Performance of spleen stiffness measurement to rule out high-risk varices in patients with porto-sinusoidal vascular disorder.

BACKGROUND AND AIMS: Baveno VII consensus suggests that screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa as they have a low probability of high-risk varices (HRV). Conversely, screening endoscopy is required in all patients with porto-sinusoidal vascular disorder (PSVD). This study aimed to evaluate the performance of SSM-VCTE to rule out HRV in patients with PSVD and signs of portal hypertension. APPROACH AND RESULTS: We retrospectively included patients with PSVD, ≥1 sign of portal hypertension, without a history of variceal bleeding, who underwent an SSM-VCTE within 2 years before or after an upper endoscopy in 21 VALDIG centers, divided into a derivation and a validation cohort. One hundred fifty-four patients were included in the derivation cohort; 43% had HRV. By multivariable logistic regression analysis, SSM-VCTE >40 kPa and serum bilirubin ≥1 mg/dL were associated with HRV. SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL had a sensitivity of 96% to rule out HRV and could spare 38% of screening endoscopies, with 4% of HRV missed, and a 95% negative predictive value. In the validation cohort, including 155 patients, SSM combined with bilirubin could spare 21% of screening endoscopies, with 4% of HRV missed and a 94% negative predictive value. CONCLUSIONS: This study gathering a total of 309 patients with PSVD showed that SSM-VCTE ≤40 kPa combined with bilirubin <1 mg/dL identifies patients with PSVD and portal hypertension with a probability of HRV <5%, in whom screening endoscopy can be spared.

Portal vein thrombosis: diagnosis, management, and endpoints for future clinical studies.

Portal vein thrombosis (PVT) refers to the development of a non-malignant obstruction of the portal vein, its branches, its radicles, or a combination. This Review first provides a comprehensive overview of all aspects of PVT, namely the specifics of the portal venous system, the risk factors for PVT, the pathophysiology of portal hypertension in PVT, the interest in non-invasive tests, as well as therapeutic approaches including the effect of treating risk factors for PVT or cause of cirrhosis, anticoagulation, portal vein recanalisation by interventional radiology, and prevention and management of variceal bleeding in patients with PVT. Specific issues are also addressed including portal cholangiopathy, mesenteric ischaemia and intestinal necrosis, quality of life, fertility, contraception and pregnancy, and PVT in children. This Review will then present endpoints for future clinical studies in PVT, both in patients with and without cirrhosis, agreed by a large panel of experts through a Delphi consensus process. These endpoints include classification of portal vein thrombus extension, classification of PVT evolution, timing of assessment of PVT, and global endpoints for studies on PVT including clinical outcomes. These endpoints will help homogenise studies on PVT and thus facilitate reporting, comparison between studies, and validation of future studies and trials on PVT.

Making sense of scattering: Seeing microstructure through shear waves.

The physics of shear waves traveling through matter carries fundamental insights into its structure, for instance, quantifying stiffness for disease characterization. However, the origin of shear wave attenuation in tissue is currently not properly understood. Attenuation is caused by two phenomena: absorption due to energy dissipation and scattering on structures such as vessels fundamentally tied to the material's microstructure. Here, we present a scattering theory in conjunction with magnetic resonance imaging, which enables the unraveling of a material's innate constitutive and scattering characteristics. By overcoming a three-order-of-magnitude scale difference between wavelength and average intervessel distance, we provide noninvasively a macroscopic measure of vascular architecture. The validity of the theory is demonstrated through simulations, phantoms, in vivo mice, and human experiments and compared against histology as gold standard. Our approach expands the field of imaging by using the dispersion properties of shear waves as macroscopic observable proxies for deciphering the underlying ultrastructures.

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.

Factors associated with high costs of patients with metabolic dysfunction-associated steatotic liver disease: an observational study using the French CONSTANCES cohort.

