Thyroid function, adipokines and mitokines in metabolic dysfunction-associated steatohepatitis: A multi-centre biopsy-based observational study.

BACKGROUND AND AIMS: Thyroid axis is currently under investigation as a therapeutic target in metabolic dysfunction-associated steatotic liver disease (MASLD). Thyroid function was examined herein in the full spectrum of disease. METHODS: Subjects were recruited and had liver biopsies in two Gastroenterology-Hepatology Clinics (Greece and Australia) and one Bariatric-Metabolic Surgery Clinic (Italy). The main working sample was n = 677 subjects with MASLD after excluding subjects with abnormal free thyroxine levels. Participants were classified according to thyroid-stimulating hormone (TSH) standard criteria: Subclinical hyperthyroidism (<0.4 uIU/mL); Euthyroidism with relatively low (0.4 to <2.5 uIU/mL); euthyroidism with relatively high (2.5-4.0 uIU/mL); subclinical hypothyroidism (>4 uIU/mL). RESULTS: TSH as a continuous variable was positively associated with significant fibrosis (F ≥ 2), metabolic dysfunction-associated steatohepatitis (MASH) and at-risk MASH. Subclinical hypothyroidism was associated with fibrosis F ≥ 2 (odds ratio [OR] = 3.47, 95% confident interval [CI] [1.50, 8.05], p = .02), MASH (OR = 3.44, 95% CI [1.48, 7.98] p = .001) and at-risk MASH (OR = 3.88, 95% CI [1.76, 8.55], p = .001), before and after controlling for adiposity, central obesity, and insulin resistance. When leptin, adiponectin, or growth differentiation factor-15 were examined as moderators, significance was lost. Sex-specific analysis revealed a strong association between TSH and the presence of significant fibrosis among women, eliminated only when adipokines/mitokines were adjusted for. Restricted cubic spline analysis revealed associations between TSH and liver outcomes (p-values < .01) with inflection points for fibrosis F ≥ 2 being 2.49, for MASH being 2.67 and for at-risk MASH being 6.96. CONCLUSIONS: These observations provide support for studies on the administration of thyroid hormone in MASLD therapeutics for subclinical hypothyroidism and liver-specific thyroid receptor agonists for subjects across the TSH continuum.

Circulating hormones in biopsy-proven steatotic liver disease and steatohepatitis: A Multicenter Observational Study.

BACKGROUND: The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. PURPOSE: To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages. METHODS: This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited. RESULTS: We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD. CONCLUSIONS: Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.

Liver biopsy-based validation, confirmation and comparison of the diagnostic performance of established and novel non-invasive steatotic liver disease indexes: Results from a large multi-center study.

BACKGROUND: Non-invasive tools (NIT) for metabolic-dysfunction associated liver disease (MASLD) screening or diagnosis need to be thoroughly validated using liver biopsies. PURPOSE: To externally validate NITs designed to differentiate the presence or absence of liver steatosis as well as more advanced disease stages, to confirm fully validated indexes (n = 7 NITs), to fully validate partially validated indexes (n = 5 NITs), and to validate for the first time one new index (n = 1 NIT). METHODS: This is a multi-center study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374, including 237 patients with metabolic-dysfunction associated steatohepatitis (MASH)) and Controls (n = 81) were recruited. A complete validation analysis was performed to differentiate the presence of MASLD vs. Controls, MASH vs. metabolic-dysfunction associated steatotic liver (MASL), histological features of MASH, and fibrosis stages. RESULTS: The index of NASH (ION) demonstrated the highest differentiation ability for the presence of MASLD vs. Controls, with the area under the curve (AUC) being 0.894. For specific histological characterization of MASH, no NIT demonstrated adequate performance, while in the case of specific features of MASH, such as hepatocellular ballooning and lobular inflammation, ION demonstrated the best performance with AUC being close to or above 0.850. For fibrosis (F) classification, the highest AUC was reached by the aspartate aminotransferase to platelet ratio index (APRI) being ~0.850 yet only with the potential to differentiate the severe fibrosis stages (F3, F4) vs. mild or moderate fibrosis (F0-2) with an AUC > 0.900 in patients without T2DM. When we excluded patients with morbid obesity, the differentiation ability of APRI was improved, reaching AUC = 0.802 for differentiating the presence of fibrosis F2-4 vs. F0-1. The recommended by current guidelines index FIB-4 seemed to differentiate adequately between severe (i.e., F3-4) and mild or moderate fibrosis (F0-2) with an AUC = 0.820, yet this was not the case when FIB-4 was used to classify patients with fibrosis F2-4 vs. F0-1. Trying to improve the predictive value of all NITs, using Youden's methodology, to optimize the suggested cut-off points did not materially improve the results. CONCLUSIONS: The validation of currently available NITs using biopsy-proven samples provides new evidence for their ability to differentiate between specific disease stages, histological features, and, most importantly, fibrosis grading. The overall performance of the examined NITs needs to be further improved for applications in the clinic.

