Liver biopsy assessment by pathologists remains the gold standard for diagnosing metabolic dysfunction-associated steatotic liver disease (MASLD). Current automated image analysis tools for patient risk stratification are often proprietary or not applicable to whole slide images (WSIs). Here, we introduce "Liver-Quant," an open-source Python package for quantifying steatosis and fibrosis in liver WSIs.

Liver-Quant leverages colour and morphological features to measure Steatosis Proportionate Area (SPA) and Collagen Proportionate Area (CPA). We evaluated the method using an internal dataset of 414 WSIs from adult patients (Leeds Teaching Hospitals NHS Trust, 2016-2022) and an external public dataset (109 WSIs). Semi-quantitative scores were extracted from pathological reports. The Spearman rank coefficient (ρ) assessed correlations between computed SPA/CPA and pathologist scores.

Steatosis quantification showed a substantial correlation (ρ = 0.92), while fibrosis quantification yielded a moderate correlation (ρ = 0.51). We further investigated the impact of three staining dyes (Van Gieson (VG), Picro Sirius Red (PSR), and Masson's Trichrome (MTC)) on fibrosis quantification (n = 18). Stain normalisation yielded excellent agreement in CPA measurements across all three stains. Without normalisation, PSR achieved the strongest correlation with human scores (ρ = 0.9) followed by VG (ρ = 0.8) and MTC (ρ = 0.59). Finally, we explored the impact of apparent magnification on SPA and CPA. High-resolution images (0.25 or 0.50 μm per pixel (MPP)) were necessary for accurate SPA measurement, while lower resolution (10 MPP) sufficed for CPA measurements.

Liver-Quant offers an open-source solution for rapid and precise MASLD quantification in WSIs applicable to multiple histological stains.

Autoimmune hepatitis (AIH) is a rare immune-mediated chronic liver disease that is diagnosed based on a combination of biochemical, immunologic, and histologic features and the exclusion of other causes of liver disease. According to the new consensus criteria of the International Autoimmune Hepatitis Pathology Group (IAIHPG), the likely histologic features include a chronic hepatitis pattern of injury with a lymphoplasmacytic portal infiltrate, interface activity, and portal-based fibrosis. More than mild lobular hepatitis with any of the above features can also be diagnosed as likely AIH in the absence of features of another liver disease. Centrilobular injury with prominent hepatocellular necrosis and mononuclear inflammation may represent an acute-onset disease and indicate possible AIH in the absence of concurrent liver disease. Kupffer cell hyaline bodies and portal lymphocyte apoptosis are significantly associated with AIH, whereas emperipolesis and hepatocellular rosette formation are nonspecific features indicative of disease severity. Liver histology is an integral part of the clinical diagnostic scoring system and is required to confirm or support AIH diagnosis. Substitution of the histologic component of the simplified AIH scoring system with the consensus IAIHPG criteria has been proposed to optimize clinical diagnosis. This review explores the significant role of histopathology in AIH by analyzing its main features and current histologic diagnostic criteria, different AIH presentations, differential diagnosis, assessment of concurrent liver disease, and identification of AIH variants with primary cholangiopathy.

To achieve a historical perspective, the chronological changes in primary liver cancer over a 20-year period were investigated at a single institution, focusing on shifts in etiology and the impact on imaging and pathological findings using The Liver Imaging Reporting and Data System.

A retrospective study of surgically resected primary liver cancer in 680 patients from 2001 to 2020 resulted in 434 patients with 482 nodules being analyzed. Dynamic contrast-enhanced computed tomography imaging and the Liver Imaging Reporting and Data System 2018 classification were employed. Two pathologists and two radiologists independently evaluated specimens and images.

This study highlighted a significant decline in cases of viral hepatitis and cirrhosis in primary liver cancer patients but an increase in intrahepatic cholangiocarcinoma and scirrhous hepatocellular carcinoma. Notably, there was a rise in non-viral hepatitis cases, potentially pointing toward an increase in steatohepatitic hepatocellular carcinoma cases in the future. Intrahepatic cholangiocarcinoma, scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma tumors exhibited slightly different distributions in the Liver Imaging Reporting and Data System classification compared with ordinary hepatocellular carcinoma, which may reflect the presence of fibrosis and lipid in tumor parenchyma.

Consistent with past reports, this study demonstrated the emergence of primary liver cancer against a backdrop of non-viral and non-cirrhotic liver. Liver Imaging Reporting and Data System has been consistently useful in diagnosing primary liver cancer; however, among the histological subtypes of hepatocellular carcinoma, an increase is anticipated in scirrhous hepatocellular carcinoma and steatohepatitic hepatocellular carcinoma, which may present imaging findings different from those of ordinary hepatocellular carcinoma. This development may necessitate a reevaluation of the current approach for diagnosing and treating hepatocellular carcinoma based solely on imaging.

