Systemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation.

This study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH: hepatic venous pressure gradient ≥10 mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n = 164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed markers of inflammation (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]).

IL-6, CD163, and vWF were higher (p <0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p <0.05) at 1 year in patients with CSPH, with a greater rise in those who developed decompensation. CD163 was higher (p <0.01) in patients who decompensated at baseline and 1 and 2 years. FABP was elevated (p <0.01) in patients with CSPH compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p <0.01). LPS was higher (p <0.01) in patients with CSPH than in those with subclinical PH and controls and increased at 1 year regardless of decompensation development.

Inflammation and bacterial products are present in the systemic circulation in patients with compensated cirrhosis and CSPH. Progressive inflammation precedes the first decompensation.

Systemic inflammation drives cirrhosis progression during the decompensated stage, but its role in the compensated stage is unclear. We evaluated biomarkers of systemic inflammation, intestinal barrier integrity and bacterial translocation in patients with compensated cirrhosis and their dynamics in relation to the first decompensation. We demonstrate that low-grade inflammation and bacterial products are present in the systemic circulation in compensated cirrhosis, provided clinically significant portal hypertension has developed. We also show that worsening of systemic inflammation precedes the development of first clinical decompensation.

Background: Portal hypertension is a major complication of chronic liver diseases, leading to serious issues such as esophageal variceal bleeding. The increase in portal vein pressure is driven by both an organic component and a functional component, including tonic contraction of hepatic stellate cells. These processes result in a pathological rise in intrahepatic vascular resistance, stemming from partial impairment of hepatic microcirculation, which is further exacerbated by abnormalities in extrahepatic vessels, including increased portal blood flow. Objectives: This review aims to provide a comprehensive overview of the evolving pharmacological therapies for portal hypertension, with consideration and discussion of pathophysiological mechanisms, clinical complications, and pharmacogenetic considerations, highlighting potential directions for future research. Methods: A review of recent literature was performed to evaluate current knowledge and potential therapeutic strategies in portal hypertension. Results: For over 35 years, non-selective beta-blockers have been the cornerstone therapy for portal hypertension by reducing portal vein inflow as an extrahepatic target, effectively preventing decompensation and variceal hemorrhages. However, since not all patients exhibit an adequate response to non-selective beta-blockers (NSBBs), and some may not tolerate NSBBs, alternative or adjunctive therapies that enhance the effects of NSBBs on portal pressure are being investigated in preclinical and early clinical studies. Conclusions: A better understanding of pharmacogenetic factors and pathophysiological mechanisms could lead to more individualized and effective treatments for portal hypertension. These insights highlight potential directions for future research.

Low-grade chronic inflammation may impact liver disease. We investigated the extent to which circulating GlycA, a glycoprotein biomarker of low-grade inflammation, and high-sensitivity C-reactive protein (hs-CRP) are altered in patients with cirrhosis and liver transplant recipients (LTRs) and examined their associations with all-cause mortality. Plasma GlycA (nuclear magnetic resonance spectroscopy) and hs-CRP (nephelometry) were assessed in 129 patients with cirrhosis on the waiting list for liver transplantation and 367 LTRs (TransplantLines cohort study; NCT03272841) and compared with 4837 participants from the population-based PREVEND cohort. GlycA levels were lower, while hs-CRP levels were higher in patients with cirrhosis compared to PREVEND participants (p < 0.001). Notably, GlycA increased, but hs-CRP decreased after transplantation. In LTRs, both GlycA and hs-CRP levels were higher than in PREVEND participants (p < 0.001). Survival was impaired in patients with cirrhosis and LTRs with the highest GlycA and the highest hs-CRP tertiles. In Cox regression analysis, GlycA remained associated with mortality in cirrhotic patients after adjusting for potential confounders and for hs-CRP (HR per 1-SD increment: 2.34 [95% CI 1.07-5.13]), while the association with hs-CRP after adjusting was lost. In LTRs, both GlycA and hs-CRP were also associated with mortality (adjusted HR: 1.60 [95% CI: 1.2-2.14] and 1.64 [95% CI: 1.08-2.51], respectively) but not independent of each other. GlycA increases while hs-CRP decreases after liver transplantation. Both inflammatory markers may be associated with all-cause mortality in cirrhotic patients and LTRs, while the association for GlycA seems at least as strong as that for hs-CRP.

Cirrhosis-associated immune dysfunction refers to the concurrent systemic inflammation and immunoparesis evident across the disease spectrum of chronic liver disease, ranging from the low-grade inflammatory plasma milieu that accompanies compensated disease to the intense high-grade inflammatory state with coexistent severe immune paralysis that defines acute decompensation and acute-on-chronic liver failure. Systemic inflammation plays a crucial role in the disease course of cirrhosis and is a key driver for acute decompensation and the progression from compensated to decompensated cirrhosis. Severe systemic inflammation is fundamental to the development of organ dysfunction and failure and, in its most extreme form, acute-on-chronic liver failure. Systemic inflammation propagates the development of hepatic encephalopathy and hepatorenal syndrome-acute kidney injury. It may also be involved in the pathogenesis of further complications such as hepatocellular carcinoma and mental illness. Those patients with the most profound systemic inflammation have the worst prognosis. Systemic inflammation exerts its negative clinical effects through a number of mechanisms including nitric oxide-mediated increased splanchnic vasodilation, immunopathology, and metabolic reallocation.

