Original Article. Asymptomatic gall stones revisited. Avinash Supe ABSTRACT

Transcription

1 Tropical Gastroenterology 2011;32(3): Original Article Asymptomatic gall stones revisited Avinash Supe ABSTRACT Department of GI Surgery, Seth GS Medical College and KEM Hospital Parel, Mumbai , India Correspondence: Dr. Avinash Supe India has a large burden of individuals harboring asymptomatic gallstones. Based on Markov model decision and cost analysis, selective and concomitant cholecystectomy is recommended for special indications like hemolytic disorders and stones in endemic areas. Expectant management should be adopted in all others. The evolution of laparoscopy should not alter the indications of cholecystectomy. Since more than 90% patients with asymptomatic gallstones remain clinically silent, routine laparoscopic cholecystectomy is not indicated for the vast majority of subjects with asymptomatic cholelithiasis. Although laparoscopic cholecystectomy has become much safer, there remains associated morbidity and mortality. The risks of the operation outweigh the complications if stones are left in-situ. Patients should be counseled about the natural history and available management options, their advantages and disadvantages, and should be part of the decision making process. Prophylactic routine cholecystectomy for asymptomatic stones is not recommended. However, laparoscopic cholecystectomy should be performed selectively or concomitantly in a specific subgroup of patients. KEYWORDS: Asymptomatic gallstones, concomitant cholecystectomy, prophylactic cholecystectomy Introduction Asymptomatic gallstones are being increasingly diagnosed today, mainly as a result of the widespread use of ultrasonography for the evaluation of patients for unrelated or vague abdominal complaints. Gallstones are now prevalent all over the world and about 10-20% of the adult population has gallstones. 1 In India, out of 800 million adult population, approximately 15% (120 millions) have gallstones. Asymptomatic gallstone disease has a benign natural course; the progression of asymptomatic to symptomatic is relatively low with about 2% become symptomatic each year. 1 The majority of patients rarely develop gallstone related complications without first having at least one episode of biliary pain (colic). Most common symptoms are upper abdominal pain, biliary colic, and dyspepsia. Biliary colic is defined as a steady right upper quadrant abdominal pain lasting for more than half an hour, which may be associated with radiation to the back and nausea and may force patients to stop their activities. Dyspepsia is defined as the presence of three or more of the following symptoms: belching, flatulence, nausea, intolerance to fatty food, bloating of the abdomen, epigastric discomfort, and acid regurgitation. The complications of gallstones include acute cholecystitis (including empyema, when the gallbladder is filled with pus), acute gallstone pancreatitis, obstructive jaundice, and rarely small bowel obstruction (gallstone ileus). The distinction between symptomatic and asymptomatic gallstones can be difficult because symptoms can be mild and Tropical Gastroenterology 2011

2 Asymptomatic gall stones 197 varied. The annual incidence of complications of gallstones in asymptomatic patients is 0.3% acute cholecystitis, 0.2% obstructive jaundice, 0.04% to 1.5% of acute pancreatitis and rarely gallstone ileus. 2 Moderate and severe complications of gallstones have higher morbidity and mortality rates (close to 1%). Laparoscopic cholecystectomy though now commonly performed has a risk of 0.2% biliary injury and 0.05% mortality. 3,4 In the pre-laparoscopic era, open cholecystectomy was generally performed for symptomatic disease. Minimally invasive laparoscopic cholecystectomy has refuelled the discussion about the optimal management of asymptomatic gallstones. In a country like India, where the population is large (1200 million), the magnitude of the problem is huge. A Markov model was prepared to understand the scope of the problem. (Figure 1), (Table1). 2,5,6 Figure 1: Markov model for asymptomatic gall stones in India. Adult popoulation 800 million (The population 1200 millions -2010)

3 198 Tropical Gastroenterology 2011;32(3): Table 1: Variable Probabilities used in preparing Markov Model Asymptomatic gallstones extent of the problem Asymptomatic cholelithiasis refers to the condition when gallstones are detected in the absence of gallstone related symptoms such as biliary pain or gallstone-related complications. Though complications are easy to diagnose, differentiating vague dyspeptic symptoms from biliary pain is not very easy. Therefore there is over-diagnosis of symptomatic stones, consequently providing no relief to some of the patients who undergo surgery. However the fact that patients with such non-specific symptoms sometimes benefit from cholecystectomy indicates that cholelithiasis to a certain extent contributes to vague clinical picture. Natural history of gallstones Value Number of patients developing mild symptoms 2% 1 (from asymptomatic gall stones) every year Number of patients developing moderate and 