Background Early diagnosis of liver cirrhosis in patients with chronic liver disease (CLD) can help delay/prevent complications and thereby improve survival. The currently available diagnostic modalities for the non-invasive assessment of hepatic fibrosis, especially FibroScan, are costly and not widely available, whereas various non-invasive scores for the assessment of fibrosis are cumbersome. Hence, we aimed to develop an easy and simple score for predicting cirrhosis in patients from Eastern India suffering from CLD with a better diagnostic accuracy. Methodology This cross-sectional, observational study was conducted between September 2019 and September 2021 in East India. Our study participants were patients who had CLD of etiologies such as alcohol-related liver disease, non-alcoholic fatty liver disease, chronic viral hepatitis B, chronic viral hepatitis C, primary biliary cholangitis, and autoimmune hepatitis, who had undergone FibroScan of the liver. All demographic details were noted, and the patients were subjected to physical examination, followed by hematological as well as biochemical investigations, including liver function tests. Non-invasive scores (such as aspartate aminotransferase (AST) to platelet ratio index (APRI) and Fibrosis-4 score (FIB-4) and red cell distribution width (RDW) to platelet ratio (RPR)) were computed, and their diagnostic accuracy for prediction of advanced fibrosis and cirrhosis were evaluated by receiver operating characteristic curve (ROC curve) analysis with comparison of area under the ROC curves. Pearson correlation and logistic regression analysis were also performed to study the association of these scores with advanced fibrosis and cirrhosis. Results The area under the ROC (AUROC) curve of the APRI score, FIB-4 score, RPR, and RPR × AST for prediction of advanced liver fibrosis was 0.817, 0.799, 0.706, and 0.811, respectively. Similarly, the AUROC of the above scores for the prediction of cirrhosis was 0.889, 0.858, 0.797, and 0.898. However, the product of RPR and AST was superior than APRI and FIB-4 for predicting cirrhosis. An RPR × AST value above the cut-off of 4.818 can help predict liver cirrhosis with 85.7% sensitivity and 85.5% specificity. Pearson correlation and logistic regression analysis also proved the association of these scores with liver fibrosis. Conclusions RPR is a simple, inexpensive, and easily available marker for predicting liver cirrhosis. Nevertheless, the variable RPR × AST can predict liver cirrhosis in patients with CLD with even greater diagnostic accuracy.

Noninvasive tests are crucial for the management and follow-up of patients with autoimmune hepatitis, but their validation is limited because of insufficient data.

To investigate the diagnostic performance of three fibrosis noninvasive tests [FibroTest, vibration-controlled transient elastography (VCTE), and the fibrosis-4 index (FIB-4) and two activity biomarkers (alanine aminotransferase (ALT) and ActiTest].

This study enrolled 103 patients for whom liver biopsy, hepatic elastography results, and laboratory markers were available. Diagnostic performance was assessed with receiver operating characteristic (ROC) curves, the Obuchowski measure (OM), and the Bayesian latent class model.

FibroTest and VCTE outperformed FIB-4 in cases of significant fibrosis (≥ F2), with areas under the ROC curve of 0.83 [95% confidence interval (CI): 0.73-0.90], 0.86 (95%CI: 0.77-0.92), and 0.71 (95%CI: 0.60-0.80), respectively. The mean (standard error) OM values were 0.92 (0.01), 0.93 (0.01), and 0.88 (0.02) for FibroTest, VCTE, and FIB-4, respectively; FibroTest and VCTE performed comparably, and both were superior to FIB-4 (P = 0.03 and P = 0.005). The areas under the ROC curve values for activity biomarkers were 0.86 (95%CI: 0.76-0.92) for ActiTest and 0.84 (95%CI: 0.73-0.90) for ALT (P = 0.06). The OM values for ActiTest and ALT were 0.92 (0.02) and 0.90 (0.02), respectively (P = 0.005).

FibroTest and VCTE outperformed FIB-4 according to the OM. FibroTest-ActiTest facilitated the evaluation of both fibrosis and activity.

Compromised gill health is a critical cause of forfeited welfare in Atlantic salmon farming. Detecting and quantifying the early onset of gill disease is important to reveal initial inflicting stimuli. We collected gill samples of 45 Atlantic salmon from 2 commercial recirculating aquaculture systems (RASs) spanning fry-to-market-size fish with no clinical signs of gill disease. Gill samples were assessed histologically by 3 independent raters with different levels of experience. Semiquantitative scoring for 7 types of gill changes was carried out for 10 filaments per gill (450 filaments total) over 3 rounds on anonymized samples. Scores were summarized for each type of gill change. The assumed clinical relevance for each change was transformed into a category score, followed by an assessment of agreement within (intra) and between (inter) raters. A generalized linear model estimated the difference in score levels between raters. For each rater, intra-rater agreement was high for 6 gill changes and moderate for 1 gill change. Inter-rater agreement was moderate to almost-perfect, except for 2 gill changes; generalized linear model regression revealed systematic differences in score usage between the raters. Our scoring protocol worked satisfactorily for mucous cell amount, lamellar clubbing, lamellar hypertrophy and/or hyperplasia, and aneurysms, despite different levels of expertise in histologic evaluation. Intra-rater agreement was consistent, but differences existed for interlamellar hypercellularity, lamellar inflammation, and degeneration. Scoring subclinical gill changes is a challenge, and our scoring system for mild-to-moderate lesions may enable early intervention to limit the detrimental effects of poor gill health in RAS farming.

