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Biliary Lipids and Bile Acid Pool Size After Vagotomy in Man
0016-5085178/7504-0608$02.00/0 GASTROENTEROLOGY 75:608-611 , 1978 Copyright I[) 1978 by the Am erica n Gastroenterological Association
Vol. 75 , No. 4
Printed in U.S A .
BILIARY LIPIDS AND BILE ACID POOL SIZE AFTER VAGOTOMY IN MAN
Evidence against a predisposition to gallstones JERROLD M. STEMPEL, M.D . , AND WILLIAM
c.
DUANE, M.D.
Section of Gastroenterology, Department of Medicine, Veterans Administration Hospital, and University of Minnesota Hospital, Minneapolis, Minnesota
Eight male subjects who had previously undergone vagotomy and pyloroplasty were found to have significantly larger bile acid pools than did a group of matched control subjects. Associated with these expanded pools was a significantly lower molar per cent cholesterol of gallbladder bile in the vagotomy group. These findings are the opposite of those expected in a group predisposed to cholesterol cholelithiasis, suggesting that vagotomy, at least in males, does not predispose to cholesterol gallstones. If such stones form after vagotomy, they presumably do so by a mechanism not presently appreciated. Truncal vagotomy is alleged to predispose to cholesterol gallstone disease, although this contention is controversiaL 1- 7 A prerequisite for the development of cholesterol gallstones is the presence of more cholesterol in bile than can be held in solution by the solubilizing lipids, bile acid and lecithin.8 This relative excess of cholesterol occurs both as a consequence of increased cholesterol secretion and an abnormally small pool of bile acid. ~~. 10 If vagotomy actually does predispose to cholelithiasis, abnormal supersaturation of bile and perhaps abnormal reduction of the bile acid pool should be present in vagotomy patients. That possibility is examined in the present report. Methods Eight male subjects, free from medical problems by published criteria, 11 served as a control group. Bile acid pool size and kinetics had been measured on these subjects for other investigations using [14 C]cholic and [ 14 C]chenodeoxycholic (New England Nuclear, Boston, Mass.) as isotope dilution markers. Pool sizes were determined both by the method of Lindstedt 12 and by a one-sample technique which we have previously validated and shown to be precise to ±2.6%. 13 Quadruplicate values for gallbladder bile lipid composition, lithogenic index, and bile acid composition, determined as previously described" were also available for all control subjects. For bile lipid composition mean coefficient of variation Received February 22 , 1978. Accepted May 31, 1978. Address requests for reprints to: William C. Duane, M.D., Gastroenterology Section-111D, Veterans Administration Hospital, 54th Street and 48th Avenue South, Minneapolis, Minnesota 55417. Dr. Duane is a recipient of a Research Associateship from the Veterans Administration. Dorothy Wiegand provided excellent technical assistance. The nursing and dietetic staff of the Special Diagnostic and Treatment Unit of the Veterans Administration Hospital skillfully cared for the study subjects. Juanita C. Olson, Valarie Wesley, and Donna Hicks carefully prepared the manuscript. 608
based on these four samples was 0.098 for cholesterol, 0.090 for phospholipid, and 0.026 for bile acid. Male patients who had undergone truncal vagotomy and pyloroplasty (V&P) 1 to 5 years earlier were located by review of the records of the Minneapolis Veterans Administration Hospital. Patients with associated diseases or without histological proof of transection of two vagal trunks were excluded. No patient had lost weight as a result of surgery. For each of the control subjects, a V &P patient was selected so as to be matched within 10% for age and ideal body weight. One control subject was matched twice because the first V&P patient selected refused study. The selected V&P patients were hospitalized on a metabolic ward where measurements of bile acid pool size and gallbladder bile lipid composition were performed exactly as had been done for control subjects. In addition, basal and maximal acid secretory rates were determined on each V &P patient using standard techniques. 14 The risk of Hollander testing for research purposes could not be justified. Oral cholecystography was performed on all ofthe vagotomy patients. All but two of the control subjects had oral cholecystograms (which were normal). The two exceptions were both asymptomatic young males with low molar per cent cholesterol values (5.34 and 5.31). Statistical analysis was by paired t-test using a one-sided P-value. Written informed consent was obtained from all 16 subjects before study. Study protocols were approved by the Subcommittee on Human Studies of the Minneapolis Veterans Administration Hospital.
