Endocrine (2024) 84:541–548

https://doi.org/10.1007/s12020-023-03634-x

ORIGINAL ARTICLE

Transition from Hashimoto thyroiditis to Graves’s Disease: an

unpredictable change?
Alberto Vassallo1 Francesca Ferrari1 Luigi di Filippo1 Andrea Giustina
● ● ●
1 ●
Paola Loli 1

Received: 4 October 2023 / Accepted: 25 November 2023 / Published online: 20 December 2023
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2023

Abstract
Purpose Hashimoto thyroiditis and Graves’s disease are two related autoimmune disorders, representing the leading causes
of hypothyroidism and hyperthyroidism. Autoimmune hypothyroidism is generally irreversible but very rarely, some
patients would shift to hyperthyroidism. The aim of the study was to seek for possible clinical predictors of the transition
from hypo to hyperthyroidism in patients with Hashimoto thyroiditis and to outline their clinical phenotype.
Methods Twelve patients with overt autoimmune hypothyroidism who had at least one transition from hypothyroidism to
autoimmune hyperthyroidism were compared with 294 consecutive patients with autoimmune hypothyroidism and 69
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consecutive patients with autoimmune hyperthyroidism that accessed the outpatient clinic over six months. Demographic,
hormonal data and autoantibodies titers were compared.
Results Prevalence of smoking habit was significantly higher in switchers compared to controls. Switchers showed a
significantly higher prevalence of personal and familial history of non-thyroidal autoimmune disorders. TSH levels were
significantly lower in the switcher group during the hypothyroid phase and levothyroxine dose required was lower. TSH
concentrations were significantly lower while free fT4 and free fT3 values were higher in GD patients compared to switchers
during the hyperthyroid phase despite comparable TRAb levels. Prevalence and type of hyperthyroid symptoms and
orbitopathy were similar between switchers and GD group. Mean dose of anti-thyroid drugs was significantly higher in GD
patients compared to switchers. No differences were observed in the remission rate from hyperthyroidism between the two
groups, despite switchers showed a significantly lower time-to-remission.
Conclusions Conversion of Hashimoto Thyroiditis towards Graves’ disease is a rare phenomenon which can occur almost at
any time after the development of autoimmune hypothyroidism. Our findings suggest active surveillance of hypothyroid
patients who require frequent reduction of levothyroxine during follow up and testing for TSHR antibodies in these patients.
Keywords Hashimoto thyroiditis Graves disease Transition Autoimmune disease TSAb - TSBAb
● ● ● ●

Introduction direct activation of TSH receptor (TSHR) by anti-thyrotropin

receptor autoantibodies (TRAb) [3]. Variable titers of antibody
Hashimoto thyroiditis (HT) is a chronic autoimmune disorder against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb)
due to an immunologic attack with destructive characteristics are detectable in patients with Hashimoto thyroiditis [4]. In a
and very common evolution towards hypothyroidism [1, 2]. minority of adult hypothyroid patients (about 10%), TSH
This is in contrast to the stimulatory immunopathological receptor antibodies which block thyrotropin action (TSBAb)
process and very different clinical presentation of Graves’ are found [5]. The progression to overt, irreversible hypothyr-
disease (GD), a related thyroid autoimmune disorder due to the oidism is generally the outcome of autoimmune thyroiditis.
Occasionally patients affected by autoimmune hypo-
thyroidism would shift to hyperthyroidism eventually
returning to hypothyroidism. This occurrence is however
* Paola Loli highly uncommon and in fact less than a hundred cases
[email protected] have been reported in the literature, generally as case
1 reports. The literature data on clinical phenotype of subjects
Institute of Endocrine and Metabolic Sciences, Università Vita-
Salute San Raffaele and IRCCS Ospedale San Raffaele, affected by HT transitioning to hyperthyroidism or clinical
Milan, Italy predictors of transition are scanty.
542 Endocrine (2024) 84:541–548

