Letizia Maria Fatti

Prevalence and pathogenesis of sleep apnea and lung disease in acromegaly

Respiratory disorders are common and important complications in acromegaly. Patients suffering from acromegaly display a 1.6–3.3 fold increase in mortality rate, which is due to respiratory disorders in 25% of cases. In these patients, mortality for lung disease is 2–3 fold higher than in the general population. Every portion of the respiratory system may be involved. Deformities of facial bones, edema and hypertrophy of the mucosae and pharyngeal and laryngeal cartilages, enlargement of the tongue and inspiratory collapse of the hypopharinx, all may contribute to respiratory alterations. Nasal polyps, “hormonal rhinitis”, changes of the voice and snoring are common occurrences. Though rarely, a laryngocele may ensue. Pneumomegaly is frequently observed and, as suggested by functional studies, might be due to an increased number rather than volume of the alveoli. An obstructive respiratory syndrome caused by mucosal thickening of the upper airways and bronchi is observed in 25% of female and 70% of male patients. The sleep apnea syndrome (SAS) affects 60–70% of acromegalic patients. SAS may be of obstructive, central or mixed type. Obstructive SAS is the prevailing form in acromegaly. It is due to intermittent obstruction of upper airways with preserved activity of the respiratory center, as testified by the remarkable thoracic and abdominal respiratory efforts. The pathogenesis of the central type of SAS is more complex. Narrowing of the upper airways may induce reflex inhibition of the respiratory center. Moreover, increased GH levels and, possibly, defects in the somatostatinergic pathways, may increase the ventilatory response of the respiratory center to carbon dioxide, thereby leading to respiratory arrest. In the mixed type of SAS, the phenomena underlying the other two forms coexist. Oxygen desaturation concomitant with the apneic episodes accounts for the frequent nocturnal wakening and diurnal drowsiness. Among the clinical correlates of SAS, arterial hypertension is of particular interest due to the close correlation existing between the two disorders. Sleep deprivation related to SAS seems per se to favor the appearance of hypertension. Moreover, short lasting hypoxemia may induce prolonged elevations of blood pressure, mediated by decreased endothelial generation of nitric oxide. Thus, since cardiovascular events are the main cause of mortality in patients with acromegaly, it is reasonable to hypothesize that SAS is involved in the reduced life span of these patients.

Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome

Patients with active Cushing’s syndrome have an increased thrombotic tendency. We chose to reassess the mechanism underlying the thrombophilic state associated with this clinical condition using sensitive markers of coagulation and fibrinolysis activation in 17 patients with active disease. The results were compared with those obtained in 12 Cushing’s patients successfully treated by surgery and in 20 normal individuals. The general pattern of results in patients with active disease was the finding of increased levels of von Willebrand factor (VWF: Ag), a marker of enhanced metabolic function of endothelial cells (VWF:Ag 181±42 vs 110±43, p<0.001 in normal subjects), accompanied by signs of heightened thrombin and plasmin generation, expressed by high levels of thrombin-antithrombin (TAT 5.59±3.6 vs 3.06±0.92 ng/ml in controls, p<0.01) and plasmin-antiplasmin complexes (PAP 407±176 vs 245±67 ng/ml in controls, p<0.01). VWF:Ag and TAT values were significantly higher in hypertensive than in normotensive patients with active disease (205±40 vs 155±26 U/dl, p<0.05 and 7.49±3.7 vs 3.45±1.8, p<0.01, respectively). Plasma levels of plasminogen activator inhibitor type 1 were higher, though not to a statistically significant extent, in patients with active disease compared to controls (12.8±12.3 vs 5.6±7.4 IU/ml, NS) and positively correlated with body mass index (r=0.66, p<0.01). After surgical control of Cushing’s syndrome, there was a partial or complete reversal of the abnormalities to values similar to those found in normal individuals. Our data suggest that the thrombophilic state present in patients with active Cushing’s syndrome is related to an enhanced metabolic function of endothelial cells; this in turn may be caused by an heightened production of thrombin with secondary hyperfibrinolysis. Primary prophylaxis with anticoagulants is recommended in these patients when they are exposed to a thrombophilic condition such as surgery.

Effects of treatment with somatostatin analogues on QT interval duration in acromegalic patients

Objective  Cardiovascular disease is a major contributor to the increased mortality of acromegalic patients. Prolongation of the QT interval is considered an established risk factor for potentially fatal cardiac arrhythmias, an event frequently observed in acromegaly. Changes in ventricular repolarization have been observed with the use of octreotide, one of the somatostatin analogues (SSA) currently used for the medical treatment of this disease. Furthermore, octreotide is listed among the drugs able to prolong the QT interval. Thus, we elected to study the effects of long‐term SSA administration on QT duration and left ventricular mass (LVM) in a group of acromegalic patients.