Given the inherent limitations of invasive biopsy and the insufficient accuracy of liver-related serum biomarkers, there is an urgent need for the development of reliable, non-invasive imaging techniques for the diagnosis of liver fibrosis. This study aims to investigate the correlation between magnetic resonance imaging (MRI) T1/T2 mapping sequences and biomarkers of collagen deposition and ongoing systemic inflammation, and to evaluate the potential of T1/T2 mapping as a non-invasive method for the accurate diagnosis of liver fibrosis.

A mouse model of carbon tetrachloride (CCl4)-induced liver fibrosis was established and T1/T2 mapping were performed at different weeks of treatment. The histopathological analysis, collagen quantification, and inflammatory factors measurements (IL-1, IL-6, TNF-α) were conducted to correlate MRI parameters with collagen deposition and inflammation. Statistical analysis was performed using IBM SPSS Statistics (version 22.0, Chicago, IL, USA) and Origin 2018 (OriginLab Corporation, Northampton, MA, USA).

The principal findings indicated that T1 and T2 values exhibited a progressive increase with the severity of fibrosis, demonstrating a positive correlation with collagen deposition and inflammatory factors, especially the hydroxyproline content (r = 0.880, P < 0.001). The HYP content exhibited a progressive increase with advancing fibrosis stages (ρ = 0.914, P < 0.001). Similarly, T1 values increased significantly across fibrosis stage(ρ = 0.854, P < 0.001). Statistical comparison of these coefficients revealed no significant difference (Z = 1.031, P = 0.303). ROC curve analysis showed that T1 mapping was more accurate than T2 mapping in detecting collagen deposition and inflammation.

This study highlighted the potential of T1/T2 mapping as non-invasive and quantitative biomarkers for diagnosing and staging liver fibrosis, providing new insights into the onset and progression of liver fibrosis.

Traditional liver fibrosis staging via percutaneous biopsy suffers from sampling bias and variable inter-pathologist agreement, highlighting the need for more objective techniques. Deep learning models for disease staging from medical images have shown potential to decrease diagnostic variability, with recent weakly supervised learning strategies showing promising results even with limited manual annotation.

To study the clustering-constrained attention multiple instance learning (CLAM) approach for staging liver fibrosis on trichrome whole slide images (WSIs) of children and young adults.

This is an ethics board approved retrospective study utilizing 217 trichrome WSI from pediatric liver biopsies for model development and testing. Two pediatric pathologists scored WSI using two liver fibrosis staging systems, METAVIR and Ishak. Cases were then secondarily categorized into either high- or low-stage liver fibrosis and used for model development. The CLAM pipeline was used to develop binary classification models for histological liver fibrosis. Model performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, and Cohen's Kappa.

The CLAM models showed strong diagnostic performance, with sensitivities up to 0.76 and AUCs up to 0.92 for distinguishing low- and high-stage fibrosis. The agreement between model predictions and average pathologist scores was moderate to substantial (Kappa: 0.57-0.69), whereas pathologist agreement on the METAVIR and Ishak scoring systems was only fair (Kappa: 0.39-0.46).

CLAM pipeline showed promise in detecting features important for differentiating low- and high-stage fibrosis from trichrome WSI based on the results, offering a promising objective method for liver fibrosis detection in children and young adults.

Accurate and reliable diagnosis and monitoring of hepatic fibrosis is increasingly important given the variable natural history in chronic liver disease (CLD) and expanding antifibrotic therapeutic options targeting reversibility of early-stage cirrhosis. This highlights the need to develop more refined and effective noninvasive techniques for the dynamic assessment of fibrogenesis and fibrolysis.

We conducted a literature review on PubMed, from 1 December 1970, to 1 November 2024, to evaluate and compare available blood-based and imaging-based noninvasive tools for hepatic fibrosis diagnosis and monitoring. Simple scores such as FIB-4 and NAFLD fibrosis score are suitable for excluding significant or advanced fibrosis, while tertiary centers should adopt complex scores and liver stiffness measurement as part of a secondary diagnostic and more comprehensive evaluation. Moreover, the advent of multiomics for high-resolution molecular profiling, and integration of artificial intelligence for noninvasive diagnostics holds promise for revolutionizing fibrosis monitoring and treatment through novel biomarker discovery and predictive omics-based algorithms.

The increased shift toward noninvasive diagnostics for liver fibrosis needs to align with personalized medicine, enabling more effective, tailored management strategies for patients with liver disease in the future.

Vessels encapsulating tumor clusters (VETC) pattern is tumor vasculature of HCC and is a predictor of prognosis and therapeutic efficacy. Recent radiological studies have demonstrated the predictability of VETC from preoperative images, but the mechanisms of image formation are not elucidated. This study aims to determine the relationship between VETC and intratumor heterogeneity in Gd-EOB-DTPA-enhanced magnetic resonance imaging (EOB-MRI) and to provide its pathological evidence.

Radiologists visually classified preoperative arterial- and hepatobiliary-phase EOB-MRI images of 204 surgically resected HCCs into patterns based on heterogeneity and signal intensity; these classifications were validated using texture analysis. Single and multiplex immunohistochemistry for CD34, h-caldesmon, and OATP1B3 were performed to evaluate VETC, arterial vessel density (AVD), and OATP1B3 expression. Recurrence-free survival was assessed using the generalized Wilcoxon test. The contribution of clinicoradiological factors to the prediction of VETC was evaluated by random forest and least absolute shrinkage and selection operator regression.

