Data Synthesis: For women, but less so for men, obesity is a strong risk factor for gallstones, and this risk is increased during weight loss. Between 10% and 25% of obese men and women may develop gallstones within a few months of beginning a very low calorie diet, and perhaps one third of these will develop symptoms of gallstones. Persons with the highest body mass index before weight loss and those who lose weight most rapidly appear to be at the greatest risk for gallstones. Treatment with ursodeoxycholic acid (ursodiol) during weight loss dieting is the only proven prevention for the formation of gallstones. Issues to be resolved include how different diets affect the risk for developing gallstones, the identification of other risk factors for gallstone formation during weight loss, the effect of weight loss among people with preexisting gallstones, and the optimum means of preventing gallstones during weight loss.

Conclusions: During weight loss, particularly among the obese, an increased risk exists for symptomatic gallstone formation. This acute risk offers the opportunity to investigate the cause of gallstones and possibly to prevent them.

Methods

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The published medical literature used to address these issues was identified through a MEDLINE search on the terms gallstones with obesity or reducing diets from 1966 to 1992. This search was supplemented by a manual search of bibliographies, a weekly Current Contents (ISI, Philadelphia, Pennsylvania) search from 1991 to 1992 of all articles with the words gallstones or gallbladder in the title, and discussions with experts on gallstones or weight loss dieting. References and conclusions were all based on human studies.

Formation and Detection of Gallstones

Most gallstones in the United States are thought to be cholesterol gallstones; the remaining are pigmented gallstones, which are chemically different and have a different set of risk factors. In reality, the distribution of gallstone types is not accurately known in most clinical or any epidemiologic studies. At least three physical conditions appear necessary for the formation of cholesterol gallstones [2-4]. The first is cholesterol supersaturation of bile, a precondition of cholesterol crystallization. The cholesterol saturation index, based on the relative concentrations of cholesterol, bile salts, and phospholipids, is a commonly used indicator of the presence of a saturation defect. A cholesterol saturation index greater than 1 is considered supersaturated. Cholesterol supersaturation is common and probably occurs at some point in nearly all people. The second physical condition is the presence of a kinetic defect that accelerates cholesterol crystal nucleation and growth in supersaturated bile. Several antinucleating and pronucleating proteins, perhaps derivatives of gallbladder mucin, have been implicated as kinetic factors. Cholesterol crystal formation (visible by microscopy) followed by sludge formation (visible by gallbladder ultrasonography) are thought to be necessary precursors to cholesterol gallstone formation. The third requirement for gallstone formation is gallbladder hypomotility, which produces stasis of bile in the gallbladder, increased cholesterol supersaturation, and opportunities for cholesterol crystallization as well as gallstone formation and growth. In vivo, gallbladder hypomotility is measured by increased fasting volume, increased contracted volume, and decreased ejection fraction. Perhaps two of these three physical conditions, a kinetic defect and gallbladder hypomotility, may also predispose persons to pigment gallstone formation [5].

Persons with gallstones may remain asymptomatic for life or may have life-threatening complications. In the past, most epidemiologic studies of gallstones were based on the clinical recognition of the symptoms from gallstones, most frequently resulting in cholecystectomy. With the widespread use of ultrasonography, many more asymptomatic gallstones have been recognized. In ultrasonographic studies, gallstone disease is generally defined as the presence of gallstones or the surgical absence of the gallbladder. Ultrasonographic studies of the general population have shown that most persons with gallstones are asymptomatic.

Obesity and Gallstone Disease

Obesity is an important risk factor for gallstone disease, more so for women than for men. Ultrasonographic studies and cohort studies of gallstone disease have frequently used body mass index (BMI = weight in kg/[height in m]²) to approximate obesity. In general, these studies have shown that overweight women with a BMI of 30 kg/m² or more have at least double the risk for gallstone disease as women of normal weight with a BMI less than 25 kg/m² [6-12]. With more severe obesity, the risk increases further. The Nurses Health Study [12], which followed nearly 90 000 women for 8 years, found a substantial increase in the incidence of clinically recognized gallstone disease with increasing BMI and particularly among women with a BMI of at least 30 kg/m². The incidence per 100 000 person-years of follow-up was 1012 (BMI, 30 to 35 kg/m²), 1287 (BMI, 35 to 40 kg/m²), 1504 (BMI, 40 to 45 kg/m²), and 2091 (BMI, 45 kg/m² or more). These rates were 3.7 to 7.4 times the incidence of gallstone disease among women with a BMI of less than 24 kg/m (²). This study [12], although the largest ever done, used self-reported weights and relied on clinically recognized gallstone disease, which may occur more commonly among the obese with gallstones than among thinner persons with gallstones [9]. Despite these potential biases, it is obvious that obesity clearly confers a significant risk for gallstone disease among women.

