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Original Research |
Department of Pediatrics, Columbia University, New York (L.L.W., M.C.B., L.C.), New York
Child Health Center, AHF, Valhalla (B.A.S., L.B.), New York
Address reprint requests to: C.L. Williams, M.D., M.P.H., Department of Pediatrics, Columbia University, 630 West 168th Street, New York, NY 10032.
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ABSTRACT |
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 TOPFOOTNOTES ABSTRACT INTRODUCTIONMETHODSRESULTSREFERENCES |
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Methods: The present study was a 13 week open cross-over study designed to evaluate the effects of plant stanol ester in healthy two to five year old preschool children. After a one week lead-in, eligible children were randomly assigned to begin with either Diet Phase A (plant stanol ester) or Phase B (wheat bran fiber). Each diet phase was four weeks long, followed by a two-week wash-out, and then cross-over to the alternate diet. During Diet Phase A children consumed three eight-gram servings of a spread, each containing one gram of plant stanols, for total daily dose of three grams. During Diet Phase B, children added five grams of dietary fiber to their diet for the first two weeks and then ten grams for the second two weeks.
Results: Overall, for the whole study group, plant-stanol-ester spread use yielded a decrease in total cholesterol of 19.9 mg/dL (12.4% reduction from baseline) and a 14.6 mg/dL decrease in LDL cholesterol (15.5% reduction from baseline). There were no significant changes in HDL-cholesterol or triglyceride levels. A predominately insoluble dietary fiber supplement derived from wheat bran, as expected, yielded a small but non-significant decrease in total cholesterol of 6.1 mg/dL, a four percent reduction from baseline.
Conclusions: Results demonstrated that preschool age children could adhere to a program requiring consumption of three daily servings of spread containing plant stanol ester and that this level of consumption resulted in a significant decrease in total cholesterol and LDL cholesterol after a four week period. In addition, consumption of plant stanol ester was not associated with any short-term adverse health effects.
Key words: plant stanol esters, children, lipids, fiber
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INTRODUCTION |
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TOPFOOTNOTESABSTRACTINTRODUCTIONMETHODSRESULTSREFERENCES |
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The treatment of choice for hypercholesterolemia in childhood is dietary modification: initially the NCEP Step I diet and, subsequently, the Step II diet. In both diets, decrease of saturated fat and dietary cholesterol is emphasized, along with control of total fat calories and balance of fatty acid intake (Table 1) [1]. Since pharmacologic treatment is generally reserved for children and adolescents over 10 years of age with severe hypercholesterolemia (LDLC of 190 mg/dl or greater) [1–4], the vast majority of children with mild or moderate hypercholesterolemia will be candidates only for non-pharmacologic therapy. For this reason, there is significant interest in dietary supplements which may safely and effectively enhance the cholesterol-lowering effects of the NCEP Step I and Step II diets. Candidates for such dietary supplements have included soy protein, garlic, dietary fiber and plant stanols [5]. It is recommended, however, that all Americans over two years of age follow a fat-modified "heart healthy" NCEP Step I diet, since a population approach in which the mean total cholesterol level in the whole population is shifted downward even slightly will have the greatest impact on reducing overall cardiovascular disease mortality [6].
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METHODS |
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TOPFOOTNOTESABSTRACTINTRODUCTIONMETHODSRESULTSREFERENCES |
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The study was conducted as an open, two period cross-over design, with random assignment to one of two dietary treatment sequences: A/B or B/A. Children in the A/B group consumed the plant stanol supplement first and crossed over to the dietary fiber supplement second, while children in the B/A group followed the reverse order. Dietary treatment A consisted of four weeks of supplemental plant stanols, while dietary treatment B consisted of four weeks of supplemental dietary fiber. Subjects were randomly assigned to either the A
B (A/B group) or BA (B/A group) sequence. Treatments were separated by a washout period of two weeks. Diet Phase A consisted of a four-week period during which children consumed a Plant Stanol Ester-containing spread (BenecolTM provided by McNeil Consumer Healthcare, Ft. Washington, PA) as a substitute for their usual spread. The goal was for children to consume three eight-gram servings of the test spread, with each eight-gram serving containing one gram of plant stanols (1.5 grams of plant stanol ester). Total daily consumption was approximately three grams of plant stanols. Specific instructions on use and storage of the spread were provided to parents, and parents were asked to save and return used containers. Diet Phase B consisted of four weeks during which additional dietary fiber was consumed. During the first two weeks of Phase B, children consumed one serving of Raisin Bran (1.4 ounces of bran flakes and 0.4 of an ounce of raisins; 3/4 of a cup of cereal; five grams dietary fiber). During the second two weeks of Phase B, children consumed two servings of Raisin Bran daily (10 grams of dietary fiber). The cereal was provided by the Kellogg Company (Battle Creek, MI). Parents were asked to save and return empty or unused cereal boxes.
