The first MASH drug therapy on the horizon: Current perspectives of resmetirom.

The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) poses a significant global health challenge, affecting over 30% of adults worldwide. MASLD is linked to increased mortality rates and substantial healthcare costs, primarily driven by its progression to metabolic dysfunction-associated steatohepatitis (MASH), which can lead to severe liver complications including cirrhosis and hepatocellular carcinoma. Despite its growing burden, effective pharmacotherapy for MASLD/MASH has been lacking until the recent conditional approval of resmetirom by the FDA. Resmetirom, a liver-targeted thyroid hormone receptor-ß selective drug, has shown promise in clinical trials for treating non-cirrhotic MASH with moderate to advanced fibrosis. It has demonstrated efficacy in reducing hepatic fat content, improving liver histology (both MASH resolution and fibrosis improvement), and ameliorating biomarkers of liver damage without significant effects on body weight or glucose metabolism. Notably, resmetirom also exhibits favourable effects on circulating lipids, potentially reducing cardiovascular risk in MASLD/MASH patients. The safety profile of resmetirom appears acceptable, with gastrointestinal adverse events being the most common, though generally mild or moderate. However, long-term surveillance is warranted to monitor for potential risks related to thyroid, gonadal, or bone diseases. Clinical implementation of resmetirom faces challenges in patient selection and monitoring treatment response, and will heavily rely on non-invasive tests for liver fibrosis assessment. Nonetheless, resmetirom represents a landmark breakthrough in MASLD/MASH treatment, paving the way for future therapeutic strategies aiming to mitigate the multifaceted risks associated with this complex metabolic liver disease.

Risk of hepatitis B virus reactivation in oncological patients treated with tyrosine kinase inhibitors: A case report and literature analysis.

Hepatitis B virus (HBV) reactivation (HBVr) represents a severe and potentially life-threatening condition, and preventive measures are available through blood test screening or prophylactic therapy administration. The assessment of HBVr traditionally considers factors such as HBV profile, including hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen, along with type of medication (chemotherapy; immunomodulants). Nevertheless, consideration of possible patient's underlying tumor and the specific malignancy type (solid or hematologic) plays a crucial role and needs to be assessed for decision-making process.

Accuracy, Reliability, and Comprehensibility of ChatGPT-Generated Medical Responses for Patients With Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is an increasing global health problem and is expected to become the leading indication for liver transplantation.1 There are no approved NAFLD-specific pharmacotherapies, and lifestyle modification is the primary recommended therapy.2 Innovative approaches to facilitate the implementation and long-term maintenance of lifestyle changes are needed to address the challenging and complex nature of the management of NAFLD, which recently was renamed as metabolic dysfunction-associated steatotic liver disease, to overcome the limitations and stigma of the previous name.3,4 Artificial intelligence (AI)-powered chatbots have been shown to provide effective personalized support and education to patients, with the potential to complement health care resources. The OpenAI Foundation's AI chatbot, Chat Generative Pretrained Transformer (ChatGPT), has attracted worldwide attention for its remarkable performance in question-answer tasks.5-7 This study evaluated the accuracy, completeness, and comprehensiveness of chatGPT's responses to NAFLD-related questions, with the aim of assessing its performance in addressing patients' queries about the disease and lifestyle behaviors.

Incidence and predictors of hepatocellular carcinoma in patients with autoimmune hepatitis.

