|Year : 2022 | Volume
| Issue : 2 | Page : 154-158
Association of autoimmune thyroiditis with latent autoimmune diabetes of adults (LADA): A study from North India
Himalina S Sangma1, Anshul Singh1, Anubha Srivastava2, Ram Siya Singh3, Vatsala Misra1
1 Department of Pathology, M.L.N. Medical College, Prayagraj, Uttar Pradesh, India
2 Department of Medicine, M.L.N. Medical College, Prayagraj, Uttar Pradesh, India
3 Department of E.N.T., M.L.N. Medical College, Prayagraj, Uttar Pradesh, India
|Date of Submission||21-Oct-2021|
|Date of Acceptance||03-Feb-2022|
|Date of Web Publication||21-Jul-2022|
Dr. Himalina S Sangma
Department of Pathology, M.L.N. Medical College, Lowther Road, George Town, Prayagraj 211019, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Objective: The aim of this work was to study the association of autoimmune thyroiditis (AIT) in the patients of latent autoimmune diabetes of adult (LADA). Materials and Methods: The subjects included were more than 30 years of age, presenting with the deranged glycemic profile. After GAD65 autoantibody testing, they were grouped into LADA positive and LADA negative groups. Simultaneously, a thyroid workup for the presence of AIT was done. Statistical Analysis: The Student’s unpaired t test and chi-square test (χ2 test) were used to test for the significance of the difference in AIT between LADA and type 2 diabetes mellitus (T2DM) subjects as applicable. A value of P < 0.05 was taken as significant. Results: A total of 77 patients were included in the study. The mean age was 48 ± 13 years and M:F ratio was 1:3. A high frequency of AIT was found in the LADA group (80%) when compared to the true T2DM group (35%). Mean values of both anti-thyroid peroxidase antibody (anti-TPO) and anti-thyroglobulin antibody (anti-TG) antibodies were found to be significantly different between LADA and T2DM. Percentage positivity for anti-TPO, anti-TG, as well as combined anti-TPO and anti-TG were also found to be significantly different. Conclusion: Based on the significant association of AIT with LADA found in our study, we recommend all AIT patients to undergo simultaneous screening for LADA for a multimodal treatment.
Keywords: GAD65 positive diabetes, slowly evolving immune mediated diabetes of adults, thyroid dysfunction, type 1.5 diabetes
|How to cite this article:|
Sangma HS, Singh A, Srivastava A, Singh RS, Misra V. Association of autoimmune thyroiditis with latent autoimmune diabetes of adults (LADA): A study from North India. J Diabetol 2022;13:154-8
|How to cite this URL:|
Sangma HS, Singh A, Srivastava A, Singh RS, Misra V. Association of autoimmune thyroiditis with latent autoimmune diabetes of adults (LADA): A study from North India. J Diabetol [serial online] 2022 [cited 2022 Nov 29];13:154-8. Available from: https://www.journalofdiabetology.org/text.asp?2022/13/2/154/351753
| Introduction|| |
The most commonly encountered diabetes are type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Both these forms of diabetes are different from each other genetically, demographically, clinically as well as have different treatment regimens. Latent autoimmune diabetes of adult (LADA) is an intermediate between these two; hence, it is also known as type 1.5 diabetes. It shows overlapping features between T1DM and T2DM because similar to T1DM, it shows the presence of autoantibodies against islet cells, notably the GAD65 antibody whereas similar to T2DM, it has adult onset of presentation.,
Autoimmune thyroiditis (AIT) has been reported fairly consistent in patients of T1DM.,,, Thyroid autoimmunity has also been noted in several studies done on T2DM patients, although the association is not that high as for T1DM.,, Although the etiopathogenesis of LADA is not completely understood till now, it is mainly proposed to be an autoimmune disease and hence is frequently reported to be associated with other autoimmune diseases (polyendocrinopathy) such as celiac disease, adrenal autoimmunity, and thyroid autoimmunity, the latter said to be the most common one present in LADA patients with the reported co-association ranging from 22.1% to 33.3% in the studies done till date worldwide.,,,
To the best of our efforts in the search for literature, we could not find any study from India that has been done to evaluate the association of AIT with LADA. Therefore, in this study, we attempted to study the prevalence of AIT in LADA patients. AIT was diagnosed based on the status of thyroid-stimulating hormone (TSH), anti-thyroid peroxidase antibodies (anti-TPOab), and anti-thyroglobulin antibodies (anti-TGab), whereas LADA was diagnosed based on GAD65 antibody status.
| Materials and Methods|| |
A total of 77 patients who were more than 30 years of age and presented with altered glycemic profiles (HbA1c>5.7%) to the medicine OPD of our institute were selected for this study. They were then subjected to GAD65 antibody test followed by complete workup for thyroid gland in the ENT department that included testing for AIT based on TSH, anti-TPO, and anti-TG.
