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

Hashimoto thyroiditis (HT) is a chronic autoimmune disorder
due to an immunologic attack with destructive characteristics
and very common evolution towards hypothyroidism [1, 2].
This is in contrast to the stimulatory immunopathological
process and very different clinical presentation of Graves’
disease (GD), a related thyroid autoimmune disorder due to the
* Paola Loli
loli.paola@hsr.it
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,
Milan, Italy
receptor autoantibodies (TRAb) [3]. Variable titers of antibody
against thyroglobulin (TgAb) and thyroid peroxidase (TPOAb)
are detectable in patients with Hashimoto thyroiditis [4]. In a
minority of adult hypothyroid patients (about 10%), TSH
receptor antibodies which block thyrotropin action (TSBAb)
are found [5]. The progression to overt, irreversible hypothyr-
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
highly uncommon and in fact less than a hundred cases
have been reported in the literature, generally as case
affected by HT transitioning to hyperthyroidism or clinical
predictors of transition are scanty.
542
The aim of the present study was to look for possible
clinical predictors of the transition from hypo to hyperthyr-
oidism in patients with Hashimoto thyroiditis by comparing
patients with an initial diagnosis of autoimmune hypothyr-
oidism and at least one transition to autoimmune hyperthyr-
oidism with patients with autoimmune hypothyroidism (HT)
and patients with autoimmune hyperthyroidism.
Patients and methods
Study design and patients
This was a retrospective case control study. Twelve patients,
come to our observation from 2020 to 2022, with an initial
diagnosis of overt autoimmune hypothyroidism and who had,
in their history, at least one transition from hypothyroidism to
TSHR induced hyperthyroidism (switchers) were compared
with patients with autoimmune hypothyroidism (HT) and
patients with hyperthyroidism secondary to Graves disease
(GD) selected among all patients with thyroid dysfunction of
any origin that consecutively accessed our endocrine unit
between 1st January 2022 and 30th June 2022.
The inclusion criteria were as follows: males and females
with HT or GD and age ≥ 18.
The presence of autoimmune hypothyroidism (HT) was
defined by TSH levels over the upper reference range, serum
thyroid peroxidase autoantibodies and/or anti-thyroglobulin
autoantibodies (TPOAb or TgAb) titers above the upper
limits of the reference ranges. The presence of a thyroid US
pattern consistent with thyroiditis as sole evidence of disease
was not considered sufficient for inclusion.
The presence of hyperthyroidism secondary to Graves’
disease (GD) was defined by suppressed TSH concentrations,
presence of elevated free thyroxine (fT4) and free triio-
dothyronine (fT3) concentrations and the presence of anti-TSH
receptor antibodies (TRAb). All the patients with a diagnosis
of hypo or hyperthyroidism of other origin were excluded.
The criteria for the definition of the “switch” in the his-
tory of a patient were the existence of a previous diagnosis
of autoimmune hypothyroidism (HT) as described before,
and at least one change in thyroid function from hypothyr-
oidism to hyperthyroidism. The selection of the study
cohort, as well as exclusion criteria, are presented in Fig. 1
Based on the aforementioned criteria, 375 patients with
autoimmune thyroid dysfunction were included among a
total of 685 patients: 294 patients with hypothyroidism, 69
with new onset or recurrent hyperthyroidism and 12 patients
with an initial diagnosis of autoimmune hypothyroidism
who had at least one transition from hypothyroidism to
autoimmune hyperthyroidism.
All adult patients (age ≥18 years) affected by auto-
immune thyroid disorders were included in an
Endocrine (2024) 84:541–548
epidemiologic monocentric register approved by the Local
Ethics Committee complying with the Declaration of Hel-
sinki. A signed informed consent was obtained for all
patients participating in the study.
Assessed tools and variables
The patients recruited underwent a systematic evaluation of
demographic and hormonal data as well as thyroid ultra-
sound features (size, normal, increased or reduced echo-
genicity, and presence or absence of nodules): age, sex,
pregnancies (yes/no), smoking habits (current smoker),
family, and personal history for autoimmune diseases.
