Di Stefano M, Pesatori EV, Manfredi GF, et al. Non-celiac gluten sensitivity in patients with severe abdominal pain and bloating: the accuracy of ALCAT 5. Clin Nutr ESPEN. 2018;28:127-131.
This study compared results obtained from a specific antigen leukocyte cellular activation test (ALCAT) with those obtained with a standard double-blind, placebo-controlled gluten challenge in a group of patients with clinically suspected non-celiac gluten sensitivity (NCGS).
To determine if the ALCAT test could be used to support clinical suspicion of NCGS
Twenty-five patients (3 men and 22 women), mean age 32, with long histories of abdominal symptoms were enrolled. All the patients reported their symptoms on a gluten-containing diet, considered gluten to be the causal agent, and judged bloating and abdominal pain as the most severe of their symptoms. These symptoms were confirmed by the completion of a questionnaire, before entry. The mean duration of these 2 main symptoms was 10±4 years. The presence of organic conditions was excluded by endoscopic or radiologic procedures, abdominal ultrasound, and routine blood tests, including thyroid function tests and celiac disease serology. None of the patients suffered from wheat allergy.
Study Parameters Assessed
All participants underwent the ALCAT 5 test during the 3 months before beginning a gluten-containing diet. The results of this test were blinded to both the patient and investigators during the next phases of the study. During the period from the ALCAT 5 test to the study entry, patients followed a gluten-containing diet.
The ALCAT 5 is a variation of the ALCAT test used to evaluate food sensitivities. Specifically, it is an in vitro test evaluating the toxic effect of gluten on neutrophils by exposing them to a gluten-containing extract of cereals. Results of the test are obtained through an automated measurement of neutrophil size and volume following their incubation with gluten-containing cereal extracts.
Patients followed a gluten-free diet for more than 6 weeks before the actual start of the study. Patients were tested for non-celiac gluten sensitivity (NCGS) using the Salerno protocol.1 Patients consumed 10 capsules daily that contained either wheat gluten (500 mg/capsule) or placebo (rice starch, 500 mg/capsule). Though cumbersome, this protocol is the way NCGS is currently diagnosed.
The Salerno protocol is considered the gold standard test for NCGS. Symptom data from this study were evaluated using Cohen’s kappa statistic (Cohen’s k) to look for agreement between the ALCAT 5 findings and the Salerno results.
After blinded administration of gluten (Salerno protocol), 13 out of 25 (52%) patients showed an increase in the severity of abdominal pain, and 11 out of 25 (44%) showed an increase in the severity of abdominal bloating. Considering these 2 symptoms together, in 16 patients out of 25 (64%), blinded gluten administration induced an increase of abdominal pain and/or bloating. The ALCAT 5 test proved to be positive in 20 patients and negative in 5 patients. In 16 patients out of 25 the result of ALCAT 5 agreed with the Salerno protocol results (64%). In particular, both tests were positive in 14 patients and negative in 2 patients.
ALCAT 5 and blinded gluten challenge results showed the 2 tests were concordant in 12 out of 25 patients (48%) when abdominal pain was considered as the main symptom and in 13 out of 25 patients (52%) when bloating was considered as the main symptom. However, the concordance of the 2 tests improved if the modification of both symptoms was considered: in 16 out of 25 patients (64%) the severity of at least 1 of the 2 symptoms during gluten capsule intake was >30% than its severity during placebo capsule intake. In this case, ALCAT 5 and blinded gluten challenge results were concordant in 16 out of 25.
The positive predictive value (PPV) of the ALCAT 5 was only 65%, while the negative predictive value (NPV) was 40%.
The entire diagnostic entity that people are calling NCGS remains poorly defined and confusing. We are all familiar with patients who claim to be gluten-intolerant despite not having celiac disease. What exactly these individuals are suffering from is unclear. The ALCAT 5 test was intended to identify which of these individuals might benefit from a gluten-free diet and which individuals will not.
