are performed annually in the United States, and associated health costs are high. .... ing 1,802 Mexican Americans and 1,188 non-Hispanic Cau- casians.
Coronary Risk Factors and Clinical Gallbladder Disease: An Approach to the Prevention of Gallstones? ANDREW K. DIEHL, MD, MSC, STEVEN M. HAFFNER, MD, MPH, HELEN P. HAZUDA, PHD, AND MICHAEL P. STERN, MD Abstract: We examined the relationship of "coronary" risk factors to clinical gallbladder disease prevalence in a cross-sectional survey. Persons with hypercholesterolemia, hypertriglyceridemia, or low high-density-lipoprotein cholesterol levels had elevated risks for clinical gallbladder disease. Smokers of 20 pack-years or more and infrequent users of alcohol had increased risks, as did persons
with hypertension or diabetes mellitus. After adjusting for age, body mass index, ethnicity, and the coronary variables, relationships persisted for diabetes in women (OR = 1.8) and frequent alcohol use in men (OR = 0.3). The proportion of gallbladder disease related to all coronary risk factors was estimated to be 52 per cent. (Am J Public Health 1987; 77:841-845.)
Introduction Gallstone disease is a major contributor to morbidity in Western countries. Nearly half a million cholecystectomies are performed annually in the United States, and associated health costs are high.' In his 1966 landmark study of risk factors for gallbladder disease, Friedman concluded that "in general, those that might be considered primarily environmental in nature (thus having important preventive implications) showed little or no relation to the disease."2 Indeed many important risk factors for cholelithiasis, including age, gender, race/ethnic group, and family history, cannot be modified. Other attributes associated with risk, such as obesity and childbearing, are not promising targets for interventions. Nevertheless, several recent reports have found gallbladder disease prevalence to be inversely related to measures of socioeconomic status, even after potential confounding factors are taken into account.3 4 Socioeconomic standing is associated with a constellation of habits, activities, dietary preferences, and exposures, some of which may be amenable to change. The identification of such "environmental" risk factors might suggest strategies to reduce the incidence of gallstones. The relation of cholelithiasis to coronary heart disease has been debated for many years. Friedman, critically reviewing the accumulated evidence in 1968, concluded that there is no strong association between gallbladder disease and coronary disease,5 and one recent study reported no important relation.6 However, since 1979 three studies have found persons with gallbladder disease to be at increased risk for ischemic heart disease. Petitti, et al, in a case control study of vascular disease in women, found those with gallbladder disease to have a relative risk of 6.6 for myocardial infarction.7 Bortnichak, et al, from a longitudinal cohort analysis of the Framingham population relating history of cholecystectomy to the subsequent development of coronary outcomes, found an increased risk in both sexes.8 Finally, Wysowski et al, while performing a case-control study examining breast cancer and gallbladder disease, found an unexpectedly strong association between gallbladder disease history and history of myocardial infarction.9 Data from the San Antonio Heart Study, a population-based survey exam-
ining cardiovascular risk factors, provided us an opportunity to explore the relation of coronary risk factors to gallbladder
From the Divisions of General Medicine (Diehl) and Clinical Epidemiology (Haffner, Hazuda, Stem), Department of Medicine, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284-7879. Address reprint requests to Dr. Diehl at that address. This paper, submitted to the Journal October 20, 1986, was revised and accepted for publication January 5, 1987.