1.3% and 0.2% severe symptoms (from asymptomatic gall stones) every year Operative Mortality 5/10000 Complications 1/1000 Persistent symptoms after surgery 15% Other causes of mortality 6.4/1000 per year (India Population Project) There is no innocent gall stone William Mayo It is unfortunate that so few appreciate from what small causes diseases come Charles Mayo Though this was the dictum 100 years ago, now there is enough evidence that most incidentally discovered, clinically silent gallstones rarely have clinical significance. Most patients live and die with their gallstones having never caused pain or other medical problems. A longitudinal follow up study of asymptomatic gallstones showed that over 20 year period only 18% of patients developed biliary pain and mean yearly probability of development of 2% during first 5 years, 1% during second 5 years, 0.5% during third 5 years. 7 In summary most studies indicate that the progression of asymptomatic to symptomatic disease is relatively low. The major concern is the possible development of a severe potentially life threatening complication, such as severe pancreatitis or acute suppurative cholangitis. In majority of patients these complications develop without any preceding episode of biliary colic. From a practical point of view, it would be very important for both the patient and physician if it is recognized which sub group of asymptomatic patients will become symptomatic, but this is not easily possible. Some authors have tried to classify patients into two groups: low risk group and high-risk group. 8 This study plans to use clinical decision analysis and published data to compare the clinical effectiveness and cost of management strategies for asymptomatic gallstones. Clinical starting points The analysis applies to patients who are diagnosed with gallstones that are detected in the absence of related symptoms such as biliary pain or complications such as acute cholecystitis, acute pancreatitis or bile duct complications. The study also examines other significant co-morbidities. Clinical strategies Controversies surrounding routine cholecystectomy for asymptomatic gallstones are far from resolved. Four clinical strategies were evaluated. These included 1) expectant treatment for all and surgery if needed; 2) routine prophylactic laparoscopic cholecystectomy for all; 3) selective cholecystectomy for patients with factors predicting severe outcome and expectant for rest; 4) concomitantly during another intraabdominal operation for an unrelated pathologic condition. 1. Expectant management ( wait and see ) Watchful waiting is the most reasonable treatment for these patients as majority of them remain asymptomatic throughout their life. This approach avoids overtreatment (an unnecessary surgical procedure under general anesthesia) in the vast majority of asymptomatic patients who will never develop symptoms. The disadvantage of this approach is that the patient can suffer a potentially severe or even lethal complication of gallstone disease, such as cholecystitis or severe acute pancreatitis, and may need emergency surgery with increased morbidity and mortality or may develop gallbladder cancer usually at a more advanced age. Considering that the vast majority of asymptomatic patients remain asymptomatic throughout their life and that most asymptomatic patients develop symptoms before the occurrence of complications, prophylactic surgical therapy is not justified. 9,10 According to the NIH Consensus Conference report 11 the availability of laparoscopic cholecystectomy should not expand the indications for gallbladder removal.

4 Asymptomatic gall stones 199 Table 2: Life expectancies, mortalities and risks for management of cholelithiasis by sex, incidence and age (based on Kottke et al medical decision making 1984) 22 Incidence Age Life expectancy Smoothed Life expectancy Lifetime risk Life expectancy Risk without stones operative (wait and see) of death from difference complications ratio mortality gall bladder Men Low (0.0139/y) Intermediate (0.0329/yr) High (0.0481/yr) Women Low (0.0139/yr) Intermediate (0.0329/yr) High (0.0481/yr) Routine prophylactic laparoscopic cholecystectomy ( Operate now ): Currently, laparoscopic cholecystectomy is the gold standard in the management of cholelithiasis, given the safety and ease of performance and the many well-known advantages of this approach over conventional open cholecystectomy, including shorter hospital stay, lesser need for postoperative analgesia, better cosmetic results, fast recovery to full preoperative activity, and avoidance of long-term complications (i.e. incisional hernia). 12 About 22 years after its introduction, laparoscopic cholecystectomy is considered to be a safe operation, with low morbidity and overall mortality approximating 0.05% in different studies, depending on the age and fitness of the patients. 13 Though laparoscopic surgery has advantages it has a small risk of complications such as bile duct injury, bile leak and other morbidity. In view of this, prophylactic cholecystectomy is not accepted as routine therapy by most surgeons. 