BACKGROUND & AIMS: Despite its high prevalence in the western world metabolic dysfunction-associated steatotic liver disease (MASLD) does not benefit from targeted pharmacological therapy. We measured healthcare utilisation and identified factors associated with high-cost MASLD patients in France. METHODS: The prevalent population with MASLD (including non-alcoholic steatohepatitis) in the CONSTANCES cohort, a nationally representative sample of 200,000 adults aged between 18 and 69, was linked to the French centralised national claims database (SNDS). Study participants were identified by the fatty liver index (FLI) over the period 2015-2019. MASLD individuals were classified according as "high-cost" (above 90th percentile) or "non-high cost" (below 90th percentile). Factors significantly associated with high costs were identified using a multivariate logistic regression model. RESULTS: A total of 14,437 predominantly male (69%) participants with an average age of 53 ± SD 12 years were included. They mainly belonged to socially deprived population groups with co-morbidities such as diabetes, high blood pressure, mental health disorders and cardiovascular complications. The average expenditure was €1860 ± SD 4634 per year. High-cost MASLD cost €10,863 ± SD 10,859 per year. Conditions associated with high-cost were mental health disorders OR 1.79 (1.44-2.22), cardiovascular diseases OR 1.54 (1.21-1.95), metabolic comorbidities OR 1.50 (1.25-1.81), and respiratory disease OR 1.50 (1.11-2.00). The 10% high-cost participants accounted for 58% of the total national health care expenditures for MASLD. CONCLUSION: Our results emphasize the need for comprehensive management of the comorbid conditions which were the major cost drivers of MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in European countries, affecting 4­50% of the European population. Confirmation of diagnosis requires liver biopsy which is an invasive procedure. We studied the healthcare costs of patients with MASLD in order to identify cost predictors and cost drivers. We found that patients cost on average €1860 per year. Conditions associated with high-cost were mental health disorders, cardiovascular diseases, metabolic comorbidities, and respiratory disease.

Macroscopic Characterization of Hepatocellular Carcinoma: An Underexploited Source of Prognostic Factors.

The macroscopic appearance of a tumor such as hepatocellular carcinoma (HCC) may be defined as its phenotype which is de facto dictated by its genotype. Therefore, macroscopic characteristics of HCC are unlikely random but rather reflect genomic traits of cancer, presumably acting as a valuable source of information that can be retrieved and exploited to infer prognosis. This review aims to provide a comprehensive overview of the available data on the prognostic value of macroscopic characterization in HCC. A total of 57 studies meeting eligible criteria were identified, including patients undergoing liver resection (LR; 47 studies, 83%) or liver transplant (LT; 9 studies, 16%). The following macroscopic variables were investigated: tumor size (n = 42 studies), number of nodules (n = 28), vascular invasion (n = 24), bile duct invasion (n = 6), growth pattern (n = 15), resection margin (n = 11), tumor location (n = 6), capsule (n = 2) and satellite (n = 1). Although the selected studies provided insightful data with notable prognostic performances, a lack of standardization and substantial gaps were noted in the report and the analysis of gross findings. This topic remains incompletely covered. While the available studies underscored the value of macroscopic variables in HCC prognostication, important lacks were also observed. Macroscopic characterization of HCC is likely an underexploited source of prognostic factors that must be actively explored by future multidisciplinary research.

Role of the fatty pancreatic infiltration in pancreatic oncogenesis.

