Myosteatosis is closely associated with sarcopenia and significantly worse outcomes in patients with cirrhosis.

BACKGROUND AND AIM: Sarcopenia and myosteatosis are common in patients with cirrhosis. This study aimed to determine the prevalence of these muscle changes, their interrelations and their prognostic impact over a 12-month period. METHODS: We conducted a prospective multicentre study involving 433 patients. Sarcopenia and myosteatosis were evaluated using computed tomography scans. The 1-year cumulative incidence of relevant events was assessed by competing risk analysis. We used a Fine-Gray model adjusted for known prognostic factors, to evaluate the impact of sarcopenia and myosteatosis on mortality, hospitalization, and liver decompensation. RESULTS: At enrolment, 166 patients presented with isolated myosteatosis, 36 with isolated sarcopenia, 135 with combined sarcopenia and myosteatosis and 96 patients showed no muscle changes. The 1-year cumulative incidence of death in patients with either sarcopenia and myosteatosis (13.8%) or isolated myosteatosis (13.4%) was over twice that of patients without muscle changes (5.2%) or with isolated sarcopenia (5.6%). The adjusted subhazard ratio for death in patients with muscle changes was 1.36 (95% CI 0.99, 1.86) (P=0.058). The cumulative incidence of hospitalization was significantly higher in patients with combined sarcopenia and myosteatosis than in patients without muscle changes (adjusted subhazard ratio 1.18, 95% CI 1.04 to 1.35). The cumulative incidence of liver decompensation was greater in patients with combined sarcopenia and myosteatosis (p=0.018) and those with isolated sarcopenia (p=0.046) than in patients without muscle changes. Lastly, we found a strong correlation between function tests and frailty scores with the presence of muscle changes. CONCLUSIONS: Myosteatosis, whether alone or combined with sarcopenia, is highly prevalent in patients with cirrhosis and is associated with significantly worse outcomes. The prognostic role of sarcopenia should always be evaluated in relation to the presence of myosteatosis. IMPACT AND IMPLICATIONS: This study investigates the prognostic role of muscle changes in patients with liver cirrhosis. The novelty of this study is the multicentre, prospective nature and the distinguishing impact of individual muscle changes and their combination on prognosis in cirrhosis. This study highlights the prognostic role of myosteatosis, especially when combined with sarcopenia. On the other hand, the relevance of sarcopenia could be mitigated when considered together with myosteatosis. The implication from these findings is that sarcopenia should never be evaluated individually and that myosteatosis may have a dominant role in the prognosis of patients with liver cirrhosis.

Clinical, experimental and pathophysiological effects of Yaq-001: a non-absorbable, gut-restricted adsorbent in models and patients with cirrhosis.

OBJECTIVE: Targeting bacterial translocation in cirrhosis is limited to antibiotics with risk of antimicrobial resistance. This study explored the therapeutic potential of a non-absorbable, gut-restricted, engineered carbon bead adsorbent, Yaq-001 in models of cirrhosis and acute-on-chronic liver failure (ACLF) and, its safety and tolerability in a clinical trial in cirrhosis. DESIGN: Performance of Yaq-001 was evaluated in vitro. Two-rat models of cirrhosis and ACLF, (4 weeks, bile duct ligation with or without lipopolysaccharide), receiving Yaq-001 for 2 weeks; and two-mouse models of cirrhosis (6-week and 12-week carbon tetrachloride (CCl4)) receiving Yaq-001 for 6 weeks were studied. Organ and immune function, gut permeability, transcriptomics, microbiome composition and metabolomics were analysed. The effect of faecal water on gut permeability from animal models was evaluated on intestinal organoids. A multicentre, double-blind, randomised, placebo-controlled clinical trial in 28 patients with cirrhosis, administered 4 gr/day Yaq-001 for 3 months was performed. RESULTS: Yaq-001 exhibited rapid adsorption kinetics for endotoxin. In vivo, Yaq-001 reduced liver injury, progression of fibrosis, portal hypertension, renal dysfunction and mortality of ACLF animals significantly. Significant impact on severity of endotoxaemia, hyperammonaemia, liver cell death, systemic inflammation and organ transcriptomics with variable modulation of inflammation, cell death and senescence in the liver, kidneys, brain and colon was observed. Yaq-001 reduced gut permeability in the organoids and impacted positively on the microbiome composition and metabolism. Yaq-001 regulated as a device met its primary endpoint of safety and tolerability in the clinical trial. CONCLUSIONS: This study provides strong preclinical rationale and safety in patients with cirrhosis to allow clinical translation. TRIAL REGISTRATION NUMBER: NCT03202498.

