Cholelithiasis

An estimated 10 to 20 percent of adults in the United States have gallstones. The prevalence is greater in women than in men (20 percent versus 8 percent, on autopsy) and increases with advancing age. Many, if not most, patients with cholelithiasis are asymptomatic, and many cases remain undetected. Nevertheless, approximately 1 million new cases of symptomatic cholelithiasis are diagnosed each year. In the United States, the annual cost of treating gallstone disease is more than $1 billion.[1-3]

This article reviews the initial diagnosis and management of cholelithiasis and describes some of the most recent treatment options and recommendations.

Clinical Presentation

Although cholelithiasis is frequently asymptomatic, the classic clinical presentation is severe, steady, aching pain occurring in the epigastric or right upper quadrant of the abdomen and often radiating to the right scapula or shoulder. The pain is typically described as having a sudden onset, with gradual resolution over several hours. It is sometimes associated with the ingestion of large meals or meals high in fat, and it may be accompanied by nausea and vomiting.

On physical examination, patients may be febrile and are rarely icteric. Abdominal tenderness is usually elicited, and the classic Murphy's sign (pain on inspiration while the right upper quadrant is palpated) may be positive.

Laboratory findings associated with acute cholecystitis include leukocytosis, mildly elevated serum bilirubin levels (in about 25 percent of cases) and elevated alkaline phosphatase levels.[3] The diagnosis is generally confirmed by radiologic or ultrasonographic identification of gallstones in the gallbladder.

Initial Management

It is currently estimated that patients with asymptomatic cholelithiasis have a 1 to 2 percent risk of developing symptoms or complications in a given year.[3] Intervention is seldom warranted for asymptomatic patients. One study[4] determined that if prophylactic cholecystectomy were performed in asymptomatic patients (with an average complication rate), life expectancy would actually decrease by four days in a 30-year-old man and by 18 days in a 50-year-old man. Some asymptomatic patients with cholelithiasis may benefit from prophylactic treatment if they have disease states that increase their risk for complications (e.g., sickle cell disease, gallbladder anomaly, exceptionally large stones).

If asymptomatic gallstone disease is detected, patients should be made aware of the presence of the gallstones, educated about potential symptoms and informed about appropriate actions to take if symptoms develop.

Management of patients who present with severe acute cholecystitis is aimed at reducing symptoms and achieving stabilization before definitive treatment options are considered. Gallbladder activity is minimized by withholding food and liquids and, if necessary, removing stomach contents by nasogastric suction. Serum electrolyte balance and hydration should be maintained, and pain should be approriately managed. Meperidine (Demerol) or pentazocine (Talwin) are often used, because they seem to cause less spasm of the sphincter of Oddi than do other narcotic analgesics. Once the patient is stable, definitive therapeutic options can be considered.

All patients experiencing symptomatic cholelithiasis are at increased risk for further complications (such as cholangitis), and the need for cholecystectomy or another intervention should be evaluated.[3]

Surgical Treatment

OPEN CHOLECYSTECTOMY

Open cholecystectomy was first performed by Langenbuch in Berlin around 1882 and, until recently, was the undisputed standard treatment for symptomatic cholelithiasis. The decision to operate is based on the clinical implications of the disease and on the patient's risk of complications from intervention. Although any stone-related symptom is an indication for intervention, some patients may be at increased risk of complications from the intervention itself. Additional indications for intervention that may be weighed against the risk are listed in Table 1.[3]

Complications of open cholecystectomy are similar to those occurring with general laparotomy and include bleeding, infection, rupture of viscus and complications related to anesthesia. The incidence of such complications ranges from 5 to 10 percent when surgery has been delayed until the inflammation has resolved. Recovery time after surgery averages three to seven days in the hospital and three to six weeks at home.[5,6] Reported mortality rates are 0.1 to 0.3 percent in uncomplicated cases.[7-10] Studies have found mortality rates as low as zero percent and as high as 1.3 percent. In patients more than 70 years of age, mortality rates may be as high as 5 percent.[1,3,11,12]

LAPAROSCOPIC CHOLECYSTECTOMY

Laparoscopic techniques, which have been used for years in the field of gynecology, have recently been adapted to cholecystectomy, in an effort to decrease complications, recovery time and cost.

