Intraepithelial lymphocytosis (IEL) is a microscopic finding, not a disease itself. It refers to an abnormally high concentration of immune cells called lymphocytes within the inner lining, or epithelium, of the small intestine. The presence of these extra cells indicates that the digestive tract is experiencing irritation, inflammation, or an immune response. This microscopic observation serves as a signal to medical professionals that an underlying issue needs to be identified and addressed.
The Biological Role and Location of IELs
IELs are specialized T-lymphocytes that reside in a unique location, nestled between the epithelial cells that form the intestinal barrier. This strategic positioning allows them to serve as the immediate, first line of immune defense against foreign substances encountered through food or pathogens in the gut. They are a component of the gut-associated lymphoid tissue, a large part of the body’s immune system.
In a healthy small intestine, these cells are present in a regulated number, typically fewer than 5 to 10 IELs for every 100 epithelial cells. When the intestine is exposed to a threat, IELs become activated and rapidly increase in number to mount a defense. This increased presence, or lymphocytosis, is a response to protect the intestinal barrier and eliminate infected or damaged cells.
These lymphocytes possess both conventional and unconventional T-cell characteristics, allowing them to respond to antigens. Their function includes producing various molecules that regulate inflammation and activating natural killer cells to destroy problematic cells. The increase in their count reflects an active state of immune surveillance and irritation within the intestinal wall.
Primary Conditions Associated with IEL Accumulation
The finding of intraepithelial lymphocytosis in a small intestinal biopsy points toward a number of potential underlying conditions. The most well-known and significant cause is Celiac Disease (CD), an autoimmune condition triggered by the ingestion of gluten. Elevated IEL counts are often the earliest histological sign of Celiac Disease, representing what is categorized as Marsh Stage 1.
In Celiac Disease, this lymphocytic increase occurs before the more severe architectural damage to the intestinal lining begins. Patients who present at this early stage may experience classic gastrointestinal distress, such as chronic diarrhea, abdominal pain, and bloating, or they may present with symptoms of malnutrition.
However, intraepithelial lymphocytosis is not exclusive to Celiac Disease and can occur in a wide range of other scenarios, which may be grouped as “non-Celiac enteropathies.” Common non-Celiac causes include:
- Certain medications, notably non-steroidal anti-inflammatory drugs (NSAIDs), which can irritate the intestinal lining.
- Infections, such as those caused by the bacterium Helicobacter pylori or other viral and parasitic infections.
- Other inflammatory conditions of the digestive tract, like Crohn’s disease or microscopic colitis.
In a substantial number of cases, despite extensive investigation, no specific cause is identified, and these are classified as “idiopathic” or unexplained lymphocytosis. Identifying the specific cause is crucial, as the appropriate management strategy depends entirely on the underlying trigger.
The Diagnostic Process and Histological Grading
The detection of intraepithelial lymphocytosis requires a procedure known as an upper endoscopy, during which a physician obtains small tissue samples, or biopsies, from the small intestine, typically the duodenum. These tissue samples are then sent to a pathologist for microscopic examination and quantification of the immune cells present.
The pathologist’s task is to count the number of lymphocytes within the epithelial layer relative to the epithelial cells themselves. The count is expressed as the number of IELs per 100 epithelial cells. While the normal range is typically less than 20 IELs per 100 epithelial cells, the accepted threshold for defining lymphocytosis is generally established at greater than 25 IELs per 100 epithelial cells.
The severity of the finding is formally graded using the Marsh classification system, which assesses not only the IEL count but also any associated architectural damage. Marsh Stage 1 is specifically defined by an increased IEL count with an otherwise normal villous structure. More advanced stages, such as Marsh Stage 3, indicate progressively severe damage, including the blunting or shortening of the villi responsible for nutrient absorption.
Management Strategies Based on Underlying Cause
Treatment for intraepithelial lymphocytosis is directed at resolving the underlying condition that caused the immune cells to accumulate. For cases where the finding is linked to Celiac Disease, the management involves strict adherence to a lifelong, gluten-free diet (GFD). The GFD eliminates the trigger for the autoimmune response, allowing the small intestine to heal and the IEL count to normalize over time.
When non-Celiac causes are identified, the management strategy changes dramatically. If the lymphocytosis is due to an offending medication, such as an NSAID, the drug is typically discontinued, which can lead to the resolution of the increased IEL count. If an infection, like H. pylori, is the cause, the patient is treated with antibiotics to eradicate the pathogen.
For cases deemed idiopathic, where no cause can be identified despite a thorough investigation, the strategy often involves “watchful waiting” or surveillance. In many of these unexplained cases, the IEL count may spontaneously normalize. The focus shifts to monitoring the patient for the potential future development of a specific disease.