Results Meal total bile acid pool by the one-sample method was larger in the vagotomy group (8370 1-LmoL) than in the control group (5810 1-LmoL), a difference significant at the P < 0.05 level (Table 1). This expansion of total pool included significant expansions of both cholic pool (2820 1-Lmoles vagotomy, 2020 pmoles control, P < 0.05) and chenodeoxycholic pool (3630 p.moles vagotomy, 2000 1-Lmoles control, P < 0.025) measured by the one-sample method. Mean deoxycholic pool was not significantly different between the two groups (table 1).
609
BILIARY LIPIDS AFTER VAGOTOMY
October 1978 TABLE
1. Bile acid pools by the one-sample method Chenodeoxycholic
Cholic Control
Vagotomy
Control
Vagotomy
1490 3330 2030 2260 2770 1320 2260 690
2910 693 1840 3030 4900 4290 2290 2620
1620 2340 2430 2240 2310 1720 2470 833
Deoxycholic
Total
Control
Vagotomy
Control
Vagotomy
4250 1090 2880 3760 6500 4540 3200 2820
2370 712 520 2230 2240 1390 3500 1060
1230 2100 1200 2340 3850 1220 1500 1430
5540 6410 5000 6780 7430 4500 8230 2620
8520 3890 5910 9230 15270 10100 7130 6960
2000 3630 p < 0.025
1750
1860 NS"
!'-moles
Mean 2020 2820 p < 0.05
5810 8370 p < 0.05
" NS, not significant.
Average total bile acid pool measured by the method of Lindstedt was also significantly larger in the vagotomy group (7370 1-Lmoles) than in the control group (4290 /-(-moles, P < 0.025). Chenodeoxycholic pool by the Lindstedt method in the vagotomy group was 3390 compared to 1460 1-Lmoles in the control group (P < 0.025). Differences in the cholic pool determined by the method of Lindstedt were only of borderline statistical significance (2329 1-Lmoles vagotomy, 1530 1-Lmoles control, P = 0.10). Bile acid kinetics derived from these studies revealed mean cholic synthesis to be 751 1-Lmoles per day in the vagotomy group and 768 1-Lmoles per day m the control group. Mean synthesis of chenodeoxycholic was 605 1-Lmoles per day in the vagotomy patients and 517 /-(-moles per day in the controls. Neither difference in synthesis approached statistical significance. Average fractional turnover rate of chenodeoxycholic appeared slower in the vagotomy patients (0.24 day- 1) than in the control group (0.52 day- 1 , P < 0.10). Fractional turnover rate of cholic in the vagotomy group averaged 0.46 day- 1 compared to 0.66 day- 1 in the control group, a difference that did not reach statistical significance. Thus, although variability in bile acid kinetic parameters was large enough to preclude statistically significant differences, the trend in these parameters suggested that slow ·fractional turnover rather than high synthesis was the mechanism for expansion of the bile acid pool in the vagotomy subjects. Average molar per cent cholesterol in the vagotomy group was 5.96 versus 7.06 in the control group (P < 0.05). This reduction in relative cholesterol content of bile was accompanied by higher molar per cents of both bile acid and phospholipid in the vagotomy group relative to control, but the differences were of borderline statistical significance (P < 0.10, table 2). Mean lithogenic index based on the solubility limits of Admirand and Small8 was 0.62 in the vagotomy patients and 0.81 in the control group (P < 0.05). When calculated with the solubility limits ofHegardt and Dam 15 and Holzbach et al., IIi these saturation indices were 1. 03 vagotomy and 1.10 control, a difference that did not reach statistical significance (P < 0.20).
