Chapter 52: Gallstone Disease PDF

Access Provided by: Greenberger's CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, 4e Chapter 52: Gallstone Disease Stephen D. Zucker ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Major risk factors for cholesterol gallstones include age >50, female sex, Nativ...

Access Provided by: Greenberger's CURRENT Diagnosis & Treatment Gastroenterology, Hepatology, & Endoscopy, 4e Chapter 52: Gallstone Disease Stephen D. Zucker ESSENTIALS OF DIAGNOSIS ESSENTIALS OF DIAGNOSIS Major risk factors for cholesterol gallstones include age >50, female sex, Native American or Mexican ethnicity, genetic predisposition, family history, pregnancy and parity, estrogens, obesity, and the metabolic syndrome. Gallstones are often found incidentally during abdominal ultrasonography, which has >95% sensitivity for cholesterol stones ≥1.5 mm. In ~80% of cases gallstones remain asymptomatic; in symptomatic patients, biliary colic is almost always present, often radiating to the right scapula or shoulder. Laparoscopic cholecystectomy is indicated in patients with symptomatic gallstones. Major complications of gallstone disease requiring treatment are acute cholecystitis, choledocholithiasis, obstructive jaundice, cholangitis, and pancreatitis. Acute cholangitis caused by an obstructing gallstone should be treated by endoscopic removal of the stone under antibiotic coverage as soon as possible. GENERAL CONSIDERATIONS Gallstone disease represents a considerable health burden in Western industrialized countries, with a prevalence of 10–15% and a 5­year incidence of 2–4%. In the United States, approximately 600,000 cholecystectomies are performed annually at a cost of approximately $6.5 billion. Both genetic and environmental factors have been shown to play a role in the development of gallstone disease. The clinical manifestations of gallstones include episodic abdominal pain, acute cholecystitis, obstructive jaundice, cholangitis, and pancreatitis. In Western industrialized countries, the vast majority of gallstones are comprised principally of cholesterol; hence, cholelithiasis can be regarded primarily as a disturbance of cholesterol elimination. A complex solubilizing system is required to keep cholesterol in solution in the bile. If this system fails, or if its capacity is exceeded by hypersecretion of cholesterol, cholesterol precipitates within the gallbladder, and gallstones may develop. PATHOGENESIS There are two major classes of gallstones. Cholesterol stones, which account for more than 85% of all gallstones in Western countries, are comprised primarily of cholesterol with variable admixtures of calcium salts, bile pigments, proteins, and fatty acids. Pigment stones comprise the remaining 15% of gallstones and are principally composed of calcium bilirubinate, with a cholesterol content of less than 20%. Pigment stones are further subdivided into black pigment stones, which develop in the gallbladder, and brown pigment stones, which form within the biliary system. A. Cholesterol Stones Because cholesterol has poor aqueous solubility, bile acids and phospholipids are required for adequate solubilization of cholesterol in the bile, through the formation of mixed micelles (Figure 52–1). When the cholesterol concentration in bile exceeds the solubilizing capacity of bile acids and Downloaded phospholipids2025­2­17 2:20 P Your (termed cholesterol IP is supersaturation), unstable cholesterol­rich vesicles aggregate into large multilamellar vesicles, from which Chapter 52: Gallstone Disease, Stephen D. Zucker Page 1 / 15 cholesterol crystals precipitate. If not expeditiously expelled from the gallbladder, these crystals become entrapped in gallbladder mucin gel, where ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility they grow and agglomerate to form stones. into black pigment stones, which develop in the gallbladder, and brown pigment stones, which form within the biliary system. Access Provided by: A. Cholesterol Stones Because cholesterol has poor aqueous solubility, bile acids and phospholipids are required for adequate solubilization of cholesterol in the bile, through the formation of mixed micelles (Figure 52–1). When the cholesterol concentration in bile exceeds the solubilizing capacity of bile acids and phospholipids (termed cholesterol supersaturation), unstable cholesterol­rich vesicles aggregate into large multilamellar vesicles, from which cholesterol crystals precipitate. If not expeditiously expelled from the gallbladder, these crystals become entrapped in gallbladder mucin gel, where they grow and agglomerate to form stones. Figure 52–1. Biliary secretion and solubilization of cholesterol. Cholesterol is secreted by the ABC­binding cassette (ABC) transporter ABCG5/G8, phosphatidylcholine by the multidrug­resistance p­glycoprotein 3 (MDR3; ABCB4), and bile acids by the bile salt export pump (BSEP; ABCB11). Cholesterol and phosphatidylcholine reach the bile as metastable