Publications by authors named "Gianluca Aimaretti"

107 Publications

Interaction between thrombin potential and age on early clinical outcome in patients hospitalized for COVID-19.

J Thromb Thrombolysis 2021 Jun 10. Epub 2021 Jun 10.

Dipartimento Di Medicina Traslazionale, Università del Piemonte Orientale, Azienda Ospedaliero-Universitaria Maggiore Della Carità, Via Solaroli 17, 28100, Novara, NO, Italy.

Patients with Coronavirus Disease-2019 (COVID-19) have haemostatic dysfunction and are at higher risk of thrombotic complications. Although age is a major risk factor for outcome impairment in COVID-19, its impact on coagulative patterns here is still unclear. We investigated the association of Endogenous Thrombin Potential (ETP) with thrombotic and haemorrhagic events according to different ages in patients admitted for COVID-19. A total of 27 patients with COVID-19-related pneumonia, without need for intensive care unit admission or mechanical ventilation at hospital presentation, and 24 controls with non-COVID-19 pneumonia were prospectively included. ETP levels were measured on admission. Patients were evaluated for major adverse cardiovascular events (MACE: cardiovascular death, myocardial infarction, stroke, transient ischemic attack, venous thromboembolism) and bleeding complications [according to Bleeding Academic Research Consortium (BARC) definition] during in-hospital stay. COVID-19 patients had similar ETP levels compared to controls (AUC 93 ± 24% vs 99 ± 21%, p = 0.339). In the COVID-19 cohort, patients with in-hospital MACE showed lower ETP levels on admission vs those without (AUC 86 ± 14% vs 95 ± 27%, p = 0.041), whereas ETP values were comparable in patients with or without bleeding (AUC 82 ± 16% vs 95 ± 26%, p = 0.337). An interaction between age and ETP levels for both MACE and bleeding complications was observed, where a younger age was associated with an inverse relationship between ETP values and adverse event risk (p 0.018 for MACE and 0.050 for bleeding). Patients with COVID-19 have similar thrombin potential on admission compared to those with non-COVID-19 pneumonia. In younger COVID-19 patients, lower ETP levels were associated with a higher risk of both MACE and bleeding.
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http://dx.doi.org/10.1007/s11239-021-02497-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190736PMC
June 2021

Simple Parameters from Complete Blood Count Predict In-Hospital Mortality in COVID-19.

Dis Markers 2021 13;2021:8863053. Epub 2021 May 13.

Università del Piemonte Orientale UPO, Novara, Italy.

Introduction: The clinical course of Coronavirus Disease 2019 (COVID-19) is highly heterogenous, ranging from asymptomatic to fatal forms. The identification of clinical and laboratory predictors of poor prognosis may assist clinicians in monitoring strategies and therapeutic decisions.

Materials And Methods: In this study, we retrospectively assessed the prognostic value of a simple tool, the complete blood count, on a cohort of 664 patients ( 260; 39%, median age 70 (56-81) years) hospitalized for COVID-19 in Northern Italy. We collected demographic data along with complete blood cell count; moreover, the outcome of the hospital in-stay was recorded.

Results: At data cut-off, 221/664 patients (33.3%) had died and 453/664 (66.7%) had been discharged. Red cell distribution width (RDW) ( 10.4; < 0.001), neutrophil-to-lymphocyte (NL) ratio ( 7.6; = 0.006), and platelet count ( 5.39; = 0.02), along with age ( 87.6; < 0.001) and gender ( 17.3; < 0.001), accurately predicted in-hospital mortality. Hemoglobin levels were not associated with mortality. We also identified the best cut-off for mortality prediction: a NL ratio > 4.68 was characterized by an odds ratio for in-hospital mortality (OR) = 3.40 (2.40-4.82), while the OR for a RDW > 13.7% was 4.09 (2.87-5.83); a platelet count > 166,000/L was, conversely, protective (OR: 0.45 (0.32-0.63)).

Conclusion: Our findings arise the opportunity of stratifying COVID-19 severity according to simple lab parameters, which may drive clinical decisions about monitoring and treatment.
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http://dx.doi.org/10.1155/2021/8863053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123088PMC
June 2021

[Economic burden of diabetic patients with established atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease.]

Recenti Prog Med 2021 Apr;112(4):302-310

Faculty of Economics, Economic Evaluation and HTA (EEHTA), CEIS, University of Rome "Tor Vergata", Roma - Institute for Leadership and Management in Health, Kingston University London, London, UK.

Objectives: The analysis aimed to quantify the number and costs of patients with type 2 diabetes and atherosclerotic cardiovascular disease or with risk factors for atherosclerotic cardiovascular disease from the Regional Health Service (RHS) perspective of the Marche region.

Materials And Methods: A cost of illness (COI) model was developed to estimate the economic burden associated with diabetes and established atherosclerotic cardiovascular disease or risk factors for atherosclerotic cardiovascular disease. Data were extrapolated from the administrative database of the Marche region and specific inclusion criteria for enrolling patients were adapted from DECLARE-TIMI 58 clinical trial. RHS perspective (drugs, hospitalizations, monitoring cost) and 1 and 4-year time horizons were considered.

Results: The analysis estimated a total number of 92,205 diabetic patients in Marche region in 2014. Of these, 66,306 were patients (5.9% of the resident population) with established atherosclerotic cardiovascular disease (13,104 patients) or risk factors for atherosclerotic cardiovascular disease (53,202 patients). The annual expenditure associated with patients analysed amounted to € 98.8 million (average cost per patient € 1,480) in Marche region. Of these, 52% was associated with hospitalizations. Considering a 4-year time horizon, the overall economic burden rises to over € 301 million per year with an average cost per patient of € 4,545. Stratifying patients between patients hospitalized for heart failure and patients not hospitalized for heart failure, the average annual cost per patient was equal to € 15,896 and equal to € 3,998 respectively.

Conclusions: An important epidemiological and economic burden associated with type 2 diabetes patients were estimated from the analysis due to the disease and the associated comorbidities. The ability to prevent comorbidity risks, especially cardiovascular ones, represents not only a clinical advantage but also a positive reduction in expenditure. Early and effective intervention represents the best strategy to avoid or slow down the evolution of complications of the disease.
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http://dx.doi.org/10.1701/3584.35689DOI Listing
April 2021

Neuroinflammation and Hypothalamo-Pituitary Dysfunction: Focus of Traumatic Brain Injury.

Int J Mol Sci 2021 Mar 7;22(5). Epub 2021 Mar 7.

Division of Endocrinology, University Hospital "Maggiore della Carità", 28100 Novara, Italy.

