In this article, the two authors present their opposing points of view concerning the likelihood that glucocorticoids will be replaced by newly developed biological agents in active, moderate to severe thyroid-associated ophthalmopathy (TAO). TAO is a vexing, disfiguring and potentially blinding autoimmune manifestation of thyroid autoimmunity. One author expresses the opinion that steroids are nonspecific, frequently fail to improve the disease, and can cause sometimes serious side-effects. He suggests that glucocorticoids should be replaced as soon as possible by more specific and safer drugs, once they become available. The most promising of these are biological agents. The other author argues that glucocorticoids are proven effective and are unlikely to be replaced by biologicals. He reasons that while they may not uniformly result in optimal benefit, they have been proven effective in many reports. He remains open minded about alternative therapies such as biologicals but remains skeptical that they will replace steroids as the first line therapy for active, moderate to severe TAO without head-to-head comparative clinical trials demonstrating superiority. Despite these very different points of view, both authors are optimistic about the availability of improved medical therapies for TAO, either as single agents or in combination. Further, both agree that better treatment options are needed to improve the care of our patients with active moderate to severe TAO.
Terry J Smith and Luigi Bartalena
Luigi Bartalena, Sandra Brogioni, Lucia Grasso and Enio Martino
Interleukins are proteins belonging to the family of cytokines, which are soluble pleiotropic mediators known to intervene quantitatively and qualitatively in the regulation of the immune response (1), in the orchestration of complex processes such as inflammation, hematopoiesis and wound healing (2), and also in normal physiological functions including bone formation and resorption (3) and the endometrial cycle (4).
Lymphocytes, macrophages and fibroblasts are the most important sources of cytokines, the synthesis of which takes place also in numerous other cell types, including brain, pituitary, gastrointestinal tract, kidney and adrenal glands (see Ref. 5 for a review). Cytokines can exert their action locally as paracrine or autocrine factors but are also capable of acting as hormone-like substances at sites distant from their synthesis, affecting various cell functions and enabling communication among different cell types, representing a link between the neuroendocrine system and the immune system (6).
The effects of several
Maria Laura Tanda, Fausto Bogazzi, Enio Martino and Luigi Bartalena
Enio Martino, Furio Pacini, Paolo Vitti and Luigi Bartalena
Percutaneous ethanol injection (PEI) has been proposed for the management of small hepatocellular carcinomas as an alternative modality of treatment devoid of the complications related to surgery in this kind of patient (1–4). Likewise, PEI has been used for liver and peritoneal metastases of abdominal tumors (1), offering the possibility to attack lesions unlikely to be controlled by surgery and/or chemotherapy. The mechanism of action of ethanol appears to be related to cellular dehydration followed by coagulative necrosis and vascular thrombosis and occlusion.
On the other hand, the use of PEI has also been proposed for non-malignant nodular lesions, such as parathyroid adenomas causing either primary (5, 6) or secondary (7) hyperparathyroidism. This modality of treatment appears to be particularly suitable for patients with chronic renal failure in whom the surgical risk of parathyroidectomy is high.
In 1990, Livraghi et al. (8) suggested that autonomous single thyroid nodules can be
Luca Tomisti, Giuseppe Rossi, Luigi Bartalena, Enio Martino and Fausto Bogazzi
Considering the different pathogenic mechanisms of the two main forms of amiodarone-induced thyrotoxicosis (AIT), we ascertained whether this results in a different onset time as well.
Design and methods
We retrospectively analyzed the clinical records of 200 consecutive AIT patients (157 men and 43 women; mean age 62.2±12.6 years) referred to our Department from 1987 to 2012. The onset time of AIT was defined as the time elapsed from the beginning of amiodarone therapy and the first diagnosis of thyrotoxicosis, expressed in months. Factors associated with the onset time of AIT were evaluated by univariate and multivariate analyses.