VETC was frequently found in tumors with arterial-phase heterogeneous hyper-enhancement patterns and in tumors with hepatobiliary-phase heterogeneous hyperintense/isointense patterns (HBP-Hetero). AVD and OATP1B3 expression positively correlated with signal intensity in the arterial and hepatobiliary phases, respectively. Intratumor spatial analysis revealed that AVD and OATP1B3 expression were lower in VETC regions than in tumor regions without VETC. Patients with HBP-Hetero tumors had shorter recurrence-free survival. Machine learning models highlighted the importance of serum PIVKA-II, tumor size, and enhancement pattern of arterial and hepatobiliary phase for VETC prediction.

VETC is associated with local reductions of both AVD and OATP1B3 expression, likely contributing to heterogeneous enhancement patterns in EOB-MRI. Evaluation of the arterial and hepatobiliary phases of EOB-MRI would enhance the predictability of VETC.

Hepatitis C virus (HCV) infection is a significant risk factor for liver cirrhosis and hepatocellular carcinoma (HCC). Traditionally, the primary prevention strategy for HCV-associated HCC has focused on removing infection through antiviral regimes. Currently, highly effective direct-acting antivirals (DAAs) offer extraordinary success across all patient categories, including cirrhotics. Despite these advancements, recent studies have reported that even after sustained virologic response (SVR), individuals with advanced liver disease/cirrhosis at the time of DAA treatment may still face risks of HCC occurrence or recurrence. Based on this premise, this review tries to shed light on the multiple mechanisms that establish a tumorigenic environment, first, during chronic HCV infection and then, after eventual viral eradication by DAAs. Furthermore, it reviews evidence reported by recent observational studies stating that the use of DAAs is not associated with an increased risk of HCC development but rather, with a significantly lower chance of liver cancer compared with DAA-untreated patients. In addition, it seeks to provide some practical guidance for clinicians, helping them to manage HCC surveillance of patients who have achieved SVR with DAAs.

To evaluate the diagnostic value of the FibroScan-AST (FAST) score, non-alcoholic fatty liver fibrosis score (NFS), FibroScan, and liver fibrosis index (FIB-4) for identifying fibrotic non-alcoholic steatohepatitis (NASH) in patients with chronic hepatitis B (CHB) with metabolic dysfunction-associated fatty liver disease (MAFLD).

All patients with CHB and MAFLD who underwent liver biopsy at the Zhenjiang Third Hospital affiliated with Jiangsu University between August 2010 and December 2022 were included in the analysis. The diagnostic accuracy of FAST, NFS, FibroScan, and FIB-4 for diagnosing NASH and liver fibrosis were evaluated based on the area under the receiver-operating characteristic curve (AUC).

A total of 156 patients with CHB combined with MAFLD were included, including 69 with NASH and fibrosis stage 2 or higher (NASH+F ≥ 2), and 16 with NASH and cirrhosis (NASH+F4). The AUC of FAST, NFS, liver stiffness measurement (LSM), and FIB-4 for diagnosing NASH+F ≥ 2 was 0.739 (p < 0.001), 0.643 (p = 0.006), 0.754 (p < 0.001), and 0.665 (p = 0.003), respectively. The specificity of FAST, NFS, LSM, and FIB-4 was 67%, 51.8%, 78.6% and 76.8%, respectively, and the sensitivity was 75%, 78.6%, 67.9%, and 53.6%, respectively. No significant differences were found between groups. The AUC of FAST, NFS, LSM, and FIB-4 for diagnosing NASH+F4 was 0.650 (p = 0.038), 0.725 (p = 0.001), 0.851 (p < 0.001), and 0.560 (p = 0.533), respectively. The specificity of the FAST, NFS, LSM, and FIB-4 was 55.9%, 50.0%, 71.6%, and 75.5%, respectively and the sensitivity was 80.0%, 100%, 100%, and 50.0%, respectively. The differences between AUCs of FIB-4 and FAST compared with LSM were 0.291 and 0.201, respectively (p < 0.05).

In patients with CHB combined with MAFLD, FAST did not have better accuracy than NFS and FIB-4 for predicting fibrotic NASH, whereas LSM had better accuracy than FAST and FIB-4.

Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2-/- mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers - the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.

The Baveno VII guidelines were proposed to identify which patients could safely avoid screening esophagogastroduodenoscopy (EGD) for gastroesophageal varices. We aimed to evaluate the frequency of gastric neoplasia in compensated advanced chronic liver disease (cACLD) patients who underwent EGD for screening of gastroesophageal varices (GOEV) compared to a healthy population.

Retrospective study that enrolled all cACLD patients who underwent EGD for GOEV screening (January 2008-June 2018) in a tertiary reference center. cACLD patients were compared with asymptomatic healthy individuals who underwent EGD in a private hospital setting (April 2017-March 2018).

We evaluated 1845 patients (481 cACLD patients, 1364 healthy individuals). A significantly higher frequency of gastric neoplasia was observed in patients with cACLD compared to healthy individuals (4.0% vs. 1.0 %; p < 0.001). Rare histopathological subtypes (WHO Classification) accounted for 28.7 % of gastric carcinoma cases in the cACLD cohort. Seven cases of gastric neoplasia (36.8 % of gastric neoplasia cases in the cACLD patients) were diagnosed in patients who, according to the Baveno VII criteria, would have not been submitted to EGD.