Results from early studies of this new technique were encouraging. Only about 5 percent of laparoscopic cholecystectomies must be converted intraoperatively to open cholecystectomy.[12,13] Morbidity of laparoscopic cholecystectomy appears to be related to the experience of the surgeon but is generally comparable to that of open cholecystectomy - 5 to 10 percent. Mortality is also similar to that of open cholecystectomy, with a rate of zero to 1 percent.[12,14]

The great advantage of laparoscopy is in recovery time. Hospital stays average one to two days, and patients are usually able to return to work three to seven days after surgery.[5-12-15] Laparoscopic cholecystectomy was initially reserved for uncomplicated cases, and open cholecystectomy was mandatory for problem cases, such as advanced cholecystitis, abdominal sepsis, ileus, bleeding disorders, pregnancy or morbid obesity. This convention is changing, however, and studies are currently examining the use of laparoscopic cholecystectomy in patients with acute illness.[16] Laparoscopic cholecystectomy may also be useful in more complicated cases.

Complications of laparoscopic cholecystectomy include those inherent to laparoscopy, listed in Table 2.[5] The incidence of these complications is approximately 1 percent.[6] Additional complications specific to laparoscopic cholecystectomy include bile duct injury, missed stones, bile leak, perihepatic collections and ruptured gallbladder. Altogether, complications are estimated at 5 percent, although data are still being compiled.[12] Preoperative conditions, such as adhesions, inflammation and variations in biliary anatomy, increase the incidence of complications.

CHOICE OF SURGICAL PROCEDURE

When compared with open cholecystectomy, laparoscopic cholecystectomy tends to result in longer operating room time, higher operating room costs and a higher incidence of bile duct injury, which is associated with higher mortality. However, laparoscopic cholecystectomy also results in shorter hospital stays (and thus, a comparable overall hospital cost) and fewer pulmonary complications, since postoperative pain caused by a large incision is avoided.[14]

Open cholecystectomy and laparoscopic cholecysectomy have similar overall morbidity and mortality rates. Laparoscopic cholecystectomy is associated with a lower incidence of intra-abdominal adhesions, wound site hernia and scar formation. Postoperative pain is also reduced, and recovery time is shorter.[17] The total hospital cost of laparoscopic cholecystectomy was about $300 less than that of open cholecystectomy in one study.[14]

Open cholecystectomy hs one significant advantage over laparoscopic cholecystectomy, in that it allows for common bile duct exploration. Stone removal can be a problem with laparoscopic cholecystectomy, but that difficulty can be dealt with in several ways, including intra- and extracorporeal lithotripsy, stone dissolution and, most commonly, sphincterotomy.

Nonsurgical Treatment

Many nonsurgical treatment options for cholelithiasis are currently being explored, including extracorporeal shock-wave lithotripsy, stone dissolution, sphincterotomy and percutaneous gallbladder drainage. These methods are often chosen when symptomatic patients are not suitable candidates for surgery. The problem with nonsurgical therapy is that the gallbladder is left intact, with a significant risk of symptom recurrence. Recurrence rates have been estimated at 10 to 20 percent in the first six months after nonsurgical treatment.[18] Within the first seven years after treatment, a 50 percent recurrence rate is expected; 10 percent of those patients are symptomatic.[1]

EXTRACORPOREAL SHOCK-WAVE LITHOTRIPSY

Extracorporeal shock-wave lithotripsy was first used for urolithiasis and has been fairly successful, with reports indicating that 90 percent of stones pass through the ureters after lithotripsy.[1] Extracorporeal shock-wave lithotripsy works by passing sound was through water and focusing them on a specific stone. Wave amplitude is increased rapidly, causing a rise in energy and producing mechanical stress. This stress causes disintegration of the stone into fragments that are small enough to pass through the ureter.