The incidence of traumatic brain injury (TBI) has increased over the last years with an important impact on public health. Many preclinical and clinical studies identified multiple and heterogeneous TBI-related pathophysiological mechanisms that are responsible for functional, cognitive, and behavioral alterations. Recent evidence has suggested that post-TBI neuroinflammation is responsible for several long-term clinical consequences, including hypopituitarism. This review aims to summarize current evidence on TBI-induced neuroinflammation and its potential role in determining hypothalamic-pituitary dysfunctions.
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http://dx.doi.org/10.3390/ijms22052686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961958PMC
March 2021

Clinical outcome with different doses of low-molecular-weight heparin in patients hospitalized for COVID-19.

J Thromb Thrombolysis 2021 Mar 1. Epub 2021 Mar 1.

Azienda Ospedaliero-Universitaria Maggiore della Carità, Novara, Italy.

A pro-thrombotic milieu and a higher risk of thrombotic events were observed in patients with CoronaVirus disease-19 (COVID-19). Accordingly, recent data suggested a beneficial role of low molecular weight heparin (LMWH), but the optimal dosage of this treatment is unknown. We evaluated the association between prophylactic vs. intermediate-to-fully anticoagulant doses of enoxaparin and in-hospital adverse events in patients with COVID-19. We retrospectively included 436 consecutive patients admitted in three Italian hospitals. Outcome according to the use of prophylactic (4000 IU) vs. higher (> 4000 IU) daily dosage of enoxaparin was evaluated. The primary end-point was in-hospital death. Secondary outcome measures were in-hospital cardiovascular death, venous thromboembolism, new-onset acute respiratory distress syndrome (ARDS) and mechanical ventilation. A total of 287 patients (65.8%) were treated with the prophylactic enoxaparin regimen and 149 (34.2%) with a higher dosing regimen. The use of prophylactic enoxaparin dose was associated with a similar incidence of all-cause mortality (25.4% vs. 26.9% with the higher dose; OR at multivariable analysis, including the propensity score: 0.847, 95% CI 0.400-0.1.792; p = 0.664). In the prophylactic dose group, a significantly lower incidence of cardiovascular death (OR 0.165), venous thromboembolism (OR 0.067), new-onset ARDS (OR 0.454) and mechanical intubation (OR 0.150) was observed. In patients hospitalized for COVID-19, the use of a prophylactic dosage of enoxaparin appears to be associated with similar in-hospital overall mortality compared to higher doses. These findings require confirmation in a randomized, controlled study.
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http://dx.doi.org/10.1007/s11239-021-02401-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919624PMC
March 2021

Insulin/IGF Axis in Breast Cancer: Clinical Evidence and Translational Insights.

Biomolecules 2021 01 19;11(1). Epub 2021 Jan 19.

Department of Translational Medicine, University of Eastern Piedmont, Via Solaroli 17, 28100 Novara, Italy.

Background: Breast cancer (BC) is the most common neoplasm in women. Many clinical and preclinical studies investigated the possible relationship between host metabolism and BC. Significant differences among BC subtypes have been reported for glucose metabolism. Insulin can promote tumorigenesis through a direct effect on epithelial tissues or indirectly by affecting the levels of other modulators, such as the insulin-like growth factor (IGF) family of receptors, sex hormones, and adipokines. The potential anti-cancer activity of metformin is based on two principal effects: first, its capacity for lowering circulating insulin levels with indirect endocrine effects that may impact on tumor cell proliferation; second, its direct influence on many pro-cancer signaling pathways that are key drivers of BC aggressiveness.

Methods: In the present review, the interaction between BC, host metabolism, and patients' prognosis has been reviewed across available literature evidence.

Conclusions: Obesity, metabolic syndrome, and insulin resistance are all involved in BC growth and could have a relevant impact on prognosis. All these factors act through a pro-inflammatory state, mediated by cytokines originated in fat tissue, and seem to be related to a higher risk of BC development and worse prognosis.
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http://dx.doi.org/10.3390/biom11010125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835955PMC
January 2021

Primary Pituitary Lymphoma As Rare Cause Of A Pituitary Mass And Hypopituitarism In Adulthood.

Endocr Pract 2020 Nov;26(11):1337-1350

Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Torino, Italy.

Objective: Differential diagnosis of nonadenomatous sellar masses causing hypopituitarism is still a challenge. Among these masses, growing evidence has demonstrated that primary pituitary lymphoma is a specific and emerging entity. The aim of our study was to describe our experience with a case of primary pituitary lymphoma and to perform a review of the available literature.

Methods: We searched relevant databases up to March 2020, identifying 36 suitable articles basing on inclusion criteria (primary pituitary lymphoma in adult immunocompetent subjects). Overall, 43 cases were included in the review, adding a new case diagnosed and treated in our hospital. Epidemiologic data, clinical presentation, hormonal status, radiologic findings, pathology, treatment, and outcome were extracted.

Results: Mean age at diagnosis was 58.9 years, without gender difference. Symptoms related to mass were common (52.3%), in particular cranial nerve palsy (70.5%), headache (56.8%), and alteration in visual field (40.9%). Impaired hormonal status was detected in 89.7% of patients; of them, 58.9% presented with anterior pituitary failure (partial or total), while 25.6% presented with panhypopituitarism. Overall, diabetes insipidus was present in 30.8% and hyperprolactinemia in 41.0% of patients. The majority of patients presented a radiologically invasive mass in the suprasellar region and cavernous sinus (65.9% and 40.9%, respectively) and histologic diagnosis of diffuse B-cell lymphoma (54.5%).

Conclusion: The differential diagnosis of sellar and parasellar masses causing hypopituitarism should include primary pituitary lymphoma, even in absence of systemic symptoms or posterior pituitary dysfunction. The disease has a heterogeneous pattern, so a collaboration between endocrinologists, neuroradiologists, neurosurgeons, and hematologists is desirable.
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http://dx.doi.org/10.4158/EP-2020-0286DOI Listing
November 2020

Dynamic tests in pituitary endocrinology: pitfalls in interpretation during aging.

Neuroendocrinology 2021 Jan 15. Epub 2021 Jan 15.

