WEEK 2: Biliary and pancreatic pathology

Question 1

Describe the anatomy of the biliary system.

Answer 1

Bile is produced from the liver and stored in the gall bladder.

Gall bladder&raquo_space;> Cystic duct + Common hepatic duct&raquo_space;> Common bile duct + Major pancreatic duct (Duct of Wirsung) joins to form the ampulla of Vater (Hepatopancreatic ampulla) which opens into the first part of the duodenum via Major papillae controlled by the sphincter of Oddi.

Question 2

State the 4 main components of the biliary system.

Answer 2

Gallbladder
Cystic duct
Hepatic ducts
Common bile duct

Question 3

Describe anatomy of the gall bladder.

Surface anatomy quadrant?
Function of the gall bladder?

Answer 3

1. The gallbladder is a gastrointestinal organ located within the right hypochondrial region of the abdomen. This intraperitoneal, pear-shaped sac lies within a fossa formed between the inferior aspects of the right and quadrate lobes of the liver.
2. The primary function of the gallbladder is to concentrate and store bile which is produced by the liver.

As part of the gustatory response, the stored bile is then released from the gallbladder in response to cholecystokinin.

Question 4

Discuss anatomical structure of the gall bladder.

Answer 4

The gallbladder has a storage capacity of 30-50ml and, in life, lies anterior to the first part of the duodenum. It is typically divided into three parts:

Fundus – the rounded, distal portion of the gallbladder. It projects into the inferior surface of the liver in the mid-clavicular line.

Body – the largest part of the gallbladder. It lies adjacent to the posteroinferior aspect of the liver, transverse colon and superior part of the duodenum.

Neck – the gallbladder tapers to become continuous with the cystic duct, leading into the biliary tree.

The neck contains a mucosal fold, known as Hartmann’s Pouch. This is a common location for gallstones to become lodged, causing cholestasis.

Question 5

What is The Biliary Tree?

Answer 5

The biliary tree is a series of gastrointestinal ducts allowing newly synthesised bile from the liver to be concentrated and stored in the gallbladder (prior to release into the duodenum).

Question 6

Describe the biliary tree.

Answer 6

Hepatocytes via canaliculi&raquo_space;> Intralobular ducts&raquo_space;> Collecting ducts&raquo_space;> Right and left hepatic ducts&raquo_space;> Common hepatic ducts&raquo_space;> Common bile duct + Major pancreatic duct (Duct of Wirsung) joins to form the ampulla of Vater (Hepatopancreatic ampulla) which opens into the first part of the duodenum via Major papillae controlled by the sphincter of Oddi.

1. Bile is initially secreted from hepatocytes and drains from both lobes of the liver via canaliculi, intralobular ducts and collecting ducts into the left and right hepatic ducts.
2. These ducts amalgamate to form the common hepatic duct, which runs alongside the hepatic vein.
3. As the common hepatic duct descends, it is joined by the cystic duct – which allows bile to flow in and out of the gallbladder for storage and release. At this point, the common hepatic duct and cystic duct combine to form the common bile duct.
4. The common bile duct descends and passes posteriorly to the first part of the duodenum and head of the pancreas. Here, it is joined by the main pancreatic duct, forming the hepatopancreatic ampulla (commonly known as the ampulla of Vater) – which then empties into the duodenum via the major duodenal papilla. This papilla is regulated by a muscular valve, the sphincter of Oddi.

Question 7

Describe vasculature to the gall bladder.

Answer 7

1. Celiac trunk
2. Common hepatic artery
3. Proper hepatic artery
4. Right hepatic artery
5. Cystic artery

NOTE:
Proper Hepatic Artery: The proper hepatic artery is a continuation of the common hepatic artery within the liver. It further divides into branches that supply blood to the liver lobes. Along its course, the proper hepatic artery gives off the cystic artery, which is crucial for supplying blood to the gallbladder.

Right Hepatic Artery: The right hepatic artery is a branch of the proper hepatic artery. It travels towards the right lobe of the liver, providing it with oxygenated blood. In some cases, the cystic artery may arise directly from the right hepatic artery instead of the proper hepatic artery.

Question 8

Discuss innervation and lymph drainage of the gall bladder.

Answer 8

1. Innervation
   The gallbladder receives parasympathetic, sympathetic and sensory innervation.

*The coeliac plexus carries sympathetic and sensory fibers, while the Vagus nerve delivers parasympathetic innervation.

*Parasympathetic stimulation produces contraction of the gallbladder, and the secretion of bile into the cystic duct due to relaxation of the sphincter of Oddi. The majority of this response, however, is mediated by circulating cholecystokinin as part of the gustatory response.

2. Lymph Drainage
   Lymph from the gallbladder drains into the cystic lymph nodes, situated at the gallbladder neck.

The cystic nodes then empty into the hepatic lymph nodes, and ultimately, the coeliac lymph nodes.

Question 9

1. State the components of gall stones.
2. What is the medical term for gall stones?

Answer 9

Clinical Relevance: Gallstones
Cholelithiasis, commonly known as gallstones, are small lumps of cholesterol, bile salts or a mixture of the two, which may form within the gallbladder. They are relatively common and often asymptomatic.

However, they may be associated with pain, jaundice and systemic upset (depending on the location of the gallstone, and the presence or absence of associated infection or inflammation).

Question 10

Define the following terms.

1. Cholelithiasis
2. Cholecystitis
3. Choledocholithiasis
4. Cholangitis
5. Cholecystectomy

Answer 10

Different terminologies are applied to distinguish between these pathologies:

1. Cholelithiasis – uncomplicated gallstones
   Biliary colic – typically right upper quadrant pain following a fatty meal as gallstones obstruct the cystic duct during contraction of the gallbladder. Not associated with systemic upset
2. Cholecystitis – inflammation of the gallbladder. Pain is often associated with nausea, vomiting or fever
3. Choledocholithiasis – gallstone within the common bile duct. Often causes deranged liver function tests.
4. Cholangitis – infection of the common bile duct often secondary to choledocholithiasis. Typically presents with right upper quadrant pain, fever and jaundice (Charcot’s Triad)
5. Once diagnosed, most symptomatic patients have surgical removal of the gallbladder (cholecystectomy); which is now often performed via laparoscopic (keyhole) surgery during the acute phase or once recovery has taken place (often at 6 weeks). In the interim, patients are prescribed analgesia and antibiotics when required.