The aim of the present study was to look for possible epidemiologic monocentric register approved by the Local
clinical predictors of the transition from hypo to hyperthyr- Ethics Committee complying with the Declaration of Hel-
oidism in patients with Hashimoto thyroiditis by comparing sinki. A signed informed consent was obtained for all
patients with an initial diagnosis of autoimmune hypothyr- patients participating in the study.
oidism and at least one transition to autoimmune hyperthyr-
oidism with patients with autoimmune hypothyroidism (HT) Assessed tools and variables
and patients with autoimmune hyperthyroidism.
The patients recruited underwent a systematic evaluation of
demographic and hormonal data as well as thyroid ultra-
Patients and methods sound features (size, normal, increased or reduced echo-
genicity, and presence or absence of nodules): age, sex,
Study design and patients pregnancies (yes/no), smoking habits (current smoker),
family, and personal history for autoimmune diseases.
This was a retrospective case control study. Twelve patients, Among laboratory variables TSH, free T3, free T4, TPOAb
come to our observation from 2020 to 2022, with an initial and TgAb in control patients with hypo and hyperthyroidism
diagnosis of overt autoimmune hypothyroidism and who had, and in the hypothyroid phase in switcher patients, TRAb
in their history, at least one transition from hypothyroidism to titers in hyperthyroid control patients and in the hyperthyroid
TSHR induced hyperthyroidism (switchers) were compared phase for the switcher group were obtained. We also eval-
with patients with autoimmune hypothyroidism (HT) and uated time elapsed between hypo- and hyperthyroidism for
patients with hyperthyroidism secondary to Graves disease the switcher group, US features at outpatient evaluation time
(GD) selected among all patients with thyroid dysfunction of for all groups, Levothyroxine doses (LT4) in both HT and
any origin that consecutively accessed our endocrine unit switcher group, presence or absence of Graves’ ophthalmo-
between 1st January 2022 and 30th June 2022. pathy, presence or absence of hyperthyroid symptoms, type
The inclusion criteria were as follows: males and females of treatment and drug dosage for hyperthyroidism Remission
with HT or GD and age ≥ 18. time for both GD group and switchers were also considered.
The presence of autoimmune hypothyroidism (HT) was
defined by TSH levels over the upper reference range, serum Laboratory assays were not centralized
thyroid peroxidase autoantibodies and/or anti-thyroglobulin
autoantibodies (TPOAb or TgAb) titers above the upper All variables, with the exception of FT3, FT4 and TSH, are
limits of the reference ranges. The presence of a thyroid US referred to as normal or above the specific reference range
pattern consistent with thyroiditis as sole evidence of disease (and reported as percentages).
was not considered sufficient for inclusion.
The presence of hyperthyroidism secondary to Graves’ Statistical analyses
disease (GD) was defined by suppressed TSH concentrations,
presence of elevated free thyroxine (fT4) and free triio- Descriptive statistics were obtained for all study variables.
dothyronine (fT3) concentrations and the presence of anti-TSH Categorical variables were summarized as counts and per-
receptor antibodies (TRAb). All the patients with a diagnosis centages. Kolmogorov–Smirnov normality test was performed
of hypo or hyperthyroidism of other origin were excluded. (p > 0.05) and continuous variables were expressed as means
The criteria for the definition of the “switch” in the his- and standard deviations (SD). Fisher exact test or χ2 test and
tory of a patient were the existence of a previous diagnosis Student’s t-test (t test) or analysis of variance (ANOVA) test
of autoimmune hypothyroidism (HT) as described before, were employed to determine the statistical significance of
and at least one change in thyroid function from hypothyr- differences in proportions and means, respectively. All statis-
oidism to hyperthyroidism. The selection of the study tical tests were two-sided. P value of <0.05 was considered
cohort, as well as exclusion criteria, are presented in Fig. 1 statistically significant. Statistical analysis was conducted
Based on the aforementioned criteria, 375 patients with using IBM SPSS Statistics (IBM SPSS Statistics for Windows,
autoimmune thyroid dysfunction were included among a Version 23.0. Armonk, NY: IBM Corp.).
total of 685 patients: 294 patients with hypothyroidism, 69
with new onset or recurrent hyperthyroidism and 12 patients Results
with an initial diagnosis of autoimmune hypothyroidism
who had at least one transition from hypothyroidism to A total of 375 patients were enrolled in the study. The
autoimmune hyperthyroidism. switcher group comprised 12 (3.2%) patients, the GD group
All adult patients (age ≥18 years) affected by auto- 69 (18.4%) patients, and the HT group 294 (78.6%)
immune thyroid disorders were included in an patients. Overall, 83.4 % of patients were females.
Endocrine (2024) 84:541–548 543