Among laboratory variables TSH, free T3, free T4, TPOAb
and TgAb in control patients with hypo and hyperthyroidism
and in the hypothyroid phase in switcher patients, TRAb
titers in hyperthyroid control patients and in the hyperthyroid
phase for the switcher group were obtained. We also eval-
uated time elapsed between hypo- and hyperthyroidism for
the switcher group, US features at outpatient evaluation time
for all groups, Levothyroxine doses (LT4) in both HT and
switcher group, presence or absence of Graves’ ophthalmo-
pathy, presence or absence of hyperthyroid symptoms, type
of treatment and drug dosage for hyperthyroidism Remission
time for both GD group and switchers were also considered.
Laboratory assays were not centralized
All variables, with the exception of FT3, FT4 and TSH, are
referred to as normal or above the specific reference range
(and reported as percentages).
Statistical analyses
Descriptive statistics were obtained for all study variables.
Categorical variables were summarized as counts and per-
centages. Kolmogorov–Smirnov normality test was performed
(p > 0.05) and continuous variables were expressed as means
and standard deviations (SD). Fisher exact test or χ2 test and
Student’s t-test (t test) or analysis of variance (ANOVA) test
were employed to determine the statistical significance of
differences in proportions and means, respectively. All statis-
tical tests were two-sided. P value of <0.05 was considered
statistically significant. Statistical analysis was conducted
using IBM SPSS Statistics (IBM SPSS Statistics for Windows,
Version 23.0. Armonk, NY: IBM Corp.).
Results
A total of 375 patients were enrolled in the study. The
switcher group comprised 12 (3.2%) patients, the GD group
69 (18.4%) patients, and the HT group 294 (78.6%)
patients. Overall, 83.4 % of patients were females.
Endocrine (2024) 84:541–548
Fig. 1 Study population
Anti-TPO Ab and anti-TG Ab were present in 309
(82.4%) and 251 (66.9%) patients, respectively.
Table 1 shows individual data on the transition phase
from hypo to hyperthyroidism in the group of switchers;
detailed information on TSH and thyroid hormone levels
after withdrawing LT4 and before starting anti-thyroid
drugs and the time lapse between the withdrawal of LT4
and the start of anti-thyroid drugs is reported.
Comparison among HT, GD and “switchers”
Age and sex distribution did not differ significantly among
the three groups; a significantly higher prevalence of anti-
TPO and anti-TG autoantibodies was observed in the
switcher and HT compared to GD patients (Table 2).
In the whole cohort, 20.1% of patients were smokers. In
particular we observed a significantly higher prevalence of
543
smokers in the switchers group compared to HT and GD
groups (Table 2).
Overall, 91 patients (24.3%) were affected by other
concomitant non-thyroidal autoimmune diseases. The most
prevalent were connective tissue diseases (5.3%), T1DM
(2.7%) and Addison disease (2.9%). We observed a sig-
nificantly higher prevalence of concomitant non-thyroidal
autoimmune diseases in the switchers group compared to
the HT and GD groups (Table 2).
One hundred twenty seven patients (33.8%) reported a
positive familiar history for autoimmune disorders, with a
non-significant trend toward higher prevalence in the
switcher group with 8 out of 12 patients, compared to 91 out
of 294 in HD and 28 out of 69 in GD groups (Table 2).
Eighty-one patients (21.6%) presented a positive familiar
history for endocrine non-thyroidal autoimmune disorders
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
A shift in balance between thyroid stimulating and
blocking antibodies is a possible mechanism underlying the
change in the thyroid functional state [8]. Consistent with
this hypothesis are the coexistence of TSBAb and TSAb in
approximately 20-30% of patients with Graves’ disease
[9, 10], the evidence that the proportion of blocking and
stimulating antibodies can change over time [11, 12] and
the demonstration of the presence of TSBAb during the
hypothyroid state and TSAb during the hyperthyroid state in
one patient [13].