Parents were instructed to keep records of the child’s daily diet intake, diary of spread use and bowel movements. Parents were each provided with a scale (Sunbeam Digital Scale, No. 6025) and instructed on collecting and weighing stools on specified days. Baseline measures of stool weights were obtained on Days 6 and 7 of the first week. Both average and total stool weight at baseline (Days 6 and 7) were similar in both treatment groups; however, children in the A/B group passed slightly fewer stools per day than the B/A group (1.16 vs. 0.92/day; p<.05). Height, weight, blood pressure, heart rate and skinfold measures were also assessed at baseline as well as at the completion of each diet phase and final follow-up visit.
Total Cholesterol, HDL-Cholesterol and Triglycerides
were measured in the morning after an overnight fast of about 12 hours. LDL-cholesterol was calculated using the Friedewald formula. Although studies indicate that fasting and non-fasting levels of total and HDL-cholesterol do not differ significantly [8], fasting blood samples were necessary to accurately measure triglycerides and calculate LDL-cholesterol. Capillary blood tests were performed because of the young age (ages two to five years) of the children and the need for multiple measurements throughout the 13-week study.
Cholesterol measurements were performed immediately after obtaining the blood sample using the Cholestech LDX Analyzer [9]. This instrument is one of the few fully automated desktop analyzers which can provide a lipid profile on a very small quantity of whole blood (35 uL), obtained by fingerstick. In addition to requiring far less blood than other desktop analyzers, the blood sample does not have to be microfuged to obtain plasma, requires a single cassette and provides results in five minutes with a printed hard copy of the data. With respect to accuracy, Cholestech results for TC, HDLC and triglycerides correlate highly with a standard laboratory method using serum, with correlation coefficients of .98, .97 and .99 respectively [10]. Both external and internal quality control procedures were employed. As part of routine testing procedures, internal quality control procedures were performed daily on each instrument prior to any tests being run. Multilevel quality control samples were assayed for the Cholestech LDX Analyzer, with determination of both accuracy and precision of the instrument.
Height and Weight
were determined with a highly accurate electronic scale with automatic calibration (Seca) [11], which was monitored for accuracy using standard weights. Height and weight were recorded twice for each child at each measurement time. Body Mass Index (kg/m2) was calculated for each child [12]. Skinfolds were measured at three sites (triceps, subscapular, and suprailiac) using the Lange skinfold caliper [13], and values were compared with age and race-specific values from NHANES III survey data [14]. These sites were chosen since they have been frequently measured in major epidemiologic studies of children; they include both peripheral and central sites, and they can usually be accessed without completely undressing the child. Measurements were made twice at each site. Blood Pressure was measured with the child in a seated position by a trained technician using a Dinamapp automatic blood pressure machine [15] and following a standard protocol. BP was measured twice (one minute apart) and the average of these values was calculated. First and fifth Korotkoff sounds were recorded as systolic and diastolic blood pressure respectively, in accordance with the latest National High Blood Pressure Education Task Force on BP measurements in children and adolescents [16].
Dietary Intake
was assessed by means of a 24-hour diet recall obtained from the child’s mother by a registered dietitian on a weekly basis throughout the study. Baseline and week-one recalls were obtained at the time of the clinic visit. Recalls for other weeks were obtained by a random unannounced telephone interview with the mother. The daily food diary kept by the parent was used as a starting point for the recall interview. A multiple pass technique was used, consisting of a first pass quick list (from the food diary), a second pass detailed description and a third pass review [17]. Dietary data was entered into the computer while conducting the recall interview with the parent and analyzed for nutrient content using the Minnesota Nutrient Data System (NDS) [18].
