Dynamic Tests in Pituitary Endocrinology: Pitfalls in Interpretation during Aging.

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 cutoffs requiring validation in the elderly. This review aims to analyze 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.

Acquired Partial Lipodystrophy: Clinical Management in a Pregnant Patient.

Background: Pregnancy represents an additional challenge to the complex clinical picture of lipodystrophy disorders, and the management of such conditions with related comorbidities has been underreported. This work aims to outline the risk associated with a pregnancy event for women dealing with acquired partial lipodystrophy and the need for diverse but specialized care. Case: We report on the successful pregnancy outcome of a 28-year-old woman with an acquired partial form of lipodystrophy related to an allogenic bone marrow transplant that occurred at pediatric age. Although metabolic control was challenging, glucose levels progressively improved during the pregnancy, and triglycerides increased less than expected. The periodic monitoring of leptin levels showed a progressive increase with a peak in the third trimester (41.53 ng/mL), followed by a fast decline the day after giving birth, with a lower basal level than the prepregnancy period. However, preterm delivery occurred associated with cardiac complications in the mother. Results: A total of 12 studies were retrieved concerning women aged 14 to 38 years with various lipodystrophy phenotypes. Diabetes and hypertriglyceridemia were the most common comorbidities. Most women had successful pregnancies despite gestational complications (including miscarriages), preterm and emergency deliveries, and newborns undergoing partum or postpartum transient or chronic complications. Conclusion: Lipodystrophy disorders expose both mothers and children to very high risk. Intensive monitoring and care of all potential clinical complications should be planned and carried out by a multidisciplinary team before, during, and after the pregnancy. Leptin secretion during pregnancy should be investigated more deeply in these patients.

[18F]FDG-PET/CT in adrenal lesions: diagnostic performance in different clinical settings.

PURPOSE: Data regarding [18F]FDG-PET/CT for the characterization of adrenal lesions are limited. Most of the studies proposed the tumor-to-liver maximum standardized uptake values (SUVratio) > 1.5 as the best cut off to predict malignancy. The aim of the study was to calculate the optimum cut off in a heterogeneous population with adrenal lesions and evaluate the diagnostic performance SUVratio >1.5. PATIENTS AND METHODS: Retrospective analysis of adrenal lesions undergoing [18F]FDG-PET/CT (2013-2022) for different reasons (atypical adrenal incidentalomas, extra adrenal tumor staging). The diagnosis of benignity was assessed by: (i) histology; (ii) stability or minimal diameter increase (<20%/<5 mm) on 12-months follow-up for non-operated patients. The optimal SUVratio and performance of SUVratio >1.5 were calculated by ROC curves. RESULTS: Forty-two consecutive lesions (diameter 36.1 ± 20.3 mm, 6 bilateral) underwent [18F]FDG-PET/CT (19F, age 61.2 ± 11.7 years). Twenty-nine lesions were benign, 11 malignant [8 metastases (2 bilateral) and 1 adrenocortical carcinoma (ACC)] and 2 pheochromocytomas. The SUVratio cut-off in our population was 1.55 (Sn 100%, Sp 73.7%, AUC 0.868), with similar values excluding pheochromocytomas and metastases (SUVratio cut-off 1.49, Sn 100%, Sp 96.3%, AUC 0.988). The SUVratio cut-off of 1.5 showed 100% Sn, 87% Sp, 73% PPV, and 100% NPV. CONCLUSION: [18F]FDG-PET/CT could help in decision making process avoiding unnecessary surgery. The SUVratio cut-off of 1.5 has a good performance in a heterogenous population.

A new mutation in the CAVIN1/PTRF gene in two siblings with congenital generalized lipodystrophy type 4: case reports and review of the literature.

