598
Letters to the Editor
model was utilized. This was the same as in our study and is the consistent practice in the literature when performing a metaanalysis. With that being mentioned, we do agree that more large randomized trials may be beneficial for a dose-dependent meta-analysis, but at this point it appears that M–G is an inferior bowel preparation as compared with PEG. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Zhang Z. Is polyethylene glycol superior to miralax-gatorade in bowel preparations for colonoscopy? Am J Gastroenterol 2015;110: 596–597 (this issue). 2. Siddique S, Lopez KT, Hinds AM et al. Miralax with gatorade for bowel preparation: a metaanalysis of randomized controlled trials. Am J Gastroenterol 2014;109:1566–74. 3. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions The Cochrane Collaboration. 2011, http://handbook. cochrane.org/ 4. Zhang ZF, Duan ZJ, Wang LX et al. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies. BMC Gastroenterol 2014;14:23. 1 Division of Gastroenterology & Hepatology, University of Missouri Health Sciences Center, Columbia, Missouri, USA; 2Division of Gastroenterology, University of California, Irvine, California, USA. Correspondence: Matthew L. Bechtold, MD, FACP, FASGE, FACG, Division of Gastroenterology & Hepatology, University of Missouri Health Sciences Center, CE405, DC 043.00, Five Hospital Drive, Columbia, Missouri 65212, USA. E-mail: [email protected]
Dysbiosis in Celiac Disease Patients With Persistent Symptoms on Gluten-Free Diet: A Condition Similar to that Present in Irritable Bowel Syndrome Patients? Giovanni Marasco, MD1, Antonio Colecchia, MD1 and Davide Festi, MD1 doi:10.1038/ajg.2015.54
The American Journal of GASTROENTEROLOGY
nature publishing group
To the Editor: We read with great interest the article by Wacklin et al. (1) regarding duodenal microbiota composition in celiac disease (CD) patients, who, although on a long-term gluten-free diet (GFD), still suffered from persistent symptoms. The main objective was to evaluate whether an altered intestinal microbiota was associated in CD patients on GFD with persisting gastrointestinal symptoms. CD patients with persistent symptoms showed a higher relative abundance of Proteobacteria, a lower abundance of Bacteroidetes and Firmicutes, and a reduced microbial richness in comparison with patients without symptoms. From a clinical point of view, only one patient had a previous diagnosis of the irritable bowel syndrome (IBS), and IBS-specific questionnaire (Rome III) (2) was not performed during GFD. We would like to stress that, between the different hypotheses suggested by the Authors, some symptoms referred by the patients on GFD could be related to IBS. In fact, a recent meta-analysis showed that the pooled prevalence of IBS-type symptoms in patients with treated CD was 38.0% (3). In the present study, some IBS-like symptoms are present in 9 out 17 (53%) of the patients. In IBS patients, there is a strong mucosal immune activation predominantly characterized by infiltration of mast cells and T lymphocytes, which produces serineproteases, histamine, and prostaglandins (4). These mediators could be involved in changes of intestinal sensory-motor function in these subjects, in the presence of a low-grade inflammation, that could sensitize both intrinsic primary efferent and extrinsic primary afferent neurons. This condition could lead to neural and muscle dysfunction (i.e., altered intestinal motility and visceral sensitivity) and, finally, to symptom development. The immune activation in low-grade inflammation may be the consequence of a perturbation of gut microbiota (4). Moreover, gut microbiota changes reported in IBS patients (5) are similar to those documented by Wacklin et al. (1), namely the reduction of Bacteroidetes and of bacterial richness in CD patients with persistent symptoms. On the other hand, dysbiosis could be also directly associated with GFD; in fact, it has been
showed that GFD could produce changes in gut microbiota through a reduction in fructans that are known to have a prebiotic action (6). Thus, in our opinion, some CD patients on GFD with persistent symptoms could have IBS manifestations, and according to the suggestion by Wacklin et al. (1), we think that in CD patients with persistent symptoms a treatment with probiotics and/or prebiotics could be useful. CONFLICT OF INTEREST Guarantor of the article: Giovanni Marasco, MD. Specific author contributions: All authors contributed equally in the writing of the letter. Financial support: None. Potential competing interest: None.
