sign in sign up
<<
Home , Autoimmune thyroiditis, Deiodinase, Euthyroid sick syndrome, Goitre, Iodothyronine deiodinase, Thyroid peroxidase

Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA / M. Cutolo G-CSF in RA patients / H. NakamuraEDITORIAL et al.

Euthyroid sick syndrome and inhibitory effect of sera on the activity of 5'- in systemic sclerosis

I. Molnár1, L. Czirják2

13rd Department of Internal Medicine, Kenézy County and Teaching Hospital, Debrecen;

2Nephrological Center and 2nd Department of Internal Medicine, Clinical Immunology Unit, University of Pécs, Medical Faculty, Pécs, Hungary.

Abstract Objective Our aim was to demonstrate the occurrence of euthyreoid sick syndrome in patients with systemic sclerosis (SSc). Furthermore, the presence of anti-thyroid antibodies and their relationship to thyroid 5'-deiodinase activity was investigated. Methods The activity of thyroid 5'-deiodinase was measured by 5' outer ring-deiodination using the sera of patients with

SSc (n = 21), undifferentiated connective tissue disease (n = 12), and secondary (n = 19) and primary (n = 11) Raynaud’s syndrome (RP). Patients with acute cardiovascular events at the time of the study (n = 16) were investigated as controls.

Results

Low FT3 (FT3 < 2.5 pg/ml) was frequently demonstrated in all the patient groups (9/21, 3/12, 10/19 and 8/11, respectively). The high frequency of a FT3/FT4 ratio < 0.2 representing euthyreoid sick syndrome was also often found in SSc (14 cases) and primary (12 cases) and secondary (6 cases) RP patients. Anti-thyroid antibody was detected in 17 patients with SSc and in 7, 8 and 3 cases with undifferentiated connec- tive tissue disease, secondary and primary Raynaud’s phenomenon, respectively, and in none of the controls. The inhibiting effect of sera on the activity of thyroid 5'-deiodinase was higher in patients with anti-thyroid

peroxidase antibodies compared to antibody negative cases (P < 0.01). An inverse correlation was shown between the levels of anti- antibodies and the decreased activity of thyroid 5'-deiodinase

(r = - 0.6111, P < 0.02) in patients with low FT3. Conclusion The low FT3 or FT3/FT4 ratio observed supports the hypothesis that is often present in SSc. Anti-thyroid antibody is also frequently detected in SSc and the positive sera inhibit the activity of thyroid 5'-deiodinase, which can contribute to the low FT3 or FT3/FT4 ratio. Anti-thyroid peroxidase antibod- ies may play an additive role in the development of low FT3 levels via the inhibiting effect of thyroid 5'-deiodinase. The low FT3 levels may directly influence the already impaired microcirculation in SSc by increasing the systemic vascular resistance. Key words Euthyreoid sick syndrome, systemic sclerosis, deidodinase, anti-thyroid antibody.

Clinical and Experimental Rheumatology 2000; 18: 719-724.

719 5'-deiodinase activity in systemic sclerosis / I. Molnár et al.

Ildikó Molnár MD, PhD; László Czirják Introduction = 11) RP and 16 control patients were MD, DSc. Systemic sclerosis (SSc) is a connective investigated. The in Please address correspondence and tissue disease characterized by fibrosis, the SSc patients (mean age 45 ± 12 yrs, reprint requests to: Dr Ildikó Molnár, obliterative vasculopathy and microvas- one male) were screened according to a 3rd Department of Internal Medicine, cular lesions. The presence of abnormal standard protocol (18). Three patients Kenézy County and Teaching Hospital, thyroid function and anti-thyroid anti- with diffuse (dcSSc) and 18 patients with H-4043 Debrecen, Bartók B.u.2-26., bodies has been demonstrated in SSc (1, limited cutaneous (lcSSc) SSc were in- Hungary. E-mail: [email protected] 2). The most frequent thyroid abnormal- vestigated. Eight patients (2 with dcSSc Received on February 16, 2000; accepted ity in SSc is (3-6). Low and 6 with lcSSc) had anti-topoisomer- in revised form on September 8, 2000. T3 syndrome has not been described as ase I (anti-Scl-70) antibody. Only 3 pa- © Copyright CLINICAL AND a thyroid function abnormalty in patients tients (all with lcSSc) exhibited anti-cen- EXPERIMENTAL RHEUMATOLOGY 2000. with SSc, however (7). Our previous stu- tromere antibody (ACA). dy revealed a strong correlation between The diagnosis of the patients with un- the levels of anti-thyroid peroxidase differentiated connective tissue disease

