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BACKGROUND Observational studies showed that exposure to exogenous insulin increases fracture risk. However, it remains unclear whether the observed association is a function of the severity of underlying type 2 diabetes mellitus, complications, therapies, comorbidities, or all these factors combined. That being so, and because of the relative infrequency of these events, it is important to study this further in a large-database setting. QUESTION/PURPOSES: (1) Is switching from oral antidiabetic agents to insulin associated with an increased fracture risk? (2) How soon after switching does the increased risk appear, and for how long does this increased risk persist? METHODS Data from healthcare utilization databases of the Italian region of Lombardy were used. These healthcare utilization databases report accurate, complete, and interconnectable information of inpatient and outpatient diagnoses, therapies, and services provided to the almost 10 million residents in the region. The 216,624 patients on treatment with oral antidiabetic therapy from 2005 to 2009 were followed until 2010 to identify those who modified their antidiabetic therapy (step 1 cohort). Among the 63% (136,307 patients) who experienced a therapy modification, 21% (28,420 patients) switched to insulin (active exposure), and the remaining 79% (107,887 patients) changed to another oral medication (referent exposure). A 1:1 high-dimension propensity score matching design was adopted for balancing patients on active and referent exposure. Matching failed for 3% of patients (926 patients), so the cohort of interest was formed by 27,494 insulin-referent couples. The latter were followed until 2012 to identify those who experienced hospital admission for fracture (outcome). A Cox proportional hazard model was fitted to estimate the hazard ratio (HR) for the outcome risk associated with active-exposure (first research question). Between-exposure comparison of daily fracture hazard rates from switching until the 24 successive months was explored through the Kernel-smoothed estimator (second research question). RESULTS Compared with patients on referent exposure, those who switched to insulin had an increased risk of experiencing any fracture (HR = 1.5 [95% CI 1.3 to 1.6]; p < 0.001). The same risk was observed for hip and vertebral fractures, with HRs of 1.6 (95% CI 1.4 to 1.8; p < 0.001) and 1.8 (95% 1.5 to 2.3; p < 0.001), respectively. Differences in the daily pattern of outcome rates mainly appeared the first 2 months after switching, when the hazard rate of patients on active exposure (9 cases for every 100,000 person-days) was higher than that of patients on referent exposure (4 cases for every 100,000 person-days). These differences persisted during the remaining follow-up, though with reduced intensity. CONCLUSIONS We found quantitative evidence that switching from oral antidiabetic therapy to insulin is associated with an increased fracture risk, mainly in the period immediately after the start of insulin therapy. The observed association may result from higher hypoglycemia risk among patients on insulin, which leads to a greater number of falls and resulting fractures. However, although our study was based on a large sample size and highly accurate data, its observational design and the lack of clinical data suggest that future research will need to replicate or refute our findings and address the issue of causality, if any. Until then, though, prescribers and patients should be aware of this risk. Careful control of insulin dosage should be maintained and measures taken to reduce fall risk in these patients. LEVEL OF EVIDENCE Level III, therapeutic study.

Context Laparoscopic sleeve gastrectomy (LSG) is a recognized effective procedure of bariatric surgery, but a poor response in weight loss may still represent a clinical problem. To date there are no validated predictors useful to better perform patient selection. Objective To establish the association of baseline anthropometric, metabolic, and psychologic features with the percent total weight loss (%TWL) and percent excess weight loss (%EWL) 12 months after surgery. Design Retrospective longitudinal analysis of a set of data about obese patients attending the outpatient service of a single obesity center from June 2016 to June 2019. Patients A total of 106 obese patients underwent LSG with presurgery evaluation and follow-up at 12 months after surgery. Main outcome Weight loss 12 months after LSG. Results Patients who achieved a %TWL higher than the observed median (≥34%) were younger, with a lower fasting plasma glucose and glycated hemoglobin, with a lower prevalence of hypertension and with a lower score in the impulsiveness scale, compared with patients with a %TWL Conclusion Metabolic and psychologic features at baseline were independently associated with weight loss and explained a non-negligible effect on the response to LSG. These data suggest that careful metabolic and psychologic profiling could help in sharper indications and personalized pre- and postsurgical follow-up protocols in candidates for LSG.

