Most patients with Graves' disease have some degree of ocular involvement, but only 3-5% of them develop severe ophthalmopathy (1). The reasons why only such a minority of patients with Graves' disease have severe expression of the ophthalmopathy remain to be elucidated. One possible explanation is that non-severe ophthalmopathy and severe ophthalmopathy are two different disorders with different genetic backgrounds; alternatively, they might be part of a spectrum of different conditions ranging from absent ocular involvement to most severe ophthalmopathy. In this case, external variables (i.e. environmental factors) must contribute to the nature of the expression of the disease. How important are they? How far can our intervention on environmental factors go towards reducing the risk of progression of the ophthalmopathy? In other words, to which extent, if any, is Graves' ophthalmopathy preventable? The aim of this mini-review is to address the above issues.
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L Bartalena, C Marcocci, and A Pinchera
SJ Bonnema, L Bartalena, AD Toft, and L Hegedus
In routine use for more than 50 years, radioiodine ((131)I) is generally considered safe and devoid of major side effects. Therefore, it is surprising that relatively many aspects of radioiodine therapy are controversial, as illustrated by recent international questionnaire studies. Our review aims at highlighting three of these areas - namely, the influence of (131)I on the course of Graves' ophthalmopathy, the possible radioprotective effects of antithyroid drugs, and the use of (131)I in large goitres. (131)I therapy carries a small (but definite) risk of causing progression of Graves' ophthalmopathy. Identification of risk factors (thyroid dysfunction, high level of thyroid-stimulating hormone (TSH) receptor antibodies, cigarette smoking) allows the identification of patients at risk and the institution of concomitant glucocorticoid treatment, thereby hindering progression of eye disease. On the basis, largely, of retrospective data, it appears that carbimazole (or methimazole), if stopped 3-5 days before treatment, does not influence the outcome of (131)I therapy. Simultaneous thyrostatic medication most probably reduces the efficacy of (131)I, as does restarting it within 7 days. Propylthiouracil seems to have a more prolonged radioprotective effect than carbimazole. Surgery is the treatment of first choice in patients with a large goitre. However, in the case of patient ineligibility or preference, (131)I therapy may be an option. The treatment has a favourable effect on tracheal compression and inspiratory capacity, but the reduction in thyroid volume is only 30-40%. Inpatient treatment, necessitated by the large doses, makes the treatment cumbersome. Controversy related to radioiodine therapy is mainly based on the lack of adequate prospective randomised studies comparing efficacy, side effects, cost and patient satisfaction.
L Bartalena, F Bogazzi, S Brogioni, L Grasso, and E Martino
C. Marcocci, L. Bartalena, F. Bogazzi, M. Panicucci, and A. Pinchera
Abstract. Eye disease was associated with hyperthyroidism in 202 of 221 patients with active Graves' ophthalmopathy (91.4%) and was not accompanied by thyroid hyperfunction (euthyroid Graves' disease) in the remaining 19 (8.6%). All the latter patients had some mild thyroid abnormalities (thyroid autoantibodies, negative TRH test, negative T3 suppression test, goitre). Sex distribution analysis evidenced a higher prevalence in females with a female/male ratio of 2.1 which was, however, significantly lower (P < 0.05) than that observed in control (Graves' disease patients without overt ophthalmopathy (female/male ratio = 3.4)). Patients with euthyroid Graves' disease showed a female/male ratio of 0.7. Age distribution revealed a peak prevalence in the 5th decade of life, identical to that of Graves' disease without ophthalmopathy. A close temporal relationship between the onset of hyperthyroidism and the onset of ophthalmopathy was found, since in about 85% of the patients the first ocular manifestations occurred within ±18 months around the onset of hyperthyroidism.