BACKGROUND AND AIMS: Autoimmune hepatitis (AIH) is a rare chronic liver disease of unknown aetiology; the risk of hepatocellular carcinoma (HCC) remains unclear and risk factors are not well-defined. We aimed to investigate the risk of HCC across a multicentre AIH cohort and to identify predictive factors. METHODS: We performed a retrospective, observational, multicentric study of patients included in the International Autoimmune Hepatitis Group Retrospective Registry. The assessed clinical outcomes were HCC development, liver transplantation, and death. Fine and Gray regression analysis stratified by centre was applied to determine the effects of individual covariates; the cumulative incidence of HCC was estimated using the competing risk method with death as a competing risk. RESULTS: A total of 1,428 patients diagnosed with AIH from 1980 to 2020 from 22 eligible centres across Europe and Canada were included, with a median follow-up of 11.1 years (interquartile range 5.2-15.9). Two hundred and ninety-three (20.5%) patients had cirrhosis at diagnosis. During follow-up, 24 patients developed HCC (1.7%), an incidence rate of 1.44 cases/1,000 patient-years; the cumulative incidence of HCC increased over time (0.6% at 5 years, 0.9% at 10 years, 2.7% at 20 years, and 6.6% at 30 years of follow-up). Patients who developed cirrhosis during follow-up had a significantly higher incidence of HCC. The cumulative incidence of HCC was 2.6%, 4.6%, 5.6% and 6.6% at 5, 10, 15, and 20 years after the development of cirrhosis, respectively. Obesity (hazard ratio [HR] 2.94, p = 0.04), cirrhosis (HR 3.17, p = 0.01), and AIH/PSC variant syndrome (HR 5.18, p = 0.007) at baseline were independent risk factors for HCC development. CONCLUSIONS: HCC incidence in AIH is low even after cirrhosis development and is associated with risk factors including obesity, cirrhosis, and AIH/PSC variant syndrome. IMPACT AND IMPLICATIONS: The risk of developing hepatocellular carcinoma (HCC) in individuals with autoimmune hepatitis (AIH) seems to be lower than for other aetiologies of chronic liver disease. Yet, solid data for this specific patient group remain elusive, given that most of the existing evidence comes from small, single-centre studies. In our study, we found that HCC incidence in patients with AIH is low even after the onset of cirrhosis. Additionally, factors such as advanced age, obesity, cirrhosis, alcohol consumption, and the presence of the AIH/PSC variant syndrome at the time of AIH diagnosis are linked to a higher risk of HCC. Based on these findings, there seems to be merit in adopting a specialized HCC monitoring programme for patients with AIH based on their individual risk factors.

Exploring the link: Porto-sinusoidal vascular disorder and inflammatory bowel disease - A comprehensive narrative review.

Porto-sinusoidal vascular disorder (PSVD) encompasses a group of vascular disorders characterized by lesions involving the portal venules and sinusoids, independent of the presence of portal hypertension (PH), and for which liver biopsy is essential for diagnosis. PSVD has been shown to be common in patients with immune-mediated diseases, including inflammatory bowel disease (IBD). The association between PSVD and the use of thiopurines and thioguanine in patients with IBD has been well established. In addition, research suggests an association between PSVD and IBD, even in cases where patients haven't been exposed to specific medications, probably related to changes in intestinal permeability. The identification and management of patients with known IBD and PSVD is a challenge for gastroenterologists. This narrative review aims to summarize the currently available data on the association between IBD and PSVD and provide practical suggestions for the management of this group of patients.

Hepatitis C Virus Infection in the Elderly in the Era of Direct-Acting Antivirals: Evidence from Clinical Trials and Real Life.

The introduction of direct-acting antiviral agents (DAAs) into clinical practice has revolutionized the therapeutic approach to patients with chronic hepatitis C virus (HCV) infection. According to the most recent guidelines, the first line of treatment for HCV infection involves the use of one of three pan-genotypic DAA combinations, sofosbuvir/velpatasvir (SOF/VEL), glecaprevir/pibrentasvir (GLE/PIB), and sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX). These drugs have been shown to be effective and safe in numerous clinical trials and real-world studies, but special populations have been neglected. Among the special populations to be treated are elderly patients, whose numbers are increasing in clinical practice. The management of these patients can be challenging, in particular due to multiple comorbidities, polypharmacotherapy, and potential drug-drug interactions. This narrative review aims to summarize the current scientific evidence on the efficacy and safety of DAAs in the elderly population, both in clinical trials and in real-life settings. Although there is still a paucity of real-world data and no clinical trials have yet been conducted in the population aged ≥ 75 years old, some considerations about the efficacy and safety of DAAs in the elderly can be made based on the results of these studies. The pan-genotypic associations of DAAs appear to be as efficacious and safe in the elderly population as in the general population; this is both in terms of similar sustained virologic response (SVR) rates and similar frequencies of adverse events (AEs). However, further studies specifically involving this patient population would be necessary to confirm this evidence.

