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Cholestasis is a clinical and laboratory syndrome indicating impaired bile production or excretion. One of the hallmark symptoms of cholestasis is pruritus. Itch can be severe and debilitating for patients, impacting their quality of life similarly to pain, and, in some cases, it can be refractory. Current therapies like anion exchange resins and rifampicin, offer partial relief but with side effects. Effective, well-tolerated treatments are urgently needed. This literature review examines existing options (bile acid sequestrants, antihistamines, opioid antagonists, sertraline, and rifampicin) and explores novel therapies (monoclonal antibodies, PPAR agonists, and bile-acid-based therapies). We analyze mechanisms, limitations, and adverse effects to aid clinicians and researchers. Novel approaches include monoclonal antibodies to inhibit bile recirculation and PPAR agonists targeting pruritus signaling. Despite the limited current options, ongoing research promises better treatments for cholestatic pruritus, addressing its distressing impact. In summary, cholestasis-associated pruritus poses a significant challenge with limited treatments. Advancements in understanding its pathophysiology offer hope for more effective therapies in the future. [ABSTRACT FROM AUTHOR]

Frailty is a multidimensional syndrome predominantly studied in the elderly, characterized by reduced resistance to stressors due to diminished physiological reserve and resilience. Advances in surgical techniques and immunosuppressive drugs have improved long-term survival rates in solid organ transplant recipients, yet the 10-year survival is satisfying. However, liver transplant recipients have a noteworthy risk of developing frailty status. After liver transplant, frailty can be favored by socioeconomic, cultural, and health-related factors, leading to increased risks of hospitalization, morbidity, and mortality. Various tools for frailty assessment exist, but none are universally validated for post-transplant patients. The integration of socioeconomic and psychological factors into frailty evaluation could improve quality of life and long-term outcomes for transplant recipients. Multidisciplinary approaches, including psychosocial support, are essential for managing frailty and enhancing the overall care of transplanted patients. This narrative review aims to comprehensively address the principal frailty risk factors associated with liver transplantation. [ABSTRACT FROM AUTHOR]

Background: The risk of hepatocarcinoma in HCV cirrhotic patient responders after treatment with DAAs decrease, but HCC still occurs. A correlation between specific miRNAs and the development of hepatocarcinoma have been highlighted. Aim: To investigate miRNA expression in HCV-infected cirrhotic patients treated with DAAs, regarding whether or not they developed HCC at follow-up. Methods: A total of 73 outpatients with HCV-related cirrhosis treated with DAAs were enrolled, 28 of which had HCC. Samples were collected at the start and at the end of treatment. In the screening phase, 172 miRNAs were analyzed at baseline. Differentially expressed miRNAs were validated in the entire cohort. Results: In the validation phase, at baseline and in patients treated for 12 weeks, miR-28-5p was confirmed to be more highly expressed in the HCC group compared to the non-HCC group. In all of the patients treated for 12 weeks, at end of the treatment we found a significant downregulation in miR-132-3p, miR-133b-3p, miR-221-3p and miR-324-3p. In the HCC group, miR-28-5p was significantly downregulated after DAA therapy as well as in HCC patients treated for 24 weeks. Conclusion: In the HCC group, miR28-5p was differently expressed both at baseline and at the end of therapy with DAAs. This difference in expression should suggest its involvement in HCC development. [ABSTRACT FROM AUTHOR]

Aim: Healthy lifestyle and appropriate diet are of critical importance after liver transplant (LT). We provided an analysis of the main patterns of physical activity and found factors associated with physical activity itself. Methods: Clinically stable LT recipients were enrolled between June and September 2021. Patients completed a composite questionnaire about physical activity, adherence to Mediterranean Diet (MD), quality of life (QoL), and employment. Correlations were analysed using the Pearson coefficients while different subgroups were compared by t-test for independent samples or ANOVAs. Multivariable logistic regression analysis was conducted to find predictors of inactivity. Results: We enrolled 511 subjects (71% males, mean age 63 ± 10.8 years). One hundred and ninety-three patients reported high level of physical activity, 197 a minimal activity and 121 declared insufficient activity. Among these latter, 29 subjects were totally inactive. Considering the 482 LT recipients performing some kind of physical activity, almost all reported a low-quality, non-structured activity. At multivariate analysis, time from LT (odds ratio 0.94, 95% CI 0.89–0.99, p = 0.017), sedentary lifestyle (odds ratio 0.99, 95% CI 0.19–0.81, p = 0.012), low adherence to MD (odds ratio 1.22, 95% CI 1.01–1.48, p = 0.049), and low level of QoL (physical dimension) (odds ratio 1.13, 95% CI 1.08–1.17, p < 0.001), were independently associated with total inactivity. Conclusion: A large portion of LT recipients report an insufficient level of physical activity or are wholly inactive. Inactivity increases with time from LT and was strongly associated with suboptimal diet and low QoL. [ABSTRACT FROM AUTHOR]

Liver transplantation represents a chief therapeutic approach for acute liver failure, end-stage liver disease and hepatocellular carcinoma. Despite witnessing advancements in short- and medium-term survival over recent decades, attributed to refinements in surgical techniques and immunosuppressive protocols, long-term mortality remains impervious to modification. Notably, cardiovascular disease emerges as a predominant cause of mortality among liver transplant recipients. This trend is accentuated by the increasing prominence of non-alcoholic steatohepatitis-related cirrhosis as an indication for liver transplantation. Moreover, the administration of immunosuppressive agents is intricately linked to the degradation of the metabolic profile in liver transplant recipients, thereby contributing to the initiation or exacerbation of cardiovascular risk factors, such as hypertension, diabetes, and dyslipidaemia. In addition, the post-liver transplantation period is marked by a decline in lifestyle quality and a failure to acknowledge the psychological distress experienced by patients throughout the transplant process. These factors can precipitate a deterioration in the patient's metabolic profile, exacerbated by suboptimal therapeutic compliance. This narrative review aims to comprehensively address the principal metabolic disorders intricately associated with liver transplantation. [ABSTRACT FROM AUTHOR]