(TPO) antibodies and the low T3 in SSc (UCTD) (mean age 39 ± 17 yrs, one male) (8, 9). These findings suggested that the was based on the criteria used by previ- association of autoimmune ous investigators including Calvo-Alén with SSc could be responsible for the low et al. (19) and Alarcón et al. (20) with levels of T3. substantial modifications. UCTD com- Recent data on thyroid metabo- prises a group of patients with a systemic lism highlight the importance of the de- disorder that lacks definitive character- iodinase (10). The role of de- istics of any specific, well-defined con- iodinase enzymes in the thyroid hormone nective tissue disease. Well defined con- metabolism is well-known, as well as nective tissue diseases [predominantly their effects in euthyroid sick or low T3 systemic sclerosis (SSc), systemic lupus syndrome (11). Three deiodinase isotypes erythematosus (SLE), rheumatoid arthri- are involved in the maintance of the in- tis or Sjögren’s syndrome] may develop tracellular T3 concentration (DI, DII, later in many cases. The majority of pa- DIII). The conversion of T4 to active hor- tients with UCTD tend to remain in a mone T3 is mediated by 5'- permanently stable clinical-laboratory (DI and DII) as 5' outer ring-deiodination condition during follow up. Cases with (12). The conversion of T4 to inactive hor- UCTD should exhibit one of the follow- mone rT3 is mediated by 5-deiodinases ing principle symptoms: (1) Raynaud’s (DI and DIII) as 5 inner ring-deiodina- phenomenon (RP); (2) unexplained non- tion. The decreased levels of T3 in SSc erosive, symmetric polyarthritis; and (3) can arise from a defect of T4 deiodina- isolated keratoconjunctivitis sicca, ac- tion via different effects (, lipid companied by at least 3 of the following peroxidation, drugs) on the enzymatic signs or symptoms: (1) Raynaud’s phe- activities of the deiodinases (13,14). nomenon; (2) arthritis or arthralgia; (3) The aim of our present study was to dem- rash/dermatitis, alopecia, oral ulcers, or onstrate the relationship between the UV light sensitivity; (4) keratoconjunc- presence of anti-TPO antibodies and the tivitis sicca; (5) lung fibrosis, alveolitis low levels of FT3 hormone through the and/or decreased diffusing capacity and inhibiting effect of sera on the activity decreased vital capacity; (6) / of thyroid 5'-deiodinase in patients with pyrosis with oesophageal dysmotility; SSc. Patients with undifferentiated con- (7) cardiac involvement; (8) pleuritis/ nective tissue disease (UCTD), and sec- pericarditis; (9) otherwise unexplained ondary and primary Raynaud’s phenom- peripheral neuropathy/central nervous enon (RP) seemed to be reasonable groups system symptoms; (10) proteinuria, cy-

to use for comparison (15, 16). RP is of- lindruria, hematuria or signs of tubular ten the first clinical sign of SSc and it nephropathy; (11) sclerodactyly, swollen may precede the onset of scleroderma by fingers, oedema of the fingers or skin several years (17). ulcers; (12) otherwise unexplained el- evated ESR/CRP; (13) positive antinu- Materials and methods clear antibody test with homogeneous, Subjects fine speckled, nucleolar, anticentromere

Patients with SSc (n = 21), UCTD (n = staining pattern (on HEp-2 cells by in- 12), or secondary (n = 19) or primary (n direct immunofluorescence) or specific

