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Gallstone disease: Pathophysiology, Epidemiology, Natural History, and Treatment Options
NEW CHALLENGES IN INTERNAL MEDICINE
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GALLSTONE DISEASE Pathophysiology, Epidemiology, Natural History, and Treatment Options John C. Bowen, MD, Howard 1. Brenner, MD, William A. Ferrante, MD, and William F. Maule, MD
Gallstone disease is ubiquitous in the United States, affecting approximately 10% to 20% of the population. Most patients are unaware of the disease and remain asymptomatic for life. However, a small percentage develops symptoms necessitating treatment. In the United States, 500,000 cholecystectomies are performed annually at an estimated cost of 3 billion dollars.26 Surgical cholecystectomy remains the treatment of choice for symptomatic stones; however, in recent years, nonsurgical treatment of gallstones has been investigated. This article reviews the pathophysiology, epidemiology, and natural history of gallstones; comments on nonsurgical treatments; and reviews newer forms of surgical therapy including laparoscopic cholecystectomy. The majority of gallstones are cholesterol stones (80%); the remainder are pigmented. Cholesterol cholelithiasis results from cholesterol supersaturation of bile, decreased nucleation time, and gallbladder hypomotility. Cholesterol supersaturation may occur because of hypersecretion of cholesterol with a normal bile acid pool or with normal cholesterol secretion in conjunction with a diminished bile acid pool. Cholesterol secretion is a function of the sum of the amount of bile acid produced by the liver, from the enzyme HMG CoA reductase plus the quantity delivered to the liver through lipoprotein minus the amount used to make bile salts or re circulate lipoproteins. The bile acid From the Department of Surgery (JCB) and the Section on Gastroenterology, Department of Internal Medicine (HIB and WAF), Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, and the Section on Gastroenterology, Department of Internal Medicine, Ochsner Clinic of Baton Rouge, Baton Rouge, Louisiana (WFM) THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76 • NUMBER 5 • SEPTEMBER 1992
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pool is determined by the production of bile in the liver and its subsequent enterohepatic circulation. 14 Seven-alpha hydroxylase, the enzyme responsible for conversion of hepatic cholesterol to bile acids, is decreased in patients with cholesterol gallstones. These patients also have overactivity of their HMG CoA reductase. The bile acid pool may be decreased by disease processes such as terminal ileal resection, which eliminates the absorptive surface to complete the enterohepatic circulation I and causes the development of gallstones even with normal cholesterol secretion. Not all patients with lithogenic bile develop stones, which suggests that other factors are implicit in the pathophysiologic process. Nucleation time, the rate at which crystals form in bile, has been shown to decrease from 2 weeks in control patients to only a few days in patients with gallstones. Carey and Cahalane 6 have proposed that mucin glycoproteins, which are secreted under prostaglandin control, decrease nucleation time. Kibe et aP7 have suggested that apoproteins Al and A2 may act as inhibitors of nucleation and thus prevent gallstone formation. The third factor in the pathogenesis of gallstones is hypomotility of the gallbladder, in which incomplete and infrequent emptying of the contents of the gallbladder allows stasis of bile and crystal formation. Patients with these conditions have an increased incidence of gallstone formation. Pigmented stones, which account for 20% of all stones, are either black or brown. Black stones form in the gallbladder as a result of increased levels of unconjugated bilirubin, which binds with calcium carbonate to allow for precipitation. Brown stones form in the bile ducts secondary to stasis and infection. Stasis allows a nidus for stone formation and bacteria release beta-glucuronidase, which allows increased levels of unconjugated bilirubin to develop within the duct itselF Major risk factors for cholesterol gallstones include female gender, pregnancy, obesity, age, some genetic predispositions, weight reduction, and ileal disease. Female sex hormones increase the lithogenicity of bile and decrease gallbladder motility.4 Obesity is associated with a linear increase in gallstone formation. Activity of HMG CoA reductase is increased in obese patients, resulting in hypersecretion of cholesterol into bile. Maclure et al, 19 in a study of 88,000 nurses, found no threshold weight at which this process began. Recent interest has focused on the role of weight reduction in gallstone formation. It is estimated that 25% of obese men and women develop gallstones during weight loss. Probably another 25% of this population develop crystals. These observations are usually made in patients who lose weight rapidly (in excess of 2 to 2.5 pounds per week), especially with fad diets. Possible explanations for this process are a noncontracting gallbladder with stasis during fasting and a decrease in nucleation time. Aspirin, by blocking prostaglandins, has been shown to increase nucleation time and prevent stone formation in these persons. IS, 18 As a person ages, the activity of 7-alpha hydroxylase decreases and the activity of HMG CoA reductase increases, with an associated
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increase in the rate of gallstone formation. There is evidence of disparity in gallstone formation among ethnic groups. Among Pima Indians there is a 70% incidence of gallstones by middle age, whereas some tribes in Africa have rates as low as 3%. The role of diet and environment has yet to be determined. As previously mentioned, ileal disease or resection, which decreases the bile salt pool, increases the likelihood of the development of cholesterol gallstones. Patients with hemolytic anemia and increased levels of unconjugated bilirubin are at increased risk for pigmented stones. Cirrhosis is a known risk factor, but the mechanisms are not well understood. The incidence of pigmented stones in patients with cirrhosis has been estimated to be as high as 60%.39 Proposed mechanisms are hypersplenism with hemolysis and increased levels of estrogen. 12 Gallstones are categorized as asymptomatic, associated with biliary colic, and associated with complications of cholelithiasis. Once stones are symptomatic or present with complications, there is little debate that therapeutic intervention is necessary. The question of what to do about asymptomatic gallstones has prevailed since the turn of the century. In 1911, William Mayo said the innocent gallstone was a myth. 23 More recently, Gracie and Ransohoff!3 studied faculty members of the University of Michigan and found that, over a IS-year period, only 18% of subjects developed symptoms. They also showed that the risk of symptoms diminished with time and that most patients developed symptoms within the first few years of the discovery of stones. Because of these findings, asymptomatic stones are not treated. Data on symptomatic uncomplicated stones are scant. McSherry et aF4 showed that approximately SO% of patients' symptoms worsened over a mean period of 64 months. Therefore, it is generally accepted that once the patient becomes symptomatic, some form of therapeutic intervention is indicated. THERAPY FOR GALLBLADDER STONES
Medical intervention in gallstone disease may include any measure taken to remove symptomatic gallstones from the gallbladder or biliary tree except laparoscopy or laparotomy. Initial apprehension that dissolving or shattering gallbladder stones might produce jaundice or pancreatitis in a substantial number of patients has not been sustained in clinical trials. Gallstone Dissolution Oral Agents. Chenodiol (chenodeoxycholic acid) accumulates in relatively high concentration in the functioning gallbladder after oral ingestion and dissolves gallstones by incorporating water-insoluble cholesterol crystals into water-soluble micelles. Ursodiol (ursodeoxy-
