Alimentary Pharmacology and Therapeutics Invited Commentaries Furthermore, there is even evidence for adverse events with supplementation of vitamin D or its analogues. The vitamin D analogue seocalcitol, for example, did not show any survival benefit in patients with advanced hepatocellular carcinoma (HCC) in a large multicenter placebo-controlled trial.4 Thus, we consider vitamin D first of all a prognostic parameter.5 However, most European patients with HCC suffer from advanced liver fibrosis or cirrhosis when developing HCC. Osteopenia, and even osteoporosis, are common among patients with chronic liver diseases.6 In such patients vitamin D supplementation is recommended.6 Before initiation of vitamin D supplementation we prefer to determine vitamin D levels to rule out overdosage which may have itself adverse effects. Therefore, we disagree with the reluctance for vitamin D level determination proposed by Dan and Lim.3 Recently, a relationship of low vitamin D levels with HCC development has been proposed.7 Patients with hepatitis B virus infection were shown to have low vitamin D levels even in early stages of liver disease without substantial fibrosis and morbidity.8 In such patients, confounders for vitamin D serum levels such as malnutrition, immobility, reduced sunlight exposure, as well as reduction in (25)-hydroxylation of vitamin D, can be ruled out. Therefore, we think it may be appropriate to test vitamin D serum levels in patients with chronic liver disease to clarify the necessity of vitamin D supplementation which may prevent bone loss, but perhaps also others complications.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.5
Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease
coeliac disease and is not meaningfully influenced by Helicobacter pylori infection. However, this interpretation of results is partially questionable in that children with functional recurrent abdominal pain (RAP) may not be a normal control population, and this study has not considered that LD may actually point to pathology in these patients. To explore this possibility, two questions should be answered – are there known associations with H. pylori and RAP and LD and RAP? Spee et al.3 undertook a meta-analysis of 38 studies to examine the relationship of H. pylori, RAP and other gastrointestinal symptoms in children. This concluded that H. pylori was not associated with RAP, with an overall odds ratio of 1.0 (95% confidence interval: 0.76– 1.31) and this current study can be added in support of these conclusions. However, is there evidence that RAP
M. M. Walker*, P. R. Harris Diez† & J. E. Crabtree‡ *Anatomical Pathology, University of Newcastle, Callaghan, NSW, Australia. † Division of Pediatrics, School of Medicine Pontificia Universidad Catolica de Chile, Santiago, Chile. ‡ Leeds Institute Biomedical and Clinical Sciences, St. James’s University Hospital, Leeds, UK. E-mail: [email protected] doi:10.1111/apt.12779
This study by Guz-Mark et al.1 purports that lymphocytic duodenosis2 (LD) is common in children without 1430
REFERENCES 1. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76– 89. 2. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014; 348: g1903. 3. Dan YY, Lim SG. Commentary: vitamin D deficiency and liver cancer – cause, effect or myth? Aliment Pharmacol Ther 2014; 39: 1429. 4. Beaugrand M, Sala M, Degos F, et al. Treatment of advanced hepatocellular carcinoma (HCC) by seocalcitol (a vit D analogue): an international randomized double-blind placebo-controlled study in 747 patients. J Hepatol 2005; 42(S2): 17. 5. Finkelmeier F, Kronenberger B, K€ oberle V, et al. Severe 25hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther 2014; 39: 1204–12. 6. Gua~ nabens N, Pares A. Management of osteoporosis in liver disease. Clin Res Hepatol Gastroenterol 2011; 35: 438–45. 7. Fedirko V, Duarte-Salles T, Bamia C, et al. Pre-diagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology 2014; doi: 10.1002/hep.27079 [Epub ahead of print]. 8. Farnik H, Bojunga J, Berger A, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology 2013; 58: 1270–6.
Aliment Pharmacol Ther 2014; 39: 1427-1431 ª 2014 John Wiley & Sons Ltd
Invited Commentaries is associated with LD? In our studies investigating upper gastrointestinal pathology in a cohort of children in Chile with respect to RAP, H. pylori and other concurrent infection, we showed that low-grade inflammation in the duodenum, manifest by increased intraepithelial lymphocytes (IELs), was associated with RAP (>20 in 74/105 patients) compared with controls (P = 0.04).4 A higher IEL count was also positively associated with parasite infection, seen in nine patients (P = 0.02). We also found that RAP was not associated with H. pylori as in this current study. While this study adds to the literature that RAP is not associated with H. pylori, the use of children with RAP as a control group may not be a true reflection of normal, and low-grade inflammation as reflected by LD, may represent pathology in RAP. An ideal control group is difficult in children due to ethical considerations, but perhaps those with endoscopy for nonmucosal disease (e.g. foreign body removal) may give a truer representation of normal histology in this age group.