720 -pituitary-adrenocortical and -gonadal axis in RA / M. Cutolo5'-deiodinase activity in systemic sclerosis / EDITORIALI. Molnár et al. positivity (anti-dsDNA, nase was detected in the thyroid super- roid peroxidase antigen fractions were anti-SS-A, anti-Rnp, anti-centromere, natant of 100,000 g. Human thyroglobu- used for the detection of anti-Htg and anti-topoisomerase I, repeatedly positive lin (Htg) fraction was purified from post- anti-TPO antibodies, respectively. 100 ml anti-cardiolipin IgG or IgM by ELISA microsomal saline extracts (supernatant patient sera (diluted 1:100) were added test); and (14) abnormal nailfold capillar- of 70,000 g) of toxic by ammoni- to the wells of the plate for 2 hr at room microscopy findings compatible with the um sulphate fractionation and sepharose temperature. Goat anti-human IgG anti- presence of scleroderma capillary pat- 6B (Pharmacia, Sweden) chromatogra- body conjugated with horseradish per- tern. phy after Hamada et al. (22). Thyroid oxidase (SIGMA, USA) as secondary

Secondary RP (mean age 42 ± 12 yrs, 17 peroxidase (TPO) fraction was prepared antibody (indilution 1: 5000) was cho- females, 2 males) was based on the cri- from porcine thyroid tissue after Taurog sen for the detection of the primary auto- teria of LeRoy and Medsger (21). In our et al. using digestion with trypsin (35 kU/ antibodies. O-phenylene-diamine (OPD, present study, a special group of patients g protein, Merck, Germany), ion-ex- Reanal, Hungary) was used as substrate with RP was formed. Clinically all of change chromatography (DE-52, What- and the optical density (O.D.) values these cases exhibited RP as the exclu- man, UK) and solubilization with deoxy- were read at 492 nm (MPR4 MicroPlate sive predominating clinical symptom but cholate in the 100,000 g supernatant (23). automatic ELISA reader, Belgium). The they had no signs of internal organ in- The protein concentration was measured results were given as an ELISA index: volvement. In addition to the clinical in- by Lowry’s method and stored (without the ratio of O.D. of the patient sample vestigation, chest radiograph, spirom- protease inhibitor) frozen at -40°C (24). and the mean O.D. of controls. When the etry/diffusion capacity, Schirmer’s test, O.D. value of the given sample exceeded barium swallow or gastrofiberoscopy, Outer ring the control value of mean + 2SD, the re- urine analysis, and serum creatinine ki- assay sult was regarded as positive for the in- nase were performed in all cases. Thus, Thyroid homogenates (11 mg protein/50 vestigated antibody. ELISA indices (mean these cases in addition to Raynaud phe- ml) were incubated with 20 ml undiluted ± SD) in the control group were as fol- nomenon also had either antinuclear an- and non-decomplementated patient sera lows: for anti-Htg 0.89 ± 0.21 and for tibody positivity, a scleroderma capillary and 50 ml dithiothreitol (20 mM, DTT, Re- anti-TPO 0.94 ± 0.2. pattern or digital pitting, ulcerations or anal, Hungary) and 50 ml 125I-T4 (100,000 gangrene, but they definitely did not ex- cpm, Isotope Institute, Budapest, Hun- Determination of thyroid hibit any internal organ manifestations gary) for 90 min at 37°C in a final vol- The levels of (FT4, (such as pulmonary interstitial changes, ume of 250 ml (25). The reaction was FT3, TSH) were determined with a lumi- oesophageal dysmotility/reflux oesopha- stopped by 100 ml bovine serum albu- nescence immunoassay (LIA-MAT, Byk gitis, renal symptoms). The expression mine (5% BSA, Sigma, USA), and im- Sangtec, Germany). The normal values "patients with secondary RP" is used for mediately followed by the addition of for thyroid hormones were as follows: this special group of RP patients. 300 ml trichloroacetic acid (10%, Reanal, for FT4 7.72 - 23.18 pmol/l, for FT3 2.5 The patients with primary RP (mean age Hungary). The supernatant containing - 4.5 pg/ml, and for TSH 0.3 - 3 mIU/l. 37 ± 13 yrs, no males) had exclusively acid-soluble radioiodine was separated RP and were used as negative controls. from the precipitate containing iodothy- Statistics None of these patients received corticos- ronines and both were measured in a Student’s paired t-test and linear corre- teroid therapy at the time of the study. gamma counter (Gamma NZ 322, Hun- lation with GraphPad Prism (USA) were Euthyroid in the patient’s medi- gary). The results were extrapolated at 1 used for the statistical analysis. cal history was found in 4 cases of SSc, pmol/l T4 in the patient serum. To deter- 5 cases of UCTD, 2 cases of secondary mine the Km of iodothyronine deiodi- Results RP and 3 cases of primary RP. nase for T4 0, 0.6, 1.8, 3.8 ng/100 ml non- Two patients (from subset of dcSSc and Sixteen patients with acute cardiovascu- radioactive T4 were added to the thyroid UCTD) had subclinical hypothyroidism lar disease (7 to 10 days after myocar- supernatant that already contained en- and one patient with SSc had subclini- dial infarction) (mean age 30 ± 10 yrs, 3 dogenous T4 (1.7 nmol/l). The activity cal at the time of the males) were investigated as controls. The of thyroid 5'-deiodinase was expressed investigation. Low levels of FT3 (FT3 < levels of thyroid hormones in the con- as pmol of T4 converted per mg/min pro- 2.5 pg/ml) were detected in 9 cases of trol group reflected the changes like an tein. The maximum velocity (Vmax) and SSc, one case of UCTD, 10 cases of sec- euthyroid sick syndrome. Km (nM) were calculated using Line- ondary and 8 cases of primary RP (Ta- weaver-Burk analysis. ble I). No difference was demonstrated Methods between the subsets of dcSSc and lcSSc Preparation of thyroid fractions Indirect linked immunosorbent either in the levels of FT3 (2.95 ± 0.79 Human thyroid tissue was obtained dur- assay (ELISA) pg/ml vs 2.99 ± 1.59 pg/ml, NS) or in TM ing an operation from a patient with goi- 96-well plates (Dynatech Immulon , the ratio of FT3 / FT4 (0.16 ± 0.02 vs 0.21 tre. The homogenate was centrifugated USA) were coated with 0.5 mg/100 ml ± 0.14, NS). The decrease in the levels at 800 g and different fractions were antigen fractions (diluted in carbonate of FT3 was significant in primary RP made by various centrifugation (10,000 buffer, 0.2 M, pH 9.6) and incubated over- compared to the controls (2.21 ± 0.84 vs g, 100,000 g). The activity of 5'-deiodi- night at 4°C (26). and thy- 3.44 ± 0.42 pg/ml, P < 0.002). The levels