We found an increased frequency of gastric neoplasia in patients with cACLD in comparison with healthy individuals. In countries with intermediate-high risk for GC, continuing to perform EGD could be beneficial.

The aim of this study was to evaluate the role of serum human epididymis protein 4 (HE4) as a non-invasive biomarker for the diagnosis of liver fibrosis in children with chronic liver diseases (CLD). This case-control study was conducted at Benha University Hospital, Egypt, involving 60 children with CLD and 60 healthy children as a control group. HE4 levels were measured by ELISA and compared with liver biopsy results. The CLD group had significant higher HE4 (median: 110.7, IQR: 96.7-120.4 pmol/L) compared to control group (median 42.07, IQR: 41.67-43.05 pmol/L), p < .001. HE4 levels increased significantly with the degree of fibrosis and histological activity index. At a cutoff point >48.3 pmol/L, HE4 diagnosed cases with mild fibrosis with a sensitivity of 95% and specificity of 91.3%. At a cutoff point >144.3 pmol/L, HE4 diagnosed cases with severe fibrosis with a sensitivity of 98% and specificity of 93.1%. Serum HE4 is a potential non-invasive marker for detecting liver fibrosis and its severity in children with CLD.

Perioperative risks associated with acute hepatitis, cirrhosis, and chronic kidney disease are substantial and prevalence of underlying chronic kidney or liver disease is rising; surgeries in these populations have accordingly become more common. Optimal perioperative management in both cases is paramount; this article focuses on understanding disease pathophysiology, a targeted preoperative evaluation, accurate estimation of perioperative risk, and anticipation and management of common postoperative complications.

Autotaxin (ATX) is a newly identified liver fibrosis biomarker; however, its clinical usefulness remains unclear. Therefore, we analyzed the changes in patients with chronic hepatitis B virus infection treated with nucleos(t)ide analogs (NAs) to evaluate its usefulness. We also investigated the predictors of hepatocellular carcinoma development, including ATX, in patients with chronic hepatitis B based on their clinical characteristics.

This retrospective study included 179 patients with hepatitis B virus infection treated with NAs for >2 years. First, we measured the ATX levels before and up to 10 years after initiating entecavir (therapy for 88 patients whose serial ATX levels could be measured before and during entecavir therapy. Subsequently, for 179 patients whose ATX levels could be measured at the commencement of NAs, we examined the factors involved in developing hepatocellular carcinoma, including ATX.

The ATX levels showed a gradual and significant decrease during the observation period of up to 10 years. Multivariable analysis showed that a baseline ATX/upper limits of normal ratio ≥1.214, age, and alkaline phosphatase levels were independent risk factors for hepatocellular carcinoma development. The combination of age and ATX/upper limits of normal ratio was used to stratify the high-risk groups for liver carcinogenesis.

A decrease in ATX levels up to 10 years after the commencement of therapy suggested that ATX is a helpful biomarker in evaluating fibrosis in patients undergoing long-term NA therapy. Furthermore, this study showed that combining age and the baseline ATX/upper limits of normal ratio may help identify high-risk carcinogenesis groups.

Treatment strategies for preventing liver fibrosis have not yet been established. Letrozole, widely used for breast cancer, has recently been reported to suppress liver fibrosis in murine models. Therefore, we aimed to validate the suppressive effects of letrozole on liver fibrosis in the clinical setting. From 2006 to 2020, 23 consecutive patients who received continuous letrozole treatment for 24 months or more and had a liver fibrosis marker FIB-4 index of ≥ 2.30, were included. Forty-three patients who underwent anastrozole treatment for 24 months or more and had a liver fibrosis marker FIB-4 index of ≥ 2.30, were also included as controls. The Fisher exact, chi-square, unpaired Student t, and paired Student t test were used to analyze the data. The patient characteristics were similar between the letrozole- and anastrozole-treated patient groups. Among the letrozole-treated patients, the mean FIB-4 index tended to decline during letrozole treatment; a significant decrease was observed at 18 and 24 months compared with the baseline values (p = 0.044 and p = 0.013). In addition, the mean aspartate aminotransferase-to-platelet ratio index (APRI) decreased during letrozole treatment; the values at 18 and 24 months were significantly lower than those at baseline (p = 0.024 and p = 0.026). In contrast, among anastrozole-treated patients, the mean FIB-4 index and APRI did not change during anastrozole treatment. When changes in the FIB-4 index were further examined in a limited number of patients with a FIB-4 index ≥ 2.67, a significant reduction in the FIB-4 index at 24 months compared with baseline was also observed in letrozole-treated patients (p = 0.023), but not in anastrozole-treated patients. In conclusion, our findings support a possible suppressive effect of letrozole on liver fibrosis in the clinical setting. Further studies are required to better understand the pharmacological effects of letrozole.

