Luca Manetti

Cigarette Smoking and Treatment Outcomes in Graves Ophthalmopathy

Cigarette smoking is a risk factor for Graves ophthalmopathy [1]. Ophthalmopathy is more frequent and tends to be more severe in smokers than in nonsmokers [2]. Smoking may influence ophthalmopathy through direct irritative effects or by modulating immune reactions that occur in Graves ophthalmopathy [1]. Radioiodine therapy for Graves hyperthyroidism seems to be associated with an increased risk for progression of ophthalmopathy [3-5], but this view is not shared by all investigators [6, 7]. Discrepant results may be related to confounding variables, one of which may be smoking. Severe Graves ophthalmopathy can be treated with medical therapy, usually by glucocorticoids with or without orbital radiation therapy or by orbital decompression [8]. Results of medical treatment are not always satisfactory, and the reasons for nonuniform treatment outcome are not fully understood. We sought to determine whether cigarette smoking influences the untoward effects of radioiodine therapy on ophthalmopathy and the effectiveness of medical therapy for severe ophthalmopathy. Methods Patients Study 1 Study 1 included 300 patients receiving radioiodine treatment for Graves hyperthyroidism with mild or no ophthalmopathy. Mild ophthalmopathy was defined as proptosis less than 22 mm, intermittent or no diplopia, absence of optic neuropathy, and mild conjunctival and periorbital inflammation. Exclusion criteria were severe ophthalmopathy, large goiter requiring thyroidectomy, and contraindications to glucocorticoids. The 300 patients, who previously took part in a study analyzing the effect of radioiodine on ophthalmopathy [5], were assigned by computer-generated random numbers to treatment with radioiodine alone or radioiodine followed by a 3-month course of oral prednisone (initial dosage, 0.4 to 0.5 mg/kg of body weight per day) [3]. Five patients in the radioiodine plus prednisone group were lost to follow-up. Smoking habits did not differ in the two groups. Study 2 This retrospective study included 150 consecutive patients with severe ophthalmopathy (110 women and 40 men; mean age, 41 years [range, 30 to 63 years]) treated from 1989 to 1995 with orbital radiation therapy (20 Gy per eye) and high-dose oral prednisone (initial dose, 80 to 100 mg) [9]. The prednisone dose was gradually tapered, and therapy was discontinued after 6 months. Severe ophthalmopathy was defined as proptosis of 22 mm or more, inconstant or constant diplopia, and marked inflammatory soft-tissue changes with or without optic neuropathy. The study was approved by the institutional review board, and informed consent was obtained from patients. Smoking Habits The number of cigarettes smoked was measured in pack-years, expressed as x = a x b/c, where a = number of cigarettes smoked per day, b = number of years of smoking, and c = 20 cigarettes per pack. Patients who had refrained from smoking for less than 1 year were considered smokers. Smokers were subdivided into light ( 10 pack-years), moderate (11 to 19 pack-years), and heavy smokers ( 20 pack-years). Ocular Evaluation Ocular evaluation, performed by one examiner who was blinded to treatment and smoking groups, included assessment of soft-tissue changes; measurement of proptosis (by Hertel exophthalmometry), ocular tension, and lid width; evaluation of eye muscle function (Hess chart or computerized perimetry); and determination of visual acuity. The activity score was determined according to the method of Mourits and colleagues [10], which includes consideration of seven manifestations (spontaneous retrobulbar pain, pain with eye movements, eyelid erythema, eyelid edema, conjunctival injection, chemosis, and swelling of the caruncle); one point was given to any manifestation, for a score from 0 (no activity) to 7 (very high activity). Each patient provided a self-assessment evaluation sheet. Appearance, progression, and alleviation of ophthalmopathy were defined according to major and minor criteria [5]. Major criteria were variations in exophthalmometer readings and lid width of 2 mm or more, diplopia (intermittent, inconstant, or constant), variations in activity score of 2 points or more, and changes in visual acuity of 1/10 or more. Minor criteria were variations in soft tissues or self-assessment. Appearance, progression, and alleviation of ophthalmopathy were defined by changes in at least two major criteria and one minor criterion [5]. Statistical Analysis Differences in the prevalence of smokers in the two studies were analyzed by using a chi-square test with Yates correction for continuity. Exact binomial 95% CIs were calculated for all proportions. Patients in study 1 were included in an intention-to-treat analysis in which the effects of radioiodine or radioiodine plus prednisone on ophthalmopathy were evaluated according to the predefined criteria outlined above. Role of the Study Sponsor Neither funding source had a role in the collection, analysis, or