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An integrated healthcare pathway model for metabolic-dysfunction associated steatotic liver disease (MASLD) is recommended for a comprehensive evaluation of the metabolic health. In this prospective study we aimed to assess prevalence and predictors of steatotic liver disease (SLD) and significant liver fibrosis (SLF) in consecutive patients first referred for type 2 diabetes mellitus (T2DM) or SLD in two different settings (diabetology and hepatology clinics) of the "AOU Città della Salute e della Scienza di Torino" University Hospital. All patients underwent vibration-controlled transient elastography for liver stiffness measurement (LSM) and controlled attenuation parameter (CAP), and echocardiography with speckle tracking analysis. SLD was defined by CAP>247 dB/m. SLF was defined by LSM>7 kPa. Diastolic dysfunction was defined by mitral E/E' ratio>9 and systolic dysfunction by left ventricular global longitudinal strain (GLS)>-18. 544 patients (59% in the liver clinic group [LCG] and 41% in the diabetes clinic group [DCG]) were enrolled. In the LCG all patients fulfilled the criteria for MASLD; prevalence of T2DM and obesity were 21.8% and 42.7%; 4.7% were referred to the DCG for first diagnosed or decompensated T2DM. Median LSM was 5.1 [4.6 – 6.3] kPa and SLF was detected in 17.8% of cases. In the DCG prevalence of obesity was 52.0% and median LSM was 4.9 [4.1 – 5.9] kPa. SLD was present in 67.7% of cases, of which 59.6% MASLD, 1.3% ALD (alcohol-related liver disease) and 6.7% metALD. SLF was detected in 13.5% of cases, which were referred to the LCG for hepatological evaluation. A known cardiovascular disease (CVD) was found in 9.7% and 50.2% of patients in the LCG and DCG, respectively. A high Framingham risk score (>20%) was detected in 12.9% in the LCG and 1.3% in the DCG. Prevalence of diastolic and systolic dysfunctions in those without CVD were 27.4% and 18.2% in the LCG and 8.9% and 3.6% in the DCG. In the LCG, Body Mass Index (BMI) and T2DM were the strongest predictors of SLF (aOR 1.13[95%CI 1.06-1.21], p=0.0002 and 5.66 [95%CI 2.64-12.07], p<0.001). In the DCG, only transaminases were independent predictors of SLF (aOR 1.11 [95%CI 1.04-1.19], p=0.001), while BMI was the only predictor of SLD (aOR 1.09 [95%CI 1.03-1.16], p=0.001). Two thirds of SLD in the non-hepatology setting are due to MASLD and associated with BMI. Prevalence of SLF is similar in hepatology and non-hepatology settings, but presence of T2DM results in the strongest association independent of other metabolic risk factors. A higher prevalence of pre-clinical CVD is detected in the hepatology setting by advanced echocardiography, consistent with a higher 10-year risk of CVD-related mortality. This study was funded by the Italian Ministry for Education, University and Research (MIUR) under the programme 'Dipartimenti di Eccellenza 2018-2022′ Project code D15D18000410001. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a sexually dimorphic condition, characterized by a high prevalence in men compared to premenopausal women, but the reverse is true after menopause. Steroids, including glucocorticoids and sex hormones, regulate both glucose and lipid metabolism, and their perturbation may exert a detrimental effect on metabolic pathways promoting liver damage. The aim of this study was to shed light on sexual dimorphism in patients with MASLD through a targeted steroidomic approach. We enrolled 463 consecutive patients (males n=275 [59%]; females n=188 [41%]) with biopsy-proven MASLD and 112 healthy controls (HC) (males n=55 [49%]; females n=57 [51%]). A panel of 26 steroids (including glucocorticoids, androgens and their representative glucuro- and sulpho-conjugated metabolites) was measured by liquid chromatography coupled to tandem mass spectrometry. For statistical analysis, we stratified the whole cohort according to sex and age, using 50 years(y) as a cut-off. Advanced fibrosis was defined as F≥3. By comparing MASLD subjects and HC, we observed an increase in glucocorticoid levels in MASLD men<50y, and an increase in testosterone levels in MASLD women ≥50y compared to the corresponding HC groups. Concerning MASLD group, the prevalence of F≥3 was 36% (men/women 31%/45%, p=0.061). Similarly, we observed an increase in glucocorticoids levels in both MASLD men and women <50y with F≥3 compared to those without advanced hepatic fibrosis. In addition, in MASLD women with F≥3, regardless of age, we observed an increase in androgens metabolites, but a decrease in sulphate compounds. In patients with MASLD, we identified different steroids profiles according to gender and age that varied according to the severity of hepatic fibrosis. Further studies are needed to understand the molecular basis of sexual dimorphism in the context of MASLD. Funded by HORIZON-HLTH-2023-ENVHLTH-02 program for the consortium EDC-MASLD, g.a. n. 101136259. [ABSTRACT FROM AUTHOR]

