Malignancy and mortality in people with coeliac disease: population based cohort study
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《英国医生杂志》
1 Division of Epidemiology and Public Health, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, 2 School of Medical and Surgical Sciences, University of Nottingham, Nottingham City Hospital, Nottingham NG5 1PB
Correspondence to: J West joe.west@nottingham.ac.uk
Abstract
Early studies reported a twofold increase in risk of mortality and greatly increased risks of lymphoproliferative malignancies in people with coeliac disease.1-6 These studies were mostly small or not population based, and the findings probably do not reflect risks today.1-6 Data from Sweden's hospital inpatient register showed more modest increases in the risks in people with coeliac disease, but still found an excess risk of certain malignancies and death.7 8 In contrast, two studies showed a decrease in the risk of breast cancer in people with coeliac disease, the reasons for which are not clear.4 8 We carried out a large population based cohort study in people with coeliac disease to provide robust estimates of the absolute and relative risks of malignancy and mortality.
Methods
Our cohorts included 4732 people with coeliac disease and 23 620 matched controls, contributing 18 923 and 94 323 person years at risk, respectively. Of the people with coeliac disease, 3143 (66.4%) were prevalent cases. The cohorts were closely matched for sex and on age at entry to follow up (table 1). More current smokers were present in the control cohort (15.4% v 13.0%) than coeliac disease cohort and more people were underweight (body mass index 18.5) in the coeliac disease cohort (4.2% v 1.2%).
Table 1 Details on observation time and personal characteristics of coeliac disease cohort and control cohort. Values are numbers (percentages) unless stated otherwise
Malignancy
Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy. The overall rate of any malignancy for the coeliac cohort was 72.0 per 10 000 person years compared with 55.9 per 10 000 person years for the control cohort, giving around a 30% increase in the risk of any malignancy among people with coeliac disease (hazard ratio 1.29, 95% confidence interval 1.06 to 1.55; table 2). The absolute excess rate of any malignancy was 16 per 10 000 person years. For malignancy subgroups we found an increase in the risk of gastrointestinal cancer (hazard ratio 1.85) and lymphoproliferative disease (4.80) and decreases in the risk of breast cancer (0.35) and lung cancer (0.34) in the coeliac cohort compared with the control cohort. When we restricted our analyses to the year after diagnosis, most of the hazard ratios were increased (see table 2). After excluding events within the year of follow up after diagnosis the risks were generally decreased. The absolute excess rate of any malignancy in this period was 6 per 10 000 person years.
Table 2 Overall number of events, rates per 10 000 person years, crude and adjusted hazard ratios for coeliac cohort compared with control cohort (reference group)
Mortality
Overall, there were 237 deaths among people in the coeliac cohort and 902 in the control cohort, giving overall crude mortalities of 125.3 and 95.7 per 10 000 person years, respectively. These rates corresponded to a hazard ratio of 1.31 (95% confidence interval, 1.13 to 1.51). The absolute excess rate was 30 per 10 000 person years. The risk in the year after diagnosis was considerably higher (hazard ratio 1.97, 1.50 to 2.59) compared with that later (1.17, 0.98 to 1.38). The absolute excess rate when deaths were excluded within the year of follow up after diagnosis was 17 per 10 000 person years (see table 2).
The adjusted estimates for all analyses were similar to the crude analyses (see table 2). When we stratified our analyses by prevalent or incident status, having excluded events in the year after diagnosis, the hazard ratios for overall malignancy were 1.11 (0.86 to 1.44) and 1.03 (0.59 to 1.79), respectively. For mortality, the hazard ratio for the prevalent group was 1.09 (0.90 to 1.33) and for the incident group was 1.46 (1.04 to 2.07). When we repeated our analyses restricted to only those people with coeliac disease who had had at least one gluten-free prescription, we found no important differences in the risk estimates (overall malignancy hazard ratio 1.20, 0.97 to 1.45; mortality 1.20, 1.07 to 1.45). No clear evidence was found against the proportional hazards assumption in any of the presented models.
Discussion
Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358: 356-61.
Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci 1999;44: 2538-41.
Cooper BT, Holmes GK, Ferguson R, Cooke WT. Celiac disease and malignancy. Medicine (Baltimore) 1980;59: 249-61.
Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterology 1989;97: 265-71.
Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989;30: 333-8.
Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002;287: 1413-9.
Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163: 1566-72.
Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology 2002;123: 1428-35.