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cholic acid) has similar properties and also increases the fraction of cholesterol dissolved in bile as liquid crystals. Neither medication is effective for calcium bilirubinate (pigmented) stones. Early success in uncontrolled trials led to the National Cooperative Gallstone Study (NCGS),36 in which approximately 900 patients with cholelithiasis and functioning gallbladders were randomized to receive one of two fixed doses of chenodiol (750 mg/d versus 375 mg/d) or a placebo. Fewer than 15% of patients receiving high-dose therapy and 5% receiving low-dose chenodiol had complete stone dissolution during the 2-year trial. The study was criticized for employing inadequate doses of medication; however, even with increased doses (12-15 mg/kg) and alternative agents (ursodiol, 8-10 mg/kg), dissolution therapy has not significantly reduced the need for open cholecystectomy in patients in the United States. The ideal patient for oral dissolution therapy is lean, mildly symptomatic, and has a single, small «20 mm) stone. Unfortunately, fewer than 1 of 5 patients evaluated for cholecystectomy meets these criteria,20 and fewer than 60% of these selected patients are stone free after 24 months of therapy.29 Mild, usually reversible alterations in liver transaminases occur in 25% of patients taking chenodiol but do not occur in those taking ursodiol. Dose-related, intermittent cramping and diarrhea complicate therapy with both medications but usually resolve with continued use or dose reduction. Simultaneous administration of both agents at reduced doses may increase efficacy and reduce the incidence of side effects. 29 Stone recurrence after successful therapy occurs in about 10% of patients each year41 but may decline after the fifth year. Recurrences are not reliably prevented by maintenance therapy with smaller doses of chenodioPl or ursodiol. 41 The cost of medical therapy includes a medication expense of $1500-2000 per year plus office visits and ultrasound monitoring. Parenteral Agents. Methyl-tertiary-butyl ether (MTBE) is an effective lipid solvent that dissolves cholesterol gallstones when it is injected directly into the gallbladder. 40 A percutaneous approach following conscious sedation has been employed most frequently, with considerable success. After the lumen of the gallbladder is punctured with a fine needle, a guide wire is inserted and a 5-Fr catheter (1. 7 mm in diameter) is coiled around the stones in the most dependent portion of the gallbladder lumen. MTBE mixed with radiopaque contrast material is injected into the gallbladder in small aliquots and continuously replaced with fresh solution. Intermittent fluoroscopic monitoring prevents overflow into the biliary tree or duodenum. Leakage into the peritoneal space is minimized by passage of the catheter through the liver parenchyma and puncture of the adjacent gallbladder wall. Manual delivery of MTBE by syringe has been superseded by an automated pump system that minimizes overflow and radiation exposure. Thistle and colleagues40 reported that efficacy was not dependent on stone number or volume and that 72 of 75 patients had greater than 95% reduction in stone volume after less than 15 hours of therapy. Side effects were minor and included anesthesia, duodenal inflammation, and reversible alterations in liver chemistries when MTBE escaped the
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gallbladder. Leakage into the peritoneal cavity was infrequent and resulted in no significant problems. Major advantages of MTBE therapy include low procedural cost and rapid stone dissolution. A functioning gallbladder is not required to ensure efficacy, and cholesterol stones with calcified rims and parenchymal calcifications have been dissolved. Successful MTBE therapy is not dependent on the percutaneous approach; endoscopic placement of standard nasobiliary catheters into the gallbladder has been reported, and a German groupll developed a special catheter system that facilitates endoscopic cannulation of the gallbladder via the cystic duct. The endoscopic approach has the advantage of providing access to stones in the common bile duct, although the potential for leakage into the duodenum or biliary radicals limits MTBE usage in choledocholithiasis. The main obstacles to widespread adoption of MTBE therapy are the need for parenteral administration, the risk of gallstone recurrence following complete stone dissolution, and the risk of symptoms in patients with residual debris in the gallbladder after therapy. Four of 21 patients with complete clearance of stones following MTBE had recurrence of stones within 16 months, and almost half of patients with fragments «5 mm) remaining in the gallbladder after therapy retained the debris after more than 6 months of follow-up. However, fewer than 10% of patients with recurrent or residual stones required cholecystectomy for symptoms during a follow-up interval of up to 42 months. Gallstone Lithotripsy
Gallstones can be eliminated by extracorporeal shockwave lithotripsy using technology originally developed for eliminating kidney stones. 3 General or peridural anesthesia was used initially, but with technical refinements providing better acoustic focusing and improved interfacing between the patient and the shock wave generator, conscious sedation is now routine. Patients must be carefully selected because efficacy of treatment depends on a small stone burden and an unimpeded acoustic pathway. The best results are obtained with single stones smaller than 20 mm in diameter. The task of lithotripsy is to reduce the stones to small fragments that can be dissolved with oral bile salts (vide supra) or pass without symptoms into the duodenum. Alternatively, lithotripsy may be used to fracture large calcified stones for parenteral dissolution by MTBE. The Munich group32 evaluated 711 patients treated with either a modified kidney machine or the Dornier MPL 9000, which was specifically designed for biliary lithotripsy. Over 80% of patients with a single stone smaller than 20 mm in diameter had complete fragmentation (residual debris <3 mm in diameter) of calculus. After lithotripsy, oral ursodiol or a combination of ursodiol and chenodiol produced complete clearance of stone fragments in up to 83% of patients after 1 year of
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therapy. Results in patients with multiple (3 or fewer) stones were less impressive; only about one third had complete clearance of fragments. In a similar trial at 10 centers in the United States,35 600 symptomatic patients underwent lithotripsy using the Dornier MPL 9000. All patients had three or fewer radiolucent stones measuring 5 to 30 mm in diameter and functioning gallbladders. One half of the patients were randomized to ursodiol following lithotripsy and the other half received placebo. Fewer than 50% of patients had complete stone fragmentation «5 mm in diameter), and only 21 % of patients receiving ursodiol and 9% of patients receiving placebo were free of stones 6 months after initiating treatment. In the group with a single stone smaller than 20 mm in diameter who were randomized to ursodiol, only 35% were free of stones after 6 months of treatment. In a smaller US multicenter trial in which the Medstone instrument was used,s all patients had follow-up therapy with ursodiol. Thirtyfour of 67 patients (51 %) with a solitary stone smaller than 20 mm in diameter were cleared of residual fragments after 6 months. None of the 48 patients with stones larger than 20 mm in diameter had clearance after lithotripsy and ursodiol therapy for a similar period. Although there were procedural differences between the three studies, it is not clear why efficacy was so dramatically reduced in the American experience. In October 1989, the US Food and Drug Administration refused to approve either instrument for general use in the United States. Side effects from lithotripsy, including transient alterations in liver chemistries, hematuria, skin bruising, and petechia, have been mild and infrequent. Complications, including biliary pain from residual stones (35%), pancreatitis, jaundice, and need for cholecystectomy «2% each), were no more prevalent than in the placebo group of the NCGS trial. Stone recurrence rates are similar to those recorded in oral bile salt therapy trials. Therapy with oral bile salts requires a functioning gallbladder, protracted administration, and a small stone volume to ensure efficacy. Although stones can be fragmented by extracorporeal lithotripsy in only one or two sessions, complete clearance of stone fragments has the same limitations as primary bile salt therapy. Neither procedure is advocated for patients with severe symptoms or acute cholecystitis, and both are contraindicated in pregnancy. Fewer than 20% of patients fulfill the criteria for treatment with either modality, and in the United States, neither therapy has proved particularly effective. The capital and personnel costs of biliary lithotripsy limit its application to centers with a high volume of patients who refuse cholecystectomy. Despite theoretic and practical advantages, MTBE has not been widely applied, probably because of the need for parenteral administration and questions about stone recurrence. In summary, it is unlikely that medical therapy will reduce surgical intervention for gallbladder stones until there are dramatic improvements in efficacy; a more likely role for medical intervention is therapy that will decrease cholesterol crystal nucleation in patients at high risk for stones.
