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DECISION Publications

2024

  • Alcohol- associated hepatitis: a neutrophile disease?
    Maximilan Joseph Brol, Ali Canbay; Jonel Trebicka, Gut
    Published: 24 September 2024
    Excerpt:
    Alcohol- associated hepatitis (AH) is the acute deterioration of alcohol- related liver disease (ArLD) with rapid onset or worsening of jaundice, which, in severe cases, may transition to acute- on- chronic liver failure (ACLF) with extremely high short- term mortality, increasing with the number and severity of hepatic and extra- hepatic organ dysfunction. Systemic inflammation is a hallmark, driving acute decompensation (AD) towards ACLF. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multifactorial and as yet not fully understood pathogenesis. […]
  • Letter: Association between terlipressin and multidrug-resistant organism rectal colonization: Authors’ reply
    Marcus M. Mücke, Wenyi Gu, Javier Fernandez, Jonel Trebicka; Alimentary Pharmacology and Therapeutics
    Published: 5 September 2024
  • Long-term effects of daylight saving time on driving fatigue
    Federico Orsini, et al., Heliyon
    Published: 15 August 2024
    Abstract:
    The study of the relationship between Daylight Saving Time (DST) and road safety has yielded contrasting results, most likely in relation to the inability of crash-database approaches to unravel positive (ambient lighting-related) and negative (circadian/sleep-related) effects, and to significant geographical differences in lighting-related effects. The aim of this study was to investigate the effects of DST on driving fatigue, as measured by driving-based, physiological and subjective indicators obtained from a driving simulator experiment. Thirty-seven participants (73 % males, 23 ± 2 years) completed a series of 50-min trials in a monotonous highway environment: Trial 1 was in the week prior to the Spring DST transition, Trial 2 in the following week, and Trial 3 in the fourth week after the transition. Thirteen participants returned for Trial 4, in the week prior to the Autumn switch to civil time, and Trial 5 in the following week. Significant adverse effects of DST on vehicle lateral control and eyelid closure were documented in Trial 2 and Trial 3 compared to Trial 1, with no statistical differences between Trials 2 and 3. Further worsening in vehicle lateral control was documented in Trials 4 and 5. Eyelid closure worsened up to Trial 4, and improved in Trial 5. Participants were unaware of their worsening performance based on subjective indicators. In conclusion, DST has a detrimental impact on driving fatigue during the whole time during which it is in place. Such an impact is comparable, for example, to that associated with driving with a blood alcohol concentration of 0.5 g/L.
  • A robust clustering strategy for stratification unveils unique patient subgroups in acutely decompensated cirrhosis
    Sara Palomino-Echeverria, et al., Journal of Translational Medicine
    Published: 27 June 2024
    Abstract:
    Background: Patient heterogeneity poses significant challenges for managing individuals and designing clinical trials, especially in complex diseases. Existing classifications rely on outcome-predicting scores, potentially overlooking crucial elements contributing to heterogeneity without necessarily impacting prognosis.
    Methods: To address patient heterogeneity, we developed ClustALL, a computational pipeline that simultaneously faces diverse clinical data challenges like mixed types, missing values, and collinearity. ClustALL enables the unsupervised identification of patient stratifications while filtering for stratifications that are robust against minor variations in the population (population-based) and against limited adjustments in the algorithm’s parameters (parameter-based).
    Results: Applied to a European cohort of patients with acutely decompensated cirrhosis (n = 766), ClustALL identified five robust stratifications, using only data at hospital admission. All stratifications included markers of impaired liver function and number of organ dysfunction or failure, and most included precipitating events. When focusing on one of these stratifications, patients were categorized into three clusters characterized by typical clinical features; notably, the 3-cluster stratification showed a prognostic value. Re-assessment of patient stratification during follow-up delineated patients’ outcomes, with further improvement of the prognostic value of the stratification. We validated these findings in an independent prospective multicentre cohort of patients from Latin America (n = 580).
    Conclusions: By applying ClustALL to patients with acutely decompensated cirrhosis, we identified three patient clusters. Following these clusters over time offers insights that could guide future clinical trial design. ClustALL is a novel and robust stratification method capable of addressing the multiple challenges of patient stratification in most complex diseases.
  • Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt
    Giulia Ilaria Bagarolo, Shruti Bhargava, et al., npj Gut and Liver
    Published: 10 June 2024
    Abstract:
    ortal hypertension develops in patients with advanced chronic liver diseases (CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt (TIPS) is a treatment option for portal hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal hypertension before and after TIPS intervention to identify and characterise potential mediators influencing gut-liver cross-talk. The plasma of 23 patients displaying advanced CLD with portal hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric (LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99-118), Histone-lysine N-methyltransferase(MLL3)(3019-3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614-630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF), uric acid, dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel potential biomarkers for portal hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.
  • Imaging-based diagnosis of sarcopeniafor transplant-free survival in primarysclerosing cholangitis
    Pedram Keshoofi, et al., BMC Gastroenterolgy
    Published: 25 April 2024
    Abstract:
    Background
    Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC.
    Methods
    A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause.
    Results
    Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141).
    Conclusion
    Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation.
  • Prognosis algorithms for acute decompensation of cirrhosis and ACLF
    Shantha R. Valainathan, Qing Xie, Vicente Arroyo, Pierre-Emmanuel Rautou. Liver International
    Published: 9 April 2024
    Abstract:
    Accurate prediction of survival in patients with cirrhosis is crucial, as patients who are unlikely to survive in the short-term need to be oriented to liver transplantation and to novel therapeutic approaches. Patients with acute decompensation of cirrhosis without or with organ dysfunction/failure, the so-called acute-on-chronic liver failure (ACLF), have a particularly high short-term mortality. Recognizing the specificity of this clinical situation, dedicated classifications and scores have been developed over the last 15 years, including variables (e.g. organ failures and systemic inflammation) not part of the formerly available cirrhosis severity scores, namely Child-Pugh score or MELD. For patients with acute decompensation of cirrhosis, it led to the development of a dedicated score, the Clif-C-AD score, independently validated. For more severe patients, three different scoring systems have been proposed, by European, Asian and North American societies namely Clif-C-ACLF, AARC score and NASCELD-ACLF respectively. These scores have been validated, and are widely used across the world. The differences and similarities between these scores, as well as their validation and limitations are discussed here. Even if these scores and classifications have been a step forward in favouring homogeneity between studies, and in helping making decisions for individual patients, their predictive value for mortality can still be improved as their area under the ROC curve does not exceed .8. Novel scores including biomarkers reflecting the pathophysiology of acute decompensation of cirrhosis might help reach that goal.
  • Opportunities and barriers in omics-based biomarker discovery for steatotic liver diseases
    Maja Thiele, et al., Journal of Hepatology
    Published: 28 March 2024
    Summary:
    The rising prevalence of liver diseases related to obesity and excessive use of alcohol is fuelling an increasing demand for accurate biomarkers aimed at community screening, diagnosis of steatohepatitis and significant fibrosis, monitoring, prognostication and prediction of treatment efficacy. Breakthroughs in omics methodologies and the power of bioinformatics have created an excellent opportunity to apply technological advances to clinical needs, for instance in the development of precision biomarkers for personalised medicine. Via omics technologies, biological processes from the genes to circulating protein, as well as the microbiome – including bacteria, viruses and fungi, can be investigated on an axis. However, there are important barriers to omics-based biomarker discovery and validation, including the use of semi-quantitative measurements from untargeted platforms, which may exhibit high analytical, inter- and intra-individual variance. Standardising methods and the need to validate them across diverse populations presents a challenge, partly due to disease complexity and the dynamic nature of biomarker expression at different disease stages. Lack of validity causes lost opportunities when studies fail to provide the knowledge needed for regulatory approvals, all of which contributes to a delayed translation of these discoveries into clinical practice. While no omics-based biomarkers have matured to clinical implementation, the extent of data generated has enabled the hypothesis-free discovery of a plethora of candidate biomarkers that warrant further validation. To explore the many opportunities of omics technologies, hepatologists need detailed knowledge of commonalities and differences between the various omics layers, and both the barriers to and advantages of these approaches.
  • Recent advances in the prevention and treatment of decompensated cirrhosis and acute- on- chronic liver failure (ACLF) and the role of biomarkers
    Jonel Trebicka, et al., Gut
    Published: 25 March 2024
    Abstract:
    The progression of cirrhosis with clinically significant portal hypertension towards decompensated cirrhosis remains clinically challenging and the evolution towards acute- on- chronic liver failure (ACLF), with one or more extrahepatic organ failures, is associated with very high mortality. In the last decade, significant progress has been made in the understanding of the mechanisms leading to decompensation and ACLF. As portal hypertension advances, bacterial translocation across an impaired gut barrier culminates in endotoxaemia, systemic inflammation and cirrhosis- associated immune dysfunction (CAID). Gut- derived systemic inflammation and CAID have become the logical targets for innovative therapies that prevent hepatic decompensation episodes and the progression to ACLF. Furthermore, classification of disease and biomarker discovery to personalise care have advanced in the field. This review discusses progress in biomarker discovery and personalisation of treatment in decompensated cirrhosis and ACLF.
  • Soluble urokinase plasminogen activator receptor levels predict survival in patients with portal hypertension undergoing TIPS
    Sven H. Loosen, et al., JHEP Reports
    Published: 4 March 2024
    Highlights:

