Research Article Open Access
Thyroid Involvement In Behçet’s Disease
Salem Bouomrani 1,2*, SafaTrabelsi1, Mouna Guermazi1,2, Nesrine Regaïeg1
1Department of Internal medicine.Military Hospital of Gabes.Gabes 6000. Tunisia
2Sfax Faculty of Medicine.University of Sfax.Sfax 3029. Tunisia
*Corresponding author: Salem Bouomrani, Department of Internal medicine, Military Hospital of Gabes.Gabes 6000. Tunisia. Tel: +00216 98977555; E-mail:@
Received: December 5, 2018; Accepted: January 11, 2019; Published: January 21, 2019
Citation:Bouomrani S, Trabelsi S, Guermazi M, Regaïeg N (2019) Thyroid Involvement In Behçet’s Disease. Int J Thyro Disord Ther 1(1): 1-7.
Abstract
Thyroid disorders are among the most common endocrine diseases with a global prevalence estimated at 10%. Autoimmunity plays a crucial role in the majority of cases of thyroid dysfunctions. Frequent association of these thyropathies with other systemic and/or organ-specific dysimmune pathologies, including systemic antibodiesassociated vasculitis is reported. However, thyroid disorders remain exceptional and unusual during other systemic vasculitis especially those of medium and large vessels and only sporadic observations are reported.

As a result, the exact significance of thyroid involvement during systemic vasculitis is not well known: fortuitous association? Specific endocrine involvement of the angiitis? Or two conditions of the same predisposing profile?

Behçet’s disease (BD) is a systemic vasculitis of vessels of all types and all sizes, particularly common in young subjects, and with an important clinical polymorphism. Thyroid involvement is rarely studied in this disease.

The aim of this paper is to review thyroid dysfunctions during BD and their possible pathogenic mechanisms.

Keywords: Behçet’s disease; Vasculitis; Thyroid disorders; Thyroid gland; Hypothyroidism; Autoimmunity;
Abbreviations
TSH: thyroid stimulating hormone,
TT4: total thyroxine, T3: triiodothyronine,
fT4: free thyroxine,
anti-Tg: anti-thyroglobulinantibodies,
anti-TPO: anti-thyroid peroxidaseantibodies.
Introduction
Thyroid disorders are among the most common endocrine diseases and are often primary due to damage of the thyroid gland itself [1-5]. Their global prevalence is estimated at 10% and are by far dominated by subclinical or asymptomatic forms (hypo- or hyper-thyroidism); overt or symptomatic forms are much rarer [6].

Autoimmunity plays a crucial role in the majority of cases of thyroid dysfunction (Hashimoto’s thyroiditis, Graves’ disease, postpartum lymphocytic thyroiditis, Riedel’s fibrous thyroiditis, DeQuervain’ssubacute thyroiditis) [7]. Frequent association of these thyropathies with other systemic and/or organ-specific dysimmune pathologies [7,8], including systemic antibodies-mediatedvasculitis such as granulomatosis with polyangiitis(GPA), eosinophilicgranulomatosis with polyangiitis (EGPA), microscopic polyangiitis (MPA) [9-12], cryoglobulinemia [13,14], and vasculitis of connective tissue diseases [7,8,12]. The common dysimmunesignature is at the base of the pathogenesis of the two affections.

In addition to these “dysimmune/autoimmune” angiitis, endocrine and especially thyroid disorders remain exceptional during systemic vasculitis [15]. They are mostly reported in association with angiitis of small size vessels suggesting a direct attack of the glandular parenchyma by the inflammatory vasculitic process [16]. Thyroid involvement during other systemic primary vasculitis (vasculitis of medium and large size vessels) is unusual [17] and only sporadic observations are reported [18-24].

As a result, the exact significance of thyroid dysfunctions during systemic vasculitis is not well known: fortuitous association?Specific endocrine involvement of vasculitis?Or two specific conditions of the same predisposing profile?[15].

Behçet’s disease (BD) is a systemic vasculitis of vessels of all types (arteries, veins, and capillaries) and all size (small, medium, and large) particularly common in young subjects [25]. Its typical clinical presentation is that of recurrent oral and genital aphthousulcers and anterior uveitis with hypopyon[26]. The systemic manifestations of this vasculitis are very polymorphous, often severe and potentially fatal, affecting the heart and vessels (angio-Behçet), the nervous system (neuro-Behçet), the digestive tract (entero-Behçet), the eyes (oculo-Behçet), kidneys, lungs, joints, etc. .. [27-32].