Aging and age-related diseases represent hot topics of current research. Progressive damage in morphology and function of cells and tissue characterizes the normal process of aging, that is influenced by both genetic and environmental factors. The ability of each individual to adapt to these stressors defines the type of aging and the onset of age-related diseases (i.e. metabolic syndrome, inflammatory disorders, cancer and neurodegenerative diseases). The endocrine system plays a critical role in this process, because of its complex relationships with brain, immune system, and skeletal muscle; thus, alterations in hormonal networks occur during aging to maintain homeostasis, with consequent under- or overactivity of specific hypothalamic-pituitary-peripheral hormone axes. On the other hand, the increase in life expectancy has led to increasing incidence of age-related diseases, including endocrine disorders, which may prompt assessment of endocrine function in aging individuals. In this context, there is growing awareness that natural changes of endocrine physiology and physiopathology occurring with increasing age may necessitate age-driven diagnostic cut-offs requiring validation in the elderly. This review aims to analyse the available literature on the hormone response to the most important dynamic tests currently used in the clinical practice for the screening of anterior pituitary-related diseases, to underline pitfalls in interpretation during aging.
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http://dx.doi.org/10.1159/000514434DOI Listing
January 2021

Phenotypes Associated With MEN1 Syndrome: A Focus on Genotype-Phenotype Correlations.

Front Endocrinol (Lausanne) 2020 18;11:591501. Epub 2020 Nov 18.

Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant inherited tumor syndrome, associated with parathyroid, pituitary, and gastro-entero-pancreatic (GEP) neuroendocrine tumors (NETs). MEN1 is usually consequent to different germline and somatic mutations of the tumor suppressor gene, although phenocopies have also been reported. This review analyzed main biomedical databases searching for reports on gene mutations and focused on aggressive and aberrant clinical manifestations to investigate the potential genotype-phenotype correlation. Despite efforts made by several groups, this link remains elusive to date and evidence that aggressive or aberrant clinical phenotypes may be related to specific mutations has been provided by case reports and small groups of MEN1 patients or families. In such context, a higher risk of aggressive tumor phenotypes has been described in relation to frameshift and non-sense mutations, and predominantly associated with aggressive GEP NETs, particularly pancreatic NETs. In our experience a novel heterozygous missense mutation at in exon 6 was noticed in a MEN1 patient operated for macro-prolactinoma, who progressively developed recurrent parathyroid adenomas, expanding gastrinomas and, long after the first MEN1 manifestation, a neuroendocrine uterine carcinoma. In conclusion, proof of genotype-phenotype correlation is limited but current evidence hints at the need for long-term interdisciplinary surveillance in patients with aggressive phenotypes and genetically confirmed MEN1.
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http://dx.doi.org/10.3389/fendo.2020.591501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708377PMC
June 2021

Insights into non-classic and emerging causes of hypopituitarism.

Nat Rev Endocrinol 2021 02 27;17(2):114-129. Epub 2020 Nov 27.

Endocrinology, Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.

Hypopituitarism is defined as one or more partial or complete pituitary hormone deficiencies, which are related to the anterior and/or posterior gland and can have an onset in childhood or adulthood. The most common aetiology is a sellar or suprasellar lesion, often an adenoma, which causes hypopituitarism due to tumour mass effects, or the effects of surgery and/or radiation therapy. However, other clinical conditions, such as traumatic brain injury, and autoimmune and inflammatory diseases, can result in hypopituitarism, and there are also genetic causes of hypopituitarism. Furthermore, the use of immune checkpoint inhibitors to treat cancer is increasing the risk of hypopituitarism, with a pattern of hormone defects that is different from the classic patterns and depends on mechanisms that are specific for each drug. Moreover, autoantibody production against the pituitary and hypothalamus has been demonstrated in studies investigating the development or worsening of some cases of hypopituitarism. Finally, evidence suggests that posterior pituitary damage can affect oxytocin secretion. The aim of this Review is to summarize current knowledge on non-classic and emerging causes of hypopituitarism, so as to help clinicians improve early identification, avoid life-threatening events and improve the clinical care and quality of life of patients at risk of hypopituitarism.
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http://dx.doi.org/10.1038/s41574-020-00437-2DOI Listing
February 2021

Fatality rate and predictors of mortality in an Italian cohort of hospitalized COVID-19 patients.

Sci Rep 2020 11 26;10(1):20731. Epub 2020 Nov 26.

Department of Translational Medicine, Università del Piemonte Orientale UPO, Via Solaroli 17, 28100, Novara, NO, Italy.

Clinical features and natural history of coronavirus disease 2019 (COVID-19) differ widely among different countries and during different phases of the pandemia. Here, we aimed to evaluate the case fatality rate (CFR) and to identify predictors of mortality in a cohort of COVID-19 patients admitted to three hospitals of Northern Italy between March 1 and April 28, 2020. All these patients had a confirmed diagnosis of SARS-CoV-2 infection by molecular methods. During the study period 504/1697 patients died; thus, overall CFR was 29.7%. We looked for predictors of mortality in a subgroup of 486 patients (239 males, 59%; median age 71 years) for whom sufficient clinical data were available at data cut-off. Among the demographic and clinical variables considered, age, a diagnosis of cancer, obesity and current smoking independently predicted mortality. When laboratory data were added to the model in a further subgroup of patients, age, the diagnosis of cancer, and the baseline PaO/FiO ratio were identified as independent predictors of mortality. In conclusion, the CFR of hospitalized patients in Northern Italy during the ascending phase of the COVID-19 pandemic approached 30%. The identification of mortality predictors might contribute to better stratification of individual patient risk.
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http://dx.doi.org/10.1038/s41598-020-77698-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692524PMC
November 2020

Exploring extra dimensions to capture saliva metabolite fingerprints from metabolically healthy and unhealthy obese patients by comprehensive two-dimensional gas chromatography featuring Tandem Ionization mass spectrometry.

Anal Bioanal Chem 2021 Jan 3;413(2):403-418. Epub 2020 Nov 3.

Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 10125, Torino, Italy.

This study examines the information potential of comprehensive two-dimensional gas chromatography combined with time-of-flight mass spectrometry (GC×GC-TOF MS) and variable ionization energy (i.e., Tandem Ionization™) to study changes in saliva metabolic signatures from a small group of obese individuals. The study presents a proof of concept for an effective exploitation of the complementary nature of tandem ionization data. Samples are taken from two sub-populations of severely obese (BMI > 40 kg/m) patients, named metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Untargeted fingerprinting, based on pattern recognition by template matching, is applied on single data streams and on fused data, obtained by combining raw signals from the two ionization energies (12 and 70 eV). Results indicate that at lower energy (i.e., 12 eV), the total signal intensity is one order of magnitude lower compared to the reference signal at 70 eV, but the ranges of variations for 2D peak responses is larger, extending the dynamic range. Fused data combine benefits from 70 eV and 12 eV resulting in more comprehensive coverage by sample fingerprints. Multivariate statistics, principal component analysis (PCA), and partial least squares discriminant analysis (PLS-DA) show quite good patient clustering, with total explained variance by the first two principal components (PCs) that increases from 54% at 70 eV to 59% at 12 eV and up to 71% for fused data. With PLS-DA, discriminant components are highlighted and putatively identified by comparing retention data and 70 eV spectral signatures. Within the most informative analytes, lactose is present in higher relative amount in saliva from MHO patients, whereas N-acetyl-D-glucosamine, urea, glucuronic acid γ-lactone, 2-deoxyribose, N-acetylneuraminic acid methyl ester, and 5-aminovaleric acid are more abundant in MUO patients. Visual feature fingerprinting is combined with pattern recognition algorithms to highlight metabolite variations between composite per-class images obtained by combining raw data from individuals belonging to different classes, i.e., MUO vs. MHO.Graphical abstract.
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http://dx.doi.org/10.1007/s00216-020-03008-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7806578PMC
January 2021

Atypical Progeroid Syndrome and Partial Lipodystrophy Due to Gene p.R349W Mutation.