    • suPAR concentrations were significantly higher in HV samples compared to PV samples.
    • HV suPAR concentrations correlated with PV concentration, presence of ascites, kidney injury, and Child-Pugh and MELD scores.
    • Patients with lower suPAR levels have significantly better short- and long-term survival following TIPS insertion.
    • In an independent validation cohort, higher suPAR concentrations in peripheral vein blood indicated poor transplant-free survival after TIPS.
  • Acute and non-acute decompensation of liver cirrhosis (47/130)
    Martin S. Schulz, Paolo Angeli & Jonel Trebicka, Liver International
    Published: 1 March 2024
    Abstract:
    In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.
  • Terlipressin therapy is associated with increased risk of colonisation with multidrug-resistant bacteria in patients with decompensated cirrhosis
    Markus Mücke, et al., Alimentary Pharmacology & Therapeutics
    Published: 27 February 2024
    Abstract:
    Background
    Patients with cirrhosis are susceptible to develop bacterial infections that trigger acute decompensation (AD) and acute-on-chronic liver failure (ACLF). Infections with multidrug-resistant organisms (MDRO) are associated with deleterious outcome. MDRO colonisation frequently proceeds MDRO infections and antibiotic therapy has been associated with MDRO colonisation.
    Aim
    The aim of the study was to assess the influence of non-antibiotic medication contributing to MDRO colonisation.
    Methods
    Three hundred twenty-four patients with AD and ACLF admitted to the ICU of Frankfurt University Hospital with MDRO screening were included. Regression models were performed to identify drugs associated with MDRO colonisation. Another cohort (n = 129) from Barcelona was included to validate. A third multi-centre cohort (n = 203) with metagenomic sequencing data of stool was included to detect antibiotic resistance genes.
    Results
    A total of 97 patients (30%) were identified to have MDRO colonisation and 35 of them (11%) developed MDRO infection. Patients with MDRO colonisation had significantly higher risk of MDRO infection than those without (p = 0.0098). Apart from antibiotic therapy (odds ratio (OR) 2.91, 95%-confidence interval (CI) 1.82–4.93, p < 0.0001), terlipressin therapy in the previous 14 days was the only independent covariate associated with MDRO colonisation in both cohorts, the overall (OR 9.47, 95%-CI 2.96–30.23, p < 0.0001) and after propensity score matching (OR 5.30, 95%-CI 1.22–23.03, p = 0.011). In the second cohort, prior terlipressin therapy was a risk factor for MDRO colonisation (OR 2.49, 95% CI 0.911–6.823, p = 0.075) and associated with risk of MDRO infection during follow-up (p = 0.017). The validation cohort demonstrated that antibiotic inactivation genes were significantly associated with terlipressin administration (p = 0.001).
    Conclusions
    Our study reports an increased risk of MDRO colonisation in patients with AD or ACLF, who recently received terlipressin therapy, while other commonly prescribed non-antibiotic co-medications had negligible influence. Future prospective trials are needed to confirm these results.
  • Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study
    Simona Bartimoccia, et al., Internal and Emergency Medicine
    Published: 26 February 2024
    Abstract:
    Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow’s triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6–40) and 31 cm/s (14–79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = – 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.
  • Stage of fibrosis is not a predictive determinant of weight loss in patients undergoing bariatric surgery
    Maximilian Joseph Brol, et al., Surgery for Obesity and Related Diseases
    Published: 24 February 2024
    Highlights:

    • Stage of hepatic fibrosis does not predict postbariatric weight-loss results.
    • Therefore, stage of hepatic fibrosis should not influence the indication for metabolic surgery.
    • Age and presence of Type 2 diabetes mellitus have negative impact on postbariatric weight-loss.
  • Personalised human albumin in patients with cirrhosis and ascites: design and rationale for the ALB-TRIAL – a randomised clinical biomarker validation trial
    Nikolaj Torp, et al., BMJ Open
    Published: 14 February 2024
    Abstract:
    Introduction
    Human albumin is used in the treatment of complications of cirrhosis. However, the use of long-term human albumin administration is costly and resource demanding for both patients and healthcare systems. A precision medicine approach with biomarkers to predict human albumin treatment response, so-called predictive biomarkers, could make this a viable treatment option in patients with cirrhosis and ascites.
    Methods and analysis
    ALB-TRIAL is a multinational, double-blind, placebo-controlled randomised controlled trial. We aim to validate a predictive biomarker, consisting of a panel of circulating metabolites, to predict the treatment response to human albumin in patients with cirrhosis and ascites. All enrolled patients are stratified into a high-expected or low-expected effect stratum of human albumin based on the biomarker outcome. After stratification, patients in each group are randomised into either active treatment (20% human albumin) or corresponding placebo (0.9% NaCl) every 10th day for 6 months. The primary outcome is the cumulative number of liver-related events (composite of decompensation episodes, transjugular intrahepatic shunt insertion, liver transplantation and death). Key secondary outcomes include time-to-event analysis of primary outcome components, an analysis of the total healthcare burden and a health economic analysis.
    Ethics and dissemination
    The trial obtained ethical and regulatory approval in Denmark, Germany, the Netherlands, Belgium, Hungary and Spain through the Clinical Trials Information System (CTIS) from 13 February 2023, while UK approvals from the Health Regulatory Authority, Medicines and Healthcare products Regulatory Agency and Research Ethics Committee are pending. Findings will be published in peer-reviewed journals, presented at conferences, communicated to relevant stakeholders and in the public registry of CTIS, following trial completion.
  • Operating under pressure: Is there a place for preoperative TIPS?
    Michael Praktiknjo, Jonel Trebicka; JHEP Reports
    Published: 9 February 2024
    Excerpt:
    Cirrhosis as a comorbidity is responsible for almost half of cirrhosis-related hospitalisations, while the burden of liver disease has been steadily increasing, particularly in the Western world, largely due to metabolic dysfunction-associated steatotic liver disease (MASLD) and alcohol-related liver disease.1 With improved long-term survival for patients with cirrhosis, surgery is becoming more common in this vulnerable patient population.2 Portal hypertension (PHT) is the major driver of acute decompensation (AD), acute-on-chronic liver failure (ACLF) and mortality for patients with cirrhosis, especially in the context of surgery. […]
  • The Role of Hypoxia-Inducible Factor 1 Alpha in Acute-on-Chronic Liver Failure
    Marcus M. Mücke, et al., Int. J. Mol. Sci
    Published: 26 January 2024
    Abstract:
    Acute-on-chronic liver failure (ACLF) is associated with increased mortality. Specific therapy options are limited. Hypoxia-inducible factor 1 alpha (HIF-1α) has been linked to the pathogenesis of chronic liver disease (CLD), but the role of HIF-1α in ACLF is poorly understood. In the current study, different etiologies of CLD and precipitating events triggering ACLF were used in four rodent models. HIF-1α expression and the intracellular pathway of HIF-1α induction were investigated using real-time quantitative PCR. The results were verified by Western blotting and immunohistochemistry for extrahepatic HIF-1α expression using transcriptome analysis. Exploratory immunohistochemical staining was performed to assess HIF-1α in human liver tissue. Intrahepatic HIF-1α expression was significantly increased in all animals with ACLF, regardless of the underlying etiology of CLD or the precipitating event. The induction of HIF-1α was accompanied by the increased mRNA expression of NFkB1 and STAT3 and resulted in a marked elevation of mRNA levels of its downstream genes. Extrahepatic HIF-1α expression was not elevated. In human liver tissue samples, HIF-1α expression was elevated in CLD and ACLF. Increased intrahepatic HIF-1α expression seems to play an important role in the pathogenesis of ACLF, and future studies are pending to investigate the role of therapeutic HIF inhibitors in ACLF.
  • Endoscopic procedures in hepatology: Current trends and new developments
    Wim Laleman et al., Journal of Hepatology
    Published: January 2024
    Summary:
    Gastrointestinal endoscopy has long been a reliable backbone in the diagnosis and management of hepatobilary disorders and their complications. However, with evolving non-invasive testing, personalised medicine has reframed the utility and necessity of endoscopic screening. Conversely, the growing interest and use of endoscopic ultrasound (EUS) and advanced endoscopy within gastrointestinal units has also opened novel diagnostic and therapeutic avenues for patients with various hepatobiliary diseases. The integration of “advanced endoscopy” within the practice of hepatology is nowadays referred to as “endo-hepatology”. In essence, endo-hepatology consists of two pillars: one focusing primarily on disorders of the liver parenchyma, vascular disorders, and portal hypertension, which is mainly captured via EUS, while the other targets the hepatobiliary tract via endoscopic retrograde cholangiopancreatography and advanced imaging. Applications under the umbrella of endo-hepatology include, amongst others, EUS-guided liver biopsy, EUS-guided portal pressure gradient measurement, coil and glue embolisation of gastric varices as well as cholangioscopy. As such endo-hepatology could become an attractive concept wherein advanced endoscopy might reinforce the medical management of patients with hepatobiliary disorders and their complications after initial basic work-up. In this review, we discuss current trends and future developments within endo-hepatology and the remaining hurdles to overcome.