Ethical approval was taken from the institutional ethics committee. Written consent was taken from all the subjects as well as controls
This was a cross-sectional case-control study conducted over a period of 1 year (April 2020–2021).
Inclusion criteria: All the patients (M/F) more than 30 years of age with HbA1c level of 5.7% or more exclusion criteria:
- All the patients (M/F) with HbA1c level of 5.7% or more but less than 30 years of age and/or
- Subjects already on insulin treatment for DM or on anti-thyroid medications.
10 mL of blood was collected in serum separator tubes for TSH, anti-TPO, anti-TG, and anti-GAD65 antibody testing.
- [A] The GAD65 test was performed by using ELISA (kit by Bioassay Technology Laboratory, Shanghai, China).
The reference value of 1.6 ng/mL (corresponding to 5U/mL) was considered as cut-off level.
Standard curve range was 0.05–10 ng/mL; sensitivity was 0.021–10 ng/mL;
precision/CV (%): intra-assay <8% and inter-assay <10%.
- [B] TSH, anti-TPO, and anti-TG were performed by chemiluminescent microparticle immunoassay.
Reference value for TSH: 0.35–4.94 uIU/mL,
Reference value for anti-TPO ab: <5.61 IU/mL and
Reference value for anti-TG ab: <4.11 IU/mL
The Student’s unpaired t test was used to compare and assess the significance of difference for the mean values of TSH, anti-TPO, and anti-TG antibody. Chi-square test (χ2 test) was used to test for the significance of difference in their percentage positivity between LADA and T2DM subjects. Both were done using the Graph pad Prism Scientific Software, San Diego, California. A value of P < 0.05 was considered significant uniformly.
| Results|| |
In this study, a total of 77 patients were included that were analyzed for GAD65 antibody. Based on their GAD65 status, they were divided into two groups: GAD65 positive (LADA) and GAD65 negative group (true T2DM). 51.95% of our cases turned out to be GAD positive confirming them to be LADA actually.
Thyroid dysfunction (TD) was measured by TSH testing and overall frequency of TD was higher in LADA (65%) than in true T2DM (48.6%). We noted that hypothyroidism (56%) was the more common TD followed by hyperthyroidism (44%).
Isolated anti-TPO positivity was seen in 17.5% of LADA which was only 3% in T2DM. On the contrary, isolated anti-TG positivity was seen in 5% of LADA compared to 16% in T2DM. Combined positivity for both anti-TPO and anti-TG antibodies were seen in 57.5% of the LADA, which was again much higher when compared to 16% combined positivity seen in true T2DM group, whereas 20% were Antibody negative in LADA compared to 65% in T2DM [Figure 1] and [Figure 2]. This was found to be significant.
|Figure 1: Percentage positivity of parameters determining autoimmune thyroiditis in latent autoimmune diabetes of adult (LADA) patients|
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|Figure 2: Percentage positivity of parameters determining autoimmune thyroiditis in type 2 diabetes mellitus (T2DM) patients|
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We also noted that the frequency of overall anti-TPO antibody was higher (75%) in the LADA group compared to T2DM group (19%). Similarly, overall anti-TG antibody frequency was also higher in LADA than in the T2DM group (62.5% and 32%, respectively). Both anti-TPO and anti-TG as well as the combination of these two were significantly different between LADA and T2DM (P = 0.00001; 0.00832; 0.000187, respectively).