3. Selective cholecystectomy: There is lot of literature on performing laparoscopic cholecystectomy in select subgroup of patients with asymptomatic cholelithiasis, who are at greater risk for the development of symptoms or complications. 7,14 The clear indications 15 include: a) suspicion/risk of malignancy, b) gallstones associated with gallbladder polyps >1 cm in diameter, c) calcified (porcelain) gallbladder, d) some ethnic groups or subjects living in areas with high prevalence of gallbladder cancer associated with gallstones (Uttar Pradesh and Bihar in north India, American Indians, Mexican Americans, Colombia, Chile, Bolivia), e) presence of large (>3 cm) gallstones, f) asymptomatic cholelithiasis associated with choledocholithiasis, g) Transplant patients (before or during transplantation), h) chronic hemolytic conditions (sickle cell anemia). The relative indications include: a) increased risk of conversion from asymptomatic to symptomatic disease, b) life expectancy >20 years, c) calculi >2 cm in diameter, d) calculi <3 mm and patent cystic duct, e) nonfunctioning gallbladder, f) diabetes mellitus, g) vague dyspeptic symptoms in the presence of gallstones. The questionable indications are: a) patients living in an area remote from medical facilities and b) incidental (concomitant) cholecystectomy during another abdominal operation. Though it is beyond the scope of this paper to discuss in detail about each factor, three indications are discussed in detail as relevant to India. a) Gallbladder carcinoma - Gallbladder cancer, although rare in most Caucasian populations, is amongst the most frequently observed cancers in native populations of North and South America, and in the Maori population of New Zealand, possibly as a

5 200 Tropical Gastroenterology 2011;32(3): result of early onset of gallstones. It is higher in north Indian states. 16 The increased incidence of gallstones (at an early age) in these ethnic groups may be due to the presence of cholesterol lithogenic genes that are highly prevalent in these populations. The risk of gallbladder cancer is approximately four times higher in cases with gallstones than in those without. It is estimated that about 80% of patients developing gallbladder carcinoma have gallstones, especially large stones (>3 cm). The risk of underlying malignancy is also high in patients with gallbladder polyps larger than 10 mm in diameter. Calcified or porcelain gallbladder is associated with carcinoma in 13 25% of patients. Though prophylactic cholecystectomy is not advised for all asymptomatic patients, it is strongly recommended for select subgroup of patients where gallbladder cancer is prevalent. Kapoor et al have argued against routine prophylactic cholecystectomy while conceding that considering higher incidence of gallbladder carcinoma in endemic areas of north India, prophylactic cholecystectomy may be considered for a young woman who has a large gallstone or gallbladder packed with stones. 16 Prophylactic cholecystectomy is indicated in patients with gallbladder polyps larger than 10 mm in diameter and in patients with large gallstones (>3 cm). b) Chronic hemolytic syndromes: Sickle cell disease (SCD) is common in parts of India. Patients suffering from chronic hemolytic syndromes like SCD are at 58% increased risk for gallstone development at a young age due to repeated hemolytic crises. Two thirds of these patients are likely to develop symptoms. 17 The onset of gallstones at a young age in SCD raises the lifetime risk of biliary complications. Therefore cholecystectomy for asymptomatic cholelithiasis is advisable in SCD patients. c) Diabetes - Prophylactic cholecystectomy has been recommended for diabetic patients with silent gallstones. 18 This is based on the belief that diabetic patients belong to the high-risk group for the development of complications of gallstone disease (such as infected bile, gangrenous changes and perforation of the gallbladder) that are more severe than in the general population. Earlier reports noted that the risk of acute cholecystitis and subsequent peri-operative morbidity and mortality was significantly higher in diabetic compared to nondiabetic patients. It is believed that the autonomic neuropathy in diabetics may mask the pain and other clinical signs and hence delay the diagnosis. Therefore, diabetics were considered a high-risk group and prophylactic cholecystectomy was recommended. However, other researchers have shown benign course of gallstones in diabetics with low risk of major complications. 19 The cumulative percentage symptoms and complications of gallstones were found to be similar among diabetic patients. Therefore, there is no clear benefit of prophylactic cholecystectomy in diabetic patients with asymptomatic gallstones, because surgery neither appears to increase either the duration or improve the quality of life; but may in fact reduce it. 20 Early elective cholecystectomy is advocated once symptoms develop. 