Acute liver failure (ALF) is defined as rapid onset coagulopathy and encephalopathy in patients without a prior history of liver disease. We performed untargeted and targeted serum proteomics to delineate processes occurring in adult patients with ALF and to identify potential biomarkers.

Sera of 319 adult patients with ALF (∼50% acetaminophen [APAP]-related cases) were randomly selected from admission samples of the multicenter USA Acute Liver Failure Study Group consortium and subdivided into discovery/validation cohorts. They were analyzed using untargeted proteomics with mass spectroscopy and a serum cytokine profiling and compared with 30 healthy controls. The primary clinical outcome was 21-day transplant-free survival. Single-cell RNAseq data mapped biomarkers to cells of origin; functional enrichment analysis provided mechanistic insights. Novel prognostic scores were compared with the model for end-stage liver disease and ALFSG prognostic index scores.

In the discovery cohort, 117 proteins differed between patients with ALF and healthy controls. There were 167 proteins associated with APAP-related ALF, with the majority being hepatocyte-derived. Three hepatocellular proteins (ALDOB, CAT, and PIGR) robustly and reproducibly discriminated APAP from non-APAP cases (AUROCs ∼0.9). In the discovery cohort, 37 proteins were related to 21-day outcome. The key processes associated with survival were acute-phase response and hepatocyte nuclear factor 1α signaling. SERPINA1 and LRG1 were the best individual discriminators of 21-day transplant-free survival in both cohorts. Two models of blood-based proteomic biomarkers outperformed the model for end-stage liver disease and ALFSG prognostic index and were reproduced in the validation cohort (AUROCs 0.83-0.86) for 21-day transplant-free survival.

Proteomics and cytokine profiling identified new, reproducible biomarkers associated with APAP etiology and 21-day outcome. These biomarkers may improve prognostication and understanding of the etiopathogenesis of ALF but need to be independently validated.

Acute liver failure (ALF) is a sudden, and severe condition associated with high fatality. More sensitive and specific prognostic scores are urgently needed to facilitate decision-making regarding liver transplantation in patients with ALF. Our proteomic analysis uncovered marked differences between acetaminophen and non-acetaminophen-related ALF. The identification of routinely measurable biomarkers that are associated with 21-day transplant-free survival and the derivation of novel prognostic scores may facilitate clinical management as well as decisions for/against liver transplantation. Further studies are needed to quantify less abundant proteins. Although we used two cohorts, our findings still need to be independently and prospectively validated.

Von Willebrand factor (vWF) plays a key role in hemostasis and is reported to be related to the outcome of advanced chronic liver disease. The present study aimed to investigate the relationship between vWF and other potential variables and portal vein thrombosis (PVT) in patients with decompensated cirrhosis.

Consecutive cirrhotic patients with gastroesophageal varices were admitted to our hospital between January 2020 and September 2022. Patients were prospectively recruited and divided into PVT and non-PVT groups. We collected clinical tests, biochemical tests, coagulation tests, and hemostatic protein profile data to explore the associated factors of PVT.

A total of 128 patients were enrolled including 60 patients with PVT and 68 patients without PVT. Plasma levels of vWF [odds ratio (OR) = 1.015, 95% confidence interval (CI): 1.005-1.025, P = 0.005], D-dimer (OR = 1.967, 95% CI: 1.141-3.389, P = 0.015), and decreased portal vein velocity (PVV) (OR = 0.852, 95% CI: 0.769-0.944, P = 0.002) were the variables independently associated with the existence of PVT. Area under the curve (AUC) analyses for vWF, D-dimer, and PVV were 0.779, 0.848, and 0.832, respectively. A nomogram model was established involving the three parameters, and the AUC was 0.919 (95% CI: 0.869-0.969). In the internal validation using bootstrap, the AUC was 0.919 (95% CI: 0.868-0.970).

Higher vWF levels were related to PVT in patients with decompensated cirrhosis, indicating that vWF might serve as a relevant factor for PVT, and a nomogram containing vWF, D-dimer, and PVV could be an important tool for PVT identification in cirrhotic patients.

Chronic liver disease is a cluster of disorders associated with complex haemodynamic alterations, which is characterised by structural and functional disruptions of the intrahepatic and extrahepatic vasculature. 'Vasomics' is an emerging omics discipline that comprehensively analyses and models the vascular system by integrating pathophysiology of disease, biomechanics, medical imaging, computational science and artificial intelligence. Vasomics is further typified by its multidimensional, multiscale and high-throughput nature, which depends on the rapid and robust extraction of well-defined vascular phenotypes with clear clinical and/or biological interpretability. By leveraging multimodality medical imaging techniques, vascular functional assessments, pathological image evaluation, and related computational methods, integrated vasomics provides a deeper understanding of the associations between the vascular system and disease. This in turn reveals the crucial role of the vascular system in disease occurrence, progression and treatment responses, thereby supporting precision medicine approaches. Pathological vascular features have already demonstrated their key role in different clinical scenarios. Despite this, vasomics is yet to be widely recognised. Therefore, we furnished a comprehensive definition of vasomics providing a classification of existing hepatic vascular phenotypes into the following categories: anatomical, biomechanical, biochemical, pathophysiological and composite.

