Understanding Intraepithelial Lymphocytosis : Causes, Symptoms, and Treatment

1. What is Intraepithelial Lymphocytosis

   Intraepithelial lymphocytosis is a complex immunological phenomenon in which the white blood cell count increases within the epithelial layer of the tissue or organ. It is most commonly seen affecting the gastrointestinal tract, particularly the small intestine, but can also occur in other mucosal surfaces like skin and respiratory tract. It is characterized by 20-25 lymphocytes per 100 epithelial cells, which are the main cells lining the gastrointestinal tract.⁽¹⁾ Excessive lymphocyte activity is associated with gut damage and is linked with GI disorders and celiac disease.

   Functions of intraepithelial lymphocytes include: 

   • Producing molecules that help in reducing inflammation
   • Activating natural killer cells that help destroy infected or damaged cells
   • Producing molecules that may increase inflammation

   Excessive activity of natural killer cells is linked to autoimmune conditions like Crohn’s disease and ulcerative colitis.⁽²⁾

2. Importance of Understanding Intraepithelial Lymphocytosis

   Understanding intraepithelial lymphocytosis is significant for the following reasons: 

   • Intraepithelial lymphocytosis can be indicative of various conditions including celiac disease, non-celiac gluten sensitivity, and certain infectious diseases. Diagnosing it can help in early intervention.
   • It can be helpful in differentiating gluten and non-gluten sensitivity which is crucial for treatment approaches.
   • Regular monitoring of intraepithelial lymphocytosis provides valuable information about disease progression and response to treatment.
   • Sometimes celiac disease may become refractive and may not respond to the standard treatment. This may signal the need for more aggressive management strategies to prevent complications.
   • Sometimes in viral or bacterial enteropathies, the presence of elevated intraepithelial lymphocytes may indicate an ongoing immune response. This can help guide appropriate treatment strategies.
   • Addressing intraepithelial lymphocyte-associated conditions can be helpful in preventing complications and long-term sequelae.
   • It can also facilitate advancements in understanding immune-mediated conditions and mucosal immunology and broaden medical knowledge.

Intraepithelial lymphocytosis is often observed in the gastrointestinal tract. The common causes and associated symptoms include:⁽³⁾

• Celiac Disease: It is an autoimmune disease triggered by ingestion of gluten. It leads to an abnormal response in the small intestine causing damage to the villi and an increase in intraepithelial lymphocytes.

People with celiac disease may show the following symptoms: 

• Diarrhea
• Pain in the abdomen and bloating
• Nausea and vomiting
• Constipation
• Weight loss
• Nutritional deficiencies
• Fatigue
• Headaches
• Joint pain
• Dermatitis herpetiform
• Mouth ulcers
• In children, there may be a failure to thrive and delayed growth and puberty

• Non-Celiac Gluten Sensitivity: This is characterized by gastrointestinal symptoms similar to celiac disease but without autoimmune response and damage to intestinal villi. Some individuals with non-celiac gluten sensitivity may exhibit intraepithelial lymphocytosis.

The symptoms in people with non-celiac gluten sensitivity include:

• Pain in the abdomen and bloating
• Nausea and vomiting
• Diarrhea and constipation
• Fatigue
• Headache
• Joint pain
• Brain fog
• Peripheral neuropathy 

• Refractory Celiac Disease: It is a rare and severe type of celiac disease that does not respond to a gluten-free diet. There is intraepithelial lymphocytosis despite strict adherence to a gluten-free diet.

Individuals with refractory celiac disease may present the following symptoms:

• Worsening of symptoms
• Severe diarrhea
• Profound weight loss

• Infectious Causes: Certain viral infections may lead to an increase in intraepithelial lymphocytes in the gastrointestinal tract. Bacterial infection in the gastrointestinal tract caused by Campylobacter jejuni or Clostridium difficile can lead to an inflammatory response and an increase in intraepithelial lymphocytes. Some of the parasitic infections such as giardiasis and cryptosporidiosis can lead to intraepithelial lymphocytosis due to immune response against the parasites.

In the case of the infection, the symptoms would be:

• Diarrhea
• Abdominal pain and cramping
• Nausea and vomiting
• Fever
• Malaise
• Fatigue

• Collagenous Sprue: This is a rare condition associated with increased intraepithelial lymphocytes, along with a thickened collagen band in the small intestine.

