Pathology of the Gallbladder, Extrahepatic Biliary Tract, and Pancreas

Question 1

What are bile salts and lecithins? Are they water soluble or insoluble?

Answer 1

1. Bile salts - bile acids made from cholesterol, conjugated to glycine or taurine. Water soluble, and the primary component of bile
2. Lecithins - phosphatylcholine, water-insoluble

Question 2

Other than bile salts and lecithins, what are the other components of bile?

Answer 2

Cholesterol
Proteins - probably acting as the nidus for stone formation
Bilirubin

Question 3

How does bilirubin get made and transported to the liver?

Answer 3

Made in reticuloendothelial system (i.e. spleen)

Heme -> biliverdin = open chain form of heme porphyrin ring

Unconjugated bilirubin made from biliverdin, and transported via albumin in blood (UCB is water insoluble, needs to be conjugated)

Question 4

What is the fate of bilirubin once it enters the intestine?

Answer 4

Bacteria in the gut deconjugate it to urobilinogen.

Urobilinogen can be excreted in stool after being made into stercobilin -> gives the stool its brown color.

Some urobilinogen is reabsorbed -> can be excreted again in bile, or transported to kidneys where it is oxidized to urobilin -> gives the urine its yellow color.

Question 5

What is the fate of bile salts when they enter the intestines?

Answer 5

They are partially deconjugated from glycine / taurine

95% of these will be reabsorbed in the terminal ileum (same site as B12), will return via portal vein, and be used against after conjugation (used 20 times on average)

Question 6

What is the most common congenital anomaly of the gallbladder?

Answer 6

Phrygian cap -> fundus (body, as opposed to neck and cystic duct) of the gallbladder folded inward

Question 7

What are choledochal cysts and what are the possible complications?

Answer 7

Dilatations or outpouchings of the COMMON bile duct (think choledocholithiasis)

possible complications:

1. choledocholithiasis
2. cholangitis - infection of pouches
3. biliary tract obstruction
4. bile duct carcinoma

Question 8

What are the causes of biliary atresia?

Answer 8

Failure to form (rarer) or early destruction (within 2 mo of birth) of extrahepatic biliary tree (probably due to inflammation from infection leading to stricture and destruction of the bile duct)

Question 9

What are the consequences of biliary atresia?

Answer 9

Bile ducts -> progressive fibrosis may cause extrahepatic to become intrahepatic atresia

Liver - cholestasis causes portal tract infiltration, fibrosis, and bile duct proliferation = secondary biliary cirrhosis

Question 10

What is the treatment for biliary atresia?

Answer 10

Early surgical correction if restricted to extraheptic bile ducts

Liver and bile duct transplant if intrahepatic spread

Question 11

What are the types of gallstones and which one predominates in the US?

Answer 11

1. Cholesterol - predominates in US

2. Pigment (bilirubin)

Question 12

What is the pathogenesis of cholesterol stones?

Answer 12

Supersaturation of bile with cholesterol due to:
1. Increased biliary secretion of cholesterol
or
2. Decreased secretion of bile salts to solubilize

+ bile stasis in gallbladder = increased cholesterol stone nucleation + excess mucin (produced by epithelium in gallbladder) = stones

Question 13

What are the risk factors for cholesterol stone formation?

Answer 13

1. Developed countries
2. Native American ethnicity
3. Increased secretion of bile - advanced age, estrogen (obesity, women, OCPs, pregnancy)
4. Gallbladder hypomotility - rapid weightloss, fasting, or neurogenic

Question 14

How do cholesterol stones appear grossly and are they radio-opaque or translucent?

Answer 14

Can be pure cholesterol -> clear to yellow, rarer

Mixed stones -> >50% cholesterol and bile pigments, most common

They are radiolucent, must be detected with ultrasound

Question 15

What gallbladder pathology is commonly seen with choesterol stones and what is the cause? How does it appear grossly and microscopically?

Answer 15

Cholesterolosis - aggregates of foamy macrophages within the subepithelium of gallbladder. Grossly -> little yellow deposits within the mucosa.

Increased bile cholesterol increases cholesterol absorption by gallbladder mucosa -> accumulate in subepithelium

Question 16

What is the pathogenesis of pigment gallstones?

Answer 16

Increased UNconjugated bilirubin in bile which is not water soluble -> aggregation of calcium salts, mucin, and cholesterol

Question 17

What are the risk factors for pigment gallstones?