4. Concomitant cholecystectomy - Concomitant cholecystectomy for asymptomatic cholelithiasis (diagnosed either preoperatively or intra-operatively) during a planned abdominal operation is a common clinical scenario. Several studies showed a high (up to 70%) incidence of symptoms and/or complications from the biliary system (such as biliary colic, acute cholecystitis, jaundice) in patients with asymptomatic cholelithiasis following laparotomy for unrelated conditions (bariatric surgery, transplant and other interventions). Cholecystectomy was required in a large percentage (up to 40%) of these patients within 1 year of the initial operation. 21 The aim of incidental cholecystectomy in such cases is to prevent postoperative cholecystitis or the later development of symptoms. Addition of cholecystectomy does not portend added risk to the patient. Cholecystectomy related complications can be avoided by using proper surgical technique, including adequate exposure, by performing an uncomplicated primary operation, and by appropriate patient selection taking into account co-morbidities and general health. Obviously, this strategy is not recommended for high-risk patients, with significant co-morbidity, where a minimal operating and anesthesia time is advisable for an uneventful recovery. The performance of concomitant cholecystectomy may be more difficult in case of a pelvic

6 Asymptomatic gall stones 201 (gynecologic) procedure, because it may require an additional or extended incision. However, this poses no problem if the pelvic procedure is conducted laparoscopically. Risk ratios and life expectancy To evaluate further, one can use risk ratio and life expectancy as differing analytical techniques. 22 Risk ratio was defined as the probability of dying of gallbladder surgery or disease if wait and see approach was chosen, divided by the probability of dying of gallbladder surgery if operate now modality was chosen. Life expectancy difference was defined as the life expectancy if the operate now approach was chosen minus the life expectancy with wait and see approach. The findings are compiled in (Table 2). It is evident that with intermediate symptom incidence the risk ratio strongly favored prophylactic cholecystectomy while other incidences favor a wait and see approach. Kottke 22 also stated that risk ratio can project a course of action that is different from that predicted by life expectancy analysis. He concluded that risk ratio and life expectancy are inadequate for clinical decisions and do not capture all information necessary for informed decisions. In a vast country like India the incidence of gallstone disease varies a lot. While north India, Uttar Pradesh and Bihar have a high incidence, south Indian states record low incidence of this condition. The type of gallstone disease is also variable, diabetes is rising rapidly and incidence of carcinoma of gallbladder is high in some areas. This information impacts decision-making for operating silent gallstones in specific populations. Predictors of symptom development/persistence Festi et al 5 evaluated different predictors of symptom development/persistence such as age, sex, presence of comorbidities (diabetes, liver cirrhosis, peptic ulcer and inflammatory bowel disease), family history and characteristics of both gallstones (number and size) and the gallbladder (function, morphology). In patients who developed symptoms, only the presence of gallstones >1.5 cm was predictive of change in the clinical picture (odds ratio [OR] 1.79, 95% confidence interval [CI] ), while increasing age was the only observed predictor of the persistence of symptoms in patients with a stable clinical picture (OR = 0.96, 95% CI ). None of the variables could reliably predict the appearance of complications except for the presence of diabetes in patients with mild symptoms (OR = 8.8, 95% CI , p<0.03). In particular no relationship was documented between gallstone size and the risk of developing complications. The health care implications for state run medical institutions will be colossal if routine prophylactic cholecystectomy were to be practiced for all asymptomatic cases of cholelithiasis. Every patient who is diagnosed with gallstones whether symptomatic or asymptomatic, would require to be worked up and operated for the same. In private sector, though the load on the system would be tremendous, the monetary implications would be positive. In contrast, government sector resources allocated to health care would have to be moderately increased to accommodate the added burden since a laproscopic cholecystectomy costs around $50-70 for the patient. However the healthcare personnel and their efforts have to be taken into account in public sector institution since most of the burden of surgery is borne by the state. The exact details of this monetary burden on the national infrastructure cannot be assessed due to differential rates of admission to the hospitals and since the charges are not billed to the patient. But it can be safely assumed that the added expenditure accrued to the state funds will be sizeable enough to warrant strong evidence of patient benefit to mandate its implementation. In consideration of the current financial state of Indian health care facilities it is evident that prophylactic cholecystectomy for all asymptomatic patients will incur a much higher cost to the patients and health care infrastructure is therefore not advisable as a routine management strategy for these asymptomatic patients (Table 3,4). Selective cholecystectomy is good option to reduce higher costs of acute complications. Table 3: Cost analysis based on insurance companies ratesfollowing rates were considered for cost analysis in private healthcare sector Cost Value in Dollars (converted into dollars from actual costs in India) Hospital costs Elective uncomplicated surgery $ 1000 Acute complications moderate $ 2500 OPD costs Each visit surgery $ 10 Expectant management per year (no pain) $ 10 Expectant Management mild symptoms $ 100 Acute complications severe $ 3500