Question 11

Define Charcot’s triad.

Discuss the 3 components.

Answer 11

Charcot’s triad is a classic clinical presentation associated with acute cholangitis; a serious condition characterized by inflammation of the bile ducts typically due to obstruction.

Typically presents with right upper quadrant pain, fever and jaundice (Charcot’s Triad)

1. Fever: Patients with acute cholangitis often present with a fever, which is usually high-grade and may be accompanied by chills and rigors. The fever is a response to the inflammation and infection in the biliary system.
2. Jaundice: Jaundice refers to the yellowing of the skin and sclerae (the whites of the eyes) due to the buildup of bilirubin in the bloodstream. In acute cholangitis, jaundice occurs because the inflamed or obstructed bile ducts prevent bile from flowing normally into the intestines, leading to its accumulation in the bloodstream.
3. Right Upper Quadrant Abdominal Pain: Patients often experience pain or discomfort in the right upper quadrant of the abdomen, where the gallbladder and liver are located. This pain can vary in intensity and may be described as sharp, cramping, or constant. The pain typically arises due to distension of the bile ducts and inflammation of the liver and surrounding tissues.

Question 12

State the 4 main Common pathology of the biliary system.

Answer 12

1. Gallstone disease (CHOLELITHIASIS)
2. Cholecystitis>(CHOLECYSTITIS)
3. Carcinoma of the gallbladder> (CHOLANGIOCARCINOMA)
4. Biliary Cirrhosis

Question 13

Gallstones

Q: How do gallstones develop?

Answer 13

1. *Gallstones occur when bile forms solid particles (stones) in the gallbladder.
   *The stones form when the amount of cholesterol or bilirubin in the bile is high.
   *Other substances in the bile may promote the formation of stones.
   *Gallstones form when bile stored in the gallbladder hardens (solidify) into pieces of stone-like material.
   *Bile is a bitter yellow or green fluid secreted by liver hepatocytes
   *Then stored in the gallbladder and used in the digestion of fats

NOTE: Stone formation inside the gallbladder and kidney are serious and painful diseases

Question 14

Gallbladder contraction pushes bile into the common bile duct which carries it to the small intestine, where it carries out fat digestion role.

State the components of bile.

Answer 14

The composition of bile includes water, cholesterol, fats, bile salts, proteins, and bilirubin.

Generally, if there is too much cholesterol then it will form into crystals that eventually grow into stones.

In conditions, when bilirubin is too high then this will also contribute to stone formation.

Question 15

State factors that affect the composition of gallstones.

Answer 15

The composition of gallstones is affected by such factors as

Age, diet, geographical region, obesity, weight loss, and ethnicity among others

Question 16

Gallstones can be broadly grouped based on their major chemical compositions.

State the 3 main types of gallstones.

Answer 16

They can be divided into the following three main types:
(i) cholesterol stones
(ii) pigment stones
(iii) mixed stones

Question 17

Discuss cholesterol gallstones.

Answer 17

1. These are the most common type of gallstones made of cholesterol.
2. Cholesterol is one of the substances secreted by the liver cells into bile. In this process, the liver eliminates excess cholesterol from the body.
3. Fatty cholesterol should dissolve in bile so that it can be carried through the ducts.
4. If the liver secretes too much cholesterol (greater than the amount of bile acids and lecithin), some of the cholesterol remains undissolved.
5. Similarly, if the liver does not secrete enough bile acids and lecithin, some of the cholesterol also does not dissolve.

Thus, in both cases, the undissolved cholesterol sticks together and forms particles of cholesterol that grow in size and eventually form larger gallstones

Question 18

Discuss Pigment gallstones.

Answer 18

These are defined as any brown to black stones and composed of calcium salts, phosphate, carbonate, and other types of anions.

Pigment is a waste product formed from hemoglobin is a protein that carries oxygen throughout the body in red blood cells (RBCs).

Old RBCs targeted for destruction is changed into bilirubin and released into the blood. Bilirubin is removed from the blood by the liver.

The liver modifies the bilirubin and secretes the modified bilirubin into bile. If there is too much bilirubin in bile, the bilirubin combines with other chemical constituents within bile to form pigments of brown color.

Question 19

Discuss Mixed gallstones.

Answer 19

These types of stones are a mixture of cholesterol and pigment stones of varying proportions of cholesterol and bilirubinate salts.

They are also composed of other components such as calcium carbonate, calcium phosphate, bilirubin, calcium bilirubinate, calcium palmitate, and calcium stearate.

Due to their calcium content, they are often radiographically visible.

Question 20

Discuss the factors affecting the pathogenesis of cholesterol gallstones.

Answer 20

1. Age
2. Obesity
3. Female gender
4. Female hormones
5. Oral contraceptives
6. Pregnancy
7. Weight reduction
8. Diet
9. Diabetes and liver diseases.
10. Reduced gall bladder motility
11. Prolonged fasting
12. Reduced bile secretion
13. Bile salt diarrhea

Question 21

Gallstones can block flow of bile if they move from the gallbladder and lodge in the ducts that carry bile from the liver to the small intestine.

Outline all the ducts that can be obstructed.

Answer 21

1. Gallstones can block flow of bile if they move from the gallbladder and lodge in the ducts that carry bile from the liver to the small intestine.

The obstructed ducts
(i) hepatic ducts
(ii) cystic duct
(iii) common bile duct

Bile trapped in these ducts can cause inflammation in the gallbladder, the ducts, and in the liver.

Question 22

Q: What other ducts open into the common bile duct, and what do they carry?

Q: What can happen if gallstones pass through the common bile duct, and what is the resulting condition?

Q: What are some warning signs of gallstone pancreatitis, and what can happen if it is left untreated?