Oral cholecystograms showed opacification of the gallbladder in all cases. Only one patient in the vagotomy group had gallstones. This same patient also had the highest molar per cent cholesterol in the vagotomy group (9.48 molar per cent, table 2), suggesting that his gallstones formed as a result of this excess cholesterol relative to the solubilizing lipids. Discussion We have found abnormally large bile acid pools after vagotomy confirming two previous studies in animal models. 17 • 18 To our knowledge, postvagotomy bile acid pool size has been reported in human beings only once. 19 In that study a reduction in taurocholate pool was found using labeled taurocholate as the isotopic tracer. Pool sizes of other bile acids as well as total bile acid pool size were not reported. Moreover, the data that were reported may be unreliable inasmuch as administration of labeled taurocholate with subsequent measurement of taurocholate specific activity can produce large errors in estimates of pool size. 2° Finally, that report, unlike the present study, was not controlled for age, sex, and degree of obesity. Judging from comparison of several separate studies, women appear to have smaller pools of bile acid than do men. 9• 10• 2 1• 22 Furthermore, obesity is a well established determinant of bile lipid composition. 23 Failure to control for these variables might therefore be very deceptive in evaluating effects of vagotomy. The exact mechanism responsible for expansion of the bile acid pool by vagotomy has not been defined in the present study. Our studies and those from other laboratories suggest that bile acid pool size is regulated to a large extent by emptying rate of the gallbladder.24 • 25 Measurements of gallbladder emptying rate after vagotomy have generally been normal.26 • 27 On the other hand, radiographic measurements indicate enlargement of the gallbladder after vagotomy.26• 2 7 With concentrating function unimpaired, an enlarged gallbladder must accommodate more bile acid. Such an increase in storage capacity could at least partially account for the expanded pools found in our vagotomy patients. Finally, nothing in our results excludes the possibility that the pyloroplasty contributed to expansion of bile TABLE
2. Gallbladder bile lipid composition
Cholesterol
Mean
Control
Vagotomy
5.34 5.31 5.23 7.25 8.66 6.60 6.65 11.40
5.13 6.16 4.01 4.49 5.37 5.38 7.65 9.48
7.06 5.96 p < 0.05
Phospholipid Control Vagotomy molar per cent
15.5 18.7 16.4 20.8 22.6 21.4 20.2 24.8
19.5 18.8 18.4 15.0 17.8 18.6 18.3 18.6
20.0 18.1 p < 0.10
Bile acid Control
Vagotomy
79.2 76.0 78.3 71.0 68.7 72.0 73.2 63.9
75.4 75.0 77.6 80.5 76.8 76.0 74. 1 72.0
72.9 75.9 p < 0.10
Vol. 75, No. 4
STEMPEL AND DUANE
610
acid pool size in our subjects. However, it seems unlikely that the pyloroplasty was the sole cause for the enlarged pools because in at least one animal model, vagotomy without pyloroplasty caused expansion of the bile acid pool. IH Several studies suggest that there is an increased incidence of gallstones after surgical vagotomy, although others deny that a relationship exists. 1- 7 Clave and Gaspar~ found evidence of gallbladder disease in 22.8% of 92 patients with V&P compared with 8.2% expected by the Framingham study. 2 H A remarkable feature of this study was a 28% incidence in the 30- to 50-year age group which is 3 to 4 times that expected from the Framingham study. In another study, Tompkins et al. found a 16% incidence of gallstones after vagotomy and drainage.a Neither of these two studies were controlled for degree of obesity, sex, age, or any other variables necessitating comparison of prevalence data to that reported in the Framingham study. It is important to note, however, that the Framingham study included almost no patients with silent stones because routine oral cholecystograms were not performed as part of the study protocol. Because post vagotomy subjects would be likely to have high incidence ofnonbiliary gastrointestinal symptoms for which an oral cholecystogram would be done, a number of silent stones might be inadvertently discovered in this group. Thus, what appears to be an increased prevalence of stones in vagotomy subjects may simply be an increased appreciation of silent stones. According to present theories of pathogenesis, excess biliary cholesterol, relative to bile acid and lecithin, is a prerequisite for cholesterol gallstone formation. 8 Such an imbalance in biliary lipid composition arises in part because of abnormally small bile acid pools. 9• 10• 21 In sharp contrast to cholelithiasis patients, our vagotomy 2.0
-4000
r=-0.80 p<.02
0
4000
8000
FIG. 1. Difference in molar per cent cholesterol versus difference in total bile acid pool size (one sample method) for each of the eight matched pairs. The magnitude of abnormality in bile acid pool size correlated significantly with the magnitude of improvement in biliary lipid composition. Similar linear regression analysis of difference in individual bile acid pool sizes revealed correlation coefficients of - 0.67 for chenodeoxycholic, -0.61 for cholic, and - 0.49 for deoxycholic (data not plotted). Thus, no individual bile acid pool was more closely associated with molar per cent cholesterol than was total bile acid pool.
