Familial combined hyperlipidemia (FCH) is a very common inherited lipid disorder, characterized by a high risk of developing cardiovascular (CV) disease and metabolic complications, including insulin resistance (IR) and type 2 diabetes mellitus (T2DM). The prevalence of non-alcoholic fatty liver disease (NAFLD) is increased in FCH patients, especially in those with IR or T2DM. However, it is unknown how precociously metabolic and cardiovascular complications appear in FCH patients. We aimed to evaluate the prevalence of NAFLD and to assess CV risk in newly diagnosed insulin-sensitive FCH patients. From a database including 16,504 patients, 110 insulin-sensitive FCH patients were selected by general practitioners and referred to the Lipid Center. Lipid profile, fasting plasma glucose and insulin were determined by standard methods. Based on the results of the hospital screening, 96 patients were finally included (mean age 52.2 ± 9.8 years; 44 males, 52 females). All participants underwent carotid ultrasound to assess carotid intima media thickness (cIMT), presence or absence of plaque, and pulse wave velocity (PWV). Liver steatosis was assessed by both hepatic steatosis index (HSI) and abdomen ultrasound (US). Liver fibrosis was non-invasively assessed by transient elastography (TE) and by fibrosis 4 score (FIB-4) index. Carotid plaque was found in 44 out of 96 (45.8%) patients, liver steatosis was found in 68 out of 96 (70.8%) and in 41 out of 96 (42.7%) patients by US examination and HSI, respectively. Overall, 72 subjects (75%) were diagnosed with steatosis by either ultrasound or HSI, while 24 (25%) had steatosis excluded (steatosis excluded by both US and HSI). Patients with liver steatosis had a significantly higher body mass index (BMI) compared to those without (p < 0.05). Steatosis correlated with fasting insulin (p < 0.05), liver stiffness (p < 0.05), BMI (p < 0.001), and inversely with high-density lipoprotein cholesterol (p < 0.05). Fibrosis assessed by TE was significantly associated with BMI (p < 0.001) and cIMT (p < 0.05); fibrosis assessed by FIB-4 was significantly associated with sex (p < 0.05), cIMT (p < 0.05), and atherosclerotic plaque (p < 0.05). The presence of any grade of liver fibrosis was significantly associated with atherosclerotic plaque in the multivariable model, independent of alcohol habit, sex, HSI score, and liver stiffness by TE (OR 6.863, p < 0.001). In our cohort of newly diagnosed, untreated, insulin-sensitive FCH patients we found a high prevalence of liver steatosis. Indeed, the risk of atherosclerotic plaque was significantly increased in patients with liver fibrosis, suggesting a possible connection between liver disease and CV damage in dyslipidemic patients beyond the insulin resistance hypothesis.

Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2–F3–F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.

The predictive factors of long-term clinical benefits in patients with hepatitis C virus (HCV)—related liver cirrhosis after Direct Antiviral Agents (DAA) treatment are still undefined. The aim of this study was to identify any predictors of liver failure, hepatocellular carcinoma (HCC) and/or death in patients with compensated liver cirrhosis who achieved the sustained virological response (SVR). To this purpose, 324 consecutive cirrhotic patients who started DAA treatment from 1 April 2015 to 31 December 2016 were retrospectively analyzed. All patients were followed up for a median time of 63 months (range 19–77) through clinical/biochemical/instrumental examinations performed at baseline and after stopping the DAA treatment. At the end of the evaluation, 230 (71%) individuals showed stable clinical liver disease over time, 43 (13.3%) developed HCC, and 24 (7.4%) developed hepatic decompensation without HCC. Overall, 49 (15,1%) patients died. Multivariate regression analysis showed that hepatic decompensation was significantly associated with at baseline older age, higher liver stiffness, higher spleen longitudinal size values and hypergammaglobulinemia (p = 0.003, p = 0.005, p = 0.001, p = 0.029, respectively). HCC development was significantly associated with hypergammaglobulinemia (p < 0.001). Death was associated with older age and hypergammaglobulinemia (p < 0.001 and p = 0.007, respectively). Finally, survival analysis confirmed that patients with gamma globulin levels ≥ 1.8 gr/dl had a significantly higher risk of death compared to those with gamma globulin levels < 1.8 gr/dl (p < 0.001). In conclusion, hypergammaglobulinemia before starting DAA therapy represents a strong predictor of hepatic decompensation, HCC and death in cirrhotic patients even after HCV clearance.

