Fausto Bogazzi

More on smoking habits and Graves' ophthalmopathy.

Since a relationship between cigarette smoking and the occurrence of Graves’ ophthalmopathy has been recently postulated, we reviewed the smoking habits of 1730 women, including subjects without thyroid disease, with nontoxic goiter (NTG), toxic nodular goiter or toxic adenoma (TNG), Hashimoto’s thyroiditis (HT), Graves’ disease without ophthalmopathy (GD) or with ophthalmopathy (GO). The prevalence of smokers in NTG, TNG and HT was about 30%, not different from that of controls. Smokers were 47.9% in GD and 64.2% in GO groups. The latter figures were highly different from those of the other groups and also from each other. The percentage of heavy smokers was higher in patients with more severe ophthalmopathy. No clear explanation for this phenomenon can be offered. The absence of a high prevalence of smokers among patients with nontoxic goiter, nonautoimmune hyperthyroidism and Hashimoto’s thyroiditis, limits the impact that smoking might have had in the pathogenesis of goiter, hyperthyroidism and autoimmune phenomena of GD and GO.

Thyroid function differently affects serum cystatin C and creatinine concentrations.

Cystatin C (Cys C) is a cysteine protease inhibitor produced at a constant rate by nucleated cells, filtered through the glomerular membrane and reabsorbed by kidney tubular cells. Aim of this cross-sectional and longitudinal study was to assess serum Cys C and creatinine (Crea) concentrations in thyroid dysfunction. One hundred and eighty-one patients, 26 with untreated non-toxic nodular goiter, 58 with hyperthyroidism, 31 on L-T4 suppressive therapy for non-toxic nodular goiter, 35 with short-term hypothyroidism after L-T4 withdrawal to perform whole body scan for thyroid cancer, 11 with long-term hypothyroidism due to chronic autoimmune thyroiditis and 20 patients with mild hypothyroidism were enrolled in the study. Fifty-seven age- and sex-matched normal subjects served as controls. Serum Cys C, Crea, free T4 (FT4), FT3 and TSH were assessed. Thirty hyperthyroid patients and 35 short-term hypothyroid patients were followed prospectively until euthyroidism was reached by methimazole or L-T4 therapy. The cross-sectional study showed that mean serum Crea concentrations were significantly reduced in overt hyperthyroid or subclinical hyperthyroid patients, while it was increased in overt hypothyroid patients, but not in mild hypothyroidism. Conversely, serum Cys C levels were significantly increased in overt hyperthyroid patients compared to controls (p<0.05), and significantly decreased in short-term, long-term and mild hypothyroids (p<0.05, p<0.05, p<0.01, respectively). However, 36 (62%) hyperthyroid patients and 50 (76%) hypothyroid patients had normal serum Cys C values. In the prospective study, restoration of euthyroidism by either methimazole or L-T4 therapy was associated with normalization of mean serum Cys C concentrations. In conclusion, thyroid dysfunction affects serum Cys C concentration, possibly influencing the production rate of the protein. However, the observation that hyper- or hypothyroid patients have normal serum Cys C levels limits its use as a marker of peripheral thyroid hormone effect.

Effects of amiodarone administration during pregnancy on neonatal thyroid function and subsequent neurodevelopment

Amiodarone, a benzofuranic derivative, iodine-rich drug, has been used in pregnancy for either maternal or fetal tachyarrhythmias. Amiodarone, its main metabolite (desethylamiodarone) and iodine are transferred, albeit incompletely, through the placenta, resulting in a relevant fetal exposure to the drug and iodine overload. Since the fetus acquires the capacity to escape from the acute Wolff-Chaikoff effect only late in gestation, the iodine overload may cause fetal/neonatal hypothyroidism and goiter. Among the reported 64 pregnancies in which amiodarone was given to the mother, 11 cases (17%) of hypothyroidism in the progeny (10 detected at birth, 1 in utero) were reported, 9 non-goitrous (82%) and 2 (18%) associated with goiter. Hypothyroidism was transient in all cases, and only 5 infants were treated short-term with thyroid hormones. Only 2 newborns had transient hyperthyroxinemia, associated with low serum TSH concentrations in one. Neurodevelopment assessment of the hypothyroid infants, when carried out, showed in some instances mild abnormalities, most often reminiscent of the Non-verbal Learning Disability Syndrome; however, these features were also reported in some amiodarone-exposed euthyroid infants, suggesting that there might be a direct neurotoxic effect of amiodarone during fetal life. Breast-feeding was associated with a substantial ingestion of amiodarone by the infant, but in the few cases followed it did not cause changes in the newborn’s thyroid function. In conclusion, amiodarone therapy during pregnancy may cause fetal/neonatal hypothyroidism and, less frequently, goiter. Thus, the use of amiodarone in pregnancy should be limited to maternal/fetal tachyarrhythmias which are resistant to other drugs or life-threatening. If amiodarone is used during gestation, a careful fetal/neonatal evaluation of thyroid function and morphology is warranted. It seems prudent to advise that fetal/ neonatal hypothyroidism be treated, as soon as the diagnosis is made, even in utero, to avoid neurodevelopment abnormalities, although the latter may occur independently of hypothyroidism. If breast-feeding is allowed, careful evaluation of the infant’s thyroid function and morphology is required because of the continuing exposure of the infant to the drug.

Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress.

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased mark...

Orbital radiotherapy combined with high dose systemic glucocorticoids for Graves’ ophthalmopathy is more effective than radiotherapy alone: results of a prospective randomized study

We have carried out a prospective study to investigate whether orbital radiotherapy combined with high dose systemic glucocorticoids is more effective than orbital radiotherapy alone for Graves’ ophthalmopathy. Thirty consecutive patients with relevant and active Graves’ ophthalmopathy were randomly assigned to treatment either with orbital radiotherapy combined with systemic glucocorticoids (Group 1, n =15) or with orbital radiotherapy alone (Group 2, n = 15). The final evaluation was made 6–9 months after beginning treatment. Two patients in each group were lost to follow-up. Ocular involvement and response to treatment were evaluated by the ophthalmopathy index and by clinical assessment. Mean ophthalmopathy index values were 5.85 in Group 1 and 5.46 in Group 2 (p = NS) before treatment, and 2.46 in Group 1 and 3.61 in Group 2 after treatment (p = 0.0001 and p = 0.003 vs initial value, respectively). The mean ophthalmopathy index decrease in Group 1 (−3.39) was significantly greater (p = 0.043) than that in Group 2 (−1.85). Favorable responses on clinical ground occurred in 9 patients (69%) in Group 1 and in 5 patients (38%) in Group 2. The difference was particularly evident on soft tissue changes and extraocular muscle involvement. Severe eye muscle restriction was substantially unaffected by either treatment. In conclusion, the association of orbital irradiation and high dose systemic glucocorticoids in the treatment of severe Graves’ ophthalmopathy provides more favorable responses than orbital radiotherapy alone.

Approach to the Patient with Amiodarone-Induced Thyrotoxicosis

Amiodarone, a benzofuranic iodine-rich antiarrhythmic drug, causes thyroid dysfunction in 15-20% of cases. Although amiodarone-induced hypothyroidism poses no particular problem, amiodarone-induced thyrotoxicosis (AIT) is a diagnostic and therapeutic challenge. There are two main forms of AIT: type 1, a form of iodine-induced hyperthyroidism, and type 2, a drug-induced destructive thyroiditis. However, mixed/indefinite forms exist that may be caused by both pathogenic mechanisms. Type 1 AIT usually occurs in abnormal thyroid glands, whereas type 2 AIT develops in apparently normal thyroid glands (or small goiters). Diagnosis of thyrotoxicosis is easy, based on the finding of increased free thyroid hormone concentrations and suppressed TSH levels. Thyroid radioactive iodine (RAI) uptake values are usually very low/suppressed in type 2 AIT, most commonly low or low-normal, but sometimes normal or increased in type 1 AIT despite the iodine load. Color flow Doppler sonography shows absent hypervascularity in type 2 and increased vascularity in type 1 AIT. Mixed/indefinite forms may have features of both AIT types. Thionamides represent the first-line treatment for type 1 AIT, but the iodine-replete gland is not very responsive; potassium perchlorate, by inhibiting thyroid iodine uptake, may increase the response to thionamides. Type 2 AIT is best treated by oral glucocorticoids. The response very much depends on the thyroid volume and the severity of thyrotoxicosis. Mixed/indefinite forms may require a combination of thionamides, potassium perchlorate, and steroids. RAI is usually not feasible in AIT due to low RAI uptake values. Thyroidectomy represents a valid option in cases resistant to medical therapy.

