Published: 24-02-2023 08:26 | Updated: 24-02-2023 08:28

Normal gastrointestinal biopsy not protective against later IBD

Woman suffering from a stomach pain
Photo: Sora Shimazaki, Pexels

A Swedish study which followed more than 450,000 individuals after lower or upper gastrointestinal biopsy, suggests that symptoms of IBD (inflammatory bowel disease) may start significantly before disease shows up on biopsy. The results were published in the open access journal PLOS Medicine on Feb 23.

Jiangwei Sun
Jiangwei Sun, postdoc at Karolinska Institutet. Photo: Lin Li

Dr. Jiangwei Sun of Karolinska Institutet and collaborators from Örebro University (Sweden) and Massachusetts General Hospital (US) found that individuals with a gastrointestinal (GI) biopsy that comes back normal still have a heightened risk of IBD in the years following that normal biopsy than their population references and biopsy-free full siblings.

IBD is a chronic disease of the GI tract and subtypes mainly include Crohn’s disease and ulcerative colitis. The disease is typically diagnosed with a GI biopsy, taken during an endoscopy. In clinical practice, the most frequent finding on an endoscopy is a normal biopsy, and evidence suggests a persistently decreased risk of colorectal cancer for up to ten years after a normal biopsy. However, the association between a normal biopsy and a later diagnosis of IBD has been unclear; some studies have hinted that IBD may have a symptomatic period before diagnosis is possible.

Study population

The researchers used a Sweden-wide database of GI biopsy reports from 1965 to 2016 to identify 200,495 individuals with a normal lower GI biopsy and 257,192 individuals with a normal upper GI biopsy. They also identified more than 2 million matched population references from the Swedish Total Population Register, and nearly half a million siblings of the biopsied individuals who were alive and had not had their own GI biopsy from the Swedish Multi-Generation Register.

Follow-up and results

During a median follow up time of 10 years, 4,853 individuals (2.4%) with a normal lower GI biopsy developed IBD, compared to 0.4% of the population references. This translated to one additional IBD case for every 37 individuals during the 30 years after a normal lower GI biopsy. The individuals with normal lower GI biopsy had a higher risk of overall IBD (HR=5.56; 95%CI: 5.28-5.85), ulcerative colitis (HR=5.20; 95%CI: 4.85-5.59) and Crohn’s disease (HR=6.99; 95%CI: 6.38-7.66) than the population references. The risks were 3.27 (95%CI: 3.05-3.51) for overall IBD, 3.27 (95%CI: 2.96-3.61) for ulcerative colitis, and 3.77 (95%CI: 3.34-4.26) for Crohn’s disease compared to their siblings. A normal upper GI biopsy was also associated with an increased risk of Crohn's disease compared to both the population references and siblings (HR=2.93; 95%CI: 2.68-3.21 and HR= 2.39; 95%CI: 2.10-2.73). The study was limited by a lack of data on the indications for each patient’s biopsy, patients’ lifestyle, medical background, and genetics.

Clinical implications

“Endoscopic biopsy with normal mucosa was associated with an elevated IBD incidence for at least 30 years. This may suggest a substantial symptomatic period of IBD and incomplete diagnostic examinations in patients with early IBD,” says first author Jiangwei Sun, Postdoc at the Department of Medical Epidemiology and Biostatistics.

Last author professor Jonas F Ludvigsson at the same department adds: “Clinicians should be aware of the long-term increased risk of IBD in those with symptoms requiring GI investigation but with a finding of histologically normal mucosa.”

This study was supported by the Swedish Research Council, FORTE, the Karolinska Institutet, and the Chinese Scholarship Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.


Sun J, Fang F, Olén O, Song M, Halfvarson J, Roelstraete B, Khalili H, Ludvigsson JF. Long-term risk of inflammatory bowel disease after endoscopic biopsy with normal mucosa: A population-based, sibling-controlled cohort study in Sweden. PLoS Med. 2023 Feb 23;20(2):e1004185. doi: 10.1371/journal.pmed.1004185.