© 1987 American Journal of Public Health 0090-0036/87$1.50
AJPH July 1987, Vol. 77, No. 7
disease. Methods The San Antonio Heart Study was a population-based health survey performed between October 1979 and November 1982. Its primary purpose was to assess the prevalence of diabetes and other cardiovascular risk factors in a bicultural sample of Mexican Americans and non-Hispanic Caucasians. Subjects from 25 to 64 years of age were randomly selected from three neighborhoods: two low-income census tracts in an almost exclusively Mexican American section of the city where a highly traditional Mexican American cultural orientation has been maintained; two middle-income census tracts that have approximately equal numbers of Mexican Americans and non-Hispanic Caucasians; and a cluster of highincome census tracts that is about 90 per cent non-Hispanic Caucasian and 10 per cent Mexican American. Only Mexican Americans were sampled in the low-income tracts, and approximately equal numbers of each ethnic group were sampled in the other neighborhoods, where stratified random sampling was performed. Offspring of interethnic marriages, Hispanics of non-Mexican heritage, and Orientals were excluded from this analysis. Detailed descriptions of the sampling procedures have been published previously.'1'2 Data collection consisted of a home interview followed by a medical examination in a mobile clinic. Response rates to the home interview ranged from 85.3 per cent to 89.0 per cent in different neighborhoods. Of those interviewed, 97 per cent were deemed eligible for the medical examination; reasons for exclusion included moving out of the area and the discovery of pregnancy after the interview. Response rates to the medical examination by neighborhood ranged from 68.9 per cent to 80.4 per cent. Full details of the response rates have been published previously. "I The presence of gallbladder disease was determined from the home interview, as described elsewhere.3 Briefly, gallbladder disease was considered to be present if the participant responded "yes" to the question, "Have you had your gallbladder removed?" Disease was also considered present if the participant answered "yes" to "Have you ever had an X-ray taken of your gallbladder?", and answered "stones" to "What did the doctor say the X-ray showed?" Gallbladder disease was considered absent if the patient denied cholecystectomy and reported never having had cholecystography, or reported previous cholecystography with normal findings. A small number of participants who had undergone cholecystography with equivocal findings and had 841
DIEHL, ET AL.
not had gallbladder surgery were considered to have uncertain status, and were not included in this analysis. Use of cigarettes and alcohol were also determined at the home interview. Participants classified themselves as current smokers, former smokers, or never smokers (fewer than 50 cigarettes smoked during entire life). In addition, cumulative cigarette consumption in pack-years was determined. Alcohol use was categorized according to responses to the question, "About how often do you drink some kind of alcoholic beverage, including beer, wine, liquor, etc?" Other cardiovascular risk factors were determined at the medical examination. Weight and height, recorded with the participant wearing an examination gown after removing his or her shoes and upper garments, were used to calculate the body mass index (weight (kg)/height (m)2). The systolic (first phase) and diastolic (fifth phase) blood pressures were measured to the nearest even digit using a random-zero sphygmomanometer (Hawksley-Gelman, London, England) on the right arm of the seated participant following at least a five-minute rest. Three readings were recorded for each individual, and the average of the second and third readings were defined as the patient's blood pressure. Plasma samples for glucose, triglycerides, and total and high-density lipoprotein (HDL) cholesterol were drawn after the participant had fasted at least 12 hours. Measurement techniques for the determinations of lipids and lipoproteins have been described previously."I A 75-gram glucose equivalent load (Glucola, Ames Co., Elkhart, Indiana) was then given. Subsequent samples for plasma glucose were drawn one and two hours after the load. Glucose concentrations were measured using an Abbott Bichromatic Analyzer (Abbott Laboratories, South Pasadena, California). Hypertension was defined as diastolic blood pressure -95 mmHg, or "currently taking antihypertensive drugs." A history of antihypertensive medication was elicited at the time of the home interview. An effort was made to confirm this information at the time of the medical examination. For purposes of this report, only those participants whose medication status was confirmed by direct inspection of the bottle in which the drug had been dispensed by the pharmacist or who were able to provide the exact name of the antihypertensive drug used were considered