unilamellar vesicles, which are converted into water­soluble stable mixed micelles by the bile acids. If the secretion of cholesterol into bile exceeds the solubilizing capacity of bile acids and phospholipids, cholesterol­rich vesicles remain, which aggregate into large unstable multilamellar vesicles from which cholesterol crystals precipitate. These crystals may aggregate and form cholesterol stones. Recent evidence indicates that a variant in the hepatocanalicular cholesterol transporter gene ABCG8 contributes to the risk of cholesterol gallstone formation (for details see text). While an excess of biliary cholesterol in relation to its carriers (phospholipids and bile acids) is a sine qua non for the formation of cholesterol gallstones, cholesterol supersaturation alone is not sufficient for stone formation. Indeed, nearly 50% of adults manifest supersaturated bile over the course of a day, yet only a minority develop gallstones. Bile stability, mediated by inhibitors and promoters of cholesterol crystal nucleation, as well as gallbladder stasis, are essential factors in the pathogenesis of cholesterol gallstones: 1. Cholesterol supersaturation The supersaturation of bile with cholesterol may result from hypersecretion of cholesterol, hyposecretion of bile acids and/or phospholipids, or a combination of both. The transport of biliary lipids from the hepatocyte into the bile canaliculus is mediated by several key canalicular membrane transport proteins (Figure 52–1), including the cholesterol transporter (ABCG5/ABCG8), the bile salt export pump (BSEP; ABCB11), and the multidrug resistance p­glycoprotein 3 (MDR3; ABCB4) which translocates phosphatidylcholine across the canalicular membrane. Cholesterol hypersecretion is the most common cause of bile supersaturation. It may result from enhanced synthesis of cholesterol, increased hepatic uptake of endogenous (via low­density lipoproteins) or exogenous (via chylomicrons) cholesterol, and/or augmented canalicular transport of cholesterol into bile. An inappropriately low rate of cholesterol 7α­hydroxylation, the rate­limiting step in the conversion of cholesterol to bile acids, also can increase cholesterol secretion into bile. Additionally, reduced enterohepatic cycling of bile acids as a result of impaired ileal uptake with resultant fecal loss can play a role by decreasing the bile acid pool. 2. Destabilization of bile Most individuals with supersaturated bile do not develop gallstones because the time necessary for cholesterol crystals to nucleate and grow exceeds Downloaded 2025­2­17 the duration of 2:20isPheld time the bile Your IP isgallbladder. The stability of phospholipid­cholesterol vesicles depends not only on the cholesterol in the Chapter 52: Gallstone Disease, Stephen D. Zucker Page 2 / 15 concentration, ©2025 McGrawbut also Hill. Allon the balance Rights Reserved.between Termsinhibitors of Use and promoters Privacy Policyof Notice cholesterol crystal formation. A principal protein that promotes Accessibility cholesterol nucleation is gallbladder mucin, a mixture of glycoproteins that layers at the mucosal surface of the gallbladder wall (Figure 52–2). Release of mucin is stimulated by deoxycholic acid. The influence of promoting and inhibiting factors on the appearance of crystals in bile is termed the cholesterol secretion into bile. Additionally, reduced enterohepatic cycling of bile acids as a result of impaired ileal uptake with resultant fecal loss can Access Provided by: play a role by decreasing the bile acid pool. 2. Destabilization of bile Most individuals with supersaturated bile do not develop gallstones because the time necessary for cholesterol crystals to nucleate and grow exceeds the duration of time the bile is held in the gallbladder. The stability of phospholipid­cholesterol vesicles depends not only on the cholesterol concentration, but also on the balance between inhibitors and promoters of cholesterol crystal formation. A principal protein that promotes cholesterol nucleation is gallbladder mucin, a mixture of glycoproteins that layers at the mucosal surface of the gallbladder wall (Figure 52–2). Release of mucin is stimulated by deoxycholic acid. The influence of promoting and inhibiting factors on the appearance of crystals in bile is termed the “nucleation time,” which is much shorter in gallbladder bile from patients with cholesterol gallstones than in equally supersaturated gallbladder bile from normal subjects. Figure 52–2. Formation, growth, and aggregation of cholesterol crystals in the mucin gel layered at the mucosal surface of the gallbladder wall (for details see text). 