Serum NT-pro-BNP Levels Predict Cardiovascular Events in Acromegaly Patients.

BACKGROUND: Acromegaly is associated with an increased risk of fatal and non-fatal cardiovascular (CV) events. Controlling acromegaly decreases, but does not normalize this risk. Brain natriuretic peptide (BNP) assessment is used in the general population for the diagnosis of heart failure and to predict ischemic recurrences and mortality. This is a retrospective, longitudinal, monocenter study that evaluates the role of serum N-terminal fragment of BNP (NT-pro-BNP) for predicting CV events in acromegaly patients. METHODS: Serum NT-pro-BNP levels were measured in 76 patients with acromegaly (23 males, 57.7±1.5 years), and compared with other predictors of CV events. NT-pro-BNP cut-off value discriminating the occurrence of CV events was determined by ROC analysis. CV events were recorded during a follow-up of 78.6±6.4 months. RESULTS: CV events occurred in 9.2% of patients. Mean log(NT-pro-BNP) concentration was higher in patients who experienced CV events than in those who did not (p<0.01) and in patients who died due to CV events than in those who died due to other causes (p<0.01). Based on the ROC curve, a cut-off value of 91.55 pg/mL could predict CV events (OR 19.06). Log(NT-pro-BNP) was lower in surgically treated patients by surgery (p<0.05), and in those cured by neurosurgery (p<0.02). CONCLUSIONS: High NT-pro-BNP value is an independent middle-term predictor of fatal or non-fatal CV events in patients with acromegaly. According to this parameter, surgically treated patients show lower CV risk than those managed with medical therapy, especially if the disease is cured.

Methylome Analysis in Nonfunctioning and GH-Secreting Pituitary Adenomas.

Pituitary adenomas (PAs), usually benign lesions, can sometimes present with "aggressive" features (rapid growth, local invasiveness, scarce response to conventional treatments). Despite the fact that a few genetic alterations have been associated to this clinical behavior, the role of epigenetic modifications, mainly methylation and miRNAs activity, is now opening new frontiers in this field. We evaluated the methylation profile of 21 PA (11 GH-omas, 10 nonfunctioning tumors-NFPAs) samples from TNS surgery and 5 normal pituitaries, collected at our neurosurgery between 2015 and 2017. DNA was extracted and sequenced, selecting 184,841 target regions. Moreover, methylation profiles were correlated with demographic, radiological, and clinicopathological features. NFPAs showed higher methylation levels vs. GH-omas, with 178 differentially methylated regions (DMRs) mainly consisting of noncoding and intronic sequences, and mostly localized in the open sea regions. We also found three hypermethylated genes (C7orf50, GNG7, and BAHCC1) involved in tumorigenesis processes and potentially influencing pituitary tumor pathophysiology. Among the clinicopathological features, only the maximum diameter resulted significantly higher in NFPAs. Our data provide further evidence of the complex epigenetic background of pituitary tumors. In line with the current literature, we confirmed a significant prevalence of hypermethylation in NFPAs vs. GH-omas, whose pathophysiological consequence is yet to be defined.

Global epidemiology of acromegaly: a systematic review and meta-analysis.

OBJECTIVE: To date, no systematic reviews and meta-analysis on the global epidemiology of acromegaly are available in the literature. The aims of this study are to provide a systematic review and a meta-analysis of the global epidemiology of acromegaly and to evaluate the quality of study reporting for the identified studies. METHODS: MEDLINE, EMBASE and The Cochrane Library databases were searched for studies assessing the epidemiology of acromegaly from inception until 31 January 2020. We included original observational studies written in English, reporting acromegaly prevalence and/or incidence for a well-defined geographic area. Two reviewers independently extracted data and performed quality assessments. Prevalence and incidence pooled estimates were derived by performing a random-effects meta-analysis. RESULTS: A total of 32 studies were included in the systematic review, and 22 of them were included in the meta-analysis. The pooled prevalence of acromegaly was 5.9 (95% CI: 4.4-7.9) per 100 000 persons, while the incidence rate (IR) was 0.38 (95% CI: 0.32-0.44) cases per 100 000 person-years. For both prevalence and IR, considerable between-study heterogeneity was found (I2 = 99.3 and 86.0%, respectively). The quality of study reporting was rated as the medium for 20 studies and low for 12 studies. CONCLUSIONS: Although the largest amount of heterogeneity was due to the high precision of the studies' estimates, data source and geographic area could represent relevant study-level factors which could explain about 50% of the total between-study variability. Large-scale high-quality studies on the epidemiology of acromegaly are warranted to help the public health system in making decisions.

