Malignancy and mortality in people with coeliac disease: population based cohort study.
ABSTRACT To quantify the risks of malignancy and mortality in people with coeliac disease compared with the general population.
Population based cohort study.
General practice research database.
4732 people with coeliac disease and 23,620 matched controls.
Hazard ratios for malignancy and mortality.
Of the 4732 people with coeliac disease, 134 (2.8%) had at least one malignancy and 237 (5.0%) died. The overall hazard ratios were: for any malignancy 1.29 (95% confidence interval 1.06 to 1.55), for mortality 1.31 (1.13 to 1.51), for gastrointestinal cancer 1.85 (1.22 to 2.81), for breast cancer 0.35 (0.17 to 0.72), for lung cancer 0.34 (0.13 to 0.95), and for lymphoproliferative disease 4.80 (2.71 to 8.50). The increased risk was primarily in the first year after diagnosis, with the risk for only lymphoproliferative disease remaining significantly raised thereafter. After excluding events in the year after diagnosis, the hazard ratio for malignancy was 1.10 (0.87 to 1.39) and for mortality was 1.17 (0.98 to 1.38), giving absolute excess rates of 6 and 17 per 10,000 person years, respectively.
People with coeliac disease have modest increases in overall risks of malignancy and mortality. Most of this excess risk occurs in the year of follow up after diagnosis. People with coeliac disease also have a noticeably reduced risk of breast cancer. The mechanism of this merits further attention as it may provide insights into the cause of this common malignancy.
- SourceAvailable from: Janaína Luz Narciso-SchiavonJournal of Research and Development. 11/2014; 2(1).
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ABSTRACT: OBJECTIVES:The association between celiac disease and malignancies is well recognized. In Finland, the prevalence of clinically diagnosed adult celiac disease is 0.6%. In this large, population-based cohort, we aimed at a realistic projection of the cancer risk.METHODS:In the period 2002-2011, the register comprised 32,439 adult celiac patients. This was linked with the Finnish Cancer Registry, which covers over 98% of diagnosed malignancies. The standardized incidence ratio (SIR) was calculated for the malignancies, on the basis of incidence figures for the whole population. A time-stratified analysis was made in celiac patients diagnosed after 2004 (n=11,991). Lifestyle factors, including smoking habits and obesity, were not obtainable.RESULTS:The overall incidence ratio of malignant diseases was not increased (SIR 0.94; 95% confidence intervals 0.89-0.98), but it was ≥5 years from the diagnosis of celiac disease (1.31, 1.04-1.63). The SIRs for non-Hodgkin lymphoma (NHL; 1.94; 1.62-2.29), small-intestinal cancer (4.29; 2.83-6.24), colon cancer (1.35; 1.13-1.58), and basal cell carcinoma of the skin (1.13; 1.03-1.22) were increased, whereas those for lung cancer (0.60; 0.48-0.74), pancreatic cancer (0.73; 0.53-0.97), bladder cancer (0.53; 0.35-0.77), renal cancer (0.72; 0.51-0.99), and breast cancer (0.70; 0.62-0.79) were decreased. SIR for NHL immediately after the diagnosis of celiac disease was 2.56 (1.37-4.38).CONCLUSIONS:There was no increased SIR of cancer in the whole series, but SIR was increased after 5 years from the diagnosis of celiac disease. The risk of breast and lung cancers was decreased. The risk of small-intestinal cancer and NHL was increased, but to a lesser extent than previously described.Am J Gastroenterol advance online publication, 22 July 2014; doi:10.1038/ajg.2014.194.The American Journal of Gastroenterology 07/2014; · 9.21 Impact Factor
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ABSTRACT: A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD.Gut 06/2014; · 13.32 Impact Factor
Malignancy and mortality in people with coeliac disease: population
based cohort study
Joe West, Richard F A Logan, Chris J Smith, Richard B Hubbard, Timothy R Card
Objective To quantify the risks of malignancy and mortality in
people with coeliac disease compared with the general
Design Population based cohort study.
Setting General practice research database.
