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Are adverse food reactions linked to irritable bowel syndrome?
THE AMERICAN JOURNAL OF GASTROENTEROLOGY Copyright © 1998 by Am. Coll. of Gastroenterology Published by Elsevier Science Inc.
Vol. 93, No. 11, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00412-2
Are Adverse Food Reactions Linked to Irritable Bowel Syndrome? Anna M. Niec, BSc., M. Nutr. Diet, Brad Frankum, B. Med. (Hons), F.R.A.C.P., and Nicholas J. Talley, M.D., Ph.D., F.R.A.C.P., F.A.C.G. Department of Medicine, University of Sydney, Nepean Hospital, Penrith, Australia
Objective: We undertook to determine whether adverse food reactions play a role in irritable bowel syndrome (IBS). Methods: A systematic review of the literature using Medline (1980 –1996), targeting IBS and adverse food reactions, was performed. All clinical trials whereby dietary exclusion was followed by food challenge were selected. Each study was reviewed using a structured format to examine methodological issues and study outcomes. Results: Of the seven studies included, the positive response to an elimination diet ranged from 15% to 71%; double-blind placebo-controlled challenges identified problem foods in 6% to 58% of cases. Milk, wheat, and eggs were most frequently identified to cause symptom exacerbation; of the foods identified the most common trait was a high salicylate content. Foods high in amines were also identified. Studies of diarrhea-predominant IBS identified a higher percentage of adverse food reactions. However, all studies had major limitations in their trial designs, including inadequate patient selection, appropriateness of—and duration of— exclusion diets, and methods of food challenge. Conclusion: Whether adverse reactions to foods are a key factor in exacerbating IBS symptoms or whether dietary manipulation is a valid treatment option is unclear. Carefully designed controlled clinical trials are now needed to specifically test the potential role of adverse food reactions in diarrhea-predominant IBS. (Am J Gastroenterol 1998;93:2184 –2190. © 1998 by Am. Coll. of Gastroenterology)
the treatment of IBS has been seriously questioned (7). On the other hand, food intolerance has been implicated in the pathogenesis of IBS in a number of studies but the foods identified to be relevant have been highly variable (8). We wished to critically examine the evidence available on the role of adverse food reactions in IBS. We aimed to identify which foods may be the common culprits, and to critically assess whether exclusion diets are a useful therapeutic modality in IBS. MATERIALS AND METHODS A comprehensive computerized literature search was performed using Medline from 1980 to November 1996 inclusive, under the MeSH terms “food allergy,” “food intolerance,” and “adverse food reactions.” A total of 32 publications were located, and the reference lists of each were reviewed for completeness. Included in the analysis were all clinical trials in which dietary exclusion was used, followed by testing with foods either in the form of capsules or open food challenge. This is considered the optimal method for establishing food sensitivities (9). Papers not written in English or those addressing IBS in children were excluded, as were any publications in the form of letters and abstracts (as data were incomplete or preliminary). One trial, which compared the efficacy of elimination diet with oral sodium cromoglycate (10), was excluded because subjects were not challenged with foods. All studies that fulfilled the inclusion criteria were reviewed in a standard manner based on the Rome Working Team recommendations for the design of IBS trials (11). The following information was extracted from each study: 1. Subject selection. Population type, whether the patient population was consecutive, refusal and dropout rates, and the definition of IBS used; 2. Research protocol. Randomization, baseline period, treatment method, presence of control group, blinding, follow-up, and analysis; 3. Measures. Baseline measures, concurrent drug use, compliance, and outcome measures. A quality score was applied to the studies with 1 point being given for each of the following characteristics: baseline characteristics described, adequate definition of IBS,
INTRODUCTION Irritable bowel syndrome (IBS) accounts for a large proportion of the workload in clinical gastroenterology yet its etiology remains poorly understood (1, 2). A number of factors have been implicated, including postinfectious intestinal damage (3), psychological distress (4), and diet (5). Management of IBS remains largely unsatisfactory, in part because few truly efficacious pharmacological approaches are available (6). The value of a high-fiber diet in Received Jan. 15, 1998; accepted June 22, 1998. 2184
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TABLE 1 Subject Selection and Results Number Included
Dropouts
Results
Bentley et al. (12)
Reference
Not clear
27
8/27 (29.6%)
Farah et al. (13)
Gastroenterology clinic attendees with symptoms suggestive of food intolerance
49
0%
14/21 (67%) remission after ED; 10/21 (47.7%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge 13/49 (26.5%) remission after ED; 8/49 (16.3%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge
Not stated, except “patients with IBS” Symptom-free subjects from Study 1
25
0%
6
0%
Selected patients from Study 1 Outpatients with IBS IBS patients, source unclear
5
0%
Jones et al. (14) Study 1 Study 2
Study 3 McKee et al. (15) Nanda et al. (16)
Population Type
40 200
Not stated 11/200 (5.5%)
Petitpierre et al. (17)
Allergy clinic attendees, gastroenterology clinic attendees with IBS
24
0%
Zwetchkenbaum and Burakoff (18)
IBS patients, source unclear
10
1/10 (10%)
14/21 (67%) specific offending foods found; 10/12† DB challenges provoked symptoms. Rectal prostaglandin levels significantly elevated after challenges; 100% symptomatic with SB challenges 6/40 (15%) remission during ED 91/189 (47.9%) remission during ED; 73/189 (38.6%) specific offending foods found by open food challenge 7/24 (29.2%) symptoms unchanged; 3/24 (12.5%) remission with ED but negative challenges; 14/24 (58.3%) specific offending foods found and confirmed by blind challenges 6/9 (66.7%) symptoms unchanged with ED; 3/9 (33.3%) remission with ED, challenges negative; 0/9 (0%) AFRs identified
* ED 5 elimination diet; DB 5 double blind; AFR 5 adverse food reactions. † 10/12 (83%) of test solutions identified correctly.
concurrent drug use accounted for, blinding of outcomes employed, adequate duration and composition of elimination diet, adequate washout period between challenges, exclusion of disaccharide malabsorbers, and adequate followup. The maximal score attainable was 8; therefore we set a priori an acceptable cutoff score of $ 5 out of 8. RESULTS A total of seven studies fulfilled the inclusion criteria (12–18). Methodological issues Patient population. Four of seven studies failed to describe the origin of their study populations (12, 14, 16, 18) (Table 1). The others were derived from outpatient clinic populations. Small sample sizes limited the power of all the negative studies (12, 14, 15, 17, 18). Consecutive sample. Only three of seven studies recruited subjects on a consecutive basis (13–15). Refusers and dropouts. Only one study documented refusal of subjects to enter the study with a rate of 16% (14).
