Background and Aims: While the ANSWER trial has demonstrated improved survival with long-term albumin treatment in patients with ascites, a benefit was not observed in some other studies. Study design, heterogeneity in study cohorts and albumin dose have been hypothesized to explain these discrepancies. We aimed to assess the effects of long-term albumin treatment – administered in a real-life outpatient setting – on liver-related mortality in cirrhosis patients with ascites.Methods: 878 cirrhosis patients with ascites as index decompensation between 2003-2024 from four tertiary care centers in Europe were included. 106 patients (11.7%) receiving longterm (i.e., more than > 30 days) i.v. albumin therapy. Patients were characterized from time of albumin treatment initiation or first decompensation. We performed inverse probability of treatment weighting (IPTW) adjusting for age, sex, MELD-Na and etiologic cure to account for differences in disease severity in multivariable cox regression analyses of liver-related mortality.Results: The main patient characteristics were balanced between patients receiving long-term albumin [ivALB (+)] and those w/o albumin treatment [ivALB(-)]: median age: 60.2 vs 56.9 years (p = 0.008) and MELD-Na 14 vs 15 (p = 0.231). Median ivALB(+) treatment dose was 40 grams per week (mostly 20% 200mL) and patients were treated for 11.1 (IQR: 5.0 – 20.3) months. During a median follow-up of 46.5/36.4 months in ivALB(-)/ivALB(+) patients, 44.4%/35.9% died including 39.0%/27.2% liver-related deaths, and 12.3%/17.5% underwent liver transplantation (LT). Incidence of liver-related mortality at 36 months was 38.8% in the ivALB(-) vs. 34.4% in the ivALB(+) patients (log-rank p = 0.100). Cox proportional hazards regression with IPTW for ivALB(+) treatment showed that next to age (aHR per year: 1.04 [95%CI: 1.02-1.06]; p < 0.001), MELD-Na (aHR per point: 1.07 [95%CI: 1.04-1.10]; p < 0.001), female sex (aHR: 0.58 [95%CI: 0.42-0.81]; p = 0.001) and etiologic cure (aHR: 0.56 [95%CI: 0.36-0.88]; p=0.012) - long-term ivALB(+) therapy was associated with significantly reduced risk of liver-related death (aHR: 0.65 [95%CI: 0.42-0.99]; p = 0.048).Conclusions: Acknowledging the limitations related to retrospective design and nonstandardized treatment schedules, long-term ivALB(+) treatment significantly reduced liverrelated mortality in our cohort of cirrhosis patients with ascites.

Background: Understanding the aetiology, stage of disease at diagnosis, and patterns of decompensation of cirrhosis is essential to define prognosis and optimize management. This study aimed to describe the current clinical presentation of cirrhosis in Italy, characterize disease stages, and identify factors associated with hepatic decompensation.Patients and Methods: The SORPRESA study is a prospective, multicentre cohort conducted in 11 tertiary hepatology centres across Italy during 2024. Patients with a new diagnosis of cirrhosis or first clinical presentation were consecutively enrolled. Baseline demographic, socioeconomic, etiological, clinical, and laboratory data were recorded. Disease progression across three stages (compensated, first decompensation, multiple decompensations) was assessed using cumulative ordinal logistic regression. Covariates included aetiology (Alcohol Liver Disease, ALD; metabolic dysfunction–associated steatosis liver disease, MASLD; MetALD; HCV infection; HBV infection; autoimmune liver disease; other aetiologies) age, sex, obesity (BMI ≥30 kg/m²), diabetes, education, employment, family situation, and housing conditions. A multinomial logistic regression model was then applied to distinguish between types of first decompensation, with three outcome levels: compensated disease, acute decompensation (AD), and non-acute decompensation (NAD).Results: A total of 1,195 patients were included (mean age 64 ± 11.6 years; 73% male): 232 had ALD, 345 MASLD, 80 MetALD, 246 HCV, 159 HBV, 72 autoimmune, and 63 other aetiologies. Overall, 609 patients had compensated and 586 decompensated cirrhosis; among the latter, 416 experienced a first decompensation (232 AD, 184 NAD) and 170 multiple events. Aetiology emerged as the strongest predictor of progression: compared with ALD/MetALD, MASLD (OR = 0.67, 95% CI 0.48–0.96, p = 0.027) and viral/other causes (OR = 0.58, 95% CI 0.43–0.79, p < 0.001) were associated with lower risk of worsening. Obesity was protective only in the first transition (OR = 0.57, p < 0.001), suggesting an “obesity paradox.” Living alone due to widowhood/divorce (“forced solitude”) showed a borderline risk effect (OR = 1.39, p = 0.051). In the multinomial model, ALD significantly increased the relative risk ratio of both AD (RRR = 1.85, p = 0.001) and NAD (RRR = 2.08, p < 0.001) at first decompensation compared to compensated disease.Conclusions: Alcohol-related and metabolic-associated liver diseases, together with social isolation, are linked to adverse outcomes of liver cirrhosis. These findings highlight the need for an integrated approach combining medical and social interventions to improve prognosis in patients with cirrhosis.