In view of the important clinical polymorphism, its diagnosis is often based on diagnostic criteria, the most used of which are those of the International Study Group for Behçet’s Disease (International Study Group for Bethet’s Disease (ISGBD)) of 1999 [33] (table 1). New international criteria for the diagnosis of BD were established in 2006, revised in 2010 and recently in 2013.

The final criteria were published in 2014 “The International Criteria for Behcet’s Disease (ICBD)” (table 2) [34], and characterized by a sensitivity of 93.9% and a specificity of 92.1%; far better than the long-standing 1990 ISGBD criteria where the sensitivity is only 81.2% and the specificity is 95.9%.

The aim of this paper is to review thyroid dysfunctions during BDand their possible pathogenic mechanisms.
Table 1: Diagnostic criteria of Behcet’s disease according to the ISGBD 1990 [33].

Criterion

Description

Major criterion

recurrent oral aphthousulcers observed by a doctor or patient with at least three episodes during the last 12 months

Minor criteria

Recurrent genital ulcer

Aphthous ulceration or scarring observed by a physician or reported reliably by patient

Skin lesions

Erythemanodosum-like lesions, pseudofolliculitis, papulopustular lesions, or acneiform nodules.

Eye involvement

Anterior or posterior uveitis or retinitis/retinal vasculitis  documented by an ophthalmologist

Positive pathergy test

Performed with oblique insertion of a ≤21-gauge needle under sterile conditions and interpreted by a physician at 24-48 hours

Diagnosis= major criterion + at least two minor criteria.
ISGBD: the International Study Group for Behcet’s Disease.
Table 2: The International Criteria for Behcet’s Disease (ICBD 2014) [34].

Signs/symptoms

Points

Oral aphthosis

2

Genital aphthous ulcer

2

Ocular injuries

2

Cutaneous lesions

1

Central nervous system involvement

1

Vascular manifestations

1

Positive pathergy test

1

Diagnosis = if total score of four points or more.
a. Endocrine involvement during BD
Endocrine involvement in BD is rare and little known, and the review of the world’s literature finds only a few cases of pituitary gland, pituitary stalk, adrenalgland, ovarian, testicles involvement, and a clear resistance to insulin [35-43].

The exact mechanism of these attacks remains unclear. Associated autoimmune disease seems more plausible than direct attacks (via the underlying systemic vasculitis that characterizes BD) despite the hyper-vascularization of almost all endocrine glands [36].

Pituitary involvement (partial or total: panhypopituitarism) is most frequent during BD by specific inflammatory vascular mechanism (hypothalamic-pituitary leukocytoclasticvasculitis) because the pituitary gland is the best vascularized organ of the human body [ 41] and some of these endocrinopathies, particularly prolactin, growth hormone (GH), and dihydroepiandrosterone sulfate (DHEAS) disturbances appear to be correlated with Behcet’sdisease activity [40].
b.Thyroid gland involvement during BD
Affections of the thyroid gland during BD are the least known and the least reported. The first study to have systematically screened for thyroid function in BD was that ofMuderrisoglu H et al, conducted in 1988, testing the baseline fT4, T3, and TSH in 13 patients with BD would not have shown any abnormality [42].

Then, Aksu K et al, in 1999 in a small sample of Turkish patients with BD, concluded that baseline thyroid tests (T3, fT4, and TSH) were within the normal range of the general population [20] .

Larger scale, comparative, and dynamic studies of thyroid function and thyrotropic axis during BD followed one another:

- The study by Cebeci F et al, comparing 124 Turkish patients with BD to a sex- and age-matched healthy population sample, did not show significant differences in the frequency of autoimmune thyroiditis, positivity of anti-thyroid antibodies : anti-Tg and/ or anti-TPO antibodies, frequency of hypothyroidism, frequency of uncomplicated hypothyroidism, frequency of autoimmune hyperthyroidism, and the mean value of TSH between the two groups. In contrast, the mean value of fT4 was significantly lower during BD compared to the general population: 1.11 ± 0.19 ng/dl versus 1.21 ± 0.19 ng/dl, p = 0.000 [ 21].

- The clinical-biological and radiological study of Ersoy R et al, comparing 50 subjects with BD to a matched sample of healthy controls found no significant difference between the two groups in the mean values of TSH, T3 and fT4, the prevalence of antithyroid antibodiespositivity, thyroid morphological abnormalities (goiter, nodule, atrophy, etc..) and the thyroid volume appreciated by imaging [44].