Decompensated cirrhosis (DC) is prone to recurrent episodes of decompensation following the initial event. This study aimed to identify the risk factors for subsequent decompensation and assess their impact on the outcomes of patients hospitalized for DC.

Patients with DC were divided into two groups based on the occurrence of new decompensated events during hospitalization. Logistic regression analysis was employed to identify risk factors for new decompensation. The Cox proportional hazards model was used to evaluate the relationship between new decompensation and short-term mortality risk in these patients.

The study cohort consisted of 339 patients with DC, with a median age of 57 years. During hospitalization, 83 patients (24.5%) experienced new decompensated events, with bacterial infections (BIs) being the most common (n = 46, 13.6%). Multivariate analysis revealed that the Model for End-Stage Liver Disease (MELD) score at admission (OR = 1.06, 95% CI: 1.02-1.11, P = 0.005) was the sole risk factor for new decompensation during hospitalization. Patients who experienced new decompensation had significantly higher 28-day (28.9% vs. 7.0%, P < 0.001) and 90-day (33.7% vs. 15.2%, P < 0.001) transplant-free mortality compared to those who did not. After adjusting for white cell count, C-reactive protein, and MELD score, new decompensation during hospitalization was identified as an independent risk factor for 28-day and 90-day mortality (HR = 2.63, 95% CI: 1.42-4.87, P = 0.002 and HR = 1.73, 95% CI: 1.04-2.88, P = 0.033, respectively).

Patients with high MELD scores are susceptible to new decompensation during hospitalization, and the occurrence of new decompensation adversely affects short-term mortality in patients with DC.

The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value.

We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint.

Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001.

High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.

The transition from compensated to decompensated cirrhosis is crucial, drastically reducing prognosis from a median survival of over 10 years to 2 years. There is currently an unmet need to accurately predict decompensation. We systematically reviewed and meta-analysed data regarding biomarker use to predict decompensation in individuals with compensated cirrhosis.

PubMed and EMBASE database searches were conducted for all studies from inception until February 2024. The study was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Quality of Prognosis Studies framework was used to assess the risk of bias. The meta-analysis was conducted with a random effects model using STATA software.

Of the 652 studies initially identified, 63 studies (n=31 438 patients) were included in the final review, examining 49 biomarkers. 25 studies (40%) were prospective with the majority of studies looking at all-cause decompensation (90%). The most well-studied biomarkers were platelets (n=17), Model for End-Stage Liver Disease (n=17) and albumin (n=16). A meta-analysis revealed elevated international normalised ratio was the strongest predictor of decompensation, followed by decreased albumin. However, high statistical heterogeneity was noted (l2 result of 96.3%). Furthermore, 21 studies were assessed as having a low risk of bias (34%), 26 (41%) moderate risk and 16 (25%) high risk.

This review highlights key biomarkers that should potentially be incorporated into future scoring systems to predict decompensation. However, future biomarker studies should be conducted with rigorous and standardised methodology to ensure robust and comparable data.

To evaluate for correlation between MRI paraspinous muscle (PSM) enhancement and clinical measures of cirrhosis severity (CMCS) utilizing established imaging biomarkers of sarcopenia as comparison.

Retrospective evaluation of 224 patients (mean age 59.6± 9.7 years, 135 males and 89 females) with liver cirrhosis who underwent contrast-enhanced MRI between August 2021 and August 2022 was performed. Assessed variables included: body mass index (BMI), varices and ascites present on imaging (VPI and API), albumin, total bilirubin (Tbili), international normalized ratio (INR), creatinine, MELD score, as well as history of paracentesis (PH), spontaneous bacterial peritonitis, and variceal bleed (VBH). These variables were compared to PSM skeletal muscle index (SMI), PSM signal fat fractions (sFF), and PSM contrast enhancement fraction (CEFR) calculated on arterial (CEFR-ART), portal venous (CEFR-PV), and delayed (CEFR-DEL) phases collected on MRI.

Patients with MELD>17, PH, and VPI had lower PSM CEFR-ART (0.06vs. 0.11, p = 0.01; 0.07vs. 0.11, p = 0.01; and 0.09vs. 0.13, p = 0.03, respectively). PSM CEFR-ART correlated negatively with MELD. Patients with MELD>17 and PH had lower PSM CEFR-PV (0.16vs. 0.23, p = 0.02; 0.18 vs. 0.23, p = 0.01, respectively). PSM CEFR-PV correlated positively with albumin and negatively with Tbili, INR, and MELD. PSM CEFR-DEL correlated negatively with Tbili and MELD. Patients with API, PH, and VBH had lower PSM SMI (4.68vs. 5.59, p<0.001; 4.37vs. 5.48, p<0.001; 4.78vs. 5.35, p = 0.04, respectively). PSM SMI correlated negatively with Tbili and positively with BMI. PSM sFF correlated positively with BMI, PSM CEFR-PV, and PSM CEFR-DEL.

PSM CEFR is significantly reduced on MRI in patients with clinical manifestations of severe liver cirrhosis. Further investigation into PSM CEFR's usefulness as an imaging biomarker for evaluating liver disease severity is warranted.

