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Analysis of gallbladder bile in morbid obesity
Analysis of Gallbladder Bile in Morbid Obesity Joel B. Freeman, MD, Iowa City, Iowa Paul D. Meyer, PhD, Iowa City, Iowa Kenneth J. Printen, MD, Iowa City, Iowa Edward E. Mason, MD, Iowa City Iowa Lawrence DenBesten, MD, Iowa City, Iowa
Cholesterol gallstones are found in 10 per cent of the North American population [I ] and are two to three times more frequent in patients who are more than 20 per cent of their ideal weight [21. At the University of Iowa Hospitals, gastric bypass [3] is the preferred procedure for the surgical management of morbid obesity that has not responded to medical management. Eighty-eight of the 238 patients (37 per cent) operated on have had gallstones detected either before (28 patients), at the time of operation (54 patients), or after gastric bypass (6 patients). An increased incidence of gallstone formation after treatment of obesity by jejunoileal bypass has also been reported [4,.5]. To date, the frequent occurrence of cholelithiasis in obese surgical patients has been accepted with complacency and the lipid composition of the gallbladder bile has not been reported previously. The purpose of this study was to measure the chemical composition of gallbladder bile in the morbidly obese patient and to compare these data with similar measurements from nonobese patients. Material and Methods Seven women and four men without gallstones, aged seventeen to fifty-seven years and with a mean weight of 137 f 9 kg, were studied. Each patient weighed at least 100 per cent in excess of ideal weight, based on age, sex, and height. At the time of gastric bypass, the gallbladder was aspirated through a 20 gauge needle, taking care not to contaminate the bile with blood. In four patients, From the Department of Surgery, University and Veterans Administration Hospitals, University of Iowa. Iowa City, Iowa. Reprint requests should be addressed to Dr Joel B. Freeman, Department of Surgery, University Hospitals, University of Iowa. Iowa City, Iowa 52240. Presented at the Fifteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, San Francisco, California, May 21 and 22, 1974.
Votume 129, February 1975
hepatic bile was also obtained through a 2.5 gauge scalp vein positioned in the common duct. All bile was collected within forty-five minutes of the induction of anesthesia. It was immediately cultured and centrifuged at 3,000 rpm for twenty minutes. The sediment, was examined under polarized light for cholesterol crystals and calcium bilirubinate pigment. Cholesterol, phospholipid, and bile acids were determined by technics that have been described [S]. The bile from eleven patients of normal body weight, who were without gallstones and were undergoing elective abdominal surgery, was analyzed in identical fashion. None of the patients received laxatives or antibiotics in preparation for surgery. St,atistical comparisons were performed using t,he Student t test and results are expressed as the mean & the standard error.
Resutts The molar percentages (total moles of each of the respective biliary lipids divided by the sum of the moles of all three lipids and multiplied by 100) were plotted on triangular coordinates after the method of Admirand and Small (71. (Figure 1.) The bile from all of the obese patients fell outside the micellar zone, which depicts the upper limits of cholesterol solubility, whereas the bile from all but one of the control patients fell within the micellar zone. The mean molar percentage of cholesterol was 13 f 0.7 mM per cent, which is well above both the normal range of 7 to 9 mM per cent and the mean cholesterol level of 6.6 f 0.5 mM per cent measured in the nonobese patients (p < 0.001). Cholesterol crystals were found in four of eleven obese patients (36 per cent) and in none of the controls. Calcium bilirubinate pigment was not found in any patient. The mean cholesterol concentration in the bile of the obese patients was
163
Freeman
Morbid 0 Normal ??
et al
Obesity Weight
Percent
Bile Salt
Figure I. 7% location of the bile of each of the obese and nonobese patients when ptotted on triangu/ar coordinates. The curved line depicts the upper ttmtts of chotesterol solubility in bile.