interpretation of the data or in the decision to submit the paper for publication. Results Study 1 Among patients who received radioiodine alone, 23 (15.3% [95% CI, 10% to 22%]) had progression of ophthalmopathy. Ocular conditions were unchanged in the remaining 127 patients [5]. Among patients who received radioiodine plus prednisone, 0 had progression and 50 of 75 (66.7% [CI, 55% to 77%]) had alleviation of eye disease [5]. In the group that received radioiodine alone, ophthalmopathy progressed in 4 of 68 nonsmokers (5.9% [CI, 3% to 9%]) and 19 of 82 smokers (23.2% [CI, 13% to 33%]) (P = 0.007). In the group that received radioiodine plus prednisone, ophthalmopathy was alleviated in 37 of 58 nonsmokers (63.8% [CI, 51% to 78%]) and 13 of 87 smokers (14.9% [CI, 10% to 22%]) (P < 0.001) (Table 1). Table 1. Smoking Behavior and Outcome of Mild Graves Ophthalmopathy Study 2 Of 150 consecutive patients, 85 (57%) were smokers. Sixty patients (40%) had an excellent or good response to therapy and 59 (39.3%) had a moderate response. Ophthalmopathy remained unchanged in 26 patients (17.3%) and progressed in 5 (4.3%). Duration of ophthalmopathy did not differ among groups. Sixty-one of 65 nonsmokers (93.8% [CI, 90% to 98%]) and 58 of 85 smokers (68.2% [CI, 57% to 78%]) (P < 0.001) responded to therapy (Table 2). Thirty-three of the 58 smokers who responded to therapy (56.9% [CI, 45% to 68%]) and 5 of 27 nonresponders (18.5% [CI, 9% to 29%]) were light smokers (P = 0.01). Table 2. Smoking Behavior and Outcome of Treatment of Severe Graves Ophthalmopathy with Orbital Radiation Therapy and High-Dose Glucocorticoids Discussion The results of our randomized study showed that cigarette smoking was associated with progression of mild ophthalmopathy, seen in 15% of patients after radioiodine therapy. In addition, smoking was associated with reduced efficacy of glucocorticoids given concomitantly with radioiodine. In the retrospective study, smoking and degree of smoking seemed to adversely affect the outcome of orbital radiation therapy and high-dose glucocorticoid treatment in patients with severe ophthalmopathy. Cigarette smoking is a risk factor for Graves ophthalmopathy. The prevalence of smoking is higher in patients with Graves disease who have ophthalmopathy than in those who do not have ophthalmopathy [1], and some [2, 11, 12] but not all [13] studies show a relation between degree and duration of smoking and severity of ophthalmopathy. Tallstedt and associates [4] reported that progression of ophthalmopathy after radioiodine therapy was more frequent in smokers than in nonsmokers, although differences were not statistically significant. Similarly, in a small series of Chinese women, Kung and coworkers [14] found no differences between smokers and nonsmokers in the progression of ophthalmopathy after radioiodine therapy. The differences between our results and those of previous studies may be explained by the larger number of patients and the consequent greater power of our study. Ethnic factors may also be important: Asian patients have a lower risk for ophthalmopathy, and the prevalence of smoking among Asian women is low [11]. Medical management of severe ophthalmopathy mostly relies on orbital radiation therapy or treatment with high-dose steroids, but results are not always favorable [8]. This may be related to several factors, including the long duration or limited activity of ophthalmopathy [8]. Our results suggest that smoking also negatively affects treatment outcome. Of note, several smokers in study 1 had no progression of ophthalmopathy after radioiodine therapy, and the condition improved with concomitant prednisone treatment. Similarly, in study 2, several smokers had excellent or good responses to orbital radiation therapy and high-dose glucocorticoid therapy. This implies that cigarette smoking is only one of many risk factors involved in the progression of ophthalmopathy. Identification of such risk factors should be a goal of future research so that treatment may be improved and disease may be prevented. The mechanisms by which cigarette smoking may affect the course of Graves ophthalmopathy and its response to treatment are largely unknown [1]. Besides having direct irritative effects, smoking may affect immune reactions occurring in the retro-orbital space [15]. Cytokines present in the retro-orbital tissues of patients with Graves ophthalmopathy [16] exert several actions relevant to the pathogenesis of the disease, including induction of expression of MHC class II molecules, heat-shock proteins, and adhesion molecules [16]. Cytokines also stimulate orbital fibroblasts to proliferate and to secrete glycosaminoglycans; the latter are responsible for most manifestations of the disease [15]. Smoking may intervene in cytokine-mediated paracrine and autocrine actions because smoking-induced hypoxia in the retrobulbar space stimulates the release of cytokines [17]. Interleukin-1 may play a pivotal role in this context, and interleuki