From Prioritization to Universal Treatment: Successes and Challenges of Hepatitis C Virus Elimination in Italy.

Italy has had the highest prevalence of hepatitis C virus (HCV) infection and mortality from HCV-related liver cancer in Europe. Although direct-acting antivirals (DAA) were initially restricted to persons with advanced fibrosis, their use has since been extended to all infected individuals; more than 244 000 persons have been treated to date. HCV liver-related mortality is expected to decline by 75% by 2030, achieving the World Health Organization target for mortality. However, Italy risks failing to meet the overall goal of eliminating HCV infection by 2030. In this light, €71.5 million have been allocated for screening initially specific target populations (persons who inject drugs, prison inmates, and the 1969-1989 birth cohort). Herein, we outline the challenges and recommendations for how to move Italy toward HCV elimination, including expanding screening programs in other populations, increasing awareness through strategic communication, sustaining DAA access, and tailoring care models to meet the needs of key populations.

Forecasting the long-term impact of COVID-19 on hepatitis C elimination plans in Italy: A mathematical modelling approach.

BACKGROUND: Italy has a high HCV prevalence, and despite the approval of a dedicated fund for 'Experimental screening' for 2 years, screening has not been fully implemented. We aimed to evaluate the long-term impact of the persisting delay in HCV elimination after the Coronavirus disease 2019 (COVID-19) pandemic in Italy. METHODS: We used a mathematical, probabilistic modelling approach evaluating three hypothetical 'Inefficient', 'Efficient experimental' and 'WHO Target' screening scenarios differing by treatment rates over time. A Markov chain for liver disease progression evaluated the number of active infections, decompensated cirrhosis (DC), hepatocellular carcinoma (HCC) and HCV liver-related deaths up to the years 2030 and 2050. RESULTS: The 'WHO Target' scenario estimated 3900 patients with DC and 600 with HCC versus 4400 and 600 cases, respectively, similar for both 'Inefficient' and 'Efficient experimental' screening up to 2030. A sharp (10-fold) decrease in DC and HCC was estimated by the 'WHO Target' scenario compared with the other two scenarios in 2050; the forecasted number of DC was 420 cases versus 4200 and 3800 and of HCC <10 versus 600 and 400 HCC cases by 'WHO Target,' 'Inefficient' and 'Efficient experimental' scenarios, respectively. A significant decrease of the cumulative estimated number of liver-related deaths was observed up to 2050 by the 'WHO Target' scenario (52000) versus 'Inefficient' or 'Efficient experimental' scenarios (79 000 and 74 000 liver-related deaths, respectively). CONCLUSIONS: Our estimates highlight the need to extensively and efficiently address HCV screening and cure of HCV infection in order to avoid the forecasted long-term HCV adverse outcomes in Italy.

Ursodeoxycholic Acid Does Not Improve COVID-19 Outcome in Hospitalized Patients.

Ursodeoxycholic acid (UDCA) was demonstrated to reduce susceptibility to SARS-CoV-2 infection in vitro and improve infection course in chronic liver diseases. However, real-life evidence is lacking. We analyzed the impact of UDCA on COVID-19 outcomes in patients hospitalized in a tertiary center. Between January 2020 and January 2023, among 3847 patients consecutively hospitalized for COVID19, 57 (=UDCA group) were taking UDCA. The UDCA and the control groups (n = 3790) did not differ concerning comorbidities including diabetes mellitus type 2 (15.8% vs. 12.8%) and neoplasia (12.3% vs. 9.4%). Liver diseases and vaccination rate were more common in the UDCA group (14.0% vs. 2.5% and 54.4% vs. 30.2%, respectively). Overall mortality and CPAP treatment were 22.8 % and 15.7% in the UDCA, and 21.3% and 25.9% in the control group. Mortality was similar (p = 0.243), whereas UDCA was associated with a lower rate of CPAP treatment (OR = 0.76, p < 0.05). Treatment with UDCA was not an independent predictor of survival in patients hospitalized for COVID-19.