26.1 f 3.6 mM/L compared with 15.0 f 1.6 mM/L in the controls (p < 0.002). (Table I.) Phospholipids were 51.7 f 7.2 mM/L in the obese patients compared with 40.0 f 3.4 mM/L in the controls (p > 0.05), and bile salts were 131 f 19 mM/L in the obese patients compared with 169 f 16 mM/L in the controls (p > 0.05). The lithogenic index [a], a reflection of the cholesterol-solubilizing capacity of bile, is expressed as the millimolar ratio of bile acids plus phospholipids to cholesterol and measured 6.3 f 0.4 in the obese patients versus 14.8 f 1.0 in the nonobese patients (p < 0.001). The hepatic bile was markedly supersaturated with cholesterol (22 f 3 mM per cent). However, the actual cholesterol concentration of hepatic bile was only 16.3 f 5.8 mM/L compared with 30.0 f 5.2 mM/L in the gallbladder bile from the same four patients (p < 0.05) whereas the bile acid concentrations were 53 f 15 mM/L and 153 f 19 mM/L for hepatic and gallbladder bile, respectively (p < 0.05). There were no complications from aspiration of the gallbladder or common ducts. All aerobic and anaerobic cultures of the bile were sterile. Comments There was a very clear biochemical distinction between the bile of the obese and that of the nonobese patient, substantiating the well known clinical association of obesity with gallstone formation. The bile of all obese patients was supersaturated
164
with respect to cholesterol concentration and was outside the micellar zone when plotted on triangular coordinates. In contrast, the bile of all but one of the nonobese patients fell within the micellar zone. Cholesterol is completely insoluble in water and is maintained in solution by virtue of the detergent action of bile acids and phospholipids. Bile is termed “lithogenic” when it contains more cholesterol than can remain in solution. This may be due to either an increase in the amount of cholesterol or a decrease in the amount of bile salts or phospholipids. Admirand and Small [7] showed a clear separation between the bile of patients with and without gallstones by plotting the relative molar percentages of each of the three biliary lipids on triangular coordinates. Although some recent studies have failed to confirm such a clear distinction [9,10], it is generally accepted that patients who are at risk of developing cholesterol gallstones more frequently have lithogenic bile prior to the appearance of stones [I I 1. In Chippewa and Pima Indians an analogous situation exists in that the incidence of gallstones is also three times that of the general population [12,13]. Bile from Indian women who do not have gallstones is more saturated than is the bile from normal white control subjects. This bile has an abnormally low lithogenic index quantitatively similar to that measured in our obese patients as well as to that found in Caucasians with gallstones. However, gallstones are seldom found in the dog or the East African Masai tribesmen, both of whom have markedly unsaturated bile. In the fasting state, all subjects with gallstones and the majority of those without gallstones secrete supersaturated hepatic bile. In American Indians, however, the degree of supersaturation of hepatic bile is greater than that of normal controls and also greater than that of their own gallbladder bile [14]. In both respects, this is similar to the data from our obese patients. The supersaturated hepatic bile in Indians is due to a reduction in the size of the bile acid pool and not to excess cholesterol. Our data for obese subjects do not establish the mechanism of lithogenic bile formation which could be due to either a rise in cholesterol excretion into bile, a reduction in the bile acid pool, or both. Studies of bile acid and cholesterol pool kinetics in obese patients are currently in progress. The increased cholesterol concentration in the bile of obese persons may be due, in part, to excessive dietary intake of cholesterol. The production and turnover of cholesterol in obese subjects are
The
American Journal of Surgery
Gallbladder
TABLiZ
I
Results of Analysis of the Biliary
lipids from theGallbladder
Lithogenic Index is Represented
Bile in Morbid Obesity
Bile of Eleven Obese and Eleven Nonobese Patients
PL+ BS by the Fraction CH >
Cholesterol Subject
(mWL)
Phospholipids
Bile Salts
(mM/L)
(mWL)
Cholesterol (% total moles)
Phospholipids (% total moles)
Bile Salts (% total moles)
PL+ BS CH
Obese Patients 1 2 3 4 5 6 7 8 9 10 11 Mean SEM
7.9 11.2 16.6 36.3 37.3 42.7 36.4 34.8 19.6 22.4 21.4 26.1 3.6