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.

Microvascular density and vascular endothelial growth factor expression in normal pituitary tissue and pituitary adenomas

Microvessel density (MVD) represents a measure of angiogenesis and may be used as an indicator of neoplastic aggressiveness. Vascular endothelial growth factor (VEGF) plays a pivotal role as angiogenic promoter by stimulating endothelial cell proliferation and migration and enhancing vascular permeability. The aim of this study was to investigate MVD and VEGF expression in human pituitary adenomas and normal pituitary gland tissues by immunohistochemistry, and to correlate data with clinical characteristics. Fragments from 46 pituitary adenomas (18 non-functioning, 12 ACTH-secreting, 12 GH-secreting, 4 PRL-secreting) and 19 specimens of normal anterior pituitary gland obtained at surgery were evaluated. MVD in normal anterior pituitary was significantly higher than in tumors (69.2±28.5 vs 29.3±19.7; p<0.0001). Within adenomas, no difference was found in MVD when different histotype, size, sex, age, rate of recurrence or medical pre-surgical treatment were considered. The degree of vascularity was somewhat related only to clinical invasiveness, as evaluated by pre-surgical MRI grading (grade 0 p<0.05 vs grade 1 and vs grade 2). No statistically significant difference in VEGF expression was found between normal tissue and adenomas and among tumors of different histotype (p= 0.3978). Size, sex, age, rate of recurrence and medical pre-surgical treatment did not influence VEGF expression. No correlation was found between MVD and VEGF expression. In conclusion, MVD was reduced in pituitary adenomas with respect to normal gland. VEGF expression is however well preserved in adenomas and this might contribute to adequate tumoral vascular supply with complex mechanisms other than endothelial cells proliferation.

Prevalence of thyroid diseases in patients with acromegaly: results of an Italian Multi-center Study

Acromegaly is frequently associated with the presence of thyroid disorders, however the exact prevalence is still controversial. An Italian multicenter study was performed on 258 patients with active acromegaly (high levels of IGF-I and lack of suppression of serum GH levels below 2 μg/l after an OGTT). The control group was represented by 150 patients affected by non-functioning and PRL-secreting pituitary adenomas. Two hundred and two out of 258 acromegalic patients (78%) were affected by thyroid disorders with a significantly higher prevalence with respect to the control group (27%, p<0.0001). One hundred and three patients presented (39.9%) non-toxic nodular goiter, 46 (17.8%) non-toxic diffuse goiter, 37 (14.3%) toxic nodular goiter, 1 toxic diffuse goiter (0.4%), 12 (4.6%) Hashimoto’s thyroiditis, 3 (1.2%) thyroid cancer. Two patients presented a co-secreting TSH pituitary adenoma. Thirty-six patients had been previously treated for various thyroid abnormalities. Among the 222 acromegalic patients never treated for thyroid disorders thyroid ultrasonography was performed on 194 subjects. Thyroid volume in patients with thyroid abnormalities was 28±17.5 ml (median 23) while it was 10.8±3.6 ml (median 10) in patients without thyroid disorders (p<0.0001). Thyroid volume was correlated with the estimated duration of acromegaly (r=0.7, p<000.1), but not with age or with serum GH, IGF-I and TSH concentrations. Thyroid volume was higher in acromegalic patients than in the above control population (23.5±16.9 ml vs 13.9±12.8 ml, p<0.0001). In 62 acromegalic patients 101 fine-needle biopsies of thyroid nodules were performed; 7 nodules were suspicious and the patients were submitted to thyroid surgery: papillary thyroid carcinoma was found in 3 patients. In conclusion, in a large series of acromegalic patients an increased prevalence of thyroid disorders (78%), particularly non-toxic nodular goiter, has been observed. Thyroid volume, evaluated by ultrasonography, was correlated to the estimated duration of acromegaly. Finally, the prevalence of thyroid carcinoma was slightly increased than in the general population.

Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery

OBJECTIVES To evaluate whether patients with Cushings syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE). DESIGN Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery. PATIENTS AND METHODS Forty patients with active CS (36 with Cushings disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery. RESULTS CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, α(2) antiplasmin, P=0.0004, thrombin-antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and α(2) antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushings pituitary adenoma had VTE (P=0.04). CONCLUSIONS Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

Cabergoline therapy and the risk of cardiac valve regurgitation in patients with hyperprolactinemia: a meta-analysis from clinical studies

Dopamine agonists have been associated with increased risk of cardiac valve regurgitation in patients with Parkinson’s disease. Whether these drugs might be harmful for patients with hyperprolactinemia is still unsettled. Occasional case reports and 7 studies on the relationship between cabergoline and cardiac valve regurgitation have been published so far. Overall, cabergoline has been considered a safe therapy, although some studies suggested an increased prevalence of cardiac valve regurgitation. The aim of this meta-analysis was to assess the effects of cabergoline on cardiac valve regurgitation. Eligible studies were all trials using cabergoline in patients with either tumor or non-tumor hyperprolactinemia. Our search was updated to October 2008. Pooled data from the 6 selected studies showed that treatment with cabergoline was associated with increased risk of tricuspid valve regurgitation (fixed effects: prevalence ratio=1.40; 95% confidence interval: 1.17-1.67); on the contrary, patients treated with cabergoline and control subjects did not differ in prevalence of aortic or mitral valve regurgitation. This meta-analysis shows that patients with hyperprolactinemia treated with cabergoline are at increased risk of regurgitation of the tricuspid valve. However, regurgitation was only an echocardiographic finding since no patient had symptoms of valvular disease. This meta-analysis underscores that echocardiography is recommended in all patients with hyperprolactinemia who are candidate to be treated with or are under cabergoline therapy; monitoring cardiac valves is also recommended although precise follow-up for these patients will be likely provided by future longitudinal studies.

Usefulness of salivary cortisol in the diagnosis of hypercortisolism: comparison with serum and urinary cortisol

OBJECTIVE Several tests have been proposed to diagnose patients with Cushings syndrome (CS). The aims of the study were: i) to evaluate the performance of salivary cortisol (SC) in hypercortisolism and ii) to compare SC with serum cortisol (SeC) and urinary cortisol. DESIGN AND PATIENTS This was a diagnostic study. Twenty-seven patients with untreated Cushings disease (CD untr), 21 women consuming oral contraceptive pill (OCP), 18 pregnant women, and 89 healthy subjects (controls) were enrolled. METHODS SC and SeC at baseline and after the low-dose dexamethasone suppression test (LDDST) and urinary free cortisol (UFC) were measured. RESULTS Midnight SC had a sensitivity of 100% in the CD untr group and a specificity of 97.7% in the controls. Specificity remained high (95.2%) in women taking OCP, while in pregnant women, it decreased to 83.3%. SC after the LDDST showed a sensitivity of 96.3% in the CD untr group; specificity was 97.7% in the controls and 90.5% in OCP women. Midnight SeC had a sensitivity of 100% in the CD untr group. SeC after the LDDST had a sensitivity of 100% in the CD untr group while specificity was 97.7% in the controls and 61.9% in women taking OCP. For UFC, sensitivity was 92.6% in the CD untr group while specificity was 97.7% in the controls and 100% in the OCP group. CONCLUSIONS SC is a reliable parameter for the diagnosis of severe hypercortisolism, with high sensitivity and specificity. In women during pregnancy or taking OCP, the measurement of SC, identifying the free fraction, could be helpful to exclude CS.

