Gallbladder and pancreatic pathology

Gallbladder and Extrahepatic bile ducts
Congenital anomalies are rare
Agenesis, atresia, duplication, heterotopic tissue including gastric, adrenal, pancreatic and thyroid elements have been reported.

There are also congenital anomalies of the common bile duct forming cysts and diverticula.

Gall stones
Risk factors for gall stones formation

Pathogenesis
Bile formation is the only significant pathway for elimination of excess cholesterol from the body, either as free cholesterol or as bile salts.
Cholesterol is rendered water-soluble by aggregation with bile salts and lecithins.
When cholesterol concentrations exceed the solubilizing capacity of bile (supersaturation), Cholesterol can no longer remain dispersed and crystallizes out of solution.


Cholesterol gallstone
Formation enhanced by
Hypomobility of the gallbladder (stasis), which promotes nucleation.
Mucus hypersecretion, with consequent trapping of the crystals.


Cholesterol gallstones
They can occur singly, but most often there are several stones, with faceted surfaces resulting from their apposition.
Most cholesterol stones are radiolucent, although as many as 20% may have sufficient calcium carbonate to be radiopaque.



Pigment stones
More likely in the presence of unconjugated bilirubin in the biliary tree, as occurs in hemolytic anemias and infections of the biliary tract.
The precipitates are primarily insoluble calcium bilirubinate salts.

Pigment stones
May arise anywhere in the biliary tree and are classified into black and brown stones.

Black pigment stones are found in sterile gallbladder bile.
Brown stones are found in infected intrahepatic or extrahepatic ducts.

The stones contain calcium salts of unconjugated bilirubin and lesser amounts of other calcium salts, mucin glycoproteins, and cholesterol.

Black stones are usually small in size, fragile to the touch, and numerous.
Brown stones tend to be single or few in number
and to have a soft, greasy, soaplike consistency that results from the presence of retained fatty acid salts released by the action of bacterial phospholipases on biliary lecithins.
Because of calcium carbonates and phosphates, 50% to 75% of black stones are radiopaque. Brown stones, which contain calcium soaps, are radiolucent.
Pigmented stones, gallbladder

Cholecystitis
Inflammation of the gallbladder may be acute, chronic, or acute superimposed on chronic, and almost always occurs in association with gallstones.

Morphology
Acute cholecystitis
Gallbladder usually is enlarged and tense, and it assumes a bright red or blotchy, violaceous color, the latter imparted by subserosal hemorrhages.
The serosa frequently is covered by a fibrinous, or in severe cases, fibrinopurulent exudate.
In 90% of cases, stones are present, often obstructing the neck of the gallbladder or the cystic duct.
The gallbladder lumen is filled with cloudy or turbid bile that may contain fibrin, blood, and frank pus.
Empyema of the gallbladder means that the contained exudate is mostly pus.

Chronic cholecystitis
Morphology
Extremely variable and sometimes subtle.
The presence of stones within the gallbladder, even in the absence of acute inflammation, often is taken as sufficient justification for the diagnosis.
The gallbladder may be contracted, of normal size, or enlarged.
Mucosal ulcerations are infrequent; the submucosa
and subserosa often are thickened from fibrosis.
In the absence of superimposed acute cholecystitis, mural lymphocytes are the only signs of inflammation.

Cholecystitis almost always occurs in association with cholelithiasis, although in about 10% of cases it occurs in the absence of gallstones.
• Obstructive lesions of the extrahepatic bile ducts in adults can give rise to ascending infection (cholangitis) and secondary biliary cirrhosis.
• Infants born with congenital biliary atresia present with neonatal cholestasis and require liver transplantation for cure.

Tumors
Benign:
Papillomas
Mucous gland adenomas
Adenomyomas
when smooth muscle proliferates around an adenoma.


Malignant:
Adenocarcinoma of the gallbladder is the most common tumor of the gallbladder.
It is associated with chronic cholecystitis and cholelithiasis, more common in women than men.

Microscopically:
usually well differentiated; rare cases of undifferentiated or giant cell carcinomas are reported.
The symptoms are similar to chronic cholecystitis, treatment is often delayed and may be uncurable by the time they are operated.
Carcinomas of the bile duct or the ampulla of Vater cause obstructive jaundice.
Carcinoma of the bile duct may be associated with inflammatory bowel disease.



Pathology of pancreas

Pancreas
complex lobulated organ with distinct endocrine and exocrine elements.

The endocrine portion constitutes only 1% to 2% of the pancreas and is composed of about 1 million cell clusters, the islets of Langerhans; these cells secrete insulin, glucagon, and somatostatin.

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

The exocrine pancreas
Acinar cells that produce the digestive enzymes.
The ductules and ducts that convey them to the duodenum.
The acinar cells are responsible for the synthesis of digestive enzymes, which are mostly made as inactive pro-enzymes that are stored in zymogen granules.

pancreatitis
Acute:
Autodigestion of organ by premature pancreatic enzyme activation.
Chronic:
Fibrosis, inflammation, and loss of exocrine tissue.