3. Stasis of bile in the gallbladder If the gallbladder emptied all supersaturated bile completely before crystals had formed, stones would not be able to grow. Hence, prolonged retention of bile within the gallbladder is another important prerequisite for lithogenesis. A high percentage of patients with gallstones manifest impaired gallbladder emptying. Studies of gallbladder motility using ultrasonography have shown that patients with gallstones have increased fasting and residual gallbladder volume, and that fractional emptying of the gallbladder is diminished (Figure 52–3). The incidence of gallstones is increased in conditions associated with reduced or infrequent gallbladder emptying, such as fasting, parenteral nutrition, or pregnancy, and in patients using drugs that inhibit gallbladder motility (eg, octreotide, loperamide). Gallbladder hypomotility during fasting results from lack of gallbladder stimulation; consequently, the risk of stone formation during parenteral nutrition can be decreased by administration of cholecystokinin. During pregnancy, both the fasting volume and the residual volume of the gallbladder rise with serum progesterone, which inhibits smooth muscle contractility and impairs emptying. Figure 52–3. Impaired gallbladder emptying after a test meal in patients with gallstones measured by ultrasonography. (Data from Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27–31.) Downloaded 2025­2­17 2:20 P Your IP is Chapter 52: Gallstone Disease, Stephen D. Zucker Page 3 / 15 ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Figure 52–3. Access Provided by: Impaired gallbladder emptying after a test meal in patients with gallstones measured by ultrasonography. (Data from Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27–31.) B. Pigment Stones Pigment stones are comprised primarily of bilirubin and form when appreciable levels of unconjugated bilirubin, which is poorly water soluble, are present within the bile. Bilirubin is conjugated in the liver by the 1A1 isoform of the enzyme UDP­glucuronosyltransferase (UGT1A1) to form the water­ soluble bilirubin diglucuronide, which is secreted across the bile canaliculus by the multidrug resistance­associated protein 2 (MRP2; ABCC2). Pigment stones are sub­categorized as black pigment stones, which principally consist of calcium bilirubinate and form in the gallbladder. They occur in patients who have chronic hemolytic states (eg, sickle cell anemia), cirrhosis, Gilbert syndrome, or cystic fibrosis, all of which lead to augmented levels of unconjugated bilirubin in the bile (Table 52–1). There also is an increased incidence of black pigment stones in patients with bile salt malabsorption (eg, ileal disease, ileal resection), which increases solubilization of bilirubin in the colon, thereby enhancing its enterohepatic cycling. Table 52–1. Major risk factors for pigment stones. Associated conditions Chronic hemolysis Pernicious anemia Liver cirrhosis Cystic fibrosis Chronic biliary tract infections Biliary parasites Ileal disease/Crohn’s disease Ileal resection or bypass Brown pigment stones are comprised of calcium salts and unconjugated bilirubin, with varying amounts of cholesterol and protein. They result from the generation of unconjugated bilirubin within the biliary system through the action of the bacterial enzymes β­glucuronidase, phospholipase A1, and conjugated bile acid hydrolase, which act to deconjugate bilirubin glucuronides. Brown pigment stones typically form in the setting of bile stasis and chronic infection of the biliary system, as seen in patients with strictures (eg, primary sclerosing cholangitis, ischemic cholangiopathy), parasitic disorders (eg, Clonorchis sinensis, Ascaris lumbricoides), or congenital abnormalities (eg, Caroli’s disease). Gurusamy KS, Davidson BR. Gallstones. BMJ. 2014;348:g2669. [PubMed: 24755732] Downloaded 2025­2­17K,2:20 Lammert F, Gurusamy P Your Ko CW, et al.IPGallstones. is Nat Rev Dis Primers. 2016;2:16024. Chapter 52: Gallstone Disease, Stephen D. Zucker Page 4 / 15 [PubMed: 27121416] ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368:230–239. chronic infection of the biliary system, as seen in patients with strictures (eg, primary sclerosing cholangitis, ischemic cholangiopathy), parasitic disorders (eg, Clonorchis sinensis, Ascaris lumbricoides), or congenital abnormalities (eg, Caroli’s disease). Access Provided by: Gurusamy KS, Davidson BR. Gallstones. BMJ. 2014;348:g2669. [PubMed: 24755732] Lammert F, Gurusamy K, Ko CW, et al. Gallstones. Nat Rev Dis Primers. 2016;2:16024. [PubMed: 27121416] Portincasa P, Moschetta A, Palasciano G. Cholesterol gallstone disease. Lancet. 