Participants 4732 people with coeliac disease and 23 620
Main outcome measures Hazard ratios for malignancy and
Results Of the 4732 people with coeliac disease, 134 (2.8%)
had at least one malignancy and 237 (5.0%) died. The overall
hazard ratios were: for any malignancy 1.29 (95% confidence
interval 1.06 to 1.55), for mortality 1.31 (1.13 to 1.51), for
gastrointestinal cancer 1.85 (1.22 to 2.81), for breast cancer 0.35
(0.17 to 0.72), for lung cancer 0.34 (0.13 to 0.95), and for
lymphoproliferative disease 4.80 (2.71 to 8.50). The increased
risk was primarily in the first year after diagnosis, with the risk
for only lymphoproliferative disease remaining significantly
raised thereafter. After excluding events in the year after
diagnosis, the hazard ratio for malignancy was 1.10 (0.87 to
1.39) and for mortality was 1.17 (0.98 to 1.38), giving absolute
excess rates of 6 and 17 per 10 000 person years, respectively.
Conclusions People with coeliac disease have modest increases
in overall risks of malignancy and mortality. Most of this excess
risk occurs in the year of follow up after diagnosis. People with
coeliac disease also have a noticeably reduced risk of breast
cancer. The mechanism of this merits further attention as it
may provide insights into the cause of this common
Early studies reported a twofold increase in risk of mortality and
greatly increased risks of lymphoproliferative malignancies in
people with coeliac disease.1–6These studies were mostly small or
not population based, and the findings probably do not reflect
risks today.1–6Data 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 8In 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 8We 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
The UK general practice research database was established in
1987 and is the largest longitudinal database in primary care. It
contains the medical records of more than 8 million patients.
When people are seen in primary care in the United Kingdom,
information on important medical diagnoses, hospital letters,
discharge summaries, and prescriptions are entered onto a desk-
top computer.The data from practices entering information into
the general practice research database are audited regularly, and
at least 95% of data on morbidity and prescribing must be
included for the practice to be contributing data that are consid-
ered up to standard.9
Our study population has been described in detail elsewhere.10In
brief, between June 1987 and April 2002 we extracted the
records of all people within the general practice research
database with a recorded diagnosis of coeliac disease. We
selected five controls matched to each person with coeliac
disease by age, sex, and general practice. Controls were alive and
contributing data on the date of the first prospective, up to
standard, record of coeliac disease or prescription for a
gluten-free product for people with coeliac disease. We excluded
controls who had any record of a gluten-free prescription or a
non-specific reference to coeliac disease, such as gluten-free diet
or gluten sensitivity.
Each person with coeliac disease was assigned a date of diag-
nosis,defined as the first date of recognised coeliac disease.Since
general practitioners enter some data for important historical
events retrospectively, in some cases this date preceded the start
of their up to standard record. We assigned controls a “pseudo-
diagnosis” date identical to their matched case. We defined inci-
dent people with coeliac disease as those whose date of diagnosis
for coeliac disease or first prescription for a gluten-free product
occurred at least one year after the start of their record on the
general practice research database. All other people with coeliac
disease were defined as prevalent.
Outcomes and potential confounders
Outcomes included the date of first occurrence of any
malignancy or of a specific malignancy subgroup and date of
death during up to standard data.We defined all malignancies by
using the relevant codes in the general practice research
database mapped to codes 140-208 and 230-234 from the inter-
national classification of diseases, ninth revision. The subgroups
we chose were gastrointestinal cancers (codes 150-154), lung
cancer (162-163), breast cancer (174-175), prostate cancer (185),
and lymphoproliferative disease (200-202). Follow up in our
study began at the date of the first prospectively recorded code
Cite this article as: BMJ, doi:10.1136/bmj.38169.486701.7C (published 21 July 2004)
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for coeliac disease or prescription for a gluten-free product, and
we used the matched case’s relevant date for controls.
We extracted information on height, weight, and smoking
status from the whole of each person’s data period. Body mass
index (weight (kg)/(height (m)2)) was calculated for people over
15 years of age.
Initially we calculated the crude incidence of cancer and mortal-
ity for both the coeliac and the control cohorts. We used Cox
regression modelling (release 7.0; Stata Statistical Software) to
estimate the hazard ratio, comparing outcomes in the coeliac
cohort with those in the control cohort. We checked the propor-
tional hazards assumption of each model using log-log plots.
The possible confounding effects of age, sex, body mass index,
and smoking status were assessed by using a series of multivari-
able models. Missing data for confounders were fitted as a sepa-
rate category to ensure that nested models contained the same
number of people. We fitted multiplicative interaction terms to
assess possible interactions between coeliac disease status and
age or sex.
