Hepatitis E Virus: What More Do We Need to Know?

Hepatitis E virus (HEV) infection is typically a self-limiting, acute illness that spreads through the gastrointestinal tract but replicates in the liver. However, chronic infections are possible in immunocompromised individuals. The HEV virion has two shapes: exosome-like membrane-associated quasi-enveloped virions (eHEV) found in circulating blood or in the supernatant of infected cell cultures and non-enveloped virions ("naked") found in infected hosts' feces and bile to mediate inter-host transmission. Although HEV is mainly spread via enteric routes, it is unclear how it penetrates the gut wall to reach the portal bloodstream. Both virion types are infectious, but they infect cells in different ways. To develop personalized treatment/prevention strategies and reduce HEV impact on public health, it is necessary to decipher the entry mechanism for both virion types using robust cell culture and animal models. The contemporary knowledge of the cell entry mechanism for these two HEV virions as possible therapeutic target candidates is summarized in this narrative review.

Updating the Clinical Application of Blood Biomarkers and Their Algorithms in the Diagnosis and Surveillance of Hepatocellular Carcinoma: A Critical Review.

The most common primary liver cancer is hepatocellular carcinoma (HCC), and its mortality rate is increasing globally. The overall 5-year survival of patients with liver cancer is currently 10-20%. Moreover, because early diagnosis can significantly improve prognosis, which is highly correlated with tumor stage, early detection of HCC is critical. International guidelines advise using α-FP biomarker with/without ultrasonography for HCC surveillance in patients with advanced liver disease. However, traditional biomarkers are sub-optimal for risk stratification of HCC development in high-risk populations, early diagnosis, prognostication, and treatment response prediction. Since about 20% of HCCs do not produce α-FP due to its biological diversity, combining α-FP with novel biomarkers can enhance HCC detection sensitivity. There is a chance to offer promising cancer management methods in high-risk populations by utilizing HCC screening strategies derived from new tumor biomarkers and prognostic scores created by combining biomarkers with distinct clinical parameters. Despite numerous efforts to identify molecules as potential biomarkers, there is no single ideal marker in HCC. When combined with other clinical parameters, the detection of some biomarkers has higher sensitivity and specificity in comparison with a single biomarker. Therefore, newer biomarkers and models, such as the Lens culinaris agglutinin-reactive fraction of Alpha-fetoprotein (α-FP), α-FP-L3, Des-γ-carboxy-prothrombin (DCP or PIVKA-II), and the GALAD score, are being used more frequently in the diagnosis and prognosis of HCC. Notably, the GALAD algorithm was effective in HCC prevention, particularly for cirrhotic patients, regardless of the cause of their liver disease. Although the role of these biomarkers in surveillance is still being researched, they may provide a more practical alternative to traditional imaging-based surveillance. Finally, looking for new diagnostic/surveillance tools may help improve patients' survival. This review discusses the current roles of the most used biomarkers and prognostic scores that may aid in the clinical management of HCC patients.

Predictors of serious adverse events and non-response in cirrhotic patients with primary biliary cholangitis treated with obeticholic acid.

BACKGROUND & AIMS: Obeticholic acid (OCA) has recently been restricted in patients with primary biliary cholangitis (PBC) with "advanced cirrhosis" because of its narrow therapeutic index. We aimed to better define the predicting factors of hepatic serious adverse events (SAEs) and non-response in cirrhotic patients undergoing OCA therapy. METHODS: Safety and efficacy of treatment were evaluated in a cohort of consecutive PBC cirrhotic patients started with OCA. OCA response was evaluated according to the Poise criteria. Risk factors for hepatic SAEs and non-response were reported as risk ratios (RR) with 95% confidence intervals (CIs). RESULTS: One hundred PBC cirrhotics were included, 97 Child-Pugh class A and 3 class B. Thirty-one had oesophageal varices and 5 had a history of ascites. Thirty-three per cent and 32% of patients achieved a biochemical response at 6 and 12 months respectively. Male sex (adjusted-RR 1.75, 95%CI 1.42-2.12), INR (1.37, 1.00-1.87), Child-Pugh score (1.79, 1.28-2.50), MELD (1.17, 1.04-1.30) and bilirubin (1.83, 1.11-3.01) were independently associated with non-response to OCA. Twenty-two patients discontinued OCA within 12 months: 10 for pruritus, 9 for hepatic SAEs (5 for jaundice and/or ascitic decompensation; 4 for upper digestive bleeding). INR (adjusted-RR 1.91, 95%CI 1.10-3.36), lower albumin levels (0.18, 0.06-0.51), Child-Pugh score (2.43, 1.50-4.04), history of ascites (3.5, 1.85-6.5) and bilirubin (1.30, 1.05-1.56), were associated with hepatic SAEs. A total bilirubin≥1.4 mg/dl at baseline was the most accurate biochemical predictor of hepatic SAEs under OCA. CONCLUSIONS: An accurate baseline assessment is crucial to select cirrhotic patients who can benefit from OCA. Although OCA is effective in one third of cirrhotics, bilirubin level ≥1.4 mg/dl should discourage from its use.

