M. L. Tanda

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.

Long-term outcome of thyroid function after amiodarone-induced thyrotoxicosis, as compared to subacute thyroiditis

Background: Two main forms of amiodarone-induced thyrotoxicosis (AIT) exist: type 1 AIT is a condition of true hyperthyroidism developing in patients with pre-existing thyroid disorders, and usually requires thyroid ablative treatment. On the other hand, type 2 AIT is a form of destructive thyroiditis occurring in normal thyroids, the management of which usually consists in glucocorticoid treatment. Aim: To assess the long-term outcome of thyroid function in a prospective study of type 2 AIT patients, as compared to patients with De Quervain’s subacute thyroiditis (SAT). Patients and Methods: Sixty consecutive patients with type 2 AIT were evaluated during oral glucocorticoid treatment (oral prednisone 30 mg/day, gradually tapered and withdrawn over a 3-month period) and followed for 38±4 months (range 6–72) thereafter. Sixty consecutive patients with SAT, referred to our Institutes during the same period and treated with the same therapeutic schedule, served as controls. Results: Type 2 AIT patients were older (p<0.0001) and showed a larger male preponderance (M:F 3.6:1 vs 0.5:1, p<0.0001) than SAT patients. Mean serum free T4 (FT4) and free T3 (FT3) concentrations at diagnosis were increased in both conditions, but higher in type 2 AIT than in SAT (FT4 47.6±18.8 and 29.6±8.3 pmol/l, respectively, p<0.0001; FT3 15.4±7.0 and 11.2±3.0 pmol/l, respectively, p<0.001). Correction of thyrotoxicosis was obtained in all patients in both groups, but restoration of euthyroidism occurred earlier in SAT than in type 2 AIT (p=0.006). Ten type 2 AIT patients (17%) and 3 SAT patients (5%, p<0.03) became permanently hypothyroid after glucocorticoid withdrawal and required levothyroxine replacement. Conclusions: A relevant proportion of type 2 AIT patients develop permanent hypothyroidism after correction of thyrotoxicosis. Thus, periodic surveillance of thyroid status is required after type 2 AIT.

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.

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.

Potassium perchlorate only temporarily restores euthyroidism in patients with amiodarone-induced hypothyroidism who continue amiodarone therapy

Context: Amiodarone-induced hypothyroidism (AIH) may occur in patients with or without underlying thyroid disorders. In the latter, restoration of euthyroidism, after amiodarone discontinuation, can be facilitated and accelerated by a short course of potassium perchlorate (KClO4). However, it is unknown whether KClO4 may exert similar effects on thyroid function of AIH patients if amiodarone treatment is continued. Objective: To evaluate the effects of KClO4 on thyroid function in AIH patients (without underlying thyroid disease) while continuing amiodarone treatment. Design and patients: An open, prospective study of 10 consecutive AIH patients without underlying thyroid abnormalities referred to a tertiary referral center, and treated with KClO4 (600 mg/day) for a period of 26±13 days (range, 15–45 days). An additional, historical group of 12 consecutive patients with subclinical AIH left untreated while continuing or after withdrawing amiodarone was retrospectively evaluated as to the outcome of thyroid function. Measurement: Serum free T4, free T3, and TSH concentrations were measured at booking, during KClO4 treatment and after withdrawing the drug. Results: In the prospective study, KClO4 treatment restored euthyroidism in all patients within 28±11 days (range, 15–45 days). After KClO4 with drawal, however, all patients became hypothyroid again after 45±15 days (range, 30–60 days). Two patients developed mild leukopenia (1 case) or a slight increase in serum creatinine levels (1 case), which promptly normalized after KClO4 withdrawal. In the historical group, followed for at least 12 months, euthyroidism was spontaneously and stably achieved after an average of 6 months in 5 patients in whom amiodarone could be discontinued, while subclinical hypothyroidism persisted in 7 patients in whom amiodarone had to be continued. Conclusions: KClO4 very effectively restores normal thyroid function in AIH patients without underlying thyroid abnormalities, despite the fact that amiodarone therapy is continued. However, euthyroidism does not persist after KClO4 is withdrawn; in addition, spontaneous recovery of euthyroidism does not seem to occur in this subset of AIH patients, unless amiodarone is discontinued. Therefore, also in view of its potential side-effects, KClO4 cannot be recommended as a first-line treatment for AIH if amiodarone needs to be continued, while LT4 replacement is recommended under these circumstances, with periodical reassessment of thyroid function.

