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* Department of Foods and Nutrition and Department of Statistics, Purdue University, West Lafayette, Indiana
3 To whom correspondence should be addressed. E-mail: savaiano{at}purdue.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • lactose intolerance • milk intolerance • meta-analysis • lactose digestion • flatulence
Osteoporosis is the most readily identifiable health issue associated with inadequate calcium intake and is responsible for >1.5 million fractures annually (1–3). The Institute of Medicine has set the Adequate Intake (AI) levels for calcium at 1,000 mg per day for men and women and 1,300 mg for adolescents (4) to maximize bone density and minimize the risk for osteoporosis. Calcium intake depends, in large part, on an intake of dairy foods, and hence, the Dietary Guidelines for Americans (5) recommends consuming 3 cups/d of fat-free or low-fat milk or equivalent milk product. Data from the National Health and Nutrition Examination Survey, 1999–2000, support the observation that calcium intake is less than desirable (6). The average calcium intake among 8,604 subjects including all ages except nursing infants and children was 863 mg per day based on data from one 24-h dietary recall.
Despite the importance of dairy products, many individuals avoid these foods to prevent symptoms believed to result from lactose maldigestion (7,8). However, masked studies have shown no significant differences in symptoms after the ingestion of single servings of dairy foods containing lactose such as the 12.5 g lactose found in 240 mL (1 cup) milk as compared with 240 mL lactose-hydrolyzed milk (9). Most of these studies are very small in size, thus limiting our understanding of the actual incidence of lactose intolerance symptoms in certain populations. Therefore, we conducted a meta-analysis of existing literature to quantitatively determine the severity of symptoms of lactose intolerance from existing clinical trials. We also used meta-analysis to estimate the incidence of lactose intolerance symptoms by comparing the occurrence of symptoms among lactose maldigesters after consuming milk or other lactose-containing foods compared with placebo under masked conditions.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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A total of 53 articles were identified as potentially relevant, and additional references from these articles were examined. Two reviewers independently reviewed each article to determine whether the study met the criteria for eligibility for further analysis: crossover study design with a lactose-free or low-lactose product (0–4 g) and an equivalent product containing an amount of lactose likely to be found in a meal (7–25 g), an attempt to mask subjects to the lactose content of each product, and symptom responses clearly reported as a rating of severity or frequency of occurrence by lactose exposure level; results from lactose maldigesters separate from lactose digesters or ill subjects, and age of subjects >4 y. Fourteen of the articles were excluded for lack of a lactose-free control or for a study design not masked (11–24). Ten articles were excluded because of unclear reporting of symptoms (25–34). Five articles had cross-sectional study designs or results that were not separated by disparate groups (7,8,35–37). Two articles were excluded because the lactose dose was too high (38,39), and 1 article specifically examined pharmacological effects (40). Therefore, 21 articles were eligible for inclusion.
If symptoms were reported following multiple levels of lactose, the symptomatic response to the lactose amount closest to a serving of milk (12 g) was used. In studies in which test products varied in fat content, symptomatic responses to the test products with the lowest fat content were selected. Within an article, the trials using a lactose-hydrolyzed product as control were used in preference to trials using a product accompanied by an oral enzyme control. In 1 article (41), results were presented for 2 samples of subjects. The data from the group with the lowest prevalence of past GI symptoms were used for this meta-analysis. One study (42) identified lactose maldigesters as symptomatic and asymptomatic; data from the former group were used.
Six studies used a quantitative scale for measuring self-reported severity of symptoms (42–47). Ten studies reported symptoms as incidence without regard to severity of the symptoms (41,48–56); and 5 studies reported both symptom occurrence and severity (57–61).