Answer 22

A: Other ducts, including the pancreatic duct, open into the common bile duct. The pancreatic duct carries digestive enzymes out of the pancreas.

A: Most of the time, when gallstones pass through the common bile duct, they can cause inflammation in the pancreas, leading to a condition called gallstone pancreatitis. This condition is extremely painful and critically dangerous.

A: Warning signs of gallstone pancreatitis include fever, jaundice, and unrelieved pain. If left untreated, this condition can lead to death.

Question 23

Outline Complications of Gallstones

Answer 23

1. Empyema of the gallbladder: Gallbladder with obstructed cystic duct may be distended with pus (purulent exudate).
2. Gangrenous cholecystitis: Gallbladder transformed into a green-black necrotic organ.
3. Acute gaseous or emphysematous cholecystitis: It is due to invasion of gas-formingorganisms (such as clostridia and coliforms).
4. Perforation of the gallbladder: It is due to secondary bacterial infection.
5. Bile peritonitis: It may result from the discharge of bile from the distended gallbladder into the peritoneal cavity.
6. Pericholecystic abscess, abscesses in the liver or abdominal cavity.
7. Fistula into the intestine or duodenum: Perforations may lead to fistula formation with neighboring organs such as small or large intestine creating a cholecystenteric fistula.
8. Gallstone ileus: Through the fistula, large gallstone can pass into the bowel result in gallstone ileus or intestinal obstruction

Question 24

Q: What is cholecystitis?

Q: What are the possible forms of cholecystitis?

Answer 24

A: Cholecystitis is inflammation of the gallbladder.

A: Cholecystitis may manifest as acute, chronic, or acute superimposed on chronic inflammation.

Question 25

Q: What is the primary association of cholecystitis?

Q: What is a significant indication for abdominal surgery?

Q: How does the occurrence of cholecystitis relate to that of gallstones?

Answer 25

A: Cholecystitis always occurs in association with gallstones.

A: Cholecystitis is one of the most common indications for abdominal surgery.

A: The occurrence of cholecystitis closely parallels that of gallstones.

NOTE:
So, when someone says that the occurrence of cholecystitis closely parallels that of gallstones, they mean that when you have gallstones, there’s a good chance you might also get cholecystitis.

It’s like saying if you have a bunch of pebbles in your gallbladder, there’s a higher chance it might get swollen and sore too.

They kind of go hand in hand.

Question 26

Define Acute Calculous Cholecystitis.

Answer 26

Acute calculous cholecystitis is a sudden and severe inflammation of the gallbladder caused by the presence of gallstones.

Question 27

Q: What is the primary cause of acute calculous cholecystitis in about 90% of cases?

Q: What are the three factors that can bring about inflammation of the gallbladder?

Answer 27

In about 90% of cases as a complication due to obstruction of the neck or cystic duct by gallstones.

The inflammation of gallbladder may be brought out by three factors namely,
-Chemical inflammation
-Mechanical inflammation
-Bacterial inflammation

Question 28

Discuss chemical inflammation of the gall bladder.

Answer 28

Inflammation of the obstructed gallbladder may be due to chemical irritation.

1. Production of lysolecithin: The phospholipase from the epithelium gallbladder may act on lecithin present in bile and release toxic lysolecithin can cause chemical inflammation.
2. Decreased glycoprotein: Normally, glycoprotein produced by gallbladder mucosa has protective role. Its decreased production leads to the direct mucosal cell damage.
3. Supersaturation of bile with cholesterol: It may cause toxic damage to the epithelium.
4. Prostaglandins: These are released within the wall of the distended gallbladder and contribute to inflammation of mucosa and wall of the gallbladder.

Question 29

Discuss Mechanical inflammation of the gall bladder.

Answer 29

Obstruction of the cystic duct increases intraluminal pressure and distention of the gallbladder

*Leads to disturbance of motility (dysmotility) of the gallbladder.

*Results in obstruction of venous flow and ischemia of the gallbladder mucosa and wall.

Question 30

Discuss Bacterial inflammation of the gall bladder.

Answer 30

*It may play a role in acute cholecystitis

*But usually, bacterial invasion is a secondary event.

*The most frequent organisms include Escherichia coli, Klebsiella species, Streptococcus species, and Clostridium species.

Question 31

Define Acute Acalculous Cholecystitis.

Outline the risk factors for Acute Acalculous Cholecystitis.

Answer 31

In summary, acute acalculous cholecystitis is a sudden and severe inflammation of the gallbladder that occurs without the presence of gallstones.

Risk factors: include
– Major trauma and burns
– Sepsis with hypotension and multisystem organ failure
– Immunosuppression
– Diabetes mellitus
– Nonbiliary major surgical operations
– Systemic infections (tuberculosis, syphilis, actinomycosis, etc.).

Question 32

What is the main pathogenic event in acute acalculous cholecystitis?

State the contributing factors to the main event.

Answer 32

Ischemic injury: It is the main pathogenic event in acute acalculous cholecystitis.

Contributing factors:

These include inflammation and edema of the wall compromising blood flow
*Dehydration
*Gallbladder stasis
*Accumulation of microcrystals of cholesterol (biliary sludge).

Question 33

Define BILIARY CIRRHOSIS.

Answer 33

In biliary cirrhosis, the progressive damage and inflammation of the small bile ducts lead to a buildup of bile in the liver, causing damage to liver cells and eventually leading to cirrhosis.

Question 34

Discuss the 2 classifications of biliary cirrhosis.

Answer 34

Classification

1. Secondary biliary cirrhosis: It develops due to prolonged obstruction of the extrahepatic biliary tree.
2. Primary biliary cirrhosis: It is a probably an autoimmune disorder of the intrahepatic biliary tree.

Question 35

Define intrahepatic biliary tree.

Answer 35

The intrahepatic biliary tree refers to the bile ducts located within the liver.

These ducts start as tiny canals called bile canaliculi, which collect bile produced by liver cells (hepatocytes). The bile canaliculi merge to form larger ducts known as intrahepatic bile ductules or canals of Hering.