-
14.5 21.7 30.5 78.8 78.2 67.0 76.8 70.0 42.8 53.2 36.0 51.7 7.2
28 45 67 191 186 164 203 180 115 170 96 131 19
16 15 15 12 12 16 12 12 11 9 14 13.0 0.7
29 28 27 26 26 24 24 24 24 22 23 25 1
55 57 58 62 62 60 64 64 65 69 63 63.0 1.9
5.3 5.7 5.7 7.3 7.3 5.3 5.3 5.3 5.9 10.1 6.2 6.3 0.4
5 7 5 6 8 10 6 5 7 6 8 6.6 0.5
15 24 16 14 22 21 20 17 17 20 16 18 1
80 69 79 80 70 69 74 78 76 74 76 75.0 1.3
19.0 13.2 19.0 15.7 11.5 9.0 15.6 19.0 13.3 15.7 11.5 14.8 1.0
Controls 1 2 3 4 5 6 7 8 9 10 11 Mean SEM
6.4 7.4 12.5 18.2 19.4 19.8 18.9 11.2 18.9 12.0 20.6 15.0 1.6
17.6 24.7 40.8 43.5 49.3 39.7 60.4 38.1 45.1 41.1 44.4 40.0 3.4
96 70 197 245 160 131 221 176 206 152 204 169 16
more than twice those in nonobese subjects and are directly proportional to the size of body fat stores 1151. A high cholesterol diet results in supersaturated bile and gallstones in both mice [16] and prairie dogs [S], neither of which normally form stones. In man, Sarles, Hauton, and Planche [17] have shown a direct relation between increased caloric consumption and the formation of cholesterol gallstones. In a previous report from this laboratory, the feeding of a high cholesterol diet caused the formation of supersaturated bile and cholesterol crystals in man [18]. Man, in contrast to most other animal species, has a liver with a limited capacity for converting cholesterol to bile acids [I1 ]. Consequently, most animals have markedly unsaturated bile and a virtual absence of gallstone formation whereas human subjects are predisposed to gallstone formation especially when they are obese. The bile acid pool is reduced in lean patients with gallstones (191 and in Indian women who have not yet
Vohime 129, February 1975
formed gallstones [12]. If we speculate that a similar bile acid deficiency exists in obese patients who, in addition, both consume and synthesize more cholesterol, these factors combined could explain their inordinately high incidence of gallstones. The reduced bile acid pool is a particularly important consideration in patients undergoing jejunoileal bypass, an operation which by itself will reduce the size of the bile acid pool. Patients with a diseased or resected ileum also have a higher incidence of gallstones, and the administration of chenodeoxycholic acid will reduce the degree of supersaturation of the gallbladder bile [20]. To date, the only alternate proposal for preventing gallstone formation after jejunoileal bypass has been to perform “prophylactic” cholecystectomy at the time of surgery [4]. In theory, gastric bypass might also increase the incidence of gallstones because food no longer passes through the distal stomach but goes directly into the small bowel through a short looped re-
165
Freeman
et al
trocolic gastroenterostomy. Actually there is regurgitation into the afferent loop, and studies by Thomas and Mason [ZI ] in dogs with pancreatic pouches showed normal pancreatic secretion after gastric bypass, indicating that there was stimulation of pancreozymin-cholecystokinin after a meal. The occurrence of gallstones in 6 of 238 patients (6.8 per cent) after gastric bypass is probably a result of the abnormal gallbladder bile present at the time of surgery rather than gallbladder stasis. It is even conceivable that the gallbladder bile will become less lithogenic as a consequence of the weight loss that follows gastric bypass. Summary Thirty-seven per cent of our grossly obese patients selected for gastric bypass had cholesterol gallstones. To document the composition of the biliary lipids prior to weight loss, the bile taken from eleven obese patients at the time of gastric bypass was analyzed and the results compared with those in eleven nonobese patients undergoing elective surgery. There was extreme supersaturation of both gallbladder and hepatic bile in all obese patients. The gallbladder bile of all obese patients fell well outside the micellar zone whereas the bile from all but one of the controls fell within the micellar zone. These data provide biochemical support for the clinical association of obesity and cholesterol gallstone formation and are evidence against the possibility that gastric bypass is a lithogenic operation.
7.
8.
9.
10.
11. 12. 13.
14.
.15. 16.
17. 18.
19.
References 20. 1. Newman HF, Northup JD: Autopsy incidence of gallstones. Int Abstr Surg 109: 1, 1959. 2. Friedman GD, Kannel WB, Dawber TR: The epidemiology of gallbladder disease. J Chron Dis 19: 273, 1966.
166
21.
