Clinical and Subclinical Autoimmune Thyroid Disorders in Systemic Sclerosis

European Journal of Endocrinology (2007) 156 431–437 ISSN 0804-4643

CLINICAL STUDY Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis Alessandro Antonelli, Clodoveo Ferri1, Poupak Fallahi, Massimiliano Cazzato2, Silvia Martina Ferrari, Marco Sebastiani1 and Ele Ferrannini Metabolism Unit, Department of Internal Medicine and CNR Institute of Clinical Physiology, University of Pisa, via Roma, 67, 56100 Pisa, Italy, 1Rheumatology Unit, Department of Internal Medicine, University of Modena & Reggio Emilia, Modena, Italy and 2Rheumatology Unit, Department of Internal Medicine, University of Pisa, Pisa, Italy (Correspondence should be addressed to A Antonelli; Email: [email protected])

Abstract Objective: Several studies have reported the association of systemic sclerosis (SSc) with thyroid autoimmune disorders, but most of them have neither an appropriate control group nor include a complete thyroid work-up. Design: The aim of our study was to evaluate the prevalence of thyroid disorders in a large number of patients with SSc using a complete clinical evaluation. Methods: Thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, antithyroglobulin and antithyroid-peroxidase (AbTPO) autoantibodies, thyroid ultrasonography and blood flow and fine needle aspiration were performed in 202 SSc patients versus 404 gender- and age-matched controls from the general population, with similar iodine intake, to evaluate the prevalence of clinical and subclinical thyroid disorders. Results: Odds ratio (OR) for female SSc versus controls was: for subclinical hypothyroidism, 3.2 (95% CI)Z1.8–5.7); for clinical hypothyroidism, 14.5 (95% CIZ2.3–90.9); for AbTPO positivity, 2.7 (95% CIZ1.8–4.1); for hypoechoic pattern, 3.2 (95% CIZ2.2–4.7); for thyroid autoimmunity, 3.7 (95% CIZ2.6–5.4); for thyroid volume !6 ml, 1.8 (95% CIZ1.2–2.7). OR for thyroid autoimmunity in male SSc versus controls was 10.8 (95% CIZ2.2–52.4). Mean values of TSH in female SSc, and of AbTPO in female and male SSc were higher (P!0.01) than in controls. We observed three cases of Graves’ disease in female SSc versus zero in controls (PZ0.0140), and two cases of papillary thyroid cancer in SSc patients. Conclusions: Thyroid function, AbTPO and ultrasonography should be tested as part of the clinical profile in SSc patients. Females, subjects with positive AbTPO and hypoechoic and small thyroid should have thyroid function follow-up and appropriate treatment in due course.

European Journal of Endocrinology 156 431–437

Introduction work-up (thyroid scan was evaluated only in the study by De Keyser et al. (12), while thyroid ultrasonography, Progressive systemic sclerosis (SSc) or diffuse sclero- which has been progressively becoming one of the most derma is a connective tissue disease of unknown important tools in the diagnosis of thyroid disorders, has etiology, characterized by vascular abnormalities, never been evaluated in SSc patients). For other thyroid multiorgan ﬁbrosis and complex immune system disorderssuchasGraves’disease(20–22), central alterations (1–6). hypothyroidism (23), euthyroid sick syndrome (24), The association of SSc with thyroid ﬁbrosis (7, 8), thyroid nodules and thyroid cancer (23, 25, 26) only hypothyroidism (8–15) and thyroid autoimmunity anecdotal reports are present in the literature. (8–19) has been reported by several studies in a wide The aim of our study was to evaluate the prevalence range of variability.However, most of them do not have an of clinical and subclinical thyroid disorders in a wide appropriate control group to evaluate the relative risk or group of patients with SSc by assessing thyroid odds ratio (OR) of hypothyroidism (8–14),evenifthreeof morphology at ultrasound examination and detecting them reported a higher mean TSH level in SSc patients thyroid hormones and antithyroid autoantibodies, in than in controls (10, 12, 13). Furthermore, none take into comparison with an age- and sex-matched control account iodine intake, which is a major determinant of group from the same geographic area with a similar thyroid disorders, and do not include a complete thyroid status of iodine intake (27).

