Possible link between Hashimoto's thyroiditis and oral lichen planus: A novel association found

Abstract

Objectives:
Hashimoto's thyroiditis as well as lichen planus has been associated to a number of disorders, generally of auto-immune origin. A novel possible association between oral lichen planus (OLP) and Hashimoto's thyroiditis (HT) is here proposed on the basis of a cross-sectional survey.

Materials and methods:
One hundred and five unrelated OLP patients were considered. Diagnosis of HT was based on positive serum anti-TPO, anti-Tg, TSH levels and the typical ultrasound pattern of the thyroid gland.

Results:
In the present survey, the prevalence of HT in the OLP group was 14.3 % whereas the prevalence of HT-related hypothyroidism in the general population was reported to be equal to 1 %. By Fisher's exact test, it was revealed that the difference between our data and historical prevalence of HT was found statistically significant.

Conclusion:
Actually, there is no definitive hypothesis that could explain the coexistence of OLP and HT. However, considering the onset timing of HT followed by OLP in 93.3 % of our series, we suspected a causal or predisposing role for HT. Specifically, we believe that in HT patients, circulating thyroid antibodies could contribute to trigger an organ-specific auto-immune response also in the oral mucosa or skin, leading to the development of LP lesions.

Clinical relevance:
Because of the large number of cases of asymptomatic chronic auto-immune thyroiditis, it would be useful that women over 40 years of age affected by OLP were screened for thyroid dysfunction, particularly HT.

Full text

SHORT COMMUNICATION
Possible link between Hashimoto's thyroiditis and oral lichen planus:
a novel association found
Lorenzo Lo Muzio & Andrea Santarelli &
Giuseppina Campisi & MariaGrazia Lacaita &
Gianfranco Favia
Received: 1 February 2012 / Accepted: 30 May 2012 / Published online: 15 June 2012
#
Springer-Verlag 2012
Abstract
Objectives Hashimoto's thyroiditis as well as lichen planus
has been associated to a number of disorders, generally of
auto-immune origin. A novel possible association between
oral lichen planus (OLP) and Hashimoto's thyroiditis (HT)
is here proposed on the basis of a cross-sectional survey.
Materials and methods One hundred and five unrelated
OLP patients were considered. Diagnosis of HT was based
on positive serum anti-TPO, anti-Tg, TSH levels and the
typical ultrasound pattern of the thyroid gland.
Results In the present survey, the prevalence of HT in the
OLP group was 14.3 % whereas the pre valen ce of HT-
related hypothyroidism in the general population was
reported to be equal to 1 %. By Fisher's exact test, it was
revealed that the difference between our data and historical
prevalence of HT was found statistically significant.
Conclusion Actually, there is no definitive hypothesis that
could explain the coexistence of OLP and HT. However,
considering the onset timing of HT followed by OLP in
93.3 % of our series, we suspected a causal or predisposing
role for HT. Specifically, we believe that in HT patients,
circulating thyroid antibodies could contribute to trigger an
organ-specific auto-immune response also in the oral muco-
sa or skin, leading to the development of LP lesions.
Clinical relevance Because of the large number of cases of
asymptomatic chronic auto-immune thyroiditis, it would be
useful that women over 40 years of age affected by OLP
were screened for thyroid dysfunction, parti cularly HT.
Keywords Hashimoto's thyroiditis
.
Oral lichen planus
.
Autoimmunity
.
Circulating thyroid antibodies
Introduction
A novel possible association between oral lichen planus
(OLP) and Hashimoto's thyroiditis (HT) is here proposed
on the basis of a cross-sectional survey. Lichen planus has
been associated to a number of disorders, generally of auto-
immune origin: myasthenia gravis, Sjogren's syndrome, ul-
cerative colitis, psoriasis, thymoma, lupus erythematous,
coeliac disease [1]. Likewise, Sjogren's syndrome, lupus
erythematous, type 1 diabetes, pernicious anaemia, surrenal
deficiency and Grave's dise ase were conside red as HT-
associated disorders [2]. To the best of our knowledge, no
one reported so far the association between OLP and HT.
Patients and methods
Between May 2005 and April 2010, within a series of 105
unrelated OLP patients, we observed 15 cases (14.3 %) with
coexistence of HT (Table 1). Diagnosis of OLP was con-
firmed clinically and histologically in all cases, according to
L. Lo Muzio
Department of Surgical Sciences, University of Foggia,
Foggia, Italy
A. Santarelli (*)
Department of Clinic Specialistic and Stomatological Sciences,
Polytechnic University of Marche,
Via Tronto,
10-60126 Ancona, Italy
e-mail: andrea.santarelli@univpm.it
G. Campisi
Department of Oral Sciences, University of Palermo,
Palermo, Italy
M. Lacaita
:
G. Favia
Department of Dental Sciences and Surgery, University of Bari,
Bari, Italy
Clin Oral Invest (2013) 17:333–336
DOI 10.1007/s00784-012-0767-4