(1) Background: Despite the advantages of COVID-19 vaccination, rare cases of acute hepatitis developing after the administration of the COVID-19 vaccine or the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have been reported. The aim of the study is to describe a case series of patients who experienced the onset of acute hepatitis, with or without autoimmune features, following SARS-CoV-2 vaccination or infection and to hypothesize a genetic susceptibility in the pathogenesis. (2) Methods: A group of patients with acute onset hepatitis following SARS-CoV-2 vaccination or infection were evaluated in our hepatology outpatient clinic, where they underwent biochemical and autoimmune tests. Hepatitis A (HAV), B (HBV), and C virus (HCV), cytomegalovirus (CMV), Epstein–Barr virus (EBV), and human immunodeficiency virus (HIV) infections were excluded. Patients with a diagnosis of autoimmune hepatitis (AIH) or drug-induced liver injury (DILI) underwent HLA typing and histological testing. (3) Results: Five patients experienced new-onset AIH after COVID-19 vaccination, one of which developed mild symptoms after vaccination that strongly worsened during subsequent SARS-CoV-2 infection. One patient had AIH relapse after COVID-19 vaccination while on maintenance immunosuppressive treatment. All of them had HLA DRB1 alleles known to confer susceptibility to AIH (HLA DRB1*03,*07,*13,*14), and in three of them, HLA DRB1*11 was also detected. Two patients developed acute hepatitis without autoimmune hallmarks which resolved spontaneously, both positive for HLA DRB1*11. (4) Conclusions: An association between AIH and COVID-19 vaccine or infection can be hypothesized in individuals with a genetic predisposition. In patients without autoimmune features and spontaneous improvement of hypertransaminasemia, the diagnosis of drug-induced liver injury (DILI) is probable. Further studies are needed to determine the presence of an actual association and identify a possible role of HLA DRB1*11 in the pathogenesis of acute liver injury after SARS-CoV2 vaccination or infection. [ABSTRACT FROM AUTHOR]

Purpose: From the beginning of the Severe Acute Respiratory Syndrome CoronaVirus-2 (SARS-CoV2) pandemic, different cases of a cholangiopathy with features of secondary sclerosing cholangitis in critically ill patients (SSC-CIP) have been reported. Patients developing it are generally recovering from severe Coronavirus disease 19 (COVID-19) and required intensive care unit (ICU) admission and mechanical ventilation. Many of them have been administered with ketamine during their ICU stay. The pathogenesis of this novel disease is still debated, and, since prognosis is poor, efforts are needed in order to better understand it.Patients and Methods: In this review, we focused our attention on COVID-19 SSC clinical, imaging, and histology findings in order to clarify the different pathogenetic options, particularly in regard of the ischemic-direct viral damage and ketamine-related theories, beginning with a recapitulation of SSC-CIP and ketamine-induced cholangiopathy in abusers. The research has been conducted using PubMed and Google Scholar databases. Key-words were "Secondary Sclerosing Cholangiopathy", "SSC-CIP", "Secondary Sclerosing Cholangiopathy in critically ill patients", "Ketamine and cholangiopathy", "Ketamine abusers and liver disease", "Ketamine-related cholangiopathy", "SARS-CoV2 infection and liver disease", "post Covid-19 secondary sclerosing cholangitis", "Covid-19 cholangiopathy".Results: Many authors, based on the clinical, histological, imaging, and prognostic features of the disease, have pointed out the similarities between post COVID-19 SSC and SSC-CIP; however, peculiar features in the former were not previously observed. Therefore, a direct viral cytopathic action and SARS-CoV2-related coagulopathy are considered the most likely causes. On the other hand, ketamine, with the available data, cannot be surely linked as the main determinant cause of cholangiopathy. Moreover, ketamine-induced cholangitis (KIC) presentation is different from post COVID-19 SSC. Its role as a cofactor precipitating the disease cannot be ruled out.Conclusion: Post COVID-19 SSC is a rare clinical entity following severe COVID-19 disease. The most accepted theory is that a sum of different insults determines the disease: biliary ischemia, direct viral damage, toxic bile, possibly worsened by ketamine and hyperinflammation due to the cytokine storm. Given the severe prognosis of the disease, with persistent cholangiopathy, organ failure, and orthotopic liver transplantation (OLT), further study on this novel clinical entity is needed. [ABSTRACT FROM AUTHOR]