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TREATMENT OF COMMON DUCT STONES
Common duct stones may occur de novo years after cholecystectomy, but most symptomatic common duct calculi are found before cholecystectomy or during operation for cholelithiasis. About 5% of cholecystectomies are complicated by the presence of common duct stones, necessitating common duct exploration or intraoperative choledochoscopy and stone extraction. Calculi can also be removed after operation via a T-tube placed in the common duct during surgery. All types of common duct intervention during surgery increase operative morbidity. Nonsurgical intervention has dramatically changed the treatment of common duct stones since the introduction of endoscopic sphincterotomy (ES) in 1974. After successful catheterization of the common duct, a wire diathermy knife is used to cut the common duct sphincter and enlarge the orifice of the ampulla of Vater. Balloon catheters, wire retrieval baskets, or stone crushing devices are routinely used to remove or destroy stones up to 10 mm in diameter. Successful clearance of the common duct occurs in greater than 85% of patients. 16 Complications, including cholangitis or sepsis, retroperitoneal perforation, pancreatitis, and bleeding, occur in fewer than 10% of patients, and mortality occurs in fewer than 2%.9 Long-term complications from endoscopic ablation of the ampullary sphincter are rare. Although ES may precipitate acute cholecystitis, ES without cholecystectomy has been advocated for elderly or infirm patients with gallbladder stones and common duct obstruction but no evidence of acute cholecystitis. 22, 37 Siegel et aP7 showed that the risk of subsequent cholecystitis (9%), emergent (2%) or elective (9%) surgery, and biliary death (0.3%) after successful ES was relatively low in this group of high-risk patients. In some patients, large stones or atypical anatomy preclude adequate sphincterotomy. Mono-octanoin 27 instilled through a nasobiliary catheter has dissolved or reduced the diameter of common duct stones with some «50%) success, and MTBE has also been used in small trials. 25 Extracorporeal lithotripsy may be used to fracture large stones that cannot be removed following ES.33 Recently, pulsed-dye laser lithotripsy has been shown to be safe and effective when administered endoscopically by fiberoptic catheters or special small-bore "daughter" endoscopes delivered to the common duct during endoscopic cholangiography.s Unfortunately, equipment cost limits use of this technique to a few centers specializing in endoscopic therapy. SURGICAL TREATMENT
The impetus to avoid open cholecystectomy and discover a minimalist method to treat gallstone disease successfully has resulted in a search for nonsurgical treatments, all of which have been shown in most patients to have significant limitations in applicability and effec-
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tiveness. However, the relatively recent development of laparoscopic cholecystectomy appears to be the exception. Its introduction in 1988 in France by DuBois and colleagues 10 and, at approximately the same time, in the United States by Reddick and Olsen30 has eliminated the incision, the major drawback to open cholecystectomy, while achieving complete removal of the gallbladder and its contained calculi. The procedure's popularity with surgeons and patients has been extraordinary, and the rapidity of application has exceeded the ability of peerreviewed journals to publish timely clinical trials. A major concern was that a rash of new complications would occur before the pitfalls of the procedure were delineated and guidelines for training and awarding credentials were established. Another concern has been the commercialism involved in the development and sale of the technology necessary to carry out the procedure. There can be no doubt that the rapidity with which surgeons were trained in the rudiments of the procedure was attributable in no small part to the support of industry and the profit motive. Industry stood to gain by the competitive frenzy that led to rapid dissemination of the procedure and the concomitant sale of video equipment, special instruments, and laser devices. Skeptics feared that this was another expensive fad that would soon fall by the wayside, as biliary lithotripsy appears to have done. However, their worst fears have not come to pass. The incidence of complications, although definitely related to experience and the learning curve, has proved to be acceptable. Initial reports suggest that bile duct injury, the most feared complication of laparoscopic cholecystectomy, occurs during the early learning phase at a rate of approximately 0.4% to 10%, compared with a rate of 0.2% for standard open cholecystectomy.2, 28, 34 It is clear that, at least in the beginning, there was an incremental increase in the risk of bile duct injury, but other complications such as cautery/laser burns and trocar injuries have been reported infrequently. These problems may be attributable to unfamiliarity with the instrumentation and with the dissection and identification of structures through a two-dimensional video image. Nevertheless, it seems reasonable to assume that with increased experience the incidence of complications will gradually diminish to a level consistent with that of open cholecystectomy. The advantages of reduced disability and cost and improved cosmesis seem worth the effort to develop and disseminate the technique to the more than 500,000 patients who undergo cholecystectomy in the United States annually. Now that the procedure is well established, it must be made as safe and cost effective as possible. The greatest economic impact of the procedure may be the rapid return to work of employed patients. Selection of Patients
The indications for laparoscopic cholecystectomy are identical to those of open cholecystectomy. However, certain pre-existing condi-
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tions and anatomic problems make the procedure technically difficult to perform. In the early experience, acute inflammation, pregnancy, common duct stones, a coagulopathy, and previous upper abdominal surgery were considered possible contraindications. At present, none of these is considered a contraindication, with the possible exception of extensive previous upper abdominal surgery, which is known to cause dense adhesions, making it impossible to achieve pneumoperitoneum and to lyse adhesions. Morbid obesity is a deterrent only if pneumoperitoneum cannot be achieved because of uncertainty as to the depth of the peritoneal cavity. With the use of longer trocars and Verres needles, laparoscopic cholecystectomy can now be performed on nearly all obese patients. Pregnancy has been considered a contraindication. However, after obstetric consultation, we performed laparoscopic cholecystectomy without complication in a patient who was 14 weeks pregnant. The limitation here is the size of the uterus, which in the later stages of pregnancy may limit the ability to puncture and insufflate the peritoneal cavity safely. Cholecystectomy in a cirrhotic patient remains a formidable procedure whether it is done laparoscopically or through an open incision. Conversion of a laparoscopic procedure to open cholecystectomy is reported in approximately 4% to 8% of cases for a myriad of causes. These include morbid obesity, anatomic anomalies, uncontrolled bleeding, escape of numerous stones into the peritoneal cavity, and gangrene of the gallbladder. Our current practice is to initiate all cholecystectomies with laparoscopy unless we are sure that pneumoperitoneum cannot be achieved safely or unless a concomitant upper abdominal operation is required. With experience, increasingly difficult laparoscopic procedures are being performed safely and effectively. Equipment and Methods
Most of the equipment used in laparoscopic cholecystectomy has been available to gynecologists for years. 3 ! High-resolution video equipment is critical to the success of laparoscopic cholecystectomy. In some respects, the image seen on the television monitor is better than that normally seen during open cholecystectomy. An important difference, however, is that the image is two-dimensional. In addition, because the viewpoint is different, experience is required to interpret the anatomy correctly. Another essential piece of equipment is the carbon dioxide insufflator used to create a pneumoperitoneum. The new insufflators are capable of delivering maximum flow rates of 4 to 10 LI min of carbon dioxide to achieve and maintain pneumoperitoneum. A special needle (Verres) with a spring-loaded sheath to protect the intraperitoneal organs from injury is used to insufflate the abdominal cavity. After pneumoperitoneum is established, a trocar is introduced into the peritoneum and a 10-mm telescope attached to a camera is inserted, usually through the umbilicus. A diagnostic laparoscopy is
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then carried out, and three additional trocars are inserted into the peritoneal cavity, through which a variety of instruments can be passed. Special instruments are then passed through the trocars to provide traction and dissect Calot's triangle. By these maneuvers, the identity of the cystic duct and artery can be safely ascertained. An intra operative cholangiogram can be performed by incising the cystic duct and passing a cannula into it. The cystic artery and duct are then clipped both proximally and distally with two clips each before they are divided. While retracting upward on the gallbladder, the surgeon removes it from the liver bed using a thermal source to cut and coagulate the adventitial attachments. Through the umbilical trocar, a large grasping forceps is used to grasp the cystic duct of the gallbladder. After decompression of bile and, if necessary, stones, the gallbladder is delivered from the peritoneal cavity through the umbilical incision. Management of Common Duct Stones
Laparoscopic cholecystectomy poses new dilemmas in the management of common duct stones. Two technical limitations, neither of which has yet been satisfactorily resolved, have altered the usual approach to common duct stones. First, although it is technically possible to perform intraoperative cholangiography with laparoscopy, it can be technically demanding and sometimes virtually impossible. Second, if a stone is found intraoperatively, its removal through the laparoscope is not yet feasible under routine circumstances. To counter these limitations, it has become necessary that the criteria for preoperative endoscopic retrograde cholangiography (ERC) be broadened. Although the option of open cholecystectomy is always present, most patients wish to avoid it and prefer to have either ERC preoperatively to clear the common bile duct or, if necessary, postoperatively to remove a common bile duct stone found during laparoscopic cholecystectomy. Therefore, open cholecystectomy with common bile duct exploration is now reserved for cases in which stones in the common bile duct cannot be removed preoperatively via retrograde endoscopy or in which the cause of biliary obstruction is in doubt. We have evolved a protocol at the Ochsner Clinic for managing these problems. Preoperative screening with ERC of patients at high risk and intraoperative screening with cholangiography of patients at slightly increased risk for common duct stones should detect nearly all occult stones in the biliary tree. This assumption must be confirmed by future analysis of clinical data. The possibility of finding a common duct stone intraoperatively is discussed with each patient, and their wishes regarding open common bile duct exploration versus postoperative ERC with endoscopic stone extraction are determined. So far, none of our patients has preferred conversion to open cholecystectomy over postoperative endoscopic stone extraction. Fortunately, in the first 251 laparoscopic cholecystectomies, open exploration to remove re-
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tained common duct stones that could not be removed during postoperative ERC has been unnecessary. Nevertheless, this possibility is discussed with the patient, and consent for this protocol is obtained. As techniques and instrumentation improve, laparoscopic extraction of common duct stones is likely to become commonplace and may obviate this potential problem. Early Clinical Results
Application of laparoscopic cholecystectomy to the treatment of gallstone disease began at the Ochsner Clinic in May 1990. Over the ensuing 14 months, 271laparoscopic cholecystectomies were attempted by seven surgeons, and 251 cases were successfully completed. Twenty cases (7%) were converted to open cholecystectomy. Initially, we selected only patients with chronic disease. However, as experience increased, the indications and application of the procedure were broadened to include virtually all patients who required cholecystectomy, including patients with acute cholecystitis or previous upper abdominal surgery and four asymptomatic patients. The age range was from 11 to 83 years, with an average age of 48 years. There were 197 women and 74 men. The hospital stay for these patients ranged from 1 to 26 days, with an average stay of 1. 9 days. However, 166 of 251 patients treated successfully (66%) remained for only 1 day and 43 patients (17%) remained for 2 days (Fig. 1).14 Four patients required readmission to the hospital for problems directly related to the laparoscopic cholecystectomy, and two of these required reoperation. Three major complications occurred, each involving a different surgeon; however, all three procedures were performed early in the surgeon's experience (Table 1). The most serious complication was a bile duct injury that required a subsequent choledochojejunostomy. One patient developed a bile leak from the cystic duct that was controlled by a stent placed endoscopically in the common bile duct. 200 (/)
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1
2
3
4
5
6
7
8 9 1011 1213
Hospital Days Figure 1. Distribution of postoperative hospital days in 251 consecutive patients who underwent laparoscopic cholecystectomy.
