Downloaded from http://gut.bmj.com/ on June 3, 2015 - Published by group.bmj.com
Gut Online First, published on December 5, 2014 as 10.1136/gutjnl-2014-308567 Commentary
Do different patients with coeliac disease have different mortality rates? Federico Biagi, Gino Roberto Corazza Although mortality of patients with coeliac disease has being studied for >25 years, it is not yet clear whether it is higher than in the general population. In the first years after the diagnosis of coeliac disease, some studies showed a definitely increased mortality rate that, however, decreases over time. On the other hand, other studies showed that this was not always the case (reviewed in ref 1). All these studies are difficult to compare because they differ widely from each other for epidemiological and clinical reasons. To explain these apparently contrasting results, we suggested that mortality rates were different because patients with coeliac disease were different, especially regarding the type of clinical presentation and age at diagnosis of coeliac disease. We also hypothesised that the quantity of gluten consumed before the diagnosis of coeliac disease could have a role in inducing complications and thus influencing mortality rate.1 In the last few years, mortality of patients with coeliac disease was the focus of studies that were not based on clinically collected patients with coeliac disease but on data from patients with coeliac disease recorded in massive databases. The study by Sultan et al2 is one of them. This and other studies show that overall mortality of patients with coeliac disease is not increased compared with the general population.2–5 Does this mean that the previous studies showing an increased mortality rate for patients with coeliac disease were actually all wrong? As usual, the truth is likely somewhere in the middle. Although these database studies benefit from a huge statistical power, we cannot be sure that they represent the ideal tool for studying this issue. First of all, the accuracy of these diagnoses is a reason for concern. Nowadays, misdiagnoses of coeliac disease are very common and confirmation of the initial diagnosis of coeliac disease is required before making a
Coeliac Centre/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Correspondence to Dr F Biagi, Coeliac Centre/1st Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, P.le Golgi, 19, Pavia 27100, Italy; [email protected]
diagnosis of refractory coeliac disease.6 7 On the other hand, patients with coeliac disease are well known to have a significant diagnostic delay, most often because they were labelled as patients affected by irritable bowel syndrome.8 Since all these database studies take into account thousands of patients with coeliac disease and controls, is it not possible that a considerable proportion of patients with coeliac disease were included among the controls and non-coeliac subjects were included among patients with coeliac disease? And is it not possible that mortality rates of patients with coeliac disease were levelled and flattened by these ’misplacements’? A confirmation of this concern could be the observation that some of the results obtained by these studies are contrasting and difficult to explain. For example, the highest risk of developing enteropathyassociated T-cell lymphoma, a ferocious complication of coeliac disease with a dismal prognosis, was found in patients with a Marsh type 3 lesion, while the risk was lower in patients with a Marsh type 2 lesion.4 However, a similar study, performed in the same population, showed that mortality of patients with coeliac disease diagnosed with a Marsh type 2 lesion was higher than that of patients with coeliac disease with a Marsh type 3 lesion.3 In the last few years, quite a few studies investigated the mortality of undiagnosed, undetected coeliac disease. The most accurately performed ones suggested that mortality is not increased in these patients.4 9 This further supports the observation that the type of clinical presentation is of paramount importance in determining the risk of complications and thus mortality rates.10 So, if we assume that only patients with coeliac disease with frank symptoms of malabsorption at diagnosis are affected by an increased mortality rate, is it not possible that the database studies did not show an overall increased mortality because silent and non-classical/minor patients, nowadays the majority of patients with coeliac disease, ’diluted’ the patients with classical/major symptoms? It must be very difficult, if not impossible, to evaluate the clinical picture through a database. Again, some evidence seems to suggest that mortality of patients with coeliac disease on a strict gluten-free Biagi F, et al. Gut Month 2014 Vol 0 No 0