J Endocr Soc 2020 Oct 1;4(10):bvaa108. Epub 2020 Aug 1.

Obesity and Lipodystrophy Center, Endocrinology Unit, University Hospital of Pisa, Pisa, Italy.

Atypical progeroid syndrome (APS) comprises heterogeneous disorders characterized by variable degrees of fat loss, metabolic alterations, and comorbidities that affect skeleton, muscles, and/or the heart. We describe 3 patients that were referred to our center for the suspicion of lipodystrophy. They had precocious aging traits such as short stature, mandibular hypoplasia, beaked nose, and partial alopecia manifesting around 10 to 15 years of age recurrently associated with: (1) partial lipodystrophy; (2) proteinuric nephropathy; (3) heart disease (rhythm disorders, valvular abnormalities, and cardiomyopathy); and (4) sensorineural hearing impairment. In all patients, genetic testing revealed a missense heterozygous lamin A/C gene () mutation c.1045 C > T (p.Arg349Trp). Ten patients with p.R349W mutation have been reported so far, all presenting with similar features, which represent the key pathological hallmarks of this subtype of APS. The associated kidney and cardiac complications occurring in the natural history of the disease may reduce life expectancy. Therefore, in these patients a careful and periodic cardiac and kidney function evaluation is required.
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http://dx.doi.org/10.1210/jendso/bvaa108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474543PMC
October 2020

Fat-Free Mass Is Better Related to Serum Uric Acid Than Metabolic Homeostasis in Prader-Willi Syndrome.

Nutrients 2020 08 25;12(9). Epub 2020 Aug 25.

Division of Auxology, IRCCS Istituto Auxologico Italiano, 28824 Piancavallo (VB), Italy.

: Prader-Willi syndrome (PWS) is conventionally regarded as a model of genetic obesity carrying a metabolically healthier profile and fat compartmentalization than subjects with non-syndromic obesity. Serum uric acid (sUA) is a recognized surrogate marker of metabolic derangement. As no information is currently available on sUA levels in adults with PWS, we aimed to analyze sUA in a large cohort of adult patients with PWS in comparison to a control counterpart; secondly, we aimed to investigate the metabolic and non-metabolic determinants of sUA in PWS. : A cross-sectional study was conducted on 89 consecutive adult patients with genetically confirmed PWS spanning a wide BMI range (17.2-56.7 kg/m). As controls, 180 age-, sex- and BMI-matched healthy controls were included. sUA levels were analyzed in relation to the PWS status, metabolic variables, hormone status, body composition, and resting energy expenditure (REE). Bivariate correlation and multivariable regression studies were used to test for predictors of sUA in PWS. : Despite having similar BMI values, patients with PWS presented with higher FM ( < 0.0001), lower FFM ( < 0.0001) and REE values than controls ( < 0.0001). In PWS, sUA levels were non-significantly different between subjects with and without obesity (5.4 ± 1.3 vs. 4.9 ± 1.1 mg/dL, = 0.09), and did not vary significantly in relation to genotype, sex steroid or GH replacement, as well as psychiatric treatments. Rates of hyperuricaemia (19.1% vs. 33.7%, < 0.01) and absolute sUA levels were lower in patients with PWS compared to controls owing to significant differences between subgroups with obesity (5.5 ± 1.4 vs. 6.6 ± 1.6 mg/dL, < 0.0001). In merged populations, sUA increased in parallel with age, BMI, FM, FFM, REE, glucolipid homeostasis, and inflammatory markers. In a separate analysis in PWS, however, sUA correlations with BMI, FM, and inflammatory markers were null. Stepwise multivariable regression analysis in the PWS group adjusted for karyotype, age, sex, FM, FFM, obesity, triglycerides, and HDL cholesterol, showed that sUA levels were independently associated with FFM (β = 0.35, < 0.0001) and, albeit less significantly, with triglycerides (β = 0.23, < 0.05). The introduction of height-normalized FFM (FFM index) in the regression model, however, abrogated the predictive role of FFM on sUA. : FFM mass is a strong predictor of sUA. PWS is associated to lower sUA levels than controls likely due to genetic predisposition to different body composition and healthier metabolic phenotype. Further studies are warranted to assess purine metabolism and the clinical significance of the FFM index in PWS.
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http://dx.doi.org/10.3390/nu12092583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551470PMC
August 2020

Methimazole Treatment and Risk of Acute Pancreatitis: A Population-based Cohort Study.

J Clin Endocrinol Metab 2020 12;105(12)

Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.

Context: A warning has been recently issued by the European Medicine Agency (EMA) regarding a potential increased risk of acute pancreatitis (AP) in methimazole (MMI) users.

Objective: To investigate the association between MMI and the diagnosis of AP in a population-based study.

Materials And Methods: A retrospective analysis of administrative health databases was conducted (2013-2018). Relevant data were obtained from: (1) inhabitants registry, (2) hospital discharge records (ICD-9-CM 577.0), and (3) drug claims registry (ATC H03BB02). We evaluated AP risk in MMI users in 18 months of treatment, stratifying results by trimester. Poisson regression was used to estimate the age- and sex-adjusted rate ratios (RR), and the relative 95% confidence intervals (CI), comparing rates of AP between MMI users and nonusers. The absolute risk of AP in MMI users was also calculated.

Results: A total of 23 087 new users of MMI were identified. Among them, 61 hospitalizations occurred during the study period. An increase in AP risk was evident during the first 3 trimesters of therapy (RR 3.40 [95% CI: 2.12-5.48]; RR 2.40 [95% CI: 1.36-4.23]; RR 2.80 [95% CI: 1.66-4.73]), but disappeared thereafter. The AP absolute risk in MMI users during the first 18 months of treatment was less than 0.4% in all sex and age classes.

