Ursodeoxycholic acid is a bile salt that reduces cholesterol secretion into bile and improves biliary cholesterol solubility. It is used to dissolve cholesterol gallstones [19-22]. Its properties have led to the hypothesis that it could prevent the formation of cholesterol gallstones in certain high-risk populations. Two previous studies showed that ursodeoxycholic acid could reduce the incidence of gallstone formation in persons participating in a very-low-calorie diet program [12] and after bariatric surgery [18]. These preliminary reports inspired two multicenter, randomized, double-blind, placebo-controlled trials to determine the optimum dose at which ursodeoxycholic acid could prevent gallstone formation in patients having rapid weight reduction. We evaluated approximately 1000 patients participating in a very-low-calorie liquid protein diet program. A similar study [23] done in parallel with ours evaluated the effects of ursodeoxycholic acid during weight reduction in more than 300 patients having proximal gastric bypass surgery at 10 surgical weight loss centers. Taken together, these studies clearly show that the prophylactic use of ursodeoxycholic acid is highly effective for the prevention of gallstone formation in patients having rapid weight reduction.

Methods

Top Methods Results Discussion Author & Article Info References

Patients

We recruited patients from 31 Health Management Resources-affiliated diet centers throughout the United States that agreed to collaborate in this trial. All patients at these centers were informed of the risk for gallstone formation while dieting and were asked whether they would participate in a study to prevent gallstone formation. To be accepted into this trial, all patients had to 1) have a body mass index of 38 kg or more; 2) be between 18 and 70 years of age; 3) be willing to participate in the Health Management Resources very-low-calorie diet plan for 16 weeks; and 4) have normal serum potassium and calcium levels. Women of childbearing age had to have a negative serum pregnancy test result. Patients were excluded from the study if they had any one the following: 1) previous cholecystectomy; 2) gallstones or gallbladder sludge on ultrasonogram; 3) hypersensitivity to bile acids or eggs; 4) a history of hypothyroidism or the Cushing syndrome; 5) an eating disorder or other psychological problem that would interfere with participation in the diet program; 6) use of oral bile salt preparations, aluminum-based antacids, or lithium; 7) long-term use of nonsteroidal anti-inflammatory agents (including aspirin) or antihyperlipidemic agents [including cholestyramine] within 2 weeks of entering into the trial; and 8) a total bilirubin level of more than 2.0 mg/dL, a serum creatinine level of more than 2.0 mg/dL, or an alanine aminotransferase level of more than 133 µkat/L. Diuretic therapy had to be discontinued at least 1 day before trial entry.

A total of 1004 consecutive patients who met all entry criteria and agreed to participate were enrolled in the trial. The study was approved by the human investigations review committee at each of the participating centers and by the medical review boards of Health Management Resources, Inc., and Ciba-Geigy Pharmaceutical Company. Informed consent was obtained from all participants before study entry.

Study Design

If a patient met all entry criteria and agreed to participate in the study, a baseline ultrasonogram of the gallbladder was obtained and all exclusion criteria were reviewed. If gallstones, gallbladder sludge, or both were identified, or if any other exclusion criteria were present, the patient was not entered into the trial. All other patients were entered into the study and randomly assigned to receive either placebo, 300 mg of ursodeoxycholic acid once daily, 600 mg of ursodeoxycholic acid in two divided doses daily, or 1200 mg of ursodeoxycholic acid in two divided doses daily. Blocks of four patients at each of the 31 centers were used in the randomization. Treatment groups were blinded using a double-dummy technique. All patients were provided with two coded medication bottles (one for the morning and one for the evening); each bottle contained either placebo or ursodeoxycholic acid in capsules that were identical in appearance. Patients were instructed to take two pills from the morning bottle and two pills from the evening bottle daily. Thus, each patient took two capsules twice daily. Each patient began taking coded medication on the first day that he or she began the Health Management Resources diet plan and continued to take it throughout the entire 16-week program.