2006;368:230–239. [PubMed: 16844493] C. Epidemiology & Genetics Gallstones In the third National Health and Nutrition Examination Survey (NHANES III), a large cross­sectional epidemiologic study of the U.S. population, the overall prevalence of gallstones in the United States was 7.9% in men and 16.6% in women, with a progressive increase after age 20. The prevalence was high in Mexican Americans (men: 8.9%, women: 26.7%), intermediate for non­Hispanic whites (men: 8.6%, women: 16.6%), and low for African Americans (5.3% in men, 13.9% in women). Overall gallstone prevalence rates in Europe, as ascertained from large abdominal ultrasound surveys of adults aged 30–69, are similar to those in the NHANES III study. The prevalence of gallstone disease is lower in Asian populations (ranging from 3% to 15%) and very low (10 mm in presence of gallbladder stones ­ Direct evidence of stone in bile ducts by ultrasound Low probability for simultaneous bile duct stones ­ Common bile duct not dilated ­ GGT, alkaline phosphatase, and ALT within normal limits ALT, alanine aminotransferase; GGT, γ­glutamyl transferase. If ultrasonography is nondiagnostic, clinical symptoms and signs should guide further diagnostic measures. If there is high suspicion for choledocholithiasis, endoscopic retrograde cholangiography (ERC) is indicated because it permits simultaneous therapeutic intervention (endoscopic papillotomy and stone extraction). The sensitivity and specificity of ERC for the detection of bile duct stones is greater than 90%. However, routine ERC prior to laparoscopic cholecystectomy is not recommended, as the prevalence of choledocholithiasis in patients with gallbladder stones is low, ranging from 5% to 15%, and the risk of ERC is nontrivial. In situations where the index of suspicion for choledocholithiasis is intermediate, endoscopic ultrasound or MRCP (see Figure 9–36) should be considered prior to performing an ERC. A meta­analysis of five randomized controlled studies reported similar sensitivity (93% vs 85%) and specificity (96% vs 93%) of endoscopic ultrasound and MRCP for identification of bile duct stones. Endoscopic ultrasound has the advantage of permitting the rapid transition to therapeutic ERC if choledocholithiasis is encountered. C. Ascending Cholangitis The characteristic presentation of ascending cholangitis includes biliary pain (typically in the right upper quadrant and/or epigastrium), jaundice, and spiking fevers with chills. These clinical features, termed Charcot’s triad, have a 36% specificity and 93% specificity for cholangitis. Leukocytosis is typical, and blood cultures are positive in about 75% of cases, the most common organisms being E. coli (25–50%), Klebsiella (15–20%), enterococcus (10–20%), and Enterobacter (5–10%). D. Biliary Pancreatitis Biliary pancreatitis occurs when gallstones pass through the ampulla of Vater leading to ampullary spasm, fibrosis, and obstruction with consequent biliopancreatic reflux. In patients with gallstones, 4–8% will ultimately develop biliary pancreatitis, which can be the first manifestation of gallstone disease. A serum lipase greater than three times the upper limit of normal is a main diagnostic criteria. The most common liver enzyme abnormality is the ALT level, with a three­fold elevation having a positive predictive value of approximately 95% in diagnosing biliary pancreatitis. E. Biliary Fistula Bilioenteric fistulas are spontaneous communications between the biliary system and the gastrointestinal tract that develop in 1–2% of patients with gallstones. The most common clinical manifestations are ascending cholangitis or a bile acid malabsorption syndrome similar to postcholecystectomy, although patients can be asymptomatic. In approximately 60% of cases, the fistulas are located between the gallbladder and the duodenum. Passage of large stones through a fistula can cause gastric outlet obstruction as a result of impaction in the proximal duodenum (Bouveret syndrome), or gallstone ileus should the gallstone become lodged in the terminal ileum. In the absence of prior biliary intervention, aerobilia (air in the biliary system) on cross­sectional imaging is a suggestive finding. TREATMENT A. Surgical2025­2­17 Downloaded Therapy2:20 P Your IP is Chapter 52: Gallstone Disease, Stephen D. Zucker Page 10 / 15 1. Asymptomatic ©2025 McGraw Hill.gallstones All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Prophylactic cholecystectomy in individuals with asymptomatic gallstones is not recommended because the risks of biliary colic, biliary complications, gallstone ileus should the gallstone become lodged in the terminal ileum. In the absence of prior biliary intervention, aerobilia (air in the biliary Access Provided by: system) on cross­sectional imaging is a suggestive finding. TREATMENT A. Surgical Therapy 1. Asymptomatic gallstones Prophylactic cholecystectomy in individuals with asymptomatic gallstones is not recommended because the risks of biliary colic, biliary complications, and/or gallbladder cancer are low. Sixty to eighty percent of individuals with asymptomatic gallstones remain asymptomatic over follow­up periods as long as 25 years. The probability of developing symptoms within the first 5 years after diagnosis is 2–4% per year, decreasing to 1–2% per year thereafter. Treatment of patients with asymptomatic gallstones does not prolong life expectancy because the likelihood of biliary complications (0.1– 0.3% per year) is counterbalanced by the operative risk. Moreover, the overall costs of expectant management (cholecystectomy performed only when symptoms occur) are lower than those of a prophylactic