This review highlights the critical considerations for monitoring patients who achieve sustained virological response (SVR) after direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) infection. Despite the remarkable success of DAAs, challenges persist in managing long-term risks, including hepatocellular carcinoma (HCC), liver decompensation, and extrahepatic manifestations, necessitating a tailored follow-up approach.

Recent studies emphasize that SVR does not eliminate risks for complications, particularly in patients with advanced fibrosis or cirrhosis. Advances in noninvasive tools, such as transient elastography and blood-based markers, have improved assessment of portal hypertension and liver function dynamics post-SVR. HCC surveillance remains critical for high-risk groups. Additionally, SVR improves extrahepatic conditions like mixed cryoglobulinemia and non-Hodgkin lymphoma, though careful monitoring for recurrence or associated risks is advised. Reinfection in high-risk populations underscores the importance of structured prevention and retreatment strategies.

Tailored follow-up of post-SVR patients remains essential. Future research should focus on refining predictive tools for late complications and optimizing surveillance strategies, balancing cost-effectiveness with clinical outcomes.

Over the past several years, there has been a wealth of new data pertaining to the management of complications of cirrhosis, resulting in several important updates to best practices and consensus guidelines. Despite these advancements and numerous recent targeted quality initiatives, hospitalizations resulting from complications of cirrhosis remain frequent, costly and associated with poor patient outcomes. An emphasis on evidence-based management of hospitalized patients with decompensated cirrhosis has the potential to decrease readmission rates and length of stay while improving overall patient outcomes. Herein, we provide an updated, evidence-based overview of the optimal inpatient management of the most frequently encountered complications associated with cirrhosis.

Cardiac dysfunction in patients with liver disease has been recognized since the 1950s. Initially attributed to shared risk factors, it is now evident that cardiac dysfunction in patients with cirrhosis can occur in the absence of known cardiac, that is, coronary artery and valvular heart disease, and across all etiologies for cirrhosis. In 1996, this myocardial dysfunction was termed cirrhotic cardiomyopathy (CCM). The pathophysiologic mechanisms underlying CCM include impaired beta-adrenergic membrane function and circulating proinflammatory and cardiotoxic substances. In 2005, the first diagnostic criteria for CCM were introduced enabling greater sensitivity and accuracy of diagnosis. Since 2005, advancements in echocardiographic methods and a better understanding of the pathophysiology of cardiac dysfunction in patients with cirrhosis necessitated a revision of CCM criteria. Changes in CCM criteria included the removal of blunted contractile or heart rate response on stress testing and the addition of global longitudinal systolic strain. The refinement of criteria for diastolic dysfunction was also incorporated into the new diagnostic approach. Since 2020, the prevalence of the disorder and clinical considerations for pretransplant, peritransplant, and posttransplant patients with cirrhosis have been further evaluated, and CCM was found to adversely impact clinical outcomes during all 3 phases of care. Future research considerations should address the timing of universal echocardiographic screening for patients with cirrhosis, the utility of biomarkers in aiding CCM diagnosis, the impact of CCM on right heart function, and the role of anti-remodeling agents after liver transplant.

The classification of steatotic liver disease (SLD) has evolved, incorporating all conditions characterized by hepatic lipid accumulation. SLD represents a continuum of disorders that are shaped by the dynamic factors of alcohol intake and cardiometabolic risk factors. This updated classification has profound implications for both the management and research of SLD, especially with the new distinct category of patients with both metabolic and alcohol-related liver disease. In this Perspective, we highlight the pivotal role of alcohol within the SLD framework. We introduce the 'SLD burden paradox': a concept illustrating the disparity in which metabolic dysfunction-associated steatotic liver disease is more prevalent, yet individuals with SLD and excessive alcohol intake (such as in metabolic and alcohol-related liver disease and in alcohol-related liver disease) account for greater global liver-related morbidity and mortality. We explore strategies to mitigate the effect of SLD on morbidity and mortality, emphasizing the importance of early detection and reducing stigma associated with alcohol intake. Our discussion extends to methods for assessing and monitoring alcohol intake together with the critical role of managing cardiometabolic risk factors in patients across the SLD spectrum. Conclusively, we advocate for a coordinated care framework that adopts a person-centric approach when managing SLD, aiming to improve outcomes and patient care.

The Baveno VII consensus recommends spleen stiffness measurement (SSM) for the detection of clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease (cACLD). We aimed to evaluate the performance of SSM-based algorithms.

Consecutive cACLD individuals who underwent hepatic venous pressure gradient measurement, liver stiffness measurement (LSM), and SSM measured with the dedicated 100-Hz probe by vibration-controlled transient elastography were prospectively enrolled.

