Report: Autoimmune Thyroiditis Prevalence in Type 1 Diabetes Children

This report presents a study evaluating children and adolescents with clinically diagnosed type 1 diabetes and autoimmune thyroid anomalies. The study investigates the frequency of autoimmune thyroiditis, including subclinical hypothyroidism, and its association with factors like anti-TPO antibodies, vitamin D deficiency, and diabetic ketoacidosis (DKA). The research highlights the importance of thyroid function screening, especially in females, and its impact on glycemic control. Key findings reveal a higher prevalence of autoimmune thyroiditis in females with T1D, increased DKA levels in those with hypothyroidism, and a link between vitamin D deficiency and AIH. The study emphasizes the need for regular monitoring and improved management strategies, particularly in the initial stages of poorly controlled T1D. The report also discusses the impact of AIH on HbA1c levels and the potential implications for patient outcomes, advocating for new standards of HbgA1C level for children. The report also addresses the relationship between the development of AIH and factors like age and gender of the participants.

Discussion
The study elavuates the children along with adolescents with clinically
diagnosed type 1 diabetes who frequently presents with autoimmune
thyroid anomalies. Lack of standardized policy prompting the accurate
method for the screening of the childrenand adolescents for thyroid
function tests and analyzing autoantibodies lead to the independent
design of this study to examine the frequency of autoimmune thyroiditis
in children and adolescents with clinical manifestation of type 1 diabetes.
Subclinical range of hypothyroidism were also considered where the TSH
levels were high while T3 and T4 levels of free thyroxine were with the
range as they are early symptoms related to autoimmune thyroiditis
(Carvalho et al., 2013). Evidence based studies recommends tests to be
performed at the time of establishment of the disease followed by a
period of metabolic rest and repeating the clinical diagnosis tests at
regular six months intervals (ADA 2018). Patients who show elevated TSH
but normal free thyroxine levels must also be screened recurrently to
check the prognosis of the disease and control the onset therapeutically.
Chilren with type 1 diabetes with no immediate signs of thyroid disorders
must also be monitored regularly for precautionary measures.
1

The recognition of type 1 diabetes mellitus as an auto immune disease
has been well established along with its direct association with organ
specific other diseases namely adrenal insufficiency, autoimmune
hypothyroidism, anemia, and so on (Duntas, Orgiazzi and Brabant 2011).
However, the parameters linked with the association of type 1 diabetes
mellitus with autoimmune hypothyroidism are still under research.
Although the fact that there is a increased occurrence of autoimmune
hypothyroidism in patients with type 1 diabetes mellitus along with
heightened anti-TPO antibodies, the casuse behind this amplified
frequency is still obscure.
The prevalence of subclinical hypothyroidism and its progression in
females with type 2 diabetes mellitus has been well documented along
with higher occurrence of organ specific autoimmunity in the endocrine
glands (Sharifi, Ghasemi and Mousavinasab 2008). The genetic alliance of
the receptors of vitamin D and its polymorphs are shown to have
relationship with hypothyroidism (Vogel, Strassburg and Manns 2002). The
dietary intake of vitamin D supplementation has direct consequence on
the prevalent risk in type 1 diabetes (Brekke and Ludvigsson 2007).
2

The association of the severerity of hypothyroidism with the prevalence
rate of diabetic ketoacidosis (DKA) at preliminary analysis in young
patients diagnosed with type 1 diabetes mellitus was investigated by
Norström et al. (2018). Evaluation of the medical data of the pediatric
participants revealed 9.6% of children diagnosed with type 1 diabetes
mellitus had hypothyroidism and was associated with elevated DKA levels
when compared to children with type 1 diabetes mellitus and normal
ranges of thyroid function. In addition, type 1 diabetes mellitus positive
children with hypothyroidism had considerably higher level of anti-TPO
antibodies when there was noted parental consanguinity (p =0.01), and
familial history of typr 1 diabetes mellitus (p = 0.02) within the first
degree relations. Therefore, prevalence of autoimmune hypothyroidism
amongst children with type 1 diabetes mellitus is more aggressive during
initial presentation of poorly controlled type 1 diabetes mellitus which also
proposes better management and care when detected (Fatourechi et al.,
2017) .
Significant increase of anti thyroid peroxidise antibody (anti TPO antibody)
in children with type 1 diabetes along with autoimmune thyroiditis has
been noted however its clinical prevalence is been researched on now.
Saare, Peet and Tillmann (2018) evaluated the level of anti TPO antibody
in the blood serum and its occurrence in clinical manisfested cases of type
1 diabetes in children with clinically diagnosed hypothyroidism. They
observed female children with type 1 diabetes had higher incidence of
developing autoimmune thyroiditis with significantly higher anti TPO
concentration (>100 kU/L) (Saare, Peet and Tillmann 2018).
3

