Adriana Lai

Diagnosis and management of amiodarone‐induced thyrotoxicosis in Europe: results of an international survey among members of the European Thyroid Association

objective  To determine how expert European thyroidologists assess and treat amiodarone‐induced thyrotoxicosis (AIT).

Diagnosis and management of amiodarone-induced thyrotoxicosis : similarities and differences between North American and European thyroidologists

Objective  To investigate how North American thyroidologists assess and treat amiodarone‐induced thyrotoxicosis (AIT) and to compare the results with those of the same questionnaire‐based survey previously carried out among European thyroidologists.

Prevalence and natural history of Graves’ orbitopathy in the XXI century

Graves’ orbitopathy (GO) is an autoimmune disorder and the main extrathyroidal expression of Graves’ disease. There is a spectrum of ocular involvement in Graves’ disease, from complete absence of symptoms and signs to sight-threatening conditions. The prevalence of GO varies in different published series of Graves’ patients, due to confounding factors (new diagnosis vs long-lasting disease, way of defining and assessing ocular involvement, treatment of hyperthyroidism with potentially GO-modifying treatments, such as radioiodine). Recent studies, however, suggest that most Graves’ patients have mild or no GO at presentation, while moderate-to-severe GO is rare, and sight-threatening GO (mostly due to dysthyroid optic neuropathy) is exceptional in non-tertiary referral centers. The natural course of GO is incompletely defined, particularly in patients with moderate-to-severe GO, because these patients require prompt and disease-modifying therapies for orbital disease. In patients with mild GO at presentation, progression to severe forms is rare, while partial or complete remission is frequent. Progression of pre-existing GO or de novo occurrence of GO is more likely in smokers. There seems to be a trend towards a decline in progression of GO, possibly due to a better control of risk factors (cigarette smoking, thyroid dysfunction, etc.) and a closer interaction between endocrinologists and ophthalmologists allowing an improved integrated management of thyroid and orbital disease.

An update on medical management of Graves' ophthalmopathy.

Graves’ ophthalmopathy (GO), the most frequent extrathyroidal manifestation of Graves’ disease, is a disorder of autoimmune origin, the pathogenic mechanisms of which are still incompletely understood. Although GO is severe in only 3–5% of affected individuals, quality of life is severely impaired even in patients with mild GO. Management of severe GO can be either medical or surgical (orbital decompression, eye muscle or lid surgery). Medical management relies on the use of highdose systemic glucocorticoids or orbital radiotherapy, either alone or in combination. Studies carried out in the last 5 yr have shown that glucocorticoids are more effective through the iv route than through the oral route. However, particular attention should be paid to possible liver toxicity of iv glucocorticoids. Recent randomized clinical trials have, with one exception, confirmed that orbital radiotherapy is an effective and safe therapeutic procedure for GO. At variance with previous encouraging data, recent randomized clinical trials have shown that currently available SS analogs are not very effective in the management of GO. Antioxidants might have a role, at least in mild forms of GO. Particular attention should be paid to correction of risk factors (cigarette smoking, thyroid dysfunction, radioiodine therapy) involved in GO progression.

Relationship between management of hyperthyroidism and course of the ophthalmopathy

The relationship between treatment for hyperthyroidism and course of Graves’ ophthalmopathy (GO) has been and still is a matter of debate. Literature often presents conflicting data, due to several influencing factors, such as selection bias, nonrandomized and uncontrolled or retrospective features of many studies, non-standardized evaluation of ocular changes. However, it seems clear that neither antithyroid drug treatment nor thyroidectomy affect the natural course of GO, while radioiodine therapy may cause, in about 15% of cases, GO progression. The latter is more likely in patients who smoke, have pre-existing GO and more severe hyperthyroidism, or whose post-radioiodine hypothyroidism is not promptly corrected by L-thyroxine. GO progression after radioiodine therapy can be prevented by concomitantly treating patients with glucocorticoids, thus making radioiodine therapy a safe procedure also in GO patients. The presence of GO should not, therefore, influence the choice of treatment for hyperthyroidism. Should antithyroid drug treatment or thyroidectomy be selected for patients with mild ophthalmopathy, no treatment for GO is necessary, while a short course of moderate doses of glucocorticoids is advised if radioiodine therapy is chosen. In patients with severe GO, treatment of hyperthyroidism and management of GO proceed independently of each other, and either definitive (radioiodine or thyroidectomy) or conservative (antithyroid drugs) treatment for hyperthyroidism can be selected while treating GO. The authors’ preference goes to the former, because it depletes intrathyroidal autoreactive T lymphocytes and removes thyroid antigens, which are likely to be involved in the pathogenesis of autoimmune reactions of the ophthalmopathy.