The gastrointestinal symptoms of collagenous sprue may be similar to that of celiac disease along with:

• Malabsorption-related symptom
• Chronic diarrhea
• Weight loss
• Nutritional deficiencies
• Severe symptoms in some cases 

• Drug-Induced Enteropathy: Certain medications such as non-steroidal anti-inflammatory drugs and chemotherapeutic agents can increase intraepithelial lymphocytes as a part of gastrointestinal side effects.⁽⁴⁾
• Auto-Immune Enteropathy: It is an autoimmune disorder in which the body’s immune system mistakenly attacks the cells of the small intestine, resulting in intraepithelial lymphocytosis.

There may be:

• Profound diarrhea
• Weight loss
• Abdominal pain
• Nutritional deficiencies
• Dehydration and electrolyte imbalance 

• Microscopic Colitis: It is primarily a condition of the colon but can also affect the small intestine. It is characterized by diarrhea and increased intraepithelial lymphocytes.

The symptoms of microscopic colitis include:

• Chronic and watery diarrhea
• Abdominal pain and cramping
• Weight loss

Not all people with intraepithelial lymphocytosis may experience all the symptoms. A thorough clinical examination is important for accurate diagnosis and management.

The first step in diagnosing intraepithelial lymphocytosis involves taking a tissue sample from the affected area, most commonly the gastrointestinal tract, particularly in the small intestine via endoscopy. The sample is then examined under a microscope by a pathologist to look for histological features. The number of intraepithelial lymphocytes is counted by the pathologist per 100 epithelial cells.

In some cases, immunochemical staining may be performed on the tissue sample to further characterize the lymphocytes. This can help differentiate different types of lymphocytes and provide additional information.

Additional tests may be ordered, depending on the clinical context. This is to identify the underlying cause of intraepithelial lymphocytosis. This may include: 

• Serological testing
• Genetic testing for celiac disease
• Specialized test for other associated conditions

The histopathological findings of intraepithelial lymphocytosis must be interpreted in the context of the patient’s clinical presentation, medical history, and other diagnostic results.

It is important to rule out other conditions that may mimic or coexist with intraepithelial lymphocytosis such as infections, autoimmune disorders, and drug-induced enteropathies.

Effective communication between the pathologist, gastroenterologist, and other specialists is an important part of patient care.

The aim of the treatment is to target the underlying condition. The potential treatment options include:

Strict adherence to a gluten-free diet is the main treatment option for celiac disease and non-celiac gluten sensitivity. It may involve avoiding all sources of gluten, including wheat, barley, and rye.

The medication includes anti-inflammatory medications, antidiarrheal medication, antiemetics, and pain relievers for abdominal discomfort. Immunomodulatory drugs or biologic agents may be considered for severe or refractory cases. In some cases, corticosteroids may be prescribed to suppress the immune response and alleviate symptoms.

In case of nutritional deficiencies supplementation of vitamins and minerals such as iron, calcium, vitamin D, and B vitamins may be needed. In some, intravenous nutrition may be needed.

Some cases may benefit from dietary modifications under the guidance of a healthcare professional. Certain trigger foods may be asked to be avoided.

Regular follow-up with a healthcare provider is important for monitoring symptom improvement, dietary compliance, and nutritional status.

An individual with intraepithelial lymphocytosis needs to closely follow up with the healthcare team to develop a tailored plan based on individual needs.

The outlook for intraepithelial lymphocytosis varies widely for individuals. It is often positive with proper treatment.

In people with celiac disease who strictly follow a gluten-free diet, the prognosis is excellent.⁽⁵⁾

Crohn’s disease decreases the quality of life and the life expectancy is also reduced.⁽⁶⁾ This occurs due to an increased risk of gastrointestinal cancers and other complications.

In people with ulcerative colitis, the life expectancy rates are comparable to those of people without this condition.⁽⁷⁾ It is seen that about 5% of people with ulcerative colitis develop colon cancer

Intraepithelial lymphocytosis serves as a histological marker for various underlying diseases including celiac disease, non-celiac gluten sensitivity, infectious causes, and autoimmune conditions. Accurate diagnosis and appropriate management are crucial to improve patient outcomes and quality of life.

Tailored treatment approaches are essential. These range from gluten-free diets for celiac disease to immunosuppressive therapies for refractory cases. Close monitoring, nutritional support, and symptomatic treatment further contribute to comprehensive care.

Intraepithelial lymphocytosis is not a gastrointestinal illness. It is a sign of an underlying problem and involves treating the underlying cause.