Statistical Analysis:
The Kolmogorov-Smirnov test procedure (SPSS, Ver 8.0) compared the observed cumulative distribution function for each blood lipid variable and stool weight both at the beginning and end of the interventions with the normal distribution. Since no distribution differed significantly from the normal distribution, paired sample t tests were used to compare the means of outcome measures.
For each child, the differences in total cholesterol between the diet phases and baseline were calculated, and t tests determined whether the means of these differences were statistically significant at the .05 level. In addition to looking at the effects of diet in the two study groups separately, the groups were combined and the measures for children in both groups at the end of the spread phase were compared to those at the end of the bran phase. Thus in matched pair t tests, each child’s measure at the end of the spread phase was compared to his or her value at the end of the bran phase.
It was estimated that a final sample size of 16 was required for the study, considering use of a cross-over design, matched pair t tests, anticipated treatment effects and standard deviations of the primary outcome variables. Five additional subjects were enrolled to assure an adequate final sample.
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RESULTS |
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TOPFOOTNOTESABSTRACTINTRODUCTIONMETHODSRESULTSREFERENCES |
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Consumption of Dietary Fiber was assessed by (1) review of the daily food records for consumption of Raisin Bran (RB) or RB products (cookies, muffins, bread) according to schedule and (2) diary of cereal use. By the end of the four weeks of dietary fiber supplement, there was no significant difference between the groups in the average amount consumed. Overall, 74% of the children consumed at least 30 grams of fiber a week during the first two weeks. During the second two weeks, 53% consumed at least 60 grams of fiber per week—averaging slightly less than the goal amount of 70 grams per week.
Dietary Intake:
Twenty-four hour dietary recalls were used to determine usual nutrient intake at Day 1 and Day 7. The differences for each nutrient was compared for these two baseline measures for Group A/B and Group B/A separately. Among 16 measures, the only significant difference between Day 1 and Day 7 was for beta-carotene consumption in group B/A. Thus, an averaging of nutrient intake on Days 1 and 7 was considered appropriate for baseline measures. There was no significant difference between Groups A/B and B/A at baseline for any of the 16 nutrient measures.
Fiber intake increased significantly for both groups A/B and B/A during their respective bran diet phases, increasing from a baseline of 7.71 g/d in group AB to 14.52 g/d after four weeks of bran supplement (p<.001), and similarly increasing from a baseline of 8.78 g/d in group BA to 16.20 g/d after bran supplementation (p<.001). Both groups demonstrated a significant increase in total calories at the end of the bran diet phase compared to baseline. Group A/B received significantly fewer of their calories from saturated fats during two weeks of the bran phase and in the last control week compared to baseline. They consumed significantly more carbohydrates at the end of the bran phase. Group B/A also consumed more carbohydrates at the end of their bran diet phase. Additionally, they increased their total fat and saturated fat consumption during the spread phase. However, this increase might have been independent of their use of spread since their total fat and saturated fat consumption continued to be significantly increased during the final two weeks of follow-up.
Consumption of iron, zinc, vitamin A and vitamin E increased significantly during some of the bran phase, while significant increases in vitamin A and vitamin E consumption were associated with plant stanol spread use in both AB and BA groups (Table 3). No significant decreases in vitamin or mineral consumption were associated with either diet phase in either group. Both bran and spread use was associated with an increase in energy intake and an increase in total fat consumed. With spread use, however, the additional fat consumed was from monounsaturated and polyunsaturated fatty acids, and not saturated fat. (Table 4)
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Body Weight:
There was no difference in amount of weight gained during the spread diet phases and the bran diet phases. While the 19 children were using spread, they gained an average of .56 pounds (sd=.71). When they were on the bran diet, they gained .30 pounds on average (sd=.72). These differences were not statistically significant (t=1.04, 18 df, p=.31).