Walley T, Mantgani A. The UK general practice research database. Lancet 1997;350: 1097-9.
West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 2003;125: 429-36.
Hollowell J. The general practice research database: quality of morbidity data. Popul Trends 1997;87: 36-40.
Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302: 766-8.
Lewis JD, Brensinger C, Bilker WB, Strom BL. Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease. Pharmacoepidemiol Drug Saf 2002;11: 211-8.
Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium-channel blockers and risk of cancer. Lancet 1997;349: 525-8.
Logan RF, Tucker G, Rifkind EA, Heading RC, Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. BMJ 1983;286: 95-7.
Sanders DS, Hurlstone DP, Stokes RO, Rashid F, Milford-Ward A, Hadjivassiliou M, et al. Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire. Postgrad Med J 2002;78: 31-3.
Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease. Dig Dis Sci 2003;48: 395-8.
Murray JA, van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton LJ. Trends in the identification and clinical features of celiac disease in a North American community, 1950-2001. Clin Gastroenterol Hepatol 2003;1: 19-27.
Faggiano F, Partanen T, Kogevinas M, Boffetta P. Socioeconomic differences in cancer incidence and mortality. In: Kogevinas M, Pearce N, Susser M, Boffetta P, eds. Social inequalities and cancer. Lyon: International Agency for Research on Cancer, 1997: 65-176. (IARC Scientific publications No 138).
Snook JA, Dwyer L, Lee-Elliott C, Khan S, Wheeler DW, Nicholas DS. Adult coeliac disease and cigarette smoking. Gut 1996;39: 60-2.
West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52: 960-5.(Joe West, Wellcome resear)
Correspondence to: J West joe.west@nottingham.ac.uk
Abstract
Early studies reported a twofold increase in risk of mortality and greatly increased risks of lymphoproliferative malignancies in people with coeliac disease.1-6 These studies were mostly small or not population based, and the findings probably do not reflect risks today.1-6 Data from Sweden's hospital inpatient register showed more modest increases in the risks in people with coeliac disease, but still found an excess risk of certain malignancies and death.7 8 In contrast, two studies showed a decrease in the risk of breast cancer in people with coeliac disease, the reasons for which are not clear.4 8 We carried out a large population based cohort study in people with coeliac disease to provide robust estimates of the absolute and relative risks of malignancy and mortality.
Methods
Our cohorts included 4732 people with coeliac disease and 23 620 matched controls, contributing 18 923 and 94 323 person years at risk, respectively. Of the people with coeliac disease, 3143 (66.4%) were prevalent cases. The cohorts were closely matched for sex and on age at entry to follow up (table 1). More current smokers were present in the control cohort (15.4% v 13.0%) than coeliac disease cohort and more people were underweight (body mass index 18.5) in the coeliac disease cohort (4.2% v 1.2%).
Table 1 Details on observation time and personal characteristics of coeliac disease cohort and control cohort. Values are numbers (percentages) unless stated otherwise
Malignancy
Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy. The overall rate of any malignancy for the coeliac cohort was 72.0 per 10 000 person years compared with 55.9 per 10 000 person years for the control cohort, giving around a 30% increase in the risk of any malignancy among people with coeliac disease (hazard ratio 1.29, 95% confidence interval 1.06 to 1.55; table 2). The absolute excess rate of any malignancy was 16 per 10 000 person years. For malignancy subgroups we found an increase in the risk of gastrointestinal cancer (hazard ratio 1.85) and lymphoproliferative disease (4.80) and decreases in the risk of breast cancer (0.35) and lung cancer (0.34) in the coeliac cohort compared with the control cohort. When we restricted our analyses to the year after diagnosis, most of the hazard ratios were increased (see table 2). After excluding events within the year of follow up after diagnosis the risks were generally decreased. The absolute excess rate of any malignancy in this period was 6 per 10 000 person years.
Table 2 Overall number of events, rates per 10 000 person years, crude and adjusted hazard ratios for coeliac cohort compared with control cohort (reference group)
Mortality
Overall, there were 237 deaths among people in the coeliac cohort and 902 in the control cohort, giving overall crude mortalities of 125.3 and 95.7 per 10 000 person years, respectively. These rates corresponded to a hazard ratio of 1.31 (95% confidence interval, 1.13 to 1.51). The absolute excess rate was 30 per 10 000 person years. The risk in the year after diagnosis was considerably higher (hazard ratio 1.97, 1.50 to 2.59) compared with that later (1.17, 0.98 to 1.38). The absolute excess rate when deaths were excluded within the year of follow up after diagnosis was 17 per 10 000 person years (see table 2).