Objective Few studies investigated the role of different predictors of advanced liver fibrosis in unselected populations. Here, we estimate the prevalence of steatosis and fibrosis in the general United States population by means of transient elastography and evaluate the impact of blood pressure (BP) and diabetes on disease severity. Methods This is a cross-sectional study of United States adults participating in the 2017-2018 cycle of the National Health and Nutrition Examination Survey. Participants underwent a transient elastography examination, and liver steatosis and fibrosis were estimated through the controlled attenuation parameter (CAP) score and liver stiffness measurement (LSM), respectively. Results Four thousand, three hundred and seventy-one participants had reliable transient elastography and BP readings. Steatosis (CAP ≥ 248 dB/m), advanced fibrosis (LSM ≥ 9.6 kPa) and cirrhosis (LSM ≥ 13 kPa) were present in 56.9, 5.5 and 2.9% of participants, respectively. After controlling for potential confounders, risk of steatosis increased proportionally going from participants with optimal (reference) to those with normal [odds ratio (OR) 1.24, 95% confidence interval (CI) 0.83-1.86], high normal (OR 1.41, 95% CI 1.01-1.97) and elevated BP (OR 1.64, 95% CI 1.21-2.21), whereas no significant association was found between BP status and liver fibrosis. Conversely, presence of diabetes increased the risk of both steatosis (OR 2.15, 95% CI 1.49-3.11) and advanced fibrosis (OR 2.25, 95% CI 1.36-3.72). Conclusion Liver steatosis and fibrosis are highly prevalent in the multiethnic United States adult population, raising concerns for future incidence of cirrhosis and its complications. BP status was associated with a progressively higher risk of steatosis, whereas obesity and diabetes were consistently associated with both steatosis and fibrosis.

Aims Liver steatosis, a typical finding in patients with type 2 diabetes (T2D), can lead to cirrhosis and hepatocellular carcinoma. The aim of the present study is to estimate the awareness of liver disease among patients with T2D and whether it differs according to the degree of liver fibrosis estimated by transient elastography (TE). Methods This is a population-based cross-sectional study. We included all patients with T2D that participated in the 2017–2018 cycle of the National Health and Nutrition Examination Survey and underwent a TE examination. Presence of liver steatosis and fibrosis was assessed by the median values of controlled attenuation parameter and liver stiffness measurement, respectively. Results Among the 825 patients included in the analysis, 8.1% (95% CI 5.1%-12.7%) of patients with steatosis were aware of having a liver condition. Even if awareness increased proportionally with increasing severity of organ damage, it remained limited even among patients with advanced fibrosis (17.9%, 95% CI 8.8%-33.3%). Conclusions Despite increasing evidence of a frequent hepatic involvement associated with poor prognosis, awareness of suffering of advanced liver disease in patients with T2D is remarkably low, likely reflecting little recognition also among the team of health care professionals.

Purpose The purpose of this study was to evaluate the impact of pre-existing diabetes on in-hospital mortality in patients admitted for Coronavirus Disease 2019 (COVID-19). Methods This is a single center, retrospective study conducted at Policlinico di Monza hospital, located in the Lombardy region, Northern Italy. We reviewed medical records of 373 consecutive adult patients who were hospitalized with COVID-19 between February 22 and May 15, 2020. Data were collected on diabetes status, comorbid conditions and laboratory findings. Multivariable logistic regression was performed to evaluate the effect of diabetes on in-hospital mortality after adjustment for potential confounding variables. Results Mean age of the patients was 72 ± 14 years (range 17–98), 244 (65.4%) were male and 69 (18.5%) had diabetes. The most common comorbid conditions were hypertension (237 [64.8%]), cardiovascular disease (140 [37.7%]) and malignant neoplasms (50 [13.6%]). In-hospital death occurred in 142 (38.0%) patients. In the multivariable model older age (Relative Risk [RR] 1.06 [1.04–1. 09] per year), diabetes (RR 1.56 [1.05–2.02]), chronic obstructive pulmonary disease (RR 1.82 [1.13–2.35]), higher values of lactic dehydrogenase and C-reactive protein were independently associated with in-hospital mortality. Conclusion In this retrospective single-center study, diabetes was independently associated with a higher in-hospital mortality. More intensive surveillance of patients with this condition is to be warranted.

The advent of Sodium Glucose Transporter 2-inhibitors (SGLT2-i) in recent years gave endocrinologists the opportunity to actively treat and prevent heart failure (HF) in patients with type 2 diabetes (T2DM). While the relationship between T2DM and HF has been extensively reviewed, previous works focused mostly on epidemiology, pathophysiology and treatment of HF in T2DM. The aim of our work was to aid health care professionals in identifying individuals at high risk for this dreadful complication. Recent guidelines recommend to use drugs with proven cardiovascular benefits (Glucagon-like peptide-1 receptor agonists (GLP1-RA) and SGLT2-i) in patients with previous cardiovascular disease (CVD) and to prefer SGLT2-i in patients with known HF. In everyday clinical practice, the choice between these two drug classes in patients without known HF or atherosclerotic CVD is mostly arbitrary and based on the side effect profile. Recently, risk stratification tools to estimate HF incidence have been developed in order to guide treatment with a view to bring precision medicine into diabetes care. With this purpose, we provide a review of the tools able to predict HF incidence for patients in primary CVD prevention as well as risk of future hospitalizations for patients with known HF.