Printen KJ, Mason EE: Gastric surgery for relief of m?rbii obesity. Arch Surg.106: 426, 1973. Barber JC, Mayden WF, Thompson BW: Intestinal bypass operations for obesity. Am J Surg 126: 669, 1973. Payne JH, DeWind L. Schwab E, Kern WH: Surgical treatment of morbii obesity. Arch Surg 106: 432,1973. Brenneman DE, Connor WE, Forker EL, DenBesten L: The formation of abnormal bile and cholesterol gallstones from dietary cholesterol in the prairie dog. J C/in /west 51: 1495.1972. Admirand WH, Small DM: The physicochemical basis of cholesterol gallstone formation in man. J C/in invest 47: 1043, 1968. Metzger AL, Heymsfiild S, Grundy SM: The liiogentc indexa numerical expression for the relative liienicity of bile. Gestroenterology 62: 499, 1972. l-feller F, Bouchiir IA: Cholesterol and bile salt studies on the bile of patients with cholesterol gallstones. Gut 14: 83, 1973. Holzbach RT, Marsh M, Olszewski M, Holan K: Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 52: 1467, 1973. Wheeler HO: Pathogenesis of gallstones. Surg C/in North Am 53: 963, 1973. Thistle JL, Schoenfield LJ: Liiogenic bile among young Indii an women. N Engl J Med 284: 177, 1973. Vlahcevic ZR, Bell CC, Gregory DH, Buker G, Juttijudata P, Swell L: Relationship of bile acid pool size to the formation of lithogenic bile in female Indians of the southwest. Gastroenterology 62: 73, 1972. Metzger AL, Adler R, Heymsfield S, Grundy SM: Diurnal variation in biliiry lipid composition. N Engl J A&d 288: 333, 1973. Nestel PJ, Schbeibman PH, Ahrens EH: Cholesterol metabolism in human obesity. J C/in invest 52: 2389, 1973. Caklwell FT, Levitsky K, Rosenberg B: Dietary production and dissolution of cholesterol gallstones in the mouse. Am J Physioi 209: 473. 1965. Sarles H, Hauton J, Planche NW Diet, cholesterol gallstones and composition of the bile. Am JDig LM 15: 251, 1970. DenBesten L, Connor WE, Bell S: The effect of dietary cho lesterol on the composition of human bile. Surgery 73: 266, 1973. Vlahcevic ZR, Cooper B, Buhac I, Farrar JT, Swell L: Diminished bile acid pool size in patients with gallstones. Gastroenterology 59: 165, 1970. Dowling RH. Bell GD, White J: Liiogenic bile in patients wlth ileal dysfunction. Gut 13: 415, 1972. Thomas JW. Mason EE: The effects of gastric exclusion operations on pancreatic exocrine secretion. Surgery 75: 461.1974.
The American Journal oi Surgery
Cholesterol gallstones are found in 10 per cent of the North American population [I ] and are two to three times more frequent in patients who are more than 20 per cent of their ideal weight [21. At the University of Iowa Hospitals, gastric bypass [3] is the preferred procedure for the surgical management of morbid obesity that has not responded to medical management. Eighty-eight of the 238 patients (37 per cent) operated on have had gallstones detected either before (28 patients), at the time of operation (54 patients), or after gastric bypass (6 patients). An increased incidence of gallstone formation after treatment of obesity by jejunoileal bypass has also been reported [4,.5]. To date, the frequent occurrence of cholelithiasis in obese surgical patients has been accepted with complacency and the lipid composition of the gallbladder bile has not been reported previously. The purpose of this study was to measure the chemical composition of gallbladder bile in the morbidly obese patient and to compare these data with similar measurements from nonobese patients. Material and Methods Seven women and four men without gallstones, aged seventeen to fifty-seven years and with a mean weight of 137 f 9 kg, were studied. Each patient weighed at least 100 per cent in excess of ideal weight, based on age, sex, and height. At the time of gastric bypass, the gallbladder was aspirated through a 20 gauge needle, taking care not to contaminate the bile with blood. In four patients, From the Department of Surgery, University and Veterans Administration Hospitals, University of Iowa. Iowa City, Iowa. Reprint requests should be addressed to Dr Joel B. Freeman, Department of Surgery, University Hospitals, University of Iowa. Iowa City, Iowa 52240. Presented at the Fifteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, San Francisco, California, May 21 and 22, 1974.
Votume 129, February 1975
hepatic bile was also obtained through a 2.5 gauge scalp vein positioned in the common duct. All bile was collected within forty-five minutes of the induction of anesthesia. It was immediately cultured and centrifuged at 3,000 rpm for twenty minutes. The sediment, was examined under polarized light for cholesterol crystals and calcium bilirubinate pigment. Cholesterol, phospholipid, and bile acids were determined by technics that have been described [S]. The bile from eleven patients of normal body weight, who were without gallstones and were undergoing elective abdominal surgery, was analyzed in identical fashion. None of the patients received laxatives or antibiotics in preparation for surgery. St,atistical comparisons were performed using t,he Student t test and results are expressed as the mean & the standard error.
