Abstract
Although the primary cause of morbidity and mortality in people with cystic fibrosis (CF) is lung disease, 1 significant involvement of the digestive system occurs as well. Mutations in the CF transmembrane regulator (CFTR) gene also modulate the properties of epithelial ion channels other than respiratory channels that affect the gastrointestinal (GI) and pancreatic milieu. 2 As in the airways, defects in CFTR alter the epithelial surface fluid, mucus viscosity, and pH, increasing risk of stasis through the various GI hollow epithelial-lined structures. Understanding the morbidity and manifestation mechanism of the GI symptoms of CF is very important for understanding and treating CF as a multisystem disease. As the pathogenic origin of GI manifestation, dysbiosis of the gut microbiome, low-grade GI inflammation, and increased GI permeability have been reported. These three pathophysiological causes also lead to the pathogenesis of other chronic GI disorders, such as irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Based on these connections, it is thought that symptoms appear to be similar because they share much pathophysiology. Many of the symptoms reported by CF patients (bloating, constipation, abdominal discomfort, etc.) are very similar to IBS symptoms found in the Rome criteria. 3 Therefore, it is necessary to systematically and objectively evaluate the appearance mode and severity of GI symptoms of CF.
In the August 2019 issue of the United European Gastroenterology Journal, Hayee et al. report for the first time a comprehensive study of the extent and impact of chronic GI symptoms in patients with CF in a large cohort of unselected patients. 4 In their study, many symptoms reported by CF patients were reminiscent of those seen in IBS, and more CF patients had symptoms that met the Rome IV criteria for IBS than would be expected in the general population (5.5% in the UK) as they described; the IBS-SSS (IBS-symptom severity score) was used for the assessment of GI symptoms in CF. 5 Hayee et al. also used an evaluation tool [GSRS (GI symptom rating scale) 6 ] that encompasses both upper and lower GI symptoms, and found that more patients reported more severe symptoms, albeit broadly in line with IBS-SSS score. However, there was a group of patients who did not score highly in SSS but reported significant symptoms in GSRS, suggesting that the latter may be a more appropriate tool in terms of sensitivity. In conclusion, Hayee et al. reported that, as IBS-SSS increased, patients reported a higher frequency of moderate and severe symptoms in GSRS, with most symptoms being due to the lower GI tract.
Although the mechanisms of GI symptoms in CF have not been investigated in detail, it is known that guanylyl cyclase (GC) is involved in the pathogenesis of CF, as it is known to be implicated in functional or chronic idiopathic constipation. As linaclotide—recently approved for the indication to IBS-C and chronic idiopathic constipation in some countries including Japan7,8—blocks GC and improves complete spontaneous bowel movements, fecal condition, and abdominal pain/discomfort, this drug would be also expected to be useful in the treatment of constipation symptoms in CF. Further understanding of GI symptom generation, pathophysiological origins, and assessment method for monitoring symptoms will be necessary to apply this agent to the possible treatment of CF.
As the life span of CF patients has increased in recent years, there is no doubt that the opportunity to see CF patients with GI symptoms is increasing. However, until now, there has been no validated evaluation method for the type and severity of GI symptom in patients with CF. It is very significant that Hayee et al. have attempted to develop an evaluation system for GI symptoms in CF patients by modifying self-administered questionnaires such as IBS-SSS and GSRS.
The Rome Committee has a history of organizing diagnostic criteria and treatment options for functional GI disorders (FGIDs) that had previously been unclear, 9 and of helping to explore and develop new therapeutic options. This attempt by Hayee et al. will play an important role in the development of new therapeutic agents by establishing clear and valid symptom evaluation criteria, as in the Rome committee process. I hope that, through their attempts, a validated method for assessing GI symptoms with CF can be established and appropriate therapeutic agents developed.