Effects of medical therapies for acromegaly on glucose metabolism

OBJECTIVE Abnormalities of glucose metabolism are common findings of acromegaly. However, robust evidence on whether therapy with somatostatin analogs (SSAs) or pegvisomant (PEG) differently affects glucose metabolism is lacking. The purpose of this study was to evaluate the effects of therapy with SSAs, PEG, or their combination on glucose metabolism in a large series of acromegalic patients. DESIGN This was a historical-prospective study. Among 50 consecutive acromegalic patients under SSA therapy, acromegaly in 19 patients was controlled. PEG used in combination with SSA therapy allowed the control of acromegaly in the remaining 31 patients and was then continued as monotherapy in 18 patients. METHODS The following parameters were evaluated at the diagnosis of acromegaly and during DIFFERENT TREATMENTS: fasting plasma glucose (FPG) and insulin concentrations, insulin sensitivity (QUICK-I), homeostasis model assessment of insulin resistance (HOMA2-IR), and plasma glucose and insulin concentrations during the oral glucose tolerance test (OGTT). Comparison was made using analysis for paired data. RESULTS Insulin resistance improved when acromegaly was controlled with therapy with SSAs, PEG, or SSA+PEG. However, FPG concentrations were higher during SSA therapy (alone or combined with PEG) than at the diagnosis of acromegaly, even when corrected for disease activity, whereas they were reduced during PEG therapy. Mean glucose concentrations during the OGTT were higher in patients receiving SSA therapy than in those receiving PEG therapy. In addition, the prevalence of diabetes or impaired glucose tolerance was higher during SSA therapy than at diagnosis or during PEG therapy and was not influenced by disease control. CONCLUSIONS Medical therapies for acromegaly reduce insulin resistance and increase insulin sensitivity; on the contrary, glucose indexes may be differently affected by SSA or PEG therapy.

Diagnosis and treatment of autoimmune hypophysitis: A short review

Medical therapy of autoimmune hypophysitis with immunosuppressive drugs can be effective to induce remission of the disease by treating both pituitary dysfunction and compression symptoms. We describe the case of a 41-yr-old man with autoimmune hypophysitis in whom prednisone therapy induced remission of the disease but was followed by a sudden relapse after withdrawal. A second trial of corticosteroid was started and succeeded in inducing remission of the disease. Eight months after the second withdrawal pituitary function was restored, pituitary mass had disappeared, only partial diabetes insipidus remained unchanged. Review of the literature identified 30 articles, among case reports and case series, reporting a total of 44 cases of autoimmune hypophysitis treated with glucocorticoids and/or azathioprine. Combining all the cases, medical therapy resulted to be effective in reducing the pituitary mass in 84%, in improving anterior pituitary function in 45%, and in restoring posterior pituitary function in 41 %. Clinical aspects of autoimmune hypophysitis are discussed and a possible algorithm for the diagnosis and treatment of the disease is proposed.

Adrenal morpho-functional alterations in patients with acromegaly

Acromegaly is associated with a greater morbidity and higher incidence of tumors, possibly due to the permissive role of elevated GH and IGF-I levels. In the general population, adrenal masses are frequently discovered (prevalence 1–5%) at computed tomography (CT). We evaluated the prevalence of adrenal lesions in patients with acromegaly. We studied 94 acromegalic patients, 54 females (mean age 55.0±16.0 yr) and 40 males (mean age 50±14 yr) referred to 5 Endocrinology Units between 2001–2003; 49 had active disease and 45 had been treated with surgery and/or were controlled with medical therapy. Abdominal CT showed adrenal lesions in 27 patients; 9 of them had unilateral masses (10%) with benign features (diameter 0.5–3 cm) and 18 had hyperplasia (14 monolateral and 4 bilateral), with no significant differences between patients with active vs controlled disease, and with no correlation between prevalence of masses and duration of disease, GH and IGF-I levels. Hormone study (urinary free cortisol, catecholamines/metanephrines, upright plasma renin activity and aldosterone, morning plasma ACTH and low-dose dexamethasone suppression test) disclosed no major endocrine alterations. During a 1-yr follow-up, the adrenal masses increased in size in 3 cases and 1 patient also developed subclinical Cushing’s syndrome. Adrenal lesions seem more frequent in acromegaly than in the general population, but no single factor (GH/IGF-I levels or disease duration) predicts them. The masses appear to be benign and non-hypersecreting, but a longer follow-up is recommended to disclose any changes in their morphofunctional state