A novel model for predicting diabetes remission after bariatric surgery based on the measurement of C-peptide and creatinine in serum: A pilot study.

BACKGROUND AND AIMS: Bariatric surgery is effective for treating type 2 diabetes (T2D) in patients with obesity, although a significant proportion of these patients do not achieve diabetes remission after the surgery even after significant weight loss and metabolic improvement. C-peptide is a valuable marker of beta cell function and insulin secretion, but renal function must be considered when interpreting measurements in patients with T2D. The study aims to investigate the association of serum levels of C-peptide adjusted for creatinine with diabetes remission and glycemic target achievement after bariatric surgery in patients with obesity and T2D. METHODS AND RESULTS: Prospective data from a cohort of 84 patients with obesity and T2D submitted to Roux-en-Y gastric bypass (RYGB) were collected at baseline and at least a 6-month follow up. A multivariate binomial regression model showed that Ln(C-peptide/creatinine) and age were significantly associated with 6-month T2D remission. The area under the curve for the receiver operating characteristic analysis (AUROC) to predict remission was 0.87, and more accurate than the AUROC based on C-peptide levels alone (0.75). The same model was also able to predict achieving an HbA1c target of 7 % (53 mmol/mol) (AUROC 0.96). CONCLUSION: In conclusion, Ln(C-peptide/creatinine) ratio could be a useful tool in predicting T2D remission and target achievement after RYGB surgery, providing a more accurate reflection of beta cell function in bariatric patients.

Association between Albumin Alterations and Renal Function in Patients with Type 2 Diabetes Mellitus.

Diabetic kidney disease (DKD) is a major cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to investigate whether albumin structural alterations correlate with DKD severity and evaluate whether native and reduced albumin concentrations could complement the diagnosis of DKD. To this end, one hundred and seventeen T2DM patients without (n = 42) and with (n = 75) DKD (DKD I-III upon KDIGO classification) were evaluated; the total albumin concentration (tHA) was quantified by a bromocresol green assay, while structural alterations were profiled via liquid chromatography-high-resolution mass spectrometry (LC-HRMS). The concentrations of native albumin (eHA, effective albumin) and reduced albumin (rHA) were subsequently assessed. The HRMS analyses revealed a reduced relative amount of native albumin in DKD patients along with an increased abundance of altered forms, especially those bearing oxidative modifications. Accordingly, both eHA and rHA values varied during the stages of progressive renal failure, and these alterations were dose-dependently correlated with renal dysfunction. A ROC curve analysis revealed a significantly greater sensitivity and specificity of eHA and rHA than of tHA for diagnosing DKD. Importantly, according to the multivariate logistic regression analysis, the eHA was identified as an independent predictor of DKD.

Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort. METHODS: We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC. RESULTS: MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006). CONCLUSIONS: The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.

Improved glycaemic control in patients with type 2 diabetes has a beneficial impact on NAFLD, independent of change in BMI or glucose lowering agent.

BACKGROUND AND AIM: The current focus of the treatment of Non-Alcoholic Fatty Liver Disease (NAFLD) is lifestyle intervention with the aim of significant weight loss alongside aggressive cardiovascular risk reduction. NAFLD is tightly associated with type 2 diabetes (T2D) and obesity. In patients with T2D, glucose lowering agents that promote weight loss have shown a beneficial impact on NAFLD. However, it remains unclear as to whether glucose lowering can improve NALFD in patients with T2D, independent of weight loss. METHODS AND RESULTS: In a retrospective analysis of data from 637 people with T2D, we examined the longitudinal impact of optimizing glycaemic control with DPP-IV inhibitors, GLP-1RAs and SGLT2 inhibitors on Fatty liver index (FLI) and Fibrosis score 4 (Fib-4) adjusting for changes in BMI and choice of glucose lowering regimen over a 12-month period. Multiple linear regression analysis demonstrated a significant correlation between the change in glycated haemoglobin and change in FLI after adjustment for change in BMI, age, sex, and drug class (R = 0.467, p = 0.031). The greatest reduction in FLI was observed in patients with the largest reduction in glycated haemoglobin (p < 0.0001). The probability of improvements in FLI with optimization of glycaemic control was similar with all 3 glucose lowering agents, despite differences in weight reduction. Similar relationships were observed examining the changes in glycaemic control and Fib-4. CONCLUSIONS: Improvements in glucose control that are independent of weight loss are associated with improvement in NAFLD and should form an integral part of the management patients with co-existent NAFLD and T2D.