An association of gallstone disease and obesity in men has been more difficult to show. Several studies, which found an association of BMI with gallstone disease among women, did not find an association among men [8-11, 13]. Interestingly, two studies that clearly indicated an increased risk for gallstone disease among men were done among men of Japanese descent. In a study [14] using oral cholecystography or ultrasonography among members of the Japanese Self Defense Force, the odds of gallstone disease developing in men with a BMI of at least 25 kg/m² were twice that of men with a BMI of less than 22.5 kg/m². A large prospective study of Japanese-American men in Hawaii found a 60% increase in risk among men in the highest quartile of BMI (>25.8 kg/m²) relative to men in the lowest quartile of BMI (<21.7 kg/m²) [15]. Several studies may not have had adequate statistical power to detect an effect of obesity among men, because gallstone disease is less common among men than women. However, it is also possible, and of greater interest, that obesity does not confer nearly the same risk for gallstone disease among men as it does among women.

Obesity is associated with excessive hepatic secretion of cholesterol that results in bile supersaturated with cholesterol [16-18]. Nucleating and antinucleating factors have not been compared between the obese and nonobese. However, one study [19] found nucleation times among morbidly obese persons without gallstones comparable to those of patients with pigmented gallstones and longer than those of patients with cholesterol gallstones. Thus obesity may not confer a nucleation defect. Most [20-23], but not all [24], studies have not observed impairment of gallbladder motility among the obese compared with leaner persons.

A subject related to obesity is regional distribution of fat. High central or truncal adiposity relative to limb or lower extremity adiposity is positively correlated with obesity and is an independent risk factor for several conditions for which obesity is also a risk factor, such as coronary artery disease and non-insulin-dependent diabetes mellitus [25]. The ratios of either the waist-to-hip circumference or the subscapular-to-triceps skinfold thickness have been used as a measure of central adiposity. Gallstone disease has been associated with central adiposity in three studies, only one of which evaluated gallstone prevalence. In this study [26], a sample of 838 men ages 40 to 69 years registered at clinics in East Bristol, England, had gallbladder ultrasonography [26]. The prevalence of gallstone disease increased with quartile of waist-to-hip circumference ratio from 4.4% for men in the lowest quartile to 9.4% for men in the highest quartile (prevalence ratio of 2.1, 95% CI, 1.0 to 4.6). Body mass index was not associated with gallstone disease among these men. Two other studies were cross-sectional and relied on self-reports of gallstones. Among more than 30 000 obese women participating in a weight control program, the prevalence of a self-reported history of gallstone disease was highest among women with the highest waist-to-hip ratio, but the strength of the association was less than for hypertension or diabetes [27]. A high subscapular-to-triceps skinfold ratio was associated with self-reported gallstone disease among women only in a sample from San Antonio, Texas [28]. An association of skinfold ratios with subsequent hospitalization could not be found in the first National Health and Nutrition Examination Survey or with an ultrasonographic diagnosis of gallstones in the Hispanic Health and Nutrition Examination Survey [11]. A pathophysiologic mechanism for central adiposity and gallstone formation has not been reported. Based on the few available studies, central adiposity does not appear to play as major a role in the pathogenesis of gallstones as it does in the pathogenesis of coronary artery disease and non-insulin-dependent diabetes.

Weight Loss and Gallstone Disease

Epidemiologic studies among specific populations have helped to define the risk for gallstone disease among persons losing weight. During follow-up of the Nurses Health Study cohort, the incidence of clinically recognized gallstones was determined after collection of self-reported heights and weights obtained 2 years apart [12]. Compared with women whose weight changed less than 4 kg, women who lost 4 to 10 kg had a 44% increase in the risk for gallstone disease with the weight loss, and women who lost more than 10 kg had a 94% increase in the risk for gallstone disease when controlling for BMI and other risk factors for gallstones. A study in Maastricht, the Netherlands, evaluated the relative contributions of BMI and a history of dieting (yes or no) among 151 men and women who were hospitalized for acutely symptomatic gallstones compared with community controls [29]. Using univariate analysis, a history of dieting doubled the risk for gallstones, but this association largely disappeared with control for the confounding effects of BMI. In an ultrasonographic study of a representative sample from Copenhagen County, Denmark, men with a history of more than one "slimming treatment" (weight loss of more than 5 kg) had a statistically significant doubling of gallstone disease prevalence (11.0% compared with 5.2%) [9]. Women had a statistically nonsignificant 79% increase in gallstone disease prevalence with more than one slimming treatment (17.9% compared with 10.2%). Among men, but not women, the association was statistically significant after adjustment for all other risk factors, including highest body mass index ever (a nonsignificant risk factor among men). In the first U.S. National Health and Nutrition Examination Survey, a history of dieting among women (but unknown degree of weight change) was associated with an increase (67%; P = 0.001) in incidence of hospitalization with gallstones during the following 10 years [30].