patients had abnormally large bile acid pools and unusually low relative cholesterol content of bile. The larger the difference in pool size . between any given matched pair, the greater the difference in relative cholesterol content of bile (fig. 1), suggesting that enlargement of the pool was responsible for improved biliary lipid composition after vagotomy. Assuming that these findings apply to the entire population of patients undergoing vagotomy, and in the absence of a controlled study of gallstone incidence in such patients, there seems to be little reason to suppose that vagotomy predisposes to cholesterol gallstone formation. If such stones do arise with an increased incidence after vagotomy, they apparently form by mechanisms not presently appreciated. REFERENCES 1. Griffiths JMT, Holmes G: Cholecystitis following gastric sur· gery. Lancet 2:780-782, 1964
2. Clave RA, Gaspar MR: Incidence of gallbladder disease after vagotomy. Am J Surg 118:169-176, 1969 3. Tompkins RK, Kraft AR, Zimmerman E, et al: Clinical and biochemical evidence of increased gallstone formation after complete vagotomy. Surgery 71:196-200, 1972 4. Cowie AGA, Clark CG: The lithogenic effect of vagotomy. Br J Surg 59:365-367, 1972 5. Majoor CLH, Suren TJJ: Gallbladder complications following resection of stomach for peptic ulcer. Br Med J 2:8-11, 1947 6. Mujahed Z, Evans JA: The relationship of cholelithiasis to vagotomy. Surg Gynecol Obstet 133:656-658, 1971 7. Costello C: Vagotomy and gallstones. Postgrad Med 47:141-143, 1970 8. Admirand WH, Small DM: The physiochemical basis of cholesterol gallstone formation in man. J Clin Invest 47:1043- 1052, 1968 9. Vlahcevic ZR, Bell CC, Buhac I, et al: Diminished bile acid pool size in patients with gallstones. Gastroenterology 59:165-173, 1970 10. Vlahcevic ZR, Bell CC, Gregory DH, et a!: Relationship of bile
acid pool size to the formation of lithogenic bile in female Indians of the southwest. Gastroenterology 62:73-83, 1972 11. Duane WC, Ginsberg RL, Bennion LJ: Effects of fasting on bile acid metabolism and biliary lipid composition in man. J Lipid Res 17:211-219, 1976 12. Lindstedt S: The turnover of cholic acid in man. Acta Physiol Scand 40:1-9, 1957 13. Duane WC, Adler RD, Bennion LJ, et al: Determination of bile acid pool size in man: a simplified method with advantages of increased precision, shortened analysis time, and decreased isotope exposure. J Lipid Res 16:155-158, 1975 14. Cannon DC: Examination of gastric and duodenal contents. In Clinical Diagnosis by Laboratory Methods. Fourteenth edition. Edited by I Davidsohn JB Henry. Philadelphia, WB Saunders Co, 1969, p 768- 774 15. Hegardt FG, Dam H: The solubility of cholesterol in aqueous solutions of bile salts and lecithin. Z Ernaehrungswiss 10:223233, 1971 16. Holzbach RT, Marsh M, Olszewski M, et a!: Cholesterol solubility in bile. J Clin Invest 52:1467- 1479, 1973 17. White TT, Tournut RA, Scharplatz D, et a!: The effect of
vagotomy on biliary secretions and bile salt pools in dogs. Ann Surg 179:406-411, 1974 18. Ho K, Drummond JL: Circadian rhythm of biliary excretion and its control mechanisms in rats with chronic biliary drainage. Am J Physiol 229:1427- 1437, 1975 19. Arnesjo B, Stahl E: Taurocholate metabolism after truncal
October 1978
BILIARY LIPIDS AFTER VAGOTOMY
vagotomy and pyloroplasty or antral resection. Scand J Gastroenterol 9:601-606, 1974 20. Hoffman NE, Hofmann AF: Metabolism of steroid and amino acid moieties of conjugated bile acids in man. Gastroenterology 67:887-897, 1974