The Health Management Resources diet was a 520-kcal/d liquid protein diet containing 50 g of protein, 79 g of carbohydrate, and 1 to 3 g of fat (depending on the particular preparation selected). All patients consumed this diet 3 to 5 times daily for 16 weeks and were instructed not to consume any other food. Supplements providing 100% to 150% of the U.S. recommended daily allowance of vitamins and minerals were supplied for each patient. Consumption of noncaloric fluids (water and diet or club sodas) was not limited. Each patient was evaluated biweekly throughout the study. At each visit, body weight and all adverse experiences that had occurred since the previous visit were recorded. Patients were instructed to return all medication bottles and unused medications to their study center. Compliance with study medication was assessed by pill count.

Gallbladder ultrasonography was repeated after 8 weeks of dieting and after 16 weeks of dieting or termination from the trial, or both. Gallstones and gallbladder sludge were defined using standard and well-accepted criteria [24]. Radiologists from each of the 31 participating centers met and agreed to these criteria before the start of the study. Although the radiologists were aware that the patients were participants in this study, they were blinded to the particular group to which each patient had been assigned. The reading of the radiologist at each site was considered final, and these findings were not reviewed by a single central radiologist. If a patient was found to have developed one or more gallstones, his or her participation in the trial was complete. No further weight loss data were collected from these patients as part of the trial. Gallbladder sludge was not considered a primary end point. Patients who developed sludge were informed of this and were continued in the trial.

Bile Analysis

Thirty-two patients from a single Health Management Resources center (Austin Diagnostic Center, Austin, Texas) volunteered to participate in bile analysis. Each of these patients had endoscopy to obtain bile for analysis before starting the diet and at the completion of the trial. All patients had routine upper endoscopy while under conscious sedation (midazolam, 2 mg to 4 mg) in the morning, after an overnight fast. The tip of the endoscope was advanced into the second portion of the duodenum, and the ampulla of Vater was visualized. An intravenous dose of sincalide (Kinevac, 0.02 to 0.06 µg/kg) was then administered to stimulate gallbladder contraction. As bile entered the duodenum, it was aspirated through the suction port of the endoscope and collected.

Bile samples were immediately centrifuged at 25 000 g for 30 minutes, and a sample of the sediment was examined for cholesterol crystals with a polarizing microscope (magnification, x 400). The supernatant was frozen for later analysis by the primary investigator.

All bile samples were thawed and analyzed as a single batch. Total phospholipid levels were determined by the method of Bartlett [25]. Cholesterol was determined in whole bile after appropriate dilution with an assay kit (Sigma Chemical Co., St. Louis, Missouri). The bile salt composition of each bile sample was determined using reverse-phase, high-performance liquid chromatography in a Waters model 600 system (Waters Chromatography, Milford, Massachusetts) as described previously [26]. The percentage of total bile acids that were conjugates of ursodeoxycholic acid (tauro-plus glyco-) was assessed. The cholesterol saturation index of each bile sample was calculated from tables developed by Carey [27] using the computer program of Kuroki and colleagues [28]. Four patients did not have enough bile collected to allow paired analysis of cholesterol saturation and assessment of the percentage of ursodeoxycholic acid.

Statistical Analysis

The Ciba-Geigy Pharmaceutical Company was responsible for overseeing data collection and data analysis. The sample size for this study was calculated to be 113 patients per study group (n = 452). This was calculated using an overall significance level of 0.05 to assure an 80% power to detect a difference between an estimated 20% incidence for gallstone formation in the placebo group and a 5% incidence in the ursodeoxycholic acid treatment groups. Because the drop-out rate of persons in diet programs is known to approach 50%, a sample at least 2.25 times larger than the estimate was enrolled.

