Francesca Dassie

Ambulatory Arterial Stiffness Indexes in Acromegaly

OBJECTIVE Acromegaly is associated with increased cardiovascular morbidity and mortality and with specific heart and vascular abnormalities. The aim of our study was to investigate arterial stiffness using the ambulatory arterial stiffness index (AASI) and symmetric AASI (Sym-AASI), two indexes derived from 24-h ambulatory blood pressure monitoring (ABPM), in a group of normotensive and hypertensive patients with active acromegaly, compared with normotensive controls (NOR-CTR) or hypertensive controls (HYP-CTR). SUBJECTS AND METHODS Ninety-six consecutive patients with active acromegaly (46 males, mean age 49±14 years) underwent 24-h ABPM and evaluation of cardiovascular risk factors. Based on ABPM measurement, acromegalic patients were divided into 64 normotensive (normotensive acromegalic patients (NOR-ACRO)) and 32 hypertensive (hypertensive acromegalic patients (HYP-ACRO)) patients, and were compared with 35 normotensive (NOR-CTR) and 34 hypertensive (HYP-CTR) age-, sex,- and ABPM-matched control subjects. RESULTS The AASI and Sym-AASI indexes were significantly higher in acromegalic patients than in controls, either in the normotensive (NOR-ACRO vs NOR-CTR, P<0.0001 for AASI and P=0.005 for Sym-AASI) or in the hypertensive (HYP-ACRO vs HYP-CTR, P=0.01 for AASI and P=0.01 for Sym-AASI) group. Multiple logistic regression analysis showed a significant association of the highest AASI tertile with serum IGF1 (P=0.034) in the whole acromegalic group. CONCLUSION AASIs are increased in acromegaly, independent of blood pressure (BP) elevation, and may have an important role in predicting cardiovascular risk in this disease.

Endothelial Progenitor Cells Are Reduced in Acromegalic Patients and Can Be Restored by Treatment With Somatostatin Analogs

CONTEXT Acromegaly increases cardiovascular risk, possibly due to the high prevalence of classical risk factors. However, in vitro studies show a protective role of GH/IGF-1 on the endothelium. OBJECTIVE The objective of the study was to investigate circulating endothelial progenitor cells (EPCs), a marker of vascular regeneration, in acromegalic patients and how they are affected by acromegaly treatment. DESIGN This was a cross-sectional case-control and observational study. SETTING The study was conducted at a tertiary ambulatory referral endocrinology center. PATIENTS Forty-three acromegalic patients (26 active; 17 inactive) and 43 control subjects matched by age, gender, and degree of glucose tolerance participated in the study. INTERVENTION Circulating EPCs were quantified by flow cytometry based on the expression of CD34, CD133, and kinase insert domain-containing receptor (KDR). Nine patients with active acromegaly were reevaluated after 24 weeks of treatment with somatostatin analogs (SSAs). MAIN OUTCOME MEASURE Differences in EPC levels between patients and controls were measured. RESULTS Acromegalic patients showed a significant reduction of the total CD34(+)KDR(+) EPC population compared with controls, which was more evident in patients without diabetes or hypertension. More definite CD34(+)CD133(+)KDR(+) EPCs were reduced in patients with active compared with those with inactive acromegaly and compared with controls. The number of CD34(+)CD133(+)KDR(+) EPCs correlated with IGF-1 levels (r = -0.45; P < .001), fasting plasma glucose (r = -0.40; P = .004), and the homeostasis model assessment index of insulin resistance (r = -0.32; P = .026). CD34(+)CD133(+)KDR(+) EPCs increased 2-fold after SSA treatment. CONCLUSIONS Acromegalic patients have a reduced endothelial regenerative capacity, possibly due to activation of the GH/IGF-1, rather than concomitant risk factors. Treatment with SSAs can restore immature EPCs to normal levels.

Ovarian tumors secreting insulin.

AbstractCombined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation.

Ambulatory Arterial Stiffness Indexes in Cushing’s Syndrome

Long-standing exposure to endogenous cortisol excess is associated with high cardiovascular risk. The aim of our study was to investigate arterial stiffness, which has been recognized as an independent predictor of adverse cardiovascular outcome, in a group of patients with Cushings syndrome. Twenty-four patients with Cushings syndrome (3 males, mean age 49±13 years; 20 pituitary-dependent Cushings disease and 4 adrenal adenoma) underwent 24-h ambulatory blood pressure monitoring (ABPM) and evaluation of cardiovascular risk factors. The Ambulatory Arterial Stiffness Index (AASI) and symmetric AASI (sAASI) were derived from ABPM tracings. Cushing patients were divided into 8 normotensive (NOR-CUSH) and 16 hypertensive (HYP-CUSH) patients, and were compared with 8 normotensive (NOR-CTR) and 16 hypertensive (HYP-CTR) control subjects, matched for demographic characteristics, 24-h ABPM and cardiometabolic risk factors. The AASI and sAASI indexes were significantly higher in Cushing patients than in controls, either in the normotensive (p=0.048 for AASI and p=0.013 for sAASI) or in the hypertensive (p=0.004 for AASI and p=0.046 for sAASI) group. No difference in metabolic parameters was observed between NOR-CUSH and NOR-CTR or between HYP-CUSH and HYP-CTR groups. AASI and sAASI were both correlated with urinary cortisol in patients with endogenous hypercortisolism (Spearmans rho=0.40, p=0.05, and 0.61, p=0.003, respectively), while no correlation was found in controls. Both AASI and sAASI are increased in Cushing syndrome, independent of BP elevation, and may represent an additional cardiovascular risk factor in this disease. The role of excess cortisol in arterial stiffness has to be further clarified.