21. Bell CC, Vlahcevic ZR, Prazich J, et a!: Evidence that a diminished bile acid pool precedes the formation of cholesterol gallstones in man. Surg Gynecol Obstet 136:961-965, 1973 22. Danzinger RG, Hofmann AF, Thistle JL, et a!: Effect of oral chenodeoxycholic acid on bile acid kinetics and biliary lipid composition in women with cholelithiasis. J Clin Invest 52:28092821, 1973 23. Bennion LJ, Grundy SM: Effects of obesity and caloric intake on biliary lipid metabolism in man. J Clin Invest 56:996-1011, 1975
611
24. Hanson KC, Duane WC: Role of the gallbladder in regulation of bile acid metabolism in man (abstr). Gastroenterology 71:910, 1976 25. Hepner GW: Effect of decreased gallbladder stimulation on
enterohepatic cycling and kinetics of bile acids. Gastroenterology 68:1574-1581, 1975 26. Inberg MV, Vuorio M: Human gallbladder function after selective gastric and total abdominal vagotomy. Acta Chir Scand 135:625-633, 1969 27. Fagerberg S, Grevsten S, Johansson H, et a!: Vagotomy and gallbladder function. Gut 11:789-793, 1970 28 . Friedman GD, Kannel WB, Dawber TR: The epidemiology of
gallbladder disease: observations in the Framingham study. J Chronic Dis 19:273-292, 1966
Vol. 75 , No. 4
Printed in U.S A .
BILIARY LIPIDS AND BILE ACID POOL SIZE AFTER VAGOTOMY IN MAN
Evidence against a predisposition to gallstones JERROLD M. STEMPEL, M.D . , AND WILLIAM
c.
DUANE, M.D.
Section of Gastroenterology, Department of Medicine, Veterans Administration Hospital, and University of Minnesota Hospital, Minneapolis, Minnesota
Eight male subjects who had previously undergone vagotomy and pyloroplasty were found to have significantly larger bile acid pools than did a group of matched control subjects. Associated with these expanded pools was a significantly lower molar per cent cholesterol of gallbladder bile in the vagotomy group. These findings are the opposite of those expected in a group predisposed to cholesterol cholelithiasis, suggesting that vagotomy, at least in males, does not predispose to cholesterol gallstones. If such stones form after vagotomy, they presumably do so by a mechanism not presently appreciated. Truncal vagotomy is alleged to predispose to cholesterol gallstone disease, although this contention is controversiaL 1- 7 A prerequisite for the development of cholesterol gallstones is the presence of more cholesterol in bile than can be held in solution by the solubilizing lipids, bile acid and lecithin.8 This relative excess of cholesterol occurs both as a consequence of increased cholesterol secretion and an abnormally small pool of bile acid. ~~. 10 If vagotomy actually does predispose to cholelithiasis, abnormal supersaturation of bile and perhaps abnormal reduction of the bile acid pool should be present in vagotomy patients. That possibility is examined in the present report. Methods Eight male subjects, free from medical problems by published criteria, 11 served as a control group. Bile acid pool size and kinetics had been measured on these subjects for other investigations using [14 C]cholic and [ 14 C]chenodeoxycholic (New England Nuclear, Boston, Mass.) as isotope dilution markers. Pool sizes were determined both by the method of Lindstedt 12 and by a one-sample technique which we have previously validated and shown to be precise to ±2.6%. 