Transplantation of the liver in combination with other organs is an increasingly performed procedure. Over the years, continuous improvement in survival could be realized through careful patient selection and refined organ preservation techniques, in spite of the challenges posed by aging recipients and donors, as well as the increased use of steatotic liver grafts. Herein, we revisit the epidemiology, allocation policies in different transplant zones, indications, and outcomes with regard to simultaneous organ transplants involving the liver, that is combined heart-liver, liver-lung, liver-kidney, and multivisceral transplantation. We address challenges surrounding combined organ transplantation such as equity, utility, and logistics of dual organ implantation, but also advantages that come along with combined transplantation, thereby focusing on molecular mechanisms underlying immunoprotection provided by the liver to the other allografts. In addition, the current standing and knowledge of machine perfusion in combined organ transplantation, mostly based on center experience, will be reviewed. Notwithstanding all the technical advances, shortage of organs, and the lack of universal eligibility criteria for certain multi-organ combinations are hurdles that need to be tackled in the future.

Decompensated-cirrhosis encompasses several stages with different prognosis, such as bleeding, ascites and bleeding-plus-ascites. Development of further-decompensation worsens survival, while non-selective β-blockers (NSBBs) can modify the risk. However, how this applies to each stage is uncertain. We aimed to investigate, in each stage of decompensated-cirrhosis, the influence of further-decompensation on mortality and whether changes in portal-pressure (HVPG) under NSBBs influence these outcomes.

Patients with variceal bleeding were consecutively included differentiating those with bleeding-alone from those who also had ascites. Patients with ascites and high-risk varices referred for primary-prophylaxis were also investigated. A baseline haemodynamic study was performed and was repeated after 1-3-months under NSBBs. Outcomes were investigated by competing-risk.

Totally 103 patients had bleeding-alone, 186 bleeding-plus-ascites and 187 ascites-alone. Mean follow-up was 32-months (IQR, 12-60). Patients with bleeding-plus-ascites had higher HVPG and were more hyperdynamic than patients with ascites-alone and these than those with bleeding-alone. At each stage, the mortality risk was more than twice in patients developing further-decompensation vs. those without (p < .001). In each stage, HVPG-decrease under NSBBs showed better discrimination to predict further-decompensation than the baseline MELD, Child-Pugh or HVPG, by time-dependent ROC-curves (c-statistic >70%). At each stage, patients without HVPG-decreases, either ≥10% or ≥20% from the baseline, had higher risk of further-decompensation (sHR from 2.43 to 6.73, p < .01) and worse survival.

In each stage of decompensated cirrhosis, mortality risk significantly and very markedly increase with further-decompensation. HVPG-non-response to NSBBs may adequately stratify the risk of further decompensation and death, in each stage. This suggests potential benefit with pre-emptive therapies in HVPG-non-responders at each-stage.

The prevalence of cirrhotic cardiomyopathy (CCM) has been reported as high as 60%-70% in patients with liver cirrhosis and is associated with various negative outcomes. There has been a growing understanding of CCM over recent years. Indeed, the development of imaging techniques has enabled new diagnostic criteria to be proposed by the Cirrhotic Cardiomyopathy Consortium. However, important unanswered questions remain over pathophysiological mechanisms, optimal diagnostic modalities and potential treatment options. While there has been an increasing volume of literature evaluating CCM, there is a lack of clarity on its implications in acute decompensation, acute-on-chronic liver failure and following interventions such as transjugular intrahepatic portosystemic shunt insertion and liver transplantation. This review aims to summarise the literature in these challenging domains and suggest where future research should focus. We conclude that systemic inflammation and structural myocardial changes are likely to be crucial in the pathophysiology of the disease, but the relative contribution of different components remains elusive. Furthermore, future studies need to use standardised diagnostic criteria for CCM as well as incorporate newer imaging techniques assessing both myocardial structure and function. Finally, while specific treatments are currently lacking, therapeutics targeting systemic inflammation, microbial dysbiosis and bacterial translocation are promising targets and warrant further research.

Measurement of hepatic venous pressure gradient (HVPG) effectively mirrors the severity of portal hypertension (PH) and offers valuable insights into prognosis of liver disease, including the risk of decompensation and mortality. Additionally, HVPG offers crucial information about treatment response to nonselective beta-blockers and other medications, with its utility demonstrated in clinical trials in patients with PH. Despite the widespread dissemination and validation of noninvasive tests, HVPG still holds a significant role in hepatology. Physicians treating patients with liver diseases should comprehend the HVPG measurement procedure, its applications, and how to interpret the results and potential pitfalls.