Patients with gallstone disease must meet certain criteria to be considered candidates for treatment with extracorporeal shock-wave lithotripsy. These criteria, along with selected contraindications, are listed in Table 3.[2] In addition, the stone must be in a position that allows the waves to be focused on it without contacting the long bones or the lungs. These guidelines effectively eliminate 80 to 90 percent of patients with gallstones.[1,19]

Extracorporeal shock-wave lithotripsy has not been approved by the U.S. Food and Drug Administration for the treatment of cholelithiasis. In practice, however, this treatment is typically combined with other methods, such as oral dissolution agents, sphincterotomy and percutaneous dissolution or drainage.[20] Even with the combination of these methods, patients often require more than one treatment (in one study,[21] 28 percent required further treatment). Many patients require additional treatment for stones trapped in the bile ducts and eventually have recurrences.

In addition to its role as a primary treatment, lithotripsy has been investigated as adjunctive therapy for failed endoscopic stone retrieval and for retained ductal stones after laparoscopic cholecystectomy. The success rate of lithotripsy after failed endoscopic retrieval is about 60 to 80 percent.[21]

Lithotripsy is expensive. Open cholecystectomies (with an average hospital stay of three days) have a mean hospital cost of $3,685.[19] Lithotripsy, which includes an average of one year of bile acid therapy and fewer than three days in the hospital, has a cost of $15,087.[19]

Although extracorporeal shock-wave lithotripsy has a mortality rate of essentially zero, it does have some complications, including cutaneous petechiae (14 percent), hemobilia (8 percent), gross hematuria (6 to 37 percent), biliary sepsis (4 percent) and pancreatitis (1.5 percent).[3,19,20]

Aside from the recurrence rate, another complication of extracorporeal shockwave lithotripsy involves the passage of stone fragments through the bile ducts. There are no peristaltic waves in the bile ducts, as in the ureters, and the diameter of the bile ducts is smaller than that of the ureters. Gallstones must be fragmented to less than 3 mm in diameter to pass through bile ducts.[1] Although 80 to 90 percent of gallstones are fragmented by extracorporeal shock-wave lithotripsy, 20 to 80 percent of patients are left with fragments larger than 5 mm.[19,21] (These patients (as many as 35 percent) are at risk for stone impaction and biliary colic.[3,19] Most of these complications are reversible, but pancreatitis and biliary sepsis are of substantial concern, and choleductal occlusion requires further treatment.

INDIRECT DISSOLUTION

Stone dissolution is another possible nonsurgical treatment for cholelithiasis. It may be accomplished indirectly by ingestion of bile acids, which act by desaturating cholesterol in the bile. One of the early agents was chenodiol (chenodeoxycholic acid; Chenix), which - at a dosage of 10 to 15 mg per kg per day - results in diarrhea, mild transient elevation of transaminase levels (25 percent of cases) and an increase in plasma cholesterol levels.

Ursodiol (ursodeoxycholic acid; Actigall) was later developed and, at a dosage of 5 to 10 mg per kg per day, had none of the side effects of chenodeoxycholic acid, but, in persons treated with this agent, 10 percent of stones calcified.[3,22] Occasionally, these two drugs are combined in an attempt to improve results.

Any patient with radiolucent stones less than 15 mm in diameter and a functioning gallbladder is a potential candidate for oral bile acid therapy (approximately 25 percent of patients in one study).[23,24] With this treatment, stones are successfully dissolved in 38 percent of patients. The success rate rises to 50 to 60 percent for high-cholesterol stones, which are radiolucent and "float" on ultrasound. Because better results are achieved with smaller stones, bile acid therapy is often combined with lithotripsy. Oral dissolution is less effective for pigmented, radiopaque, calcified or large (greater than 15 mm) stones. If the gallbladder is poorly visualized on an oral cholecystogram, the oral bile acids are not likely to be adequately concentrated.[3,23]