Promoting weight loss and psychological well-being in patients with obesity: A sequential combination of behavioural lifestyle intervention and well-being therapy.

Behavioural lifestyle interventions focused on diet and physical activity are a cornerstone for the treatment of obesity. However, their effects vary substantially across individuals in terms of magnitude and durability. Personalized approaches that target psychological well-being may be promising to facilitate healthy behaviours and sustained weight loss. This preliminary study aimed to explore whether the sequential combination of behavioural lifestyle intervention (BLI) and well-being therapy (WBT) may result in more favourable outcomes than BLI alone in promoting weight loss (primary outcome) and improving psychological well-being, distress, dietary behaviours and physical activity (secondary outcomes). A total of 83 patients with obesity were randomly assigned to BLI/WBT (N = 38) or BLI group (N = 45). The BLI group received a 12-week behavioural weight loss programme, whereas the BLI/WBT group received the same programme followed by an additional 4-week WBT, adapted for group interventions. Data were collected at pretreatment (baseline, T1), at the end of BLI/WBT (T2), at 6-month (T3) and 12-month (T4) follow-ups. There was a significant weight loss in both treatment groups at T2, T3 and T4. The BLI/WBT group showed greater improvements in depressive symptoms at T3 and T4, in autonomy at T2, in personal growth at T4 and in global well-being at T4 compared with BLI group. WBT yielded no additional effect on weight loss. However, the secondary outcomes indicate that WBT may have enduring effects that reduce vulnerability to psychological distress in patients with obesity. In order to confirm these preliminary findings and explore whether a more intensive and individualized WBT can foster sustained weight loss, future studies are needed.

Risk of binge eating disorder in patients with metabolic dysfunction-associated steatotic liver disease.

PURPOSE: Very few data exist on the association between metabolic dysfunction-associated steatotic liver disease (MASLD) and eating disorders. The study aimed to evaluate the presence of binge eating disorder (BED), in MASLD subjects. METHODS: Demographic, clinical investigation, anthropometric measurements and laboratory were collected in 129 patients with MASLD (34.1% males; age, 53.7 years; BMI, 34.4 kg/m2) addressed by general practitioners to a hospital-based unit of metabolic disorders. The risk of binge eating was tested by the binge eating scale (BES); values in the range 17-26 were considered "possible" BED, values > 26 were considered "probable" BED. Hepatic steatosis and fibrosis were tested by surrogate biomarkers and imaging (transient elastography). Calorie intake and lifestyle were self-assessed by questionnaires. RESULTS: Possible BED was present in 17.8% of cases, probable BED in another 7.6%, and were neither associated with gender, obesity class, diabetes, features of metabolic syndrome, nor with presence and severity of hepatic steatosis and fibrosis. Also steatosis grade by CAP and fibrosis stage by liver stiffness did not correlate with BES. However, an association was present between the daily caloric intake and "possible" BED (odds ratio, 1.14; 95% confidence interval, 1.05-1.24; "probable" BED, 1.21; 1.07-1.37), after adjustment for confounders. CONCLUSION: Binge eating, as scored by BES, is present in a significant proportion of MASLD cases screened for metabolic disorders in a specialized center. It may impact behavioral treatment, reducing the chance of weight loss without systematic psychological support. LEVEL OF EVIDENCE: Level III, cohort analytic study.

[How to optimize Audit&Feedback: experience from the EASY-NET programme]. / Come rendere più efficace l'Audit&Feedback: riflessioni dal programma di rete EASY-NET.

This is the second of a series of papers dedicated to the EASY-NET research programme (NET-2016-02364191). The rationale, structure and methodologies are described in the previous contribution. Scientific literature demonstrated that Audit & Feedback (A&F) is an effective strategy for continuous quality improvement and its effectiveness varies considerably according to factors that are currently little known. Some recent publication pointed out, with the contribution of an international group of experts, 15 suggestions to optimize A&F and developed a tool to evaluate their application. This tool, called REFLECT-52, includes 52 items related to the 15 suggestions and organized into four categories relating to the "Nature of the desired action", to the "Nature of the data available for feedback", to the "Feedback Display" and to the "Intervention delivery". Then, the aim of this work was to evaluate the level of adherence of A&F interventions tested in EASY-NET to suggestions from the literature by using a slightly adapted version of the REFLECT-52 tool, in its original language. In EASY-NET, 14 A&F interventions with different characteristics and in different clinical and organizational contexts were tested in seven Italian regions, each of these was evaluated by the respective research groups. Overall, the level of adherence was high in three of the four categories analysed, with some difficulties reported regarding the nature of the data available for feedback. In fact, contrary to what the literature suggests, it was not possible to send repeated feedback for some interventions and, in some cases, the data available for feedback presented a delay longer than one year. In summary, this analysis has confirmed a high level of compliance of the interventions tested with the suggestions from the literature, but it has also allowed researchers to identify critical aspects that need to be addressed for the future development of these strategies.

