What is the diagnosis and treatment approach for low stool Immunoglobulin A (IgA)?

Diagnosis and Management of Low Stool IgA

Low stool IgA levels indicate potential mucosal immune dysfunction and warrant evaluation for conditions such as selective IgA deficiency, celiac disease, or inflammatory bowel disease.

Understanding Low Stool IgA

Stool IgA is an important marker of intestinal mucosal immunity. Immunoglobulin A (IgA) is the predominant antibody class in mucosal secretions, with the intestine being the largest producer - approximately 80% of antibody-secreting cells are found in the intestine, producing grams of IgA daily 1. Low stool IgA levels can indicate:

• Selective IgA deficiency (most common primary immunodeficiency)
• Partial IgA deficiency
• Compromised mucosal immune function
• Potential underlying gastrointestinal disorders

Diagnostic Approach

Step 1: Confirm IgA Status with Serum Testing

• Measure total serum IgA levels to determine if the patient has selective IgA deficiency (defined as serum IgA < 0.05 g/L with normal levels of other immunoglobulins) 2
• Partial IgA deficiency is diagnosed when serum IgA is > 0.05 g/L but still 2 standard deviations below normal levels 2

Step 2: Screen for Celiac Disease

• Celiac disease is significantly associated with IgA deficiency, with approximately 2-3% of celiac patients having IgA deficiency 3
• For patients with normal serum IgA:
  • Test for IgA tissue transglutaminase antibodies (tTG-IgA) and IgA endomysial antibodies (EMA-IgA) 4
• For patients with low serum IgA:
  • Use IgG-based testing: IgG-tTG and IgG deaminated gliadin peptides (DGP) 3, 4

Step 3: Evaluate for Inflammatory Bowel Disease (IBD)

• Consider fecal inflammatory markers like calprotectin and lactoferrin 3
• The incidence of IgA nephropathy is higher in IBD patients (3.0%), particularly in those with Crohn's disease (5.3%) compared to ulcerative colitis (0.9%) 5

Step 4: Endoscopic Evaluation

• If celiac disease is suspected based on positive serology, perform upper endoscopy with multiple duodenal biopsies (at least 6 specimens) 3, 4
• Obtain one or two biopsies of the duodenal bulb and at least four of the distal duodenum 4
• Look for villous atrophy and increased intraepithelial lymphocytes

Step 5: Rule Out Other Conditions

• Consider other causes of seronegative enteropathy if celiac testing is negative but symptoms persist 4
• Evaluate for:
  • Parasitic infections (e.g., Giardia lamblia)
  • Small intestinal bacterial overgrowth
  • Autoimmune enteropathy
  • Common variable immunodeficiency
  • Inflammatory conditions (Crohn's disease, eosinophilic enteritis)

Management Approach

For Confirmed Selective IgA Deficiency:

• Most individuals with selective IgA deficiency are asymptomatic and may not require specific treatment 6
• Monitor for increased risk of:
  • Recurrent infections (particularly respiratory and gastrointestinal)
  • Allergic disorders
  • Autoimmune manifestations (diabetes mellitus, Graves disease, celiac disease) 6
• Implement preventive measures:
  • Regular dental care (as oral manifestations may occur) 6
  • Vaccination according to standard schedules
  • Prompt treatment of infections

For Celiac Disease:

• Implement a strict, lifelong gluten-free diet with complete elimination of wheat, rye, and barley 3
• Important: Do not start a gluten-free diet before diagnostic testing is complete, as this will limit the accuracy of both serologic and histologic results 4
• If already on a gluten-free diet, a gluten challenge is needed before testing (1-3 slices of gluten-containing bread daily for 1-3 months) 4
• Provide nutritional assessment and supplementation for any deficiencies (iron, folate, vitamin B12) 3
• Monitor with serological testing (anti-TG2 antibodies) at 6 months, 12 months, and annually thereafter 3

For IBD:

• Management depends on the specific type and severity of IBD
• Consider the impact of anti-integrin antibody therapies (vedolizumab, ontamalimab, etrolizumab) on IgA biology, as these may lower stool IgA levels 1

Clinical Considerations and Pitfalls

• Low stool IgA may be present in children with partial IgA deficiency, correlating with low salivary IgA levels 2
• Patients with IgA deficiency may have increased translocation of specific bacterial taxa associated with elevated levels of systemic IgG targeting fecal microbiota 7
• The symptomatology and immune dysregulation in selective IgA deficiency are concentrated in patients who are also fecal IgA deficient 7
• Do not accept diagnoses like esophagitis, erosions, or peptic ulcer disease as the sole cause of associated symptoms without completing the full diagnostic workup 4
• Helicobacter pylori should be sought by non-invasive testing if symptoms persist after normal endoscopic evaluation, and eradicated if present 4

By following this structured approach, clinicians can effectively diagnose and manage patients with low stool IgA, addressing underlying conditions that may contribute to morbidity, mortality, and reduced quality of life.