What lymphocytic immune processes can have gastrointestinal (GI) manifestations?

Lymphocytic Immune Processes with Gastrointestinal Manifestations

Several lymphocytic immune processes can affect the gastrointestinal tract, with microscopic colitis, celiac disease, and immune checkpoint inhibitor enterocolitis being the most clinically significant conditions that require prompt recognition and management. These conditions are characterized by lymphocytic infiltration in various parts of the GI tract and can significantly impact patient morbidity, mortality, and quality of life.

Microscopic Colitis

Microscopic colitis (MC) is a common lymphocytic disorder of the GI tract with two main subtypes:

• Lymphocytic colitis (LC): Characterized by:

  • Increased intraepithelial lymphocytes (IELs) in the colonic mucosa (10-65 per 100 surface epithelial cells, median 30)
  • Normal colonic architecture without collagen deposition
  • Predominantly affects women
  • Presents with chronic watery diarrhea 1

• Collagenous colitis (CC): Characterized by:

  • Subepithelial collagen deposition
  • Can also involve increased IELs
  • Can extend to involve terminal ileum and upper GI tract 1

Variant Forms

• Cryptal lymphocytic colitis (IELs in cryptal epithelium)
• Paucicellular lymphocytic colitis (patchy distribution with lower IEL density)
• MC with giant cells 1

Celiac Disease

Celiac disease is an autoimmune disorder triggered by gluten that frequently coexists with other lymphocytic GI disorders:

• Approximately one-third of celiac disease patients show features of lymphocytic colitis 1
• Conversely, about one-fourth of lymphocytic colitis patients have celiac disease 1
• Characterized by:
  • Duodenal intraepithelial lymphocytosis
  • Villous atrophy
  • Production of highly specific IgA and IgG autoantibodies to tissue transglutaminase 2, 3
  • Systemic manifestations beyond the GI tract 3

Immune Checkpoint Inhibitor (ICI) Enterocolitis

ICI therapy can lead to immune-related adverse events affecting the GI tract:

• Presents as diarrhea in up to 40% of patients on ICI therapy
• Severe enterocolitis occurs in 2-5% of patients on PD-1/PD-L1 inhibitors and ~10% on CTLA-4 inhibitors 1
• Two histological patterns:
  • Active colitis with neutrophilic crypt micro-abscesses and epithelial cell apoptosis
  • Lymphocytic colitis with increased intraepithelial lymphocytes 1
• Upper GI involvement and pseudo-obstruction can also occur 1

Other Lymphocytic GI Disorders

Lymphocytic Gastritis

• Characterized by increased IELs in the gastric mucosa
• 15 times more common in patients with microscopic colitis than in the general population 4
• Important to exclude H. pylori infection and celiac disease 5

Lymphocytic Esophagitis

• Less well-characterized condition
• 3 times more common in patients with microscopic colitis 4
• Has been found to affect children with distal Crohn's disease 1

Post-Infectious Irritable Bowel Syndrome (PI-IBS)

• Features lymphocytic infiltration in the intestinal mucosa
• Characterized by:
  • Increased lamina propria T lymphocytes
  • Increased epithelial T lymphocytes
  • Increased mast cells surrounded by nerve fibers in terminal ileum mucosa 1
  • Altered cytokine expression (increased IL-1β, IFN-γ; decreased IL-10) 1

Clinical Significance and Associations

The clustering of lymphocytic disorders in the GI tract is clinically significant:

• 13.7% of patients with microscopic colitis have another lymphocytic disorder vs. 5.9% of those without MC 4
• Patients with lymphocytic colitis have higher rates of comorbid lymphocytic disorders than those with collagenous colitis (OR 1.74) 4
• These associations suggest a common underlying etiology affecting both upper and lower GI tract 4

Diagnostic Approach

When suspecting a lymphocytic immune process in the GI tract:

1. Endoscopy with biopsies is the gold standard for diagnosis

   • Include biopsies from both endoscopically normal and abnormal areas
   • Sample multiple sites including terminal ileum and upper GI tract

2. Serological testing:

   • Celiac serology (tissue transglutaminase IgA and total IgA)
   • Inflammatory markers (CRP, ESR)
   • Consider testing for hepatitis B, C, HIV, and TB prior to immunosuppressive therapy 1

3. Stool studies to exclude infectious causes:

   • C. difficile testing
   • Stool cultures or pathogen panels
   • Consider ova and parasite testing based on risk factors 1

Treatment Considerations

Treatment depends on the specific lymphocytic disorder:

• Celiac disease: Strict gluten-free diet 3
• Microscopic colitis: Budesonide is often effective 6
• ICI enterocolitis: Corticosteroids for mild cases; infliximab for severe or refractory cases 1
• PI-IBS: Symptom-directed therapy and consideration of probiotics 1

Medication Considerations

• Mercaptopurine can be used for inflammatory conditions but carries risks of hepatotoxicity and immunosuppression 7
• Budesonide has fewer systemic glucocorticoid effects than conventional steroids 6

Pitfalls and Caveats

• Lymphocytic infiltration can be patchy, requiring multiple biopsies for accurate diagnosis
• Normal-appearing mucosa on endoscopy does not exclude microscopic inflammation
• Always exclude celiac disease in patients with lymphocytic colitis 1
• Consider medication-induced lymphocytic infiltration (e.g., NSAIDs, PPIs, SSRIs)
• Reintroduction of immune checkpoint inhibitors after enterocolitis poses high risk of relapse 1

Understanding these lymphocytic immune processes is essential for proper diagnosis and management of patients with GI symptoms, as early recognition and appropriate treatment can significantly improve outcomes and quality of life.