Liver fibrosis is a key process in the progression of chronic liver disease to cirrhosis. Currently, early diagnosis and precise staging of liver fibrosis remain great challenges. Extracellular matrix (ECM) molecules expressed specifically during liver fibrosis are ideal targets for bioimaging and detection of liver fibrosis. Here, we report that fluorescent probes based on a nucleic acid aptamer (ZY-1) targeting cellular fibronectin (cFN), a critical ECM molecule significantly accumulating during liver fibrosis, are promising bioimaging agents for the staging of liver fibrosis. In the work, the outstanding binding affinity of ZY-1 to cFN was validated through an in vitro model of human-derived hepatic stellate cells (HSCs). Subsequently, we constructed different ZY-1-based fluorescent probes and explored the real-time imaging performance of these fluorescent probes in CCl4-induced mouse models of different liver fibrosis stages. The ZY-1-based fluorescent probes, for the first time, effectively identified and distinguished early-stage liver fibrosis (stage 3 of Ishak 6) from advanced liver fibrosis (stage 5 of Ishak 6). The proof-of-concept study provides compelling evidences that ZY-1-based probes are a promising tool for the early diagnosis and staging of liver fibrosis and paves the way for further development of clinical-related diagnosis strategies for fibrotic diseases of the liver and other organs. STATEMENT OF SIGNIFICANCE: Currently, early diagnosis and accurate staging of liver fibrosis continue to present significant challenges. This study demonstrates that fluorescent probes based on the nucleic acid aptamer ZY-1, which targets cellular fibronectin (cFN)-a crucial extracellular matrix (ECM) molecule that significantly accumulates during liver fibrosis-are promising bioimaging agents for staging liver fibrosis. The ZY-1-based fluorescent probes effectively identified and differentiated early-stage liver fibrosis from advanced liver fibrosis. This proof-of-concept study not only provides compelling evidence that ZY-1-based probes show promise for the early diagnosis and staging of liver fibrosis but also paves the way for further investigations into the use of ZY-1 in detecting other diseases associated with cFN.

There is an unmet clinical need for non-invasive imaging biomarkers that could replace liver biopsy in the management of patients with autoimmune hepatitis (AIH). In this study, we sought to evaluate the diagnostic accuracy of a simple uncorrected, non-contrast T1 mapping for detecting fibrosis and inflammation in AIH patients using histopathology as a reference standard.

Over 3 years, 33 patients with AIH were prospectively studied using a multiparametric liver MRI protocol which included T1 mapping. Biopsies were performed up to 3 months before imaging, and a standardized histopathological score for fibrosis (F0-F4) and inflammatory activity (PPA0-4) was used as a reference. Statistical analysis included independent t test, Mann-Whitney U-test, and ROC (receiver operating characteristic) analysis.

T1 mapping values were significantly higher in patients with advanced fibrosis (F0-2 vs. F3-4; p < 0.015), significant fibrosis (F0-1 vs. F2-4; p < 0.005), and significant inflammatory activity (PPA 0-1 vs. PPA 2-4 p = 0.048). Moreover, the technique demonstrated a good diagnostic performance in detecting significant (AUC 0.856) and advanced fibrosis (AUC 0.835), as well as significant inflammatory activity (AUC 0.763).

A rapid, simple, uncorrected, non-contrast T1 mapping sequence showed satisfactory diagnostic performance in comparison with histopathology for detecting significant tissue inflammation and fibrosis in AIH patients, being a potential non-invasive imaging biomarker for monitoring disease activity in such individuals.

The prediction of liver-related events (LRE) after sustained virological response (SVR) in HCV-advanced chronic liver disease (ACLD) patients is crucial. We aimed to evaluate incidence and risk factors of LRE in HCV-cirrhotic patients after SVR and to assess dynamic changes of liver stiffness in participants without LRE at the end of follow-up. We enrolled 575 consecutive patients with HCV-ACLD treated with DAAs and followed up for 5 years after SVR12. Overall, 98 (17%) patients developed any type of event, and HCC was the most frequent LRE. The incidence rate was 1.6 per 100 person-years (p/y) for both HCC and hepatic decompensation. Baseline LSM ≥ 20 kPa was the only independent predictor of hepatic decompensation, while LSM ≥ 20 kPa and male sex were independent predictors of HCC development. Among the 341 participants without LRE and with paired LSM, any LSM reduction was observed in 314 (92.1%), and half of them showed a decrease of LSM ≥ 20%. Among patients without LRE, 27.3% of participants without ≥20% LSM decrease at 2 years achieved the 5-year goal; in contrast, 31.6% of participants with ≥20% LSM decrease at 2 years lost it at 5 years. These findings provide evidence that baseline LSM is a tool to stratify patients at risk of developing LRE; the dynamic changes of LSM value suggest the need for monitoring this parameter over time.

Liver diseases have a global prevalence of 25%, accounting for 4% of all deaths worldwide, and are associated with a 36% increased risk of fatal and nonfatal cardiovascular events. Metabolic dysfunction-associated steatotic liver disease constitutes the liver expression of metabolic syndrome and represents the primary type of liver disease. Microscopical analysis of biopsies, which allows the evaluation of a small portion of tissue with inferences made to the entire organ, is considered the gold standard for determining the presence of liver diseases. However, potential sampling errors in liver biopsies are conceivable because the obtained tissue represents only a tiny fraction of the entire liver mass and may not accurately reflect the true pathological state. Studies have demonstrated the existence of sampling errors in liver biopsies, particularly concerning the severity of inflammation, degree of fibrosis, and the presence of cirrhosis. Also, clinical studies have shown that histopathological abnormalities are better detected in humans when liver samples are collected from both the right and the left lobes. However, a gap exists in clinical investigation to clarify the role of differences between these lobes in improving the diagnostic and prognostic for liver diseases. Building upon the heterogeneous nature of pathological alterations observed in liver lobes, this perspective review provided recommendations to enhance the precision of diagnosis and prognostic accuracy of liver diseases.