q 2007 Society of the European Journal of Endocrinology DOI: 10.1530/EJE-06-0591 Online version via www.eje-online.org

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Materials and methods more (78% vs 82% respectively), without any signi- ﬁcant difference between the two groups. Subjects

SSc patients In total, 202 SSc patients consecutively Methods referred to the Rheumatology Units of the Universities of Neck ultrasonography and fine-needle aspiration Pisa and Modena (from 1999 to 2004) were recruited into the study. SSc was classified according to the American Thyroid ultrasonography was performed both in patients College of Rheumatology 1980 preliminary criteria (5). and in controls. Neck ultrasonography was performed by Standardized criteria were followed for the evaluation of the same (blinded) operator using a Esaote AU5 clinico-serological features, main visceral organ involve- (Florence, Italy) with a sectorial 7.5 MHz transducer. ment and disease activity as previously described (3, 4). Thyroid volume was calculated using the ellipsoid Skin sclerosis was observed in all patients (diffuse 16%, formula, as described (30–32). The presence of hypo- intermediate 25% or limited 59%); visceral involvement echoic and dyshomogeneous echogenicity was arbitrarily included: peripheral vascular system, 93%; gastrointes- rated at three levels (0, normal echogenicity; 1, slight tinal system, 56%; lung, 62%; joint/tendons, 18%; heart, hypoechoic and dyshomogeneous pattern; 2, severely 31%; kidney, 8%. The prevalence of autoantibodies, hypoechoic and dyshomogeneous pattern) in order to evaluated according to standard methodologies (3), was: evaluate structural abnormalities of thyroid tissue antinuclear 93%, anticentromere 35%, antitopoisome- associated with thyroid autoimmunity (30–32).The rase I (anti-Scl-70) 39%. presence of thyroid nodules was recorded; nodules with a diameter O10 mm were submitted to ultrasonography- guided fine-needle aspiration (FNA), which was per- Control group – general population Each of the SSc formed by the same operator using a free-hand method, patients eligible for the study was matched, by sex and as already described (30–32). age, one-to-two with a control group of subjects of the background population from the same geographic area (North-West Tuscany). This control group was Thyroid blood flow Thyroid blood flow (TBF) was extracted from a larger sample of 1640 subjects in a studied in all patients by color-flow Doppler (CFD) (31– population-based survey of thyroid disorders (28, 29). 33). The CFD pattern was defined as follows: a) normal Iodine intake differs within Tuscany, and reliable data (or type 0) when TBF was limited to peripheral thyroid on local iodine intake based on urinary iodine excretion arteries; b) type I when TBF was mildly increased; c) are available (27). Extraction of either control group type II when TBF was clearly increased; d) type III when from the original populations was performed by finding TBF was markedly increased (31–33). the closest age match (G3 years) to each case within either gender. When more than one age-match was available per case, the choice was made at random. Laboratory evaluation This included measurement of Subjects with history of rheumatic diseases or with serum levels of thyroid-stimulating hormone (TSH; symptoms or signs of rheumatic disorders at physical reference range 0.3–3.6 mU/ml), free triiodothyronine examination were excluded from the control group. (FT3), free thyroxine (FT4), antithyroglobulin (AbTg) Patients or controls on medications that may and antithyroid peroxidase antibody titers (AbTPO). influence thyroid function (i.e. amiodarone, lithium, Circulating FT3 and FT4 were measured by commercial etc.) were preliminarily excluded from the study (three RIA kits (AMERLEX-MAB FT3/FT4 Kit; Amersham). patients and two controls). All patients and controls Serum TSH (DiaSorin, Stillwater, MN, USA), AbTPO and underwent a complete clinical evaluation, with special AbTg (ICN Pharmaceuticals, Costa Mesa, CA, USA) attention paid to risk factors for thyroid disorders were evaluated by IRMA methods. For AbTg and (family history of thyroid disease, residence in iodine- AbTPO positivity was set at O100 IU/ml and O deficient areas and smoking habits). The SSc patients 100 IU/ml respectively. Values are given as meanGS.D. and controls had similar gender distributions (females/ males: 91/9% in both SSc and controls) and mean age for normally distributed variables. AntiTSH-receptor (55G13 vs 54G9 years respectively) by the matching autoantibodies (TRAb) were measured in patients with procedure; no significant difference was observed the use of a radioreceptor assay (Radim, Pomezia, Italy; regarding family history of thyroid disease (41 and normal range 0–1 IU/ml). 43% respectively) or smoking habit (19 and 23% The study was approved by the institutional ethics respectively). The majority of SSc and control subjects committee, and all subjects gave their informed written had resided in an iodine-deficient area for 20 years or consent to participate.