Clinical Consequences of Variable Results in the Measurement of Free Thyroid Hormones: Unusual Presentation of a Family with a Novel Variant in the THRB Gene Causing Resistance to Thyroid Hormone Syndrome.

INTRODUCTION: Resistance to thyroid hormone ß (RTHß) is an inherited syndrome caused by dominant negative variants in the THRB gene (NM_000461.5). The clinical picture of RTHß is variable, and patients harboring the same variant may display different degrees of disease severity. CASE PRESENTATION: A 30-year-old man presented with thyrotoxicosis and central hyperthyroidism and was found to have a novel variant in the exon 10 of THRB gene (c.C1282G, p.L428V), located within the third hot spot region of the C-terminal of the receptor. Surprisingly, the same variant was found in two other relatives with an apparent normal thyroid function at initial screening. After exclusion of a TSH-secreting adenoma and serum interference in the proband, and the finding that exogenous levothyroxine failed to suppress the TSH in the brother affected by nodular goiter, relatives' thyroid function tests (TFTs) were reassessed with additional analytical method revealing biochemical features consistent with RTHß in all carriers of the p.L428V variant. Functional studies showed a slightly impaired in vitro transcriptional activity of p.L428V. Interestingly' the expression of the human p.L428V thyroid hormone receptor beta in the zebrafish embryo background generated a phenotype consistent with RTHß. CONCLUSION: Variable results of TFTs on some immunoassays can be a cause of RTHß diagnostic delay, but the genotype-phenotype correlation in this family and functional studies support p.L428V as a novel THRB variant expanding the spectrum of gene variants causing RTHß. In vivo, rather than in vitro, functional assays may be required to demonstrate the dominant negative action of THRB variants.

Cardiometabolic Risk in Acromegaly: A Review With a Focus on Pasireotide.

Acromegaly is a disease due to chronic GH excess and a consequent rise in IGF-1 levels. This rare endocrine condition is associated with metabolic alterations such as hyperglycaemia, dyslipidaemia, and systemic arterial hypertension, which, in addition to GH excess-related cardiovascular changes, play critical roles in increasing cardiovascular risk and mortality rates. Biochemical control of acromegaly, achieved by means of surgical, and/or medical treatment, positively impacts on cardiovascular risk factors and metabolic alterations, reducing overall patient mortality. However, treatment modalities of acromegaly and disease control differently impact on glucose homeostasis and lipid changes, and consequently on cardiometabolic risk. In this regard, pasireotide was shown to significantly influence glucose metabolism. This review summarizes the cardiometabolic consequences of acromegaly and its treatment, focusing on available data around the effects of medical therapy with pasireotide on factors that influence cardiometabolic risk.

Somatic Deletion in Exon 10 of Aryl Hydrocarbon Receptor Gene in Human GH-Secreting Pituitary Tumors.