From July 2021 to August 2024, a total of 395 patients were screened, and 185 cACLD cases were enrolled, of which 101 patients had CSPH. An SSM > 50 kPa demonstrated a positive predictive value (PPV) of 98.0% and a specificity of 98.8% for ruling in CSPH, correctly identifying 47.5% (48/101) of CSPH cases. Sensitivity analysis revealed that in 60 patients with aetiology removal or suppression, SSM > 50 kPa achieved both a PPV and specificity of 100%. Among the 125 patients with ongoing aetiologies, the PPV and specificity were 96.4% and 98.3%, respectively. Across HBV (with or without viral suppression) and non-HBV subgroups, the PPV and specificity consistently exceeded 90%. In decision curve analysis, SSM > 50 kPa provided the highest net benefit compared with other elastography-based algorithms when threshold probabilities exceeded 0.8.

We prospectively validated that SSM > 50 kPa, measured using the spleen-dedicated probe, is sufficient for identifying CSPH in individuals with cACLD.

NCT04820166.

Two main stages are differentiated in patients with advanced chronic liver disease (ACLD), one compensated (cACLD) with an excellent prognosis, and the other decompensated (dACLD), defined by the appearance of complications (ascites, variceal bleeding and hepatic encephalopathy) and associated with high mortality. Preventing the progression to dACLD might dramatically improve prognosis and reduce the burden of care associated with ACLD. Portal hypertension is a major driver of the transition from cACLD to dACLD, and a portal pressure of ≥10 mmHg defines clinically significant portal hypertension (CSPH) as the threshold from which decompensating events may occur. In recent years, innovative studies have provided evidence supporting new strategies to prevent decompensation in cACLD. These studies have yielded major advances, including the development of noninvasive tests (NITs) to identify patients with CSPH with reasonable confidence, the demonstration that aetiological therapies can prevent disease progression and even achieve regression of cirrhosis, and the finding that non-selective β-blockers can effectively prevent decompensation in patients with cACLD and CSPH, mainly by reducing the risk of ascites, the most frequent decompensating event. Here, we review the evidence supporting new strategies to manage cACLD to prevent decompensation and the caveats for their implementation, from patient selection using NITs to ancillary therapies.

It is unclear if the risk of hepatic decompensation or hepatocellular carcinoma (HCC) differs between patients with compensated alcohol-related liver disease (ALD)- and metabolic dysfunction-associated steatotic liver disease (MASLD)-cirrhosis. We investigated the risk to develop hepatic decompensation or HCC based on ALD or MASLD as the underlying etiology of cirrhosis.

All patients with a new diagnosis in hospital-based outpatient care of ALD- or MASLD-cirrhosis in Sweden between 2002 and 2020 were identified using national registers. Hepatic decompensation was analyzed as a composite outcome with HCC. Cox regression was employed to compare rates of hepatic decompensation or HCC, and subsequent death.

1660 patients with ALD-cirrhosis and 943 patients with MASLD-cirrhosis were identified. The median ages were 64 years (IQR 57-70) and 69 years (IQR 62-75) in patients with ALD- and MASLD-cirrhosis, respectively. Patients with ALD-cirrhosis consisted of 69.4 % males, compared to 47.6 % males in the MASLD-cirrhosis group. 581 (35 %) patients with ALD-cirrhosis and 284 (30 %) patients with MASLD-cirrhosis developed hepatic decompensation or HCC (median follow-up time: 25 months), resulting in an adjusted hazard ratio of 1.12 (ALD- vs. MASLD-cirrhosis, 95 %-confidence interval=0.88-1.41). The adjusted risk of mortality afterwards was lower in patients with ALD-cirrhosis compared to patients with MASLD-cirrhosis (adjusted hazard ratio 0.62, 95 %-confidence interval=0.39-0.97).

The risk of hepatic decompensation or HCC is comparable in patients with ALD- and MASLD-cirrhosis, but the risk of mortality after a decompensation event or HCC tends to be higher in patients with MASLD-cirrhosis.

tTo assess the evolving role of endoscopy assessment for esophageal varices in cirrhosis.

The approach to screening endoscopy for varices has significantly changed in the last 10 years with the refinement of non-diagnostic tests. Non-invasive diagnostic methods have reduced the need of upper endoscopies for variceal screening in patients with compensated cirrhosis, focusing primarily on those with ambiguous risk assessments or contraindications to non-selective beta-blockers (NSBBs). In contrast, decompensated cirrhosis patients require more frequent endoscopic evaluations due to their heightened risk of complications and the potential benefit of combination therapy (NSBBs + variceal ligation). In patients with hepatocellular carcinoma (HCC) the performance of non-invasive tests is suboptimal and most patients require endoscopy. Emerging applications of artificial intelligence (AI) can assist in patient triage and the interpretation of endoscopic findings, potentially improving care. Further research is essential to validate these technologies within clinical practice and optimize their integration into patient management strategies.