as currently taking antihypertensive drugs. Diabetes mellitus was diagnosed according to the National Diabetes Data Group criteria.'3 Participants who gave a history of diabetes but who did not meet these criteria were considered to be diabetic provided that they were currently taking either insulin or oral antidiabetic drugs.'2 Participants were categorized as having normal, borderline, or high triglyceride levels according to National Institutes of Health (NIH) Consensus Conference definitions.'4 Because of their relatively small numbers, persons with borderline and high triglyceride values (-250 mg/dl) were combined in the analysis. Moderate (75th-9Oth percentile for the US population) and severe hypercholesterolemia (>90th percentile) were also defined using Consensus Conference criteria. 15 The study population was further categorized by quartile of HDL-cholesterol. Cutpoints between quartiles were determined separately for each sex. Because sex, age, and ethnicity are recognized risk factors for cholelithiasis,2'3"16 analyses of coronary risk factors were initially stratified by these variables using the Statistical Package for the Social Sciences software. 17 Summary prevalences of clinical gallbladder disease according to levels of each coronary variable were standardized for age (using 10-year intervals), sex, and ethnic group using the 842
direct method, with the total population base for each factor serving as the standard population. Because obesity, ethnic group, and age are strongly related to both gallbladder disease and coronary risk factors, we performed multivariate analyses for each sex using the logistic regression program PLR of the BMDP statistical package.'8 Results for age, ethnicity, and body mass index are not reported, since these are not considered "coronary risk factors" in the present context and their relations with gallbladder disease have been described previously.3 Unstandardized beta-coefficients were employed to calculate odds ratios, and 95 per cent confidence intervals for the odds ratio were determined using Miettinen's test-based method.'9 Finally, the proportion of gallbladder disease related to coronary risk factors was determined.20 Results The study population comprised 2,990 subjects, including 1,802 Mexican Americans and 1,188 non-Hispanic Caucasians. There were 1,687 women and 1,303 men. Because participation in the medical examination was lower than for the home interview, analyses employing physical measurements and plasma or setum assays are based on a smaller
sample (n
2,125).
The prevalence of clinical gallbladder disease according to levels of coronary risk factors is shown in Table 1. All prevalences are standardized for age, sex, and ethnic group. Subjects with severe hypercholesterolemia had a higher prevalence of clinical gallbladder disease than those with moderate hypercholesterolemia, who in turn had a higher rate than normals. A prominent inverse relation of clinical gallTABLE 1-Prevalence of Clinical Gallbladder Disease by Levels of Coronary Risk Factors
Prevalence
Risk Factor
MY
1. Total Cholesterol
Normalt 2.
3.
4.
5.
6.
7. 8.
8.0 9.9 13.5
Moderate hypercholesterolemiat Severe hypercholesterolemiat HDL-Cholesterol First quartile Second quartile Third quartile Fourth quartile Triglycerides Normalt Borderline and frank hypertriglyceridemiat Alcohol use Less than once/month Once/month to twice/week Three times/week or more Smoking status Current smoker Former smoker Never smokedt Lifetime cigarette consumption None Up to 20 pack-years 20 pack-years or more Diabetes mellitust Present Absent Hypertensiont Present Absent
12.3 8.2 8.1 6.9 8.3
19.8 10.3 8.9 6.9 9.2 8.9 9.2 9.0 8.9 10.8
17.7 8.2 11.4 8.6
*Adjusted for age, sex, and ethnic group by the direct method. tSee text for definitions.
AJPH July 1987, Vol. 77, No. 7
CORONARY RISK FACTORS AND GALLBLADDER DISEASE TABLE 2-Association of Coronary Risk Factors with Clinical Gallbladder Disease-Women
Variable
SE(b)
Odds Ratio*
95% Confidence interval
0.070 0.330
0.276 0.261
1.00 1.07 1.39
0.62, 1.81 0.83, 2.32
-0.451 -0.353 -0.436
-
0.264 0.253 0.273
1.00 0.64 0.70 0.65
0.38, 1.07 0.43, 1.15 0.38, 1.11
b
1. Total cholesterol
Normalt Moderate hypercholesterolemiat Severe hypercholesterolemiat 2. HDL-cholesterol First quartile Second quartile Third quartile Fourth quartile 3. Triglycerides
Normalt Borderline and frank hypertriglyceridemiat 4. Alcohol use Less than once/month Once/month to twice/week Three times/week or more 5. Lifetime cigarette consumption None Up to 20 pack-years 20 pack-years or more 6. Diabetes mellitust Absent Present 7. Hypertensiont Absent
Present
-
-
1.00
0.332
1.74
0.91, 3.33
-
-
-0.153 0.159
0.212 0.301
1.00 0.86 1.17
0.57, 1.30 0.65, 2.09
1.00 0.99 1.07
0.66, 2.21 0.58, 1.99
1.00 1.83
1.07, 3.14
1.00 1.16
0.66, 2.01
0.555
-
-
-0.005 0.066
0.208 0.300
-
0.606 -
0.152
-
0.276 -
0.287
*Adjusted for age, ethnic group, body mass index, and other coronary variables. tSee text for definitions.