Answer 17

1. Chronic hemolysis -> increased biliary excretion of conjugated bilirubin, and a small percentage always becomes unconjugated
2. Biliary tract infections -> microbial deconjugation of bile acids
3. Gallbladder hypomotility -> thickens bile

Question 18

What are the two morphological types of pigment stones? What causes them? Are they radio-opaque or translucent?

Answer 18

Black - occur in chronic hemolysis -> majority are radio-opaque from complexing with calcium. Multiple and smooth.

Brown - occur in biliary tract infections -> soft and soapy, radiotranslucent

Question 19

What are the four F’s of cholelithiasis risk factors?

Answer 19

Female
Fat
Fertile (pregnant)
Forty

Question 20

What are the possible complications of cholelithiasis?

Answer 20

1. *Acute cholecystitis
2. Hydrops of gallbladder due to chronic obstruction
3. Choledocholithiasis -Obstruction of the common bile duct
4. Chronic cholecystitis
5. Gallstone ileus
6. Carcinoma of the gallbladder

Question 21

What are some severe variants of acute cholecystitis? Include also one complication of an ulcer forming during this time.

Answer 21

1. Empyema of gallbladder - bag of pus
2. Gangrene and perforation - if ischemia is very severe, hemorrhagic necrosis of gallbladder wall

Ulceration:
3. Fistula tracts -> ulceration forms in wall which allows attachment to nearby loop of duodenum

Question 22

What are the possible complications of choledocholithiasis?

Answer 22

1. Cholestasis with secondary biliary cirrhosis
2. Ascending cholangitis with possible liver abscess formation
3. Pancreatitis - if stone is wedged right before ampulla of Vater

Question 23

What is a gallstone ileus and how does it occur?

Answer 23

Large stone plugging the lumen of the duodenum
-> occurs due to formation of a fistula tract thru gall bladder, allowing stones to leak into duodenum and obstruct lumen

Question 24

What is the most common type of cholecystitis and its pathogenesis?

Answer 24

Calculous cholecystitis - obstruction of neck of gallbladder via a stone = retention of bile, gallbladder distention, and vascular compression in the wall (venous congestion, causing hemorrhagic infarct overtime)

Question 25

What are the risk factors for the less common type of cholecystitis (acalculous)?

Answer 25

Critically ill patients - occurs without stone, due to hypomotility or hypoperfusion - > Cystic duct obstruction by concentrated bile with excessive reabsorption due to dehydration and hypomotility - > poor vascular perfusion (during shock) - > bacterial infection

Question 26

How will acute cholecystitis appear grossly? Microscopically?

Answer 26

Enlarged, erythematous gallbladder with thick edematous wall due to inflammation / hyperemia. Dull serosal opacities, appearing whitish-yellow (pus), maroonish (blood), and greenish-black (bile) Microscopically - acute inflammatory infitlrate with ulceration and necrosis

Question 27

What are the clinical signs and symptoms of acute cholecystitis?

Answer 27

RUQ pain, fever with increased WBC count w/neutrophilia, nausea / vomiting, loss of appetite (causes gallbladder contraction)

Question 28

What are the potential complications of acute cholecystitis?

Answer 28

1. Gallbladder perforation -> peritonitis. Especially in gangrenous type. 2. Secondary bacterial infection with abscess formation 3. Fistula tracts

Question 29

What are the predisposing factors to chronic cholecystitis, and what are the characteristic microscopic features?

Answer 29

Chronic cholelithiasis and bacterial contamination Chronic inflammation - lymphocytes, macrophages, plasma cells, and fibrosis Rokitansky-Aschoff sinuses - mucosal diverticula seen in gallbladder wall due to contraction against thick gallbladder wall

Question 30

What is the most well-described variant of chronic cholecystitis, how should it be treated, and why?

Answer 30

Porcelain gallbladder - shrunken gallbladder with marked dystrophic calcification seen on Xray -> treatment is cholecystectomy to prevent transformation to adenocarcinoma of gallbladder

Question 31

What is it called when you have chronic cholecystitis marked by a small, chronically obstructed gallbladder filled with clear, mucinous secretions?

Answer 31

Hydrops of the gallbladder

Question 32

What are the clinical features of chronic cholecystitis?

Answer 32

Biliary colic-like symptoms - nausea/vomiting and dull RUQ exacerbated by eating fatty foods (stimulates CCK-mediated gallbladder contraction)

Question 33

Who tends to get carcinoma of the gallbladder? What IS it?

Answer 33

Classically, elderly women with a history of cholelithiasis, especially causing chronic cholecystitis with porcelain gallbladder It is cancer of the glandular epithelium of the gallbladder wall

Question 34

How is diagnosis of gallbladder carcinoma usually made and what's the prognosis?