High-dose intramuscular octreotide in patients with acromegaly inadequately controlled on conventional somatostatin analogue therapy: a randomised controlled trial

OBJECTIVE In acromegaly, 25-50% of patients respond inadequately to conventional long-acting somatostatin analogue (SSA) therapy. Response may be improved by increasing SSA frequency or dose. This study evaluated the biochemical efficacy and safety of high-dose octreotide in patients with acromegaly. DESIGN A 24-week prospective, multicentre, randomised, open-label trial conducted from 12 December 2005 to 23 October 2007 in patients with persistently uncontrolled acromegaly despite > or =6 month conventional SSA therapy. METHODS Patients with > or =50% reduction in GH levels during previous SSA treatment were randomised to high-dose (60 mg/28 days) or high-frequency (30 mg/21 days) octreotide i.m. injection. Primary end-points were week 12 and 24 reduction in serum IGF1 and GH from baseline. Secondary end points included IGF1 normalisation and tumour shrinkage rates, and safety/tolerability evaluations. RESULTS Significantly, more patients (10 out of 11) achieved week 24 IGF1 reduction in the high-dose than the high-frequency group (8 out of 15; P<0.05). In the high-dose group only, week-24 IGF1 values were significantly reduced (P=0.02) versus baseline. Normalisation of IGF1 occurred only with the high-dose regimen (4/11; P=0.02). Out of 14 patients experiencing adverse events, 5 reported drug-related gastrointestinal effects. No dose-response relationship was seen. Safety parameters were similar between treatment groups, apart from a slight decrease in HbA1c in the high-dose group only. CONCLUSION High-dose octreotide treatment is safe and effective (normalisation of IGF1 levels) in a subset of patients with active acromegaly inadequately controlled with long-term SSA. Individualised octreotide doses up to 60 mg/28 days may improve outcomes of SSA therapy.

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).

Adverse Effects of Thyroid Hormone Preparations and Antithyroid Drugs

SummaryThyroid hormone preparations, especially thyroxine, are widely used either at replacement doses to correct hypothyroidism or at suppressive doses to abolish thyrotropin (thyroid-stimulating hormone) secretion in patients with differentiated thyroid carcinoma after total thyroidectomy or with diffuse/ nodular nontoxic goitre. In order to suppress thyrotropin secretion, it is necessary to administer slightly supraphysiological doses of thyroxine. Possible adverse effects of this therapy include cardiovascular changes (shortening of systolic time intervals, increased frequency of atrial premature beats and, possibly, left ventricular hypertrophy) and bone changes (reduced bone density and bone mass), but the risk of these adverse effects can be minimised by carefully monitoring serum free thyroxine and free liothyronine (triiodothyronine) measurements and adjusting the dosage accordingly.Thionamides [thiamazole (methimazole), carbimazole, propylthiouracil] are the most widely used antithyroid drugs. They are given for long periods of time and cause adverse effects in 3 to 5% of patients. In most cases, adverse effects are minor and transient (e.g. skin rash, itching, mild leucopenia). The most dangerous effect is agranulocytosis, which occurs in 0.1 to 0.5% of patients. This life-threatening condition can now be effectively treated by granulocyte colony-stimulating factor administration. Other major adverse effects (aplastic anaemia, thrombocytopenia, lupus erythematosus-like syndrome, vasculitis) are exceedingly rare.

Amiodarone and the thyroid: a 2012 update.

Amiodarone-induced thyroid dysfunction occurs in 15–20% of amiodarone-treated patients. Amiodarone-induced hypothyroidism (AIH) does not pose relevant problems, is easily controlled by L-thyroxine replacement, and does not require amiodarone withdrawal. Most frequently AIH develops in patients with chronic autoimmune thyroiditis. Amiodarone-induced thyrotoxicosis (AIT) is most frequently due to destructive thyroiditis (type 2 AIT) causing discharge of thyroid hormones from the damaged, but otherwise substantially normal gland. Less frequently AIT is a form of hyperthyroidism (type 1 AIT) caused by the iodine load in a diseased gland (nodular goiter, Graves’ disease). A clearcut differentiation between the two main forms is not always possible, despite recent diagnostic advances. As a matter of fact, mixed or indefinite forms do exist, contributed to by both thyroid damage and increased thyroid hormone synthesis. Treatment of type 1 (and mixed forms) AIT is based on the use of thionamides, a short course of potassium perchlorate and, if treatment is not rapidly effective, oral glucocorticoids. Glucocorticoids are the first-line treatment for type 2 AIT. Amiodarone should be discontinued, if feasible from a cardiac standpoint. Continuation of amiodarone has recently been associated with a delayed restoration of euthyroidism and a higher chance of recurrence after glucocorticoid withdrawal. Whether amiodarone treatment can be safely reinstituted after restoration of euthyroidism is still unknown. In rare cases of AIT resistance to standard treatments, or when a rapid restoration of euthyroidism is advisable, total thyroidectomy represents a valid alternative. Radioiodine treatment is usually not feasible due to the low thyroidal iodine uptake.