The first external validation of the Dallas steatosis index in biopsy-proven Non-alcoholic fatty liver Disease: A multicenter study.

AIMS: A new non-invasive tool (NIT) for non-alcoholic fatty liver disease (NAFLD) proposed in 2022 by the multi-ethnic Dallas Heart Study, i.e. the Dallas Steatosis Index (DSI), was validated herein using for the first time the gold standard i.e. liver biopsy-proven NAFLD. METHODS: This is a multicenter study based on samples and data from two Gastroenterology-Hepatology Clinics (Greece and Australia) and one Bariatric-Metabolic Surgery Clinic (Italy). Overall, n = 455 patients with biopsy-proven NAFLD (n = 374) and biopsy-proven controls (n = 81) were recruited. RESULTS: The ability of DSI to correctly classify participants as NAFLD or controls was very good, reaching an Area Under the Curve (AUC) = 0.887. The cut-off point that could best differentiate the presence vs. absence of NAFLD corresponded to DSI = 0.0 (risk threshold: 50% | Sensitivity: 0.88; Positive Predictive Value (PPV): 93.0%; F1-score = 0.91). DSI demonstrated significantly better performance characteristics than other liver steatosis indexes. Decision curve analysis revealed that the benefit of DSI as a marker to indicate the need for invasive liver assessment was confirmed only when higher DSI values, i.e. ≥ 1.4, were used as risk thresholds. DSI performance to differentiate disease progression was inadequate (all AUCs < 0.700). CONCLUSIONS: DSI is more useful for disease screening (NAFLD vs. controls) than to differentiate diseases stages or progression. The value of any inclusion of DSI to guidelines needs to be further studied.

Development and validation of an interpretable machine learning-based calculator for predicting 5-year weight trajectories after bariatric surgery: a multinational retrospective cohort SOPHIA study.