operative approach. This dictum remains true in patients with diabetes mellitus, in whom asymptomatic gallstones also are low risk. Prophylactic cholecystectomy has been recommended for individuals with a porcelain gallbladder, a rare condition where the inner wall of the gallbladder becomes hardened and calcified as a result of chronic inflammation (see Figure 9–38), because of an increased risk of gallbladder carcinoma. However, recent studies have found the associated risk of malignancy in patients with porcelain gallbladder to be substantially lower than originally thought, raising debate about surgical versus conservative management and leading some to advocate for noninvasive monitoring of asymptomatic patients with serial abdominal ultrasound. Routine prophylactic cholecystectomy for patients undergoing bariatric surgery is no longer recommended due to a low likelihood of subsequent biliary complications and an increased risk of postoperative complications. 2. Symptomatic gallstones In addition to analgesic therapy, patients with symptomatic gallstones should be offered elective laparoscopic cholecystectomy as it provides a permanent cure and is cost­effective when compared with open cholecystectomy. Currently, over 93% of all cholecystectomies are initiated by laparoscopy, with approximately 4–7% necessitating conversion to an open procedure. A meta­analysis of randomized studies comparing laparoscopic and open cholecystectomy found identical complication rates but, on the average, a 3­day shorter hospital stay and a 3­week shorter convalescence for the former. In patients with liver cirrhosis (Child class A or B) and portal hypertension, laparoscopic cholecystectomy also appears to be superior to open cholecystectomy. 3. Preoperative diagnostic studies Preoperative ultrasonography should be performed, not only to diagnose gallbladder stones, but also for detection of potential complications. Preoperative determination of liver enzymes (alkaline phosphatase, aminotransferases) and serum bilirubin also is helpful to assess the likelihood of concurrent choledocholithiasis or pre­existing liver disease. Predictors of bile duct stones include a common bile duct diameter greater than 6–8 mm and elevated alkaline phosphatase and serum bilirubin levels. In patients with acute cholecystitis, an ALT >3 times the upper limit of normal, an elevated alkaline phosphatase, and a common bile duct diameter >6 mm had a 78% sensitivity for choledocholithiasis. In case of uncertainty, an endoscopic ultrasound or an MRCP can be considered. Buxbaum JL, Abbas Fehmi SM, Sultan S, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89:1075–1105. [PubMed: 30979521] Chisholm PR, Patel AH, Law RJ, et al. Preoperative predictors of choledocholithiasis in patients presenting with acute calculous cholecystitis. Gastrointest Endosc. 2019;89:977–983. [PubMed: 30465770] Lam R, Zakko A, Petrov JC, et al. Gallbladder disorders: a comprehensive review. Dis Mon. 2021;67(7):101130. [PubMed: 33622550] Rumsey S, Winders J, MacCormick AD. Diagnostic accuracy of Charcot’s triad: a systematic review. ANZ J Surg. 2017;87: 232–238. [PubMed: 28213923] Van Geenen EJM, van der Peet DL, Bhagirath P, et al. Etiology and diagnosis of acute biliary pancreatitis. Nat Rev Gastroenterol Hepatol. 2010;7:495– Downloaded 2025­2­17 2:20 P Your IP is 502. Chapter 52: Gallstone Disease, Stephen D. Zucker Page 11 / 15 [PubMed: ©2025 20703238] McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibility Williams E, Beckingham I, El Sayed G, et al. Updated guidelines on the management of common bile duct stones (CBDS). Gut. 2017;66:765–782. [PubMed: 33622550] Access Provided by: Rumsey S, Winders J, MacCormick AD. Diagnostic accuracy of Charcot’s triad: a systematic review. ANZ J Surg. 2017;87: 232–238. [PubMed: 28213923] Van Geenen EJM, van der Peet DL, Bhagirath P, et al. Etiology and diagnosis of acute biliary pancreatitis. Nat Rev Gastroenterol Hepatol. 2010;7:495– 502. [PubMed: 20703238] Williams E, Beckingham I, El Sayed G, et al. Updated guidelines on the management of common bile duct stones (CBDS). Gut. 2017;66:765–782. [PubMed: 28122906] B. Nonsurgical Therapy 1. Oral bile acid dissolution In selected patients who have gallbladder stones with mild and infrequent episodes of biliary pain and in the absence of other complications, gallstone dissolution with ursodeoxycholic acid (UDCA) can be considered. UDCA reduces cholesterol saturation and produces a lamellar liquid crystalline phase in bile that allows for the dispersion of cholesterol from stones. In carefully selected patients with radiolucent (noncalcified) stones that are smaller than 5–10 mm in diameter and with a functioning gallbladder, UDCA (10–15 mg/kg/day orally) can induce complete resolution of gallstones in up to 50%. However, stone dissolution is slow, requiring as long as 18 months to achieve. Gallstones larger than 15 mm rarely dissolve, and pigment stones are not responsive to UDCA. Following completion of therapy, stones recur in 30–50% of patients within 3–5 years, which is why UDCA treatment generally is limited to those who refuse or are poor candidates for cholecystectomy. 