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Table 1. MAJOR COMPLICATIONS IN 251 LAPAROSCOPIC CHOLECYSTECTOMIES
Complication Bile duct injury Cystic duct bile leak Abscess secondary to intraperitoneal stone Total major complications
Outcome Choledochojejunostomy; well Endoscopic stent; well Drainage of abscess; well
Cases Per Individual Surgeon
Number (%)
3 16 6
1 (004) 1 (004) 1 (004)
3 (1.2)
Another patient developed an intra-abdominal abscess approximately 3 weeks after laparoscopic cholecystectomy in the area of a retained gallstone. The abscess was drained, and the patient recovered fully. Therefore, the overall major complication rate was 1.2%. The most common complaints after laparoscopic cholecystectomy have been right upper quadrant and right shoulder pain lasting 24 to 72 hours, which was believed to be due to retained intraperitoneal gas causing diaphragmatic irritation, and postcholecystectomy diarrhea, which was noted in the records of 13 of 251 patients, although it probably occurred more frequently. Otherwise healthy patients were able to return to normal activities, including work, within 3 to 14 days. Patient acceptance of the procedure has been universal. There have been minor wound problems such as cellulitis around the trocar sites, occasional purulent drainage, and even discharge of stone fragments from the umbilicus. Nevertheless, patients realize that the reduction in disability, rapid return to normal activity, and absence of a major incision are worth these minor inconveniences. A variety of procedures have been carried out concomitantly with laparoscopic cholecystectomy, including liver biopsy, Meckel's diverticulectomy, appendectomy, and lysis of adhesions. In addition, two patients have had laparoscopic cholecystectomy preceding open pelvic operations to limit the extent of the incision needed to accomplish the two procedures. A prospective analysis of 1518 laparoscopic cholecystectomies performed in 29 hospitals in the southern United States surveyed the relatively early experience of 59 surgeons. 38 These surgeons converted 4.7% of cases to conventional open cholecystectomy. A total of 82 complications occurred in 78 patients, representing a rate of 5.1 %. A total of seven (0.5%) common or hepatic duct injuries occurred intraoperatively. Interestingly, the incidence of bile duct injury within the first 13 cases of each participant's experience was 2.2% compared with 0.1 % after that. There was one death in the series 3 days after surgery for an unrelated problem. Schirmer and associates 34 reported the results of their first 152 laparoscopic cholecystectomies. They converted 8.5% of these to an open operation and reported a 4% major complication rate, including one bile duct injury, for an incidence of 0.66%. Peters et aF8 recently reported the results of their first 100 consecutive lapa-
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roscopic cholecystectomies performed over a 6-month period. There were no deaths and a morbidity rate of 8%. There was one minor bile duct injury (1 %) requiring laparotomy and T-tube insertion, two postoperative bile collections, and one clinical diagnosis of retained stones that passed spontaneously. Four patients (4%) required conversion to open cholecystectomy because of technical difficulties with the dissection. As published reports have become available and as the authors have gained personal experience in more than 200 procedures, it has become clear that a significant learning curve is associated with laparoscopic cholecystectomy. Furthermore, the ramifications of performing the procedure are complex and require a wide range of experience and technical ability to cope with the variety of problems that occur. For these reasons, laparoscopic cholecystectomy must be performed by surgeons who have the training and skill not only to treat gallstones but to manage their complications and unexpected problems. As with all new procedures, it is important that each surgeon be trained to a level consistent with current practice. At the outset, it was normal for an experienced surgeon to attend a 2-day course involving didactic lectures, observe a slightly more experienced surgeon performing the procedure, and practice the procedure in an animal model. In the near future, this will be inadequate preparation; surgeons will have to become apprentices to gain the hands-on experience necessary to reach the current level of practice. Furthermore, future training of residents will be crucial to achieve consistently the results that are equal or superior to those of standard cholecystectomy.
SUMMARY In 1991, only symptomatic gallstones should be treated. The treatment of choice for all gallstones continues to be surgical removal. Except for stones in the common bile duct, which are amenable to removal by endoscopic papillotomy, nonsurgical treatment of gallstones should be investigated further before it can have widespread applicability. The major challenge in the future may be medical prevention of gallstone formation in susceptible individuals. Laparoscopic cholecystectomy seems to have moved to the forefront of surgical therapy in patients who are candidates for the procedure.
References 1. Andersson H, Bosaeus I, Fasth 5, et al: Cholelithiasis and urolithiasis in Crohn's disease. Scand J Castroenterol 22:253, 1987 2. Andren-Sandberg A, Alinder C, Bengmark S: Accidental lesions of the common bile duct at cholecystectomy: Pre- and perioperative factors of importance. Ann Surg 201:328, 1985
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3. Barkun ANG, Ponchon T: Extracorporeal biliary lithotripsy: Review of experimental studies and a clinical update. Ann Intern ;vIed 112:126, 1990 4. Braverman DZ, Johnson ML, Kern F Jr: Effects of pregnancy and contraceptive steroids on gallbladder function. N Engl J Med 302:362, 1980 5. Burnett 0, Ertan A, Jones R, et al: Use of external shock-wave lithotripsy and adjuvant ursodiol for treatment of radiolucent gallstones: A national multicenter study. Dig Dis Sci 34:1011, 1989 6. Carey MC, Cahalane MJ: Whither biliary sludge? Gastroenterology 95:508, 1988 7. Cetta FM: Bile infection documented as initial event in the pathogenesis of brown pigment biliary stones. Hepatology 6:482, 1986 8. Cotton PB, Kozarek RA, Schapiro RH, et al: Endoscopic laser lithotripsy of large bile duct stones. Gastroenterology 99:1128, 1990 9. Cotton PB, Lehman G, Vennes L et al: Endoscopic sphincterotomy complications and their management: An attempt at consensus. Gastrointest Endosc 37:383, 1991 10. DuBois F, !card P, Berthelot G, et al: Coelioscopic cholecystectomy: Preliminary report of 36 cases. Ann Surg 211:60, 1990 11. Foerster EC, Matek W, Domschke W: Endoscopic retrograde cannulation of the gallbladder: Direct dissolution of gallstones. Gastrointest Endosc 36:444, 1990 12. Fornari F, Civardi G, Buscarini E, et al: Cirrhosis of the liver: A risk factor for development of cholelithiasis in males. Dig Dis Sci 35:1403, 1990 13. Gracie W A, Ransohoff OF: The natural history of silent gallstones: The innocent gallstone is not a myth. N Engl J Med 307:798, 1982 14. Hay DW, Carey MC: Pathophysiology and pathogenesis of cholesterol gallstone formation. Semin Liver Dis 10:159, 1990 15. Hood K, Gleeson 0, Ruppin DC, et al: Prevention of gallstone recurrence by nonsteroidal anti-inflammatory drugs. Lancet 2:1223, 1988 16. Jacobson IM (ed): ERCP: Diagnostic and Therapeutic Applications. New York, Elsevier, 1989 17. Kibe A, Holzbach RT, LaRusso NF, et al: Inhibition of cholesterol crystal formation by apoliproteins in supersaturated model bile. Science 225:514, 1984 18. Lee SP, Carey MC, LaMont ]T: Aspirin prevention of cholesterol gallstone formation in prairie dogs. Science 211:1429, 1981 19. Maclure KM, Hayes KC, Colditz GA, et al: Weight, diet, and the risk of symptomatic gallstones in middle-aged women. N Engl J Med 321:563, 1989 20. Magnuson JH, Lillemoe KO, Pitt HA: How many Americans will be eligible for biliary lithotripsy? Arch Surg 124:1195, 1989 21. Marks JW, Lan S-P: The Steering Committee: Low-dose chenodiol to prevent gallstone recurrence after dissolution therapy. Ann Intern Med 100:376, 1984 22. Martin OF, Tweedle DE: Endoscopic management of common duct stones without cholecystectomy. Br] Surg 74:209, 1987 23. Mayo WT: "Innocent" gallstones: A myth. JAMA 56:1021, 1911 24. McSherry CK, Ferstenberg H, Calhoun WF, et al: The natural history of diagnosed gallstone disease in symptomatic and asymptomatic patients. Ann Surg 202:59, 1985 25. Murray WR, Laferla G, Fullarton GM: Choledocholithiasis-in vivo stone dissolution using methyl tertiary butyl ether (MTBE). Gut 29:143, 1988 26. National Center for Health Statistics: 1987 Summary: National Hospital Discharge Survey. Hyattsville, MD: National Center for Health Statistics, 1988. Advance Data from Vital and Health Statistics, No. 139. om·ls Publication No. (PHS) 88-150 27. Palmer KR, Hofmann AF: Intraductal mono-octanoin for the direct dissolution of bile duct stones: Experience in 343 patients. Gut 27:196, 1986 28. Peters ]H, Ellison EC, Innes JT, et al: Safety and efficacy of laparoscopic cholecystectomy. Ann Surg 213:3, 1991 29. Podda M, Zuin M, Battezzati PM, et al: Efficacy and safety of a combination of chenodeoxycholic acid and ursodeoxycholic acid for gallstone dissolution: A comparison with ursodeoxycholic acid alone. Gastroenterology 96:222, 1989 30. Reddick EL Olsen DO: Laparoscopic laser cholecystectomy. A comparison with minilap cholecystectomy. Surg Endosc 3:131, 1989 31. Sackier JM, Berci G: Diagnostic and interventional laparoscopy for the general surgeon. Con temp Surg 37:15, 1990