Context Growing evidence suggests that appropriate levothyroxine (LT4) replacement therapy may not correct the full set of metabolic defects afflicting individuals with hypothyroidism. Objective To assess whether obese subjects with primary hypothyroidism are characterized by alterations of the resting energy expenditure (REE). Design Retrospective analysis of a set of data about obese women attending the outpatients service of a single obesity center from January 2013 to July 2019. Patients A total of 649 nondiabetic women with body mass index (BMI) > 30 kg/m2 and thyrotropin (TSH) level 0.4–4.0 mU/L were segregated into 2 groups: patients with primary hypothyroidism taking LT4 therapy (n = 85) and patients with normal thyroid function (n = 564). Main outcomes REE and body composition assessed using indirect calorimetry and bioimpedance. Results REE was reduced in women with hypothyroidism in LT4 therapy when compared with controls (28.59 ± 3.26 vs 29.91 ± 3.59 kcal/kg fat-free mass (FFM)/day), including when adjusted for age, BMI, body composition, and level of physical activity (P = 0.008). This metabolic difference was attenuated only when adjustment for homeostatic model assessment of insulin resistance (HOMA-IR) was performed. Conclusions This study demonstrated that obese hypothyroid women in LT4 therapy, with normal serum TSH level compared with euthyroid controls, are characterized by reduced REE, in line with the hypothesis that standard LT4 replacement therapy may not fully correct metabolic alterations related to hypothyroidism. We are not able to exclude that this feature may be influenced by the modulation of insulin sensitivity at the liver site, induced by LT4 oral administration.

Several studies reported an association between nonalcoholic fatty liver disease (NAFLD) and the risk of incident hypertension. The objective of this systematic review and meta-analysis was to obtain a precise and reliable estimate of the nature and magnitude of this association. We systematically searched Ovid-MEDLINE up to March 2021 for observational studies in which NAFLD was diagnosed in adults using blood-based panels, imaging techniques or liver biopsy and with a follow-up ≥1 year. Measures of association from individual studies were meta-analyzed using random-effects models. Of the 1108 titles initially scrutinized, we included 11 cohort studies with data on 390 348 participants (52% male) and a mean follow-up of 5.7 years. In the overall analysis, NAFLD was associated with a moderately increased risk of incident hypertension (hazard ratio 1.66; 95% confidence interval (CI), 1.38-2.01; test for overall effect z = 5.266; P

BackgroundCardiovascular disease (CVD) risk is higher in patients with nonalcoholic fatty liver disease (NAFLD).AimTo evaluate whether this can be attributed to the link between NAFLD and known CVD risk factors or to an independent contribution of liver steatosis and fibrosis.MethodsThis is an analysis of data from the 2017-2018 cycle of the National Health and Nutrition Examination Survey. We included participants older than 40 years with available data on vibration-controlled transient elastography (VCTE) and without viral hepatitis and significant alcohol consumption. Steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. History of CVD was self-reported and defined as a composite of coronary artery disease and stroke/transient ischemic attacks.ResultsAmong the 2734 included participants, prevalence of NAFLD was 48.6% (95% CI 45.1-51.4), 316 participants (9.7%, 95% CI 8.1-11.6) had evidence of significant liver fibrosis and 371 (11.5%, 95% CI 9.5-13.9) had a history of CVD. In univariate analysis, patients with CVD had a higher prevalence of steatosis (59.6% vs 47.1%, p=0.013), but not fibrosis (12.9% vs 9.3%, p=0.123). After adjustment for potential confounders in a multivariable logistic regression model, neither steatosis nor significant fibrosis were independently associated with CVD and heart failure.ConclusionsIn this population-based study, we did not identify an independent association between steatosis and fibrosis and CVD. Large prospective cohort studies are needed to provide a more definitive evidence on this topic.

Introduction: Obese (OB) patients are at increased risk of chronic kidney disease, but it is still unclear whether this can be attributed to obesity per se or to the associated metabolic derangements. The aim of this study was to evaluate the relative impact of obesity and metabolic syndrome (MS) on kidney disease. Methods: This is a cross-sectional study based on data obtained in the 2005–2016 cycles of the National Health and Nutrition Examination Survey. We included all adult participants with available data on body mass index, estimated glomerular filtration rate (eGFR), urine albumin to creatinine ratio (UACR), and each of the MS components. Primary outcomes were eGFR Results: The studied population comprised 12,335 participants. OB participants without MS (OB+ MS−) were younger and more commonly female. After adjustment for potential confounders, compared with OB− MS− participants, an increased prevalence of albuminuria and reduced eGFR were present in both OB− MS+ groups and the OB+ MS+ groups, but not in the OB+ MS− groups. When each of the MS components was evaluated separately, elevated blood pressure and low high-density lipoprotein cholesterol were associated with both UACR and reduced eGFR, while elevated blood glucose and triglycerides were only associated with UACR. Waist circumference was not associated with any of the renal outcomes. Discussion/Conclusion: This large cross-sectional study suggests that MS and not obesity is associated with kidney damage and that the OB+ MS− phenotype does not seem to carry an increased risk of kidney disease.