Although pancreatic precancerous lesions are known to be related to obesity and fatty pancreatic infiltration, the mechanisms remain unclear. We assessed the role of fatty infiltration in the process of pancreatic oncogenesis and obesity. A combined transcriptomic, lipidomic and pathological approach was used to explore neoplastic transformations. Intralobular (ILF) and extralobular (ELF) lipidomic profiles were analyzed to search for lipids associated with pancreatic intraepithelial neoplasia (PanINs) and obesity; the effect of ILF and ELF on acinar tissue and the histopathological aspects of pancreatic parenchyma changes in obese (OB) and non-obese patients. This study showed that the lipid composition of ILF was different from that of ELF. ILF was related to obesity and ELF-specific lipids were correlated to PanINs. Acinar cells were shown to have different phenotypes depending on the presence and proximity to ILF in OB patients. Several lipid metabolic pathways, oxidative stress and inflammatory pathways were upregulated in acinar tissue during ILF infiltration in OB patients. Early acinar transformations, called acinar nodules (AN) were linked to obesity but not ELF or ILF suggesting that they are the first reversible precancerous pancreatic lesions to occur in OB patients. On the other hand, the number of PanINs was higher in OB patients and was positively correlated to ILF and ELF scores as well as to fibrosis. Our study suggests that two types of fat infiltration must be distinguished, ELF and ILF. ILF plays a major role in acinar modifications and the development of precancerous lesions associated with obesity, while ELF may play a role in the progression of PDAC.

Biliary tract cancers: French national clinical practice guidelines for diagnosis, treatments and follow-up (TNCD, SNFGE, FFCD, UNICANCER, GERCOR, SFCD, SFED, AFEF, SFRO, SFP, SFR, ACABi, ACHBPT).

INTRODUCTION: This document is a summary of the French intergroup guidelines of the management of biliary tract cancers (BTC) (intrahepatic, perihilar and distal cholangiocarcinomas, and gallbladder carcinomas) published in September 2023, available on the website of the French Society of Gastroenterology (SNFGE) (www.tncd.org). METHODS: This collaborative work was conducted under the auspices of French medical and surgical societies involved in the management of BTC. Recommendations were graded in three categories (A, B and C) according to the level of scientific evidence until August 2023. RESULTS: BTC diagnosis and staging is mainly based on enhanced computed tomography, magnetic resonance imaging and (endoscopic) ultrasound-guided biopsy. Treatment strategy depends on BTC subtype and disease stage. Surgery followed by adjuvant capecitabine is recommended for localised disease. No neoadjuvant treatment is validated to date. Cisplatin-gemcitabine chemotherapy combined to the anti-PD-L1 inhibitor durvalumab is the first-line standard of care for advanced disease. Early systematic tumour molecular profiling is recommended to screen for actionable alterations (IDH1 mutations, FGFR2 rearrangements, HER2 amplification, BRAFV600E mutation, MSI/dMMR status, etc.) and guide subsequent lines of treatment. In the absence of actionable alterations, FOLFOX chemotherapy is the only second-line standard-of-care. No third-line chemotherapy standard is validated to date. CONCLUSION: These guidelines are intended to provide a personalised therapeutic strategy for daily clinical practice. Each individual BTC case should be discussed by a multidisciplinary team.

