s called porcelain gallbladder, and increases
the risk for cancer
 Xanthogranulomatous cholecystitis – hugely thick gallbladder wall, but
gallbladder is shrunk with chronic inflammation, necrosis, and hemorrhage
 Hydrops of the gallbladder – atrophy and chronic inflammation of obstructed
gallbladders cause only a clear secretion
o Chronic cholecystitis isn’t as obvious as acute
 Usually characterized by recurrent attacks of either steady or colicky epigastric
or right upper quadrant pain
 Often also sea nausea, vomiting, and intolerance for fatty foods
Need to diagnose cholecystitis quick because these things could happen:
o Infection
o Gallbladder perforation
o Gallbladder ruptures and causes peritonitis
o A fistula forms that drains bile into organs, lets in air and bacteria into the bile tree, and
can cause a gallstone-caused intestinal obstruction (ileus)
Choledocholithiasis – stones in the bile ducts of the bile tree
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More common in Asians
Bile duct stones are usually pigmented, and cause bile tract infections
Choledocholithiasis can be asymptomatic, or show symptoms from obstruction, pancreatitis,
cholangitis, liver abscess, biliary cirrhosis, and acute calculous cholecystitis
Cholangitis – bacterial infection of the bile ducts
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Cholangitis can happen from any lesion that obstructs bile flow (most often by
choledocholithiasis)
Ascending cholangitis – infection of intrahepatic biliary radicles
The infecting organism is usually enteric gram negatives like E. coli, klebsiella, enterococcus, or
enterobacter
Symptoms of cholangitis are fever, chills, abdominal pain, jaundice, and acute inflammation of
the wall of the bile ducts and neutrophils in the lumen
Suppurative cholangitis is the most severe form – purulent bile fills and distends the bile ducts
Choledocholithiasis and cholangitis often happen together
A major cause of neonatal cholestasis (bile flow out of liver is blocked) is biliary atresia
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Biliary atresia – obstruction of the lumen of the extrahepatic bile tree within the first 3 months
of life
Biliary atresia is characterized by progressive inflammation and fibrosis of the bile ducts
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Biliary atresia is the most common cause of death from liver disease in early childhood
Two forms of biliary atresia, based on when the lumen is blocked:
o Fetal biliary atresia - Bile tree doesn’t form right
 less common, and often includes other problems with organs forming
o Perinatal biliary atresia – bile tree forms right, but then is destroyed after brith
 Much more common
 Thought to be caused by virus or autoimmunity
Morphology of biliary atresia:
o Shows inflammation and fibrosis causing constriction of the hepatic or common bile
ducts
o Also shows progressive inflammation and destruction of the bile tree
o 2/3 of cases show features of biliary obstruction, like bile duct proliferation, portal tract
edema and fibrosis, and cholestasis (bile backing up into the liver)
o Cirrhosis will develop within 3-6 months if biliary atresia isn’t treated
o Biliary atresia can be corrected by surgery (Kasai procedure) when it’s type 1 (limited to
the common duct) or type 2 (in the liver bile ducts)
 90% of patients though have type 3 biliary atresia (there’s also obstruction of
bile ducts at or above the porta hepatis) which can’t be treated with surgery
Treat biliary atresia with liver and bile duct transplants
o w/o treatment, patient usually doesn’t make it two years
choledochal cysts – rare congenital dilations of the common bile duct
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Most often seen in kids younger than 10, and more often girls
Choledochal cysts show jaundice and/or recurrent colic abdominal pain
Can present as dilations int eh common bile duct, diverticuli of extrahepatic ducts, or
choledochoceles (cysts that protrude into the duodenum’s lumen)
Choledochal cysts predispose to stone formation, stenosis, pancreatitis, and obstructive
problems
Clinically important bile tract tumors are those that affect the epithelium lining the biliary tree
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Adenomas – benign epithelial tumors
Inflammatory polyps – mucosal projectioins with a surface stroma filled with inflammatory cells
and lipid filled macrophage
Carcinoma of the gallbladder is the most common cancer of the extrahepatic bile tract
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Happens more often in women, and most often in your 70’s
Gallbladder carcinoma is rarely able to be removed, and 5 year survival rate is low
Gallstones are the most important risk factor for gallbladder carcinoma (involved in 95% of
cases)
o But only half a % of people with gallstones develop cancer after 20 years
o The cancer is thought to come from the chronic inflammation from the gallstone
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Gallbladder carcinomas have two patterns of growth: infiltrating and exophytic
o Infiltrating – more common, penetrates the gallbladder wall
o Exophytic – shows a cauliflower-like mass grow into the lumen and the wall
o Most common site affected is the fundus or neck of the gallbladder
o Most carcinomas fo the gallbladder are adenocacrinomas
o Most gallbladder carcinomas have invaded the liver by the time they’re discovered
o Shows abdominal pain, jaundice, anorexia, nausea, and vomiting