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

Acute variceal bleeding (AVB), a life-threatening complication of liver cirrhosis, can be effectively treated by endoscopy, but there is a risk of early rebleeding after endoscopic variceal treatment (EVT). Thrombocytopenia is the most common hemostatic abnormality in liver cirrhosis. However, it is still unclear about whether thrombocytopenia increases the failure of EVT in cirrhotic patients with AVB.

We investigated the association between thrombocytopenia and the failure of EVT in cirrhotic patients with AVB.

International multicenter, retrospective study.

Overall, 2467 cirrhotic patients with acute gastrointestinal bleeding who were enrolled into an international multicenter study between September 30, 2020 and June 30, 2023 were retrospectively screened. Thrombocytopenia was defined as platelet count below 150 × 109/L and further classified as mild (100 × 109/L-150 × 109/L), moderate (50 × 109/L-100 × 109/L), and severe (<50 × 109/L). A 1:1 propensity score matching (PSM) analysis was performed. Five-day failure to control bleeding was evaluated.

Overall, 1079 patients were included, of whom 923 (85.5%) had thrombocytopenia, including mild (n = 241), moderate (n = 445), and severe (n = 237) thrombocytopenia. PSM analysis demonstrated that the rate of 5-day failure to control bleeding was not significantly different between patients with and without thrombocytopenia (mild: (12/153) 7.8% vs (7/153) 4.6%, p = 0.236; moderate: (9/155) 5.8% vs (7/155) 4.5%, p = 0.608; or severe: (5/132) 3.8% vs (7/132) 5.3%, p = 0.555).

Thrombocytopenia may not influence the efficacy of EVT in cirrhotic patients with AVB.

Several chronic liver injuries can result in liver fibrosis, a wound-healing response defined by an excessive buildup of diffuse extracellular matrix (ECM). Liver fibrosis may progress to liver cirrhosis, liver failure, or hepatocellular carcinoma. Many cellular routes are implicated in the fibrosis process; however, hepatic stellate cells appear to be the main cell type involved. Curcumin, a polyphenolic substance extracted from the Curcuma longa plant, has a diversity of pharmacologic impacts, including anti- inflammatory, antioxidant, antiproliferative and antiangiogenic actions. The anti-fibrotic property of curcumin is less clear, but curcumin's ability to influence inflammatory cytokines, inflammatory pathways, the expression of pro-apoptotic (up-regulated) and anti- apoptotic (down-regulated) proteins, and its ability to lower oxidative stress likely underlie its anti-fibrotic properties. In this review, we investigate and analyze the impact of curcumin on several disorders that lead to liver fibrosis, and discuss the therapeutic applications of curcumin for these disorders.

Cirrhosis is one of the major causes of morbidity and mortality worldwide and the second leading cause of digestive disease mortality. Portal hypertension is the main driver of cirrhosis-related complications such as ascites and variceal bleeding. Portal hypertension is defined as a hepatic venous pressure gradient >5 mm Hg, although it is clinically significant and associated with clinical complications when >10 mm Hg.

Therefore, detection of clinically significant portal hypertension (CSPH) in chronic advanced liver disease or compensated cirrhosis is of paramount importance to guide the management of these patients.

This study aimed at revising the non-invasive and invasive tools for assessment of portal hypertension and risk stratification for CSPH in patients with chronic liver disease.

Esophagogastric varices (EGV) are a serious complication of hepatitis C virus (HCV)-related liver cirrhosis (HCV-LC). In most cases, portal hypertension improves after a sustained virologic response (SVR) is achieved with direct-acting antiviral (DAA) treatment; however, in some cases, EGV exacerbation occurs after HCV elimination. We investigated whether von Willebrand factor (VWF) and a disintegrin-like metalloproteinase with thrombospondin type-1 motif 13 (ADAMTS13) can predict EGV progression with HCV-LC after SVR achievement.

This retrospective study enrolled 47 patients with HCV-LC who achieved an SVR after DAA treatment. Eighteen patients experienced EGV progression after the SVR was achieved (EGV progression group). Twenty-nine patients did not experience EGV progression after the SVR was achieved (non-EGV progression group). Plasma VWF antigen levels and ADAMTS13 activity were measured the day before DAA treatment.

The EGV progression group had significantly higher plasma VWF antigen levels (p = 0.00331) and VWF-to-ADAMTS13 ratios (p = 0.000249) than the non-EGV progression group. Multivariate logistic regression models found that a VWF-to-ADAMTS13 ratio >2.3 was the only risk factor for EGV progression after the SVR was achieved (hazard ratio [HR], 18.4; 95% confidence interval [CI], 3.08-109; p = 0.00138). During the observation period, patients with a VWF-to-ADAMTS13 ratio >2.3 had a significantly higher cumulative incidence of EGV progression after SVR achievement than patients with a VWF-to-ADAMTS13 ratio ≤2.3 (HR, 6.4; 95% CI, 1.78-22.96; p = 0.0044).

The VWF-to-ADAMTS13 ratio before DAA treatment for HCV could predict EGV progression after SVR achievement.

Compensated advanced chronic liver disease (cACLD) identifies patients at risk for clinically significant portal hypertension (CSPH), and thus, for liver-related complications. The limited availability of liver stiffness measurements (LSM) impedes the identification of patients at risk for cACLD/CSPH outside of specialized clinics. We aimed to develop a blood-based algorithm to identify cACLD by fibrosis-4 (FIB-4) and CSPH by von Willebrand factor/platelet count ratio (VITRO).