It could be hypothesized that the less severe and faster
course of hyperthyroidism in “switchers”, might be the
result of the simultaneous presence of TSBAb and TSAb in
patients shifting from a previous hypothyroid state.
However, since in the present study thyrotropin receptor
antibodies were determined with immunological methods
that cannot distinguish between TSAb and TSBAb and
detect mainly TSAb, we cannot prove this hypothesis.
An alternative explanation for the less severe and “short-
remitting” hyperthyroidism might be the process of thyroid
damage due to chronic lymphocytic thyroiditis that over-
comes the stimulatory effects of TSAb, reducing the func-
tional parenchyma over time even with high TSAb levels.
On the opposite side, when in the hypothyroid state,
patients subsequently shifting to hyperthyroidism had less
severe hypothyroidism. Even in this context one might
speculate that the coexistence of TSAb might have coun-
teracted the thyroid damage due to lymphocytic thyroiditis
or the effect of TSBAb.
The distinction between these possibilities would have
needed a systematic thyroid US monitoring to recognize
thyroid atrophy presenting at the onset of disease which
attends TSBAb induced hypothyroidism in contrast to
thyroid atrophy developing at advanced stages in Hashi-
moto’s thyroiditis [14]. As to the immunological markers,
the distinction between hypothyroidism caused by HT or
TSBAb may be difficult because the humoral markers of
HT, TPOAbs and TgAbs frequently coexist with TSHR
antibodies, as the prevalence of TSBAb has been reported
in about 20% of patients with atrophic autoimmune thyr-
oiditis and in about 9% of patients with goitrous auto-
immune thyroiditis [15].
The pathophysiological mechanism underlying the shift in
thyrotropin receptor antibodies subtype and/or activity
remains still unsolved. A role of LT4 therapy has been
hypothesized in view of its effect on autoantibodies to the
TSH receptor (TSAb and TSBAb) in hypothyroid patients
[8, 16]. Four hypothyroid patients that shifted to hyperthyr-
oidism in the present report were not on replacement therapy
with LT4, which stands against this hypothesis. Moreover,
mean dosage of LT4 administered to correct hypothyroidism
in this group was significantly lower compared with the LT4
dosage in patients with irreversible hypothyroidism.
Endocrine (2024) 84:541–548
In the present study we observed a significantly higher
proportion of smokers in the group of switchers compared
to HD and GD groups, an occurrence that has not been
reported previously. Cigarette smoking has been causally
linked to the development of multiple autoimmune diseases,
acting as a major environmental stressor that can sig-
nificantly cause imbalance in normal immune homeostasis.
Although a shift Th1/Th2 occurs in multiple autoimmune
chronic disorders [17], cigarette smoking might foster the
switch in thyroid autoimmunity by inhibition of Th1
response, which is predominant in Hashimoto thyroiditis
immune pathophysiology, and enhancement of Th2
response, a leading actor in the pathogenesis of Graves’
diseases and Graves’ ophthalmopathy [18, 19].
A relevant clinical observation arising from our study is
that patients prone to switch from hypothyroidism to
hyperthyroidism have a higher prevalence of other auto-
immune diseases compared to patients with irreversible
hypothyroidism and hyperthyroidism, suggesting an
increased susceptibility to immunological disfunctions. In
addition, they have a more prevalent family history of other
autoimmune endocrine and non-endocrine diseases.
The association between the transition from HD to GD
and non-thyroidal autoimmune diseases has been rarely
reported in literature, and the real prevalence of other auto-
immune disorders in these patients is not established.
