BACKGROUNDInfection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown. METHODSWe conducted a randomized, multicenter, open-label, parallel-group trial involving hospitalized patients with decompensated cirrhosis who had a serum albumin level of less than 30 g per liter at enrollment. Patients were randomly assigned to receive either targeted 20% human albumin solution for up to 14 days or until discharge, whichever came first, or standard care. Treatment commenced within 3 days after admission. The composite primary end point was new infection, kidney dysfunction, or death between days 3 and 15 after the initiation of treatment. RESULTSA total of 777 patients underwent randomization, and alcohol was reported to be a cause of cirrhosis in most of these patients. A median total infusion of albumin of 200 g (interquartile range, 140 to 280) per patient was administered to the targeted albumin group (increasing the albumin level to ≥30 g per liter), as compared with a median of 20 g (interquartile range, 0 to 120) per patient administered to the standard-care group (adjusted mean difference, 143 g; 95% confidence interval [CI], 127 to 158.2). The percentage of patients with a primary end-point event did not differ significantly between the targeted albumin group (113 of 380 patients [29.7%]) and the standard-care group (120 of 397 patients [30.2%]) (adjusted odds ratio, 0.98; 95% CI, 0.71 to 1.33; P = 0.87). A time-to-event analysis in which data were censored at the time of discharge or at day 15 also showed no significant between-group difference (hazard ratio, 1.04; 95% CI, 0.81 to 1.35). More severe or life-threatening serious adverse events occurred in the albumin group than in the standard-care group. CONCLUSIONSIn patients hospitalized with decompensated cirrhosis, albumin infusions to increase the albumin level to a target of 30 g per liter or more was not more beneficial than the current standard care in the United Kingdom.

Background The estimated worldwide prevalence of non-alcoholic fatty liver disease (NAFLD) in adults is 25%; however, prevalence in young adults remains unclear. We aimed to identify the prevalence of steatosis and fibrosis in young adults in a sample of participants recruited through the Avon Longitudinal Study of Parents and Children (ALSPAC), based on transient elastography and controlled attenuation parameter (CAP) score. MethodsIn this population-based study, we invited active participants of the ALSPAC cohort to our Focus@24+ clinic at the University of Bristol (Bristol, UK) between June 5, 2015, and Oct 31, 2017, for assessment by transient elastography with FibroScan, to determine the prevalence of steatosis and fibrosis. FibroScan data were collected on histologically equivalent fibrosis stage (F0-F4) and steatosis grade (S0-S3); results with an IQR to median ratio of 30% or greater were excluded for median fibrosis results greater than 7•1 kPa, and CAP scores for steatosis were excluded if less than ten valid readings could be obtained. Results were collated with data on serology (including alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transferase) and exposures of interest: alcohol consumption (via the Alcohol Use Disorder Identification Test for Consumption [AUDIT-C] and the Diagnostic and Statistical Manual of Mental Disorders-5 criteria for alcohol use disorder), body-mass index (BMI), waist-to-height ratio, socioeconomic status (based on predefined ALSPAC markers), and sex. We used logistic regression models to calculate odds ratios (ORs) for the effect of exposures of interest on risk of steatosis and fibrosis, after dichotomising the prevalences of fibrosis and steatosis and adjusting for covariates (excessive alcohol intake [hazardous drinking, AUDIT-C score ≥5; or harmful drinking, evidence of alcohol use disorder], social class, smoking, and BMI). Findings 10 018 active ALSPAC participants were invited to our Focus@24+ clinic, and 4021 attended (1507 men and 2514 women), with a mean age of 24•0 years (IQR 23•0-25•0). 3768 CAP scores were eligible for analysis. 780 (20•7% [95% CI 19•4-22•0]) participants had suspected steatosis (S1-S3; ≥248 dB/m), with 377 (10•0%) presenting with S3 (severe) steatosis (≥280 dB/m). A BMI in the overweight or obese range was positively associated with steatosis when adjusted for excessive alcohol consumption, social class, and smoking (overweight BMI: OR 5•17 [95% CI 4•11-6•50], p<0•0001; obese BMI: 27•27 [20•54-36•19], p<0•0001). 3600 participants had valid transient elastography results for fibrosis analysis. 96 participants (2•7% [95% CI 2•2-3•2]) had transient elastography values equivalent to suspected fibrosis (F2-F4; ≥7•9 kPa), nine of whom had values equivalent to F4 fibrosis (≥11•7 kPa). Individuals with alcohol use disorder and steatosis had an increased risk of fibrosis when adjusted for smoking and social class (4•02 [1•24-13•02]; p=0•02).Interpretation One in five young people had steatosis and one in 40 had fibrosis around the...