Prospective head-to-head comparison of non-invasive scores for diagnosis of fibrotic MASH in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-invasive scores have been proposed to identify patients with fibrotic, metabolic dysfunction-associated steatohepatitis (MASH), who are at the highest risk of progression to complications of cirrhosis and may benefit from pharmacologic treatments. However, data in patients with type 2 diabetes (T2DM) are lacking. The aim of this multicenter prospective study was to perform a head-to-head comparison of FAST (FibroScan-aspartate aminotransferase [AST]), MAST (MRI-AST), MEFIB (magnetic resonance elastography [MRE] plus FIB-4), and FNI (fibrotic NASH index) for detecting fibrotic MASH in patients with T2DM. METHODS: A total of 330 outpatients with T2DM and biopsy-proven metabolic dysfunction-associated steatotic liver disease (MASLD) from the QUID-NASH study (NCT03634098), who underwent FibroScan, MRI-proton density fat fraction and MRE at the time of liver biopsy were studied. The main outcome was fibrotic MASH, defined as NAS ≥4 (with at least one point for each parameter) and fibrosis stage ≥2 (centrally reviewed). RESULTS: All data for score comparisons were available for 245 patients (median age 59 years, 65% male, median BMI 31 kg/m2; fibrotic MASH in 39%). FAST and MAST had similar accuracy (AUROCs 0.81 vs. 0.79, p = 0.41) but outperformed FNI (0.74; p = 0.01) and MEFIB (0.68; p <0.0001). When using original cut-offs, MAST outperformed FAST, MEFIB and FNI when comparing the percentage of correctly classified patients, in whom liver biopsy would be avoided (69% vs. 48%, 46%, 39%, respectively; p <0.001). When using cut-offs specific to our population, FAST outperformed FNI and MAST (56% vs. 40%, and 38%, respectively; p <0.001). CONCLUSION: Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. IMPACT AND IMPLICATIONS: Among patients with type 2 diabetes (T2DM), identifying those with metabolic dysfunction-associated steatohepatitis and significant fibrosis, who are the most at risk of developing clinical liver-related outcomes and who may benefit from pharmacologic treatments, is an unmet need. In this prospective multicenter study, we compared four non-invasive scores, three based on imaging (MRI or ultrasound technologies) and one on laboratory blood tests, for this purpose, using original and study-specific cut-offs. Our findings show that FAST, MAST, MEFIB and FNI are accurate non-invasive tools to identify patients with T2DM and fibrotic MASH in secondary/tertiary diabetes clinics. Cut-offs adapted to the T2DM population should be considered. TRIAL REGISTRATION NUMBER: NCT03634098.

Primary liver cancer classification from routine tumour biopsy using weakly supervised deep learning.

Background & Aims: The diagnosis of primary liver cancers (PLCs) can be challenging, especially on biopsies and for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We automatically classified PLCs on routine-stained biopsies using a weakly supervised learning method. Method: We selected 166 PLC biopsies divided into training, internal and external validation sets: 90, 29 and 47 samples, respectively. Two liver pathologists reviewed each whole-slide hematein eosin saffron (HES)-stained image (WSI). After annotating the tumour/non-tumour areas, tiles of 256x256 pixels were extracted from the WSIs and used to train a ResNet18 neural network. The tumour/non-tumour annotations served as labels during training, and the network's last convolutional layer was used to extract new tumour tile features. Without knowledge of the precise labels of the malignancies, we then applied an unsupervised clustering algorithm. Results: Pathological review classified the training and validation sets into hepatocellular carcinoma (HCC, 33/90, 11/29 and 26/47), intrahepatic cholangiocarcinoma (iCCA, 28/90, 9/29 and 15/47), and cHCC-CCA (29/90, 9/29 and 6/47). In the two-cluster model, Clusters 0 and 1 contained mainly HCC and iCCA histological features. The diagnostic agreement between the pathological diagnosis and the two-cluster model predictions (major contingent) in the internal and external validation sets was 100% (11/11) and 96% (25/26) for HCC and 78% (7/9) and 87% (13/15) for iCCA, respectively. For cHCC-CCA, we observed a highly variable proportion of tiles from each cluster (cluster 0: 5-97%; cluster 1: 2-94%). Conclusion: Our method applied to PLC HES biopsy could identify specific morphological features of HCC and iCCA. Although no specific features of cHCC-CCA were recognized, assessing the proportion of HCC and iCCA tiles within a slide could facilitate the identification of cHCC-CCA. Impact and implications: The diagnosis of primary liver cancers can be challenging, especially on biopsies and for combined hepatocellular-cholangiocarcinoma (cHCC-CCA). We automatically classified primary liver cancers on routine-stained biopsies using a weakly supervised learning method. Our model identified specific features of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Despite no specific features of cHCC-CCA being recognized, the identification of hepatocellular carcinoma and intrahepatic cholangiocarcinoma tiles within a slide could facilitate the diagnosis of primary liver cancers, and particularly cHCC-CCA.

Spatial characterisation of ß-catenin-mutated hepatocellular adenoma subtypes by proteomic profiling of the tumour rim.