REFERENCES 1. Wacklin P, Laurikka P, Lindfors K et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am J Gastroenterol 2014;109:1933–41. 2. Drossman DA. Rome III: The Functional Gastrointestinal Disorders Degnon Associates: McLean, VA, 2006. 3. Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol 2013;11:359–65. 4. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open? Am J Gastroenterol 2006;101:1295–8. 5. Hong SN, Rhee PL. Unraveling the ties between irritable bowel syndrome and intestinal microbiota. World J Gastroenterol 2014;20:2470–81. 6. AJ Moshfegh, Friday JE, Goldman JP et al. Presence of inulin and oligofructose in the diets of Americans. J Nutr 1999;129:1407S–11S. 1 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. Correspondence: Giovanni Marasco, MD, Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, Bologna 40138, Italy. E-mail: [email protected]
Response to Marasco et al. Pirjo Wacklin, PhD1, Pilvi Laurikka2, Katri Lindfors, PhD3, Jaana Mättö, PhD4, Kalle Kurppa, MD3 and Katri Kaukinen, MD2, 5 doi:10.1038/ajg.2015.59
VOLUME 110 | APRIL 2015 www.amjgastro.com
Letters to the Editor
nature publishing group
To the Editor: We thank Dr Marasco et al. (1) for their important comments regarding on our recently published paper (2). The authors addressed that the persisting symptoms in some of the celiac disease patients of our study could be related to irritable bowel syndrome (IBS). We agree with Marasco et al. that we cannot to fully exclude the possibility that the celiac disease patients suffered from concomitant IBS, as was already discussed in the original paper (2). IBS and celiac disease are often characterized with very similar symptoms, and can be difficult to distinguish on clinical basis (3). As Marasco et al. also pointed out, there are certain immunological markers and histological findings associated with IBS. However, none of these have been shown to be pathognomonic for the condition and the diagnosis is still based on clinical symptoms and exclusion of other diseases (4). It would be therefore very difficult, if not impossible, to define whether the persistent symptoms were caused by IBS or celiac disease, or both. It should nevertheless be emphasized that the participants were not visiting a clinic for their intestinal symptoms. Instead, they considered themselves healthy while they were invited to participate to this follow-up study, which suggest that they would not fulfill the Rome III criteria for IBS. In any case, the lack of well-establish medical treatment for IBS perhaps makes the official diagnosis rather irrelevant from a patient’s viewpoint. We agree with Marasco et al. that a long-term gluten-free diet may also have significant effect on microbiota composition. The role of prebiotics and/or probiotics supplement is intriguing in this context and certainly is an issue for further prospective studies. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1. Marasco G, Colecchia A, Festi D. Dysbiosis in celiac disease patients with persistent symptoms on gluten-free diet: a condition similar to that present in irritable bowel syndrome patients? Am J Gastroenterol 2015;110:598 (this issue) 2. Wacklin P, Laurikka P, Lindfors K et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent
© 2015 by the American College of Gastroenterology
symptoms on a long-term gluten-free diet. Am J Gastroenterol 2014;109:1933–41. 3. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left door open? Am J Gastroenterol 2006;101:1295–8. 4. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91. 1
SalWe, Strategic Centre for Science, Technology and Innovation in Health and Wellbeing, Espoo, Finland; 2School of Medicine, University of Tampere, Tampere, Finland; 3Tampere Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland; 4Finnish Red Cross Blood Service, Helsinki, Finland; 5Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. Correspondence: Kalle Kurppa, MD, Tampere Centre for Child Health ResearchUniversity of Tampere and Tampere University Hospital, Finn Medi 3, Biokatu 10, Tampere 33520, Finland. E-mail: kalle.kurppa@uta.fi
Focal Liver Lesions Suspected of Being Cholangiocarcinomas Nicola Zanini, MD1, Elio Jovine, MD2 and Giovanni Landolfo, MD1 doi:10.1038/ajg.2015.56
To the Editor: It was with great interest that we read the clinical guidelines regarding the management of focal liver lesions that was recently published in the Journal, “ACG Clinical Guideline: The Diagnosis and Management of Focal Liver Lesions” (1). In general, the best clinical guidelines are those in which extensive coverage of the issue and a concise summary of recommendations are well balanced. From this point of view, the ACG guidelines have hit the mark. However, as good guidelines should not examine a single issue too deeply, we would like to share one comment regarding the management of lesions that are suspected of being intrahepatic cholangiocarcinomas (ICCAs). ICCAs may be difficult to differentiate from metastatic lesions by imaging and histology. If a liver lesion that is suspected of being an ICCA is surgically resectable,
