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 Clinical features: 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).

Pigment stone Cholesterol stone Pigment stones Bilirubin calcium salt is predominant Pigment stones Black pigment – cirrhosis, hemolytic anemia (hemoglobinopathy, red cell disorders) Brown pigment – Asian patients (infection) Content : Crystalline cholesterol monohydrate is predominant

Pathogenesis Pigment stone Cholesterol 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.

Pathology Cholesterol stones : 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. 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.

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 : Clinical features : 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

Acute acalculous CS: In acute calculous 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) 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

Pathogenesis of acute calculous cholecystitis Compromise mucosal blood flow 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 Increase intraluminal pressure Distended gall bladder Prostaglandin released Mucosal and mural inflammation

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 : Pathology: 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

Can result from any lesions obstructing the bile flow : 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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