The Role of Transjugular Intrahepatic Portosystemic Shunt for the Management of Ascites in Patients with Decompensated Cirrhosis.

The development and progression of ascites represent a crucial event in the natural history of patients with cirrhosis, predisposing them to other complications and carrying a heavy impact on prognosis. The current standard of care for the management of ascites relies on various combinations of diuretics and large-volume paracenteses. Periodic long-term albumin infusions on top of diuretics have been recently shown to greatly facilitate the management of ascites. The insertion of a transjugular intrahepatic portosystemic shunt (TIPS), an artificial connection between the portal and caval systems, is indicated to treat patients with refractory ascites. TIPS acts to decrease portal hypertension, thus targeting an upstream event in the pathophysiological cascade of cirrhosis decompensation. Available evidence shows a significant benefit on ascites control/resolution, with less clear results on patient survival. Patient selection plays a crucial role in obtaining better clinical responses and avoiding TIPS-related adverse events, the most important of which are hepatic encephalopathy, cardiac overload and failure, and liver failure. At the same time, some recent technical evolutions of available stents appear promising but deserve further investigations. Future challenges and perspectives include (i) identifying the features for selecting the ideal candidate to TIPS; (ii) recognizing the better timing for TIPS placement; and (iii) understanding the most appropriate role of TIPS within the framework of all other available treatments for the management of patients with decompensated cirrhosis.

Impact of Sarcopenia on the Survival of Patients with Hepatocellular Carcinoma Treated with Sorafenib.

BACKGROUND AND AIMS: Sarcopenia has been associated with poor outcomes in patients with cirrhosis and hepatocellular carcinoma. We investigated the impact of sarcopenia on survival in patients with advanced hepatocellular carcinoma treated with Sorafenib. METHODS: A total of 328 patients were retrospectively analyzed. All patients had an abdominal CT scan within 8 weeks prior to the start of treatment. Two cohorts of patients were analyzed: the "Training Group" (215 patients) and the "Validation Group" (113 patients). Sarcopenia was defined by reduced skeletal muscle index, calculated from an L3 section CT image. RESULTS: Sarcopenia was present in 48% of the training group and 50% of the validation group. At multivariate analysis, sarcopenia (HR: 1.47, p = 0.026 in training; HR 1.99, p = 0.033 in validation) and MELD > 9 (HR: 1.37, p = 0.037 in training; HR 1.78, p = 0.035 in validation) emerged as independent prognostic factors in both groups. We assembled a prognostic indicator named "SARCO-MELD" based on the two independent prognostic factors, creating three groups: group 1 (0 prognostic factors), group 2 (1 factor) and group 3 (2 factors), the latter with significantly worse survival and shorter time receiving treatment.

Predictors of clinical trajectories of patients with acutely decompensated cirrhosis. An external validation of the PREDICT study.

BACKGROUND AND AIMS: The PREDICT study recently showed that acutely decompensated (AD) patients with cirrhosis can present three different clinical phenotypes in the 90 days after admission: (1) pre-ACLF, developing acute-on-chronic liver failure (ACLF); (2) unstable decompensated cirrhosis (UDC), being re-admitted for AD without ACLF and (3) stable decompensated cirrhosis (SDC), not presenting readmission or ACLF. This study aimed to externally validate the existence of these three distinct trajectories and to identify predictors for the occurrence of each trajectory. METHODS: Baseline data, 3-month ACLF and readmission incidence and 1-year survival were analysed in a prospective cohort of patients admitted for AD. A multinomial multivariable model was used to evaluate the association between baseline features and clinical trajectories. RESULTS: Of the 311 patients enrolled, 55% met the criteria for SDC, 18% for UDC and 27% for pre-ACLF, presenting a significantly different 1-year mortality: pre-ACLF 65%, UDC 46%, SDC 21% (p < .001). The presence of hepatic encephalopathy (HE) was associated with UDC (p = .043), while the absence of ascites to SDC (p = .017). Among laboratory parameters, an increase in MELD-Na (p = .001) and C-reactive protein (p = .009) and a decrease in haemoglobin (p = .004) and albumin (p = .008) levels were associated with pre-ACLF. CONCLUSION: The present study confirms that AD patients have three different clinical trajectories with different mortality rates. Besides the severity of cirrhosis, the association with C-reactive protein supports the predominant role of systemic inflammation in ACLF pathophysiology. Finally, HE is associated with the UDC phenotype highlighting the need for better management of this complication after discharge.