bladder disease prevalence with quartile of HDL-cholesterol was observed, with those in the lowest quartile having a rate almost twice that of the highest. Persons with borderline or frank hypertriglyceridemia had the highest standardized prevalence observed, more than twice that of normals. Frequency of alcohol use was also inversely related to clinical gallbladder disease prevalence, with regular drinkers having rates substantially lower than those who drink infrequently. Although rates did not vary with respect to current cigarette smoking status, those with a lifetime consumption of 20 pack-years or more had a slightly higher prevalence. Finally, subjects with diabetes mellitus or hypertension had higher prevalences than those without these diseases. The relationships presented in Table 1 do not, however, take obesity into account. Excess body weight is associated both with cholelithiasis and with most of the coronary risk factors considered here. In addition, several of the coronary risk variables are strongly correlated with each other (e.g., alcohol use and HDL-cholesterol; HDL-cholesterol and triglycerides). To deal with such potential confounding, we performed logistic regression analyses for each sex, using presence or absence of clinical gallbladder disease as the dependent variable, and age, ethnicity, body mass index (three levels), and the coronary risk factors as independent or predictor variables. (Note that we do not consider body mass index to be a "coronary risk factor" in this context). The findings of these analyses are shown in Tables 2 and 3. For each coronary risk variable, the "normal" or lowest level has been used as a reference for abnormal or higher values. In general, relationships of coronary risk factors to clinical gallbladder disease are similar to, but weaker than, those in Table 1. Most of the relations mirror those established for coronary heart disease. Hypercholesterolemia, hypertriglycAJPH July 1987, Vol. 77, No. 7
eridemia, diabetes mellitus, and a moderate smoking history are associated with increased risk. Regular alcohol use has a protective effect in men. Among women, those with the
lowest levels of HDL-cholesterol are at highest risk. Those of both sexes with hypertension have only minimally elevated odds ratios for clinical gallbladder disease. To estimate the total contribution of coronary risk factors (exclusive of body mass index), we calculated the proportion of gallbladder disease attributable to coronary risk factors using the equation (M - m) + M, where M is the prevalence of clinical gallbladder disease in the entire population (n = 2,990), and m is the prevalence, standardized for age, sex, and ethnic group, in those with no coronary risk factors (i.e., no hypertension or diabetes, less than 20 pack-years of smoking, alcohol use at least once a month, normal triglycerides and cholesterol, and HDL-cholesterol above first quartile; n = 51 1).20 The proportion related to these coronary risk factors is 52.3 per cent. Discussion The principal finding of this study is that the commonly acknowledged risk factors for coronary heart disease also appear to carry risk for cholelithiasis. This finding confirms and extends observations by others. Petitti, et al, in a similar study of 868 adult female twins, also found clinical gallbladder disease prevalence to be positively related to total, LDL-, and VLDL-cholesterol, and triglycerides, and inversely related to HDL-cholesterol in unadjusted analyses. In a multiple logistic regression controlling for age, obesity, and other coronary factors, she found an elevated odds ratio for cigarette smokers, a protective effect of higher HDLcholesterol levels, and an apparent protective effect of alcohol use.2' Others have demonstrated inverse relation843