BACKGROUND: Weight loss trajectories after bariatric surgery vary widely between individuals, and predicting weight loss before the operation remains challenging. We aimed to develop a model using machine learning to provide individual preoperative prediction of 5-year weight loss trajectories after surgery. METHODS: In this multinational retrospective observational study we enrolled adult participants (aged ≥18 years) from ten prospective cohorts (including ABOS [NCT01129297], BAREVAL [NCT02310178], the Swedish Obese Subjects study, and a large cohort from the Dutch Obesity Clinic [Nederlandse Obesitas Kliniek]) and two randomised trials (SleevePass [NCT00793143] and SM-BOSS [NCT00356213]) in Europe, the Americas, and Asia, with a 5 year follow-up after Roux-en-Y gastric bypass, sleeve gastrectomy, or gastric band. Patients with a previous history of bariatric surgery or large delays between scheduled and actual visits were excluded. The training cohort comprised patients from two centres in France (ABOS and BAREVAL). The primary outcome was BMI at 5 years. A model was developed using least absolute shrinkage and selection operator to select variables and the classification and regression trees algorithm to build interpretable regression trees. The performances of the model were assessed through the median absolute deviation (MAD) and root mean squared error (RMSE) of BMI. FINDINGS: 10 231 patients from 12 centres in ten countries were included in the analysis, corresponding to 30 602 patient-years. Among participants in all 12 cohorts, 7701 (75·3%) were female, 2530 (24·7%) were male. Among 434 baseline attributes available in the training cohort, seven variables were selected: height, weight, intervention type, age, diabetes status, diabetes duration, and smoking status. At 5 years, across external testing cohorts the overall mean MAD BMI was 2·8 kg/m2 (95% CI 2·6-3·0) and mean RMSE BMI was 4·7 kg/m2 (4·4-5·0), and the mean difference between predicted and observed BMI was -0·3 kg/m2 (SD 4·7). This model is incorporated in an easy to use and interpretable web-based prediction tool to help inform clinical decision before surgery. INTERPRETATION: We developed a machine learning-based model, which is internationally validated, for predicting individual 5-year weight loss trajectories after three common bariatric interventions. FUNDING: SOPHIA Innovative Medicines Initiative 2 Joint Undertaking, supported by the EU's Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, Type 1 Diabetes Exchange, and the Juvenile Diabetes Research Foundation and Obesity Action Coalition; Métropole Européenne de Lille; Agence Nationale de la Recherche; Institut national de recherche en sciences et technologies du numérique through the Artificial Intelligence chair Apprenf; Université de Lille Nord Europe's I-SITE EXPAND as part of the Bandits For Health project; Laboratoire d'excellence European Genomic Institute for Diabetes; Soutien aux Travaux Interdisciplinaires, Multi-établissements et Exploratoires programme by Conseil Régional Hauts-de-France (volet partenarial phase 2, project PERSO-SURG).

Bariatric-metabolic surgery versus lifestyle intervention plus best medical care in non-alcoholic steatohepatitis (BRAVES): a multicentre, open-label, randomised trial.

BACKGROUND: Observational studies suggest that bariatric-metabolic surgery might greatly improve non-alcoholic steatohepatitis (NASH). However, the efficacy of surgery on NASH has not yet been compared with the effects of lifestyle interventions and medical therapy in a randomised trial. METHODS: We did a multicentre, open-label, randomised trial at three major hospitals in Rome, Italy. We included participants aged 25-70 years with obesity (BMI 30-55 kg/m2), with or without type 2 diabetes, with histologically confirmed NASH. We randomly assigned (1:1:1) participants to lifestyle modification plus best medical care, Roux-en-Y gastric bypass, or sleeve gastrectomy. The primary endpoint of the study was histological resolution of NASH without worsening of fibrosis at 1-year follow-up. This study is registered at ClinicalTrials.gov, NCT03524365. FINDINGS: Between April 15, 2019, and June 21, 2021, we biopsy screened 431 participants; of these, 103 (24%) did not have histological NASH and 40 (9%) declined to participate. We randomly assigned 288 (67%) participants with biopsy-proven NASH to lifestyle modification plus best medical care (n=96 [33%]), Roux-en-Y gastric bypass (n=96 [33%]), or sleeve gastrectomy (n=96 [33%]). In the intention-to-treat analysis, the percentage of participants who met the primary endpoint was significantly higher in the Roux-en-Y gastric bypass group (54 [56%]) and sleeve gastrectomy group (55 [57%]) compared with lifestyle modification (15 [16%]; p<0·0001). The calculated probability of NASH resolution was 3·60 times greater (95% CI 2·19-5·92; p<0·0001) in the Roux-en-Y gastric bypass group and 3·67 times greater (2·23-6·02; p<0·0001) in the sleeve gastrectomy group compared with in the lifestyle modification group. In the per protocol analysis (236 [82%] participants who completed the trial), the primary endpoint was met in 54 (70%) of 77 participants in the Roux-en-Y gastric bypass group and 55 (70%) of 79 participants in the sleeve gastrectomy group, compared with 15 (19%) of 80 in the lifestyle modification group (p<0·0001). No deaths or life-threatening complications were reported in this study. Severe adverse events occurred in ten (6%) participants who had bariatric-metabolic surgery, but these participants did not require re-operations and severe adverse events were resolved with medical or endoscopic management. INTERPRETATION: Bariatric-metabolic surgery is more effective than lifestyle interventions and optimised medical therapy in the treatment of NASH. FUNDING: Fondazione Policlinico Universitario A Gemelli, Policlinico Universitario Umberto I and S Camillo Hospital, Rome, Italy.

