on behalf of the RELIEF study group Acute-on-chronic liver failure (ACLF) is a frequent cause of death in cirrhosis. Albumin dialysis with the molecular adsorbent recirculating system (MARS) decreases retained substances and improves hemodynamics and hepatic encephalopathy (HE). However, its survival impact is unknown. In all, 189 patients with ACLF were randomized either to MARS (n 5 95) or to standard therapy (SMT) (n 5 94). Ten patients (five per group) were excluded due to protocol violations. In addition, 23 patients (MARS: 19; SMT: 4) were excluded from per-protocol (PP) analysis (PP population n 5 156). Up to 10 6-8-hour MARS sessions were scheduled. The main endpoint was 28-day ITT and PP survival. There were no significant differences at inclusion, although the proportion of patients with Model for Endstage Liver Disease (MELD) score over 20 points and with spontaneous bacterial peritonitis (SBP) as a precipitating event was almost significantly greater in the MARS group. The 28-day survival was similar in the two groups in the ITT and PP populations (60.7% versus 58.9%; 60% versus 59.2% respectively). After adjusting for confounders, a significant beneficial effect of MARS on survival was not observed (odds ratio [OR]: 0.87, 95% confidence interval [CI] 0.44-1.72). MELD score and HE at admission and the increase in serum bilirubin at day 4 were independent predictors of death. At day 4, a greater decrease in serum creatinine (P 5 0.02) and bilirubin (P 5 0.001) and a more frequent improvement in HE (from grade II-IV to grade 0-I; 62.5% versus 38.2%; P 5 0.07) was observed in the MARS group. Severe adverse events were similar. Conclusion: At scheduled doses, a beneficial effect on survival of MARS therapy in patients with ACLF could not be demonstrated. However, MARS has an acceptable safety profile, has significant dialysis effect, and nonsignificantly improves severe HE.

Albumin concentration is diminished in patients with liver failure. Albumin infusion improves survival of cirrhotic patients with spontaneous bacterial peritonitis, and it is hypothesized that this may be due in part to its detoxifying capabilities. The aim of this study was to perform detailed quantitative and qualitative assessment of albumin function in patients with cirrhosis. Healthy controls and patients with acute deterioration of cirrhosis requiring hospital admission (n ‫؍‬ 34) were included. Albumin function was assessed using affinity of the fatty acid binding sites using a spin label (16 doxyl-stearate) titration and electron paramagnetic resonance spectroscopy and ischemia-modified albumin (IMA) was measured. Twenty-two patients developed acute-on-chronic liver failure. Twelve were treated with the Molecular Adsorbents Recirculating System (MARS) and 10 with standard medical therapy. For each parameter measured, the patients' albumin had reduced functional ability, which worsened with disease severity. Fifteen patients died, and IMA, expressed as an albumin ratio (IMAR), was significantly higher in nonsurvivors compared with survivors (P < 0.001; area under the receiver operating curve ‫؍‬ A lbumin is the major plasma protein and constitutes around 50% of the cell free protein in healthy individuals. It is produced exclusively in the liver, and therefore its concentration is reduced during hepatic dysfunction. 1 Following the Cochrane meta-analysis describing potential harmfully effect of albumin infusion in critically ill patients, there has been a reexamination of the use of albumin infusions for volume replacement. However, the results of the recently published SAFE study have provided new data confirming the safety of albumin infusion in critically ill patients. 2,3 Liver failure results in multiple organ dysfunction, and mortality rates without liver transplantation remain unacceptably high. 4 However, recovery is associated with complete reversal of multiorgan dysfunction. At present, in patients with cirrhosis, albumin is used mainly to replenish the circulating volume. With increasing severity of cirrhosis, there is a progressive increase in cardiac output, which is associated with a progressive reduction in individual organ blood flow. This peculiar circulatory disturbance is thought to occur as a result of splanchnic

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

The pathophysiological basis of acute-on-chronic liver failure (ACLF) is unclear but systemic inflammatory response is thought to be important. In patients with ACLF, the molecular adsorbents recirculating system (MARS) improves individual organ function, but the effect of MARS on the proposed mediators of systemic inflammatory response is unclear. The present study was designed to determine the effect of MARS on the cytokine profile, oxidative stress, nitric oxide, and ammonia. A total of 18 patients with alcohol-related ACLF due to inflammation-related precipitants were randomized to receive standard medical therapy (SMT) alone, or with MARS therapy over 7 days. Plasma cytokines, malondialdehyde (MDA), free radical production, nitrate / nitrite (NOx), and ammonia were measured. Encephalopathy improved significantly with MARS (P < .01), but not with SMT. Mean arterial pressure and renal function remained unchanged. No significant change of plasma cytokines and ammonia levels were observed in either group. Plasma MDA levels did not change either. There was a fall in NOx (P < .05) with MARS, but not with SMT. In conclusion, in inflammation-related ACLF patients, albumin dialysis using MARS results in improvement of encephalopathy, independent of changes of ammonia or cytokines, without improving blood pressure or renal function. These results should temper the liberal use of MARS until further data is available. (Liver

The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short and long-term prognosis. This review focuses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that the liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver support strategies to enhance the recovery process.