These ductules gradually join together to form larger intrahepatic bile ducts, which ultimately coalesce to form the right and left hepatic ducts.

The right and left hepatic ducts exit the liver and join to form the common hepatic duct, which carries bile out of the liver.

Question 36

Discuss extrahepatic biliary tree.

Answer 36

Extrahepatic Biliary Tree:

The extrahepatic biliary tree refers to the bile ducts located outside the liver.

It includes the common hepatic duct, which exits the liver and receives bile from the intrahepatic ducts.

Near the junction of the common hepatic duct with the cystic duct (which comes from the gallbladder), there is a dilation called the ampulla of Vater, where the common hepatic duct joins with the pancreatic duct.

The combined duct formed by the union of the common hepatic duct and the cystic duct is called the common bile duct.

The common bile duct then transports bile from the liver and gallbladder to the duodenum, the first part of the small intestine, where bile aids in the digestion of fats.

Question 37

Secondary Biliary Cirrhosis

1. Definition
2. Etiology in:
   i) Adults
   ii) Children

Answer 37

Definition: Cirrhosis developing secondary to prolonged obstruction of the extrahepatic biliary tree.

Etiology
*In adults:
-Extrahepatic cholelithiasis (gallstones)
-Malignant tumors of the biliary tree or head of the pancreas
-Strictures due to previous surgical procedures.

*In children:
-Biliary atresia
-Cystic fibrosis
-Choledochal cysts (a cystic anomaly of the extrahepatic biliary tree)
-Paucity of bile duct syndromes (insufficient intrahepatic bile ducts).

Question 38

Primary Biliary Cirrhosis (PBC)
1. Definition
2. Epidemiology
-Gender?
-Age?

Answer 38

Definition: PBC is a progressive chronic autoimmune liver disease characterized by nonsuppurative, inflammatory destruction of intrahepatic bile ducts (cholangitis).

*Gender: It usually affects middle-aged women, with a female to male ratio of more than 6:1.
*Age: It may occur between the 20 to 80 years of age, with peak incidence between 40 to 50 years of age.

Question 39

Discuss the Etiology and Pathogenesis of Primary Biliary Cirrhosis.

Answer 39

The exact cause of PBC is not known but immune mechanisms are clearly involved in its pathogenesis.

*Genetic and environmental factors play a role in the pathogenesis of the PBC.

Mechanism of intrahepatic bile destruction:
Many mechanisms have been proposed and these include:
– Aberrant expression of MHC class II molecules on bile duct epithelial cells
– Accumulation of autoreactive T cells around bile ducts
– Antimitochondrial antibodies to hepatocytes or other antibodies against cellular components (nucleus and cytoplasmic proteins)

– The characteristic autoantibody detected in PBC is antimitochondrial antibodies.
They target the E2 component of the pyruvate dehydrogenase complex (PDC-E2).

PDC-E2–specific T cells are also detected in these patients, supporting immune-mediated pathogenesis.

Consequences of bile duct destruction leads to impaired secretion of bile, cholestasis and inflammatory reaction in the portal tract.

This results in hepatic damage, fibrosis and ends up in cirrhosis and liver failure.

Cirrhosis develops several years after the onset of disease
Most patients are diagnosed at a pre-cirrhotic stage.

Question 40

Discuss the Morphology of Primary Biliary Cirrhosis.

Answer 40

Gross
Early-stage and late stages, end-stage

1.Weight increase (because of inflammation).
-Bile stasis, stains the liver green.

2. Liver weight is decreased.
   *The nodules are less than 3 mm in diameter (micro-nodular cirrhosis)
3. Later may show macro-nodules.

Question 41

Discuss microscopy of primary biliary cirrhosis.

Answer 41

Inflammation and injury to bile duct epithelial cells.

-Dense collection of lymphocytes, macrophages and plasma cells.

-Lymphocytes may form lymphoid follicles and few with germinal centers.

-Noncaseating epithelioid granulomas may be seen in the portal tracts.

-Proliferation of bile ductules and fibrosis

-Necrosis of the adjacent periportal hepatic parenchyma.

Question 42

Discuss laboratory findings in Primary biliary Cirrhosis.

Answer 42

1. Serum alkaline phosphatase (markers of cholestasis),
2. Glutamyl transferase and cholesterol are raised. 3. Hyperbilirubinemia occurs in late stages.
3. Antimitochondrial antibodies are characteristic and are essential for the diagnosis of PBC.

Question 43

Outline Clinical Features of primary biliary cirrhosis.

Answer 43

Insidious in onset.
Commonly present with pruritus, fatigue, and abdominal discomfort.

2. Skin pigmentation (due to melanin deposition), eyelid xanthelasmas (cholesterol-rich macrophages), steatorrhea, osteomalacia and/or osteoporosis (due to malabsorption of vitamin D).
3. Cirrhotic stage: Jaundice, hepatic decompensation, portal hypertension and variceal bleeding develop.

Question 44

State the prognosis of Primary Biliary Cirrhosis.

Treatment?

Answer 44

Increased risk of hepatocellular carcinomas.

Cause of death: Liver failure, massive hemorrhage from esophageal varices and intercurrent infection.

Treatment: Liver transplantation.

Question 45

What is CHOLANGIOCARCINOMA (CCA)?

Site?

Answer 45

Cholangiocarcinoma (CCA), also known as bile duct cancer, is a type of cancer that originates in the cells lining the bile ducts.

It is the second most common hepatic malignant tumor of liver.

Site: Cholangiocarcinoma can occur in any part of the bile ducts, which include the intrahepatic (within the liver), perihilar (at the junction where the right and left hepatic ducts merge to form the common hepatic duct), and distal (outside the liver, closer to the small intestine) segments.

The location of the tumor can affect treatment options and prognosis.