Certain heavy metals have been correlated to an elevated risk of inflammation-related diseases and mortality. Nevertheless, the intricate relationships between metal exposure, inflammation and mortality remain unknown. We included 3741 adults with measurements of ten urinary heavy metals in the National Health and Nutritional Examination Survey (NHANES) 2005-2010, followed up to December 31, 2019. Low-grade systemic inflammation was evaluated by various markers, including C-reactive protein (CRP) and ratios derived from regular blood tests. We assessed associations between heavy metal and all-cause mortality using multivariate COX regressions. Then we assessed the mediation effect of low-grade systemic inflammation on the associations via Sobel Test. To gauge the systemic inflammatory potential of the multi-metal mixture and its correlation with all-cause mortality, a Metal Mixture Inflammatory Index (MMII) was developed using reduced rank regression (RRR) models. The association between MMII and all-cause mortality was explored via multivariate COX regressions. Cadmium, antimony and uranium displayed positive associations with mortality, with hazard ratios (HR) ranging from 1.18 to 1.46 (all P-FDR < 0.05). Mediation analyses revealed that the associations between specific heavy metals (cadmium and antimony) and mortality risk were slightly mediated by the low-grade systemic inflammation markers, with mediation proportions ranging from 3.11 % to 5.38 % (all P < 0.05). MMII, the weighted sum of 9 heavy metals, significantly predicted platelet-to-lymphocyte ratio (PLR) and CRP (β = 0.10 and 1.16, all P < 0.05), was positively associated with mortality risk (HR 1.28, 95 % CI 1.14 to 1.43). Exposure to heavy metals might increase all-cause mortality, partly mediated by low-grade systemic inflammation. MMII, designed to assess the potential systemic inflammatory effects of exposure to multiple heavy metals, was closely related to the all-cause mortality risk. This study introduces MMII as an approach to evaluating co-exposure and its potential health effects comprehensively.

Quick sequential organ failure assessment (qSOFA) is believed to identify patients at risk of poor outcomes in those with suspected infection. We aimed to evaluate the ability of modified qSOFA (m-qSOFA) to identify high-risk patients among those with acutely deteriorated chronic liver disease (CLD), especially those with acute-onchronic liver failure (ACLF).

We used data from both the Korean Acute-on-Chronic Liver Failure (KACLiF) and the Asian Pacific Association for the Study of the Liver ACLF Research Consortium (AARC) cohorts. qSOFA was modified by replacing the Glasgow Coma Scale with hepatic encephalopathy, and an m-qSOFA ≥2 was considered high.

Patients with high m-qSOFA had a significantly lower 1-month transplant-free survival (TFS) in both cohorts and higher organ failure development in KACLiF than those with low m-qSOFA (Ps<0.05). Subgroup analysis by ACLF showed that patients with high m-qSOFA had lower TFS than those with low m-qSOFA. m-qSOFA was an independent prognostic factor (hazard ratios, HR=2.604, 95% confidence interval, CI 1.353-5.013, P=0.004 in KACLiF and HR=1.904, 95% CI 1.484- 2.442, P<0.001 in AARC). The patients with low m-qSOFA at baseline but high m-qSOFA on day 7 had a significantly lower 1-month TFS than those with high m-qSOFA at baseline but low m-qSOFA on day 7 (52.6% vs. 89.4%, P<0.001 in KACLiF and 26.9% vs. 61.5%, P<0.001 in AARC).

Baseline and dynamic changes in m-qSOFA may identify patients with a high risk of developing organ failure and short-term mortality among CLD patients with acute deterioration.

The increase in prevalence of liver disease globally will lead to a substantial incremental burden on intensive care requirements. While liver transplantation offers a potential life-saving intervention, not all patients are eligible due to limitations such as organ availability, resource constraints, ongoing sepsis or multiple organ failures. Consequently, the focus of critical care of patients with advanced and decompensated cirrhosis turns to liver-centric intensive care protocols, to mitigate the high mortality in such patients.

Provide an updated and comprehensive understanding of cirrhosis management in critical care, and which includes emergency care, secondary organ failure management (mechanical ventilation, renal replacement therapy, haemodynamic support and intensive care nutrition), use of innovative liver support systems, infection control, liver transplantation and palliative and end-of life care.

We conducted a structured bibliographic search on PubMed, sourcing articles published up to 31 March 2024, to cover topics addressed. We considered data from observational studies, recommendations of society guidelines, systematic reviews, and meta-analyses, randomised controlled trials, and incorporated our clinical expertise in liver critical care.

Critical care management of the patient with cirrhosis has evolved over time while mortality remains high despite aggressive management with liver transplantation serving as a crucial but not universally available resource.

Implementation of organ support therapies, intensive care protocols, nutrition, palliative care and end-of-life discussions and decisions are an integral part of critical care of the patient with cirrhosis. A multi-disciplinary approach towards critical care management is likely to yield better outcomes.

The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis.

Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999.

In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis.

Non-selective β-blockers (NSBBs) and endoscopic variceal-ligation (EVL) have similar efficacy preventing first variceal bleeding. Compensated and decompensated cirrhosis are markedly different stages, which may impact treatment outcomes. We aimed to assess the efficacy of NSBBs vs EVL on survival in patients with high-risk varices without previous bleeding, stratifying risk according to compensated/decompensated stage of cirrhosis.

By systematic review, we identified RCTs comparing NSBBs vs EVL, in monotherapy or combined, for primary bleeding prevention. We performed a competing-risk, time-to-event meta-analysis, using individual patient data (IPD) obtained from principal investigators of RCTs. Analyses were stratified according to previous decompensation of cirrhosis.