Fig. 1 Study population

Anti-TPO Ab and anti-TG Ab were present in 309 smokers in the switchers group compared to HT and GD
(82.4%) and 251 (66.9%) patients, respectively. groups (Table 2).
Table 1 shows individual data on the transition phase Overall, 91 patients (24.3%) were affected by other
from hypo to hyperthyroidism in the group of switchers; concomitant non-thyroidal autoimmune diseases. The most
detailed information on TSH and thyroid hormone levels prevalent were connective tissue diseases (5.3%), T1DM
after withdrawing LT4 and before starting anti-thyroid (2.7%) and Addison disease (2.9%). We observed a sig-
drugs and the time lapse between the withdrawal of LT4 nificantly higher prevalence of concomitant non-thyroidal
and the start of anti-thyroid drugs is reported. autoimmune diseases in the switchers group compared to
the HT and GD groups (Table 2).
Comparison among HT, GD and “switchers” One hundred twenty seven patients (33.8%) reported a
positive familiar history for autoimmune disorders, with a
Age and sex distribution did not differ significantly among non-significant trend toward higher prevalence in the
the three groups; a significantly higher prevalence of anti- switcher group with 8 out of 12 patients, compared to 91 out
TPO and anti-TG autoantibodies was observed in the of 294 in HD and 28 out of 69 in GD groups (Table 2).
switcher and HT compared to GD patients (Table 2). Eighty-one patients (21.6%) presented a positive familiar
In the whole cohort, 20.1% of patients were smokers. In history for endocrine non-thyroidal autoimmune disorders
particular we observed a significantly higher prevalence of with a significant higher prevalence in the switcher group
544 Endocrine (2024) 84:541–548

Table 1 Individual data on the transition phase from hypo to hyperthyroidism in the group of switchers
Patient N. 1 2 3 4 5 6 7 8 9 10 11 12

