Significant Association Between the Use of Different Proton Pump Inhibitors and Microscopic Colitis

A Nationwide Danish Case-control Study

Ole K. Bonderup; Gunnar L. Nielsen; Michael Dall; Anton Pottegård; Jesper Hallas


Aliment Pharmacol Ther. 2018;48(6):618-625. 

In This Article

Abstract and Introduction


Background: Microscopic colitis causes chronic watery diarrhoea and has previously been associated with the use of proton pump inhibitors.

Aim: To explore the association between proton pump inhibitor use and microscopic colitis, including its dependency on timing, dose and choice of proton pump inhibitor.

Methods: Within a 10-year period, we identified 10 652 patients with a first-time diagnosis of microscopic colitis, including 6254 (59%) with collagenous colitis and 4398 (41%) with lymphocytic colitis. All microscopic colitis cases were histologically confirmed in the Danish Pathology Register. Information on proton pump inhibitor use was obtained from the Danish Prescription Register. In this case-control study, we estimated the adjusted odds ratios (aOR) for the association between proton pump inhibitor use and risk of microscopic colitis using conditional logistic regression while adjusting for potential confounders.

Results: We found strong associations between current proton pump inhibitor use and both collagenous colitis (aOR 6.98; 95% CI: 6.45–7.55) and lymphocytic colitis (aOR 3.95; 95% CI: 3.60–4.33). This association was observed with all PPIs. The strongest association was with the current use of lansoprazole for both collagenous colitis (aOR 15.74; 95% CI: 14.12–17.55) and lymphocytic colitis (aOR 6.87; 95% CI: 6.00–7.86). When considering timing, ORs were highest for current use of proton pump inhibitor and lower for recent or past exposure. No clear dose-response pattern was observed.

Conclusions: We found a strong association between microscopic colitis and ongoing use of proton pump inhibitors, especially lansoprazole.


Microscopic colitis is characterised by chronic diarrhoea in patients with macroscopically normal or near-normal mucosa at colonoscopy. Thus, diagnosis relies on specific histological findings in colon biopsies. Microscopic colitis consists of two main entities, lymphocytic colitis and collagenous colitis.[1] The two subtypes share histopathological features, characterised by a marked increase in intraepithelial lymphocytes, and a thickened subepithelial collagen band additionally characterises collagenous colitis.[2] Epidemiological studies have shown that microscopic colitis has been diagnosed more frequently in recent decades. In a recent Danish study, we reported a continuous increase in the incidence rates of microscopic colitis from 4.6 to 24.7 per 100 000 person-years from 2002 to 2011.[3] However, the aetiology of microscopic colitis is largely unknown and its pathogenesis is not well described. Diversion of the faecal stream with a temporary ileostomy in patients with collagenous colitis results in the resolution of histological changes in the colonic mucosa, indicating luminal factors in its pathogenesis.[4] Furthermore, a variety of factors are suspected, and drug consumption has been suggested to act as an environmental risk factor and has been implicated as a causative or triggering agent of microscopic colitis.[5] Moreover, the use of proton pump inhibitors (PPI) has increased rapidly within recent decades,[6] and the association between PPI use and microscopic colitis has been consistently replicated in a number of studies.[7–9] In a previous study, we demonstrated an increased odds ratio (OR) for microscopic colitis in patients with prescriptions for PPIs, but we were unable to differentiate between individual PPIs.[7] However, some important aspects of this association have been poorly elucidated.[10] First, it is unclear whether the association between PPI and microscopic colitis applies equally to lymphocytic colitis and collagenous colitis. Second, some studies have suggested a specific risk with lansoprazole.[11,12] However, this finding is predominantly based on case reports or small-scale case-control studies; large-scale studies, which include validated outcomes, are lacking. Third, the pattern of PPI use that is most likely to produce microscopic colitis is unknown; for example, is there a dose-response effect and/or an association with timing of PPI use? Finally, the magnitude of the risk has not been adequately described. In light of the sparse evidence for these aspects, we conducted new analyses in an updated and extended version of our dataset based on high-quality Danish Health Registries to examine the risk of microscopic colitis between different PPIs, effect of timing of PPI use and dependency on PPI dose. Furthermore, we explored the potential differences between collagenous colitis and lymphocytic colitis.