Of 25 RCTs eligible, 14 failed to provide IPD and 11 were included, comprising 1400 patients (656 compensated, 744 decompensated), treated with NSBBs (N = 625), EVL (N = 546) or NSBB+EVL (N = 229). Baseline characteristics were similar between groups. Overall, mortality risk was similar with EVL vs. NSBBs (subdistribution hazard-ratio (sHR) = 1.05, 95% CI = 0.75-1.49) and with EVL + NSBBs vs either monotherapy, with low heterogeneity (I2  = 28.7%). In compensated patients, mortality risk was higher with EVL vs NSBBs (sHR = 1.76, 95% CI = 1.11-2.77) and not significantly lower with NSBBs+EVL vs NSBBs, without heterogeneity (I2  = 0%). In decompensated patients, mortality risk was similar with EVL vs. NSBBs and with NSBBs+EVL vs. either monotherapy.

In patients with compensated cirrhosis and high-risk varices on primary prophylaxis, NSBBs significantly improved survival vs EVL, with no additional benefit noted adding EVL to NSBBs. In decompensated patients, survival was similar with both therapies. The study suggests that NSBBs are preferable when advising preventive therapy in compensated patients.

Portal hypertension (PH), defined as a pathological increase in the portal vein pressure, has different aetiologies and causes. Intrahepatic PH is mostly secondary to the presence of underlying liver disease leading to cirrhosis, characterized by parenchymal changes with deregulated accumulation of extracellular matrix and vascular abnormalities; liver sinusoidal endothelial cells and hepatic stellate cells are key players in PH progression, able to influence each other. However, PH may also develop independently of parenchymal damage, as occur in portosinusoidal vascular disorder (PSVD), a group of clinical and histological entities characterized by portal vasculature dysfunctions. In this particular group of disorders, the pathophysiology of PH is still poorly understood. In the last years, several genetic studies, based on genome-wide association studies or whole-exome sequencing analysis, have highlighted the importance of genetic heritability in PH pathogenesis, both in cirrhotic and non-cirrhotic cases. The common PNPLA3 p.I148M variant, one of the main determinants of the susceptibility to steatotic liver disease, has also been associated with decompensation in patients with PH. Genetic variations at loci influencing coagulation, mainly the ABO locus, may directly contribute to the pathogenesis of PH. Rare genetic variants have been associated with familiar cases of progressive PSVD. In this review, we summarize the recent knowledges on genetic variants predisposing to PH development, contributing to better understand the role of genetic factors in PH pathogenesis.

Liver diseases affect the heart and the vascular system. Cardiovascular complications appear to be a leading cause of death in patients with non-alcoholic fatty liver disease (NAFLD) and cirrhosis. The predominant histological changes in the liver range from steatosis to fibrosis to cirrhosis, which can each affect the cardiovascular system differently. Patients with cirrhotic cardiomyopathy (CCM) and NAFLD are at increased risk of impaired systolic and diastolic dysfunction and for suffering major cardiovascular events. However, the pathophysiological mechanisms behind these risks differ depending on the nature of the liver disease. Accurate assessment of symptoms by contemporary diagnostic modalities is essential for identifying patients at risk, for evaluating candidates for treatment, and prior to any invasive procedures. This review explores current perspectives within this field.

Point-of-care echocardiography (POC-Echo) is an essential intensive care hemodynamic monitoring tool.

To assess POC-Echo parameters [i.e., cardiac index (CI), systemic vascular resistance index (SVRI) and cirrhotic cardiomyopathy (CCM) markers] and serum biomarkers in predicting circulatory failure (need for vasopressors) and mortality in patients with acute-on-chronic liver failure (ACLF) having sepsis-induced hypotension.

We performed serial POC-Echo within 6 hours (h) of presentation and subsequently at 24, 48 and 72 h in patients with ACLF and sepsis-induced hypotension admitted to our liver intensive care unit. Clinical data, POC-Echo data and serum biomarkers were collected prospectively.

We enrolled 120 patients [59% men, aged 49 ± 12 years, 56% alcohol-related disease and median MELDNa of 30 (27-32)], of whom 68 (56.6%) had circulatory failure, with overall mortality of 60%. CCM was present in 52.5%. The predictors of circulatory failure were CI (aHR -1.5; p = 0.021), N-terminal brain natriuretic peptide (aHR -1.1; p = 0.007) and CCM markers; e' septal mitral velocity (aHR -0.5; p = 0.039) and E/e' ratio (aHR -1.2; p = 0.045). Reduction in CI by 20% and SVRI by 15% at 72 h predicted mortality with a sensitivity of 84% and 72%, and specificity 76% and 65%, respectively (p < 0.001). The MELD-CCM model and CLIF-CCM model were computed as MELDNa + 1.815 × E/e' (septal) + 0.402 × e' (septal) and CLIF-C ACLF + 1.815 × E/e' (septal) + 0.402 × e' (septal), respectively, based on multivariable logistic regression. Both scores outperformed MELDNa (z-score = -2.073, p = 0.038) and CLIF-C ACLF score (z score = -2.683, p-value = 0.007), respectively, in predicting 90-day mortality.

POC-Echo measurements such as CCM markers (E/e' and e' velocity) and change in CI reliably predict circulatory failure and mortality in ACLF with severe sepsis. CCM markers significantly enhanced the CLIF-C ACLF and MELDNa predictive performance.