The global NAFLD policy review and preparedness index: Are countries ready to address this silent public health challenge?

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent, yet largely underappreciated liver condition which is closely associated with obesity and metabolic disease. Despite affecting an estimated 1 in 4 adults globally, NAFLD is largely absent on national and global health agendas. METHODS: We collected data from 102 countries, accounting for 86% of the world population, on NAFLD policies, guidelines, civil society engagement, clinical management, and epidemiologic data. A preparedness index was developed by coding questions into 6 domains (policies, guidelines, civil awareness, epidemiology and data, NAFLD detection, and NAFLD care management) and categorising the responses as high, medium, and low; a multiple correspondence analysis was then applied. RESULTS: The highest scoring countries were India (42.7) and the United Kingdom (40.0), with 32 countries (31%) scoring zero out of 100. For 5 of the domains a minority of countries were categorised as high-level while the majority were categorised as low-level. No country had a national or sub-national strategy for NAFLD and <2% of the different strategies for related conditions included any mention of NAFLD. National NAFLD clinical guidelines were present in only 32 countries. CONCLUSIONS: Although NAFLD is a pressing public health problem, no country was found to be well prepared to address it. There is a pressing need for strategies to address NAFLD at national and global levels. LAY SUMMARY: Around a third of the countries scored a zero on the NAFLD policy preparedness index, with no country scoring over 50/100. Although NAFLD is a pressing public health problem, a comprehensive public health response is lacking in all 102 countries. Policies and strategies to address NAFLD at the national and global levels are urgently needed.

A psycho-educational intervention for the prevention of foot lesions in people with diabetes: Report of a clinical audit.

BACKGROUND AND AIMS: Motivational approaches may help target the psychological aspects of self-care, improving adherence to good practices in individuals with diabetes. The present study was designed to test the feasibility and effectiveness of a psychoeducational program for diabetic foot prevention or disease progression. METHODS AND RESULTS: Eighty-one subjects with or at high risk of foot ulcer development entered a program consisting of six 120-min group sessions, conducted by a podiatrist and an expert in psycho-education. Occurrence/recurrence of lesions in a 3-year follow-up was compared with 172 cases with similar risk score (IWGDF score 2019), receiving education at any 6-month podiatric visit (standard-of-care). Motivation to self-care and competence were assessed by specific questionnaires. The experimental program increased adherence to follow-up. The prevalence of foot lesions was higher at baseline and was remarkably reduced at any time-point in patients attending the psychoeducational program, whereas it remained relatively stable in standard care (around 10% of cases). The cumulative incidence was lower in the psychoeducational program (13.2, 95% CI 9.2-18.0 per 100 patient-year vs. 26.1; 95% CI 22.1-30.2); time to new lesions was increased (P = 0.022). Cox proportional hazard analysis confirmed an overall reduction of lesions in the psychoeducational program (HR 0.34; 95% CI 0.18-0.66; P < 0.001), after adjustment for confounders. The program was associated with significant changes in competence and motivation to self-care. CONCLUSION: A psychoeducational approach is both feasible and effective to support patients with diabetes at high risk of first or recurrent foot lesions, increasing their adherence to self-care practices.

