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Pathophysiology of diseases of (Gallbladder, Biliary tree, and Pancreas) Prepared by Dr Ibrahim Mousa Maaroof Higher Diploma student M.B.Ch.B. Dr Sarmad Nadhem Ismael Higher Diploma student M.B.Ch.B. Supervised by Assist. Prof. Dr Baderkhan Saeed Ahmed Assist. Prof. Dr Azhy Muhammed Dewana 9 January...

Pathophysiology of diseases of (Gallbladder, Biliary tree, and Pancreas) Prepared by Dr Ibrahim Mousa Maaroof Higher Diploma student M.B.Ch.B. Dr Sarmad Nadhem Ismael Higher Diploma student M.B.Ch.B. Supervised by Assist. Prof. Dr Baderkhan Saeed Ahmed Assist. Prof. Dr Azhy Muhammed Dewana 9 January 2024 1 GALLBLADDER AND BILIARY TREE 9 January 2024 2 BENIGN CONDITIONS OF GALLBLADDER AND BILIARY TREE 9 January 2024 3 CHOLELITHIASIS - INCIDENCE 1. Found in 12% of general population 2. Majority (80%) are asymptomatic. 3. Predisposing conditions a. Sex distribution—twice as common in women b. Age—found in 20% of adults older than 40 years and 30% of adults older than 50 c. Medical—obesity, pregnancy, rapid weight loss, total parenteral nutrition, diabetes, pancreatitis, chronic hemolytic states, malabsorption, Crohn disease, spinal cord injuries, increased triglycerides, decreased high-density lipoprotein d. Drugs—exogenous estrogens, clofibrate, octreotide, ceftriaxone e. Ethnic factors—Pima Indians, other Native Americans, Scandinavians, persons living in Chile 9 January 2024 4 CAUSATIVE FACTORS Three principal defects contribute to gallstone formation. 1. Cholesterol supersaturation—most critical to stone formation a. Three major constituents in bile: (1) Bile salts—primary: cholic and chenodeoxycholic acids; secondary: deoxycholic and lithocholic (2) Phospholipids—90% lecithin (3) Cholesterol—Bile containing excess cholesterol relative to bile salts and lecithin is predisposed to gallstone formation 2. Accelerated nucleation a. Mucin and bilirubin are pronucleators associated with increased stone formation. 3. Gallbladder hypomotility/stasis 9 January 2024 5 TYPES OF GALLSTONES 1. Mixed (75%) a. Most common, relatively small in size, usually multiple b. Predominantly cholesterol (at least 50% of content) 2. Pure cholesterol (10%) a. Often solitary with large, round configuration b. Usually not calcified 3. Pigment (15%) a. Result from bilirubin precipitation b. More common in women and Asian individuals c. Black pigment—associated with cirrhosis and chronic hemolytic states d. Brown pigment—usually associated with biliary infection and more ommon in biliary tree than in gallbladder e. Approximately 50% are radiopaque. 9 January 2024 6 9 January 2024 7 SYMPTOMATIC CHOLELITHIASIS A. BILIARY COLIC Defined as pain arising from the gallbladder without established inflammation or infection 1. Pathology—results from intermittent obstruction of the cystic duct by stone 2. Natural history a. Rate of recurrence is between 50% and 70% after first episode. b. Risk for development of biliary complications is 1%–2% per year. 3. Complications a. Prolonged obstruction can lead to acute cholecystitis. b. Stones may pass into the CBD, resulting in choledocholithiasis, cholangitis, or pancreatitis. 9 January 2024 8 B. ACUTE CALCULOUS CHOLECYSTITIS Defined as pain arising from inflammation of the gallbladder wall 1. Pathology a. Impacted stone in the cystic duct results in prolonged obstruction. b. Stasis of bile damages gallbladder mucosa, resulting in the release of enzymes and inflammatory mediators. c. Histology ranges from mild acute inflammation to edema to necrosis and perforation of the gallbladder wall. d. Forty percent of bile cultures are positive for bacteria in this setting. (1) Usually single-organism growth (2) Most likely organisms include Escherichia coli, Klebsiella, Enterococcus, Enterobacter. 9 January 2024 9 2. Natural history a. Seventy-five percent of cases report previous attack of biliary pain. b. If untreated, 80% resolve within 7–10 days. c. Complications develop in approximately 17%. 3. Complications a. If left untreated and the cystic duct remains obstructed, the gallbladder can fill with a clear mucoid fluid—hydrops of the gallbladder. (1) This can lead to ischemia/necrosis/perforation of gallbladder wall. b. Results are gangrenous cholecystitis 7% of the time, gallbladder empyema (6%), perforation (3%), and emphysematous cholecystitis (<1%). 