Oesophageal varices predict complications in compensated advanced non-alcoholic fatty liver disease.

Background & Aims: We aimed to evaluate the impact of oesophageal varices (OV) and their evolution on the risk of complications of compensated advanced chronic liver disease (cACLD) caused by non-alcoholic fatty liver disease (NAFLD). We also assessed the accuracy of non-invasive scores for predicting the development of complications and for identifying patients at low risk of high-risk OV. Methods: We performed a retrospective assessment of 629 patients with NAFLD-related cACLD who had baseline and follow-up oesophagogastroduodenoscopy and clinical follow-up to record decompensation, portal vein thrombosis (PVT), and hepatocellular carcinoma. Results: Small and large OV were observed at baseline in 30 and 15.9% of patients, respectively. The 4-year incidence of OV from absence at baseline, and that of progression from small to large OV were 16.3 and 22.4%, respectively. Diabetes and a ≥5% increase in BMI were associated with OV progression. Multivariate Cox regression revealed that small (hazard ratio [HR] 2.24, 95% CI 1.47-3.41) and large (HR 3.86, 95% CI 2.34-6.39) OV were independently associated with decompensation. When considering OV status and trajectories, small (HR 2.65, 95% CI 1.39-5.05) and large (HR 4.90, 95% CI 2.49-9.63) OV at baseline and/or follow-up were independently associated with decompensation compared with the absence of OV at baseline and/or follow-up. The presence of either small (HR 2.8, 95% CI 1.16-6.74) or large (HR 5.29, 95% CI 1.96-14.2) OV was also independently associated with incident PVT. Conclusion: In NAFLD-related cACLD, the presence, severity, and evolution of OV stratify the risk of developing decompensation and PVT. Impact and implications: Portal hypertension is the main driver of liver decompensation in chronic liver diseases, and its non-invasive markers can help risk prediction. The presence, severity, and progression of oesophageal varices stratify the risk of complications of non-alcoholic fatty liver disease. Easily obtainable laboratory values and liver stiffness measurement can identify patients at low risk for whom endoscopy may be withheld, and can also stratify the risk of liver-related complications.

Glecaprevir/Pibrentasvir is safe and effective in Italian patients with chronic hepatitis C aged 75 years or older: A multicentre study.

BACKGROUND: Glecaprevir and Pibrentasvir (G/P) determine high rates of sustained virological response (SVR) with optimal safety profile in patients with chronic hepatitis C virus (HCV) infection. The efficacy and safety of G/P in Caucasian patients aged 75 years and older have not been widely analysed. METHODS: This is a retrospective multicentre real-world study enrolling all consecutive patients 75 years and older who received G/P between October 2017 and January 2022 at five referral centres in Italy. SVR was analysed by intention-to-treat (ITT) and per-protocol analyses (PP). RESULTS: A total of 570 patients met the inclusion criteria and were analysed: mean age was 80 (75-97) years, 356 (62%) were females, 52% (298/570) had HCV-1, 44% (252/570) had HCV-2 and 137 (24%) patients had liver cirrhosis. Four hundred and sixty-three (81%) patients were taking at least one concomitant drug, with 144 (25%) taking ≥5 concomitant drugs. G/P was given for 8 weeks in 488 patients (86%). During treatment, 48 patients (8%) reported side effects, with 10 (2%) patients discontinuing treatment prematurely. Two patients developed treatment-unrelated serious adverse events. Overall, the SVR rate was 97.9% (558/570) by ITT analysis and 99.6% (558/560) by PP analysis. SVR rates remained consistently high among subgroup analysis stratified by genotype, treatment duration, fibrosis stage and concomitant medications. CONCLUSIONS: Treatment with G/P achieved 97.9% SVR rates in HCV patients older than 75 years of age. Safety was optimal with only 2% of patients discontinuing early.