On-treatment serum albumin level can guide long-term treatment in patients with cirrhosis and uncomplicated ascites.

BACKGROUND & AIMS: The ANSWER study reported that long-term albumin administration in patients with cirrhosis and uncomplicated ascites improves survival. During treatment, serum albumin increased within a month and remained stable thereafter. In this post hoc analysis, we aimed to determine whether on-treatment serum albumin levels could guide therapy. METHODS: Logistic regression was used to assess the association between baseline serum albumin and mortality, as well as to determine on-treatment factors associated with mortality and to predict the achievement of a given on-treatment serum albumin level. Survival was assessed by Kaplan-Meier estimates and second-order polynomial regression. Patients whose on-treatment serum albumin remained below normal were compared with a subset of patients from the control arm matched by principal score. RESULTS: Baseline serum albumin was closely associated with 18-month mortality in untreated patients; albumin treatment almost effaced this relationship. On-treatment serum albumin and MELD-Na at month 1 were the sole independent variables associated with mortality. Second-order polynomial regression revealed that survival improved in parallel with increased 1-month on-treatment serum albumin. Kaplan-Meier estimations showed that any value of 1-month on-treatment serum albumin (0.1 g/dl intervals) in the range 2.5-4.5 g/dl discriminated patient survival. In the normal range of serum albumin, the best discriminant value was 4.0 g/dl. Compared to untreated patients, survival even improved in patients whose on-treatment serum albumin remained below normal. CONCLUSION: Baseline serum albumin per se should not guide the decision to start albumin therapy. Conversely, 1-month on-treatment serum albumin levels are strongly associated with outcomes and could guide the use of albumin - 4.0 g/dl being the target threshold. However, even patients whose serum albumin remains below normal benefit from long-term albumin administration. LAY SUMMARY: The ANSWER study has shown that long-term albumin administration improves survival and prevents the occurrence of major complications in patients with cirrhosis and ascites. This study shows that the achievement of these beneficial effects is related to a significant increase in serum albumin concentration. Even though the best results follow the achievement of a serum albumin concentration of 4 g/dl, a survival benefit is also achieved in patients who fail to normalise serum albumin.

Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial.

BACKGROUND: Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. METHODS: We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. FINDINGS: From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. INTERPRETATION: In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. FUNDING: Italian Medicine Agency.

Restaging Patients With Hepatocellular Carcinoma Before Additional Treatment Decisions: A Multicenter Cohort Study.