Determinants of clinical response to empirical antibiotic treatment in patients with cirrhosis and bacterial and fungal infections-Results from the ICA "Global Study" (EABCIR-Global Study).

BACKGROUND: The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study." METHODS: Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures. RESULTS: From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27). CONCLUSIONS: Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.

Physical Prehabilitation in Patients who Underwent Major Abdominal Surgery: A Comprehensive Systematic Review and Component Network Meta-Analysis Using GRADE and CINeMA Approach.

BACKGROUND: Physical prehabilitation is recommended before major abdominal surgery to ameliorate short-term outcomes. METHODS: A frequentist, random-effects network meta-analysis (NMA) was performed to clarify which type of preoperative physical activity among aerobic exercise (AE), inspiratory muscle training (IMT), and resistance training produces benefits in patients who underwent major abdominal surgery. The surface under the P-score, odds ratio (OR), or mean difference (MD) with a 95% confidence interval (CI) were reported. The results were adjusted by using the component network approach. The critical endpoints were overall and major morbidity rate and mortality rate. The important but not critical endpoints were the length of stay (LOS) and pneumonia. RESULTS: The meta-analysis included 25 studies. The best approaches for overall morbidity rate were AE and AE + IMT (OR = 0.61, p-score = 0.76, and OR = 0.66, p-score = 0.68). The best approaches for pneumonia were AE + IMT and AE (OR = 0.21, p-score = 0.91, and OR = 0.52, p-score = 0.68). The component analysis confirmed that the best incremental OR (0.30; 95% CI 0.12-0.74) could be obtained using AE + IMT. The best approach for LOS was AE alone (MD - 1.63 days; 95% CI - 3.43 to 0.18). The best combination of components was AE + IMT (MD - 1.70; 95% CI - 2.06 to - 1.27). CONCLUSIONS: Physical prehabilitation reduces the overall morbidity rate, pneumonia, and length of stay. The most relevant effect of prehabilitation requires the simultaneous use of AE and IMT.

Development and internal validation of a multivariable model for the prediction of the probability of 1-year readmission to the emergency department for acute alcohol intoxication.

To develop and internally validate a multivariable logistic regression model (LRM) for the prediction of the probability of 1-year readmission to the emergency department (ED) in patients with acute alcohol intoxication (AAI). We developed and internally validated the LRM on a previously analyzed retrospective cohort of 3304 patients with AAI admitted to the ED of the Sant'Orsola-Malpighi Hospital (Bologna, Italy). The benchmark LRM employed readmission to the same ED for AAI within 1 year as the binary outcome, age as a continuous predictor, and sex, alcohol use disorder, substance use disorder, at least one previous admission for trauma, mental or behavioral disease, and homelessness as the binary predictors. Optimism correction was performed using the bootstrap on 1000 samples without replacement. The benchmark LRM was gradually simplified to get the most parsimonious LRM with similar optimism-corrected overall fit, discrimination and calibration. The 1-year readmission rate was 15.7% (95% CI 14.4-16.9%). A reduced LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness, performed nearly as well as the benchmark LRM. The reduced LRM had the following optimism-corrected metrics: scaled Brier score 17.0%, C-statistic 0.799 (95% CI 0.778 to 0.821), calibration in the large 0.000 (95% CI - 0.099 to 0.099), calibration slope 0.985 (95% CI 0.893 to 1.088), and an acceptably accurate calibration plot. An LRM based on sex, age, at least one previous admission for trauma, mental or behavioral disease, and homelessness can be used to estimate the probability of 1-year readmission to ED for AAI. To begin proving its clinical utility, this LRM should be validated in external cohorts.

Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis.

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.

Mechanisms and treatment approaches for ACLF.

Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome characterized by decompensation of cirrhosis, severe systemic inflammation and organ failures. ACLF is frequently triggered by intra- and/or extrahepatic insults, such as bacterial infections, alcohol-related hepatitis or flares of hepatic viruses. The imbalance between systemic inflammation and immune tolerance causes organ failures through the following mechanisms: (i) direct damage of immune cells/mediators; (ii) worsening of circulatory dysfunction resulting in organ hypoperfusion and (iii) metabolic alterations with prioritization of energetic substrates for inflammation and peripheral organ 'energetic crisis'. Currently, the management of ACLF includes the support of organ failures, the identification and treatment of precipitating factors and expedited assessment for liver transplantation (LT). Early LT should be considered in patients with ACLF grade 3, who are unlikely to recover with the available treatments and have a mortality rate > 70% at 28 days. However, the selection of transplant candidates and their prioritization on the LT waiting list need standardization. Future challenges in the ACLF field include a better understanding of pathophysiological mechanisms leading to inflammation and organ failures, the development of specific treatments for the disease and personalized treatment approaches. Herein, we reviewed the current knowledge and future perspectives on mechanisms and treatment of ACLF.

Albumin administration in internal medicine: A journey between effectiveness and futility.

Albumin is the most abundant circulating protein and provides about 70% of the plasma oncotic power. The molecule also carries many other biological functions (binding, transport and detoxification of endogenous and exogenous compounds, antioxidation, and modulation of inflammatory and immune responses). Hypoalbuminemia is a frequent finding in many diseases, representing usually only a biomarker of poor prognosis rather than a primary pathophysiological event. Despite that, albumin is prescribed in many conditions based on the assumption that correction of hypoalbuminemia would lead to clinical benefits for the patients. Unfortunately, many of these indications are not supported by scientific evidence (or have been even disproved), so that a large part of albumin use is nowadays still inappropriate. Decompensated cirrhosis is the clinical area where albumin administration has been extensively studied and solid recommendations can be made. Besides prevention and treatment of acute complications, long-term albumin administration in patients with ascites has emerged in the last decade has a potential new disease-modifying treatment. In non-hepatological settings, albumin is widely used for fluid resuscitation in sepsis and critical illnesses, with no clear superiority over crystalloids. In many other conditions, scientific evidence supporting albumin prescription is weak or even absent. Thus, given its high cost and limited availability, action is needed to avoid the use of albumin for inappropriate and futile indications to ensure its availability in those conditions for which albumin has been demonstrated to have a real effectiveness and an advantage for the patient.

Hepatic encephalopathy increases the risk for mortality and hospital readmission in decompensated cirrhotic patients: a prospective multicenter study.

Introduction: Hepatic encephalopathy (HE) affects the survival and quality of life of patients with cirrhosis. However, longitudinal data on the clinical course after hospitalization for HE are lacking. The aim was to estimate mortality and risk for hospital readmission of cirrhotic patients hospitalized for HE. Methods: We prospectively enrolled 112 consecutive cirrhotic patients hospitalized for HE (HE group) at 25 Italian referral centers. A cohort of 256 patients hospitalized for decompensated cirrhosis without HE served as controls (no HE group). After hospitalization for HE, patients were followed-up for 12 months until death or liver transplant (LT). Results: During follow-up, 34 patients (30.4%) died and 15 patients (13.4%) underwent LT in the HE group, while 60 patients (23.4%) died and 50 patients (19.5%) underwent LT in the no HE group. In the whole cohort, age (HR 1.03, 95% CI 1.01-1.06), HE (HR 1.67, 95% CI 1.08-2.56), ascites (HR 2.56, 95% CI 1.55-4.23), and sodium levels (HR 0.94, 95% CI 0.90-0.99) were significant risk factors for mortality. In the HE group, ascites (HR 5.07, 95% CI 1.39-18.49) and BMI (HR 0.86, 95% CI 0.75-0.98) were risk factors for mortality, and HE recurrence was the first cause of hospital readmission. Conclusion: In patients hospitalized for decompensated cirrhosis, HE is an independent risk factor for mortality and the most common cause of hospital readmission compared with other decompensation events. Patients hospitalized for HE should be evaluated as candidates for LT.