721 5'-deiodinase activity in systemic sclerosis / I. Molnár et al.

Table I. The levels of thyroid hormones in patients with systemic sclerosis (SSc), undifferentiated connective tissue disease (UCTD), secondary and primary Raynaud’s phenomenon (RP), and controls.

Anti-thyroglobulin Ab Anti-thyroid peroxidase Ab ELISA indes ELISA index Age (yrs.) TSH FT4 FT3 FT3/FT4 mean ± SD mean ± SD Patient groups (mean ± SD) (0.3 - 3 mlU/l) 7.72 - 23.18 2.5 - 4.5 (pos. cases / total) (pos. cases / total)

SSc (n = 21) 45 ± 12 1.29 ± 1.21 16.14 ± 3.52a 2.99 ± 1.5 0.2 ± 0.13c 1.35 ± 0.44d 2.06 ± 0.81a (12/21) (17/21)

UCTD (n = 12) 39 ± 17 1.2 ± 1.86 16.42 ± 2.3a 4.59 ± 3.01 0.29 ± 0.21 1.13 ± 0.36 1.43 ± 0.46e (3/12) 7/12)

Secondary RP 42 ± 12 1.19 ± 0.49 15.08 ± 2.96 3.63 ± 5.03 0.23 ± 0.28 1.15 ± 0.5 1.4 ± 0.82a (n = 19) (5/19) (8/19)

Primary RP 37 ± 13 3.33 ± 6.25 10.15 ± 2.44 2.21 ± 0.84b 0.23 ± 0.11d 0.8 ± 0.33 1.08 ± 0.53 (n = 11) (1/11) (3/11)

