Patients with biopsy-confirmed celiac disease had a higher relative rate of solid organ transplantation than matched population comparators in a nationwide Swedish cohort study, although the absolute risk remained low.
The association was strongest for liver transplantation, followed by kidney transplantation. Heart transplantation was not statistically significantly associated with celiac disease, although event counts were low and confidence intervals were wide.
Researchers evaluated 41,277 patients with biopsy-confirmed celiac disease diagnosed in Sweden between 2000 and 2023 and 196,863 matched comparators from the general population. Patients were identified through the nationwide ESPRESSO histopathology cohort, and celiac disease was defined by small intestinal villous atrophy on biopsy. Comparators were matched by age, sex, county of residence, and calendar year. Mean follow-up was 12.1 years.
The primary analysis excluded patients who had undergone solid organ transplantation before celiac disease diagnosis. Solid organ transplantation included liver, kidney, heart, lung, and simultaneous heart-lung transplantation.
During follow-up, 85 patients with celiac disease underwent solid organ transplantation compared with 111 matched comparators, corresponding to incidence rates of 17.0 vs 4.6 per 100,000 person-years. Transplantation occurred in approximately 0.2% of patients with celiac disease during follow-up. After adjustment for education, non-celiac autoimmune disease, and prior outpatient health care utilization, celiac disease was associated with an adjusted hazard ratio of 2.76 for solid organ transplantation.
Liver transplantation accounted for the strongest association. There were 41 liver transplantations among patients with celiac disease and 20 among comparators, corresponding to incidence rates of 8.2 vs 0.8 per 100,000 person-years. The adjusted hazard ratio for liver transplantation was 7.26.
Kidney transplantation also occurred more often among patients with celiac disease. There were 31 kidney transplantations among patients with celiac disease and 67 among comparators, corresponding to incidence rates of 6.2 vs 2.8 per 100,000 person-years and an adjusted hazard ratio of 1.85.
Heart transplantation was uncommon in both groups. There were 10 heart transplantations among patients with celiac disease and 22 among comparators. The adjusted hazard ratio was 2.35, but the association did not reach statistical significance.
In stratified analyses, the association between celiac disease and solid organ transplantation was more pronounced among male patients and among patients diagnosed with celiac disease at age 60 years or older. Among male patients, the adjusted hazard ratio was 5.60. Among patients diagnosed at age 60 years or older, the adjusted hazard ratio was 6.65.
Associations were not statistically significant among female patients, patients diagnosed before age 18 years, patients born outside Nordic countries, patients with more than 12 years of education, patients diagnosed between 2017 and 2023, or patients followed for 10 years or longer after celiac disease diagnosis.
Several sensitivity analyses supported the main findings. In a sibling-comparator analysis, patients with celiac disease remained at higher risk for solid organ transplantation than their unaffected siblings. In that analysis, the adjusted hazard ratio for any solid organ transplantation was 2.37, and the association was strongest for liver transplantation.
However, the investigators also found that patients with celiac disease were more likely than comparators to have undergone solid organ transplantation before celiac disease diagnosis. This finding suggests that the relationship may be present both before and after celiac disease diagnosis and makes temporality difficult to interpret. The investigators noted that increased risk of transplantation before celiac disease diagnosis may also be influenced by undiagnosed celiac disease.
The study did not show a statistically significant difference in solid organ transplantation risk between patients with mucosal healing and those with persistent villous atrophy on follow-up biopsy. Among patients with celiac disease who had follow-up small intestinal biopsy, the adjusted hazard ratio for transplantation in those with mucosal healing vs persistent villous atrophy was 0.92.
In a post hoc descriptive analysis of liver transplant recipients, autoimmune hepatitis accounted for a higher proportion of liver transplantations among patients with celiac disease than among comparators, whereas alcohol-associated liver disease accounted for a lower proportion. Among patients with celiac disease who underwent liver transplantation, 27% had autoimmune hepatitis, 12% had liver disease associated with alcohol abuse, and 10% had hepatocellular carcinoma. Among matched comparators who underwent liver transplantation, 20% had liver disease associated with alcohol abuse, while autoimmune hepatitis and hepatocellular carcinoma were each reported in 2 or fewer patients. The small numbers and suppressed comparator counts limit interpretation.
The investigators noted several limitations. The study was observational and cannot establish a causal relationship between celiac disease and solid organ transplantation. The analysis lacked data on the specific underlying indication for transplantation in patients with celiac disease and comparators, although the investigators examined selected liver-related diagnoses in a post hoc analysis. The study also lacked data on gluten-free diet adherence. Registry-based studies may be subject to misclassification, and surveillance bias is possible because patients with celiac disease may have more frequent health care contact than the general population. The investigators adjusted for prior health care utilization and performed a sibling-comparator analysis, but they noted that this possible bias could not be fully eliminated. The study findings may not be generalizable to non-Nordic countries.
The investigators concluded that patients with celiac disease were more likely to undergo solid organ transplantation than matched comparators, particularly liver transplantation. They suggested that clinicians should screen patients with celiac disease for abnormal liver function tests and chronic liver disease. They also suggested that screening individuals with end-stage organ disease for celiac disease may be worthwhile, and that screening patients at early stages of chronic kidney disease, particularly immune-mediated disease, may also be considered.
Further studies are needed to investigate the mechanisms behind these associations and to examine whether prompt celiac disease diagnosis and gluten-free diet initiation affect transplant risk.
Study disclosures were reported in the manuscript. Jonas F. Ludvigsson, MD, PhD, reported coordinating an unrelated study funded by Janssen; receiving support from Merck/MSD for unrelated inflammatory bowel disease research and for work reviewing national health care registers in China; and participating in an ongoing celiac disease research collaboration with Takeda.