Pathogenesis
Autodigestion of the pancreatic substance by inappropriately activated pancreatic enzymes.
The zymogen forms of pancreatic enzymes must be enzymatically cleaved to be activated; trypsin is central in this process, so activation of trypsin is a critical triggering event in acute pancreatitis.
If trypsin is inappropriately generated from its proenzyme trypsinogen, it can activate itself as well as other proenzymes (e.g., phospholipases and elastases) that can then take part in the process of autodigestion.
Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems.

Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis :
1. Pancreatic duct obstruction.
Impaction of a gallstone or biliary sludge, or extrinsic compression of the ductal system by a mass blocks ductal flow, increases intraductal pressure, and allows accumulation of an enzyme rich interstitial fluid.
Since lipase is secreted in an active form, local fat necrosis may result.
Injured tissues, periacinar myofibroblasts, and leukocytes then release proinflammatory cytokines that promote local inflammation and interstitial edema through a leaky microvasculature.
Edema further compromises local blood flow, causing vascular
insufficiency and ischemic injury to acinar cells.

2. Primary acinar cell injury.
This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas.
3.Defective intracellular transport of proenzymes within acinar cells.
In normal acinar cells, digestive enzymes intended for zymogen granules (and eventually extracellular release) and hydrolytic enzymes destined for lysosomes are transported in discrete pathways after synthesis in the endoplasmic reticulum.


Mechanisms of pancreatitis due to alcohol consumption
Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi (the muscle regulating the tone at the ampulla of Vater).
Alcohol has direct toxic effects on acinar cells, including induction of oxidative stress in acinar cells, which leads to membrane damage.
Chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts.

Morphology
(1) Microvascular leakage causing edema.
(2) Necrosis of fat by lipases.
(3) Acute inflammatory reaction.
(4) Proteolytic destruction of pancreatic parenchyma.
(5) Destruction of blood vessels leading to interstitial hemorrhage.

Mild form acute pancreatitis
Interstitial edema
Focal areas of fat necrosis in the pancreatic substance and peripancreatic fat.
Fat necrosis results from enzymatic destruction of fat cells.

More severe forms
such as acute necrotizing pancreatitis
Necrosis of pancreatic tissue affects acinar and
ductal tissues as well as the islets of Langerhans.
Vascular damage causes hemorrhage into the parenchyma of the pancreas.
Macroscopically
The pancreas exhibits red-black hemorrhagic
areas interspersed with foci of yellow-white, chalky fat necrosis.

Chronic pancreatitis
• Ductal obstruction by concretions. Many of the inciting agents in chronic pancreatitis (e.g., alcohol) increase the protein concentration of pancreatic secretions, and these proteins can form ductal plugs.
• Toxic-metabolic. Toxins, including alcohol and its metabolites, can exert a direct toxic effect on acinar cells, leading to lipid accumulation, acinar cell loss, and eventually parenchymal fibrosis.


Oxidative stress. Alcohol-induced oxidative stress may generate free radicals in acinar cells, leading to membrane damage, and subsequent expression of chemokines like interleukin-8 (IL-8), which recruits mononuclear inflammatory cells. Oxidative stress also promotes the fusion of lysosomes and zymogen granules with resulting acinar cell necrosis, inflammation, and fibrosis.


Chronic pancreatitis
Gross
The gland is hard, sometimes with extremely dilated ducts and visible calcified concretions.

Microscopical
Variable dilation of the pancreatic ducts; there is a relative sparing of the islets of Langerhans.
Variable size of acini or acinar loss is a constant feature, usually with a chronic inflammatory infiltrate around remaining lobules and ducts.
The ductal epithelium may be atrophied or hyperplastic or exhibit squamous metaplasia, and ductal concretions may be noted.
The remaining islets of Langerhans become embedded in the sclerotic tissue and may fuse and appear enlarged; eventually they also disappear.



Pancreatic cancer
Age: It is primarily a disease of the elderly population, with 80% of cases occurring between the ages of 60 and 80.
The strongest environmental influence is smoking, which doubles the risk.
Chronic pancreatitis and diabetes mellitus are also both associated with an increased risk of pancreatic cancer.
Familial clustering of pancreatic cancer has been reported, and a growing number of inherited genetic defects are now recognized that increase pancreatic cancer risk. For example, germline mutations of the familial breast/ovarian cancer gene BRCA2 are seen in approximately 10% of cases arising in persons of Ashkenazi Jewish heritage.

• Pancreatic cancer probably arises from noninvasive precursor lesions (most commonly, PanINs), developing by progressive accumulation of characteristic mutations of oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., CDKN2A/p16, TP53, and SMAD4).
• Typically, these neoplasms are ductal adenocarcinomas that produce an intense desmoplastic response.
• Most pancreatic cancers are diagnosed at an advanced stage, accounting for the high mortality rate.
• Obstructive jaundice is a feature of carcinoma of the head of the pancreas; many patients also experience debilitating pain.