Rotondi et al. [20] reported that compared with patients with
isolated Graves disease, patients with Graves disease asso-
ciated with endocrine and non endocrine autoimmune dis-
eases had a higher rate of transition from hypo to
hyperthyroidism. Gonzalez-Aguillera et al. [6] found a pre-
valence of 10% of thyro-gastric syndrome with anti-gastric
parietal cells antibodies positivity in patients who converted
from HD to Graves; Taşkaldıran et al. [21] recently reported
the conversion from Hashimoto’s Thyroiditis to Graves’
Disease in a type 1 diabetic patient following the COVID-19
vaccination; Asano and Kenzaka [22] reported on a func-
tional transition supposed to be triggered by the onset of
Guillain-Barré syndrome; Kafrouni et al. [14] described a
patient going through recurrent hospitalization due to myas-
thenia gravis exacerbations, suggesting a possible role of
environmental triggers like vaccinations, viral infections and
emotional/physical stress in the pathogenesis of the switch.
The relation with endogenous immunological predis-
posing factors in patients transitioning from hypothyroidism
to hyperthyroidism is supported by our observation of a
trend toward a higher prevalence of familiar autoimmune
disorders in comparison to HD and GD patients, a topic
never addressed in previous reports on transition in thyroid
function. In particular we observed a significantly higher
prevalence of familial endocrine non-thyroidal autoimmune
disorders, without differences in prevalence of familial
thyroidal disorders.
Endocrine (2024) 84:541–548
The difference in familial history of autoimmune dis-
eases could be a bias related to the small number of patients.
However, since family and population studies confirm that
AITD susceptibility genes can be categorized as either
thyroid specific (Tg, TSHR) or immune-modulating (AIRE,
CTLA-4, FOXP3, HLA) [23], we could speculate that
thyroid specific genes have a strong influence on heritability
of thyroid diseases but a neutral impact on the conversion
from hypo to hyperthyroidism, while immune-modulating
genes, which play a pivotal role in antigen presentation and
T cells function, may constitute the genetic substrate to the
pathogenesis of the transition between the two thyroidal
phenotypes. Not surprisingly, most patients undergoing
thyroid function switch were middle aged females as the
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
from hypothyroidism to hyperthyroidism was about 9 years,
lower than 20 and 27 years previously reported [24, 25], but
higher than the reported average conversion time of 12-24
months (18). We found no relation with pregnancy and/or
breastfeeding, although this occurrence has already been
described both during gestation and post-partum period
[26, 27]. Two female patients when shifting to hyperthyr-
oidism developed Graves orbitopathy, an incidence com-
parable to that of GD according to most recent
epidemiological data [28]. Similarly comparable to those of
GD patients were the severity and NOSPECS class [29].
Our study has some limitations. The retrospective design,
the monocentric cohort and the relative limited sample size.
Another limiting factor is that TRAbs were not evaluated in
hypothyroid patients nor were US features at diagnosis of
hypothyroidism available, to discriminate between thyroid
atrophy presenting at the onset of disease in contrast to
thyroid atrophy usually developing at advanced stages in
Hashimoto’s thyroiditis [14, 30].
Despite these limitations, this study provides some sug-
gestions as to the phenotypic differences between patients
with HD and GD and patients who switch from one extreme
to another of the AITD spectrum.
Conclusion
Far from changing the management of HT and GD patients,
our findings can improve awareness of this rare clinical
syndrome, suggesting active surveillance of hypothyroid
patients who require frequent reduction of levothyroxine
during follow up, and testing for TSHR antibodies in these
patients. Based on our data it could be suggested to test for
TSHR, at the diagnosis of HT, those patients with a clinical
phenotype more prone to experience a functional change of
thyroid activity.
547
Author contributions All authors contributed equally.
Compliance with ethical standards
Conflict of interest The authors declare no competing interest.
Consent to partecipate Informed consent to participate in the study
was obtained from all participants.
Consent for publication Not applicable because of the complete
anonymity of the data presented in the article.
Ethical approval All adult patients (age ≥18 years) affected by auto-
immune thyroid disorders were included in an epidemiologic mono-
centric register approved by the Local Ethical Committee complying
with the Declaration of Helsinki.
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