Diagnostic accuracy of tTG level in Paediatric Celiac Disease

The diagnostic accuracy of tissue transglutaminase IgA (tTG-IgA) levels in pediatric celiac disease was assessed in a large North American study involving 4019 children under 18 years from 12 hospitals across Canada and the United States between 2016–2021. Here are the key findings related to the diagnostic accuracy of tTG-IgA levels:

### **1. Overall Diagnostic Accuracy:**

• Elevated tTG-IgA levels predicted biopsy-confirmed celiac disease with a **positive predictive value (PPV) of 82.6%**. This indicates that while tTG-IgA is a good diagnostic tool, it is not perfect.

### **2. High-Level Antibody Threshold (≥10x Upper Limit of Normal [ULN]):**

• Among children with tTG-IgA levels **≥10 times the ULN**, the PPV rose significantly to **94.9%**, showing strong predictive value.
• However, this threshold is not absolute, as **5% of children with tTG-IgA ≥10x ULN did not have diagnostic histology**, including **2% with completely normal biopsies**. This highlights the risk of relying solely on serology for diagnosis.

### **3. False Positives Exist:**

• Even at high antibody levels, some children do not have biopsy-confirmed celiac disease. This underscores the importance of histological confirmation to avoid misdiagnosis and unnecessary dietary restrictions.

### **4. Laboratory Variability:**

• The performance of tTG-IgA assays varied widely between laboratories:
• For elevated tTG-IgA values, PPV ranged from **71.5% to 88.8%**.
• For tTG-IgA levels **≥10x ULN**, PPV ranged from **89.3% to 97.3%**.
• This variability highlights the need for standardized testing protocols and thresholds across laboratories.

### **5. Impact of Comorbidities:**

• **Type 1 Diabetes:** Children with type 1 diabetes showed lower predictive accuracy, with a PPV of **89%** at tTG-IgA levels **≥10x ULN**, suggesting comorbid conditions may affect test performance.
• **Down Syndrome:** Limited data was available for children with Down syndrome, but they often have higher baseline autoantibody levels, which could complicate interpretation.

### **6. EMA Testing:**

• Endomysial IgA antibody (EMA) testing provided only marginal improvement in specificity. Surprisingly, **76% of non-celiac children with high tTG-IgA levels also tested positive for EMA**, indicating that EMA is not completely reliable in ruling out false positives.

### **7. Potential Early Signal:**

• Some children with high tTG-IgA levels but normal biopsies may later develop celiac disease. This suggests that elevated antibodies could precede visible intestinal damage, warranting close monitoring of such cases.

### **8. Premature Gluten Restriction:**

• Concerns were raised about children being unnecessarily placed on gluten-free diets based solely on serology without biopsy confirmation. This can impose significant dietary, social, and psychological burdens, especially in North America.

### **9. Clinical Confirmation is Essential:**

• Experts emphasize that elevated tTG-IgA levels, even at **≥10x ULN**, should always be confirmed by a gastroenterologist and biopsy before initiating a gluten-free diet. This ensures diagnostic accuracy and prevents unnecessary lifelong dietary restrictions.

### **10. Unanswered Questions:**

• The study highlighted unanswered questions regarding why some children have persistently high tTG-IgA levels without enteropathy. Further research is needed to understand this phenomenon.

### **11. Prospective Monitoring:**

• Children with high tTG-IgA levels but normal biopsies should be monitored closely over time, as they may develop celiac disease later.

### **12. Guideline Implications:**

• While elevated tTG-IgA levels are highly suggestive of celiac disease, biopsy remains the gold standard for diagnosis in North America. Unlike European guidelines, which allow non-biopsy diagnosis under strict conditions, North American guidelines continue to emphasize histological confirmation.

### **Clinical Implication:**

• Elevated tTG-IgA levels are highly suggestive but not definitive for pediatric celiac disease. Diagnosis must be confirmed histologically to ensure accuracy, avoid unnecessary dietary restrictions, and account for variability in assay performance and comorbid conditions.

In summary, while tTG-IgA levels, especially at high thresholds (≥10x ULN), demonstrate strong predictive value for celiac disease, they are not infallible. Biopsy remains essential for definitive diagnosis in pediatric patients to avoid misdiagnosis, unnecessary lifestyle changes, and ensure proper management.