Session 29: Gallbladder and Extrahepatic bile duct Pathology

Session 29: Gallbladder and Extrahepatic bile duct Pathology

• Felician Sikujua (MD)

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Learning tasks

Learning tasks

At the end of this session, students are expected to be able to:

Describe cholelithiasis.

Describe pathological changes seen in cholecystitis.

Explain choledolithiasis.

Explain cholangitis.

Explain biliary atresia.

Explain gallbladder tumors.

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Disorders of the gallbladder

Disorders of the gallbladder

Cholelithiasis (gallstones) accounts for more than 95% of these diseases.

Cholecystitis (Inflammation of gallbladder).

Gallbladder tumors.

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Disorders of the Extrahepatic biliary tract

Disorders of the Extrahepatic biliary tract

Choledocholithiasis.

Cholangitis.

Secondary biliary cirrhosis.

Biliary atresia.

Tumors.

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Cholelithiasis (Gallstones)

Cholelithiasis (Gallstones)

Cholelithiasis means gallstone disease.

There are two (2) main types of gallstones

Cholesterol stones.

Containing crystalline cholesterol monohydrate.

Pigment stones.

Made of bilirubin calcium salts.

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Pathogenesis

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.

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Steps involved in cholesterol gallstone formation

Steps involved in cholesterol gallstone formation

Cholesterol gallstone formation involves five (5) simultaneously occurring conditions

Super-saturation of the bile with cholesterol.

Hypomobility of the gallbladder (stasis), which promotes nucleation.

Establishment of nucleation sites by micro-precipitates of calcium salts.

Mucus hyper-secretion to trap the crystals

Aggregation into stones.

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Steps involved in cholesterol gallstone formation cont…

Steps involved in cholesterol gallstone formation cont…

Formation of pigment stones is more likely in the presence of unconjugated bilirubin in the biliary tree, as occurs in hemolytic anemias and infections of the biliary tract.

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Risk factors for cholesterol gallstones

Risk factors for cholesterol gallstones

Advancing age.

Female sex hormones.

Female gender

Oral contraceptives

Pregnancy

Obesity and insulin resistance.

Rapid weight reduction.

Gallbladder stasis.

Inborn disorders of bile acid metabolism.

Dyslipidemia syndromes.

Heredity.

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Risk factors for pigment gallstones

Risk factors for pigment gallstones

Chronic hemolysis (e.g., sickle cell anemia, hereditary spherocytosis).

Biliary infection.

Gastrointestinal disorders: ileal disease (e.g., Crohn disease), ileal resection or bypass, cystic fibrosis with pancreatic insufficiency.

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Morphology: Gallstones

Morphology: Gallstones

Cholesterol stones arise exclusively in the gallbladder and consist of 50% to 100% cholesterol.

Pure cholesterol stones are pale yellow.

Increasing proportions of calcium carbonate, phosphates, and bilirubin impart gray-white to black discoloration.

They are ovoid and firm.

They can occur singly, but most often there are several, 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.

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Morphology: Gallstones cont…

Morphology: Gallstones cont…

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.

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Morphology: Gallstones cont…

Morphology: Gallstones cont…

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, soap like consistency

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.

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Complications of gallstones

Complications of gallstones

More severe complications include

Empyema of gallbladder.

Perforation.

Fistulas.

Inflammation of the biliary tree.

Obstructive cholestasis.

Pancreatitis.

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Cholecystitis

Cholecystitis

It is an inflammation of the gallbladder.

It can may be acute, chronic, or acute superimposed on chronic.

It is almost always occurs in association with gallstones.

Thus the most common cause of cholecystitis is gallstones.

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Acute cholecystitis

Acute cholecystitis

According to the cause, acute cholecystitis can be classified as

Acute calculous cholecystitis

Acute acalculous cholecystitis

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Acute calculous cholecystitis

Acute calculous cholecystitis

Acute inflammation of a gallbladder that contains stones is termed as acute calculous cholecystitis

It is precipitated by obstruction of the gallbladder neck or cystic duct.

It is the most common major complication of gallstones.

Acute calculous cholecystitis is initially the result of chemical irritation and inflammation of the gallbladder wall in the setting of obstruction to bile outflow.

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Acute calculous cholecystitis cont…

Acute calculous cholecystitis cont…

The action of phospholipases derived from the mucosa hydrolyzes biliary lecithin to lysolecithin, which is toxic to the mucosa.

The normally protective glycoprotein mucous layer is disrupted, exposing the mucosal epithelium to the direct detergent action of bile salts.

Prostaglandins released within the wall of the distended gallbladder contribute to mucosal and mural inflammation.

Distention and increased intraluminal pressure also may compromise blood flow to the mucosa.

These events occur in the absence of bacterial infection; only later may bacterial contamination develop.