The data was generated from 241 children diagnosed with T1DM with
accurate medical reports dated between 2003 to 2015. Statistical analysis
was based on their thyroid function and the presence of anti-TPO thyroid
antibodies. The examinations were conducted on 127 females and 114
males and their ages were grouped into four categories, depicting infants,
yound children, children and adolescents. Critical evaluation revealed 34
participants who tested positive for anti-TPO antibodies of which 20 were
females and 14 were males whereas 14 patients comprising of 13 females
and 1 male were identified with AIH along with subclinical levels of auto
immune hypothyroism in 10 of the participants. Twenty seven children
(11.2%) with clinically established T1DM tested positive for anti-TPO
antibodies with standard functional thyroid. The study highlighted higher
rate of prevalence of female patients (70.7%, P < 0.001) presenting with
positive anti-TPO antibodies compared to only 11.9% (P < 0.001) of males
with signs of anti-TPO antibodies. This statistical data is concurrent with
other studies which signifies females with T1DM showing higher
occurrences of developing thyroidal anomalies as compared to males with
T1DM (Sharifi et al., 2008). However, direct eveidence of females with
T1DM having an elevated presentation of anti-TPO antibodies compared to
that of males with T1DM is unique and established in this study with
critical analysis and data based evidences. Amongst the 70.7% females
with T1DM who were tested positive for the anti-TPO antibodies, 85%
were adolescents between the ages of 12 to 18.
4

Thirty six percent of the patients with AIH had tested positive for anti-TPO
antibodies when diagnosed with T1DM for the first time. The average time
gap in those participants with T1DM before onset of clinical AIH ranged
between 4 to 16 years time. Research based evidences shows positive
relation between diabetes and autoimmune hypothyroidism in adolescent
children which might lead even further decrease of insulin sensitivity
(Cutolo, 2014). Norström et al. (2018)had also reported results parallel
with this study thereby establishlish the dependability of the fact that
predominance of autoimmune hypothyroidism in the midst of children
with type 1 diabetes mellitus is more antagonistic during the initial
appearance of inadequately controlled type 1 diabetes mellitus.
Initial diagnosis of diabetic ketoacidosis was the foremost medical
symptom for 50% of the T1DM patients diagnosed with clinical AIH. The
result derived from this study is concurrent with the results of Saare, Peet
and Tillmann (2018). The co existence of autoimmune hypothyroidism and
type 1 diabetes mellitus has been rarely reported thus making this study
significant in drawing attention to this correlation between the two. This
study provides evidence in establishing the mean age of type 1 diabets
mellitus onset as 8.58 years and the average age of autoimmune
hypothyroidism onset was determined as 9.42 years whereas the mean
time in those participants with T1DM before onset of clinical AIH was
found to be 3.86 years of age.
5

Possible relationships between patient with T1DM eventually developing
AIH and the parameters influencing such correlation are covariates
namely the age, and gender of the participants. There are evidence based
studies available suggesting direct correlation between women with type
2 diabetes and their prevalence and progression of subclinical
hypothyroidism (Chubb et al., 2005) but congregated data is not available
on the possible association between patient with T1DM developing AIH
(Sharifi, Ghasemi and Mousavinasab 2008). The relation with age seemed
non significant as the p-value observed after statistical analysis was less
that 0.1 and 0.131 data for contingency coefficient. However, frequency of
females patients with T1DM eventually developing AIH seemed much
higher. Female gender predominated in the group of children and
adolescents with T1DM and AIH (93%; p=<0.0003) thereby female gender
established a significant relationship with AIHT as p.value (0.000) is less
than 0.05, and the relation is weak with Contingency Coefficient equals
0.194 whereas the male participants with T1DM showed a much lesser
frequency of developing AIH (50%; p=<0.0003) .
6