diet is reduced compared with the general population.10 If this should be the case, is it possible to suggest that database studies did not show an increased mortality because the reduced mortality of patients with coeliac disease on a strict gluten-free diet ‘counter-balanced’ the increased mortality of patients on a poor gluten-free diet? To conclude, although the study of Sultan et al2 provides evidence that mortality of patients with coeliac disease is similar to that of the general population, in our opinion this conclusion should be taken with care. In view of the comments raised in this commentary, we are not sure that mortality is not increased in patients with coeliac disease. However, we feel that in patients with coeliac disease mortality rate varies in different types of patients with coeliac disease, adherence to a gluten-free diet, type of clinical presentation and age at diagnosis being the most important discriminant factors. Since we do not know the natural history of untreated silent coeliac disease, this cannot be considered a good reason for not suggesting a strict gluten-free diet to silent patients with coeliac disease too. However, it can be a good point to start tailoring follow-up modalities of patients with coeliac disease according to the specific clinical characteristics of each individual patient. So, patients with coeliac disease diagnosed in the first two or three decades of life or because of familiarity or minor symptoms could be followed up on a clinical and serological basis only. On the other hand, in order to diagnose complications as soon as they arise, patients with coeliac disease diagnosed later in life and because of frank symptoms of malabsorption could be followed up on a regular basis with duodenal biopsy and other instrumental procedure, analogously to what is nowadays performed in patients affected by atrophic gastritis or colonic polyps. Acknowledgements We are grateful to Susan West for reading and correcting the manuscript. Contributors FB and GRC wrote the paper. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed. To cite Biagi F, Corazza GR. Gut Published Online First: [ please include Day Month Year] doi:10.1136/ gutjnl-2014-308567 Received 14 November 2014 Revised 19 November 2014 Accepted 20 November 2014
▸ http://dx.doi.org/10.1136/gutjnl-2014-308285
1
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on June 3, 2015 - Published by group.bmj.com
Commentary Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-308567
REFERENCES 1 2
3
2
Biagi F, Corazza GR. Mortality in celiac disease. Nat Rev Gastroenterol Hepatol 2010;7:158–62. Abdul Sultan A, Crooks CJ, Card T, et al. Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis. Gut Published Online First: 24 Oct 2014. doi:10.1136/gutjnl-2014-308285. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–8.
4
5
6
7
Canavan C, Logan RF, Khaw KT, et al. No difference in mortality in undetected coeliac disease compared with the general population: a UK cohort study. Aliment Pharmacol Ther 2011;34:1012–19. Elfström P, Granath F, Ekström Smedby K, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst 2011;103:436–44. Biagi F, Bianchi PI, Campanella J, et al. The impact of misdiagnosing celiac disease at a referral centre. Can J Gastroenterol 2009;23:543–5. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease—guidelines
8
9
10
from the British Society of Gastroenterology. Gut 2014;63:1210–28. Corazza GR, Brusco G, Andreani ML, et al. Previous misdiagnosis and diagnostic delay in adult celiac sprue. J Clin Gastroenterol 1996;22:324–5. Godfrey JD, Brantner TL, Brinjikji W, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology 2010;139:763–9. Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358:356–61.