Complications are not uncommon and inclyde cystic duct obstruction (20 percent) and inflammatory reactions such as biliary colic, pancreatitis and acute cholecystitis (16 percent).[23,25] Patients with these complications usually require cholecystectomy. Recurrence rates are similar to those of other nonsurgical methods. Over a five-year period, the rate of recurrence appears to be 50 percent; 10 percent of these patients are symptomatic.[3,18,23]

DIRECT DISSOLUTION

Another option rarely used for stone dissolution is direct application of chemical agents through percutaneous transhepatic injection or by a retrogade route during endoscopy. In the 1970s, agents such as diethyl ether, chloroform, heparin, clofibrate and saline were used to flush the gallbladder in an attempt to dissolve stones. Direct dissolution is believed to work primarily by flushing and/or forcing the stones through the ducts. Because ether boils at body temperature, the expanding pressure from gas formation is thought to force stones through the bile duct. This process, however, may exacerbate the patient's pain. Chloroform is toxic and often caused lethargy, pancreatitis, cholangitis and hemorrhagic duodenal ulcers. Heparin and saline have few side effects but have not successfully dissolved stones.[26]

Two chemicals are commonly available for dissolution: mono-octanoin and methyl tert-butyl ether. Mono-octanoin appears to have a success rate of 83 percent. Side effects are limited to nausea, vomiting, pain and diarrhea.[27] Treatment takes three to 21 days in the hospital.[28]

Methyl tert-butyl ether is infused through a fluoroscopically placed percutaneous transhepatic catheter. To limit toxicity to the duodenal mucosa, it is repeatedly infused and aspirated; this cycle is done four to six times per minute for five hours a day, over a period of one to three days.

An alkyl ether, methyl tert-butyl has a boiling point of 55 [degrees]C (131 [degrees]F). It does not form gas inside the gallbladder, thus avoiding the potential problems of diethyl ether. Because several less time-consuming and safer methods of disrupting stones are available, direct dissolution is rarely used. It is used mainly as an occasional adjunct to other nonsurgical methods, or it may be tried after other methods fail.

The best results direct dissolution are obtained with radiolucent stones. One study[29] found dissolution to be successful in 95 percent of patients. Of these patients, 28 percent were completely free of stones and 68 percent had residual debris less than 5 mm in diameter. Spontaneous clearance eventually occurred in 30 percent of the patients with residual debris, but 14 percent continued to have symptoms. Twenty percent of the patients who originally had complete resolution experienced a recurrence within 16 months.

Approximately 30 percent of patients in this study[29] had nausea and vomiting during infusion. Mild transient elevation of liver enzyme levels occurred in 6 percent, and 4 percent had increased serum bilirubin levels (greater than 2 mg per dL). Sedation, intravascular hemolysis and mild transient leukocytosis occasionally occurred when methyl tert-butyl ether spilled over into the peritoneum. Major risks include leakage of bile, blood or solvent into the peritoneum or liver parenchyma. Approximately 90 percent of methyl tert-butyl ether is excreted through the lungs.[28,29]

SPHINCTEROTOMY

Endoscopic sphincterotomy was first described in 1974.[30] The procedure involves passing an endoscope through the stomach into the duodenum, locating the bile duct and dividing the sphincter. Endoscopic sphincterotomy is useful in patients who have a residual ductal stone after cholecystectomy. Endoscopic sphincterotomy is also indicated in patients with a ductal stone who are not good surgical candidates. It is occasionally used in conjunction with other treatment methods, such as lithotripsy or bile acid dissolution.

Endoscopic sphincterotomy, when used alone, allows the passage of ductal stones in 80 to 90 percent of selected patients. When combined with lithotripsy to fragment larger ductal stones, success rates may increase to 90 to 95 percent.[5,24] Although the complication rate is only 7 to 9 percent, the complications that occur tend to be more serious than those found in other procedures, including surgery. The more severe complications include perforated duodenum or duct (1 percent), hemorrhage (1 percent), acute pancreatitis and sepsis.[31]

DRAINAGE

Percutaneous transhepatic drainage is occasionally used in patients who are not surgical candidates or in patients with severe symptoms, to help relieve inflammation prior to surgery. It has been used experimentally to drain stones and debris after lithotripsy. Many patients treated with percutaneous transhepatic drainage later require surgery, but, since the patient is more stable, surgical morbidity and mortality rate are thought to be lower. Percutaneous transhepatic drainage is also used to diagnose acute cholecystitis and to stabilize patients when ductal drainage is inhibited by hepatic inflammation.