Hepatitis A and hepatitis E are relatively common causes of liver disease. Both viruses are mainly transmitted through the faecal–oral route and, consequently, most outbreaks occur in countries with poor sanitation. An important role of the immune response as the driver of liver injury is also shared by the two pathogens. For both the hepatitis A (HAV) and hepatitis E (HEV) viruses, the clinical manifestations of infection mainly consist of an acute disease with mild liver injury, which results in clinical and laboratory alterations that are self-limiting in most cases. However, severe acute disease or chronic, long-lasting manifestations may occur in vulnerable patients, such as pregnant women, immunocompromised individuals or those with pre-existing liver disease. Specifically, HAV infection rarely results in fulminant hepatitis, prolonged cholestasis, relapsing hepatitis and possibly autoimmune hepatitis triggered by the viral infection. Less common manifestations of HEV include extrahepatic disease, acute liver failure and chronic HEV infection with persistent viraemia. In this paper, we conduct a non-systematic review of the available literature to provide a comprehensive understanding of the state of the art. Treatment mainly consists of supportive measures, while the available evidence for aetiological treatment and additional agents in severe disease is limited in quantity and quality. However, several therapeutic approaches have been attempted: for HAV infection, corticosteroid therapy has shown outcome improvement, and molecules, such as AZD 1480, zinc chloride and heme oxygenase-1, have demonstrated a reduction in viral replication in vitro. As for HEV infection, therapeutic options mainly rely on the use of ribavirin, and some studies utilising pegylated interferon-alpha have shown conflicting results. While a vaccine for HAV is already available and has led to a significant reduction in the prevalence of the disease, several vaccines for HEV are currently being developed, with some already available in China, showing promising results. [ABSTRACT FROM AUTHOR]

Background/Aims Bulevirtide (BLV) is an entry inhibitor for chronic hepatitis delta (CHD). In an ongoing Phase 3 study, BLV 2- or 10-mg monotherapy was effective and safe at 96 weeks (W). Here, we present 144W results. Methods 150 patients were randomised: Arm A (delayed treatment), observed for 48W followed by BLV 10 mg/d for 96W (n=51); Arm B, BLV 2 mg/d for 144W (n=49); Arm C, BLV 10 mg/d for 144W (n=50). Efficacy endpoints included virologic response (VR; undetectable HDV RNA or ≥2 log10 decline from baseline [BL]), alanine aminotransferase (ALT) normalisation, combined response (CR; VR+ALT normalisation), and undetectable HDV RNA (target not detected). Univariate logistic regression determined baseline predictors of undetectable HDV RNA at 144W for patients in Arms B/C who completed 144W and had BL HDV RNA ≥250 IU/mL. Predictors with p<.05 were significant. Results At 144W, 49/51, 45/49, and 44/50 patients in Arms A, B, and C remained in study. Arms B and C had similar rates of CR, VR, and ALT normalisation at 144W (Figure 1). Undetectable HDV RNA rates were 29% in Arm B and 50% in Arm C at 144W. Mean (SD) change from BL to 144W in hepatitis B surface antigen (HBsAg) was −0.36 (0.596) and − 0.19 (0.39) with BLV 2 and 10 mg. BL predictors of 144W undetectable HDV RNA included lower HDV RNA and lower HBsAg (Figure 2). There was no progression to liver-related outcomes over 144W except for 1 case of mild ascites in a patient with BL cirrhosis; there were no drug discontinuations, serious adverse events, or deaths attributed to BLV. Conclusion Long-term BLV remained safe and effective. Improvements in virologic and biochemical markers support the clinical benefits of long-term BLV therapy. [ABSTRACT FROM AUTHOR]

The hepatitis B virus (HBV) infection leads to chronic hepatitis, cirrhosis, and hepatocarcinoma. However, about 20% of patients experience extrahepatic manifestations such as polyarteritis nodosa, non-rheumatoid arthritis, non-Hodgkin lymphoma, cryoglobulinemic vasculitis, and glomerulonephritis. These influence the patient's morbidity, quality of life and mortality. The treatment of an HBV infection is based on nucleotide analogues (NAs) which are safe and effective for the suppression of HBV-DNA in almost 100% of cases. A few studies have shown that NAs induce a viral response and an improvement of extrahepatic diseases. There is a lack of a thorough analysis of the available treatments for extrahepatic HBV manifestations. In 90% to 100% of cases, the NAs stop the HBV replication, and they produce a clinical response in the majority of patients with mild to moderate extrahepatic signs/symptoms. Arthritis can definitely disappear after the HBV elimination and, in some cases, the HBV eradication following NAs therapy appears to improve the renal function in HBV-related nephropathies. Plasma exchange can be used in subjects who are suffering from the most aggressive forms of cryoglobulinemic vasculitis and glomerulonephritis, progressive peripheral neuropathy, and life-threatening cases, and this can be combined with glucocorticosteroids and antiviral agents. In selected refractory patients, the use of rituximab in conjunction with NAs therapy can be considered. The review provides an update on extrahepatic conditions that are linked to HBV and the impact of treating HBV with NAs. [ABSTRACT FROM AUTHOR]

More than 250 million people worldwide are currently infected with hepatitis B, despite the effectiveness of vaccination and other preventive measures. In terms of treatment, new therapeutic approaches are rapidly developing, promising to achieve the elimination of infected cells and the complete cure of infection. The on-treatment monitoring of these innovative antiviral treatments will require the implementation of new virological tools. Therefore, new biomarkers are being evaluated besides the traditional virological and serological assays in order to obtain information on different steps of the viral replication cycle and to monitor response to therapy more accurately. The purpose of this work is to describe both standard and innovative tools for chronic hepatitis B treatment monitoring, and to analyse their potential and feasibility. [ABSTRACT FROM AUTHOR]

Introduction and objectives: De novo malignancies represent an important cause of death for liver transplant recipients. Our aim was to analyze predictors of extra-hepatic non-skin cancer (ESNSC) and the impact of ESNSC on the long-term outcome. Patients: We examined data from patients transplanted between 2000 and 2005 and followed-up in five Italian transplant clinics with a retrospective observational cohort study. Cox Regression was performed to identify predictors of ESNSC. A 1:2 cohort sub-study was developed to analyze the impact of ESNSC on 10-year survival. Results: We analyzed data from 367 subjects (median follow-up: 15 years). Patients with ESNSC (n = 47) more often developed post-LT diabetes mellitus (DM) (57.4% versus 35,9%, p = 0.004). At multivariate analysis, post-LT DM independently predicted ESNSC (HR 1.929, CI 1.029-3.616, p = 0.040). Recipients with ESNSC showed a lower 10-year survival than matched controls (46,8% versus 68,1%, p = 0.023). Conclusions: Post-LT DM seems to be a relevant risk factor for post-LT ESNSC. ESNSC could have a noteworthy impact on the long-term survival of LT recipients. [ABSTRACT FROM AUTHOR]