All patients with a normal baseline gallbladder ultrasonogram and at least one ultrasonogram after baseline were included in the final data analysis. A total of 216 patients withdrew prematurely from the trial without having an ultrasonogram after baseline. Thus, 788 patients were included in the final data analysis. All data presented in this report were derived from the evaluation of these 788 patients. Data from each patient group are expressed as mean ±SD. Body mass index is expressed as kg/m². The chi-square test was used to determine whether the rates of gallstone and gallbladder sludge formation in the various treatment groups differed significantly. The Bonferroni procedure was used to adjust for multiple comparisons. Differences in the cholesterol saturation index and in the percentage of ursodeoxycholic acid in bile samples from the four study samples were evaluated using analysis of covariance. The Dunnett procedure was used for multiple comparisons between the treatment and placebo groups. The Tukey-Krammer procedure was used to compare the three treatment groups.

Results

Top Methods Results Discussion Author & Article Info References

Patients

A total of 1004 patients were enrolled in the trial. Of these, 216 were not included in the final data analysis. Four of the 216 were excluded because they had gallstones or gallbladder sludge on their initial ultrasonogram; 2 were excluded because they had not had a baseline ultrasonogram; and 210 were excluded because they did not have any follow-up ultrasonograms. The remaining 788 patients all had at least one follow-up ultrasonogram and were included in the final analysis. Six hundred of the 788 completed the 16-week diet program.

Of the 1004 patients enrolled in the trial, 404 withdrew prematurely. The major reason for early termination was voluntary withdrawal from the diet program (n = 255 [25.4%]). The percentage of patients who voluntarily withdrew from the trial did not differ among any of the four treatment groups (23% of patients receiving placebo, 28% of patients receiving 300 mg/d of ursodeoxycholic acid, 25% of patients receiving 600 mg/d of ursodeoxycholic acid, and 26% of patients treated with 1200 mg/d of ursodeoxycholic acid). Gallstone formation was the second most common reason for premature withdrawal (n = 52 [5.2%]). Thirty-one other patients developed gallstones; these were seen on the final ultrasonogram after completion of the 16-week diet program. Compliance with study medication for all patients in the trial was 93.6%. No differences were evident among the four patient groups. Only 17 (1.7%) patients were lost to follow-up; the number of patients lost to follow-up was similar in all groups.

Ursodeoxycholic acid was well tolerated: Only 18 (1.8%) patients withdrew from the trial because of adverse experiences (5 of these had received placebo and 13 had received ursodeoxycholic acid). The frequency of reported adverse experiences was similar in patients receiving placebo and in patients receiving ursodeoxycholic acid and was unrelated to dose. The most common adverse experiences were constipation (26% of those receiving placebo; 27% of those receiving ursodeoxycholic acid), headache (30% of those receiving placebo; 27% of those receiving ursodeoxycholic acid), diarrhea (24% of those receiving placebo; 23% of those receiving ursodeoxycholic acid), dizziness (16% of those receiving placebo; 17% of those receiving ursodeoxycholic acid), and upper respiratory infections (13% of those receiving placebo; 16% of those receiving ursodeoxycholic acid).

The age, sex, and race of the members of the entire study sample (788 patients included in and 216 patients excluded from the final analysis) are presented in Table 1. Overall, 66% of the patients in the trial were women and 88% were white. The mean age was 40.1 years (range, 18 to 68 years). No significant differences were seen with regard to sex, race, or age among any of the groups. Of the 669 women enrolled in the trial, 18% were using oral contraceptives or were receiving postmenopausal estrogen therapy. No differences in the rate of estrogen use were seen among any of the treatment groups.

Weight Reduction on the Diet Program

As noted above (see Methods), patients were withdrawn from the trial when they developed gallstones. Thus, patients who did not develop gallstones remained in the diet program longer and lost more weight, on average, than patients who did develop gallstones. Because measurements of absolute weight loss were biased by this study design, differences in weight loss among patient groups were evaluated by analyzing the rate of weight loss and the rate of loss in body mass index (Table 2).