Perhaps the most striking finding in this study was not that this test produced weak predictive value but that patient self-assessment was such a poor predictor of gluten sensitivity. The participants in this study were all certain that they felt better on gluten-free diets and that eating gluten worsened their bloating and pain. Yet the blinded dosing of gluten only elicited symptoms in about half of the study participants; 52% had an “increase in the severity of abdominal pain” and 44% “showed an increase in the severity of abdominal bloating.”
Comparison of results of the gluten challenge and the ALCAT 5 test showed that a concordance was evident in 64% of cases. Put another way, only about half of the people responded to gluten the way they had assumed they would. The ALCAT 5 test could predict who these people would be 64% of the time. Keep in mind, flipping a coin as a random tool to guess who these people were would be correct about half the time. As the authors write, “Considering the single symptoms separately or together, results indicate that the agreement between the tests was no better than would be expected by chance.”
Perhaps the most striking finding in this study was not that this test produced weak predictive value but that patient self-assessment was such a poor predictor of gluten sensitivity.
It should not come as a surprise that the ALCAT 5 test failed to diagnose NCGS. How do you test for something that may or may not be due to the patient’s self-diagnosed cause? As this study suggests, not very well.
Gluten causes celiac disease in about 1% of the population (though the exact percentage is open for debate). Yet about 12% of the population believes that eating gluten triggers symptoms. This percentage continues to increase. The research has gone back and forth and there is still no definitive test or even distinct biomarkers associated with this “condition.”
In 2011 Biesiekierski et al reported results of a placebo-controlled trial in patients with irritable bowel syndrome (IBS). These patients tested negative for celiac but were sure a no-gluten diet controlled their symptoms. A total of 34 patients were fed either gluten or placebo each day for 6 weeks. In the gluten group, 13 of 19 (68%) reported that their symptoms were not adequately controlled. In the placebo group, 6 of 15 (40%) complained of inadequate symptom control. These results suggested that there was something about gluten that was a problem even in non-celiac patients.2
Biesiekierski performed a similarly designed study published in 2013 with very dissimilar results. Participant perceptions shifted away from gluten and toward FODMAPs (fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) as the causative agents for their symptoms. In keeping, only 8% of these 37 patients appeared to react to gluten with worsening symptoms.3
The existence of NCGS was affirmed in a 2015 study by Antonio di Sabatino. In a crossover trial of 61 patients with suspected NCGS, the severity of overall symptoms increased significantly during 1 week in which participants received small amounts of gluten (slightly more than 4 g per day) compared with placebo.4
A separate 2015 study was less convincing. Zanini et al ran a blinded placebo-controlled re-challenge, giving gluten to 35 patients with self-reported NCGS. Only 34% had a gluten-specific response. Nearly half of the patients responded negatively to a placebo consisting of gluten-free flours. Do we assume that half of these people are sensitive to corn and potato starch? That is unlikely, and we may have to settle with the explanation that this population is sensitive to nocebo effects.5
As mentioned, FODMAP sensitivity has been suggested as a possible explanation for some cases of IBD and possibly NCGS.6 However, in the Zanini study just mentioned, the placebo control was extremely low in FODMAPs, so another explanation is needed.
More recently blame is turning away from gluten to fructans. Foods that contain gluten often contain fructans, which are a type of FODMAP. So, when people pursue a gluten-free diet, they are unwittingly cutting their FODMAP (fructan) intake by about half.
Some of the most convincing data in support of fructans as the culprit comes from a 2018 paper by Skodje et al, who ran 59 people through a double-blind crossover challenge similar to that used in the NCGS trials. In this case, participants were randomly placed on diets containing gluten (5.7 g), fructans (2.1 g), or placebo. Following a minimum 7-day washout period (until the symptoms induced by the previous challenge were resolved), participants crossed over into a different group, until they completed all 3 challenges (gluten, fructan, and placebo). Discomfort scores varied significantly during the different food trials. The discomfort scores were significantly higher during the fructan portion of the trial than during the gluten portion. There was no difference in scores between the gluten and placebo portions of the trial.7 Thus, it appeared that fructans could be to blame rather than gluten in these patients.
