Intraepithelial lymphocyte cut-off for diagnosing coeliac disease: ≥20 vs ≥25 per 100 enterocytes

Summary

The IEL threshold used to flag possible coeliac disease in duodenal biopsies has fallen progressively in the literature, from 40, to 30, to 25, and more recently to 20 per 100 enterocytes. The cut-off with the strongest evidence base, and the one embedded in the major textbooks and the BSG-aligned UK practice, is ≥25/100. A cut-off of ≥20/100 is more sensitive but less specific, and is most defensible as a trigger for further workup rather than as a stand-alone diagnostic line.

The case for ≥25/100

The pivotal study is Hayat et al. (J Clin Pathol 2002), which derived an upper limit of normal of approximately 25 IELs per 100 enterocytes in well-orientated duodenal biopsies, replacing the older Marsh figure of 40. This threshold has been supported in subsequent work, including the Veress group and Mahadeva et al., and was reinforced by Walker et al. (Histopathology 2010) in the context of Marsh 1 lesions where the IEL count is the principal abnormality.

≥25/100 balances sensitivity and specificity in routine practice, is reproducible between observers when counted in well-orientated villi, and is the threshold reflected in standard texts (Shepherd & Warren; Day, Morson and Dawson’s Gastrointestinal Pathology) and in BSG guidance.

The case for ≥20/100

Subsequent work, in particular from the Finnish coeliac group (Järvinen and colleagues), has shown that counts in the 20–25 range, in patients with positive TTG, compatible HLA (DQ2/DQ8) and suggestive clinical features, are frequently associated with coeliac disease. A strict ≥25 cut-off therefore misses a clinically meaningful minority of cases, especially at the early Marsh 1 end of the spectrum.

Järvinen and colleagues also highlighted the value of counting IELs at the villous tip as an adjunctive measure (>5 IELs per 20 enterocytes at the tip), which improves sensitivity for early gluten-sensitive enteropathy independent of the global 100-enterocyte count.

Practical interpretation

  • <20/100: within normal limits.
  • 20–25/100: borderline. Correlate with serology, HLA status, drug history (NSAIDs, PPIs), H. pylori status, and clinical picture. Coeliac disease should be mentioned in the differential but not diagnosed on histology alone.
  • ≥25/100: abnormal. Raises coeliac disease and its mimics — H. pylori-associated duodenitis, NSAIDs, PPIs, SIBO, autoimmune enteropathy, common variable immunodeficiency, tropical sprue, and Giardia.

Bottom line

If a single threshold has to be picked, ≥25 IELs per 100 enterocytes is the better cut-off: it has the strongest published basis, it is the figure embedded in BSG-aligned practice and the major reference texts, and it is reasonably reproducible. ≥20 is defensible as a more sensitive trigger for further investigation, but should not be used as a stand-alone diagnostic threshold in the absence of supporting serology, HLA and clinical context.

Key references

  • Hayat M, Cairns A, Dixon MF, O’Mahony S. Quantitation of intraepithelial lymphocytes in human duodenum: what is normal? J Clin Pathol 2002;55:393–394.
  • Mahadeva S, Wyatt JI, Howdle PD. Is a raised intraepithelial lymphocyte count with normal duodenal villous architecture clinically relevant? J Clin Pathol 2002;55:424–428.
  • Walker MM, Murray JA, Ronkainen J, et al. Detection of celiac disease and lymphocytic enteropathy by parallel serology and histopathology in a population-based study. Gastroenterology 2010;139:112–119.
  • Järvinen TT, Collin P, Rasmussen M, et al. Villous tip intraepithelial lymphocytes as markers of early-stage coeliac disease. Scand J Gastroenterol 2004;39:428–433.
  • Ludvigsson JF, Bai JC, Biagi F, et al. Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology. Gut 2014;63:1210–1228.