Elastosonographic evaluation of thyroid nodules in acromegaly

OBJECTIVE Ultrasound-elastography (US-E) appears to be a helpful tool for the diagnosis of thyroid cancer. In acromegaly, the prevalence of thyroid cancer is still debated. The aims of this study were to evaluate thyroid nodules in acromegaly and to establish the accuracy of US-E in providing information on their nature, using cytological analysis as a reference. SUBJECTS AND METHODS US-E was applied to 90 nodules detected in 25 acromegalic patients and to 94 nodules found in 31 non-acromegalic goitrous subjects. The lesions were classified according to the elasticity scores (ES) as soft (ES 1-2) or hard (ES 3-4). Fine needle aspiration cytology could be performed in 60.8% of hard nodules in acromegalics and in 86.7% of hard nodules in controls. RESULTS The prevalence of hard nodules was significantly higher in the whole group of acromegalic patients than in controls (56.8 vs 16.0%, P<0.0001). The prevalence of hard nodules in patients with active acromegaly (68.9%) was greater, though not to a statistically significant extent, than that observed in cured (44.4%) and controlled (52.5%) patients. Cytology revealed malignancy or suspect malignancy in four of the nodules of non-acromegalic subjects and in none of the nodules of acromegalic patients. CONCLUSIONS This study has demonstrated a high prevalence of stiff thyroid nodules in acromegaly, greater than that found in non-acromegalic goitrous subjects. In acromegalics, hard nodules appeared not to be malignant on cytopathological examination and are probably of fibrous nature. Thus, US-E appears to be of limited value for the diagnosis of thyroid cancer in acromegaly.

Screening for hypothyroidism in older hospitalized patients with anemia: a new insight into an old disease.

to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. She was involved in study concept and design, acquisition of all data, analysis and interpretation of all data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Dr. Arfanakis was involved with acquisition of neuroimaging data, interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual contact. Drs. Kelly, Buchman, Morris, and Barnes were involved with acquisition of serum data, interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Dr. Bennett was involved with acquisition of neuroimaging and participant data, interpretation of the data, drafting of the manuscript, and critical revision of the manuscript for important intellectual content. Ms. Rajendran was involved in study concept and design; acquisition, postprocessing, analysis, and interpretation of all data; and drafting of the manuscript. Sponsor’s Role: The sponsors had no role in the design of the study, the collection or interpretation of the data, or in the preparation of the manuscript.

The diagnosis of GH deficiency in obese patients: a reappraisal with GHRH plus arginine testing after pharmacological blockade of lipolysis

BACKGROUND The diagnosis of GH deficiency (GHD) in obese patients is complicated by the reduced GH secretion associated with overweight. A GH response to GHRH+arginine lower than 4.2 microg/l is currently considered indicative of GHD in obesity. The aim of the study was to investigate the effect of acute pharmacological blockade of lipolysis on the GH response to GHRH+arginine in obese patients. PATIENTS AND METHODS Two groups of patients were studied: 12 obese patients with proven GHD and 14 patients with essential obesity. On separate occasions, two tests were carried out in each patient: GHRH+arginine and GHRH+arginine preceded by acipimox. RESULTS The mean GH peak after GHRH+arginine was significantly lower in hypopituitary patients than in subjects with essential obesity. Acipimox significantly increased the mean GH response in patients with essential obesity, but not in hypopituitary subjects. All hypopituitary patients and 7/14 patients with essential obesity displayed GH peaks lower than 4.2 microg/l after GHRH+arginine: the GH response to the test increased after acipimox pretreatment in five of these seven essentially obese subjects. After acipimox administration, free fatty acids (FFAs) significantly fell in both groups with comparable mean absolute decreases. All IGF1 values were normal in both groups of subjects. CONCLUSIONS Our study has demonstrated that the acipimox-induced acute reduction of circulating FFA levels increases mean somatotropin response to GHRH+arginine in patients with essential obesity, whereas it has no effect in hypopituitary subjects. The current criterion for the diagnosis of GHD in obese patients may be misleading. Indeed, subjects affected by third degree obesity, like most of our patients, may be erroneously classified as really GH-deficient and started on an expensive unjustified treatment. It appears therefore that the current criteria for the diagnosis of GHD in obesity should be reconsidered in the light of further studies also taking into account different body mass index groups.

Increased lipid peroxidation in adult GH-deficient patients: Effects of short-term GH administration