a diagnostic biopsy may not be required because its results would not change the management strategy. However, the patient should not be referred to surgery before the hypothesis of a metastatic lesion from an unknown primary tumor has been ruled out. This issue is not discussed in the paper, and we would like to point this out. As ICCAs are characterized by radiological behavior similar to that of metastatic tumors, and as metastasis to the liver is more common than a primary ICCA (2), a thorough evaluation should be carried out to assess the possibility of a separate primary malignancy. A complete evaluation should include upper and lower gastrointestinal endoscopy, chest imaging, and, for women, a mammogram (3). Extensive preoperative efforts should be carried out to avoid missing a primary tumor and seriously affecting the prognosis of the patient, delaying, at best, or preventing, at worst, potentially curative therapy. Of course, the ACG guidelines are not intended to be a comprehensive textbook regarding the management of cholangiocarcinomas; we are aware that limited space is reserved for the discussion of clinical issues, such as the one we have raised here. Nonetheless, we believe that the guidelines will be a must-read for clinicians and a quick “go-to” guide for appropriate management, and any possible misleading interpretation should be avoided. REFERENCES 1. Marrero JA, Ahn J, Rajender Reddy K et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol 2014;109:1328–47. 2. Maithel SK, Gamblin TC, Kamel I et al. Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer 2013;119:3929–42. 3. Dodson RM, Weiss MJ, Cosgrove D et al. Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 2013;217:736–50. 1
Department of Surgery, San Marino State Hospital, Borgo Maggiore, Republic of San Marino; 2 Department of Surgery, AUSL Bologna Maggiore Hospital, Bologna, Italy. Correspondence: Nicola Zanini, MD, Department of Surgery, San Marino State Hospital, Via Scialoja, 1, Borgo Maggiore 47893, Republic of San Marino. E-mail: [email protected]
The American Journal of GASTROENTEROLOGY
599
Letters to the Editor
model was utilized. This was the same as in our study and is the consistent practice in the literature when performing a metaanalysis. With that being mentioned, we do agree that more large randomized trials may be beneficial for a dose-dependent meta-analysis, but at this point it appears that M–G is an inferior bowel preparation as compared with PEG. CONFLICT OF INTEREST The authors declare no conflict of interest. REFERENCES 1. Zhang Z. Is polyethylene glycol superior to miralax-gatorade in bowel preparations for colonoscopy? Am J Gastroenterol 2015;110: 596–597 (this issue). 2. Siddique S, Lopez KT, Hinds AM et al. Miralax with gatorade for bowel preparation: a metaanalysis of randomized controlled trials. Am J Gastroenterol 2014;109:1566–74. 3. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions The Cochrane Collaboration. 2011, http://handbook. cochrane.org/ 4. Zhang ZF, Duan ZJ, Wang LX et al. The serotonin transporter gene polymorphism (5-HTTLPR) and irritable bowel syndrome: a meta-analysis of 25 studies. BMC Gastroenterol 2014;14:23. 1 Division of Gastroenterology & Hepatology, University of Missouri Health Sciences Center, Columbia, Missouri, USA; 2Division of Gastroenterology, University of California, Irvine, California, USA. Correspondence: Matthew L. Bechtold, MD, FACP, FASGE, FACG, Division of Gastroenterology & Hepatology, University of Missouri Health Sciences Center, CE405, DC 043.00, Five Hospital Drive, Columbia, Missouri 65212, USA. E-mail: [email protected]
Dysbiosis in Celiac Disease Patients With Persistent Symptoms on Gluten-Free Diet: A Condition Similar to that Present in Irritable Bowel Syndrome Patients? Giovanni Marasco, MD1, Antonio Colecchia, MD1 and Davide Festi, MD1 doi:10.1038/ajg.2015.54
The American Journal of GASTROENTEROLOGY
nature publishing group
To the Editor: We read with great interest the article by Wacklin et al. (1) regarding duodenal microbiota composition in celiac disease (CD) patients, who, although on a long-term gluten-free diet (GFD), still suffered from persistent symptoms. The main objective was to evaluate whether an altered intestinal microbiota was associated in CD patients on GFD with persisting gastrointestinal symptoms. CD patients with persistent symptoms showed a higher relative abundance of Proteobacteria, a lower abundance of Bacteroidetes and Firmicutes, and a reduced microbial richness in comparison with patients without symptoms. From a clinical point of view, only one patient had a previous diagnosis of the irritable bowel syndrome (IBS), and IBS-specific questionnaire (Rome III) (2) was not performed during GFD. We would like to stress that, between the different hypotheses suggested by the Authors, some symptoms referred by the patients on GFD could be related to IBS. In fact, a