- The analysis of baseline thyroid tests by Akdeniz S et al in 30 patients with BD showed no significant difference compared to a group of healthy controls matched for age and sex for thyroid hormones and their free fractions including T3, TT4, fT3 and fT4. In contrast, TSH was significantly lower in the group with BD compared to the general population: 1.28 ± 0.688 μIU/ml versus 1.83 ± 1.06 μIU/ml, p = 0.02 indicating deficiency of central origin [41].

This hypothesis was confirmed by the dynamic tests with assay of the TSH response at 20 and 60 minutes after an injection of TRH. The response in the group with BD was significantly lower than in the group of healthy controls (TSH at 20 minutes: 9.63 ± 5.3 μIU/ml versus 15.29 ± 0.33 μIU/ml, p=0, 03 and TSH at 60 minutes: 8.4 ± 4.89 μIU/ml versus 11.07 ± 5.23 μIU/ml, p=0.05) confirming the pituitary origin of thyroid hormone deficiency [41].

- The study of Karakus S et al, performed in 43 patients with BD of both sexes and different ages had not shown significant differences for all thyroid biologic tests (fT4 and TSH) compared to two groups controls: subjects with systemic lupus erythematosus and healthy subjects matched for age and sex. On the other hand, the T3 level was significantly higher in the Behçet group compared to healthy subjects (p1=0.002) and those with systemic lupus erythematosus (p2=0.006) while remaining within the normal range for all patients and had no clinical impact [40]. In the Behçet group, no statistically significant difference was observed for the various thyroid hormones measured (T3, fT4 and TSH) according to the active or inactive status of the disease or whether or not there was severe visceral involvement of the disease, especially ocular [40].
c. Mechanisms of thyroid involvement in BD
Involvement of the thyroid gland during BD can result from two main mechanisms [21]:

- Specific direct attacks: leukocytoclasticvasculitis of the thyroid arteries (thyroid involvement by thyroid vasculitis),

- Autoimmune disease: associated autoimmune thyroiditis because of the dysimmuneprofile that presents the BD.
d. A direct damage of the thyroid gland by BD vasculitis
The thyroid as a richly vascularized organ may be a preferred target during vasculitis of Behçet’s disease [21,44] whereas thyroid involvement is rarely studied in this pathology [21,44]. Exceptionally some sporadic cases of functional disorders (hypoor hyper-thyroidism) have been reported during BD [45,46] as well as some cases of thyroid cancer, and more rarely some morphological abnormalities (nodules and goiter) [21, 47-50].

Thus, the 13th International Conference on Behçet’s Disease (13th ICBD) held in Austria in 2008 had recognized thyroid gland involvement as a possible rare event in BD; the various thyropathies mentioned were: Graves’ disease, Hashimoto’s thyroiditis, thyroid nodule (s) and diffuse goiter [51].

The significant decrease in fT4 levels during BD compared to the general population in the Cebeci F et alseries, and the absence of any thyroid immunological abnormalities, is suggestive of a direct thyroid parenchymal involvement by the vasculitic process [21].

Morphological changes in the thyroid gland can be seen during BD, without having any impact on the hormonal functioning of the gland; this again testifies to the vasculitic mechanism of thyroid glandular involvement during BD [21]. The authors recommend the morphological and hormonal investigations of the thyroid during BD rather than the thyroid immunological test, which does not seem to have any diagnostic or prognostic implications [21].
e. An association between two dysimmune diseases
The Lockwood CM et al study, once again, suggests the major role of auto-reactive T cells in the pathogenesis of BD [52]. This mechanism represents another hypothetical pathway that can explain, in part, the thyroid dysfunction during BD, since the role of these lymphocytes is well documented in the pathogenesis of thyroid autoimmune thyroiditis [53] mainly via “thyroglobulinreactive T cells”[54].

Indeed, the experimental study of Kolypetri P et al, had demonstrated that self-reactive T cells are required both for the development and maintenance of spontaneous autoimmune thyroiditis (Spontaneous Autoimmune Thyroiditis, SAIT): It is the epitope p2549-2560 of thyroglobulin which contains thyrosin at position 2553 (T4p2553), which induces a strong specific response of self-reactive T cells generating autoimmune thyroiditis in NOD.H2(h4) mice [55].