The International Society for Pediatric and Adolescent Diabetes (ISPAD)
has lowered its recommended range of blood glucose level in children
diagnosed with type 1 diabetes as reflected by the recent scientific
evidences. Several concurrent studies have shown previous set target of
HbgA1C level at 8.5 percent have greater chances of causing risk to the
children with prolonged hyperglycemia such as renal and cardiovascular
diseases. Such chronic ailments which were then believed to be caused
only in adults however studies now reflect a different scenario of children
with renal and cardiac conditions with HbgA1C level of 8 to 8.5 percent.
The new standard range for HbgA1C level in children has been
recommended to be kept under 7.5 percent. The impact of AIH on HbgA1C
level in children and adolescents with T1DM is significant as autoimmune
hypothyroidism decreases insulin sensitivity even further thus causing a
added increase in the HbgA1C level in children and adolescents with
T1DM with already heightened HbgA1C levels. The children and
adolescents with AIH showed increased glycemic control impairment. The
table (4) indicating mean difference values of HgA1c values between the
clinical AIH group, subclinical AIH group, group with positive Abs and the
euthyroid group revealed that the children diagnosed with clinical AIH
showed a significant higher level of HgA1c (11.4893) than the other
groups.
7

Vitamin D has various noncalcemic roles in the body which includes
functions in the T cell-medicated immunity and has shown association
with inflammatory bowel syndrome, type 1 diabestes, lupus, and so on
(Deluca and Cantorna, 2001). Proper intake of vitamin D supplements
during pregnancy reduces chances of infants developing type 1 diabetes
and being associated with diabetes related autoantibodies (Brekke and
Ludvigsson 2007). Ensuring sufficient supplementation of vitamin D for
the infants could facilitate reversing the growing trend of the occurrence
of type 1 diabetes (Hyppönen et al., 2001). Recent study by Komisarenko
and Bobryk (2018) predicted the probability of combination of various
endocrine diseases inclusive of autoimmune thyroiditis during decrease in
vitamin D circulation level along with amplification of several metabolic
diseases and greatly contribute to complications in diabetes mellitus. The
study also states that regular supplementation of vitamin D in patients
diagnosed with diabetes mellitus and autoimmune thyroiditis will diminish
levels of the pro inflammatory cytokines therefore is efficient in the
treatment of endocrine disease (Komisarenko and Bobryk 2018).
8

The relationship between children and adolescents participants with T1DM
diagnosed with hypothyroidism and deficiency of vitamin D has been
ascertained in this study. Vitamin D deficiency was present in 69% of
children and adolescents who suffered from T1DM and AIH concurrently
(p=0.02). Among the autoimmune hypothyoidism cases, children with
overt or clinical hypothyroidism had higher prevalence of Vitamin D
deficiency compared with children with subclinical hypothyroidism and
who had positive Anti-TPO antibodies or children without AIH. One unit
increase in Vitamin D status was associated with 18.6% reduction in odds
of AIH (Odds 0.814, p=0.051). This result is concomitant with the research
analysis by Komisarenko and Bobryk (2018). The table (5) indicates the
association between hypothyroidism and vitamin D deficiency as the odds
of being patient with clinical AIHT increases by (8.230) times given
patients with VitD deficiency according to non VitD deficiency.
The interface between the prognosis of hypothyroidism and the rate of
prevalence of diabetic ketoacidosis (DKA) at preliminary stage of
diagnosis in children and adolescents with T1DM was studied. Assessment
of the incidence of ketoacidosis at the commencement of type 1 diabetes
in children with autoimmune thyroditis had notably lower rate of
prevalence compared to the patients without autoimmune thyroditis in a
study conducted by Park et al., (2000).
9

Amongst the participants chosen for the study, ten of the participants with
autoimmune hypothyroidism showed diabetic ketoacidosis as the first
clinical representation of their type 1 diabetes mellitus. This accounted for
70% with a significant p-value of <0.0007 in comparison to 16% of
patients with clinically diagnosed type 1 diabetes mellitus who had
standard thyroid function. They also had elevated levels of HbA1C at the
time of enrolment in to the study (11.16±1.73 vs. 9.52±1.79, P = <0.013)
when compared with the patients with T1DM with normal thyroid function.
Fifty percent of the participants tested positive for anti-TPO antibodies
with levels above 100 in the serum. A hundred percent of the patients
who were diagnosed with type 1 diabetes mellitus along with autoimmune
hypothyroidism at the same time had presented with diabetic ketoacidosis
during their preliminary analysis and this is supported by extensive
research performed by Park et al., (2000).
The binary logistic regression model analysed and tabulated in table (8)
signified presence of five independent parameters associated with the
clinical occurrence and prevalence of autoimmune hypothyroidism. These
variables determined and examined in this study included (i) gender, (ii)
adolescence; (iii) anti-TPO antibodies of levels above 100, (iv) age during
the diagnosis of T1DM and (v) vitamin D deficiency.
10