Liver cirrhosis is a common cause of morbidity and mortality worldwide. Excessive alcohol consumption and metabolic associated steatotic liver disease are the most common etiological factors of cirrhosis in our region. Cirrhosis occurs in two well-differentiated phases, compensated and decompensated, depending on the absence or presence of complications, respectively. Current therapeutic strategies are aimed at controlling these complications (such as ascites, hepatic encephalopathy, bacterial infections, or digestive hemorrhage, among others) or performing a liver transplant if there are no contraindications. However, it is important to eliminate the etiological factor responsible for the disease, as this can lead to the disappearance of complications, a state known as recompensation. This article proposes an updated review of the epidemiology of cirrhosis and its main causes, and offers an overview of the clinical features and treatment of the disease's complications, in addition to outlining future lines of research in this field.

Hepatic encephalopathy (HE) is a debilitating neurological condition associated with cirrhosis, characterized by cognitive impairment ranging from minimal to overt symptoms. It significantly impacts patients' quality of life and substantially burdens healthcare systems. This review examines current prophylactic strategies for HE, focusing on established treatments, emerging therapies, and predictive tools to identify high-risk patients. Traditional treatments such as lactulose and rifaximin remain the cornerstone of HE management, effectively reducing ammonia levels and preventing recurrence. However, novel approaches like L-ornithine L-aspartate, albumin infusions, and antioxidants like resveratrol show promise in further improving outcomes by addressing underlying pathophysiological mechanisms, including systemic inflammation and gut dysbiosis. Developing predictive models, such as the AMMON-OHE score and clinical-genetic risk assessments, enhances the ability to tailor preventive interventions to individual patient profiles. These advancements are crucial in mitigating the incidence of overt HE, reducing hospital admissions, and improving patient survival rates. The future of HE management lies in personalized medicine, targeting specific inflammatory and metabolic pathways, with the potential integration of genetic manipulation. Continued research is essential to refine these strategies, ultimately aiming to improve the prognosis and quality of life for cirrhotic patients at risk of HE.

Hepatocellular carcinoma (HCC) is expected to become the third most common cause of cancer death worldwide by 2030. The increase in HCC is in large part due to the rising prevalence of risk factors such as type 2 diabetes mellitus (T2DM). Up to 1 in 20 people living with T2DM have liver cirrhosis, and they have a 1% to 2% incidence of HCC per year. Patients with cirrhosis enter surveillance for HCC to identify early-stage, curable tumours. A diagnosis of T2DM does not mandate testing to identify patients with cirrhosis, with testing restricted to those with additional risks. There has never been a trial and nested cost-effectiveness evaluation comparing screening all patients with T2DM for cirrhosis against usual care.

The study will use a multi-centre, unblinded individual randomised controlled trial design. The aim will be to determine the effectiveness and cost-effectiveness of screening all adults with T2DM to identify those at high risk of HCC. The recruitment strategy has been supported by patient and public involvement (PPI). Participants will be identified via an automated search of primary care records and invited to participate via text. 320 participants will be randomised for screening. The screening will include measurement of bio-markers for liver fibrosis (ELF and Fib-4) and vibration-controlled transient elastography. Another 320 participants will be randomised to standard care. Demographic and medical history data will be collected at baseline from all participants. Outcome data will be collected remotely from healthcare records. The primary outcome is the proportion of participants in each arm who are referred to HCC surveillance following testing for liver disease within 12 months of randomisation. The results will be used to calculate the incremental cost-effectiveness ratio of screening via a Markov model.

The results of this study will be presented directly to National Health Service England. Additional dissemination via conference proceedings and publication will be supported by our PPI team. Ethical approval was granted by the West of Scotland Research Ethics Service on 2 August 2023, REC reference 23/WS/0102.

ISRCTN17017677.

Portal hypertension (PH) leads to life-threatening clinical manifestations such as bleeding from gastro-oesophageal varices, ascites and its complications, and portosystemic encephalopathy. It can develop because of advanced chronic liver disease (ACLD) or due to rarer causes such as vascular liver disease. Reference standard methods to assess PH in ACLD include the measurement of hepatic venous pressure gradient and endoscopy, which have limitations due to their high resource utilisation and invasiveness. Non-invasive tests (NITs) have entered clinical practice and allow invasive procedures to be reserved for patients with indeterminate findings on NITs or for specific clinical questions. In this review, we present an update on the role of NITs, and in particular ultrasound elastography, to diagnose PH in ACLD and vascular liver disease, and to stratify the risk of liver-related events. We also provide insights into the open research questions and design of studies in this field.

Whether non-invasive tests (NITs) can accurately select patients with cirrhosis requiring non-selective beta-blockers (NSBBs) for clinically significant portal hypertension (CSPH) and prevention of decompensation is unclear. Our aim was to test the performance of NIT-based algorithms for CSPH diagnosis using the prospective PREDESCI cohort. We investigated whether a new algorithm combining NITs with endoscopy could improve performance.

We included patients with compensated cirrhosis and available liver elastography who were screened during the trial. The performance of models based on liver stiffness measurement (LSM) and platelet count was evaluated. An algorithm considering endoscopy for patients with inconclusive results (the "grey zone") was then developed and validated in an independent cohort of 195 patients in whom spleen stiffness was also available.