Adverse Effects:
Seventeen of the nineteen children experienced at least one adverse event during the course of the study; thirteen (68%) reported at least one gastrointestinal event during the diet phases of the study (an eight week period). However, ten children (53%) experienced at least one gastrointestinal event during the non-diet phases (a five week period). Five children (26%) experienced five or more gastrointestinal events during the course of the study, four with more of the events occurring during the bran phase than the spread phase. In total, there were 23 gastrointestinal events reported during the spread phase and 46 gastrointestinal events occurring during the bran phase. Of the 46 events occurring during the bran phase, most (91%) occurred when the serving size was doubled. Overall, the frequencies for reported gastrointestinal symptoms were less than those observed at baseline.
Blood Lipids:
Baseline lipid measures were obtained on Day 1 and again on Day 7 prior to initiation of the first diet phase. Since neither A/B nor B/A groups showed significant differences between the Day 1 and Day 7 measures for total cholesterol or any other blood lipids, averages of the Day 1 and Day 7 measures were taken as baseline measures. Table 5 compares total cholesterol levels at baseline with those at the middle and end of each diet phase, the beginning and end of the wash-out phase and the post-treatment control period. The A/B group, who consumed plant stanol spread in the first diet phase, showed a statistically significant decrease in total cholesterol at the end of diet phase 1, Day 35. During the wash-out period, cholesterol levels rebounded close to the baseline level. At the end of the second diet phase and two weeks post-treatment, total blood cholesterol levels did not differ from the baseline level. This group clearly shows a decrease in total cholesterol associated with the use of spread and this effect does not persist when spread is no longer ingested. There was no demonstrable effect of the consumption of raisin bran cereal on total cholesterol.
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Triglycerides were significantly decreased in the A/B group in the middle of the spread phase (-27.6 mg/dL) and at the end of the raisin bran phase compared to baseline. Triglyceride levels in the B/A group were lower during the study weeks compared to baseline, but only significantly lower two weeks post-treatment. As with the A/B group, the B/A group experienced the largest drop in triglycerides (30.4 mg/dL) in the middle of the spread period. Taken together, there was no difference between the groups at Days 35 and 77 (t=.20, df=17, p=.84). Table 6 summarizes the overall effects of spread and raisin bran on blood lipids. The measures for children in both groups combined at the end of the spread phase are compared to those at the end of the bran phase. Thus, in matched pair t tests, each child’s measure at the end of the spread phase is compared to his or her value at the end of the bran phase. Total cholesterol and LDL were significantly lower at the end of the spread phase than at the end of the bran phase. There were no differences between bran and spread in HDL or triglycerides levels.
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Stool Measures:
Stool output was measured in terms of the average weight of the stools over the last two days of each week of the study and the number of bowel movements per week. The average stool weight was significantly different from baseline in both groups at the end of the respective bran diet phases after the bran supplement was doubled (Table 7). Group A/B also showed a statistically significant increase in stool weight compared to baseline at the end of the wash-out period following spread use, and in the middle of the bran phase, before the supplement was doubled. Taken together, the differences between the groups at Days 35 and 77, the ends of the diet phases, are significant, t=3.86, df=17, p=.001.
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Both dietary interventions were associated with increases in consumption of some vitamins and minerals. Participation in the bran intervention was associated with an increase in fiber and carbohydrate consumption as expected. The effect of the dietary interventions on consumption of saturated fat varied somewhat, however, between the AB and BA groups, and this difference appeared to reflect differing group patterns in use of whole versus low fat or skim milk with cereal.
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DISCUSSION |
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The most prevalent risk factors for CVD in the pediatric population include hypercholesterolemia, obesity, cigarette smoking, physical inactivity and elevated blood pressure. "Borderline high" cholesterol (170 to 199 mg%) affects approximately 30% of U.S. children, and "high" cholesterol (200 mg% and above) affects about 10%. Thus overall, approximately 40% of U.S. children over two years of age could benefit from some reduction in blood cholesterol levels [1].