Objective/Purpose: The aryl hydrocarbon receptor (AHR) pathway plays a critical role in the biology of Growth Hormone (GH)-secreting pituitary tumor (somatotropinoma). Germline rs2066853 AHR variant was found to be more frequent among acromegaly patients and associated with a more severe disease with larger invasive somatropinoma, and with resistance to somatostatin analogs treatment in patients living in polluted areas. However, no somatic changes in AHR gene have been reported so far in acromegaly patients. On that basis, the aim of the study was to assess at the somatic level the AHR gene status encompassing exon 10 region, also because of the high rate of variants found in this genomic region. Methods: A cohort of 13 patients aged 20-76 years with biochemical, clinical and histological diagnosis of somatotropinoma was studied. DNA and RNA from pituitary tumor histological samples have been extracted and analyzed by PCR and direct sequencing for AHR gene variants, and compared with corresponding patients' germline DNA as well as normal pituitary tissue as reference control. Results: A degenerated letter codes in the region corresponding to AHR exon 10 (c.1239-c.2056) was detected in somatotropinomas-derived DNA but not in that of matched germline and pituitary normal tissue. By multiple PCR and sequencing analysis, we observed amplification only before codon 1246 and after codon 1254, confirming the presence of a tumor-restricted somatic deletion in the 5' upstream region of AHR exon 10. Analysis of PCR-amplified cDNA revealed a wildtype sequence of exon 9 and 10 in normal pituitary tissue, and a wildtype sequence of exon 9 and 10 up to codon 1246 and no sequence after the deletion region (c.1246-c.1254) in 6 out of 9 tumor samples. Patients carrying the germline rs2066853 AHR variant showed no somatic LOH at the corresponding genetic locus. Conclusion: This is the first demonstration of a recurrent somatic deletion in the exon 10 of the AHR gene in somatotropinomas. The functional impact of this genetic finding needs to be clarified.

First report on persistent remission of acromegaly after withdrawal of long-term pegvisomant monotherapy.

The GH-receptor antagonist pegvisomant (PEG) reduces peripheral IGF-1 synthesis and is used to treat acromegaly patients resistant or intolerant to somatostatin analogues (SSA). Medical therapy is generally life-long in patients with acromegaly, since disease remission is very uncommon after SSA discontinuation and has never been reported after PEG withdrawal. Here, we report for the first time the cases of two acromegaly patients treated with PEG monotherapy for many years because of resistance to SSA, who persistently maintained normal serum IGF-1 levels after PEG withdrawal. The first patient autonomously discontinued PEG treatment after 8 years, while in the second case we stopped the treatment after 11 years, because slight hypertransaminasemia occurred. After PEG discontinuation, in both cases IGF-1 values remained persistently normal and GH during OGTT regularly suppressed. To date, both patients are still in remission. Therefore, we suggest that PEG could exert unknown antitumoral effects in pituitary tumor cells and that long-term PEG treatment can induce acromegaly remission in some patients.

Visceral adiposity index as an indicator of cardiometabolic risk in patients treated for craniopharyngioma.

PURPOSE: Craniopharyngioma is associated with metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index has been proposed as a marker of visceral adipose tissue dysfunction and of the related cardiometabolic risk. The role of the visceral adiposity index has never been explored in craniopharyngioma patients. We assessed the cardiometabolic risk on the basis of the visceral adiposity index in craniopharyngioma patients. METHODS: We evaluated data of 24 patients treated for craniopharyngioma in a single-centre. We investigated the relationship among patients' clinical and biochemical features, cardiovascular risk -assessed by the Framingham and the atherosclerotic cardiovascular disease risk scores-, visceral adiposity index and adipose tissue dysfunction severity. RESULTS: Increased visceral adiposity index was found in 8 patients (33%). Adipose tissue dysfunction resulted to be severe, moderate or mild in 5, 2 and 1 cases. Increased visceral adiposity index significantly correlated with the occurrence of metabolic syndrome (p 0.027), IRI (p 0.001), triglycerides (p < 0.001), HOMA-IR (p < 0.001) and with lower ISI-Matsuda (p 0.005) and HDL-cholesterol (p < 0.001). Higher degree of adipose tissue dysfunction associated with increased insulin resistance. No gender difference was found for visceral adiposity index, adipose tissue dysfunction severity, and cardiovascular risk scores. Patients with adulthood onset craniopharyngioma showed higher Framingham risk score (p 0.004), atherosclerotic cardiovascular disease 10-year (p < 0.001) and lifetime (p 0.018) risk scores than those with childhood onset disease. CONCLUSIONS: Visceral adiposity index is increased in one third of our patients with craniopharyngioma, even if metabolic syndrome does not occur. Increased visceral adiposity index and adipose tissue dysfunction severity correlate with insulin sensitivity parameters, do not correlate with Framingham or atherosclerotic cardiovascular disease risk scores, and are not influenced by gender and age of disease onset.