Lipodystrophy syndromes are characterized by a progressive metabolic impairment secondary to adipose tissue dysfunction and may have a genetic background. Congenital generalized lipodystrophy type 4 (CGL4) is an extremely rare subtype, caused by mutations in the polymerase I and transcript release factor (PTRF) gene. It encodes for a cytoplasmatic protein called caveolae-associated protein 1 (Cavin-1), which, together with caveolin 1, is responsible for the biogenesis of caveolae, being a master regulator of adipose tissue expandability. Cavin-1 is expressed in several tissues, including muscles, thus resulting, when dysfunctional, in a clinical phenotype characterized by the absence of adipose tissue and muscular dystrophy. We herein describe the clinical phenotypes of two siblings in their early childhood, with a phenotype characterized by a generalized reduction of subcutaneous fat, muscular hypertrophy, distinct facial features, myopathy, and atlantoaxial instability. One of the siblings developed paroxysmal supraventricular tachycardia leading to cardiac arrest at 3 months of age. Height and BMI were normal. Blood tests showed elevated CK, a mild increase in liver enzymes and triglycerides levels, and undetectable leptin and adiponectin concentrations. Fasting glucose and HbA1c were normal, while Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) was mildly elevated. Both patients were hyperphagic and had cravings for foods rich in fats and sugars. Genetic testing revealed a novel pathogenic mutation of the CAVIN1/PTRF gene (NM_012232 exon1:c T21A:p.Y7X) at the homozygous state. The diagnosis of lipodystrophy can be challenging, often requiring a multidisciplinary approach, given the pleiotropic effect, involving several tissues. The coexistence of generalized lack of fat, myopathy with elevated CK levels, arrhythmias, gastrointestinal dysmotility, and skeletal abnormalities should prompt the suspicion for the diagnosis of CGL4, although phenotypic variability may occur.

Bone Response to Weight Loss Following Bariatric Surgery.

Obesity is a global health challenge that warrants effective treatments to avoid its multiple comorbidities. Bariatric surgery, a cornerstone treatment to control bodyweight excess and relieve the health-related burdens of obesity, can promote accelerated bone loss and affect skeletal strength, particularly after malabsorptive and mixed surgical procedures, and probably after restrictive surgeries. The increase in bone resorption markers occurs early and persist for up to 12 months or longer after bariatric surgery, while bone formation markers increase but to a lesser extent, suggesting a potential uncoupling process between resorption and formation. The skeletal response to bariatric surgery, as investigated by dual-energy X-ray absorptiometry (DXA), has shown significant loss in bone mineral density (BMD) at the hip with less consistent results for the lumbar spine. Supporting DXA studies, analyses by high-resolution peripheral quantitative computed tomography (HR-pQCT) showed lower cortical density and thickness, higher cortical porosity, and lower trabecular density and number for up to 5 years after bariatric surgery. These alterations translate into an increased risk of fall injury, which contributes to increase the fracture risk in patients who have been subjected to bariatric surgery procedures. As bone deterioration continues for years following bariatric surgery, the fracture risk does not seem to be dependent on acute weight loss but, rather, is a chronic condition with an increasing impact over time. Among the post-bariatric surgery mechanisms that have been claimed to act globally on bone health, there is evidence that micro- and macro-nutrient malabsorptive factors, mechanical unloading and changes in molecules partaking in the crosstalk between adipose tissue, bone and muscle may play a determining role. Given these circumstances, it is conceivable that bone health should be adequately investigated in candidates to bariatric surgery through bone-specific work-up and dedicated postsurgical follow-up. Specific protocols of nutrients supplementation, motor activity, structured rehabilitative programs and, when needed, targeted therapeutic strategies should be deemed as an integral part of post-bariatric surgery clinical support.

Beyond bariatric surgery and weight loss medicaments. A systematic review of the current practice in obesity rehabilitative inpatient programs in adults and pediatrics.