DIEHL, ET AL. TABLE 3-Association of Coronary Risk Factors with Clinical Gallbladder Disease-Men
Variable 1. Total cholesterol Normalt Moderate hypercholesterolemiat Severe hypercholesterolemiat 2. HDL-cholesterol First quartile Second quartile Third quartile Fourth quartile 3. Triglycerides Normalt Borderline and frank hypertriglyceridemiat 4. Alcohol use Less than once/month Once/month to twice/week Three times/week or more 5. Lifetime cigarette consumption None Up to 20 pack-years 20 pack-years or more 6. Diabetes mellitust Absent Present 7. Hypertensiont Absent Present
b
SE(b)
Odds Ratio*
95% Confidence interval
1.00 1.70 1.62
0.68, 4.27 0.67, 3.91
0.531 0.484
0.470 0.450
0.470 0.110 0.370
0.501 0.563 0.549
1.00 1.60 1.12 1.45
0.60, 4.27 0.37, 3.37 0.49, 4.24
-
1.00
-
0.493
1.33
0.51, 3.50
-
-
0.024 -1.100
0.415 0.516
1.00 1.03 0.33
0.45, 2.31 0.12, 0.92
1.00 0.95 2.13
0.35, 2.57 0.84, 5.41
1.00 1.71
0.63, 4.65
1.00 1.25
0.47, 3.29
-
0.285
-
-
-
-
-0.048 0.756
0.505 0.476
-
0.536 -
0.221
-
0.512 -
0.494
-
-
-
-
-
-
*Adjusted for age, ethnic group, body mass index, and other coronary variables. tSee text for definitions.
ships of gallbladder disease with HDL-cholesterol in univariate analyses,22-23 although relationships with total cholesterol have not been found in most studies.2 6'22'23 Gallbladder disease has been associated with hypertriglyceridemia in studies using a variety of research designs.22'24'25 The relation of cigarette smoking to clinical gallbladder disease has received little attention. Although some reports were negative,2"16 both Petitti et al,2' and Layde, et al,4 found elevated risks among smokers. Most examinations of alcohol use have demonstrated a protective effect.22627 Whether persons with diabetes are at increased risk for gallstone disease remains uncertain, although recent reports suggest that they may be.'6'28'29 Studies examining the relation of blood pressure to clinical gallbladder disease have, like ours, been negative.2"6 One common link between the risk factors for coronary heart disease and gallbladder disease may be hyperinsulinemia. Hyperinsulinemia has been linked to obesity, hypertriglyceridemia, and future development of non-insulin dependent diabetes mellitus.30 In three prospective studies of coronary heart disease, hyperinsulinemia has been found a risk factor.3'~33 Scragg, et al, have associated hyperinsulinemia with gallbladder disease in a case control study.22 Mexican Americans have excess rates of gallbladder disease even after controlling for obesity.3'628 It is thus of interest that non-diabetic Mexican Americans have hyperinsulinemia relative to non-Hispanic Caucasians even after adjustment for overall adiposity and upper body adiposity.34 A limitation of this study is its definition of "clinical" gallbladder disease. Only persons who had undergone cholecystectomy or who had gallstones documented by cholecystography were counted as cases. Because those with asymptomatic stones were not identified, our prevalence 844
determinations underestimate the true prevalence of cholelithiasis. Moreover, this definition of "clinical" disease could have resulted in biased findings. Persons with diabetes, hypertension, or coronary disease may visit the doctor more frequently than others. Minor abdominal complaints voiced at these visits may result in cholecystography revealing "silent" gallstones. The extent of such bias, if any, cannot be estimated. On the other hand, a strength of this study is the quality of its measurement of the coronary risk factors themselves. Our findings may