Controls (n = 16) 30 ± 10 1.88 ± 0.78 9.28 ± 1.7 3.44 ± 0.42 0.38 ± 0.08 0.89 ± 0.21 0.94 ± 0.2 ap < 0.0001; bp < 0.002; cp < 0.001; dp < 0.01; ep < 0.004 in comparison with controls using Student’s paired t-test. of FT4 in SSc and UCTD were signifi- UCTD (7/12), and in secondary RP (8/ respectively). cantly higher than those in controls. The 19) and primary RP (3/11). The presence The addition of patient sera to the thy- ratio of FT3 / FT4 was markedly decreas- of anti-Htg was frequent in SSc only (1/ roid fraction decreased the activity of ed in patients with SSc and primary RP 3 in dSSc and 11/18 in lSSc) [in UCTD thyroid 5'-deiodinase significantly in the in comparison with the controls (0.2 ± (3/12), secondary RP (5/19), primary RP SSc (2.88 ± 0.61 pmol/mg/min, P < 0.13, P < 0.001 and 0.23 ± 0.11, P < 0.01 (1/11)]. No positive cases for anti-thy- 0.0001), UCTD (2.86 ± 0.38 pmol/ml/ vs 0.38 ± 0.08, respectively). roid antibody were found among the con- min, P < 0.0004) and secondary RP (3.23 The levels of TSH were in the normal trols. Positive tests for Scl-70 and ACA ± 0.81 pmol/mg/min, P < 0.0001) in range in all patient groups. Anti-TPO were found in 8 and 3 cases of SSc, whose comparison with the control (4.99 ± 1.04 positive cases were frequently found in levels of FT3 were in the normal range pmol/mg/min) (Fig. 1). The Vmax and SSc (2/3 in dcSSc and 15/18 in lcSSc), (2.77 ± 1.09 pg/ml and 3.83 ± 2.29 pg/ml, Km of the activity of 5'-deiodinase in the thyroid fraction was determined using Linewear-Burk analysis (Vmax = 1.39 pmol/mg/min, Km = 6.82*10-3 nM). The

anti-TPO positive (N = 33) sera inhibited the activity of thyroid 5'-deiodinase ra- ther than sera of anti-TPO negative (N =

24) (2.96 ± 0.52 vs 3.61 ± 1.15 pmol/mg/

min, P < 0.01) (Fig. 2). An inverse corre- lation was demonstrated between the lev- els of anti-TPO antibodies and the ac- tivity of thyroid 5'-deiodinase in the pa- tients with decreased FT3 (r = - 0.6111,

P < 0.02) (Fig. 3). Nine out of 11 patients (SSc 5, UCTD 3, secondary RP 3) with

increased FT3 (> 4.5 pg/ml) had anti- TPO positivity. The activity of thyroid 5'-deiodinase in patients with elevated FT3 was decreased compared to controls (2.96 ± 0.53 vs 4.99 ± 1.04, P < 0.0001). These enzyme activities did not show any association with the levels of anti- Fig. 1. Effect of sera from patients with systemic sclerosis (SSc), undifferentiated connective tissue disease (UCTD), or Raynaud’s phenomenon (RP) (either the secondary or primary form) and controls on TPO. The activity of thyroid 5'-deiodi- the activity of thyroid 5'-deiodinase. The mean ± SD was the follows: for controls (n = 16) 4.99 ± 1.04 nase was lower (but not significantly) in pmol/mg/min; for SSc (n = 21) 2.88 ± 0.61 pmol/mg/min; for UCTD (n = 12) 2.86 ± 0.38 pmol/mg/min; the subsets of dcSSc, positive for Scl-70 for secondary RP (n = 19) 3.23 ± 0.81 pmol/mg/min and for primary RP (n = 11) 4.65 ± 0.84 pmol/mg/ and ACA compared to those with lcSSc, min. negative for Scl-70 and ACA.

722 Hypothalamus-pituitary-adrenocortical and -gonadal axis in RA / M. Cutolo5'-deiodinase activity in systemic sclerosis / EDITORIALI. Molnár et al. thyroid 5'-deiodinase. The tissue-specific activities of deiodinases (thyroid, , , skin, cardiac and skeletal mus- cles, brain) could be decreased by cyto- kines (IL-6, TNFa ), drugs (glucocorti- coids, , iodinated radiocon- trasts) and nutrition deficiency (seleni- um) (13, 30). Elevated levels of IL-6 and TNFa decreased the activity of thyroid 5'-deiodinase in our patients with SSc (31). deficiency, which is an additional factor to the blocking effects on deiodinase enzymes, has also been described in SSc (32). Patients with low FT3 exhibit the clinical signs of high systemic vascular resistance, low cardiac output and impaired oxygen uptake and metabolism of skeletal muscle (33). It seems that the low level of FT3 with its Fig. 2. Effect of patient sera with positive and negative tests for anti-thyroid peroxidase antibody on the direct vascular effect may contribute to activity of thyroid 5'-deiodinase. the impaired tissue perfusion not only in cardiovascular diseases but also in SSc