Postoperative acute kidney injury (AKI) increases morbidity and mortality after liver transplantation (LT). Novel methods of assessing AKI including cystatin C (CyC) and neutrophil gelatinase-associated lipocalin (NGAL) have been identified as potential markers of AKI. We compare the ability of standard renal markers (serum creatinine [sCr], estimated glomerular filtration rate [eGFR] and intensive therapy unit organ failure scores with CyC and NGAL to predict AKI within the first 48 hours after LT. 95 patients (median age 50 [interquartile range ¼ 41-59], 60% male) underwent LT (25% with acute liver failure). AKI was defined according to the Acute Kidney Injury Network criteria. Severe AKI was classified as !stage 2. NGAL (urine [u] and plasma [p]) and CyC concentrations taken immediately after transplantation on admission to the Liver Intensive Care Unit were compared with standard markers of renal function. Predictive ability was assessed using the area under the curve generated by receiver operator characteristic analysis (AUROC) and logistic regression. Day 0 sCr, uNGAL, pNGAL, CyC, and eGFR predicted AKI as did SOFA (Sequential Organ Failure Assessment) and APACHE II (Acute Physiology and Chronic Health Evaluation II) scores. APACHE II and pNGAL were the most powerful predictors of severe AKI (APACHE II AUROC ¼ 0.87 [0.77-0.97], P < 0.001; pNGAL AUROC ¼ 0.87 [0.77-0.92], P < 0.001). Using multivariate logistic regression, APACHE II (odds ratio 1.64/point [95% confidence interval ¼ 1.22-2.21, P ¼ 0.001] and pNGAL [odds ratio ¼ 1.01/ng/mL [95% confidence interval ¼ 1.00-1.02], P ¼ 0.002) retained independent significance. A ''renal risk score'' using APACHE II > 13 and pNGAL > 258 ng/mL was calculated with a score of !1 having a 100% sensitivity and 76% specificity for severe AKI. In conclusion, a combination of NGAL and APACHE II predicts AKI with high sensitivity and specificity after LT. Liver Transpl 16:1257-1266, 2010. V C 2010 AASLD.Received March 14, 2010; accepted July 15, 2010.Renal dysfunction is common after liver transplantation (LT). The incidence of acute renal failure complicating the posttransplant period varies between 48% and 94% 1 and affects both short-term and long-term outcome. Mortality in those requiring renal replacement therapy (RRT) may be as high as 40% at 90 days, rising to 54% at 1 year.2 Although many risk factors for developing renal dysfunction posttransplant have been investigated, the greatest impact on outcome is in patients who develop de novo renal impairment, especially in those who require RRT.2 Patients with low glomerular filtration rates (GFR) at 1 month post-LT are also at risk of developing severe renal dysfunction at 5 years post-LT 3 and the need for dialysis in LT recipients has been reported to be as high as 18% at 5 years.