Luigi Bartalena, Maria L Tanda, Eliana Piantanida, and Adriana Lai
F Bogazzi, L Bartalena, S Brogioni, A Burelli, L Manetti, ML Tanda, M Gasperi, and E Martino
OBJECTIVE: Thyroid blood flow is greatly enhanced in untreated Graves' disease, but it is not known whether it is due to thyroid hormone excess or to thyroid hyperstimulation by TSH-receptor antibody. To address this issue in vivo patients with different thyroid disorders were submitted to color flow doppler sonography (CFDS). SUBJECTS AND METHODS: We investigated 24 normal subjects, and 78 patients with untreated hyperthyroidism (49 with Graves' hyperthyroidism, 24 with toxic adenoma, and 5 patients with TSH-secreting pituitary adenoma (TSHoma)), 19 patients with thyrotoxicosis (7 with thyrotoxicosis factitia, and 12 with subacute thyroiditis), 37 euthyroid patients with goitrous Hashimoto's thyroiditis, and 21 untreated hypothyroid patients with Hashimoto's thyroiditis. RESULTS: Normal subjects had CFDS pattern 0 (absent or minimal intraparenchimal spots) and mean intraparenchimal peak systolic velocity (PSV) of 4.8+/-1.2cm/s. Patients with spontaneous hyperthyroidism due to Graves' disease, TSHoma, and toxic adenoma had significantly increased PSV (P<0.0001, P=0.0004, P<0.0001 respectively vs controls) and CFDS pattern. Patients with Graves' disease had CFDS pattern II (mild increase of color flow doppler signal) in 10 (20%) and pattern III (marked increase) in 39 cases (80%). Mean PSV was 15+/-3cm/s. Patients with toxic adenoma had CFDS pattern I (presence of parenchymal blood flow with patchy uneven distribution) in 2 (8%), pattern II in 16 (70%) and pattern III in 5 (22%). Mean PSV was 11+/-2.4cm/s. Patients with TSHoma showed CFDS pattern I in one case (20%) and pattern II in 4 (80%). Mean PSV was 14.8+/-4.2cm/s. Patients with thyrotoxicosis had normal PSV (4.2+/-1. 1cm/s in subacute thyroiditis, 4+/-0.8cm/s in thyrotoxicosis factitia, P=not significant vs controls) and CFDS pattern 0. Untreated euthyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern 0, and mean PSV (4.3+/-0.9cm/s; P=not significant vs controls). Untreated hypothyroid patients with goitrous Hashimoto's thyroiditis had CFDS pattern I in 14 cases (67%), pattern II in 4 (19%) and pattern 0 in 3 (14%) and mean PSV (5.6+/-1. 4cm/s) was higher than that of controls (P=0.026). CONCLUSIONS: An increase in both intrathyroidal vascularity and blood velocity was observed in patients with spontaneous hyperthyroidism but not in thyrotoxicosis due to either ingestion of thyroid hormones or to a thyroidal destructive process. The slightly increased vascularity and blood velocity observed in patients with hypothyroid Hashimoto's thyroiditis suggests that thyroid stimulation by either TSH-receptor antibody or TSH is responsible for the increased thyroid blood flow.
F Bogazzi, L Bartalena, S Brogioni, A Burelli, F Raggi, F Ultimieri, C Cosci, M Vitale, G Fenzi, and E Martino
OBJECTIVE: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. MATERIALS AND METHODS: The reporter construct ME-TRE-TK-CAT or TSHbeta-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHbeta genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRbeta into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)beta. RESULTS: Addition of 1 micromol/l T4 or T3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5- and 12.5-fold respectively. Amiodarone or DEA (1 micromol/l) increased CAT activity by 1.4- and 3.4-fold respectively. Combination of DEA with T4 or T3 increased CAT activity by 9.4- and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRbeta was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 micromol/l DEA decreased the T3-dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T3), whereas amiodarone was ineffective. Addition of 1 micromol/l DEA to T3-containing medium reduced the T3-TR-mediated down-regulation of TSH-TRE to 55%. CONCLUSIONS: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.