Three of seven studies documented dropout rates, which were 5.5% (16), 10% (18), and 30% (12), respectively; the reasons for dropout were poorly documented. Case definition. No study included in this review made specific reference to the Rome or Manning criteria (19, 20). Only one trial (16) had selection criteria consistent with either of these standardized approaches. Farah et al. (13) included nonspecific functional gastrointestinal symptoms and did not use IBS as an entry criteria, although their study population appeared to resemble the usual IBS population closely enough to allow for inclusion in this analysis. The remaining five studies (12, 14, 15, 17, 18) had a range of working definitions for IBS and consistency was lacking between them. Details of the methods used to exclude other causes of IBS-like symptoms were given in five studies (14 –18). Patterns of IBS symptoms differed between trials. Some studies (12–14) recruited patients with mainly diarrheapredominant symptoms, while the others did not subclassify their subjects, resulting in more heterogenous populations. McKee et al. (15) found that IBS subjects who suffered
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predominantly from diarrhea tended to improve on the elimination diet, while subjects suffering constipation as the main complaint failed to improve. The highest response rates to an elimination diet (67%) were found in the study that recruited patients with diarrhea as the predominant symptom (14). Four of the papers (12, 13, 17, 18) sought to identify the possibility of true food allergy in IBS subjects. The diagnosis of food allergy depends on a consistent clinical history and evidence of IgE response to a food allergen, demonstrated by a positive skin prick test or serum RAST. Skin prick testing to food allergens was performed in three studies (12, 13, 17) and RAST testing in one (17). These failed to identify food allergy in two studies (12, 13), but there was a correlation between positive testing and positive challenges in one study (17). Research protocol. No studies reviewed were randomized so there were no comparisons made between treated and untreated subjects and diet was used in all cases. Baseline period. McKee et al. (15) and Zwetchkenbaum and Burakoff (18) recorded abdominal symptoms for a period of 3 wk and 2 wk, respectively, before introduction of the elimination diet. Baseline observation periods were not included in any of the other studies (Table 2). Symptom severity and frequency was not recorded either before or after commencement of the diet in three studies (12, 14, 17). Treatment method. While all studies used an elimination diet as their treatment form, the compositions and the duration of the diets differed widely between the reports. Zwetchkenbaum and Burakoff (18) designed diets based on patient diaries, which suggested a link between certain foods and IBS symptoms. Four of seven studies used elimination diets that failed to exclude all sources of salicylates (13, 14, 16, 17) and two failed to exclude amines (13, 16). The duration of the elimination diets varied substantially between the studies, ranging between 4 days (14) and 3 wk (16). One study (12) failed to specify the duration of the elimination diet. The method in which adverse food reactions were identified varied between studies, although stepwise reintroduction of foods, followed by challenges of open (15, 16, 18) or both open and blind (12–14, 17) types of any suspect foods were most common. None of the studies considered the role of sorbitol or fructose malabsorption, but lactose malabsorption was excluded in two studies (15, 18). Control groups. None of the studies employed a control group of IBS sufferers who were not on the elimination diets. Trial length. An adequate length of time for treatment in IBS trials has been defined as 8 –12 wk (6, 11). Four studies (12, 14, 15, 18) stopped the treatment after identification of adverse food reaction and made no attempt to extend the treatment period by tailoring individual diets, excluding problem foods. In those trials the maximum length of treatment time was 3 wk. Three of the studies (13, 16, 17) extended the treatment length by asking their subjects to
AJG – Vol. 93, No. 11, 1998 continue on modified diets after identification of adverse food reactions. Nanda et al. (16) found that 80% of the subjects were still following their modified diets at on average of 14.7 months after commencement of the individually tailored diets; all but one had apparent ongoing benefits. Three subjects from the original sample in Farah et al. (13) continued on individual exclusion diets for a period of up to 18 months and remained well. Petitpierre et al. (17) followed-up their subjects at 6 months and found that 71% remained well. Blinding. Open food challenges alone were used to identify adverse food reactions in three trials (15, 16, 18). Open and blind challenges were used in four other trials (12–14, 17). Double-blind challenges were used only in three trials (12–14). In the studies that followed the positive open challenges with blind challenges, the positive results were not consistently repeated (12, 13). In both studies, eight subjects who reacted positively to open challenges underwent a challenge with the same foods in a double-blind fashion; only 37.5% of the open food challenges were confirmed by this method. The foods identified by both open and blind food challenges were yeast, milk, egg, peas, and coffee. Jones et al. (14) used double-blind challenges without open food challenges; 83% of the test substances and 92% of control solutions were correctly identified. Wheat, banana, corn, and potato were identified to cause adverse food reactions. Baseline characteristics. Race and socioeconomic status were not reported, except in the study by Nanda et al. (16), where age, gender, and socioeconomic class were shown to not affect the likelihood to respond to the elimination diet. One study (14) failed to document any demographic information. Previous and concurrent therapy. Only one study (16) mentioned the previous use of other treatments by subjects. In this study subjects were required to have failed conventional therapy before entry. The authors also documented that subjects were asked to stop all medications while on the elimination diet. Compliance. Nanda et al. (16) stated that their subjects were kept under regular review to help ensure compliance. They also noted that those who responded to the exclusion diet had a significantly greater weight loss than nonresponders, suggesting that poor compliance may indeed have been a factor in treatment failure. The other studies all failed to document any monitoring of adherence to the diet. Outcome measures. Most studies used a system of diaries and questionnaires to record symptoms (13, 15, 16, 18). Two studies failed to report their method for monitoring subjects’ progress (12, 17). Jones et al. (14) measured multiple laboratory parameters including rectal prostaglandin E2 levels, which were significantly higher on test than on placebo days. Unfortunately no record was made of whether this was related to symptom exacerbation.