Background and aims: Chronic liver disease (CLD) is asymptomatic for many years before its clinical manifestation, which often occurs in the terminal stages of the disease and is therefore associated with high mortality. Therefore, screening is key to allow early diagnosis of CLD and halt disease progression. Over the years, non-invasive blood tests (NITs) ​​have been developed to identify CLD with fibrosis. The aim of this study was to assess the accuracy of AST to Platelet Ratio Index (APRI test), fibrosis-4 index (FIB-4) and NAFLD fibrosis score (NFS) to identify liver fibrosis in a large cohort of healthy subjects from the Veneto Region.Method: From October 2020 to January 2025, 3,003 subjects resident in Veneto aged>40 years, without history of CLD, active malignancies or severe extrahepatic diseases were enrolled in the study. At the baseline evaluation, demographic and clinical data were collected, including alcohol consumption and metabolic risk factors. Standard lab parameters (blood count, transaminases, albumin, cholesterol, triglycerides) were also collected and NITs were subsequently calculated. Liver fibrosis was assessed by liver stiffness measurement (LSM) using vibration controlled transient elastography (Fibroscan®, Echosens, France). An LSM≥8.0 kPa was considered the cutoff for significant fibrosis and compared with validated thresholds for non-invasive tests (APRI ≥0.7, FIB-4 ≥1.3, and NFS ≥ -1.455).Results: Mean age was 58.7±8.8 years, 59% were women. Most subjects had at least one metabolic risk factor (38.1%), including obesity (12.5%), metabolic syndrome (13.0%), type 2 diabetes [T2D] (2.2%), hazardous alcohol consumption (>14/21 UA for women/men (3.3%). The prevalence of LSM≥8kPa was 4.3%, LSM≥10kPa was 2.1% and LSM≥15kPa was 0.7%. Prevalence of patients with ALT≥1.5 the upper normal limit was 2.1%. Median value for APRI was 0.25 (IQR 0.20-0.32), for FIB-4 1.27 (IQR 0.99-1.63) and for NFS -1.97 (IQR -2.66,-1.30). All three non-invasive tests had low discrimination ability for LSM≥8kPa (AUROC for APRI 0.58, 95% CI 0.53-0.64; AUROC for FIB-4 0.58, 95% CI 0.53-0.63; AUROC for NFS 0.65, 95% CI 0.61-0.70; Table 1). Interestingly, 52 out of the 127 subjects with LSM≥8.0 kPa (40.9%) had a FIB-4<1.3. Even higher percentages were found considering APRI and NFS low risk thresholds (94.5% and 50.4%, respectively). In patients with at least one risk factor for liver disease who had a valid LSM (obesity, high risk alcohol consumption, diabetes; n=980), the FIB-4, APRI and NFS still missed a relevant proportion of patients with LSM≥8.0 kPa.Conclusion: The currently recommended NITs for liver fibrosis perform poorly in the general population, missing more than 40% of individuals at high risk of significant liver fibrosis. There is therefore a need to develop new biomarkers, or their combination thereof, to improve liver fibrosis screening in the general population.This project was funded by the Ministry of Health (RF-2018-12366098)

Liver failure is associated with severe lipid alterations, including pronounced reductions of high-density lipoprotein cholesterol (HDL-C) levels that are also of prognostic value. In the present study, we developed an optimized prognostic model based on HDL-C and other readily available blood parameters for survival prediction in patients with acutely decompensated (AD) cirrhosis. We measured HDL-C in biobanked plasma samples of patients recruited from the large prospective CANONIC and PREDICT cohorts. Multivariable competing risk analysis was performed with death as the event of interest and liver transplantation (LT) as the competing risk. Cox proportional hazards regression was used to construct a new prognostic model, and its performance was evaluated using the C-index and compared with other prognostic scores using the Integrated Discrimination Index statistics test. We analyzed 1035 patients with AD/ACLF (median age 59 y; 70% male; ACLF at inclusion 20%; etiology alcohol 59%). Multivariable analysis yielded 6 independent prognostic variables associated with 90-day survival: age, HDL-C, creatinine, sodium, WBC, and INR, which were incorporated in a new prognostic model termed CLIF-C HDL score. The new model showed superior discrimination ability for the prediction of 90-day mortality by C-index of 0.768 for CLIF-C HDL score versus 0.735 for MELD-Na ( p <0.001) versus 0.738 for MELD 3.0 ( p <0.001). This superior performance of the CLIF-C HDL score was confirmed in 2 external validation cohorts (Turin, n=338; Vienna, n=185). The new prognostic CLIF-C HDL score yields superior accuracy for the prediction of short-term mortality in AD cirrhosis as compared with other prognostic scores.