From another meaning, the study by Soy M et al, seeking to catalog systemic diseases, particularly those of dys-immune mechanism, in association with autoimmune thyropathies, had objectified a frequency of 18% of recurrent aphtosis stomatitis (a major sign of BD) in subjects with autoimmune hypothyroidism [56]. Similarly, the study by Arnaout MA et al, Seeking to quantify the prevalence of abnormalities of thyroid tests in patients followed for connective tissue diseasesand systemic vasculitis (including BD), had objectified :subclinical and/or overt hypothyroidism in two/24 patients with BD (8.3%), and positive antithyroid antibodies, independent of the clinical presentation of underlying thyropathy, in two patients/24 with BD (8.3%) [43].
f. Iatrogenic association between BD and thyroid dysfunction
The association of thyropathy with BD may be iatrogenic: Some therapies used during BD may influence thyroid function, as such:

The treatment of BD with CAMPATH-1H, a humanized anti- CD52 that causes lymphocyte depletion, may be the cause of primary hypothyroidism. The Lockwood CM et al study, reporting 18 patients with active BD requiring treatment with a single course of CAMPATH-1H at 134 mg to achieve remission in 72% of cases, noted the appearance of primary hypothyroidism in two patients(11% of cases) [52].

Similarly, the study by Mohammad AJ et al, conducted in patients with refractory BD requiring the use of Alemtuzumab® (anti-CD52), reported subclinicalautoimmune thyropathies as a complication of this treatment in 25% of patients[57].

Interferon biotherapy, which is increasingly used in severe forms of BD [58,59], may be the cause of autoimmune hypothyroidism particularly in patients who already have asymptomatic antithyroid antibodies[59,60]. It should also be recalled that cases of Behçet induced by treatment with interferon α2a and interferon-ϓ have been reported [60]. The possible induction of thyropathy and BD by recombinant interferon suggests a dys-immune origin common to these two conditions (predisposing dys-immune profile that will subsequently be amplified and maintained by this molecule) [60].

Finally, it should be noted that long-term corticosteroid therapy, a treatment frequently prescribed during BD, may also influence thyroid biological tests [41].
g. Other anecdotic thyropathies associated to BD
Certain conditions, which are far from rare in BD, particularly depression and schizophrenia, may alter or rather influence thyroid tests [41]; in fact, these manifestations are frequent during the course of BD with neurological involvement (neuro- Behçet) which is seen in 2.5 to 49% of cases [61,62]. Depression is particularly frequent during BD: the study of Ishchenko DA et al, had objectified it in 40% of patients with BD (28.3% of recurrent depressive disorders and 11.7% of mild to moderate depressive episodes) [63]. Its prevalence can reach 86% at the beginning of the disease according to some authors [64]. As for schizophrenia, it is much rarer during BD [65].

Finally, there are two anecdotal cases of thyroid damage during BD:

- Chung SY et al, reported an original case of tuberculous thyroiditis in a woman with BD [66]. As a result, the possibility of infectious thyroiditis must always be kept in mind since BD is an immunosuppressive condition with often long-term systemic corticosteroids and immunosuppressive therapy.

- Similarly, another anecdotal case of “Black thyroid” associated with a hyalinizing trabecular tumor has been reported in a 42-year-old patient with an underlying BD, without giving any idea about the values of thyroid tests [67].

These various possible disorders of the thyroid gland during Behçet’s disease and their mechanisms are summarized in Figure 1 (Figure.1).
Figure 1: Schematic summary of the various possible involvement of the thyroid gland during Behçet’s disease, and their mechanisms
Conclusion
Affection of the thyroid gland during the BD seems to be far from a mere coincidence. Several findings of temporal and evolutionary concordance argue in favor of a causal association. Autoimmunity plays a major role in this association, suggesting a common immunological mechanism involved in the genesis of these two conditions (autoimmune thyoiditis and BD). Direct and specific thyroid involvement of BD seems much rarer (thyroid vasculitis). The possibility of thyroid cancer must also be evoked and sought after because of the proven carcinogenicity of BD.

Thyroid injury during BD can sometimes be severe and condition the prognosis hence the particular interest of a systematic screening, recommended by several authors, with static thyroid tests and thyroid imaging in any patient having a BD.

The early detection of these lesions makes it possible to take care of them adequately and in time thus improving the prognosis of this systemic vasculitis which can be fatal.
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