13 Quadruplicate values for gallbladder bile lipid composition, lithogenic index, and bile acid composition, determined as previously described" were also available for all control subjects. For bile lipid composition mean coefficient of variation Received February 22 , 1978. Accepted May 31, 1978. Address requests for reprints to: William C. Duane, M.D., Gastroenterology Section-111D, Veterans Administration Hospital, 54th Street and 48th Avenue South, Minneapolis, Minnesota 55417. Dr. Duane is a recipient of a Research Associateship from the Veterans Administration. Dorothy Wiegand provided excellent technical assistance. The nursing and dietetic staff of the Special Diagnostic and Treatment Unit of the Veterans Administration Hospital skillfully cared for the study subjects. Juanita C. Olson, Valarie Wesley, and Donna Hicks carefully prepared the manuscript. 608
based on these four samples was 0.098 for cholesterol, 0.090 for phospholipid, and 0.026 for bile acid. Male patients who had undergone truncal vagotomy and pyloroplasty (V&P) 1 to 5 years earlier were located by review of the records of the Minneapolis Veterans Administration Hospital. Patients with associated diseases or without histological proof of transection of two vagal trunks were excluded. No patient had lost weight as a result of surgery. For each of the control subjects, a V &P patient was selected so as to be matched within 10% for age and ideal body weight. One control subject was matched twice because the first V&P patient selected refused study. The selected V&P patients were hospitalized on a metabolic ward where measurements of bile acid pool size and gallbladder bile lipid composition were performed exactly as had been done for control subjects. In addition, basal and maximal acid secretory rates were determined on each V &P patient using standard techniques. 14 The risk of Hollander testing for research purposes could not be justified. Oral cholecystography was performed on all ofthe vagotomy patients. All but two of the control subjects had oral cholecystograms (which were normal). The two exceptions were both asymptomatic young males with low molar per cent cholesterol values (5.34 and 5.31). Statistical analysis was by paired t-test using a one-sided P-value. Written informed consent was obtained from all 16 subjects before study. Study protocols were approved by the Subcommittee on Human Studies of the Minneapolis Veterans Administration Hospital.
Results Meal total bile acid pool by the one-sample method was larger in the vagotomy group (8370 1-LmoL) than in the control group (5810 1-LmoL), a difference significant at the P < 0.05 level (Table 1). This expansion of total pool included significant expansions of both cholic pool (2820 1-Lmoles vagotomy, 2020 pmoles control, P < 0.05) and chenodeoxycholic pool (3630 p.moles vagotomy, 2000 1-Lmoles control, P < 0.025) measured by the one-sample method. Mean deoxycholic pool was not significantly different between the two groups (table 1).
609
BILIARY LIPIDS AFTER VAGOTOMY
October 1978 TABLE
1. Bile acid pools by the one-sample method Chenodeoxycholic
Cholic Control
Vagotomy
Control
Vagotomy
1490 3330 2030 2260 2770 1320 2260 690
2910 693 1840 3030 4900 4290 2290 2620
1620 2340 2430 2240 2310 1720 2470 833
Deoxycholic
Total
Control
Vagotomy
Control
Vagotomy
4250 1090 2880 3760 6500 4540 3200 2820
2370 712 520 2230 2240 1390 3500 1060
1230 2100 1200 2340 3850 1220 1500 1430
5540 6410 5000 6780 7430 4500 8230 2620
8520 3890 5910 9230 15270 10100 7130 6960
2000 3630 p < 0.025
1750
1860 NS"
!'-moles
Mean 2020 2820 p < 0.05
5810 8370 p < 0.05
" NS, not significant.