Novel immunomodulating agents for Graves orbitopathy.

Graves orbitopathy (GO), the major extrathyroidal expression of Graves disease, is a disorder of autoimmune origin. Although its natural history is incompletely understood, it undergoes an initial period of inflammation (active phase), then stabilizes (plateau or static phase), and finally spontaneously remits (inactivation phase). Remission is, however, inevitably partial, and residual cosmetic and/or functional ocular abnormalities are responsible for a marked impairment in the quality of life of affected individuals. The ideal situation would be to prevent GO occurrence, but this is impossible under most circumstances. Nevertheless, an active control of factors such as cigarette smoking and thyroid dysfunction, which are known to be associated with an increased risk of GO occurrence and exacerbation (Table 1), is essential. When GO is mild and its activity is low, an expectant strategy (“wait-and-see”) may be justified, and treatment may be limited to topical agents (artificial tears, ointments, prisms). When GO is full-blown, active, and moderate to severe, its management still relies after many decades on the use of glucocorticoids, most commonly given intravenously, with or without associated orbital radiotherapy. Inactive (burnt-out) GO is not responsive to immunosuppressive therapy and may require orbital decompression, if exophthalmos is severe with corneal exposure, or dysthyroid optic neuropathy is present. Because many patients ultimately are unhappy with treatment outcome, rehabilitative surgery (orbital decompression, squint surgery, eyelid surgery) for cosmetic and/or functional disturbances is needed in at least one third of patients. Thus, medical therapy of GO has changed very little in the last 30 to 40 years and still is based on “jurassic” treatments. What are the reasons for this disappointing lack of progress? Several factors contribute to it, including the incomplete understanding of GO pathogenesis, and late intervention, the latter often being related to the lack of a “global” strategy for the management of thyroid disease and eye disease. Early intervention is a major issue, because medical treatment is effective only in the active phase of the disease and should possibly be applied within 1 year from the onset of GO. The pathogenesis of GO is incompletely understood. The leading pathogenic hypothesis, which takes in account the association and temporal link of thyroid disease and orbital disease, is that GO is an autoimmune disorder triggered by autoreactive T-lymphocytes reacting with 1 or more antigens shared by thyroid and orbital tissues. According to this hypothesis, intrathyroidal autoreactive T-lymphocytes might reach the orbit, where they recognize the common antigen (or antigens) presented by antigen-presenting cells, such as dendritic cells, macrophages and B-lymphocytes. After antigen recognition, a cascade of events would be triggered, leading to secretion of a number of cytokines, which, in turn, stimulate fibroblast proliferation, preadipocyte differentiation in adipocytes, and secretion of glycosaminoglycans from fibroblasts. The latter, in view of their hydrophilic features, attract water leading to edema of periocular tissue. The increased orbital content (fibroadipose tissue, extraocular muscles infiltrated by inflammatory cells) explain mechanically most clinical manifestations of GO. Experimental evidence supports this hypothesis. For example, autologous T-lymphocytes of GO patients can stimulate proliferation of orbital fibroblasts, and this effect requires overexpression of class II major histocompatibility complex antigens and costimulators on antigen-presenting cells, because it can be abrogated by coexposure to antibodies to class II major histocompatibility complex or CD40. Different patterns of cytokine production from orbital T-cells have been reported, with a prevalent T-helper (Th)1 pattern [secretion of interleukin (IL)-2, interferon, Accepted for publication January 9, 2008. Presented by Professor Bartalena as a plenary lecture at the 38th Annual Fall Meeting of the American Society of Ophthalmic Plastic and Reconstructive Surgery, New Orleans, LA, November 9–10, 2007. This work was partially supported by grants from the Italian Ministry of University and Research (MUR, Rome) and the University of Insubria at Varese to Luigi Bartalena. Address correspondence and reprint requests to Luigi Bartalena, Department of Clinical Medicine, University of Insubria, Division of Endocrinology, Ospedale di Circolo, Viale Borri, 57, 21100 Varese, Italy. E-mail: l.bartalena@libero.it or luigi.bartalena@uninsubria.it