ACKNOWLEDGEMENT Declaration of personal interests: None. Declaration of funding interests: This study was funded under the Sixth Framework Programme of the European Union, Project CONTENT (INCO-DEV-3-032136), CONICYT/BM RUE #29 and FONDECYT #1100654.
Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease – authors’ reply
so, outside of formal prospective studies, for the sake of serving as controls. Regardless, the importance of our findings, namely: that Helicobacter pylori does not meaningfully influence intraepithelial lymphocyte (IEL) count, and has no effect on IEL count in coeliac disease, are not compromised by the selection of the control group.
A. Guz-Mark*, N. Zevit*,† & R. Shamir*,† *Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel. † The Sackler Faculty of Medicine, Tel-Aviv University, Petach Tikva, Israel. E-mail: [email protected] doi:10.1111/apt.12791
We thank Dr Walker et al. for their comments.1 In our article, we have indeed discussed in length that patients with functional abdominal pain may not be equivalent to completely healthy subjects as a control group.2 Ethical barriers prevent us from having a healthy control group of children. Furthermore, we do not routinely biopsy children who ingest foreign bodies, and do not find it appropriate to do
Aliment Pharmacol Ther 2014; 39: 1427-1431 ª 2014 John Wiley & Sons Ltd
REFERENCES 1. Guz-Mark A, Zevit N, Morgenstern S, Shamir R. Duodenal intraepithelial lymphocytosis is common in children without coeliac disease, and is not meaningfully influenced by Helicobacter pylori infection. Aliment Pharmacol Ther 2014; 39: 1314–20. 2. Walker MM, Murray JA. An update in the diagnosis of coeliac disease. Histopathology 2011; 59: 166–79. 3. Spee LA, Madderom MB, Pijpers M, van Leeuwen Y, Berger MY. Association between Helicobacter pylori and gastrointestinal symptoms in children. Pediatrics 2010; 125: e651–69. 4. Rakhra GS, Villagran A, Harris PR, Walker MM, Crabtree JE. Increased duodenal intra epithelial lymphocytes (IELs) are associated with recurrent abdominal pain and parasite infection but not Helicobacter pylori in a paediatric Chilean cohort. Gastroenterology 2012; 142(Suppl. 1): S–379.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Walker MM, Harris Diez PR, Crabtree JE. Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease. Aliment Pharmacol Ther 2014; 39: 1430–1. 2. Guz-Mark A, Zevit N, Morgenstern S, Shamir R. Duodenal intraepithelial lymphocytosis is common in children without coeliac disease, and is not meaningfully influenced by Helicobacter pylori infection. Aliment Pharmacol Ther 2014; 39: 1314–20.
1431
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.5
Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease
coeliac disease and is not meaningfully influenced by Helicobacter pylori infection. However, this interpretation of results is partially questionable in that children with functional recurrent abdominal pain (RAP) may not be a normal control population, and this study has not considered that LD may actually point to pathology in these patients. To explore this possibility, two questions should be answered – are there known associations with H. pylori and RAP and LD and RAP? Spee et al.3 undertook a meta-analysis of 38 studies to examine the relationship of H. pylori, RAP and other gastrointestinal symptoms in children. This concluded that H. pylori was not associated with RAP, with an overall odds ratio of 1.0 (95% confidence interval: 0.76– 1.31) and this current study can be added in support of these conclusions. However, is there evidence that RAP
M. M. Walker*, P. R. Harris Diez† & J. E. Crabtree‡ *Anatomical Pathology, University of Newcastle, Callaghan, NSW, Australia. † Division of Pediatrics, School of Medicine Pontificia Universidad Catolica de Chile, Santiago, Chile. ‡ Leeds Institute Biomedical and Clinical Sciences, St. James’s University Hospital, Leeds, UK. E-mail: [email protected] doi:10.1111/apt.12779
This study by Guz-Mark et al.1 purports that lymphocytic duodenosis2 (LD) is common in children without 1430
REFERENCES 1. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol 2014; 2: 76– 89. 2. Chowdhury R, Kunutsor S, Vitezova A, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014; 348: g1903. 3. Dan YY, Lim SG. Commentary: vitamin D deficiency and liver cancer – cause, effect or myth? Aliment Pharmacol Ther 2014; 39: 1429. 4. Beaugrand M, Sala M, Degos F, et al. Treatment of advanced hepatocellular carcinoma (HCC) by seocalcitol (a vit D analogue): an international randomized double-blind placebo-controlled study in 747 patients. J Hepatol 2005; 42(S2): 17. 5. Finkelmeier F, Kronenberger B, K€ oberle V, et al. Severe 25hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther 2014; 39: 1204–12. 6. Gua~ nabens N, Pares A. Management of osteoporosis in liver disease. Clin Res Hepatol Gastroenterol 2011; 35: 438–45. 7. Fedirko V, Duarte-Salles T, Bamia C, et al. Pre-diagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology 2014; doi: 10.1002/hep.27079 [Epub ahead of print]. 8. Farnik H, Bojunga J, Berger A, et al. Low vitamin D serum concentration is associated with high levels of hepatitis B virus replication in chronically infected patients. Hepatology 2013; 58: 1270–6.