Context It is still debated whether nonalcoholic fatty liver disease (NAFLD) may be a risk factor for reduced bone mineral density (BMD), and it is not known whether liver fibrosis, the major predictor of future development of liver-related events in NAFLD, has an influence on BMD. Objective To assess whether liver steatosis and fibrosis are associated with reduced BMD in the general US population. Methods We performed a cross-sectional analysis of the population-based 2017–2018 cycle of the National Health and Nutrition Examination Survey (NHANES), in which vibration-controlled transient elastography (VCTE) and dual-energy x-ray absorptiometry (DXA) of the femoral neck were simultaneously available. Controlled attenuation parameter (CAP) ≥ 274 dB/m was considered indicative of liver steatosis, while a median liver stiffness measurement (LSM) ≥ 8 kPa indicated the presence of significant liver fibrosis. We included all participants older than 50 years with reliable VCTE and femoral neck DXA results (925 men and 859 women). The main outcome measures were femoral neck BMD values indicative of osteopenia or osteoporosis. Results Steatosis and significant fibrosis were highly prevalent in the studied population, being present in 53.1% and 9.6% of men and 44.2% and 8.0% of women, respectively. In univariate analysis, liver steatosis was associated with a lower prevalence of osteoporosis in both men and women, while no difference was noted according to the degree of liver fibrosis. After adjustment for potential confounders, including age, BMI, race/ethnicity, cigarette smoking, and diabetes, neither CAP nor LSM were significantly associated with reduced BMD in both sexes. Conclusion Liver steatosis and fibrosis are not associated with femoral DXA-based diagnosis of osteopenia or osteoporosis in the US population older than 50 years.

Data are limited on the epidemiological implications of the recent change in terminology from nonalcoholic fatty liver disease (NAFLD) to metabolic dysfunction-associated fatty liver disease (MAFLD). We therefore performed a cross-sectional study of adults recruited in the 2017-2018 National Health and Nutrition Examination Survey, a representative sample of the general US population. The prevalence of NAFLD and MAFLD based on controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) obtained through vibration-controlled transient elastography (VCTE) were 37.1% (95% CI 34.0-40.4) and 39.1% (95% CI 36.3-42.1), respectively, with higher rates among Hispanic individuals. Agreement between the two definitions was high (Cohen's κ 0.92). Patients with NAFLD and MAFLD also showed similar risk of advanced liver fibrosis (7.5% and 7.4% respectively). Our results suggest that the recent change in diagnostic criteria did not affect the prevalence of the condition in the general United States population.

Aims: Hypothalamus-pituitary-adrenal (HPA) axis hyperactivity was suggested to be associated with the metabolic syndrome (MS), obesity and diabetes. The aim of this study was to test whether hypercortisolism was associated with altered glucose homeostasis and insulin resistance, hypertension and dyslipidemia in a homogeneous population of obese patients. Materials/Methods: In retrospective analysis of a set of data about obese patients attending the outpatient service of a single obesity centre between January 2013 and January 2020, 884 patients with BMI >30 kg/m2 were segregated in two subgroups: patients with urinary free cortisol (UFC) higher than normal (UFC+; n = 129) or within the normal range (UFC−; n = 755). Results: The overall prevalence of UFC+ was 14.6% and double test positivity (morning cortisol >1.8 mcg/dL following overnight dexamethasone suppression test, ODST) was detected in 1.0% of patients. Prediabetes (OR 1.74; 95%CI 1.13-2.69; p = 0.012) and diabetes (OR 2.03; 95%CI 1.21-3.42; p = 0.008) were associated with higher risk of UFC+ when analysis was adjusted for confounding variables. Conversely, hypertension and dyslipidemia were not related to UFC+. Within the individuals with normal FPG and HbA1c, those with higher estimated insulin resistance (HOMA2-IR) maintained a higher risk of UFC+ (OR 2.84, 95%CI 1.06-7.63; p = 0.039) and this relationship was weakened only when the body fat percentage was included into the model. Conclusions: In obese patients, hypercortisolism was more frequent across the entire spectrum of altered glucose homeostasis including the very early stages; this relation could not be detected for the other criteria of the MS, as waist, hypertension and atherogenic dyslipidemia.