2. Extracorporeal shock wave lithotripsy Following the introduction of laparoscopic cholecystectomy, this nonsurgical therapeutic modality has been abandoned mainly because of high rates of stone recurrence (11–29% at 2 years, 60–80% at 10 years). Extracorporeal shock wave lithotripsy has maintained a limited role in the treatment of bile duct stones resistant to endoscopic extraction. 3. Medical prophylaxis of cholesterol gallstones UDCA can prevent gallstone formation in obese patients during rapid weight loss (>1.5 kg/week). A minimal dose of 500 mg/day is recommended until constant body weight is attained. May GR, Sutherland LR, Shaffer EA. Efficacy of bile acid therapy for gallstone dissolution: a meta­analysis of randomized trials. Aliment Pharmacol Ther. 1993;7:139–148. [PubMed: 8485266] Paumgartner G, Pauletzki J, Sackmann M. Ursodeoxycholic acid treatment of cholesterol gallstone disease. Scand J Gastroenterol Suppl. 1994;204:27–31. [PubMed: 7824875] Shiffman ML, Kaplan GD, Brinkman­Kaplan V, et al. Prophylaxis against gallstone formation with ursodeoxycholic acid in patients participating in a very­low­calorie diet program. Ann Intern Med. 1995;122:899–905. [PubMed: 7755224] Stokes CS, Gluud LL, Casper M, et al. Ursodeoxycholic acid and diets higher in fat prevent gallbladder stones during weight loss: a meta­analysis of randomized controlled trials. Clin Gastroenterol Hepatol. 2014;12:1090–1100. [PubMed: 24321208] C. Interventional Management of Gallstone Complications 1. Cholecystitis Patients with acute cholecystitis should undergo early elective laparoscopic cholecystectomy, ideally within 24–72 hours of hospital admission. A large Downloaded 2025­2­17 2:20 P Your IP is European randomized multicenter trial of immediate (within 24 hours of admission) versus delayed laparoscopic cholecystectomy, demonstrated Page 12 /a15 Chapter 52: Gallstone Disease, Stephen D. Zucker lower morbidity (11.6% vs 34.4%) and shorter length of stay (5.4 vs 10.0 days) in the early ©2025 McGraw Hill. All Rights Reserved. Terms of Use Privacy Policy Notice Accessibilityintervention group, with no difference in conversion rates to open cholecystectomy. Two large observational studies came to similar conclusions, while a more recent meta­analysis of 77 case­control studies showed that laparoscopic cholecystectomy within 72 hours was associated with decreased mortality, fewer complications (bile duct injuries, wound  Access Provided by: C. Interventional Management of Gallstone Complications 1. Cholecystitis Patients with acute cholecystitis should undergo early elective laparoscopic cholecystectomy, ideally within 24–72 hours of hospital admission. A large European randomized multicenter trial of immediate (within 24 hours of admission) versus delayed laparoscopic cholecystectomy, demonstrated a lower morbidity (11.6% vs 34.4%) and shorter length of stay (5.4 vs 10.0 days) in the early intervention group, with no difference in conversion rates to open cholecystectomy. Two large observational studies came to similar conclusions, while a more recent meta­analysis of 77 case­control studies showed that laparoscopic cholecystectomy within 72 hours was associated with decreased mortality, fewer complications (bile duct injuries, wound infections), lower conversion rates, reduced length of stay, and less blood loss. From admission until operation the patient should be kept NPO with intravenous hydration and careful control of serum electrolytes. Administration of antibiotics targeting gram negative and anaerobic organisms (eg, piperacillin/tazobactam, cefoxitin, cefotaxime, ceftriaxone with metronidazole, ciprofloxacin or levofloxacin with metronidazole) generally is recommended; although, subsequent definitive surgery is necessary as antibiotic treatment alone fails acutely in over 20% of cases. Continuing antibiotics beyond the day of surgery has not been shown to alter postoperative infection rates. While percutaneous drainage of the gallbladder (cholecystostomy) is an option for patients considered to be at high operative risk, this intervention should be entertained very selectively as it is associated with substantial morbidity. A recent randomized controlled trial comparing laparoscopic cholecystectomy versus percutaneous cholecystostomy in 142 high­risk patients (Apache II score ≥7) found similar mortality, but significantly higher rates of major complications (65% vs 12%), need for reintervention (66% vs 12%), recurrence of biliary disease (53% vs 5%), and prolonged length of hospital stay (9 vs 5 days) in the cholecystostomy group. Percutaneous catheter removal should only be performed if cystic duct patency has been established by cholangiography and sufficient time has elapsed to ensure that the fistulous tract has matured (generally 3 