2023

  • Role of endoscopy in hepatology
    Wim Laleman, et al., Digestive and Liver Disease
    Published: 26 December 2023
    Abstract:
    The growing and evolving field of EUS and advanced hepatobiliary endoscopy has amplified traditional upper gastrointestinal endoscopy and unveiled novel options for remaining unsolved hepatobiliary issues, both diagnostically and therapeutically. This conceptually appealing and fascinating integration of endoscopy within the practice of hepatology is referred to as ‘endo-hepatology’. Endo-hepatology focuses on the one hand on disorders of the liver parenchyma and liver vasculature and of the hepatobiliary tract on the other hand. Applications hanging under the umbrella of endohepatology involve amongst others EUS-guided liver biopsy, EUS-guided portal pressure measurement, EUS-guided portal venous blood sampling, EUS-guided coil & glue embolization of gastric varices and spontaneous portosystemic shunts as well as ERCP in the challenging context of (decompensated cirrhosis) and intraductal cholangioscopy for primary sclerosing cholangitis. Although endoscopic proficiency however does not necessarily equal in an actual straightforward end-solution for currently persisting (complex) hepatobiliary situations. Therefore, endohepatology continues to generate high-quality data to validate and standardize procedures against currently considered (best available) “golden standards” while continuing to search and trying to provide novel minimally invasive solutions for persisting hepatological stalemate situations. In the current review, we aim to critically appraise the status and potential future directions of endo-hepatology.
  • Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis
    Adrià Juanola, Ann Thu Ma, et al., Gut
    Published: 7 December 2023
    Abstract:
    Background 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.
    Methods 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.
    Results 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).
    Conclusion Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.
  • Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial
    Thit M. Kronborg, et al., Hepatology Communications
    Published: December 2023
    Abstract:
    Background:
    Patients with cirrhosis and portal hypertension face a high risk of complications. Besides their anti-inflammatory and antifibrotic effects, statins may reduce portal pressure and thus the risk of complications and mortality. We aimed to investigate the effects of atorvastatin on hospital admissions, mortality, inflammation, and lipidomics in cirrhosis with portal hypertension.
    Methods:
    We performed a double-blinded, randomized, placebo-controlled clinical trial among patients with cirrhosis and portal hypertension. Atorvastatin (10–20 mg/d) was administered for 6 months. We measured splanchnic hemodynamics, analyzed inflammatory markers, and performed lipidomics at baseline and after 6 months.
    Results:
    Seventy-eight patients were randomized, with 38 patients allocated to atorvastatin and 40 patients to placebo. Fifty-nine patients completed 6 months of intervention. Comparisons between changes in each group were calculated. Liver-related complications and mortality were similar between the groups. The HVPG and Model for End-stage Liver Disease score did not change between groups (p=0.95 and 0.87, respectively). Atorvastatin decreased 3 of 42 inflammatory markers, CD62-L-selectin, matrix metalloproteinases-2, and TNF-α (p-values: 0.005, 0.011, and 0.023, respectively), while lipidomics was not significantly changed.
    Conclusions:
    In patients with cirrhosis, atorvastatin was safe to use, but did not reduce mortality, the risk of liver-related complications, or the HVPG. Atorvastatin induced minor anti-inflammatory effects and minor effects on lipids during a 6-month treatment period.
  • Autophagy and extracellular vesicles in the liver endothelium: friends or foes?
    Louise Biquard & Pierre-Emmanuel Rautou. Hepatology International
    Published: 9 November 2023
    Graphical Abstract:

    Role of autophagy in liver sinusoidal endothelial cells (LSECs) and their interaction with hepatic stellate cells (HSC). EndoMT endothelial to mesenchymal transition, EV extracellular vesicle, HSC hepatic stellate cells, LSECs liver sinusoidal endothelial cells, MVB multivesicular body, NO nitric oxide.
  • Epidemiology of liver transplantation and post-LT complications in Germany: nationwide study (2005–2018)
    Wenyi Gu, et al.; European Journal of Gastroenterology & Hepatology
    Published: November 2023
    Abstract:
    Background
    To date, liver transplantation (LT) is the only curative treatment for cirrhosis and early-diagnosed progressive acute liver failure (ALF). However, LT results in morbidities and mortality even post-LT. Different comorbidities may follow and further increase mortality and morbidity. In this study, we investigated the outcomes and their trends over a period of 14 years among hospitalized patients evaluated for LT, transplant and post-LT in Germany.
    Methods
    This German nationwide study investigated the number of admissions of patients hospitalized for evaluation of LT and post-LT on related comorbidities and complications between 2005 and 2018 based on the DRG system with ICD-10/OPS codes. 14 745 patients were put on the LT waiting list and 12 836 underwent LT during the observational period.
    Results
    The LT number decreased by 2.3% over time, while the waiting list mortality rate increased by 5%. By contrast, the in-hospital mortality rate decreased by 3%, especially in ALF patients (decrease of 16%). Interestingly, admissions of post-LT patients for complications almost doubled, driven mainly by complications of immunosuppression (tripled). Importantly, post-LT patients with acute kidney injury (20.2%) and biliodigestive anastomosis (18.4%) showed the highest in-hospital mortality rate of all complications.
    Conclusion
    In conclusion, the decrease in LT leads most probably to the increased in-hospital mortality of patients on the waiting list. Interestingly, in-hospital mortality decreased in LT patients. Post-LT comorbidities requiring hospitalization increased in the observational period and management of patients post-LT with AKI or biliodigestive anastomosis should be addressed.
  • Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET)
    Emmanuel Weiss et al. Gut
    Published: 6 October 2023; Correction published: 1 November 2023
    Abstract:
    Background and aims: Current prognostic scores of patients with acutely decompensated cirrhosis (AD), particularly those with acute-on-chronic liver failure (ACLF), underestimate the risk of mortality. This is probably because systemic inflammation (SI), the major driver of AD/ACLF, is not reflected in the scores. SI induces metabolic changes, which impair delivery of the necessary energy for the immune reaction. This investigation aimed to identify metabolites associated with short-term (28-day) death and to design metabolomic prognostic models.
    Conclusions: Models including metabolites (CLIF-C MET) reflecting SI, mitochondrial dysfunction and sympathetic system activation are better predictors of short-term mortality than scores based only on organ dysfunction (eg, MELDNa), especially in patients with ACLF.
  • Blood Endotoxin Levels as Biomarker of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis
    Josefin Soppert, et al. Clinical Gastroenterology and Hepatology
    Published: October 2023
    Abstract:
    Background & Aims
    Growing evidence supports a role of gut-derived metabolites in nonalcoholic fatty liver disease (NAFLD), but the relation of endotoxin levels with gut permeability and NAFLD stage remains unclear. This systematic review with meta-analysis aims to provide further insights.
    Methods
    PubMed, Embase, and Cochrane Library were searched for studies published until January 2022 assessing blood endotoxins in patients with NAFLD. Meta-analyses and univariate/multivariate meta-regression, as well as correlation analyses, were performed for endotoxin values and potential relationships to disease stage, age, sex, parameters of systemic inflammation, and metabolic syndrome, as well as liver function and histology.
    Results
    Forty-three studies were included, of which 34 were used for meta-analyses. Blood endotoxin levels were higher in patients with simple steatosis vs liver-healthy controls (standardized mean difference, 0.86; 95% confidence interval, 0.62–1.11) as well as in patients with nonalcoholic steatohepatitis vs patients with nonalcoholic fatty liver/non-nonalcoholic steatohepatitis (standardized mean difference, 0.81; 95% confidence interval, 0.27–1.35; P = .0078). Consistently, higher endotoxin levels were observed in patients with more advanced histopathological gradings of liver steatosis and fibrosis. An increase of blood endotoxin levels was partially attributed to a body mass index rise in patients with NAFLD compared with controls. Nevertheless, significant increases of blood endotoxin levels in NAFLD retained after compensation for differences in body mass index, metabolic condition, or liver enzymes. Increases in blood endotoxin levels were associated with increases in C-reactive protein concentrations, and in most cases, paralleled a rise in markers for intestinal permeability.
    Conclusion
    Our results support blood endotoxin levels as relevant diagnostic biomarker for NAFLD, both for disease detection as well as staging during disease progression, and might serve as surrogate marker of enhanced intestinal permeability in NAFLD.
  • Use and outcome of TIPS in hospitalized patients in Germany: A Nationwide study (2007–2018)
    Wenyi Gu, et al., Hepatology Communications
    Published: October 2023
    Abstract:
    Background:
    The number of complications in patients admitted for cirrhosis has increased over time. Portal hypertension is the driver of many complications of cirrhosis. TIPS placement is the most effective treatment of portal hypertension. The aim of this study was to analyze the use and impact of TIPS placement in the last decade in a nationwide study in Germany.
    Methods:
    We analyzed 14,598 admissions of patients for TIPS insertions in Germany from 2007 to 2018 using the DRG system, 12,877 out of 2,000,765 total admissions of patients with cirrhosis. All diagnoses and procedures were coded according to ICD-10-CM and OPS codes. The data were analyzed, focusing on the number of admissions and in-hospital mortality.
    Results:
    The number of TIPS placements increased over the last decade. In-hospital mortality of cirrhotic patients with TIPS decreased when it was placed for severe bleeding (15.2% [TIPS] vs. 19.5% [endoscopy treatment]), ascites (8.7% [TIPS] vs. 14.4% [paracentesis]), and hepatorenal syndrome (HRS) (17.1% [TIPS] vs. 43.3% [no-TIPS]). In the case of bleeding, TIPS significantly decreased in-hospital mortality and also in ascites and HRS. During hospitalization, 22.6% admissions of patients with TIPS insertion showed HE. However, in-hospital mortality in patients admitted with HE grades 1 or 2 and TIPS was lower than in patients without TIPS. In the logistic regression, a higher HE grade(3 and 4), infection, and circulatory disease were found to be independently associated with in-hospital mortality in patients with TIPS insertion.
    Conclusion:
    Our nationwide study demonstrates that TIPS insertion is increasingly used in Germany. TIPS improves outcomes, especially in patients with ascites and HRS, regardless of lower HE grades, while higher HE grades, infection, and circulatory diseases seem to be associated with risk of in-hospital mortality.
  • Assessment of portal hypertension severity using machine learning models in patients with compensated cirrhosis
    Jiří Reiniš, Oleksandr Petrenko, et al. Journal of Hepatology
    Published: 21 September 2023
    Highlights:

