THE NATURAL COURSE OF GALLSTONE DISEASE

GASTROENTEROLOGY Copyright 1966 by The Williams & Wilkins Co. Vol. 50, 3 Printed in U.S.A. THE NATURAL COURSE OF GALLSTONE DISEASE Eleven-year review of 781 nonoperated cases ANDERS WENCKERT, M.D., AND BERTIL ROBERTSON, M.L. Department of Surgery, Allmanna Sjukhuset, Malmo, Sweden That gallstones are frequently found at autopsy of subjects who have apparently gone through life without symptoms of their stones, indicates that many people may have gallstones without ever becoming aware of it. Torvik and Hoivik 1 from Scandinavia report a frequency of 19.5% in autopsy material. In Malmo, the frequency of gallstones is still higher. In this city 60% of all deaths occur in its hospital. Of these, 99% are autopsied (Ekelund 2 ). A recent study by the department of pathology revealed that gallstones had been sur ically removed or demonstrated at autopsy m 55% of all adult females and in 25% of all adult males (Linell, personal communication). A review of the hospital records indicates that the gallstones had frequently been asymptomatic. Postmortem studies, however, teach us little of the natural history of the disease the incidence, or the nature of its complica tions. Such a review would require a long follow-up of untreated cases. Such investigations have been performed but usually on relatively small and therefore less informative series (e.g. by TruesdelI,3 Clagett,4 Comfort et ai. 5 ). An extensive investigation of 526 patients with surgically untreated gallstones has been reported by Lund. 6 One-thIrd to one-half of these developed serious symptoms within 20 years. This paper is concerned with the natural history of gallstone disease in patients with diagnosed, but surgically untreated gallstones. ReceiYed June 28, 1965. Accepted October 29 WOO. ' Address requests for reprints to: Dr. Anders Wenckert, University Department of Surgery, Malmo General Hospital, Malmo, Sweden. 376 Material The original material consisted of all (1501) patients in the city of Malmo (about 210,000 inhabitants in 1952) in whom cholecystography performed for the first time between 1951 and 1952 revealed either gallstones or a nonfunctining gall bladder. All diagnostic radiological procedures in Malmo were at that time performed in its only hospital. Cholecystography was done with oral Bilitrast. The diagnosis was based only on X-ray findings. The results of the cholecystography are given in table 1. Since oral cholecystography was not routinely supplemented by intravenous cholangiography, the diagnosis cannot be regarded as absolutely certain in the nonfunctioning group. However the degree of reliability of the diagnosis can be assessed by c?mpring he results of the primary exammation WIth the findings made at operation, autopsy or, to a certain extent with cholecystograms taken later. Of th 150.1 primary examinations, the X-ray diagnosis was confirmed in 1011 cases. In these the diagnosis was proved correct in 998 cases: 874 by operation, 51 by autopsy, and 73 by later cholecystography. In 13 cases (1.3%) no disease of the gall bladder was found. In the remaining 490 cases the diagnosis was based on a single cholecystographic examination. The reliability of oral cholecystography in this material agrees with the experience of other authors (e.g. Baker and Hodgson 7 and Lund 6 ). It might have been interesting to have compared the course of the disease preceding and following the primary examination. However, the history before the primary examination is difficult to evaluate in a

March 1966 NATURAL COURSE OF GALLSTONE DISEASE 377 TABLE 1. Findings at cholecystography, 1951-1952 Finding Groupa Total cent A B C ------- - Soli tary stone... 8 63 108 179 12 Multiple stones... 49 212 283 544 36 N onfunctioning gall bladder... 71 259 448 778 52 Totals......... 128 534 839 1501 a Group A = Operated without delay after primary cholecystography; group B = operated or complicated within 1 year; group C = material reviewed. retrospective study. Therefore, the history of the disease prior to the primary examination was not considered in the analysis of the results. Thus the primary material included patients with both severe and mild symptoms. To simplify analysis the material was divided into three groups (fig. 1): Group A consisted of all patients operated upon without delay after primary cholecystography. Group B consisted of all patients (excluding group A), who had been operated upon, who had either died or had had complications of the gallstone disease within 1 year of the primary examination. In many of these patients operation was offered at the time of primary cholcystography, but was postponed for 1 or more months. Group C consisted of all patients who had neither operation nor