Background: The Barcelona Clinic Liver Cancer staging system considers, among patients with HCC, “ideal candidates” (ICs) for hepatic resection (HR) those with a single lesion, normal bilirubin, and without clinically significant portal hypertension (CSPH). We compared the outcome of HR between ICs and non-ICs. Methods: Retrospective analysis was conducted on Child–Pugh A patients. CSPH was defined by the presence of gastroesophageal varices and/or platelet count <100,000/mm³. Hyperbilirubinemia was accepted up to 2 mg/dL. The selected 1057 patients were distributed in 3 calendar periods (2000–2022). Results: In all calendar periods, non-ICs were more prevalent than ICs. Among non-ICs, the proportion of patients with isolated CSPH did not change over time (from 22.6% to 30.3%; p=0.359), while patients with multinodular HCC (mHCC) increased (from 35.5% to 50.2%; p=0.042). Patients with hyperbilirubinemia decreased (from 20.4% to 10.1%; p=0.036), likewise those with hyperbilirubinemia+CSPH (from 21.5% to 9.4%; p=0.005). Over a median follow-up of 41.0 months, median overall survival was higher in ICs compared to non-ICs (104.9 vs. 75.3 months; p<0.001). However, compared to ICs, median overall survival did not differ in patients with isolated CSPH (93.1 mo; p=0.432) or isolated hyperbilirubinemia (86.0 mo; p=0.356), while it was lower in those with hyperbilirubinemia+CSPH (60.0 mo; p<0.001) or mHCC (61.9 mo; p<0.001). Compared to ICs, only hyperbilirubinemia+CSPH patients showed a higher perioperative mortality. Conclusions: In real-world practice, among resected patients, the proportion of non-ICs has remained constantly higher than that of non-ICs since 2000. HR can be offered to Child–Pugh A patients with CSPH or modest hyperbilirubinemia without compromising its outcome. For patients with 2 of these features or mHCC, which generate a poorer prognosis, studies comparing HR versus non-surgical therapies are warranted.

Background and Aims: Accuracy of Baveno criteria for avoiding endoscopy in patients with hepatocellular carcinoma (HCC) is uncertain, and systematic upper gastrointestinal endoscopy (UGE) may not be necessary. We evaluated Baveno VI criteria performance in this population and developed an alternative non-invasive rule to exclude esophagogastric varices of any grade, rather than high-risk varices (HRV). Methods: Patients with BCLC 0-C HCC and compensated advanced chronic liver disease (cACLD) from Italian Liver Cancer (ITA.LI.CA) database, with available liver stiffness measurement (LSM), UGE, and blood tests within six months of diagnosis, were included. Independent predictors of varices identified by logistic regression were combined through grid-search to derive a rule-out strategy (SAPHE-R), validated by bootstrap-resampling and in an independent cohort (Vienna). Results: The derivation cohort comprised 598 patients (age, 69 years; male sex, 75.3%; viral etiology, 69.3%; BCLC 0/A, 77.9%; ALBI 1, 54.2%; varices, 33.4%; HRV, 11.2%). Baveno VI criteria missed 8.5% of varices and 6.0% of HRV, sparing 31.1% of UGE. Independent predictors of varices were incorporated into SAPHE-R (LSM≤16 kPa, platelet count ≥160×10⁹/L, ALBI grade 1), which missed 4.0% of varices (HRV 3.0%, spared UGE 17.6%). In the validation cohort (n=149), SAPHE-R missed 4.8% of varices (HRV 3.1%, spared UGE 14.8%). Results remained consistent in sensitivity analyses. In an exploratory analysis, no HVPG-defined CSPH was observed among SAPHE-R rule-out patients (0/22). Conclusions: Baveno VI criteria showed suboptimal performance in patients with HCC and cACLD, whereas SAPHE-R provided a reliable non-invasive strategy to rule out varices, facilitating variceal risk assessment in patients with HCC.