Patients with (suspected) compensated chronic liver disease undergoing FIB-4+LSM were included in the LSM/FIB-4 cohorts from Vienna and Salzburg. The HVPG/VITRO cohorts included patients undergoing HVPG-measurement + VITRO from Vienna and Bern.LSM/FIB-4-derivation-cohort: We included 6143 patients, of whom 211 (3.4%) developed hepatic decompensation. In all, 1724 (28.1%) had LSM ≥ 10 kPa, which corresponded to FIB-4 ≥ 1.75. Importantly, both LSM (AUROC:0.897 [95% CI:0.865-0.929]) and FIB-4 (AUROC:0.914 [95% CI:0.885-0.944]) were similarly accurate in predicting hepatic decompensation within 3 years. FIB-4 ≥ 1.75 identified patients at risk for first hepatic decompensation (5 y-cumulative incidence:7.6%), while in those <1.75, the risk was negligible (0.3%).HVPG/VITRO-derivation cohort: 247 patients of whom 202 had cACLD/FIB-4 ≥ 1.75 were included. VITRO exhibited an excellent diagnostic performance for CSPH (AUROC:0.889 [95% CI:0.844-0.934]), similar to LSM (AUROC:0.856 [95% CI:0.801-0.910], p = 0.351) and the ANTICIPATE model (AUROC:0.910 [95% CI:0.869-0.952], p = 0.498). VITRO < 1.0/ ≥ 2.5 ruled-out (sensitivity:100.0%)/ruled-in (specificity:92.4%) CSPH. The diagnostic performance was comparable to the Baveno-VII criteria.LSM/FIB-4-derivation cohort findings were externally validated in n = 1560 patients, while HVPG/VITRO-derivation-cohort findings were internally (n = 133) and externally (n = 55) validated.

Simple, broadly available laboratory tests (FIB-4/VITRO) facilitate cACLD detection and CSPH risk stratification in patients with (suspected) liver disease. This blood-based approach is applicable outside of specialized clinics and may promote early intervention.

Posthepatectomy liver failure (PHLF), complications of portal hypertension, and disease recurrence determine the outcome for hepatocellular carcinoma (HCC) patients undergoing liver resection. This study aimed to evaluate the von Willebrand factor antigen (vWF-Ag) as a non-invasive test for clinically significant portal hypertension (CSPH) and a predictive biomarker for time to recurrence (TTR) and overall survival (OS).

The study recruited 72 HCC patients with detailed preoperative workup from a prospective trial (NCT02118545) and followed for complications, TTR, and OS. Additionally, 163 compensated patients with resectable HCC were recruited to evaluate vWF-Ag cutoffs for ruling out or ruling in CSPH. Finally, vWF-Ag cutoffs were prospectively evaluated in an external validation cohort of 34 HCC patients undergoing liver resection.

In receiver operating characteristic (ROC) analyses, vWF-Ag (area under the curve [AUC], 0.828) was similarly predictive of PHLF as indocyanine green clearance (disappearance rate: AUC, 0.880; retention rate: AUC, 0.894), whereas computation of future liver remnant was inferior (AUC, 0.756). Cox-regression showed an association of vWF-Ag with TTR (per 10%: hazard ratio [HR], 1.056; 95% confidence interval [CI] 1.017-1.097) and OS (per 10%: HR, 1.067; 95% CI 1.022-1.113). In the analyses, VWF-Ag yielded an AUC of 0.824 for diagnosing CSPH, with a vWF-Ag of 182% or lower ruling out and higher than 291% ruling in CSPH. Therefore, a highest-risk group (> 291%, 9.7% of patients) with a 57.1% incidence of PHLF was identified, whereas no patient with a vWF-Ag of 182% or lower (52.7%) experienced PHLF. The predictive value of vWF-Ag for PHLF and OS was externally validated.

For patients with resectable HCC, VWF-Ag allows for simplified preoperative risk stratification. Patients with vWF-Ag levels higher than 291% might be considered for alternative treatments, whereas vWF-Ag levels of 182% or lower identify patients best suited for surgery.

The prognostic performance of von Willebrand factor (VWF) may vary across clinical stages of advanced chronic liver disease (ACLD). Therefore, we investigated the evolution of VWF and other biomarkers throughout the full ACLD spectrum and evaluated their stage-specific prognostic utility.

We retrospectively included Viennese ACLD patients with available information on hepatic venous pressure gradient (HVPG), C-reactive protein (CRP)/VWF levels and outcomes. ACLD stages were defined according to D'Amico et al. We included an external validation cohort from Padua.

We observed gradual increases in VWF throughout ACLD stages. In contrast, HVPG levelled off in decompensated ACLD (dACLD), whereas MELD showed only minor changes in the early stages and CRP did not increase until stage 3. VWF was associated with hepatic decompensation/liver-related death in compensated ACLD (cACLD) in a fully adjusted model, while it was not independently predictive of ACLF/liver-related death in dACLD. After backward selection, HVPG/CRP/VWF remained the main predictors of hepatic decompensation/liver-related death in cACLD. Notably, the performance of the non-invasive CRP/VWF-based model was comparable to invasive HVPG-based models (C-index:0.765 ± 0.034 vs. 0.756 ± 0.040). The discriminative ability of the CRP/VWF-based model was confirmed in an external validation cohort using another VWF assay which yielded systematically lower values.