9 January 2024 10 CHOLEDOCHOLITHIASIS Choledocholithiasis is the occurrence of stones in the bile ducts. CAUSATIVE FACTORS AND NATURAL HISTORY 1. Up to 15% of patients with gallstones have CBD stones. 2. Primary CBD stones (rare) a. Brown pigment stones often form as a result of bacterial action on phospholipids and bile and form de novo in the duct usually as a result of obstruction. b. Those with a history of biliary sphincterotomy are at greater risk. 9 January 2024 11 3. Secondary CBD stones (more common) a. Cholesterol stones and black pigment stones form in the gallbladder and pass into the CBD. 4. CBD stones may remain asymptomatic for years and pass silently into the duodenum. 5. Laboratory values can be normal; however, increases in serum bilirubin, alkaline phosphatase, or amylase are often seen. 9 January 2024 12 CHOLANGITIS CAUSATIVE FACTORS AND PATHOPHYSIOLOGY 1. Eighty-five percent of cases are caused by impacted stone in the bile ducts, resulting in stasis of bile in the presence of bacteria. 2. Pus under pressure in the bile ducts leads to rapid bacteremia and sepsis. 3. Other causes include neoplasm, strictures, parasitic infections, and congenital abnormalities. 4. Most common organisms include E. coli, Klebsiella, Pseudomonas, enterococci, and Proteus. a. Anaerobic organisms (Bacteroides and Clostridium) in 15% of cases 9 January 2024 13 ACALCULOUS CHOLECYSTITIS A. EPIDEMIOLOGY AND PATHOGENESIS 1. Most cases occur in the setting of prolonged fasting, immobility, and hemodynamic instability. a. With prolonged fasting, the gallbladder is not stimulated by cholecystokinin to empty and bile stagnates in the lumen. b. Dehydration can lead to formation of extremely viscous bile, which may obstruct or irritate the gallbladder. 9 January 2024 14 c. Bacteremia may result in the seeding of the stagnant bile. d. Septic shock with resultant mucosal hypoperfusion can result in ischemia of the gallbladder wall. 2. Less commonly, it may occur in children, patients with vascular disease or systemic vasculitis, bone marrow transplant recipients, immunocompromised patients, and patients receiving cytotoxic drugs via the hepatic artery. 9 January 2024 15 OTHER DISORDERS OF THE GALLBLADDER A. BILIARY DYSKINESIA 1. Delayed gallbladder emptying in the absence of stones or sludge is predictive of pain relief after cholecystectomy. 2. Low gallbladder ejection fraction also predicts outcome. a. Ejection fraction less than 35% is considered abnormal. b. Cholecystectomy improves symptoms 67%–90% of the time. 3. Both delayed emptying and gallbladder ejection fraction can be detected with HIDA scan. 9 January 2024 16 B. BILIARY SLUDGE 1. Generally a complication of biliary stasis 2. Pathogenesis, natural history, and treatment—similar to gallstones 3. Commonly found in patients in the intensive care unit 4. Less chance of recurrence after single episode of colic 9 January 2024 17 C. MIRIZZI SYNDROME 1. Stone impacted in the gallbladder neck or cystic duct compresses the common hepatic duct, resulting in bile duct obstruction and jaundice. 2. This is found in 1% of patients undergoing cholecystectomy. 3. Type I—compression of hepatic duct by large stone a. Subsequent inflammation can result in a stricture of the hepatic duct. 4. Type II—cholecystocholedochal fistula from stone erosion into the hepatic duct 9 January 2024 18 D. GALLSTONE ILEUS Bowel obstruction resulting from impaction of gallstone in the intestinal lumen 1. Cause of obstruction in less than 1% of patients younger than 70 years; 5% in patients older than 70 2. Results from erosion of a large gallstone (>2.5 cm) into the intestinal lumen via a cholecystenteric fistula a. Most commonly into the duodenum but also can erode into the colon or stomach 3. Complete obstruction generally occurs in the terminal ileum where the bowel lumen is the narrowest. 