The natural history of MASLD results from environmental and genetic factors, impacting hepatic and extrahepatic outcomes. This study aims to elucidate the incidence of clinical outcomes, and the impact of non-invasive tests (NITs) and genetic factors. A retrospective study was conducted on patients undergoing vibration-controlled transient elastography (VCTE) for liver stiffness measurement (LSM), with at least 6 months follow-up. Other etiologies than MASLD, previous decompensation or hepatocarcinoma (HCC) were excluded. Significant liver fibrosis was defined by LSM≥8 Kpa, clinically significant portal hypertension (CSPH) by LSM≥25 Kpa. Primary endpoints included incidence of major adverse liver outcomes (MALOs): cirrhosis, liver decompensation (ascites, encephalopathy, variceal bleeding), HCC and liver transplant. 504 patients were selected (61.7% males, median age 59 years [IQR 50.0-67.0]), with a median follow-up of 45.5 months [9.5-94.5]. Median LSM was 6.4 Kpa [5.0-9.0], 21% had PNPLA3 GG. Overall, 11.3% experienced MALOs (33.3% liver decompensation), 2.6% died (46.2% liver-related events). Significant fibrosis increased MALOs incidence (log rank p<0.0001, HR14.4, 95%CI 5.5-13.3). CSPH raised liver decompensation occurrence (p=0.007, HR 6.1, 95%CI 3.3-22.4). Type 2 diabetes (T2D) and PNPLA3 GG increased MALOs incidence (p<0.001, HR 3.8, 95%CI 2.03-6.2; p=0.004, HR 2.3, 95%CI 1.38-5.61). Obese/overweight patients had higher MALOs incidence than lean individuals (p=0.008, HR 2.67, 95% Cl 1.31-3.94). Multivariable Cox regression analysis showed that significant fibrosis by LSM was independently associated with MALOs (aHR 18.5, p<0.0001, 95%Cl 5.65-60.7). Overweight/obesity and T2D increase incidence of MALOs. LSM by VCTE and PNPLA3 genotyping are useful tools for risk stratification. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) may contribute to cardiac impairment through diastolic dysfunction. Non-invasive tests (NITs) for liver fibrosis offer valuable tools for risk stratification, though their utility in identifying patients with early or established diastolic dysfunction remains uncertain. Identify the association between liver NITs (FIB-4 and liver stiffness measurement [LSM]) and echocardiographic markers of diastolic dysfunction. We prospectively enrolled 150 MASLD patients without cardiovascular disease history. All patients underwent clinical-biochemical evaluation, vibration-controlled transient elastography for LSM, echocardiography with speckle tracking analysis. Significant fibrosis was defined by FIB-4 >1.3 or LSM ≥7 kPa. Diastolic dysfunction was defined by mitral E/E' ratio >9, while early diastolic dysfunction was defined by left atrial strain reservoir (LARS) (<22%) and left atrial stiffness index (LASi) ≥25 kPa. Pericardial fat was also assessed. Increased FIB-4 was found in 23,3% patients (median age 62) with prevalence of type 2 diabetes (T2DM), hypertension and dyslipidemia respectively at 20%, 74,3%, 62,9%. For low FIB-4 group (median age 49), prevalences were 15%, 36,5%, 55,7%. Obesity overall was 43,9%. Compared to patients with low FIB-4, those with FIB-4 >1.3 had increased E/E' ratio, LASI and pericardial fat (respectively median 8.0 [6,0 – 9,2], p =0.007; 0.34 kPa [0,20 - 0,42], p <0.0001; 12.5 mm [8,5 – 17,2], p <0.0001), and had reduced LARS (26.5% [19,0 – 33,0], p <0.0001). In a 3 model multivariable regression analysis, FIB-4 >1.3 was independently associated with diastolic dysfunction (aOR 3.41 [1.08 – 10.74]) and early diastolic dysfunction (aOR for reduced LARS 10.03 [2.01 – 49.8]; aOR for reduced LASi 4.24 [1.16 – 15.5]). Finally, FIB-4 displayed Area Under the Curve (AUC) of 0.83 for the prediction of reduced LARS. In MASLD patients without cardiac disease, FIB-4 may be useful to identify a higher risk with early cardiac dysfunction, suggesting tailored echocardiography surveillance [ABSTRACT FROM AUTHOR]