Maximum weight loss and maximum decrease in body mass index for all patients participating in the diet trial were 24.9 kg ±9.9 kg (range, 3.2 kg to 60.5 kg) and 8.6 kg/m² ±3.0 kg/m² (range, 1 kg/m² to 18 kg/m²), respectively. These variables did not differ appreciably among any of the four study groups. Rate of weight loss averaged 5.8 kg/month ±2.6 kg/month (range, –0.9 kg/month to 14.5 kg/month). On average, all patients had a decrease of 4.6% ±1.9% in their initial body mass index per month during the diet program (range, 3.3% to 9.4%). No differences in rate of weight loss or percentage rate of loss in body mass index existed between the four study groups.

Gallstone Formation during Weight Reduction

The percentage of patients who developed gallstones during this trial is shown in Figure 1. Overall, 57 of 202 (28% [CI, 22% to 35%]) patients who received placebo developed gallstones within 16 weeks of starting the diet plan. In contrast, gallstones formed in only 15 of 185 patients (8% [CI, 5% to 13%]) treated with 300 mg/d of ursodeoxycholic acid, 7 of 201 (3% [CI, 1% to 7%]) patients treated with 600 mg/d of ursodeoxycholic acid, and 4 of 200 (2% [CI, 0.5% to 5%]) patients treated with 1200 mg/d of ursodeoxycholic acid. The rate of gallstone formation was significantly lower in the groups treated with ursodeoxycholic acid than in the group receiving placebo. In addition, the incidence of gallstone formation was significantly lower in patients treated with 600 mg/d (P = 0.05) or 1200 mg/d (P < 0.01) of ursodeoxycholic acid than in patients treated with 300 mg/d of ursodeoxycholic acid. No significant difference in gallstone formation was seen between patients treated with 600 mg/d and those treated with 1200 mg/d of ursodeoxycholic acid.

View larger version (24K): [in this window] [in a new window]   Figure 1. Percentage of patients who developed gallstones during the diet program. The fractions above each bar indicate the number of patients who developed gallstones in each group over the total number of patients in each group. Solid bars represent men; open bars represent women. Values for all doses of ursodeoxycholic acid in both men and women were significantly lower than those for placebo. For women, values for the 600 mg/d dose of ursodeoxycholic acid were significantly lower than those for the 300 mg/d dose. UDCA = ursodeoxycholic acid.

The mean time from the onset of dieting to the development of gallstones was 76.2 days (range, 42 days to 133 days). This time did not differ among the four treatment groups; that is, patients who received placebo did not develop gallstones in less time than patients receiving ursodeoxycholic acid. Similarly, men and women did not differ in time to development of gallstones. However, because ultrasonographic studies were done only at 8 and 16 weeks (except in those patients who had ultrasonography when they voluntarily left the trial), time to development of gallstones should be considered only a rough estimate.

Gallbladder sludge alone, without gallstone formation, was seen in 7% of patients receiving placebo and 3% of patients treated with ursodeoxycholic acid. No difference in the incidence of gallbladder sludge was apparent between patients receiving placebo and those receiving ursodeoxycholic acid. Similarly, the rate of sludge formation did not differ among any of the ursodeoxycholic acid treatment groups. The formation of gallbladder sludge was not a primary end point in this trial. All patients who developed gallbladder sludge before 16 weeks remained in the trial and continued with the diet program.

Relation between Initial Body Weight and Gallstone Formation

The effect of initial body weight on the incidence of gallstone formation during weight reduction was examined in patients receiving placebo. This examination could not be done for patients treated with ursodeoxycholic acid because too few of these patients developed gallstones (26 of 586). No relation existed between initial body weight and gallstone formation. Gallstones developed in 27% of patients who weighed less than 109 kg (240 lbs) before dieting; in 29% of patients who weighed 109 kg to 127.3 kg before dieting; in 30% of patients who weighed 127.4 kg to 145.5 kg before dieting; and in 26% of patients who weighed more than 145.5 kg (320 lbs) before dieting.