Background & Aims: Hepatocellular adenomas (HCAs) are rare, benign, liver tumours classified at the clinicopathological, genetic, and proteomic levels. The ß-catenin-activated (b-HCA) subtypes harbour several mutation types in the ß-catenin gene (CTNNB1) associated with different risks of malignant transformation or bleeding. Glutamine synthetase is a surrogate marker of ß-catenin pathway activation associated with the risk of malignant transformation. Recently, we revealed an overexpression of glutamine synthetase in the rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA compared with the rest of the tumour. A difference in vascularisation was found in this rim shown by diffuse CD34 staining only at the tumour centre. Here, we aimed to characterise this tumour heterogeneity to better understand its physiopathological involvement. Methods: Using mass spectrometry imaging, genetic, and proteomic analyses combined with laser capture microdissection, we compared the tumour centre with the tumour rim and with adjacent non-tumoural tissue. Results: The tumour rim harboured the same mutation as the tumour centre, meaning both parts belong to the same tumour. Mass spectrometry imaging showed different spectral profiles between the rim and the tumour centre. Proteomic profiling revealed the significant differential expression of 40 proteins at the rim compared with the tumour centre. The majority of these proteins were associated with metabolism, with an expression profile comparable with a normal perivenous hepatocyte expression profile. Conclusions: The difference in phenotype between the tumour centres and tumour rims of exon 3 S45-mutated b-HCA and exon 7/8-mutated b-HCA does not depend on CTNNB1 mutational status. In a context of sinusoidal arterial pathology, tumour heterogeneity at the rim harbours perivenous characteristics and could be caused by a functional peripheral venous drainage. Impact and implications: Tumour heterogeneity was revealed in ß-catenin-mutated hepatocellular adenomas (b-HCAs) via the differential expression of glutamine synthase at tumour rims. The combination of several spatial approaches (mass spectrometry imaging, genetic, and proteomic analyses) after laser capture microdissection allowed identification of a potential role for peripheral venous drainage underlying this difference. Through this study, we were able to illustrate that beyond a mutational context, many factors can downstream regulate gene expression and contribute to different clinicopathological phenotypes. We believe that the combinations of spatial analyses that we used could be inspiring for all researchers wanting to access heterogeneity information of liver tumours.

Visco-Elastic Parameters at Three-Dimensional MR Elastography for Diagnosing Non-Alcoholic Steatohepatitis and Substantial Fibrosis in Mice.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and is a growing cause of liver cirrhosis and cancer. The performance of the magnetic resonance elastography (MRE) visco-elastic parameters in diagnosing progressive forms of NAFLD, including nonalcoholic steatohepatitis (NASH) and substantial fibrosis (F ≥ 2), needs to be clarified. PURPOSE: To assess the value of three-dimensional MRE visco-elastic parameters as markers of NASH and substantial fibrosis in mice with NAFLD. STUDY TYPE: Prospective. ANIMAL MODEL: Two mouse models of NAFLD were induced by feeding with high fat diet or high fat, choline-deficient, amino acid-defined diet. FIELD STRENGTH/SEQUENCE: 7T/multi-slice multi-echo spin-echo MRE at 400 Hz with motion encoding in the three spatial directions. ASSESSMENT: Hepatic storage and loss moduli were calculated. Histological analysis was based on the NASH Clinical Research Network criteria. STATISTICAL TESTS: Mann-Whitney, Kruskal-Wallis tests, Spearman rank correlations and multiple regressions were used. Diagnostic performance was assessed with areas under the receiver operating characteristic curves (AUCs). P value <0.05 was considered significant. RESULTS: Among the 59 mice with NAFLD, 21 had NASH and 20 had substantial fibrosis (including 8 mice without and 12 mice with NASH). The storage and loss moduli had similar moderate accuracy for diagnosing NASH with AUCs of 0.67 and 0.66, respectively. For diagnosing substantial fibrosis, the AUC of the storage modulus was 0.73 and the AUC of the loss modulus was 0.81, indicating good diagnostic performance. Using Spearman correlations, histological fibrosis, inflammation and steatosis, but not ballooning, were significantly correlated with the visco-elastic parameters. Using multiple regression, fibrosis was the only histological feature independently associated with the visco-elastic parameters. CONCLUSION: MRE in mice with NAFLD suggests that the storage and loss moduli have good diagnostic performance for detecting progressive NAFLD defined as substantial fibrosis rather than NASH. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY STAGE: 2.