BACKGROUND AND AIMS:The benefit of long-term albumin (LTA) in improving survival and reducing complications in patients with cirrhosis and ascites is not consistently observed across studies, possibly reflecting differences in patient populations and treatment regimens. This study aimed to determine whether baseline serum albumin (SA) levels can predict which patients are most likely to benefit from LTA therapy. METHODS:A post hoc analysis of the ANSWER trial was performed in 431 patients randomized to receive standard medical treatment (SMT) alone or SMT plus human albumin (SMT + HA). The interaction between baseline SA and LTA was investigated using competing-risk survival analysis. The primary endpoint was 18-month survival. Secondary endpoints included the incidence of cirrhosis-related complications and hospitalizations. RESULTS:A significant treatment-by-albumin non-linear interaction was found (p = 0.010), indicating heterogeneity of treatment effect across baseline SA levels with the upper bound of the region of statistically demonstrable benefit occurring at approximately 3.2 g/dL (sHR 0.53, 95% CI 0.28-0.99). In patients with SA ≤ 3.2 g/dL, 18-month survival was significantly higher in the SMT + HA group compared with SMT alone (HR 0.47, 95% CI 0.29-0.77; p = 0.0021). No significant survival difference could be demonstrated in patients with SA > 3.2 g/dL (HR 1.04, 95% CI 0.41-2.63; p = 0.93). Regardless of baseline SA levels, LTA was associated with improved ascites control and reduced rates of complications and hospitalizations. CONCLUSIONS:LTA provides survival and morbidity benefits in patients with mild-to-moderate hypoalbuminemia, whereas in patients with normal SA levels, its benefit appears mainly limited to morbidity reduction. Baseline SA may therefore help in prioritizing LTA therapy when resources are constrained.

BACKGROUND & AIMS:Hepatocellular Carcinoma (HCC) is a leading cause of death and the large majority of HCC occurs in the setting of cirrhosis. Nevertheless, its impact on the development of decompensation in these patients has not been investigated, yet. Our aim was to investigate the role of HCC in the development of decompensating events in patients with cirrhosis. METHODS:Clinical data of outpatients with cirrhosis from two Italian tertiary centers (Padua and Milan) were collected and followed prospectively from January 2000 to December 2021, until the end of the study, death, or liver transplantation. Demographic, clinical, and laboratory data were collected. The primary outcome was the development of decompensating events after the diagnosis of HCC. HCC and effective etiological treatment were considered as a time-varying covariate for the statistical analysis. RESULTS:Overall, 1,176 patients with cirrhosis of any etiology were enrolled (Padua 876, Milan 300), and 358 (30.4%) developed HCC. In the study cohort (Padua cohort), patients who developed HCC on compensated cirrhosis had a higher risk of developing the first decompensation event (hazard ratio [HR] = 4.05; p <0.001), primarily occurring as ascites (HR = 4.79; p <0.001), hepatic encephalopathy (HR = 3.68; p <0.001), and gastrointestinal bleeding (HR = 2.98; p = 0.004). All these findings were confirmed in the extended cohort (Milan cohort). HCC remained an independent predictor of first decompensation even considering the study period in two eras (2000-2013 and 2014-2021) (HR 3.64, 95% CI 2.10-6.31, 2000-2013; HR 4.95, 95% CI 1.62-15.1, 2014-2021). CONCLUSIONS:The occurrence of HCC is associated with a high risk of first decompensation. Further prospective studies are needed to confirm these results. IMPACT AND IMPLICATIONS:HCC frequently arises in patients with cirrhosis and is associated with poor clinical outcomes, particularly in the presence of decompensating events. Although cirrhosis progresses from a compensated to a decompensated stage characterized by severe complications, the contribution of HCC to this transition remains inadequately understood and underinvestigated. This multicenter study demonstrates that the occurrence of HCC in compensated patients with cirrhosis significantly increases the risk of first decompensation. These results highlight the importance for hepatologists and researchers to include HCC in algorithms aiming to stratify the risk of decompensation in patients with HCC and cirrhosis, thereby enhancing patient management strategies.