The median onset time of thyrotoxicosis was 3.5 months (95% CI 2–6 months) in patients with type 1 AIT (AIT1) and 30 months (95% CI 27–32 months, P<0.001) in those with type 2 AIT (AIT2). Of the total number of patients, 5% with AIT1 and 23% with AIT2 (P=0.007) developed thyrotoxicosis after amiodarone withdrawal. Factors affecting the onset time of thyrotoxicosis were the type of AIT and thyroid volume (TV).
The different pathogenic mechanisms of the two forms of AIT account for different onset times of thyrotoxicosis in the two groups. Patients with preexisting thyroid abnormalities (candidate to develop AIT1) may require a stricter follow-up during amiodarone therapy than those usually recommended. In AIT1, the onset of thyrotoxicosis after amiodarone withdrawal is rare, while AIT2 patients may require periodic tests for thyroid function longer after withdrawing amiodarone.
Luigi Bartalena, Lucia Grasso, Sandra Brogioni and Enio Martino
Bartalena L, Grasso L, Brogioni S, Martino E. Interleukin 6 effects on the pituitary–thyroid axis in the rat. Eur J Endocrinol 1994;131:302–6. ISSN 0804–4643
It has been postulated recently that cytokines, and in particular interleukin 1 (IL-1) and tumor necrosis factor-α TNF-α), may have a role in the pathogenesis of the changes of serum thyroid hormone concentrations that are encountered in patients with non-thyroidal illness (NTI). Many of the IL-1 and TNF-α effects are believed to be mediated by the induction of IL-6 synthesis, which might, therefore, represent an important mediator of thyroid hormone changes in NTI. To address this problem, male Wistar rats were injected subcutaneously with 2.5 μg of recombinant human IL-6 (rhIL-6, in 500 μl of saline solution), with 2.5 μg of rhIL-6 preincubated with 100 μl of anti-IL-6 neutralizing antibody or with saline solution alone (control group). Administration of rhIL-6 resulted in a significant decrease of thyroxine (T4) from 82 ± 4 nmol/l (mean± sem) to a nadir of 33 ± 3 nmol/l (p < 0.0001) after 48 h, and of triiodothyronine (T3) from 1.6 ± 0.1 to 0.8 ± 0.1 nmol/l after 48 h (p < 0.0001). A slight decrease in serum T4 and T3 concentrations also was observed in the control group, but the lowest values (T4, 66 ± 3 nmol/l; T3, 1.2 ± 0.1 nmol/l) were significantly higher (p < 0.0001) than in IL-6-treated rats. The IL-6-induced changes could be prevented by preincubation of rhIL-6 with its neutralizing antibody. Slight but not significant changes occurred in serum reverse T3 (rT3) concentration, so that the T4/rT3 ratio remained substantially unchanged after rhIL-6 injection, whereas the T4/T3 ratio decreased significantly from 53.6 to 39.9 (p < 0.02) in IL-6-treated rats. The effects of IL-6 on thyrotropin (TSH) were investigated after rendering the rats hypothyroid by methimazole administration for 3 weeks. Serum TSH decreased from 19.0 ± 6.8 to 13.3 ± 3.8 μg/l after 48 h (p < 0.01) in IL-6-treated rats, while it increased from 17.2 ± 2.8 to 25.8 ± 4.0 μg/l (p < 0.01) in the control group. These results show that a single injection of rhIL-6 causes a decrease in serum T4, T3 and TSH concentrations in the rat, without affecting serum rT3 levels. This is compatible with a predominantly central effect of the cytokine. The apparent lack of inhibition of 5′-deiodinating activity, a key feature of NTI, suggests that IL-6, if involved, is only one of the factors responsible for the changes of thyroid hormone secretion and metabolism observed in NTI.