VWF is the only biomarker that gradually increases across all ACLD stages. It is of particular prognostic value in cACLD, where a CRP/VWF-based model is equivalent to an invasive HVPG-based model. Systematic differences in VWF underline the importance of interlaboratory surveys. Moreover, our findings reinforce the notion that, already in cACLD, inflammation is a key disease-driving mechanism.

Clinically significant portal hypertension (CSPH) in patients with compensated advanced chronic liver disease indicates an increased risk of decompensation and death. While invasive methods like hepatic venous-portal gradient measurement is considered the gold standard, non-invasive tests (NITs) have emerged as valuable tools for diagnosing and monitoring CSPH. This review comprehensively explores non-invasive diagnostic modalities for portal hypertension, focusing on NITs in the setting of hepatitis B and hepatitis C virus-related cirrhosis. Biochemical-based NITs can be represented by single serum biomarkers (e.g., platelet count) or by composite scores that combine different serum biomarkers with each other or with demographic characteristics (e.g., FIB-4). On the other hand, liver stiffness measurement and spleen stiffness measurement can be assessed using a variety of elastography techniques, and they can be used alone, in combination with, or as a second step after biochemical-based NITs. The incorporation of liver and spleen stiffness measurements, alone or combined with platelet count, into established and validated criteria, such as Baveno VI or Baveno VII criteria, provides useful tools for the prediction of CSPH and for ruling out high-risk varices, potentially avoiding invasive tests like upper endoscopy. Moreover, they have also been shown to be able to predict liver-related events (e.g., the occurrence of hepatic decompensation). When transient elastography is not available or not feasible, biochemical-based NITs (e.g., RESIST criteria, that are based on the combination of platelet count and albumin levels) are valid alternatives for predicting high-risk varices both in patients with untreated viral aetiology and after sustained virological response. Ongoing research should explore novel biomarkers and novel elastography techniques, but current evidence supports the utility of routine blood tests, LSM, and SSM as effective surrogates in diagnosing and staging portal hypertension and predicting patient outcomes.

Portal vein thrombosis (PVT) is a commonthsn complication after splenectomy in patients with cirrhosis. However, the predictors of postoperative PVT are not known.

To investigate the predictors of PVT after splenectomy in patient with cirrhosis.

A total of 45 patients with cirrhosis who underwent splenectomy were consecutively enrolled from January 2017 to December 2018. The incidence of PVT at 1 months, 3 months, and 12 months after splenectomy in patients with cirrhosis was observed. The hematological indicators, biochemical and coagulation parameters, and imaging features were recorded at baseline and at each observation point. The univariable, multivariable, receiver operating characteristic curve and time-dependent curve analyses were performed.

The cumulative incidence of PVT was 40.0%, 46.6%, and 48.9% at 1 months, 3 months, and 12 months after splenectomy. Multivariable analysis showed that portal vein diameter (PVD) ≥ 14.5 mm and monthsdel‎ end-stage liver disease (MELD) score > 10 were independent predictors of PVT at 1 months, 3 months, and 12 months after splenectomy (P < 0.05). Time-dependent curve showed that the cumulative incidence of PVT was significantly different between patients with MELD score ≤ 10 and > 10 (P < 0.05). In addition, the cumulative incidence of PVT in the PVD ≥ 14.5 mm group was significantly higher than that in the PVD < 14.5 mm group (P < 0.05).

Wider PVD and MELD score > 10 were independent predictors of PVT at 1 months, 3 months, and 12 months after splenectomy in patient with cirrhosis.

The liver is the central metabolic organ and produces 85-90% of the proteins found in plasma. Accordingly, the plasma proteome is an attractive source of liver disease biomarkers that reflects the different cell types present in this organ, as well as the processes such as responses to acute and chronic injury or the formation of an extracellular matrix. In the first part, we summarize the biomarkers routinely used in clinical evaluations and their biological relevance in the different stages of non-malignant liver disease. Later, we describe the current proteomic approaches, including mass spectrometry and affinity-based techniques, that allow a more comprehensive assessment of the liver function but also require complex data processing. The many approaches of analysis and interpretation and their potential caveats are delineated. While these advances hold the promise to transform our understanding of liver diseases and support the development and validation of new liver-related drugs, an interdisciplinary collaboration is needed.

We aimed to assess the feasibility and reliability of sequential ultrasonographic and elastographic monitoring in acute liver failure (ALF).

Observational study.

ALF is a rare, life-threatening disease that requires intensive care admission and often liver transplant, where the accurate selection of patients is crucial. Liver elastography is a noninvasive tool that can measure hepatic stiffness, but previous results have been inconclusive in ALF.

Patients admitted between October 2021 and March 2023 to the Liver Intensive Therapy Unit at King's College Hospital with ALF were recruited, with healthy control (HC) individuals and acute-on-chronic liver failure (ACLF) used as controls.

None.

Average shear wave velocity was recorded with ElastPQ on the right and left liver lobes and the spleen. Portal vein flow, hepatic artery resistive index, and peak systolic velocity were also recorded. Physiologic and histologic data were used for comparison.

