Disorders of gall bladder

Dr Nor Hidayah Abu Bakar,M.D, M.Path (Anatomic Pathologist), Medical

Lecturer,FPSK, UNISZA

Disorders of the gall bladder

• Disorders of the biliary tract affects significant portion of the world’s population.

• >95% of biliary tract disease is due to cholelithiasis (gallstone)

• Bile is secreted by liver and in between meals, it is stored in gall bladder

Learning Objectives

• Describe the aetiology and pathogenesis, the pathology, and the clinical manifestations of cholesterol and pigment gallstones

• Describe the pathology of acute and chronic cholecystitis (Rokitansky-Aschoff sinus)

• Describe the pathology and the clinical manifestations of gallbladder carcinoma

Cholelithiasis

• Affect 10-20% of adult population in developed countries

• Prevalence : certain populations are more prone than others (US, Western Europe)

• Clinical features:– 70-80% are asymptomatic– Excruciating pain localised to the right upper quadrant or epigastric region

• 2 main types of gall stones :– Cholesterol stones– Pigment stones

• In the West, about 90% are cholesterol stones.• Pigment gall stone is predominant in non-

Western population – associated with bacterial infection of biliary tree and parasitic infestations.

Cholelithiasis -cont• Risk factors :

– Prevalence increase with age – associated with metabolic syndrome and obesity. More common in women (2x)

– Ethnic and geographic. Cholesterol stone is more common in Native American population, related to biliary cholesterol hypersecretion.

– Hereditary : positive family history of stones, inborn error of metabolism associated with impaired bile salt synthesis and secretion

– Environmental factors :• Estrogenic influence ( OCP and pregnancy) - increase expression of

hepatic lipoprotein receptors →stimulates HMG Co-A reductase activity →enhance cholesterol uptake and synthesis → excess biliary secretion of cholesterol.

• Clofibrate (lipid lowering agent) increase hepatic HMG Co-A reductase → reduce cholesterol 7-α hydroxylase activity → decrease conversion of cholesterol to bile acids

• Obesity, rapid weight loss also increase biliary cholesterol secretion.– Acquired disorders : gall bladder stasis and reduced gall bladder motility

( in pregnancy, rapid weight loss, spinal cord injury).

Cholesterol stone• Content : Crystalline cholesterol

monohydrate is predominant

Pigment stone• Bilirubin calcium salt is

predominant

• Pigment stones– Black pigment – cirrhosis,

hemolytic anemia (hemoglobinopathy, red cell disorders)

– Brown pigment – Asian patients (infection)

PathogenesisCholesterol stone Pigment stone

• Pathogenesis of pigment stone:– Hemolytic anemias and

infections of the biliary tract → increased unconjugated bilirubin in the biliary tree → form precipitates : insoluble calcium bilirubinate salts.

PathologyCholesterol stones :

– Gross : pale yellow, ovoid, firm, single to multiple with faceted surfaces

– Mostly radiolucent, 20% is radio opaque due to the presence of calcium carbonate content.

Pigment stones:

– Black stone (in sterile gall bladder bile)- small size, fragile to touch, numerous, 50-70% are radioopaque

– Brown stone (in infected intrahepatic or extrahepatic ducts)- single to a few, soft, greasy, soaplike consistency due to presence of retained fatty acids released by bacterial phospholipases on biliary lecithins, radiolucent.

– Stone content : calcium salts of unconjugated bilirubin, lesser amounts of other calcium salts, mucin glycoproteins and cholesterol.

Summary :

• Complications :– Inflammation of gall

bladder (cholecystitis)– Empyema– Perforation,– Fistulas

• Complications-cont– Inflammation of biliary tree

(cholangitis)– Obstructive cholestasis– Pancreatitis– Erode adjacent bowel and

cause intestinal obstruction (gallstone ileus)

Summary:

Summary

Cholecystitis

• Def: Inflammation of the gall bladder• Can be divided into– Acute cholecystitis– Chronic cholecystitis– Acute superimposed on chronic

Acute cholecystitis• Can be divided into :

– Acute Calculous CS: 85-90% of the cases. Most common complication of gall stones and emergency cholecystectomy

– Acute Acalculous CS (10-15% of cases)

• Clinical features :– progressive right upper quadrant or

epigastric pain– Mild fever– Anorexia– Tachycardia– Sweating– Nausea– Vomiting– +-hyperbilirubinemia– mild to moderate leukocytosis– Mild ↑serum alkaline phosphatase

• In acute calculous CS : – previous episodes of pain– May constitute acute

medical emergency– May also present with

mild symptoms, resolved without medical intervention, attacks subsides in 7-10 days