Non-invasive biomarkers for the assessment of treatment response are highly needed in the clinical setting for Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). This study evaluates the role of Controlled Attenuation Parameter (CAP) by Vibration-Controlled Transient Elastography and PNPLA3 gene variants for the assessment of weight loss and BMI reduction in MASLD patients undergoing a 6-month dietary intervention. 94 MASLD patients were randomly assigned to 3 arms: Mediterranean Diet (MD), Low-Charb Diet (LCD), and Control Diet (CD). Inclusion criteria were BMI 26-35 kg/m², CAP≥248 dB/m, Liver Stiffness Measurement (LSM)<12 kPa. Primary endpoints was ≥7% weight loss. Clinical/biochemical parameters and VCTE were assessment at baseline and after 6 months. Median age was 50.5 [IQR 43.0-61.0] years and 71.3% was male. Type 2 diabetes (T2D) was present in 17% of cases and PNPLA3 GG was present in 19.1% of cases. After 6 months, 28.7% of patients achieved ≥7% weight loss, with the highest proportion in LCD group (36.2%). In all patients achieving weight loss, CAP significantly decreased (from median 294 to median 246 dB/m, p<0.0001), as compared to CAP changes that were observed in those who did not achieve weight loss (inter-group p-value=0.001). Delta CAP values were higher in LCD group (p=0.040). A stepwise increase in the delta CAP values was observed across incremental weight loss categories (<5%, 5-10%,>10%) (p=0.02). In patients achieving≥7% weight loss, delta CAP values were higher in patients with CC/CG genotype (p=0.0004), as compared to GG carriers (p=0.79). In patients with MASLD undergoing lifestyle intervention, weight loss≥7% was associated with significant decreases in CAP values. PNPLA3 genotyping may be useful for further patient stratification. [ABSTRACT FROM AUTHOR]

Several genetic factors have been associated to liver disease onset and progression in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). In particular, genetic variants predisposing to liver fat accumulation (i.e. PNPLA3, TM6SF2, MBOAT7, GCKR, and HSD17B13) were associated with increased risk of hepatocellular carcinoma (HCC) development. We aimed to investigate the association between genetic variants and prognosis of patients with MASLD-HCC. A total of 225 MASLD patients (median age: 74, IQR 49–97 years; males: 195, 86.7%) with a diagnosis of HCC were retrospectively enrolled. Most patients had an early stage HCC (BCLC: 0/A, n=145, 64.4%); patients with BCLC stage D were excluded from the analysis. Genotyping for PNPLA3 rs738409 C>G, MBOAT7 rs641738 C>T, TM6SF2 rs58542926 C>T, GCKR rs780094 C>T, HSD17B13 rs72613567: TA was performed by real-time allelic discrimination assay (TaqMan SNP Genotyping Assay, Applied Biosystems). Primary end-point was overall survival (OS). Overall, median OS was 29.1 (95%CI 21.4–32.7) months. Among the five genetic variants analysed, only MBOAT7 rs641738 showed significant results at survival analysis. Specifically, patients who carried the TT risk genotype (n=59) showed reduced OS compared to those with CC/CT genotype (n=167) (OS=19.8, 95%CI 16.4–27.0 months vs. 32.2, 95%CI 28.5–53.9 months, respectively; p=0.007). At multivariate logistic regression analysis, MBOAT7 rs641738 TT genotype resulted associated to reduced OS (OR=1.62, 95%CI 1.04–2.51) independently from BCLC stage (OR=2.12, 95%CI 1.68–2.68). MBOAT7 rs641738 (C>T) variant was associated to poor prognosis in patients with MASLD-HCC. In such patients, MBOAT7 rs641738 genotyping may be useful to improve clinical management and to support decision-making. Project PNC 0000001 D3 4 Health, The National Plan for Complementary Investments to the NRRP, funded by the European Union – NextGenerationEU. [ABSTRACT FROM AUTHOR]

Metabolic Associated Steatotic Liver Disease (MASLD) is the most prevalent chronic liver disease. It can progress to metabolic steatohepatitis (MASH), resulting in cirrhosis and hepatocellular carcinoma. A large fraction of MASLD heritability remains unexplained, and few genomic data are available in the Italian population. Genome-wide association studies (GWAS) offer a powerful method to identify genetic risk variants for risk stratification and therapeutic strategies. The Milano BioBank is a multi-center effort which is gathering genomic and phenotypic data of Italian individuals enriched for the presence of metabolic dysfunction and MASLD (currently n=5875). Global Screening Array 3.0 (Illumina) and Michigan Imputation Server (GRCh38 TOPMed freeze 5) were used for SNP detection and imputation. We considered as main outcome the Fibrosis-4 Index (FIB-4) and secondary the Fibrotic NASH Index (FNI) and liver enzymes, as first-line clinical tests to identify at-risk MASLD (quantitative traits) adjusting the REGENIE regression models for age, sex, BMI, ethnicity. We confirmed a genome-wide significant association of PNPLA3 locus with FIB-4 and FNI (rs738409 p.I148M; β=0.132, p= 3.06*10-22 and β=0.233, p=3.59*10-16 respectively) and with circulating ALT (rs3747207; β=0.145, p=2.64*10-16), AST (rs738408; β=0.186, p=1.48*10-23), and GGT (rs738409;β=0.109, p=1.28*10-11) levels. Additionally, HAPLN4 - TM6SF2 locus was associated with FNI (current top hit rs150641967 intronic variant; β=0.374, p=5.55*10-10), ERLIN1 locus was associated with circulating ALT (rs10883451; β=-0.099, p=2.64*10-9) while GGT1 (rs2073397, β=0.157, p=4.21*10-22), RORA (rs339969, β=0.108, p=5.84*10-11) and EXOC3L4 (rs944002, β=0.108, p=8.22*10-10) loci associated with GGT. We confirmed that single nucleotide polymorphisms in genes involved in hepatic lipid retention are the main genetic determinants of at risk of MASLD in the Italian population. These findings reinforce the role of PNPLA3 as a key genetic determinant of MASLD, suggest the possible presence of additional contributors to liver disease at the TM6SF2 locus and support the use of FNI to detect fibrosing MASH. [ABSTRACT FROM AUTHOR]

non-invasive assessment of advanced fibrosis in Non-Alcoholic Fatty Liver Disease (NAFLD) is crucial for the identification of patients at greatest risk of progression. Among non-invasive tests, AGILE 3+ and AGILE 4 have been recently proposed, combining liver stiffness measurement (LSM) by vibration-controlled transient elastography (FibroScan) with clinical-biochemical variables. we aimed to assess the accuracy of AGILE 3+ and AGILE 4 for the identification of advanced fibrosis (F3-F4) and cirrhosis (F4), respectively, against LSM in individuals with biopsy-proven NAFLD. we retrospectively included 315 biopsy-proven NAFLD patients. No clinical, radiological or biochemical signs of cirrhosis were present at inclusion. Clinical-biochemical data and LSM were collected at time of the biopsy. median age was 48 (IQR 38-47) years, 62% were male. Median LSM was 7.5 kPa (IQR 5.8-10.1). Advanced fibrosis was present in 28%, cirrhosis in 10% and NASH in 28% of cases. Eighty subjects had type 2 diabetes. At Area Under the Curve (AUC) analysis, LSM had a value of 0.807 (Se 70%, Sp 80%) for advanced fibrosis and 0.877 (Se 88%, Sp 76%) for cirrhosis. AGILE 3+ had AUC of 0.77 for advanced fibrosis (cut-off by Youden index 0.30, Se 68%, Sp 78%), while AGILE 4 had AUC of 0.78 for cirrhosis (cut-off by Youden index 0.11, Se 55%, Sp 89%). Comparison of AUC showed that AGILE 3+ was similar to LSM for identifying advanced fibrosis (DeLong p= 0.254). Similarly, AUC comparison between LSM and AGILE 4 for cirrhosis was not different (DeLong p =0.739). when compared to LSM, AGILE 3+ and AGILE 4 had similar accuracy for the detection of advanced fibrosis and cirrhosis in NAFLD patients. This research was supported by the Italian MIUR "Dipartimenti di Eccellenza 2018-2022" D15D18000410001 and by Horizon 2020, no.777377, LITMUS. [ABSTRACT FROM AUTHOR]

The Patatin-like phospholipase domain–containing 3 (PNPLA3) rs738409 single nucleotide polymorphism (SNP) is one of the major genetic determinant of NAFLD and is strongly regulated by changes in energy balance and dietary factors. The aim of this study was to investigate the association between the PNPLA3 rs738409 SNP, nutrient intake and NAFLD severity. PNPLA3 -rs738409 genetic variant was genotyped in 181 patients with hepatic steatosis who completed the EPIC Food Frequency Questionnaire. Liver steatosis was evaluated by Controlled Attenuation Parameter (CAP) (Fibroscan®530). According to the established cut-off, a CAP value ≥300 was used to identify steatosis (S3). Subsequently, a validation analysis was performed in 47 biopsy-proven NAFLD where significant steatosis was classified as steatosis ≥ 33% and advance fibrosis as ≥F3 according to Kleinert score. Anthropometric, clinical and biochemical parameters were collected at the time of enrolment. Overall, median age was 53 years (IQR 44;62) and 60.22% of patients were male. 102 subjects (56.35%) had severe steatosis and showed increased liver stiffness (p <0.001), AST (p =0.003) and ALT levels (p <0.001) compared to those with CAP<300. At logistic regression analyses we found that the interaction between carbohydrates intake and the carriers of the PNPLA3 G risk allele was significantly associated with severe steatosis (p =0.001). The same result was confirmed in a subgroup of patients who underwent liver biopsy, were the interaction between carbohydrate intake and PNPLA3 SNP was significantly associated with steatosis ≥33% and advanced fibrosis (≥F3) (p =0.017 and p =0.050, respectively) The intake of greater than or equal to 48% carbohydrate carrying the CG/GG allele of PNPLA3 rs738409 may increase the risk of steatosis and fibrosis in patients with NAFLD. This work has received support from EU/EFPIA/IM2 Joint Undertaking (LITMUS grant no.777377) and Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" n.D15D18000410001. [ABSTRACT FROM AUTHOR]