Background and aims Seasonal variations in several risk factors for cardiovascular events (CVD) were described. Here, we evaluate the impact of seasonal variations in blood pressure (BP), lipid profile and glycemic control on estimated CVD risk in patients with type 2 diabetes (T2D). Methods and results Retrospective monocentric study of patients with T2D who were visited at least once in the winter period and once in the summer period, less than 8 months apart, for which data related to systolic (S) BP, diastolic (D) BP, body mass index, glycosylated hemoglobin (HbA1c), total cholesterol, HDL cholesterol and smoking habit were available on both occasions. The 10-year CVD risk was calculated using the UKPDS risk engine and the ASCVD risk estimator. As many as 411 patients were included in the study. Significant within-patient differences between summer and winter were found for the absolute risk of events assessed with both calculators (Δs-w UKPDS-CHD: −1.33%, Δs-w UKPDS-Stroke: −0.84%, Δs-w ASCVD: −2.21%). The seasonal change in SBP was the main responsible for the change in risk estimated with both the UKPDS-Stroke (r2 = 0.43) and the ASCVD (r2 = 0.50) scores, while the change in total cholesterol was the main determinant of the change in risk for the UKPDS-CHD (r2 = 0.34). A significant correlation was identified between changes in temperature and changes in SBP (ρ = 0.130, p = 0.008), but not in other risk factors. Conclusions Seasonal variations in the classic CVD risk factors influence the risk estimated using validated calculators.

Background Nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD) are frequent and progressive conditions that share traditional risk factors: obesity, type 2 diabetes and hypertension. Aims To evaluate whether an independent relationship exists between liver steatosis and fibrosis and different CKD phenotypes. Methods Cross sectional study based on data from the 2017–18 cycle of the National Health and Nutrition Examination Survey. Vibration controlled transient elastography (VCTE) was performed in a US representative sample allowing the simultaneous assessment of liver steatosis (CAP: controlled attenuation parameter) and fibrosis (LSM: liver stiffness measurement) and their relationships with CKD phenotypes (albuminuria and reduced estimated glomerular filtration rate, eGFR). Results 4746 adult participants had a complete VCTE exam. Prevalence of liver steatosis and significant fibrosis was 33.7% (95%CI: 30.9–36.6%) and 8.9% (95%CI: 7.5–10.5%), respectively. Logistic regression analysis showed that liver fibrosis, but not steatosis, was associated with albuminuria (OR 2.19, 95%CI: 1.49–3.20) and albuminuria or reduced eGFR (OR 2.18, 95%CI: 1.59–3.00) also when adjusted for age, sex, ethnicity, BMI, diabetes, blood pressure categories, glycated haemoglobin, use of renin-angiotensin-aldosterone system blockers and CAP. Conclusions In the general US population liver fibrosis assessed using VCTE is associated with CKD, and in particular with the albuminuric phenotype, regardless of traditional risk factors.

Background Sodium glucose transporter 2 inhibitors (SGLT2-i) reduce renal and cardiovascular events in patients with type 2 diabetes (T2D) and their use is recommended by the 2020 KDIGO guidelines in patients with T2D and chronic kidney disease (CKD). The aim of this study is to estimate the proportion of patients with T2D and CKD in the US that should be treated with these agents for renal and cardiovascular protection. Methods We conducted a retrospective analysis of 2005–2018 National Health and Nutrition Examination Survey (NHANES) data. We focused on participants with a prior diagnosis of diabetes or that met diagnostic criteria for diabetes during the survey, with the exclusion of probable type 1 diabetic patients. Inclusion criteria for completed and ongoing renal and cardiovascular outcome trials in patients with CKD were applied. Results We estimated that 35.3% of patients with T2D in the US (projected to 8.96 million) should be treated with SGLT2-i according to the 2020 KDIGO guidelines. Moreover, 2.9–10.1% (projected to 0.75–2.55 million) met the inclusion criteria for dedicated kidney outcome trials, which were focused on a population of individuals with proteinuria. Conclusions About a third of patients with T2D in the US should be treated with an SGLT2-i. While compelling evidence of renal protection is present for patients with proteinuria, all patients with CKD obtain a cardiovascular benefit with this class of drugs.

Aim To assess and compare the persistence with drug therapy between patients treated with glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2-I) therapy. Methods The 126,493 residents of the Lombardy Region (Italy) aged ≥ 40 years newly treated with metformin during 2007–2015 were followed until 2017 to identify those who started therapy with GLP1-RA or SGLT2-I. To make GLP1-RA and SGLT2-I users more comparable, a 1:1 matched cohort design was adopted. Matching variables were sex, age, and adherence to the first-line therapy with metformin. Log-binomial regression models were fitted to estimate the propensity to 1-year treatment persistence in relation to the therapeutic strategy. Results The final matched cohort was composed by 1,276 GLP1-RA─SGLT2-I pairs. About 24% and 29% of cohort members respectively on GLP1-RA and SGLT2-I discontinued the drug treatment. Compared with patients starting SGLT2-I, those on GLP1-RA had 15% (95% confidence interval, 3–25%) lower risk of discontinuation of the treatments of interest and 45% (28–57%) lower risk of discontinuing any antidiabetic drug therapy. Persistence was better among GLP1-RA users who received a once-weekly administration. Conclusions In a real-life setting, patients who were prescribed a GLP1-RA exhibited more frequently better persistence to treatment than those prescribed a SGLT2-I therapy.