Relation between Gallstone Formation and Weight Reduction

The relation between the rate of weight reduction and gallstone formation for both men and women is shown in Figure 2. As noted above, because so few patients receiving ursodeoxycholic acid developed gallstones, no relation between the rate of weight reduction and gallstone formation could be detected. Thus, Figure 2 shows data collected only from those patients who received placebo. In women, the incidence of gallstone formation increased with the rate of weight loss (Figure 2, top). Only 9% (CI, 3% to 20%) of women who lost 0 kg to 4.5 kg per month (0 lbs to 10 lbs) developed gallstones. This increased to 32% (CI, 20% to 46%) in women who lost more than 4.5 kg to 6.8 kg per month (> 10 lbs to 15 lbs); to 65% (CI, 43% to 84%) in those who lost more than 6.8 kg to 9.1 kg per month (> 15 lbs to 20 lbs); and to 100% (CI, 29% to 100%) in women who lost more than 9.1 kg per month (20 lbs) with this diet program. For women, the relation between gallstone formation and the rate of weight loss was significant. No gallstones developed in two women who gained weight during the trial.

View larger version (22K): [in this window] [in a new window]   Figure 2. Weight loss, body mass, and gallstone formation. Fractions above each bar indicate the number of patients who developed gallstones in each group over the total number of patients in each group. Solid bars represent men; open bars represent women. Top. Relation between the rate of weight loss and gallstone formation in patients treated with placebo. The stepwise increase seen in women was significant. No significant relation between rate of weight loss and gallstone formation was present in men. Bottom. Relation between the percentage decrease in body mass index and gallstone formation in patients treated with placebo. BMI = body mass index.

When gallstone formation was analyzed with respect to the percentage decrease in body mass index per month, a similar pattern was seen (Figure 2, bottom). The rate of gallstone formation increased stepwise with decreasing body mass index per month in women but not in men.

Bile Analysis

Cholesterol crystals developed in 25% of patients (2 of 8) receiving placebo. No crystals developed in patients treated with ursodeoxycholic acid, regardless of dose. No significant changes in cholesterol saturation index were seen during the diet program in any of the four treatment groups. The mean cholesterol saturation index increased by only 0.03 ±0.53 in the placebo group. In contrast, the mean cholesterol saturation index decreased by 0.52 ±0.86 in patients treated with 300 mg/d and by 0.21 ±1.14 in patients treated with 1200 mg/d of ursodeoxycholic acid. These differences were not significant.

No significant change in the percentage of ursodeoxycholic acid in the bile pool was seen in patients receiving placebo. In contrast, the percentage of ursodeoxycholic acid increased stepwise with increasing doses of ursodeoxycholic acid as follows: 14.0% ±11.3% for 300 mg/d, 21.3% ±14.2% for 600 mg/d, and 33.6% ±21.6% for 1200 mg/d. This increase was significant (P < 0.05).

Discussion

Top Methods Results Discussion Author & Article Info References

We have shown that prophylactic use of ursodeoxycholic acid during dieting significantly reduced the incidence of gallstone formation in both men and women. Gallstones developed in 28% of patients receiving placebo compared with just 8% of patients treated with 300 mg/d of ursodeoxycholic acid and 3% of patients treated with 600 mg/d of ursodeoxycholic acid. No further reduction in gallstone formation was seen in patients treated with 1200 mg/d of ursodeoxycholic acid. Thus, the optimum dose for gallstone prophylaxis appears to be 600 mg/d; that is, 4 to 5 mg/kg. This is approximately one half the dose used for the dissolution of cholesterol gallstones [20, 21] and one third that used to treat cholestatic disorders [29].

Obesity and rapid weight reduction are well accepted risk factors for the development of gallstones. Several epidemiologic studies have shown that the prevalence of gallstone disease increases with increasing body weight, increasing body mass index, or both [5-9]. Studies by Broomfield and coworkers [12] and Liddle and colleagues [13] have shown that approximately 25% of persons who did not previously have gallstones formed them in as little as 16 weeks while participating in very-low-calorie, liquid-protein, weight loss diets. These diets contained 0 to 2 g fat per day and were similar to the diet used in this study. In contrast, a recent uncontrolled trial suggested that diets containing increased calories and fat reduce the risk for gallstone formation during dieting [30]. Larger trials are needed to confirm this important finding.

