Significance of Intraepithelial Lymphocytosis of the small intestine and its differential diagnosis

Description: Intraepithelial lymphocytes (IELs) are a normal component of the small intestinal mucosa. Normal individuals may have up to 40 IELs per 100 epithelial cells, a level that has been used in the Marsh Classification for gluten sensitivity. More recently, some have suggested that greater than 25 IELs per 100 epithelial cells defines abnormal. Conditions associated with a normal villous architecture with increased IELs would seem to represent mild or early manifestations of a pathologic process.

Causes of increased IELs in architecturally normal small bowel biopsies:

Gluten-sensitive enteropathy
In recent years, increased intraepithelial lymphocytes have been touted as a sensitive indicator of GSE or at least suggest that GSE should be strongly considered. The reported prevalence of GSE as the cause in increased IELs in architecturally small intestinal biopsies ranges from 9-40%. Despite mild changes on biopsy, these patients can have significant signs and symptoms which correlate better with the length of involvement rather than the degree of villous abnormality. Also keep in mind that GSE changes can be patchy and that biopsies showing normal villous architecture may not be representative.

The nuances of serologic testing will not be discussed here. However, the likelihood of a positive test correlates with the degree of mucosal injury. Thus, negative serology does not exclude a diagnosis of GSE with a Marsh type 1 pattern.

Hypersensitivity to other ingested proteins
Hypersensitivity to non-gluten components of food are associated with increased IELs, although villous atrophy is usually present.

Organisms such as Giardia, Cryptosporidium, viruses and Helicobacter may result in increased IELs of the duodenum. Bacterial overgrowth may also result in this pattern.

NSAIDs and PPIs have been implicated.

Autoimmune/Immunologic Diseases
Reported conditions have included Hashimoto’s thyroiditis, Graves’s disease, RA, psoriasis, MS, SLE, ankylosing spondylitis, PSS, glomerulonephritis and autoimmune enteropathy.

IgA deficiency, common variable immunodeficiency, UC, Crohn’s, lymphocytic and collagenous colitis and diffuse lymphocytic gastroenteritis may result in small intestinal intraepithelial lymphocytosis.

Intestinal T-cell lymphoma

Intraepithelial lymphocytosis without definitive diagnosis
A number of patients will have increased IELs and non-specific symptoms for which no specific diagnosis can be made.

In summary, up to 2.5% of proximal small intestinal biopsies will display increased intraepithelial lymphocytes in the absence of villous architectural changes. The causes for this change are many and are not specific to gluten-sensitive enteropathy, though 9% to 40% of such patients will have gluten-sensitive enteropathy.

The author’s suggested comment for cases in which intraepithelial lymphocytosis is the diagnosis:

“The finding of intraepithelial lymphocytosis with preserved villous architecture is a non-specific immunological phenomenon that has a large number of potential causes. A mild histological manifestation of gluten sensitivity is one of these causes. Unfortunately, celiac serology may be negative even is patients that subsequently prove to be gluten sensitive. Other causes of this appearance include infective enteritis, H. pylori infection, a drug effect eg NSAIDs, and autoimmune disease. In many cases a specific cause is not identified.”


Brown I, Mino- Kenudson M, Deshpande V, Lauwers G. Intraepithelial Lymphocytosis in Architecturally Preserved Proximal Small Intestinal Mucosa. Arch Pathol Lab Med 2006;130:1020-1024.