Résumé Objectif Déterminer si la progression au sein des carrières hospitalo-universitaires est plus difficile pour les femmes que pour les hommes et, le cas échéant, la nature et le niveau des freins à cette progression. Méthodes Extraction des effectifs médicaux temps plein dans un groupe hospitalier parisien, par la plateforme SIGAPS ; enquête par un questionnaire en ligne sur les choix de carrière et les freins ressentis chez des hommes et des femmes médecins occupant un poste de titulaire. La population étudiée comporte 181 praticiens hospitaliers et 141 médecins hospitalo-universitaires, dont 49 maîtres de conférence–praticiens hospitaliers et 92 professeurs des universités–praticiens hospitaliers (PU–PH). Résultats Les femmes représentent 49 % des effectifs médicaux et seulement 15 % des PU–PH. Cette sous-représentation des femmes PU–PH est plus importante en anesthésie-réanimation et moins dans les disciplines médicotechniques. Il n'y a pas de différence en matière de production scientifique, de statut marital et de parentalité entre les femmes et les hommes hospitalo-universitaires. En revanche, il existe une différence d'attitudes, mise en évidence par l'échelle de prise de risque EVAR, ainsi que dans le poids des obligations familiales et les préjugés ressentis par les femmes lors de la sélection universitaire. Conclusion Le plafond de verre existe au sein d'un des plus grands groupe hospitaliers français. Les critères de sélection universitaire devraient évoluer pour limiter le désavantage des femmes lié à un engagement familial plus important et à des attitudes moins centrées sur la compétition et la prise de risque. Abstract Objective To determine whether career development in academic medicine is more difficult for women than for men, and, if any, the nature and level of barriers to this progression. Methods Extraction of full-time medical staff in a Parisian hospital group, through the SIGAPS platform; an online questionnaire survey of career choices and barriers experienced by full-time male and female physicians. The study population comprises 181 hospital practitioners and 141 academic physicians (49 associate professors and 92 full professors). Results Women represent 49% of the medical staff but 15% of full professors. This underrepresentation of women is more important among intensivists/anesthesiologists than technique-based specialists (such as radiologists, biologists...). There is no difference in scientific output, marital status and parenthood between women and men. On the other hand, there is a difference in attitudes highlighted by the EVAR risk-taking scale as well as in the burden of familial involvement and the prejudices felt by women during the academic selection process. Conclusion The glass ceiling exists in one of the largest French hospital group. Career development principles promote merit, but should decrease the benefit of "masculine" attitudes in the competition for academic positions. Academic selection criteria should evolve to limit the disadvantage of women related to deeper familial involvement and less competitive strategies and risk-taking attitudes. [ABSTRACT FROM AUTHOR]

Individuals with Non-Alcoholic Fatty Liver Disease (NAFLD) have abnormal myocardial energy metabolism and reduced coronary functional capacity, even in the absence of risk factors for cardiovascular disease (CVD). We aimed to evaluate diastolic and systolic function in NAFLD individuals with preserved ejection fraction without overt CVD. We prospectively included 95 patients (median age 53.0 [IQR 44.5-62.5] years, male sex 44.6%) with ultrasound-diagnosed NAFLD undergoing echocardiographic evaluation, which included speckle tracking analysis with left ventricular global longitudinal strain (GLS) measurement (Philips, Andover, US). Diastolic dysfunction was defined by mitral