months) or, alternatively, if the patient becomes a candidate for definitive surgical management. Endoscopic ultrasound guided directed drainage of the gallbladder is a new option generally reserved for patients who are poor candidates for other interventions. If cholecystectomy cannot be performed within 1–5 days of presentation (eg, delayed diagnosis, medical comorbidities), it is generally performed within 6 weeks after the acute cholecystitis has subsided. Complications of cholecystitis, such as diffuse peritonitis with suspected perforation, gangrene, or empyema require nuanced surgical management. Bagla, P, Sarria, JC, Riall TS. Management of acute cholecystitis. Curr Opin Infect Dis. 2016;29:508–513. [PubMed: 27429137] Gutt CN, Encke J, Koninger J, et al. Acute cholecystitis: early versus delayed cholecystectomy, a multicenter randomized trial (ACDC study, NCT00447304). Ann Surg. 2013;258:385–393. [PubMed: 24022431] Loozen CS, van Santvoort HC, van Duijvendijk P, et al. Laparoscopic cholecystectomy versus percutaneous catheter drainage for acute cholecystitis in high­risk patients (CHOCOLATE): multicentre randomized clinical trial. BMJ. 2018;363:k3965. [PubMed: 30297544] Papi C, Catarci M, D’Ambrosio L, et al. Timing of cholecystectomy for acute calculous cholecystitis: a meta­analysis. Am J Gastroenterol. 2004;99:147– 155. [PubMed: 14687156] Van Dijk AH, de Reuver PR, Tasma TN, et al. Systematic review of antibiotic treatment for acute calculous cholecystitis. BJS. 2016;103:797–811. [PubMed: 27027851] 2. Choledocholithiasis Data on the natural history of symptomatic choledocholithiasis indicate that recurrent colic occurs in more than 50% of the patients and complications in nearly 25%; hence, symptomatic bile duct stones should be removed. Asymptomatic bile duct stones appear to be more benign than symptomatic stones, with long­term retrospective studies suggesting a 17% incidence of complications at 5 years and a 20% rate of spontaneous passage. Conversely, patients with asymptomatic choledocholithiasis have a substantially increased risk of post­ERCP complications (14–32%), presumably due to the high likelihood of a non­dilated common bile duct leading to more difficult and prolonged cannulation times. These data suggest that decision­ making regarding Downloaded biliary 2:20 2025­2­17 stonePextraction in patients with asymptomatic choledocholithiasis should be individualized. Your IP is Chapter 52: Gallstone Disease, Stephen D. Zucker Page 13 / 15 Patients with symptomatic ©2025 McGraw bile duct Hill. All Rights stones who Reserved. have Terms undergone of Use prior Privacy cholecystectomy Policy should be offered endoscopic stone extraction. If endoscopic Notice Accessibility transpapillary therapy is not possible or fails, percutaneous transhepatic intervention or surgical therapy may be employed. Patients with simultaneous gallbladder and bile duct stones benefit from therapeutic splitting, with ERC performed either before or after cholecystectomy. If the Data on the natural history of symptomatic choledocholithiasis indicate that recurrent colic occurs in more than 50% of the patients and complications Access Provided by: in nearly 25%; hence, symptomatic bile duct stones should be removed. Asymptomatic bile duct stones appear to be more benign than symptomatic stones, with long­term retrospective studies suggesting a 17% incidence of complications at 5 years and a 20% rate of spontaneous passage. Conversely, patients with asymptomatic choledocholithiasis have a substantially increased risk of post­ERCP complications (14–32%), presumably due to the high likelihood of a non­dilated common bile duct leading to more difficult and prolonged cannulation times. These data suggest that decision­ making regarding biliary stone extraction in patients with asymptomatic choledocholithiasis should be individualized. Patients with symptomatic bile duct stones who have undergone prior cholecystectomy should be offered endoscopic stone extraction. If endoscopic transpapillary therapy is not possible or fails, percutaneous transhepatic intervention or surgical therapy may be employed. Patients with simultaneous gallbladder and bile duct stones benefit from therapeutic splitting, with ERC performed either before or after cholecystectomy. If the probability of simultaneous choledocholithiasis is high, preoperative endoscopic papillotomy (EPT) and stone extraction are preferred in most hospitals. EPT and cholecystectomy should not be performed on the same day to exclude complications of EPT before surgery. If the probability of choledocholithiasis is low, preoperative ERC should not be the standard; rather—depending on availability—less­invasive diagnostic procedures can be considered. Both endosonography and MRC have high sensitivity and specificity for the detection of bile duct stones. In centers with high expertise, laparoscopic cholecystectomy may be combined with intraoperative cholangiogram and laparoscopic removal