– Recurrence is common

• Acute acalculous CS:– Insidious symptoms, obscured

by underlying condition precipitating the attacks

– Predisposing conditions :• Major, non biliary surgery• Severe trauma (eg: from motor

vehicle crashes)• Severe burns• Sepsis• Dehydration• Gall bladder stasis and sludging• Vascular compromise• Bacterial contamination

– May complicate in gangrene and perforation (more than Calculous CS)

Pathogenesis of acute calculous cholecystitis

stones

obstruction to bile outflow

inflammation of gall bladder wall due to phospholipases from the mucosa hydrolyzes biliary lecithin to lysolecithin

(toxic to the mucosa)

disrupt normal protective

glycoprotein layer

exposed the mucosal epithelium to the direct detergent

action of bile salts

Distended gall bladder

Prostaglandin released

Mucosal and mural

inflammation

Increase intraluminal

pressure

Compromise mucosal blood

flow

Pathogenesis of Acute acalculous cholecystitis

• Risk factors : sepsis with hypotension and multisystem organ failure, immunosuppression, major trauma, diabetes mellitus, infections

• Impaired blood flow to cystic artery (end artery)→ compromised blood flow → ischaemia of gall bladder

• Inflammation and edema of gall bladder wall compromising blood flow, accumulation of microcrystals of cholesterol ( biliary sludge), viscous bile, and gall bladder mucous →cystic duct obstruction

Pathology of acute cholecystitis• Gross :

– Enlarged, tense, edematous, red or violaceous colour (subserosal haemorrhage)

– Fibrinous /fibrinopurulent exudate covering the serosa

– +- stones obstructing the neck or cystic duct

– Lumen contains blood and pus (empyema)

– Green black necrotic

• Microscopic : – acute inflammation in the wall – mucosal ulceration.– May be associated with abscess

formation or gangrenous necrosis.

Chronic cholecystitis

• May be a sequelae of repeated bouts of mild to severe acute cholecystitis

• Associated with cholelithiasis > 90% of cases• Pathogenesis : supersaturation of bile

predisposes to both chronic inflammation and stone formation.

• 1/3 of cases : E.coli and enterococci can be isolated from the bile

• Clinical features :– recurrent attacks of epigastric or right upper quadrant pain– Nausea, vomiting and intolerance to fatty foods.

• Pathology:– Gross : • smooth and glistening to dull serosa (subserosal

fibrosis)• thickened wall, opaque gray-white appearance• Uncomplicated cases, lumen contains clear, green,

mucoid bile and stones with normal mucosa

• Microscopic : – Reactive proliferation of mucosa– Inflammation (lymphocytes, plasma cells, and

macrophages in the mucosa and in the subserosal fibrous tissue). May be minimal.

– Prominent outpouching of the mucosal epithelium through the wall (Rokitansky Aschoff sinuses)

– Marked subepithelial and subserosal fibrosis– +-Superimposed acute inflammation– +-Extensive calcification within the wall

→porcelain gall bladder →increase risk of cancer

• Xanthogranulomatous cholecystitis: massively thickened wall with shrunken, nodular, chronically inflamed with foci of necrosis and haemorrhage.

• Hydrops of the gall bladder : atrophic, chronically obstructed gall bladder containing only clear secretion

Complications of cholecystitis• Bacterial superinfection with

cholangitis or sepsis• Gall bladder perforation and local

abscess formation• Gall bladder rupture with diffuse

peritonitis• Biliary enteric (cholecystenteric)

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

• Aggravating of preexisting medical illness, with cardiac, pulmonary, renal or liver decompensation

• Porcelain gall bladder with increased risk of cancer

• Treatment : Cholecystectomy

Disorders of extrahepatic bile ducts

• Choledocholithiasis and cholangitis• Secondary biliary cirrhosis• Biliary atresia

Choledocholithiasis and cholangitis

• Choledocholithiasis = presence of stones within the biliary tree• In Western nation, almost all stones derived from the

gallbladder• In Asia, higher incidence of primary ductal and intrahepatic,

pigmented stone formation• 10% are asymptomatic• Sx develop secondary to

– Biliary obstruction– Cholangitis– Hepatic abscess– Chronic liver disease with secondary biliary cirrhosis– Acute calculous cholecystitis

• Cholangitis = acute inflammation of the wall of bile ducts due to bacterial infection

• Can result from any lesions obstructing the bile flow :– Choledocholithiasis– Surgery involving the billiary tree– Tumours– Indwelling stents / catheter– Acute pancreatitis– Benign strictures

• Bacteria enter the biliary tree mostly through the Sphincter of Oddi, and some through hematogenous route.