Prognostic assessment of patients with hepatocellular carcinoma (HCC) at the time of diagnosis remains controversial and becomes even more complex at the time of restaging when new variables need to be considered. The aim of the current study was to evaluate the prognostic utility of restaging patients before proceeding with additional therapies for HCC. Two independent Italian prospective databases were used to identify 1,196 (training cohort) and 648 (validation cohort) consecutive patients with HCC treated over the same study period (2008-2015) who had complete restaging before decisions about additional therapies. The performance of the Italian Liver Cancer (ITA.LI.CA) prognostic score at restaging was compared with that of the Barcelona Clinic Liver Cancer, Hong Kong Liver Cancer, and Cancer of the Liver Italian Program systems. A multivariable Cox survival analysis was performed to identify baseline, restaging, or dynamic variables that were able to improve the predictive performance of the prognostic systems. At restaging, 35.3% of patients maintained stable disease; most patients were either down-staged by treatment (27.2%) or had disease progression (37.5%). The ITA.LI.CA scoring system at restaging demonstrated the best prognostic performance in both the training and validation cohorts (c-index 0.707 and 0.722, respectively) among all systems examined. On multivariable analysis, several variables improved the prognostic ability of the ITA.LI.CA score at restaging, including progressive disease after the first treatment, Model for End-Stage Liver Disease at restaging, and choice of nonsurgical treatment as additional therapy. A new ITA.LI.CA restaging model was created that demonstrated high discriminative power in both the training and validation cohorts (c-index 0.753 and 0.745, respectively). CONCLUSION: Although the ITA.LI.CA score demonstrated the best prognostic performance at restaging, other variables should be considered to improve the prognostic assessment of patients at the time of deciding additional therapies for HCC.

Real-life glecaprevir/pibrentasvir in a large cohort of patients with hepatitis C virus infection: The MISTRAL study.

BACKGROUND AND AIMS: It is paramount to identify predictors of treatment failure with direct antiviral agents in 'field-practice' patients, including people who inject drugs (PWID). Data on the efficacy of glecaprevir/pibrentasvir (GLE/PIB) in a field-practice scenario are scant. The multicentre MISTRAL study enrolled 1177 patients, including PWID, to assess real-life efficacy and safety of GLE/PIB and to identify the predictive factors for this treatment. METHODS: This was a prospective, longitudinal study. The outcome variable was the rate of sustained virological response (SVR) at week 12. RESULTS: A total of 123 patients (10%) were infected from hepatitis C virus (HCV) 3. METAVIR fibrosis score was F4 in 104 subjects (9%); 118 patients (10%) were PWID. Overall, 1163/1177 (99%) patients achieved SVR. The baseline clinical factors discriminating between treatment success and treatment failure were age at treatment (P = 0.031) and creatinine level (P = 0.034). SVR rates were not influenced by gender, substance abuse, previous treatment, treatment duration, fibrosis or chronic kidney disease stage. Compared with non-substance users, the 118 PWID exhibited a significantly different genotype pattern distribution (χ2  < 0.001). A total of 40/118 (33.9%) of substance users were HCV3 compared to 83/1056 (7.9%) non-substance users. Only 6 patients (0.5%) reported a serious adverse event. CONCLUSIONS: The MISTRAL study provides evidence of GLE/PIB efficacy in a field-practice scenario in a highly epidemic HCV area in southern Italy; it unveiled significant differences in genotype distribution among the most underserved and difficult-to-treat patient subgroups including PWID.

Rate of non-response to ursodeoxycholic acid in a large real-world cohort of primary biliary cholangitis patients in Italy.

Background and aim: Response to ursodeoxycholic acid (UDCA) is crucial for the prediction of primary biliary cholangitis (PBC) prognosis, and different response criteria were validated and proposed by reference centers for PBC. To date, rates of non-response to UDCA from real-world series are lacking.Methods: Hepatology/Gastroenterology centers belonging to 'Club Epatologi Ospedalieri' (CLEO) and 'Associazione Italiana Gastroenterologi Ospedalieri' (AIGO) were invited to participate in the study, and asked to extract all patients followed for PBC, without any selection or exclusion, and fill in the database provided.Results: Thirty-four centers were enrolled throughout Italy, for a total of 713 patients. None of these centers, except one, had a hepatology outpatient clinic devoted to the care of patients with autoimmune liver diseases. After excluding 79 cases of PBC/autoimmune hepatitis overlaps, 634 patients were analyzed: mean age, 64.4 ± 12.0 years; 91.2% females; F/M 10.3/1. For patients with at least 1 year of UDCA treatment (583), rates of non-response to UDCA were evaluated according to the Paris-I/-II, Toronto and GLOBE criteria, and compared with those in the original cohorts: 27% vs 39% in Paris-I cohort; 39.6% vs 52% in Paris-II; 20.1% vs 43.5% in Toronto; 15.7% vs 30% in GLOBE (age-specific cutoffs). Mean alkaline phosphatase levels on UDCA treatment, and the age-adjusted prevalence of F3/F4 fibrosis, appeared lower in this PBC population than in reference cohorts.Conclusions: A mean ∼15% better response to UDCA is observed in a real-world PBC population, probably due to migration of some of most severe/advanced cases to PBC referral centers.