We included 170 patients from the PREDESCI cohort. An LSM ≥25 kPa alone (Baveno VII criteria) or combined with an LSM >20 kPa plus thrombocytopenia (AASLD criteria) ruled-in CSPH with positive predictive values of 88% and 89%, respectively. However, 37%-47% patients fell into the grey zone while at high risk of decompensation or death. Performing endoscopy in inconclusive cases identified patients with varices that, when reclassified as high-risk for CSPH, significantly reduced the grey zone to 22%. In this algorithm, 86% of patients with CSPH were correctly classified as high risk. The diagnostic performance was confirmed in the external validation cohort, where combining Baveno VII criteria with spleen stiffness showed similar accuracy to the model using endoscopy.

Algorithms based only on LSM and platelet count are suboptimal to identify NSBB treatment candidates. Performing endoscopy in patients with indeterminate findings from NITs improved diagnostic performance and risk stratification. Endoscopy may be substituted by spleen stiffness for stratifying risk in the grey zone.

The PREDESCI trial demonstrated that non-selective beta-blockers prevent decompensation in patients with clinically significant portal hypertension (CSPH). Still, it is unclear whether we can select treatment candidates using non-invasive tests to assess the presence of CSPH without measuring HVPG (hepatic venous pressure gradient). In the prospective cohort of patients screened during the PREDESCI trial, we showed that algorithms based on liver stiffness and platelet count had suboptimal performance, mainly due to a high rate of indeterminate results. Performing endoscopy on patients in the grey zone significantly increased the number correctly characterized as having CSPH and improved the risk stratification for decompensation or death on long-term follow-up. These findings were validated in an independent cohort. In addition, a model using spleen stiffness instead of endoscopy showed similar diagnostic performance in the external validation cohort, suggesting that adequate risk stratification to select treatment candidates can be achieved with a fully non-invasive algorithm.

Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients.

From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients' OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1-19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75-37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85-16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69-2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28-2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98-5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34-0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25-0.93).

Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS.

Noninvasive tests (NITs) are used in all aspects of liver disease management. Their most prominent break-through since the millennium has been in advancing early detection of liver fibrosis, but their use is not limited to this. In contrast to the symptom-driven assessment of decompensation in patients with cirrhosis, NITs provide not only opportunities for earlier diagnoses but also accurate prognostication, targeted treatment decisions, and a means of monitoring disease. NITs can inform disease management and decision-making based on validated cutoffs and standardized interpretations as a valuable supplement to clinical acumen. The Baveno VI and VII consensus meetings resulted in tangible improvements to pathways of care for patients with compensated and decompensated advanced chronic liver disease, including the combination of platelet count and transient elastography to diagnose clinically significant portal hypertension. Furthermore, circulating NITs will play increasingly important roles in assessing the response to interventions against ascites, variceal bleeding, HE, acute kidney injury, and infections. However, due to NITs' wide availability, there is a risk of inaccurate use, leading to a waste of resources and flawed decisions. In this review, we describe the uses and pitfalls of NITs for hepatic decompensation, from risk stratification in primary care to treatment decisions in outpatient clinics, as well as for the in-hospital management of patients with acute-on-chronic liver failure. We summarize which NITs to use when, for what indications, and how to maximize the potential of NITs for improved patient management.

Ascites is the most common complication from cirrhosis related to portal hypertension and depicts the onset of hepatic decompensation. Ranging from uncomplicated to refractory ascites, the progression carries prognostic value by reflecting the deterioration of underlying cirrhosis and portal hypertension. Diuretics have been the mainstay of treatment to control ascites, but the side effects heighten when the dosage is escalated. Non-selective beta-blockers (NSBBs) are widely used nowadays to prevent hepatic decompensation and variceal hemorrhage. However, with worsening systemic vasodilation and inflammation when ascites progresses, patients on NSBBs are at risk of hemodynamic collapse leading to renal hypoperfusion and thus hepatorenal syndrome. Long-term albumin infusion was studied to prevent the progression of ascites. However, the results were conflicting. Sodium-glucose cotransporter-2 inhibitors are under investigation to control refractory ascites. With that, patients with refractory ascites may require regular large-volume paracentesis. With an aging population, more patients are put on anti-thrombotic agents and their risks in decompensated cirrhosis and invasive procedures have to be considered. In general, decompensated cirrhosis with ascites poses multiple issues to pharmacological treatment. In the present review, we discuss the challenges and controversies in the pharmacological treatment of ascites.

Gastroesophageal varices are portosystemic collaterals formed due to portal hypertension. The primary consequence and leading cause of death in cases of gastroesophageal varices is bleeding. Although variceal hemorrhage mortality has decreased due to early diagnosis of gastroesophageal varices, prophylaxis, and therapy, these procedures are still difficult to perform in many underdeveloped nations. When the dose of nonselective b-blockers is optimized to the highest acceptable dosage to reach the therapeutic goal, the benefit of reducing the risk of variceal bleeding is greatest. B-blocker optimization is unknown in our nation and Africa.