Resutts The molar percentages (total moles of each of the respective biliary lipids divided by the sum of the moles of all three lipids and multiplied by 100) were plotted on triangular coordinates after the method of Admirand and Small (71. (Figure 1.) The bile from all of the obese patients fell outside the micellar zone, which depicts the upper limits of cholesterol solubility, whereas the bile from all but one of the control patients fell within the micellar zone. The mean molar percentage of cholesterol was 13 f 0.7 mM per cent, which is well above both the normal range of 7 to 9 mM per cent and the mean cholesterol level of 6.6 f 0.5 mM per cent measured in the nonobese patients (p < 0.001). Cholesterol crystals were found in four of eleven obese patients (36 per cent) and in none of the controls. Calcium bilirubinate pigment was not found in any patient. The mean cholesterol concentration in the bile of the obese patients was
163
Freeman
Morbid 0 Normal ??
et al
Obesity Weight
Percent
Bile Salt
Figure I. 7% location of the bile of each of the obese and nonobese patients when ptotted on triangu/ar coordinates. The curved line depicts the upper ttmtts of chotesterol solubility in bile.
26.1 f 3.6 mM/L compared with 15.0 f 1.6 mM/L in the controls (p < 0.002). (Table I.) Phospholipids were 51.7 f 7.2 mM/L in the obese patients compared with 40.0 f 3.4 mM/L in the controls (p > 0.05), and bile salts were 131 f 19 mM/L in the obese patients compared with 169 f 16 mM/L in the controls (p > 0.05). The lithogenic index [a], a reflection of the cholesterol-solubilizing capacity of bile, is expressed as the millimolar ratio of bile acids plus phospholipids to cholesterol and measured 6.3 f 0.4 in the obese patients versus 14.8 f 1.0 in the nonobese patients (p < 0.001). The hepatic bile was markedly supersaturated with cholesterol (22 f 3 mM per cent). However, the actual cholesterol concentration of hepatic bile was only 16.3 f 5.8 mM/L compared with 30.0 f 5.2 mM/L in the gallbladder bile from the same four patients (p < 0.05) whereas the bile acid concentrations were 53 f 15 mM/L and 153 f 19 mM/L for hepatic and gallbladder bile, respectively (p < 0.05). There were no complications from aspiration of the gallbladder or common ducts. All aerobic and anaerobic cultures of the bile were sterile. Comments There was a very clear biochemical distinction between the bile of the obese and that of the nonobese patient, substantiating the well known clinical association of obesity with gallstone formation. The bile of all obese patients was supersaturated
164
with respect to cholesterol concentration and was outside the micellar zone when plotted on triangular coordinates. In contrast, the bile of all but one of the nonobese patients fell within the micellar zone. Cholesterol is completely insoluble in water and is maintained in solution by virtue of the detergent action of bile acids and phospholipids. Bile is termed “lithogenic” when it contains more cholesterol than can remain in solution. This may be due to either an increase in the amount of cholesterol or a decrease in the amount of bile salts or phospholipids. Admirand and Small [7] showed a clear separation between the bile of patients with and without gallstones by plotting the relative molar percentages of each of the three biliary lipids on triangular coordinates. Although some recent studies have failed to confirm such a clear distinction [9,10], it is generally accepted that patients who are at risk of developing cholesterol gallstones more frequently have lithogenic bile prior to the appearance of stones [I I 1. In Chippewa and Pima Indians an analogous situation exists in that the incidence of gallstones is also three times that of the general population [12,13]. Bile from Indian women who do not have gallstones is more saturated than is the bile from normal white control subjects. This bile has an abnormally low lithogenic index quantitatively similar to that measured in our obese patients as well as to that found in Caucasians with gallstones. However, gallstones are seldom found in the dog or the East African Masai tribesmen, both of whom have markedly unsaturated bile. In the fasting state, all subjects with gallstones and the majority of those without gallstones secrete supersaturated hepatic bile. In American Indians, however, the degree of supersaturation of hepatic bile is greater than that of normal controls and also greater than that of their own gallbladder bile [14]. In both respects, this is similar to the data from our obese patients. The supersaturated hepatic bile in Indians is due to a reduction in the size of the bile acid pool and not to excess cholesterol. Our data for obese subjects do not establish the mechanism of lithogenic bile formation which could be due to either a rise in cholesterol excretion into bile, a reduction in the bile acid pool, or both. Studies of bile acid and cholesterol pool kinetics in obese patients are currently in progress. The increased cholesterol concentration in the bile of obese persons may be due, in part, to excessive dietary intake of cholesterol. The production and turnover of cholesterol in obese subjects are