Question 46

Outline Risk Factors for CHOLANGIOCARCINOMA (CCA)

Answer 46

1. Primary Sclerosing Cholangitis (PSC): PSC is a chronic liver disease characterized by inflammation and scarring of the bile ducts, which can increase the risk of cholangiocarcinoma.
2. Congenital Fibro-polycystic Diseases: Conditions such as Caroli disease and choledochal cysts are congenital (present from birth) abnormalities of the bile ducts that can predispose individuals to cholangiocarcinoma.
3. Hepatitis C Virus (HCV) Infection: Chronic infection with hepatitis C virus (HCV) is associated with an increased risk of developing cholangiocarcinoma.
4. Previous Exposure to Torotrast: Torotrast, a contrast agent formerly used in radiography of the biliary tract, has been linked to an elevated risk of cholangiocarcinoma in individuals who were exposed to it.
5. Chronic Infection by Opisthorchis sinensis: Opisthorchis sinensis, a liver fluke found in certain regions of Asia, can infect the bile ducts and cause chronic inflammation, increasing the risk of cholangiocarcinoma.

Question 47

Discuss Classification CHOLANGIOCARCINOMA (CCA).

Answer 47

CCA is classified according to their location.
1. Intrahepatic (about 10%)

2. Extrahepatic forms (about 80–90%)
   – Perihilar tumors (50–60% of all CCAs):
   These are known as Klatskin tumors and are located at the junction of the right and left hepatic ducts forming the common hepatic duct.
3. Distal bile duct (bile duct carcinomas) tumors (20–30%): They arise near the ampulla of Vater.
   They also include periampullary carcinomas

They consist of adenocarcinoma of the duodenal mucosa and pancreatic carcinoma.

Question 48

Discuss Morphology CHOLANGIOCARCINOMA (CCA).

1. Gross
2. Microscopy

Answer 48

Gross
*Extrahepatic CCAs: These are usually small lesions and appear as firm, gray nodules within the bile duct wall.
*Intrahepatic CCAs: They develop in the intrahepatic portal tract.
Microscopy

*Adenocarcinomas: Well-differentiated adenocarcinomas consist of well-defined glandular and tubular structures lined by cuboidal to low columnar epithelial cells.
*Marked desmoplasia: It is characterized by dense collagenous stroma separating the glandular structures.

NOTE: Adenocarcinoma is a type of cancerous tumor that can occur in several parts of the body. It is defined as neoplasia of epithelial tissue that has glandular origin, glandular characteristics, or both.

Question 49

The pancreas is really two organs packaged into one organ.

Q: How is the pancreas anatomically divided, and what are its main functions?

Q: What are the main disorders associated with the endocrine portion of the pancreas?

Answer 49

1. The exocrine portion that makes up the bulk of this organ is a major source of enzymes that are essential for digestion.
2. The endocrine portion constitutes only 1% to 2% of the pancreas and is composed of the islets of Langerhans; these cells secrete insulin, glucagon, and somatostatin.

The most significant disorders of the endocrine pancreas are diabetes mellitus and neoplasms.

*Diabetes mellitus is characterized by impaired insulin production or function, leading to abnormal blood sugar levels.
*Neoplasms refer to abnormal growths or tumors, which can be benign or malignant, arising from the cells of the endocrine pancreas.

Question 50

Define CONGENITAL ANOMALIES.

Discuss the 5 congenital anomalies of the pancreas.

Answer 50

Congenital anomalies, also known as birth defects or congenital disorders, are structural or functional abnormalities present at birth.

1. Agenesis: Agenesis refers to the absence or underdevelopment of an organ or tissue. In the context of the pancreas, pancreatic agenesis refers to the complete absence of the pancreas or a significant portion of it. This condition can lead to serious complications and typically requires medical intervention.
2. Pancreas Divisum: Pancreas divisum is a congenital anomaly where the pancreas fails to fuse properly during embryonic development.

This results in the pancreatic ducts not joining together as they normally would. Pancreas divisum can lead to recurrent pancreatitis (inflammation of the pancreas) due to impaired drainage of pancreatic secretions.

3. Annular Pancreas: Annular pancreas is a rare congenital anomaly where a band of pancreatic tissue surrounds the duodenum, the first part of the small intestine. This can cause narrowing or obstruction of the duodenum, leading to symptoms such as vomiting, abdominal pain, and intestinal blockage.
4. Ectopic Pancreas: Ectopic pancreas, also known as pancreatic heterotopia, refers to pancreatic tissue that is located in abnormal locations outside of the normal pancreas.

This tissue can be found anywhere along the gastrointestinal tract, most commonly in the stomach or small intestine.

Ectopic pancreas typically does not cause symptoms but can occasionally lead to complications such as inflammation or obstruction.

5. Congenital Cysts: Congenital cysts of the pancreas are fluid-filled sacs or pouches that develop during fetal development or shortly after birth.

These cysts may be solitary or multiple and can vary in size. Some congenital cysts are asymptomatic and may be discovered incidentally, while others can cause symptoms such as abdominal pain, jaundice, or complications such as infection or rupture.

Question 51

Define pancreatitis.

Discuss its classification.

Answer 51

Inflammation of the pancreas.

Inflammatory disorders of the pancreas are divided into acute and chronic forms.

*In acute pancreatitis, function can return to normal if the underlying cause of inflammation is removed.

*By contrast, chronic pancreatitis causes irreversible destruction of exocrine pancreas.

Question 52

Discuss acute pancreatitis.

Answer 52

1. The impaction of gallstones within the common bile duct

Results into impeding the flow of pancreatic enzymes through the ampulla of Vater (“gallstone pancreatitis”);

2. This is closely followed by pancreatitis secondary to excessive alcohol intake.

Question 53

Discuss Etiologic Factors in Acute Pancreatitis.

Answer 53

Alcohol
Hyperthyroidism
Hypercalcemia
Hyperlipoproteinemia
Gall stones
Trauma
Iatrogenic injury
Perioperative injury
Shock
Atheroembolism
Vasculitis
Mumps
Coxsackie virus

Question 54

Discuss PANCREATITIS Etiology
1. Alcohol

Answer 54

Various causes of acute pancreatitis are presented in previous table.
Alcoholism and gallstones account for about 80% of the cases.