Identification of liver transplant biopsy phenotypes associated with distinct liver biological markers and allograft survival.

The intricate association between histologic lesions and circulating antihuman leucocyte antigen donor-specific antibodies (DSA) in liver transplantation (LT) requires further clarification. We conducted a probabilistic, unsupervised approach in a comprehensively well-annotated LT cohort to identify clinically relevant archetypes. We evaluated 490 pairs of LT biopsies with DSA testing from 325 recipients transplanted between 2010 and 2020 across 3 French centers and an external cohort of 202 biopsies from 128 recipients. Unsupervised archetypal analysis integrated all clinico-immuno-histologic parameters of each biopsy to identify biopsy archetypes. The median time after LT was 1.17 (interquartile range, 0.38-2.38) years. We identified 7 archetypes distinguished by clinico-immuno-histologic parameters: archetype #1: severe T cell-mediated rejection (15.9%); #2: chronic rejection with ductopenia (1.8%); #3: architectural and microvascular damages (3.5%); #4: (sub)normal (55.9%); #5: mild T cell-mediated rejection (4.9%); #6: acute antibody-mediated rejection (6.5%); and #7: chronic rejection with DSA (11.4%). Cell infiltrates vary in the archetype. These archetypes were associated with distinct liver biological markers and allograft outcomes. These findings remained consistent when stratified using the patient's age or indications for LT, with good performance in the external cohort (mean highest probability assignment = 0.58, standard deviation ± 0.17). In conclusion, we have identified clinically meaningful archetypes, providing valuable insights into the intricate DSA-histology association, which may help standardize liver allograft pathology classification.

Rivaroxaban Prophylaxis in Noncirrhotic Portal Vein Thrombosis.

BACKGROUND: In patients with noncirrhotic chronic portal vein thrombosis (PVT), the benefit of long-term anticoagulation is unknown. We assessed the effects of rivaroxaban on the risk of venous thromboembolism and portal hypertension-related bleeding in such patients. METHODS: In this multicenter, controlled trial, we randomly assigned patients with noncirrhotic chronic PVT without major risk factors for thrombosis to receive either rivaroxaban 15 mg/day or no anticoagulation. The primary end point was 2-year thrombosis-free survival. Secondary end points included the occurrence of site-specific thromboses and major bleeding events. RESULTS: A total of 111 participants were enrolled in the trial, with a mean age of 50.4±13.2 years; 58% of participants were men. An unplanned interim analysis was requested by the independent data safety monitoring board (DSMB) after 10 thrombotic events occurred. The thrombosis incidence rate was 0 per 100 person-years in the rivaroxaban group and 19.71 per 100 person-years (95% confidence interval, 7.49 to 31.92) in the no anticoagulation group (log-rank P=0.0008) after a median follow-up of 11.8 months. Based on the interim analysis, the DSMB recommended switching patients from the no anticoagulation group to anticoagulation. After a median follow-up of 30.3 months (intraquartile range, 24.3 to 47.8), major bleeding occurred in two patients receiving rivaroxaban and in one patient not receiving anticoagulation. No deaths occurred. CONCLUSIONS: After a median follow-up of 11.8 months, among patients with noncirrhotic chronic PVT without major risk factors for thrombosis, daily rivaroxaban reduced the incidence of venous thromboembolism and did not increase major bleeding events. (Funded by grants from the French Ministry of Health and the Association de Malades des Vaisseaux du foie; ClinicalTrials.gov number, NCT02555111.)