Multiclass HCV resistance to direct-acting antiviral failure in real-life patients advocates for tailored second-line therapies.

BACKGROUND & AIMS: Despite the excellent efficacy of direct-acting antivirals (DAA) reported in clinical trials, virological failures can occur, often associated with the development of resistance-associated substitutions (RASs). This study aimed to characterize the presence of clinically relevant RASs to all classes in real-life DAA failures. METHODS: Of the 200 virological failures that were analyzed in 197 DAA-treated patients, 89 with pegylated-interferon+ribavirin (PegIFN+RBV) and 111 without (HCV-1a/1b/1g/2/3/4=58/83/1/6/24/25; 56.8% treatment experienced; 65.5% cirrhotic) were observed. Sanger sequencing of NS3/NS5A/NS5B was performed by home-made protocols, at failure (N=200) and whenever possible at baseline (N=70). RESULTS: The majority of the virological failures were relapsers (57.0%), 22.5% breakthroughs, 20.5% non-responders. RAS prevalence varied according to IFN/RBV use, DAA class, failure type and HCV genotype/subtype. It was 73.0% in IFN group vs 49.5% in IFN free, with the highest prevalence of NS5A-RASs (96.1%), compared to NS3-RASs (75.9% with IFN, 70.5% without) and NS5B-RASs (66.6% with IFN, 20.4% without, in sofosbuvir failures). In the IFN-free group, RASs were higher in breakthrough/non-responders than in relapsers (90.5% vs 40.0%, P<.001). Interestingly, 57.1% of DAA IFN-free non-responders had a misclassified genotype, and 3/4 sofosbuvir breakthroughs showed the major-RAS-S282T, while RAS-L159F was frequently found in sofosbuvir relapsers (18.2%). Notably, 9.0% of patients showed also extra target RASs, and 47.4% of patients treated with ≥2 DAA classes showed multiclass resistance, including 11/11 NS3+NS5A failures. Furthermore, 20.0% of patients had baseline-RASs, which were always confirmed at failure. CONCLUSIONS: In our failure setting, RAS prevalence was remarkably high in all genes, with a partial exception for NS5B, whose limited resistance is still higher than previously reported. This multiclass resistance advocates for HCV resistance testing at failure, in all three genes for the best second-line therapeutic tailoring.

Significant decrease of saturation index in erythrocytes membrane from subjects with non-alcoholic fatty liver disease (NAFLD).

BACKGROUND: The lipidomic profiling of erythrocyte membranes is expected to provide a peculiar scenario at molecular level of metabolic and nutritional pathways which may influence the lipid balance and the adaptation and homeostasis of the organism. Considering that lipid accumulation in the cell is important in promoting tissue inflammation, the purpose of this study is to analyze the fatty acid profile in red blood cell membranes of patients with Non-Alcoholic Fatty Liver Disease (NAFLD), in order to identify and validate membrane profiles possibly associated with the degree of hepatic damage. METHODS: This work presents data obtained at baseline from 101 subjects that participated to a nutritional trial (registration number: NCT02347696) enrolling consecutive subjects with NAFLD. Diagnosis of liver steatosis was performed by using vibration-controlled elastography implemented on FibroScan. Fatty acids, extracted from phospholipids of erythrocyte membranes, were quantified by gas chromatography method. RESULTS: The subjects with severe NAFLD showed a significant decrease of the ratio of stearic acid to oleic acid (saturation index, SI) compared to controls, 1.281 ± 0.31 vs 1.5 ± 0.29, respectively. Low levels of SI in red blood cell membranes, inversely associated with degree of liver damage, suggest that an impairment of circulating cell membrane structure can reflect modifications that take place in the liver. Subjects with severe NAFLDalso showed higher levels of elongase 5 enzymatic activity, evaluated as vaccenic acid to palmitoleic acid ratio. CONCLUSIONS: Starting from these evidences, our findings show the importance of lipidomic approach in the diagnosis and the staging of NAFLD.