The right ventricle (RV) is intricately linked in the clinical presentation of critical illness; however, the basis of this is not well-understood and has not been studied as extensively as the left ventricle. There has been an increased awareness of the need to understand how the RV is affected in different critical illness states. In addition, the increased use of point-of-care echocardiography in the critical care setting has allowed for earlier identification and monitoring of the RV in a patient who is critically ill. The first part of this review describes and characterizes the RV in different perioperative states. This second part of the review discusses and analyzes the complex pathophysiologic relationships between the RV and different critical care states. There is a lack of a universal RV injury definition because it represents a range of abnormal RV biomechanics and phenotypes. The term "RV injury" (RVI) has been used to describe a spectrum of presentations, which includes diastolic dysfunction (early injury), when the RV retains the ability to compensate, to RV failure (late or advanced injury). Understanding the mechanisms leading to functional 'uncoupling' between the RV and the pulmonary circulation may enable perioperative physicians, intensivists, and researchers to identify clinical phenotypes of RVI. This, consequently, may provide the opportunity to test RV-centric hypotheses and potentially individualize therapies.

Although portal vein thrombosis (PVT) was thought to deteriorate portal hypertension and contribute to poor prognosis, risk stratification remains unclear. This study aimed to evaluate its effect on the risk of variceal rehemorrhage and to develop a competitive risk model in cirrhotic patients with PVT.

Cirrhotic patients with and without PVT admitted for acute variceal hemorrhage were retrospectively included after matching (1:1) for age, gender and etiology of cirrhosis from two tertiary centers with 1-year follow-up. Those with PVT were subsequently divided into the training and validation cohorts. Cox regression analysis was performed to identify risk factors and develop a competitive risk model, of which the predictive performance and optimal decision threshold were evaluated by C-index, competitive risk curves, calibration curves and decision curve analysis.

Among 398 patients, PVT significantly increased the variceal rehemorrhage risk. Multivariate Cox regression analysis identified that the Child-Turcotte-Pugh score (P = 0.013), chronic PVT (P = 0.025), C-reactive protein (P < 0.001), and aspartate aminotransferase (P = 0.039) were independently associated with variceal rehemorrhage, which were incorporated into the competitive risk model, with high C-index (0.804 and 0.742 of the training and validation cohorts, respectively), risk stratification ability, and consistency. The optimal decision range of the threshold probability was 0.2-1.0.

We confirmed the adverse effect of PVT on variceal rehemorrhage and developed a competitive risk model for variceal rehemorrhage in cirrhotic patients with PVT, which might be conveniently used for clinical decision-making.

Portal hypertension (PH) constitutes a pivotal factor in the progression of cirrhosis, giving rise to severe complications and a diminished survival rate. The transjugular intrahepatic portosystemic shunt (TIPS) procedure has undergone significant evolution, with advancements in stent technology assuming a central role in managing PH-related complications. This review aims to outline the progression of TIPS and emphasizes the significant influence of stent advancement on its effectiveness. Initially, the use of bare metal stents (BMSs) was limited due to frequent dysfunction. However, the advent of expanding polytetrafluoroethylene-covered stent grafts (ePTFE-SGs) heralded a transformative era, greatly enhancing patency rates. Further innovation culminated in the creation of ePTFE-SGs with controlled expansion, enabling precise adjustment of TIPS diameters. Comparative analyses demonstrated the superiority of ePTFE-SGs over BMSs, resulting in improved patency, fewer complications, and higher survival rates. Additional technical findings highlight the importance of central stent placement and adequate stent length, as well as the use of smaller calibers to reduce the risk of shunt-related complications. However, improving TIPS through technical means alone is inadequate for optimizing patient outcomes. An extensive understanding of hemodynamic, cardiac, and systemic factors is required to predict outcomes and tailor a personalized approach. Looking forward, the ongoing progress in SG technology, paired with the control of clinical factors that can impact outcomes, holds the promise of reshaping the management of PH-related complications in cirrhosis.

Ascites is a frequent complication of cirrhosis. In intensive care units, initial hemodynamic assessment is frequently performed by echocardiography. This study evaluated the feasibility and usefulness of early hemodynamic assessment in the gastroenterology ward.

This observational cohort study prospectively included all patients admitted to a teaching hospital's gastroenterology unit for decompensated cirrhosis. A gastroenterologist with minimal training and an intensivist both performed an echocardiography exam. The primary outcome was inter-rater agreement and reliability for three echocardiography parameters: visual LVEF (Left Ventricular Ejection Fraction), subaortic VTI (velocity time integral) and E wave velocity. Secondary outcomes were agreement for presence of pleural effusion, description of 3 hemodynamics profiles (hypovolemic, hyperkinetic and intermediate), and 28-day mortality.

From March 2018 to March 2020, 53 patients were included. The median age was 62 years and 81% were men. Patients presented mostly advanced liver disease, with 43% Child-Pugh C and median MELD score of 15.2. The limits of agreement between intensivists and gastroenterologists for subaortic VTI were - 6.6 to 7.2 cm, and ranged from - 0.6 to 0.37 m.s-1 for E wave velocity. Clinically significant differences between intensivists and gastroenterologists were found in 22% for subaortic VTI and 24.5% for E wave velocity. Reliability was good for subaortic VTI (ICC: 0.79, 95% CI [0.58; 0.9;]) and moderate for E wave velocity (0.53, 95% CI [0.19; 0.74]). The three hemodynamics profiles had different prognosis, with a 28-day mortality for Hypovolemic, Intermediate and Hyperkinetic group of 31, 18, and 4%, respectively.