Average total bile acid pool measured by the method of Lindstedt was also significantly larger in the vagotomy group (7370 1-Lmoles) than in the control group (4290 /-(-moles, P < 0.025). Chenodeoxycholic pool by the Lindstedt method in the vagotomy group was 3390 compared to 1460 1-Lmoles in the control group (P < 0.025). Differences in the cholic pool determined by the method of Lindstedt were only of borderline statistical significance (2329 1-Lmoles vagotomy, 1530 1-Lmoles control, P = 0.10). Bile acid kinetics derived from these studies revealed mean cholic synthesis to be 751 1-Lmoles per day in the vagotomy group and 768 1-Lmoles per day m the control group. Mean synthesis of chenodeoxycholic was 605 1-Lmoles per day in the vagotomy patients and 517 /-(-moles per day in the controls. Neither difference in synthesis approached statistical significance. Average fractional turnover rate of chenodeoxycholic appeared slower in the vagotomy patients (0.24 day- 1) than in the control group (0.52 day- 1 , P < 0.10). Fractional turnover rate of cholic in the vagotomy group averaged 0.46 day- 1 compared to 0.66 day- 1 in the control group, a difference that did not reach statistical significance. Thus, although variability in bile acid kinetic parameters was large enough to preclude statistically significant differences, the trend in these parameters suggested that slow ·fractional turnover rather than high synthesis was the mechanism for expansion of the bile acid pool in the vagotomy subjects. Average molar per cent cholesterol in the vagotomy group was 5.96 versus 7.06 in the control group (P < 0.05). This reduction in relative cholesterol content of bile was accompanied by higher molar per cents of both bile acid and phospholipid in the vagotomy group relative to control, but the differences were of borderline statistical significance (P < 0.10, table 2). Mean lithogenic index based on the solubility limits of Admirand and Small8 was 0.62 in the vagotomy patients and 0.81 in the control group (P < 0.05). When calculated with the solubility limits ofHegardt and Dam 15 and Holzbach et al., IIi these saturation indices were 1. 03 vagotomy and 1.10 control, a difference that did not reach statistical significance (P < 0.20).
Oral cholecystograms showed opacification of the gallbladder in all cases. Only one patient in the vagotomy group had gallstones. This same patient also had the highest molar per cent cholesterol in the vagotomy group (9.48 molar per cent, table 2), suggesting that his gallstones formed as a result of this excess cholesterol relative to the solubilizing lipids. Discussion We have found abnormally large bile acid pools after vagotomy confirming two previous studies in animal models. 17 • 18 To our knowledge, postvagotomy bile acid pool size has been reported in human beings only once. 19 In that study a reduction in taurocholate pool was found using labeled taurocholate as the isotopic tracer. Pool sizes of other bile acids as well as total bile acid pool size were not reported. Moreover, the data that were reported may be unreliable inasmuch as administration of labeled taurocholate with subsequent measurement of taurocholate specific activity can produce large errors in estimates of pool size. 2° Finally, that report, unlike the present study, was not controlled for age, sex, and degree of obesity. Judging from comparison of several separate studies, women appear to have smaller pools of bile acid than do men. 9• 10• 2 1• 22 Furthermore, obesity is a well established determinant of bile lipid composition. 23 Failure to control for these variables might therefore be very deceptive in evaluating effects of vagotomy. The exact mechanism responsible for expansion of the bile acid pool by vagotomy has not been defined in the present study. Our studies and those from other laboratories suggest that bile acid pool size is regulated to a large extent by emptying rate of the gallbladder.24 • 25 Measurements of gallbladder emptying rate after vagotomy have generally been normal.26 • 27 On the other hand, radiographic measurements indicate enlargement of the gallbladder after vagotomy.26• 2 7 With concentrating function unimpaired, an enlarged gallbladder must accommodate more bile acid. Such an increase in storage capacity could at least partially account for the expanded pools found in our vagotomy patients. Finally, nothing in our results excludes the possibility that the pyloroplasty contributed to expansion of bile TABLE