Hepatitis D double reflex testing of all hepatitis B carriers in low-HBV- and high-HBV/HDV-prevalence countries.

Hepatitis D virus (HDV) infection occurs as a coinfection with hepatitis B and increases the risk of hepatocellular carcinoma, decompensated cirrhosis, and mortality compared to hepatitis B virus (HBV) monoinfection. Reliable estimates of the prevalence of HDV infection and disease burden are essential to formulate strategies to find coinfected individuals more effectively and efficiently. The global prevalence of HBV infections was estimated to be 262,240,000 in 2021. Only 1,994,000 of the HBV infections were newly diagnosed in 2021, with more than half of the new diagnoses made in China. Our initial estimates indicated a much lower prevalence of HDV antibody (anti-HDV) and HDV RNA positivity than previously reported in published studies. Accurate estimates of HDV prevalence are needed. The most effective method to generate estimates of the prevalence of anti-HDV and HDV RNA positivity and to find undiagnosed individuals at the national level is to implement double reflex testing. This requires anti-HDV testing of all hepatitis B surface antigen-positive individuals and HDV RNA testing of all anti-HDV-positive individuals. This strategy is manageable for healthcare systems since the number of newly diagnosed HBV cases is low. At the global level, a comprehensive HDV screening strategy would require only 1,994,000 HDV antibody tests and less than 89,000 HDV PCR tests. Double reflex testing is the preferred strategy in countries with a low prevalence of HBV and those with a high prevalence of both HBV and HDV. For example, in the European Union and North America only 35,000 and 22,000 cases, respectively, will require anti-HDV testing annually.

SARS-CoV-2 Infection, Inflammation, Immunonutrition, and Pathogenesis of COVID-19.

The COVID-19 pandemic, caused by the coronavirus, SARS-CoV-2, has claimed millions of lives worldwide in the past two years. Fatalities among the elderly with underlying cardiovascular disease, lung disease, and diabetes have particularly been high. A bibliometrics analysis on author's keywords was carried out, and searched for possible links between various coronavirus studies over the past 50 years, and integrated them. We found keywords like immune system, immunity, nutrition, malnutrition, micronutrients, exercise, inflammation, and hyperinflammation were highly related to each other. Based on these findings, we hypothesized that the human immune system is a multilevel super complex system, which employs multiple strategies to contain microorganism infections and restore homeostasis. It was also found that the behavior of the immune system is not able to be described by a single immunological theory. However, one main strategy is "self-destroy and rebuild", which consists of a series of inflammatory responses: 1) active self-destruction of damaged/dysfunctional somatic cells; 2) removal of debris and cells; 3) rebuilding tissues. Thus, invading microorganisms' clearance could be only a passive bystander response to this destroy-rebuild process. Microbial infections could be self-limiting and promoted as an indispensable essential nutrition for the vast number of genes existing in the microorganisms. The transient nutrition surge resulting from the degradation of the self-destroyed cell debris coupled with the existing nutrition state in the patient may play an important role in the pathogenesis of COVID-19. Finally, a few possible coping strategies to mitigate COVID-19, including vaccination, are discussed.

Safety and effectiveness of 8 weeks of Glecaprevir/Pibrentasvir in challenging HCV patients: Italian data from the CREST study.