Study quality was independently evaluated using previously published recommendations (62,63). Reports were reviewed by 2 individuals for the presence or absence of 11 factors of a well-designed study, e.g., level of masking, clear definition of exclusion criteria, sampling frame, and experimental design. The maximum achievable score was 13. After completing the quality scoring of the 21 reports, each reviewer rescored 6 reports a minimum of 1 week later. The intrareviewer reliabilities were r = 0.99 (P = 0.007) for reviewer 1 and r = 0.76 (P = 0.078) for reviewer 2, indicating acceptable reliability of scoring. The interreviewer reliability was excellent, r = 0.85, (P < 0.001). Therefore, the final study quality score was an average between the 2 reviewers. Studies at or above the group median, 9.5, were considered of highest quality.
Data synthesis and statistical analysis. Symptom effect size was defined as the mean self-reported severity of symptom rating following a lactose dose less the mean self-reported severity of symptom rating following the placebo, divided by the pooled SD of both values. This method was selected from Pettiti (64, p. 123) for studies using different scales to measure effect (responses). This severity of symptom effect size was calculated from data collected at the longest time reported from exposure.
The SEM or SD was calculated from the raw data points directly or measured in the error bars of graphic displays (42,46,58,60). The SD was estimated for 4 studies (57,58,60,61) by dividing the interquartile range by 1.36. In one study (47), averages for symptom response were reported by lactose maldigesters experiencing symptoms and lactose maldigesters experiencing major symptoms. These 2 groups were pooled using standard methods (64).
Symptom effect sizes were calculated from the 11 eligible studies by type of symptom among the lactose maldigesters. The summary estimates of symptom effect were calculated with weights based on sample size and sample variance (64). The pooled symptom effect size and a 95% confidence interval (CI) were calculated for each reported symptom based on the number of studies providing data on each endpoint, that is, abdominal bloating (n = 4), abdominal pain (n = 6), degree of loose stools or diarrhea (n = 3), flatulence (n = 6), 3–4 symptoms combined (n = 5), bowel movements, frequency/d (n = 3), diarrhea, frequency/d (n = 3), and passage of flatus, frequency/d (n = 4).
The difference in incidence of symptoms was computed using the proportion of total subjects reporting symptoms after lactose and after placebo (64). We defined incidence difference as the proportion of individuals reporting symptoms following the lactose exposure less the proportion of individuals reporting symptoms following the placebo, divided by the pooled SD of the 2 proportions (64). Some reports divided occurrence of symptoms into mild and severe. These were combined as positive for symptoms. Incidence differences were calculated from the 15 eligible studies by symptom among the lactose maldigesters. The summary estimates of incidence differences were calculated with weights based on sample size (64). The pooled incidence difference and a 95% confidence interval (CI) were calculated for abdominal bloating (n = 4), abdominal pain (n = 6), degree of loose stools or diarrhea (n = 4), flatulence (n = 5), and multiple symptoms combined (n = 11). P-values < 0.05 were considered significant.
The effect sizes for all pooled estimates were examined with a chi-square test for homogeneity to test the hypothesis that the studies were derived from a population with similar effect sizes (64). Any differences in homogeneity were examined by subgroup analysis.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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7–25 g/dose. All eligible reports were described as randomized with regard to treatment order. Seven studies (42–44,46,58,60,61) of the 11 reporting symptoms were double-masked to the lactose exposure at time of administration, and 11 (41,50–56,58,60,61) of the 15 studies reporting incidence of symptoms were double-masked.
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2 = 3.72 with 3 df; P > 0.75). Frequency of flatulence as a measure of severity after consumption of lactose was significantly greater than that after placebo; pooled symptom effect size was 0.51 (95% CI 0.08 to 0.95). When this estimate was restricted to the highest-quality studies (42–44), the frequency of flatulence was not significantly greater for the lactose exposure compared with placebo. The pooled symptom effect size for frequency of flatulence among the highest-quality studies was 0.35 (95% CI –0.12 to 0.82).