recent meta-analysis showed that the pooled prevalence of IBS-type symptoms in patients with treated CD was 38.0% (3). In the present study, some IBS-like symptoms are present in 9 out 17 (53%) of the patients. In IBS patients, there is a strong mucosal immune activation predominantly characterized by infiltration of mast cells and T lymphocytes, which produces serineproteases, histamine, and prostaglandins (4). These mediators could be involved in changes of intestinal sensory-motor function in these subjects, in the presence of a low-grade inflammation, that could sensitize both intrinsic primary efferent and extrinsic primary afferent neurons. This condition could lead to neural and muscle dysfunction (i.e., altered intestinal motility and visceral sensitivity) and, finally, to symptom development. The immune activation in low-grade inflammation may be the consequence of a perturbation of gut microbiota (4). Moreover, gut microbiota changes reported in IBS patients (5) are similar to those documented by Wacklin et al. (1), namely the reduction of Bacteroidetes and of bacterial richness in CD patients with persistent symptoms. On the other hand, dysbiosis could be also directly associated with GFD; in fact, it has been
showed that GFD could produce changes in gut microbiota through a reduction in fructans that are known to have a prebiotic action (6). Thus, in our opinion, some CD patients on GFD with persistent symptoms could have IBS manifestations, and according to the suggestion by Wacklin et al. (1), we think that in CD patients with persistent symptoms a treatment with probiotics and/or prebiotics could be useful. CONFLICT OF INTEREST Guarantor of the article: Giovanni Marasco, MD. Specific author contributions: All authors contributed equally in the writing of the letter. Financial support: None. Potential competing interest: None.
REFERENCES 1. Wacklin P, Laurikka P, Lindfors K et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent symptoms on a long-term gluten-free diet. Am J Gastroenterol 2014;109:1933–41. 2. Drossman DA. Rome III: The Functional Gastrointestinal Disorders Degnon Associates: McLean, VA, 2006. 3. Sainsbury A, Sanders DS, Ford AC. Prevalence of irritable bowel syndrome-type symptoms in patients with celiac disease: a meta-analysis. Clin Gastroenterol Hepatol 2013;11:359–65. 4. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left the door open? Am J Gastroenterol 2006;101:1295–8. 5. Hong SN, Rhee PL. Unraveling the ties between irritable bowel syndrome and intestinal microbiota. World J Gastroenterol 2014;20:2470–81. 6. AJ Moshfegh, Friday JE, Goldman JP et al. Presence of inulin and oligofructose in the diets of Americans. J Nutr 1999;129:1407S–11S. 1 Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy. Correspondence: Giovanni Marasco, MD, Department of Medical and Surgical Sciences, University of Bologna, via Massarenti 9, Bologna 40138, Italy. E-mail: [email protected]
Response to Marasco et al. Pirjo Wacklin, PhD1, Pilvi Laurikka2, Katri Lindfors, PhD3, Jaana Mättö, PhD4, Kalle Kurppa, MD3 and Katri Kaukinen, MD2, 5 doi:10.1038/ajg.2015.59
VOLUME 110 | APRIL 2015 www.amjgastro.com
Letters to the Editor
nature publishing group
To the Editor: We thank Dr Marasco et al. (1) for their important comments regarding on our recently published paper (2). The authors addressed that the persisting symptoms in some of the celiac disease patients of our study could be related to irritable bowel syndrome (IBS). We agree with Marasco et al. that we cannot to fully exclude the possibility that the celiac disease patients suffered from concomitant IBS, as was already discussed in the original paper (2). IBS and celiac disease are often characterized with very similar symptoms, and can be difficult to distinguish on clinical basis (3). As Marasco et al. also pointed out, there are certain immunological markers and histological findings associated with IBS. However, none of these have been shown to be pathognomonic for the condition and the diagnosis is still based on clinical symptoms and exclusion of other diseases (4). It would be therefore very difficult, if not impossible, to define whether the persistent symptoms were caused by IBS or celiac disease, or both. It should nevertheless be emphasized that the participants were not visiting a clinic for their intestinal symptoms. Instead, they considered themselves healthy while they were invited to participate to this follow-up study, which suggest that they would not fulfill the Rome III criteria for IBS. In any case, the lack of well-establish medical treatment for IBS perhaps makes the official diagnosis rather irrelevant from a patient’s viewpoint. We agree with Marasco et al. that a long-term gluten-free diet may also have significant effect on microbiota composition. The role of prebiotics and/or probiotics supplement is intriguing in this context and certainly is an issue for further prospective studies. CONFLICT OF INTEREST The authors declare no conflict of interest.