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32. Sackmann M, Pauletzki L Sauerbruch T, et al: The Munich Gallbladder Lithotripsy Study: Results of the first 5 years with 711 patients. Ann Intern Med 114:290, 1991 33. Sauerbruch T, Stern M, The Study Group for Shock-Wave Lithotripsy of Bile Duct Stones: Fragmentation of bile duct stones by extracorporeal shock waves: A new approach to biliary calculi after failure of routine endoscopic measures. Gastroenterology 96:146, 1989 34. Schirmer BD, Edge SB, Dix L et al: Laparoscopic cholecystectomy: Treatment of choice for symptomatic cholelithiasis. Ann Surg 213:665, 1991 35. Schoenfield L], Berci G, Carnovale RL, et al: The effect of ursodiol on the efficacy and safety of extracorporeal shock-wave lithotripsy of gallstones: The Dornier National Biliary Lithotripsy Study. N Engl J Med 323:1239, 1990 36. Schoenfield L], Lachin JM, The Steering Committee and the National Cooperative Gallbladder Study Group: Chenodiol (chenodeoxycholic acid) for dissolution of gallstones: The National Cooperative Gallbladder Study. A controlled trial of efficacy and safety. Ann Intern Med 95:257, 1981 37. Siegel JH, Safrany L, Ben-Zvi JS, et al: Duodenoscopic sphincterotomy in patients with gallbladders ill situ: Report of a series of 1272 patients. Am J Gastroenterol 83:1255, 1988 38. Southern Surgeons Club: A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med 324:1073, 1991 39. Steinberg HV, Beckett WW, Chezmar JL, et al: Incidence of cholelithiasis among patients with cirrhosis and portal hypertension. Gastrointest Radiol 13:347, 1988 40. Thistle JL, May GR, Bender CE, et al: Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med 320:633, 1989 41. Villa nova N, Bazzoli F, Taroni F, et al: Gallstone recurrence after successful oral bile acid treatment: A 12-year follow-up study and evaluation of long-term postdissolution treatment. Gastroenterology 97:726, 1989
Address reprint requests to John C. Bowen, MD Ochsner Clinic 1514 Jefferson Highway New Orleans, LA 70121
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GALLSTONE DISEASE Pathophysiology, Epidemiology, Natural History, and Treatment Options John C. Bowen, MD, Howard 1. Brenner, MD, William A. Ferrante, MD, and William F. Maule, MD
Gallstone disease is ubiquitous in the United States, affecting approximately 10% to 20% of the population. Most patients are unaware of the disease and remain asymptomatic for life. However, a small percentage develops symptoms necessitating treatment. In the United States, 500,000 cholecystectomies are performed annually at an estimated cost of 3 billion dollars.26 Surgical cholecystectomy remains the treatment of choice for symptomatic stones; however, in recent years, nonsurgical treatment of gallstones has been investigated. This article reviews the pathophysiology, epidemiology, and natural history of gallstones; comments on nonsurgical treatments; and reviews newer forms of surgical therapy including laparoscopic cholecystectomy. The majority of gallstones are cholesterol stones (80%); the remainder are pigmented. Cholesterol cholelithiasis results from cholesterol supersaturation of bile, decreased nucleation time, and gallbladder hypomotility. Cholesterol supersaturation may occur because of hypersecretion of cholesterol with a normal bile acid pool or with normal cholesterol secretion in conjunction with a diminished bile acid pool. Cholesterol secretion is a function of the sum of the amount of bile acid produced by the liver, from the enzyme HMG CoA reductase plus the quantity delivered to the liver through lipoprotein minus the amount used to make bile salts or re circulate lipoproteins. The bile acid From the Department of Surgery (JCB) and the Section on Gastroenterology, Department of Internal Medicine (HIB and WAF), Ochsner Clinic and Alton Ochsner Medical Foundation, New Orleans, and the Section on Gastroenterology, Department of Internal Medicine, Ochsner Clinic of Baton Rouge, Baton Rouge, Louisiana (WFM) THE MEDICAL CLINICS OF NORTH AMERICA VOLUME 76 • NUMBER 5 • SEPTEMBER 1992
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pool is determined by the production of bile in the liver and its subsequent enterohepatic circulation. 14 Seven-alpha hydroxylase, the enzyme responsible for conversion of hepatic cholesterol to bile acids, is decreased in patients with cholesterol gallstones. These patients also have overactivity of their HMG CoA reductase. The bile acid pool may be decreased by disease processes such as terminal ileal resection, which eliminates the absorptive surface to complete the enterohepatic circulation I and causes the development of gallstones even with normal cholesterol secretion. Not all patients with lithogenic bile develop stones, which suggests that other factors are implicit in the pathophysiologic process. Nucleation time, the rate at which crystals form in bile, has been shown to decrease from 2 weeks in control patients to only a few days in patients with gallstones. Carey and Cahalane 6 have proposed that mucin glycoproteins, which are secreted under prostaglandin control, decrease nucleation time. Kibe et aP7 have suggested that apoproteins Al and A2 may act as inhibitors of nucleation and thus prevent gallstone formation. The third factor in the pathogenesis of gallstones is hypomotility of the gallbladder, in which incomplete and infrequent emptying of the contents of the gallbladder allows stasis of bile and crystal formation. Patients with these conditions have an increased incidence of gallstone formation. Pigmented stones, which account for 20% of all stones, are either black or brown. Black stones form in the gallbladder as a result of increased levels of unconjugated bilirubin, which binds with calcium carbonate to allow for precipitation. Brown stones form in the bile ducts secondary to stasis and infection. Stasis allows a nidus for stone formation and bacteria release beta-glucuronidase, which allows increased levels of unconjugated bilirubin to develop within the duct itselF Major risk factors for cholesterol gallstones include female gender, pregnancy, obesity, age, some genetic predispositions, weight reduction, and ileal disease. Female sex hormones increase the lithogenicity of bile and decrease gallbladder motility.4 Obesity is associated with a linear increase in gallstone formation. Activity of HMG CoA reductase is increased in obese patients, resulting in hypersecretion of cholesterol into bile. Maclure et al, 19 in a study of 88,000 nurses, found no threshold weight at which this process began. Recent interest has focused on the role of weight reduction in gallstone formation. It is estimated that 25% of obese men and women develop gallstones during weight loss. Probably another 25% of this population develop crystals. These observations are usually made in patients who lose weight rapidly (in excess of 2 to 2.5 pounds per week), especially with fad diets. Possible explanations for this process are a noncontracting gallbladder with stasis during fasting and a decrease in nucleation time. Aspirin, by blocking prostaglandins, has been shown to increase nucleation time and prevent stone formation in these persons. IS, 18 As a person ages, the activity of 7-alpha hydroxylase decreases and the activity of HMG CoA reductase increases, with an associated
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increase in the rate of gallstone formation. There is evidence of disparity in gallstone formation among ethnic groups. Among Pima Indians there is a 70% incidence of gallstones by middle age, whereas some tribes in Africa have rates as low as 3%. The role of diet and environment has yet to be determined. As previously mentioned, ileal disease or resection, which decreases the bile salt pool, increases the likelihood of the development of cholesterol gallstones. Patients with hemolytic anemia and increased levels of unconjugated bilirubin are at increased risk for pigmented stones. Cirrhosis is a known risk factor, but the mechanisms are not well understood. The incidence of pigmented stones in patients with cirrhosis has been estimated to be as high as 60%.39 Proposed mechanisms are hypersplenism with hemolysis and increased levels of estrogen. 12 Gallstones are categorized as asymptomatic, associated with biliary colic, and associated with complications of cholelithiasis. Once stones are symptomatic or present with complications, there is little debate that therapeutic intervention is necessary. The question of what to do about asymptomatic gallstones has prevailed since the turn of the century. In 1911, William Mayo said the innocent gallstone was a myth. 23 More recently, Gracie and Ransohoff!3 studied faculty members of the University of Michigan and found that, over a IS-year period, only 18% of subjects developed symptoms. They also showed that the risk of symptoms diminished with time and that most patients developed symptoms within the first few years of the discovery of stones. Because of these findings, asymptomatic stones are not treated. Data on symptomatic uncomplicated stones are scant. McSherry et aF4 showed that approximately SO% of patients' symptoms worsened over a mean period of 64 months. Therefore, it is generally accepted that once the patient becomes symptomatic, some form of therapeutic intervention is indicated. THERAPY FOR GALLBLADDER STONES
Medical intervention in gallstone disease may include any measure taken to remove symptomatic gallstones from the gallbladder or biliary tree except laparoscopy or laparotomy. Initial apprehension that dissolving or shattering gallbladder stones might produce jaundice or pancreatitis in a substantial number of patients has not been sustained in clinical trials. Gallstone Dissolution Oral Agents. Chenodiol (chenodeoxycholic acid) accumulates in relatively high concentration in the functioning gallbladder after oral ingestion and dissolves gallstones by incorporating water-insoluble cholesterol crystals into water-soluble micelles. Ursodiol (ursodeoxy-