The role of alexithymia in quality of life impairment in patients with chronic hepatitis C during antiviral treatment.

This study aimed to investigate the role of alexithymia in the quality of life of patients with chronic hepatitis C treated with antiviral therapy. A consecutive sample of 124 patients were evaluated at baseline, during, and 6months after treatment with interferon and ribavirin. At baseline past mood disorders and alexithymia and, at each index visit, adverse events, psychological distress, and disease-specific quality of life were assessed with validated instruments. Patients with past mood disorders and alexithymia had impaired levels of quality of life, psychological distress, and treatment-related adverse events. However, after controlling for covariates, poor quality of life was independently predicted by alexithymia and psychological distress before (R(2)=0.60) and 6months after (R(2)=0.69) the antiviral treatment while during treatment (at 3months and the end of therapy) by depression and somatic adverse events (R(2)=0.67 and 0.69, respectively). Alexithymia rather than history of mood disorders resulted to be an independent predictor of impaired quality of life not only before but also 6months after the end of treatment. Given the association with proneness to health-compromising behaviors, clinicians are encouraged to pay closer attention to long-term psychological and somatic effects of antiviral treatment in patients with alexithymic characteristics.

Genetic Associations of Alexithymia in Predicting Interferon-Induced Depression in Chronic Hepatitis C.

BACKGROUND: Previous studies have shown that alexithymia is associated with gene polymorphisms that regulate the availability of serotonin (5-HT) in the brain. Since the 5-HT network is involved in interferon (IFN)-induced depression, this paper aimed to investigate the role of alexithymia and the functional gene variants of the 5-HT1A receptor (HTR1A) and the 5-HT transporter (5-HTTLPR) in induction of depression during antiviral treatment. METHODS: The depressive symptoms of 130 consecutive patients with chronic hepatitis C and no current psychopathology were measured during treatment with IFN and ribavirin (6-12 months) and at a 6-month follow-up. At baseline, alexithymia and 2 genotypes (5-HTTLPR and HTR1A) were also assessed. RESULTS: Patients with homozygosity for HTR1A-G and 5-HTTLPR long alleles had significantly higher levels of alexithymia. After controlling for sociodemographic and disease-related factors, alexithymia and HTR1A-G polymorphism, both separately (20-22%) and jointly (14-16%), significantly and independently predicted the development of IFN-induced depression. CONCLUSIONS: Subjects carrying HTR1A-G and 5-HTTLRP double long alleles are more vulnerable to alexithymia. Also patients with a higher level of alexithymia and the HTR1A-G gene variant are more vulnerable to experiencing IFN-induced depressive symptoms. The clinical implications of targeting alexithymia and HTR1A receptors as a possible treatment option for mood disorders should be investigated in further studies.

Identification of naïve HCV-1 patients with chronic hepatitis who may benefit from dual therapy with peg-interferon and ribavirin.

BACKGROUND & AIMS: The pool of HCV genotype 1 patients likely to be cured by peg-interferon and ribavirin remains to be quantified. METHODS: In 1045 patients treated with peg-interferon and ribavirin, two therapeutic strategies were confronted: the first one evaluated only baseline variables associated with sustained virological response (SVR), and the second one included the rapid virologic response (RVR) in addition to baseline predictors. An 80% SVR rate was the threshold to retain a strategy as clinically relevant. RESULTS: Overall, 414 patients (39.6%) attained SVR. In the first strategy, the hierarchy of features independently associated with SVR was IL28B CC genotype (OR 5.082; CI 3.637-7.101), low (<400,000 IU) viremia (OR 2.907; CI 2.111-4.004), F0-F2 fibrosis (OR 1.631; CI 1.122-2.372) and type 2 diabetes (OR 0.528; CI 0.286-0.972). In the alternative strategy, SVR was associated with RVR (OR 6.273; CI 4.274-9.208), IL28B CC genotype (OR 3.306; CI 2.301-4.751), low viremia (OR 2.175; CI 1.542-3.070), and F0-F2 fibrosis (OR 1.506; CI 1.012-2.242). Combining the favorable baseline variables, the rates of SVR ranged from 42.4% to 83.3%, but only 66 patients (6.3%, overall) with all predictors could be anticipated to reach the >80% SVR threshold. Only 26.6% of no-RVR patients attained SVR. Among the 255 RVR patients, the likelihood of SVR was 61.8% in those with unfavorable predictors, 80% in the presence of a single predictor, and 100% when both predictors were present. By using this model, 200 patients (19.1%) were predicted to have an 80% chance of being cured with dual therapy. CONCLUSIONS: A consistent subset of naïve HCV-1 patients, identified by some baseline characteristics and RVR, may benefit from dual treatment with peg-interferon and ribavirin.