Clinical studies of persons having rapid weight loss using very low calorie diets have provided strong evidence of an increased risk for gallstones among the obese who lose large amounts of weight [31-35] (Table 1). All of these studies excluded patients with previously undetected gallstones before treatment (about 4% to 8% [32, 33, 35, 36]) and then evaluated all available patients for the development of gallstones after weight loss. One study [31] was a clinical trial that determined the incidence of biliary cholesterol crystals and gallstones among 51 obese women and 17 obese men (mean percentage of ideal body weight >170%) randomized to treatment with the bile acid ursodeoxycholic acid (ursodiol, Actigall; Summit Pharmaceuticals, Summit, New Jersey), aspirin, or placebo during a 16-week, 520-kcal-per-day (1 g fat, 55 g protein, and 79 g carbohydrate) weight-loss program. The development of gallstones was rapid among the placebo-treated group. At 4 weeks, 2 of 18 placebo-treated patients had developed gallstones and 8 others had developed gallstone precursors in the form of microstones or crystals. Three weeks after completion of the program, gallstones had formed in 5 of 19 of the placebo-treated group, 0 of 18 of the ursodeoxycholic acid-treated group, and 2 of 14 of the aspirin-treated group. Two of the 7 patients who developed gallstones had biliary colic; 1 required surgery. Gallstones spontaneously disappeared during a period of 36 months in 4 of the other 6 who were followed with regular ultrasound examinations. A subsequent study [32] of the same diet by the same group of investigators found that 27 of 248 (10.9%) obese persons having rapid weight loss developed gallstones within 16 weeks. This was a much lower incidence of gallstones than occurred in the placebo-treated group of the previous study, but the difference was statistically borderline (rate ratio, 0.41; CI, 0.20 to 1.12; P = 0.08). Patients were older, follow-up was slightly shorter, and rate of participation was lower than in the clinical trial, where clinical follow-up was more intensive. At a different center, but also among obese patients who adhered to a similar diet, gallstones developed in 4 of 51 patients after 4 weeks of dieting and they developed in an additional 9 patients after 8 weeks of dieting [33]. Three of these patients had cholecystectomy for biliary pain. After 6 months of follow-up of the 8 patients in whom gallstones developed during the diet, no gallstones could be found in 4 and the other 4 remained asymptomatic. Among a control group of 26 obese, nondieting patients, none had gallstones during follow-up. Contrary to these experiences, in a study in Italy [34], gallstones developed in none of 34 obese persons undergoing a 500 kcal/d diet for 90 days within 6 months despite an average 6.6 kg/m² reduction in BMI. Maintenance of gallbladder motility was considered the main protective factor. New gallstones developed in only 2 of 38 participants in a study with a more relaxed diet of 800 to 840 kcal/d (15% to 25% from fat), although the study duration was only 10 weeks [35]. An additional study using a higher caloric intake (1200 kcal/d) and higher fat content (21% of calories from fat) found that no gallstones developed among 34 patients after 16 weeks [36]. This diet was similar to the diet that has resulted in most cases of litigation [1].

Gallstones are also common among obese patients undergoing rapid weight loss after proximal gastric bypass surgery [37-39]. However, it has not been possible to evaluate the effect of weight loss independently of the multiple effects of major abdominal surgery [40, 41]. Weight loss also tends to be greater after surgery. Nevertheless, it is reasonable to assume that the risk for gallstone formation with weight loss dieting would be no greater than the 37.8% risk observed from a compilation of the two surgical series with ultrasound follow-up [37, 38]. Follow-up among the surgical patients was longer than among the diet-treated patients, but nearly all of the new cases of gallstones probably occurred within the first few months of surgery [38]. Further, the natural history of gallstones, once formed, is probably similar for diet-treated patients (24% symptomatic) and surgical patients (40% symptomatic).