1. Alcohol: It causes acute pancreatitis usually in individuals who consume large quantities of alcohol.

A polymorphism in the detoxifying enzyme uridine 5-diphosphate (UDP) glucuronyl transferase increases the risk for alcoholic induced pancreatitis.

The male to-female ratio is 6: 1.

2. Gallstones: It is responsible for acute pancreatitis in about 30% to 60% of cases.

The frequency of acute pancreatitis is inversely proportional to the size of gallstones. The male to-female ratio is 1: 3

3. Genetic factors: No cause is identified in about 10% to 20% of patients and are termedidiopathic.

Some of these may have a genetic basis. Tree susceptibility genes have beenidentified:

• Mutation in cationic trypsinogen (PRSS1) gene: It is the most common genetic defect,which results in resistance to trypsin hydrolysis.
• Mutation in the pancreatic trypsin inhibitor gene (serine protease inhibitor, Kazal type 1; SPINK1): SPINK1 gene is essential for the inactivation of trypsin and for the prevention of the autodigestion of the pancreas by activated trypsin.
  Mutation of this gene causes inappropriate activation of trypsin, which in turn can activate otherdigestive proenzymes resulting in pancreatitis.
• Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene.

4. Drugs:
   They cause pancreatitis either by a hypersensitivity reaction or by the generation of toxic metabolite.

Question 55

Discuss Acute Interstitial or Edematous Pancreatitis.

Answer 55

The changes depend on the duration and severity of the process.

Morphologically, acute pancreatitis is classified into 3 types.

1. Acute Interstitial or Edematous Pancreatitis
   * It is a mild and reversible process.
   * Microscopy: It shows interstitial edema and mild infiltration by polymorphonuclear leukocytes.Necrosis or hemorrhage is not seen.

Question 56

Discuss Acute Necrotizing Pancreatitis.

Answer 56

• Pancreas

– It is enlarged and swollen and shows red-black areas of hemorrhage with foci of yellow-white, chalky fat necrosis.

Fat necrosis is due to the action of lipase on triglycerides, which release fatty acids from the fat cells.

– The fatty acids combine with calcium to form insoluble salts (calcium soaps). This process of soap formation is known as saponification.

-The calcification may reduce the level of blood calcium, sometimes to such an extent of causing neuromuscular irritability.

Microscopy

• Edema of interstitial tissue: It due to leakage of fluid from the microvasculature.

. Acute inflammation: Seen in the interstitial tissue.

• Enzymatic fat necrosis. It appears as granular blue with ghost outlines of the necrotic cells.
• Destruction of parenchyma of the pancreas: acinar and ductal tissues as well as the islets of Langerhans are necrotic due to proteolytic digestion.
• Destruction of blood vessels: The activated elastase destroys blood vessel and leads to interstitial hemorrhage.

Question 57

Discuss Acute Hemorrhagic Pancreatitis*

Answer 57

It usually develops in middle age (peak incidence at 60 years) and associated with high morbidity and mortality.

• Gross: It shows extensive necrosis, hemorrhage and fat necrosis within the pancreatic parenchyma.

In severe cases, marked hemorrhage may convert the pancreas into a large retroperitoneal hematoma.

Question 58

Discuss Pathogenesis of acute pancreatitis.

Answer 58

1. Autodigestion of the Pancreatic SubstanceAccording to this theory, pancreatitis develops due to premature (inappropriate) activation of proteolytic pancreatic enzymes leads to a process of autodigestion.
2. Activation of Pancreatic EnzymesPancreatic enzymes are synthesized in an inactive proenzyme form (e.g. trypsinogen, chymotrypsinogen, proelastase, and lipolytic enzymes, such as phospholipase A2) and become.

Question 59

Premature activation of pancreatic enzymes, particularly trypsin, before their secretion from the acinar cells, is responsible for acute pancreatitis.

What are some factors that can activate trypsin prematurely?

What are the actions of trypsin in the pancreas during acute pancreatitis?

How does trypsin contribute to the activation of the kinin, clotting, and complement systems?

Answer 59

A: Factors that can activate trypsin prematurely include endotoxins, exotoxins, viral infections, ischemia, and anoxia.

A: Trypsin, once activated prematurely, can convert many proenzymes into their active forms.

For example, it can convert proelastase to elastase, which damages the elastic fibers of blood vessels, and pro-phospholipase to phospholipase, which degrades fat cells.

A: Trypsin acts on the kinin system by converting prekallikrein to kallikrein. It also activates Hageman factor (factor XII), which in turn activates the clotting and complement systems.

Question 60

Discuss Mechanism of Alcohol-induced Pancreatitis.

Answer 60

1. Obstruction of small ductules by proteinaceous plugs: Chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid form inspissated protein plugs
   →obstruct small pancreatic ducts. They lead to pancreatitis similar to duct obstruction.
2. Abnormal sphincter of Oddi spasm: Alcohol increases pancreatic exocrine secretion and causes contraction of the sphincter of Oddi (the muscle at the ampulla of Vater)
   →pancreatitis.
3. Direct toxic effects on acinar cells: This may be caused by alcohol and its metabolic by products.
4. Increased amounts of proteases in pancreatic secretions: Found in alcoholic patients.

Question 61

Discuss clinical features of acute pancreatitis.

Answer 61

1. Abdominal pain: It is constant and intense
   It is referred to the upper back and its severity varies from mild to severe.

• Other symptoms: These include anorexia, nausea, and vomiting.

Question 62

Discuss Laboratory Findings for acute pancreatitis.

Answer 62

• Leukocytosis: found in moderate to severe acute pancreatitis.
• Serum amylase: It is marked elevated during the first 24 hours.

.Serum lipase: It is raised within 72 to 96 hours and follows elevated amylase.
* Glycosuria: It occurs in 10% of cases.
* Hypocalcemia: It is due to precipitation of calcium soaps in necrotic fat.
* Direct visualization of the pancreas: By radiography.

Question 63

Discuss Complications of acute pancreatitis.