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cholic acid) has similar properties and also increases the fraction of cholesterol dissolved in bile as liquid crystals. Neither medication is effective for calcium bilirubinate (pigmented) stones. Early success in uncontrolled trials led to the National Cooperative Gallstone Study (NCGS),36 in which approximately 900 patients with cholelithiasis and functioning gallbladders were randomized to receive one of two fixed doses of chenodiol (750 mg/d versus 375 mg/d) or a placebo. Fewer than 15% of patients receiving high-dose therapy and 5% receiving low-dose chenodiol had complete stone dissolution during the 2-year trial. The study was criticized for employing inadequate doses of medication; however, even with increased doses (12-15 mg/kg) and alternative agents (ursodiol, 8-10 mg/kg), dissolution therapy has not significantly reduced the need for open cholecystectomy in patients in the United States. The ideal patient for oral dissolution therapy is lean, mildly symptomatic, and has a single, small «20 mm) stone. Unfortunately, fewer than 1 of 5 patients evaluated for cholecystectomy meets these criteria,20 and fewer than 60% of these selected patients are stone free after 24 months of therapy.29 Mild, usually reversible alterations in liver transaminases occur in 25% of patients taking chenodiol but do not occur in those taking ursodiol. Dose-related, intermittent cramping and diarrhea complicate therapy with both medications but usually resolve with continued use or dose reduction. Simultaneous administration of both agents at reduced doses may increase efficacy and reduce the incidence of side effects. 29 Stone recurrence after successful therapy occurs in about 10% of patients each year41 but may decline after the fifth year. Recurrences are not reliably prevented by maintenance therapy with smaller doses of chenodioPl or ursodiol. 41 The cost of medical therapy includes a medication expense of $1500-2000 per year plus office visits and ultrasound monitoring. Parenteral Agents. Methyl-tertiary-butyl ether (MTBE) is an effective lipid solvent that dissolves cholesterol gallstones when it is injected directly into the gallbladder. 40 A percutaneous approach following conscious sedation has been employed most frequently, with considerable success. After the lumen of the gallbladder is punctured with a fine needle, a guide wire is inserted and a 5-Fr catheter (1. 7 mm in diameter) is coiled around the stones in the most dependent portion of the gallbladder lumen. MTBE mixed with radiopaque contrast material is injected into the gallbladder in small aliquots and continuously replaced with fresh solution. Intermittent fluoroscopic monitoring prevents overflow into the biliary tree or duodenum. Leakage into the peritoneal space is minimized by passage of the catheter through the liver parenchyma and puncture of the adjacent gallbladder wall. Manual delivery of MTBE by syringe has been superseded by an automated pump system that minimizes overflow and radiation exposure. Thistle and colleagues40 reported that efficacy was not dependent on stone number or volume and that 72 of 75 patients had greater than 95% reduction in stone volume after less than 15 hours of therapy. Side effects were minor and included anesthesia, duodenal inflammation, and reversible alterations in liver chemistries when MTBE escaped the
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gallbladder. Leakage into the peritoneal cavity was infrequent and resulted in no significant problems. Major advantages of MTBE therapy include low procedural cost and rapid stone dissolution. A functioning gallbladder is not required to ensure efficacy, and cholesterol stones with calcified rims and parenchymal calcifications have been dissolved. Successful MTBE therapy is not dependent on the percutaneous approach; endoscopic placement of standard nasobiliary catheters into the gallbladder has been reported, and a German groupll developed a special catheter system that facilitates endoscopic cannulation of the gallbladder via the cystic duct. The endoscopic approach has the advantage of providing access to stones in the common bile duct, although the potential for leakage into the duodenum or biliary radicals limits MTBE usage in choledocholithiasis. The main obstacles to widespread adoption of MTBE therapy are the need for parenteral administration, the risk of gallstone recurrence following complete stone dissolution, and the risk of symptoms in patients with residual debris in the gallbladder after therapy. Four of 21 patients with complete clearance of stones following MTBE had recurrence of stones within 16 months, and almost half of patients with fragments «5 mm) remaining in the gallbladder after therapy retained the debris after more than 6 months of follow-up. However, fewer than 10% of patients with recurrent or residual stones required cholecystectomy for symptoms during a follow-up interval of up to 42 months. Gallstone Lithotripsy
Gallstones can be eliminated by extracorporeal shockwave lithotripsy using technology originally developed for eliminating kidney stones. 3 General or peridural anesthesia was used initially, but with technical refinements providing better acoustic focusing and improved interfacing between the patient and the shock wave generator, conscious sedation is now routine. Patients must be carefully selected because efficacy of treatment depends on a small stone burden and an unimpeded acoustic pathway. The best results are obtained with single stones smaller than 20 mm in diameter. The task of lithotripsy is to reduce the stones to small fragments that can be dissolved with oral bile salts (vide supra) or pass without symptoms into the duodenum. Alternatively, lithotripsy may be used to fracture large calcified stones for parenteral dissolution by MTBE. The Munich group32 evaluated 711 patients treated with either a modified kidney machine or the Dornier MPL 9000, which was specifically designed for biliary lithotripsy. Over 80% of patients with a single stone smaller than 20 mm in diameter had complete fragmentation (residual debris <3 mm in diameter) of calculus. After lithotripsy, oral ursodiol or a combination of ursodiol and chenodiol produced complete clearance of stone fragments in up to 83% of patients after 1 year of
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therapy. Results in patients with multiple (3 or fewer) stones were less impressive; only about one third had complete clearance of fragments. In a similar trial at 10 centers in the United States,35 600 symptomatic patients underwent lithotripsy using the Dornier MPL 9000. All patients had three or fewer radiolucent stones measuring 5 to 30 mm in diameter and functioning gallbladders. One half of the patients were randomized to ursodiol following lithotripsy and the other half received placebo. Fewer than 50% of patients had complete stone fragmentation «5 mm in diameter), and only 21 % of patients receiving ursodiol and 9% of patients receiving placebo were free of stones 6 months after initiating treatment. In the group with a single stone smaller than 20 mm in diameter who were randomized to ursodiol, only 35% were free of stones after 6 months of treatment. In a smaller US multicenter trial in which the Medstone instrument was used,s all patients had follow-up therapy with ursodiol. Thirtyfour of 67 patients (51 %) with a solitary stone smaller than 20 mm in diameter were cleared of residual fragments after 6 months. None of the 48 patients with stones larger than 20 mm in diameter had clearance after lithotripsy and ursodiol therapy for a similar period. Although there were procedural differences between the three studies, it is not clear why efficacy was so dramatically reduced in the American experience. In October 1989, the US Food and Drug Administration refused to approve either instrument for general use in the United States. Side effects from lithotripsy, including transient alterations in liver chemistries, hematuria, skin bruising, and petechia, have been mild and infrequent. Complications, including biliary pain from residual stones (35%), pancreatitis, jaundice, and need for cholecystectomy «2% each), were no more prevalent than in the placebo group of the NCGS trial. Stone recurrence rates are similar to those recorded in oral bile salt therapy trials. Therapy with oral bile salts requires a functioning gallbladder, protracted administration, and a small stone volume to ensure efficacy. Although stones can be fragmented by extracorporeal lithotripsy in only one or two sessions, complete clearance of stone fragments has the same limitations as primary bile salt therapy. Neither procedure is advocated for patients with severe symptoms or acute cholecystitis, and both are contraindicated in pregnancy. Fewer than 20% of patients fulfill the criteria for treatment with either modality, and in the United States, neither therapy has proved particularly effective. The capital and personnel costs of biliary lithotripsy limit its application to centers with a high volume of patients who refuse cholecystectomy. Despite theoretic and practical advantages, MTBE has not been widely applied, probably because of the need for parenteral administration and questions about stone recurrence. In summary, it is unlikely that medical therapy will reduce surgical intervention for gallbladder stones until there are dramatic improvements in efficacy; a more likely role for medical intervention is therapy that will decrease cholesterol crystal nucleation in patients at high risk for stones.