Forty patients with ALF, 22 patients with ACLF, and 9 HC individuals were included in the study. At admission, liver stiffness measurement (LSM) of the right lobe was statistically different between HC individuals (5.6 ± 2 kPa), ALF (31.7 ± 17 kPa), and ACLF (76.3 ± 71 kPa) patients (ALF vs. ACLF, p = 0.0301). Spleen size and stiffness discriminated between ALF (10.4 ± 2 cm and 21.4 ± 16.6 kPa) and ACLF (14 ± 2.3 cm and 42.6 ± 26 kPa). At admission, LSM was not different between ALF patients who spontaneously survived versus patients who died or were transplanted in the following 90 days. However, the trend over the first 10 days of admission was different with a peak of LSM at day 5 in spontaneous survivors followed by reduction during the recovery phase. ALF patients with poor prognosis showed a persistently increased LSM.

In ALF stiffness peaks at day 5 of admission with subsequent reduction in patients spontaneously surviving, showing significant difference according to the prognosis at day 7 of admission. LSM might be useful in distinguishing acute from acute-on-chronic liver failure together with spleen volume and stiffness.

Patients with cirrhosis develop complex alterations in primary hemostasis that include both hypocoagulable and hypercoagulable features. This includes thrombocytopenia, multiple alterations of platelet function, and increased plasma levels of von Willebrand factor. Contrary to the historical view that platelet dysfunction in cirrhosis might be responsible for an increased bleeding tendency, the current theory posits a rebalanced hemostasis in patients with cirrhosis. Severe thrombocytopenia is not indicative of the bleeding risk in patients undergoing invasive procedures and does not dictate per se the need for pre-procedural prophylaxis. A more comprehensive and individualized risk assessment should combine hemostatic impairment, the severity of decompensation and systemic inflammation, and the presence of additional factors that may impair platelet function, such as acute kidney injury and bacterial infections. Although there are multiple, complex alterations of platelet function in cirrhosis, their net effect is not yet fully understood. More investigations evaluating the association between alterations of platelet function and bleeding/thrombosis may improve risk stratification in patients with decompensated cirrhosis. Besides hemostasis, the assessment of von Willebrand factor Ag and ADP-induced, whole-blood platelet aggregation normalized by platelet count (VITRO score and PLT ratio) are promising biomarkers to predict the risk of hepatic decompensation and survival in both compensated and decompensated patients. Further investigations into the in vivo interplay between platelets, circulating blood elements, and endothelial cells may help advance our understanding of cirrhotic coagulopathy. Here, we review the complex changes in platelets and primary hemostasis in cirrhosis and their potential clinical implications.

Portal hypertension often precedes the development of advanced fibrosis in patients with Metabolic dysfunction-associated steatotic liver disease (MASLD) and may accelerate disease progression to cirrhosis. We aimed to evaluate whether prioritization tools accurately predict survival in patients with MASLD and clinically significant portal hypertension (CSPH). We retrospectively identified patients diagnosed with esophageal or gastric varices (EGV). Laboratory results, endoscopy reports and outcomes of patients with MASLD were compared to patients with advanced stage chronic liver disease (CLD) of other etiologies. During the study period 326 patients were diagnosed with EGV. 88 (26.9%) had MASLD, 113 (34.6%) viral hepatitis (VH), 63 (19.3%) alcoholic liver disease (ALD) and 62 (19%) both VH and ALD (VHALD). EGV bleeding events were significantly more frequent in patients with MASLD (36.3%), compared to VH (28.3%), ALD (30.1%) and VHALD (25.8%), respectively (p < 0.01). Mean Model for End-Stage Liver Disease (MELD)-Na score surrounding 1 year of first event of EGV bleeding was significantly lower in MASLD patients compared to all other etiologies (p = 0.02). At a MELD-Na score of 11-20, cumulative survival rate was significantly lower in MASLD patients compared to all other etiologies (log rank p < 0.01). MASLD patients present with EGV bleeding at lower MELD-Na scores compared to other etiologies of CLD. MELD-Na score may therefore underestimate disease severity and risk of death in patients with MASLD and CSPH.

Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications.

We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not.

Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46).

Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.

Endothelial dysfunction and portal hypertension (PH) are reflected by increased von Willebrand factor antigen (VWF-Ag) levels in advanced chronic liver disease (ACLD). This study investigated VWF release and cleavage and their association with PH and clinical outcomes.

Levels of VWF-Ag, VWF-N (VWF-propeptide), and VWF-A (VWF processed by the main VWF-cleaving protease ADAMTS13) were assessed in 229 patients with clinically stable ACLD (hepatic venous pressure gradient [HVPG] ≥ 6 mmHg; absence of bacterial infections or acute decompensation) undergoing HVPG-measurement. Liver-healthy individuals served as controls (n = 24).

VWF-Ag and VWF-N were similarly accurate for the identification of clinically significant PH (CSPH; HVPG ≥ 10 mmHg) in compensated ACLD (AUROC: VWF-Ag 0.748; VWF-N 0.728). ADAMTS13 activity was similar between patients with ACLD and controls and did not correlate with PH and disease severity, whereas VWF cleavage decreased in patients with CSPH (i.e., VWF-Ag/-A-ratio increased). In vitro VWF activity strongly reflected VWF-Ag levels (Spearman's r = 0.874, p < 0.001), but decreased (vs. controls) in patients with CSPH when normalized to VWF-Ag levels (VWF-activity/-Ag-ratio). VWF-Act/-Ag ratio correlated negatively with ADAMTS13 activity (r =- 0.256, p < 0.001). ADAMTS13 activity was independently predictive for (i) portal vein thrombosis (PVT) and (ii) hepatic decompensation or liver-related death.