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Acute acalculous cholecystitis

Acute acalculous cholecystitis

Most cases occur in seriously ill patients.

Some of the most common predisposing insults are

Major nonbiliary surgery.

Severe trauma (e.g., from motor vehicle crashes).

Severe burns.

Sepsis.

Other contributing factors include dehydration, gallbladder stasis and sludging, vascular compromise, and, ultimately, bacterial contamination.

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Morphological changes in acute cholecystitis

Morphological changes in acute cholecystitis

In acute cholecystitis, the gallbladder usually is enlarged and tense.

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.

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Morphological changes in acute cholecystitis cont…

Morphological changes in acute cholecystitis cont…

When the contained exudate is mostly pus, the condition is referred to as empyema of the gallbladder.

In mild cases the gallbladder wall is thickened, edematous, and hyperemic.

In more severe cases the gallbladder is transformed into a green-black necrotic organ—a condition termed gangrenous cholecystitis.

On histologic examination, inflammatory reactions are not distinctive and consist of the usual patterns of acute inflammation

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Serious complications of acute cholecystitis

Serious complications of acute cholecystitis

Bacterial superinfection with cholangitis or sepsis.

Gallbladder perforation and local abscess formation.

Gallbladder rupture with diffuse peritonitis.

Biliary enteric (cholecystenteric) fistula, with drainage of bile into adjacent organs, entry of air and bacteria into the biliary tree and potentially gallstone-induced intestinal obstruction (ileus).

Aggravation of preexisting medical illness, with cardiac, pulmonary, renal, or liver decompensation.

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Chronic cholecystitis

Chronic cholecystitis

Chronic cholecystitis may be the sequel to repeated bouts of acute cholecystitis, but in most instances it develops without any history of acute attacks.

Like acute cholecystitis it is almost always associated with gallstones.

However, gallstones do not seem to have a direct role in the initiation of inflammation or the development of pain.

Because chronic acalculous cholecystitis causes symptoms and morphologic alterations similar to those seen in the calculous form.

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Chronic cholecystitis cont…

Chronic cholecystitis cont…

Supersaturation of bile predisposes the patient to both chronic inflammation and in most instances, stone formation.

Microorganisms, usually Escherichia coli and Enterococci, can be cultured from the bile in only about one third of cases.

Unlike acute calculous cholecystitis, stone obstruction of gallbladder outflow in chronic cholecystitis is not a requisite.

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Morphology:Chronic cholecystitis

Morphology:Chronic cholecystitis

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.

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Choledocholithiasis

Choledocholithiasis

It is the presence of stones within the biliary tree.

Almost all stones are derived from the gallbladder, usually pigmented, stone formation.

Symptoms may develop because of

Biliary obstruction.

Cholangitis.

Hepatic abscess.

Chronic liver disease with secondary biliary cirrhosis.

Acute calculous cholecystitis.

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Cholangitis

Cholangitis

Cholangitis is the term used for acute inflammation of the wall of bile ducts, almost always caused by bacterial infection of the normally sterile lumen.

It can result from

Any lesion obstructing bile flow, (choledocholithiasis)

Surgery involving the biliary tree.

Other causes include tumors, indwelling stents or catheters, acute pancreatitis, and benign strictures.

Bacteria most likely enter the biliary tract through the sphincter of Oddi, rather than by the hematogenous route.

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Cholangitis cont…

Cholangitis cont…

Ascending cholangitis refers to the propensity of bacteria, once within the biliary tree, to infect intrahepatic biliary ducts.

The usual pathogens are E. coli, Klebsiella, Enterococci, Clostridium, and Bacteroides.

Two or more organisms are found in half of the cases.

In some world populations, parasitic cholangitis is a significant problem.

Fasciola hepatica or schistosomiasis, Clonorchis sinensis or Opisthorchis viverrini, Cryptosporidiosis in persons with acquired immunodeficiency syndrome.

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Cholangitis cont…

Cholangitis cont…

Bacterial cholangitis usually produces fever, chills, abdominal pain, and jaundice.

The most severe form of cholangitis is suppurative cholangitis, in which purulent bile fills and distends bile ducts, with an attendant risk of liver abscess formation.

Because sepsis rather than cholestasis is the predominant risk in cholangitic patients, prompt diagnosis and intervention are imperative.

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Secondary Biliary Cirrhosis

Secondary Biliary Cirrhosis

Prolonged obstruction of the extrahepatic biliary tree results in profound damage to the liver itself.

The most common cause of obstruction is extrahepatic cholelithiasis.

Other obstructive conditions include biliary atresia, malignancies of the biliary tree and head of the pancreas, and strictures resulting from previous surgical procedures.

Secondary inflammation resulting from biliary obstruction initiates periportal fibrogenesis, which eventually leads to scarring and nodule formation, generating secondary biliary cirrhosis.