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Statistical analysis Since female gender is a well- and two with clinical hypothyroidism) and in two recognized risk factor for thyroid disorders, levels of controls. On the whole, indices of thyroid autoimmunity TSH, FT3,FT4, AbTPO and AbTg were compared only (AbTg, AbTPO or ultrasonographic diagnosis of among subjects of the same gender. Mean group values thyroiditis) were significantly more frequent in SSc were compared by using one-way ANOVA for normally than in controls (Fig. 1). In contrast, there was no distributed variables, otherwise by the Mann–Whitney statistically significant difference in the prevalence of subclinical hyperthyroidism (defined as TSH! 0.2 mU/ U test. The c2-test or the OR were used to compare ml with FT and FT within normal range) between the categorical variables. 4 3 two groups (Table 1). The prevalence of Graves’ disease (30–32) [established from the clinical presentation: presence of a diffuse goiter (varying in size from normal Results to very large), thyroid hormones (clinical hyperthyroid- ! Results in female SSc and female controls ism defined as TSH 0.2 mU/ml with FT3 above the normal range), thyroid autoantibodies measurements TSH levels and AbTPO titers were significantly higher in (presence of TRAb), thyroid ultrasonography (decreased, SSc than in control women (Table 1). Subclinical dyshomogeneous echogenicity, and diffuse goiter), and hypothyroidism (defined as TSHO3.6 mU/ml with FT4 thyroid scan (diffuse uptake in the thyroid)] was and FT3 within normal range) and clinical hypothyroid- significantly higher in SSc than in controls (Table 1). ism (defined as TSHO3.6 mU/ml with FT4 below the Thyroid volume was significantly lower and a small normal range) were significantly more common in SSc thyroid (defined as thyroid volume !6 ml) was signi- than in controls. The mean value of TSH was 4.5G ficantly more frequent in SSc than in controls. Thyroid 2.0 mU/ml (range 3.6–14.4) in SSc with subclinical enlargement (defined as a thyroid volume O20 ml) was hypothyroidism, 34.2G48.0 mU/ml (range 14.6– not significantly different in the two groups, as was the 143.5) in patients with clinical hypothyroidism and prevalence of thyroid nodules. 5.6G2.2 mU/ml (range 3.6–11.1) in controls with One case of papillary thyroid cancer (suspected by subclinical hypothyroidism. The prevalence of subjects FNA and confirmed by histology) was observed in with positive AbTPO was significantly higher in the SSc female SSc, with none in controls. group than in controls. A thyroid hypoechoic pattern, often a sign of inflammatory involvement of thyroid P<0.05 tissue (30–32), was more frequent in SSc than in 60 controls. Thyroid autoimmunity was diagnosed by ultrasonography in the absence of positive AbTg or AbTPO in 12 SSc (six with subclinical hypothyroidism 50 P<0.05 Table 1 Comparison of thyroid status between female patients with 40 systemic sclerosis (SSc) and female controls (C). 30 SSc C P P<0.05