Background: Obesity treatment strategies mainly include outpatient lifestyle modification, drugs and bariatric surgery. Voluntary rehabilitative inpatient programs are gaining relevance as potential alternative settings of care that focus on weight loss and prevention of weight regain through a multidisciplinary approach, but their prevalence is still limited due to the high costs. Aim: Considering the lack of evidence in this area, the objective of this study is to systematically review the currently available literature on non-pharmacological and non-surgical inpatient programs aimed at weight loss, to clarify the efficacy and the characteristics of these interventions. Methods: Proper English language articles from 2000 to 2022 were searched on relevant databases. Quality assessment was performed by two different authors using ROB2 and robvis tools. Adult and pediatric studies were reviewed separately and their characteristics were systematically displayed. Results: 36 articles were included (20 on adults, 16 on children, and adolescents) for a total of 5,510 individuals. The multidisciplinary approach was mainly comprehensive of a low-calorie diet, scheduled physical activity, and psychological support based on behavioral treatment. Educational and cooking sessions were present at a lower rate. Globally, inpatient weight loss programs showed a consistent efficacy in reducing body weight and inducing beneficial effects on quality of life, psychological well-being, eating behavior, physical performance, and fatigue. Follow-up data were scarce, but with a high percentage of patients regaining weight after a short period. Conclusion: Weight loss inpatient rehabilitation is a promising area that has evidence of all-rounded success in the amelioration of several aspects related to obesity. Nevertheless, it appears to be quite inconsistent in preserving these benefits after the intervention. This might slow the innovation process in this area and preclude further investments from national healthcare. Personalized and enriched programs could show greater impact when focusing on the behavioral and educational aspects, which are crucial points, in particular in pediatrics, for setting up a long-lasting lifestyle modification. More studies are therefore necessary to evaluate long-term efficacy based on the different work-up models.

Regulation of GH and GH Signaling by Nutrients.

Growth hormone (GH) and insulin-like growth factor-1 (IGF-I) are pleiotropic hormones with important roles in lifespan. They promote growth, anabolic actions, and body maintenance, and in conditions of energy deprivation, favor catabolic feedback mechanisms switching from carbohydrate oxidation to lipolysis, with the aim to preserve protein storages and survival. IGF-I/insulin signaling was also the first one identified in the regulation of lifespan in relation to the nutrient-sensing. Indeed, nutrients are crucial modifiers of the GH/IGF-I axis, and these hormones also regulate the complex orchestration of utilization of nutrients in cell and tissues. The aim of this review is to summarize current knowledge on the reciprocal feedback among the GH/IGF-I axis, macro and micronutrients, and dietary regimens, including caloric restriction. Expanding the depth of information on this topic could open perspectives in nutrition management, prevention, and treatment of GH/IGF-I deficiency or excess during life.

Case Report: Liraglutide for Weight Management in Beckwith-Wiedemann Syndromic Obesity.

Genetic obesity, including syndromic and non-syndromic forms, represents a minority of cases compared to essential obesity but gene dysregulations lead to complex clinical conditions that make their management particularly difficult. Among them, Beckwith-Wiedemann syndrome (BWS) is a multisystem human genomic imprinting disorder characterized by overgrowth. We describe the first case of liraglutide treatment in an 18-year-old boy patient affected by BWS complicated by macroglossia, cryptorchidism, nephroblastoma, organomegaly, microscopic lymphocytic colitis, pharmacologically treated arterial hypertension, obesity, and obstructive sleep apnea syndrome. He presented a normal cognitive development. Body mass index at the time of first transition visit in the adult endocrinology department at the age of 18-years-old was 40.6 kg/m2 without glucose metabolism impairment. Lifestyle interventions failed because of poor compliance. During 20 months of 3.0 mg liraglutide treatment, a weight loss of 19 kg (-13.3%) and BMI reduction of 6.8 points were registered without side effects. To date, liraglutide treatment was effective on obesity in 7 subjects with Prader Willy Syndrome and 14 with melanocortin-4 receptor mutations. The efficacy of liraglutide in BWS could be related to a crosstalk among glucagon-like peptide (GLP)-1 system, mechanisms related to the cyclin-dependent kinase inhibitor 1C (CDKN1C), and dopamine mesolimbic circuit. Clinical trials aiming at a tailored medicine in genetic obesity are needed.

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

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 (F 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) (χ 2 10.4; p < 0.001), neutrophil-to-lymphocyte (NL) ratio (χ 2 7.6; p = 0.006), and platelet count (χ 2 5.39; p = 0.02), along with age (χ 2 87.6; p < 0.001) and gender (χ 2 17.3; p < 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/µL 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.

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

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 PaO2/FiO2 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.