The Effect of Long-Term Intake of cis Unsaturated Fats on the Risk for Gallstone Disease in Men

Context Some people believe that high dietary intakes of cis unsaturated fat decrease cholesterol gallstone disease. Contribution This prospective, population-based study involving 45756 middle-aged and older men found that during 14 years of follow-up, high compared with low intakes of both monounsaturated and polyunsaturated fatty acids were associated with fewer self-reported cases of symptomatic gallstone disease. Cautions The study compared high and low intakes of fatty acids; it did not determine optimal amounts of unsaturated fat intake. Implications Long-term intake of high amounts of total dietary cis unsaturated fat seems to be associated with decreased risk for gallstone disease in men. The Editors Gallbladder disease is a major source of morbidity in the United States. It affects approximately 10% to 25% of U.S. adults (1). Each year, more than 800000 hospitalizations in the United States are attributed to gallstone disease (2). In most western countries, including the United States, cholesterol gallstones account for approximately 80% to 90% of the stones removed in patients between the ages of 30 and 60 years (3). Thus, preventive measures to reduce the incidence of gallstones may decrease the burden of gallbladder disease. Cholesterol gallstones have many causes; one of the most important causes is hypersecretion of cholesterol into the biliary tree (4). Hyperinsulinemia has been associated with increased bile cholesterol saturation and may enhance cholesterol gallstone formation (5), and gallstone disease is thought to be a manifestation of the insulin resistance syndrome (6). Studies report (7, 8) that diets high in polyunsaturated and monounsaturated fatty acids (see Glossary) relative to low-fat, high-carbohydrate diets have beneficial effects on insulin sensitivity. In addition, in animal experiments, monounsaturated and polyunsaturated fats can inhibit cholesterol cholelithiasis and, therefore, may protect against cholesterol gallstone disease in humans (9-11). However, earlier epidemiologic studies on the relationship between consumption of polyunsaturated and monounsaturated fatty acids and risk for gallstone disease are sparse and provide no convincing evidence (12-16). Published studies have been limited by inadequate dietary assessment, short follow-up periods, incomplete control of confounding, or small number of end points. In cross-sectional or casecontrol studies, changes in diet caused by symptoms of gallstones could influence assessment of dietary intake. We therefore examined dietary intakes of monounsaturated and polyunsaturated fatty acids in relation to the occurrence of gallstone disease in a large cohort of U.S. male health professionals. Methods Study Sample The Health Professionals Follow-up Study began in 1986 when 51529 U.S. male dentists (58%), veterinarians (20%), optometrists (7%), osteopathic physicians (4%), and podiatrists (3%) who were 40 to 75 years of age returned a questionnaire by mail regarding diet, medications, and medical history. Follow-up questionnaires were sent every 2 years to update information on exposures and to ascertain the occurrence of newly diagnosed illnesses, including gallstone disease. Diet was assessed in 1986, 1990, 1994, and 1998. At baseline, we excluded men who reported a cholecystectomy or a diagnosis of gallstone disease before 1986, men with a diagnosis of cancer before 1986, men with a daily energy intake outside the range of 800 to 4200 kcal/d, and men with 70 or more blank food items on the questionnaire. After exclusions, the study sample consisted of 45756 eligible men who were followed from 1986 to 2000. The average follow-up rate for biennial questionnaires was greater than 94% in each 2-year follow-up cycle. Diet Assessment Dietary information was derived from a 131-item semi-quantitative food-frequency questionnaire (17). We asked participants to indicate the frequency, on average, of consuming a typical serving size of selected foods during the previous year. Respondents could choose from 9 options, ranging from never or less than once per month to 6 or more times per day. Nutrient scores were computed by multiplying the frequency of consumption of each unit of food from the semi-quantitative food-frequency questionnaire by the nutrient content of the specified portion according to food composition tables (18). Previous reports have described the semi-quantitative food-frequency questionnaire, including fat intake and the procedures used for calculating nutrient and caloric intake, as well as data on reproducibility and validity in this cohort (19, 20). The validity of the semi-quantitative food-frequency questionnaire was assessed in a random sample of 127 participants living in the Boston, Massachusetts, area. We compared nutrient intakes from the semi-quantitative food-frequency questionnaire with 2 detailed 1-week