To assess ascertainment bias (whether the increased risk of
cancer was related to increased investigation as a result of having
a diagnosis of coeliac disease or cancer) we examined the hazard
ratios for each outcome within the year after diagnosis and dur-
ing follow up. To assess the validity of our findings for possible
misclassification of coeliac disease status, we restricted our analy-
ses to only those people with coeliac disease who had had at least
one prescription for a gluten-free product. To assess the possibil-
ity of survival bias we stratified our censored analysis by
prevalent or incident status.
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 dis-
ease,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%).
Of the 4732 people with coeliac disease, 134 (2.8%) had at least
one malignancy. The overall rate of any malignancy for the coe-
liac 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.
Overall, there were 237 deaths among people in the coeliac
cohort and 902 in the control cohort, giving overall crude mor-
talities 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 mor-
tality, 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 haz-
ards assumption in any of the presented models.
People with coeliac disease are at a modestly increased risk of
malignancy and mortality than the general population. The risks
were most apparent in the year after diagnosis, and the
decreased risks thereafter suggest that some of the overall excess
risk was likely to be due to ascertainment. Although people with
coeliac disease had an increased risk of gastrointestinal and lym-
phoproliferative malignancy compared with the general popula-
tion they had around one third the risk of breast or lung cancer.
A potential weakness of epidemiological studies using
routinely collected data such as that in the general practice
Table 1 Details on observation time and personal characteristics of coeliac
disease cohort and control cohort. Values are numbers (percentages) unless
Median observed time (years)
Total observed time (years)
Age groups at entry to follow
Body mass index*:
>18.5 to 25.0
>25.0 to 30.0
Coeliac disease cohort
Control cohort (n=23
10 102 (42.8)
10 159 (43.0)
*Weight (kg)/(height (m)2).
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research database is the validity of diagnostic data for each per-
son, particularly histological status; the diagnosis of coeliac
disease has not been specifically validated in the database. One
study looked in detail at the accuracy of the diagnosis of inflam-
matory bowel disease (92%) and one similarly evaluated cancer
diagnoses ( > 90%).11–14Furthermore,to increase the specificity of
the diagnosis, we restricted our analyses to people with coeliac
disease who had at least one prescription for a gluten-free prod-
uct. In these analyses there were no substantial changes in the
The likelihood of detecting an occult or overt malignancy
may be increased during the investigation of coeliac disease and
conversely coeliac disease is more likely to be detected during
the investigation of cancer. The excess risk of gastrointestinal
malignancy is therefore likely to be attributable to the more
detailed investigation of gastrointestinal symptoms, particularly
at presentation. We were able to assess the effect of potential
confounders such as body mass index and smoking status on risk
of malignancy and mortality. We found no evidence of
confounding despite incomplete data and the likely heterogene-
ous nature of those people with missing data.
The risks of overall malignancy and mortality in people with
coeliac disease suggest more modest increases than in other
studies. The most recent study found slightly greater risks of
malignancy (standardised incidence ratio 1.3) and mortality
(standardised mortality ratio 2.0) compared with our study.7 8
These greater risks may reflect more severe disease at presenta-
tion or a period effect, as all the patients had been admitted to
hospital at least once and follow up ended at least six years ear-
lier than in our study. People being diagnosed more recently
seem to have less severe disease.15–18Most other studies have
found increased risks of twofold or more for malignancy or mor-
tality.1 2 4 5
Two previous studies have also suggested a decreased risk of
breast cancer among women with coeliac disease, but it is not
clear whether these were chance observations.4 8It seems
unlikely that socioeconomic status is an important confounder
in this relation as breast cancer has been consistently associated
with higher socioeconomic groups, and there is no evidence that
people with coeliac disease are of lower socioeconomic status.19
The reduction in incidence of lung cancer found by us is in
keeping with recent studies, which showed that people with coe-
liac disease report smoking less even before they were diagnosed
as having the disease.20 21That the reduced incidence is still
apparent after adjusting for smoking status is surprising, but our
data on smoking were incomplete so residual confounding
remains a possibility.