TABLE 2 Trial Design: Research Protocol Baseline Period
Type of AFRs Under Investigation
Disaccharide Absorption Excluded
Bentley et al. (12)
Not measured
Hypersensitivity, intolerance
No
Farah et al. (13)
Not measured
Intolerance, allergy
No
Jones et al. (14) Study 1
Not measured
Intolerance
No
Study 2
Not measured
Intolerance
No
Study 3
Not measured
Intolerance
No
McKee et al. (15)
3 wk
Intolerance
Lactose
Nanda et al. (16)
Not measured
Intolerance
No
Petitpierre et al. (17)
Not measured
Hypersensitivity, intolerance
No
Low allergenic; salicylates present; duration, 3 wk
Zwetchkenbaum and Burakoff (18)
2 wk
Hypersensitivity, intolerance
Lactose
Exclusion of foods and same-food families linked to IBS symptoms from food diaries; duration, 2 wk
Reference
2187
Treatment: Baseline Elimination Diet
Challenge Protocol
Follow-Up
Low allergenic; excluded all sources of salicylates, amines, glutamates, and artificial additives; unknown duration Low allergenic; salicylates and amines present; duration, 2 wk
Open food 3 days apart; DBPC in responders DBPC; open food 1 wk apart in responders
3 responders remained well; duration not stated
Low allergenic; likely to contain significant sources of salicylates and possibly amines; duration, 1 wk (Study 1) Study 2: same diet during challenges only Study 3: same diet, 4 days
Open food, daily;
Not recorded
DB nasogastric daily; SB disguised in unspecified flavored soup daily Open, unspecified frequency
Not recorded
Low allergenic; excluded all sources of salicylates, amines, glutamates, and artificial additives; duration, 1 wk Low allergenic; salicylates and amines present; duration, 3 wk
DBPC 5 double-blind placebo-controlled; DB 5 double blind; SB 5 single blind; IBS 5 irritable bowel syndrome; AFR 5 adverse food reaction.
Open for 2 days
Open and singleblind; unspecified frequency Open for 2 days 2 days apart
6–18 months
Not recorded
Not recorded
14.7 months average for responders; 12.5 months for nonresponders 6 months
Not recorded
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AJG – Vol. 93, No. 11, 1998 TABLE 3 Foods Identified to Cause Adverse Food Reactions in the Irritable Bowel Syndrome
Adverse Food Reactions Identified to:
Number of Studies
Confirmed by Open Challenge
Confirmed by Double-Blind Challenge
Milk Wheat Egg Dairy products
6/7 4/7 4/7 ?
Yes Yes Yes Yes
Yes Yes Yes —
Corn Peas Tea Coffee Potato Nuts Wine Citrus fruit Tomato
1/7 2/7 2/7 4/7 2/7 2/7 1/7 2/7 1/7
Yes — Yes Yes Yes Yes Yes Yes —
Yes Yes — Yes Yes Yes Yes — Yes
Chocolate Banana Tuna fish Celery Yeast
1/7 2/7 1/7 1/7 1/7
Yes Yes Yes Yes —
— Yes Yes Yes Yes
Significant Source Of:
Skin Prick Test
Lactose
Positive* Positive* Positive* —
— — Lactose, possibly other additives if processed Salicylates Salicylates Salicylates Salicylates Salicylates Salicylates Salicylates, amines Salicylates, amines Salicylate, amines, glutamates Amines Amines Amines
— — — — Positive* Positive* — — Positive* — Positive* Positive* Positive*
* Petitpierre et al. (17).
Study outcomes Table 3 summarizes the positive challenge results from all studies. Milk, wheat, and eggs were identified as the most frequent causes of exacerbation of IBS symptoms, using both open and double-blind placebo-controlled challenges. Coffee was identified in four studies; tea, nuts, peas, and potato were identified in two studies each, and corn was identified in one study. Interestingly, the common trait of all of these foods is their high salicylate content (with the exception of potato, which can be low to moderate depending on the type, but is a staple food and is likely to be consumed frequently and in considerable quantities). Similarly, foods high in amines were identified as problem foods in a number of studies, although less often than foods high in salicylates. Only one study (17) identified positive responses to artificial food additives, namely, sodium benzoate, sodium nitrate, erythrosine, and carmitic acid. Few patients were followed-up beyond the study period, making assessment of the long-term value of dietary manipulation difficult. The studies that attempted to do so (12, 13, 16, 17) found a tendency toward long-term benefit of dietary manipulation. Overall quality None of the trials reviewed met five or more of the eight criteria required for study validity and interpretability. One study satisfied only one of these criteria (14), three studies satisfied two of eight criteria (12, 15, 17), and two studies satisfied three criteria (13, 16). The study by Zwetchenbaum and Burakoff (18) satisfied half of the criteria.