Basically, it’s turned into a mess. By the fall of 2015, we found Gibson8 and Zanini arguing back and forth via editorials and letters in the pages of Alimentary Pharmacology and Therapeutics: Is NCGS real or not?9
This gluten debate is not just academic; it is increasingly relevant. Eating gluten-free has become a lifestyle choice. According to a 2013 report from the NPD Group (a market research organization), about one-third of the US population believes they would be healthier if they went gluten-free.10 Yet a review published in New Scientist concluded there is no evidence that avoiding gluten is in any way beneficial for the vast majority of people, despite the claims of a few sensationalist books.11 The same publication later observed that, for whatever reason, “a gluten-free diet has become a lifestyle accessory for many, especially the more educated and financially privileged.”12
Global sales of gluten-free food rose 12.6% in 2016, and gluten-free food sales is a billion-dollar industry.13
This NCGS situation is reminiscent of Chinese restaurant syndrome. Our younger readers may not remember this. In 1968 a paper came out describing monosodium glutamate (MSG) symptom complex or, to use its common name, Chinese restaurant syndrome, which was supposedly triggered by MSG, the food additive commonly used in Chinese restaurants to enhance flavors. Descriptions of MSG-induced asthma, urticaria, angioedema, headaches, and rhinitis prompted some to suggest that MSG could be a trigger in patients presenting with these conditions. Many people were certain they suffered from reactions to MSG and were adamant about avoiding exposure. Even today, Chinese restaurant menus will state “NO MSG” to reassure these people. Yet most, if not all, of these associations have been disproven.14-17 The harder researchers looked at it, the more elusive the syndrome became. Perhaps NCGS will turn out to be a similar phenomenon. There are still questions to answer before NCGS is accepted as a real diagnosis.18 At this point NCGS remains an undefined disorder.19 There are no defining biomarkers for the condition.20
There are other possible explanations for the NCGS phenomenon. While the most plausible is that FODMAPs, particularly fructans, trigger the symptoms, there are a few other potential causes that should stay on our differential. Too much fiber in the diet is so obvious some patients will not think of it and continue to take increasingly greater quantities, sometimes on the advice of their physicians who are treating IBS. Probiotics have been linked with discomfort and brain fog,21 so they should also be considered as a potential culprit. A commentary on this probiotics study appears in the November issue of Natural Medicine Journal.22
The problem with the ALCAT 5 test may be that the lab assumed NCGS would be akin to a food allergy, triggering immune reactions. If NCGS exists, it may be more like a food intolerance, an indigestible constituent in wheat provoking symptoms in a manner more like lactose intolerance than celiac disease.
To quote a December 2018 review: “It is imperative to base food allergy diagnosis on well-defined criteria, avoiding ‘alternative’ tests that are available to the general public. Non-celiac gluten sensitivity is a misnomer and should be abandoned in favor of non-celiac wheat intolerance, an entity suffering from lack of biomarkers and still not convincingly described in children.”23
- Catassi C, Elli L, Bonaz B, Bouma G, Carroccio A, Castillejo G, et al. Diagnosis of non-celiac gluten sensitivity (NCGS): the Salerno Experts' criteria. Nutrients. 2015;7:4966e77.
- Biesiekierski JR, Newnham ED, Irving PM, et al. Gluten causes gastrointestinal symptoms in subjects without celiac disease: a double-blind randomized placebo-controlled trial. Am J Gastroenterol. 2011;106(3):508-514.
- Biesiekierski JR, Peters SL, Newnham ED, Rosella O, Muir JG, Gibson PR. No effects of gluten in patients with self-reported non-celiac gluten sensitivity after dietary reduction of fermentable, poorly absorbed, short-chain carbohydrates. Gastroenterology. 2013;145(2):320-328.
- Di Sabatino A, Volta U, Salvatore C, et al. Small amounts of gluten in subjects with suspected nonceliac gluten sensitivity: a randomized, double-blind, placebo-controlled, cross-over trial. Clin Gastroenterol Hepatol. 2015;13(9):1604-1612.