Low haemoglobin level predicts early hospital readmission in patients with cirrhosis and acute decompensation.

Background & Aims: Patients with decompensated cirrhosis present frequent hospitalisations with a relevant clinical and socio-economic impact. This study aims to characterise unscheduled readmissions up to 1-year follow-up and identify predictors of 30-day readmission after an index hospitalisation for acute decompensation (AD). Methods: We performed a secondary analysis of a prospectively collected cohort of patients admitted for AD. Laboratory and clinical data at admission and at discharge were collected. Timing and causes of unscheduled readmissions and mortality were recorded up to 1 year. Results: A total of 329 patients with AD were included in the analysis. Acute-on-chronic liver failure was diagnosed in 19% of patients at admission or developed in an additional 9% of patients during the index hospitalisation. During the 1-year follow-up, 182 patients (55%) were rehospitalised and 98 (30%) more than once. The most frequent causes of readmission were hepatic encephalopathy (36%), ascites (22%), and infection (21%). Cumulative incidence of readmission was 20% at 30 days, 39% at 90 days, and 63% at 1 year. Fifty-four patients were readmitted for emergent liver-related causes within 30 days. Early readmission was associated with a higher 1-year mortality (47 vs. 32%, p = 0.037). Multivariable Cox regression analysis showed that haemoglobin (Hb) ≤8.7 g/dl (hazard ratio 2.63 [95% CI 1.38-5.02], p = 0.003) and model for end-stage liver disease-sodium score (MELD-Na) >16 at discharge (hazard ratio 2.23 [95% CI 1.27-3.93], p = 0.005), were independent predictors of early readmission. In patients with MELD-Na >16 at discharge, the presence of Hb ≤8.7 g/dl doubles the risk of early rehospitalisation (44% vs. 22%, p = 0.02). Conclusion: Besides MELD-Na, a low Hb level (Hb ≤8.7 g/dl) at discharge emerged as a new risk factor for early readmission, contributing to identification of patients who require closer surveillance after discharge. Impact and Implications: Patients with decompensated cirrhosis face frequent hospitalisations. In the present study, type and causes of readmissions were analysed during 1-year follow-up in patients discharged after the index hospitalisation for an acute decompensation of the disease. Early (30-day) liver-related readmission was associated with higher 1-year mortality. The model for end-stage liver disease-sodium score and low haemoglobin at discharge were identified as independent risk factors for early readmissions. Haemoglobin emerged as a new easy-to-use parameter associated with early readmission warranting further investigation.

Update in the Treatment of the Complications of Cirrhosis.

Cirrhosis consists of 2 main stages: compensated and decompensated, the latter defined by the development/presence of ascites, variceal hemorrhage, and hepatic encephalopathy. The survival rate is entirely different, depending on the stage. Treatment with nonselective ß-blockers prevents decompensation in patients with clinically significant portal hypertension, changing the previous paradigm based on the presence of varices. In patients with acute variceal hemorrhage at high risk of failure with standard treatment (defined as those with a Child-Pugh score of 10-13 or those with a Child-Pugh score of 8-9 with active bleeding at endoscopy), a pre-emptive transjugular intrahepatic portosystemic shunt (TIPS) improves the mortality rate and has become the standard of care in many centers. In patients with bleeding from gastrofundal varices, retrograde transvenous obliteration (in those with a gastrorenal shunt) and/or variceal cyanoacrylate injection have emerged as alternatives to TIPS. In patients with ascites, emerging evidence suggests that TIPS might be used earlier, before strict criteria for refractory ascites are met. Long-term albumin use is under assessment for improving the prognosis of patients with uncomplicated ascites and confirmatory studies are ongoing. Hepatorenal syndrome is the least common cause of acute kidney injury in cirrhosis, and first-line treatment is the combination of terlipressin and albumin. Hepatic encephalopathy has a profound impact on the quality of life of patients with cirrhosis. Lactulose and rifaximin are first- and second-line treatments for hepatic encephalopathy, respectively. Newer therapies such as L-ornithine L-aspartate and albumin require further assessment.

Sympathetic nervous activation, mitochondrial dysfunction and outcome in acutely decompensated cirrhosis: the metabolomic prognostic models (CLIF-C MET).