Therapy Iodine + LT4 / LT4 LT4 LT4 LT4 Iodine + LT4 / LT4 LT4
selenium selenium
Last LT4 Dose (mcg) 25 25 25 57 75 50 75 25
Last TSH in LT4 (mU/L) 0,02 0,514 0,72 0,34 0,01 0,012 0,595 0,005
Last fT4 in LT4 (ng/dl) 4,41 1,28 1,43 1,74 1,17 1,87
Last fT3 in LT4 (pg/ml) 2,97 3,3 3,6 6
First TSH after LT4 discontinuation 0,124 0,015 0,43 0,2 0,005 0,06 0,05 0,02 0,1 0,018 0,007
(mU/L)
First fT4 after LT4 discontinuation 1,73 1,57 1,46 2,08 1,58 1,53 0,9 1,26 1,38 1,67 1,63
(ng/dl)
First fT3 after LT4 discontinuation 5,60 4,33 5,2 4,82 4,43 3,25 3,48 2,97 5,5 4,33 5,12
(pg/ml)
Time between LT4 discontinuation and 3.5 M 1M 2M 2M 4M 3M 3M 4M 3M 4M 6M 1M
GD diagnosis (months)
TSH at GD phase (mU/L) 0,010 0,02 0 0,115 0,005 0,005 0,01 0,01 0,015 0,03 0,005 0,007
fT4 at GD phase (ng/dl) 2,55 1,39 3,5 1,19 2,5 1,87 1,35 1,21 1,07 1,73 1,62 1,59
fT3 at GD phase (pg/ml) 11 4,53 4,79 3 6,75 3,52 3,63 3,23 5,45 6,84 4,68
fT3/ft4 ratio 0,43 0,33 0,14 0,25 0,27 0,26 0,3 0,3 0,32 0,42 0,29
TRAb value (UI/L) 14 4,1 9 2,1 3,18 23 7,63 18.5 30,48 8,5 7,67 5,84
TRAb/ULN 8 2,4 5,14 1,2 1,81 11,5 4,4 10,6 15,25 4,8 14 3,3
Laboratory reference range of thyroid function test and anti-thyrotropin receptor antibodies for each switcher patient (patients undergoing blood
test in the same laboratory are grouped together)
Patient 1, 8: TSH 0.25-4.5 mU/L, fT4 0.89-1.76 ng/dl, fT3 2-3.5 pg/ml, TRAb <1.75
Patient 2: TSH 0.4-4.5, Ft4 0.89-1.7 ng/dl, fT3 2-4.4 pg/ml, TRAb <1.7 UI/L
Patient 3, 4, 5, 7, 10,12: TSH 0.25-5 mU/L, Ft4 0.9-1.7 ng/dl, Ft3 2-4.4, TRAb <1.75 UI/L
Patients 6: TSH 0.27-4.2 mU/L, fT4 0.9-1.7 ng/dl, fT3 2-4.4 pg/ml, TRAb <2 UI/L
Patient 9: TSH 0.45-4.6 mU/L, fT4 0.89-1.76, fT3 2-3.5 pg/ml, TRAB < 2 UI/L
Patient 11: TSH 0.25-5 mU/L, Ft4 0.9-1.7 ng/dl, Ft3 2-4.4, TRAb <0.55 UI/L

Table 2 Demographic and

Switcher (n.12) Graves’ (n.69) Hashimoto (n.294)
biochemical comparisons
between the three (switcher, GD Age, years 41.75 ( ± 19) 50.2 ( ± 17) 48.7 ( ± 17)
and HD) groups
Female gender, n. (%) 11 (91.6%) 56 (81.2%) 246 (83.7%)
Anti-TPO Ab, n. (%) 9 (75%) 32 (46.4%) 268 (91.2%)
Anti-Tg Ab, n. (%) 11 (91.6%)a 17 (24.6%) 223 (75.9%)
b
Smokers, n. (%) 6 (50%) 19 (27.5%) 48 (16.3%)
Non-thyroidal autoimmune diseases, n. (%) 7 (58.3%)c 14 (20.3%) 70 (23.8%)
Familiar autoimmune disorders, n. (%) 8 (66.6 %)d 28 (40.6%) 91 (31%)
Familiar non-thyroidal endocrine autoimmune 7 (58.3%)c 9 (13%) 65 (22.1%)
disorders, n. (%)
Familiar thyroidal autoimmune disorders, n. (%) 8 (66.6%) 37 (53.6%) 126 (42.9%)
TPOAb anti-thyroid peroxidase antibodies, TGAb anti-thyroglobulin antibodies
a
P < 0.001 for the comparison with Graves’ group
b
P < 0.009 for the comparison with Hashimoto and Graves’ groups
c
P < 0.01 for the comparison with Graves’ and Hashimoto groups
d
P < 0.02 for the comparison with Hashimoto group

with 7 out of 12 patients, compared to 65 out of 294 in HT autoimmune disorders, and no statistical differences were
and 9 out of 69 in GD groups (Table 1). 171 patients observed regarding their prevalence among the three groups
(45.6%) reported a positive familiar history for thyroidal (Table 2).
Endocrine (2024) 84:541–548 545

Comparison between HT and “switchers” Table 4 Biochemical, clinical, and therapeutic comparisons between
the switcher and GD groups