Background: Hepatorenal syndrome (HRS-AKI) is a life-threatening type of Acute Kidney Injury that occurs in patients with advanced cirrhosis and ascites. The use of terlipressin and albumin is the recommended treatment. The response to terlipressin is traditionally evaluated after 48h and the dose is escalated in patients in whom serum creatinine (SCr) has not decreased by 25% from baseline. In 2024, the ADQI/ICA consensus recommended anticipating the response to terlipressin at 24h and increasing the dose in case SCr has not decreased by 25% from baseline. Aim: The aim of the study was to evaluate the applicability of the ADQI/ICA recommendations on early response to terlipressin for HRS-AKI and to develop new criteria for response to HRS-AKI at 24h. Methods: We did a retrospective study in patients with cirrhosis and HRS-AKI treated with terlipressin and albumin. Clinical and biochemical data were collected at baseline, and after 24h, 48h and at the end of treatment. We followed patients until death, LT or the end of follow-up (90days). The primary endpoint was the response at 48h (defined as a reduction of SCr>25% vs baseline). The secondary endpoints were the resolution of HRS-AKI, (defined as SCr<133 umol/l at the end of treatment) and survival at 90days. Death and LT were considered competing events for the resolution of HRS-AKI. Results: We enrolled 108 patients. Median creatinine at the start of treatment was 242 µmol/L (IQR 203.5–306.8 µmol/L). Overall, 16 patients had a reduction of SCr>25% at 24h (14.8%) and 40 patients had a reduction of SCR>25% at 48h (37%). Among the patients who achieved an early response 94% had confirmed response at 48h. However, 25 out of 40 responders at 48h, were erroneously classified as non-responders at 24h (62.5%). Therefore, we analyzed the discrimination ability for early response at 48 h of ΔSCr at 24h to identify a new threshold for non-response at 24h. The area under the ROC was 0.87 (0.80-0.94) and the best threshold for non-response was a ΔSCr>0% (an increase in SCr vs baseline). Among patients with ΔSCr>0% (33%), only 5% had a response at 48h. Reversal of HRS-AKI was found in 56 patients. Early non-responders (patients who had an increase of SCr levels at 24h and a reduction<25% at 48h) were less likely to achieve a resolution of HRS-AKI (24h: 25%vs65%, p<0.001; 48h: 40%vs73%, p<0.001). Early non-responders had a significantly lower probability of 90day survival than those without (24h: 20%vs52%; p<0.001; 48h: 34%vs54%; p=0.044). Conclusion: The current recommendation of ADQI/ICA misclassified 62% of responders at 48h as non-responder, with the risk of unnecessary escalation of treatment with terlipressin. We developed a new definition of non-response at 24h that can reduce the misclassification and allow early escalation of therapy in about one third of patients with HRS-AKI. The new definition of non-response is associated with a lack of HRS-AKI resolution and lower probability of survival.