Variation in genes encoding for interferon λ-3 and λ-4 in the prediction of HCV-1 treatment-induced viral clearance.

BACKGROUND & AIMS: In patients with chronic HCV-1 infection, recent evidences indicate that determination of a dinucleotide polymorphism (ss469415590, ΔG/TT) of a new gene, designated IFN λ-4, might be more accurate than the 12979860CC type of the IL28B locus in predicting sustained virological response (SVR) following peg-interferon and ribavirin. In addition, combined genotyping of different SNPs of the IL28B locus was shown to help dissect patients most prone to SVR among those with rs12979860CT. We examined whether single or combined genotyping of two IL28B SNPs, rs12979860 and rs8099917, and ss469415590 variation might improve the prediction of SVR. RESULTS: In the study cohort of 539 patients, 38% had SVR. The SNPs 12979860CC, rs8099917TT, and rs469415590TT/TT correlated significantly with SVR (68%, 50%, and 67%). Carriers of either the triplotype rs12979860CC_ss469415590TT/TT_rs8099917TT or the diplotype rs12979860CC_ss469415590TT/TT had the highest SVR rate (72%). In carriers of the rs12979860 T allele, neither the rs8099917 nor the ss469415590 improved the response prediction. After pooling this finding with data from previous studies, in rs12979860 T heterozygous individuals the co-presence of the rs8099917TT SNP was associated with improved response prediction. CONCLUSION: In HCV-1 patients, the rs12979860 polymorphism appeared as the hit SNP better predicting response following peg-interferon and ribavirin treatment. Additional ss469415590 or rs8099917 genotyping had no added benefit for response prediction. In the subset of carriers of the rs12979860 T allele, genotyping of the rs8099917 SNP was unhelpful in the present investigation, but may inform clinical prediction of treatment response when our data were pooled with previous investigations.

Tumor Immune Microenvironment in Intrahepatic Cholangiocarcinoma: Regulatory Mechanisms, Functions, and Therapeutic Implications.

Treatment options for intrahepatic cholangiocarcinoma (iCCA), a highly malignant tumor with poor prognosis, are limited. Recent developments in immunotherapy and immune checkpoint inhibitors (ICIs) have offered new hope for treating iCCA. However, several issues remain, including the identification of reliable biomarkers of response to ICIs and immune-based combinations. Tumor immune microenvironment (TIME) of these hepatobiliary tumors has been evaluated and is under assessment in this setting in order to boost the efficacy of ICIs and to convert these immunologically "cold" tumors to "hot" tumors. Herein, the review TIME of ICCA and its critical function in immunotherapy. Moreover, this paper also discusses potential avenues for future research, including novel targets for immunotherapy and emerging treatment plans aimed to increase the effectiveness of immunotherapy and survival rates for iCCA patients.

Gender Differences in Liver Steatosis and Fibrosis in Overweight and Obese Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease before and after 8 Weeks of Very Low-Calorie Ketogenic Diet.