INTRODUCTION: Glecaprevir/pibrentasvir (G/P) has demonstrated high rates (>95%) of sustained virologic response at posttreatment Week 12 (SVR12) in treatment-naïve (TN) patients with hepatitis C virus (HCV) infection and compensated cirrhosis (CC). Here, in a key real-world subset of TN Italian patients with CC, we evaluated the effectiveness and safety of 8-week G/P treatment, including subgroups of interest such as those with genotype 3 (GT3) infection, elderly patients, and those with more advanced liver disease. METHODS: Subanalysis of Italian patients enrolled in the CREST study. The full analysis set (FAS) included all patients enrolled in the study; the modified analysis set (MAS) excluded patients who discontinued G/P for nonvirologic failure or who had missing SVR12 results. Primary and secondary endpoints included SVR12 and safety, respectively. RESULTS: Of 42 patients included in the FAS, 1 discontinued for unknown reasons, and 2 had missing SVR12 data, leaving 39 patients included in the MAS. At treatment initiation, 74% of patients had ≥1 comorbidity, and 62% were receiving concomitant medications, including some that may potentially interact with G/P. SVR12 was achieved in 100% of patients in the MAS, and in 95% in the FAS. In subgroups of interest, the proportion of patients achieving SVR12 in the MAS (and FAS) was: 100% (94%) for patients ≥65 years, 100% (86%) for GT3, and 100% (100%) for patients with platelet count <150 × 109/L and FibroScan® >20 kPa. Overall, 2 (5%) patients had an adverse event and neither were serious. CONCLUSION: Results from this real-world Italian cohort demonstrated the safety and effectiveness of 8-week G/P, with SVR12 rate >95%, even in elderly patients. These findings further support real-world evidence of the use of short-course G/P treatment in all patients with CC, including those with GT3, and those with advanced liver disease.

Clinical features and management issues of NAFLD-related HCC: what we know so far.

INTRODUCTION: Nonalcoholic fatty liver disease (NAFLD) is replacing viral hepatitis as the leading cause of chronic liver disease and hepatocellular carcinoma (HCC) in many Western countries. NAFLD-associated HCC usually affects older patients with multiple comorbidities, frequently develops in the absence of cirrhosis, and is often diagnosed later with worse chance of survival. The worse prognosis is also due to limited surveillance strategies and a lower efficacy of standard treatments. AREAS COVERED: We evaluate the available literature to understand the current surveillance strategies and treatment limitations in the workup of NAFLD-associated HCC, focusing on the differences with HCC associated with other liver diseases. EXPERT OPINION: In this review we discuss epidemiology and risk factors for HCC in NAFLD patients and address key HCC surveillance and management issues. Although most data are still preliminary, the detection of non-cirrhotic NAFLD patients at increased risk for HCC and the potential adoption of novel screening tools could lead to accurate and suitable HCC surveillance and management strategies for NAFLD patients.

Securing wider EU commitment to the elimination of hepatitis C virus.

In 2016, the Hepatitis B and C Public Policy Association (HepBCPPA), gathered all the main stakeholders in the field of hepatitis C virus (HCV) to launch the now landmark HCV Elimination Manifesto, calling for the elimination of HCV in the EU by 2030. Since then, many European countries have made progress towards HCV elimination. Multiple programmes-from the municipality level to the EU level-were launched, resulting in an overall decrease in viremic HCV infections and liver-related mortality. However, as of 2021, most countries are not on track to reach the 2030 HCV elimination targets set by the WHO. Moreover, the COVID-19 pandemic has resulted in a decrease in HCV diagnoses and fewer direct-acting antiviral treatment initiations in 2020. Diagnostic and therapeutic tools to easily diagnose and treat chronic HCV infection are now well established. Treating all patients with chronic HCV infection is more cost-saving than treating and caring for patients with liver-related complications, decompensated cirrhosis or hepatocellular carcinoma. It is more important than ever to reinforce and scale-up action towards HCV elimination. Yet, efforts urgently need the dedicated commitment of policymakers at all governmental and policy levels. Therefore, the third EU Policy Summit, held in March 2021, featured EU parliamentarians and other key decision makers to promote dialogue and take strides towards securing wider EU commitment to advance and achieve HCV elimination by 2030. We have summarized the key action points and reported the 'Call-to-Action' statement supported by all the major relevant European associations in the field.