When comparing the switcher group in the hypothyroid Switcher Graves’ (n.69) P value
phase and the HT group, we observed significantly lower (n.12)
TSH levels in the switchers, in presence of similar fT3 and TSH, mU/L 0.02 ( ± 0.03) 0.008 ( ± 0.01) 0.23
fT4 levels (Table 3). Consistent with this observation, fT3, pg/mL 5.27 ( ± 2.4) 9.16 ( ± 5.1) 0.002
patients that subsequently transitioned to hyperthyroidism fT4, pg/mL 18.2 ( ± 7.5) 31.6 ( ± 16.1) <0.001
required lower doses of levothyroxine to control hypo- fT3/fT4 ratio 0.3 ( ± 0.1) 0.34 ( ± 0.1) 0.24
thyroidism in comparison to controls with HT, both as mean TRAb, UI/L 11.65 ( ± 8.9) 10.74 ( ± 10.5) 0.76
daily dose and as a mean dose per Kg (Table 3).
Methimazole dose, mg 7.25 ( ± 3.8) 13.6 ( ± 7.9) <0.001
Hyperthyroid symptoms, 12 (100%) 61 (88%) 0.47
Comparison between GD and “switchers” n. (%)
Thyroid orbitopathy, 2 (18.2%) 11 (15.9%) >0.99
Patients with GD showed a significantly lower prevalence n. (%)
of anti-TG Ab with respect to switchers, whereas the pre- Remission, n. (%) 5 (41.6%) 31 (44.9%) 0.99
valence of anti-TPO Ab was comparable between the two Remission time, months 7.9 ( ± 4.4) 17.5 ( ± 10.7) 0.016
groups (Table 2).
TPOAb anti-thyroid peroxidase antibodies, TGAb anti-thyroglobulin
In comparison to patients transitioning to hyperthyroid- antibodies, TRAb anti-thyrotropin receptor antibodies
ism, patients with GD showed lower TSH concentrations
and significantly higher free fT4 and free fT3 values,
whereas fT3/fT4 ratios and TRAbs levels were comparable state. The data collected allow to detect some characteristics
(Table 4). A similar prevalence and type of hyperthyroid of these patients, both in the hypo and hyperthyroid state,
symptoms and orbitopathy was observed in the two groups that differentiate them from subjects with irreversible
(Table 4). autoimmune hypothyroidism and hyperthyroidism.
Most patients were treated with antithyroid drugs; 5 Compared with patients with irreversible hypothyroid-
subjects received propylthiouracil (one among the switchers ism, patients that subsequently switch to hyperthyroidism
and 4 among the GD group) and 72 methimazole. To are more often smokers and suffer less severe hypothyr-
control hyperthyroidism patients with GD required a sig- oidism as suggested by a lower concentration of TSH at the
nificantly higher mean dose of thionamide compared to the diagnosis and lower mean daily dose of thyroxine needed to
switchers (Table 4). normalize TSH. Similarly, during the hyperthyroid phase,
No differences were observed in the remission rate their hyperthyroidism is milder that in patients with Graves’
between the two groups (switcher 41.6% vs GD 44.9%). disease at onset, requires lower doses of antithyroid drugs
However, a significantly lower time-to-remission was and goes into remission faster.
observed in the switcher group compared to the GD group In spite of the fact that hypo and hyperthyroidism are very
(Table 4). closely related diseases sharing pathogenetic mechanisms
and pathologic picture, the development of Graves’ disease
in the background of Hashimoto’s thyroiditis is a extremely
Discussion rare occurrence, reported in 1.2% of patients according to
the largest series in the literature [6]. The mechanism
In the present study we looked for clinical characteristics underlying this functional change is still unknown.
that might outline the phenotype of subjects with auto- Based on the present data, a destructive thyroiditis as the
immune hypothyroidism transitioning to a hyperthyroid cause of the functional shift is not a tenable explanation
since all “shifters” showed circulating TSAb and persis-
Table 3 Biochemical and therapeutic comparisons between the tence of hyperthyroidism over the time lapse between
switcher and HT groups withdrawal of LT4 therapy and diagnosis of Graves disease.
Switcher (n.12) Hashimoto (n.294) P value Two types of thyrotropin receptor antibodies are
TSH, mU/L 6.02 ( ± 0.7) 10.58 ( ± 16.2) 0.007 involved in the pathogenesis of autoimmune hyperthyroid-
fT3, pg/mL 2.02 ( ± 1.2) 2.53 ( ± 1.1) 0.66 ism and hypothyroidism: antibodies that stimulate the
fT4, pg/mL 8.7 ( ± 1.6) 14.6 ( ± 21.5) 0.12 thyroid (TSAb) by activating the TSHR are the direct cause
Levothyroxine dose, mcg 42.85 ( ± 27.8) 68.38 ( ± 28.5) 0.025 of Graves’ disease and antibodies which block thyrotropin
Levothyroxine dose per kg 0.7 ( ± 0.49) 1.1 ( ± 0.43) 0.009 action (TSBAb) by acting as competitive inhibitors of TSH
TPOAb anti-thyroid peroxidase antibodies, TGAb anti-thyroglobulin binding to the TSH receptor and are occasionally respon-
antibodies sible for hypothyroidism [7].
546 Endocrine (2024) 84:541–548