4. Bouveret syndrome—gallstone impaction in pylorus or duodenum resulting in symptoms of gastric outlet obstruction 9 January 2024 19 E. EMPHYSEMATOUS CHOLECYSTITIS 1. Infection of the gallbladder wall with gas-forming bacteria, usually anaerobes 2. More common in individuals with diabetes and can rapidly progress to gangrene and perforation 3. Prompt cholecystectomy is imperative. F. CALCIFIED “PORCELAIN” GALLBLADDER 1. Intramural calcification of the gallbladder wall 2. Seen on CT or abdominal radiograph 3. Gallbladder carcinoma in 20% 4. Prophylactic treatment with open or lap chole 9 January 2024 20 MALIGNANT CONDITIONS OF GALLBLADDER AND BILIARY TREE 9 January 2024 21 GALLBLADDER CANCER 1. In the United States, 1.2 cases per 100,000 people annually; worldwide, sixth most common gastrointestinal tumor and represents more than 80% of biliary tumors 2. Found in 0.1%–0.5% of all cholecystectomy specimens 3. Associated with gallstones in more than 90% of cases 4. Increased incidence in certain ethnic groups—Alaskan, Native Americans 5. Other factors—porcelain gallbladder, cholecystenteric fistulas, anomalous pancreaticobiliary junction, inflammatory bowel disease, Mirizzisyndrome 6. Male/female ratio of 1:2 7. Adenocarcinoma—most common cell type; 82% of cases 8. Grave prognosis, with 5-year survival rates of less than 5% in untreated patients and median overall survival less than 6 months; 50% of patients with lymph node disease at time of diagnosis 9 January 2024 22 BILE DUCT CANCER (CHOLANGIOCARCINOMA) A. GENERAL CONSIDERATIONS 1. Rare cancer. Accounts for only 2%–3% of malignancies 2. Divided into intrahepatic or extrahepatic cholangiocarcinoma 3. Known risk factors for cholangiocarcinoma (causes of chronic inflammation of bile ducts: primary sclerosing cholangitis, choledochal cysts, chronic Salmonella typhi infection, and parasitic infections [liverflukes]). 4. CEA and CA 19-9 levels may be elevated and can be useful for postoperative surveillance. 9 January 2024 23 B. INTRAHEPATIC CHOLANGIOCARCINOMA 1. This is the second most common liver cancer after hepatocellular carcinoma (HCC). It originates from intrahepatic bile ducts. 2. In most patients, the tumor is discovered incidentally. 3. Most patients do not have underlying liver disease. C. EXTRAHEPATIC CHOLANGIOCARCINOMA 1. A total of 60%–70% arise in perihilar region (Klatskin tumors), 20%– 25% arise in distal bile duct (periampullary), and less than 10% are multifocal. 2. Reported 5-year survival is a dismal 10%–20%. with improved survival. 9 January 2024 24 Pancreas Pathophysiology 9 January 2024 25 Pancreatitis Acute pancreatitis (AP) • Acute pancreatitis is a common cause of emergency admission to Hospital • The disease is relatively rare in children, but all adult age groups may be affected • AP is a disorder whose pathogenesis remains obscure and for which treatment is largely supportive . • The overall mortality for AP is approximately 10 % , but in its most severe form , which is characterized by pancreatic hemorrhage and necrosis, can increase the mortality to 20% to 30%. 9 January 2024 26 Etiology • Gallstones • Hyperlipidemia • Ethanol • Hypercalcemia • Iatrogenic causes • Infectious agents ERCP Viruses ( e . g . , m umps and coxsackie B viruses; H IV) Abdominal operations Bacteria ( e . g . , Salmonella and Shigella species; hemorrhagic E. coli) Cardiopulmonary bypass Biliary parasites ( e . g . , Ascaris lumbricoides) • Trauma • Genetic causes • Neoplasms (e.g., pancreatic cancer) Hereditary pancreatitis • Pancreas divisum Cystic fibrosis • Sphincter of Oddi spasm • Vasculitis (e.g., systemic lupus erythematosus and polyarteritis nodosa) • Medications • Toxins • Ischemia • Pregnancy Parathion Scorpion venom 9 January 2024 27 Gallstone pancreatitis 9 January 2024 28 Complications Pancreatic pseudocysts • A pseudocyst is defined as fluid collection over 4 weeks old that is surrounded by a defined wall made up of fibrous tissue and surrounding organs. • It occurs as a consequence of a ductal leak or as a complication of severe inflammation and, therefore , consists mostly of pancreatic secretions. • They are known as pseudocysts because they lack the discrete epithelial lining definitive of true cysts . 