Conclusions: Our results support the EMA warning, suggesting an increased risk of AP associated with MMI use. However, such an increase seems limited to the first months of MMI treatment. Moreover, in absolute terms, the probability of AP is low among patients, well below 1%.
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http://dx.doi.org/10.1210/clinem/dgaa544DOI Listing
December 2020

Molecular characterisation and clinical correlation of papillary thyroid microcarcinoma.

Endocrine 2021 Jan 3;71(1):149-157. Epub 2020 Jul 3.

Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Città della Salute e della Scienza, Torino, Italy.

Purpose: Papillary thyroid microcarcinoma (mPTC) is defined as a papillary thyroid cancer sized 10 mm or less. Despite their generally indolent clinical course and good prognosis, a subset of mPTCs shows potentially aggressive behaviour.

Methods: To search for predictors of clinical outcome of mPTCs, we retrospectively evaluated the genetic tumour profile of 100 patients (23 M/77 F, mean age ± SD 53.8 ± 13.4 years) with histologically confirmed mPTCs through analysis of BRAF, NRAS and TERT promoter mutations as well as RET/PTC translocations.

Results: Mean follow-up period was 8.4 ± 3.6 years. In 55 cases, mPTC were detected incidentally after surgery. Capsular invasion, bilateralism and multifocality were found in 11/100, 17/100 and 24/100 cases, respectively, while lymph-nodes metastases were present at diagnosis in 9/100 cases. After 3.5 ± 2.0 years, tumour relapse occurred in 6/100 cases and was locoregional in five (two in the thyroid bed, three in laterocervical lymph-nodes), while lung metastasis occurred in one case. Biochemical persistence of disease was seen in 1/100 case. Mutations occurred in 55/100 cases; BRAF was the most frequently detected (49/100) and was associated with higher tumour size, bilateralism and follicular variant but not with capsular invasion. RET/PTC rearrangements were found in 2/100 cases, NRAS in 4/100, while no mutations of TERT promoter gene were detected. Despite the observed association between BRAF mutation and unfavourable histopathological features, we found no direct association with tumour recurrence, distant metastases and mortality.

Conclusion: In our study, the search for the most frequent genetic alterations as prognostic markers in mPTCs would not have changed the therapeutic strategy.
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http://dx.doi.org/10.1007/s12020-020-02380-8DOI Listing
January 2021

The role of metabolic setting in predicting the risk of early tumour relapse of differentiated thyroid cancer (DTC).

Eur J Clin Nutr 2020 07 9;74(7):1038-1046. Epub 2020 Jun 9.

Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Background: The role of insulin resistance and adipocytokines in determining the phenotype and recurrence of differentiated thyroid cancer (DTC) is still unknown. In a previous study, we observed an association between metabolic setting, circulating adipocytokines and thyroid cancer phenotype. The aim of this study was to evaluate the clinical follow-up of patients with DTC and the predictive role of metabolic setting on the risk of tumour relapse.

Methods: Between September 2016 and January 2017, 57 patients were admitted to our institution to undergo total thyroidectomy because of suspected DTC. Thirty patients with post-surgical histological diagnosis of DTC were included in the study. Each subject underwent pre-surgical analysis of anthropometric parameters, thyroid function and autoimmunity, glucose metabolism, insulin resistance (HOMA-IR) and levels of unacylated and acylated ghrelin, obestatin, leptin and adiponectin. Tumour recurrence at 1 and 3 years from diagnosis was assessed.

Results: Most patients were females (21F, 9M) with a median age at diagnosis of 50.0 (41.0-58.8). At baseline, overweight was found in 7 patients and obesity in 6 cases. Insulin resistance was detected in 14 patients. Overall, 17 patients (56.7%) underwent radioiodine treatment after surgery. During the follow-up, we observed a persistent biochemical disease in one patient whereas tumour relapse was found in six patients at 1 year from diagnosis (lymph node metastases) and in one patient at 3 years from diagnosis (lung metastases). Independently from age, sex, stage of disease and the presence of lymph node metastasis at diagnosis, higher BMI, leptin and insulin levels as well as HOMA-IR were associated with a higher risk of tumour relapse (p < 0.05 for all).

Conclusions: Our results highlight a possible role for BMI, leptin and insulin resistance as predictors of early DTC relapse.
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http://dx.doi.org/10.1038/s41430-020-0671-yDOI Listing
July 2020

Immunomodulatory Effects of Vitamin D in Thyroid Diseases.

Nutrients 2020 May 16;12(5). Epub 2020 May 16.

Department of Translational Medicine, University of Piemonte Orientale UPO, 28100 Novara, Italy.

Vitamin D is a secosteroid with a pleiotropic role in multiple physiological processes. Besides the well-known activity on bone homeostasis, recent studies suggested a peculiar role of vitamin D in different non-skeletal pathways, including a key role in the modulation of immune responses. Recent evidences demonstrated that vitamin D acts on innate and adaptative immunity and seems to exert an immunomodulating action on autoimmune diseases and cancers. Several studies demonstrated a relationship between vitamin D deficiency, autoimmune thyroid disorders, and thyroid cancer. This review aims to summarize the evidences on the immunomodulatory effect of vitamin D on thyroid diseases.
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http://dx.doi.org/10.3390/nu12051444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7284826PMC
May 2020

Pathophysiological Role and Therapeutic Implications of Vitamin D in Autoimmunity: Focus on Chronic Autoimmune Diseases.

Nutrients 2020 Mar 17;12(3). Epub 2020 Mar 17.

Department of Translational Medicine, Università del Piemonte Orientale UPO, 28100 Novara, Italy.

Vitamin D is a pleiotropic secosteroid yielding multiple actions in human physiology. Besides the canonical regulatory activity on bone metabolism, several non-classical actions have been described and the ability of vitamin D to partake in the regulation of the immune system is particularly interesting, though far stronger and convincing evidence has been collected in in vitro as compared to in vivo studies. Whether vitamin D is able to regulate at physiological concentrations the human immune system remains unproven to date. Consequently, it is not established if vitamin D status is a factor involved in the pathogenesis of immune-mediated diseases and if cholecalciferol supplementation acts as an adjuvant for autoimmune diseases. The development of autoimmunity is a heterogeneous process, which may involve different organs and systems with a wide range of clinical implications. In the present paper, we reviewed the current evidences regarding vitamin D role in the pathogenesis and management of different autoimmune diseases.
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http://dx.doi.org/10.3390/nu12030789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146294PMC
March 2020

Comparable efficacy with similarly low risk of hypoglycaemia in patient- vs physician-managed basal insulin initiation and titration in insulin-naïve type 2 diabetic subjects: The Italian Titration Approach Study.