of common duct stones if present. After successful endoscopic or percutaneous removal of bile duct stones in patients with cholelithiasis, cholecystectomy should be performed. This recommendation is based on a study that randomized patients to expectant management versus early laparoscopic cholecystectomy following endoscopic sphincterotomy and clearance of choledocholithiasis. Within a median follow­up of approximately 5 years, 24% of patients with the gallbladder left in situ returned with further biliary events (cholangitis, acute cholecystitis, biliary pain, jaundice) as compared with only 7% (cholangitis, biliary pain) in the cholecystectomy group. Cholecystectomy should be performed early, preferably during the same hospital admission. A randomized study showed that recurrent biliary events occurred in 17 out of 47 patients (36%) whose laparoscopic cholecystectomy was delayed for 6– 8 weeks, but in only 1 out of 49 patients who underwent early laparoscopic cholecystectomy within 72 hours after endoscopic sphincterotomy. Buxbaum JL, Abbas Fehmi SM, Sultan S, et al. ASGE guideline on the role of endoscopy in the evaluation and management of choledocholithiasis. Gastrointest Endosc. 2019;89:1075–1105. [PubMed: 30979521] Nawara H, Ibrahim R, Abounozha S, et al. Best evidence topic: should patients with asymptomatic choledocholithiasis be treated differently from those with symptomatic or complicated disease? Ann Med Surg (Lond). 2021;62:150–153. [PubMed: 33520213] Reinders JS, Goud A, Timmer R, et al. Early laparoscopic cholecystectomy improves outcomes after endoscopic sphincterotomy for choledochocystolithiasis. Gastroenterology. 2010;138:2315–2320. [PubMed: 20206179] Schiphorst AH, Besselink MG, Boerma D, et al. Timing of cholecystectomy after endoscopic sphincterotomy for common bile duct stones. Surg Endosc. 2008;22:2046–2050. [PubMed: 18270768] 3. Cholangitis Patients with acute cholangitis caused by an obstructive gallstone should undergo urgent endoscopic removal of the stone (emergently in patients with sepsis). A randomized study has shown a significant advantage of an endoscopic versus a surgical approach with regard to complications and mortality. Immediate systemic antibiotic therapy is indicated to prevent septic complications (see section on Cholecystitis for antibiotic selection). If stone extraction fails, a biliary stent should be placed. Lai EC, Mok FP, Tan ES, et al. Endoscopic biliary drainage for severe acute cholangitis. N Engl J Med. 1992;326:1582–1586. [PubMed: 1584258] 4. Biliary pancreatitis While most cases of acute gallstone pancreatitis are mild and resolve spontaneously, in the absence of cholangitis, patients should be managed expectantly (NPO, intravenous fluids, analgesics) regardless of severity. A recent randomized trial involving patients with severe gallstone pancreatitis Downloaded 2025­2­17 2:20 P Your IP is found no benefit of urgent ERCP with sphincterotomy over conservative treatment with regard to major complications or mortality. In the presence of Chapter 52: Gallstone Disease, Stephen D. Zucker Page 14 / 15 cholangitis, ©2025 McGraw biliary stone Hill. extraction All Rights within 24Terms Reserved. hours of is Use indicated. AfterPolicy Privacy resolution of acute Notice pancreatitis, cholecystectomy and removal of residual bile Accessibility duct stones should be performed prior to discharge from the hospital.  Access Provided by: 4. Biliary pancreatitis While most cases of acute gallstone pancreatitis are mild and resolve spontaneously, in the absence of cholangitis, patients should be managed expectantly (NPO, intravenous fluids, analgesics) regardless of severity. A recent randomized trial involving patients with severe gallstone pancreatitis found no benefit of urgent ERCP with sphincterotomy over conservative treatment with regard to major complications or mortality. In the presence of cholangitis, biliary stone extraction within 24 hours is indicated. After resolution of acute pancreatitis, cholecystectomy and removal of residual bile duct stones should be performed prior to discharge from the hospital. Schlepers NJ, Hallensleben ND, Besselink MG, et al. Urgent endoscopic retrograde cholangiopancreatography with sphincterotomy versus conservative treatment in predicted severe acute gallstone pancreatitis (APEC): a multicentre randomized controlled trial. Lancet. 2020:396:167–176. [PubMed: 32682482] Van Baal MC, Besselink MG, Bakker OJ, et al. Timing of cholecystectomy after mild biliary pancreatitis: a systematic review. Ann Surg. 2012;255:860– 866. [PubMed: 22470079] Zhong FP, Wang K, Tan XQ, et al. The optimal timing of laparoscopic cholecystectomy in patients with mild gallstone pancreatitis: a meta­analysis. Medicine (Baltimore). 2019;98:e17429. [PubMed: 31577759] Downloaded 2025­2­17 2:20 P Your IP is Chapter 52: Gallstone Disease, Stephen D. Zucker Page 15 / 15 ©2025 McGraw Hill. All Rights Reserved. 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