Introduction: Hepatic cirrhosis represents the final stage of most chronic liver diseases and is commonly driven by viral, alcoholic, metabolic, or mixed etiologies. In recent years, both the epidemiology and clinical presentation of cirrhosis have been rapidly evolving; however, contemporary national data characterizing this scenario are lacking.Aims: To describe the current epidemiological profile and initial clinical presentation of hepatic cirrhosis in Italy during 2024.Patients and Methods: In this prospective, multicenter study, patients with cirrhosis were consecutively enrolled from 11 tertiary hepatology centers evenly distributed across Italy. Eligible participants included individuals with a new diagnosis of cirrhosis or those presenting for the first time to these centers in 2024. Demographic, socioeconomic, etiological, clinical, and laboratory parameters were collected at baseline. The relative impact of individual risk factors was explored using a Pareto chart analysis.Results: Among 1,195 enrolled patients, metabolic dysfunction–associated steatosis liver disease (MASLD) was the most prevalent etiology (345 patients, 28.8%), following by viral etiology (245 patients, 20.5%), Alcohol Liver Disease, (ALD) (232 patients, 19.4%) and other causes (122 patients, 10.2%), but 251 patients (21.0%) had a mixed etiology (Met-ALD, Met- virus, ALD-virus, Met-ALD-virus). In the Pareto analysis of individual risk factors, arterial hypertension ranked first, followed by type 2 diabetes mellitus, alcohol abuse, obesity, HCV infection, HBV infection (figure 1). Despite the growing metabolic burden, viral hepatitis remains a major contributor, representing 41.2% (202 patients of 490) of etiology, among patients at their access to the centers, but with cirrhosis already known, confirming the persistent epidemiological weight of viral etiologies despite antiviral therapies and vaccination programs.Conclusions: This study highlights the evolving epidemiology of cirrhosis, characterized by the increasing contribution of MASLD and the predominance of early-stage, compensated disease (Child-Pugh A) at diagnosis. The comorbidity profile associated with cirrhosis is also emphasized: among the risk factors, arterial hypertension was the most prevalent, although diabetes and obesity exert a more direct pathogenetic impact on hepatic injury. Viral hepatitis continues to impose a considerable clinical burden, underscoring the need to reinforce vaccination strategies, screening programs, and linkage-to-care pathways. Finally, these findings demonstrate how, nowadays, the complexity of managing cirrhosis has increased, being hepatic risk factors frequently overlapped (with one in five patients exhibiting multiple comorbidities), thereby contributing to an increased disease burden.

Background and Aims: Preliminary results from the PRECIOSA trial (AASLD congress 2025) suggested that patients with normal serum albumin (SA) concentrations may not have a survival benefit from long-term albumin (LTA). We investigated whether baseline SA influences survival and other clinical outcomes in patients receiving LTA.Methods: This is a post-hoc analysis of the ANSWER randomized clinical trial including 431 patients with cirrhosis and uncomplicated grade 2 or 3 ascites randomized to receive standard medical treatment (SMT) alone or SMT + human albumin (HA) (40 g twice weekly for two weeks, then 40 g weekly) for up to 18 months. To identify the most discriminatory baseline SA threshold, candidate cut-offs between 2.5 and 4.2 g/dL (0.1 g/dL increments) were tested. For each value, 18-month survival was compared between treatment arms using the log-rank test, and the cut-off with the lowest p value was selected. The primary endpoint was 18-month survival; secondary endpoints included the incidence rates (IR) of cirrhosis-related complications. Comparisons were conducted within subgroups stratified by baseline SA concentration.Results: At baseline, patients randomized to the two arms did not differ in SA concentration (SMT 3.1±0.5 vs. SMT+HA 3.1±0.6 g/dL, p=0.86). The baseline SA cut-off associated with the greatest survival benefit was 3.2 g/dL. Overall, 275 patients (64%) had baseline SA ≤3.2 g/dL (132 SMT, 143 SMT+HA). The 18-month survival was significantly higher in SMT+HA than SMT in patients with baseline SA ≤3.2 g/dL (HR 0.47, 95%CI 0.29-0.77, p=0.002), while it was similar in patients with SA >3.2 g/dL (HR 1.04, 95%CI 0.41-2.63, p=0.93). In contrast, the cumulative incidence of paracentesis was lower in the SMT+HA group compared to SMT either in patients with SA ≤3.2 g/dL (HR 0.45 95% CI 0.31-0.65, p<0.001) and in those with SA >3.2 g/dL (HR 0.52 95% CI 0.32-0.87, p=0.010). Similarly, the reduction of complications (i.e., spontaneous bacterial peritonitis, non-SBP infections, grade III/IV hepatic encephalopathy) observed in patients receiving LTA was similar in those presenting at baseline either SA ≤3.2 g/dL or SA >3.2 g/dL).Conclusion: Baseline SA concentration can be used to identify those patients with uncomplicated grade 2-3 ascites who receive the greatest survival benefit from LTA, while the advantage associated with LTA in managing ascites and other complications appears to be independent of baseline SA. This finding suggests that patients with at least mild to moderate hypoalbuminemia are the best candidates to receive LTA and could be prioritized in healthcare settings with limited resources.