Comparison of the mean values of TSH, anti-TPO antibody, and anti-TG antibody revealed higher levels of all the three in the LADA group than in the true T2DM group. The difference was significant for anti-TPO antibody and anti-TG antibody between these two groups (P = 0.0351 and 0.0499, respectively). However, TSH levels showed no significant difference [Table 1].
|Table 1: Comparison of baseline characteristics between LADA and true T2DM|
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| Discussion|| |
LADA is an autoimmune disease, which pathophysiologically is more closely related to T1DM, whereas in perspective of clinical presentation like late onset and initial independence from insulin for at least 6 months to 1 year of diagnosis, is frequently misdiagnosed and treated as T2DM., Basically, LADA is a form of T1DM with slowly evolving beta-cell dysfunction due to autoantibody production; hence, World Health Organization (WHO) has termed it as slowly evolving immune-mediated diabetes of adult. It can show a myriad of autoantibodies like islet cell antibodies (ICAb), antibodies to insulin (IAb), antibodies to “tyrosine phosphatase – likeprotein” (IA-2Ab), and glutamic acid decarboxylase antibodies (GADAb). Among the GAD antibody, GAD65 isomer is the most consistently reported in studies done to date.,
The prevalence of LADA reported varies around the world ranging from also was 1.7% to as high as 59%.,,,,,,, In India also, a few studies done on LADA show the prevalence differing from region to region such as in two studies from North India by Sachan et al. and Kumar et al., the prevalence of 1.5% and 6.5% was reported respectively, whereas in a study from South India the LADA prevalence of 32% was documented. In our study, we found a 51.95% prevalence for LADA. Being an autoimmune disease, LADA is shown to be associated with other autoimmune disorders like celiac disease, thyroid, and adrenal autoimmunity.,, However, its association with AIT is the one most frequently reported, similar to its other two counterparts: T1DM and T2DM., This increased risk of thyroid autoimmunity in LADA patients, supports the theory of autoimmune poly-endocrine syndrome.,
In this study, we determined the presence of thyroid autoimmunity by the measurement of TSH, anti-TPO antibody, and anti-TG antibody in LADA and T2DM subjects. AIT was much more commonly found in the LADA subjects (80%) when compared to true T2DM (35%). In LADA subjects, the positivity of overall anti-TPO antibody, anti-TG antibody and combined anti-TPO antibody and anti-TG antibodies were 75%, 62.5%, and 57.5%, respectively, all the three of which were higher when compared to T2DM where they were 19%, 32%, and 16%, respectively. Significance of difference was seen for all the three anti-TPO, anti-TG as well as combined anti-TPO and anti-TG antibodies. Similar to our study, a higher association of AIT with LADA as compared to T2DM was reported by Matejková-Behanová et al. (33.3% vs.17.4%) and Akbar et al. (27% vs.4%). Also anti-TPO antibodies were more commonly seen in LADA than in T2DM and in women more than in men.,,, Buzzetti et al., in their study found anti-TPO antibodies more prevalent in GADA high titer group when compared to GADA low titer group though with a male predominance in the high titer group. Matejková-Behanová et al. and Kucera et al. in their respective study evaluated both Anti-TPO and Anti-TG antibodies in LADA patients and T2DM patients. They too found both these antibodies much more prevalent in LADA as compared to T2DM. Also, the anti-TPO antibodies were much more frequently present than anti-TG antibodies (26.7% vs. 9.7% in LADA [anti-TPO]; 13.3% vs. 5.8% in T2DM [anti-TG]) and (22.1% vs. 9.4% in LADA [anti-TPO]; 8.82% vs. 3.53% in T2DM [anti-TG]).
In our study, on comparing mean values of anti-TPO and anti-TG antibodies between LADA and true T2DM, we found significantly higher values of both the antibodies in LADA than in true T2DM (140.7 ± 285.75 vs. 26 ± 75.4 [anti-TPO] and 73.03 ± 183.08 vs. 6.2 ± 8.9 [anti-TG]), respectively. This was in concordance with the study of Kucera et al., where higher mean values of anti-TPO and anti-TG antibodies were seen in LADA patients compared to T2DM, though the difference was significant only for anti-TPO antibodies. Buzzetti et al. too observed a higher median for anti-TPO antibodies in LADA (in both the low and high GADA titer groups) in comparison to T2DM and it was found to be significantly different.
Our study showed TD higher in LADA (65%) than in true T2DM (48.6%) with hypothyroidism (56%) more common than hyperthyroidism (44%). This was in concordance with the study by Akbar et al. who reported TD to be more common in LADA (42%) than T2DM (7%). There too hypothyroidism was more prevalent than hyperthyroidism (38% vs. 4%).
The limitations of our study were as follows:
- The sample size was not huge. It was due to the massive impact of the COVID pandemic on the routine healthcare services.