Luigi Bartalena, Istituto di Endocrinologia, University of Pisa, Viale del Tirreno 64, 56018 Tirrenia-Pisa, Italy
Luigi Bartalena, Maria L Tanda, Eliana Piantanida and Adriana Lai
Luigi Bartalena, Fausto Bogazzi, Maria Laura Tanda, Luca Manetti, Enrica Dell'Unto and Enio Martino
The effects of smoking on the function of endocrine glands have been investigated extensively but still are to be elucidated fully. It is widely recognized that the most important component of the smoke produced from the burning of tobacco, in terms of endocrine effects, is nicotine. Nicotine acts through the interaction with acetylcholine receptors, but it seems likely that others among the numerous smoke products may somehow influence endocrine homeostasis.
The present paper will focus on the relationship between smoking and variations in thyroid economy or the occurrence of thyroid dysfunction.
Several studies have been carried out to ascertain whether smoking is associated with variations in thyroid economy. The rationale for these investigations was dictated by the observation that smoking is associated with a decrease in body mass, and, conversely, refrain from smoking is often accompanied by an increase in body mass (1). These changes might be mediated
Elio Roti, Luigi Bartalena, Roberta Minelli, Mario Salvi, Eliana Gardini, Antonio Pistolesi, Enio Martino and Lewis E Braverman
Roti E, Bartalena L, Minelli R, Salvi M, Gardini E, Pistolesi A, Martino E, Braverman LE. Circadian thyrotropin variations are preserved in normal pregnant women. Eur J Endocrinol 1995;133:71–4. ISSN 0804–4643
Serum thyrotropin (TSH) concentration circadian rhythm is abolished in many endocrine and nonendocrine diseases. In the present study we have measured serum TSH concentration over 24 h every 2 h in second and third trimester pregnant women. During the 24-h period, serum free thyroxine and free triiodothyronine concentrations did not change significantly. In contrast, serum TSH concentrations demonstrated significant circadian variations both in the second and third trimester pregnant women (p<0.02 and p <0.005, respectively). In summary, second and third trimester pregnancy is associated with a normal circadian TSH rhythm.
Elio Roti, Centro per lo Studio, Prevenzione, Diagnosi e Cura delle Tireopatie, University of Parma, via Gramsci 14, 1-43100 Parma, Italy
Elisabetta Cecconi, Maurizio Gasperi, Maura Genovesi, Fausto Bogazzi, Lucia Grasso, Filomena Cetani, Massimo Procopio, Claudio Marcocci, Luigi Bartalena and Enio Martino
Objective: To investigate, in a large group of postmenopausal primary hyperparathyroidism (PHP) women, whether the concomitance of GH deficiency (GHD) may contribute to the development of changes in bone mineral density (BMD).
Design: GH secretion, bone status and metabolism were investigated in 50 postmenopausal women with PHP and in a control group of 60 women with no evidence of PHP, matched for age, age at menopause and body mass index (BMI).
Methods: GH response to growth hormone-releasing hormone (GHRH)+arginine (Arg), femoral neck BMD (g/cm2) by dual energy X-ray absorptiometry, BMI, serum-ionized calcium, parathyroid hormone (PTH) and markers of bone remodelling were evaluated in all patients and controls.
Results: Among PHP patients, GH secretion was reduced (8.8 ± 4.2 μg/l, range 1.1–16.5 μg/l) in 34 patients and normal (28.7 ± 11.8 μg/l, range 17.9–55.7 μg/l) in the remaining 16 (P < 0.05), no women in the control group had GHD (peak GH 33.8 ± 10.9 μg/l, range 21.7 ± 63.2 μg/l). Osteoporosis (T-score < − 2.5) and osteopenia (T-score > −2.5 and < −1) were found in 73.5 and 17.6% of GHD patients, in 37.5 and 43.7% of patients with normal GH secretion and 3.1 and 27% of controls. T-score and BMD were not correlated with ionized calcium, age, age at menopause, BMI, GH peak and IGF-I but were correlated with serum PTH levels in both groups. T-score was correlated with serum levels of markers of bone remodelling only in PHP patients with GHD.
Conclusions: Concomitant impairment of GH secretion may play a pathogenetic role in the occurrence of changes in bone mass observed in PHP and contribute to make them more severe.