Searching for LADA in patients with Hashimoto's thyroiditis: A tool for the prevention of LADA

ABSTRACT

Autoimmune thyroid diseases (AITD), such as Hashimoto's thyroiditis (HT), frequently co‐occur with autoimmune diabetes, including latent autoimmune diabetes in adults (LADA). While guidelines recommend thyroid autoantibody screening in patients with autoimmune diabetes, the reverse approach—screening for diabetes‐related autoantibodies in AITD patients—is not routinely practiced. Given the substantial link between glutamic acid decarboxylase antibodies (GADA) and both thyroid and β‐cell autoimmunity, we recommend frequent GADA testing in AITD patients, especially those with HT. This screening technique may discover LADA early, leading to timely glycaemic monitoring and treatment measures to protect β‐cell function and reduce diabetes complications.

Hashimoto's thyroiditis (HT) is an autoimmune disorder characterized by chronic inflammation of the thyroid gland, leading to hypothyroidism. It is marked by the presence of thyroid‐specific autoantibodies, such as antithyroid peroxidase (TPO) and anti‐thyroglobulin (TG) antibodies ¹ . Numerous studies have highlighted the relationship between thyroid autoimmunity and type 1 diabetes (T1D), leading many health organizations, such as The American Diabetes Association (ADA) ² , ³ , to recommend thyroid antibody screening for children, adolescents, and adults with T1D. Furthermore, an even stronger correlation has been observed between autoimmune thyroid disease (AITD) and latent autoimmune diabetes in adults (LADA). The latter is a form of diabetes that shares features with both type 1 and type 2 diabetes. It is characterized by the presence of islet autoantibodies, such as antiglutamic acid decarboxylase (GAD) antibodies, and a slower progression to insulin dependence compared to classic T1D ⁴ .

Indeed, the correlation between LADA and AITD appears to be particularly strong when high titers of glutamic acid decarboxylase antibodies (GADA) are present. A study by Jin et al. demonstrated that high titers of GADA are a strong predictor of the development of thyroid autoimmunity in both T1D and LADA patients. This finding is supported by the observation that LADA patients with high GADA titers have a higher prevalence of thyroid antibodies and thyroid dysfunction compared to those with lower GADA titers ⁵ . Additionally, Gougourelas et al. found that the presence of GADA was a significant predictor of LADA and HT ⁶ . The co‐occurrence of LADA with AITD can indeed impact glucose control and diabetes complications. Indeed, patients affected by both diseases often require higher daily insulin dosages and may experience more frequent episodes of diabetic complications, such as diabetic neuropathy ⁷ .

The knowledge about the interplay between autoimmune diabetes and AITD can, however, serve yet another purpose, by enabling the identification of patients with previously undiagnosed autoimmune diabetes within a cohort of AITD patients, particularly those with HT. Given this potential, we propose that GAD antibody testing be always considered for patients with HT. This will help identify individuals at risk for progressing to autoimmune diabetes, therefore preventing a late diabetes diagnosis, consequently reducing the potential of diabetic ketoacidosis or cardiovascular events before the development of the disease (Table 1).

Table 1.

Prevalence of autoantibodies in HT and LADA

Autoantibody	Hashimoto's thyroiditis (HT)	Latent autoimmune diabetes in adults (LADA)	Key findings
Antithyroid peroxidase (TPO)	High prevalence (~90%)	Moderate (~20–30%)	Common marker of thyroid autoimmunity. Elevated levels are indicative of HT
Antithyroglobulin (TG)	High prevalence (~70%)	Moderate (~10–20%)	Often found in HT; presence in LADA suggests overlapping autoimmunity
Glutamic acid decarboxylase antibodies (GADA)	Low prevalence (~10%)	High prevalence (~70–90%)	Strongest predictor of autoimmune diabetes; higher levels are linked to thyroid autoimmunity
Islet antigen‐2 (IA‐2A)	Low prevalence (~5–10%)	Moderate (~20–50%)	Associated with faster β‐cell destruction in autoimmune diabetes
Zinc transporter 8 (ZnT8A)	Very low prevalence (<5%)	Moderate (~20–30%)	Present in early‐stage autoimmune diabetes; indicates ongoing autoimmunity
Insulin autoantibodies (IAA)	Very low prevalence (<5%)	Moderate (~20–30%)	More common in younger LADA patients; associated with early autoimmune response

The prevalence rates are approximate and can vary based on the population studied and diagnostic criteria used.