The
American Journal of Surgery
Gallbladder
TABLiZ
I
Results of Analysis of the Biliary
lipids from theGallbladder
Lithogenic Index is Represented
Bile in Morbid Obesity
Bile of Eleven Obese and Eleven Nonobese Patients
PL+ BS by the Fraction CH >
Cholesterol Subject
(mWL)
Phospholipids
Bile Salts
(mM/L)
(mWL)
Cholesterol (% total moles)
Phospholipids (% total moles)
Bile Salts (% total moles)
PL+ BS CH
Obese Patients 1 2 3 4 5 6 7 8 9 10 11 Mean SEM
7.9 11.2 16.6 36.3 37.3 42.7 36.4 34.8 19.6 22.4 21.4 26.1 3.6
-
14.5 21.7 30.5 78.8 78.2 67.0 76.8 70.0 42.8 53.2 36.0 51.7 7.2
28 45 67 191 186 164 203 180 115 170 96 131 19
16 15 15 12 12 16 12 12 11 9 14 13.0 0.7
29 28 27 26 26 24 24 24 24 22 23 25 1
55 57 58 62 62 60 64 64 65 69 63 63.0 1.9
5.3 5.7 5.7 7.3 7.3 5.3 5.3 5.3 5.9 10.1 6.2 6.3 0.4
5 7 5 6 8 10 6 5 7 6 8 6.6 0.5
15 24 16 14 22 21 20 17 17 20 16 18 1
80 69 79 80 70 69 74 78 76 74 76 75.0 1.3
19.0 13.2 19.0 15.7 11.5 9.0 15.6 19.0 13.3 15.7 11.5 14.8 1.0
Controls 1 2 3 4 5 6 7 8 9 10 11 Mean SEM
6.4 7.4 12.5 18.2 19.4 19.8 18.9 11.2 18.9 12.0 20.6 15.0 1.6
17.6 24.7 40.8 43.5 49.3 39.7 60.4 38.1 45.1 41.1 44.4 40.0 3.4
96 70 197 245 160 131 221 176 206 152 204 169 16
more than twice those in nonobese subjects and are directly proportional to the size of body fat stores 1151. A high cholesterol diet results in supersaturated bile and gallstones in both mice [16] and prairie dogs [S], neither of which normally form stones. In man, Sarles, Hauton, and Planche [17] have shown a direct relation between increased caloric consumption and the formation of cholesterol gallstones. In a previous report from this laboratory, the feeding of a high cholesterol diet caused the formation of supersaturated bile and cholesterol crystals in man [18]. Man, in contrast to most other animal species, has a liver with a limited capacity for converting cholesterol to bile acids [I1 ]. Consequently, most animals have markedly unsaturated bile and a virtual absence of gallstone formation whereas human subjects are predisposed to gallstone formation especially when they are obese. The bile acid pool is reduced in lean patients with gallstones (191 and in Indian women who have not yet
Vohime 129, February 1975
formed gallstones [12]. If we speculate that a similar bile acid deficiency exists in obese patients who, in addition, both consume and synthesize more cholesterol, these factors combined could explain their inordinately high incidence of gallstones. The reduced bile acid pool is a particularly important consideration in patients undergoing jejunoileal bypass, an operation which by itself will reduce the size of the bile acid pool. Patients with a diseased or resected ileum also have a higher incidence of gallstones, and the administration of chenodeoxycholic acid will reduce the degree of supersaturation of the gallbladder bile [20]. To date, the only alternate proposal for preventing gallstone formation after jejunoileal bypass has been to perform “prophylactic” cholecystectomy at the time of surgery [4]. In theory, gastric bypass might also increase the incidence of gallstones because food no longer passes through the distal stomach but goes directly into the small bowel through a short looped re-
165
Freeman
et al
trocolic gastroenterostomy. Actually there is regurgitation into the afferent loop, and studies by Thomas and Mason [ZI ] in dogs with pancreatic pouches showed normal pancreatic secretion after gastric bypass, indicating that there was stimulation of pancreozymin-cholecystokinin after a meal. The occurrence of gallstones in 6 of 238 patients (6.8 per cent) after gastric bypass is probably a result of the abnormal gallbladder bile present at the time of surgery rather than gallbladder stasis. It is even conceivable that the gallbladder bile will become less lithogenic as a consequence of the weight loss that follows gastric bypass. Summary Thirty-seven per cent of our grossly obese patients selected for gastric bypass had cholesterol gallstones. To document the composition of the biliary lipids prior to weight loss, the bile taken from eleven obese patients at the time of gastric bypass was analyzed and the results compared with those in eleven nonobese patients undergoing elective surgery. There was extreme supersaturation of both gallbladder and hepatic bile in all obese patients. The gallbladder bile of all obese patients fell well outside the micellar zone whereas the bile from all but one of the controls fell within the micellar zone. These data provide biochemical support for the clinical association of obesity and cholesterol gallstone formation and are evidence against the possibility that gastric bypass is a lithogenic operation.