OBJECTIVE Type 2 diabetes mellitus (T2DM) is an important risk factor for the progression of metabolic liver disease to advanced fibrosis. Here, we provide an estimate of the prevalence of steatosis and fibrosis in U.S. adults with T2DM on the basis of transient elastography (TE) and identify factors associated with these conditions. RESEARCH DESIGN AND METHODS This is a cross-sectional study of U.S. adults with T2DM participating in the 2017–2018 cycle of the National Health and Nutrition Examination Survey who were evaluated by TE. Hepatic steatosis and fibrosis were diagnosed by the median value of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. RESULTS Among the 825 patients with reliable TE examination results, 484 (53.7%) were assessed using the M probe and 341 (46.3%) using the XL probe. Liver steatosis (CAP ≥274 dB/m), advanced fibrosis (LSM ≥9.7 kPa), and cirrhosis (LSM ≥13.6 kPa) were present in 73.8% (95% CI 68.5%–78.5%), 15.4% (95% CI 12.2%–19.0%), and 7.7% (95% CI 4.8%–11.9%) of patients, respectively. The mean ± SE age of patients with advanced fibrosis and cirrhosis was 63.7 ± 2.2 years and 57.8 ± 1.6 years, respectively. In the multivariable logistic regression model, BMI, non-Black race, and ALT levels were independent predictors of steatosis; and BMI, non-Black race, and AST and γ-glutamyltranspeptidase levels were independent predictors of advanced fibrosis. CONCLUSIONS Prevalence of both liver steatosis and fibrosis is high in patients with T2DM from the United States and obesity is a major risk factor. Our results support the screening of these conditions among patients with diabetes.

Background & Aims Metabolic-associated fatty liver disease (MAFLD) is common among adolescents, but the prevalence of significant fibrosis in this age group is not known. We aimed to estimate the prevalence of MAFLD and significant (≥F2) fibrosis by transient elastography (TE) in adolescents in the United States. Methods We analyzed TE data from participants 12–18 years old included in the National Health and Nutrition Examination Survey 2017–2018 (data available from 867 adolescents). Steatosis was evaluated by the median controlled attenuation parameter (CAP) and fibrosis by median liver stiffness measurement. Results Two-hundred forty participants (24.16%; 95% CI, 21.07–27.24) had any degree of steatosis (CAP≥248 dBm), 123 participants (11.6%; 95% CI, 9.19–14.06) had S3 steatosis (CAP≥280 dBm), and 51 participants (4.4%; 95% CI, 2.51–6.33) had significant fibrosis (liver stiffness ≥7.4 kPa). Multivariate analyses revealed that body mass index (odds ratio [OR] per unit increase, 1.2; 95% CI, 1.2–1.4), sex (OR female vs male participants , 0.5; 95% CI, 0.4–0.7), ethnicity (OR, Hispanic vs non-Hispanic white, 4.5; 95% CI, 1.7–11.8), and hypertension (OR, 3.5; 95% CI, 1.3–9.9) were associated with S3 steatosis, whereas body mass index (OR, 1.1 per unit increase; 95% CI, 1.0–1.2) and ethnicity (OR, non-Hispanic black vs non-Hispanic white, 3.9; 95% CI, 1.2–13.2) were associated with significant fibrosis. High proportions of participants with fibrosis were in the normal weight category (35%) and had normal levels of alanine aminotransferase (78%). Conclusions Prevalence of MAFLD and significant fibrosis are alarmingly high in adolescents in the National Health and Nutrition Examination Survey 2017–2018. Levels of alanine aminotransferase and blood biomarkers do not correctly identify adolescents with more advanced disease. Effective noninvasive strategies to differentiate simple steatosis from progressive forms are urgently needed.

Background: Bariatric surgery is a valuable therapeutic option in the treatment of obesity but the outcomes show a large subject-to-subject variability yet to be explained. Thyroid function may represent an involved factor and we have only few controversial data about its influence. Subjects/methods: We retrospectively assessed using a longitudinal approach the relation between baseline TSH levels and short-term (6 and 12 months) weight loss in 387 euthyroid patients who underwent laparoscopic gastric banding (LAGB; n = 187) or sleeve gastrectomy (SG; n = 200). Results: After LAGB, patients with low-normal TSH levels (0.40–1.40 mUI/L) had higher percent total weight loss, ∆BMI and percent excess weight loss when compared to patients with normal (1.41–2.48 mUI/L) and high-normal (2.49–4.00 mUI/L) TSH (p < 0.05). Conversely, no association was detected after SG (p = 0.17). The multivariable regression analysis showed that also baseline BMI (6–12 months) and HOMA2-IR (only at 6 months) were independently associated with the outcomes. Conclusions: TSH levels may influence the short-term weight loss response after LAGB. The lack of association after SG suggests that the influence of baseline endocrine and metabolic factors may not be relevant for procedures with greater and more immediate calorie intake restriction.