DISCUSSION Adverse food reactions may play an important role in IBS, as many patients report an exacerbation of symptoms after food ingestion. However, this could represent a nonspecific but enhanced intestinal response to eating. The available literature examined in this review, unfortunately, does not provide uniform evidence that food sensitivities are important in IBS. Trials evaluating IBS with diarrhea as the predominant symptom reported a higher rate of responders to the elimination diets and were able to identify a higher number of adverse food reactions (12–14). This suggests that there may be a higher prevalence of adverse food reactions in IBS sufferers where diarrhea is the predominant characteristic, but this remains to be established. There were numerous methodological limitations identified in the literature. For example, a number of studies have shown that exacerbation of symptoms occurs in IBS subjects after ingesting fructose and sorbitol mixtures (21, 22). Both fructose and sorbitol appear naturally in fruits in varying amounts (22), and sorbitol is a frequent ingredient in dietetic foods. Jain (22) showed that ingestion of 10 g sorbitol, equivalent to 4 –5 sugar-free mints or two medium pears, produced moderate discomfort in 10% and severe discomfort in 17% of healthy subjects. The intestinal symptoms experienced by the subjects were consistent with IBS, namely, abdominal pain, bloating, and diarrhea, with symptoms lasting up to 6 h after ingestion. Failure to exclude sorbitol or fructose malabsorbers may also have confounded the results of the studies conducted, particularly those that
AJG – November 1998 TABLE 4 Recommendations for Investigating Adverse Food Reactions in Irritable Bowel Syndrome 1. Compare pretreatment characteristics of the groups, including IBS symptoms and history of atopy 2. Stratify by the type of disturbed defecation in IBS subjects (or consider restricting the study to diarrhea-predominant) 3. Exclude disaccharide malabsorption, in particular lactose and fructose 4. Exclude sorbitol malabsorption 5. Monitor and account for the use of concurrent medication 6. Document use and success of prior treatments for IBS 7. Exclude medications containing salicylates or antihistamines 8. Exclude true food allergy prior to challenge procedures although this is rare; skin prick tests to foods have a good negative predictive value 9. Administer a low-allergenic diet excluding all sources of salicylates, amines, glutamates, and artificial additives 10. Trial elimination diet for at least 3 wk 11. Monitor compliance with the elimination diet 12. Use double-blind placebo-controlled capsule challenges; open challenges are unacceptable 13. Allow for at least a 48-h washout period between each challenge 14. Allow for a 3-day rest period after a positive challenge 15. Use validated, reliable, and responsive-to-change tools for recording outcome measures 16. Follow-up responders on diets excluding identified adverse food reactions for at least 12 wk
allowed pears in the elimination diets (14, 15). Similarly, lactose intolerance was not excluded in a number of studies that used milk challenges (12, 14, 16, 17). Most investigators failed to exclude all sources of salicylates, amines, and glutamates from their elimination diets (13, 14, 16, 17). These are natural, pharmacologically active substances that are believed to cause adverse food reactions, inducing symptoms such as nausea, vomiting, recurrent abdominal pain, flatulence, and bouts of diarrhea (23). Failure to exclude these substances may have led to a lower response rate to the elimination diet in these studies. Indeed, a high level of salicylates or amines was a feature in a significant number of foods identified as problem foods. We postulate, based on the limited available literature, that salicylates and to a lesser extent amines largely explain apparent food intolerance in IBS. The gold standard for investigating adverse food reactions remains the double-blind placebo-controlled capsule challenge. Unfortunately, in three of the studies reviewed only open food challenges were used (15, 16, 18). Open food challenges may be seriously biased because a psychologically mediated response to the ingested food may occur because of suggestion or adverse conditioning (8). In the diagnosis of pharmacologically mediated food intolerance, the open food challenge is further complicated, as most foods contain a mixture of salicylates, amines, and glutamates, and each has the potential to cause an adverse food reaction. The ability of masking the test substance in a food vehicle (e.g., soup, as in the study of Jones et al. [14]) remains limited. Further, the flavorings used to prevent
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recognition of the test substance are likely to be a source of salicylates, as most flavoring essences are rich in salicylates. In conclusion, the hypothesis that food sensitivities play an important role in IBS is not well supported by the available literature. Despite the lack of consistency and frequent methodological flaws in the studies included in this review, the following were common findings. Diarrheapredominant IBS subjects may respond better to an elimination diet; significantly more of these subjects experienced symptom remission while on the diet. Milk, wheat, egg, and foods high in salicylates or amines were consistent problem foods across a number of studies. Well-designed studies are now needed to evaluate these issues. Based on the results, recommendations for optimizing the investigation of adverse food reactions in IBS in future studies are summarized in Table 4. Reprint requests and correspondence: N. J. Talley, Professor of Medicine, Department of Medicine, University of Sydney, Nepean Hospital, Penrith, 2751, N.S.W., Australia.
REFERENCES 1. Thompson WG. Irritable bowel syndrome—pathogenesis and management. Lancet 1993;341:1569 –72. 2. Zighelboim J, Talley NJ. What are functional bowel disorders? Gastroenterology 1993;104:1196 –1201. 3. Gwee KA, Graham JC, Mckendrick MW, et al. Psychometric scores and persistence of irritable bowel after infectious diarrhoea. Lancet 1996;347:150 –3. 4. Drossman DA, Talley NJ, Leserman J, et al. Sexual and physical abuse and gastrointestinal illness: Review and recommendations. Ann Intern Med 1995;123:782–94. 5. Rumessen JJ, Gudmand-Hoyer E. Functional bowel disease: Malabsorption and abdominal distress after ingestion of fructose, sorbitol, and fructose-sorbitol mixtures. Gastroenterology 1988;95:694 –700. 6. Klein K. Controlled treatment trials in the irritable bowel syndrome: A critique. Gastroenterology 1988;95:232– 41. 7. Francis CY, Whorwell PJ. Bran and irritable bowel syndrome—time for reappraisal. Lancet 1994;344:39 – 40. 8. Ferguson A. Mechanism in adverse reactions to foods. The gastrointestinal tract. Allergy 1995;50 (20 suppl):32– 8. 9. Ferguson A. Definitions and diagnosis of food intolerance and food allergy: Consensus and controversy. J Pediatr 1992;121:S7–S11. 10. Stefanini GF, Saggioro A, Alvisi V, et al. Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrhoeic type. Scand J Gastroenterol 1995;30:535– 41. 11. Talley NJ, Nyre´n O, Drossman DA, et al. The irritable bowel syndrome: Toward optimal design of controlled treatment trials. Gastroenterol Int 1993;6:189 –211. 12. Bentley SJ, Pearson DJ, Rix KJ. Food hypersensitivity in irritable bowel syndrome. Lancet 1983;ii:295–7. 13. Farah DA, Calder I, Benson L, et al. Specific food intolerance: Its place as a cause of gastrointestinal symptoms. Gut 1985;26:164 – 8. 14. Jones VA, McLaugghlan P, Shorthouse M, et al. Food intolerance: A major factor in the pathogenesis of irritable bowel syndrome. Lancet 1982;ii:115–7. 15. McKee AM, Prior A, Whorwell PJ. Exclusion diets in irritable bowel syndrome: Are they worthwhile? J Clin Gastroenterol 1987;9:526 – 8. 16. Nanda R, James R, Smith H, et al. Food intolerance and the irritable bowel syndrome. Gut 1989;30:1099 –1104. 17. Petitpierre M, Gumowski P, Girard JP. Irritable bowel syndrome and hypersensitivity to food. Ann Allerg 1985;54:538 – 40.