Reliability of hemodynamic assessment by gastroenterologists was good, while agreement was unsatisfactory, advocating for further training. Transthoracic echocardiography can differentiate hypovolemia from hyperkinetic states. The role of transthoracic echocardiography in managing decompensated cirrhosis requires further study.

NCT03650660.

The current literature provides a body of evidence on C-Reactive Protein (CRP) and its potential role in inflammation. However, most pieces of evidence are sparse and controversial. This critical state-of-the-art monography provides all the crucial data on the potential biochemical properties of the protein, along with further evidence on its potential pathobiology, both for its pentameric and monomeric forms, including information for its ligands as well as the possible function of autoantibodies against the protein. Furthermore, the current evidence on its potential utility as a biomarker of various diseases is presented, of all cardiovascular, respiratory, hepatobiliary, gastrointestinal, pancreatic, renal, gynecological, andrological, dental, oral, otorhinolaryngological, ophthalmological, dermatological, musculoskeletal, neurological, mental, splenic, thyroid conditions, as well as infections, autoimmune-supposed conditions and neoplasms, including other possible factors that have been linked with elevated concentrations of that protein. Moreover, data on molecular diagnostics on CRP are discussed, and possible etiologies of false test results are highlighted. Additionally, this review evaluates all current pieces of evidence on CRP and systemic inflammation, and highlights future goals. Finally, a novel diagnostic algorithm to carefully assess the CRP level for a precise diagnosis of a medical condition is illustrated.

Experimental data suggest that bacterial translocation (BT) promotes systemic inflammation, portal hypertension, and circulatory dysfunction in advanced chronic liver disease (ACLD).

Patients with ACLD undergoing hepatic venous pressure gradient (HVPG) measurement and absence of acute decompensation or infections were included (n = 249). Serum biomarkers of BT (lipopolysaccharide [LPS], lipoteichoic acid [LTA], bacterial DNA [bactDNA]), systemic inflammation and markers of circulatory dysfunction were assessed. T-cell subsets in intestinal biopsies (n = 7 ACLD, n = 4 controls) were analyzed by flow cytometry.

Patients had a median HVPG of 18 (12-21) mmHg and 56% had decompensated ACLD. LPS (0.04 [0.02-0.06] vs. 0.64 [0.30-1.06] EU/mL), LTA (4.53 [3.58-5.97] vs. 43.2 [23.2-109] pg/mL), and detection of bactDNA (≥ 5 pg/mL; 5% vs. 41%) were markedly higher in patients with ACLD than healthy controls (n = 40; p < 0.001) but were similar between different clinical stages of compensated and decompensated ACLD and displayed no meaningful correlation with HVPG and systemic hemodynamics. TNF-α and IL-10 correlated with LPS (Spearman's rs = 0.523, p < 0.001/rs = 0.143, p = 0.024) but not with LTA. Presence of bactDNA was associated with higher LPS (0.54 [0.28-0.95] vs. 0.88 [0.32-1.31] EU/mL, p = 0.001) and TNF-α (15.3 [6.31-28.1] vs. 20.9 [13.8-32.9] pg/mL). Patients with ACLD exhibited a decreased CD4:CD8-ratio and increased TH1-cells in the intestinal mucosa as compared to controls. During a median FU of 14.7 (8.20-26.5) months, bacterial antigens did not predict decompensation or liver-related death (in contrast to HVPG, IL-6, and MAP) as well as infections at 24 months.

BT occurs already in early ACLD stages and triggers a systemic inflammatory response via TNF-α and IL-10. Interestingly, BT markers showed no clear correlation with portal hypertension and circulatory dysfunction in patients with stable ACLD.

NCT03267615.

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.

Portal hypertension (PH) is the most common complication ofcirrhosis and represents the main driver of hepatic decompensation. The overarching goal of PH treatments in patients with compensated cirrhosis is to reduce the risk of hepatic decompensation (i.e development of ascites, variceal bleeding and/or hepatic encephalopathy). In decompensated patients, PH-directed therapies aim at avoiding further decompensation (i.e. recurrent/refractory ascites, variceal rebleeding, recurrent encephalopathy, spontaneous bacterial peritonitis or hepatorenal syndrome) and at improving survival. Carvedilol is a non-selective beta-blocker (NSBB) acting on hyperdynamic circulation/splanchnic vasodilation and on intrahepatic resistance. It has shown superior efficacy than traditional NSBBs in lowering PH in patients with cirrhosis and may be, therefore, the NSBB of choice for the treatment of clinically significant portal hypertension. In primary prophylaxis of variceal bleeding, carvedilol has been demonstrated to be more effective than endoscopic variceal ligation (EVL). In patients with compensated cirrhosis carvedilol achieves higher rate of hemodynamic response than propranolol, resulting in a decreased risk of hepatic decompensation. In secondary prophylaxis, the combination of EVL with carvedilol may prevent rebleeding and non-bleeding further decompensation better than that with propranolol. In patients with ascites and gastroesophageal varices, carvedilol is safe and may improve survival, as long as no impairment of the systemic hemodynamic or renal dysfunction occurs, with maintained arterial blood pressure as suitable safety surrogate. The target dose of carvedilol to treat PH should be 12.5 mg/day. This review summarizes the evidence behind Baveno-VII recommendations on the use of carvedilol in patients with cirrhosis.