Objective: Adult GH deficiency (GHD) syndrome is characterized by increased risk of atherosclerosis and hence of cardio- and cerebrovascular mortality. Oxidative stress appears to play an important role in early atherogenesis. Oxidized LDL represents an important predictor of cardiovascular risk and is mainly responsible for oxidative damage of the endothelium. Its concentrations are increased in GHD, but the association between this abnormality and oxidative stress is still unclear, due to the discordant results yielded by the few available studies. Design and methods: In 13 GHD patients, plasma lipid peroxide concentrations were measured before and after a 4-month treatment with recombinant human GH (rhGH) and compared with those of 13 age-and sex-matched controls. In the same subjects, the so-called “lag-time”, an index of anti-oxidant activity and thus of plasma oxidative balance, was also measured using a fluorescence kinetics method. Results: Before treatment, peroxide levels were significantly higher in patients than in controls (374.0±31.52 vs 268.0±8.51 U.C., p<0.01), whereas the lag-time was significantly lower (113.0±10.70 vs 168.0±7.80 min, p<0.01). RhGH administration to patients resulted both in a significant decrease in lipid peroxide levels (from 374.0±31.52 to 336.0±33.17 U.C., p<0.01) and a significant prolongation of lag-time (from 113.0±10.70 to 144.0±15.00 min, p<0.01). After treatment, both parameters were no longer significantly different in patients and controls. Lagtime and peroxide levels at baseline did not show any correlation with IGF-I concentrations in GHD patients. After replacement therapy, however, lag-time was positively (r2= 0.62, p<0.01), and peroxide levels negatively (r2=0.41, p<0.05), correlated with IGF-I levels. Conclusions: These data support the view that adult GHD syndrome is characterized by an unbalance between pro- and anti-oxidant factors with marked preponderance of the former. This abnormality, likely contributing to the increased atherogenic risk of GHD patients, is corrected by short-term GH administration at a dose able to increase, although not to fully normalize, IGF-I levels.

25 hydroxyvitamin D deficiency and its relationship to autoimmune thyroid disease in the elderly

Background: Low 25(OH) vitamin D levels have been associated with several autoimmune diseases and recently with autoimmune thyroiditis (AT). The aim of the study was to investigate the association of AT with low 25(OH) vitamin D levels in the elderly. Methods: One hundred sixty-eight elderly subjects (mean age: 81.6 ± 9.4 years) were enrolled. Serum levels of 25(OH) vitamin D, anti-thyroid peroxidase (TPO-Ab), anti-thyroglobulin (TG-Ab) antibodies, free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) were measured. Results: The prevalence of AT was significantly higher in subjects with vitamin D deficiency (25(OH) vitamin D < 20 ng/mL) when compared with subjects with normal 25(OH) vitamin D (25(OH) vitamin D ≥ 20 ng/mL) levels (28% vs. 8%, respectively, p = 0.002). Patients with AT and vitamin D deficiency had a comparable hormonal profile compared to patients with AT and vitamin D sufficiency in terms of TSH (p = 0.39), FT3 (p = 0.30), FT4 (p = 0.31), TG-Ab (0.44) and TPO-Ab (0.35). Interestingly, a significant correlation between 25(OH) vitamin D and TPO-Ab (r = −0.27, p = 0.03) and FT3 (r = 0.35, p = 0.006) has been found in subjects with AT while no correlation was found between 25(OH) vitamin D levels and TG-Ab (r = −0.15, p = 0.25), TSH (r = −0.014, p = 0.09) and FT4 (r = 0.13, p = 0.32). Conclusions: These findings suggest that vitamin D deficiency was significantly associated with AT in the elderly. Therefore, the screening for AT should be suggested in subjects with vitamin D deficiency.

Isolated corticotrophin deficiency presenting with pericardial effusion

Isolated ACTH deficiency is a rare disorder often presenting with long-standing aspecific symptoms combined with unusual clinical presentations. We here describe a patient in whom pericardial effusion was part of the clinical presentation and fully resolved on steroid at replacement dosage, highlighting the possibility of hypoadrenalism as an additional cause of pericardial effusion of unknown origin.

Thyroid nodules in acromegaly: The role of elastography

INTRODUCTION Ultrasound elastography (US-E) is a helpful tool for the diagnosis of thyroid cancer. In acromegaly, multinodular goiter is a common occurrence while the prevalence of thyroid cancer is still matter of debate. Our aims were to evaluate thyroid nodules in acromegaly and to assess the accuracy of US-E in providing information on their nature (benign vs. malignant) using cytological analysis as a reference. MATERIALS AND METHODS US-E was performed in 25 patients with acromegaly (active in 10 cases, medically controlled in 8, and cured by pituitary surgery in 7), each of whom had at least one solid thyroid nodule. A total of 90 nodules were classified according to the elastography scores (ES): ES1 and ES2 for soft nodules, ES3 and ES4 for an elastic lesions. FNAC was performed in 78.6% of the ES 4 lesions and 54.1% of the ES 3 nodules. RESULTS Fourteen of the 90 nodules (15.5%) displayed an ES of 1, 25 (27.7%) an ES of 2, 37 (41.3%) an ES of 3, and 14 (15.5%) an ES of 4. The prevalence of hard nodules in patients with active acromegaly (68.9%) was greater than that observed in patients with cured (44.4%) or controlled (52.5%) acromegaly. The prevalence of hard nodules in the total series (56.7%) was higher than that reported in nonacromegalic goitrous subjects. All thyroid nodules subjected to FNAC were negative for malignant cells and follicular lesions. DISCUSSION Acromegaly (particularly active forms) is associated with a high prevalence of stiff thyroid nodules that exceeds that observed in nonacromegalic patients with goiters (33.7%). However, these nodules were never malignant at cytology, and their firmness is probably due to fibrosis. US-E therefore appears to be of limited value for the diagnosis of thyroid cancer in patients with acromegaly.