Most of the modest increases in the relative and absolute risk
of malignancy and mortality in people with coeliac disease
occurs in the year after diagnosis, and although there are notice-
ably increased risks of some malignancies such as gastrointesti-
nal cancers and lymphoma there are substantial reductions in
the risk of other, common, cancers such as those of the lung and
breast. The findings for lung and breast cancer are of interest
because of possible genetic, nutritional, or environmental factors
that may protect people with coeliac disease against certain
malignancies. By understanding the mechanism of protection in
people with coeliac disease we may gain insight into the causes of
Table 2 Overall number of events, rates per 10 000 person years, crude and adjusted hazard ratios for coeliac cohort compared with control cohort
Condition and cohort
Overall First year of follow up after diagnosisFollow up beyond year after diagnosis
Hazard ratio (95%
ratio† (95% CI)
ratio† (95% CI)
1.29 (1.06 to 1.55) 1.31
(1.08 to 1.59)
(1.45 to 2.96)
1.10 (0.87 to 1.39)
1.85 (1.22 to 2.81)1.95
(1.27 to 3.00)
(1.40 to 7.83)
1.65 (0.99 to 2.76)
0.35 (0.17 to 0.72) 0.31
(0.15 to 0.63)
(0.18 to 2.04)
0.24 (0.10 to 0.60)
0.34 (0.13 to 0.95)0.37
(0.13 to 1.02)
(0.05 to 3.09)
0.37 (0.11 to 1.20)
4.80 (2.71 to 8.50)4.27
(2.36 to 7.74)
(2.65 to 20.24)
3.40 (1.58 to 7.34)
0.99 (0.41 to 2.38)1.05
(0.42 to 2.57)
(0.14 to 12.19)
1.03 (0.38 to 2.76)
1.31 (1.13 to 1.51) 1.39
(1.20 to 1.61)
(1.59 to 2.76)
1.23 (1.04 to 1.47)
*Numbers vary as participants with event on same date or before start of follow up were excluded.
†Adjusted for age, sex, body mass index, and smoking status.
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We thank the staff of the Epidemiology and Pharmacology Information
Core for their help with providing and formatting the data.
Contributors: JW designed the study and carried out most of the data man-
agement, analyses, interpretation, and writing of this study; he will act as
guarantor for the paper. RFAL, CJS, RBH, and TRC contributed to the
design, analyses, interpretation, and writing.
Funding: Wellcome Trust (grant No 063800).
Competing interests: None declared.
Ethical approval: Scientific and Ethical Advisory Group of the general
practice research database.
1Corrao 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
Cooper BT, Holmes GK, Ferguson R, Cooke WT. Celiac disease and malignancy. Medi-
cine (Baltimore) 1980;59:249-61.
Logan RF, Rifkind EA, Turner ID, Ferguson A. Mortality in celiac disease. Gastroenterol-
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.
6 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 derma-
titis herpetiformis. Gastroenterology 2002;123:1428-35.
Walley T, Mantgani A. The UK general practice research database. Lancet
10 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.
11 Hollowell J. The general practice research database: quality of morbidity data. Popul
12 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.
13 Lewis JD, Brensinger C, Bilker WB, Strom BL. Validity and completeness of the Gen-
eral Practice Research Database for studies of inflammatory bowel disease.
Pharmacoepidemiol Drug Saf 2002;11:211-8.
14 Jick H, Jick S, Derby LE, Vasilakis C, Myers MW, Meier CR. Calcium-channel blockers
and risk of cancer. Lancet 1997;349:525-8.
15 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
16 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.
17 Lo W, Sano K, Lebwohl B, Diamond B, Green PH. Changing presentation of adult
celiac disease. Dig Dis Sci 2003;48:395-8.
18 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.
19 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).
20 Snook JA, Dwyer L, Lee-Elliott C, Khan S, Wheeler DW, Nicholas DS. Adult coeliac dis-
ease and cigarette smoking. Gut 1996;39:60-2.
21 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
(Accepted 3 June 2004)
Division of Epidemiology and Public Health, University of Nottingham, Queen’s
Medical Centre, Nottingham NG7 2UH
Joe West Wellcome research training fellow in clinical epidemiology
Richard F A Logan professor
Richard B Hubbard reader
Timothy R Card Wellcome research training fellow
School of Medical and Surgical Sciences, University of Nottingham, Nottingham
City Hospital, Nottingham NG5 1PB
Chris J Smith research fellow
Correspondence to: J West email@example.com
What is already known on this topic
People with coeliac disease may be at increased risk of
gastrointestinal malignancy and lymphoma
These risks have not been quantified in contemporary,
population based studies
What this study adds
People with coeliac disease have a modestly increased risk
of malignancy and mortality
Most of the excess risk occurs in the year after diagnosis
The risk of breast cancer is about a third that of the general
The risk of lung cancer is about a third that of the general
population, probably because people with coeliac disease
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