most recent diagnostic criteria [3]. All patients were
screened for the presence of IgG anti-HCV antibodies by
third-generation ELISA, and positive results were con-
firmed by means of second-generation RIBA. As exclusion
criteria, patients suspected to have drug- or dental
restoration-related oral lichenoid lesions were not consid-
ered in the present survey as well as patients who were HCV
positive and/or undertaking interferon therapy.
HT is, by strict criteria, a histologic diagnosis; however,
in clinical practice, expression of TPOAb and a hypoechoic
thyroid ultrasound (US) pattern are clinical criteria for the
diagnosis of HT [4]. In the presen t series, diagnosis of HT
was based on positive serum anti-TPO, anti-Tg, TSH levels
and typical US pattern of the thyroid gland.
Results
Fifteen patients out of 105 fulfilling the inclusion criteria
had HT. In the majority of cases (14 out of 15), thyroiditis
has preceded the onset of OLP, while only in one case was
thyroid dysfunction diagnosed after OLP.
Nine patients received Eutirox
®
(L-thyroxine) 50 mg/dai-
ly, five patients were given 100 mg/day and the others have
not yet started any therapy for thyroiditis. Even if one case
of lichenoid lesions with Eu tirox
®
(by thyroxine ove ras-
sumption) has been reported in literature [5], it does not
seem to matter in our series.
Of the 15 cases of histologically confirmed OLP with the
coexistence of HT, all but one were female, consistent with
the major incidence of auto-immune disorders in the female
gender.
In the present survey, the prevalence of HT in the OLP
group was 14.3 % whereas the prevalence of HT-related
hypothyroidism in the general population was reported to
be equal to 1 % [6]. By Fisher's exact test, it was revealed
that the difference between our data and historical preva-
lence of HT was found statistically significant (p<0.0003,
OR0 14.29, 95 % CI0 1.9, 106.2).
Discussion
Although the fortuitous coexistence of OLP and HT is
properly taken into account by us, prevalence of HT in
OLP patients was found to be higher than in the general
population (1 % from iodine-sufficient regions) [6], and
a certain immuno-pathogenetic similarity had to be
considered.
The onset of auto-immune diseases, specifically en docri-
nopathies, is multifactorial in character and includes genetic
predisposition, external etiological factors and microenvi-
ronment alterations in target organs. Actually, the genetic
predisposition is of great value. The most important genetic
factor seems to be the polymorphism of the major histocom-
patibility complex [7]. Data on HLA haplotypes in HT
showed an association of goitrous HT with HLA-DR5 and
atrophic HT with DR3. The association of HT with HLA-
DR3 in Caucasians has been confirmed, and the association
of HT with HLA-DQw7 has also been reported [6]. Genetic
control has been also considered to play a role in O LP
development even if immunogenetic studies have given
controversial results [8]. Indeed, cutaneous idiopathic LP
is frequently associated with the HLA-DR1 allele, whereas
Table 1 The most important
clinical findings in a series of 15
OLP patients with HT
↑ Elevated with respect to the
range values, ↓ diminished with
respect to the range values
a
In our laboratory, the following
normal ranges were established:
T4, 5.5 to 12.0 g/dL; T3, 60 to
190 ng/dL
b
Thyroid nodules evident by
echography
c
In our laboratory, the following
normal range was establi shed:
TSH, 0.4 to 4.5 IU/mL
d
Values of antithyroid autoanti-
bodies higher than 10 IU/mL
were considered positive
Number Sex Age Thyroid
function
a
Thyroid
nodules
b
TSH
c
Anti-TG
d
Anti-TPO
d
Oral lichen
planus
Initial Now
1F44↓↓2 ↑ ++ + Reticular/plaque
2F46↓↓Multiple ↑ ++++ ++++ Reticular/plaque
3F61↑↓2 ↑ ++ ++ Reticular
4F46↓↓3 ↑ ++ + Reticular/plaque
5F47↓↓Multiple ↑ ++ ++ Reticular/plaque
6F35↓↓Multiple ↑ ++ ++ Reticular/plaque
7F42↑↓Goitre ↑ + + Reticular/plaque
8F49↓↓2 ↑ ++++ ++++ Plaque
9F38↑↓3 ↑ ++ ++ Reticular
10 F 61 ↓↓Multiple ↑ +++ +++ Plaque
11 F 63 ↓↓1 ↑ ++++ ++++ Reticular
12 F 51 ↑↓Multiple ↑ ++ ++ Plaque
13 F 33 ↓↓Multiple ↑ ++ + Reticular/plaque
14 F 41 ↓↓Multiple ↑ ++ ++ Reticular/plaque
15 M 62 ↓↓1 ↑ ++++ ++++ Reticular
334 Clin Oral Invest (2013) 17:333–336