Objective: Visit-to-visit variability in SBP is a risk factor for cardiovascular disease (CVD) in type 2 diabetes (T2DM) but little is known on whether in T2DM this differs according to presence or absence of previous CVD. Methods: We retrospectively assessed the coefficient of variation (standard deviation/mean) of mean SBP (SBP-CV) in 970 patients (44% with established CVD) attending at least four times our secondary care diabetes clinic in 2015–2016 to estimate their risk of CVD-related events using the 10-year UKPDS Risk Engine. Results: Patients with established CVD had a higher SBP-CV (10.3 ± 4.8%) than patients without CVD (8.9 ± 4.3%; P < 0.001) as confirmed by the progressively higher prevalence of established CVD in tertiles of SBP-CV (36.6, 46.1, and 52.0%; P < 0.001), in association with more aggressive and complex drug regimens. On the basis of the 10-year UKPDS Risk Engine, higher SBP-CV values were associated with increased risks of the CVD outcomes regardless of the previous history of CVD in multivariate models. Conclusion: Visit-to-visit variability of SBP was greater in T2DM patients with that in those without previous history of CVD, and maintained an independent association with higher estimated risk of CVD-related events regardless of the history of CVD, suggesting that its prognostic significance is relevant in the entire CVD continuum of patients with T2DM.

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is prevalent in patients with type 2 diabetes. Here, we estimate the proportion of patients with type 2 diabetes that should be referred to hepatologists according to the European Association for the Study of the Liver (EASL)-European Association for the Study of Diabetes (EASD)-European Association for the Study of Obesity (EASO) Guidelines and evaluate the association between non-invasive biomarkers of steatosis and fibrosis and diabetic complications.Research design and methodsThis is a retrospective analysis of type 2 diabetes patients who attended on a regular basis our diabetes clinic between 2013 and 2018 (n=2770). Steatosis was assessed using Fatty Liver Index (FLI), Hepatic Steatosis Index and NAFLD Ridge Score and fibrosis using NAFLD Fibrosis Score (NFS), Fibrosis-4 (FIB-4), aspartate aminotransferase (AST) to platelet ratio index (APRI) and AST/alanine aminotransferase (ALT) ratio. Outcome measures were altered albumin excretion rate (AER), chronic kidney disease (CKD) and cardiovascular disease (CVD).ResultsThe prevalence of advanced fibrosis varied from 1% (APRI) to 33% (NFS). The application of the guidelines using a sequential combination of FLI and FIB-4 would lead to referral of 28.3% of patients when using standard FIB-4 cut-offs, while this number dropped to 13.4% when age-adjusted FIB-4 thresholds were applied. A higher prevalence of altered AER was associated with liver steatosis (FLI: OR: 3.49; 95% CI 2.05 to 5.94, pConclusionsWhile specific fibrosis scores identify different proportion of patients with advanced fibrosis, the use of age-adjusted FIB-4 cut-offs leads to a drop in gray-zone results, making referrals to hepatologists more sustainable. Interestingly non-invasive biomarkers were consistently associated with a different pattern of diabetic complications.

Nonalcoholic fatty liver disease (NAFLD) is common in patients with hypertension but controversy exists as to whether screening for this condition should be performed. Here, we evaluate the prevalence of NAFLD and advanced fibrosis in US adults across blood pressure categories and estimate the number of patients who require referral to hepatologists. In this cross-sectional analysis of 11 489 adults from the 2005 to 2016 National Health and Nutrition Examination Survey, participants were segregated as having optimal, normal, high normal, and elevated blood pressure according to the 2018 European Society of Cardiology/Hypertension guidelines. NAFLD was defined using the US fatty liver index, whereas fibrosis was assessed using the NAFLD fibrosis score, fibrosis-4, and Hepamet Fibrosis Score. NAFLD prevalence increased progressively from optimal (16.5%) to normal (34.5%), high normal (39.9%), and elevated blood pressure (50.2%, P