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18. Zwetchkenbaum J, Burakoff R. The irritable bowel syndrome and food hypersensitivity. Ann Allerg 1988;61:47–9. 19. Drossman DA, Thompson WG, Talley NJ, et al. Identification of subgroups of functional gastrointestinal disorders. Gastroenterol Int 1990;3:159 –72. 20. Talley NJ, Phillips SF, Melton LJ, et al. Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 1990;31:77– 81.
AJG – Vol. 93, No. 11, 1998 21. Fernandez-Banares F, Esteve-Pardo M, de Leon R, et al. Sugar malabsorption in functional bowel disease: Clinical implications. Am J Gastroenterol 1993;88:2044 –50. 22. Jain NK. Sorbitol intolerance in adults. Am J Gastroenterol 1985;80: 678 – 81. 23. Allen DH, Van Nunen S, Loblay R, et al. Adverse reactions to foods. Med J Aust 1984;141:S37–S42.
Vol. 93, No. 11, 1998 ISSN 0002-9270/98/$19.00 PII S0002-9270(98)00412-2
Are Adverse Food Reactions Linked to Irritable Bowel Syndrome? Anna M. Niec, BSc., M. Nutr. Diet, Brad Frankum, B. Med. (Hons), F.R.A.C.P., and Nicholas J. Talley, M.D., Ph.D., F.R.A.C.P., F.A.C.G. Department of Medicine, University of Sydney, Nepean Hospital, Penrith, Australia
Objective: We undertook to determine whether adverse food reactions play a role in irritable bowel syndrome (IBS). Methods: A systematic review of the literature using Medline (1980 –1996), targeting IBS and adverse food reactions, was performed. All clinical trials whereby dietary exclusion was followed by food challenge were selected. Each study was reviewed using a structured format to examine methodological issues and study outcomes. Results: Of the seven studies included, the positive response to an elimination diet ranged from 15% to 71%; double-blind placebo-controlled challenges identified problem foods in 6% to 58% of cases. Milk, wheat, and eggs were most frequently identified to cause symptom exacerbation; of the foods identified the most common trait was a high salicylate content. Foods high in amines were also identified. Studies of diarrhea-predominant IBS identified a higher percentage of adverse food reactions. However, all studies had major limitations in their trial designs, including inadequate patient selection, appropriateness of—and duration of— exclusion diets, and methods of food challenge. Conclusion: Whether adverse reactions to foods are a key factor in exacerbating IBS symptoms or whether dietary manipulation is a valid treatment option is unclear. Carefully designed controlled clinical trials are now needed to specifically test the potential role of adverse food reactions in diarrhea-predominant IBS. (Am J Gastroenterol 1998;93:2184 –2190. © 1998 by Am. Coll. of Gastroenterology)
the treatment of IBS has been seriously questioned (7). On the other hand, food intolerance has been implicated in the pathogenesis of IBS in a number of studies but the foods identified to be relevant have been highly variable (8). We wished to critically examine the evidence available on the role of adverse food reactions in IBS. We aimed to identify which foods may be the common culprits, and to critically assess whether exclusion diets are a useful therapeutic modality in IBS. MATERIALS AND METHODS A comprehensive computerized literature search was performed using Medline from 1980 to November 1996 inclusive, under the MeSH terms “food allergy,” “food intolerance,” and “adverse food reactions.” A total of 32 publications were located, and the reference lists of each were reviewed for completeness. Included in the analysis were all clinical trials in which dietary exclusion was used, followed by testing with foods either in the form of capsules or open food challenge. This is considered the optimal method for establishing food sensitivities (9). Papers not written in English or those addressing IBS in children were excluded, as were any publications in the form of letters and abstracts (as data were incomplete or preliminary). One trial, which compared the efficacy of elimination diet with oral sodium cromoglycate (10), was excluded because subjects were not challenged with foods. All studies that fulfilled the inclusion criteria were reviewed in a standard manner based on the Rome Working Team recommendations for the design of IBS trials (11). The following information was extracted from each study: 1. Subject selection. Population type, whether the patient population was consecutive, refusal and dropout rates, and the definition of IBS used; 2. Research protocol. Randomization, baseline period, treatment method, presence of control group, blinding, follow-up, and analysis; 3. Measures. Baseline measures, concurrent drug use, compliance, and outcome measures. A quality score was applied to the studies with 1 point being given for each of the following characteristics: baseline characteristics described, adequate definition of IBS,
INTRODUCTION Irritable bowel syndrome (IBS) accounts for a large proportion of the workload in clinical gastroenterology yet its etiology remains poorly understood (1, 2). A number of factors have been implicated, including postinfectious intestinal damage (3), psychological distress (4), and diet (5). Management of IBS remains largely unsatisfactory, in part because few truly efficacious pharmacological approaches are available (6). The value of a high-fiber diet in Received Jan. 15, 1998; accepted June 22, 1998. 2184
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2185
TABLE 1 Subject Selection and Results Number Included
Dropouts
Results
Bentley et al. (12)
Reference
Not clear
27
8/27 (29.6%)
Farah et al. (13)
Gastroenterology clinic attendees with symptoms suggestive of food intolerance
49
0%
14/21 (67%) remission after ED; 10/21 (47.7%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge 13/49 (26.5%) remission after ED; 8/49 (16.3%) specific offending foods found; 3/8 (37.5%) confirmed by DB challenge
Not stated, except “patients with IBS” Symptom-free subjects from Study 1
25
0%
6
0%
Selected patients from Study 1 Outpatients with IBS IBS patients, source unclear
5
0%
Jones et al. (14) Study 1 Study 2
Study 3 McKee et al. (15) Nanda et al. (16)
Population Type
40 200
Not stated 11/200 (5.5%)
Petitpierre et al. (17)
Allergy clinic attendees, gastroenterology clinic attendees with IBS
24
0%
Zwetchkenbaum and Burakoff (18)
IBS patients, source unclear
10
1/10 (10%)
14/21 (67%) specific offending foods found; 10/12† DB challenges provoked symptoms. Rectal prostaglandin levels significantly elevated after challenges; 100% symptomatic with SB challenges 6/40 (15%) remission during ED 91/189 (47.9%) remission during ED; 73/189 (38.6%) specific offending foods found by open food challenge 7/24 (29.2%) symptoms unchanged; 3/24 (12.5%) remission with ED but negative challenges; 14/24 (58.3%) specific offending foods found and confirmed by blind challenges 6/9 (66.7%) symptoms unchanged with ED; 3/9 (33.3%) remission with ED, challenges negative; 0/9 (0%) AFRs identified
* ED 5 elimination diet; DB 5 double blind; AFR 5 adverse food reactions. † 10/12 (83%) of test solutions identified correctly.
