Orphanet Journal of Rare Diseases | Clinical and immunological characteristics of autoimmune thyroid disease in inborn errors of immunity

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This study systematically reviewed the status of autoimmune thyroid disease (AITD) in 45 adult patients with inborn errors of immunity (IEI), revealing a high prevalence of AITD (15.5%) and identifying immunological features associated with AITD, such as elevated NK cell percentage, which provides important reference for thyroid disease screening in IEI patients.

 

Literature Overview
The article titled "Autoimmune thyroid disease in inborn errors of immunity: a retrospective perspective", published in the Orphanet Journal of Rare Diseases, reviews and summarizes the prevalence, clinical and immunological features of autoimmune thyroid disease in individuals with inborn errors of immunity. The study highlights the limitations of thyroid antibody testing in IEI patients and the supplementary diagnostic value of thyroid ultrasound.

Background Knowledge
Autoimmune thyroid disease (AITD) primarily includes Hashimoto’s thyroiditis (HT) and Graves’ disease (GD), which are common organ-specific autoimmune disorders. The incidence in females is significantly higher than in males. HT is typically associated with positive anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies, whereas GD is linked to thyrotropin receptor antibodies (TRAb). Inborn errors of immunity (IEI) are a group of inherited immune system disorders, often accompanied by immune dysregulation and autoimmunity. Due to antibody production defects or immunoglobulin replacement therapy (IGRT), patients may present with negative or false-positive antibody results, increasing the complexity of AITD diagnosis. Additionally, some IEI subtypes (e.g., CVID, IPEX, Hyper-IgM) have been reported to be highly associated with AITD, although the exact mechanisms remain unclear. Therefore, a systematic evaluation of AITD presentation, immunological features, and diagnostic strategies in IEI is of significant importance.

 

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Study Methods and Experiments
This single-center retrospective study included 45 IEI patients aged ≥18 years, excluding those with selective IgA deficiency. Data were extracted from electronic medical records, encompassing demographics, clinical manifestations, immunological parameters, thyroid function, antibody status, and ultrasound features. AITD was defined by the following criteria: 1) positive anti-TPO, anti-Tg, or TRAb; 2) ultrasound features of thyroiditis; 3) presence of thyroid dysfunction or history of L-thyroxine treatment. SN-CAT was defined as ultrasound evidence of thyroiditis with negative antibodies. Statistical analysis was performed using SPSS 28 with t-tests, Mann–Whitney U tests, and chi-square tests for intergroup comparisons.

Key Findings and Insights

• Among 45 IEI patients, 15.5% (7/45) were diagnosed with AITD, including 6 cases of Hashimoto’s thyroiditis (HT) and 1 case of seronegative chronic autoimmune thyroiditis (SN-CAT).
• 85.7% of AITD patients were positive for anti-TPO, and 60.0% for anti-Tg. TRAb was not detected in any patient, indicating that Graves’ disease (GD) is rare in IEI patients.
• All AITD patients had normal thyroid function at evaluation, yet 57.1% were receiving L-thyroxine treatment, suggesting the presence of subclinical or occult thyroid dysfunction.
• The CD16⁺56⁺ NK cell percentage was significantly higher in the AITD group compared to the non-AITD group (16.34% ± 14.53% vs 7.63% ± 5.20%, p = 0.010), suggesting a potential role of NK cells in thyroid autoimmunity.
• 26.6% of patients exhibited non-AITD thyroid abnormalities, including isolated antibody positivity (24.4%) and solitary nodules (2.2%).
• No significant gender difference was observed (p = 0.225), though females comprised 85.7% of AITD patients, consistent with the general population.
• Thyroid antibody testing in IEI patients may yield false-positive or false-negative results; therefore, ultrasound and clinical evaluation should be integrated to enhance diagnostic specificity.

Implications and Future Directions
This study underscores the necessity of systematic thyroid function and structural evaluation in IEI patients even in the absence of overt clinical symptoms. Given that AITD in IEI may present with seronegativity, elevated NK cell counts, and normal thyroid function, future studies should include larger and genetically diverse cohorts to confirm these findings. Additionally, further exploration of immune cell subsets in AITD pathogenesis and the diagnostic utility of thyroid ultrasound in IEI is warranted.

 

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Conclusion
This study identified a high prevalence of AITD (15.5%) in an adult IEI cohort, predominantly consisting of HT and SN-CAT. The findings reveal a significant increase in NK cell percentage, suggesting that immune dysregulation may play a pivotal role in thyroid autoimmunity. Given the limitations in antibody testing among IEI patients, integrating thyroid function tests, ultrasound, and immunophenotyping can improve the diagnostic accuracy of AITD. Future larger prospective cohort studies are necessary to further elucidate the genetic and immunological factors involved in AITD and to optimize screening strategies.

 

Makbule Seda Bayrak Durmaz, Betul Ozdel Ozturk, Begum Gorgulu Akin, Fikriye Kalkan, and Sadan Soyyiğit. Autoimmune thyroid disease in inborn errors of immunity: a retrospective perspective. Orphanet Journal of Rare Diseases.