REFERENCES 1. Marasco G, Colecchia A, Festi D. Dysbiosis in celiac disease patients with persistent symptoms on gluten-free diet: a condition similar to that present in irritable bowel syndrome patients? Am J Gastroenterol 2015;110:598 (this issue) 2. Wacklin P, Laurikka P, Lindfors K et al. Altered duodenal microbiota composition in celiac disease patients suffering from persistent
© 2015 by the American College of Gastroenterology
symptoms on a long-term gluten-free diet. Am J Gastroenterol 2014;109:1933–41. 3. Barbara G. Mucosal barrier defects in irritable bowel syndrome. Who left door open? Am J Gastroenterol 2006;101:1295–8. 4. Longstreth GF, Thompson WG, Chey WD et al. Functional bowel disorders. Gastroenterology 2006;130:1480–91. 1
SalWe, Strategic Centre for Science, Technology and Innovation in Health and Wellbeing, Espoo, Finland; 2School of Medicine, University of Tampere, Tampere, Finland; 3Tampere Centre for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland; 4Finnish Red Cross Blood Service, Helsinki, Finland; 5Department of Internal Medicine, Tampere University Hospital, Tampere, Finland. Correspondence: Kalle Kurppa, MD, Tampere Centre for Child Health ResearchUniversity of Tampere and Tampere University Hospital, Finn Medi 3, Biokatu 10, Tampere 33520, Finland. E-mail: kalle.kurppa@uta.fi
Focal Liver Lesions Suspected of Being Cholangiocarcinomas Nicola Zanini, MD1, Elio Jovine, MD2 and Giovanni Landolfo, MD1 doi:10.1038/ajg.2015.56
To the Editor: It was with great interest that we read the clinical guidelines regarding the management of focal liver lesions that was recently published in the Journal, “ACG Clinical Guideline: The Diagnosis and Management of Focal Liver Lesions” (1). In general, the best clinical guidelines are those in which extensive coverage of the issue and a concise summary of recommendations are well balanced. From this point of view, the ACG guidelines have hit the mark. However, as good guidelines should not examine a single issue too deeply, we would like to share one comment regarding the management of lesions that are suspected of being intrahepatic cholangiocarcinomas (ICCAs). ICCAs may be difficult to differentiate from metastatic lesions by imaging and histology. If a liver lesion that is suspected of being an ICCA is surgically resectable,
a diagnostic biopsy may not be required because its results would not change the management strategy. However, the patient should not be referred to surgery before the hypothesis of a metastatic lesion from an unknown primary tumor has been ruled out. This issue is not discussed in the paper, and we would like to point this out. As ICCAs are characterized by radiological behavior similar to that of metastatic tumors, and as metastasis to the liver is more common than a primary ICCA (2), a thorough evaluation should be carried out to assess the possibility of a separate primary malignancy. A complete evaluation should include upper and lower gastrointestinal endoscopy, chest imaging, and, for women, a mammogram (3). Extensive preoperative efforts should be carried out to avoid missing a primary tumor and seriously affecting the prognosis of the patient, delaying, at best, or preventing, at worst, potentially curative therapy. Of course, the ACG guidelines are not intended to be a comprehensive textbook regarding the management of cholangiocarcinomas; we are aware that limited space is reserved for the discussion of clinical issues, such as the one we have raised here. Nonetheless, we believe that the guidelines will be a must-read for clinicians and a quick “go-to” guide for appropriate management, and any possible misleading interpretation should be avoided. REFERENCES 1. Marrero JA, Ahn J, Rajender Reddy K et al. ACG clinical guideline: the diagnosis and management of focal liver lesions. Am J Gastroenterol 2014;109:1328–47. 2. Maithel SK, Gamblin TC, Kamel I et al. Multidisciplinary approaches to intrahepatic cholangiocarcinoma. Cancer 2013;119:3929–42. 3. Dodson RM, Weiss MJ, Cosgrove D et al. Intrahepatic cholangiocarcinoma: management options and emerging therapies. J Am Coll Surg 2013;217:736–50. 1
Department of Surgery, San Marino State Hospital, Borgo Maggiore, Republic of San Marino; 2 Department of Surgery, AUSL Bologna Maggiore Hospital, Bologna, Italy. Correspondence: Nicola Zanini, MD, Department of Surgery, San Marino State Hospital, Via Scialoja, 1, Borgo Maggiore 47893, Republic of San Marino. E-mail: [email protected]
The American Journal of GASTROENTEROLOGY
599