Biagi F, et al. Gut Month 2014 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on June 3, 2015 - Published by group.bmj.com
Do different patients with coeliac disease have different mortality rates? Federico Biagi and Gino Roberto Corazza Gut published online December 5, 2014
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/12/05/gutjnl-2014-308567
These include:
References
This article cites 9 articles, 2 of which you can access for free at: http://gut.bmj.com/content/early/2014/12/05/gutjnl-2014-308567#BIBL
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Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
Gut Online First, published on December 5, 2014 as 10.1136/gutjnl-2014-308567 Commentary
Do different patients with coeliac disease have different mortality rates? Federico Biagi, Gino Roberto Corazza Although mortality of patients with coeliac disease has being studied for >25 years, it is not yet clear whether it is higher than in the general population. In the first years after the diagnosis of coeliac disease, some studies showed a definitely increased mortality rate that, however, decreases over time. On the other hand, other studies showed that this was not always the case (reviewed in ref 1). All these studies are difficult to compare because they differ widely from each other for epidemiological and clinical reasons. To explain these apparently contrasting results, we suggested that mortality rates were different because patients with coeliac disease were different, especially regarding the type of clinical presentation and age at diagnosis of coeliac disease. We also hypothesised that the quantity of gluten consumed before the diagnosis of coeliac disease could have a role in inducing complications and thus influencing mortality rate.1 In the last few years, mortality of patients with coeliac disease was the focus of studies that were not based on clinically collected patients with coeliac disease but on data from patients with coeliac disease recorded in massive databases. The study by Sultan et al2 is one of them. This and other studies show that overall mortality of patients with coeliac disease is not increased compared with the general population.2–5 Does this mean that the previous studies showing an increased mortality rate for patients with coeliac disease were actually all wrong? As usual, the truth is likely somewhere in the middle. Although these database studies benefit from a huge statistical power, we cannot be sure that they represent the ideal tool for studying this issue. First of all, the accuracy of these diagnoses is a reason for concern. Nowadays, misdiagnoses of coeliac disease are very common and confirmation of the initial diagnosis of coeliac disease is required before making a
Coeliac Centre/First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy Correspondence to Dr F Biagi, Coeliac Centre/1st Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, P.le Golgi, 19, Pavia 27100, Italy; [email protected]
diagnosis of refractory coeliac disease.6 7 On the other hand, patients with coeliac disease are well known to have a significant diagnostic delay, most often because they were labelled as patients affected by irritable bowel syndrome.8 Since all these database studies take into account thousands of patients with coeliac disease and controls, is it not possible that a considerable proportion of patients with coeliac disease were included among the controls and non-coeliac subjects were included among patients with coeliac disease? And is it not possible that mortality rates of patients with coeliac disease were levelled and flattened by these ’misplacements’? A confirmation of this concern could be the observation that some of the results obtained by these studies are contrasting and difficult to explain. For example, the highest risk of developing enteropathyassociated T-cell lymphoma, a ferocious complication of coeliac disease with a dismal prognosis, was found in patients with a Marsh type 3 lesion, while the risk was lower in patients with a Marsh type 2 lesion.4 However, a similar study, performed in the same population, showed that mortality of patients with coeliac disease diagnosed with a Marsh type 2 lesion was higher than that of patients with coeliac disease with a Marsh type 3 lesion.3 In the last few years, quite a few studies investigated the mortality of undiagnosed, undetected coeliac disease. The most accurately performed ones suggested that mortality is not increased in these patients.4 9 This further supports the observation that the type of clinical presentation is of paramount importance in determining the risk of complications and thus mortality rates.10 So, if we assume that only patients with coeliac disease with frank symptoms of malabsorption at diagnosis are affected by an increased mortality rate, is it not possible that the database studies did not show an overall increased mortality because silent and non-classical/minor patients, nowadays the majority of patients with coeliac disease, ’diluted’ the patients with classical/major symptoms? It must be very difficult, if not impossible, to evaluate the clinical picture through a database. Again, some evidence seems to suggest that mortality of patients with coeliac disease on a strict gluten-free Biagi F, et al. Gut Month 2014 Vol 0 No 0