Several studies have suggested that hepatitis C virus (HCV) may be the causative agent of some B‐cell non‐Hodgkin lymphomas (B‐NHL). Several authors have demonstrated that pegylated interferon (Peg‐IFN) plus ribavirin (RBV) can revert indolent low‐grade B‐NHL by inducing HCV eradication. Presently, the combination therapy (IFN plus RBV) has been abandoned since the direct antiviral agents (DAAs) have shown very high efficacy in achieving sustained virologic response (SVR) (range: 95%–100%). This review analyzed DAAs efficacy in HCV‐associated indolent low‐grade NHL, providing a detailed literature review. Overall, 122 B‐cell NHL patients were treated with DAAs: complete/partial hematological response, particularly in those with marginal zone lymphoma, was obtained in most cases. Hematological response, obtained either with DAAs or IFN‐based therapy, was similar. Nonetheless, DAAs therapy showed better tolerability and higher SVR. A fraction of the patients, despite SVR, underwent hematologic relapse or progression. In these cases, a recovery treatment with immunotherapy, or chemoimmunotherapy, had to be planned. In conclusion, data obtained from published studies mostly agree that HCV eradication with DAAs should be considered as the first‐line treatment in HCV‐related NHL. In fact, the chronic viral stimulation of the immune system might be the primary pathogenic mechanism in disease development and progression. [ABSTRACT FROM AUTHOR]

Background and Aims: Gaucher disease (GD) is associated with peculiar metabolic abnormalities (ie hypermetabolic state, peripheral insulin resistance, dyslipidaemia), partially reverted by enzyme replacement therapy (ERT) at the expense of weight gain. Such metabolic alterations together with an unhealthy lifestyle acquired by an ageing GD population may favour the development of liver steatosis. We aimed at evaluating the prevalence of significant liver steatosis and at identifying the factors associated with liver steatosis in a cohort of patients with type 1 GD. Methods: Twenty adult type 1 GD patients from an Italian academic referral centre were prospectively submitted to vibration‐controlled transient elastography (Fibroscan®) with controlled attenuation parameter (CAP); significant steatosis was defined as CAP values ≥250 dB/min. Results: Median CAP values were 234 [165‐358] dB/min and 8 patients (40%) had significant steatosis. Significant steatosis was associated with indices of adiposity (weight, BMI and waist circumference), high blood pressure, insulin resistance and metabolic syndrome. GD‐related variables and dose and duration of ERT were not associated with significant steatosis. In the subgroup of 16 patients on stable ERT for at least 24 months, CAP resulted significantly and positively associated with liver stiffness (rho 0.559, P =.024). Conclusions: Significant steatosis is highly prevalent in adult type 1 GD patients and is strongly associated with a worse metabolic profile, featuring metabolic dysfunction‐associated fatty liver disease (MAFLD). MAFLD may determine liver fibrosis progression in GD patients on stable ERT and may be a risk factor for long‐term liver‐related complications. [ABSTRACT FROM AUTHOR]

Introduction: In primary biliary cholangitis (PBC), macrophages are involved in liver inflammation and fibrosis. The macrophage activation markers, soluble (s)CD163 and mannose receptor (sMR) are associated with liver disease severity and prognosis in other chronic liver diseases. We aimed to investigate sCD163 and sMR in patients with PBC. Methods: We investigated PBC patients from the Italian PBC Study Group cohort and measured macrophage activation markers in serum at study enrolment. Patients were followed from enrolment until they experienced an event or were censored at their last visit. Events were defined as follows: (a) death from a liver‐related cause; or (b) liver transplantation (LT) for PBC. We used Cox regression to investigate the association between sCD163 and sMR and long‐term prognosis. Results: In total, 202 PBC patients were included. Median age was 62 years (interquartile range (IQR), 53‐71) at enrolment and 93% were women. Median sCD163 was 3.43 mg/L (IQR 2.48‐5.35) and median sMR was 0.35 mg/L (IQR 0.28‐0.45). There was an increase in sCD163 and sMR with increasing alkaline phosphatase. Two hundred and one patients were followed for a median of 8.6 years, and sCD163 and sMR predicted long‐term risk of liver‐related death or LT in univariate analyses, while sCD163 was also associated with outcome after confounder adjusting (adjusted HR = 1.14, 95% CI 1.00‐1.30). Finally, we showed an increase in the prediction accuracy of poor outcome by adding sCD163 to the UK‐PBC risk score. Conclusion: The macrophage activation markers sCD163 and sMR represent a non‐invasive measure of PBC disease severity that provides useful long‐term prognostic information. [ABSTRACT FROM AUTHOR]

