In acromegalic patients the serum levels of interleukin-33 and Resolvin D1 influence skin perfusion of hands: A pilot study.

AIM: Acromegaly is a rare chronic disease, caused by the over-secretion of growth hormone (GH), that creates a pro-inflammatory state, but the exact mechanisms by which GH or insulin-like growth factor 1 (IGF-I) act on inflammatory cells are not fully understood. Aim of the study was to evaluate Interleukin-33 (IL33) and D-series resolvins 1 (RvD1) and the skin perfusion of hands in patients with acromegaly (AP) and healthy controls (HC). METHODS: IL33 and RvD1 have been assessed in 20 AP and 20 HC. Nailfold videocapillaroscopy (NVC) was performed and skin perfusion of hands was assessed by laser speckle contrast analysis (LASCA) in both populations. RESULTS: IL33 was significantly higher in AP compared to HC [73.08 pg/ml (IQR 47.11-100.80 pg/ml) vs 41.5 4 pg/ml (IQR 20.16-55.49 pg/ml), p < 0.05] and RvD1 was significantly lower in AP than HC [36.1 pg/ml (IQR 27.88-66.21 pg/ml) vs 60.01 pg/ml (IQR 46.88-74.69 pg/ml), p < 0.05]. At LASCA, peripheral blood perfusion (PBP) was significantly lower in AP compared to HC [56.66 pU (IQR 46.29-65.44 pU) vs 87 pU (IQR 80-98 pU), p < 0.001]. The median values of ROI1 and ROI3 were significantly lower in AP compared to HC [112.81 pU (IQR 83.36-121.69 pU) vs 131 pU (IQR 108-135 pU), p < 0.05] and [59.78 pU (IQR 46.84-79.75 pU) vs 85 pU (IQR 78-98 pU), p < 0.05], respectively. The proximal-distal gradient (PDG) was observed in 8 of 20 (40 %) AP. CONCLUSION: Serum IL33 is higher in AP compared to HC; conversely, RvD1 is lower in AP compared to HC. Reduction of PBP of hands was present in AP compared to HC, probably due to endothelial dysfunction.

Partial response to first generation SSA guides the choice and predict the outcome of second line therapy in acromegaly.

INTRODUCTION: Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes. PATIENTS AND METHODS: A retrospective and multicenter study was conducted on 100 SSA-resistant acromegaly patients and treated with Pasireotide Lar (Pasi-Lar), Peg-V in monotherapy (m-Peg-V) or in combination with first gen-SSA (c-Peg-V). RESULTS: Thirty-three patients (33%) were treated with m-Peg-V, 36 (36%) with c-Peg-V and 31 with Pasi-Lar (31%). According to logistic regression, m-Peg-V was chosen in older patients (p = 0.01) and with not-invasive adenomas (p = 0.009), c-Peg-V therapy in younger patients (p = 0.001), with invasive adenomas (p = 0.02), Pasi-Lar was in invasive adenomas (p = 0.01) and in patients partially responsive to first-gen SSA (p = 0.01). At the last follow-up, 68 patients (68%) reached the acromegaly control: 22 with m-Peg-V (32.4%), 23 with c-Peg-V (33.8%) and 23 with Pasi-Lar (33.8%). Patients non-responsive to c-Peg-V had higher IGF-I levels (median 3.2 x ULN, IQR: 1.6, p < 0.001) and required higher Peg-V dosage (median 30 mg/daily IQR: 10, p = 0.002) as compared to responsive patients (median IGF-I x ULN: 2.1 IQR: 1.4; median Peg-V dosage 20 mg/daily IQR: 10). All patients responsive to Pasi-Lar were partially responsive to first gen-SSAs (p = 0.02). CONCLUSION: Our data showed that c-Peg-V and Pasi-Lar are chosen for the treatment of invasive tumors. The partial response to first gen-SSA seems to be the main determinant for the choice of Pasi-Lar and positively predicts the treatment outcome.

Giant Prolactinoma Embedded by Pseudoaneurysm of the Cavernous Carotid Artery Treated with a Tailored Therapeutic Scheme.

The coexistence of intracranial aneurysm (IA) is generally thought to be highest in patients with pituitary adenomas (PAs). Different mechanisms may play a role in aneurysm formation, but whether the PA contributes to aneurysm formation is still unclear. In the literature, there are numerous reported cases of this association; however, the analyses of the characteristics of PAs, aneurysms, and treatment management are rare and limited to a restricted number of case reports. We report a rare case of an embedded aneurysm in a macroprolactinoma treated with therapeutic management tailored to the clinical, neurological, and radiological characteristics of the patient. To select the best treatment, we reviewed the literature and reported the only cases in which the radiological characteristics of aneurysms, PAs, therapeutic management, and patient outcome are described. We aimed to understand what are the variables that determine the best therapeutic management with the best possible outcome. The presence of a large pseudoaneurysm of the internal carotid artery completely embedded in a giant macroprolactinoma is rare and needs a tailored treatment strategy. The importance of the preoperative knowledge of asymptomatic IA coexisting with PA can avoid accidental rupture of the aneurysm during surgical resection and may lead to planning the best treatment. A high degree of suspicion for an associated aneurysm is needed, and if magnetic resonance imaging shows some atypical features, digital subtraction angiography must be performed prior to contemplating any intervention to avoid iatrogenic aneurysmal rupture. Our multimodal approach with the first-line therapy of low-dose cabergoline to obtain prolactin normalization with minimum risks of aneurysms rupture and subsequent endovascular treatment with flow diverter has not been described elsewhere to our knowledge. In the cases, we suggest adopting a tailored low-dose cabergoline therapy scheme to avoid rupture during cytoreduction and initiate a close neuroradiological follow-up program.