Although current guidelines for evaluation and treatment of elevated cholesterol in childhood recommend that selected children over 10 years of age with LDL cholesterol levels of 190 mg% or higher after dietary therapy may be candidates for pharmacologic therapy, physicians and parents are often reluctant to initiate such therapy and would rather exhaust all possible avenues of dietary modification and supplements before progressing to systemically active pharmaceutical agents. The primary dietary modification prescribed for hypercholesterolemia in childhood consists primarily of the traditional Step I and Step II fat/saturated fat-modified diet [1]. Dietary total fat is limited to less than 30%E (Step I) or 27%E (Step II), and the calories lost to reduced fat are made up by increasing complex carbohydrate in the diet. In addition, saturated fat in the diet is reduced to <10%E (Step I) and <7%E (Step II) with substitution by monounsaturated fats (e.g., olive oil, canola oil, peanut butter and the like). In addition, an increase in dietary fiber intake, which includes about six grams of soluble fiber, provides an additional cholesterol lowering effect. Other dietary supplements which provide some added cholesterol lowering benefit include soy protein, garlic and fish oil, although the main effect of the latter is on triglycerides rather than cholesterol.
One of the newest dietary supplements for reducing blood cholesterol is plant sterol, (phytosterols) which in the stanol ester form is fat soluble and can now be added to a variety of foods [20–23]. Plant sterols (e.g., sitosterol, campesterol and stigmasterol) are structurally very similar to cholesterol. The 5-
saturated derivatives of sitosterol are sitostanol and campestanol. They occur in nature in trace amounts. Sitostanol has been shown to inhibit cholesterol absorption, probably through crystallization and co-precipitation. Decreased cholesterol absorption results in increased LDL-receptor activity and therefore increased removal of LDL-cholesterol from the blood stream. Sitostanol reduces cholesterol absorption and blood cholesterol levels more effectively than sitosterol and at doses lower than sitosterol. In addition, sitostanol is virtually unabsorbed by humans [24].
A number of studies have evaluated the safety and cholesterol-lowering effects of plant stanol ester in hypercholesterolemic adults, and a smaller number of studies have been conducted in children. Since plant stanol esters are tasteless and can be added to small amounts of fat in sufficiently large amounts to effectively inhibit cholesterol absorption in the intestinal tract, it is possible to incorporate them into products such as margarine, salad dressing and yogurt. They appear to be well tolerated in a wide segment of the population and could therefore be a useful adjunct in community-based interventions to reduce blood cholesterol levels and risk of cardiovascular disease. Recent reports suggest that daily consumption of a plant-stanol-ester-containing margarine developed in Finland could reduce serum total and LDL cholesterol levels by 10 to 15% [25–29].
Although current NCEP guidelines advocate cholesterol screening of children over two years of age in the presence of parental hypercholesterolemia or family history of premature cardiovascular disease [1], a relatively small number of studies have evaluated CVD risk factors in preschool children or studied the effects of various dietary interventions on normocholesterolemic or hypercholesterolemic preschoolers. It is well known, however, that FH, familial hypercholesterolemia, can readily be identified in children as early as the neonatal period and that these children usually reside in families in which typically half of the children (on average) are affected with the heterozygous form of FH and the other children in the family are unaffected [1]. Since families share meals together, however, members of FH families tend to consume the same types of foods. Therefore, dietary supplements which lower blood cholesterol should be evaluated in both normocholesterolemic and hypercholesterolemic children two years of age and older. In addition, the NCEP guidelines recognize that the most effective approach to diminishing cardiovascular disease morbidity and mortality is through a population approach by which the mean cholesterol of a given population is reduced by a small degree [1,4]. Dietary supplements which can safely reduce blood cholesterol in all individuals to a small extent are especially attractive agents in facilitating achievement of this goal.
In the present study, a margarine-like spread fortified with plant stanol ester significantly decreased serum total cholesterol and LDL cholesterol concentration by about 12.4% and 15.5% in healthy young preschool children. The decrease in total and LDL cholesterol was observed within two weeks of initiating use of the plant stanol ester spread and, in addition, returned to baseline within two weeks of discontinuing the spread. Acceptance of the spread on a daily basis in the diet of participating children was very good, resulting in a high degree of adherence to the study protocol and consumption of almost 95% of the recommended intake of spread. As a result, the daily dose of plant stanols consumed by the children (2.8 to 2.9 g/d) was similar to that in studies with older children and adults. The consumption of plant stanol ester was not associated with any short-term adverse health effects. In the whole study group, spread use yielded a mean decrease in total cholesterol of 19.9 mg/dL (-12.4% from baseline) and a mean decrease in LDL-cholesterol of 14.6 mg/dL (-15.5%). No significant changes were associated with bran use, although a small non-significant decrease in total cholesterol of 6.1 mg/dL (-4% from baseline) was observed.
