This randomized placebo-controlled study provides evidence that oral α-galactosidase can improve gas-related symptoms in children and adolescents. The efficacy of α-galactosidase was supported by a significant and parallel decrease in the severity of bloating and FPS-R score. We used the FPS-R scale in order to measure the overall degree of discomfort associated with gas-related symptoms in everyday life. This could be considered acceptable as, in our patients, bloating was the main symptom whilst abdominal pain/spasm and altered bowel habit were only occasionally present.
The significant decrease of FPS-R score occurring in the active group and the marginal change in the placebo group provides the evidence of the efficacy of α-galactosidase. The similar score values at end of treatment should be evaluated taking into account the apparent imbalance in the baseline FPS-R.
The significant effect on bloating was also confirmed by a reduction in the number of days with severe episodes of bloating. In the opinion of the authors, 2 less days of bloating over the week in the alpha-galactosidase group as compared to placebo would be clinically significant.
Gas-related symptoms are common medical problems in pediatrics; the subjective sensation of bloating with or without a visible increase of abdominal distension is one of the most common complaints faced by pediatric gastroenterologists and general pediatricians in their clinical practice. Gas-related symptoms are included in the functional gastrointestinal disorders (FGID) as there is no evidence of morphological or biochemical abnormalities. When the symptoms are mild or episodic, reassurance and dietary changes may be sufficient. However when children suffer of recurring symptoms of bloating, flatulence (wind), distension and abdominal discomfort/pain with significant impairment for children and their family, it is reasonable to have a more proactive approach to reduce symptoms. The proposed pathophysiology of gas-related symptoms includes a variety of different and overlapping mechanisms, which are difficult to recognize in clinical practice [4, 5].
Bloating and distension together with belching, aerophagia and flatulence, have been attributed to excessive intestinal gas accumulation, impaired handling of gas in the small intestine, impaired clearance from the proximal colon, psychological factors, altered gut microflora, incomplete digestion and malabsorption of carbohydrates .
We did not investigate the dietary habits of children before and during our study. Parents were instructed to continue with their usual diet over the study period in order to avoid any possible impact from a change of diet to the study results. According to clinical history and parents’ opinion, the symptoms were apparently related to meals: a fact which is also demonstrated by the bloating severity score which was lowest at the time of waking up and steadily increased during the day.
There are different strategies that may reduce intestinal gas including active charcoal, simethicone etc. [9, 10]. Recently, the use of antibiotics seems to provide significant relief of functional GI symptoms, bloating and abdominal pain, but the need for repeated treatment cycles may have an important impact on the intestinal bacterial flora [21, 22], especially in children.
In recent years, an alternative approach, based on the administration of α-galactosidase, an enzyme with amylase-like activity, seems to be effective in reducing the production of intestinal gas by breaking down non digestible oligosaccharides (NDO) before they reach the lower intestine. Indeed, the human intestine does not contain the enzyme required to digest NDO and their consequent incomplete digestion produces increased bacterial fermentation generating hydrogen, methane and carbon dioxide [13–15].
Our results show that in children with predominant gas-related symptoms, the administration of α-galactosidase significantly reduces global distress, bloating and flatulence compared to placebo, but does not significantly reduce other symptoms such as abdominal distension and spasms which generally occur in functional gastrointestinal disorder. However this is consistent with the mechanism of action of α-galactosidase. The reduced formation of gas by colonic bacteria may have been expected to have other beneficial effects on distension of colon segments and abdomen.
The strength of our findings is mitigated by the findings in some secondary efficacy endpoints. No significant changes were observed between α-galactosidase and placebo for the “physician’s overall evaluation” at end of treatment and at follow-up. This may be related to the fact that this global evaluation may include other symptoms (in addition to bloating) which are poorly responsive to α-galactosidase such as symptoms that are not gas-related. The effect of α-galactosidase on gas related symptoms does not appear to be long-lasting. The improvement observed at the end of treatment was not sustained after 2 weeks of follow-up but this is consistent with the mechanism of action of the enzyme.
The limitations of our study are the short duration of treatment (2 weeks only) and the relatively small sample compared to trials in adult populations.
There is not much information about placebo response on gas related symptoms in children in literature. In our study, we did not see apparent difference in the placebo response between children of less and above 8 years. There were no reported adverse effects during the study. Based on our study there is no safety issue related to the use of α-galactosidase in children with bloating and gas-related symptoms. This is also supported by clinical practice and post-marketing experience on the use of α-galactosidase in children as well as in adults.
Oral α-galactosidase was effective in the short-term treatment of gas-related symptoms in children who were referred to specialist care. Its use is also supported by non-toxicity, good tolerability and availability of the formulation in drops, suitable for pediatric patients.
Further longer and larger randomized controlled clinical trials are needed to assess the efficacy and usefulness of α-galactosidase in children with gas-related symptoms and to identify subgroups of patients who are more likely to respond (or fail) to this agent.
A detailed medical history may help physicians to recognize children in whom, based on the medical history, food appears to induce or favor gas-related symptoms.
A symptomatic treatment approach for these children could be beneficial: if there is no significant improvement in the main target symptom or overall symptoms after 2 weeks, a different alternative approach should be considered.
This study was placebo-controlled, as currently there is no reference treatment for gas-related symptoms in FGID. The evidence of efficacy of antiflatulents such as simethicone and activated charcoal is weak, together with that of probiotics, such as different strains of Lactobacillus or Bifidobacterium spp. Similarly, there does not appear to be any robust evidence for using antispasmodics, prokinetics or non-absorbable antibiotics if the target symptom is bloating. Our study was carried out in children who predominantly had bloating and gas-related symptoms, with no significant abdominal pain. Consequently, the beneficial results obtained in this study cannot be considered valid for children suffering from different variants of functional gastrointestinal disorder (IBS-predominant constipation or IBS-predominant diarrhea).
We acknowledge the limitations of the present study. The number of included patients is limited and their age range is wide. In addition, although the “gas-related syndrome” may be considered as a functional digestive syndrome characterized by non specific gastrointestinal symptoms, including bloating, flatulence, abdominal distension and discomfort that the patient attributes to an excess of abdominal gas, however this condition is poorly defined and overlaps with IBS. All our patients meet Rome III criteria for IBS and the American College of Gastroenterology IBS Task Force recommends that further investigations are unnecessary in young patients without alarm features with the exception of celiac disease serology. However, different diagnoses, including lactose intolerance, fructose intolerance, small bowel bacterial overgrowth and aerophagia, were not formally investigated in our patients. Finally, although we instructed the parents of our patients to continue with their usual diet over the study period, the dietary habits of our children were not formally recorded in diary during the study. For this reason, we can not relate the symptoms to the type of diet (high and low fiber intake).
This study has shown for the first time that pediatric patients with predominant gas-related symptoms had a better response than placebo in the short term use of oral α-galactosidase. The improvement of symptoms becomes evident in a few days, in particular the reduction of the severity and frequency of bloating and flatulence. This effect tends to disappear in half of patients 2 weeks after treatment withdrawal.