Our study was performed to determine whether the observation of increased IELs in patients with normal villous architecture should be specified in the histology report, or considered as part of the normal spectrum of duodenal histology. We have found a frequency of 2.2% of increased IELs with normal villous architecture in our routine duodenal biopsy series, which was similar to the frequency of histologically newly diagnosed coeliac disease.
The upper limit of normal in this series, 22 IEL/100 epithelial cells, was similar to a recent independent study from Leeds.17
Conventionally quoted data in the literature have referred to a normal range of 6–40 IELs/100 epithelial cells in the small intestine. These have been based on studies in the 1970s where jejunal capsule biopsies were routinely used.11,14,18,19
It is possible that there are normally fewer IELs in the proximal duodenum than in the jejunum, although we know of no studies that have investigated that point. Alternatively, technical variations such as thickness of histological sections may account for the difference.
Six of 14 patients with raised IEL counts but an otherwise normal duodenal biopsy had positive anti-endomysial antibodies and/or unexplained anaemia. We suggest that these patients may have latent coeliac disease. This is particularly so for the three patients with positive serology, whose coeliac antibody pattern matched those with newly diagnosed gluten sensitive enteropathy in our series compared with those with a normal histological diagnosis. IgA anti-endomysial antibodies have been shown to have a sensitivity of 97–100% and specificity of 98–99 % for coeliac disease.20
None of the patients in our study with a histologically normal duodenal biopsy had positive endomysial antibodies, confirming the accuracy of this screening test. Wahab et al
have recently shown that 12 of 38 patients with raised IELs alone will develop more typical coeliac-type histology when challenged with extra dietary gluten.10
We suggest that this may be required to prove gluten sensitivity in the six patients in our study.
The fact that the IEL counts did not decrease with a gluten free diet in two of the patients over a short space of time does not exclude latent coeliac disease. It is well recognised that IEL counts in patients with confirmed gluten sensitive enteropathy do lag behind villous architectural improvement when gluten is withdrawn from the diet.19
However, in the remaining eight patients with raised IELs in our study, a definite cause remains uncertain. This was also the case in study of Wahab et al
where 68% of patients could not be strictly classified as being gluten sensitive. A common hypothesis for the presence of increased intestinal IELs is their immunological function against antigens in the bowel lumen.1
In line with their immunological function, it has been postulated that IELs have a role in the breakdown of “oral tolerance”, which may play a part in generalised and even organ specific autoimmune diseases.16,21
This hypothesis may explain the finding of increased IELs in the two patients with primary biliary cirrhosis or idiopathic pancreatitis.
“It is well recognised that intraepithelial lymphocyte counts in patients with confirmed gluten sensitive enteropathy do lag behind villous architectural improvement when gluten is withdrawn from the diet”
The presence of gastrointestinal symptoms in the group of index cases did not differentiate them from the patients with entirely normal histology or with coeliac disease (table 2). Because approximately 15% of the normal population and up to 50% of those referred to a gastroenterological clinic have symptoms of functional bowel disease,22
this is not unexpected.
In conclusion, the finding of a raised IEL count with normal villous architecture is not uncommon. Three of the 14 patients in our study had positive anti-endomysial antibodies and a further three had otherwise unexplained anaemia. These patients may have latent coeliac disease but longterm follow up or a gluten challenge would be required to determine the real clinical relevance of this finding. Nevertheless, we consider the finding of increased IELs with normal villous architecture to be one of potential clinical importance, which should be highlighted in routine histological reports of duodenal biopsies. We recognise that further studies and follow up of these patients, particularly those presumed not to have gluten sensitivity, is needed.
Take home messages
- It is not uncommon to find a raised intraepithelial lymphocyte (IEL) count with normal villous architecture in the duodenum
- Six of the 14 patients with such a finding may have had latent coeliac disease (three had positive anti-endomysial antibodies and three had otherwise unexplained anaemia), although longterm follow up or a gluten challenge would be needed to determine the clinical relevance of this finding
- The cause in at least half of cases is not obvious at present
- The finding of a raised IEL count with normal villous architecture is of sufficient clinical importance to be highlighted in routine duodenal biopsy reports