Lean NAFLD: A Distinct Entity Shaped by Differential Metabolic Adaptation.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) affects a quarter of the adult population. A significant subset of patients are lean, but their underlying pathophysiology is not well understood. APPROACH AND RESULTS: We investigated the role of bile acids (BAs) and the gut microbiome in the pathogenesis of lean NAFLD. BA and fibroblast growth factor (FGF) 19 levels (a surrogate for intestinal farnesoid X receptor [FXR] activity), patatin-like phospholipase domain containing 3 (PNPLA3), and transmembrane 6 superfamily member 2 (TM6SF2) variants, and gut microbiota profiles in lean and nonlean NAFLD were investigated in a cohort of Caucasian patients with biopsy-proven NAFLD (n = 538), lean healthy controls (n = 30), and experimental murine models. Patients with lean NAFLD had a more favorable metabolic and histological profile compared with those with nonlean NAFLD (P < 0.05 for all). BA levels were significantly higher in NAFLD with advanced compared with earlier stages of liver fibrosis. Patients with lean NAFLD had higher serum secondary BA and FGF19 levels and reduced 7-alpha-hydroxy-4-cholesten-3-one (C4) levels (P < 0.05 for all). These differences were more profound in early compared with advanced stages of fibrosis (P < 0.05 for both). Lean patients demonstrated an altered gut microbiota profile. Similar findings were demonstrated in lean and nonlean murine models of NAFLD. Treating mice with an apical sodium-dependent BA transporter inhibitor (SC-435) resulted in marked increases in fgf15, a shift in the BA and microbiota profiles, and improved steatohepatitis in the lean model. CONCLUSIONS: Differences in metabolic adaptation between patients with lean and nonlean NAFLD, at least in part, explain the pathophysiology and provide options for therapy.

Effects of antidiabetic agents on steatosis and fibrosis biomarkers in type 2 diabetes: A real-world data analysis.

BACKGROUND & AIMS: There is intense research for drugs able to reduce disease progression in nonalcoholic fatty liver disease. We aimed to test the impact of novel antidiabetic drugs (dipeptidyl-peptidase-4 inhibitors - DPP-4Is, glucagon-like peptide-1 receptor agonists - GLP-1RAs, sodium-glucose cotransporter-2 inhibitors - SGLT-2Is) on non-invasive biomarkers of steatosis (fatty liver index, FLI) and fibrosis (Fibrosis-4 score, FIB-4) in patients with type 2 diabetes (T2D). METHODS: Clinical, anthropometric and biochemical parameters were retrospectively analysed in 637 consecutive T2D patients switched from metformin w/wo sulfonylureas and/or pioglitazone to DPP-4Is, GLP-1RAs and SGLT-2Is in a tertiary care setting. 165 patients maintained on original treatments served as controls. The effects on FLI and FIB-4 at 6- and 12-month follow-up were analysed by logistic regression after adjustment for baseline differences, computed by propensity scores, and additional adjustment for changes in glycosylated hemoglobin (HbA1c) and body mass index. RESULTS: Body mass index, HbA1c and aminotrasferases significantly decreased following switching to GLP-1RAs and SGLT2-Is, compared with both controls and DPP-4Is, whereas only HbA1c was reduced on DPP-4Is. FLI and FIB-4 were reduced on GLP-1RA and SGLT-2I; logistic regression analysis confirmed a significant improvement of both biomarkers after adjustment for propensity score. The shift of FIB-4 values towards the category ruling out advanced fibrosis was maintained after additional adjustment for confounders. These effects were confirmed in a sensitivity analysis on effect size. CONCLUSIONS: Glucagon-like peptide-1 receptor agonists and SGLT-2Is improve biomarkers of steatosis and fibrosis, in keeping with beneficial effects on liver disease progression, and should be considered the treatment of choice in T2D.

Initial treatment of diabetes in Italy. A nationwide population-based study from of the ARNO Diabetes Observatory.

BACKGROUND AND AIMS: To investigate diabetes treatment initiation and continuation in the next sixth months in newly diagnosed Italian subjects. METHODS AND RESULTS: We analyzed administrative claims of 11,300,750 Italian residents. Subjects with incident diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes occurring in 2018 but not in 2017. Incident cases were 65,932 of whom 91.4% received the prescription of a glucose lowering drug. Among the latter, those receiving a prescription of a noninsulin medication but no insulin were 84.8%, those receiving a prescription of insulin only were 9.4%, and those receiving prescriptions of both insulin and noninsulin drugs were 5.8%. Metformin was the most frequently drug initially prescribed in noninsulin treated subjects (~85%) and sulphonylurea receptor (SUR) agonists collectively ranked as second (~13%). Lispro (35%) and glargine (34%) were the most frequently prescribed molecules in subjects who were insulin treated. Differences in prescriptions were found in age categories, with increased use of SUR agonists across decades. In the first six months, as many as 50% of noninsulin treated patients continued with the initial drug, ~15% added a second agent, ~5% switched to another medication, and ~30% discontinued any glucose lowering treatment. CONCLUSIONS: These data document that current guidelines are often neglected because prescriptions of SUR agonists as first agent are still quite common and insulin is prescribed more than expected. They point out the urgent need to improve the dissemination and implementations of guidelines in diabetes care.