Hepatopulmonary syndrome (HPS) and a hyperdynamic circulation are common complications of advanced liver disease, but the relationship between HPS and cardiac index (CI) is poorly understood. We sought to compare CI in patients with and without HPS and to assess the relationship between CI and symptoms, quality of life, gas exchange, and exercise capacity among liver transplantation (LT) candidates. We performed a cross-sectional analysis within the Pulmonary Vascular Complications of Liver Disease 2 study, a multicenter prospective cohort study of patients being evaluated for LT. We excluded patients with obstructive or restrictive lung disease, intracardiac shunting, and portopulmonary hypertension. We included 214 patients (81 with HPS and 133 controls without HPS). Compared with controls, patients with HPS had a higher CI (least square mean 3.2 L/min/m 2 , 95% CI 3.1-3.4 vs. 2.8 L/min/m 2 , 95% CI 2.7-3.0, p < 0.001) after adjustment for age, sex, Model for End-stage Liver Disease-Sodium (MELD-Na) score and beta-blocker use, and a lower systemic vascular resistance. Among all LT candidates, CI was correlated with oxygenation (Alveolar-arterial oxygen gradient r =0.27, p < 0.001), intrapulmonary vasodilatation severity ( p < 0.001), and biomarkers of angiogenesis. Higher CI was independently associated with dyspnea and worse functional class and physical quality of life after adjusting for age, sex, MELD-Na, beta-blocker use, and HPS status. HPS was associated with a higher CI among LT candidates. Independent of HPS, higher CI was associated with increased dyspnea and worse functional class, quality of life, and arterial oxygenation.

The hepatic venous pressure gradient (HVPG) is currently considered the gold standard to assess portal hypertension (PH) in patients with cirrhosis. A meticulous technique is important to achieve accurate and reproducible results, and values obtained during measurement are applied in risk stratification of patients with PH, allocating treatment options, monitoring follow-up, and deciding management options in surgical patients. The use of portosystemic pressure gradients in patients undergoing placement of transjugular intrahepatic portosystemic shunts has been studied extensively and has great influence on decisions on shunt diameter. The purpose of this study was to describe the recommended technique to measure HVPG and portosystemic pressure gradient and to review the existing literature describing the importance of these hemodynamic measurements in clinical practice.

In individuals with compensated advanced chronic liver disease (cACLD), the severity of portal hypertension (PH) determines the risk of decompensation. Invasive measurement of the hepatic venous pressure gradient (HVPG) is the diagnostic gold standard for PH. We evaluated the utility of machine learning models (MLMs) based on standard laboratory parameters to predict the severity of PH in individuals with cACLD.

A detailed laboratory workup of individuals with cACLD recruited from the Vienna cohort (NCT03267615) was utilised to predict clinically significant portal hypertension (CSPH, i.e., HVPG ≥10 mmHg) and severe PH (i.e., HVPG ≥16 mmHg). The MLMs were then evaluated in individual external datasets and optimised in the merged cohort.

Among 1,232 participants with cACLD, the prevalence of CSPH/severe PH was similar in the Vienna (n = 163, 67.4%/35.0%) and validation (n = 1,069, 70.3%/34.7%) cohorts. The MLMs were based on 3 (3P: platelet count, bilirubin, international normalised ratio) or 5 (5P: +cholinesterase, +gamma-glutamyl transferase, +activated partial thromboplastin time replacing international normalised ratio) laboratory parameters. The MLMs performed robustly in the Vienna cohort. 5P-MLM had the best AUCs for CSPH (0.813) and severe PH (0.887) and compared favourably to liver stiffness measurement (AUC: 0.808). Their performance in external validation datasets was heterogeneous (AUCs: 0.589-0.887). Training on the merged cohort optimised model performance for CSPH (AUCs for 3P and 5P: 0.775 and 0.789, respectively) and severe PH (0.737 and 0.828, respectively).

Internally trained MLMs reliably predicted PH severity in the Vienna cACLD cohort but exhibited heterogeneous results on external validation. The proposed 3P/5P online tool can reliably identify individuals with CSPH or severe PH, who are thus at risk of hepatic decompensation.

We used machine learning models based on widely available laboratory parameters to develop a non-invasive model to predict the severity of portal hypertension in individuals with compensated cirrhosis, who currently require invasive measurement of hepatic venous pressure gradient. We validated our findings in a large multicentre cohort of individuals with advanced chronic liver disease (cACLD) of any cause. Finally, we provide a readily available online calculator, based on 3 (platelet count, bilirubin, international normalised ratio) or 5 (platelet count, bilirubin, activated partial thromboplastin time, gamma-glutamyltransferase, choline-esterase) widely available laboratory parameters, that clinicians can use to predict the likelihood of their patients with cACLD having clinically significant or severe portal hypertension.