The impact of excluding intrahepatic segmental vessels from regions of interest (ROIs) on liver stiffness measurement (LSM) via magnetic resonance elastography (MRE) remains uncertain.

To determine the effect of excluding intrahepatic segmental vessels from ROIs on LSM obtained from MRE.

This retrospective analysis included 95 participants who underwent successful two-dimensional gradient recalled-echo MRE before hepatic tumor resection (n = 49) or living liver donation (n = 46). The conventional LSM was determined by manually drawing ROIs on the elastogram within the 95% confidence region, staying 1 cm within the liver capsule and excluding large hilar vessels, the gallbladder, hepatic lesions, and artifacts. In addition, the modified LSM was determined by excluding intrahepatic segmental vessels. LSMs obtained by the two methods were compared with paired sample signed-rank test. Diagnostic performance for advanced fibrosis was calculated and compared using McNemar's test and Delong's test. The stage of hepatic fibrosis was assessed using surgical specimens by the METAVIR system.

The modified LSM was larger than the conventional LSM (2.4 kPa vs. 2.2 kPa in reader 1; 2.7 kPa vs. 2.4 kPa in reader 2; P < 0.001). The modified LSM showed superior sensitivity (0.841 vs. 0.659 in reader 1; 0.864 vs. 0.705 in reader 2; P < 0.05) and area under the curve (0.901 vs. 0.820 in reader 1; 0.912 vs. 0.843 in reader 2; P < 0.05) for detecting advanced fibrosis (≥F3) than conventional LSM.

The exclusion of intrahepatic segmental vessels from ROIs in MRE affected the LSM and enhanced diagnostic performance for advanced fibrosis.

Liver resection is one of the best treatments for small hepatocellular carcinoma (HCC), but post-resection recurrence is frequent. Biotherapies have emerged as an efficient adjuvant treatment, making the identification of patients at high risk of recurrence critical. Microvascular invasion (mVI), poor differentiation, pejorative macrotrabecular architectures, and vessels encapsulating tumor clusters architectures are the most accurate histologic predictors of recurrence, but their evaluation is time-consuming and imperfect. Herein, a supervised deep learning-based approach with ResNet34 on 680 whole slide images (WSIs) from 107 liver resection specimens was used to build an algorithm for the identification and quantification of these pejorative architectures. This model achieved an accuracy of 0.864 at patch level and 0.823 at WSI level. To assess its robustness, it was validated on an external cohort of 29 HCCs from another hospital, with an accuracy of 0.787 at WSI level, affirming its generalization capabilities. Moreover, the largest connected areas of the pejorative architectures extracted from the model were positively correlated to the presence of mVI and the number of tumor emboli. These results suggest that the identification of pejorative architectures could be an efficient surrogate of mVI and have a strong predictive value for the risk of recurrence. This study is the first step in the construction of a composite predictive algorithm for early post-resection recurrence of HCC, including artificial intelligence-based features.

Previous studies had confirmed that some deep learning models had high diagnostic performance in staging liver fibrosis. However, training efficiency of models predicting liver fibrosis need to be improved to achieve rapid diagnosis and precision medicine.

The deep learning framework of EfficientNetV2-S was noted because of its faster training speed and better parameter efficiency compared with other models. Our study sought to develop noninvasive predictive models based on EfficientNetV2-S framework for staging liver fibrosis.

Patients with chronic liver disease who underwent multi-parametric abdominal MRI were included in the retrospective study. Data augmentation methods including horizontal flip, vertical flip, perspective transformation and edge enhancement were applied to multi-parametric MR images to solve the data imbalance between different liver fibrosis groups. The EfficientNetV2-S models were used for the prediction of liver fibrosis stages F1-2, F1-3, F3, F4 and F3-4. We evaluated the diagnostic performance of our models in training, validation, and test sets by using receiver operating characteristic curve (ROC) analysis.

The total training time of EfficientNetV2-S was about 6 h. For differentiating of F1-2 vs F3, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 96.2 %, 96.4 % and 96.0 % in the test set. The AUC in test set was 0.559. The accuracy, sensitivity and specificity were 82.1 %, 74.5 % and 89.6 % in the test set by using EfficientNetV2-S model to differentiate F1-2 vs F3-4, and the AUC in test set were 0.763. For differentiating F1-3 vs F4, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 71.5 %, 73.4 % and 69.5 % in the test set. The AUC was 0.553 in test set. For differentiating F1-2 vs F4, the accuracy, sensitivity and specificity of our model were 84.3 %, 80.2 % and 88.3 % in the test set, and the AUC was 0.715, respectively. For differentiating F3 vs F4, the accuracy, sensitivity and specificity of EfficientNetV2-S model were 92.5 %, 89.1 % and 95.6 % in the test set, and the AUC was 0.696 in the test set.

The EfficientNetV2-S models based on multi-parametric MRI had the feasibility for staging of liver fibrosis because they showed high training speed and diagnostic performance in our study.