Background & Aims: Several non‐invasive tests (NITs) have been developed to diagnose oesophageal varices (EV), including the recent Baveno VI criteria to rule out high‐risk varices (HRV). Spleen stiffness measurement (SSM) with the standard FibroScan® (SSM@50Hz) has been evaluated. However, the EV grading could be underestimated because of a ceiling threshold (75 kPa) of the SSM@50Hz. The aims were to evaluate SSM by a novel spleen‐dedicated FibroScan® (SSM@100Hz) for EV diagnosis compared with SSM@50Hz, other validated NITs and Baveno VI criteria. Methods: This prospective multicentre study consecutively enrolled patients with chronic liver disease; blood data, endoscopy, liver stiffness measurement (LSM), SSM@50Hz and SSM@100Hz were collected. Results: Two hundred and sixty patients met inclusion criteria. SSM@100Hz success rate was significantly higher than that of SSM@50Hz (92.5% vs 76.0%, P <.001). SSM@100Hz accuracy for the presence of EV (AUC = 0.728) and HRV (AUC = 0.756) was higher than in other NITs. SSM@100Hz AUC for large EV (0.782) was higher than SSM@50Hz (0.720, P =.027). AUC for HRV with SSM@100Hz (0.780) was higher than with LSM (0.615, P <.001). The spared endoscopy rate of Baveno VI criteria (8.1%) was significantly increased by the combination to SSM@50Hz (26.5%) or SSM@100Hz (38.9%, P <.001 vs others). The missed HRV rate was, respectively, 0% and 4.7% for combinations. Conclusions: SSM@100Hz is a new performant non‐invasive marker for EV and HRV providing a higher accuracy than SSM@50Hz and other NITs. The combination of Baveno VI criteria and SSM@100Hz significantly increased the spared endoscopy rate compared to Baveno VI criteria alone or combined with SSM@50Hz. Clinical trial number: NCT02180113. [ABSTRACT FROM AUTHOR]

Liver transplant candidates and recipients are at high risk of psychological distress. Social, psychological and psychiatric patterns seem to influence morbidity and mortality of patients before and after transplant. An accurate organ allocation is mandatory to guarantee an optimal graft and recipient survival. In this context, the pre-transplant social, psychological and psychiatric selection of potential candidates is essential for excluding major psychiatric illness and for estimating the patient compliance. Depression is one of the most studied psychological conditions in the field of organ transplantation. Notably, an ineffectively treated depression in the pre-transplant period has been associated to a worst longterm recipient survival. After transplant, personalized psychological intervention might favor recovery process, improvement of quality of life and immunosuppressant adherence. Active coping strategy represents one of the most encouraging ways to positively influence the clinical course of transplanted patients. In conclusion, multidisciplinary team should act in three directions: prevention of mood distress, early diagnosis and effective treatment. Active coping, social support and multidisciplinary approach might improve the clinical outcome of transplanted patients. [ABSTRACT FROM AUTHOR]

Summary: The discrimination between active chronic hepatitis B (CHB) and the clinically quiescent infection (CIB) is not always easy, as a significant portion of patients falls in a "grey" zone. Hepatitis B core‐related antigen (HBcrAg) is a now quantifiable serological marker with potential applications in diagnosis and therapy monitoring. The aim of the present study was to evaluate the HBcrAg serum levels in HBeAg‐negative HBV infection, and its ability in identifying the clinical profile, in comparison with HBsAg serum levels. HBcrAg was retrospectively assessed on serum samples from a population of treatment‐naive HBeAg‐negative patients by ChemiLuminescent Enzyme Immunoassay (CLEIA). HBsAg and HBV‐DNA data were collected. Serological data were associated to clinical profile, defined in the subsequent follow‐up of at least 1 year. In the overall population of 160 HBeAg‐negative patients, HBcrAg results weakly correlated with qHBsAg levels (Spearman r = 0.471, P < 0.0001) and correlated closely with HBV‐DNA (Spearman r = 0.746, P < 0.0001). HBcrAg levels were significantly higher in 85 CHB patients relative to 75 CIB carriers. A value of 2.5 logU/mL produced the optimal cut‐off to identify CIB patients, with diagnostic accuracy comparable to HBsAg levels. In long‐term clinical evaluation, a single measurement of HBcrAg at the established cut‐off was optimally consistent with clinical outcome. Conversely, the HBsAg cut‐off performed well in the true quiescent phase and less in more difficult‐to‐categorize patients. In conclusion, single‐point use of HBcrAg serum levels provides an accurate identification of CIB and represents a useful tool for patient classification. [ABSTRACT FROM AUTHOR]

Background and Aims: Tenofovir disoproxil fumarate (TDF) is recommended for chronic hepatitis B (CHB) treatment, but it may induce kidney dysfunction whose management is not yet known. This Italian, multicentre, retrospective study aimed to assess the efficacy and safety of switching to entecavir (ETV) patients who developed TDF‐associated glomerular and/or tubular dysfunction. Methods: A total of 103 TDF‐treated patients were included as follows: age 64 years, 83% male, 49% cirrhotics, 98% with undetectable HBV DNA, 47% with previous lamivudine resistance (LMV‐R) and 71% previously treated with adefovir. Twenty‐nine (28%) were switched to ETV because estimated glomerular filtration rate (eGFRMDRD) was <60 mL/min, 37 (36%) because blood phosphate (P) levels were <2.5 mg/dL and 37 (36%) for both reasons. Kidney, liver and virological parameters were recorded every 4 months thereafter. Results: During 46 (4‐115) months of ETV treatment, all patients' renal parameters significantly improved as follows: creatinine from 1.30 to 1.10 mg/dL (P < 0.0001), eGFRMDRD from 54 to 65 mL/min (P = 0.002), P from 2.2 to 2.6 mg/dL (P < 0.0001) and maximal tubule phosphate reabsorption (TmPO4/eGFR) from 0.47 to 0.62 mmol/L (P < 0.0001). Thirteen patients (52%) improved their eGFRMDRD class, P levels were normalised in 13 (35%), and eight (22%) showed improvements in both parameters. Viral suppression was maintained in all but five patients (5%), all of whom had been LMV‐R. The 5‐year cumulative probability of ETV‐R was 0% in LMV‐naïve patients, and 11% in LMV‐R patients (P = 0.018). Conclusions: Entecavir is an effective and safe rescue strategy for CHB patients who develop renal dysfunction during long‐term TDF treatment. [ABSTRACT FROM AUTHOR]