To assess the optimization rate of non-selective B-blockers and associated factors among esophageal varices patients following at the University of Gondar referral hospital.

A hospital-based cross-sectional study was conducted at the University of Gondar referral hospital GI clinic, North West Ethiopia. A total of 150 patients were taken with consecutive sampling and the target populations of the study were all adult esophageal varices patients who were on non-selective B-blockers at the GI follow-up clinic. Data were collected with a structured questionnaire and both descriptive and analytical data analysis was performed. Frequency, tables, and graphs were used to represent the data.

A total of 150 patients were included in the study. From these 30.7% of patients took optimal doses of non-selective B -blockers. Patients with poor drug adherence (AOR = 4.293, [95% CI = 1.191-15.484], p-value = 0.026) and hospital admission in the last 01 year (AOR = 2.915, [95%CI = 1.076-7.893], P-value = 0.035) were significantly associated with sub-optimization of non-selective B- blockers.

Only one-third of patients received the optimal dose of non-selective B-blockers. Poor drug adherence and previous admission in the last year were significantly associated with sub-optimal dosing of non-selective B-blockers.

Liver cirrhosis is a progressive disease with high mortality. Gut microbiota derangement, increased gut permeability, bacterial translocation and chronic inflammation all drive disease progression. This trial aims to investigate whether faecal microbiota transplantation (FMT) may improve the disease course in patients with acute decompensation of liver cirrhosis.

In this Danish, multicentre, randomised, double-blinded, placebo-controlled trial, 220 patients with acute decompensation of liver cirrhosis and a Child-Pugh score≤12 will be randomised (1:1) to oral, encapsulated FMT or placebo in addition to standard of care. Before the intervention, the patients will be examined and biological samples obtained, and this is repeated at 1 and 4 weeks and 3, 6 and 12 months after the intervention. The primary outcome is the time from randomisation to new decompensation or death. Secondary endpoints include mortality, number of decompensation events during follow-up and changes in disease severity and liver function.

The Central Denmark Region Research Ethics Committee approved the trial protocol (no. 1-10-72-302-20). The results will be published in an international peer-reviewed journal, and all patients will receive a summary of the results.

ClinicalTrials.gov study identifier NCT04932577.

Some of the physiological changes that occur in pregnancy manifest in the liver. These alterations might exacerbate or improve some pre-existent liver diseases, while many conditions remain unaffected. Some hepatic manifestations during pregnancy are secondary to disorders unique to pregnancy. Due to improved management of chronic conditions and assisted conception methods, pregnancies in people with cirrhosis or after liver transplantation are increasingly common. With pregnancy also becoming more common in older people and with the rising prevalence of comorbidities, such as obesity, diabetes, and metabolic syndrome, hypertensive disorders of pregnancy and gestational diabetes are increasing in prevalance. Thus, a broad range of specialists might encounter liver abnormalities in pregnancy, necessitating an understanding of how the liver changes during pregnancy and the importance of multi-disciplinary input to mitigate maternal-fetal risks. From a global health perspective, pregnancy also offers a unique opportunity to influence disease management and initiate interventions that might influence the life course of pregnant people and their families. In this Review, we describe the challenges of diagnosing, risk stratifying, and managing liver disease in pregnancy, and explore factors that might affect future maternal health.

Background: Liver function and the presence of portal hypertension, as well as the urgency and type of surgery, are prognostic factors in advanced chronic liver disease (ACLD) patients undergoing extrahepatic major surgeries. Emergent surgery in ACLD patients has 4-10 times higher mortality rates than elective surgery. However, perioperative management improvements have been made in recent years. Methods: This is a retrospective, observational, and unicentric study of 482 patients with ACLD who underwent major surgery from 2010 to 2019. We compared baseline characteristics and postoperative mortality according to the presence of ascites, the emergency, and the surgery period. Results: In total, 140 (29%) patients had ascites, and 191 (39.6%) underwent urgent surgeries. The 90-day mortality was 2.8-fold higher in patients with ascites [HR (95%CI) 2.8 (1.6-5.0); p = 0.001] and 3-fold higher in urgent surgeries [3.0 (1.6 - 5.5); p < 0.001)]. Urgent surgeries in patients with ascites revealed the highest mortality risk [6.3 (2.7-14.8); p < 0.001)], which persisted in current (2015-2019) surgeries [12.8 (2.9-56.5); p = 0.001)]. Portal hypertension was meaningful in patients undergoing abdominal surgery. Conclusions: ascites and emergent surgery increase the mortality risk of patients with ACLD despite the recent perioperative improvements.

Decreased nitric oxide (NO) bioavailability in a cirrhotic liver contributes to high intrahepatic vascular resistance (IHVR) and portal hypertension (PHT). Nostrin is an inhibitory protein of NO synthesising enzyme endothelial NO synthase (eNOS), shown to increase in cirrhosis with PHT, however, the precise molecular mechanism is poorly documented. This study aimed to elucidate the role of Nostrin and associated derangement in hepatic NO generation in cirrhotic liver. Further, we investigate whether Nostrin could be a biomarker in the progression of cirrhosis.