A shift in balance between thyroid stimulating and In the present study we observed a significantly higher
blocking antibodies is a possible mechanism underlying the proportion of smokers in the group of switchers compared
change in the thyroid functional state [8]. Consistent with to HD and GD groups, an occurrence that has not been
this hypothesis are the coexistence of TSBAb and TSAb in reported previously. Cigarette smoking has been causally
approximately 20-30% of patients with Graves’ disease linked to the development of multiple autoimmune diseases,
[9, 10], the evidence that the proportion of blocking and acting as a major environmental stressor that can sig-
stimulating antibodies can change over time [11, 12] and nificantly cause imbalance in normal immune homeostasis.
the demonstration of the presence of TSBAb during the Although a shift Th1/Th2 occurs in multiple autoimmune
hypothyroid state and TSAb during the hyperthyroid state in chronic disorders [17], cigarette smoking might foster the
one patient [13]. switch in thyroid autoimmunity by inhibition of Th1
It could be hypothesized that the less severe and faster response, which is predominant in Hashimoto thyroiditis
course of hyperthyroidism in “switchers”, might be the immune pathophysiology, and enhancement of Th2
result of the simultaneous presence of TSBAb and TSAb in response, a leading actor in the pathogenesis of Graves’
patients shifting from a previous hypothyroid state. diseases and Graves’ ophthalmopathy [18, 19].
However, since in the present study thyrotropin receptor A relevant clinical observation arising from our study is
antibodies were determined with immunological methods that patients prone to switch from hypothyroidism to
that cannot distinguish between TSAb and TSBAb and hyperthyroidism have a higher prevalence of other auto-
detect mainly TSAb, we cannot prove this hypothesis. immune diseases compared to patients with irreversible
An alternative explanation for the less severe and “short- hypothyroidism and hyperthyroidism, suggesting an
remitting” hyperthyroidism might be the process of thyroid increased susceptibility to immunological disfunctions. In
damage due to chronic lymphocytic thyroiditis that over- addition, they have a more prevalent family history of other
comes the stimulatory effects of TSAb, reducing the func- autoimmune endocrine and non-endocrine diseases.
tional parenchyma over time even with high TSAb levels. The association between the transition from HD to GD
On the opposite side, when in the hypothyroid state, and non-thyroidal autoimmune diseases has been rarely
patients subsequently shifting to hyperthyroidism had less reported in literature, and the real prevalence of other auto-
severe hypothyroidism. Even in this context one might immune disorders in these patients is not established.
speculate that the coexistence of TSAb might have coun- Rotondi et al. [20] reported that compared with patients with
teracted the thyroid damage due to lymphocytic thyroiditis isolated Graves disease, patients with Graves disease asso-
or the effect of TSBAb. ciated with endocrine and non endocrine autoimmune dis-
The distinction between these possibilities would have eases had a higher rate of transition from hypo to
needed a systematic thyroid US monitoring to recognize hyperthyroidism. Gonzalez-Aguillera et al. [6] found a pre-
thyroid atrophy presenting at the onset of disease which valence of 10% of thyro-gastric syndrome with anti-gastric
attends TSBAb induced hypothyroidism in contrast to parietal cells antibodies positivity in patients who converted
thyroid atrophy developing at advanced stages in Hashi- from HD to Graves; Taşkaldıran et al. [21] recently reported
moto’s thyroiditis [14]. As to the immunological markers, the conversion from Hashimoto’s Thyroiditis to Graves’
the distinction between hypothyroidism caused by HT or Disease in a type 1 diabetic patient following the COVID-19
TSBAb may be difficult because the humoral markers of vaccination; Asano and Kenzaka [22] reported on a func-
HT, TPOAbs and TgAbs frequently coexist with TSHR tional transition supposed to be triggered by the onset of
antibodies, as the prevalence of TSBAb has been reported Guillain-Barré syndrome; Kafrouni et al. [14] described a
in about 20% of patients with atrophic autoimmune thyr- patient going through recurrent hospitalization due to myas-
oiditis and in about 9% of patients with goitrous auto- thenia gravis exacerbations, suggesting a possible role of
immune thyroiditis [15]. environmental triggers like vaccinations, viral infections and
The pathophysiological mechanism underlying the shift in emotional/physical stress in the pathogenesis of the switch.
thyrotropin receptor antibodies subtype and/or activity The relation with endogenous immunological predis-
remains still unsolved. A role of LT4 therapy has been posing factors in patients transitioning from hypothyroidism
hypothesized in view of its effect on autoantibodies to the to hyperthyroidism is supported by our observation of a
TSH receptor (TSAb and TSBAb) in hypothyroid patients trend toward a higher prevalence of familiar autoimmune
[8, 16]. Four hypothyroid patients that shifted to hyperthyr- disorders in comparison to HD and GD patients, a topic
oidism in the present report were not on replacement therapy never addressed in previous reports on transition in thyroid
with LT4, which stands against this hypothesis. Moreover, function. In particular we observed a significantly higher
mean dosage of LT4 administered to correct hypothyroidism prevalence of familial endocrine non-thyroidal autoimmune
in this group was significantly lower compared with the LT4 disorders, without differences in prevalence of familial
dosage in patients with irreversible hypothyroidism. thyroidal disorders.
Endocrine (2024) 84:541–548 547