7 202 Tropical Gastroenterology 2011;32(3): Table 4: Comments Cost analysis in India (1 million populations) in private sector Expectant Treatment Prophylactic Chol- Over 20 Years in $ ecystectomy in $ No Pain/ Mild pain Moderate Severe OPD fees Mild pain-expectant Mgmt Expectant-Follow up Difference $ ~ 48 Indian Rupees Over the years the incidence of reported asymptomatic gallstones has increased due to better investigations and diagnostic facilities. In last two decades minimally invasive surgery has reduced the morbidity (though mortality remains unchanged) of routine cholecystectomy. While laproscopic surgery is a simple and effective alternative with several advantages over open cholecystectomy, it has also resulted in broadening the indications of cholecystectomy and decreasing the surgical threshold for instituting surgical management in patients of asymptomatic cholelithiasis. However laparoscopy is expensive in a private sector hospital for an average Indian. In view of these observations it is pertinent to examine the scenario in the Indian setting. The Markov model presented here (Figure 1) outlines the scope of the problem and gives an idea about the need for treatment in such patients. According to most case series, patients appear to become symptomatic at the rate of 2-3% per year and require surgery in the approximate distribution as demonstrated in Figure 1. 18,22 The income of an average Indian is $85 per month. Every year 5-6% new patients are added to this pool of asymptomatic gallstones. This model has been created for first three years as an example, keeping in view the fact that majority of gallstones become symptomatic during early years and remain silent after years. Diabetes is increasing in India and is likely to reach 60 million over the next 5 years. India has two contextual issues. The distribution of gallstone disease is regional: north Indian states have higher rate than the south Indian states. The type of stones also vary as per the region due to diet variations. Second issue is the endemicity of gallbladder cancer in some northern states. These issues impact the decision making for management of asymptomatic cases. Based on previous studies 18,22,23 risk ratio and life expectancy were calculated. Expected operative mortality for elective cholecystectomy was for 25-year-old men and approximately doubled with each increasing decade. With the low incidence estimate life expectancy for men/ women with silent stones who chose to wait ranged from 40 to 7.25 years, declining with advancing age. The lifetime risk of death from gallbladder complications for men was initially for 25- year-old men, increased to at the age of 45, and then decreased again at 75 years of age. This is an interesting pattern to study. In young patients the risk of surgery is low and hence risk ratio is higher. As age advances the risk of surgery escalates and incidence of developing complications lowers. Hence we see a U pattern. On the ascending limb of this curve the risk of surgery is increasing faster than the life expectancy which is decreasing. On the descending limb life expectancy is decreasing faster than the surgical risk which is increasing. This has practical implications and one must consider laparoscopic surgery in young patients who have recently detected stones with doubtful symptoms. Surgery for elderly may be deferred if the stones are asymptomatic and have been there for longer period. Though these studies have not found single parameters as useful, this data can be used to undertake informed clinical decisions based on risks, life expectancy and complication patterns. Selective cholecystectomy appears to be a good strategy in India. Routine prophylactic cholecystectomy can be advocated in endemic areas and in young patients based on clinical and sonographic predictors of severity. Factors such as multiple stones, large size and calcified and thickened gallbladder can be used to decide upon prophylactic cholecystectomy. Cost analysis in India India has less than adequate state funding for health (2% of GDP). Hence, most patients have to pay out of their own pockets for their treatment. The insurance sector is also poorly developed in our country, with only 3% patients being covered under health insurance. The cost of prophylactic cholecystectomy would thus be much higher in India as compared to expectant treatment. Therefore, there is a case for expectant treatment based on cost-benefit analysis. To conclude routine prophylactic cholecystectomy for asymptomatic gallstones is not recommended. Based on our Markov model decision and cost analysis selective and concomitant cholecystectomy are recommended for special indications like hemolytic disorders, gallstones in endemic areas etc. Expectant management should be adopted in all others. Figure 1 depicting the model explains the magnitude of target patient population being considered here. Routine prophylactic