Drainage is successful in 90 to 100 percent of cases. Complication rates range from 6 to 10 percent, depending on the severity of the disease. Complications in patients with acute cholecystitis undergoing percutaneous transhepatic drainage include colonization of the bile with new bacteria (26 percent), catheter dislodgment (22 percent), bile leak (13 percent), duodenal puncture (4 percent) and incorrect catheter placement (4 percent).

Mortality also varies; in simple cases it is as low as 0.05 percent, but percutaneous transhepatic drainage is usually reserved for very ill patients who cannot tolerate surgery and, in these emergent cases, mortality can be as high as 40 percent. Many of these deaths are thought to be related to the underlying disease rather than to the drainage procedure itself. Recurrence rates are approximately the same as those for other nonsurgical procedures.[32-34]

REFERENCES

[1.] Vergunst H, Terpstra OT, Brakel K, Lameris JS, van Blankenstein M, Schroder FH. Extracorporeal shockwave lithotripsy of gallstones. Possibilities and limitations. Ann Surg 1989;210:565-75. [2.] Pixly F. Epidemiology. In: Bateson MC, ed. Gallstone disease and its management. Lancaster, Pa.: MTP Press, 1986. [3.] Greenberger NJ, Isselbacher KJ. Diseases of the gallbladder and bile ducts. In: Wilson JD, et al., eds. Harrison's Principles of internal medicine. 12th ed. New York: McGraw-Hill, 1991:1358-68. [4.] Ransohoff DF, Gracie WA, Wolfenson LB, Neuhauser D. Prophylactic cholecystectomy or expectant management for silent gallstones. A decision analysis to assess survival. Ann Intern Med 1983;99:19-204. [5.] Reddick EJ, Olsen DO. Outpatient laparoscopic laser cholecystectomy. Am J Surg 1990;160-458-7. [6.] Ponsky JL. Complications of laparoscopic cholecystectomy. Am J Surg 1991;161:393-5. [7.] Neugebauer E, Troidl H, Spangenberger W, Dietrich A, Lefering R. Conventional versus laparoscopic cholescytectomy and the randomized controlled trial. Cholecystectomy Study Group. Br J Surg 1991;78:150-4. [8.] Bouchier IA. Gall stones. BMJ 1990;300:592-7. [9.] Barkun JS, Barkun AN, Sampalis JS, Fried G, Taylor B, Wexler MJ, et al. Randomised controlled trial of laparoscopic versus mini cholecystectomy. The McGill Gallstone Treatment Group. Lancet 1992; 340:1116-9. [10.] Davies MG, O'Broin E, Mannion C, McGinley J, Gupta S, Shine MF, et al. Audit of open cholecystectomy in a district general hospital. Br J Surg 1992;79:314-6. [11.] Heberer G, Paumgartner G, Sauerbruch T, Sackmann M, Kramling H, Delius M, et al. A retrospective analysis of 3 years experience of an interdisciplinary approach to gallstone disease including shock-waves. Ann Surg 1988;208:274-8. [12.] The Southern Surgeons Club. A prospective analysis of 1518 laparoscopic cholecystectomies. N Engl J Med 1991;324:1073-8 [Published erratum appears in N Engl J Med 1991;325:1517-8]. [13.] Berci G, Sackier JM. The Los Angeles experience with laparoscopic cholecystectomy. Am J Surg 1991;161:382-4. [14.] Gadacz TR, Talamini MA. Traditional versus laparoscopic cholecystectomy. Am J Surg 1991;161:336-8. [15.] Laparoscopic cholecystectomy. Med Lett Drugs Ther 1990;32:115-6. [16.] Flowers JL, Bailey RW, Scovill WA, Zucker