No. 184 368 (%) Prevalence 20 Age (years) 55G12 54G9NS TSH (mU/ml) 3.6G11.6* 1.6G1.4 0.0013 G G FT4 (pmol/l) 115 5.1 117 26 NS 10 FT3 (pmol/l) 4.6G1.5 4.8G2NS AbTg (IU/ml) 121G207 66G206 NS AbTPO (IU/ml) 115G491* 24G62 0.0005 0 Subclinical hypothyroidism 31/153 (17%) 22/346 (6%) 0.0001 Clinical hypothyroidism 7/177 (4%) 1/367 (0.3%) 0.004 Subclinical hyperthyroidism 6/178 (3.3%) 22/346 (6%) NS Graves’ disease 3 (1.6%) 0 0.0140 AbTgC 35/149 (19%) 59/309 (16%) NS AbTPOC 72/112 (39%) 70/298 (19%) 0.0001 AbTPO + SSc

Hypoechoic pattern 88/96 (48%) 81/287 (22%) 0.0001 AbTPO + controls Thyroid autoimmunity 107/77 (58%) 100/268 (27%) 0.0001 Thyroid volume (ml) 10G913G14 0.0156 O

Thyroid volume 20 ml 21/163 (11%) 44/324 (12%) NS Thyroid autoimmunity SSc Thyroid volume !6 ml 54/130 (29%) 70/298 (19%) 0.008 Thyroid autoimmunity controls

Thyroid nodules 96/88 (52%) 210/158 (57%) NS Subclinical hypothyroidism SSc

Thyroid stimulating hormone, TSH; Antithyroperoxidase antibody, AbTPO; Subclinical hypothyroidism controls antithyroperoxidase antibodiesO100 IU/ml, AbTPOC; antithyroglobulin antibody, AbTg; antithyroglobulin antibodiesO100 IU/ml, AbTgC;free Figure 1 The prevalence of AbTPO positivity (AbTPOC), subclinical C triiodothyronine, FT3; free thyroxine, FT4; thyroid autoimmunity, AbTg or hypothyroidism and thyroid autoimmunity in female SSc patients was AbTPOC or ultrasonographic diagnosis of thyroiditis. signiﬁcantly higher than in controls (P!0.05; c2).