• Ascending cholangitis = propensity of bacteria to infect intrahepatic biliary ducts.

• Usual pathogens : E.coli, Klebsiella, Enterococci, Clostridium and Bacteroides.

• In some population, parasitic cholangitis also occur (Fasciola hepatica, schistosomiasis, Clonorchis sinensis or Opsthorchis viverrini, cryptosporidiosis)

• C/f bacterial cholangitis : fever, chills, abdominal pain and jaundice, suppurative cholangitis, sepsis.

Secondary biliary cirrhosis

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

• Causes of obstruction: extrahepatic cholelithiasis, biliary atresia, malignancies of the biliary tree and head of the pancreas, strictures from previous procedures

• Initial features of cholestasis are reversible with correction of obstruction.

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

Pathogenesis

Biliary atresia• Major cause of neonatal cholestasis.• Defined as complete obstruction of bile flow caused by

destruction or absence of all or part of the extrahepatic bile ducts.

• Most frequent cause of death from liver disease in early childhood

• Salient features :– 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– Periportal fibrosis and cirrhosis within 3-6 months of birth

Clinical features

• Neonatal cholestasis• Slight female predominance• Normal weight infants with postnatal weight gain• Acholic stool as disease evolves• Lab Ix : not helpful• Liver biopsy : evidence of bile ducts obstruction• Tx : liver transplantation• Withour surgical intervention, death occurs within

2 years of birth.

Summary : Diseases of the gall bladder and Extrahepatic bile ducts

• Gall bladder diseases include cholelithiasis and acute and chronic cholecystitis

• Gallstone formation is a common condition in Western countries. The great majority of the gall stones are cholesterol stones. Pigmented stones containing bilirubin and calcium are most common in Asian countries.

• 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, although in about 10% of cases, it occurs in the absence of gallstones

• Acute calculous cholecystitis is the most common reason for emergency cholecystectomy

• 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.

Carcinoma of the gall bladder

• Uncommon• Most common malignant tumour of the biliary tract• 2-6x in women• 7th decades of life• More frequent in the populations of Mexico and Chile (high

incidence of gall stones)• In US, incidence is higher in Hispanics and Native

Americans.• Etiology : (recurrent trauma and chronic inflammation)

– Gallstones are present in 60-90% of the cases– Parasitic disease of the biliary tree

Clinical features

• Insidious onset• Similar to cholelithiasis (Abd pain, jaundice,

anorexia, nausea and vomiting)• Sx of Acute cholecystitis • Accidental finding during cholecystectomy for

symptomatic gall stone• Tx : – surgical resection (including adjacent liver)– +- chemotherapy.

Pathology• Gross : exhibit exophytic or

infiltrating patterns (more common)• Poorly defined areas of diffuse

thickening and induration of the gall bladder wall covering several cm or involve the entire gall bladder

• Scirrhous and very firm• The exophytic growth grows into the

lumen as an irregular, cauliflower like mass as well as invades the underlying wall.

• Mostly diagnosed at late stage – invade liver or spread to the bile ducts or to the portal hepatic lymph nodes.

HPE : mostly are adenocarcinoma

Cholangiocarcinomas• Adenocarcinomas that arise from cholangiocytes lining the intrahepatic

and extrahepatic biliary ducts• Extrahepatic cholangiocarcinomas (2/3) of the tumours• Site : hilum (Klatskin tumour) or distal biliary tree• 50-70 years old• Asymptomatic until late stage• Poor prognosis• Risk factors : primary sclerosing cholangitis, fibropolycystic diseases of

the biliary tree, infestation by Clonorchis sinensis or Opisthorchis viverrini – chronic cholestasis and inflammation → promote somatic mutations in cholangiocytes

• Genetic changes : activating mutations in the KRAS and BRAF oncogenes and loss of function mutations in the TP53 tumour suppressor gene.

Clinical features

• Liver mass• Non specific signs and symptoms : weight loss, pain,

anorexia, ascites• If there is biliary obstruction : jaundice, acholic stool,

nausea and vomiting, weight loss• Elevated alkaline phosphatase and aminotransferases• Spread to extrahepatic sites : regional lymph nodes, lungs,

bones, adrenal glands, invasion along peribiliary nerves→to abdomen

• Tx : surgical excision , majority non curative• Mean survival time : 6-18 months

Pathology

• Micro : adenocarcinoma accompanied by abundant fibrous stroma – firm, gritty consistency

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