Diabetes Metab Res Rev 2020 09 5;36(6):e3304. Epub 2020 Apr 5.

Section of Endocrinology and Metabolism, Department of Medicine, Perugia University Medical School, Perugia, Italy.

Aims: People with uncontrolled type 2 diabetes (T2DM) often delay initiating and titrating basal insulin. Patient-managed titration may reduce such deferral. The Italian Titration Approach Study (ITAS) compared the efficacy and safety of insulin glargine 300 U/mL (Gla-300) initiation and titration using patient- (nurse-supported) or physician-management in insulin-naïve patients with uncontrolled T2DM.

Materials And Methods: ITAS was a multicentre, phase IV, 24-week, open-label, randomized (1:1), parallel-group study. Insulin-naïve adults with T2DM for ≥1 year with poor metabolic control initiated Gla-300 after discontinuation of SU/glinides, and were randomized to self-titrate insulin dose (nurse-assisted) or have it done by the physician. The primary endpoint was change in HbA . Secondary outcomes included hypoglycaemia incidence and rate, change in fasting self-monitored plasma glucose, patient-reported outcomes (PROs), and adverse events.

Results: Three hundred and fifty five participants were included in the intention-to-treat population. At Week 24, HbA reduction from baseline was non-inferior in patient- vs physician-managed arms [least squares mean (LSM) change (SE): -1.60% (0.06) vs -1.49% (0.06), respectively; LSM difference: -0.11% (95% CI: -0.26 to 0.04)]. The incidence and rates of hypoglycaemia were similarly low in both arms: relative risk of confirmed and/or severe nocturnal (00:00-05:59 hours) hypoglycaemia was 0.77 (95% CI: 0.27 to 2.18). No differences were observed for improvement in PROs. No safety concerns were reported.

Conclusions: In the T2DM insulin-naïve, SU/glinides discontinued population, patient-managed (nurse-assisted) titration of Gla-300 may be a suitable option as it provides improved glycaemic control with low risk of hypoglycaemia, similar to physician-managed titration.
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http://dx.doi.org/10.1002/dmrr.3304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7540052PMC
September 2020

Incidence and prevalence of hyperthyroidism: a population-based study in the Piedmont Region, Italy.

Endocrine 2020 07 13;69(1):107-112. Epub 2020 Feb 13.

Department of Translational Medicine, Università del Piemonte Orientale, Novara, Italy.

Purpose: Unrecognized and untreated hyperthyroidism leads to serious clinical complications with adverse outcomes for patients and increasing costs for the health care system. Hence, adequate knowledge of the epidemiological features of such condition is desirable to plan effective interventions. The aim of our study was to estimate incidence and prevalence of hyperthyroidism in the mildly iodine-deficient Italian Region of Piedmont.

Methods: A retrospective cohort study was conducted using Administrative Health Databases of the Piedmont Region, Italy (2012-2018). Hyperthyroidism cases were defined as the subjects who had at least one of the following claims: (i) hospital discharge records with hyperthyroidism diagnosis code; (ii) exemption from co-payment for hyperthyroidism; (iii) prescription of one of the following medications: methimazole, propylthiouracil, or potassium perchlorate.

Results: The overall prevalence was 756 per 100,000 inhabitants [95% CI 748-764], and the overall incidence was 81 per 100,000-person year [95% CI 80-82]. The prevalence and incidence increased with age and were two-fold higher among women than men. Women also showed two distinct peaks in incidence at the age of 30 and 50; after the age of 60, the trend became similar between sexes. With regard to the geographic distribution, an increasing gradient of incidence was observed from the northern to the south-western areas of the Region.

Conclusion: This is the first Italian study based on health databases to estimate the incidence and prevalence of hyperthyroidism in the general population. This approach can represent an inexpensive and simple method to monitor patterns of hyperthyroidism in iodine-deficient areas.
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http://dx.doi.org/10.1007/s12020-020-02222-7DOI Listing
July 2020

Irisin levels in genetic and essential obesity: clues for a potential dual role.

Sci Rep 2020 01 23;10(1):1020. Epub 2020 Jan 23.

Istituto Auxologico Italiano, IRCCS, Division of General Medicine, Ospedale S. Giuseppe, via Cadorna 90, 28824, Piancavallo di Oggebbio, (VB), Italy.

Irisin is conventionally regarded as a myokine involved in the browning of white adipose tissue, energy expenditure and glucose tolerance. Its potential link to fat accumulation and metabolic dysfunction is debated. We sought to explore the relationship between circulating irisin and components of body composition in two different phenotypes of severe obesity. For this purpose, 30 obese adults with Prader-Will syndrome (PWS) (age 35.7 ± 1.5 y, BMI 45.5 ± 1.5 kg/m) and 30 adult controls with common obesity (age 34.9 ± 1.7 y, BMI 46.8 ± 1.4 kg/m) underwent analysis of irisin levels, metabolic profile, body composition and resting energy expenditure (REE). Normal irisin levels were obtained from a group of 20 lean donors (age 32.4 ± 1.5 y, BMI 23.8 ± 0.8 kg/m). Expected differences in body composition and metabolic profile existed between study groups. PWS exhibited lower muscle mass (p < 0.001), FFM (p < 0.001), REE (p < 0.001), as well as insulin (p < 0.05), HOMA-IR (p < 0.05) and triglycerides levels (p < 0.05) than controls with common obesity. In PWS, irisin levels were significantly lower and overall less dispersed than in controls with common obesity (p < 0.05), while being similar to values recorded in lean subjects. To explore the relation between irisin and body composition in obesity, univariate correlation analysis in the obese populations as a whole showed positive associations between irisin and muscle mass (p = 0.03) as well as REE (p = 0.01), which disappeared when controlled for the PWS status. Noticeably, a positive association became evident between irisin and %FM after controlling for the PWS status (p = 0.02). Also positive were associations between irisin and insulin (p = 0.02), HOMA-IR (p = 0.02) and triglycerides (p = 0.04). In stepwise multivariable regression analysis, irisin levels were independently predicted by the PWS status (p = 0.001), %FM (p = 0.004) and triglycerides (p = 0.008). Current results suggest that obese adults with PWS harbor lower irisin levels than individuals with common obesity. The divergent models of obesity herein studied suggest a potential link between circulating irisin and muscle mass and metabolic dysfunction relating to adiposity.
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http://dx.doi.org/10.1038/s41598-020-57855-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978420PMC
January 2020

The relationship between cortisol and IGF-I influences metabolic alteration in pediatric overweight and obesity.