complication within the first year following the primary examination. In this group the course of the disease was followed for 11 years or until cholecystectomy or death intervened. Patients who were subjected to cholecystectomy were not followed up after they had left the hospital. The review is based on questionnaires or, when the patient had been admitted after 1951 to 1952, on the hospital records. In doubtful cases the patient's family physician was contacted. Only the complications seen in the hospital were included in the review. Hence, reports of fever or jaundice for which the patient was not admitted to the hospital were ignored. However, in Malmo, most patients with complication or suspected complication of biliary diseases are admitted to the hospital. Results Group A. The 128 patients who were operated upon without delay after primary cholecystography are of little interest to this study. (In 1951-1952 it was the policy at the Malmo General Hospital Department of Surgery to offer operation to all patients with recurrent or persistent jaundice, severe cholecystitis, or severe symptoms. Conservative treatment was advised for patients with only occasional uncomplicated attacks.) There was no primary mortality. Group B. (figs. 1 and 2). This group consisted of the 534 patients who either were electively operated upon, or had a complication of their disease, or who died within 1 year of the diagnosis. Of these, 35 succumbed from other diseases and nothing is known of the course of their biliary disease. Group C. The remaining 839 patients constitutes the series most important to this study (figs. 1 and 3). Of these 13 could not be traced. No information was available 126 ORIGINAL MATERiAl DEATHS rrom OTHER DISEASE FIG. 1. Survey of total material. DEATHS rroh OTHER DISEASE

- 378 WENCKERT AND ROBERTSON Vol. 50, 3 ACUTE ICTERUS CANCER CHOLE- AND/OR CYSTITIS IWICREATITIS DEATHS t tttttt tt FIG. 2. Group B: Elective operation or complication within 1 year of primary cholecystography. about the further course of the biliary disease in 38 patients who had died from other diseases. These cases were not considered in the evaluation of the further course of the biliary disease. In seven cases operation or re-examination revealed that the primary diagnosis was incorrect. This leaves 781 (93%) for the review. The results of the review are given in figure 3. Of the 781 patients, 383, or 49%, had been asymptomatic or had had only mild symptoms, while 254 (33%) had had attacks of colicky pain leading to elective operation in 173. Complications had occurred in 18% of the cases (fig. 4). In those patients who were 60 years of age or more at the time of primary cholecystography the rate of complications was found to be significantly increased (P < 0.001) (table 2). The high frequency of complications among the older patients may have been due to the fact that a larger proportion of the patients in the younger age groups were subjected to elective operation (fig. 5). But even after exclusion of the electively operated cases, the frequency of complications was still higher in the older group (P < 0.01). H we define severe symptoms or complications as recurrent colicky pains of such severity that elective operation was eventually performed, severe acute cholecystitis, icterus or pancreatitis or both (as defined in fig. 4), cancer, or ileus, then the incidence of severe symptoms or complications was 35%. MilD OR NO SYMPTOMS DEATHS SEVERE COMPLICATIONS G SYMPTOMS tv UNOPERATED OPERATED tt tttttt ttttt FIG. 3. Group C: Material reviewed. Course 1 to 11 years after primary cholecystography. DEATHS ttt CANCER OBSTIRUCTION MilD ACUTE CHOLE CYSTITIS SEVERE ACUTE CHOLE CYSTITIS tttt ttt 59 ICTERUS AND/OR PANCREATITIS FIG. 4. Complications in group C. Mild cholecystitis: symptoms of cholecystitis and a rectal temperature of 38 to 39 C for 2 days or more. Severe cholecystitis: signs of peritonitis and a rectal temperature of 39 C or more for at least 2 days. Icterus or pancreatitis, or both: serum bilirubin/hijman van den Bergh = >2 mg per 100 ml or urinary amylase/wohlgemuth = >1:512, or both. TABLE 2. Course in various age groups <60 years = >60 years Total Symptoms pacent pacent pacent tients tients tients -.---- --- Mild or none.... 265 48 118 53 383 49 Severe... 213 38 41 18 254 33 Complications.... 80 14 64 29 144 18 Totals....... 558 223 781