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The OR for female SSc with respect to controls was: (30–32), but no significant difference was shown in for subclinical hypothyroidism, 3.2 (95% CI, 1.8–5.7); their prevalence between SSc and control males for clinical hypothyroidism, 14.5 (95% CI, 2.3–90.9); for (Tables 1 and 2). AbTPO positivity, 2.7 (95% CI, 1.8–4.1); for hypoechoic SSc patients with thyroid autoimmunity had a longer pattern, 3.2 (95% CI, 2.2–4.7); for thyroid autoimmunity, disease duration than other SSc (16G11 vs 9G7 years, 3.7 (95% CI, 2.6–5.4); for thyroid volume !6 ml, 1.8 P!0.05), while no relationship between disease activity (95% CI, 1.2–2.7). and any kind of thyroid disorders was observed. No significant association was observed among the cutaneous or visceral involvement or the presence of Results in male SSc and male controls SSc-specific autoantibodies, and thyroid dysfunctions or The prevalence of male patients with positive AbTPO thyroid autoantibodies. and the AbTPO titer in SSc were significantly higher Pooling the data of female and male SSc patients, than in controls (Table 2). Thyroid autoimmunity was thyroid enlargement was significantly associated with diagnosed by ultrasonography in the absence of the presence of thyroid nodules (presence of nodules positive AbTg and AbTPO in two SSc and one control. 92% vs 44%, in presence or absence of goiter On the whole, indices of thyroid autoimmunity (AbTg, respectively; PZ0.0012), while the frequency of AbTPO, or ultrasonographic diagnosis of thyroiditis) patients with positive AbTPO (40% vs 36%, in were significantly more frequent in SSc than in presence or absence of goiter respectively) or AbTg controls. One case of papillary thyroid cancer (sus- (25% vs 17%, in presence or absence of goiter pected by FNA and confirmed by histology) was respectively) was higher in presence of goiter, even if observed in one SSc, with none in controls. No case it did not reach statistical significance; the prevalence of clinical hypothyroidism or hyperthyroidism was of hypothyroidism was lower in presence of goiter (8%) observed. The OR for male patients with SSc with than in absence of goiter (25%), even if not respect to controls for thyroid autoimmunity was 10.8 significantly (no relationship was found with the (95% CI, 2.2–52.4). other thyroid parameters). In SSc patients (Table 3), hypothyroidism was significantly associated with the presence of a small thyroid volume (!6 ml) and a General results hypoechoic pattern (no relationship was found with In each group (Tables 1 and 2) any kind of thyroid the other thyroid parameters). FNA was performed in disorders had a higher prevalence in women than in 28 SSc patients (14%) and in 54 controls (13.4%). men, with the exception of thyroid enlargement Benign thyroid lesions at cytology were found in 24 (defined as thyroid volume O20 ml). Thyroid enlarge- SSc patients (86%) and in 48 controls (89%); two ment was more frequent in men, as expected since cases of papillary thyroid cancer (suspected by FNA thyroid volume is physiologically higher in men and confirmed by histology) were observed in SSc, with none in controls; the remainders were not Table 2 Comparison of thyroid status between male patients with diagnostic (without any significant difference between SSc and male controls (C). the groups). In controls (Table 4), hypothyroidism was signi- SSc C P ficantly associated with the presence of AbTPO, AbTg, a No. 18 36 low thyroid volume (!6 ml) and a hypoechoic pattern Age (years) 51G18 50G11 NS (no relationship was found with the other thyroid TSH (mU/ml) 1.8G0.9 1.4G0.8 NS parameters). FT4 (pmol/l) 118G24 124G24 NS FT3 (pmol/l) 4.4G1 4.9G0.6 NS Comparing hypothyroid SSc and controls, a signi- AbTg (IU/ml) 43G111 14G13 NS ficantly higher prevalence of a thyroid hypoechoic AbTPO (IU/ml) 70G80 30G20 0.0062 G G pattern was observed in SSc (79% vs 21%), than in Thyroid volume (ml) 14 51812 NS Z Subclinical hypothyroidism 1/17 (6%) 0 NS controls (48% vs 52%; P 0.0243; no relationship was C AbTg 3/15 (17%) 2/34 (6%) NS found with the other thyroid parameters). AbTPOC 3/15 (17%) 0 0.0117 In controls with autoimmune thyroid disorders, TBF Hypoechoic pattern 2/16 (11%) 0 NS bore no relation to the thyroid status and was type 0 in Thyroid autoimmunity 7/11 (39%) 2/34 (6%) 0.0019 Thyroid volume O20 ml 3/15 (17%) 8/28 (22%) NS 60%, type I in 33%, type II in 7% subjects, while none Thyroid volume !6ml 0 0 NS had type III CFD pattern; a similar pattern was observed Thyroid nodules 6/12 (33%) 13/23 (36%) NS in SSc patients (type 0 in 54%, type I in 35%, type II in Subclinical hyperthyroidism 0 1/35 (3%) NS 11%, and type III in 0% of patients) with thyroid Anti-thyroid peroxidase antibody, AbTPO; antithyroperoxidase antibodiesO autoimmunity, without any statistical difference. 100 IU/ml, AbTPOC; antithyroglobulin antibody, AbTg; antithyroglobulin C Two cases of euthyroid sick syndrome (24) and no antibodiesO100 IU/ml, AbTg ; free triiodothyronine, FT3; free thyroxine, C C cases of central hypothyroidism (23) were observed in FT4; thyroid autoimmunity, AbTg or AbTPO or ultrasonographic diagnosis of thyroiditis; thyroid stimulating hormone, TSH. SSc, with none in controls.