1. Local complications
2. Systemic complications

Answer 63

LOCAL COMPLICATIONS
*Sterile pancreatic abscess
*Pancreatic pseudocysts
*Infections by gram negative organisms from the alimentary canal.

SYSTEMIC COMPLICATIONS
*Shock with acute renal tubular necrosis within the first week
*Acute respiratory distress syndrome
*Acute renal failure
*Hemolysis
*DIC
*Diffuse fat necrosis

Question 64

Discuss CHRONIC PANCREATITIS.

Answer 64

Chronic pancreatitis is characterized by long-standing inflammation that leads to

1. irreversible destruction of the exocrine pancreas,
2. followed eventually by loss of the islets of Langerhans.

Of note, recurrent bouts of acute pancreatitis regardless of etiology can evolve over time into chronic pancreatitis.

Question 65

Discuss CHRONIC PANCREATITIS Etiology.

Answer 65

1. The most common cause of chronic pancreatitis is long-term alcohol abuse.
   Less common causes of chronic pancreatitis include the following:
2. Duct Obstruction. Long-standing obstruction of pancreatic duct e.g., by pseudocysts, calculi, neoplasms, or pancreas divisum.
   * Tropical pancreatitis, a poorly characterized heterogeneous disorder seen in Africa and Asia, with a subset of cases having a hereditary basis.

• Hereditary pancreatitis due to mutations in the pancreatic trypsinogen gene (PRRS1), or the SPINK1 gene encoding a trypsin inhibitor.
• Chronic pancreatitis associated with CFTR mutations. The pathophysiology of chronic pancreatitis in cystic fibrosis.
• Autoimmune pancreatitis is a pathogenically distinct form of chronic pancreatitis

Question 66

Discuss Autoimmune Pancreatitis.

Answer 66

Presence of IgG4-secreting plasma cells in the pancreas.

Autoimmune pancreatitis is one manifestation of IgG related disease which may involve multiple tissues.

It is important to recognize because it responds to steroid therapy

Question 67

Discuss Pathogenesis of chronic pancreatitis.

Answer 67

Repeated episodes of acinar cell injury produces profibrogenic cytokines such as transforming growth factor β (TGF-β) and platelet-derived growth factor (PDGF), resulting in the proliferation of stellate cells (myofibroblasts) and produces fibrosis

Question 68

Chronic Pancreatitis Morphology can be subdivided into two major forms.

Discuss each form.
.

Answer 68

1. Non-obstructive chronic pancreatitis
   It is by far the most common form of chronic pancreatitis (~95%) and about 80% of the patients are alcoholics.

a. Pancreas is nodular, hard and may be either enlarged or atrophic.
b. Cut section may show dilated ducts and calcified concretions.
c. When the calcification is extensive, it is termed as chronic calcifying pancreatitis.

Obstructive chronic pancreatitis
It is the result of narrowing or occlusion of the pancreatic ducts.

It is most commonly due to carcinoma and stones in the ductal system.

Question 69

Discuss Chronic Pancreatitis Microscopy.

Answer 69

1. Parenchymal fibrosis: periductal, intralobular, and interlobular. It is a major feature.
2. Atrophy of acini: There is reduction in the number and size of the acini.

The islets of Langerhans are relatively resistant to chronic pancreatitis in comparison with the pancreatic acini.
However, as the disease progresses they may be reduced or disappear.

3. Dilation of the pancreatic ducts: The interlobular and intralobular pancreatic ducts are frequently dilated and their lumen show protein plugs.
4. Alterations in the duct epithelium: It shows atrophy/hyperplasia/squamous metaplasia.
5. Chronic inflammatory infiltrate: Fibrotic areas show infiltration by lymphocytes, plasma cells, and macrophages.

Question 70

Discuss Chronic Pancreatitis Clinical Features.

Answer 70

• Repeated attacks of abdominal pain or persistent abdominal and back pain.
• Silent until severe functional damage develops
  – Pancreatic exocrine insufficiency:
  Characterized by weight loss and hypoalbuminemia edema due to chronic malabsorption.

– Pancreatic endocrine insufficiency: Diabetes mellitus may
develop.

Prognosis: Long-term outlook is poor.

Question 71

Discuss PSEUDOCYST OF PANCREAS

Answer 71

Pseudocysts constitute about 75% of cysts in the pancreas.

• Pseudocyst is not true cyst and does not have any epithelial lining.

It is intimately associated with the pancreatic tissues.

• Causes: Complication of acute and chronic pancreatitis, and traumatic injury to the pancreas.

Question 72

Discuss PSEUDOCYST OF PANCREAS Morphology.

1. Gross
2. Microscopy

Answer 72

Gross
* Number: It is usually single.
* Size: It ranges from 2 to 30 cm in diameter.
* Sites: May be seen within the substance of the pancreas, or more commonly in the lesser omental sac or in the retroperitoneum between the stomach and transverse colon or between the stomach and liver.
* Lumen: It contains necrotic-hemorrhagic material rich in pancreatic enzymes (amylase).

Microscopy
The wall of the pseudocysts shows non-epithelial-lined fibrous connective tissue and necrotic pancreatic debris.

Question 73

Discuss PSEUDOCYST OF PANCREAS Complications.

Answer 73

Majority of pseudocysts resolve spontaneously.
* Pseudocyst may enlarge and compress or obstruct the duodenum or even perforate into adjacent structures.
* May be secondarily infected
→ form an abscess.
* Rarely may rupture
→ chemical or septic peritonitis or both

Question 74

PANCREATIC NEOPLASMS
Q: What are the two main types of pancreatic exocrine neoplasms?

Q: How do cystic neoplasms of the pancreas differ from solid neoplasms?

Q: Which type of pancreatic neoplasm is considered the most lethal of all malignancies?

Answer 74

A: Pancreatic exocrine neoplasms can be categorized into cystic or solid types.

A: Cystic neoplasms are characterized by fluid-filled sacs within the pancreas, whereas solid neoplasms consist of abnormal cell growth forming solid masses in the pancreas.

A: Pancreatic carcinoma, particularly pancreatic ductal adenocarcinoma, is considered one of the most lethal malignancies due to its aggressive nature and often late-stage diagnosis.

