Liver cancer international最新文献

Advances in hepatology—such as noninvasive serum biomarkers (e.g., Fibrosure since 2004), imaging techniques (e.g., MR Elastography since 2009 and FibroScan since 2013), and effective direct-acting antivirals for the treatment of chronic hepatitis C—have likely influenced liver biopsy practices. We assessed the impact of these developments on biopsy frequency and indications. Pathology database (2003–2022) was queried for reports containing ‘biopsy’ or ‘bx’ and ‘liver’ or ‘hepat’, identifying 32 842 cases. A manually reviewed subset of non-consult, non-intraoperative biopsies (22%) was categorised as: (1) lesional, (2) diagnostic (initial workup), (3) transplant (all allograft biopsies), or (4) staging/prognostic (in chronic liver disease). This manually classified dataset was divided into training and test sets to develop a machine learning algorithm evaluating the remaining 14 319 non-classified cases. Autoregressive integrated moving average (ARIMA) model was applied to correlate changes in biopsy indications to interventions. Overall, the number of liver biopsies remained steady over 20 years, with declines in in-house biopsies offset by an uptrend in outside consults. The algorithm was evaluated on the test set yielding an F1 score of 0.95, then applied to the non-classified dataset, detecting proportional decreases in staging and transplant biopsies with proportional increases in diagnostic and lesional biopsies. ARIMA analysis identified a decline in allograft biopsies associated with the approval of direct-acting antiviral agents. A machine learning approach enabled accurate large-scale classification of liver biopsies, revealing evolving biopsy practices over time. This method may be applied across disciplines to evaluate the changing practices.

Binge drinking and excessive alcohol consumption are major public health concerns, and the COVID-19 pandemic may have exacerbated these issues. We aimed to compare the prevalence of binge and excessive alcohol use, as well as advanced liver fibrosis, among U.S. adults before and after the pandemic onset. We analysed 9533 adult participants from the National Health and Nutrition Examination Survey (NHANES) between 2017 and 2023. Pre-pandemic (2017–2020) and post-pandemic (2021–2023) cycles were identified. Binge drinking was defined as ≥ 5 drinks/occasion for men or ≥ 4 for women, and excessive alcohol use as ≥ 2 drinks/day (men) or ≥ 1 (women). Advanced fibrosis was assessed using transient elastography (≥ 9.6 kPa). Logistic regression models, incorporating NHANES weights, were used to evaluate associations. Among 9533 participants, binge drinking prevalence increased from 21.5% (2017–2020) to 27.9% (2021–2023; p < 0.001), while excessive alcohol use rose from 12.5% to 14.3% (p = 0.040). Notable increases in binge drinking were observed across multiple demographic groups, especially in older adults (≥ 60 years) and women. The prevalence of advanced fibrosis also significantly increased from 6.1% to 8.4% (p = 0.011). Binge drinking was independently associated with an elevated risk of advanced fibrosis after adjusting for age, sex, and metabolic risk factors (OR = 1.496 [95% CI, 1.084–2.065]). Binge and excessive drinking increased notably in the post-pandemic period, accompanied by rising rates of advanced liver fibrosis. These findings highlight the need for proactive screening, behavioural interventions, and policy measures to limit high-risk alcohol use, particularly as populations at historically lower risk appear at higher risk.