March 1966 NATURAL COURSE OF GALLSTONE DISEASE 379 The over-all mortality rate in the total material was 1.6%. In group C, the mortality was 1.7% (table 3). When the patients with cancer (all of whom died) were excluded, the mortality rate was found to be highest in the group with severe cholecystitis. Thus, of 29 patients in group C with severe cholecystitis, who were at least 60 years old at the time of primary cholecystography, seven (24%) died. Severe complications as well as deaths were equally common in both sexes. In all of the three main groups the ratio between functioning and non functioning gall bladder was roughly 1: 1 (table 1). Severe complications (severe acute cholecystitis; icterus or pancreatitis, or both; cancer; or ileus) were about twice as common in patients with non functioning gall bladder (P < 0.001). The difference was still more impressive when the patients were grouped according to age. Of the patients who were below 60 years of age and in whom the gall bladder was functioning, severe complications occurred in 6% (18 of 292) against 27% (38 of 142) of those who were above 60 years and in whom the gall bladder was nonfunctioning. Operative cholangiography, which was regularly performed during all cholecystectomies throughout the study period, demonstrated stones in the common bile duct in 19% of all operated cases (table 4). (30 30-40- 50-60- 70- >80 AGE 39 49 59 69 79 PER CENT ELECTIVE OPERATIONS PER CENT COMPLICATIONS IN NON-OPERATED GROUP FIG. 5. cent complications and elective operations in various age groups. TABLE 3. Mortality below and above 60 years (group C) <60 years >60 years Total Symptoms,' ' ' ' ''''!l Poe.;; Poe.;; ug Po.;; u' O'.jj ' 0';:: ' 0'.;::1 z p p., z p O z p p., - - - - --- - - - - Uncomplicated.... 355 151 506 Complicated.. 203 2 0.99 72 1115.3 275 134.7 Totals... 558 2 0.4 223 11 5 781 131.7 a Uncomplicated = Mild or no symptoms; severe symptoms, unoperated; and mild acute cholecystitis. Complicated = Severe symptoms, operated; severe acute cholecystitis; icterus or pancreatitis, or both; ileus; and cancer. TABLE 4. Frequency of stones in common bile duct at cholecystectomy Group Solitary stone ---- Multiple stones Nonfunctioning gall bladder Total ;g u ;g u ' t: ' t:.... 3..,3. 1l 0 1l E 0 0,, '- s Po Po. Po. Po. 0 0 s 0 0 0,;,; 0 0 0 ou u,; ou,; Ou z in z (f) z in z in -- - - - -- - - - % % % % A and B... 68 6 251 12 283 22 602 16 C...... 43 7 101 28 100 36 244 27 Totals... 111 6 352 16 383 26 846 19 The corresponding figures were 16% for the patients operated upon within 1 year of the primary cholecystography and 27% for group C. The difference between the two latter groups was statistically significant (P < 0.001). The frequency of stones in the common duct was lowest (6%) for patients with a solitary stone at primary cholecystography and operated upon within 1 year of this (groups A and B), as compared with 36% among those in whom no filling of the gall bladder had been obtained and who were operated upon later (group C). Discussion The indications for operation for gallstones have long been debatable.

380 WENCKERT AND ROBERTSON Vol. 50, 3 Proper evaluation of the results of conservative or surgical therapy requires knowledge of the natural history of the disease. A number of patients with completely silent and surgically untreated stones would, of course, be the ideal series for such a study. But no such series is available. We therefore studied a series in which cholecystography had confirmed the presence of clinically suspected gallstone disease. In this respect then, the material is selected, but it includes all 1501 patients who had had positive findings at cholecystography in 1951 and 1952 in Malmo. Patients who were operated upon electively or developed complications within 1 year of the X-ray examination were not considered in the review. The material reviewed, 781 cases, was followed through 11 years. Of the patients, 35% developed complications (severe cholecystitis, icterus, ileus, or cancer) or such severe symptoms that elective cholecystectomy was performed. Lund 6 found that severe symptoms or complications occurred in one-third to one-half of all untreated cases within 5 to 20 years. Our results agree. As pointed out by Lund, the rate of complications and severe symptoms represents minimal figures and is not a measure of the true prognosis of untreated biliary disease because many complications and deaths had surely been prevented by surgical intervention. Moreover, since patients with severe symptoms or complications within 1 year of the cholecystography were not included in the material reviewed, these can be considered as representing mild gallstone disease. It should also be pointed out that our patients were studied for only 11 years after discovery of the disease. The frequency of complications did not decrease as the interval after the primary examination increased. Many patients had been free from symptoms from the time of the cholecystography until the day the complication made its appearance. It is probable that the number of complications and deaths would have been greater if the period