High serum osteopontin levels are associated with prevalent fractures and worse lipid profile in post-menopausal women with type 2 diabetes

Purpose: Patients with type 2 diabetes (T2DM) have increased fracture risk. Osteopontin (OPN) is a protein involved in bone remodeling and inflammation. The aim of this study was to evaluate the association of OPN with fracture prevalence and with metabolic parameters in post-menopausal women with T2DM. Methods: Sixty-four post-menopausal women with T2DM (age 67.0 ± 7.8 years, diabetes duration 8.9 ± 6.7 years), enrolled in a previous study, were followed up (3.6 ± 0.9 years). Previous fragility fractures were recorded. The FRAX score (without BMD) was calculated and biochemical parameters (plasma glucose, HbA1c, lipid profile and renal function) were assessed. Serum 25OH-vitamin D, calcium, PTH and OPN were evaluated at baseline. The association between OPN and fracture prevalence at baseline was evaluated by a logistic model. Results: OPN levels were higher in patients with previous fractures (n.25) than in patients without previous fractures at baseline (n.39) (p = 0.006). The odds of having fractures at baseline increased by 6.7 (1.9–31.4, 95% CI, p = 0.007) for each increase of 1 ng/ml in OPN levels, after adjustment for vitamin D and HbA1c levels. Fracture incidence was 4.7%. Higher OPN associated with a decrease in HDL-cholesterol (p = 0.048), after adjustment for age, basal HDL-cholesterol, basal and follow-up HbA1c and follow-up duration. 25OH-vitamin D associated with an increase in FRAX-estimated probability of hip fracture at follow-up (p = 0.029), after adjustment for age, 25OH-vitamin D and time. Conclusions: In post-menopausal women with T2DM, OPN might be a useful marker of fracture and worse lipid profile

Exome-Wide Association Study on Alanine Aminotransferase Identifies Sequence Variants in the GPAM and APOE Associated With Fatty Liver Disease

Background & Aims: Fatty liver disease (FLD) is a growing epidemic that is expected to be the leading cause of end-stage liver disease within the next decade. Both environmental and genetic factors contribute to the susceptibility of FLD. Several genetic variants contributing to FLD have been identified in exome-wide association studies. However, there is still a missing hereditability indicating that other genetic variants are yet to be discovered. Methods: To find genes involved in FLD, we first examined the association of missense and nonsense variants with alanine aminotransferase at an exome-wide level in 425,671 participants from the UK Biobank. We then validated genetic variants with liver fat content in 8930 participants in whom liver fat measurement was available, and replicated 2 genetic variants in 3 independent cohorts comprising 2621 individuals with available liver biopsy. Results: We identified 190 genetic variants independently associated with alanine aminotransferase after correcting for multiple testing with Bonferroni method. The majority of these variants were not previously associated with this trait. Among those associated, there was a striking enrichment of genetic variants influencing lipid metabolism. We identified the variants rs2792751 in GPAM/GPAT1, the gene encoding glycerol-3-phosphate acyltransferase, mitochondrial, and rs429358 in APOE, the gene encoding apolipoprotein E, as robustly associated with liver fat content and liver disease after adjusting for multiple testing. Both genes affect lipid metabolism in the liver. Conclusions: We identified 2 novel genetic variants in GPAM and APOE that are robustly associated with steatosis and liver damage. These findings may help to better elucidate the genetic susceptibility to FLD onset and progression

Rare ATG7 genetic variants predispose patients to severe fatty liver disease

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disorders and has a strong heritable component. The aim of this study was to identify new loci that contribute to severe NAFLD by examining rare variants. Methods: We performed whole-exome sequencing in individuals with NAFLD and advanced fibrosis or hepatocellular carcinoma (n = 301) and examined the enrichment of likely pathogenic rare variants vs. the general population. This was followed by validation at the gene level. Results: In patients with severe NAFLD, we observed an enrichment of the p.P426L variant (rs143545741 C>T; OR 5.26, 95% CI 2.1-12.6; p = 0.003) of autophagy-related 7 (ATG7), which we characterized as a loss-of-function, vs. the general population, and an enrichment in rare variants affecting the catalytic domain (OR 13.9; 95% CI 1.9-612; p = 0.002). In the UK Biobank cohort, loss-of-function ATG7 variants increased the risk of cirrhosis and hepatocellular carcinoma (OR 3.30; 95% CI 1.1-7.5 and OR 12.30, 95% CI 2.6-36, respectively; p <0.001 for both). The low-frequency loss-of-function p.V471A variant (rs36117895 T>C) was also associated with severe NAFLD in the clinical cohort (OR 1.7; 95% CI 1.2-2.5; p = 0.003), predisposed to hepatocellular ballooning (p = 0.007) evolving to fibrosis in a Liver biopsy cohort (n = 2,268), and was associated with liver injury in the UK Biobank (aspartate aminotransferase levels, p <0.001), with a larger effect in severely obese individuals in whom it was linked to hepatocellular carcinoma (p = 0.009). ATG7 protein localized to periportal hepatocytes, particularly in the presence of ballooning. In the Liver Transcriptomic cohort (n = 125), ATG7 expression correlated with suppression of the TNFα pathway, which was conversely upregulated in p.V471A carriers. Conclusions: We identified rare and low-frequency ATG7 loss-of-function variants that promote NAFLD progression by impairing autophagy and facilitating ballooning and inflammation. Lay summary: We found that rare mutations in a gene called autophagy-related 7 (ATG7) increase the risk of developing severe liver disease in individuals with dysmetabolism. These mutations cause an alteration in protein function and impairment of self-renewal of cellular content, leading to liver damage and inflammation