A New Device for Remote Monitoring of Vital Parameters in Acromegalic Patients: Pilot Study.

INTRODUCTION: Acromegaly is a rare disease that results from growth hormone (GH) excess. Diabetes mellitus, hypertension,cardiomyopathy, and obstructive sleep apnoea syndrome( OSAS) are frequent complications. AIM OF THE STUDY: Identify a useful system to obtain a reliable remote monitoring of glucose and the most important vital parameters in the acromegalic subjects. PATIENTS AND METHODS: Sixteen acromegalic patients (from 30 to 73 years old) were enrolled. We provided health monitor devices to the patients for continuous acquisition of physiological signals including twelve-lead electrocardiography (EKG) and nocturnal SpO2. At the same time, we applied on the same patients the blinded continuous glucose monitoring system(CGMS). RESULTS: The lowest saturation peaks at night (<80%) were achieved in patients with a known diagnosis of OSAS. A positive correlation was demonstrated between the lowest oxygen saturation values and the CGM peaks (pV <0,0001) and between the average values of oxygen saturation and CGM (pV<0,0003). Patients with a previous diagnosis of OSAS, obtained by polysomnography, showed on the multiparametric monitor recordings superimposable to their known condition. Instead we noticed a discordance in the two EKG recording: the wireless mode showed an irregular rhythm in 5/16 patients, which was not confirmed by the recording mode with cables. CONCLUSION: The health monitor device associated with CGM may be a new useful and versatile tool for fragile patients who can self-manage remote monitoring, and for physicians who can obtain real-time information for the clinical and therapeutic management of patients. It is also a useful tool for the follow-up of patients with OSAS. Moreover, once the interference of the OSAS is excluded, the CGM allows us to obtain a more reliable and accurate diagnosis of DM.

The prevalence of secondary neoplasms in acromegalic patients: possible preventive and/or protective role of metformin.

BACKGROUND: Acromegaly is a rare disease due to chronic growth hormone (GH) excess and the consequent increase in insulin-like growth factor-1 (IGF-1) levels. Both GH and IGF-1 play a role in intermediate metabolism affecting glucose homeostasis. The association between hyperinsulinemia/impaired glucose tolerance and an increased risk of cancer has been clarified. Insulin has a mitogenic effect through its interaction with the IGF-1 receptor (IGF-1R) that also binds IGF-1. On the other hand, metformin, an anti-hyperglycemic drug that decreases serum levels of insulin and IGF-1, could have a protective role in the treatment of endocrine tumors. METHODS: A retrospective, observational, multicenter study in 197 acromegalic patients, receiving/not receiving metformin, was performed to assess whether the prevalence of neoplasms might be correlated with insulin resistance and could eventually be modified by metformin treatment. RESULTS: In general, the occurrence of secondary neoplasia among our patients was significantly (pV = 0.035) associated with a positive family history of malignancy and with disease duration; a trend towards significance was observed in patients aged > 50 years. Acromegalic subjects who had undergone surgery showed a lower probability of developing a malignant tumor, whereas a higher prevalence of malignancies was observed in obese patients. No significant statistical difference was found when comparing metformin-treated or -untreated subjects for the presence of a second tumor. More interestingly, a trend towards statistical significance (pV = 0.065) was demonstrated in the metformin-treated group for the onset of a benign neoplasm. CONCLUSION: Metformin could act directly on tumor cell metabolism and may have an adjuvant role in benign lesion progression.

Continuous Glucose Monitoring System in Acromegalic Patients: Possible Role in the Assessment of Glycemia Control.

BACKGROUND: Acromegaly is characterized by an insulin resistance condition. There is a significant difference between the different types of therapy in relation to the glycometabolic framework. The blinded continuous glucose monitoring system (CGMS), throughout a period of maximum 6 days for a total of 288 glycemic registrations per day, identifies glycemic excursions and could constitute a valid device to understand the 24-hour glycemic profiles. AIM OF THE STUDY: To compare the oral glucose tolerance test (OGTT) and CGMS methods in acromegalic patients to evaluate their glycemic profiles, in relation to different treatments for acromegaly. METHODS: Thirty-five acromegalic patients were divided into 18 somatostatin analogs (SSA), 9 pegvisomant, and 8 successfully surgically treated. A 72-hour CGM was performed and, immediately after, an OGTT. RESULTS: Results obtained from OGTT: 11/35 impaired fasting glucose, 6/35 impaired glucose tolerance, and 4/35 diabetes mellitus. A positive significant correlation was demonstrated between the OGTT peak and CGM peak in all of the patients, CGM peak of patients treated with SSA and those surgically treated, OGTT average and CGM area under concentration-time curve (AUC) for hyperglycemia of patients treated with SSA and those surgically treated, and CGM AUC for hyperglycemia of patients treated with SSA and those surgically treated. CONCLUSIONS: Our results show a significantly higher response in terms of mean and peak OGTT in patients treated with SSA, both compared to the CGM study, and compared to the group of patients receiving pegvisomant. The CGM system could represent an instrument for the evaluation of the glycemic trend of acromegalic patients.