Obesity and metabolic syndrome are linked to steatotic liver disease (SLD), the most common form of chronic liver disease. Lifestyle modifications and dieting are strategies that can prevent metabolic dysfunction-associated steatotic liver disease (MASLD). The very low-calorie ketogenic diet (VLCKD) is a helpful treatment for MASLD and has been recommended for people affected by obesity; we evaluated the effect of gender on steatosis and fibrosis in a cohort of 112 overweight or obese patients undergoing an eight-week treatment with a VLCKD. Differences between the genders in terms of anthropometric measures, body composition, and metabolic indicators were examined before, during, and after the nutritional intervention. At baseline, there were significant differences between men and women in terms of anthropometric parameters, blood pressure, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), fasting insulin, hepatic markers, and lipid profile. Men had considerably higher levels of liver steatosis (measured by CAP) and liver stiffness (measured by E) under basal conditions than women. After the VLCKD, there were reductions in both genders of controlled attenuation parameter (CAP), body weight, body mass index (BMI), waist circumference, systolic and diastolic blood pressure, insulin resistance, fat mass (FM), free fat mass (FFM), and fasting blood glucose, insulin, glycated hemoglobin (HbA1c), triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, alanine transaminase (ALT), gamma-glutamyl transferase (γGT), and uric acid levels. Only in men, liver stiffness, aspartate aminotransferase (AST), creatinine, and C-reactive protein (CRP) levels significantly decreased. Moreover, men had significantly greater levels of liver steatosis: the male gender featured an increase of 23.96 points of the Fibroscan CAP. Men exhibited higher levels of steatosis and fibrosis than women, and these differences persist despite VLCKD. These gender-specific variations in steatosis and fibrosis levels could be caused by hormonal and metabolic factors, suggesting that different therapeutic strategies might be required depending on the gender.

Higher-Level Steatosis Is Associated with a Greater Decrease in Metabolic Dysfunction-Associated Steatoic Liver Disease after Eight Weeks of a Very Low-Calorie Ketogenic Diet (VLCKD) in Subjects Affected by Overweight and Obesity.

The most common form of chronic liver disease, recently defined as MASLD, is strongly linked to obesity and metabolic syndrome. Lifestyle changes are part of MASLD prevention. The very low-calorie ketogenic diet (VLCKD) is a useful option for treating MASLD and reducing liver steatosis in patients with obesity. We assessed whether a greater degree of steatosis could have a positive or negative impact on how well 8 weeks of using the VLCKD improve steatosis and fibrosis in a patient population of overweight and obese individuals. Anthropometric parameters, along with changes in hormone and metabolic biomarkers, were also assessed both before and after the dietary change. The study population included 111 overweight (14.41%) or obese subjects (85.59%) aged between 18 and 64 years; the 75 women and 36 men involved were not taking any medicine. In both the raw (0.37 95% CI 0.21; 0.52) and the multivariate models (model a: 0.439 95% CI 0.26; 0.62; model b: 0.437 95% CI 0.25; 0.63), there was a positive and statistically significant correlation between the CAP delta value and the CAP before using the VLCKD. Additionally, the liver stiffness delta was found to be positively and statistically significantly correlated with liver stiffness before the use of the VLCKD in both models: the multivariate model (model a: 0.560 95% CI 0.40; 0.71; model b: 0.498 95% CI 0.34; 0.65) and the raw model (0.52 95% CI 0.39; 0.65). Systolic and diastolic blood pressure, insulin resistance (measured by HOMA-IR), insulin, HbA1c, fasting blood glucose, total cholesterol, LDL cholesterol, HDL cholesterol and triglycerides, BMI, waist circumference, and fat mass, were all decreased (p < 0.001) following the use of the VLCKD. However, following the use of the VLCKD, there was an increase in vitamin D levels. (p < 0.001). We found that using the VLCKD for 8 weeks has a greater effect on improving steatosis and fibrosis in subjects who initially have more severe forms of these conditions.

Final Results from the First European Real-World Experience on Lusutrombopag Treatment in Cirrhotic Patients with Severe Thrombocytopenia: Insights from the REAl-World Lusutrombopag Treatment in ITalY Study.