A very rare case of nonfunctioning pituitary adenoma incidentally disclosed at 18F-FDG PET/CT.

This is a case of a 48-year-old man treated with surgery and (131)I for papillary thyroid carcinoma: a follow-up (18)F-FDG PET/CT incidentally evidenced pituitary uptake, also seen in (111)In-octreoscan as increased uptake in the sellar area. MRI confirmed a pituitary mass. The patient did not show any signs or symptoms related to this lesion; 1 year later, both PET/CT and MRI findings remained unchanged. Surgery confirmed nonfunctioning benign pituitary adenoma. This single case observed in 12,873 consecutive patients scanned in our center confirms the possibility that nonfunctioning benign pituitary adenomas may be FDG-avid: uptake mechanisms remain unknown, and targeted studies are needed.

Guidelines versus real life practice: the case of colonoscopy in acromegaly

PurposeThe aim of this study is to investigate guideline application and colonoscopy findings in real-life practice in acromegaly.MethodsWe conducted a retrospective observational non-interventional and cross-sectional analysis on 146 patients with acromegaly (ACRO) referred to our clinic. We evaluated colonoscopy data, focusing on the correlation between colonoscopy findings and hormonal/metabolic values.ResultsThe total number of colonoscopies performed in ACRO patients increased from 6 in the period 1990–1994 to 57 in the period 2010–2014. Colonoscopy procedures were performed according to guidelines in 25% of ACRO patients at diagnosis, 51% at follow-up and 11% globally (both at diagnosis and follow-up). Among the 146 ACRO patients, 68% were subjected to at least one colonoscopy and in 32% of the cases a polyp was detected during the procedure. The presence of polyps was significantly associated with mean levels of growth hormone (GH), insulin-like growth factor 1 (IGF-1), fasting glucose and insulin levels (p < 0.05). Polyps were detected in 48% of untreated patients and in 26% of patients under treatment for acromegaly (p = 0.04). The general risk of polyps and adenomatous polyps in ACRO patients was higher compared to the control population of Veneto Region, Italy (odds ratio 1.33 and 1.16, respectively). No cancerous polyps were detected in our analysis.ConclusionIn real-life practice, adherence to ACRO colonoscopy clinical guidelines was lower than expected. Among patients who underwent colonoscopy, the prevalence of colon polyps was higher for ACRO patients, suggesting the need for new strategies to ensure adherence to colonoscopy guidelines.

Preclinical markers of atherosclerosis in acromegaly: a systematic review and meta-analysis

ObjectiveMultiple studies investigated preclinical markers of peripheral vascular damage in acromegaly (ACRO) reporting discordant results. The aim of this study was to run a meta-analysis to examine whether intima media thickness (IMT), flow mediated dilation (FMD) and arterial pulse wave velocity (PWV) are affected in acromegalic patients and to assess the impact of effective treatment of growth hormone excess on these outcomes.Study selectionTwenty-seven studies comparing ACRO vs control (CON) populations and active (ACT) vs inactive (INACT) ACRO were included in the meta-analysis.Data synthesisACRO compared to CON have higher IMT (ES = 0.83, 95% C.I. 0.35–1.30), p = 0.001, impaired FMD (ES = − 1.59, 95% C.I. − 2.33 to − 0.85, p < 0.0001) and higher PWV (ES = 0.76 95% C.I. 0.37–1.16, p = 0.0001). When patients with ACT vs INACT disease were considered IMT was higher (ES = 0.43, 95% C.I. 0.02–0.84, p = 0.041) and FMD was impaired (ES = − 0.66, 95% C.I. − 1.28 to 0.04, p = 0.038) in ACT patients. Meta-regression analysis of studies comparing IMT in ACT vs INACT acromegalic patients showed a significant and inverse association between the effect size and the percent of hypertensive (p = 0.025) and diabetic (p = 0.041) patients.ConclusionsIMT, FMD and arterial stiffness are impaired in acromegaly showing that these patients may be at increased risk of atherosclerosis. In patients with active disease these preclinical markers of atherosclerosis are worse compared to patients with inactive disease but the role of diabetes and hypertension is prevailing on growth hormone excess.