Spontaneous ruptured hepatocellular carcinoma is an uncommon complication, and there are scarce data about non-cirrhotic patients. Tumor treatment is not standardized and the risk of peritoneal dissemination is unclear.

we analyzed the treatment and survival in patients with rHCC on non-cirrhotic liver.

One hundred and forty-one non-cirrhotic patients with hepatocellular carcinoma diagnosed by histology were included in a multicenter prospective registry (2018-2022). Seven of them (5%) presented with hemoperitoneum due to spontaneous rupture.

Liver disease was associated in three patients (42.9%). A single nodule was detected in three cases (42.9%). One patient had vascular invasion and none extrahepatic spread. Initial hemostatic therapy and sequential treatment was individualized. Patients with single nodule were treated: resection (one case) with recurrence at 4 months treated with TACE and sorafenib. TACE/TAE followed by surgery (two cases) one in remission 43 months later, the other had liver recurrence at 18 months and was transplanted. Patients with multiple lesions were treated: TAE/emergency surgery and subsequent systemic therapy (two cases), one received lenvatinib (1-year survival) and the other sorafenib (5-month survival). TAE and surgery with subsequent systemic therapy (one case). Initial hemostatic surgery, dying on admission (one case). No patient developed intraperitoneal metastasis. All patients with multiple lesions died by tumor. The 3-year survival rate was 42.9%.

Initial hemostasis was achieved in all patients by TAE/TACE or surgery. Subsequent treatment was individualized, based on tumor characteristics, regardless of rupture. Long-time remission could be achieved in single nodule patients.

The impact of postoperative bile leak on the prognosis of patients with hepatocellular carcinoma who underwent liver resection is controversial. This study aimed to investigate the prognostic impact of bile leak for patients with hepatocellular carcinoma who underwent liver resection.

Patients with hepatocellular carcinoma who underwent liver resection between 2009 and 2019 at Kobe University Hospital and Hyogo Cancer Center were included. After propensity score matching between the bile leak and no bile leak groups, differences in 5-year recurrence-free and overall survival rates were evaluated using the Kaplan-Meier method.

A total of 781 patients, including 43 with postoperative bile leak, were analyzed. In the matched cohort, 40 patients were included in each group. The 5-year recurrence-free survival rates after liver resection were 35% and 32% for the bile leak and no bile leak groups, respectively (P = 0.857). The 5-year overall survival rates were 44% and 54% for the bile leak and no bile leak groups, respectively (P = 0.216).

Overall, bile leak may not have a profound negative impact on the prognosis of patients with hepatocellular carcinoma who have undergone liver resection.

Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools.

Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist.

A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002).

MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria.

Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC.

Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043).

In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy.

This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

This study aimed to evaluate the diagnostic abilities of the non-invasive serum biomarkers to predict liver fibrosis staging and evaluate the progress of hepatitis B.

We enrolled 433 patients with chronic HBV infection had complete medical data available for the study, who underwent percutaneous liver biopsy. The extent of fibrosis was assessed using the modified METAVIR score. The predictive values of the non-invasive serum biomarkers were evaluated by the areas under the receiving operator characteristics curves (AUROCs) with 95% confidence intervals.

The proportion of males with progressive stages of liver fibrosis was relatively larger, and the average age of patients with cirrhosis stages is older than the non-cirrhotic stages. We found PLT, GGT, ALP, TB, FIB4 and GPR to be significantly associated with liver fibrosis in our cohort. GGT showed a sensitivity of 71.4% and specificity of 76.7% in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3), with an AUROC of 0.775 (95%CI 0.711-0.840).The AUROCs of the GPR in distinguishing cirrhosis (F4) from non-cirrhotic stages (F1-3) was 0.794 (95%CI 0.734-0.853), but it had a lower sensitivity of 59.2%. Additionally, GGT, FIB4, and GPR could differentiate advanced fibrosis (F3-4) from non-advanced fibrosis (F1-2) among individuals with chronic hepatitis B, with AUROCs of 0.723 (95%CI 0.668-0.777), 0.729 (95%CI 0.675-0.782), and 0.760 (95%CI: 0.709-0.811) respectively.

GGT was a better biomarker to distinguish cirrhosis (F4) from non-cirrhotic stages (F1-3), while GPR was a better biomarker to identify advanced fibrosis (F3-4) and non-advanced fibrosis (F1-2) in patients with chronic hepatitis B.

Liver fibrosis is the result of chronic liver injury of different etiologies produced by an imbalance between the synthesis and degeneration of the extracellular matrix and dysregulation of physiological mechanisms. Liver has a high regenerative capacity in the early stage of chronic diseases so a prompt liver fibrosis detection is important. Consequently, an easy and economic tool that could identify patients with liver fibrosis at the initial stages is needed. To achieve this, many non-invasive serum direct, such as hyaluronic acid or metalloproteases, and indirect biomarkers have been proposed to evaluate liver fibrosis. Also, there have been developed formulas that combine these biomarkers, some of them also introduce clinical and/or demographic parameters, like FIB-4, non-alcoholic fatty liver disease fibrosis score (NFS), enhance liver fibrosis (ELF) or Hepamet fibrosis score (HFS). In this manuscript we critically reviewed different serum biomarkers and formulas for their utility in the diagnosis and progression of liver fibrosis.