This study was conducted on sixty healthy subjects and 120 cirrhotic patients. In addition, liver tissue samples were collected from cirrhotic patients for the analysis of Nostrin, eNOS and inflammatory markers.

When compared to healthy controls, systemic levels of Nostrin and cGMP were elevated in compensated cirrhosis. In decompensated cirrhosis, further robust increases in Nostrin and cGMP were noted. Furthermore, Nostrin expression was considerably higher whilst reduced eNOS activity and hepatic cGMP levels in cirrhotic liver compared to control liver.

In cirrhotic patients, a robust increase in hepatic Nostrin expression may reduce eNOS activity and associated local NO generation. Furthermore, Blood Nostrin concentration was higher and parallel to disease severity and could be a key diagnostic and prognostic biomarker in cirrhotic patients with PHT.

Systemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation.

This study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH: hepatic venous pressure gradient ≥10 mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n = 164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed markers of inflammation (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]).

IL-6, CD163, and vWF were higher (p <0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p <0.05) at 1 year in patients with CSPH, with a greater rise in those who developed decompensation. CD163 was higher (p <0.01) in patients who decompensated at baseline and 1 and 2 years. FABP was elevated (p <0.01) in patients with CSPH compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p <0.01). LPS was higher (p <0.01) in patients with CSPH than in those with subclinical PH and controls and increased at 1 year regardless of decompensation development.

Inflammation and bacterial products are present in the systemic circulation in patients with compensated cirrhosis and CSPH. Progressive inflammation precedes the first decompensation.

Systemic inflammation drives cirrhosis progression during the decompensated stage, but its role in the compensated stage is unclear. We evaluated biomarkers of systemic inflammation, intestinal barrier integrity and bacterial translocation in patients with compensated cirrhosis and their dynamics in relation to the first decompensation. We demonstrate that low-grade inflammation and bacterial products are present in the systemic circulation in compensated cirrhosis, provided clinically significant portal hypertension has developed. We also show that worsening of systemic inflammation precedes the development of first clinical decompensation.

The utility of serial liver stiffness measurements (LSM) to predict decompensation in patients with compensated advanced chronic liver disease (cACLD) remains unclear. We aimed to validate whether comparing serial LSM is superior to using the current LSM to predict liver-related events (LRE) in patients with cACLD.

In this retrospective analysis of an international registry, patients with cACLD and serial LSM were followed up until index LRE. We compared the performance of both the dynamic LSM changes and the current LSM in predicting LRE using Cox regression analysis, considering time zero of follow-up as the date of latest liver stiffness measurement. Overall, 480 patients with cACLD with serial LSM were included from 5 countries. The commonest etiology of cACLD was viral (53%) and MASLD (34%). Over a median follow-up of 68 (IQR: 45-92) months, 32% experienced a LSM decrease to levels below 10kPa (resolved cACLD) and 5.8% experienced LRE. Resolved cACLD were more likely to be non-diabetic and had better liver function. While a higher value of the current LSM was associated with higher LREs, LSM changes over time (LSM slope) were not associated with LRE. In multivariable Cox regression, neither the prior LSM nor the LSM slope added predictive value to latest liver stiffness measurement.

Once the current LSM is known, previous LSM values do not add to the prediction of LREs in patients with cACLD.

Management of cirrhosis sequelae is critical in providing the most options for patients with hepatocellular carcinoma (HCC). Compensated liver disease is the ideal state for HCC patients who may require resection, locoregional therapies, or liver transplantation. Portal hypertension complications, suboptimal nutrition, and frailty are common barriers to various HCC treatments. For patients with advanced HCC, systemic therapies are altering the approach to multifocal, unresectable HCC, but similar barriers exist related to managing cirrhosis complications. Frequently, managing the underlying liver disease etiology is a key component to enabling HCC treatment.

Alpha-Glutathione-S-transferase (alphaGST) is a liver enzyme whose serum levels increase with the worsening of fibrosis in alcoholic and viral chronic hepatitis. Its usefulness in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) remains unexplored. From January 2016 to December 2017, 200 patients with MASLD and 30 controls were enrolled. AlphaGST serum levels were measured. Variables related to advanced fibrosis (AF) were selected via Principal Component Analysis (PCA), and the best cut-off (BCO) was estimated using ROC analysis. Liver stiffness measurement (LSM), NAFLD fibrosis (NFS), Fibrosis-4 (FIB-4), and BMI-AST/ALT Ratio-Diabetes (BARD) scores were determined. The first acute cardiovascular events (ACE) in ACE-naïve subjects were recorded over five years. A validation cohort of 60 MASLD patients was enrolled from January 2018 to May 2019 and followed for five years. AlphaGST levels increased with fibrosis stage (p < 0.0001) in both cohorts, showing high accuracy in predicting AF (TrC: AUC 0.89, VlC: AUC 0.89). PCA-selected variables were HbA1c, HDL, and alphaGST, forming the "FLAME" model. FLAME showed superior predictive performance for AF and ACEs compared to other models and scores. FLAME represents a novel tool that accurately predicts AF and ACEs in MASLD.

