Overview
Definition:
Celiac disease (CD) is a chronic, immune-mediated enteropathy triggered by gluten ingestion in genetically predisposed individuals, primarily affecting the small intestine
Selective IgA deficiency (sIgAD) is the most common primary immunodeficiency, characterized by a marked reduction or absence of serum IgA while other immunoglobulins are normal
The co-occurrence of CD and sIgAD presents unique diagnostic challenges due to the altered performance of standard IgA-based screening tests.
Epidemiology:
Celiac disease affects approximately 1% of the global population, with higher prevalence in populations of European descent
Selective IgA deficiency occurs in about 1 in 600 to 1 in 25,000 individuals, depending on the population
Individuals with sIgAD have a significantly higher prevalence of CD, estimated to be 5-10% of those with sIgAD
This makes screening for CD in individuals with sIgAD crucial.
Clinical Significance:
Accurate diagnosis of celiac disease is paramount to prevent long-term complications such as malnutrition, growth failure, osteoporosis, infertility, and an increased risk of certain malignancies (e.g., enteropathy-associated T-cell lymphoma)
In patients with sIgAD, relying solely on IgA-based serological markers for CD can lead to false-negative results, delaying diagnosis and management, thereby increasing the risk of these sequelae
Understanding specific testing algorithms is vital for pediatricians to ensure timely and correct diagnosis.
Clinical Presentation
Symptoms:
Typical symptoms include chronic diarrhea, abdominal pain, bloating, and weight loss
Atypical presentations are common, especially in children, and can include iron deficiency anemia unresponsive to iron therapy, short stature, delayed puberty, recurrent aphthous stomatitis, dermatitis herpetiformis, and neurological symptoms
In some cases, particularly with sIgAD, individuals may be asymptomatic, and CD is discovered incidentally during screening.
Signs:
Physical examination may reveal signs of malnutrition such as poor growth, muscle wasting, and pallor
Abdominal distension or tenderness may be present
Dermatitis herpetiformis, characterized by intensely itchy papules and vesicles, typically on elbows, knees, and buttocks, is a specific cutaneous manifestation of CD
Other findings can include signs of anemia or micronutrient deficiencies.
Diagnostic Criteria:
The revised European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) guidelines (2012) provide a framework
However, in the context of IgA deficiency, the approach needs modification
Generally, diagnosis requires: 1
Presence of CD-specific antibodies
2
Positive HLA-DQ2/DQ8 genotype (in certain situations)
3
Histological confirmation of villous atrophy and crypt hyperplasia with increased intraepithelial lymphocytes on small intestinal biopsy, AND/OR a positive response to a gluten-free diet
The diagnostic pathway must account for the absence of IgA antibodies.
Testing Strategies
Initial Screening:
In patients with suspected celiac disease and normal IgA levels, initial screening typically involves measuring tissue transglutaminase IgA (tTG-IgA) antibodies and total IgA levels
If total IgA is low or absent (consistent with sIgAD), IgA-based tests will be falsely negative
Therefore, in individuals with known or suspected sIgAD, initial screening must include both IgA-based and IgG-based autoantibodies.
Recommended Tests In SIgAD:
The recommended antibody panel for individuals with sIgAD who are being screened for celiac disease includes: 1
Total IgA level (to confirm sIgAD)
2
Tissue transglutaminase IgA (tTG-IgA) antibodies
3
Endomysial IgA (EMA-IgA) antibodies
4
Tissue transglutaminase IgG (tTG-IgG) antibodies
5
Endomysial IgG (EMA-IgG) antibodies
Alternatively, Deamidated gliadin peptide IgG (DGP-IgG) antibodies can be used as a sensitive alternative or adjunct to tTG-IgG and EMA-IgG.
Interpretation Of Results:
In the presence of sIgAD: A positive tTG-IgG or EMA-IgG (or DGP-IgG) is highly suggestive of celiac disease, even if tTG-IgA and EMA-IgA are negative
Conversely, if total IgA is normal, a positive tTG-IgA is diagnostic
If tTG-IgA and tTG-IgG are both negative in an individual with sIgAD and high clinical suspicion or positive genetics, further investigation including biopsy might be warranted.