Accurate liquid biopsy for the diagnosis of non-alcoholic steatohepatitis and liver fibrosis.

OBJECTIVE: Clinical diagnosis and approval of new medications for non-alcoholic steatohepatitis (NASH) require invasive liver biopsies. The aim of our study was to identify non-invasive biomarkers of NASH and/or liver fibrosis. DESIGN: This multicentre study includes 250 patients (discovery cohort, n=100 subjects (Bariatric Surgery Versus Non-alcoholic Steato-hepatitis - BRAVES trial); validation cohort, n=150 (Liquid Biopsy for NASH and Liver Fibrosis - LIBRA trial)) with histologically proven non-alcoholic fatty liver (NAFL) or NASH with or without fibrosis. Proteomics was performed in monocytes and hepatic stellate cells (HSCs) with iTRAQ-nano- Liquid Chromatography - Mass Spectrometry/Mass Spectrometry (LC-MS/MS), while flow cytometry measured perilipin-2 (PLIN2) and RAB14 in peripheral blood CD14+CD16- monocytes. Neural network classifiers were used to predict presence/absence of NASH and NASH stages. Logistic bootstrap-based regression was used to measure the accuracy of predicting liver fibrosis. RESULTS: The algorithm for NASH using PLIN2 mean florescence intensity (MFI) combined with waist circumference, triglyceride, alanine aminotransferase (ALT) and presence/absence of diabetes as covariates had an accuracy of 93% in the discovery cohort and of 92% in the validation cohort. Sensitivity and specificity were 95% and 90% in the discovery cohort and 88% and 100% in the validation cohort, respectively.The area under the receiver operating characteristic (AUROC) for NAS level prediction ranged from 83.7% (CI 75.6% to 91.8%) in the discovery cohort to 97.8% (CI 95.8% to 99.8%) in the validation cohort.The algorithm including RAB14 MFI, age, waist circumference, high-density lipoprotein cholesterol, plasma glucose and ALT levels as covariates to predict the presence of liver fibrosis yielded an AUROC of 95.9% (CI 87.9% to 100%) in the discovery cohort and 99.3% (CI 98.1% to 100%) in the validation cohort, respectively. Accuracy was 99.25%, sensitivity 100% and specificity 95.8% in the discovery cohort and 97.6%, 99% and 89.6% in the validation cohort. This novel biomarker was superior to currently used FIB4, non-alcoholic fatty liver disease fibrosis score and aspartate aminotransferase (AST)-to-platelet ratio and was comparable to ultrasound two-dimensional shear wave elastography. CONCLUSIONS: The proposed novel liquid biopsy is accurate, sensitive and specific in diagnosing the presence and severity of NASH or liver fibrosis and is more reliable than currently used biomarkers. CLINICAL TRIALS: Discovery multicentre cohort: Bariatric Surgery versus Non-Alcoholic Steatohepatitis, BRAVES, ClinicalTrials.gov identifier: NCT03524365.Validation multicentre cohort: Liquid Biopsy for NASH and Fibrosis, LIBRA, ClinicalTrials.gov identifier: NCT04677101.

Prevalence and predictors of non-alcoholic steatohepatitis in subjects with morbid obesity and with or without type 2 diabetes.