E. Martino, L. Bartalena, S. Mariotti, F. Aghini-Lombardi, C. Ceccarelli, F. Lippi, M. Piga, A. Loviselli, L. Braverman, M. Safran, and A. Pinchera
Abstract. Amiodarone, an iodine-rich drug, represents at the present, at least in Europe, one of the most common sources of iodine-induced thyroid dysfunction. The drug may induce both hypothyroidism and thyrotoxicosis. In spite of the large iodine intake occurring during amiodarone therapy, 131I thyroid uptake is detectable in patients with amiodarone-iodine-induced hypothyroidism, irrespective of the presence or absence of underlying thyroid disease. In contrast, in patients with amiodarone-iodine-induced thyrotoxicosis, 131I thyroid uptake is normal or even elevated in those with co-existent underlying thyroid disorders, whereas it is very low in those with an apparently normal thyroid gland. Perchlorate discharge test was performed in 8 patients with hypothyroidism and in 5 patients with hyperthyroidism induced by amiodarone: a positive test was found in all hypothyroid patients and a negative test in all hyperthyroid patients.
F Bogazzi, F Ultimieri, F Raggi, D Russo, R Vanacore, C Guida, P Viacava, D Cecchetti, G Acerbi, S Brogioni, C Cosci, M Gasperi, L Bartalena, and E Martino
OBJECTIVE: The objective of the study was to evaluate the expression and functional activity of Peroxisome proliferator-activated receptor (PPAR) gamma in pituitary adenomas from 14 consecutive acromegalic patients and to establish its role in apoptosis. SUBJECTS AND METHODS: Fourteen consecutive acromegalic patients were enrolled in the study. Wistar-Furth rats were used for in vivo studies. Expression of PPARgamma was evaluated by RT-PCR and Western blot. Apoptosis and cell cycle were assessed by FACS analysis. The effects of PPARgamma ligands on transcriptional regulation of GH gene were evaluated by RT-PCR and electromobility shift assay. RESULTS: PPARgamma was expressed in all human GH-secreting adenoma (GH-oma), in normal pituitary tissue samples (39+/-24% and 78+/-5% of immunostained nuclei respectively; P<0.0002; ANOVA), and in rat GH-secreting (GH3) cells. A PPRE-containing reporter plasmid transfected into GH3 cells was activated by ciglitazone or rosiglitazone (TZDs), indicating that PPARgamma was functionally active. Treatment of GH3 cells with TZDs increased apoptosis in a dose-dependent manner (P=0.0003) and arrested cell proliferation, reducing the number of cells in the S-phase (P<0.0001 vs untreated cells). TZDs increased the expression of TRAIL, leaving unaffected that of p53 and Bax. TZDs reduced GH concentrations in the culture media from 43.7+/-5.4 ng/ml to 2.1+/-0.3 ng/ml (P<0.0001) and in cell extracts (P<0.004). PPARgamma-RXRalpha heterodimers bound to GH promoter, inhibiting its activity and reducing GH mRNA levels (1.8 x 10(6) vs 5.7 x 10(6) transcripts respectively vs untreated cells; P<0.002). Subcutaneous GH-oma developed in rats injected with GH3 cells; tumor growth increased in placebo-treated rats and to a lesser extent in TZDs-treated animals (24.1+/-2.0 g, and 14.8+/-4.2 g respectively, P<0.03). Serum GH concentrations were lower in TZDs-treated rats than in controls (871+/-67 ng/ml vs 1.309+/-238 ng/ml; P<0.05). CONCLUSIONS: The results of this study indicate that PPARgamma controls GH transcription and secretion as well as apoptosis and growth of GH-oma; thus, TZDs have the potential of a useful tool in the complex therapeutic management of acromegalic patients.
L Bartalena, G J Kahaly, L Baldeschi, C M Dayan, A Eckstein, C Marcocci, M Marinò, B Vaidya, W M Wiersinga, and EUGOGO
Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.