Role Of Genetics:
HLA-DQ2 and HLA-DQ8 gene sequencing is essential in cases where serological testing is equivocal or when a biopsy is contraindicated or refused
The absence of both HLA-DQ2 and HLA-DQ8 essentially rules out celiac disease
In patients with sIgAD and negative serology, but high clinical suspicion, positive genetic predisposition (HLA-DQ2/DQ8) strengthens the indication for biopsy.
Diagnostic Confirmation
Intestinal Biopsy:
Small intestinal biopsy remains the gold standard for confirming celiac disease
Multiple biopsies should be taken from the second part of the duodenum
Histological findings include villous atrophy, crypt hyperplasia, and an increased number of intraepithelial lymphocytes (IELs)
In patients with sIgAD, a negative IgA-based serology does not preclude the presence of these histological changes.
Gluten Challenge:
A gluten challenge is generally not recommended for initial diagnosis in pediatric patients but may be considered in specific circumstances, such as after a prolonged period on a strict gluten-free diet where antibody levels have normalized and histology is unclear, or to confirm diagnosis after positive serology without biopsy
In the context of sIgAD, the challenge must be interpreted in conjunction with IgG-based antibody monitoring or repeat biopsy.
Biopsy Timing With SIgAD:
If IgA-based serology is negative due to sIgAD, but IgG-based antibodies (tTG-IgG, EMA-IgG, or DGP-IgG) are positive, small intestinal biopsy is recommended for definitive histological confirmation of villous atrophy
If serology is negative for both IgA and IgG, but there is strong clinical suspicion and the presence of HLA-DQ2/DQ8, biopsy is also indicated.
Management
Gluten Free Diet:
The cornerstone of celiac disease management is a strict, lifelong gluten-free diet (GFD)
All sources of wheat, barley, and rye must be eliminated
Careful label reading is essential, as gluten can be present in many processed foods, condiments, and even medications
Consultation with a dietitian experienced in celiac disease is crucial for education and adherence.
Nutritional Support:
Patients with celiac disease, especially those diagnosed after a period of malabsorption, may have deficiencies in iron, folate, vitamin D, calcium, vitamin B12, and other micronutrients
Nutritional assessment and supplementation are vital
Monitoring bone mineral density may be necessary in older children and adolescents.
Monitoring Response:
Response to a GFD is typically assessed by improvement in symptoms and normalization of antibody titers
In patients with sIgAD, IgG-based antibody titers (tTG-IgG, EMA-IgG, DGP-IgG) should be monitored
If antibody levels do not normalize or symptoms persist, adherence to the GFD should be re-evaluated, and repeat biopsy may be considered.
Complications
Associated Conditions:
Individuals with celiac disease, including those with sIgAD, are at increased risk for other autoimmune disorders (e.g., type 1 diabetes, autoimmune thyroid disease, autoimmune hepatitis), IgA nephropathy, and primary biliary cholangitis
Patients with sIgAD have an increased risk of respiratory infections due to the lack of mucosal IgA, which can be further complicated by the concurrent presence of celiac disease.
Long Term Risks:
Long-term complications of untreated or inadequately treated celiac disease include refractory celiac disease (RCD), small intestinal lymphoma (enteropathy-associated T-cell lymphoma - EATL), and adenocarcinoma of the small bowel
These risks are reduced with strict adherence to a GFD.
Management Of Complications:
Refractory celiac disease requires specialized management, often involving corticosteroids, immunosuppressants, or chemotherapy
EATL is aggressive and has a poor prognosis
management involves chemotherapy and, in select cases, stem cell transplantation
Regular screening for associated autoimmune conditions is also important.
Key Points
Exam Focus:
Always consider IgA deficiency when interpreting celiac serology
In sIgAD, IgA-based tests (tTG-IgA, EMA-IgA) will be falsely negative
Use IgG-based antibodies (tTG-IgG, EMA-IgG, DGP-IgG) and/or genetic testing (HLA-DQ2/DQ8) as primary screening tools in this population.
Clinical Pearls:
Ask about a family history of celiac disease or autoimmune disorders
Children with unexplained iron deficiency anemia, short stature, or gastrointestinal symptoms should be screened for celiac disease, with specific attention to IgA levels
Do not hesitate to order IgG-based celiac serology if IgA levels are low.
Common Mistakes:
Relying solely on IgA-based celiac antibody tests without checking total IgA levels
Missing the diagnosis of celiac disease in patients with sIgAD due to false-negative IgA serology
Inadequate patient education on the strictness of the gluten-free diet and cross-contamination risks.