Answer 34

Made incidentally after cholecystectomy (think of Bosch's story) with poorly delineated mass seen in gallbladder Prognosis is poor as metastasis to liver / adjacent structures happens before presentation

Question 35

What is a Klatskin tumor and what are its risk factors?

Answer 35

A type of carcinoma of the extrahepatic bile ducts, which is located at the origin of the common hepatic duct (before it merges with cystic duct) Risk factors for all adenocarcinomas of extrahepatic bile ducts: Older males, biliary tract infections, PSC, choledochal cysts

Question 36

What is released from the duct cells and acinar cells in the pancreas?

Answer 36

Duct cells -> bicarbonate Serous acini -> zymogen granules with digestive proteins

Question 37

What stimulates the release of the contents from duct cells and acinar cells?

Answer 37

Vagus nerve - acetylcholine Duct cells are stimulated by -> secretin, produced by S cells in duodenum Acinar cells are stimulated by -> cholecystokinin, released by I cells

Question 38

What enzymes are present in the zymogen granules of the acinar cells, and what activates the digestion cascade?

Answer 38

Trypsin, chymotrypsin, elastase, amylase, lipase, phospholipase Trypsin activated by membrane-bound enterokinase in the duodenum

Question 39

What do the two buds of the pancreas form?

Answer 39

Ventral bud - forms off of the hepatic diverticulum (off the biliary tree endoderm which will induce formation of liver) -> will form the caudal portion of the head of the pancreas as well as the uncinate process Dorsal bud - comes off of duodenum dorsally - forms the rostral portion of head of pancreas plus budy and tail

Question 40

How does the pancreatic / bile duct system develop in most people / why?

Answer 40

The dorsal pancreatic bud communicates with the duodenum via the accessory pancreatic duct (of Santorini). This will merge with the duct in the ventral pancreatic bud in most people. The large portion of the pancreas drains into the main pancreatic duct which connects with the main duct from the ventral bud, merging both the common bile duct and pancreatic duct just before emptying into the duodenum at the ampulla of Vater.

Question 41

What occurs if the ventral pancreatic bud doesn't know how to rotate in embryonic development?

Answer 41

Annular pancreas - It will rotate in both directions, around the duodenum Risk is duodenal obstruction

Question 42

What is pancreas divisum and what is the risk?

Answer 42

Incomplete fusion of the dorsal and ventral pancreatic buds, including incomplete ductal fusion - > since accessory duct of dorsal bud will be smaller than main duct, some secretions will be trapped in body of pancreas - > risk of recurrent pancreatitis

Question 43

What is it called when you have histologically normal pancreatic tissue outside of the pancreas? Where does it usually appear?

Answer 43

Ectopic pancreas, a type of choristoma Appears on wall of stomach or small intestine

Question 44

What are the causes of acute pancreatitis?

Answer 44

I GET SMASHED Idiopathic, Ischemia **Gallstones **Ethanol Trauma - i.e. MVA in children, stabbings ``` Steroids Mumps infection Autoimmune disease Scorpion stings Hypercalcemia / hypertriglyceridemia (>1000 mg/dL) ERCP - to clear stone Drugs ```

Question 45

Why do mumps, hypercalcemia, and genetic abnormalities in trypsin cause acute pancreatitis?

Answer 45

Mumps - cytotoxic T cells mediate release of activated enzymes (mumps invades glandular epithelium) Hypercalcemia - calcium is an activator of enzymes Trypsin - can cleave C3 and greatly worsen enzyme activation if constitutively active

Question 46

What is the pathogenesis of acute pancreatitis?

Answer 46

Inappropriately activated acinar enzymes and indirect activation of clotting and complement pathways via: 1. Duct obstruction (i.e. stones / alcohol) -> increased intraductal pressure 2. Acinar cell injury - > release and activation of enzymes

Question 47

How is alcohol thought to cause pancreatitis?

Answer 47

Directly injures acinar cells Causes thick, viscous excretions blocking the ducts Messes up intracellular transport of pancreatic proenzymes -> causes fusion with lysosome and activation within the cell

Question 48

In what patients will ductal obstruction cause pancreatitis? What damage does this cause?

Answer 48

Patients who have a normal main pancreatic duct merging with common bile duct before emptying into ampulla of Vater -> both can be blocked by a single stone Causes fat necrosis with secondary acute inflammation with edema, compromising local blood flow

Question 49

How does acute pancreatitis appear grossly?