7.
8.
9.
10.
11. 12. 13.
14.
.15. 16.
17. 18.
19.
References 20. 1. Newman HF, Northup JD: Autopsy incidence of gallstones. Int Abstr Surg 109: 1, 1959. 2. Friedman GD, Kannel WB, Dawber TR: The epidemiology of gallbladder disease. J Chron Dis 19: 273, 1966.
166
21.
Printen KJ, Mason EE: Gastric surgery for relief of m?rbii obesity. Arch Surg.106: 426, 1973. Barber JC, Mayden WF, Thompson BW: Intestinal bypass operations for obesity. Am J Surg 126: 669, 1973. Payne JH, DeWind L. Schwab E, Kern WH: Surgical treatment of morbii obesity. Arch Surg 106: 432,1973. Brenneman DE, Connor WE, Forker EL, DenBesten L: The formation of abnormal bile and cholesterol gallstones from dietary cholesterol in the prairie dog. J C/in /west 51: 1495.1972. Admirand WH, Small DM: The physicochemical basis of cholesterol gallstone formation in man. J C/in invest 47: 1043, 1968. Metzger AL, Heymsfiild S, Grundy SM: The liiogentc indexa numerical expression for the relative liienicity of bile. Gestroenterology 62: 499, 1972. l-feller F, Bouchiir IA: Cholesterol and bile salt studies on the bile of patients with cholesterol gallstones. Gut 14: 83, 1973. Holzbach RT, Marsh M, Olszewski M, Holan K: Cholesterol solubility in bile. Evidence that supersaturated bile is frequent in healthy man. J Clin Invest 52: 1467, 1973. Wheeler HO: Pathogenesis of gallstones. Surg C/in North Am 53: 963, 1973. Thistle JL, Schoenfield LJ: Liiogenic bile among young Indii an women. N Engl J Med 284: 177, 1973. Vlahcevic ZR, Bell CC, Gregory DH, Buker G, Juttijudata P, Swell L: Relationship of bile acid pool size to the formation of lithogenic bile in female Indians of the southwest. Gastroenterology 62: 73, 1972. Metzger AL, Adler R, Heymsfield S, Grundy SM: Diurnal variation in biliiry lipid composition. N Engl J A&d 288: 333, 1973. Nestel PJ, Schbeibman PH, Ahrens EH: Cholesterol metabolism in human obesity. J C/in invest 52: 2389, 1973. Caklwell FT, Levitsky K, Rosenberg B: Dietary production and dissolution of cholesterol gallstones in the mouse. Am J Physioi 209: 473. 1965. Sarles H, Hauton J, Planche NW Diet, cholesterol gallstones and composition of the bile. Am JDig LM 15: 251, 1970. DenBesten L, Connor WE, Bell S: The effect of dietary cho lesterol on the composition of human bile. Surgery 73: 266, 1973. Vlahcevic ZR, Cooper B, Buhac I, Farrar JT, Swell L: Diminished bile acid pool size in patients with gallstones. Gastroenterology 59: 165, 1970. Dowling RH. Bell GD, White J: Liiogenic bile in patients wlth ileal dysfunction. Gut 13: 415, 1972. Thomas JW. Mason EE: The effects of gastric exclusion operations on pancreatic exocrine secretion. Surgery 75: 461.1974.
The American Journal oi Surgery