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Table 3 Relationship between hypothyroidism (TSHO3.6 mU/ml) towards a lower hypothyroidsm prevalence in compari- and other thyroid parameters in SSc patients (female and male). son with the general population and that the current results agree closely with those reported by a popu- O ! TSH TSH lation-based survey so far in the literature (35), which 3.6 mU/ml (%) 3.6 mU/ml (%) P* showed a 8% prevalence for subclinical hypothyroidism AbTPOO10 IU/ml 46 34 NS in females over the age of 40 years (36). Interestingly, AbTPO!10 IU/ml 54 66 mean TSH value was signiﬁcantly higher in SSc than in Thyroid volume!6 ml 42 22 0.0381 Thyroid volumeO6ml 58 78 controls, in agreement with other studies (10, 12, 13). Hypoechoic pattern YES 79 33 0.0001 Autoimmune phenomena are an almost constant Hypoechoic pattern NO 21 67 feature of patients with SSc (1–6). The percentage of

2 antithyroid antibodies ranged from 12 to 52% in Antithyroid peroxidase antibody, AbTPO; *c . different studies (8–19). This wide range may be at least partially explained by application of steroids and Discussion immune suppressive drugs in SSc, and by the different Previous clinical studies demonstrated a high preva- gender and age composition (23) and iodine intake of lence of hypothyroidism in SSc; the prevalence of SSc patients. In most of the older studies AbTg were clinical hypothyroidism ranged from 2.4 to 26%, more common than antimicrosomal antibodies (11, while that of subclinical hypothyroidism ranged from 16–18), while in the more recent ones a higher 3.5 to 26% (8–14). None of these studies had an prevalence of AbTPO was found (12–15). The results appropriate control; furthermore other parameters such of our study demonstrate a significantly higher titer and as iodine status and thyroid morphology were not prevalence of AbTPO, but not of AbTg, both in female studied. More recently Innocencio et al. (15) studied 25 and in male SSc than in controls. Population studies SSc patients in comparison with a control group of 113 have shown the prevalence of AbTPO to be around 10% healthy individuals, but no significant result relating to in females (range 10–15%), and it increases with age (from 8% in females over 18 years of age to about 30% hypothyroidism was found, mainly because of the small in women over 70) (35, 36). In our female controls, the number of SSc patients. The results of our study, using prevalence of AbTPO positivity was 19%, similar or more tests and more sensitive methodology in a larger higher than that reported in some studies in SSc (18– group of 202 SSc matched with 404 controls with a 19%) (12, 14) and fully in the range of the reported age- similar exposition to iodine deficiency, demonstrate a adjusted prevalence rates for the Italian population (29, significantly higher OR for clinical and subclinical 34) and for other population-based surveys (35, 36).In hypothyroidism (with a prevalence of 4 and 17% female SSc the prevalence of AbTPO positivity was 39%, respectively) in female SSc than in controls. It should significantly higher. Similarly, an increased and signi- be stressed that the control was a sample of the general ficant prevalence (17%) of AbTPO positivity was shown population of central Italy, so the present series is a case- in SSc males than in controls. The prevalence of AbTg control study and not an epidemiological survey. from population studies have been reported to be However, the prevalence of hypothyroidism in the around 10% in females (range 10–15%) (29, 34–36), control females was substantial (6%), similar or higher which is similar to that observed in our female controls than that reported (5.8–8%) in some recent studies of (16%), while in SSc the prevalence of AbTg positivity SSc (14, 15) and fully in the range of the reported age- was 19% which is higher, even if not significant. adjusted prevalence rates for the Italian population (29, Altogether, the above mentioned data indicate a higher 34). This indicates that the control was not biased prevalence of thyroid autoimmunity in SSc, overall of female gender, compared with controls. Table 4 Relationship between hypothyroidism (TSHO3.6 mU/ml) and other thyroid parameters in controls (female and male). The presence of antithyroid antibodies was found in about half of SSc with overt hypothyroidism (11), TSHO TSH! similar to what was found in our study for AbTPO 3.6 mU/ml 3.6 mU/ml (46%). However, a higher prevalence of fibrosis of the (%) (%) P* thyroid gland, not necessarily associated with the AbTgO50 IU/ml 33 15 0.0220 typical features of Hashimoto’s thyroiditis, has been AbTg!50 IU/ml 67 85 described in SSc in several studies (7, 8, 23), suggesting AbTPOO10 IU/ml 57 16 0.0001 that hypothyroidism in SSc might be due to the fibrosis AbTPO!10 IU/ml 43 84 Thyroid volume!6 ml 47 16 0.0004 per se that is the main feature of SSc, rather than to Thyroid volumeO6ml 53 84 Hashimoto’s thyroiditis. This hypothesis is strengthened Hypoechoic pattern YES 48 18 0.0001 by our findings that hypothyroidism in SSc is signi- Hypoechoic pattern NO 52 82 ficantly associated with a thyroid hypoechoic pattern Thyroid autoimmunity YES 57 23 0.0004 and a small thyroid volume, but not with a higher Thyroid autoimmunity NO 43 77 prevalence of AbTg or AbTPO, which are instead Antithyroid peroxidase antibody, AbTPO; antithyroglobulin antibody, AbTg; *c2. significantly associated with hypothyroidism in