2. Gallbladder bile lipid composition
Cholesterol
Mean
Control
Vagotomy
5.34 5.31 5.23 7.25 8.66 6.60 6.65 11.40
5.13 6.16 4.01 4.49 5.37 5.38 7.65 9.48
7.06 5.96 p < 0.05
Phospholipid Control Vagotomy molar per cent
15.5 18.7 16.4 20.8 22.6 21.4 20.2 24.8
19.5 18.8 18.4 15.0 17.8 18.6 18.3 18.6
20.0 18.1 p < 0.10
Bile acid Control
Vagotomy
79.2 76.0 78.3 71.0 68.7 72.0 73.2 63.9
75.4 75.0 77.6 80.5 76.8 76.0 74. 1 72.0
72.9 75.9 p < 0.10
Vol. 75, No. 4
STEMPEL AND DUANE
610
acid pool size in our subjects. However, it seems unlikely that the pyloroplasty was the sole cause for the enlarged pools because in at least one animal model, vagotomy without pyloroplasty caused expansion of the bile acid pool. IH Several studies suggest that there is an increased incidence of gallstones after surgical vagotomy, although others deny that a relationship exists. 1- 7 Clave and Gaspar~ found evidence of gallbladder disease in 22.8% of 92 patients with V&P compared with 8.2% expected by the Framingham study. 2 H A remarkable feature of this study was a 28% incidence in the 30- to 50-year age group which is 3 to 4 times that expected from the Framingham study. In another study, Tompkins et al. found a 16% incidence of gallstones after vagotomy and drainage.a Neither of these two studies were controlled for degree of obesity, sex, age, or any other variables necessitating comparison of prevalence data to that reported in the Framingham study. It is important to note, however, that the Framingham study included almost no patients with silent stones because routine oral cholecystograms were not performed as part of the study protocol. Because post vagotomy subjects would be likely to have high incidence ofnonbiliary gastrointestinal symptoms for which an oral cholecystogram would be done, a number of silent stones might be inadvertently discovered in this group. Thus, what appears to be an increased prevalence of stones in vagotomy subjects may simply be an increased appreciation of silent stones. According to present theories of pathogenesis, excess biliary cholesterol, relative to bile acid and lecithin, is a prerequisite for cholesterol gallstone formation. 8 Such an imbalance in biliary lipid composition arises in part because of abnormally small bile acid pools. 9• 10• 21 In sharp contrast to cholelithiasis patients, our vagotomy 2.0
-4000
r=-0.80 p<.02
0
4000
8000
FIG. 1. Difference in molar per cent cholesterol versus difference in total bile acid pool size (one sample method) for each of the eight matched pairs. The magnitude of abnormality in bile acid pool size correlated significantly with the magnitude of improvement in biliary lipid composition. Similar linear regression analysis of difference in individual bile acid pool sizes revealed correlation coefficients of - 0.67 for chenodeoxycholic, -0.61 for cholic, and - 0.49 for deoxycholic (data not plotted). Thus, no individual bile acid pool was more closely associated with molar per cent cholesterol than was total bile acid pool.
patients had abnormally large bile acid pools and unusually low relative cholesterol content of bile. The larger the difference in pool size . between any given matched pair, the greater the difference in relative cholesterol content of bile (fig. 1), suggesting that enlargement of the pool was responsible for improved biliary lipid composition after vagotomy. Assuming that these findings apply to the entire population of patients undergoing vagotomy, and in the absence of a controlled study of gallstone incidence in such patients, there seems to be little reason to suppose that vagotomy predisposes to cholesterol gallstone formation. If such stones do arise with an increased incidence after vagotomy, they apparently form by mechanisms not presently appreciated. REFERENCES 1. Griffiths JMT, Holmes G: Cholecystitis following gastric sur· gery. Lancet 2:780-782, 1964
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