Incidence of symptoms. The overall incidence differences for a variety of symptoms after consumption of lactose compared with placebo are summarized in Figures 3 and 4. For abdominal bloating from 4 eligible studies, the pooled incidence difference was 5.9 more people per 100 reported symptoms after lactose consumption compared with placebo (95% CI –0.07 to +0.19). The 95% CI for abdominal pain also included 0. The pooled incidence difference for diarrhea was 0.15 (95% CI 0.02 to 0.28). Of the 4 studies that included incidence of diarrhea, only 1 (54) study was classified as highest quality and reported no difference in diarrhea following intake of lactose or placebo. The incidence difference for flatulence based on the highest-quality studies (54,58) included 0, i.e., –0.03 (95% CI –0.23 to 0.17).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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12 g lactose) or receiving a placebo under masked conditions. This included perceived severity of abdominal bloating, abdominal pain, degree of loose stools or diarrhea and flatulence. Even the frequency of bowel movements and diarrhea after a normal dietary lactose dose compared with placebo were not different. The only symptom perceived to be worse after lactose than placebo was frequency of flatus per day, and this symptom was not significantly worse when analysis was limited to high quality studies. The actual incidence of symptoms of abdominal bloating, abdominal pain, and flatulence were not different after an intake of lactose equivalent to a cup of milk compared with placebo. The data for incidence difference of loose stools or diarrhea were inconsistent. The differences in severity of symptoms between lactose and placebo were small despite the use of assumptions throughout the data abstraction that would potentially contribute to increased intolerance symptoms. The studies included a large proportion of adults, and symptom responses following ingestion of lower-fat dairy products were used over higher-fat choices. These 2 factors are putatively associated with risk for elevated symptom severity (65).
There are limitations of meta-analysis. Results are combined from studies that may differ in methodology and include noncomparable populations. This was especially problematic when the multiple symptom results were pooled. In almost all cases, the symptoms included in the "sum of all symptoms" reported from each study were not the same symptoms; for example, one study would include abdominal pain, flatulence, and loose stools or diarrhea, whereas another would include bloating, flatulence, and diarrhea. Thus, it was not surprising that these outcomes displayed heterogeneity. Some argue that a single summary estimate of effect should not be calculated from disparate study results (66). However, several important studies (41,50–53,55,59) only reported sum of symptoms results, and therefore the decision was made to include these studies. Their inclusion does emphasize the possible limitation of reporting 1 multiple-symptoms response rather than individual symptoms. Another problem with meta-analysis is publication bias, that is, not publishing small negative studies. On the other hand, published negative studies were included in our summary estimates because these studies are more likely to be published with regard to lactose maldigestion and intolerance.
The dose of lactose consumed is likely a key factor in determining the potential for symptoms of lactose intolerance. Unfortunately, in this analysis, there was insufficient variation in the study doses to distinguish a dose–response relationship. The dose is closely related to the amount of fluid milk consumed because fluid milk is the major source of lactose in the diet. The dose of lactose that results in symptoms in the majority of a population of maldigesters is probably near 25 g (that found in 2 cups of milk), whereas doses below 12 g are not noticeable in masked conditions (45). Johnson et al. (26) demonstrated that African American young adults who claim intolerance to moderate amounts of milk could ultimately adapt and tolerate 12 g lactose in milk after introducing and increasing milk intake over a 6- to 12-week period.
Some maldigesters who have experienced symptoms following the consumption of large amounts of milk may become psychologically sensitized to the consumption of any amount of milk (42). Subjects have complained that even a very small amount of milk in coffee results in symptoms of intolerance. Others just state that they "do not like milk" and choose to avoid it. Such avoidance of milk is likely a major obstacle in obtaining adequate calcium in the U.S. diet. Further, the recent American trend of larger portion sizes (67) exacerbates individuals consuming amounts of lactose that can be tolerated. Lactose in large servings of frozen yogurts, shakes, and milk may exceed that which can be tolerated by maldigesters. Physicians and other health care workers need to work with patients to urge consumption of single servings of dairy products throughout the day, preferably with meals (42) and reiterate that the serving size for milk is 1 cup for children and adults (5).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 This study was supported by a research grant from Dairy Management, Inc.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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