- Zanini B, Basch R, Ferraresi A, et al. Randomised clinical trial: gluten challenge induces symptom recurrence in only a minority of patients who meet clinical criteria for non‐coeliac gluten sensitivity. Aliment Pharmacol Ther. 2015;42:968-976.
- Gibson PR. Use of the low-FODMAP diet in inflammatory bowel disease. J Gastroenterol Hepatol. 2017;32 Suppl 1:40-42.
- Skodje GI, Sarna VK, Minelle IH, et al. Fructan, rather than gluten, induces symptoms in patients with self-reported non-celiac gluten sensitivity. Gastroenterology. 2018;154(3):529-539.
- Gibson PR. Editorial: noncoeliac gluten sensitivity - the controversy rages on. Aliment Pharmacol Ther. 2015;42(10):1234.
- Zanini B, Ricci C, Lanzini A. Editorial: noncoeliac gluten sensitivity - the controversy rages on. Authors' reply. Aliment Pharmacol Ther. 2015;42(10):1235.
- Percentage of U.S. adults trying to cut down or avoid gluten in their diets reaches new high in 2013, reports NPD [press release]. Chicago, IL: The NPD Group; March 6, 2013. https://www.npd.com/wps/portal/npd/us/news/press-releases/percentage-of-us-adults-trying-to-cut-down-or-avoid-gluten-in-their-diets-reaches-new-high-in-2013-reports-npd/. Accessed March 26, 2019.
- Time for some grains of truth about wheat and gluten. NewScientist. July 9, 2014. https://www.newscientist.com/article/mg22329771-600-time-for-some-grains-of-truth-about-wheat-and-gluten/. Accessed March 26, 2019.
- Warner A. That faddish gluten free diet may be raising your diabetes risk. NewScientist. March 9, 2017. https://www.newscientist.com/article/2123995-that-faddish-gluten-free-diet-may-be-raising-your-diabetes-risk/. Accessed March 26, 2019.
- Gluten-free is still going gangbusters [press release]. Rockville, MD: Packaged Facts; October 19, 2012. https://www.packagedfacts.com/about/release.asp?id=3033. 2012. Accessed March 26, 2019.
- Williams AN, Woessner KM. Monosodium glutamate 'allergy': menace or myth? Clin Exp Allergy. 2009;39(5):640-646.
- Piersma FR, Veldkamp MW, Wesselink R, et al. Can we spice up our Christmas dinner? Busting the myth of the 'Chinese restaurant syndrome'. Neth Heart J. 2017;25(12):664-668.
- Geha RS, Beiser A, Ren C, et al. Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study. J Nutr. 2000;130(4S Suppl):1058S-1062S.
- Obayashi Y, Nagamura Y. Does monosodium glutamate really cause headache? : a systematic review of human studies. J Headache Pain. 2016;17:54.
- Volta U, Caio G, Tovoli F, De Giorgio R. Non-celiac gluten sensitivity: questions still to be answered despite increasing awareness. Cell Mol Immunol. 2013;10(5):383-392.
- Reese I, Schäfer C, Kleine-Tebbe J, et al. Non-celiac gluten/wheat sensitivity (NCGS)-a currently undefined disorder without validated diagnostic criteria and of unknown prevalence: position statement of the task force on food allergy of the German Society of Allergology and Clinical Immunology (DGAKI). Allergo J Int. 2018;27(5):147-151.
- Ierardi E, Losurdo G, Piscitelli D, et al. Biological markers for non-celiac gluten sensitivity: a question awaiting for a convincing answer. Gastroenterol Hepatol Bed Bench. 2018;11(3):203-208.
- Rao S, Rehman A, Yu S, Andino NM. Brain fogginess, gas and bloating: a link between SIBO, probiotics and metabolic acidosis. Clin Transl Gastroenterol. 2018;9(6):162.
- Schor J. Probiotics may not be for everyone. Natural Medicine Journal. 2018;10(11).
- DeGeeter C, Guandalini S. Food sensitivities: fact versus fiction. Gastroenterol Clin North Am. 2018;47(4):895-908.