Radiotherapy in acromegaly: Long-term brain parenchymal and vascular magnetic resonance changes

BACKGROUND Radiation therapy (RT) effectiveness on hormonal reduction is proven in acromegaly; however, collateral long-term effects are still undetermined. This transversal neuroimaging study on a large cohort of acromegalic patients aimed to investigate the rate of parenchymal and vascular changes after RT. MATERIALS AND METHODS Thirty-six acromegalic patients underwent RT (RT+) after unsuccessful surgery and were compared to RT- acromegalic patients matched for age, gender, adenoma features, clinical and surgical history. All patients underwent magnetic resonance angiography (MRA) to investigate intracranial artery abnormalities and FLAIR sequence to assess white matter changes according to the Wahlund scale. RESULTS RT+ acromegalic patients had a higher rate of controlled disease (29/36 vs. 12/36, P<0.001). RT+ acromegalic patients had MRI/MRA evaluation 15.3±9.6 years after RT. RT+ acromegalic patients had a significantly higher Wahlund score than RT- acromegalic patients (6.03±6.41 vs. 2.53±3.66, P=0.006) due to increased white matter signal abnormalities at the level of the temporal lobes, the basal ganglia (insula) and the infratentorial regions, bilaterally. Among RT+ patients one died because of temporo-polar anaplastic astrocytoma, one suffered from a stroke due to right internal carotid artery occlusion, one presented with cystic degeneration of the temporal poles. Long-dated RT (>10 years before MR evaluation) was associated with a higher rate of RT-related white matter changes (P=0.0004). CONCLUSIONS RT seems to have created a cohort of patients with brain parenchymal changes whose clinical and cognitive impact is still unknown. These patients might require a prolonged MRI and MRA follow-up to promptly detect delayed RT-related complications and minimize their clinical consequences.

Persistent Reduction of Circulating Myeloid Calcifying Cells in Acromegaly: Relevance to the Bone–Vascular Axis

Context Acromegaly is a systemic disease characterized by persistent bone pathology and excess cardiovascular mortality. Despite multiple concomitant risk factors, atherosclerosis does not seem to be accelerated in acromegaly. Objective To compare the levels of circulating myeloid calcifying cells (MCCs), which promote ectopic calcification and inhibit angiogenesis, in individuals with and without acromegaly. Design Cross-sectional case-control study. Setting Tertiary ambulatory referral endocrinology center. Patients 44 acromegalic patients (25 active; 19 inactive), 44 control subjects matched by age, sex, risk factors, and medications, and 8 patients cured of acromegaly. Intervention MCCs were measured using flow cytometry based on the expression of osteocalcin (OC) and bone alkaline phosphatase (BAP) on monocytes and circulating CD34+ stem cells. Main Outcome Measure Differences in MCCs between patients and controls. Results OC+BAP+ MCCs were severely reduced in acromegalic compared with control patients (0.17% ± 0.02% vs 1.00% ± 0.24%; P < 0.001), as were the total OC+ and BAP+ monocytic cells. Patients with inactive acromegaly and those cured of acromegaly displayed persistently reduced levels of MCCs. In the controls, but not acromegalic patients, MCCs were increased in the presence of diabetes or cardiovascular disease. A direct correlation was noted between MCCs and parathyroid hormone (r = 0.61; P < 0.0001), supporting a link between bone biology and MCCs. Conclusions In patients with acromegaly, the levels of MCCs are reduced and remain low, even years after a complete cure. This finding might be related to low atherosclerotic calcification and the persistence of bone pathology after acromegaly remission or cure.

Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy

BACKGROUND AND AIMS Acromegaly increases the risk of cardiovascular mortality. Data on the cardiovascular risk in asymptomatic acromegaly are limited. In particular, data on coronary microvascular abnormalities are lacking. We assessed coronary flow reserve (CFR) as a marker of coronary microvascular function in asymptomatic acromegaly. METHODS We studied 40 acromegalic patients (23 male, age 52 ± 11 years) without clinical evidence of cardiovascular disease, and 40 control subjects matched for age and sex. Coronary flow velocity in the left anterior descending coronary artery was detected by transthoracic Doppler echocardiography, at rest, and during adenosine infusion. CFR was the ratio of hyperaemic to resting diastolic flow velocity. RESULTS CFR was lower in patients than in controls (2.9 ± 0.8 vs. 3.7 ± 0.6, p < 0.0001) and was abnormal (≤2.5) in 13 patients (32.5%) compared with any control subjects (0%) (p < 0.0001). CFR was inversely related to insulin-like growth factor 1 (IGF-1) levels (r = -0.5, p < 0.004). In patients with CFR≤2.5, IGF-1 was higher (756 [381-898] μg/l versus 246 [186-484] μg/l, p < 0.007) whereas growth hormone (GH) levels were similar (6.3 [2.8-13.7] μg/l versus 5 [2.8-8.9] μg/l, p = 0.8). In multivariable linear regression analysis, IGF-1 was independently associated with CFR (p < 0.0001). In multiple logistic regression analysis, IGF-1 independently increased the probability of CFR≤2.5 (p = 0.009). In four patients with active disease (all with CFR<2.5), treatment with somatostatin analogues normalized CFR. However the other four patients with active disease were not responder. CONCLUSIONS Acromegalic patients have coronary microvascular dysfunction that may be restored by therapy with somatostatin analogues. IGF-1 independently correlates with the coronary microvascular impairment, suggesting the pivotal role of this hormone in explaining the increased cardiovascular risk in acromegaly.