Incidence of diabetes mellitus in Italy in year 2018. A nationwide population-based study of the ARNO Diabetes Observatory.

BACKGROUNDS AND AIMS: To assess incidence of diabetes in Italy in 2018 by the use of administrative claims from several million residents. Differences in rates in men and women across decades of age were investigated. Incident rates of insulin or noninsulin treated subjects were also examined. METHODS AND RESULTS: We analyzed administrative healthcare claims of 11,300,750 subjects monitored by the ARNO Diabetes Observatory. Incident cases of diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes related to diabetes occurring in 2018 but not in 2017. We identified 697,208 subjects with ascertained diabetes. Incident cases were 65,932, with a rate of 5.83 per 1000 person-years (p-y). Incidence of drug-treated diabetes (n = 60,271) was 5.33 per 1000 p-y. Subjects receiving only insulin prescriptions were 5652 (rate 0.50 per 1000 p-y) and those receiving only prescriptions of noninsulin medications were 51,085 (rate 4.52 per 1000 p-y). Incidence rates progressively increased across decades until age 80 and then dropped by 25-30%. Overall, incident rates were generally higher in women aged 11-40 and in men aged ≥51. CONCLUSIONS: Recent cases represented ~10% of the population of diabetic subjects. Incidence of noninsulin-treated diabetes was almost 10-fold higher than incidence of insulin-treated diabetes. Substantial differences in incidence rates were observed in men and women of several decades of age: women more affected in adolescence and young adult age, men more affected in mature and advanced age. These data provide further understanding on the epidemiological burden of the disease in Italy.

A cross-sectional study of the public health response to non-alcoholic fatty liver disease in Europe.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a growing public health problem worldwide and has become an important field of biomedical inquiry. We aimed to determine whether European countries have mounted an adequate public health response to NAFLD and non-alcoholic steatohepatitis (NASH). METHODS: In 2018 and 2019, NAFLD experts in 29 European countries completed an English-language survey on policies, guidelines, awareness, monitoring, diagnosis and clinical assessment in their country. The data were compiled, quality checked against existing official documents and reported descriptively. RESULTS: None of the 29 participating countries had written strategies or action plans for NAFLD. Two countries (7%) had mentions of NAFLD or NASH in related existing strategies (obesity and alcohol). Ten (34%) reported having national clinical guidelines specifically addressing NAFLD and, upon diagnosis, all included recommendations for the assessment of diabetes and liver cirrhosis. Eleven countries (38%) recommended screening for NAFLD in all patients with either diabetes, obesity and/or metabolic syndrome. Five countries (17%) had referral algorithms for follow-up and specialist referral in primary care, and 7 (24%) reported structured lifestyle programmes aimed at NAFLD. Seven (24%) had funded awareness campaigns that specifically included prevention of liver disease. Four countries (14%) reported having civil society groups which address NAFLD and 3 countries (10%) had national registries that include NAFLD. CONCLUSIONS: We found that a comprehensive public health response to NAFLD is lacking in the surveyed European countries. This includes policy in the form of a strategy, clinical guidelines, awareness campaigns, civil society involvement, and health systems organisation, including registries. LAY SUMMARY: We conducted a survey on non-alcoholic fatty liver disease with experts in European countries, coupled with data extracted from official documents on policies, clinical guidelines, awareness, and monitoring. We found a general lack of national policies, awareness campaigns and civil society involvement, and few epidemiological registries.