Introduction: In the last years, nonalcoholic steatohepatitis (NASH) has become a leading indication for liver transplant (LT). After transplant, both recurrent and de novo nonalcoholic fatty liver disease (NAFLD) can be commonly diagnosed. However, dedicated surveillance programs for patients with pre- or post-transplant NAFLD are not available. Areas covered: Patients waiting for LT for NASH show specific peculiarities and would deserve targeted stratification of mortality risk. Obesity, hyperlipidemia, and diabetes mellitus can be often found after transplant. These conditions, together with immunosuppressive regimen, make LT recipients a high-risk population for both recurrent and de novo NAFLD. Development of fatty liver disease after LT has a relevant impact on both morbidity and mortality. Expert commentary: A targeted stratification of neoplastic and cardiovascular risk for patients with NASH waiting for LT would be mandatory. In both pre- and post-transplant period, NAFLD should be considered not only a liver disease but also a cardiovascular risk factor. Patients within Transplant Program, especially those with known metabolic risk factors, should be followed with personalized diagnostic and life-style interventions before and after LT. [ABSTRACT FROM AUTHOR]

Introduction: Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Treatment of chronic hepatitis C has considerably improved in the last few years thanks to the introduction of direct-acting antivirals able to achieve sustained virological response in more than 95% of patients. Successful anti-HCV treatment can halt liver disease progression and solve the HCV-related extra-hepatic manifestations, eventually reducing liver-related and overall mortality. Areas covered: With the aim to respond to unmet needs in patient's identification, universal access to antiviral therapy and treatment optimization in specific setting of HCV-infected patients, a group of Italian experts met in Stresa in May 2018. The summary of the considerations arising from this meeting and the final statements are reported in this paper. Expert commentary: All the advances on HCV cure may have a real clinical impact not only in individual patients but also at the social health level if they are applied to all infected patients, independently from the stage of liver disease. Further improvements are needed in order to attain HCV elimination, such as the development of an enhanced screening program working in parallel to the present treatment options. [ABSTRACT FROM AUTHOR]

Introduction: Direct acting antivirals have completely changed the landscape of the treatment of chronic hepatitis C. The management of the few patients who relapse to direct acting antivirals requires a careful analysis of the chances to achieve therapeutic success with a second antiviral course. In this context, the usefulness of viral resistances testing, able to detect resistance-associated substitutions in the viral sequence, is at present a matter of debate. Areas covered: The role of resistance associated substitutions is examined through the evaluation of the data from clinical trials that have assessed the impact of viral resistances on the treatment outcome. Special attention has been paid on the data from re-treatment studies. Expert commentary: The treatment failure in chronic hepatitis C is still a possible event. Therefore, additional real-world clinical data on relapse rates and on the relapse management are welcome to definitely address the clinical guidelines. At present, the testing of viral resistances is an exquisite tool for the choice of the re-treatment schedule. In the near future, widespread use of the most recently registered direct acting antivirals with high barrier to resistance will probably weaken the need of resistance testing as a support in clinical decisions. [ABSTRACT FROM AUTHOR]

Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4.Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here.Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces.Results: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B 1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244-27.060, p = 0.025).Conclusions: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching. [ABSTRACT FROM AUTHOR]

Chronic HCV infection continues to be an important concern of public health, with still a high mortality from HCV-related disease. The landscape of chronic HCV infection has been dramatically changed by the introduction of the new antiviral agents, able to cure the infection in the large majority of patients. The laboratory management of HCV infection relies on serological and molecular tests, which have undergone significant technological advancements, able to ameliorate the performance both in diagnosis of infection and in the treatment monitoring. This article describes the main laboratory tools in the chronic HCV infection, with particular emphasis on the recent changes coming along with the new therapeutic approaches. [ABSTRACT FROM AUTHOR]

In recent years, metabolomics has attracted great scientific attention. The metabolomics methodology might permit a view into transitional phases between healthy liver and nonalcoholic steatohepatitis. Metabolomics can help to analyze the metabolic alterations that play a main role in the progression of nonalcoholic steatohepatitis. Lipid, glucose, amino acid, and bile acid metabolism should be widely studied to understand the complex pathogenesis of nonalcoholic steatohepatitis. The discovery of new biomarkers would be important for diagnosis and staging of liver disease as well as for the assessment of efficacy of new drugs. Here, we review the metabolomics data regarding nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. We analyzed the main studies regarding the application of metabolomics methodology in the complex context of nonalcoholic steatohepatitis, trying to create a bridge from the basic to the clinical aspects. [ABSTRACT FROM AUTHOR]