Background and aims: Management of severe thrombocytopenia poses significant challenges in patients with chronic liver disease. Here, we aimed to evaluate the first real-world European post-marketing cohort of cirrhotic patients treated with lusutrombopag, a thrombopoietin receptor agonist, verifying the efficacy and safety of the drug. Methods: In the REAl-world Lusutrombopag treatment in ITalY (REALITY) study, we collected data from consecutive cirrhotic patients treated with lusutrombopag in 19 Italian hepatology centers, mostly joined to the "Club Epatologi Ospedalieri" (CLEO). Primary and secondary efficacy endpoints were the ability of lusutrombopag to avoid platelet transfusions and to raise the platelet count to ≥50,000/µL, respectively. Treatment-associated adverse events were also collected. Results: A total of 66 patients and 73 cycles of treatment were included in the study, since 5 patients received multiple doses of lusutrombopag over time for different invasive procedures. Fourteen patients (19%) had a history of portal vein thrombosis (PVT). Lusutrombopag determined a significant increase in platelet count [from 37,000 (33,000-44,000/µL) to 58,000 (49,000-82,000), p < 0.001]. The primary endpoint was met in 84% of patients and the secondary endpoint in 74% of patients. Baseline platelet count was the only independent factor associated with response in multivariate logistic regression analysis (OR for any 1000 uL of 1.13, CI95% 1.04-1.26, p 0.01), with a good discrimination power (AUROC: 0.78). Notably, a baseline platelet count ≤ 29,000/µL was identified as the threshold for identifying patients unlikely to respond to the drug (sensitivity of 91%). Finally, de novo PVT was observed in four patients (5%), none of whom had undergone repeated treatment, and no other safety or hemorrhagic events were recorded in the entire population analyzed. Conclusions: In this first European real-world series, lusutrombopag demonstrated efficacy and safety consistent with the results of registrational studies. According to our results, patients with baseline platelet counts ≤29,000/µL are unlikely to respond to the drug.

Prevention of influenza complications in patients with liver disease: a retrospective cohort study.

Introduction: Patients with chronic liver disease are highly prone to acquiring influenza infection diseases and experiencing associated complications. National and international guidelines recommend the influenza vaccine for patients with liver disorders to reduce the risk of influenza complications. Our study aims to evaluate the risk of flu complications faced by patients with liver disease and assess influenza vaccination coverage. Methods: The archive of hospital discharge forms was used to define the list of Apulian patients with liver disease, considering data from 2017 through 2022. The vaccination status of these patients was assessed via data collected from the Regional Immunization Database. We focused on influenza vaccine shots administered during the 2020/21, 2021/22, and 2022/23 flu seasons. Results: A declining trend across the flu seasons was observed, with a VC of 49.5% in the 2020/21 flu season, 48.1% in the 2021/22 season, and 45.0% in the 2022/23 season. Subjects with multiple comorbidities have higher vaccination rates. Additionally, the multivariate models demonstrate that vaccination compliance increases with age and is strongly associated with having received a previous influenza vaccine shot. Conclusion: The VC rates reported in our study are unsatisfactory and did not reach the minimum achievable goal (75%) the Italian Ministry of Health set. A multifactorial approach is required to raise the immunization rates and therefore protect the patients from the influenza-associated risk of collateral liver damage; the role of gastroenterologists and hepatologists is crucial, as their responsibilities should extend beyond patient care to the prevention of complications after infectious diseases.

Lifestyle Modification: Evaluation of the Effects of Physical Activity and Low-Glycemic-Index Mediterranean Diet on Fibrosis Score.

BACKGROUND: Non-Alcoholic Fatty Liver Disease (NAFLD) is one the most prevalent causes of chronic liver disease worldwide. In the absence of an approved drug treatment, lifestyle modification is the first intervention strategy. This study aimed to estimate the main effect of two different physical activity (PA) programs, and a Low-Glycemic-Index Mediterranean Diet (LGIMD), or their combined effect on liver fibrosis parameters in subjects with NAFLD. METHODS: Subjects with moderate or severe NAFLD grade of severity (n = 144) were randomly assigned to six intervention arms for three months: LGIMD, PA programs, and their combination. Data were collected at baseline, 45 days, and 90 days. Transient elastography was performed to assess the outcome. RESULTS: at 90 days, a statistically significant reduction in kPa was found among subjects following LGMID (-2.85, 95% CI -5.24, -0.45) and those following an LGIMD plus PA1 (-2.37, 95% CI -4.39, -0.35) and LGIMD plus Pa2 (-2.21, 95% CI -4.10, -0.32). The contrast between time 2 and time 1 of the LGIMD plus PA2 treatment showed a statistically significant increase, and vice versa: the contrast between time 3 and time 2 of the same treatment showed a statistically significant reduction. The PA1 and PA2 arms also showed reduced kPa, although the results did not reach statistical significance. CONCLUSIONS: The intervention arms, LGIMD, LGIMD+PA1, and LGIMD+PA2, reduced the fibrosis score.