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Downloaded from Bioscientifica.com at 09/29/2021 02:38:02PM via free access 436 A Antonelli and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2007) 156 controls. Furthermore, comparing features specifically Graves’ disease than in a very large group of controls associated with hypothyroidism between SSc and with a similar iodine status. The diagnosis of thyroid controls, a significantly higher prevalence of thyroid dysfunction in SSc may have an important impact also hypoechoic pattern was observed in SSc (79% vs 48% on the clinical manifestations of SSc; in fact, Raynaud’s respectively). These findings suggest that cellular phenomenon is more difficult to control in hypothyroid immunity may be more important than umoral individuals (44, 45), and pulmonary hypertension (46) autoimmune reactions in the pathogenesis of hypothyr- can be seriously influenced by hemodynamic changes of oidism and thyroid fibrosis in SSc, and that ultrasono- hypothyroidism. Thyroid function and ultrasonography graphy is able to detect morphological alterations of the should be tested as a part of the clinical profiling of SSc thyroid tissue that are associated with a higher risk of patients. Those who are at high risk (females, positive hypothyroidism. AbTPO, hypoechoic and small thyroid patients) should Incidence of hyperthyroidism in SSc is unknown (20– have thyroid function follow-up and appropriate 23). In a study by Mourier-Clavreul et al. in a group of treatment in due course. 18 SSc, one with Graves’ disease was shown (25). In our study, a significantly higher prevalence of Graves’ disease is observed in female SSc, while no significant difference was observed for subclinical hyperthyroidism, References mainly related to nodular goiter with functionally autonomous nodules. It is noteworthy that no case of 1 Medsger TA Jr. Systemic sclerosis (scleroderma): clinical aspects. In Graves’ disease was found among controls, similar to Arthritis and Allied Conditions, edn 14, pp 1590–1624. Ed. observations in other samples from the same population WJ Koopman, Philadelphia: Lippincott Williams & Wilkins, 2001. 2 Black CM & Denton CP. Scleroderma and related disorders in (37, 38). adults and children. In Oxford Textbook of Rheumatology, edn 3, We were not able to confirm a significantly high pp 872–895. EdsDA Isenberg, PJ Maddison, P Woo, D Glass & prevalence of central hypothyroidism (23) or of FC Breedveld, Oxford: Oxford Writing Press, 2004. euthyroid sick syndrome (24) in SSc. 3 Ferri C, Valentini G, Cozzi F, Sebastiani M, Michelassi C, La Thyroid volume in controls is fully in the range of the Montagna G, Bullo A, Cazzato M, Tirri E, Storino F, Giuggioli D, Cuomo G, Rosada M, Bombardieri S, Todesco S & Tirri G. 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