Pituitary apoplexy during pregnancy: a rare, but dangerous headache

Pituitary apoplexy is a rare endocrine emergency that occurs in a small number of patients with a pituitary tumor. It is a clinical syndrome characterized by the sudden onset of headache, nausea, vomiting, visual impairment, and decreased consciousness, caused by hemorrhage and/or infarction of the pituitary gland. Pituitary apoplexy has very rarely been described during pregnancy, when it is potentially life-threatening to both the mother and the fetus, if unrecognized. Only a few cases have been published to date. The review of the existing literature underlines that pituitary apoplexy, although rare, should be borne in mind when a pregnant woman presents with severe headache and visual defects of sudden onset. After initial management, which includes intravenous glucocorticoid therapy, fluid and electrolyte replacement, the final selection of medical or surgical treatment should result from a multidisciplinary approach involving expert specialists, keeping into account both severity of clinical presentation and gestational week.

Endpoints for screening thyroid cancer in the Republic of Korea: thyroid specialists’ perspectives

AbstractCancer screening is aimed primarily at reducing deaths from the specific cancer. Thyroid-specific cancer mortality may be the most ambitious endpoint for obtaining estimates of screening effect. Numerous observations have accumulated over the years, indicating that thyroid cancer mortality endpoint has been difficult to study and is confounded by population heterogeneity, provision of randomization, and requirement of large cohorts with sufficiently long follow-up due to the excellent prognosis of the cancer. Accordingly, it may be important to reconsider how to best measure thyroid cancer screening efficacy. Recommendations against thyroid cancer screening should be based upon trials designed to evaluate its effectiveness not only in significant reduction in cancer mortality, but also of other distinct endpoints. It is desirable to evaluate derivative endpoints that can reliably predict reductions in mortality. The term “derivative” means a variable that is related to the true endpoint and is likely to be observable before the primary endpoint. Derivative endpoints may include thyroid cancer incidence, the proportion of early-stage tumors detected, more treatable stage, the identification of small tumors (to maintain in observation), decrease in the number of people who develop metastatic disease, the increased chance of lesser extent surgery, and the application of minimally invasive approaches, as well as no need for lifelong thyroid replacement therapy, a consistent follow-up, low-dose or no RAI administration and risk factor assessments where case findings should be continuous. The Korean guidelines for thyroid cancer national-level screening were published by a relevant group of multidisciplinary thyroid experts. It was concluded that the evidence is insufficient to balance the benefits and harms of thyroid cancer screening. However, the paper seems to raise the necessary investments in future research and demand a complete analysis for derivative endpoints, and offer screening participants with complete information necessary to make decisions that will provide them with the most value when a small thyroid cancer is screen-identified.

Physical performance in newly diagnosed hypothyroidism: a pilot study

ObjectiveHypothyroidism is complicated by neuromuscular symptoms (myalgias, slowness of movements, and tiredness) and signs (easy fatigability and cramps), which may have a negative impact on general well-being and quality of life. In a pilot, prospective, controlled study, we investigated the features of muscle dysfunction in hypothyroidism by disease questionnaire, biochemical measures, and physical performance tests.Materials and MethodsFifty-seven consecutive patients with newly diagnosed hypothyroidism were enrolled, 27 subclinical (S-Hypo) and 30 overt (O-Hypo). A series of 30 euthyroid subjects, with similar demographic characteristics, served as controls. Patients were administered a short disease questionnaire and underwent laboratory exams and standardized physical tests, both at baseline and after restoration of biochemical euthyroidism.ResultsCompared to euthyroid controls, the O-Hypo group showed significantly higher prevalence of neuromuscular symptoms and significantly higher serum creatine phosphokinase (CPK) levels (p value < 0.0001). S-Hypo had slightly higher CPK levels and prevalence of neuromuscular symptoms than controls. Both S-Hypo and O-Hypo patients performed worse than controls in the six-minute walking test. Differences between patients and controls in handgrip strength test and timed chair standing test failed to reach statistical significance (although a trend was noticeable), possibly due to the small sample size. In O-Hypo, an inverse correlation was found between CPK levels and the handgrip strength test (p value < 0.001). Restoration of euthyroidism was associated with normalization of questionnaire responses, six-minute walking test, as well as serum CPK levels.ConclusionIn addition to neuromuscular symptoms, hypothyroidism is associated with abnormalities of physical performance. The six-minute walking test is the most valuable test to assess this aspect. In the pilot study, levothyroxine therapy could reverse muscle functional abnormalities.