concurrent drug use accounted for, blinding of outcomes employed, adequate duration and composition of elimination diet, adequate washout period between challenges, exclusion of disaccharide malabsorbers, and adequate followup. The maximal score attainable was 8; therefore we set a priori an acceptable cutoff score of $ 5 out of 8. RESULTS A total of seven studies fulfilled the inclusion criteria (12–18). Methodological issues Patient population. Four of seven studies failed to describe the origin of their study populations (12, 14, 16, 18) (Table 1). The others were derived from outpatient clinic populations. Small sample sizes limited the power of all the negative studies (12, 14, 15, 17, 18). Consecutive sample. Only three of seven studies recruited subjects on a consecutive basis (13–15). Refusers and dropouts. Only one study documented refusal of subjects to enter the study with a rate of 16% (14).
Three of seven studies documented dropout rates, which were 5.5% (16), 10% (18), and 30% (12), respectively; the reasons for dropout were poorly documented. Case definition. No study included in this review made specific reference to the Rome or Manning criteria (19, 20). Only one trial (16) had selection criteria consistent with either of these standardized approaches. Farah et al. (13) included nonspecific functional gastrointestinal symptoms and did not use IBS as an entry criteria, although their study population appeared to resemble the usual IBS population closely enough to allow for inclusion in this analysis. The remaining five studies (12, 14, 15, 17, 18) had a range of working definitions for IBS and consistency was lacking between them. Details of the methods used to exclude other causes of IBS-like symptoms were given in five studies (14 –18). Patterns of IBS symptoms differed between trials. Some studies (12–14) recruited patients with mainly diarrheapredominant symptoms, while the others did not subclassify their subjects, resulting in more heterogenous populations. McKee et al. (15) found that IBS subjects who suffered
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predominantly from diarrhea tended to improve on the elimination diet, while subjects suffering constipation as the main complaint failed to improve. The highest response rates to an elimination diet (67%) were found in the study that recruited patients with diarrhea as the predominant symptom (14). Four of the papers (12, 13, 17, 18) sought to identify the possibility of true food allergy in IBS subjects. The diagnosis of food allergy depends on a consistent clinical history and evidence of IgE response to a food allergen, demonstrated by a positive skin prick test or serum RAST. Skin prick testing to food allergens was performed in three studies (12, 13, 17) and RAST testing in one (17). These failed to identify food allergy in two studies (12, 13), but there was a correlation between positive testing and positive challenges in one study (17). Research protocol. No studies reviewed were randomized so there were no comparisons made between treated and untreated subjects and diet was used in all cases. Baseline period. McKee et al. (15) and Zwetchkenbaum and Burakoff (18) recorded abdominal symptoms for a period of 3 wk and 2 wk, respectively, before introduction of the elimination diet. Baseline observation periods were not included in any of the other studies (Table 2). Symptom severity and frequency was not recorded either before or after commencement of the diet in three studies (12, 14, 17). Treatment method. While all studies used an elimination diet as their treatment form, the compositions and the duration of the diets differed widely between the reports. Zwetchkenbaum and Burakoff (18) designed diets based on patient diaries, which suggested a link between certain foods and IBS symptoms. Four of seven studies used elimination diets that failed to exclude all sources of salicylates (13, 14, 16, 17) and two failed to exclude amines (13, 16). The duration of the elimination diets varied substantially between the studies, ranging between 4 days (14) and 3 wk (16). One study (12) failed to specify the duration of the elimination diet. The method in which adverse food reactions were identified varied between studies, although stepwise reintroduction of foods, followed by challenges of open (15, 16, 18) or both open and blind (12–14, 17) types of any suspect foods were most common. None of the studies considered the role of sorbitol or fructose malabsorption, but lactose malabsorption was excluded in two studies (15, 18). Control groups. None of the studies employed a control group of IBS sufferers who were not on the elimination diets. Trial length. An adequate length of time for treatment in IBS trials has been defined as 8 –12 wk (6, 11). Four studies (12, 14, 15, 18) stopped the treatment after identification of adverse food reaction and made no attempt to extend the treatment period by tailoring individual diets, excluding problem foods. In those trials the maximum length of treatment time was 3 wk. Three of the studies (13, 16, 17) extended the treatment length by asking their subjects to