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Biliary atresia

Biliary atresia

Biliary atresia is defined as a complete obstruction of bile flow caused by destruction or absence of all or part of the extrahepatic bile ducts.

It is the most frequent cause of death from liver disease in early childhood and accounts for more than half of the referrals of children for liver transplantation.

Biliary atresia is a major cause of neonatal cholestasis.

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Biliary atresia cont…

Biliary atresia cont…

The salient features of biliary atresia include

Inflammation and fibrosing stricture of the hepatic or common bile ducts.

Inflammation of major intrahepatic bile ducts, with progressive destruction of the intrahepatic biliary tree.

Florid features of biliary obstruction on liver biopsy (i.e., ductular reaction, portal tract edema and fibrosis, and parenchymal cholestasis).

Periportal fibrosis and cirrhosis within 3 to 6 months of birth.

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Tumors:Carcinoma of the Gallbladder

Tumors:Carcinoma of the Gallbladder

Although uncommon, carcinoma of the gallbladder is the most frequent malignant tumor of the biliary tract.

It is 2 to 6 times more common in women and occurs most frequently in the seventh decade of life.

Gallstones are present in 60% to 90% of cases.

Where pyogenic and parasitic diseases of the biliary tree are more common, gallstones are less important.

Presumably, gallbladders containing stones or infectious agents develop cancer as a result of recurrent trauma and chronic inflammation.

The role of carcinogenic derivatives of bile acids is unclear.

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Morphology: Cancers of the gallbladder

Morphology: Cancers of the gallbladder

Cancers of the gallbladder may exhibit exophytic or infiltrating growth patterns.

The infiltrating pattern is more common and usually appears as a poorly defined area of diffuse thickening and induration of the gallbladder wall that may cover several square centimeters or involve the entire gallbladder.

These tumors are scirrhous and very firm.

The exophytic pattern grows into the lumen as an irregular, cauliflower-like mass but at the same time also invades the underlying wall.

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Morphology: Cancers of the gallbladder cont…

Morphology: Cancers of the gallbladder cont…

Most are adenocarcinomas, which may be papillary or poorly differentiated.

About 5% are squamous cell carcinomas or demonstrate adenosquamous differentiation, and rare neuroendocrine tumors also occur.

By the time gallbladder cancers are discovered, most have invaded the liver or have spread to the bile ducts or to the portal hepatic lymph nodes.

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Cholangiocarcinomas

Cholangiocarcinomas

Cholangiocarcinomas are adenocarcinomas that arise from cholangiocytes lining the intrahepatic and extrahepatic biliary ducts.

Extrahepatic type is common and may develop at the hilum or more distally in the biliary tree.

Cholangiocarcinomas occur mostly in persons of 50 to 70 years of age.

Risk factors include primary sclerosing cholangitis, fibropolycystic diseases of the biliary tree, and infestation by Clonorchis sinensis or Opisthorchis viverrini.

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Cholangiocarcinomas cont…

Cholangiocarcinomas cont…

All risk factors for cholangiocarcinomas cause chronic cholestasis and inflammation, which presumably promote the occurrence of somatic mutations in cholangiocytes.

Morphology: Adenocarcinomas with more or less well-formed glands, accompanied by fibrous stroma (desmoplasia) yielding a firm, gritty consistency.

Intracellular mucin may be prominent.

Spread to extrahepatic sites such as regional lymph nodes, lungs, bones, and adrenal glands.

Invasion along peribiliary nerves is another route of spread to the abdomen.

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Key points

Key points

The great majority of the gallstones are cholesterol stones.

Risk factors for the development of cholesterol stones are advancing age, female gender, estrogen use, obesity, and heredity.

Cholecystitis almost always occurs in association with cholelithiasis.

Obstructive lesions of the extrahepatic bile ducts in adults can give rise to ascending infection (cholangitis) and secondary biliary cirrhosis.

Cancers of the gallbladder commonly exhibit infiltrating growth patterns.

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Review questions

Review questions

Outline five (5) steps involved in cholesterol gallstone formation.

List five (5) complications of cholelithiasis.

Outline five (5) morphological features seen in acute cholecystitis.

Mention five (5) causes of cholangitis.

What is biliary atresia?

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References

References

Kumar V. ; Abbas A. K. ; Aster J. C.;(2013): Robbins and Contran Pathologic Basis of Disease (9th Ed.) Elsevier Saunders, USA. Pg. 639-644.

Mohan H.;(2010): Text book of Pathology (6th Ed.) Jaypee Brothers Medical Publishers, India. Pg. 638-644.

Xiu P.;(2012): Crash Course Pathology (4th Ed.) Elsevier Saunders, USA. Pg. 137-139.

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