Plasma total and acylated Ghrelin concentrations in patients with clinical and subclinical thyroid dysfunction

Background: Results of circulating Ghrelin levels in hyper- or hypothyroidism are conflicting and only overt thyroid dysfunction has been evaluated. Aim: To evaluate in a large number of patients with thyroid disfunction whether: a) hyper- and hypothyroidism (clinical or subclinical) are associated with variations in both acylated (AG) and total Ghrelin (TG) concentrations, and b) correction of thyroid dysfunction is followed by variations in Ghrelin concentrations. Subjects and methods: Seventy-six hyperthyroids, 52 hypothyroids, 144 euthyroids with chronic autoimmune thyroiditis, and 109 euthyroid healthy controls were evaluated cross-sectionally and longitudinally. Results: TG and AG were significantly lower in hyperthyroids than in controls or hypothyroids; the latter 2 groups did not differ. TG was significantly lower in overt than in subclinical hyperthyroids. with a trend to a reduction also in AG levels. No differences were found between subclinical hyperthyroids and controls. After thionamide treatment, TG and AG levels in hyperthyroids did not differ from controls. L-thyroxine management of hypothyroidism was not associated with significant Ghrelin variations. Plasma Ghrelin was independent of either thyroid or gastric autoimmunity. Plasma TG was negatively correlated with serum free thyroid hormone levels in hyperthyroids but not in hypothyroids. Conclusions: Plasma Ghrelin concentrations are reduced in overt but not in subclinical hyperthyroidism and normalize after restoration of euthyroidism. Hypothyroidism is not accompanied by significant changes in circulating Ghrelin.

Solitary intrathyroidal metastasis of renal clear cell carcinoma in a toxic substernal multinodular goiter

IntroductionThyroid gland is a rare site of clinically detectable tumor metastasis.Case reportA 71-year-old woman was referred to our department for an evaluation of toxic multinodular substernal goiter. She had a history of renal clear cell carcinoma of the left kidney, which had been resected 2 years previously. US confirmed the multinodular goiter. Total thyroidectomy with neuromonitoring was performed on March 2008. A histological examination revealed a solitary metastasis of a clear cell renal cancer in a diffuse multinodular goiter. No distant metastases are detected.ConclusionAlthough uncommon, it is important for the endocrine surgeon and endocrine oncologist to be able to recognize and differentiate intrathyroid metastases from more primary common thyroid neoplasms. The diagnosis can be suspected if the patient has a thyroid tumor and a past history of extrathyroid cancer. These tumors, on the whole, tend to behave more aggressively and, in most cases, the use of multimodality therapy is recommended.

Relation between Graves’ orbitopathy and radioiodine therapy for hyperthyroidism: facts and unsolved questions*

Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease, resulting from a complex and incompletely understood interplay between endogenous factors and environmental factors. 1 Environmental factors probably play a major role and should adequately be controlled to avoid development or, at least, progression of GO. 2 The relation between radioiodine (RAI) therapy for hyperthyroidism and the course of GO has long been debated. 1

An update on the pharmacological management of hyperthyroidism due to Graves’ disease

Pharmacological treatment, usually by thionamides (carbimazole, methimazole, propylthiouracil) is, in addition to radioiodine therapy and thyroidectomy, one of the available therapies for Graves’ hyperthyroidism. Thionamides represent the treatment of choice in pregnant women, during lactation, in children and adolescents and in preparation for radioiodine therapy or thyroidectomy. Side effects are relatively frequent but are in general mild and transient. Two main regimens are available: titration method (use of the lowest dose maintaining euthyroidism; duration: 12 – 18 months) and block-and-replace method. Neither one has clear advantages in terms of outcome but the latter method is associated with more frequent side effects. Hyperthyroidism relapses in ∼ 50% of patients, to whom ablative therapy should be offered.