AJG – Vol. 93, No. 11, 1998 continue on modified diets after identification of adverse food reactions. Nanda et al. (16) found that 80% of the subjects were still following their modified diets at on average of 14.7 months after commencement of the individually tailored diets; all but one had apparent ongoing benefits. Three subjects from the original sample in Farah et al. (13) continued on individual exclusion diets for a period of up to 18 months and remained well. Petitpierre et al. (17) followed-up their subjects at 6 months and found that 71% remained well. Blinding. Open food challenges alone were used to identify adverse food reactions in three trials (15, 16, 18). Open and blind challenges were used in four other trials (12–14, 17). Double-blind challenges were used only in three trials (12–14). In the studies that followed the positive open challenges with blind challenges, the positive results were not consistently repeated (12, 13). In both studies, eight subjects who reacted positively to open challenges underwent a challenge with the same foods in a double-blind fashion; only 37.5% of the open food challenges were confirmed by this method. The foods identified by both open and blind food challenges were yeast, milk, egg, peas, and coffee. Jones et al. (14) used double-blind challenges without open food challenges; 83% of the test substances and 92% of control solutions were correctly identified. Wheat, banana, corn, and potato were identified to cause adverse food reactions. Baseline characteristics. Race and socioeconomic status were not reported, except in the study by Nanda et al. (16), where age, gender, and socioeconomic class were shown to not affect the likelihood to respond to the elimination diet. One study (14) failed to document any demographic information. Previous and concurrent therapy. Only one study (16) mentioned the previous use of other treatments by subjects. In this study subjects were required to have failed conventional therapy before entry. The authors also documented that subjects were asked to stop all medications while on the elimination diet. Compliance. Nanda et al. (16) stated that their subjects were kept under regular review to help ensure compliance. They also noted that those who responded to the exclusion diet had a significantly greater weight loss than nonresponders, suggesting that poor compliance may indeed have been a factor in treatment failure. The other studies all failed to document any monitoring of adherence to the diet. Outcome measures. Most studies used a system of diaries and questionnaires to record symptoms (13, 15, 16, 18). Two studies failed to report their method for monitoring subjects’ progress (12, 17). Jones et al. (14) measured multiple laboratory parameters including rectal prostaglandin E2 levels, which were significantly higher on test than on placebo days. Unfortunately no record was made of whether this was related to symptom exacerbation.
TABLE 2 Trial Design: Research Protocol Baseline Period
Type of AFRs Under Investigation
Disaccharide Absorption Excluded
Bentley et al. (12)
Not measured
Hypersensitivity, intolerance
No
Farah et al. (13)
Not measured
Intolerance, allergy
No
Jones et al. (14) Study 1
Not measured
Intolerance
No
Study 2
Not measured
Intolerance
No
Study 3
Not measured
Intolerance
No
McKee et al. (15)
3 wk
Intolerance
Lactose
Nanda et al. (16)
Not measured
Intolerance
No
Petitpierre et al. (17)
Not measured
Hypersensitivity, intolerance
No
Low allergenic; salicylates present; duration, 3 wk
Zwetchkenbaum and Burakoff (18)
2 wk
Hypersensitivity, intolerance
Lactose
Exclusion of foods and same-food families linked to IBS symptoms from food diaries; duration, 2 wk
Reference
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Treatment: Baseline Elimination Diet
Challenge Protocol
Follow-Up
Low allergenic; excluded all sources of salicylates, amines, glutamates, and artificial additives; unknown duration Low allergenic; salicylates and amines present; duration, 2 wk
Open food 3 days apart; DBPC in responders DBPC; open food 1 wk apart in responders
3 responders remained well; duration not stated
Low allergenic; likely to contain significant sources of salicylates and possibly amines; duration, 1 wk (Study 1) Study 2: same diet during challenges only Study 3: same diet, 4 days
Open food, daily;
Not recorded
DB nasogastric daily; SB disguised in unspecified flavored soup daily Open, unspecified frequency
Not recorded
Low allergenic; excluded all sources of salicylates, amines, glutamates, and artificial additives; duration, 1 wk Low allergenic; salicylates and amines present; duration, 3 wk
DBPC 5 double-blind placebo-controlled; DB 5 double blind; SB 5 single blind; IBS 5 irritable bowel syndrome; AFR 5 adverse food reaction.
Open for 2 days
Open and singleblind; unspecified frequency Open for 2 days 2 days apart
6–18 months
Not recorded
Not recorded
14.7 months average for responders; 12.5 months for nonresponders 6 months
Not recorded
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AJG – Vol. 93, No. 11, 1998 TABLE 3 Foods Identified to Cause Adverse Food Reactions in the Irritable Bowel Syndrome
Adverse Food Reactions Identified to:
Number of Studies
Confirmed by Open Challenge
Confirmed by Double-Blind Challenge
Milk Wheat Egg Dairy products
6/7 4/7 4/7 ?
Yes Yes Yes Yes
Yes Yes Yes —
Corn Peas Tea Coffee Potato Nuts Wine Citrus fruit Tomato
1/7 2/7 2/7 4/7 2/7 2/7 1/7 2/7 1/7
Yes — Yes Yes Yes Yes Yes Yes —
Yes Yes — Yes Yes Yes Yes — Yes
Chocolate Banana Tuna fish Celery Yeast
1/7 2/7 1/7 1/7 1/7
Yes Yes Yes Yes —
— Yes Yes Yes Yes
Significant Source Of:
Skin Prick Test
Lactose
Positive* Positive* Positive* —
— — Lactose, possibly other additives if processed Salicylates Salicylates Salicylates Salicylates Salicylates Salicylates Salicylates, amines Salicylates, amines Salicylate, amines, glutamates Amines Amines Amines
— — — — Positive* Positive* — — Positive* — Positive* Positive* Positive*
* Petitpierre et al. (17).