idiopathic OLP is not [9]. However, a linkage disequilibri-
um of the –308A TNF-α promoter polymorphism with
HLA-DR3 has reported in Caucasians [10].
Recently, the gene for cytotoxic T lymphocyt e antigen 4
(CTLA-4) has been identified, able to confer the suscepti-
bility to HT [6]. CTLA-4 is a co-stimulatory molecule
expressed on the surface of activated T cells, and it partic-
ipates in their in teraction with antigen-presenting cells
(APC) [6, 11]. Several lines of evidence have confirmed
that the presence of CTLA-4 downregulates T cell activation
[11]. This inhibitory effect have raised the possibility that
gene polymorphism or mutations altering CTLA-4 expres-
sion and/or function could result in an exaggerated T cell
activation, and since CTLA-4 is a non-specific molecule, it
is expected to confer susceptibility to autoimmunity in gen-
eral [ 6 , 11]. Thus, in a predisposed subject, an imbalance in
CTLA-4 function can lead to T cell proliferation and cyto-
kine production. Since it has been recognized that the im-
mune system is controlled by Th1/Th2 balance, both HT and
OLP are considered to be a Th1-type diseases [12, 13].
Actually, there is no definitive hypothesis that could
explain the coexistence of OLP and HT. However, consid-
ering the onset timing of HT followed by OLP in 93.3 % of
our series, we suspected a causal or p redisposing role for
HT. Specifically, we believe that in HT patients, circulating
thyroid antibodies could contribute to trigger an organ-
specific auto-immune response also in the oral mucosa or
skin, leading to the development of LP lesions. This could
be also likely to happen in cases where OLP precedes the
onset of thyroid dysfunction, since a significant proportion
of subje cts have asymptomatic chronic auto-immune thy-
roiditis with circulating thyroid antibodies [14].
Our suggestion, although speculative, seems to be sup-
ported by several findings: as the skin is commonly affected
in thyroid diseases, we hypothesize that in HT patients,
circulating thyroid antibodies could target also oral/skin
keratinocytes. Since it has been proved that keratinocytes
may express the TSH receptor as well as thyroglobulin gene
but not thyroid peroxidase one [15], anti-TGab may target
keratinocytes expressing thyroglobulin on their cell surface.
However, given t hat in HT, TPOAb are li kely to b e of
greater pathogenetic importance than anti-TG autoantibod-
ies for a number of reasons [4], it could be also postulated
that circulating anti-TPOab may cross react with an un-
known kerat inocyte membranous protein.
Once the link between thyroid antibodies and the target
on the keratinocyte surface took place, several options
would have been possible. One possibility is that Ig-
thyroid antibodies could trigger CD95 (Fas/Apo-1)-mediat-
ed apoptosis in ke ratinocytes a s Ig autoantibodies do in
pemphigus vulgaris [16]. Then, the apoptotic bodies could
be internalised and processed by surrounding keratinocytes
or APC cells leading to subsequent T cell activation.
However, we suggest also the possibility that thyroid
antibodies could have the ability to unmask epitopes in
keratinocytes, exposing the so-called “lichen planus anti-
gen”. Indeed, Sugerman proposed that, at the lesion site,
keratinocytes express a lichen planus antigen and that
known (e.g. systemic drugs, dental restorative materials,
mechanical trauma or bacterial or viral infection) or uniden-
tified agents could induce keratinocyte antigen expression
[13]. Subsequently, CD8+ cytotoxic T cells recognize the
lichen planus antigen associated with MHC class I on
lesional keratinocytes and t rigger keratinocyte apoptosis
[13]. All the same, thyroid antibodies linked on the kerati-
nocyte surface may be directly recognized as target antigens
by cytotoxic T cells.
However, specific experimental studies should address the
herein proposed hypotheses. In conclusion, our aim was to
report this novel possible association, inviting colleagues to
investigate about the coexistence of HT and OLP, especially in
terms of confirmation of epidemiological datum and respec-
tive immuno-pathogenetic rationale. On this base, it would be
useful that OLP women over 40 years of age are screened for
thyroid dysfunction, particularly HT, because of the important
number of cases of asymptomatic chronic auto-immune thy-
roiditis [14]. Furthermore, in the presence of evidence of our
suggestion, patients suffering from HT should be informed
about the risk of developing OLP lesions.
Conflict of interest The authors declare that there are no conflicts of
interest that could be perceived as prejudicing the impartiality of the
research reported.
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