    • Models that can non-invasively assess portal hypertension severity are an unmet clinical need.
    • Machine learning models trained on 3/5 laboratory parameters enabled non-invasive assessment of portal hypertension severity.
    • These models could predict portal pressures of ≥10 mmHg or ≥16 mmHg in individuals with compensated cirrhosis.
    • An online tool based on these models has been made available and can be used for portal hypertension risk stratification.
  • Editorial: Acute-on-chronic liver failure: systemic inflammation and immunosuppression
    Olaf Tyc, et al. Front. Immunol
    Published: 15 August 2023
    Introduction:
    ACLF is a severe and often fatal condition that occurs in individuals with underlying chronic liver disease when acute events precipitate its development (1). Due to the lack of therapies for ACLF, except for liver transplantation, there is a critical need to investigate its pathophysiological mechanisms (2). It is well-established that systemic inflammation plays a significant role in driving ACLF (3). However, there is limited understanding of how systemic inflammation develops and how it affects organ functions. Additionally, immunosuppression, another immune dysfunction observed in ACLF, contributes to bacterial infections and worsens the overall condition (4). Unfortunately, little is known about the development of immunosuppression during ACLF and its underlying molecular mechanisms. Consequently, ACLF remains a major challenge for clinicians and researchers. The following articles present interesting findings in the field of Acute-on-chronic Liver Failure (ACLF).
  • Controversies regarding albumin therapy in cirrhosis
    Jonel Trebicka, Guadalupe Garcia-Tsao, Hepatology
    Published: 7 August 2023
    Abstract:
    Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a “one size fits all” strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.
  • To TIPS or Not to TIPS in High Risk of Variceal Rebleeding and Acute-on-Chronic Liver Failure
    Wenyi Gu, et al., Seminars in Liver Disease
    Published: 5 July 2023
    Abstract:
    Variceal bleeding is a consequence of severe portal hypertension in patients with liver cirrhosis. Although the rate of bleeding has decreased over time, variceal bleeding in the presence of acute-on-chronic liver failure (ACLF) carries a high risk of treatment failure and short-term mortality. Treatment and/or removal of precipitating events (mainly bacterial infection and alcoholic hepatitis) and decrease of portal pressure may improve outcome of patients with acute decompensation or ACLF. Transjugular intrahepatic portosystemic shunts (TIPSs), especially in the preemptive situation, have been found to efficiently control bleeding, prevent rebleeding, and reduce short-term mortality. Therefore, TIPS placement should be considered as an option in the management of ACLF patients with variceal bleeding.
  • Mechanisms of immunity in acutely decompensated cirrhosis and acute-on-chronic liver failure
    Cornelius Engelmann, Ingrid W. Zhang, Joan Clària, Liver International
    Published: 27 June 2023
    Abstract:
    The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.
  • Acute-On-Chronic Liver Failure: Current Interventional Treatment Options and Future Challenges
    Markus Kimmann and Jonel Trebicka; Journal of Personalized Medicine
    Published: 26 June 2023
    Abstract:
    Acute-on-chronic liver failure (ACLF) is a frequent complication in patients with liver cirrhosis that has high short-term mortality. It is characterized by acute decompensation (AD) of liver cirrhosis, intra- and extrahepatic organ failure, and severe systemic inflammation (SI). In the recent past, several studies have investigated the management of this group of patients. Identification and treatment of precipitants of decompensation and ACLF play an important role, and management of the respective intra- and extrahepatic organ failures is essential. However, no specific treatment for ACLF has been established to date, and the only curative treatment option currently available for these patients is liver transplantation (LT). It has been shown that ACLF patients are at severe risk of waitlist mortality, and post-LT survival rates are high, making ACLF patients suitable candidates for LT. However, only a limited number of patients are eligible for LT due to related contraindications such as uncontrolled infections. In this case, bridging strategies (e.g., extracorporeal organ support systems) are required. Further therapeutic approaches have recently been developed and evaluated. Thus, this review focuses on current management and potential future treatment options.
  • Roles of systemic inflammatory and metabolic responses in the pathophysiology of acute-on-chronic liver failure
    Joan Clària, Vicente Arroyo, Richard Moreau, JHEP Reports
    Published: 8 June 2023
    Summary:
    Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterised by the presence of one or more organ failures, intense systemic inflammation, peripheral blood lymphopenia, and a high risk of death without liver transplantation within 28 days. Herein, we propose the hypothesis that intense systemic inflammation may lead to organ failures through five different non-mutually exclusive mechanisms. First, pathogen-associated molecular patterns and inflammatory mediators (i.e. cytokines and lipid mediators) stimulate the production of the vasorelaxant nitric oxide in the walls of splanchnic arterioles, leading to enhanced splanchnic and systemic vasodilation which, in turn, induces enhanced activity of endogenous vasoconstrictor systems causing renal vasoconstriction and acute kidney injury. Second, neutrophils that reach the systemic circulation are prone to adhere to the vascular endothelium. Cytokines and lipid mediators act on the endothelium in microvessels of vital organs, an effect that favours the migration of neutrophils (and probably other leukocytes) to surrounding tissues where neutrophils can cause tissue damage and thereby contribute to organ failure. Third, cytokines and lipid mediators promote the formation of microthrombi that impair microcirculation and tissue oxygenation. Fourth, acute inflammation stimulates intense peripheral catabolism of amino acids whose products may be metabotoxins that contribute to hepatic encephalopathy. Fifth, acute inflammatory responses, which include the production of a broad variety of biomolecules (proteins and lipids), and an increase in biomass (i.e., granulopoiesis requiring de novo nucleotide synthesis), among others, are energetically expensive processes that require large amounts of nutrients. Therefore, immunity competes with other maintenance programmes for energy. The brain stem integrates the energy demand of each organ system, with immunity considered a top priority. The brain stem may “decide” to make a trade-off which involves the induction of a dormancy programme that permits the shutdown of mitochondrial respiration and oxidative phosphorylation in peripheral organs. In the context of acutely decompensated cirrhosis, the consequence of a shutdown of mitochondrial respiration and ATP production would be a dramatic decrease in organ function.
  • Pathogenetic mechanisms and therapeutic approaches of acute-to-chronic liver failure
    Robert Schierwagen, Wenyi Gu, et al., Am J Physiol Cell Physiol
    Published: 5 June 2023
    Abstract:
    The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.
  • The rationale and study design of two phaseII trials examining the effects of BI 685509,a soluble guanylyl cyclase activator, on clinicallysignificant portal hypertension in patientswith compensated cirrhosis
    Thomas Reiberger, et al., Trials
    Published: 24 April 2023
    Abstract:
    Background
    Clinically significant portal hypertension (CSPH) drives cirrhosis-related complications (i.e. hepatic decompensation). Impaired nitric oxide (NO) bioavailability promotes sinusoidal vasoconstriction, which is the initial pathomechanism of CSPH development. Activation of soluble guanylyl cyclase (sGC), a key downstream effector of NO, facilitates sinusoidal vasodilation, which in turn may improve CSPH. Two phase II studies are being conducted to assess the efficacy of the NO-independent sGC activator BI 685509 in patients with CSPH due to various cirrhosis aetiologies.
    Methods
    The 1366.0021 trial (NCT05161481) is a randomised, placebo-controlled, exploratory study that will assess BI 685509 (moderate or high dose) for 24 weeks in patients with CSPH due to alcohol-related liver disease. The 1366.0029 trial (NCT05282121) is a randomised, open-label, parallel-group, exploratory study that will assess BI 685509 (high dose) alone in patients with hepatitis B or C virus infection or non-alcoholic steatohepatitis (NASH) and in combination with 10 mg empagliflozin in patients with NASH and type 2 diabetes mellitus for 8 weeks. The 1366.0021 trial will enrol 105 patients, and the 1366.0029 trial will enrol 80 patients. In both studies, the primary endpoint is the change from baseline in hepatic venous pressure gradient (HVPG) until the end of treatment (24 or 8 weeks, respectively). Secondary endpoints include the proportion of patients with an HVPG reduction of >10% from baseline, the development of decompensation events and the change from baseline in HVPG after 8 weeks in the 1366.0021 trial. In addition, the trials will assess changes in liver and spleen stiffness by transient elastography, changes in hepatic and renal function and the tolerability of BI 685509.
    Discussion
    These trials will enable assessment of the short-term (8 weeks) and longer-term (24 weeks) safety of BI 685509, and the effect of sGC activation by BI 685509 on CSPH due to various cirrhosis aetiologies. The trials will use central readings of the diagnostic gold standard HVPG for the primary endpoint, and changes in established non-invasive biomarkers, such as liver and spleen stiffness. Ultimately, these trials will provide key information for developing future phase III trials.
  • Myostatin is associated with the presence and development of acute-on-chronic liver failure
    Astrid Ruiz-Margáin, et al., JHEP Reports
    Published: 14 April 2023
    Highlights:

    • Sarcopenia is associated with ACLF development and outcome.
    • Myostatin is a key myokine involved in the regulation of skeletal muscle.
    • Myostatin levels are lower in patients with decompensated cirrhosis and ACLF, and positively correlate with nutritional markers.
    • Low myostatin levels are associated with the development of ACLF and decreased survival.
  • Essential lipid autacoids rewire mitochondrial energy efficiency in metabolic dysfunction-associated fatty liver disease
    Cristina López-Vicario et al. Hepatology
    Published: April 2023
    Abstract:
    Background and aim: Injury to hepatocyte mitochondria is common in metabolic dysfunction‐associated fatty liver disease. Here, we investigated whether changes in the content of essential fatty acid–derived lipid autacoids affect hepatocyte mitochondrial bioenergetics and metabolic efficiency.
    Conclusion: Our data uncover the importance of a lipid membrane composition rich in DHA and its lipid autacoid derivatives to have optimal hepatic mitochondrial and metabolic efficiency.
  • Essential role for albumin in preserving liver cells from TNFα-induced mitochondrial injury
    Marta Duran-Güell, et al. FASEB Journal
    Published: 21 February 2023
    Abstract:
    Cytokine-induced inflammation and mitochondrial oxidative stress are key drivers of liver tissue injury. Here, we describe experiments modeling hepatic inflammatory conditions in which plasma leakage leads to large amounts of albumin to reach the interstitium and parenchymal surfaces to explore whether this protein plays a role in preserving hepatocyte mitochondria against the damaging actions of the cytotoxic cytokine tumor necrosis factor alpha (TNFα). Hepatocytes and precision-cut liver slices were cultured in the absence or presence of albumin in the cell media and then exposed to mitochondrial injury with the cytokine TNFα. The homeostatic role of albumin was also investigated in a mouse model of TNFα-mediated liver injury induced by lipopolysaccharide and D-galactosamine (LPS/D-gal). Mitochondrial ultrastructure, oxygen consumption, ATP and reactive oxygen species (ROS) generation, fatty acid β-oxidation (FAO), and metabolic fluxes were assessed by transmission electron microscopy (TEM), high-resolution respirometry, luminescence-fluorimetric-colorimetric assays and NADH/FADH2 production from various substrates, respectively. TEM analysis revealed that in the absence of albumin, hepatocytes were more susceptible to the damaging actions of TNFα and showed more round-shaped mitochondria with less intact cristae than hepatocytes cultured with albumin. In the presence of albumin in the cell media, hepatocytes also showed reduced mitochondrial ROS generation and FAO. The mitochondria protective actions of albumin against TNFα damage were associated with the restoration of a breakpoint between isocitrate and α-ketoglutarate in the tricarboxylic acid cycle and the upregulation of the antioxidant activating transcription factor 3 (ATF3). The involvement of ATF3 and its downstream targets was confirmed in vivo in mice with LPS/D-gal-induced liver injury, which showed increased hepatic glutathione levels, indicating a reduction in oxidative stress after albumin administration. These findings reveal that the albumin molecule is required for the effective protection of liver cells from mitochondrial oxidative stress induced by TNFα. These findings emphasize the importance of maintaining the albumin levels in the interstitial fluid within the normal range to protect the tissues against inflammatory injury in patients with recurrent hypoalbuminemia.
  • LSD-induced increase of Ising temperature and algorithmic complexity of brain dynamics
    Giulio Ruffini, et al. PLOS Computational Biology
    Published: 3 February 2023
    Author summary:
    In this study, we aim to characterize two brain states (psychedelics-induced and placebo), as captured in functional magnetic resonance imaging (fMRI) data, with features derived from the Ising model formalism (system temperature, critical point, susceptibility) and from algorithmic complexity. Under the hypothesis that psychedelics drive the brain into a more disordered state, we study criticality features of brain dynamics under LSD in a within-subject study using the Ising model formalism and algorithmic complexity using Lempel-Ziv and the Block Decomposition methods. Personalized Ising models are created by first using BOLD fMRI data from all the subjects and conditions to create a single Ising “archetype” model—which we can interpret as the average model of the data at unit temperature—and then by adjusting the model temperature for each subject and condition. We find that the effects of LSD translate into increased BOLD signal complexity and Ising temperature, in agreement with earlier findings and predictions from existing theories of the effects of psychedelics, such as the relaxed beliefs under psychedelics (REBUS), the anarchic brain hypothesis, and the algorithmic information theory of consciousness (KT). However, in contrast with some of the previously cited theories, we find that the system in the placebo condition is already in the paramagnetic phase—above the critical point—with ingestion of LSD resulting in a shift away from Ising criticality into a more disordered state. Finally, we highlight the fact that the structural connectome can be recovered to a good degree by fitting an Ising model and that the reduction of homotopic links (direct or indirect) appears to play an important role in the slide to disorder under psychedelics.
  • The non-selective Rho-kinase inhibitors Y-27632 and Y-33075 decrease contraction but increase migration in murine and human hepatic stellate cells
    Nadine Bachtler, et al. PLOS ONE
    Published: 31 January 2023
    Abstract:
    Background
    The Rho-kinase ROCK II plays a major role in the activation of hepatic stellate cells (HSC), which are the key profibrotic and contractile cells contributing to the development of chronic liver disease. Inhibition of ROCK II ultimately blocks the phosphorylation of the myosin light chain (MLC) and thus inhibits stress fibre assembly and cell contraction. We investigated the effects of the ROCK inhibitors Y-33075 as well as Y-27632 in murine and human hepatic stellate cells.
    Methods
    Primary isolated HSC from FVB/NJ mice and the immortalized human HSC line TWNT-4 were culture-activated and incubated with Y-27632 and Y-33075 (10nM to 10μM) for 24h. Protein expression levels were analyzed by Western Blots and transcriptional levels of pro-fibrotic markers and proliferative markers were evaluated using real-time qPCR. Migration was investigated by wound-healing assay. Proliferation was assessed by BrdU assay. Contraction of HSC was measured using 3D collagen matrices after incubation with Y-27632 or Y-33075 in different doses.
    Results
    Both Rho-kinase inhibitors, Y-27632 and Y-33075, reduced contraction, fibrogenesis and proliferation in activated primary mouse HSC (FVB/NJ) and human HSC line (TWNT-4) significantly. Y-33075 demonstrated a 10-times increased potency compared to Y-27632. Surprisingly, both inhibitors mediated a substantial and unexpected increase in migration of HSC in FVB/NJ.
    Conclusion
    ROCK inhibition by the tested compounds decreased contraction but increased migration. Y-33075 proved more potent than Y27632 in the inhibition of contraction of HSCs and should be further evaluated in chronic liver disease.
  • Management of splanchnic vein thrombosis
    Laure Elkrief et al. JHEP Reports
    Published: 2 January 2023
    Key points:

    • Patients with Budd-Chiari syndrome or portal vein thrombosis in the absence of underlying liver disease should be systematically screened for myeloproliferative neoplasms.
    • The diagnosis of Budd-Chiari syndrome or portal vein thrombosis is suspected using abdominal Doppler ultrasonography and confirmed using contrast-enhanced CT or MRI; liver biopsy is generally not necessary.
    • In patients with Budd-Chiari syndrome, long-term anticoagulation is recommended; prompt identification and treatment of the causal factor have a beneficial impact on patient outcomes.
    • Spontaneous recanalization is rare in patients with portal vein thrombosis in the absence of underlying liver disease but occurs in ∼40% of patients with cirrhosis.
    • In patients with portal vein thrombosis in the absence of underlying liver disease, long-term anticoagulation is generally recommended.
    • In patients with portal vein thrombosis in the absence of underlying liver disease, preliminary data suggest that portal vein recanalization with or without TIPS is a safe option for the treatment of refractory complications of portal hypertension or portal cavernoma cholangiopathy when performed in expert centres.
    • In patients with cirrhosis and portal vein thrombosis, anticoagulation is recommended for all liver transplant candidates and, among those who are not candidates, for those with recent (<6 months) thrombosis occluding >50% of the lumen of the main portal vein.
    • In patients with cirrhosis, TIPS can be considered as the second-line option for the treatment of portal vein thrombosis, especially in case of significant concomitant complications of portal hypertension.
    • There is growing evidence demonstrating that DOACs are a safe and effective option, though high-grade evidence is still needed before making strong recommendations on the use of DOACs in patients with splanchnic vein thrombosis.
  • Genetic variation in TERT modifies the risk of hepatocellular carcinoma in alcohol-related cirrhosis: results from a genome-wide case-control study
    Stephan Buch, Hamish Innes et al. Gut
    Published online: 4 July 2022
    Abstract:
    Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis.
    Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis.

2022

  • Predicting bleeding after liver biopsy using comprehensive clinical and laboratory investigations: A prospective analysis of 302 procedures
    Julien Bissonnette, Alix Riescher-Tuczkiewicz, et al. Journal of Thrombosis and Haemostasis. 2022
    Published: December 2022
    Abstract:
    Background: Liver biopsy carries a small risk of bleeding complications. No validated clinical or laboratory tool helps predict liver biopsy–related bleeding.
    Objectives: To determine whether global hemostasis tests and/or a clinical questionnaire could identify patients at risk of liver biopsy–related bleeding.
    Results: Three hundred two patients were included: 173 underwent percutaneous and 129 transjugular liver biopsy. There were 21 bleeding episodes (7%); 20 based on ultrasonographic criteria, 1 on laboratory criteria. None of the hemostasis tests and no item of the clinical questionnaire were associated with liver biopsy–related bleeding in the overall study group. Same results were obtained in subgroup analyses focusing on patients who underwent percutaneous liver biopsy, transjugular liver biopsy, or on patients with cirrhosis. Pain 2 h after liver biopsy was more frequent in patients with liver biopsy–related bleeding (55% vs. 23% p = .002).
    Conclusion: An extensive hemostasis workup, including global hemostasis assays, does not improve prediction of liver biopsy–related bleeding. Pain 2 h after liver biopsy should alert the clinician to the possibility of procedure‐related bleeding.
  • Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis
    Sandra Torres, et al. Hepatology
    Published: August 2022
    Abstract:
    Background and Aims: Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo.
    Approach and Results: Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors.
    Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin‐1 receptor‐associated kinase and colony‐stimulating factor 1 receptor.
    Pacritinib decreased gene expression of fibrosis markers in mouse primary and human‐derived HSCs in vitro. Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C57BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease.
    Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha‐smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels.
    Conclusions: This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.
  • The rs429358 Locus in Apolipoprotein E Is Associated With Hepatocellular Carcinoma in Patients With Cirrhosis
    Hamish Innes, et al. Hepatology Communications. 2022
    Published: May 2022
    Abstract:
    The host genetic background for hepatocellular carcinoma (HCC) is incompletely understood. We aimed to determine if four germline genetic polymorphisms, rs429358 in apolipoprotein E (APOE), rs2642438 in mitochondrial amidoxime reducing component 1 (MARC1), rs2792751 in glycerol‐3‐phosphate acyltransferase (GPAM), and rs187429064 in transmembrane 6 superfamily member 2 (TM6SF2), previously associated with progressive alcohol‐related and nonalcoholic fatty liver disease, are also associated with HCC. Four HCC case‐control data sets were constructed, including two mixed etiology data sets (UK Biobank and FinnGen); one hepatitis C virus (HCV) cohort (STOP‐HCV), and one alcohol‐related HCC cohort (Dresden HCC). The frequency of each variant was compared between HCC cases and cirrhosis controls (i.e., patients with cirrhosis without HCC). Population controls were also considered. Odds ratios (ORs) associations were calculated using logistic regression, adjusting for age, sex, and principal components of genetic ancestry. Fixed‐effect meta‐analysis was used to determine the pooled effect size across all data sets. Across four case‐control data sets, 2,070 HCC cases, 4,121 cirrhosis controls, and 525,779 population controls were included. The rs429358:C allele (APOE) was significantly less frequent in HCC cases versus cirrhosis controls (OR, 0.71; 95% confidence interval [CI], 0.61‐0.84; P = 2.9 × 10−5). Rs187429064:G (TM6SF2) was significantly more common in HCC cases versus cirrhosis controls and exhibited the strongest effect size (OR, 2.03; 95% CI, 1.45‐2.86; P = 3.1 × 10−6). In contrast, rs2792751:T (GPAM) was not associated with HCC (OR, 1.01; 95% CI, 0.90‐1.13; P = 0.89), whereas rs2642438:A (MARC1) narrowly missed statistical significance (OR, 0.91; 95% CI, 0.84‐1.00; P = 0.043). Conclusion: This study associates carriage of rs429358:C (APOE) with a reduced risk of HCC in patients with cirrhosis. Conversely, carriage of rs187429064:G in TM6SF2 is associated with an increased risk of HCC in patients with cirrhosis.
  • Editorial: Portal Hypertension in Cirrhosis: From Pathogenesis to Novel Treatments
    Chandana B. Herath, Peter W. Angus, Jonel Trebicka. Frontiers in Physiology. 2022
    Published: 21 March 2022
    Abstract: This editorial discusses various aspects of portal hypertension (PHT) in cirrhosis, including its pathogenesis, complications, and potential treatments.
  • Reduced Plasma Extracellular Vesicle CD5L Content in Patients With Acute-On-Chronic Liver Failure: Interplay With Specialized Pro-Resolving Lipid Mediators
    María Belen Sánchez-Rodríguez, et al. Frontiers in Immunology. 2022
    Published: 7 March 2022
    Abstract:
    Acute-on chronic liver failure (ACLF) is a syndrome that develops in patients with acutely decompensated cirrhosis (AD). It is characterized by a systemic hyperinflammatory state, leading to multiple organ failure. Our objective was to analyze macrophage anti-inflammatory protein CD5L in plasma extracellular vesicles (EVs) and assess its as yet unknown relationship with lipid mediators in ACLF. With this aim, EVs were purified by size exclusion chromatography from the plasma of healthy subjects (HS) (n=6) and patients with compensated cirrhosis (CC) (n=6), AD (n=11) and ACLF (n=11), which were defined as positive for CD9, CD5L and CD63 and their size, number, morphology and lipid mediator content were characterized by NTA, EM, and LC-MS/MS, respectively. Additionally, plasma CD5L was quantified by ELISA in 10 HS, 20 CC and 149 AD patients (69 ACLF). Moreover, macrophage CD5L expression and the biosynthesis of specialized lipid mediators (SPMs) were characterized in vitro in primary cells. Our results indicate that circulating EVs were significantly suppressed in cirrhosis, regardless of severity, and showed considerable alterations in CD5L and lipid mediator content as the disease progressed. In AD, levels of EV CD5L correlated best with those of the SPM RvE1. Analysis of total plasma supported these data and showed that, in ACLF, low CD5L levels were associated with circulatory (p<0.001), brain (p<0.008) and respiratory (p<0.05) failure (Mann-Whitney test). Functional studies in macrophages indicated a positive feedback loop between CD5L and RvE1 biosynthesis. In summary, we have determined a significant alteration of circulating EV contents in ACLF, with a loss of anti-inflammatory and pro-resolving molecules involved in the control of acute inflammation in this condition.
  • Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion
    Yiaojie Yu, et al, Cellular and Molecular Gastroenterology and Hepatology. 2022
    Published: 23 February 2022
    Abstract:
    Background & Aims: Liver fibrosis arises from long-term chronic liver injury, accompanied by an accelerated wound healing response with interstitial accumulation of extracellular matrix (ECM). Activated hepatic stellate cells (HSC) are the main source for ECM production. MicroRNA29a (miR-29a) is a crucial antifibrotic miRNA that is repressed during fibrosis, resulting in up-regulation of collagen synthesis.
    Results: In our study, we show that TGFβ and PDGF-BB resulted in decrease of intracellular miR-29a and a pronounced increase of vesicular miR-29a release into the supernatant. Strikingly, miR-29a vesicular release was accompanied by enhanced autophagic activity and up-regulation of the autophagy marker protein LC3. Moreover, autophagy inhibition strongly prevented miR-29a secretion and repressed its targets’ expression such as Col1A1. Consistently, hepatic miR-29a loss and increased LC3 expression in myofibroblastic HSC were associated with increased serum miR-29a levels in CCl4-treated murine liver fibrosis and specimens of hepatitis C virus patients with chronic liver disease.
    Conclusion: We provide evidence that activation-associated autophagy in HSC induces release of miR-29a, whereas inhibition of autophagy represses fibrogenic gene expression in part through attenuated miR-29a secretion.
  • Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure
    Ingrid W. Zhang, et al. Journal of Hepatology. 2022
    Published online: 25 August 2021, issue published online: January 2022
    Highlights:

    • Metabolic and transcriptional phenotypes of leukocytes from patients with ACLF were assessed.
    • Two break-points were discovered in the tricarboxylic cycle of leukocytes in ACLF.
    • Biomarkers of mitochondrial dysfunction correlated with inflammation and gene sets related to leukocyte activation.
    • Leukocyte mitochondrial dysfunction is a hallmark of ACLF.
  • Two-dimensional shear wave elastography predicts survival in advanced chronic liver disease
    Jonel Trebicka, Wenyi Gu, et al. Gut. 2022
    Published: January 2021, issue published online: 11 January 2022
    Abstract:
    Objective: Liver stiffness measurement (LSM) is a tool used to screen for significant fibrosis and portal hypertension. The aim of this retrospective multicentre study was to develop an easy tool using LSM for clinical outcomes in advanced chronic liver disease (ACLD) patients.

    Results: After screening 2148 patients (16 centres), 1827 patients (55 years, 62.4% men) were included in the 2D-SWE cohort, with median liver SWE (L-SWE) 11.8 kPa and a model for end stage liver disease (MELD) score of 8. Combination of MELD score and L-SWE predict independently of mortality (AUC 0.8). L-SWE cut-off at ≥20 kPa combined with MELD ≥10 could stratify the risk of mortality and first/further decompensation in ACLD patients. The 2-year mortality and decompensation rates were 36.9% and 61.8%, respectively, in the 305 (18.3%) high-risk patients (with L-SWE ≥20 kPa and MELD ≥10), while in the 944 (56.6%) low-risk patients, these were 1.1% and 3.5%, respectively. Importantly, this M10LS20 algorithm was validated by TE-based LSM and in an additional cohort of 119 patients with valid point shear SWE-LSM.

    Conclusion: The M10LS20 algorithm allows risk stratification of patients with ACLD. Patients with L-SWE ≥20 kPa and MELD ≥10 should be followed closely and receive intensified care, while patients with low risk may be managed at longer intervals.

  • Preoperative TIPS prevents the development of postoperative acute-on-chronic liver failure in patients with high CLIF-C AD score
    Johannes Chang, Pauline Höfer, et al. JHEP Reports. 2022
    Published: 20 January 2022
    Highlights:

    • This study investigates the impact of preoperative TIPS on postsurgical ACLF.
    • Patients with preoperative TIPS, especially before visceral surgery, develop significantly lower rates of ACLF.
    • Preoperative TIPS is associated with improved postsurgical survival.
    • CLIF-C AD score >45 can be used as cut-off for patients at risk for postsurgical ACLF.
    • Selected patients might benefit from preoperative TIPS insertion.
  • Baveno VII – Renewing consensus in portal hypertension [published correction appears in J Hepatol. 2022 Apr 14;:]
    Roberto de Franchis, et al. Journal of Hepatology. 2022
    Published: 29 December 2021, Correction published: 14 April 2022
    Summary:
    To expand on the work of previous meetings, a virtual Baveno VII workshop was organised for October 2021. Among patients with compensated cirrhosis or compensated advanced chronic liver disease (cACLD – defined at the Baveno VI conference), the presence or absence of clinically significant portal hypertension (CSPH) is associated with differing outcomes, including risk of death, and different diagnostic and therapeutic needs. Accordingly, the Baveno VII workshop was entitled “Personalized Care for Portal Hypertension”. The main fields of discussion were the relevance and indications for measuring the hepatic venous pressure gradient as a gold standard, the use of non-invasive tools for the diagnosis of cACLD and CSPH, the impact of aetiological and non-aetiological therapies on the course of cirrhosis, the prevention of the first episode of decompensation, the management of an acute bleeding episode, the prevention of further decompensation, as well as the diagnosis and management of splanchnic vein thrombosis and other vascular disorders of the liver. For each of these 9 topics, a thorough review of the medical literature was performed, and a series of consensus statements/recommendations were discussed and agreed upon. A summary of the most important conclusions/recommendations derived from the workshop is reported here. The statements are classified as unchanged, changed, and new in relation to Baveno VI.
  • Effect of sarcopenia on survival in patients with cirrhosis: A meta-analysis
    Xinxing Tantai, Yi Liu, et al. Journal of Hepatology. 2022
    Published: 12 November 2021, issue published online: March 2022
    Highlights: 

    • The overall prevalence of sarcopenia among patients with cirrhosis is 37.5%, with higher prevalence in males, patients with alcohol-related liver disease, and greater severity of cirrhosis.
    • The 1-, 3-, and 5-year cumulative probabilities of survival in patients with sarcopenia were 76.6%, 64.3%, and 45.3%, respectively. By comparison, they were 93.4%, 82.0%, and 74.2%, respectively in patients without sarcopenia
    • Sarcopenia is associated with an approximately 2-fold higher risk of death in patients with cirrhosis
    • Every 1 cm2/m2 increase in L3-SMI and 1 mm/m increase in umbilicus-TPMT were associated with a 3% and 12% decrease in mortality risk, respectively.
  • Acute-on-chronic liver failure: a global disease
    Martin Schulz & Jonel Trebicka. Gut. 2022
    Published online: 12 January 2021, issue published online: January 2022
    Abstract:

    • Acute-on-chronic liver failure (ACLF) is a severe form of acute decompensation in patients with liver cirrhosis.
    • ACLF has heterogeneous definitions in different regions, making epidemiological data difficult to compare.
    • A systematic review and meta-analysis identified 30 cohort studies worldwide, including 43,206 ACLF patients and 140,835 patients without ACLF, highlighting the global significance of ACLF.
    • Bacterial infections were the most common precipitating event for ACLF globally, followed by gastrointestinal bleeding and alcohol consumption.
    • The PREDICT trial classified and evaluated precipitating events prospectively, showing that bacterial infection and severe alcoholic hepatitis were the main triggers for acute decompensation and ACLF.
    • The study emphasized the need for early identification of different acute decompensation phenotypes and individual risk stratification for disease progression.
  • Trends and the course of liver cirrhosis and its complications in Germany: Nationwide population-based study (2005 to 2018).
    Wenyi Gu, et al. Lancet Reg Health Eur
    Published: January 2022
    Abstract:
    Background
    Cirrhosis is known to have a high prevalence and mortality worldwide. However, in Europe, the epidemiology of cirrhosis is possibly undergoing demographic changes, and etiologies may have changed due to improvements in standard of care. The aim of this population-based study was to analyze the trends and the course of liver cirrhosis and its complications in recent years in Germany.
    Methods
    We analyzed the data of all hospital admissions in Germany within diagnosis-related groups from 2005 to 2018. The diagnostic records of cirrhosis and other categories of diseases were based on ICD-10-GM codes. The primary outcome measurement was in-hospital mortality. Trends were analyzed through Poisson regression of annual number of admissions. The impact of cirrhosis on overall in-hospital mortality were assessed through the multivariate multilevel logistic regression model adjusted for age, sex, and comorbidities.
    Findings
    Of the 248,085,936 admissions recorded between 2005 and 2018, a total of 2,302,171(0•94%) were admitted with the diagnosis of cirrhosis, mainly as a comorbidity. Compared with other chronic diseases, patients admitted with cirrhosis were younger, mainly male and had the highest in-hospital mortality rate. Diagnosis of cirrhosis was an independent risk factor of in-hospital mortality with the highest odds ratio (OR:6•2[95%CI:6.1-6•3]) among all diagnoses. The prevalence of non-alcoholic fatty liver disease has increased four times from 2005 to 2018, while alcoholic cirrhosis is 20 times than other etiologies. Bleeding was found to be decreasing over time, but ascites remained the most common complication and was increasing.
    Interpretation
    This nationwide study demonstrates that cirrhosis represents a considerable healthcare burden, as shown by the increasing in-hospital mortality, also in combination with other chronic diseases. Alcohol-related cirrhosis and complications are on the rise. More resources and better management strategies are warranted.

2021

  • Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction.
    Sauerbruch T, Hennenberg M, Trebicka J, Beuers U., Front. Physiol. 2021
    Published: 29 July 2021
    Abstract:
    The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
  • Mitochondrial Dysfunction in Advanced Liver Disease: Emerging Concepts.
    Ingrid W. Zhang, Cristina López-Vicario, Marta Duran-Güell, Joan Clària, Front Mol Biosci. 2021
    Published: 23 November 2021
    Abstract:
    Mitochondria are entrusted with the challenging task of providing energy through the generation of ATP, the universal cellular currency, thereby being highly flexible to different acute and chronic nutrient demands of the cell. The fact that mitochondrial diseases (genetic disorders caused by mutations in the nuclear or mitochondrial genome) manifest through a remarkable clinical variation of symptoms in affected individuals underlines the far-reaching implications of mitochondrial dysfunction. The study of mitochondrial function in genetic or non-genetic diseases therefore requires a multi-angled approach. Taking into account that the liver is among the organs richest in mitochondria, it stands to reason that in the process of unravelling the pathogenesis of liver-related diseases, researchers give special focus to characterizing mitochondrial function. However, mitochondrial dysfunction is not a uniformly defined term. It can refer to a decline in energy production, increase in reactive oxygen species and so forth. Therefore, any study on mitochondrial dysfunction first needs to define the dysfunction to be investigated. Here, we review the alterations of mitochondrial function in liver cirrhosis with emphasis on acutely decompensated liver cirrhosis and acute-on-chronic liver failure (ACLF), the latter being a form of acute decompensation characterized by a generalized state of systemic hyperinflammation/immunosuppression and high mortality rate. The studies that we discuss were either carried out in liver tissue itself of these patients, or in circulating leukocytes, whose mitochondrial alterations might reflect tissue and organ mitochondrial dysfunction. In addition, we present different methodological approaches that can be of utility to address the diverse aspects of hepatocyte and leukocyte mitochondrial function in liver disease. They include assays to measure metabolic fluxes using the comparatively novel Biolog’s MitoPlates in a 96-well format as well as assessment of mitochondrial respiration by high-resolution respirometry using Oroboros’ O2k-technology and Agilent Seahorse XF technology.

  • Early transplantation maximizes survival in severe acute-on-chronic liver failure: Results of a Markov decision process model.
    Zhang S, Suen SC, Gong CL, et al., JHEP Rep. 2021
    Published: 22 September 2021
    Highlights

    • We created a Markov decision process model to maximize overall survival ACLF-3 patients within 7 days of listing.
    • We examined three variables: earlier transplantation, organ quality, and recovery of organ failures.
    • Earlier transplantation maximizes overall survival probability, due to high waitlist mortality of patients with ACLF-3.
    • The impact of a marginal organ on post-LT mortality is less consequential than the mortality from delaying transplantation.
    • The likelihood of organ failure recovery within 7 days of listing was less than 10%.
  • Leveraging omics to understand the molecular basis of acute-on-chronic liver failure
    Joan Clària. Advances in Laboratory Medicine / Avances en Medicina de Laboratorio
    Published: 11 August 2021
    Abstract:
    Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with acutely decompensated cirrhosis. In this condition, dysbalanced immune function and excessive systemic inflammation are closely associated with organ failure and high short-term mortality. In this review, we describe how omic technologies have contributed to the characterization of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on the role of metabolomics, lipidomics and transcriptomics in profiling the triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]) and effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) that lead to activation of the innate immune system. This review also describes how omic approaches can be invaluable tools to accelerate the identification of novel biomarkers that could guide the implementation of novel therapies/interventions aimed at protecting these patients from excessive systemic inflammation and organ failure.
  • Extrahepatic Surgery in Cirrhosis Significantly Increases Portal Pressure in Preclinical Animal Models.
    Johannes Chang, Jonathan Meinke, et al., Front Physiol. 2021
    Published: 20 August 2021
    Abstract:
    Background: Liver cirrhosis is a relevant comorbidity with increasing prevalence. Postoperative decompensation and development of complications in patients with cirrhosis remains a frequent clinical problem. Surgery has been discussed as a precipitating event for decompensation and complications of cirrhosis, but the underlying pathomechanisms are still obscure. The aim of this study was to analyze the role of abdominal extrahepatic surgery in cirrhosis on portal pressure and fibrosis in a preclinical model.
    Methods: Compensated liver cirrhosis was induced using tetrachlormethane (CCL4) inhalation and bile duct ligation (BDL) models in rats, non-cirrhotic portal hypertension by partial portal vein ligation (PPVL). Intestinal manipulation (IM) as a model of extrahepatic abdominal surgery was performed. 2 and 7 days after IM, portal pressure was measured in-vivo. Hydroxyproline measurements, Sirius Red staining and qPCR measurements of the liver were performed for evaluation of fibrosis development and hepatic inflammation. Laboratory parameters of liver function in serum were analyzed.
    Results: Portal pressure was significantly elevated 2 and 7 days after IM in both models of cirrhosis. In the non-cirrhotic model the trend was the same, while not statistically significant. In both cirrhotic models, IM shows strong effects of decompensation, with significant weight loss, elevation of liver enzymes and hypoalbuminemia. 7 days after IM in the BDL group, Sirius red staining and hydroxyproline levels showed significant progression of fibrosis and significantly elevated mRNA levels of hepatic inflammation compared to the respective control group. A progression of fibrosis was not observed in the CCL4 model.
    Conclusion: In animal models of cirrhosis with continuous liver injury (BDL), IM increases portal pressure, and development of fibrosis. Perioperative portal pressure and hence inflammation processes may be therapeutic targets to prevent post-operative decompensation in cirrhosis.

2020

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