Introduction: Farnesoid X nuclear receptor is involved in the regulation of lipid and glucose metabolism, though mainly in the homeostasis of bile acids. Indeed, the agonists of farnesoid X nuclear receptor represent promising drugs. Areas covered: Obeticholic acid, a novel semisynthetic analogue of the naturally occurring bile acid, has led to encouraging preliminary results in both cholestatic and metabolic liver disease. In patients with primary biliary cholangitis, obeticholic acid determines a significant biochemical improvement although the effects on liver fibrosis are lacking. Obeticholic acid has been suggested for the treatment of nonalcoholic liver disease with good laboratory results. In cirrhotic animal models, the drug seems to reduce both portal hypertension and gut bacterial translocation. Expert commentary: The use of obeticholic acid for the treatment of primary biliary cholangitis shows satisfying results. However, some open questions remain unresolved. Herein, we provide an overview of the current knowledge about the use of obeticholic acid in the field of nonviral chronic liver diseases. We tried to give a global point of view using a translational approach. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate imaging features of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) developed after direct-acting antiviral (DAA) therapy in HCV-related cirrhosis.Methods: Retrospective cohort study on 344 consecutive patients with HCV-related cirrhosis treated with DAA and followed for 48-74 weeks. Using established imaging criteria for MVI, HCC features were analysed and compared with those in nodules not occurring after DAA.Results: After DAA, HCC developed in 29 patients (single nodule, 18 and multinodular, 11). Median interval between therapy end and HCC diagnosis was 82 days (0-318). Forty-one HCC nodules were detected (14 de novo, 27 recurrent): maximum diameter was 10-20 mm in 27, 20-50 mm in 13, and > 50 mm in 1. Imaging features of MVI were present in 29/41 nodules (70.7%, CI: 54-84), even in 17/29 nodules with 10-20 mm diameter (58.6%, CI: 39-76). MVI was present in only 17/51 HCC nodules that occurred before DAA treatment (33.3%, CI: 22-47) (p= 0.0007). MVI did not correlate with history of previous HCC.Conclusions: HCC occurs rapidly after DAA therapy, and aggressive features of MVI characterise most neoplastic nodules. Close imaging evaluations are needed after DAA in cirrhotic patients.Key Points: • In HCV cirrhosis, hepatocellular carcinoma develops soon after direct-acting antiviral therapy. • HCC presents imaging features of microvascular invasion, predictive of more aggressive progression. • Cirrhotic patients need aggressive and close monitoring after direct-acting antiviral therapy. [ABSTRACT FROM AUTHOR]

Introduction. Host lipid metabolism influences viral replication and lifecycle of hepatitis C virus. Our aim was to evaluate changes in glucose and lipid metabolism of patients with chronic hepatitis C after therapy with direct acting antivirals (DAA). Material and methods. We considered patients consecutively treated between January and November 2015 recording clinical data at baseline and week 24 of follow-up. Frozen serum samples were used for apolipoprotein A1 (apoA1), apolipoprotein B (apoB) and lipoprotein (a) [Lp(a)]. Wilcoxon test was utilized to estimate trends and Logistic Regression for predictors of lipid changes. Results. We enrolled 100 patients, mostly cirrhotic (81%) and with genotype 1b (59%). Ninety-three patients achieved sustained virological response (SVR), while 7 relapsed. Homeostasis model assessment of insulin resistance declined (from 3 to 2.7, p < 0.001); non-high density lipoprotein (HDL) cholesterol increased from 102 ± 29 to 116 ± 35 (p < 0.001), and Lp(a) from 5.6 ± 6.5 to 9.8 ± 11.5 mg/dL (p < 0.001). Rise of low-density lipoprotein/HDL and apoB/apoA1 ratio were registered (from 1.79 ± 1.10 to 2.08 ± 1.05 and from 0.48 ± 0.18 to 0.53 ± 0.18 mg/dL, p < 0.001). We conducted a subanalysis on patients with relapse. In this subgroup, no change of lipid profile was recorded. At multivariate analysis emerged that the addition of ribavirin to DAA, represented an independent predictor of increased Lp(a) (OR 3.982, 95% CI 1.206-13.144, p = 0.023). Conclusion. DAA therapy led to reduction of insulin resistance. In contrast, pro-atherogenic lipid changes were observed in patients with SVR. Further studies will be necessary to evaluate the cardiovascular balance between amelioration of glucose metabolism and negative changes of lipid profile. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the potential value of using a serological assay to quantitate the hepatitis C virus core antigen (HCV-Ag) when monitoring patients with chronic hepatitis C being treated with direct-acting antivirals (DAAs). Methods: Ninety-six patients treated with DAAs, either alone (91) or in combination with PEG interferon (5), were tested for HCV-RNA and for HCV-Ag at baseline and at weeks 2, 4, 8 and 12 during treatment and 12 weeks after completion. The concordance and correlation between the viral parameters as well as the respective kinetics during and after treatment were evaluated. Results: A sustained viral response (SVR) was achieved in 82 patients (91%), whereas 11 relapsed (R) and 1 showed a virological breakthrough while receiving treatment. HCV-RNA and HCV-Ag showed good concordance (kappa = 0.62) and correlation. No significant differences between SVR and R was observed in either assay at 2 and 4 weeks after the start of treatment. At 8 weeks, HCV-Ag showed higher accuracy than HCV-RNA (AUC: 0.74 vs. 0.55) and there was a significantly greater decrease from baseline in SVR than in R (4.01 vs. 3.36 log10; p<0.05). Conclusions: Monitoring during treatment with DAAs by using either HCV-RNA or HCV-Ag has only a limited predictive value for SVR. Since those assays are equivalent for identifying a virological relapse, HCV-Ag may be preferred from an economical and organizational perspective. [ABSTRACT FROM AUTHOR]