Study outcomes Table 3 summarizes the positive challenge results from all studies. Milk, wheat, and eggs were identified as the most frequent causes of exacerbation of IBS symptoms, using both open and double-blind placebo-controlled challenges. Coffee was identified in four studies; tea, nuts, peas, and potato were identified in two studies each, and corn was identified in one study. Interestingly, the common trait of all of these foods is their high salicylate content (with the exception of potato, which can be low to moderate depending on the type, but is a staple food and is likely to be consumed frequently and in considerable quantities). Similarly, foods high in amines were identified as problem foods in a number of studies, although less often than foods high in salicylates. Only one study (17) identified positive responses to artificial food additives, namely, sodium benzoate, sodium nitrate, erythrosine, and carmitic acid. Few patients were followed-up beyond the study period, making assessment of the long-term value of dietary manipulation difficult. The studies that attempted to do so (12, 13, 16, 17) found a tendency toward long-term benefit of dietary manipulation. Overall quality None of the trials reviewed met five or more of the eight criteria required for study validity and interpretability. One study satisfied only one of these criteria (14), three studies satisfied two of eight criteria (12, 15, 17), and two studies satisfied three criteria (13, 16). The study by Zwetchenbaum and Burakoff (18) satisfied half of the criteria.
DISCUSSION Adverse food reactions may play an important role in IBS, as many patients report an exacerbation of symptoms after food ingestion. However, this could represent a nonspecific but enhanced intestinal response to eating. The available literature examined in this review, unfortunately, does not provide uniform evidence that food sensitivities are important in IBS. Trials evaluating IBS with diarrhea as the predominant symptom reported a higher rate of responders to the elimination diets and were able to identify a higher number of adverse food reactions (12–14). This suggests that there may be a higher prevalence of adverse food reactions in IBS sufferers where diarrhea is the predominant characteristic, but this remains to be established. There were numerous methodological limitations identified in the literature. For example, a number of studies have shown that exacerbation of symptoms occurs in IBS subjects after ingesting fructose and sorbitol mixtures (21, 22). Both fructose and sorbitol appear naturally in fruits in varying amounts (22), and sorbitol is a frequent ingredient in dietetic foods. Jain (22) showed that ingestion of 10 g sorbitol, equivalent to 4 –5 sugar-free mints or two medium pears, produced moderate discomfort in 10% and severe discomfort in 17% of healthy subjects. The intestinal symptoms experienced by the subjects were consistent with IBS, namely, abdominal pain, bloating, and diarrhea, with symptoms lasting up to 6 h after ingestion. Failure to exclude sorbitol or fructose malabsorbers may also have confounded the results of the studies conducted, particularly those that
AJG – November 1998 TABLE 4 Recommendations for Investigating Adverse Food Reactions in Irritable Bowel Syndrome 1. Compare pretreatment characteristics of the groups, including IBS symptoms and history of atopy 2. Stratify by the type of disturbed defecation in IBS subjects (or consider restricting the study to diarrhea-predominant) 3. Exclude disaccharide malabsorption, in particular lactose and fructose 4. Exclude sorbitol malabsorption 5. Monitor and account for the use of concurrent medication 6. Document use and success of prior treatments for IBS 7. Exclude medications containing salicylates or antihistamines 8. Exclude true food allergy prior to challenge procedures although this is rare; skin prick tests to foods have a good negative predictive value 9. Administer a low-allergenic diet excluding all sources of salicylates, amines, glutamates, and artificial additives 10. Trial elimination diet for at least 3 wk 11. Monitor compliance with the elimination diet 12. Use double-blind placebo-controlled capsule challenges; open challenges are unacceptable 13. Allow for at least a 48-h washout period between each challenge 14. Allow for a 3-day rest period after a positive challenge 15. Use validated, reliable, and responsive-to-change tools for recording outcome measures 16. Follow-up responders on diets excluding identified adverse food reactions for at least 12 wk
allowed pears in the elimination diets (14, 15). Similarly, lactose intolerance was not excluded in a number of studies that used milk challenges (12, 14, 16, 17). Most investigators failed to exclude all sources of salicylates, amines, and glutamates from their elimination diets (13, 14, 16, 17). These are natural, pharmacologically active substances that are believed to cause adverse food reactions, inducing symptoms such as nausea, vomiting, recurrent abdominal pain, flatulence, and bouts of diarrhea (23). Failure to exclude these substances may have led to a lower response rate to the elimination diet in these studies. Indeed, a high level of salicylates or amines was a feature in a significant number of foods identified as problem foods. We postulate, based on the limited available literature, that salicylates and to a lesser extent amines largely explain apparent food intolerance in IBS. The gold standard for investigating adverse food reactions remains the double-blind placebo-controlled capsule challenge. Unfortunately, in three of the studies reviewed only open food challenges were used (15, 16, 18). Open food challenges may be seriously biased because a psychologically mediated response to the ingested food may occur because of suggestion or adverse conditioning (8). In the diagnosis of pharmacologically mediated food intolerance, the open food challenge is further complicated, as most foods contain a mixture of salicylates, amines, and glutamates, and each has the potential to cause an adverse food reaction. The ability of masking the test substance in a food vehicle (e.g., soup, as in the study of Jones et al. [14]) remains limited. Further, the flavorings used to prevent
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recognition of the test substance are likely to be a source of salicylates, as most flavoring essences are rich in salicylates. In conclusion, the hypothesis that food sensitivities play an important role in IBS is not well supported by the available literature. Despite the lack of consistency and frequent methodological flaws in the studies included in this review, the following were common findings. Diarrheapredominant IBS subjects may respond better to an elimination diet; significantly more of these subjects experienced symptom remission while on the diet. Milk, wheat, egg, and foods high in salicylates or amines were consistent problem foods across a number of studies. Well-designed studies are now needed to evaluate these issues. Based on the results, recommendations for optimizing the investigation of adverse food reactions in IBS in future studies are summarized in Table 4. Reprint requests and correspondence: N. J. Talley, Professor of Medicine, Department of Medicine, University of Sydney, Nepean Hospital, Penrith, 2751, N.S.W., Australia.
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