E/E'>9 and systolic dysfunction was defined by GLS >-18. Significant liver fibrosis (SLF) was defined by Fibrosis-4 (FIB-4) score>1.3. Obesity, type 2 diabetes (T2D), arterial hypertension and dyslipidemia were present in 43.3%, 21.1%, 46.2% and 57.8% of cases, while median FIB-4 was 0.97 [0.67-1.24]. SLF, diastolic and systolic dysfunction were found in 20%, 17% and 18.3% of the total. Higher FIB-4 levels were found in both diastolic and systolic dysfunction (p=0.003 and p=0.001). SLF was associated with diastolic dysfunction (OR 6.8 [95%CI 1.8-25.5], p=0.004), showing an Area Under the Curve of 0.76 (Se 76.9%, Sp 72.2%, PPV 33.3%, NPV 94.5%). In a multiple stepwise logistic regression model including T2D, obesity, arterial hypertension, dyslipidemia, male sex and SLF, both SLF and T2D were significantly and independently associated with diastolic dysfunction (aOR of SLF 6.2 [95%CI 1.5-25.1, p=0.011). In the same regression model for systolic dysfunction, only T2D showed a significant association (aOR 4.6 [95%CI 1.3-16.8], p=0.021). In NAFLD patients with preserved ejection fraction, SLF by FIB-4 is associated with diastolic dysfunction independently of major risk factors for CVD. Screening echocardiography may be recommended in this population. Funding: the Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" Project code D15D18000410001. [ABSTRACT FROM AUTHOR]

Oncostatin M (OSM) is a pleiotropic cytokine belonging to the interleukin (IL)-6 family that has been proposed to contribute to the progression of chronic liver diseases, hepatocellular carcinoma (HCC) development and metastasis. High levels of OSM was observed in cirrhotic patients with different etiology carrying HCC. Here we investigated the role of OSM in relation to the development of HCC in non-alcoholic steatohepatitis (NASH) background. We investigated the role of OSM in NASH-related HCC taking advantage of: a) cohort of NASH patients with/without HCC; b) mouse model of NASH-related liver carcinogenesis (DEN/CDAA protocol); c) human macrophage cell lines exposed to human recombinant OSM (hrOSM). OSM serum levels are significantly higher in patients carrying NASH-related HCC, as compared to those whit viral aetiologies, and their increase is paralleled the disease progression from simple steatosis to HCC. Noteworthy, OSM serum levels are significantly higher in patients with intermediate/advanced HCC and correlate with poor survival. In patients with NASH-related HCC, OSM is expressed in cancer cells in relation to the staging of HCC as well as to macrophages infiltrating tumour. Accordingly, OSM expression is increased in murine NASH-related liver tumours and correlates with F4/80 gene expression, suggesting an interplay between OSM and macrophages recruitment/functions in the tumor microenvironment. In particular, OSM transcript levels correlate with canonical M1and M2 macrophage polarization markers and with newly identified NASH-associated macrophages (NAM) markers (TREM-2, CD-9). The ability of OSM to promote M2 polarization, observed in human THP1 macrophages exposed to hrOSM, is due to activation of STAT3 and PI-3K/Akt signaling pathways. Patients with HCC arising on a NASH background showed increased OSM serum levels that correlate with clinical parameters and disease outcome. Experimental data highlight a pro-carcinogenic contribution for OSM in NASH, by promoting pro-tumorigenic inflammation and eventually modulating tumor escape. [ABSTRACT FROM AUTHOR]

The discrepancy in a person's sleep pattern between working days and days off is called Social Jetlag (SJL). The aim of this work was to investigate the potential impact of Mediterranean Diet (MedDiet) on the risk of significant liver fibrosis (F≥2) in individuals with non-alcoholic fatty liver disease (NAFLD), according to SJL. A total of 148 patients diagnosed with NAFLD by ultrasound underwent assessment of liver stiffness + controlled attenuation parameter (CAP) (FibroScan® 530). F≥2 was defined by liver stiffness values ≥7.1kPa. The adherence to the MedDiet was assessed by the Mediterranean diet score questionnaire; low and high adherence were defined by the median value of the score. SJL was defined by the Munich Chronotype Questionnaire as the absolute difference between mid-sleep on free days and mid-sleep on workdays. According to the median value, we defined small and large SJL. The median age was 52 (42-61.5) years and the main comorbidities were type-2 diabetes mellitus (T2DM) (26.35%), arterial hypertension (49.3%), dyslipidemia (64.9%), obstructive sleep apnea (OSAS) (5.4%), and depression (6.1%). Median liver stiffness and CAP values were 5.1kPa (F≥2; 13.5%) and 301db/m, respectively. The prevalence of large SJL was significantly higher in patients with F≤2 compared to those with F≥2 (57.46% vs. 28.57%, p=0.039), while no significant difference was found in the adherence to MedDiet between groups. At multivariate logistic regression analysis adjusted for sex, age, BMI, T2DM, OSAS, arterial hypertension, dyslipidemia, and depression, we found that the interaction between a large SJL and a high adherence to MedDiet was significantly associated to F≥2 (OR=0.02, p=0.049). Models integrating diet and SJL/sleep pattern characteristics may unveil potential pathogenetic mechanisms associated to liver fibrosis risk in patients with NAFLD. Italian Ministry for Education, University and Research (MIUR) under the programme "Dipartimenti di Eccellenza 2018-2022" n.D15D18000410001 [ABSTRACT FROM AUTHOR]

Low adherence to the Mediterranean Diet (MedDiet) has been associated with an increased risk of metabolic associated fatty liver disease (MAFLD), a clinical condition characterized by low grade chronic inflammation. The aim of this study was to assess whether the adherence to the Mediterranean diet is associated with biomarkers of inflammation in patients with MAFLD. A total of 40 patients with MAFLD were evaluated. Liver fibrosis was assessed by transient electrography (Fibroscan®530). Anthropometric, clinical and biochemical parameters were collected at enrolment. We measured the soluble CD163 (sCD163) levels by ELISA as indirect biomarker of both hepatic inflammation and fibrosis. Adherence to the MedDiet was assessed using a validated 14-item Mediterranean diet adherence questionnaire; low and high adherence were defined by the median value of the final score. Overall, the median age was 51 years (IQR 44;62), 52.00% of subjects were female and 32.00% had diabetes. Median liver stiffness was 6.6 (IQR 4.9;8.8), while sCD163 levels were 657 (IQR 553.5;813.5). Consistently, liver stiffness was significantly correlated to both MedDiet adherence and sCD163 concentrations (MedDiet: r= -0.38, p =0.006; sCD163: r=0.66, p <0.001, respectively). In addition, in patients with a low adherence to MedDiet significantly higher levels of sCD163 were observed (771.3 vs. 629.0, p =0.035). Interestingly, at multiple regression analysis, both low adherence to MedDiet adherence and sCD163 values (750-1303 ng/mL) were significantly associated with liver stiffness independently of age, sex, body mass index and diabetes. In conclusion, in subjects with MAFLD low adherence to MedDiet is associated to a pro-inflammatory profile and is associated with the degree of hepatic fibrosis. This work has received support from the EU/EFPIA Innovative Medicines Initiaive 2 Joint Undertaking (LITMUS grant no. 777377). [ABSTRACT FROM AUTHOR]

Hepatocellular Carcinoma (HCC) represents a major clinical event in the cirrhotic population, leading to a significant incidence of morbidity and mortality. To assess the prognostic value of simple non-invasive tests (NITs) for the stratification of the risk of HCC development in a Non-Alcoholic Fatty Liver Disease (NAFLD) cirrhotic population on long-term follow-up (FU). A total of 122 patients with NAFLD-cirrhosis (median age: 62 years; males 52.5%; median BMI 30.5 kg/m2; prevalence of type-2 diabetes: 57.4%) were retrospectively analyzed. Cirrhosis diagnosis was achieved by either liver histology, instrumental findings and/or clinical evidence of portal hypertension. Clinical and biochemical data were collected at the time of diagnosis; the following NITs were calculated: FIB-4, AST to Platelet Ratio Index (APRI) gamma-glutamyl transpeptidase-to-platelet ratio (GPR), BARD. During a median FU of 6 (IQR 3.2-9.3) years, 13 (10.7%) patients developed HCC. Baseline FIB-4 (HR=1.27, 95%CI 1.03–1.58, p=0.027) and GPR (HR=1.44, 95%CI 1.11–1.85, p=0.005) values resulted significantly associated to HCC occurrence. Conversely, no association was observed for APRI and BARD. Conventional FIB-4 cut-off values allowed a proper patients' stratification into 3 risk categories with different HCC incidence: FIB-4<1.3 = 0/18 (0%), FIB-4 between 1.3–3.25 = 7/73 (9.6%), and FIB-4>3.25 = 6/31 (19.4%) (Log-rank test: p=0.009). Likewise, the cumulative HCC incidence according to GPR tertiles risk groups was: 3/41 (7.3%), 4/40 (10.0%) and 6/41 (14.6%) (Log-rank test: p=0.041). Baseline FIB-4 could stratify patients with NAFLD-cirrhosis on long-term FU according to their individual risk of HCC development. In such patients, this simple NIT may be useful to optimize tailored HCC surveillance strategies. [ABSTRACT FROM AUTHOR]