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TREATMENT OF COMMON DUCT STONES
Common duct stones may occur de novo years after cholecystectomy, but most symptomatic common duct calculi are found before cholecystectomy or during operation for cholelithiasis. About 5% of cholecystectomies are complicated by the presence of common duct stones, necessitating common duct exploration or intraoperative choledochoscopy and stone extraction. Calculi can also be removed after operation via a T-tube placed in the common duct during surgery. All types of common duct intervention during surgery increase operative morbidity. Nonsurgical intervention has dramatically changed the treatment of common duct stones since the introduction of endoscopic sphincterotomy (ES) in 1974. After successful catheterization of the common duct, a wire diathermy knife is used to cut the common duct sphincter and enlarge the orifice of the ampulla of Vater. Balloon catheters, wire retrieval baskets, or stone crushing devices are routinely used to remove or destroy stones up to 10 mm in diameter. Successful clearance of the common duct occurs in greater than 85% of patients. 16 Complications, including cholangitis or sepsis, retroperitoneal perforation, pancreatitis, and bleeding, occur in fewer than 10% of patients, and mortality occurs in fewer than 2%.9 Long-term complications from endoscopic ablation of the ampullary sphincter are rare. Although ES may precipitate acute cholecystitis, ES without cholecystectomy has been advocated for elderly or infirm patients with gallbladder stones and common duct obstruction but no evidence of acute cholecystitis. 22, 37 Siegel et aP7 showed that the risk of subsequent cholecystitis (9%), emergent (2%) or elective (9%) surgery, and biliary death (0.3%) after successful ES was relatively low in this group of high-risk patients. In some patients, large stones or atypical anatomy preclude adequate sphincterotomy. Mono-octanoin 27 instilled through a nasobiliary catheter has dissolved or reduced the diameter of common duct stones with some «50%) success, and MTBE has also been used in small trials. 25 Extracorporeal lithotripsy may be used to fracture large stones that cannot be removed following ES.33 Recently, pulsed-dye laser lithotripsy has been shown to be safe and effective when administered endoscopically by fiberoptic catheters or special small-bore "daughter" endoscopes delivered to the common duct during endoscopic cholangiography.s Unfortunately, equipment cost limits use of this technique to a few centers specializing in endoscopic therapy. SURGICAL TREATMENT
The impetus to avoid open cholecystectomy and discover a minimalist method to treat gallstone disease successfully has resulted in a search for nonsurgical treatments, all of which have been shown in most patients to have significant limitations in applicability and effec-
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tiveness. However, the relatively recent development of laparoscopic cholecystectomy appears to be the exception. Its introduction in 1988 in France by DuBois and colleagues 10 and, at approximately the same time, in the United States by Reddick and Olsen30 has eliminated the incision, the major drawback to open cholecystectomy, while achieving complete removal of the gallbladder and its contained calculi. The procedure's popularity with surgeons and patients has been extraordinary, and the rapidity of application has exceeded the ability of peerreviewed journals to publish timely clinical trials. A major concern was that a rash of new complications would occur before the pitfalls of the procedure were delineated and guidelines for training and awarding credentials were established. Another concern has been the commercialism involved in the development and sale of the technology necessary to carry out the procedure. There can be no doubt that the rapidity with which surgeons were trained in the rudiments of the procedure was attributable in no small part to the support of industry and the profit motive. Industry stood to gain by the competitive frenzy that led to rapid dissemination of the procedure and the concomitant sale of video equipment, special instruments, and laser devices. Skeptics feared that this was another expensive fad that would soon fall by the wayside, as biliary lithotripsy appears to have done. However, their worst fears have not come to pass. The incidence of complications, although definitely related to experience and the learning curve, has proved to be acceptable. Initial reports suggest that bile duct injury, the most feared complication of laparoscopic cholecystectomy, occurs during the early learning phase at a rate of approximately 0.4% to 10%, compared with a rate of 0.2% for standard open cholecystectomy.2, 28, 34 It is clear that, at least in the beginning, there was an incremental increase in the risk of bile duct injury, but other complications such as cautery/laser burns and trocar injuries have been reported infrequently. These problems may be attributable to unfamiliarity with the instrumentation and with the dissection and identification of structures through a two-dimensional video image. Nevertheless, it seems reasonable to assume that with increased experience the incidence of complications will gradually diminish to a level consistent with that of open cholecystectomy. The advantages of reduced disability and cost and improved cosmesis seem worth the effort to develop and disseminate the technique to the more than 500,000 patients who undergo cholecystectomy in the United States annually. Now that the procedure is well established, it must be made as safe and cost effective as possible. The greatest economic impact of the procedure may be the rapid return to work of employed patients. Selection of Patients
The indications for laparoscopic cholecystectomy are identical to those of open cholecystectomy. However, certain pre-existing condi-
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tions and anatomic problems make the procedure technically difficult to perform. In the early experience, acute inflammation, pregnancy, common duct stones, a coagulopathy, and previous upper abdominal surgery were considered possible contraindications. At present, none of these is considered a contraindication, with the possible exception of extensive previous upper abdominal surgery, which is known to cause dense adhesions, making it impossible to achieve pneumoperitoneum and to lyse adhesions. Morbid obesity is a deterrent only if pneumoperitoneum cannot be achieved because of uncertainty as to the depth of the peritoneal cavity. With the use of longer trocars and Verres needles, laparoscopic cholecystectomy can now be performed on nearly all obese patients. Pregnancy has been considered a contraindication. However, after obstetric consultation, we performed laparoscopic cholecystectomy without complication in a patient who was 14 weeks pregnant. The limitation here is the size of the uterus, which in the later stages of pregnancy may limit the ability to puncture and insufflate the peritoneal cavity safely. Cholecystectomy in a cirrhotic patient remains a formidable procedure whether it is done laparoscopically or through an open incision. Conversion of a laparoscopic procedure to open cholecystectomy is reported in approximately 4% to 8% of cases for a myriad of causes. These include morbid obesity, anatomic anomalies, uncontrolled bleeding, escape of numerous stones into the peritoneal cavity, and gangrene of the gallbladder. Our current practice is to initiate all cholecystectomies with laparoscopy unless we are sure that pneumoperitoneum cannot be achieved safely or unless a concomitant upper abdominal operation is required. With experience, increasingly difficult laparoscopic procedures are being performed safely and effectively. Equipment and Methods
Most of the equipment used in laparoscopic cholecystectomy has been available to gynecologists for years. 3 ! High-resolution video equipment is critical to the success of laparoscopic cholecystectomy. In some respects, the image seen on the television monitor is better than that normally seen during open cholecystectomy. An important difference, however, is that the image is two-dimensional. In addition, because the viewpoint is different, experience is required to interpret the anatomy correctly. Another essential piece of equipment is the carbon dioxide insufflator used to create a pneumoperitoneum. The new insufflators are capable of delivering maximum flow rates of 4 to 10 LI min of carbon dioxide to achieve and maintain pneumoperitoneum. A special needle (Verres) with a spring-loaded sheath to protect the intraperitoneal organs from injury is used to insufflate the abdominal cavity. After pneumoperitoneum is established, a trocar is introduced into the peritoneum and a 10-mm telescope attached to a camera is inserted, usually through the umbilicus. A diagnostic laparoscopy is
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then carried out, and three additional trocars are inserted into the peritoneal cavity, through which a variety of instruments can be passed. Special instruments are then passed through the trocars to provide traction and dissect Calot's triangle. By these maneuvers, the identity of the cystic duct and artery can be safely ascertained. An intra operative cholangiogram can be performed by incising the cystic duct and passing a cannula into it. The cystic artery and duct are then clipped both proximally and distally with two clips each before they are divided. While retracting upward on the gallbladder, the surgeon removes it from the liver bed using a thermal source to cut and coagulate the adventitial attachments. Through the umbilical trocar, a large grasping forceps is used to grasp the cystic duct of the gallbladder. After decompression of bile and, if necessary, stones, the gallbladder is delivered from the peritoneal cavity through the umbilical incision. Management of Common Duct Stones