Association Between PNPLA3 rs738409 C>G Variant and Liver-Related Outcomes in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Patients with nonalcoholic fatty liver disease (NAFLD) have an increased risk for liver-related complications, such as decompensation, hepatocellular carcinoma (HCC), and death; the severity of liver fibrosis and metabolic comorbidities are the main risk factors. A single nucleotide polymorphism in patatin-like phospholipase domain-containing-3 (PNPLA3) gene is associated with higher prevalence of liver damage and HCC, but there are no data from prospective studies of outcomes of patients with this polymorphism. We investigated whether the common rs738409 variant in PNPLA3 gene associates with the occurrence of liver-related events and death in a large cohort of patients with NAFLD. METHODS: We followed 471 consecutive individuals at a hospital in Italy with a diagnosis of NAFLD based on histologic factors or a diagnosis of compensated NAFLD-related cirrhosis based on clinical factors for at least 6 months, from March 2004 through December 2018. We collected data on the occurrence of hepatic and extrahepatic outcomes, including decompensation and HCC, cardiovascular events and extrahepatic cancers, and overall and liver-related death. We detected the rs738409 G>C polymorphism in DNA from patient blood samples using the TaqMan assay. RESULTS: During a median follow-up time of 64.6 months (range 6.1-175 months) 26 cases of decompensation, 13 HCCs, and 16 deaths (12 liver-related) were recorded. All liver-related events, including liver-related death, occurred in patients with F3 fibrosis or cirrhosis. The prevalence of PNPLA3 rs738409 GG, GT, and TT genotypes was 31.8%, 45.6%, and 22.6%, respectively. After adjusting for clinical, metabolic, and histologic risk factors, PNPLA3 C>G variant was associated with a higher risk of decompensation (hazard ratio [HR], 2.10; 95% CI, 1.03-4.29; P = .04), HCC (HR, 2.68; 95% CI, 1.01-7.26; P = .04), and liver-related death (HR, 3.64; 95% CI, 1.18-11.2; P = .02) by multivariate Cox regression analysis. In the subgroup of 162 patients with F3 fibrosis or cirrhosis, we confirmed the independent association between the PNPLA3 variant and decompensation (HR, 2.00; 95% CI, 1.01-3.97; P = .04), HCC (HR, 2.66; 95% CI, 1.02-7.13; P = .04), and liver-related death (HR, 3.64, 95% CI, 1.18-11.2; P = .02). We found no association between PNPLA3 genotype and cardiovascular events, extrahepatic cancers, or overall mortality. CONCLUSIONS: Patients with NAFLD carrying PNPLA3 rs738409 G>C variant are at higher risk of liver-related events and death.

Healthcare resource utilization and costs of nonalcoholic steatohepatitis patients with advanced liver disease in Italy.

BACKGROUND AND AIMS: Nonalcoholic steatohepatitis (NASH) may progress to advanced liver disease (AdvLD). This study characterized comorbidities, healthcare resource utilization (HCRU) and associated costs among hospitalized patients with AdvLD due to NASH in Italy. METHODS AND RESULTS: Adult nonalcoholic fatty liver disease (NAFLD)/NASH patients from 2011 to 2017 were identified from administrative databases of Italian local health units using ICD-9-CM codes. Development of compensated cirrhosis (CC), decompensated cirrhosis (DCC), hepatocellular carcinoma (HCC), or liver transplant (LT) was identified using first diagnosis date for each severity cohort (index-date). Patients progressing to multiple disease stages were included in >1 cohort. Patients were followed from index-date until the earliest of disease progression, end of coverage, death, or end of study. Within each cohort, per member per month values were annualized to calculate all-cause HCRU or costs(€) in 2017. Of the 9,729 hospitalized NAFLD/NASH patients identified, 97% were without AdvLD, 1.3% had CC, 3.1% DCC, 0.8% HCC, 0.1% LT. Comorbidity burden was high across all cohorts. Mean annual number of inpatient services was greater in patients with AdvLD than without AdvLD. Similar trends were observed in outpatient visits and pharmacy fills. Mean total annual costs increased with disease severity, driven primarily by inpatient services costs. CONCLUSION: NAFLD/NASH patients in Italy have high comorbidity burden. AdvLD patients had significantly higher costs. The higher prevalence of DCC compared to CC in this population may suggest challenges of effectively screening and identifying NAFLD/NASH patients. Early identification and effective management are needed to reduce risk of disease progression and subsequent HCRU and costs.

A view on the quality of diabetes care in Italy and the role of Diabetes Clinics from the 2018 ARNO Diabetes Observatory.