- Also screening for other autoimmune dysfunctions was not done due to time and financial constraints.
- A proper follow-up could not be done which was again due to the restricted running of OPD services during both the waves of COVID pandemic in our state.
Nonetheless, the strength of this study was that despite the not-so-impressive sample size, we were able to show a significant co-association of AIT in LADA subjects which was way more higher than the true T2DM cases.
| Conclusion|| |
LADA/slowly evolving immune-mediated T1DM of adults is said to be a part of the spectrum of polyendocrine glandular syndrome, with its most frequent association with AIT. This was seen in the results of this study too. Identification of LADA patients presenting with AIT and vice versa becomes very important from the management part as these patients might be misdiagnosed T2DM, thus depriving them of appropriate treatment as well as from undergoing a comprehensive screening for various other autoimmune diseases.
Therefore, we recommend further studies on this subject on larger sample sizes and with a more extensive workup for polyendocrinopathies that may help in understanding their pathophysiology much better and also guide the clinicians in developing a more exhaustive treatment protocol for them.
We thank Dr. Gyan Prakash, MD, associate professor, Department of Preventive and Social Medicine (PSM), M.L.N. Medical College, Prayagraj for his support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Alvin CP, Kevin DN, Carmella Evans M. Diabetes mellitus. In: Jameson F, Kasper H, Longo L editors. Harrison’s Principles of Internal Medicine. USA: McGraw-Hill Education; 2018. p. 2850-82.
Matejková-Behanová M, Zamrazil V, Vondra K, Vrbíková J, Kucera P, Hill M, et al
. Autoimmune thyroiditis in non-obese subjects with initial diagnosis of type 2 diabetes mellitus. J Endocrinol Invest2002;25:779-84.
Kumar A, de Leiva A Latent autoimmune diabetes in adults (LADA) in Asian and European populations. Diabetes Metab Res Rev 2017;33:1-24. e2890. doi:10.1002/dmrr.2890.
Sougioultzoglou F, Falorni A, Kassi G, Brozzetti A, Karamitsos D, Koliakos GG Coincidence of high antiislet and antithyroid autoantibody titles in first-degree relatives of patients with type 1 diabetes. Exp Clin Endocrinol Diabetes 2005;113:85-9.
Palma CC, Pavesi M, Nogueira VG, Clemente EL, Vasconcellos Mde F, Pereira LCJr, et al
. Prevalence of thyroid dysfunction in patients with diabetes mellitus. Diabetol Metab Syndr 2013;5:58.
Hussain KSH Thyroid dysfunction in patients with diabetes mellitus at Puducherry, India: A retrospective study. Int J Adv Med 2018;5:822-24.
Souza OL, Diehl LA, Carleto LD Jr, Garcia V, Carrilho AJ, de Oliveira ML, et al
. Prevalence of thyroid autoimmunity in a group of patients with type 1 diabetes mellitus in Londrina, Pr. Arq Bras Endocrinol Metabol 2005;49:228-33.
Nair A, Jayakumari C, Jabbar PK, Jayakumar RV, Raizada N, Gopi A, et al
. Prevalence and associations of hypothyroidism in Indian patients with type 2 diabetes mellitus. J Thyroid Res 2018;2018:5386129.
Chaturvedi S, Nagtilak S, Parashar P, Rastogi A, Gupta A Thyroid dysfunction and it’s relation with Type 2 diabetes mellitus in Meerut. Int J Sci Res 2016;7:305-7.
Anil KR, Narashimha Shetty KR, Lalitha R, Shetty SB Prevalence of thyroid dysfunction among type 2 diabetes subjects in South India. Int J Clin Cases Investig 2014;5:93-100.
Kucera P, Nováková D, Behanová M, Novak J, Tlaskalová-Hogenová H, Andel M Gliadin, endomysial and thyroid antibodies in patients with latent autoimmune diabetes of adults (LADA). Clin Exp Immunol 2003;133:139-43.
Gambelunghe G, Forini F, Laureti S, Murdolo G, Toraldo G, Santeusanio F, et al
. Increased risk for endocrine autoimmunity in Italian type 2 diabetic patients with GAD 65 Autoantibodies. Clin Endocrinol 2000;52:565-73.