This study thereby gives critical intel on the prognosis of patients with
type 1 diabetes mellitus its association with autoimmune hypothyroidism.
The prevalence of female patients with type 1 diabetes mellitus with onset
of auto immune hypothyroidism is significantly high and the occurrence is
seen mainly in adoslescent children. Half of the population of the
participants tested positive for anti-TPO antibodies with levels above 100
in the serum. Observations reveal distinct impact of AIH on HbgA1C level
in children and adolescents with T1DM also and also highlights the
correlation between hypothyroidism and vitamin D deficient participants.
The rise in the trend of hypothyroidism is inversely proportional to the
increase in vitamin D supplementation during infancy.
The odds of being a patient with quantifiable AIH amplified by 0.047 times
if the patient is a female with T1DM in comparison to being a male patient
with T1DM. On reaching the age of adolescence at 12 years enhance the
probability of a child with diagoned T1DM along with clinical manifestation
of AIH augments by 6.740 times. The occurrence of positive results of
anti-TPO antibodies in the serum of children with T1DM increases the
probability of a child to be diseased with AIH by a factor of 0.178.
The statistical data thereby deduced from the study ascertains the
positive interrelation between the female gender, vitamin D deficiency,
rise in anti-TPO antibodies and the adolescent age in the pathophysiology
of type 1 diabetes mellitus and its association with autoimmune
hypothyroidism.
Limitations:
11

The limitation of the study is in its population of the participants. Taking a
higher sample group population would provide increased pool of data,
thereby enhancing the quality of statistically significant analysis.
Systemic analysis of research based articles to generate secondary data
along with evaluation of the primary data collected from the Hamad
General Hospital (HGH), Qatar in this study could widen the scope for
better statistical analysis.
Recommendations:
Further recommendation for this study includes collection of primary data
from other hospitals along with Hamad General Hospital (HGH), Qatar, so
as to increase the sample size of the participants included into the study.
This will help in enhancing the quality of data collected by minimizing
chances of errors and amplifying the eminence of the statistical analysis
of the data.
Secondary data can also be collected from systemic search and tallied
with the primary data analysis of the study for a better outlook of the
objectives aimed during the study.
Conclusion:
12

Autoimmune thyroiditis and type 1 diabetes mellitus are amongst the
most widespread autoimmune disorders in the pediatric age group in
which the autoimmunity of thyroid might be occurring in forms of
euthyroid, hyperthyroidism and the most frequently occurring
hypothyroidism. The main motive of the study comprised of assessment of
the prevalence of hypothyroidism in children with type 1 diabetes mellitus
along with determining the relationship between autoimmune thyroiditis
and the control of the glycemic level in children and adolescents with type
1 diabetes mellitus. The statistical analysis of the data collected aided in
structuring a binary logistic regression model which indicated presence of
five independent parameters linked with the clinical occurrence and
predominance of autoimmune hypothyroidism in patients with type 1
diabetes mellitus including independent variables namely gender,
adolescence, anti-TPO antibodies, age during onset of type 1 diabetes
mellitus and vitamin D deficiency. The chances of being a patient with
quantifiable autoimmune hypothyroidism amplified if the patient is a
female with type 1 diabetes mellitus in comparison to being a male
patient with type 1 diabetes mellitus. On reaching the age of adolescence
at 12 years enhance the probability of a child with diagoned type 1
diabetes mellitus along with clinical manifestation of autoimmune
hypothyroidism augmented. The occurrence of positive results of anti-TPO
antibodies in the serum of children with T1DM increases the probability of
a child to be diseased with autoimmune hypothyroidism. Therefore, it can
be well concluded that there is positive interrelation between the female
gender, vitamin D deficiency, rise in anti-TPO antibodies and the
13

adolescent age in the pathophysiology of type 1 diabetes mellitus and its
association with autoimmune hypothyroidism.
14