have implications for the primary prevention of gallstone disease. Gallbladder disease is extremely common in our society, and has a major impact on morbidity and health care expenditures.35 That its impact can be reduced is confirmed by the recent decline in its incidence in Sweden.36 In this study, coronary risk factors viewed individually had relatively weak relationships with clinical gallbladder disease, but in each instance the relation was in the same direction as that for ischemic heart disease. Moreover, when analyzed as a group, coronary heart risk factors are related to an estimated 52 per cent of the cases of clinical gallbladder disease. Although we do not suggest that the incidence of cholelithiasis can be reduced by this amount through modification of coronary risk profiles, we hypothesize that a lowering of gallstone incidence may be a serendipitous by-product of public health campaigns for the primary prevention of coronary heart disease. Randomized trials of coronary risk factor reduction may provide an opportunity to test this hypothesis. ACKNOWLEDGMENTS
We thank Drs. Richard A. Deyo and Richard L. Bauer for their thoughtful comments on earlier versions of this paper. We are also indebted to Roland
AJPH July 1987, Vol. 77, No. 7
CORONARY RISK FACTORS AND GALLBLADDER DISEASE Wong for his assistance in data analysis. Presented in part at the annual meeting of the American Federation for Clinical Research, Washington, DC, May 5, 1986. Supported by a grant from the National Heart, Lung, and Blood Institute (HL24799).
REFERENCES I. Graves EJ: 1983 Summary: National Hospital Discharge Survey. Advance Data from Vital and Health Statistics, No. 100. DHHS PubI. No. (PHS) 84-1250, 1984. 2. Friedman GD, Kannel WB, Dawber TR: The epidemiology of gallbladder disease: Observations in the Framingham study. J Chronic Dis 1966; 19:273-292. 3. Diehl AK, Rosenthal M, Hazuda HP, Comeaux PJ, Stern MP: Socioeconomic status and the prevalence of clinical gallbladder disease. J Chronic Dis 1985; 38:1019-1026. 4. Layde PM, Vessey MP, Yeates D: Risk factors for gallbladder disease: A cohort study of young women attending family planning clinics. J Epidemiol Community Health 1982; 36:274-278. 5. Friedman GD: The relationship between coronary heart disease and gallbladder disease: A critical review. Ann Intern Med 1968; 68:222-235. 6. Strom BL, Schinnar R, Crown V, Soloway R, et al: Does gallbladder removal protect against subsequent myocardial infarction? Am J Epidemiol 1986; 124:420-427. 7. Petitti DB, Wingerd J, Pellegrin F, Ramcharan S: Risk of vascular disease in women: Smoking, oral contraceptives, noncontraceptive estrogens, and other factors. JAMA 1979; 242:1150-1154. 8. Bortnichak EA, Freeman DH Jr, Ostfeld AM, Castelli WP, et al: The association between cholesterol cholelithiasis and coronary heart disease in Framingham, Massachusetts. Am J Epidemiol 1985; 121:19-30. 9. Wysowski DK, Goldberg EL, Comstock GW, Diamond EL: A study of a possible association between breast cancer and gallbladder disease. Am J Epidemiol 1986; 123:532-543. 10. Stern MP, Gaskill SP, Hazuda HP, Gardner LI, Haffner SM: Does obesity explain excess prevalence of diabetes among Mexican Americans? Results of the San Antonio Heart Study. Diabetologia 1983; 24:272-277. 11. Stern MP, Rosenthal M, Haffner SM, Hazuda HP, Franco LJ: Sex difference in the effect of sociocultural status on diabetes and cardiovascular risk factors in Mexican Americans: the San Antonio Heart Study. Am J Epidemiol 1984; 120:834-851. 12. Gardner LI Jr, Stern MP, Haffner SM, Gaskill SP, et al: Prevalence of diabetes in Mexican Americans. Relationship to per cent of gene pool derived from Native American sources. Diabetes 1984; 33:86-92. 