MEASURING GAD ANTIBODIES IN AUTOIMMUNE THYROID DISEASE

GADA is the most common antibody found in both T1D and LADA. Other autoantibodies, such as insulin autoantibodies (IAA), islet antigen‐2 autoantibodies (IA‐2A), and zinc transporter 8 autoantibodies (ZnT8A), may also be present in these conditions but generally at lower frequencies ⁸ , ⁹ . As demonstrated by Moriguchi et al., in AITD patients, T1D occurs significantly more often in those testing positive for GAD antibodies, especially in individuals with high GADA levels and IA‐2 antibody positivity ¹⁰ . On the other hand, Kawasaki et al. found that patients with Graves' disease (GD) and HT exhibit a significantly higher prevalence of GAD‐specific antibodies compared to healthy controls ¹¹ .

Furthermore, some AITD patients do not develop pancreatic autoimmunity even if positive for the relevant autoantibodies, highlighting the complexity of autoimmune interactions ¹² .

CLINICAL IMPLICATIONS AND RECOMMENDATIONS FOR SCREENING

The vigilance for signs of LADA in patients with other autoimmune diseases and the screening for GADA in diabetes patients within this group has been recommended before ¹³ , ¹⁴ . However, testing for GAD antibodies before the development of LADA through the HT group does not appear to be recognized in the current medical literature. Testing for GAD antibodies in patients with AITD is especially relevant for LADA because, unlike T1D, it is often misdiagnosed as type 2 diabetes, leading to delayed insulin therapy and suboptimal metabolic control, hence the need for enhanced screening strategies. Introducing this approach as a screening and preventive tool could enhance early detection of LADA, allowing for timely monitoring and intervention. Indeed, if a patient were to test positive for GADA, additional islet cell autoantibodies can be measured as well to better assess the risk of beta cell destruction, prompting early intervention to slow disease progression ¹⁵ . This proves to be especially important when considering that several monoclonal antibody therapies are currently being tested for the prevention of T1D, particularly during the preovert diabetic phase. One of the most notable therapies is teplizumab, a humanized monoclonal anti‐CD3 antibody, which has shown efficacy in delaying the onset of T1D in high‐risk individuals ¹⁶ , ¹⁷ . Other monoclonal antibodies under investigation include golimumab, which targets TNF alpha, and frexalimab, which targets the CD40 ligand ¹⁸ , ¹⁹ . Therefore, GAD‐positive patients with HT may represent an ideal cohort for evaluating these therapies during the preclinical phase of autoimmune diabetes, potentially expanding the scope of early intervention strategies in at‐risk individuals.

In brief, GADA antibody testing in patients with HT can enable early diagnosis of LADA and help preserve β‐cell function for a longer period. This will reduce the risk of severe complications, such as diabetic ketoacidosis, hypoglycemia, and cardiovascular events, and improve overall long‐term health outcomes.

Further investigation is warranted to evaluate the viability, finances, and long‐term advantages of introducing GADA screening as a standard preventative procedure in patients with HT. Notably, Italy, the first nation to implement universal screening programs for both T1D and Coeliac Disease, sets a noteworthy example for national screening programs ²⁰ . These extensive initiatives open the door for a preventative approach to medicine that places an emphasis on early intervention rather than reactive treatment by offering insightful information about the possible effects of early detection techniques. As precision medicine develops, initiatives like preclinical diabetes screening could become a pillar of health care, reorienting the emphasis toward early therapeutic intervention, risk assessment, and prevention to enhance patient outcomes and lessen the burden of chronic autoimmune diseases.

DISCLOSURE

No potential conflicts of interest relevant to this paper were reported for Alicja Anna Kozlowska, Maria Vittoria Messina, and Paolo Pozzilli.

Approval of the research protocol: This article is a literature review based solely on previously published data; therefore, Institutional Review Board (IRB) approval is not required or applicable.

Informed consent: The need for informed consent was waived by the ethics committee at our institution due to the retrospective observational design of the study.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

FUNDING

Alicja Anna Kozlowska has no funding to be declared; Maria Vittoria Messina has no funding to be declared; Paolo Pozzilli has no funding to be declared.

AUTHOR CONTRIBUTIONS

Alicja Anna Kozlowska Kozlowska: conceptualization (equal), writing—original draft (equal), review and editing (equal), approval of the final version submitted for publication; Maria Vittoria Messina: conceptualization (equal), writing—original draft (equal), review and editing (equal), approval of the final version submitted for publication; Paolo Pozzilli: conceptualization (equal), writing—original draft (equal), review and editing (equal), approval of the final version submitted for publication; Andrea Palermo: conceptualization (equal), writing—original draft (equal), review and editing (equal), approval of the final version submitted for publication.

DATA AVAILABILITY STATEMENT

The data that support the findings of this study are available from the corresponding author upon reasonable request.