BACKGROUNDS AND AIMS: To investigate relevant indicators of quality of care in a large population-based sample of people with diabetes representative of clinical practice in Italy in 2018. METHODS AND RESULTS: We analyzed data from 11,300,750 subjects. All administrative healthcare claims collected in 2018 were scrutinized to identify subjects with diabetes and investigate several indicators of quality of care. Subjects with diabetes were identified by anti-hyperglycemic drug prescriptions, disease-specific co-payment exemption and hospital discharge codes. Indicators of quality of care pertained to monitoring (HbA1c, creatinine, lipid profile, microalbuminuria, eye examination, ECG, ultrasonography of carotid and lower limb arteries) and diabetes treatment (anti-hyperglycemic agents in subjects with cardiovascular disease, CVD). Subjects attending and nonattending Diabetes Clinics were compared. We identified 697,208 individuals with diabetes. HbA1c was assessed at least once in the year in 62.7%, creatinine in 62.3%, total cholesterol in 59.6%, microalbuminuria in 34.3%. Frequency of eye examination was 8.2%, ECG 23.5%, carotid ultrasonography 14.3%, lower limb ultrasonography 7.6%. Among anti-hyperglycemic drugs, SGLT-2 inhibitors were prescribed to ~5% and GLP-1 receptor agonists to ~5% although the proportion of subjects with CVD was ~45%. Subjects attending Diabetes Clinics had higher figures for all these monitoring and treatment indicators. CONCLUSIONS: The implementation of national and international guidelines regarding disease monitoring and treatment is far from being satisfactory, especially among subjects nonattending Diabetes Clinics. Further efforts and investments are needed for better disseminating guidelines, more efficaciously engaging healthcare professionals and more strongly empowering the healthcare system to improve diabetes care.

Maternal PKU: Defining phenylalanine tolerance and its variation during pregnancy, according to genetic background.

BACKGROUND AND AIMS: Phenylketonuria (PKU)-affected women may become pregnant, and dietary phenylalanine (Phe) intake must be adjusted according to Phe tolerance. We report our experience with maternal PKU in relation to genotype PKU heterogeneity. METHODS AND RESULTS: A total of 10 pregnancies in 7 PKU women (7 different genotypes) were followed up as part of personalized care. Phe tolerance during preconception and pregnancy was assessed by strict dietary control and weekly Phe measurement (blood spots) in relation to genotype. Most women had stopped PKU diet during childhood or adolescence and six pregnancies were unplanned; a phenylalanine-restricted diet was reinstituted soon after conception. Women were classified according to their Phe levels at birth screening and genotype. Phe tolerance increased systematically in the course of pregnancy in all cases, but the increase was different in subjects with classic PKU (cPKU) when compared with cases with mild hyperphenylalaninemia (mHPA), both on average (+297 mg/day in cPKU vs. 597 in mHPA; P = 0.017) and as percentage (+107% in cPKU vs. +17% in mHPA). Notably, Phe tolerance also varied in the same women in the course of different pregnancies, when body weight gain was also different. Two newborns from the same cPKU mother (unplanned pregnancies on free diet) were affected by congenital alterations. CONCLUSIONS: Several factors influence metabolic phenotype in maternal PKU, to an unpredictable extent even in the same woman. The number of maternal PKU cases is growing in dedicated Nutrition Units, and the burden associated with careful management of this condition for the health care system should be adequately considered.

The association between weight maintenance and session-by-session diet adherence, weight loss and weight-loss satisfaction.

OBJECTIVE: The aim of this study was to assess the association between weight-loss maintenance and weight-loss satisfaction, adherence to diet and weight loss, all measured session-by-session during the weight-loss phase of cognitive behavioral therapy. METHODS: The present exploratory study examined a subgroup of fifty-eight patients who participated in a randomized controlled trial and who lost at least the 10% of their baseline weight. Patients were grouped into weight-loss 'Maintainers' (i.e., those who maintained a weight loss of ≥ 10% of baseline body weight at 6 months after the weight-loss phase) and 'Regainers' (i.e., those who did not maintain > 10% weight loss at 6 months after the weight-loss phase). Body weight, adherence to diet and weight-loss satisfaction were measured session-by-session during the weight-loss phase. RESULTS: Thirteen patients (22.4%) were classified as 'Regainers', and 45 (77.6%) as 'Maintainers'. Compared to 'Maintainers', 'Regainers' had a lower adherence to diet after the initial 11 weeks, and a progressively declining weight loss and weight-loss satisfaction from week 15 or 19 of the weight-loss phase. 11-week dietary adherence and 15-week weight loss were significantly associated with weight maintenance. Similar results were obtained using the amount of weight change as dependent variable. CONCLUSIONS: Adherence to diet, weight loss and weight-loss satisfaction, measured during the late weight-loss phase, are associated with weight-loss maintenance. LEVEL OF EVIDENCE: Level III, evidence obtained from well-designed cohort or case-control analytical studies.