Sept. 14, 2021 -- Overall cancer risk is slightly increased in patients older than 40 within their first year of a celiac disease diagnosis, but the risk drops within a year of diagnosis, shows a Swedish study of 47,000 people with celiac disease.
"Celiac disease is associated with an increased risk of types of cancer, and we believe that this is due to the longstanding inflammation that is induced by gluten," says study author Benjamin Lebwohl, MD, director of clinical research at the Columbia University Celiac Disease Center in New York.
Writing in the journal Clinical Gastroenterology and Hepatology, the authors explain that most studies looking at cancer risk in patients with celiac disease were done before both the widespread use of serologic testing for celiac disease and access to gluten-free food was widely available. Earlier studies linked celiac disease to gastrointestinal malignancies, such as small intestinal adenocarcinoma, and lymphomas.
A prior analysis of this Swedish cohort found that the risk of small intestinal adenocarcinoma, while low, continued for up to 10 years after diagnosis with celiac disease. In the study, which was published in Gastroenterology, the authors found the risks of small-bowel adenocarcinoma and adenomas were significantly increased in people with celiac disease, compared with those without this disease.
"We have known from prior studies that people with celiac disease are at increased risk of developing certain cancers, but there has been limited study of this risk in celiac disease in the 21st century, where there is increased recognition (leading to more prompt diagnosis) and increased access to gluten-free food options (which may allow for more effective treatment)," says Lebwohl, who is also the director of quality improvement in the division of digestive and liver diseases at Columbia University. "We aimed to determine whether there is still an increased risk of cancer in this modern era, and we found that there still is an increased risk, but this increase is small and that it diminishes beyond the first year after the diagnosis of celiac disease."
This nationwide cohort study in Sweden included 47,241 patients with celiac disease (62% female; mean age, 24), of which 64% were diagnosed since 2000. Each patient was age and sex matched to up to five controls. After a median follow-up of 11.5 years, a 1.11-fold increased risk of cancer overall was found in patients with celiac disease, compared with controls. The respective incidences of cancer were 6.5 and 5.7 per 1,000 person-years, and most of the excess risk was caused by gastrointestinal and hematologic cancer.
The overall risk of cancer was increased in the first year after celiac disease diagnosis but not afterward.
"It appears that the increased risk of cancer in people with celiac disease decreased over time, and this may be related to the beneficial effect of the gluten-free diet in the long term," Lebwohl says.
The authors suggest that cancer risk, followed by a decline to no risk, may alternatively be due to the increased monitoring and medical examinations among patients with celiac disease. Also,
symptoms of cancer, such as weight loss, may lead to broad testing that identifies celiac disease, the authors write.
For cancer subtypes, the strongest association between celiac disease and cancer was found for hematologic, lymphoproliferative, and gastrointestinal cancers. Among gastrointestinal cancer subtypes, elevated risks were found for hepatobiliary and pancreatic cancer, but not for gastric or colorectal cancer. The cancer risk in celiac disease decreased in breast and lung cancer, which the authors suggest may be attributed to lower body mass index and smoking rates, respectively, observed in individuals with celiac disease.
Certain Cancer Types Persist After 1 Year
Although there was no overall cancer risk for more than 1 year after celiac disease diagnosis, the risks of hematologic and lymphoproliferative cancers persisted. While the increased risk of gastrointestinal cancers collectively was no longer significant beyond 1 year after celiac disease diagnosis, the risk persisted for hepatobiliary and pancreatic cancer.
"We found that the risk of gastrointestinal cancers is increased in people with celiac disease, compared to the general population, but these risks vary according to the cancer type," Lebwohl says. "For instance, the risk of pancreatic cancer is increased in people with celiac disease, compared to the general population, while the risk of colon cancer in people with celiac disease is not increased, compared to the general population.
"But pancreatic cancer is far less common than colon cancer. We found that pancreatic cancer occurs in 1 in 5,000 people with celiac disease per year, whereas colorectal cancer occurred in 1 in 1,400 people per year. Taken all together, the risk of any gastrointestinal cancer was around 1 in 700 per year among people with celiac disease," Lebwohl says.
The overall cancer risk was highest in patients diagnosed with celiac disease after age 60 and was not increased in those diagnosed with celiac disease before age 40. The authors noted that in recent years, there has been a pronounced increase in the diagnosis of celiac disease in people aged over 60, an age group with a higher risk of developing severe outcomes related to refractory celiac disease. The cancer risk was similar among patients diagnosed with celiac disease before or after 2000.
Since this is an observational study, causality cannot be proven, and the authors suggested that the findings may not be applicable to settings outside of the relatively homogeneous ethnic population of Sweden.
Carol E. Semrad, MD, professor of medicine and director of clinical research in the Celiac Center at the University of Chicago Medicine, says, "This is an observational study and therefore cannot answer whether celiac disease is the cause of cancer or merely an association." She adds that "it is unknown why the risk for some cancers is higher in celiac disease.
"This paper argues against delayed diagnosis and low detection rate to explain the increase in cancer risk as those diagnosed with celiac disease prior to 2000 had the same cancer risk as those diagnosed after 2000 when diagnostic testing, earlier diagnosis, and access to a gluten-free diet were better," Semrad says.
Link to Mortality Data
The authors say increased cancer risk being restricted to the first year of diagnosis is consistent with prior celiac disease studies of morbidity and mortality.
A study published in 2019 in United European Gastroenterology looked at mortality risk in 602 patients with celiac disease from Lothian, Scotland, identified between 1979 and 1983 and
followed up from 1970 to 2016. All-cause mortality was 43% higher than in the general population, mainly from hematologic malignancies, and this risk was greatest during the first few years of diagnosis.
An analysis of cause-specific mortality in the Swedish cohort, published in 2020 in JAMA, found that celiac disease was associated with a small but statistically significant increased mortality risk. After a median follow-up of 12.5 years of 49,829 patients with celiac disease, the mortality rate was 9.7 and 8.6 deaths per 1,000 person-years, compared with the general population, respectively. People with celiac disease were at increased risk of death from cancer, cardiovascular disease, and respiratory disease. The overall mortality risk was greatest in the first year after diagnosis with celiac disease, after which the risk diminished with the establishment of the gluten-free diet but remained modestly elevated in the long term.
However, a Finnish population-based study, published in the American Journal of Gastroenterology, found no increase in overall mortality in patients with celiac disease. The study included 12,803 adults diagnosed with celiac disease between 2005 and 2014. Participants were followed for an average of 7.7 years, and mortality from all malignancies, gastrointestinal tract malignancies, or cardiovascular diseases were not increased among patients with celiac disease, compared with the general population. Mortality from lymphoproliferative diseases was increased in patients with celiac disease but was lower than previously reported.
Lebwohl and colleagues note that the incidences of cancer types vary by the age and geographical region of the study population, as does the diagnosis of celiac disease, which may explain why increased risk for cancer or cancer related-mortality in patients with celiac disease has not always been reported.
Ludvigsson coordinates a study on behalf of the Swedish IBD quality register. This study has received funding from Janssen. The remaining authors disclosed no conflicts.