Gallstone formation has also been seen in patients after surgical weight loss procedures [15-18, 23]. The most well-studied of these procedures is the Roux-en-Y gastric bypass. Approximately 25% to 35% of patients with morbid obesity develop gallstones within 6 months of having this procedure [15, 17, 23]. Of these patients, 10% to 20% eventually become symptomatic and require subsequent cholecystectomy [15, 31]. More recent studies have shown that patients having vertical banded gastroplasty have a similarly increased risk for gallstone formation [18].

Ursodeoxycholic acid is a naturally occurring bile salt preparation frequently used and well tolerated for the dissolution of cholesterol gallstones [19-22]. Broomfield and colleagues [12] were the first to suggest that ursodeoxycholic acid could be effective for the prevention of gallstones in a high-risk population; for example, in patients having diet-induced weight reduction. Similarly, Worobetz and coworkers [18] suggested that ursodeoxycholic acid could be effective prophylaxis against gallstone formation in patients having bariatric surgery. In a multicenter, randomized, double-blind, placebo-controlled study conducted in parallel to our trial, more than 300 patients having proximal gastric bypass surgery were treated with placebo or with 300 mg/d, 600 mg/d, or 1200 mg/d of ursodeoxycholic acid [23]. Gallstones developed in 32% of patients receiving placebo compared with 13% of patients receiving 300 mg/d, 2% of patients receiving 600 mg/d, and 6% of patients receiving 1200 mg/d of ursodeoxycholic acid. As in our trial, the optimum dose for gallstone prophylaxis in the surgically induced weight loss study was 600 mg/d.

Several factors are thought to be important in the pathogenesis of cholesterol gallstones. These include supersaturation of bile with cholesterol, reduction in gallbladder motility, and enhanced nucleation of cholesterol from supersaturated bile [32, 33]. The first two of these three factors have both been implicated in the pathogenesis of gallstones during weight reduction [34, 35]. Although we saw no significant change in cholesterol saturation index for patients receiving placebo, previous studies have shown that both secretion of cholesterol into bile and the cholesterol saturation index increase during weight reduction [12, 34, 36]. A reduction in gallbladder motility also occurs when patients consume a low-calorie diet, especially when the diet contains less than 10 g of fat per day [35]. Gallbladder motility is also significantly reduced after gastric surgery [37], and this may contribute to gallstone formation in patients having proximal gastric bypass surgery. The manner by which ursodeoxycholic acid prevents gallstone formation during weight reduction remains unclear. Ursodeoxycholic acid reduces cholesterol secretion into bile and may therefore reduce the cholesterol saturation index of bile [19-22]. Although this was not seen in our trial, such findings have been seen in previous weight reduction studies [12, 36]. It is also possible that ursodeoxycholic acid may affect the nucleation of cholesterol from bile by altering nucleation factors. One potential nucleation protein, gallbladder mucin, increases during dieting [12, 36] and after bariatric surgery [26, 31]. It has been suggested that therapy with ursodeoxycholic acid during dieting may prevent this increase in biliary glycoproteins [12]. In contrast, treatment with ursodeoxycholic acid increases gallbladder volume and prolongs gallbladder emptying [38]. Other, as yet unexplored, processes may further contribute to the effectiveness of ursodeoxycholic acid for gallstone prevention.

Gallbladder sludge is an entity distinctly different from gallstones. It was initially thought to be a precursor to gallstone formation, but subsequent studies have clearly shown that it is typically a transient phenomenon that does not lead to gallstone formation in most patients [39]. The formation of gallbladder sludge is associated with prolonged fasting and with a lack of gallbladder mobility [40, 41]. In our study, gallbladder sludge without gallstones developed in 2% to 3% of patients treated with ursodeoxycholic acid. This incidence was somewhat smaller than that in patients receiving placebo.