Dysgeusia is a distortion of the sense of taste whose prevalence and relationship with nutritional status in Metabolic dysfunction-associated Steatotic Liver Disease (MASLD)-related advanced chronic liver disease (ACLD) have never been systematically explored.

200 MASLD patients [60 ≤ F3 fibrosis, 70 compensated ACLD (cACLD), and 70 decompensated (dACLD)] were enrolled. At baseline, the Child-Pugh (CP) score was determined. Dietary habits, body composition, and frailty were evaluated. The European Working Group (EWGSOP2) criteria defined sarcopenia. Dysgeusia was assessed by the Dysgeusia-Total-Score (DTS). A visual analog scale identified appetite impairment (VASAI). During a 6-month follow-up, liver-related decompensation events (LRDEs) were recorded.

The prevalence of dysgeusia increased with the liver disease progression, appearing significantly higher in ACLD compared with ≤ F3 (65.7% vs 5%, p:0.003), as well as in dACLD compared to cACLD patients (58.5 vs 7.1% p < 0.0001). On 41 dACLD patients presenting dysgeusia, 37 (90.2%) showed a significant impairment of appetite levels. In dACLD, the CP score was positively correlated with both DTS (R:0.742) and VASAI (R:0.704), as well as DTS was directly correlated with VASAI (R:0.765) (all p < 0.0001). Compared with dACLD patients without dysgeusia, dysgeusia-affected dACLD patients presented a lower daily protein intake (g/kg/die) (1.55 ± 0.192 vs 1.34 ± 0.15, p < 0.0001). Sarcopenia (70.7 vs 41.3%) and frailty (69.29 vs 37.9%) were significantly more prevalent in dysgeusia-affected dACLD individuals (both p < 0.0001). These patients showed a higher risk of LRDEs occurrence during the follow-up [HR:2.205; C.I. 95%:1.186-4.099; p:0.01]. Logistic regression analysis revealed dysgeusia (aOR: 3.32), appetite impairment (aOR:1.32), sarcopenia (aOR: 3.75), and frailty (aOR:3.03) significantly associated with this outcome (all p < 0.0001).

Dysgeusia appears predominant in MASLD-dACLD and, via appetite impairment, in a close relationship with malnutrition, sarcopenia, and frailty, negatively influencing patients' outcomes.

To battle seasonal outbreaks of influenza B virus infection, which continue to pose a major threat to world health, new and improved vaccines are urgently needed. In this article, we discuss the current state of next-generation influenza B vaccine development, including both advancements and challenges. This review covers the shortcomings of existing influenza vaccines and stresses the need for more-effective and broadly protective vaccines and more-easily scalable manufacturing processes. New possibilities for vaccine development have emerged due to recent technical developments such as virus-like particle (VLP) platforms, recombinant DNA technologies, and reverse genetics. By using these methods, vaccines can be developed that elicit stronger and longer-lasting immune responses against various strains of influenza B virus. Vaccines may be more effective and immunogenic when adjuvants and new delivery mechanisms are used. Progress has been made in the development of influenza B vaccine mRNA vaccines, nanoparticle-based vaccines, and vector-based vaccines. However, there are still several obstacles to overcome before next-generation influenza B vaccines can be widely used, including the challenge of antigenic drift, the extinction of the B/Yamagata lineage, and difficulties in strain selection. There are also other challenges related to public acceptance, vaccine distribution, manufacturing complexity, and regulations. To overcome these challenges, scientists, politicians, and pharmaceutical firms must work together to expedite the development and licensing of vaccines and the establishment of immunization programs. The need for constant monitoring and quick adaptation of vaccines to match the currently circulating strains is further highlighted by the appearance of novel influenza B virus variants. To be ready for future pandemics and influenza B outbreaks, we need better vaccines and better monitoring systems.

Non-invasive models stratifying clinically significant portal hypertension (CSPH) are limited. Herein, we developed a new non-invasive model for predicting CSPH in patients with compensated cirrhosis and investigated whether carvedilol can prevent hepatic decompensation in patients with high-risk CSPH stratified using the new model.

Non-invasive risk factors of CSPH were identified via systematic review and meta-analysis of studies involving patients with hepatic venous pressure gradient (HVPG). A new non-invasive model was validated for various performance aspects in three cohorts, i.e., a multicenter HVPG cohort, a follow-up cohort, and a carvediloltreating cohort.