Laparoscopic cholecystectomy poses new dilemmas in the management of common duct stones. Two technical limitations, neither of which has yet been satisfactorily resolved, have altered the usual approach to common duct stones. First, although it is technically possible to perform intraoperative cholangiography with laparoscopy, it can be technically demanding and sometimes virtually impossible. Second, if a stone is found intraoperatively, its removal through the laparoscope is not yet feasible under routine circumstances. To counter these limitations, it has become necessary that the criteria for preoperative endoscopic retrograde cholangiography (ERC) be broadened. Although the option of open cholecystectomy is always present, most patients wish to avoid it and prefer to have either ERC preoperatively to clear the common bile duct or, if necessary, postoperatively to remove a common bile duct stone found during laparoscopic cholecystectomy. Therefore, open cholecystectomy with common bile duct exploration is now reserved for cases in which stones in the common bile duct cannot be removed preoperatively via retrograde endoscopy or in which the cause of biliary obstruction is in doubt. We have evolved a protocol at the Ochsner Clinic for managing these problems. Preoperative screening with ERC of patients at high risk and intraoperative screening with cholangiography of patients at slightly increased risk for common duct stones should detect nearly all occult stones in the biliary tree. This assumption must be confirmed by future analysis of clinical data. The possibility of finding a common duct stone intraoperatively is discussed with each patient, and their wishes regarding open common bile duct exploration versus postoperative ERC with endoscopic stone extraction are determined. So far, none of our patients has preferred conversion to open cholecystectomy over postoperative endoscopic stone extraction. Fortunately, in the first 251 laparoscopic cholecystectomies, open exploration to remove re-
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tained common duct stones that could not be removed during postoperative ERC has been unnecessary. Nevertheless, this possibility is discussed with the patient, and consent for this protocol is obtained. As techniques and instrumentation improve, laparoscopic extraction of common duct stones is likely to become commonplace and may obviate this potential problem. Early Clinical Results
Application of laparoscopic cholecystectomy to the treatment of gallstone disease began at the Ochsner Clinic in May 1990. Over the ensuing 14 months, 271laparoscopic cholecystectomies were attempted by seven surgeons, and 251 cases were successfully completed. Twenty cases (7%) were converted to open cholecystectomy. Initially, we selected only patients with chronic disease. However, as experience increased, the indications and application of the procedure were broadened to include virtually all patients who required cholecystectomy, including patients with acute cholecystitis or previous upper abdominal surgery and four asymptomatic patients. The age range was from 11 to 83 years, with an average age of 48 years. There were 197 women and 74 men. The hospital stay for these patients ranged from 1 to 26 days, with an average stay of 1. 9 days. However, 166 of 251 patients treated successfully (66%) remained for only 1 day and 43 patients (17%) remained for 2 days (Fig. 1).14 Four patients required readmission to the hospital for problems directly related to the laparoscopic cholecystectomy, and two of these required reoperation. Three major complications occurred, each involving a different surgeon; however, all three procedures were performed early in the surgeon's experience (Table 1). The most serious complication was a bile duct injury that required a subsequent choledochojejunostomy. One patient developed a bile leak from the cystic duct that was controlled by a stent placed endoscopically in the common bile duct. 200 (/)
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4
5
6
7
8 9 1011 1213
Hospital Days Figure 1. Distribution of postoperative hospital days in 251 consecutive patients who underwent laparoscopic cholecystectomy.
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Table 1. MAJOR COMPLICATIONS IN 251 LAPAROSCOPIC CHOLECYSTECTOMIES
Complication Bile duct injury Cystic duct bile leak Abscess secondary to intraperitoneal stone Total major complications
Outcome Choledochojejunostomy; well Endoscopic stent; well Drainage of abscess; well
Cases Per Individual Surgeon
Number (%)
3 16 6
1 (004) 1 (004) 1 (004)
3 (1.2)
Another patient developed an intra-abdominal abscess approximately 3 weeks after laparoscopic cholecystectomy in the area of a retained gallstone. The abscess was drained, and the patient recovered fully. Therefore, the overall major complication rate was 1.2%. The most common complaints after laparoscopic cholecystectomy have been right upper quadrant and right shoulder pain lasting 24 to 72 hours, which was believed to be due to retained intraperitoneal gas causing diaphragmatic irritation, and postcholecystectomy diarrhea, which was noted in the records of 13 of 251 patients, although it probably occurred more frequently. Otherwise healthy patients were able to return to normal activities, including work, within 3 to 14 days. Patient acceptance of the procedure has been universal. There have been minor wound problems such as cellulitis around the trocar sites, occasional purulent drainage, and even discharge of stone fragments from the umbilicus. Nevertheless, patients realize that the reduction in disability, rapid return to normal activity, and absence of a major incision are worth these minor inconveniences. A variety of procedures have been carried out concomitantly with laparoscopic cholecystectomy, including liver biopsy, Meckel's diverticulectomy, appendectomy, and lysis of adhesions. In addition, two patients have had laparoscopic cholecystectomy preceding open pelvic operations to limit the extent of the incision needed to accomplish the two procedures. A prospective analysis of 1518 laparoscopic cholecystectomies performed in 29 hospitals in the southern United States surveyed the relatively early experience of 59 surgeons. 38 These surgeons converted 4.7% of cases to conventional open cholecystectomy. A total of 82 complications occurred in 78 patients, representing a rate of 5.1 %. A total of seven (0.5%) common or hepatic duct injuries occurred intraoperatively. Interestingly, the incidence of bile duct injury within the first 13 cases of each participant's experience was 2.2% compared with 0.1 % after that. There was one death in the series 3 days after surgery for an unrelated problem. Schirmer and associates 34 reported the results of their first 152 laparoscopic cholecystectomies. They converted 8.5% of these to an open operation and reported a 4% major complication rate, including one bile duct injury, for an incidence of 0.66%. Peters et aF8 recently reported the results of their first 100 consecutive lapa-
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roscopic cholecystectomies performed over a 6-month period. There were no deaths and a morbidity rate of 8%. There was one minor bile duct injury (1 %) requiring laparotomy and T-tube insertion, two postoperative bile collections, and one clinical diagnosis of retained stones that passed spontaneously. Four patients (4%) required conversion to open cholecystectomy because of technical difficulties with the dissection. As published reports have become available and as the authors have gained personal experience in more than 200 procedures, it has become clear that a significant learning curve is associated with laparoscopic cholecystectomy. Furthermore, the ramifications of performing the procedure are complex and require a wide range of experience and technical ability to cope with the variety of problems that occur. For these reasons, laparoscopic cholecystectomy must be performed by surgeons who have the training and skill not only to treat gallstones but to manage their complications and unexpected problems. As with all new procedures, it is important that each surgeon be trained to a level consistent with current practice. At the outset, it was normal for an experienced surgeon to attend a 2-day course involving didactic lectures, observe a slightly more experienced surgeon performing the procedure, and practice the procedure in an animal model. In the near future, this will be inadequate preparation; surgeons will have to become apprentices to gain the hands-on experience necessary to reach the current level of practice. Furthermore, future training of residents will be crucial to achieve consistently the results that are equal or superior to those of standard cholecystectomy.
SUMMARY In 1991, only symptomatic gallstones should be treated. The treatment of choice for all gallstones continues to be surgical removal. Except for stones in the common bile duct, which are amenable to removal by endoscopic papillotomy, nonsurgical treatment of gallstones should be investigated further before it can have widespread applicability. The major challenge in the future may be medical prevention of gallstone formation in susceptible individuals. Laparoscopic cholecystectomy seems to have moved to the forefront of surgical therapy in patients who are candidates for the procedure.
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