diet records spaced approximately 6 months apart; all foods consumed each day were recorded on these records (17). The Pearson correlation coefficient, adjusted for energy and corrected for within-person variation, between the diet records and the dietary questionnaire was 0.75 for saturated fat (see Glossary), 0.76 for cholesterol, 0.68 for monounsaturated fat, and 0.37 for polyunsaturated fat. All nutrients were adjusted for total energy intake by using regression analysis. This approach is based on the concept that the composition of the diet, independent of total energy intake, is most relevant to dietary recommendations (19). In addition, control for calorie intake can limit misclassification in nutrient intake caused by differences in body size and physical activity level. Ascertainment of End Points The primary end point was incident symptomatic gallstone disease. In 1986 and on each follow-up questionnaire every 2 years, participants were asked whether they had undergone cholecystectomy or had received (from a physician) a diagnosis of gallstones. Participants were also asked whether the gallstone diagnosis had been confirmed by radiographic procedures or surgery and whether their gallstones were symptomatic. To verify the self-reports of surgical cholecystectomy and diagnosed but unremoved gallstones, a random sample of 441 medical records of participants who reported a cholecystectomy or gallstones were reviewed; of these, the diagnosis was confirmed in all but 5 (99%). In addition, medical chart review confirmed all self-reported symptoms and all but 1 of the self-reported diagnostic procedures. Statistical Analysis For each participant, follow-up time accrued from the month of return of the 1986 questionnaire and ended at the month of cholecystectomy, diagnosis of symptomatic gallstones, death, or the end of the study period, whichever occurred first. Men with asymptomatic gallstones or those whose gallstone diagnosis was not based on radiographic evidence and men with diagnosed cancer were excluded from subsequent follow-up. Thus, the eligible sample at risk consisted of only those who remained free of gallstone disease and cancer at the beginning of each 2-year follow-up interval. Incidence rates were calculated by dividing the number of events by person-years of follow-up in each category. Relative risks were calculated as the incidence of gallstone disease among men in different categories of dietary intake of cis unsaturated fats compared with the incidence among men in the lowest intake category, with adjustment for age in 5-year categories. Age-adjusted relative risks were calculated by using the MantelHaenszel summary estimator (21). Multivariate relative risks were computed by using the Cox proportional hazards regression model (22). To reduce within-person variation and best represent long-term dietary intakes, we used repeated measures of diet in the analyses (23). In particular, the incidence of gallstone disease was related to the cumulative average of cis unsaturated fat consumption from all available questionnaires up to the start of each 2-year follow-up interval. In multivariate analyses, we simultaneously included intake of total energy and potential confounding covariates, including biennially updated age (1-year categories), body mass index at the beginning of each 2-year follow-up interval (5 categories), weight change during the past 2 years (5 categories), physical activity (quintiles), dietary fiber (quintiles), diabetes (yes or no), thiazide diuretics (yes or no), nonsteroidal anti-inflammatory drugs (yes or no), pack-years of smoking (6 categories), alcohol intake (5 categories), caffeine intake (quintiles), and total energy intake (quintiles). We conducted tests of linear trend across increasing categories of dietary intake of cis unsaturated fats by assigning the median intake of unsaturated fats for categories (to minimize the influence of outliers) and treating these as a single continuous variable. All relative risks are presented with 95% CIs, and all reported P values are 2-sided. All analyses were performed with SAS software, version 8.2 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Sources The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results Most participants in this cohort were white (>91%). We first examined the crude distribution of relevant covariates according to average levels of both polyunsaturated and monounsaturated fats consumption among the participants (Table 1). At baseline in 1986, the median intakes of polyunsaturated and monounsaturated fats varied nearly 2-fold between the highest and lowest quintiles in the study sample. Men with a higher intake of polyunsaturated fat consumed less carbohydrate but had higher intakes of trans fat (see Glossary) and saturated fat. Men who reported a higher polyunsaturated fat intake tended to be more sedentary, to be less likely to be current smokers, and to drink less alcohol. Men wi