Organ allocation based on Model for End-Stage Liver Disease (MELD) resulted in decreased waiting list mortality in the United States. However, reports suggest an increase in resource utilization as a consequence of this. The aim of this study is to assess the correlation of MELD at transplant with post-liver transplant (LT) intensive care unit (ICU) costs. We assessed clinical and demographic variables of 402 adult patients who underwent LT at King's College Hospital, London, UK, between January 2000 and December 2003. ICU cost calculations were based on the therapeutic intervention scoring system (TISS). Graft quality was assessed using the donor risk index (DRI). Patients with a MELD score > 24 had significantly longer post-LT ICU stay (P < 0.0001) and total post-LT hospital stay (P ¼ 0.008). In addition, they had significantly increased TISS scores, ICU cost, and need for renal replacement therapy (RRT) (P < 0.001). MELD score (by point) and MELD > 24 was associated with prolonged ICU stay (P ¼ 0.004 and P ¼ 0.005, respectively). On univariate analysis, etiology of alcohol-related liver disease (ALD), repeat LT, Budd-Chiari syndrome, and refractory ascites were associated with prolonged ICU stay. Using multivariate analysis, MELD > 24, refractory ascites, ALD and Budd-Chiari syndrome were associated with prolonged ICU stay. There was no association between using grafts with higher DRI and longer ICU stay, need for RRT, increased cost, or hospital survival on univariate analyses (P ¼ not significant). Use of MELD as a method of organ allocation results in significant increase in ICU cost after LT. Using TISS as surrogate marker for ICU costs reveals that the cost implications are related to the need for RRT and prolonged ICU stay. Liver Transpl 16:668-677,

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Background and objectives Patients with decompensated cirrhosis rarely receive palliative and supportive care interventions, which are routine in other life-limiting diseases. We aimed to design and evaluate a prognostic screening tool to routinely identify inpatients with decompensated cirrhosis at high risk of dying over the coming year, alongside the development of a supportive care intervention. Design Clinical notes from consecutive patients admitted as an emergency to University Hospitals Bristol with a diagnosis of cirrhosis over two distinct 90-day periods were scrutinised retrospectively for the presence or absence of five evidence-based factors associated with poor prognosis. These were analysed against their ability to predict mortality at 1 year. 'PlanDo-Study-Act' (PDSA) methodology was used to incorporate poor-prognosis screening into the routine assessment of patients admitted with cirrhosis, and develop a supportive care intervention. Results 73 admissions were scrutinised (79.5% male, 63% alcohol-related liver disease, median age 54). The presence of three or more poorprognosis criteria at admission predicted 1-year mortality with sensitivity, specificity and positive predictive value of 72.2%, 83.8% and 81.3%, respectively, and was used as a trigger for implementing the supportive care intervention. Following modification from six PDSA cycles, prognostic screening was integrated into the assessment of all patients admitted with

In Liddle's syndrome, a rare inherited form of hypertension, epithelial sodium channel mutations appear to cause high blood pressure by increasing sodium reabsorption through sodium channels in the renal distal tubule. This increase in channel activity has not been confirmed previously by in vivo measurement. We have made transnasal potential difference measurements (effective in detection of increased sodium channel activity in cystic fibrosis) in three brothers with genetically proven Liddle's syndrome, their unaffected sister, and 40 normotensive controls. Maximum potential difference after 2 wk off treatment in the affected brothers was Ϫ 30.4 Ϯ 1.2 mV (values mean Ϯ SD, lumen-negative with respect to submucosa) and was significantly more lumen-negative than that of the control group ( Ϫ 18.6 Ϯ 6.8 mV, P ϭ 0.0228) or the unaffected sister ( Ϫ 18.25 mV, P Ͻ 0.01). The change in potential difference after topical application of 10 Ϫ 4 M amiloride was greater in the Liddle's patients, 14.0 Ϯ 2.1 mV, than in controls (7.9 Ϯ 3.9 mV, P ϭ

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin-free fraction (Af-Gc) have not been available until now. We measured actin-free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af-Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af-Gc in the evolution of organ dysfunction. In acetaminophen-induced ALF, Af-Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af-Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af-Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system.