Aliment Pharmacol Ther 2014; 39: 1427-1431 ª 2014 John Wiley & Sons Ltd
Invited Commentaries is associated with LD? In our studies investigating upper gastrointestinal pathology in a cohort of children in Chile with respect to RAP, H. pylori and other concurrent infection, we showed that low-grade inflammation in the duodenum, manifest by increased intraepithelial lymphocytes (IELs), was associated with RAP (>20 in 74/105 patients) compared with controls (P = 0.04).4 A higher IEL count was also positively associated with parasite infection, seen in nine patients (P = 0.02). We also found that RAP was not associated with H. pylori as in this current study. While this study adds to the literature that RAP is not associated with H. pylori, the use of children with RAP as a control group may not be a true reflection of normal, and low-grade inflammation as reflected by LD, may represent pathology in RAP. An ideal control group is difficult in children due to ethical considerations, but perhaps those with endoscopy for nonmucosal disease (e.g. foreign body removal) may give a truer representation of normal histology in this age group.
ACKNOWLEDGEMENT Declaration of personal interests: None. Declaration of funding interests: This study was funded under the Sixth Framework Programme of the European Union, Project CONTENT (INCO-DEV-3-032136), CONICYT/BM RUE #29 and FONDECYT #1100654.
Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease – authors’ reply
so, outside of formal prospective studies, for the sake of serving as controls. Regardless, the importance of our findings, namely: that Helicobacter pylori does not meaningfully influence intraepithelial lymphocyte (IEL) count, and has no effect on IEL count in coeliac disease, are not compromised by the selection of the control group.
A. Guz-Mark*, N. Zevit*,† & R. Shamir*,† *Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children’s Medical Center of Israel, Petach Tikva, Israel. † The Sackler Faculty of Medicine, Tel-Aviv University, Petach Tikva, Israel. E-mail: [email protected] doi:10.1111/apt.12791
We thank Dr Walker et al. for their comments.1 In our article, we have indeed discussed in length that patients with functional abdominal pain may not be equivalent to completely healthy subjects as a control group.2 Ethical barriers prevent us from having a healthy control group of children. Furthermore, we do not routinely biopsy children who ingest foreign bodies, and do not find it appropriate to do
Aliment Pharmacol Ther 2014; 39: 1427-1431 ª 2014 John Wiley & Sons Ltd
REFERENCES 1. Guz-Mark A, Zevit N, Morgenstern S, Shamir R. Duodenal intraepithelial lymphocytosis is common in children without coeliac disease, and is not meaningfully influenced by Helicobacter pylori infection. Aliment Pharmacol Ther 2014; 39: 1314–20. 2. Walker MM, Murray JA. An update in the diagnosis of coeliac disease. Histopathology 2011; 59: 166–79. 3. Spee LA, Madderom MB, Pijpers M, van Leeuwen Y, Berger MY. Association between Helicobacter pylori and gastrointestinal symptoms in children. Pediatrics 2010; 125: e651–69. 4. Rakhra GS, Villagran A, Harris PR, Walker MM, Crabtree JE. Increased duodenal intra epithelial lymphocytes (IELs) are associated with recurrent abdominal pain and parasite infection but not Helicobacter pylori in a paediatric Chilean cohort. Gastroenterology 2012; 142(Suppl. 1): S–379.
ACKNOWLEDGEMENT The authors’ declarations of personal and financial interests are unchanged from those in the original article.2 REFERENCES 1. Walker MM, Harris Diez PR, Crabtree JE. Commentary: duodenal intraepithelial lymphocytosis in children without coeliac disease. Aliment Pharmacol Ther 2014; 39: 1430–1. 2. Guz-Mark A, Zevit N, Morgenstern S, Shamir R. Duodenal intraepithelial lymphocytosis is common in children without coeliac disease, and is not meaningfully influenced by Helicobacter pylori infection. Aliment Pharmacol Ther 2014; 39: 1314–20.
1431