References:
Boelaert, K., Newby, P. R., Simmonds, M. J., Holder, R. L., Carr-Smith, J. D.,
Heward, J. M., ... and Lazarus, J. H. (2010). Prevalence and relative risk of
other autoimmune diseases in subjects with autoimmune thyroid
disease. The American journal of medicine, 123(2), 183-e1.
Brekke, H.K. and Ludvigsson, J., 2007. Vitamin D supplementation and
diabetes‐related autoimmunity in the ABIS study. Pediatric diabetes, 8(1),
pp.11-14.
Chubb, S.A.P., Davis, W.A., Inman, Z. and Davis, T.M.E., 2005. Prevalence
and progression of subclinical hypothyroidism in women with type 2
diabetes: the Fremantle Diabetes Study. Clinical endocrinology, 62(4),
pp.480-486.
Cutolo, M., 2014. Autoimmune polyendocrine syndromes. Autoimmunity
reviews, 13(2), pp.85-89.
Davies, M.J., D’Alessio, D.A., Fradkin, J., Kernan, W.N., Mathieu, C.,
Mingrone, G., Rossing, P., Tsapas, A., Wexler, D.J. and Buse, J.B., 2018.
Management of hyperglycaemia in type 1 diabetes, 2018. A consensus
report by the American Diabetes Association (ADA) and the European
Association for the Study of Diabetes (EASD). Diabetologia, 61(12),
pp.2461-2498.
Deluca, H.F. and Cantorna, M.T., 2001. Vitamin D: its role and uses in
immunology. The FASEB Journal, 15(14), pp.2579-2585.
15

Duntas, L.H., Orgiazzi, J. and Brabant, G., 2011. The interface between
thyroid and diabetes mellitus. Clinical endocrinology, 75(1), pp.1-9.
Fatourechi, A., Ardakani, H.M., Sayarifard, F. and Sheikh, M., 2017.
Hypothyroidism among pediatric patients with type 1 diabetes mellitus,
from patients’ characteristics to disease severity. Clinical Pediatric
Endocrinology, 26(2), pp.73-80.
Hage, M., Zantout, M.S. and Azar, S.T., 2011. Thyroid disorders and
diabetes mellitus. Journal of thyroid research, 2011.
Hyppönen, E., Läärä, E., Reunanen, A., Järvelin, M.R. and Virtanen, S.M.,
2001. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study.
The Lancet, 358(9292), pp.1500-1503.
Komisarenko, Y.I. and Bobryk, M.I., 2018. Vitamin D deficiency and
immune disorders in combined endocrine pathology. Frontiers in
endocrinology, 9, p.600.
Norström, F., Van Der Pals, M., Myléus, A., Hammarroth, S., Högberg, L.,
Isaksson, A., Ivarsson, A. and Carlsson, A., 2018. Impact of Thyroid
Autoimmunity on Thyroid Function in 12-year-old Children With Celiac
Disease. Journal of pediatric gastroenterology and nutrition, 67(1), pp.64-
68.
16

Park, Y.S., Kim, T.W., Kim, W.B. and Cho, B.Y., 2000. Increased prevalence
of autoimmune thyroid disease in patients with type 1 diabetes. The
Korean journal of internal medicine, 15(3), p.202.
Saare, L., Peet, A. and Tillmann, V., 2018, January. The Prevalence of
Clinically Significant anti-TPO Positivity in Children with HLA-conferred
Susceptibility to Type 1 Diabetes. In HORMONE RESEARCH IN
PAEDIATRICS (Vol. 90, pp. 605-605). ALLSCHWILERSTRASSE 10, CH-4009
BASEL, SWITZERLAND: KARGER.
Sharifi, F., Ghasemi, L. and Mousavinasab, N., 2008. Thyroid function and
anti-thyroid antibodies in Iranian patients with type 1 diabetes mellitus:
influences of age and sex. Iranian Journal of Allergy, Asthma and
Immunology, pp.31-36.
Vogel, A., Strassburg, C. P., and Manns, M. P. (2002). Genetic association
of vitamin D receptor polymorphisms with primary biliary cirrhosis and
autoimmune hepatitis. Hepatology, 35(1), 126-131.
17

18