AIM: To investigate the prevalence of biopsy-proven non-alcoholic steatohepatitis (NASH) in a cohort of patients with morbid obesity and with or without type 2 diabetes (T2D) and to find non-invasive predictors of NASH severity. METHODS: We evaluated a cohort of 412 subjects (age 19-67 years, body mass index-BMI: 44.98 kg/m2), who underwent fine-needle liver biopsy during bariatric surgery. Thirty-six percent of the subjects were affected by T2D. Liver biopsies were classified according to the Kleiner's NAFLD Activity Score (NAS). NAFLD Fibrosis Score (NFS), AST/ALT ratio, AST to Platelet ratio (APRI), fibrosis-4 score (FIB4) were calculated. A neural network analysis (NNA) was run to predict NASH severity. RESULTS: The prevalence of biopsy-proven NASH was 63% and 78% in subjects with obesity and without or with T2D, respectively. T2D doubled the risk of NASH [OR 2.079 (95% IC=1.31-3.29)]. The prevalence of NAFL increased with the increase of BMI, while there was an inverse correlation between BMI and NASH (r=-0.145 p=0.003). Only mild liver fibrosis was observed. HOMA-IR was positively associated with hepatocyte ballooning (r=0.208, p<0.0001) and fibrosis (r=0.159, p=0.008). The NNA highlighted a specificity of 77.3% using HDL-cholesterol, BMI, and HOMA-IR as main determinants of NASH. CONCLUSIONS: Our data show a higher prevalence of NASH in patients with morbid obesity than reported in the literature and the pivotal role of T2D among the risk factors for NASH development. However, the inverse correlation observed between BMI and biopsy-proven NASH suggests that over a certain threshold adiposity can be somewhat protective against liver damage. Our model predicts NASH presence with high specificity, thus helping identifying subjects who should promptly undergo liver biopsy.

Advice of General Practitioner, of Surgeon, of Endocrinologist, and Self-determination: the Italian Road to Bariatric Surgery.

PURPOSE: Bariatric surgery (BS) is considered the most efficient treatment for severe obesity. International guidelines recommend multidisciplinary approach to BS (general practitioners, endocrinologists, surgeons, psychologists, or psychiatrists), and access to BS should be the final part of a protocol of treatment of obesity. However, there are indications that general practitioners (GPs) are not fully aware of the possible benefits of BS, that specialty physicians are reluctant to refer their patients to surgeons, and that patients with obesity choose self-management of their own obesity, including internet-based choices. There are no data on the pathways chosen by physicians and patients to undergo BS in the real world in Italy. METHODS: An exploratory exam was performed for 6 months in three pilot regions (Lombardy, Lazio, Campania) in twenty-three tertiary centers for the treatment of morbid obesity, to describe the real pathways to BS in Italy. RESULTS: Charts of 2686 patients (788 men and 1895 women, 75.5% in the age range 30-59 years) were evaluated by physicians and surgeons of the participating centers. A chronic condition of obesity was evident for the majority of patients, as indicated by duration of obesity, by presence of several associated medical problems, and by frequency of previous dietary attempts to weight loss. The vast majority (75.8%) patients were self-presenting or referred by bariatric surgeons, 24.2% patients referred by GPs and other specialists. Self-presenting patients were younger, more educated, more professional, and more mobile than patients referred by other physicians. Patients above the age of 40 years or with a duration of obesity greater than 10 years had a higher prevalence of all associated medical problems. CONCLUSIONS: The majority of patients referred to a tertiary center for the treatment of morbid obesity have a valid indication for BS. Most patients self-refer to the centers, with a minority referred by a GP or by specialists. Self-presenting patients are younger, more educated, more professional, and more mobile than patients referred by other physicians. Older patients and with a longer duration of obesity are probably representative of the conservative approach to BS, often regarded as the last resort in an endless story.

Blood Hemoglobin Substantially Modulates the Impact of Gender, Morbid Obesity, and Hyperglycemia on COVID-19 Death Risk: A Multicenter Study in Italy and Spain.