9 January 2024 29 • Pseudocysts develop as a complication in 10% of patients who suffer an attack of AP. • More than half of all pseudocysts resolve within 4 to 6 weeks . After 6 weeks, spontaneous resolution is less likely and surgical intervention is indicated 9 January 2024 30 Pancreatic necrosis • Pancreatic necrosis is defined as diffuse or focal area (s) of nonviable pancreatic parenchyma, often associated with peripancreatic fat necrosis. 9 January 2024 31 Pancreatic abscesses • Pancreatic abscesses are defined as a circumscribed, intraabdominal collection of pus in proximity to the pancreas, containing little or no pancreatic necrosis. • They can be insidious; are frequently multiple; and are evenly divided among head, body, and tail of the gland. • Abscesses are frequently polymicrobial, containing Candida species as well as enteric bacteria such as Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis. 9 January 2024 32 Pancreatic fistulas • Both internal and external fistulas may result from inflammation and pancreatic duct disruption. • Fluid may track into the left pleural cavity through the retroperitoneum , causing an effusion. • Other complications include splenic vein thrombosis and false aneurysms, which may lead either to bleeding into the pancreatic duct (hemosuccus pancreaticus) or free rupture leading to hemoperitoneum 9 January 2024 33 Chronic Pancreatitis • Chronic pancreatitis is an inflammatory disease of the pancreas that is marked by the gradual destruction of pancreatic exocrine and endocrine tissues. Fibrous scar replaces the pancreatic parenchyma. • Pancreatic calcifications are seen in one-third of patients with alcoholic chronic pancreatitis. 9 January 2024 34 • Etiology 1. Alcoholism is the cause of 75% of the cases of chronic pancreatitis in the United States . 2. Less common causes include cystic fibrosis, pancreas divisum, hyperparathyroidism, familial pancreatitis, and idiopathic pancreatitis. 3. Another kind of chronic pancreatitis, possibly related to malnutrition, occurs only in certain tropical areas 9 January 2024 35 Tumors Exocrine pancreatic neoplasms 9 January 2024 36 • These tumors, which are either cystic or solid, are the most common "cystic lesions" in the pancreas and are inflammatory pseudocysts that are obviously non-neoplastic. • Although many of the cystic lesions are small and benign, they do have malignant potential. • Remember that the overall postresection survival for malignant cystic lesions is markedly better than for pancreatic ductal adenocarcinoma, which unfortunately is the most common pancreatic neoplasm 9 January 2024 37 Malignant pancreatic neoplasms • Ductal adenocarcinomas account for 90% of all malignant pancreatic cancers. • Approximately 65% arise in the pancreatic head and uncinate process, and 15 % arise in the body and tail, Twenty percent are diffuse. • Uncommon malignant conditions include acinar cell carcinoma, nonepithelial tumors , and lymphomas. • Every year, 30,000 new cases of malignant pancreatic cancers are diagnosed in the United States. 9 January 2024 38 9 January 2024 39 • Risk factors include hereditary or chronic pancreatitis, smoking, and Peutz-Jeghers syndrome. • Genetic alterations include overexpression of K-ras oncogene and inactivation of p 16 and p53. 9 January 2024 40 The histology • Is characterized by groups of infiltrating carcinoma cells often some (histological) distance apart, interspersed by a fibrous stroma, with involvement of nerves, vessels, lymphatics and lymph nodes commonly seen, even when the primary tumour is small. • Metastatic spread is most commonly to the liver and lung; 80% of patients present with either locoregional or metastatic dissemination. 9 January 2024 41 • Isolated metastases in the pancreas are rare, the most common site of origin being renal cell carcinoma, followed by lung, lobular breast carcinoma, melanoma and gastric carcinoma. • Some may benefit from resection and so where suspected, endoscopic ultra-sound with fine needle cytology is often requested to confirm the diagnosis 9 January 2024 42 REFERENCES • O'Connell, P.R., McCaskie, A.W., & Sayers, R.D. (Eds.). (2023). Bailey & Love's Short Practice of Surgery - 28th Edition • Brunicardi F, & Andersen D.K., & Billiar T.R., & Dunn D.L., & Kao L.S., & Hunter J.G., & Matthews J.B., & Pollock R.E.(Eds.), (2019). Schwartz's Principles of Surgery, 11e. 9 January 2024 43 Thank You 9 January 2024 44