One limitation of our study was the lack of long-term follow-up after patients completed the diet program and ursodeoxycholic acid prophylaxis. Thus, it is impossible to know whether the beneficial effects of ursodeoxycholic acid were long-lasting or whether gallstones developed after treatment was discontinued. Such long-term follow-up was done in the study by Sugerman and colleagues [23] in a few patients who had had gastric bypass surgery. In this study, an additional 46% of patients receiving placebo developed gallstones or gallbladder sludge 6 to 12 months after gastric bypass surgery (6 months after the completion of ursodeoxycholic acid prophylaxis). This value was significantly greater than that for patients who received ursodeoxycholic acid prophylaxis for 6 months after this surgical procedure (14%). This suggests that short-term treatment with ursodeoxycholic acid during the period of greatest risk for gallstone formation could reduce the risk for subsequent gallstone formation. Further studies about this possibility are indicated.

Approximately 12% of the U.S. population and 18% of women in the United States have gallstones [1, 2]. Most of these persons have well-defined risk factors for developing gallstones, including obesity and a history that includes participation in weight-reduction dieting and pregnancy [1, 4-6]. Despite early predictions, laparoscopic cholecystectomy has not lowered the cost of caring for patients with symptomatic gallstones [42]. Rather, the widespread acceptance of this technique has only increased the number of these procedures done annually and the health care expenditures associated with caring for patients with gallstone disease [43]. Gallstone dissolution using ursodeoxycholic acid has been shown to be a cost-effective method for the treatment of cholesterol gallstones in certain populations [44]. If shown to have a long-lasting effect, prophylaxis against gallstone formation with ursodeoxycholic acid during well-defined high-risk periods (such as those after weight loss and after giving birth) has the potential to reduce health care costs associated with the treatment of gallstones and their complications.

Presented in part at Digestive Disease Week, the annual meetings of the American Gastrointestinal Association, and the American Association for the Study of Liver Diseases, New Orleans, Louisiana, 15 May 1994.

Appendix

The following persons were responsible for conducting trials at the Health Management Resources-affiliated weight loss centers listed: J.W. Anderson, MD, Lexington, Kentucky; M.P. Basista, MD, Bloomfield, New Jersey; L.J. Bennion, MD, Sunnyvale, California; G.A. Charnock, MD, Valencia, California; R.P. Chiles, MD, Austin, Texas; J.B. Collins, MD, Spokane, Washington; R.L. Cullen, MD, Norfolk, Virginia; D.P. Derleth, MD, Wenatchee, Washington; J.L. Early, MD, Peoria, Illinois; S.C. Fox, MD, Hackensack, New Jersey; M. Gottlieb, MD, Chestnut Hill, MA; A.M. Gundry, MD, Long Beach, California; E. Gutowitz, MD, La Mesa, California; G.J. Hotchko Jr., MD, Yakima, Washington; I. Jackson, MD, Providence, Rhode Island; R.E. Kleinmann, MD, Charlotte, North Carolina; D. Kremer, MD, Portland, Oregon; J.D. Mancini, MD, Winter Park, Florida; T.A. McAfee, MD, Seattle, Washington; R.B. Miller, MD, Palm Springs, California; D.J. Morin, MD, Bristol, Tennessee; T.J. Meyers, MD, Houston, Texas; L.B. Nilsen, MD, Phoenix, Arizona; E.B. Noland, MD, Salem, Virginia; J. Saxton, MD, San Francisco, California; V. Skul, MD, Chicago, Illinois; A. Sussman, MD, Renton, Washington; M. Thompson, MD, Redondo Beach, California; G.R. Weine, MD, Morristown, New Jersey; J.H. Wheeler, MD, Atlanta, Georgia; and J.W. Wright, MD, Lynchburg, Virginia.