and primary RP (34, 35). Ischemic-re- perfusion is defined as one of the important mechanisms in the pathoge- nesis of SSc (36). The development of low FT3 without decreased activity of thy- roid 5'-deiodinase in primary RP seems to be a consequence of the activities of non-thyroid tissue specific 5'-deiodina- ses. The strong correlation between anti-TPO positivity and the inhibiting effect of pa- tient sera on the activity of thyroid 5'- deiodinase suggest that autoimmune phe- nomena are involved in the low levels of FT3 via against the pro- teins of 5'-deiodinases. TPO is the one of the major thyroid antigens and plays a key role in the iodination of tyrosyl re- Fig. 3. Correlation between the activities of thyroid 5'-deiodinase and the levels of anti-thyroid peroxidase sidues in thyroglobulin so that in the thy- antibody in patients with decreased FT3. roid hormone production. Anti-TPO an- tibodies are able to inhibit the enzyme Discussion 20% of the circulating T3 is secreted by activity of TPO (37). Autoantibodies Anti-thyroid antibodies, as a sign of a thyroid, which has DI and DII deiodinase against the proteins of thyroid 5'-deiodi- usually subclinical thyroiditis, have been isotypes. Both are characterised as selen- nases (DI and DII) may be present in described in SSc (1, 6, 8, 27). The high oenzymes (3, 28, 29). Low FT3 levels autoimmune diseases such as SSc and levels of anti-TPO and anti-Htg with represent a hypothyroid-like effect on the UCTD. On the other hand, the idea that decreased levels of FT3 and a low FT3 / cell functions and are predicted by the antibodies may be directed against the FT4 ratio were also found in SSc as in- activities of thyroid and non-thyroid tis- same epitopes of TPO and 5'-deiodinase dicated by our previous data (9). The sue specific 5'-deiodinases. 5-deiodinase (DII) seems to be speculative. However, hallmark of the euthyreoid sick syn- (DIII) catalyzes T4 to rT3 conversion 9 anti-TPO positive cases with elevated drome, the decreased ratio of FT3 / FT4 which can be associated with elevated FT3 out of the all studied patient groups (< 0.2) is a sensitive indicator of deiodi- FT3. were found to have decreased 5'-deio- nase activity. The low FT3 / FT4 ratio Our recent findings demonstrated that dinase activity. These cases suggested can be regarded as a consequence of the the sera of patients with SSc, UCTD and the possibility of autoantibodies direct- inhibition of 5'-deiodinases (DI and DII). secondary RP can inhibit the activity of ing to the enzyme protein with the both