The difference in familial history of autoimmune dis- Author contributions All authors contributed equally.
eases could be a bias related to the small number of patients.
However, since family and population studies confirm that Compliance with ethical standards
AITD susceptibility genes can be categorized as either
thyroid specific (Tg, TSHR) or immune-modulating (AIRE, Conflict of interest The authors declare no competing interest.
CTLA-4, FOXP3, HLA) [23], we could speculate that
Consent to partecipate Informed consent to participate in the study
thyroid specific genes have a strong influence on heritability
was obtained from all participants.
of thyroid diseases but a neutral impact on the conversion
from hypo to hyperthyroidism, while immune-modulating Consent for publication Not applicable because of the complete
genes, which play a pivotal role in antigen presentation and anonymity of the data presented in the article.
T cells function, may constitute the genetic substrate to the
pathogenesis of the transition between the two thyroidal Ethical approval All adult patients (age ≥18 years) affected by auto-
immune thyroid disorders were included in an epidemiologic mono-
phenotypes. Not surprisingly, most patients undergoing
centric register approved by the Local Ethical Committee complying
thyroid function switch were middle aged females as the with the Declaration of Helsinki.
majority of patients with thyroid autoimmune disease and
those in which this clinical scenario has been mainly
described [24]. In our cohort the mean time of evolution References
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