In the setting of non-alcoholic fatty liver disease(NAFLD), liver fibrosis(LF) is the most relevant prognostic factor. Several non-invasive tests have been proposed to assess LF; among them, Magnetic resonance elastography(MRE) is so far the most accurate. Compared to the traditional magnetic resonance(MR), MRE requires an additional hardware with increasing procedure costs, with limited application in clinical practice. Quantitative T1-MR imaging is an emerging tool for the evaluation of LF,but its potential use has not yet been fully investigated. We aimed to explore the correlations between T1 measured on vendor specific(vendor-T1) and LivermultiScan MOLLI(LMS-T1) sequences, with MRE and vibration controlled transient elastography(VCTE) parameters, in a cohort of NAFLD patients. Between June 2021 and October 2022, we prospectively enrolled 24 NAFLD patients who underwent concomitant MR and VCTE. We extracted the following MR data(Philips Achieva 1,5T): from MRE, stiffness measured on FFE and EPI sequences; from multiparametric liver MR, T1 with vendor specific and LMS sequences, T2, proton-density-fat-fraction(PDFF); from VCTE(Fibroscan,Echosense), stiffness and controlled attenuation parameter(CAP). Median age was 54 years(interquartile range[IQR], 45-63) and 52% of the cases were males. Median liver stiffness value by VCTE was 5.9 kPa(IQR 4.4-8.4), while median CAP value was 313 dB/m(IQR 290-334). MRE-EPI stiffness showed significant correlation with MRE-FFE stiffness(r= 0.84, p<0.001), VCTE stiffness(r= 0.71, p<0.001),T1(r= 0.61, p<0.005) and T2(r= 0.42, p<0.05). LMS-T1 correlated to MRE-FFE stiffness(r=0.537, p < 0.02), while T1 correlated to MRE-EPI stiffness(r=0.616, p< 0.005). At multivariate regression analysis adjusted for T2 and PDFF, both vendor-T1 and LMS-T1 were significantly and independently associated with MRE-EPI stiffness(t=3.64, p=0.002 and t=2.4, p=0.027, respectively). In NAFLD patients, T1 sequences may be used for the non-invasive assessment of LF. Further data from larger cohorts are needed to assess its potential use in clinical practice. Supporting grants: Italian MIUR"Dipartimenti di Eccellenza 2018-2022"D15D18000410001 and Horizon2020,no.777377,LITMUS. [ABSTRACT FROM AUTHOR]

The most important determinant of the progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) and fibrosis is insulin resistance (IR). Interferon gamma-induced protein 10 (IP-10), a proinflammatory chemokine, plays a crucial role in inflammatory diseases but its interaction with IR in the setting of NAFLD is not clear. We analysed data from 200 patients with biopsy proven NAFLD (M/F 121/79; mean age 47±12). A subgroup of 46 non-diabetic NAFLD subjects underwent tracers studies (6,6-D2-glucose and [2H5 ]glycerol). Tracers enrichment was determined by GC-MS and data were used to calculate hepatic (Hep)-IR and adipose tissue (AT)-IR components. Serum IP-10 levels were assessed by Bio-Plex (BioRad Laboratories). Overall, 81/200 (40.5%) patients had F≥2 and 151/200 (75.5%) had NASH. The prevalence of type 2 diabetes was 27.5% and 47.5% of the patients were obese. IP-10 levels significantly increased across lean to overweight to obese subjects (p=0.009), showed a stepwise increase according to the stages of hepatic fibrosis (p=0.006) and were significantly higher in patients with NASH compared to those with NAFL (457pg/ml vs 383pg/ml, p=0.039). Moreover, IP-10 levels were increased in diabetic compared to non-diabetic patients (491pg/ml vs 393pg/ml, p=0.021) and showed a significant correlation with HOMA-IR (r=0.30, p=0.006). In the subgroup of non-obese, non-diabetic NAFLD patients who underwent tracers' studies, IP-10 levels showed a significant correlation with both Hep-IR and AT-IR (r=0.32, p=0.030 and r=0.33, p=0.049, respectively). At multivariate analysis, IP-10 was independently associated to the degree of hepatic fibrosis (r p =0.3, p=0.05). IP-10 may be involved in the complex pathogenesis of NAFLD. Further studies are needed to demonstrate its causality in determining liver damage. This research has been supported by the Italian MIUR under the programme "Dipartimenti di Eccellenza 2018-2022", n.D15D18000410001 and by EU/EFPIA-IMI2 under g.a. no.777377, LITMUS [ABSTRACT FROM AUTHOR]