VWF-Ag levels and its propeptide are similarly suitable surrogates of PH in patients with compensated ACLD. ADAMTS13-Act was not linked to disease and PH severity, however, when normalized to VWF-Ag, both VWF cleavage and VWF activity were decreased in patients with CSPH, as compared to liver-healthy individuals. Low ADAMTS13-Act was associated with presumably more procoagulant VWF and adverse outcomes.

NCT03267615.

Levels of von Willebrand factor (VWF) are elevated in patients with cirrhosis, and correlate well with disease severity. In patients with decompensated cirrhosis (DC), plasma VWF is associated with mortality. The value of VWF in predicting short-term mortality risk in patients with acute-on-chronic liver failure (ACLF) is, however, unclear.

We included patients with DC (n = 111) and ACLF (n = 105). We measured VWF levels and correlated these with other laboratory parameters and prediction models for mortality. Also, we assessed the predictive value of VWF in the prediction of 90- and 30-day mortality in patients with DC and ACLF, respectively, and compared this to the predictive value of clinically used prediction models. Finally, we determined the optimal cut-off value for VWF in patients with ACLF.

Sixteen of 111 (14%) patients with DC and 35 of 105 (33%) with ACLF died within 90 and 30 days, respectively. VWF was associated with mortality and correlated closely with other prediction models. In patients with ACLF, VWF levels had a discrimination for 30-day mortality comparable with these models and accurately identified ACLF patients with high 30-day mortality risk.

Levels of VWF associate closely with risk of mortality in patients with DC and ACLF, and may have predictive utility as a laboratory marker of prognosis. Further research is warranted to assess the additional value of VWF in the prediction of mortality and associated complications in chronic liver failure syndromes.

The von Willebrand factor (vWF) is best known for its role in the hemostatic pathway, aiding platelet adhesion and aggregation, as well as circulating along with coagulation factor VIII, prolonging its half-life. However, vWF is more than a hemostatic protein and is a marker of endothelial dysfunction in patients with cirrhosis. The levels of vWF increase progressively as cirrhosis progresses. Despite its qualitative defects, it can support and carry out its hemostatic role and contribute to a pro-coagulant disbalance. Moreover, it has been shown to be a good noninvasive marker for predicting clinically significant portal hypertension (CSPH). The vWF has been shown to predict decompensation and mortality among cirrhosis patients independently of the stage of liver disease and severity of portal hypertension. Increased vWF levels in the setting of endothelial injury predict bacterial translocation and systemic inflammation. The vWF-to-thrombocyte ratio (VITRO) score adds to the diagnostic ability of vWF alone in detecting CSPH non-invasively. Not only have vWF levels been shown to help predict the risk of hepatocellular carcinoma (HCC) among cirrhosis patients, but they also predict the risk of complications post-resection for HCC and response to systemic therapies. vWF-induced portal microthrombi have been purported to contribute to the pathogenesis of acute liver failure progression as well as non-cirrhotic portal hypertension. The prospect of modulation of vWF levels using drugs such as non-selective beta-blockers, statins, anticoagulants, and non-absorbable antibiotics and its use as a predictive biomarker for the response to these drugs needs to be explored.

Fibrosis is an unavoidable consequence of chronic inflammation. Extracellular matrix deposition by fibroblasts, stimulated by multiple pathways, is the first step in the onset of chronic liver disease, and its propagation promotes liver dysfunction. At the same time, chronic liver disease is characterized by alterations in primary and secondary hemostasis but unlike previously thought, these changes are not associated with an increased risk of bleeding complications. In recent years, the role of coagulation imbalance has been postulated as one of the main mechanisms promoting hepatic fibrogenesis. In this review, we aim to investigate the function of microvascular thrombosis in the progression of liver disease and highlight the molecular and cellular networks linking hemostasis to fibrosis in this context. We analyze the predictive and prognostic role of coagulation products as biomarkers of liver decompensation (ascites, variceal hemorrhage, and hepatic encephalopathy) and liver-related mortality. Finally, we evaluate the current evidence on the application of antiplatelet and anticoagulant therapies for prophylaxis of hepatic decompensation or prevention of the progression of liver fibrosis.

Nonalcoholic steatohepatitis (NASH) is the most common chronic liver disease globally and a leading cause for liver transplantation in the US. Its pathogenesis remains imprecisely defined. We combined two high-resolution modalities to tissue samples from NASH clinical trials, machine learning (ML)-based quantification of histological features and transcriptomics, to identify genes that are associated with disease progression and clinical events. A histopathology-driven 5-gene expression signature predicted disease progression and clinical events in patients with NASH with F3 (pre-cirrhotic) and F4 (cirrhotic) fibrosis. Notably, the Notch signaling pathway and genes implicated in liver-related diseases were enriched in this expression signature. In a validation cohort where pharmacologic intervention improved disease histology, multiple Notch signaling components were suppressed.

This study determined if an accessible, serologic indicator of vascular disease activity, the von Willebrand factor antigen (vWF:Ag), was useful to assess disease activity in children with juvenile dermatomyositis (JDM), a rare disease, but the most common of the pediatric inflammatory myopathies.