To summarize the experience of the few clinical studies of weight loss dieting and gallstone formation, 12.1% of patients (47 of 390) developed gallstones during the 8 to 16 weeks of supervised very low calorie diets or shortly thereafter. This risk was less than that found after gastric bypass surgery, in which gallstones developed in 37.8% (42 of 111) of patients within 12 to 18 months of follow-up. Most persons developed gallstones concurrent with dietary therapy or with the period of greatest weight loss after gastric bypass surgery. The probability of gallstone formation during these periods was much higher than that expected of equally obese persons who were not losing weight. Approximately one third of patients on a diet and those who were surgically treated became symptomatic within a few months of gallstone formation. Among perhaps half of the asymptomatic patients, gallstones spontaneously disappeared within 1 to 2 years. From these few studies, a rough estimate of the probability of the development of symptomatic gallstones would be about 4% to 6% within 6 months to a year of the initiation of substantial weight loss. However, this estimate is largely determined by the results of one large study in which only 10.9% of dieting patients developed gallstones [32].

Unlike the studies noted above, it has not been standard practice to screen patients with ultrasonography before starting a very low calorie diet. Thus it is of clinical importance to know the risk for symptomatic gallstones after a very low calorie diet, excluding only those patients with a self-report of gallstones. In one study, symptomatic gallstones developed among 15 of 146 patients (11%) within 6 months of concluding a 16-week, 605 kcal/d diet (mean weight loss of 20.6 kg) [42]. Eight of these symptomatic patients had cholecystectomy; gallstones resolved spontaneously in three.

The physiologic effects of hypocaloric diets on obese persons have been examined in a few studies. The cholesterol saturation index increased on average in some studies [31, 43, 44], but results among individual patients have varied considerably, with the occurrence of both large increases and decreases during weight loss [16, 18, 45, 46]. The effects of very low calorie and low fat diets on biliary lipid composition depend on the balance of increased hepatic uptake of cholesterol, diminished dietary intake of cholesterol, and changes in hepatic cholesterol synthesis and bile acid secretion [18, 45]. As a result, the biliary lipid pattern may become more favorable to gallstone formation during a hypocaloric diet, but this is not a universal effect. Contrary to the mixed findings with low calorie diets, the cholesterol saturation index decreased among nearly all patients during a fast of at least several days [18, 45]. In addition, with weight stabilization after a hypocaloric diet, the cholesterol saturation index decreased to a level lower than the level before weight loss, primarily a result of diminished cholesterol secretion [16, 18]. Nucleation time decreased during weight loss [44] concurrent with an increase in bile glycoprotein concentration [47, 48]. Very low calorie, low fat diets may also have increased fasting and residual gallbladder volumes among the obese, consistent with gallbladder hypomotility [24]. The diets that have been associated with gallstone formation in most clinical studies did not have enough fat or protein to maximally stimulate gallbladder contraction [22, 49, 50].

Risk Factors for Gallstones with Weight Loss

Only one study has been of sufficient size to evaluate risk factors for gallstone formation during treatment with a very low calorie diet [32]. After 16 weeks of dieting, 27 of 248 persons developed gallstones (Table 1). Both a high absolute rate of weight loss and high initial BMI predicted the development of gallstones. The increased risk for gallstones with higher BMI was attenuated somewhat by controlling for weight loss and was only found among men. In this as in many weight loss studies, absolute weight loss was positively correlated with baseline BMI. Therefore, it was difficult to determine if absolute weight loss was acting independently of initial BMI. Relative weight loss, on the other hand, was only weakly correlated with initial BMI but was strongly associated with an increased risk for gallstones. Gallstones occurred among 21.9% of those who lost more than 24% of body weight but among less than 7% of those who lost less weight (Figure 1). Because the duration of the diet was nearly the same for all patients, it was not possible to determine whether the rate of weight loss or degree of weight loss was the more important factor in the formation of gallstones. Men had a higher cumulative incidence of gallstones (19.0%) than women (8.4%), but this was accounted for by greater weight loss and higher initial BMI among men. High serum triglyceride concentrations were associated with the development of gallstones among women. In addition to a strong positive association of serum triglyceride concentration with gallstones noted in ultrasonographic surveys [7, 8], this finding was presaged in a review of hyperlipidemia and biliary lipids that had suggested that "more information is needed with regard to weight reduction in moderately overweight, hypertriglyceridemic individuals" [51]. The study of gallstone risk factors in weight loss found that baseline characteristics could identify only 3 of the 25 patients who developed gallstones; however, 3 of the 4 patients who were predicted to develop gallstones did so.

If persons on weight reducing diets eat fewer meals and therefore increase overnight fasting periods, they may be at higher risk for development of gallstones. A U.S. population-based study found a doubling of incidence of hospitalization for gallstones among women who fasted overnight for more than 14 hours compared with women who fasted for 8 or fewer hours [30]. Fasting increases gallbladder bile lithogenicity and gallbladder volume [50, 52-55].