723 5'-deiodinase activity in systemic sclerosis / I. Molnár et al. activities of 5'- and 5-deiodinases in the Rheumatol 1994; 23: 128-32. by Western blot and immuno-precipitation. J thyroid tissue (DI). 6. LA MONTAGNA G, CARELLA C, AMATO G, Clin Endocrinol Metab 1985; 61: 120-8. The high prevalence of low FT with the FILIPPI F, TIRRI G, BELLASTELLA A: Thyroid 23. TAUROG A, LOTHROP ML, ESTABROOK RW: 3 function in systemic sclerosis. J Endocrinol Improvements in the isolation procedure for low ratio of FT3 / FT4 in primary RP Invest 1992; 15: 309-10. thyroid peroxidase: Nature of the pros- without any association with anti-TPO 7. DE KEYSER L, NARHI DC, FURST DE: Thyroid thetic group. Arch Biochem Biophys 1970; 12: antibodies suggest the role of non-im- dysfunction in a prospectively followed series 221-4. mune phenomena in the induction of de- of patients with progressive systemic sclero- 24. LOWRY OH, ROSENBROUGH NJ, FARR AL, sis. J Endocrinol Invest 1990; 13:161-9. RANDALL RJ: Protein measurement with the creased FT3. There are some recent data 8. MOLNÁR I, BALÁZS C, SZABÓ E, CZIRJÁK L: polyphenol reagent. J Biol Chem 1951; 193: that the effect of low FT3 on the vascu- Anti-thyroid antibodies and hypothyroidism in 265-75. lar lesions of RP has been improved by systemic sclerosis. J Endocrinol Invest 1992; 25. KOOPDONK-KOOL JM, DE VIJLDER JJM, the treatment of (38). 15: 311. VEENBOER: Type II and type III deiodinase 9. MOLNÁR I, BALÁZS C, SZABÓ E, CZIRJÁK L: activity in human as a function of ges- Our data indicate that the presence of Evaluation of thyroid function and anti-thy- tational age. J Clin Endocrinol Metab 1996; certain thyroid-related autoantibodies in roid autoantibodies in systemic sclerosis. Acta 81: 2154-8. SSc and UCTD may influence the activ- Derm Venereol (Stockh) 1992; 72: 112-4. 26. VOLLER A, BARTLETT A, BIDWELL DE: En- ity of thyroid 5'-deiodinase. The decrease 10. KÖHRLE J: Thyroid hormone deiodinases – A zyme immunoassay with special reference to selenoenzyme family acting as gate keepers ELISA techniques. J Clin Pathol 1978; 31: in the levels of FT3 in the positive cases to thyroid hormone action. Acta Med Austriaca 507-20. for anti-TPO correlated with the inhibi- 1996; 23: 17-30. 27. MOLTENI M, BARILI M, EISERA N: Anti-thy- tory effect of these sera on the activity 11. KÖHRLE J: Local activation and inactivation roid antibodies in Italian scleroderma patients: of thyroid 5'-deiodinase. Euthyroid sick of thyroid hormones: The deiodinase family. Association of anti-thyroid peroxidase (anti- Mol Cel Endocrinol 1999;151: 103-19. TPO) antibodies with HLA-DR15. Clin Exp syndrome is present in SSc and in pri- 12. BECKETT GJ, ARTHUR JR: The iodothyronine Rheumatol 1997; 15: 529-34. mary RP. Inhibition of the activities of deiodinases and 5'- deiodination. Bailliere’s 28. SALVATORE D, BARTHA T, HARNEY JW, non-thyroid tissue specific 5'-deiodinase Clin Endocrinol Metab 1994; 8: 285-304. LARSEN PR: Molecular biological and bio- may be also play a role in the low levels 13. BOELEN A, SCHIPHORST MCP, WIERSINGA chemical characterization of the human type 2 WM: Relationship between 3,5,3'-triiodo- selenodeiodinase. 1996; 137: of FT3, as was found in patients with thyronine and serum interleukin-8, interleukin- 3308-15. primary RP. The decreased levels of FT3 10 or interferon g in patients with nonthyroidal 29. SALVATORE D, TU H, HARNEY JW, LARSEN is an important factor for the develop- illness. J Endocrinol Invest 1996; 19: 480-3. PR: Type 2 iodothyronine deiodinase is highly ment of vascular lesions. The low FT 14. CHAURASIA SS, GUPTA P, MAITI PK et al.: expressed in human thyroid. J Clin Invest 1996; 3 Possible involvement of lipid peroxidation in 98: 962-8. represents a hypothyroid-like effect. The the inhibition of type I iodothyronine 5'-mono- 30. BOELEN A, MAAS MAW, LOWIK CWGM, direct influence of low FT3 on the vas- deiodinase activity by lead in chicken liver. J PLATVOET MC, WIERSINGA WM: Induced ill- cular system contributes to the impaired Appl Toxicol 1998; 18: 299-300. ness in interleukin-6 (IL-6) knock-out mice: A tissue microcirculation that already is 15. DANIELI MG, FRATICELLI P, FRANCESCHINI causal role of IL-6 in the development of the F: Five-year follow-up of 165 Italian patients low 3,5,3'-triiodothyronine syndrome. present in SSc. with undifferentiated connective tissue dis- Endocrinology 1996; 137: 5250-4. eases. Clin Exp Rheumatol 1999; 17: 585-91. 