8 Asymptomatic gall stones 203 cholecystectomy would amount to additional surgeries in excess of 4 million at the end of 3 years and 5000 patients suffering complications of those surgeries at an accepted complication rate of 1/1000. The magnitude of these statistics overwhelms the available expertise of laparoscopic surgery in our country and also present a significant strain on resources which will widen the deficit in the healthcare sector. The evolution of laparoscopy should not alter the indications of cholecystectomy. Because more than 90% patients with asymptomatic gallstones remain clinically silent routine laparoscopic cholecystectomy is not indicated for the vast majority of subjects with asymptomatic cholelithiasis. Laparoscopic cholecystectomy though has become safer, is associated with potential morbidity and mortality. The risks of the operation outweigh the complications if stones are left insitu. However, laparoscopic cholecystectomy should be performed selectively or concomitantly in select subgroup of patients. Patients should be counseled about the natural history and available management options, their advantages and disadvantages and should be part of the decision making process. Acknowledgement Author thanks Dr. Gaurav V. Kulkarni for his assistance in preparing this manuscript. References 1. Attili AF, De Santis A, Capri R, Repice AM, Maselli S. The natural history of gallstones: the GREPCO experience. The GREPCO group. Hepatology. 1995;21: Gurusamy KS, Davidson BR. Surgical treatment of gallstones. Gastroenterol Clin North Am. 2010;39:229 44, viii. 3. Magni P, Quaglini S, Marchetti M, Barosi G. Deciding when to intervene: a Markov decision process approach. Int J Med Informatics. 2000;60: Wu YV. Linehan DC. Bile duct injuries in the era of laparoscopic cholecystectomies. Surg Clin North Am. 2010;90: Festi D, Reggiani MLB, Attili AL, Loria P, Pazzi P, Scaioli E, et al. Natural history of gallstone disease: Expectant management or active treatment? Results from a population-based cohort study. Gastroenterol Hepatol. 2010;25: Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making. 1993;13: Lowenfels AB, Domellöf L, Lindström CG, Bergman F, Monk MA, Sternby NH. Cholelithiasis, cholecystectomy and cancer: a case control study in Sweden. Gastroenterology. 1982;83: Vauthey JN, Saldinger PF. The natural history of gallstones and asymptomatic gallstones. In: Blumgart LH, Fong Y, editors. Surgery of the liver and biliary tract. 3rd ed.new York: Elsevier; 2000.p Meshikhes AW. Asymptomatic gallstones in the laparoscopic era. J R Coll Surg Edinb. 2002;47: Patient Care Committee, Society for Surgery of the Alimentary Tract. Treatment of gallstone and gallbladder disease. SSAT patient care guidelines. J Gastrointest Surg. 2004;8: Gallstones and Laparoscopic Cholecystectomy. National Institutes of Health Consensus Statement. Vol. 10, No.3. Bethesda, MD: U.S. Department of Health and Human Services, Office of Medical Applications of Research, September 14 16, Keulemans YC, Venneman NG, Gouma DJ, van Berge Henegouwen GP. New strategies for the treatment of gallstone disease. Scand J Gastroenterol Suppl. 2002;236: Gadacz TR. Update on laparoscopic cholecystectomy, including a clinical pathway. Surg Clin North Am. 2000;80: Mulvihill SJ. Surgical management of gallstone disease and postoperative complications. Semin Gastrointest Dis. 2003;14: Sakorafas GS, Milingos D, Peros G. Asymptomatic cholelithiasis: is cholecystectomy really needed? A critical reappraisal 15 Years after the introduction of laparoscopic cholecystectomy. Dig Dis Sci. 2007;52: Kapoor VK. Cholecystectomy in patients with asymptomatic gallstones to prevent gall bladder cancer the case against. Indian J Gastroenterol. 2006;25: Serafini AN, Spoliansky G, Sfakianakis GN, Montalvo B, Jensen WN. Diagnostic studies in patients with sickle cell anemia and acute abdominal pain. Arch Intern Med. 1987;147: Patino JF, Quintero GA. Asymptomatic cholelithiasis revisited. World J Surg. 1998;22: Del Favero G, Caroli A, Meggiato T, Volpi A, Scalon P, Puglisi A, et al. Natural history of gallstones in non-insulin-dependent diabetes mellitus. A prospective 5-year follow-up. Dig Dis Sci. 1994;39: Ahmed A, Cheung RC, Keeffe EB. Management of gallstones and their complications. Am Fam Physician. 2000;61: , Bragg LE, Thompson JS. Concomitant cholecystectomy for asymptomatic cholelithiasis. Arch Surg. 1989;124: Kottke TE, Feldman RD, Albert D. The risk ratio is insufficient for clinical decisions: The case of prophylactic cholecystectomy. Med Decis Making. 1984;4: Beckingham IJ. ABC of diseases of liver, pancreas, and biliary system. Gallstone disease. BMJ. 2001;322:91 4.