Background: Hyperglycemia and obesity are associated with a worse prognosis in subjects with COVID-19 independently. Their interaction as well as the potential modulating effects of additional confounding factors is poorly known. Therefore, we aimed to identify and evaluate confounding factors affecting the prognostic value of obesity and hyperglycemia in relation to mortality and admission to the intensive care unit (ICU) due to COVID-19. Methods: Consecutive patients admitted in two Hospitals from Italy (Bologna and Rome) and three from Spain (Barcelona and Girona) as well as subjects from Primary Health Care centers. Mortality from COVID-19 and risk for ICU admission were evaluated using logistic regression analyses and machine learning (ML) algorithms. Results: As expected, among 3,065 consecutive patients, both obesity and hyperglycemia were independent predictors of ICU admission. A ML variable selection strategy confirmed these results and identified hyperglycemia, blood hemoglobin and serum bilirubin associated with increased mortality risk. In subjects with blood hemoglobin levels above the median, hyperglycemic and morbidly obese subjects had increased mortality risk than normoglycemic individuals or non-obese subjects. However, no differences were observed among individuals with hemoglobin levels below the median. This was particularly evident in men: those with severe hyperglycemia and hemoglobin concentrations above the median had 30 times increased mortality risk compared with men without hyperglycemia. Importantly, the protective effect of female sex was lost in subjects with increased hemoglobin levels. Conclusions: Blood hemoglobin substantially modulates the influence of hyperglycemia on increased mortality risk in patients with COVID-19. Monitoring hemoglobin concentrations seem of utmost importance in the clinical settings to help clinicians in the identification of patients at increased death risk.

Characterization of gut microbiota in patients with metabolic syndrome candidates for bariatric/metabolic surgery: Preliminary findings of a multi-center prospective study.

INTRODUCTION: gut microbiota (GM) seems to be involved in the pathophysiology and progression of both metabolic syndrome (MS) and obesity. The aim was to investigate GM's composition in patients with severe obesity, candidates for bariatric/metabolic surgery BMS. MATERIALS AND METHODS: Multicentre, prospective, cohort study, enrolling 84 patients with BMI 40-55 kg/m2, divided bymetabolic status (MS) inhealthy(group A), pre-MS (B), or MS (C). RESULTS: No differences were foundregarding anthropometric,nutritional parameters, except for vitamin D.As a whole the alpha and beta diversity examinations showed no statistical differences in GM profile. A total of 5/7 phyla with relative frequencies were identified above 0.1% (Actinobacteria,Bacteroidetes,Firmicutes,Proteobacteria,Verrucomicrobia).FusobacteriaandPatescibacteriarepresented the less abundant. There were no significant differences in the top ten genera.Data onBacteroidetes(inversely related to triglycerides and LDL and directly related to HDL levels) and onFirmicutes(opposite trend) relative abundances suggest no differences among the three conditions.No correlation between the relative abundance of themain phylaand plasmatic glucose levels was observed. CONCLUSIONS: In a selected cohort of patients with obesity, MS did not affect the preoperative GM's profile. Severe obesity, per se, seems to be an independent condition affecting GM.

Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis.

AIMS: To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy. MATERIALS AND METHODS: We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change. RESULTS: The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (ß = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (ß = 0.31%, P < 0.001). Treatments that were regarded as promising, such as elafibranor, simtuzumab, selonsertib, cenicriviroc, obeticholic acid and liraglutide, did not reduce either NAS or liver fibrosis significantly. CONCLUSIONS: Pioglitazione and RYGB are the most effective therapies for NASH. Antioxidants may be effective in reducing liver fibrosis. Weight loss and improvement of hepatic insulin resistance are promising approaches in the treatment of NASH.

Insulin Resistance Is Central to Long-Term Reversal of Histologic Nonalcoholic Steatohepatitis After Metabolic Surgery.