Introduction: Hepatitis C negatively changes patient quality of life even in the absence of advanced liver disease. The specific patterns of quality of life of hepatitis C positive patients waiting for transplant or after surgery are not widely studied. Areas covered: A significant percentage of infected patients show cognitive impairment, fatigue, and/or a ‘brain fog’, that cannot be explained by the liver disease. Depression can be diagnosed in one third of hepatitis C positive patients. Conflicting data are available regarding the possible role of Model for End-Stage Liver Disease score as predictor of impaired quality of life. In the first period after liver transplant, quality of life tends to increase at the pre-transplant period but in the medium and long-term period, it declines. The recurrence of hepatitis C infection represents a strong predictor of morbidity and mortality and can significantly affect the global quality of life of patients. Expert commentary: Hepatologists, surgeons and psychologists should collaborate to support infected patients in all phases of transplant including the long-term period after surgery. Education and information should be implemented especially regarding the positive role of new direct antivirals. [ABSTRACT FROM PUBLISHER]

Background Recurrent hepatitis C virus ( HCV) infection following liver transplantation is associated with accelerated progression to graft failure and reduced patient survival. Methods The Phase II, open-label SATURN study ( NCT01938625) investigated the combination of simeprevir ( SMV), daclatasvir ( DCV), and ribavirin ( RBV) administered for 24 weeks in 35 patients with recurrent HCV genotype ( GT) 1b infection after orthotopic liver transplantation ( OLT). Results High rates of both on-treatment and sustained virologic response 12 weeks after end of treatment ( SVR12) were achieved in patients who were either treatment-naïve or had failed post- OLT treatment with peginterferon and RBV. Overall, 91% of patients (32/35) achieved SVR12. The combination was generally well tolerated, with an adverse event profile consistent with that observed in previous clinical trials of SMV or DCV separately. Co-administration of SMV with cyclosporine resulted in significantly increased SMV plasma exposures, which was not the case with the co-administration of SMV with tacrolimus. Therefore, the concomitant use of SMV with cyclosporine is not recommended. Conclusion The interferon-free combination of SMV, DCV, and RBV administered for 24 weeks was shown to be effective and well tolerated in the treatment of post- OLT HCV GT1b-infected patients. [ABSTRACT FROM AUTHOR]

Today, we are witnessing a new era for the treatment of hepatitis C with excellent rates of virologic response and very good safety profiles. Among the many classes of direct-acting antivirals, the inhibitors of nonstructural protein 5A are particularly interesting. NS5A is a phosphorylated protein with a relevant role in viral replication. HCV- NS5A inhibitors show high potency, very good safety profile and high barrier to resistance. The amazing in vitro effectiveness of this class is associated with great efficacy in clinical trials in combination protocols with antivirals of other classes, with sustained virological response ( SVR) obtained in more than 90% of patients. Herein, we sought to review the current knowledge regarding the NS5A protease complex inhibitors with special emphasis on clinical efficacy and development of viral resistance. [ABSTRACT FROM AUTHOR]

Background & Aims Elastography point quantification is a novel non-invasive method for the assessment of liver fibrosis by measuring liver stiffness. The aim of this study was to evaluate the accuracy of elastography point quantification for the diagnosis of liver fibrosis and to assess impact of steatosis on liver stiffness measurement, in a cohort of patients with chronic hepatitis C. Methods In this single-centre cross-sectional study, 211 consecutive patients with chronic hepatitis C, scheduled for liver biopsy, were examined with the elastography point quantification technology. On the same day, all patients underwent clinical examination, laboratory tests and abdominal ultrasound. Results The best cut-offs of liver stiffness measurement were 6.16 kPa for the diagnosis of significant fibrosis (≥S3) and 6.79 kPa for advanced fibrosis (≥S4). Areas under the receiver operating characteristic curve were 0.831 (CI: 0.773-0.880) for significant fibrosis, and 0.954 (CI: 0.916-0.978) for advanced fibrosis. Among patients within the same fibrosis stages (S0-S2 and S3-S6; S0-S3 and S4-S6), mean liver stiffness measurement values were similar in patients with steatosis (≥10% at liver biopsy or detected by ultrasound) compared to those without. Discordance between elastography point quantification and histology were affected by the presence of BMI>30 kg/m2 ( P=.047, CI: 0.136-0.988 and P=.020, CI: 0.083-0.812 respectively). Conclusions In patients with chronic hepatitis C, elastography point quantification is an accurate non-invasive method for the diagnosis of significant and advanced fibrosis. The presence of obesity is a risk factor for misclassification of significant and advanced liver fibrosis. [ABSTRACT FROM AUTHOR]

Background & Aims The treatment of chronic hepatitis B infection ( CHB) in children is still an area of great uncertainty. Vitamin E is an immunostimulating/antioxidant compound proven to be safe and effective for the treatment of adult CHB. The aim of this phase 2 controlled study was to evaluate the safety and efficacy of vitamin E for the treatment of paediatric HBeAg-positive CHB. Methods Forty-six children were randomized in a 1:1 ratio to receive vitamin E at a dose of 15 mg/kg/day (in galenic preparation) or no treatment for 12 months and were monitored for the subsequent 12 months. Clinical, biochemical, haematological and serovirological evaluations were carried out every 3 months. Results No significant side effects were associated with the vitamin E treatment. At the end of the study, anti- HBe seroconversion was obtained in 7 of 23 (30.4%) of vitamin E-treated versus 1 of 23 (4.3%) of the control patients ( P = 0.05), while a virological response (≥2 log decrease in HBV- DNA from baseline) was observed in 9 of 23 (39.1%) vs. 2 of 23 (8.7%) respectively ( P = 0.035). Conclusions Vitamin E administration for the treatment of paediatric CHB at the tested dosage has no significant side effects and may induce anti- HBe seroconversion. Vitamin E could represent a tool for the treatment of paediatric CHB. [ABSTRACT FROM AUTHOR]