of observation had been longer. In the discussion on the natural course of gallstone disease, much space has been given to the risk of cancer developing in patients with untreated gallstones (e.g., Graham,9 McLaughlin,lO Milner,11 Newman and Northup,12 Sherlock,13 and Strauch 14 ). Our series contained five cases of cancer of the gall bladder. These cases were discovered within 1, 1, 3, 6, and 9 years, respectively, after primary cholecystography. In all these cases the gall bladder contained stones. In none was radical operation possible and all died from their cancer. This corresponds to a death rate of 0.4% of 1402 cases. Although it cannot be excluded that early cholecystectomy might have reduced this number of cases of cancer, the figures do not lend support to prophylactic cholecystectomy for cancer. However, not only the natural course of untreated gallstone disease, but also the risk of operation must be considered when deciding whether or not surgery is indicated. Table 5 gives the operative mortality in Malmo between 1954 and 1963. The over-all mortality was 1.1%. As expected, the most important causes of operative deaths were complicating inflammation, stones in the common bile duct, and advanced age of the patients. In patients Operation TABLE 5. Operations because of gallstone disease, 1954--1963 <60 years = >60 years Total Deaths cent Deaths cent Deaths cent patients deaths patients deaths patients deaths ----------------------- Cholecystectomy... 3079 4 0.13 518 4 0.8 3597 8 0.22 Choledocholithectomy... 772 10 1.3 363 20 5.5 1135 30 2.6 Cholecystostomy... 41 58 12 20.7 99 12 12.1 Miscellaneous operations... 44 41 5 12.2 85 5 5.9 Totals................. 3936 14 0.4 980 41 4.2 4916 55 1.1

March 1966 NATURAL COURSE OF GALLSTONE DISEASE 381 above 60 years of age with stones in the common bile duct the operative mortality was 5.5%, while that of uncomplicated elective operations in the group under 60 years was 0.13%. It would thus appear that the risk of late severe symptoms and complications of untreated gallstones is sufficient to indicate early elective operation even when the gallstones produce only mild symptoms. This also holds true for patients above 60 years of age at the time of diagnosis. Here, as in the younger group, the operation should preferably be performed as soon as the symptoms develop and before the occurrence of complications. Early surgery will reduce the frequency of later complications and hazardous emergency operations as well as the over-all morbidity and mortality from gallstone disease. Summary This paper is concerned with the natural history of gallstone disease in patients with diagnosed, but not surgically treated, gallstones. The material comprises all 1501 patients from the city of Malmo in whom cholecystography in 1951 or 1952 revealed either gallstones or nonfilling of the gall bladder. Of these, 781 were not operated upon and did not have complications within 1 year of the roentgen examination. These 781 patients were followed for 11 years. At least 35% developed complications (severe cholecystitis; icterus or pancreatitis or both; ileus; cancer), or such severe symptoms that elective cholecystectomy eventually was performed. REFERENCES 1. Torvik, A., and B. Hi.iivik. 1960. Gallstones in an autopsy series. Acta Chir. Scand. 120: 168-174. 2. Ekelund, G. 1963. On cancer and polyps of colon and rectum. Acta Path. Microbiol. Scand.59: 165-170. 3. Truesdell, E. D. 1944. Frequency and future of gallstones believed to be quiescent or symptomless. Ann. Surg. 119: 232-245. 4. Clagett, O. T. 1945. Diseases of the gallbladder. Surg. Clin. N. Amer. 25: 929-938. 5. Comfort, M. W., H. K. Gray, and J. M. Wilson. 1948. The silent gallstone: a 10-20 year follow-up study of 112 cases. Ann. Surg. 128: 931-937. 6. Lund, J. 1960. Surgical indications in cholelithiasis. Ann. Surg. 151: 153-162. 7. Baker, H. L., Jr., and J. R. Hodgson. 1958. Oral cholecystography: an evaluation of its accuracy. Gastroenterology 34: 1137-1145. 8. Wohlgemuth, J. 1908. Uber eine neue Methode zur quantitativen B estimmung des diastatisch en Ferments. Biochem. Z. 9: 1-9. 9. Graham, E. A. 1931. Prevention of carcinoma of the gallbladder. Ann. Surg. 93: 317--322. 10. McLaughlin, C. W., Jr. 1964. Carcinoma of the gallbladder, an added hazard in untreated calculous cholecystitis in older patients. Surgery 56: 755-759. 11. Milner, L. R. 1963. Cancer of the gallbladder. Amer. J. Gastroent. 39: 480--484. 12. Newman, H. F., and J. D. Northup. 1964. Gallbladder carcinoma m cholelithiasis. Geriatrics 19: 453--455. 13. Sherlock, S. 1955. Diseases of the liver and biliary system. Blackwell Scientific Publications, Oxford. 14. Strauch, G. O. 1960. Primary carcinoma of the gallbladder. Surgery 47: 368-383.