Cirrhotic cardiomyopathy (CCM) is prevalent in children with end-stage liver disease and associated with adverse peri-transplant outcomes. CCM in children remains poorly characterised and current definitions are restricted to derangements in left ventricular size and mass. Abnormal Left Ventricle Global Longitudinal Strain (GLS), a novel marker of subclinical systolic dysfunction, is now included in the adult definition of CCM. Its significance remains unknown in paediatric cirrhosis. We aimed to determine the prevalence and clinical significance of abnormal GLS in children with biliary atresia (BA) listed for liver transplantation (LT). Children with BA listed for LT (2013–2021), with a GLS value measured on a pre-LT 2D echocardiogram, were retrospectively evaluated. GLS values between 0% and −18% were considered abnormal per established norms. The frequency of decompensation and the need for extra-hepatic organ support while awaiting LT, and overall mortality (defined as death after listing up to 1 year post-LT) were evaluated as primary outcomes. 83 children were included in the study, median age 10 [IQR: 6, 17] months, 62% (52/83) female. The median GLS was −19.5[−17, −23] %. In the cohort, 31% (26/83) had abnormal GLS. Those with abnormal GLS had an increased frequency of decompensation on the waitlist (61% (16/26) vs. 33% (19/57); p = 0.019) and increased overall mortality (31% (8/26) vs. 7% (4/57); p = 0.007) compared to those with normal GLS. Abnormal GLS was independently associated with mortality when adjusted for age, PELD score and LV mass index. Abnormalities in GLS are prevalent and consequential in children with BA. This novel metric of subclinical systolic dysfunction should be further validated in paediatric cirrhosis to better define CCM in children and allow for risk stratification.

Efficient enrolment remains a major hurdle for MASH/MASLD trials, many of which require liver fat content (LFC) ≥ 8%. We aimed to develop and validate a predictive score based on routine clinical data, optimised for patients with type 2 diabetes (T2D) to prescreen individuals likely to have elevated LFC and thereby reduce screen failures and facilitate clinical trial enrolment. Data were pooled from multiple clinical studies (N = 1075, 53% male, age: 54 years) spanning a broad BMI and including individuals with suspected or confirmed MASLD (N = 694) and those with T2D (N = 478). LFC was quantified by MRI proton-density fat fraction (MRI-PDFF) or proton magnetic resonance spectroscopy (¹H-MRS). The study cohort was dichotomised at < 8% vs. ≥ 8% LFC, a criterion for clinical trial eligibility. Candidate models were trained and tested using multivariable logistic regression; comparators included the fatty liver index (FLI), hepatic steatosis index (HSI), and, where available, Vibration-Controlled Transient Elastography with Controlled Attenuation Parameter (VCTE-CAP). The ALERT score, based on ALT, triglycerides and T2D status, showed high accuracy for detecting LFC ≥ 8% (AUC 0.86, 95% CI 0.81–0.91), outperforming FLI (AUC 0.80, CI 0.74–0.86), HSI (AUC 0.76, CI 0.70–0.83), and VCTE-CAP (AUC 0.66, CI 0.58–0.74). Using a threshold of 0.60, ALERT achieved 91% specificity and 85% PPV. The overall screen failure rate was 5%, indicating strong enrichment for LFC ≥ 8%. The ALERT score, a simple three-variable score, enriches for LFC ≥ 8% with high specificity and PPV, offering a practical tool to streamline MASH/MASLD Phase 2–3 trial enrolment. The tool's performance in T2D and in a diverse real-world population supports its broad generalisability to current trial settings.

Hepatic diseases progress silently, leading to fibrosis, cirrhosis, and hepatocellular carcinoma. Although liver biopsy remains the gold standard for fibrosis assessment, it is limited by invasiveness and sampling variability. Non-invasive liver tests (NILTs) can mitigate biopsy-related risks. However, some NILTs are costly, and economic/implementation evidence remains limited due to small samples and variability across healthcare systems. This systematic review aimed to evaluate economic studies comparing the costs and benefits of NILTs versus liver biopsy in chronic liver disease. Comprehensive searches were conducted up to February 21, 2024, identifying cost and economic evaluation studies comparing NILTs and biopsy for fibrosis detection in individuals with hepatitis B, hepatitis C, alcoholic liver disease (ALD), and non-alcoholic fatty liver disease (NAFLD). Sources included PubMed, Embase, and Scopus, supplemented by searches in economic databases. Two reviewers independently screened, appraised, and extracted data. Of 478 studies identified, 17 met inclusion criteria, primarily from Europe and published after 2012. Most studies used cost-utility analyses adopting a public healthcare perspective and a lifetime horizon. Chronic viral hepatitis and NAFLD were the most studied conditions, with Fibroscan, Enhanced Liver Fibrosis (ELF), and FibroTest as the predominant NILTs. Outcomes included Quality-Adjusted Life Years (QALYs) and diagnostic accuracy. Incremental Cost-Effectiveness Ratios (ICERs) ranged from US$28 868 to US$150 000, influenced by factors such as test cost, screening age, and sequential strategies. Despite heterogeneity, most studies conclude that NILTs are cost-effective, particularly in combination, supporting their broader adoption in the management of chronic liver disease.