Akbar DH, Ahmed MM, Al-Mughales J Thyroid dysfunction and thyroid autoimmunity in Saudi type 2 diabetics. Acta Diabetol 2006;43:14-8.
Buzzetti R, Di Pietro S, Giaccari A, Petrone A, Locatelli M, Suraci C, et al
; Non Insulin Requiring Autoimmune Diabetes Study Group. High titer of autoantibodies to Gad identifies a specific phenotype of adult-onset autoimmune diabetes. Diabetes Care 2007;30:932-8.
Katahira M, Ogata H, Ito T, Miwata T, Goto M, Nakamura S, et al
. Association of autoimmune thyroid disease with anti-Gad antibody Elisa test positivity and risk for insulin deficiency in slowly progressive type 1 diabetes. J Diabetes Res 2018;2018:1847430.
National Committee for Clinical Laboratory Standards. Evaluation of the Linearity of Quantitative Measurement Procedures: A Statistical Approach; Approved Guideline. NCCLS document EP6-A. Wayne, PA: NCCLS; 2003.
Thakkar UG, Vanikar AV, Trivedi HL Type-1.5 diabetes mellitus with autoimmune hypothyroidism: A rare combination. Glob J Obes Diabetes Metab Syndr 2016;3:008-010.
World Health Organization. Classification of Diabetes Mmellitus. Available from: https://apps.who.int/iris/handle/10665/325182
. [Last accessed on 2021 Aug 12].
Carlsson S Etiology and pathogenesis of latent autoimmune diabetes in adults (Lada) compared to type 2 diabetes. Front Physiol 2019;10:320.
Park YS, Wang CY, Ko KW, Yang SW, Park M, Yang MC, et al
. Combinations of Hla Dr and Dq molecules determine the susceptibility to insulin-dependent diabetes mellitus in Koreans. Hum Immunol 1998;59:794-801.
Maddaloni E, Lessan N, Al Tikriti A, Buzzetti R, Pozzilli P, Barakat MT Latent autoimmune diabetes in adults in the United Arab Emirates: Clinical features and factors related to insulin-requirement. PLoS One 2015;10:e0131837.
Katulanda P, Shine B, Katulanda GW, Silva A, Asfir EL, Sheriff R, et al
. Diabetes mellitus among young adults in Sri Lanka–role of Gad antibodies in classification and treatment: The Sri Lanka young diabetes study. Diabetologia 2008;51:1368-74.
Takeda H, Kawasaki E, Shimizu I, Konoue E, Fujiyama M, Murao S, et al
; Ehime Study. Clinical, autoimmune, and genetic characteristics of adult-onset diabetic patients with Gad autoantibodies in japan (Ehime study). Diabetes Care 2002;25:995-1001.
Zinman B, Kahn SE, Haffner SM, O’Neill MC, Heise MA, Freed MI; ADOPT Study Group. Phenotypic characteristics of Gad antibody-positive recently diagnosed patients with type 2 diabetes in North America and Europe. Diabetes 2004;53:3193-200.
Roh MO, Jung CH, Kim BY, Mok JO, Kim CH The prevalence and characteristics of latent autoimmune diabetes in adults (Lada) and its relation with chronic complications in a clinical department of a university hospital in Korea. Acta Diabetol 2013;50:129-34.
Hawa MI, Kolb H, Schloot N, Beyan H, Paschou SA, Buzzetti R, et al
; Action LADA Consortium. Adult-onset autoimmune diabetes in Europe is prevalent with a broad clinical phenotype: Action Lada 7. Diabetes Care 2013;36:908-13.
Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, et al
. Ukpds 25: Autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes: UK prospective diabetes study group. Lancet 1997;350:1288-93.
Sachan A, Zaidi G, Sahu RP, Agrawal S, Colman PG, Bhatia E Low prevalence of latent autoimmune diabetes in adults in Northern India. Diabet Med 2015;32:810-3.
Guntaka M, Jangir A K, Hanmayyagari B, Satyanaraya V, Gopinath MM, Chanukya GV. Prevalence of latent autoimmune diabetes in adults: Experience from a single centre in South India. Paripex Indian J Res 2019;8:148-50.
Kalra S, Kalra B, Chatley G Prevalence of hypothyroidism in pediatric type-1 diabetes mellitus in Haryana, Northern India. Thyroid Res Pract 2012;9:12-14.
[Figure 1], [Figure 2]