Eur J Endocrinol 2020 Mar;182(3):255-264

SCDU of Pediatrics, Department of Health Sciences.

Background/objective: Data on metabolic impairments in Cushing's syndrome and GH deficiency all suggest that the relationship between cortisol and GH/IGF-I axis in obesity may have a role in the related diseases. However, studies focusing only on one of these hormones are often controversial in paediatrics. We aimed to explore the simultaneous relationship between cortisol and IGF-I with the metabolic alterations in paediatric obesity.

Subjects/methods: Retrospective cross-sectional study in a tertiary care center. We recruited 876 (441 males and 435 females) overweight and obese children and adolescents. A complete clinical and biochemical evaluation including OGTT was performed. Cortisol and IGF-I SDS were divided in quartiles and then crossed to explore the reciprocal influence of high/high, low/low, and high/low levels of each one on the metabolic alterations of obesity.

Results: Subjects in the higher quartiles of IGF-I-SDS and cortisol had an increased risk of hypertension, hypercholesterolemia, high levels of triglycerides, and reduced HDL cholesterol. Diversely, lower IGF-I-SDS quartiles were associated with higher blood glucose, insulin, insulin resistance, and reduced insulin sensitivity levels with the rise of cortisol quartiles.

Conclusions: We observed that apart from glucose metabolism that is associated with low IGF-I and high cortisol levels, the other parameters known to be associated with increased cardiovascular risk were related to high levels of both IGF-I and cortisol, even if within normal range. Cortisol and IGF-I play a complex role in the comorbidities of obesity, and the evaluation of both variables could clarify some of the discordant results.
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http://dx.doi.org/10.1530/EJE-19-0792DOI Listing
March 2020

Vitamin D as a Biomarker of Ill Health among the Over-50s: A Systematic Review of Cohort Studies.

Nutrients 2019 Oct 6;11(10). Epub 2019 Oct 6.

Department of Translational Medicine, Università del Piemonte Orientale, 28100 Novara, Italy.

Background: The association between circulating levels of vitamin D and the incidence of chronic diseases is known. The identification of vitamin D as a biomarker of physiological/pathological ageing could contribute to expanding current knowledge of its involvement in healthy ageing.

Methods: According to PRISMA guidelines, a systematic review was conducted on cohorts studying the role of 25OH-Vitamin D [25(OH)D] and 1,25(OH)-Vitamin D [1,25(OH)D] concentrations as biomarkers of healthy ageing. We consulted MedLine, Scopus, and Web of Science to search for studies on the association between vitamin D status in populations of originally healthy adults, and outcomes of longevity, illness, and physical and cognitive functionality. The quality of the studies was assessed using the Newcastle Ottawa scale.

Results: Twenty cohorts from 24 articles were selected for this review. Inverse associations were found between low 25(OH)D levels and all-cause mortality, respiratory and cardiovascular events, as well as markers relating to hip and non-vertebral fractures. Associations between 1,25(OH)D and healthy ageing outcomes gave similar results, although of lower clinical significance.

Conclusions: This systematic review pinpoints peculiar aspects of vitamin D as a multidimensional predictor of ill health in the ageing process. Further well-designed controlled trials to investigate whether vitamin D supplement results in superior outcomes are warranted in the future.
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http://dx.doi.org/10.3390/nu11102384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836048PMC
October 2019

Predictors of recurrence of pheochromocytoma and paraganglioma: a multicenter study in Piedmont, Italy.

Hypertens Res 2020 06 4;43(6):500-510. Epub 2019 Oct 4.

Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, Turin, 10126, Italy.

The available data on the natural history of pheochromocytomas and paragangliomas after radical surgery are heterogeneous and discordant. The aim of our retrospective multicenter study was to find predictors of recurrence in patients with pheochromocytomas and sympathetic paragangliomas submitted to radical surgery in Piedmont (a region in northwest Italy). We collected data from 242 patients diagnosed between 1990 and 2016. Forty-two patients (17.4%) had disease recurrence. Multivariate analysis showed that genetic mutation (HR = 3.62; 95% CI 1.44-9.13; p = 0.006), younger age (HR = 0.97; 95% CI 0.95-0.99; p = 0.031) and larger tumor size (HR = 1.01; 95% CI 1.00-1.02; p = 0.015) were independently associated with a higher recurrence risk of pheochromocytoma and paraganglioma; in pheochromocytomas, genetic mutation (HR = 3.4; 95% CI 1.00-11.48; p = 0.049), younger age (HR = 0.97; 95% CI 0.94-0.99; p = 0.02), higher tumor size (HR = 1.01; 95% CI 1.00-1.03; p = 0.043) and PASS value (HR = 1.16; 95% CI 1.03-1.3; p = 0.011) were associated with recurrence. Moreover, tumor size was the only predictor of metastatic pheochromocytoma and paraganglioma (HR = 4.6; 95% CI 1.4-15.0; p = 0.012); tumor size (HR = 3.93; 95% CI 1.2-16.4; p = 0.026) and PASS value (HR = 1.27; 95% CI 1.06-1.53; p = 0.007) were predictors of metastatic pheochromocytoma. In conclusion, our findings suggest that the recurrence of pheochromocytoma and sympathetic paraganglioma develops more frequently in younger subjects, patients with a family history of chromaffin tissue neoplasms, mutations in susceptibility genes, larger tumors and higher values of PASS. We recommend genetic testing in all patients with PPGL and strict follow-up at least on an annual basis.
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http://dx.doi.org/10.1038/s41440-019-0339-yDOI Listing
June 2020

Early Detection of Microvascular Changes in Patients with Diabetes Mellitus without and with Diabetic Retinopathy: Comparison between Different Swept-Source OCT-A Instruments.

J Diabetes Res 2019 12;2019:2547216. Epub 2019 Jun 12.

Eye Clinic, University Hospital "Maggiore della Carità", Novara, Italy.