The degree of cholesterol lowering observed in the present study is consistent with other published reports in which plant sterols and stanols were administered to children. In 1978, Schlierf et al. [37] administered sitosterol to 15 children and adolescents with familial hypercholesterolemia and found that it reduced total and LDL cholesterol by 6 to 7%. In 1992, Becker et al. [38] treated seven prepubertal, severely hypercholesterolemic children (mean baseline TC=416 mg/dL) with 6 g/d of sitosterol for three months and found that it lowered total and LDL cholesterol by 17% compared with diet alone. Subsequently, in 1993, Becker et al. [32] administered 6 g/d of sitosterol for three months followed by 1.5 g/d of sitostanol for seven months to nine severely hypercholesterolemic children with heterozygous FH (mean baseline TC=370 mg/dL) and found that sitostanol reduced LDL cholesterol significantly more so than sitosterol, despite the 4-fold lower dose (-20% LDLC after three months of sitosterol, versus -33% LDLC after three months of sitostanol and -29% after seven months of sitostanol). And more recently, in 1995, Gylling et al. [33] reported a 10 to 15% reduction in total and LDL cholesterol among 15 children with familial hypercholesterolemia (mean baseline TC=297 mg/dL) who consumed almost 3 g/d of plant stanols, similar to the present study. In a recent report by Simell et al. [39], administration of 1.5 g/d of plant stanol resulted in a total and LDL cholesterol decrease of 5.4% and 7.5%, respectively, in 75 six year old children. These children had been enrolled in the STRIP* dietary intervention study since seven months of age, with the goal of reducing their intake of saturated fat and cholesterol. Finally, in another study from Finland, Vuorio et al. [40] reported a 14% reduction in total and 17% reduction in LDL cholesterol among 12 3 to 14 year old children with heterozygous familial hypercholesterolemia who consumed 2.1 g/d of plant stanols for six weeks.
Although it was intended for the children in the present study to replace their regular spread with the plant stanol ester spread, analysis of dietary intake records and interviews indicated that, in the majority of cases, the product was added to the diet. This was reflected in increased energy and fat intake, particularly monounsaturated and polyunsaturated fat, consistent with the ingredients of the plant stanol ester spread used in the study. This appeared to occur because, since most of these young children had not been consuming three servings of margarine prior to the study, when asked to do so, they added the product to their diets, rather than substituted it for another. In a study of longer duration, or in clinical practice, fat and energy intake could be adjusted appropriately with nutrition counseling.
No significant adverse effects on gastrointestinal function were observed during consumption of the plant stanol ester spread. In addition, although the time period of this study was too short to adequately evaluate growth, height and weight changes measured during this three month study were similar in both treatment groups. The lack of adverse effects is consistent with reports from other pediatric trials. The present study was limited in that serum was not available for analysis of fat soluble vitamin levels. Due to the young age of the study participants, lipids were measured in capillary samples of blood, thus serum levels of fat soluble vitamins and carotenoids were not obtained. To date there have been mixed reports with respect to the effects of plant stanols on serum concentrations of fat soluble vitamins. Gylling et al. [33] suggested that no effect was observed on fat soluble vitamins. Becker et al. [32] reported no change in serum carotene levels. In a preliminary report by Simell et al. [39], serum concentrations of Vitamin D (25-OH-D) and vitamin A were unchanged after three months of 1.5 g/d added plant stanols, and the alpha-tocopherol/LDLC ratio was unchanged. The beta carotene/LDLC ratio, however, was significantly decreased. Vuorio et al. [40] also evaluated effects on serum concentrations of fat soluble vitamins after six weeks of plant stanol supplementation and reported reductions in the ratios of alpha and beta-carotene to cholesterol. Further studies are in progress to assess adequately the short and long term effects of plant stanol esters on blood levels of fat-soluble vitamins in children and adults.
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FOOTNOTES |
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TOPFOOTNOTESABSTRACTINTRODUCTIONMETHODSRESULTSREFERENCES |
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Received March 1, 1999. Accepted August 1, 1999.
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TOPFOOTNOTESABSTRACTINTRODUCTIONMETHODSRESULTSREFERENCES |
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