Aim Nonalcoholic fatty liver disease (NAFLD) is prevalent in patients with type 2 diabetes mellitus (T2DM), but controversy exists on whether to screen and how to manage these patients in clinical practice. Here, we estimate the number of patients with T2DM and NAFLD in the United States that should be evaluated for advanced liver fibrosis according to proposed screening strategies. Methods In this cross-sectional analysis of 2940 adult patients with T2DM (projected to 15.3 million) from the 2005–2016 National Health and Nutrition Examination Survey (NHANES) we applied validated noninvasive scores of liver steatosis and fibrosis to estimate the number of referrals to hepatologists. We followed two different approaches: (1) the flow-chart from the European Association for the Study of the Liver (EASL), Diabetes (EASD) and Obesity (EASO) guidelines; (2) a strategy recently proposed in patients with T2DM aimed at excluding advanced liver fibrosis with a negative predictive value of 100%. Results NAFLD (based on fatty liver index) was present in 78% of patients (projected to 11.9 million). According to the EASL-EASD-EASO guidelines 37.2–48.5% of patients (projected to 5.7–7.4 million) should be referred to experts, depending on the specific biomarker of fibrosis used. The second strategy, which is based sequentially on aspartate aminotransferase and Fibrosis-4 was able to exclude advanced fibrosis in 67.0% of patients. Conclusions Screening strategies based on noninvasive scores are able to exclude advanced liver fibrosis in 50–67% of patients with T2DM. Novel biomarkers or combination of tests may be necessary to reduce the need for liver biopsy and related bleeding episodes in the remaining 33–50%.

Purpose: The purpose of this study was to estimate how many individuals with severe obesity and NAFLD should be referred to hepatologists according to the EASL–EASD–EASO guidelines and whether the choice of specific indicators of liver fibrosis would significantly impact the number of referrals. Methods: This was a single-center retrospective study of 495 individuals with severe obesity screened at our institution between 2012 and 2018 for a bariatric surgery intervention. The guidelines were applied using the NAFLD Liver Fat Score (NLFS) to assess the presence of steatosis and the NAFLD fibrosis score (NFS), Fibrosis-4 (FIB-4) and Hepamet Fibrosis Score (HFS) to assess the risk of advanced fibrosis. Results: Three hundred and seventy-nine patients (76.6%) had evidence of liver steatosis. The application of the guidelines would lead to referral of 66.3% of patients using NFS, 31.7% using FIB-4 and 34.2% using HFS. When referrals due to abnormal liver function tests were excluded, these percentages dropped to 55.8%, 7.3% and 12.1%, respectively. The strongest inter-biomarker agreement was found between FIB-4 and HFS (κ = 0.86, 95% CI 0.815–0.910). Conclusion: Strict application of the guidelines in individuals with severe obesity would probably lead to over-referral, although a great variability exists among the different scores.

Aim: To investigate the relative contribution of previous gestational diabetes mellitus (GDM) and current type 2 diabetes (T2D) on the development of liver fibrosis, the strongest predictor of end-stage liver disease. Methods: This is a population-based cross-sectional study based on data from the 2017–2018 cycle of the National Health and Nutrition Examination Survey. We included women age ≥ 20 years that had delivered at least one live birth and had available data on vibration-controlled transient elastography (VCTE). Liver steatosis and fibrosis were assessed by the median value of controlled attenuation parameter (CAP) and liver stiffness measurement (LSM), respectively. Results: Among the 1699 women included in the study, 144 (10.1%, 95% CI 7.7–13.2) reported a previous diagnosis of GDM. Women with previous GDM were younger, had a higher BMI, a higher prevalence of T2D and were significantly older at the time they had the last live birth. Univariate analysis did not show a significant difference between women with and without a prior history of GDM in terms of both steatosis (44.8% vs 39.4%, p = 0.464) and fibrosis (7.5% vs 7.6%, p = 0.854). Multivariable logistic regression analysis showed that BMI, γ-glutamyltranspeptidase levels, T2D (OR 2.96, 95% CI 1.48–5.93, p < 0.01), HBV and HCV infection were associated with higher odds of significant fibrosis, while previous GDM showed a neutral effect. Conclusions: Women with previous GDM that do not develop overt T2D might not experience a poor hepatic prognosis.

Glucose transporter type 1 deficiency syndrome (Glut1 DS) is a rare neurological disorder caused by impaired glucose delivery to the brain. The clinical spectrum of Glut1 DS mainly includes epilepsy, paroxysmal dyskinesia (PD), developmental delay and microcephaly. Glut1 DS diagnosis is based on the identification of hypoglycorrhachia and pathogenic mutations of the SLC2A1 gene. Here, we report the molecular screening of SLC2A1 in 354 patients clinically suspected for Glut1 DS. From this cohort, we selected 245 patients for whom comprehensive clinical and laboratory data were available. Among them, we identified 19 patients carrying nucleotide variants of pathological significance, 5 of which were novel. The symptoms of onset, which varied from neonatal to adult age, included epilepsy, PD or non-epileptic paroxysmal manifestations. The comparison of the clinical features between the 19 SLC2A1 mutated and the 226 non-mutated patients revealed that the onset of epilepsy within the first year of life (when associated with developmental delay or other neurological manifestations), the association of epilepsy with PD and acquired microcephaly are more common in mutated subjects. Taken together, these data confirm the variability of expression of the phenotypes associated with mutation of SLC2A1 and provide useful clinical tools for the early identification of subjects highly suspected for the disease.