A total of 305 children, median age 10 years, 72.5% female, 76.5% white, with definite/probable JDM at diagnosis, were enrolled in the Ann & Robert H. Lurie Cure JM Juvenile Myositis Repository, a longitudinal database. Disease Activity Score (DAS) and vWF:Ag data were obtained at each visit. These data were analyzed using generalized estimating equation (GEE) models (both linear and logistic) to determine if vWF:Ag reflects disease severity in children with JDM. A secondary analysis was performed for untreated active JDM to exclude the effect of medications on vWF:Ag.

The vWF:Ag test was elevated in 25% of untreated JDM. We found that patients with elevated vWF:Ag had a 2.55-fold higher DAS total (CI95: 1.83-3.27, p < 0.001). Patients with difficulty swallowing had 2.57 higher odds of elevated vWF:Ag (CI95: 1.5-4.38, p < 0.001); those with more generalized skin involvement had 2.58-fold higher odds of elevated vWF:Ag (CI95: 1.27-5.23, p = 0.006); and those with eyelid peripheral blood vessel dilation had 1.32-fold higher odds of elevated vWF:Ag (CI95: 1.01-1.72, p = 0.036). Untreated JDM with elevated vWF:Ag had more muscle weakness and higher muscle enzymes, neopterin and erythrocyte sedimentation rate compared to JDM patients with a normal vWF:Ag.

vWF:Ag elevation is a widely accessible concomitant of active disease in 25% of JDM.

Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.

Acute-on-chronic liver failure (ACLF) has a high risk of short-term mortality. A disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) is a metalloproteinase that specifically cleaves multimeric von Willebrand factor (VWF). Imbalance between ADAMTS13 and VWF is associated with portal hypertension, which induces ACLF development. A previous study reported that ADAMTS13 activity (ADAMTS13:AC) and VWF antigen (VWF:Ag) are predictive biomarkers of ACLF development in patients with cirrhosis. This study investigated the changes in ADAMTS13:AC and VWF:Ag levels from before to after the development of ACLF to determine their usefulness as a prognostic biomarker in patients with ACLF. In total, 101 patients with cirrhosis were enrolled in this study. The level of ADAMTS13:AC and VWF:Ag was determined by an enzyme-linked immunosorbent assay. Cox proportional hazard regression analysis was conducted to determine independent prognostic factors for patients with liver cirrhosis in the post-ACLF group. ADAMTS13:AC levels gradually decreased in the order of non-ACLF group, pre-ACLF group, and finally post-ACLF group. VWF:Ag and the ratio of VWF:Ag to ADAMTS13:AC (VWF:Ag/ADAMTS13:AC) levels gradually increased in the order of non-ACLF group, pre-ACLF group, followed by post-ACLF group. VWF:Ag/ADAMTS13:AC and CLIF-C ACLF scores were associated with prognosis in the post-ACLF group in multivariate analysis. The cumulative survival of the post-ACLF group was significantly lower for patients with high VWF:Ag/ADAMTS13:AC (>9) compared with those with low VWF:Ag/ADAMTS13:AC (≤9) (HR: 10.72, 95% confidence interval: 1.39-82.78, p < 0.05). The VWF:Ag/ADAMTS13:AC increased according to the progression of ACLF in patients with cirrhosis and predicted prognosis in patients with cirrhosis with ACLF.

We aimed to assess the systemic and hepatic renin-angiotensin-system (RAS) fingerprint in advanced chronic liver disease (ACLD). This prospective study included 13 compensated (cACLD) and 12 decompensated ACLD (dACLD) patients undergoing hepatic venous pressure gradient (HVPG) measurement. Plasma components (all patients) and liver-local enzymes (n = 5) of the RAS were analyzed using liquid chromatography-tandem mass spectrometry. Patients with dACLD had significantly higher angiotensin (Ang) I, Ang II and aldosterone plasma levels. Ang 1-7, a major mediator of the alternative RAS, was almost exclusively detectable in dACLD (n = 12/13; vs. n = 1/13 in cACLD). Also, dACLD patients had higher Ang 1-5 (33.5 pmol/L versus cACLD: 6.6 pmol/L, p < 0.001) and numerically higher Ang III and Ang IV levels. Ang 1-7 correlated with HVPG (ρ = 0.655; p < 0.001), von Willebrand Factor (ρ = 0.681; p < 0.001), MELD (ρ = 0.593; p = 0.002) and interleukin-6 (ρ = 0.418; p = 0.047). Considerable activity of ACE, chymase, ACE2, and neprilysin was detectable in all liver biopsies, with highest chymase and ACE2 activity in cACLD patients. While liver-local classical and alternative RAS activity was already observed in cACLD, systemic activation of alternative RAS components occurred only in dACLD. Increased Ang 1-7 was linked to severe liver disease, portal hypertension, endothelial dysfunction and inflammation.

In cirrhosis, decreased portal flow velocity, thrombophilia factors, and portal hypertension are considered risk factors for portal vein thrombosis (PVT). In cirrhosis, the transformation of the stellate cells causes a progressive decrease of ADAMTS-13, while VWF multimers secretion by endothelial cells is strongly enhanced. This imbalance leads to an accumulation of ultra-large VWF multimers that in sinusoidal circulation could favor PVT both in intra- and extra-hepatic branches, mostly in decompensated cirrhosis. This prospective study was aimed at identifying possible clinical, biochemical, and hemostatic factors predictive for non-tumoral PVT in a cohort of patients with compensated cirrhosis.