13. National Diabetes Data Group: Classification and diagnosis of diabetes mellitus and other categories of glucose tolerance. Diabetes 1979; 28:1039-1057. 14. Grundy SM (panel chairman), and Consensus Development Panel: Treatment of hypertriglyceridemia. JAMA 1984; 251:1196-1200. 15. Steinberg D (chairman), and Consensus Development panel: Lowering blood cholesterol to prevent heart disease. JAMA 1985; 253:2080-2086. 16. Diehl AK, Stem MP, Ostrower VS, Friedman PC: Prevalence of clinical gallbladder disease in Mexican American, Anglo, and Black women. South Med J 1980; 73:438-441, 443. 17. Nie NH, Hull CH, Jenkins JG, et al: Statistical Package for the Social
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Sciences, 2d Ed. New York: McGraw-Hill, 1975. 18. Dixon WJ, Brown MD, Engelman L, Frane JW, et al (eds): BMDP Statistical Software. Berkeley: University of California Press, 1983. 19. Miettinen OS: Estimability and estimation in case-referent studies. Am J Epidemiol 1976; 103:226-235. 20. Kleinbaum DG, Kupper LL, Morgenstern H: Epidemiologic Research: Principles and Quantitative Methods. Belmont, CA: Lifetime Learning Publications, 1982, 160-164. 21. Petitti DB, Friedman GD, Klatsky AL: Association of a history of gallbladder disease with a reduced concentration of high-density-lipoprotein cholesterol. N Engl J Med 1981; 304:1396-1398. 22. Scragg RKR, Calvert GD, Oliver JR: Plasma lipids and insulin in gallstone disease: A case control study. Br Med J 1984; 289:521-525. 23. Nomura AMY, Stemmerman GN, Heilbrun LK, Kagan A: Cholecystectomy, serum cholesterol, and colon cancer. JAMA 1982; 247:2100. 24. Low-Beer TS: Nutrition and cholesterol gallstones. Proc Nutr Soc 1985; 44:127-134. 25. Kern F Jr: Epidemiology and natural history of gallstones. Sem Liver Dis 1983; 3:87-96. 26. Klatsky AL, Friedman GD, Siegelaub AB: Alcohol use and cardiovascular disease: The Kaiser-Permanente experience. Circulation 1981; 64(Suppl
III):32-41. 27. Scragg RKR, McMichael AJ, Baghurst PA: Diet, alcohol, and relative weight in gall stone disease: A case-control study. Br Med J 1984: 288:1113-1119. 28. Hanis CL, Ferrell RE, Tulloch BR, Schull WJ: Gallbladder disease epidemiology in Mexican Americans in Starr County, Texas. Am J Epidemiol 1985; 122:820-829. 29. Strom BL, Tamragouri RN, Morse ML, Lazar EL, et al: Oral contraceptives and other risk factors for gallbladder disease. Clin Pharmacol Ther 1986; 39:335-341. 30. Stern MP, Haffner SM: Body fat distribution and hyperinsulinemia as risk factors for diabetes and cardiovascular disease. Arteriosclerosis 1986; 6: 123-130. 31. Pyorala K: Relationship of glucose tolerance and plasma insulin to the incidence of coronary heart disease: Results from two population studies in Finland. Diabetes Care 1979; 2:131-141. 32. Ducimetiere P, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G: Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population. Diabetologia 1980; 19:205-210. 33. Welbom TA, Wearne K: Coronary heart disease incidence and cardiovascular mortality in Busselton with reference to glucose and insulin concentrations. Diabetes Care 1979; 2:154-160. 34. Haffner SM, Stern MP, Hazuda HP, Pugh JA, Patterson JK: Hyperinsulinemia in a population at high risk for non-insulin-dependent diabetes mellitus. N Engi J Med 1986; 315:220-224. 35. Ingelfinger FJ: Digestive disease as a national problem. V. Gallstones. Gastroenterology 1968; 55:102-104. 36. Norrby S, Fagerberg G, Sjodahl R: Decreasing incidence of gallstone disease in a defined Swedish population. Scand J Gastroenterol 1986;
21:158-162.
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