Trial Registration: PROSPERO: CRD42023404278

The oral cholate challenge test of liver health, intended for use in compensated advanced chronic liver disease, was launched through an Early Access Program (EAP) in 2023–2024. Tests were provided to 16 clinicians at five liver centres across the US. The tested patients (n = 129) represented a range of etiologies and stages of disease. Top clinical uses were: (1) informing the decision for endoscopy to test for varices (n = 56, 43%), (2) defining risk for large oesophageal varices (LEV) (n = 92, 71%), and (3) baseline for monitoring disease progression or treatment effects (n = 33, 26%). The test's disease severity index (DSI) stratified patients according to risk for portal hypertension and LEV: 49 (38%) low risk, 31 (24%) moderate risk and 49 (38%) high risk. The potential impact of DSI ≤ 18.3 on EGD avoidance (38%) in clinical practice replicated that which was observed in prior validation studies (41%).

Chemokine receptor type 5 (CCR5) is upregulated in the livers of patients with metabolic dysfunction–associated steatohepatitis (MASH). Leronlimab, a humanised IgG4κ monoclonal antibody, directly binds the extracellular domains of CCR5, modulates downstream signalling and potentially can slow, reverse or prevent fibrosis. The aim of this study was to evaluate the safety and efficacy of leronlimab in participants with MASH. Phase 2a, multicentre, two-part study evaluated two doses of once-weekly subcutaneous leronlimab for 13 weeks in participants with non-cirrhotic MASH diagnosed either histologically, by FibroScan, or by Shearwave ultrasound. 87 participants were enrolled: 60 were randomised to leronlimab 700 mg (n = 30) or to placebo (n = 30) (Part 1) and n = 27 allocated to the leronlimab 350 mg arm (Part 2 open-label). Baseline demographics and clinical characteristics were generally similar between Parts 1 and 2. The primary efficacy endpoint, absolute change from baseline in liver fat content assessed by MRI-PDFF at week 14, was not met for Part 1 (absolute increase of 0.42% leronlimab 700 mg versus 1.15% placebo) but was met for Part 2 (1.09% absolute reduction in the leronlimab 350 mg arm versus 1.12% increase placebo). The secondary efficacy endpoint, absolute change from baseline in MRI-cT1 at week 14, was not met for Part 1 but was met for Part 2. All drug-related adverse events were mild or moderate. This proof-of-concept study demonstrated that leronlimab has a favourable safety profile and was well tolerated. While in the open-label 350 mg arm of the study, leronlimab was associated with numerically mild antisteatotic and antifibrotic activity in patients with non-cirrhotic MASH, further evaluation in a randomised controlled trial is necessary to substantiate these results.

Trial Registration: ClinicalTrials.gov identifier: NCT04521114; https://clinicaltrials.gov/study/NCT04521114. The trial was first posted on 20 August 2020.

It has been revealed that cystic fibrosis liver disease, a rare disease, leads to endothelial aberrance with a pro-inflammatory phenotype. The mechanisms underlying endothelial aberrance remain to be explored. Furthermore, it was reported that mice with liver-specific deficiency of NAE1, a component of neddylation E1, show premature death and progressive development of multiple bloody fluid-filled cysts with up-regulated TNF signalling. Therefore, we investigated how neddylation and TNF signalling get involved in cyst formation, focusing on endothelial cells. Liver-specific deficiency of UBA3, the catalytic subunit of neddylation E1 and Tnf knockout (Tnf^−/−) mouse models were used. Histology was examined with haematoxylin and eosin staining. Serum levels of total bilirubin and direct bilirubin were measured to reflect duct injury. Fluorescent multiplex immunohistochemistry was performed to detect the number and necroptosis of endothelial cells. Neonatal liver-specific UBA3 deficiency leads to the formation of bloody cysts with signs of duct injury. CRISPR/Cas-mediated Tnf knockout fails to affect cyst formation and duct injury in Uba3^ΔLiver livers but abrogates bleeding. Liver-specific UBA3 deficiency results in a dramatic reduction of Lyve-1⁺ liver sinusoidal endothelial cells (LSECs) and a simultaneous tendency of increased CD34⁺ endothelial cells. The effects diminish in the absence of TNF-α. The reduction of LSECs upon liver-specific UBA3 deficiency is associated with enhanced necroptosis, which also diminishes in the absence of TNF-α. Neonatal liver-specific UBA3 deficiency leads to TNF-α-dependent bleeding during cyst formation through, at least partially, necroptosis-mediated damage of LSECs.

In individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) increased hepatic hepcidin gene expression, is associated with hepatic iron deposition, which is in turn associated with more severe steatohepatitis and fibrosis. We investigated single nucleotide polymorphisms (SNPs) associated with serum hepcidin level in MASLD. A targeted Genome Wide Association Studies (GWAS) was performed in individuals with biopsy-proven MASLD of European ancestry in the nonalcoholic steatohepatitis-clinical research network (NASH CRN) database I and PIVENS. Association between SNPs and serum hepcidin level was tested using PLINK2. Linear regression was performed to determine association with SNPs and serum hepcidin level in individuals with MASLD. MASLD cohort included 563 individuals, (65% female, 29% had diabetes-2, mean age = 49.7 ± 10.8 years, mean BMI = 34.8 ± 6.5 kg/m²). Mean hepcidin level was 71.6 ± 48.2 ng/ml, and mean ferritin level was 239.3 ± 270.1 ng/dl. After adjusting for age, sex, BMI, diabetes-2, and presence of hepatic iron staining, the SNP rs55959738 (T) on chromosome 6 was associated with lower serum hepcidin level (β = −0.48, se = 0.09, p = 3.29E-08) in the cohort. The association even after adjusting for PNPLA3 G allele or common pathogenic HFE variants (C282Y and H63D). The SNP rs55959738 is intergenic in location and is in linkage disequilibrium with SNORD genes. In MASLD, a novel SNP rs55959738 on chromosome 6 is associated with lower serum hepcidin level, independent of common HFE and PNPLA3 variants. Additional studies to explore the role of SNP rs55959738 on hepcidin mediated inflammation in MASLD.

The progression of chronic hepatitis caused by hepatitis C virus (HCV) is associated with abnormalities in amino acid metabolism. We aimed to characterise the changes in free amino acid (FAA) in the peripheral blood of HCV patients undergoing direct antiviral agents (DAAs). We retrospectively enrolled 183 HCV patients: 116 without hepatocellular carcinoma (HCC) treated with DAAs, and 67 with HCC (19 were treated with DAAs and 48 were not). Biochemical parameters, including 20 FAAs, were measured at four time points (before treatment, at SVR12, at SVR24, and at last follow-up) between 2006 and 2022. The mean observation period was 54 ± 25 months for patients without HCC and 42 ± 26 months for those with HCC. We examined the relationships among the branched-chain amino acid to tyrosine ratio (BTR) and clinical factors. Propensity score matching (PSM) was performed to compare outcomes in HCC patients who achieved sustained virological response (SVR) with those who did not. This was a retrospective study with no dietary intervention, and subgroup analyses were limited by sample size. In non-HCC patients, BTR significantly increased 12 weeks post-SVR and continued to increase throughout follow-up. This improvement was more marked in patients with advanced fibrosis. The changes in tyrosine were inversely correlated with those of M2BPGi, whereas those in BCAA were not. In HCC patients, those achieving SVR maintained their BTR, whereas untreated patients showed significant deterioration. After PSM, similar improvements in FAA imbalances occurred in post-SVR HCC patients. Clearance of HCV is associated with improvement of the BTR across patients with mild to advanced fibrosis or successfully treated HCC, suggesting that gradual recovery of amino acid imbalance reflects improved nutritional status.