Seventynine compensated cirrhosis patients were prospectively followed for 48 months, receiving a periodic Doppler-ultrasound liver examination associated with an extensive evaluation of clinical, biochemical, and hemostatic profile.

Five patients developed PVT (cumulative prevalence = 6.3%), occurring 4-36 months after enrollment. In logistic regression analysis, the ADAMTS-13/VWF:GpIbR ratio < 0.4 was the only independent variable significantly associated with PVT (OR 14.6, 95% C.I.:1.36-157.2, p = 0.027). A Cox-regression-analysis confirmed this finding (HR = 7.7, p = 0.027).

The ADAMTS-13/VWF ratio < 0.4 measured in compensated cirrhosis could be a reliable predictive biomarker for PVT development, paving the way to novel therapeutic strategies to prevent and treat PVT in this clinical setting.

Baveno VII proposed liver stiffness measurement (LSM)/platelet count (PLT)-based criteria ('ruled out,' LSM ≤15 kPa plus PLT ≥150 G/L; 'ruled in': LSM ≥25 kPa) for clinically significant portal hypertension (CSPH) in compensated advanced chronic liver disease (cACLD). However, a substantial proportion of patients remains 'unclassified.'

Patients with evidence of cACLD (LSM ≥10 kPa) undergoing hepatic venous pressure gradient (HVPG) measurement at the Vienna General Hospital 2004 to 2021 (derivation [2004-2016], n = 221; validation [2017-2021], n = 81) were included. The performance of noninvasive tests (NITs) including von Willebrand factor antigen to PLT ratio (VITRO) for the detection of CSPH (HVPG ≥10 mmHg) were evaluated.

Overall, viral hepatitis was the predominant (50.7%) etiology, followed by alcoholic liver disease (15.2%) and nonalcoholic steatohepatitis (13.2%); CSPH prevalence was 62.3%. In the derivation cohort, 45.7% were 'unclassified' according to Baveno VII criteria; in this group, VITRO showed an excellent diagnostic performance for the detection of CSPH (area under the receiver operating curve, 0.909; 95% confidence interval, 0.823-0.965). VITRO ≤1.5 and ≥2.5 ruled out (sensitivity, 97.7%; negative predictive value, 97.5%) and ruled in (specificity, 94.7%; positive predictive value, 91.2%), respectively, CSPH in patients who were 'unclassifiable' by Baveno VII criteria. The application of a sequential Baveno VII-VITRO algorithm reallocated 73% and 70% of 'unclassified' patients to the 'ruled in' and 'ruled out' group, respectively, while maintaining high sensitivity and negative predictive value and specificity and positive predictive value in the derivation and validation cohort, respectively. No patient allocated to the 'CSPH ruled out' group by the Baveno VII-VITRO algorithm developed decompensation within 5 years, whereas 5-year decompensation rates were negligible (4%) and substantial (23.9%) among 'unclassified' and 'CSPH ruled in' patients, respectively.

The sequential application of VITRO in patients with cACLD who were 'unclassifiable' with regard to CSPH by Baveno VII criteria substantially decreased the number of 'unclassifiable' patients to <15% and refined prognostication.

Von Willebrand factor antigen (VWF) is a non-invasive marker for clinically significant portal hypertension (HVPG≥10 mmHg) and confers HVPG-independent prognostic information. While quantification of increased VWF-levels is not relevant in the context of von Willebrand disease, highly elevated VWF may be of clinical significance in ACLD. Thus, we have modified our analytical approach to quantify very high VWF-levels (i.e.,>420%) and investigated their prognostic value.

Patients undergoing HVPG-measurement at the Vienna Hepatic Hemodynamic Lab with evidence of ACLD and information on VWF were considered. Clinical stages (CS) were defined as follows: Probable compensated ACLD (cACLD): LSM≥10kPa&HVPG<6 mmHg; 0: cACLD&6-9 mmHg; 1: cACLD&HVPG≥10 mmHg; 2: bleeding; 3: non-bleeding decompensation; 4: ≥2 decompensations.

124 (16%) of 793 patients had VWF>420%. The proportion of VWF>420% increased with disease severity (probable cACLD-0: 5(4%) vs. 1: 22(10%) vs. 2-4: 97(23%),p ≤ 0.001) as well as across HVPG (<6mmHg: 1(2%) vs. 6-9: 6(6%) vs. 10-15: 17(9%) vs. ≥16: 100(22%),p ≤ 0.001) and MELD (<10: 17(6%) vs. 10-14: 27(10%) vs. ≥15: 79(32%),p ≤ 0.001) strata. In patients with VWF>420%, median VWF was 533 (IQR:466-611)% and VWF was unrelated to HVPG (Spearman's ρ=0.139,p = 0.123), but showed direct correlations of weak/moderate strength with MELD (ρ=0.336,p < 0.001) and CRP (ρ=0.286,p = 0.001). In the subgroup with VWF>420%, VWF was predictive of decompensation/liver-related mortality (VWF per 10%; hazard ratio (HR): 1.02(95% confidence interval (95%CI): 1.01-1.04),p = 0.008, even after adjusting for other factors (VWF per 10%; adjusted HR: 1.02(95%CI: 1.00-1.05),p = 0.031).

The proportion of patients with substantially elevated VWF values steadily increases with disease progression. While VWF is not reflective of HVPG in these patients, it is correlated with hepatic dysfunction and systemic inflammation. Importantly, quantification of high values provides prognostic information.