The adjusted estimates for all analyses were similar to the crude analyses (see table 2). When we stratified our analyses by prevalent or incident status, having excluded events in the year after diagnosis, the hazard ratios for overall malignancy were 1.11 (0.86 to 1.44) and 1.03 (0.59 to 1.79), respectively. For mortality, the hazard ratio for the prevalent group was 1.09 (0.90 to 1.33) and for the incident group was 1.46 (1.04 to 2.07). When we repeated our analyses restricted to only those people with coeliac disease who had had at least one gluten-free prescription, we found no important differences in the risk estimates (overall malignancy hazard ratio 1.20, 0.97 to 1.45; mortality 1.20, 1.07 to 1.45). No clear evidence was found against the proportional hazards assumption in any of the presented models.
Discussion
Corrao G, Corazza GR, Bagnardi V, Brusco G, Ciacci C, Cottone M, et al. Mortality in patients with coeliac disease and their relatives: a cohort study. Lancet 2001;358: 356-61.
Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci 1999;44: 2538-41.
Cooper BT, Holmes GK, Ferguson R, Cooke WT. Celiac disease and malignancy. Medicine (Baltimore) 1980;59: 249-61.
Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterology 1989;97: 265-71.
Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease—effect of a gluten free diet. Gut 1989;30: 333-8.
Catassi C, Fabiani E, Corrao G, Barbato M, De Renzo A, Carella AM, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA 2002;287: 1413-9.
Peters U, Askling J, Gridley G, Ekbom A, Linet M. Causes of death in patients with celiac disease in a population-based Swedish cohort. Arch Intern Med 2003;163: 1566-72.
Askling J, Linet M, Gridley G, Halstensen TS, Ekstrom K, Ekbom A. Cancer incidence in a population-based cohort of individuals hospitalized with celiac disease or dermatitis herpetiformis. Gastroenterology 2002;123: 1428-35.
Walley T, Mantgani A. The UK general practice research database. Lancet 1997;350: 1097-9.
West J, Logan RF, Card TR, Smith C, Hubbard R. Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 2003;125: 429-36.
Hollowell J. The general practice research database: quality of morbidity data. Popul Trends 1997;87: 36-40.
Jick H, Jick SS, Derby LE. Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302: 766-8.
Lewis JD, Brensinger C, Bilker WB, Strom BL. Validity and completeness of the General Practice Research Database for studies of inflammatory bowel disease. Pharmacoepidemiol Drug Saf 2002;11: 211-8.
Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium-channel blockers and risk of cancer. Lancet 1997;349: 525-8.
Logan RF, Tucker G, Rifkind EA, Heading RC, Ferguson A. Changes in clinical features of coeliac disease in adults in Edinburgh and the Lothians 1960-79. BMJ 1983;286: 95-7.
Sanders DS, Hurlstone DP, Stokes RO, Rashid F, Milford-Ward A, Hadjivassiliou M, et al. Changing face of adult coeliac disease: experience of a single university hospital in South Yorkshire. Postgrad Med J 2002;78: 31-3.
Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult celiac disease. Dig Dis Sci 2003;48: 395-8.
Murray JA, van Dyke C, Plevak MF, Dierkhising RA, Zinsmeister AR, Melton LJ. Trends in the identification and clinical features of celiac disease in a North American community, 1950-2001. Clin Gastroenterol Hepatol 2003;1: 19-27.
Faggiano F, Partanen T, Kogevinas M, Boffetta P. Socioeconomic differences in cancer incidence and mortality. In: Kogevinas M, Pearce N, Susser M, Boffetta P, eds. Social inequalities and cancer. Lyon: International Agency for Research on Cancer, 1997: 65-176. (IARC Scientific publications No 138).
Snook JA, Dwyer L, Lee-Elliott C, Khan S, Wheeler DW, Nicholas DS. Adult coeliac disease and cigarette smoking. Gut 1996;39: 60-2.
West J, Logan RF, Hill PG, Lloyd A, Lewis S, Hubbard R, et al. Seroprevalence, correlates, and characteristics of undetected coeliac disease in England. Gut 2003;52: 960-5.(Joe West, Wellcome resear)