What causes low secretory Immunoglobulin A (sIgA) in stool?

What Causes Low Secretory IgA (sIgA) in Stool

Low secretory IgA in stool is most commonly caused by selective IgA deficiency (SIGAD), defined as serum IgA <7 mg/dL with normal IgG and IgM levels, affecting approximately 1 in 300-700 white individuals in the United States. 1, 2

Primary Immunodeficiency Causes

Selective IgA Deficiency (SIGAD) is the leading cause:

• Affects patients older than 4 years with serum IgA <7 mg/dL and normal IgG/IgM levels 1, 2
• Represents the most common primary immunodeficiency disorder 3, 4
• Prevalence is significantly lower in Asian populations (approximately 1:18,000) 1
• Family history of SIGAD or Common Variable Immunodeficiency (CVID) present in 20-25% of cases 1, 2
• Higher prevalence may occur in male patients 1

Common Variable Immunodeficiency (CVID):

• Some patients with SIGAD progress to CVID later in life 1, 2
• CVID represents the severe end of the immunodeficiency spectrum with SIGAD at the milder end 3
• Can present with late-onset opportunistic infections, gastrointestinal disease, and lymphomas 1

Good Syndrome:

• Associated with thymoma and similar immunologic features to CVID 1
• Requires thymoma excision, though this does not normalize immune function 1

Secondary and Medication-Induced Causes

Drug-induced IgA deficiency is reversible and must be investigated:

• Antiepileptic medications: phenytoin, carbamazepine, valproic acid, zonisamide 1, 2
• Anti-inflammatory drugs: sulfasalazine, NSAIDs 1, 2
• Immunomodulators: gold, penicillamine, hydroxychloroquine 1, 2
• Cessation of the offending medication often leads to reversal of IgA deficiency 1, 2

Biologic therapies affecting B-cell trafficking:

• Vedolizumab (anti-α4β7 integrin) lowers stool sIgA levels even after a single dose in healthy volunteers 5
• MAdCAM-1 blockade compromises IgA antibody-secreting cell recruitment to intestinal lamina propria 5
• These agents interfere with B-cell homing to gut-associated lymphoid tissue 5

Pathophysiologic Mechanisms

B-cell maturation defects:

• Terminal lymphocyte differentiation defect leads to underproduction of serum and mucosal IgA 3, 4
• IgA genes themselves are normal; the defect lies in B-cell maturation 3
• Alterations in TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) gene act as disease-modifying mutations 4

Genetic susceptibility:

• Certain MHC haplotypes associated with increased susceptibility 4
• Genetic basis remains incompletely understood 4

Clinical Implications and Associated Conditions

Infection risk:

• Increased susceptibility to respiratory and gastrointestinal infections, particularly Giardia lamblia 1, 2, 6
• Impaired specific antibody responses, especially to pneumococcal polysaccharide antigens 1
• Most IgA-deficient individuals remain asymptomatic due to compensatory mechanisms, including secretory IgM 5, 3

Autoimmune disease associations:

• Celiac disease is the most common association 1, 2, 3
• Autoimmune thyroid disease and type 1 diabetes 1, 2
• Atopic diseases occur frequently 1

Diagnostic Approach

Essential initial testing:

• Measure total serum IgA level to confirm deficiency 1, 2
• Only methods detecting IgA <7 mg/dL can determine true absence versus very low levels 1
• Approximately two-thirds have detectable low IgA; one-third have completely absent IgA 1

When evaluating for celiac disease in patients with low IgA:

• IgA-based tissue transglutaminase (tTG) testing will yield false-negative results 1
• Use IgG-based tests: IgG-tTG or IgG deamidated gliadin peptides 1, 2
• Consider duodenal biopsy even with negative antibodies if clinical suspicion remains high 1

Medication history is critical:

• Thoroughly investigate all current and recent medications 1, 2
• Discontinuation of causative drugs may restore IgA production 1, 2

Management Considerations

For symptomatic patients with recurrent infections:

• Aggressive antimicrobial therapy or prophylactic antibiotics for recurrent sinopulmonary infections 1, 2
• No role for IgG replacement therapy in isolated SIGAD (unlike CVID) 1
• Treat atopic disease aggressively when present 1, 2

Transfusion precautions:

• Risk of anaphylactic reactions to blood products due to anti-IgA antibodies 1, 3
• Although severe reactions are rare, some centers use IgA-deficient donor products or washed cells 1

Long-term monitoring:

• Vigilance for progression to CVID 1, 2
• Monitor for development of autoimmune diseases and malignancy 1
• Screen for celiac disease given strong association 1, 2

Common Pitfalls to Avoid

• Do not overlook medication-induced causes, as these are reversible 1, 2
• Do not rely solely on IgA-based celiac testing in patients with known or suspected IgA deficiency 1
• Do not assume all IgA-deficient patients are symptomatic—most remain asymptomatic throughout life 3, 4
• Do not ignore family history, as 20-25% have affected relatives 1, 2