diet is reduced compared with the general population.10 If this should be the case, is it possible to suggest that database studies did not show an increased mortality because the reduced mortality of patients with coeliac disease on a strict gluten-free diet ‘counter-balanced’ the increased mortality of patients on a poor gluten-free diet? To conclude, although the study of Sultan et al2 provides evidence that mortality of patients with coeliac disease is similar to that of the general population, in our opinion this conclusion should be taken with care. In view of the comments raised in this commentary, we are not sure that mortality is not increased in patients with coeliac disease. However, we feel that in patients with coeliac disease mortality rate varies in different types of patients with coeliac disease, adherence to a gluten-free diet, type of clinical presentation and age at diagnosis being the most important discriminant factors. Since we do not know the natural history of untreated silent coeliac disease, this cannot be considered a good reason for not suggesting a strict gluten-free diet to silent patients with coeliac disease too. However, it can be a good point to start tailoring follow-up modalities of patients with coeliac disease according to the specific clinical characteristics of each individual patient. So, patients with coeliac disease diagnosed in the first two or three decades of life or because of familiarity or minor symptoms could be followed up on a clinical and serological basis only. On the other hand, in order to diagnose complications as soon as they arise, patients with coeliac disease diagnosed later in life and because of frank symptoms of malabsorption could be followed up on a regular basis with duodenal biopsy and other instrumental procedure, analogously to what is nowadays performed in patients affected by atrophic gastritis or colonic polyps. Acknowledgements We are grateful to Susan West for reading and correcting the manuscript. Contributors FB and GRC wrote the paper. Competing interests None. Provenance and peer review Commissioned; internally peer reviewed. To cite Biagi F, Corazza GR. Gut Published Online First: [ please include Day Month Year] doi:10.1136/ gutjnl-2014-308567 Received 14 November 2014 Revised 19 November 2014 Accepted 20 November 2014
▸ http://dx.doi.org/10.1136/gutjnl-2014-308285
1
Copyright Article author (or their employer) 2014. Produced by BMJ Publishing Group Ltd (& BSG) under licence.
Downloaded from http://gut.bmj.com/ on June 3, 2015 - Published by group.bmj.com
Commentary Gut 2014;0:1–2. doi:10.1136/gutjnl-2014-308567
REFERENCES 1 2
3
2
Biagi F, Corazza GR. Mortality in celiac disease. Nat Rev Gastroenterol Hepatol 2010;7:158–62. Abdul Sultan A, Crooks CJ, Card T, et al. Causes of death in people with coeliac disease in England compared with the general population: a competing risk analysis. Gut Published Online First: 24 Oct 2014. doi:10.1136/gutjnl-2014-308285. Ludvigsson JF, Montgomery SM, Ekbom A, et al. Small-intestinal histopathology and mortality risk in celiac disease. JAMA 2009;302:1171–8.
4
5
6
7
Canavan C, Logan RF, Khaw KT, et al. No difference in mortality in undetected coeliac disease compared with the general population: a UK cohort study. Aliment Pharmacol Ther 2011;34:1012–19. Elfström P, Granath F, Ekström Smedby K, et al. Risk of lymphoproliferative malignancy in relation to small intestinal histopathology among patients with celiac disease. J Natl Cancer Inst 2011;103:436–44. Biagi F, Bianchi PI, Campanella J, et al. The impact of misdiagnosing celiac disease at a referral centre. Can J Gastroenterol 2009;23:543–5. Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease—guidelines
8
9
10
from the British Society of Gastroenterology. Gut 2014;63:1210–28. Corazza GR, Brusco G, Andreani ML, et al. Previous misdiagnosis and diagnostic delay in adult celiac sprue. J Clin Gastroenterol 1996;22:324–5. Godfrey JD, Brantner TL, Brinjikji W, et al. Morbidity and mortality among older individuals with undiagnosed celiac disease. Gastroenterology 2010;139:763–9. Corrao G, Corazza GR, Bagnardi V, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358:356–61.
Biagi F, et al. Gut Month 2014 Vol 0 No 0
Downloaded from http://gut.bmj.com/ on June 3, 2015 - Published by group.bmj.com
Do different patients with coeliac disease have different mortality rates? Federico Biagi and Gino Roberto Corazza Gut published online December 5, 2014
Updated information and services can be found at: http://gut.bmj.com/content/early/2014/12/05/gutjnl-2014-308567
These include:
References
This article cites 9 articles, 2 of which you can access for free at: http://gut.bmj.com/content/early/2014/12/05/gutjnl-2014-308567#BIBL
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions To order reprints go to: http://journals.bmj.com/cgi/reprintform To subscribe to BMJ go to: http://group.bmj.com/subscribe/