CONTEXT: Nonalcoholic steatohepatitis (NASH) is considered the hepatic counterpart of metabolic syndrome. OBJECTIVE: This work aimed to investigate the determinants of NASH reversal in patients undergoing biliopancreatic diversion (BPD) in a 5-year follow-up study. METHODS: This prospective study was conducted at Policlinico Universitario Agostino Gemelli. A total of 37 patients underwent fine-needle liver biopsy during BPD. Ultrasonography-guided percutaneous liver biopsy was obtained 5 years after the operation. The primary outcome of our study was histologic NASH reversal at 5-year follow-up. To better characterize the clinical variables involved in the resolution of NASH, we also compared patients without histologic NASH resolution at 5 years with those in whom NASH had disappeared. RESULTS: At follow-up, NASH had reversed in 56.5% of the patients. The NAFLD activity score (NAS) improved from 3.7 ± 0.93 to 2 ± 1.11 (P < .001). Fibrosis reversed in 16% patients (P = .022), and 32% improved (95% CI, 0.05-0.54). No significant differences in body mass index or clinical parameters changes explained the effect of surgery on NASH, apart from the measure of insulin sensitivity post surgery. The Homeostasis Model Assessment of Insulin Resistance decreased from 3.31 ±â€…1.72 at baseline to 1.73 ±â€…1.08 (P < .001) after BPD, and the Matsuda index improved from 2.66 ±â€…1.79 to 4.73 ±â€…3.05 (P < .001). The lipid profile normalized (total cholesterol from 4.75 ±â€…1.18 to 3.32 ±â€…0.77 mmol/L, P < .001; low-density lipoprotein cholesterol from 2.92 ±â€…0.91 to 1.60 ±â€…0.51 mmol/L, P = .0001; high-density lipoprotein cholesterol from 0.97 ±â€…0.33 to 1.10 ±â€…0.35 mmol/L, P = .023; triglycerides from 2.52 ±â€…1.6 to 1.47 ±â€…0.67 mmol/L, P = .003). Neural network analysis showed that the end-study Matsuda index discriminated between responders and nonresponders with high accuracy (receiver operating characteristic area under the curve = 0.98%). CONCLUSION: Remission of NASH is driven by reversal of whole-body insulin resistance post intervention.

Duodenal-jejunal bypass improves nonalcoholic fatty liver disease independently of weight loss in rodents with diet-induced obesity.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver-related mortality. NAFLD is associated with obesity, hepatic fat accumulation, and insulin resistance, all of which contribute to its pathophysiology. Weight-loss is the main therapy for NAFLD, and metabolic surgery is the most effective treatment for morbid obesity and its metabolic comorbidities. Although has been reported that Roux-en-Y gastric bypass can reverse NAFLD, it is unclear whether such effects result from reduced weight, from a lower calorie-intake, or from the direct influence of surgery on mechanisms contributing to NAFLD. We aimed to investigate whether gastrointestinal (GI) bypass surgery could induce direct effects on hepatic fat accumulation and insulin resistance, independently of weight reduction. Twenty Wistar rats on a high-fat diet underwent duodenal-jejunal-bypass (DJB) or sham operation and were pair fed (PF) for 15 wk after surgery to obtain a matched weight. Outcome measures include ectopic fat deposition, expression of genes and proteins involved in fat metabolism, insulin-signaling, and gluconeogenesis in liver and muscle. Despite no differences in body weight and calorie intake, DJB showed lower ectopic fat accumulation, improved peripheral and hepatic insulin sensitivity, and enhanced lipid droplet degradation. In both tissues, DJB increased insulin signaling, whereas hepatic key enzymes involved in gluconeogenesis and de novo lipogenesis were decreased. These findings suggest that DJB can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of NAFLD that share a mutual pathway, in which perilipin-2 (PLIN2) seems to be the main player, supporting further investigation into strategies that target the gut to treat metabolic liver diseases.NEW & NOTEWORTHY Our findings suggest that duodenal-jejunal bypass can reverse, independently of weight loss, ectopic fat deposition and insulin resistance, two features of nonalcoholic fatty liver disease that share a mutual pathway, in which perilipin-2 seems to be the main player. Our study supports further investigation into the role of proximal small intestine exclusion in the pathophysiology of nonalcoholic fatty liver disease to uncover less invasive treatments that mimic the effects of metabolic surgery and aims to prevent and treat metabolic liver disease.

A new sensitive and accurate model to predict moderate to severe obstructive sleep apnea in patients with obesity.

