No abstract

Patients with primary biliary cholangitis (PBC) who had an inadequate response to ursodiol have few treatment options. Alkaline phosphatase (ALP) and bilirubin levels correlate with the risk of liver transplant or death in PBC patients. Fibroblast growth factor (FGF) 19 is a hormone that acts directly in the liver to regulate bile acid synthesis. We evaluated NGM282, an engineered analogue of FGF19, for the treatment of PBC. In this 28‐day, double‐blind, placebo‐controlled phase 2 trial, 45 PBC patients who had an inadequate response to ursodiol were randomly assigned 1:1:1 to receive subcutaneous daily doses of either NGM282 at 0.3 mg (n = 14), 3 mg (n = 16), or placebo (n = 15). The primary endpoint was a change in ALP from baseline after 28 days of treatment. At day 28, ALP was significantly reduced with NGM282 treatment at both 0.3 mg (least‐squares mean –51.0 IU/L [standard error (SE) 15.4]) and 3 mg (–66.0 IU/L [SE 16.0]) versus placebo (3.3 IU/L [SE 14.8]), with least‐squares mean differences of –54.3 IU/L (95% confidence interval –104.2 to –4.5; P = 0.0149) and –69.3 IU/L (95% confidence interval –120.5 to –18.3; P = 0.0030), respectively. Fifty percent (7 of 14) of patients receiving NGM282 0.3 mg and 46% (6 of 13) of those receiving NGM282 3mg achieved 15% or greater reduction in ALP levels from baseline, compared with 7% (1 of 15) of patients receiving placebo. NGM282 also significantly reduced serum concentrations of transaminases and immunoglobulins. Most adverse events were grade 1 (mild) to grade 2 (moderate) in severity, with gastrointestinal disorders more frequent in the NGM282 treatment groups. No worsening of pruritus was observed with NGM282 treatment. Conclusion: NGM282 administered for 28 days resulted in significant improvements in ALP and transaminase levels compared with placebo, with an acceptable safety profile in patients with PBC. (Hepatology Communications 2018; 00:000‐000)

Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma‐derived C3A cells express anti‐inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End‐Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3‐5 days of continuous ELAD treatment plus SOC. After a minimum follow‐up of 91 days, overall survival (OS) was assessed by using a Kaplan‐Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent‐to‐treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380–393 2018 AASLD.

Seronegative hepatitis is a common cause of acute liver failure (ALF) requiring liver transplantation. The primary aim of this study was to examine outcomes following transplantation in this group and to identify factors associated with early (<2 months) mortality. Patients studied were 110 consecutive cases of seronegative ALF transplanted at the Queen Elizabeth Hospital, Birmingham, between January 1992 and January 2004. Univariate analysis of 44 pretransplantation recipient, donor, and operative variables was performed initially to identify factors associated with early posttransplantation mortality. Variables identified as significant or approaching significance were analyzed using stepwise multiple logistic regression analysis. Survival following transplantation for seronegative hepatitis was 83%, 81%, and 73% at 2, 12, and 60 months, respectively. The majority (71%) of deaths occurred within the 1st 2 months and sepsis / multiorgan dysfunction was the most common cause of early death. Univariate analysis revealed 9 variables predicting early death. Subsequent multivariate analysis identified high donor body mass index (BMI; a possible surrogate marker for hepatic steatosis) as the most important predictor of early death (P ‫؍‬ .009; odds ratio, 1.2; 95% confidence interval, 1.0-1.3). Recipient age >50 (P ‫؍‬ .015; odds ratio, 4.2; 95% confidence interval, 1.3-14.1) and nonCaucasian recipient ethnicity (P ‫؍‬ .015; odds ratio, 4.9; 95% confidence interval, 1.2-19.2) were other variables associated with early death on multivariate analysis. This study specifically examined factors that determine the early outcome of transplanted seronegative ALF patients. In conclusion, we found that donor and recipient factors identify patients who have a high chance of early death after transplantation. (Liver Transpl 2005;11:27-34.) S eronegative (also known as non-A, non-B or non-A, non-B, non-C or non-A-E, or non-A-E) acute liver failure refers to an idiopathic hepatitis resulting in acute liver failure (ALF). Well recognized causes of ALF are excluded and serological markers for hepatitis A and B serology are negative. Seronegative ALF is an important cause of liver transplantation for ALF. In the United Kingdom, seronegative ALF is the most common indication for liver transplantation in ALF, due to a steady decline in the number of patients transplanted following paracetamol (acetaminophen) overdoses. 1 Despite the frequency of liver transplantation for seronegative ALF, the etiology of this condition remains unknown. A viral etiology has been assumed, however the discoveries of the hepatitis C and E viruses and the more recent discoveries of the hepatitis G and transfusion transmitted viruses have failed to account for the majority of patients with "non-A non-B" ALF. 2 -5 Other viruses (e.g., cytomegalovirus, herpes simplex virus, Epstein-Barr virus, parvovirus B19) are rare causes of ALF and are unlikely to be implicated in the majority of seronegative ALF cases.Although the etiology of seronegative ALF remains obs...