31. SZEGEDI A, CZIRJÁK L, UNKELESS JC, BOROS Acknowledgments 16. WILLIAMS HJ, ALARCON GS, JOKS R: Early P: Serum and anti-Fc gamma R auto- We thank Csaba Balázs, MD, DSc of the undifferentiated connective tissue disease antibody measurements in patients with sys- rd (CTD). VI. An inception cohort after 10 years: temic sclerosis. Acta Derm Venereol 1996; 76: 3 Department of Internal Medicine Labo- disease remissions and changes in diagnoses 21-3. ratory for helpful contributions to the study. in well established and undifferentiated CTD. 32. LUNDBERG AC, AKESSON A, AKESSON B: Di- We also thank Tamás Pásztor, MD, for al- J Rheumatol 1999; 26: 816-25. etary intake and nutritional status in patients lowing us to use the Isotope Diagnostic Lab- 17. KALLENBERG CG: Early detection of connec- with systemic sclerosis. Ann Rheum Dis 1992; oratory for the thyroid 5'-deiodinase assay. tive tissue disease in patients with Raynaud’s 51: 1143-8. phenomenon. Rheum Dis Clin North Am 1990; 33. GOMBERG-MAITLAND M, FRISHMAN WH: 16: 11-30. Thyroid hormone and cardiovascular disease. Reference 18. NAGY Z, CZIRJÁK L: Predictors of survival in Am J 1998; 135: 187-96. 1. AKIKUSA B, KONDO Y, LEMOTO Y, LESATO K, 171 patients with systemic sclerosis (sclero- 34. ROSEN A, CASCIOLA-ROSEN L, WIGLEY F: WAKASHIN M: Hashimoto’s thyroiditis and derma). Clin Rheumatol 1997; 16: 454-60. Role of metal-catalyzed oxidation reactions in membranous nephropathy developed in pro- 19. CALVO-ALÉN J, ALARCÓN GS, BURGARD SL: the early pathogenesis of scleroderma. Curr gressive systemic sclerosis (PSS). Am J Clin Systemic lupus erythematosus: Predictors of Opin Rheumatol 1997; 9: 538-43. Pathol 1984; 81:260-3. its occurrence among a cohort of patients with 35. CERINIC MM, GENERINI S, PIGNONE A: New 2. SERUP J, HANGDRUP H: Thyroid hormones in early undifferentiated connective tissue dis- approaches to the treatment of Raynaud’s phe- generalized scleroderma. A controlled study. ease. Multivariate analyses and identification nomenon. Curr Opin Rheumatol 1997;9:544-56. Acta Derm Venereol 1986; 66: 35-8. of risk factors. J Rheumatol 1996; 23: 469-75. 36. WIGLEY FM, FLAVAHAN NA: Raynaud’s phe- 3. GORDON MB, KLEIN I, DEKKER A, RODNAN 20. ALARCON GS, WILLIAMS GV, SINGER JZ: nomenon. Rheum Dis Clin North Am 1996; 22: GP, MEDSGER TAJ: in progres- Early undifferentiated connective tissue dis- 765-81. sive systemic sclerosis: increased frequency of ease. I. Early clinical manifestation in a large 37. KACZUR V, VEREB G, MOLNÁR I, KRAJCZÁR glandular fibrosis and hypothyroidism. Ann cohort of patients with undifferentiated con- G, KISS E, FARID NR, BALÁZS CS: Effect of Intern Med 1981; 95: 431-5. nective tissue diseases compared with cohorts anti-thyroid peroxidase (TPO) antibodies on 4. KAHL LE, MEDSGER TA, KLEIN I: Prospective of well established connective tissue disease. TPO activity measured by chemiluminescence evaluation of thyroid function in patients with J Rheumatol 1991; 18: 1332-9. assay. Clin Chem 1997; 43:1392-6. systemic sclerosis (scleroderma). J Rheumatol 21. LCROY EC, MEDSGER TA: Raynaud’s phenom- 38. GLEDHILL RF, DESSEIN PH, VAN DER MER- 1986; 13: 103-7. enon: A proposal for classification. Clin Exp WE CA: Treatment of Raynaud’s phenomenon 5. ARNAOUT MA, NASRALLAH NS, EL KHAT- Rheumatol 1992; 10: 485-8. with tri-iodothyronine corrects co-existent au- EEB MS: Prevalence of abnormal thyroid func- 22. HAMADA N, GRIMM C, MORI H, DEGROOT LJ: tonomic dysfunction: Preliminary findings. tion tests in connective tissue disease. Scand J Identification of a thyroid microsomal antigen Postgrad Med J 1992; 68: 263-7.

724