Question 75

Q: What are some examples of cystic neoplasms of the pancreas?
Q: What are the risk factors associated with pancreatic carcinoma?

Answer 75

A: Examples of cystic neoplasms include serous cystadenomas, mucinous cystic neoplasms, and intraductal papillary mucinous neoplasms (IPMNs).

A: Risk factors for pancreatic carcinoma include smoking, chronic pancreatitis, obesity, diabetes, family history of pancreatic cancer, and certain genetic syndromes like hereditary pancreatitis and hereditary nonpolyposis colorectal cancer (HNPCC).

Question 76

Define PANCREATIC CARCINOMA.

Answer 76

Infiltrating ductal adenocarcinoma of the exocrine pancreas (commonly known as “pancreatic cancer”)

is the most frequent neoplasm of the pancreas (about 85% of all neoplasms).

Question 77

Q: What are the precursor lesions to pancreatic cancer known as?

How do PanINs relate to the progression of pancreatic cancer?

Answer 77

A: The precursor lesions to pancreatic cancer are called “pancreatic intraepithelial neoplasia” (PanINs).

A: Similar to colorectal cancer, PanINs represent a progression in the pancreas from non-neoplastic epithelium to well-defined noninvasive lesions in small ducts and ductules, eventually leading to invasive carcinoma.

Question 78

Discuss PANCREATIC CARCINOMA Molecular Carcinogenesis.

Answer 78

1. Telomere shortening:
   The epithelial cells in PanINs show critical shortening of telomere length, which predisposes these lesions to accumulate progressive chromosomal abnormalities and to develop invasive carcinoma.
2. Oncogene
   * Mutation of KRAS: It is an early genetic alteration, which in turn activates several intracellular signal transduction pathways and the transcription factors Fos and Jun.
3. Tumor suppressor gene
   * Inactivating mutations of p16/CDKN2A: It occurs in 90% of the cases.
   The p16 protein (product of p16) plays an important role in the control of the cell cycle, and its inactivation results in loss of cell cycle checkpoint.
   * Mutational inactivation of SMAD4: It occurs in about 55% of pancreatic cancers.
   SMAD4 is only rarely inactivated in other cancers.
   * Mutations of p53: It is found in about 75% of pancreatic cancers.

Question 79

Discuss PANCREATIC CARCINOMA Etiology.

Answer 79

• Age: It is usually found in the elderly patients and about 80% of cases occur between the ages of 60 and 80 years.
• Risk factors:
  – Cigarette smoking and alcohol use
  – Consumption of a diet rich in fats
  – Chronic pancreatitis
  – Diabetes mellitus
  – Inherited genetic defects:
  ◆ BRCA2 mutations
  ◆ Mutations in CDKN2A (p16)
  ◆ Mutation in the PALLD gene.

Question 80

Discuss the pathogenesis of PANCREATIC CARCINOMA.

Answer 80

Genetic progression of pancreatic carcinogenesis.

The progression from normal epithelium to low-grade pancreatic intraepithelial neoplasia (PanIN) (PanIN1 and PanIN2), to high-grade PanIN3, to invasive carcinoma (left to right) is associated with the accumulation of specific geneticalterations.

1. Telomere shortening
2. Mutations of the oncogene KRAS occur at early stages.
3. It is followed by inactivation of the p16 (tumor suppressor gene) at intermediate stages,
4. The inactivation of the p53, SMAD4 (DPC4), and BRCA2 tumor suppressor genes occur at late stages

Question 81

Discuss PANCREATIC CARCINOMA Morphology.

1. Location
2. Gross
3. Microscopy

Answer 81

Location: About 60% in the head, 15% in the body, and 5% in the tail; in about 20% of cancers diffusely involve the entire pancreas.

• Gross: Pancreatic carcinomas usually appear as hard, stellate, gray, white, poorly delineated and firm masses.
• Microscopy: Pancreatic ductal adenocarcinoma is graded microscopically into well differentiated, moderately differentiated, and poorly differentiated.

The tumor cells form abortive tubular structures or cell clusters and show infiltration.

The malignant glands are poorly formed and are usually lined by pleomorphic cuboidal-to-columnar epithelial cells.

Question 82

Discuss PANCREATIC CARCINOMA Spread.

Answer 82

• Local spread:
  Pancreatic cancers usually show perineural invasion. They grow along nerves and invade into the retroperitoneum.

They can directly spread into peripancreatic soft tissues, spleen, adrenals, vertebral column, transverse colon, and stomach.

• Lymphatic spread: Through lymphatics it spreads to peripancreatic, gastric, mesenteric, omental, and porta hepatic lymph nodes.
• Blood spread: It may spread to the liver, lungs, adrenal, and bones.

Question 83

Discuss PANCREATIC CARCINOMA Clinical Features.

Answer 83

Pancreatic cancers usually remain silent until they infiltrate into adjacent structures.
* Pain: It is usually the first and the outstanding symptom.

• Obstructive jaundice: It is associated with carcinoma of the head of the pancreas.

Advanced stage:

Symptoms include: weight loss, anorexia, and generalized malaise and weakness.

• Carcinomas of the body and tail of the pancreas:

It remains silent in the initial period.
* Migratory thrombophlebitis (Trousseau sign): It is characterized by spontaneouslyappearing and disappearing (migratory) thrombosis.
It is found in about 10% of patients.

It is attributable to the production of platelet-aggregating factors and procoagulants from the carcinoma or its necrotic products.

Question 84

Discuss PANCREATIC CARCINOMA Laboratory Findings.

Answer 84

Raised serum levels of many enzymes and antigens (e.g. carcinoembryonic antigen and CA19–9 antigen) are often found in pancreatic cancer.

These markers are nonspecific and lack the sensitivity.

However, they are useful in follow-up of a patient’s response to treatment.

Imaging techniques: Many imaging techniques, such as endoscopic ultrasonography and computed tomography, are useful for the diagnosis, but are not useful as screening tests.

Prognosis: The course is brief and progressive.