No data were presented in these or other studies on the risks for repeated dieting for the development of gallstones. No study has compared the risk for gallstones among weight loss diets differing in caloric content or nutrient composition. It is not known if weight loss due to increased physical activity has any effect on gallstone formation.

Prevention of Gallstones

Slower weight loss may produce fewer gallstones, but, as noted above, only one clinical study has evaluated this possibility [32]. The largest epidemiologic study found that women who reported losing at least 10 kg in a 2-year period had a higher incidence of gallstone diagnosis than did women who lost 4.0 to 9.9 kg [12]. However, this weight loss was not addressed in the context of dieting. Pharmacologic therapy during weight loss dieting has been evaluated in one clinical trial [31]. Of 18 patients treated with ursodeoxycholic acid (1200 mg/d), none developed gallstones; 2 of 14 patients treated with aspirin (1300 mg/d) developed gallstones; and 5 of 19 patients treated with placebo developed gallstones [31]. Weight loss among the three treatment groups was similar (mean, 20.9 to 25.0 kg). Compared with the placebo-treated group, only the ursodeoxycholic acid-treated group had statistically significant fewer gallstones develop. Bile acid therapy decreased cholesterol saturation during weight loss, an effect that is caused by decreased biliary cholesterol secretion [18, 31, 43, 56]. Although not statistically significant, the trend toward fewer gallstones in the aspirin-treated group raises hope that low-dose, inexpensive nonsteroidal anti-inflammatory drugs could prevent gallstones during weight loss. The somewhat arbitrary dose of aspirin chosen was several times that recommended for ischemic heart disease prevention and less than that used in therapy for rheumatologic conditions. By inhibiting the formation of prostaglandin E₂ in the gallbladder, nonsteroidal anti-inflammatory drugs may decrease the secretion of glycoproteins and may prolong nucleation time [31, 44, 47].

Preexisting Gallstones

Weight loss dieting increases the risk for gallstone formation. Whether biliary colic, acute cholecystitis, gallstone pancreatitis, and other serious complications of gallstones increase among persons with preexisting gallstones who are dieting to lose weight is unknown. No clinical variables, other than previous complications, predict complications of gallstones. Thus, although it may appear prudent to exclude persons with gallstones from participating in weight loss dieting, no evidence supports this approach.

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The increased risk for gallstone formation associated with weight loss raises the possibility of learning more about the causes of gallstone disease as well as several clinical issues. Of great importance is the need to define the factors during weight loss that lead to gallstone formation. Indeed, the high risk for developing gallstones during a short period of weight loss provides the most assessable human model to date for the study of gallstone pathogenesis and prevention. The development of an animal model of weight loss associated with gallstone formation could also be instructive for human cholesterol gallstone disease and should be actively sought.

Obese patients contemplating a weight-reducing diet, particularly a very low calorie diet, should be aware that they are at increased risk for developing symptomatic gallstones. The risk for developing gallstones needs to be defined for various diets composed of differing nutrient and caloric contents to evaluate whether diets with higher fat contents or more calories lessen the risk. Similarly, it could be determined if smaller, more frequent meals to decrease the fasting period would also lower the incidence of gallstones. Other risk factors for the occurrence of gallstones during voluntary weight loss should be defined. Preventive interventions might then be targeted toward persons who are at particularly high risk, such as hypertriglyceridemic patients with a BMI of more than 30 kg/m² who lose substantial weight during the first few weeks of dieting. Unfortunately, not enough data are available to make such a recommendation. Although ursodeoxycholic acid is an effective and safe drug, its use is impractical for most dieters. At a treatment cost of at least $4 per day for gallstone dissolution [57, 58], ursodeoxycholic acid prophylaxis during the course of a 16-week, very low calorie diet would add an additional $450 to the cost of the diet. It is not known whether a dose lower than that used to dissolve gallstones could prevent gallstones. Nevertheless, it would be valuable to determine the probability of symptomatic gallstones that would make bile acid therapy a cost-effective choice. Unlike ursodeoxycholic acid, some nonsteroidal anti-inflammatory drugs are inexpensive and may be obtained without prescription. A clinical trial would be necessary to show efficacy and safety in light of the increased frequency of gastroduodenitis, gastroduodenal ulceration, and bleeding with these agents. A study of the effects of low calorie diets on persons with preexisting gallstones is also needed. Such a study would address the issue of safety of such a diet as well as potentially help define the natural history of asymptomatic gallstones.