Obstructive sleep apnea (OSA) has a high prevalence in patients with obesity. Only patients with clinical symptoms of OSA are admitted to polysomnography; however, many patients with OSA are asymptomatic. We aimed to create and validate a population-based risk score that predicts the severity of OSA in patients with obesity.We here report the cross-sectional analysis at baseline of an ongoing study investigating the long-term effect of bariatric surgery on OSA. One-hundred sixty-one patients of the Obesity Center of the Catholic University Hospital in Rome, Italy were included in the study. The patients underwent overnight cardiorespiratory monitoring, blood chemistry analyses, hepatic ultrasound, and anthropometric measurements. The patients were divided into 2 groups according OSA severity assessed by the apnea-hypopnea index (AHI): AHI < 15 = no or mild and AHI ≥ 15 moderate to severe OSA. A statistical prediction model was created and validated. C statistics was used to evaluate the discrimination performance of the model.The prevalence of OSA was 96.3% with 74.5% of the subjects having moderate/severe OSA. Sex, body mass index, diabetes, and age were included in the final prediction model that had excellent discrimination ability (C statistics equals to 83%). An OSA risk chart score for clinical use was created.Patients with severe obesity are at a very high risk for moderate or severe OSA in particular if they are men, older, more obese, and/or with type 2 diabetes. The OSA risk chart can be useful for general practitioners and patients as well as for bariatric surgeons to select patients with high risk of moderate to severe OSA for further polysomnography.

Functional lipidomics in patients on home parenteral nutrition: Effect of lipid emulsions.

AIM: To investigate the fatty acid-based functional lipidomics of patients on long-term home parenteral nutrition receiving different intravenous lipid emulsions. METHODS: A cross-sectional comparative study was carried out on 3 groups of adults on home parenteral nutrition (HPN), receiving an HPN admixture containing an olive-soybean oil-based intravenous lipid emulsion (IVLE) (OO-IVLE; n = 15), a soybean- medium-chain triacylglycerol-olive-fish oil-based IVLE (SMOF-IVLE; n = 8) or HPN without IVLE (No-IVLE; n = 8) and 42 healthy controls (HCs). The inclusion criteria were: duration of HPN ≥ 3 mo, current HPN admixtures ≥ 2 mo and HPN infusions ≥ 2/wk. Blood samples were drawn 4-6 h after the discontinuation of the overnight HPN infusion. The functional lipidomics panel included: the red blood cell (RBC) fatty acid (FA) profile, molecular biomarkers [membrane fluidity: saturated/monounsaturated FA ratio = saturated fatty acid (SFA)/monounsaturated fatty acid (MUFA) index; inflammatory risk: n-6/n-3 polyunsaturated fatty acid (PUFA) ratio = n-6/n-3 index; cardiovascular risk: sum of n-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) = n-3 index; free radical stress: sum of FA trans isomers = %trans index] and FA pathway enzyme activity estimate (delta-9-desaturase = D9D; delta-6-desaturase = D6D; delta-5-desaturase = D5D; elongase = ELO). Statistics were carried out using nonparametric tests. The amount of each FA was calculated as a percentage of the total FA content (relative%). RESULTS: In the OO-IVLE group, the percentage of oleic acid in the RBCs was positively correlated with the weekly load of OO-IVLE (r = 0.540, P = 0.043). In the SMOF-IVLE cohort, the RBC membrane EPA and DHA were positively correlated with the daily amount of SMOF-IVLE (r = 0.751, P = 0.044) and the number of HPN infusions per week (r = 0.753; P = 0.046), respectively. The SMOF-IVLE group showed the highest EPA and DHA and the lowest arachidonic acid percentages (P < 0.001). The RBC membrane linoleic acid content was lower, and oleic and vaccenic acids were higher in all the HPN groups in comparison to the HCs. Vaccenic acid was positively correlated with the weekly HPN load of glucose in both the OO-IVLE (r = 0.716; P = 0.007) and the SMOF-IVLE (r = 0.732; P = 0.053) groups. The estimated activity of D9D was higher in all the HPN groups than in the HCs (P < 0.001). The estimated activity of D5D was lower in the SMOF-IVLE group than in the HCs (P = 0.013). The SFA/MUFA ratio was lower in all the HPN groups than in the HCs (P < 0.001). The n-6/n-3 index was lower and the n-3 index was higher in the SMOF-IVLE group in comparison to the HCs and to the other HPN groups (P < 0.001). The %trans index did not differ among the four groups. CONCLUSION: The FA profile of IVLEs significantly influenced the cell membrane functional lipidomics. The amount of glucose in the HPN may play a relevant role, mediated by the insulin regulation of the FA pathway enzyme activities.