Optical coherence tomography angiography (OCT-A) has recently improved the ability to detect subclinical and early clinically visible microvascular changes occurring in patients with diabetes mellitus (DM). The aim of the present study is to evaluate and compare early quantitative changes of macular perfusion parameters in patients with DM without DR and with mild nonproliferative DR (NPDR) evaluated by two different swept-source (SS) OCT-A instruments using two scan protocols (3 × 3 mm and 6 × 6 mm). One hundred eleven subjects/eyes were prospectively evaluated: 18 healthy controls (control group), 73 eyes with DM but no DR (no-DR group), and 20 eyes with mild NPDR (DR group). All quantitative analyses were performed using ImageJ and included vessel and perfusion density, area and circularity index of the FAZ, and vascular complexity parameters. The agreement between methods was assessed according to the method of Bland-Altman. A significant decrease in the majority of the considered parameters was found in the DR group versus the controls with both instruments. The results of Bland-Altman analysis showed the presence of a systemic bias between the two instruments with PLEX Elite providing higher values for the majority of the tested parameters when considering 6 × 6 mm angiocubes and a less definite difference in 3 × 3 mm angiocubes. In conclusion, this study documents early microvascular changes occurring in the macular region of patients at initial stages of DR, confirmed with both SS OCT-A instruments. The fact that early microvascular alterations could not be detected with one instrument does not necessarily mean that these alterations are not actually present, but this could be an intrinsic limitation of the device itself. Further, larger longitudinal studies are needed to better understand microvascular damage at very early stages of diabetic retinal disease and to define the strengths and weaknesses of different OCT-A devices.
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http://dx.doi.org/10.1155/2019/2547216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594252PMC
February 2020

Levothyroxine Replacement in Obese Adults: The Role of Metabolic Variables and Aging on Thyroid Testing Abnormalities.

J Clin Endocrinol Metab 2019 12;104(12):6265-6274

Division of Endocrinology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

Context: General rates of over- and underreplacement in levothyroxine (LT4) users with primary hypothyroidism are variably high. No information on LT4 adequacy exists in obesity.

Objective: We explored rates and factors relating to LT4 adequacy in obese patients with primary hypothyroidism.

Setting: Tertiary care center.

Design: Among 4954 consecutive obese patients admitted between 2011 and 2014, 691 hypothyroid patients receiving LT4 therapy and 691 body mass index (BMI)-, age-, and sex-matched euthyroid controls underwent analysis of thyroid function, glucolipid profile, body composition, and indirect calorimetry. LT4 users were classified into low TSH (<0.27 mU/L), euthyroid (0.27 to 4.2 mU/L), and high TSH (>4.2 mU/L).

Results: LT4 users constituted 13.9% of the incident population. TSH was low in 7.5%, high in 17.2%, and normal in 75.2% of LT4 users. Overtreatment decreased with aging and more LT4 users ≥65 years of age had normal TSH than those <65 years of age (P < 0.05). Compared with the euthyroid obese group, LT4 users showed higher adiposity, similar insulin resistance, but a healthier lipid profile. In multivariable analyses, LT4 dose was predicted by fat-free mass, hypothyroidism cause, and sex (P < 0.0001 to < 0.05). Risk of LT4 overreplacement increased with younger age (OR 0.96; 95% CI 0.94 to 0.99), higher LT4 dose (OR 2.98; 95% CI 1.44 to 6.14), and lower BMI (OR 0.93; 95% CI 0.88 to 0.99). Male sex increased the likelihood of LT4 underreplacement (OR 2.37; 95% CI 1.10 to 5.11).

Conclusions: Obesity is associated with milder rates of inadequate LT4 treatment compared with nonobese populations. LT4 adequacy increases with aging. Age, body composition, and sex are main determinants of LT4 requirements in obesity.
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http://dx.doi.org/10.1210/jc.2019-00773DOI Listing
December 2019

Circulating adipokines and metabolic setting in differentiated thyroid cancer.

Endocr Connect 2019 Jul;8(7):997-1006

Division of Endocrinology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy.

The associative link relating insulin resistance (IR) and adipokines to the occurrence and phenotype of differentiated thyroid cancer (DTC) is unknown. The aim of this study was to evaluate the relationship between IR and adipokines in DTC patients, as compared with carriers of benign thyroid diseases (BTD) and healthy controls. This observational study enrolled 77 subjects phenotyped as DTC (N = 30), BTD (N = 27) and healthy subjects (N = 20). Each subject underwent preoperative analysis of anthropometric parameters, thyroid function and autoimmunity, insulin resistance (HOMA-IR) and levels of unacylated (UAG) and acylated ghrelin (AG), obestatin, leptin and adiponectin. Multivariate regression models were used to test the predictive role of metabolic correlates on thyroid phenotypes and DTC extension. The three groups showed similar age, gender distribution, smoking habit, BMI and thyroid parameters. Obestatin was significantly higher in DTC group compared to BTD (P < 0.05) and control subjects (P < 0.0001). DTC and BTD groups showed higher levels of UAG (P < 0.01) and AG (P < 0.05). Leptin levels were comparable between groups, whereas adiponectin levels were lower in DTC compared to BTD group (P < 0.0001) and controls (P < 0.01). In parallel, HOMA-IR was higher in DTC than BTD (P < 0.05) and control group (P < 0.01). Stepwise multivariable regression analysis showed that obestatin and UAG were independent predictors of DTC (P = 0.01 for both). In an analysis restricted to the DTC group, obestatin levels were associated with the absence of lymph node metastases (P < 0.05). Our results highlight a potential association between metabolic setting, circulating adipokines and thyroid cancer phenotype.
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http://dx.doi.org/10.1530/EC-19-0262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6652238PMC
July 2019

Identification of Haptoglobin as a Readout of rhGH Therapy in GH Deficiency.

J Clin Endocrinol Metab 2019 11;104(11):5263-5273

Department of Health Sciences, University of Piemonte Orientale, Novara, Italy.

Background: GH deficiency (GHD) is characterized by a cluster of cardiovascular risk factors and subtle inflammation. We aimed to demonstrate, through a proteomic approach, molecules directly modulated by GHD and involved in the inflammatory state.

Methods: Ten children with isolated GHD were studied before and after 1 year of treatment with rhGH and compared with 14 matched controls. A two-dimensional electrophoresis plasma proteomics analysis was performed at baseline and after GH treatment to identify the top molecules modulated by GH. In vitro studies on human hepatoma (HepG2) cells were performed to validate the data.

Results: Twelve of 20 proteomic spots were predicted to be isoforms α and β of haptoglobin (Hp) and confirmed by liquid chromatography tandem mass spectrometry and Western immunoblot analyses. Hp levels were higher in patients with GHD than controls at baseline (P < 0.001) and were reduced following GH treatment (P < 0.01). In HepG2 cells, both GH and IGF-1 were able to downregulate IL-6-induced Hp secretion. Moreover, Hp secretion was restored in pegvisomant-treated HepG2 cells.

Conclusions: Hp is a molecule acting in the inflammatory state of GHD and a possible biomarker for GH treatment. Nevertheless, the contribution of other factors and the molecular pathways involved in the GH downregulation of Hp remain to be clearly defined.
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http://dx.doi.org/10.1210/jc.2019-00562DOI Listing
November 2019