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. METHODS: Two prospective multicentre large cohorts from Europe for investigating ACLF and development of ACLF, CANONIC (discovery, n=831) and PREDICT (validation, n=851), were explored by untargeted serum metabolomics to identify and validate metabolites which could allow improved prognostic modelling. RESULTS: Three prognostic metabolites strongly associated with death were selected to build the models. 4-Hydroxy-3-methoxyphenylglycol sulfate is a norepinephrine derivative, which may be derived from the brainstem response to SI. Additionally, galacturonic acid and hexanoylcarnitine are associated with mitochondrial dysfunction. Model 1 included only these three prognostic metabolites and age. Model 2 was built around 4-hydroxy-3-methoxyphenylglycol sulfate, hexanoylcarnitine, bilirubin, international normalised ratio (INR) and age. In the discovery cohort, both models were more accurate in predicting death within 7, 14 and 28 days after admission compared with MELDNa score (C-index: 0.9267, 0.9002 and 0.8424, and 0.9369, 0.9206 and 0.8529, with model 1 and model 2, respectively). Similar results were found in the validation cohort (C-index: 0.940, 0.834 and 0.791, and 0.947, 0.857 and 0.810, with model 1 and model 2, respectively). Also, in ACLF, model 1 and model 2 outperformed MELDNa 7, 14 and 28 days after admission for prediction of mortality. 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.

A case of peri­stomal ectopic variceal bleeding in a patient with decompensated cirrhosis treated with TIPS placement.

Peri-stomal variceal bleeding is an underestimated complication in patients with colostomy and portal hypertension. Due to the small number of reported cases, there is currently no unified consensus on the best treatment and several options may be available. We report a case in which TIPS placement was effective.

Correction and Prevention of Hyponatremia in Patients With Cirrhosis and Ascites: Post Hoc Analysis of the ANSWER Study Database.

INTRODUCTION: We assessed the impact of long-term albumin administration to hyponatremic patients with ascites enrolled in the ANSWER trial. METHODS: The normalization rate of baseline hyponatremia and the 18-month incidence rate of at least moderate hyponatremia were evaluated. RESULTS: The hyponatremia normalization rate was higher with albumin than with standard medical treatment (45% vs 28%, P = 0.042 at 1 month). Long-term albumin ensured a lower incidence of at least moderate hyponatremia than standard medical treatment (incidence rate ratio: 0.245 [CI 0.167-0.359], P < 0.001). DISCUSSION: Long-term albumin administration improves hyponatremia and reduces episodes of at least moderate hyponatremia in outpatients with cirrhosis and ascites.

Mortality and its association with chronic alcohol-related diseases in patients admitted to the emergency department for acute alcoholic intoxication: retrospective cohort study.

We assessed long-term mortality and its association with chronic alcohol-related diseases in patients admitted to the emergency department (ED) because of acute alcoholic intoxication (AAI). A retrospective cohort study was performed at the ED of Sant'Orsola-Malpighi Hospital, Bologna, Italy. 3304 patients, corresponding to 6415 admissions for AAI, who accessed the ED from January 1, 2005, to December 31, 2017, were studied. The ED electronic registry system was used to assess living status on 08 May 2020 and to obtain the prespecified potential predictors, i.e., age at first admission, sex, alcohol use disorder (AUD), substance use disorder (SUD), more than 1 admission to ED for trauma, mental and behavioral disorders, neurological disorders, and cardiovascular disease. The median follow-up time was 9.3 years and the time on risk was 30,053 person years (PY) with a death rate corresponding to 4.42 (95% CI 3.74-5.26) per 1000 PY (n = 133 deaths). The death rate was higher in patients with AUD (17.30) than in those without AUD (1.98) and in those with SUD (13.58) than in those without SUD (3.80). Lastly, there was a clearly higher death rate among AUD+ SUD+ (20.89) compared to AUD-SUD-patients (1.74). At multivariable Cox regression, AUD, SUD, and liver cirrhosis were strong and independent predictors of time-to-death. Using standardized mortality ratios, a clear excess of mortality was evident for all the age bands from (40-45] to (60-65] years. Mortality is higher in AAI than in the general population and chronic alcohol-related diseases are strongly associated with it.