KA. The Baltimore experience with laparoscopic management of acute cholecystitis. Am J Surg 1991;161: 388-92. [17.] Perissat J, Collet D, Vitale G, Belliard R, Sosso M. Laparoscopic cholecystectomy using intracorporeal lithotripsy. Am J Surg 1991;161:371-6. [18.] Dowling RH, Sleeson DC, Hood KA, and the British-Belgian Gallstone Study Group. Gallstone recurrence and postdissolution management. In: Paumgartner G, Stiehl A, Gerok W, eds. Bile acids and the liver. Lancaster, Pa.: MTP Press, 1987:355-67. [19.] Nealon WH, Urrutia F, Fleming D, Thompson JC. The economic burden of gallstone lithotripsy. Will cost determine its fate? Ann Surg 1991;213-645-9. [20.] Moody FG, Amerson JR, Berci G, Bland KL, Cotton PB, Graham JB, et al. Lithotripsy for bile duct stones. Am J Surg 1989;158:241-7. [21.] Barkun AN, Ponchon T. Extracorporeal biliary lithotripsy. Review of experimental studies and a clinical update. Ann Intern Med 1990;112:126-37. [22.] Hofmann AF. Medical dissolution of gallstones by oral bile acid therapy. Am J Surg 1989;158:198-204. [23.] Cheslyn-Curtis S, Russell RC. New trends in gallstone management. Br J Surg 1991;78:143-9. [24.] Way LW. Trends in the treatment of gallstone disease: putting the options into context. Am J Surg 1989;158:251-3. [25.] Gleeson D, Ruppin DC, Saunders A, Murphy GM, Dowling RH. Final outcome of ursodeoxycholic acid treatment in 126 patients with radiolucent gallstones. QJ Med 1990;76-711-29. [26.] Neoptolemos JP, Hofman AF, Moosa AR. Chemical treatment of stones in the biliary tree. Br J Surg 1986;73:515-24. [27.] Mack E. Dissolution of bile duct stones. Am J Surg 1989;158:248-50. [28.] Allen MJ, Borody TJ, Bugliosi TF, May GR, LaRusso NF, Thistle JL. Rapid dissolution of gallstones by methyl tert-butyl ether. Preliminary observations. N Engl J Med 1985;312:217-20. [29.] Thistle JL, May GR, Bender CE, Williams HJ, LeRoy AJ, Nelson PE, et al. Dissolution of cholesterol gallbladder stones by methyl tert-butyl ether administered by percutaneous transhepatic catheter. N Engl J Med 1989;320:633-9. [30.] Stain SC, Cohen H, Tsuishoyasha M, Donovan AJ. Choledocholithiasis. Endoscopic sphincterotomy or common bile duct exploration. Ann Surg 1991; 213:627-33. [31.] Sivak MV Jr. Endoscopic management of bile duct stones. Am J Surg 1989;158:228-40. [32.] Kellett MJ, Wickham JE, Russell RC. Percutaneous cholecystolithotomy. BR Med J [Clin Res] 1988; 296:453-5. [33.] Pessa ME, Hawkins IF, Vogel SB. The treatment of acute cholangitis. Percutaneous transhepatic biliary drainage before definitive therapy. Ann Surg 1987;05:389-92. [34.] Werbel GB, Nahrwold DL, Joehl RJ, Vogelzang RL, Rege RV. Percutaneous cholecystostomy in the diagnosis and treatment of acute cholecystitis in the high-risk patient. Arch Surg 1989;124:782-5.

Bryan W. Ghiloni, m.d. is a fellow in sports medicine at Sports Medicine Grant at Grant Medical Center, Columbus, Ohio. After graduating from Wright State University School of Medicine, Dayton, Ohio, Dr. Ghiloni completed a residency at Grant Medical Center, where he was chief resident. He was also a clinical instructor at the Ohio State University School of Medicine, Columbus.

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