Infundibuloneurohypophysitis associated with autoimmune thrombocytopenia and chiasmal syndrome: a case report.

Lymphocytic hypophysitis is an uncommon autoimmune disease. It may involve the adenohypophysis, neurohypophysis and pituitary stalk. It is most often encountered in pregnant women. Its diagnosis and management pose a significant challenge, as its clinical manifestation and appearance in imaging studies are difficult to distinguish from more common lesion of the sellar region (e.g., pituitary adenomas). We present the case of a 42-year-old man who presented with a chiasmatic syndrome, diabetes insipidus and hypopituitarism. Brain MRI documented a sellar lesion with suprasellar extension and optic chiasm dislocation. He underwent an endoscopic endonasal transsphenoidal resection of the mass. Histopathological examination revealed a lymphocytic hypophysitis. Visual symptoms improved dramatically postoperatively with permanent diabetes insipidus and panhypopituitarism. We discuss the indication for surgical resection in patients with inflammatory lesions extending to the suprasellar region associated with visual impairment.

Type 1 diabetes mellitus and celiac disease: endothelial dysfunction.

Many reports indicate a hypercoagulative state in diabetes mellitus as result of endothelial damage. Experimental evidence suggests that a metabolic derangement triggers a cascade of biochemical events that lead to vascular dysfunction. The net effect is to convert the endothelium from thromboresistant to thrombogenic surface. In literature, a strong association between type 1 diabetes mellitus (DM1) and celiac disease (CD) has been reported. We do not have information about the hemostatic system in these associated conditions. Our study aims at evaluating whether the presence of CD in a group of DM1 patients is associated with a different expression of some hemostatic factors and with a different manifestation and/or progression of microvascular complications of DM1 in comparison with patients with only diabetes. Ninety-four adult DM1 patients were enrolled in the study and subsequently screened for CD. Anti-endomysial antibodies (EMA) were positive in 13 of 94 DM1 patients (13.8%). CD diagnosis was confirmed by histology and organ culture. The mean age and duration of DM1 of patients also affected by CD were similar to those of only diabetic patients, but the metabolic control and the hemocoagulative parameters were significantly different between the two groups: DM1 patients also affected by CD presented significantly lower concentrations of glycosylated hemoglobin (HbA1c) (P < 0.05), cholesterol (P < 0.001), triglycerides (P < 0.001), factor VII antigen (FVII:ag) (P < 0.005), factor VII coagulant activity (FVII:c) (P < 0.05), and prothrombin degradation fragments (F1+2) (P < 0.001), as well as higher values of activated C protein (APC) (<0.001). No retinal abnormalities and no signs of renal damage were observed in DM1 patients also affected by CD. Our results suggest a potential protective role of CD in the prothrombotic state of DM1.

Atypical celiac disease as cause of increased need for thyroxine: a systematic study.

OBJECTIVE: Replacement T4 dose in hypothyroid patients bearing both chronic autoimmune thyroiditis and atypical celiac disease (CD) has been analyzed. DESIGN: Replacement T4 dose has been analyzed in 35 hypothyroid patients with Hashimoto's thyroiditis (HT) and atypical CD, as defined by the American Gastroenterological Association. We have evaluated the ability of the same dose of T4 to reach target TSH in 21 patients before and during gluten-free diet (GFD). In the remaining 14 patients, noncompliant with GFD, we analyzed replacement T4 dose and compared it with that in a similar group consisting of 68 patients with hypothyroid HT but no evidence of celiac sprue or other conditions interfering with T4 absorption. RESULTS: In patients with isolated HT, the desired serum TSH (median=1.02 mU/liter) was reached in all patients after 5±2 months of treatment at a median T4 dose of 1.31 µg/kg·d. After a similar period and dose of T4, higher levels of TSH (median=4.20 mU/liter) were observed in patients with HT and CD. In 21 CD patients, target TSH (median TSH=1.25 mU/liter) has been attained after 11±3 months of GFD without increasing T4 dose (1.32 µg/kg·d). In the remaining 14 patients, who were noncompliant with GFD, target TSH has also been achieved but at a higher T4 dose (median=1.96 µg/kg·d; +49%; P=0.0002) than in hypothyroid patients without CD. CONCLUSIONS: Atypical CD increases the need for T4. The effect was reversed by GFD or by increasing T4 dose. Malabsorption of T4 may provide the opportunity to detect CD that was overlooked until the patients were put under T4 therapy.