Clinicopathological study of a series of 92 adrenocortical carcinomas: from a proposal of simplified diagnostic algorithm to prognostic stratification.

AIMS: Pathological diagnosis of adrenocortical carcinoma relies on several microscopic features commonly used in combination in different scoring systems that are sometimes subjective and/or time consuming. The aim was to investigate the impact of individual pathological parameters in the diagnosis and prognosis of adrenocortical carcinoma. METHODS AND RESULTS: The series included 92 malignant cases and a control series of 47 adenomas, all classified according to Weiss score criteria. The presence of disruption of the reticular network, as highlighted by histochemical staining, was present in all adrenocortical carcinomas and the inclusion of at least one of the three following additional parameters - mitotic index >5/50 high-power fields (HPF), presence of necrosis and presence of vascular invasion - gave an algorithm with 100% sensitivity and specificity to recognize malignant tumours according to the Weiss system, with easier and more practical applicability. Moreover, on multivariate analysis, stage III/IV and mitotic count >9/50 HPF showed a strong adverse impact on disease-free and overall survival, leading to the identification of three risk groups affected by a significantly different prognosis. CONCLUSIONS: We have defined an easy-to-perform and highly specific and sensitive algorithm for the diagnosis and prognostic categorization of adrenocortical tumours

Impact of risk factors for gestational diabetes (GDM) on pregnancy outcomes in women with GDM

PURPOSE: In this study, we evaluated the impact of risk factors for gestational diabetes on clinical/biochemical parameters and maternal/fetal outcomes. METHODS: One hundred eighty-three (n 183) women (age 33.8 ± 5.5 years, 59% Caucasians, 41% non-Caucasians) with gestational diabetes were included in the study. Anamnestic information, anthropometric and laboratory parameters, and maternal and fetal outcomes at delivery were collected. RESULTS: Insulin therapy prevalence was higher in Asians vs Caucasians (p = 0.006), despite lower pre-pregnancy BMI in Asians (p = 0.0001) and in pre-pregnancy overweight vs normal weight patients (p = 0.04). Insulin-treated patients had higher fasting OGTT glucose than patients on diet therapy (p = 0.003). In multivariate analysis, Asian ethnicity, age ≥ 35 years and pre-pregnancy BMI ≥ 25 kg/m2 were independent predictors of insulin therapy. Cesarean section occurred more in women aged ≥ 35 years than < 35 years (p = 0.02). Duration of pregnancy and age showed inverse correlation (r - 0.3 p = 0.013). Week of delivery was lower in patients ≥ 35 years vs patients < 35 years (p = 0.013). Fasting OGTT glucose was higher in overweight than in normal weight patients (p = 0.016). 1-h OGTT glucose was lower in obese vs normal weight (p = 0.03) and overweight patients (p = 0.03). Prevalence of prior gestational diabetes was higher in overweight/obese women (p = 0.002). CONCLUSIONS: Ethnicity, age, and BMI have the heaviest impact on pregnancy outcomes

Somatostatin receptor tissue distribution in lung neuroendocrine tumours: a clinicopathologic and immunohistochemical study of 218 clinically aggressive cases

Background: The management of pulmonary neuroendocrine tumours (NETs), with special reference to clinically aggressive carcinoids and large-cell neuroendocrine carcinomas (LCNECs), is poorly standardised and data about somatostatin receptor (SSTR) expression or therapeutic guidelines for somatostatin analogue administration are still debated. Materials and methods: A series of 218 lung NETs [24 metastatic typical carcinoids (TCs), 73 atypical carcinoids (ACs), 60 LCNECs and 61 surgically resected small-cell lung carcinomas] were investigated for SSTR types 2A and 3 tissue distribution using immunohistochemistry, in correlation with clinicopathologic parameters, outcome, scintigraphy and treatment. Results: SSTRs were heterogeneously distributed with a significant progressive decrease from low- to high-grade forms. SSTR type 2A was strikingly overexpressed in metastatic TCs as compared with ACs and clinically benign TCs. SSTR tissue immunolocalization correlated with octreotide scintigraphy in 20 of 28 cases. Conclusion: The immunohistochemical determination of SSTRs, with special reference to low-grade/intermediate-grade tumours, may assist the clinical approach with somatostatin analogue-based diagnostic and therapeutic procedures in clinically aggressive pulmonary NETs