Answer 49

Scattered chalky white foci within pancreatic and abdominal fat -> fat necrosis with saponification Can be liquified tissue and hemorrhage if very severe

Question 50

How does acute pancreatitis appear microscopically?

Answer 50

Edema and acute inflammation, with proteolytic digestion of things - > fat necrosis (appears like coagulative necrosis of adipocytes with a slightly blue hue due to saponification of fatty acids via calcium deposition) - > hemorrhage due to proteolytic destruction of blood vessels

Question 51

What are the clinical manifestions of acute pancreatitis?

Answer 51

Acute abdominal pain, often radiating to the back Increased serum amylase or lipase (more specific marker)

Question 52

What are the systemic complications of acute pancreatitis and why?

Answer 52

DIC - circulating amylase and lipase damage endothelium ARDS - damage to pulmonary membranes Shock - bleeding and loss of edema fluid -> progress to renal failure Metabolic effects Extrapancreatic fat necrosis - circulating lipases

Question 53

What are the metabolic effects seen in acute pancreatitis and why?

Answer 53

Hypocalcemia - due to saponification of fat necrosis Hypoalbuminemia - loss of fluid Hyperglycemia - failure of islets to produce insulin Acidosis - due to shock with lactic acid production

Question 54

What are the localized complications of acute pancreatitis?

Answer 54

Pseudocyst - necrotic cyst lined by fibrotic granulation tissue, not epithelium Abscess - infected pseudocyst Biliary obstruction / jaundice

Question 55

What is chronic pancreatitis and what are the causes?

Answer 55

Relapsing acute pancreatitis -> progressive injury Often idiopathic, but: Adults - alcoholism Children - Cystic fibrosis May also be autoimmune, secondary to hyperlipidemia/hypercalcemia, or due to pancreas divisum

Question 56

How does chronic pancreatitis appear grossly and what is the general underlying process which causes it?

Answer 56

Grossly - Sclerotic gland with calcifications and pseudocysts Caused by ductal obstruction leading to necrosis which slowly progresses to fibrosis

Question 57

How does chronic pancreatitis appear microscopically?

Answer 57

Fibrosis with acinar atrophy, relative sparing of islets -> acini go first because of spilling of proteolytic enzymes Proteinaceous material within dilated ducts, which often have squamous metaplasia due to epithelial alterations Chronic inflammatory infiltrate

Question 58

What are the clinical manifestations of chronic pancreatitis?

Answer 58

Abdominal pain, fat malabsorption, followed later by diabetes Jaundice and duodenal obstruction may occur with chronic fibrosis / scarring

Question 59

What diseases cause true cysts in the pancreas?

Answer 59

ADPKD, von Hippel-Lindau | -> cysts are lined with epithelium (vs pseudocysts)

Question 60

What cells of the pancreas does pancreatic adenocarcinoma arise from? How is this differentiated from chronic pancreatitis?

Answer 60

Ductal cells of pancreas (acinar is insanely rare) -> differentiated from chronic pancreatitis by loss of normal lobular architecture in adenocarcinoma

Question 61

What are the major risk factors for pancreatic adenocarcinoma?

Answer 61

Smoking and chronic pancreatitis Diabetes, being black, male, and old age also play a role

Question 62

Does pancreatic cancer have a normal progression? Where does it tend to arise?

Answer 62

Yes -> sequential genetic and epigenetic alterations including early KRAS mutations to late p53 mutations Tends to arise in head of pancreas more often (where the ducts are most concentrated)

Question 63

What are the gross and microscopic appearance of pancreatic adenocarcinoma?

Answer 63

Gross - infiltrative, firm, tan tissue due to desmoplasia Microscopic - loss of normal lobular architecture with haphazard, irregularly glandular structure, desmoplasia, and **perineural invasion** -> can be painful

Question 64

Where does pancreatic adenocarcinoma spread locally if in the head vs the body/tail? Distant metastases?

Answer 64

Head -> duodenum and common bile duct Body/tail -> vertebrae, retroperitoneum Distant metastases -> regional lymph nodes, liver

Question 65

What are the clinical manifestations of pancreatic adenocarcinoma?

Answer 65

Nonspecific - weight loss, nausea/vomiting, pain Obstructive jaundice -> especially if in pancreatic head Trousseau syndrome -> best characterized in this adenocarcinoma

Question 66

What is Trousseau syndrome?

Answer 66

Migratory thrombophlebitis - redness and tenderness on palpation of extremities -> thrombosis of arms and legs due to hypercoagulability. The adenocarcinoma produces a procoagulant (probs mucin)