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View topic-related background literature as well as publications of the DECISION consortium itself. As soon as new publications are available, we list them here. All publications of DECISION will be open access for everyone, linked directly to the full-text version of the respective journal, publisher, or online repository. For PDFs of our own press releases please go to DOWNLOADS. To receive our newsletter, please subscribe here!

DECISION Publications

2024

  • 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.

2023

  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Restoration of the gut microbiota is associated with a decreased risk of hepatic encephalopathy after TIPS
    Menghao Li, Kai Li, Shihao Tang, et al. JHEP Reports. 2022
    Published: 14 February 2022
    Highlights:

    • Gut dysbiosis of the patients without HE showed significant improvement after TIPS.
    • Expansion of autochthonous taxa after TIPS was negatively correlated with the occurrence and severity of HE.
    • The changes of relationship among the microbiota in different prognostic groups were opposite.
    • Pre-TIPS gut microbiota and certain clinical indices were associated with survival.
  • 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.

2021

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