In the meta-analysis with six studies (n=819), liver stiffness measurement and platelet count were identified as independent risk factors for CSPH and were used to develop the new "CSPH risk" model. In the HVPG cohort (n=151), the new model accurately predicted CSPH with cutoff values of 0 and -0.68 for ruling in and out CSPH, respectively. In the follow-up cohort (n=1,102), the cumulative incidences of decompensation events significantly differed using the cutoff values of <-0.68 (low-risk), -0.68 to 0 (medium-risk), and >0 (high-risk). In the carvediloltreated cohort, patients with high-risk CSPH treated with carvedilol (n=81) had lower rates of decompensation events than non-selective beta-blockers untreated patients with high-risk CSPH (n=613 before propensity score matching [PSM], n=162 after PSM).

Treatment with carvedilol significantly reduces the risk of hepatic decompensation in patients with high-risk CSPH stratified by the new model.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of CSPH and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.

Portal hypertension is a hemodynamic abnormality that complicates the course of cirrhosis, as well as other diseases that affect the portal venous circulation. The development of portal hypertension compromises prognosis, especially when it rises above a certain threshold known as clinically significant portal hypertension (CSPH). In the consensus conference on Portal Hypertension promoted by the Spanish Association for the Study of the Liver and the Hepatic and Digestive diseases area of the Biomedical Research Networking Center (CIBERehd), different aspects of the diagnosis and treatment of portal hypertension caused by cirrhosis or other diseases were discussed. The outcome of this discussion was a set of recommendations that achieved varying degrees of consensus among panelists and are reflected in this consensus document. The six areas under discussion were: the relevance of clinically significant portal hypertension and the non-invasive methods used for its diagnosis and that of cirrhosis, the prevention of the first episode of decompensation and its recurrence, the treatment of acute variceal bleeding and other complications of portal hypertension, the indications for the use of TIPS, and finally, the diagnosis and treatment of liver vascular diseases.

We aimed to investigate the parameters associated with portal hypertension (PHT)-related complications occurrence in hepatocellular carcinoma (HCC) patients treated by transarterial chemoembolization (TACE), with a focus on non-selective beta blockers (NSBBs) due to their impact on preventing liver decompensation.

We included all patients with HCC for whom endoscopy was available the day of first TACE (2013-2023). The occurrence of PHT-related complications was defined as the appearance of ascites, acute variceal bleeding or hepatic encephalopathy (HE) post-TACE treatment and prior to HCC progression. Inappropriate treatment by NSBBs was defined by the lack of NSBBs in patients with small/large esophageal varices (EV).

109 patients were included (age 67 years, 80 % male) and 65 % had EV. No NSBBs prescription despite indication was observed in 32 % and 81 % of patients with large and small size EV, respectively. Median progression free survival and overall survival were 10 and 23 months, respectively, and 27 % of patients underwent LT. During the follow-up, 20 patients presented PHT-related complications with an incidence of 18 % at 12months (90 % with EV,67 % not treated by NSBB while indicated). Among them, 11 presented HCC progression, 2 were transplanted and 78 % presented liver decompensation that impaired the access to further HCC treatment. In multivariate analysis, a history of HE (HR=55.39,95 %CI[7.42-413.26]) and inappropriate NSBBs treatment (HR=4.16,95 %CI[1.45-11.81]) were associated with PHT-related complications occurrence.

The lack of NSBBs was independently associated with PHT-related complications after TACE, precluding access to further HCC treatment in 78 % of patients with HCC progression. Appropriate screening and PHT prophylaxis are needed in HCC patients who undergo TACE to improve their outcomes.

Most patients with cirrhosis have compensated disease and are cared for in primary care; however, the exact epidemiology within Australia remains largely unknown. The aim of this study was to assess cirrhosis care in an Australian primary care setting by evaluating rates of cirrhosis diagnosis, appropriate hepatocellular carcinoma (HCC) surveillance and specialist communication.

Electronic medical records in consenting general practices were reviewed using the "Liver Toolkit" to identify patients with an existing cirrhosis diagnosis. Individual cases were reviewed to identify outcomes of interest.

One hundred seventy-one patients with confirmed cirrhosis across nine general practices were identified (74% male, mean age: 61.2 years). There was significant variation in the rate of cirrhosis diagnosis between practices (range 31.7-637.9 per 100 000 patients, P < 0.0001). Patients with cirrhosis had predominately compensated disease (75% Child-Pugh A) and common etiologies of cirrhosis were alcohol (49%), hepatitis C (47%), and metabolic dysfunction-associated steatotic liver disease (29%). Forty-two patients (25%) had received appropriate HCC surveillance. Predictors of inadequate HCC surveillance were time from last specialist correspondence (odds ratio [OR] = 1.06 per month increase, 95% confidence interval [CI]: 1.02-1.10, P = 0.002) and hepatitis B (OR = 0.24, 95% CI: 0.06-0.98, P = 0.047). Specialist correspondence with primary care was older than 2 years or absent in 37% of cases.

There was a 20-fold difference in the rate of cirrhosis diagnosis between general practices within Sydney, suggesting a large proportion of patients remain undiagnosed. Three quarters of patients with diagnosed cirrhosis are not receiving appropriate HCC surveillance.