Spontaneous fluctuations in liver biochemistries in patients with compensated NASH cirrhosis: Implications for drug hepatotoxicity monitoring

Introduction: Patients with cirrhosis may have spontaneous fluctuations in liver enzymes, which may confound detection of drug-induced liver injury (DILI), but these fluctuations have not been described. Objective: We sought to quantify spontaneous liver enzyme abnormalities in patients with cirrhosis due to nonalcoholic steatohepatitis (NASH) enrolled in clinical trials. Methods: We examined the laboratory values of patients with compensated cirrhosis randomized to placebo in two clinical trials for NASH. Patients in one study were followed every 13 weeks up to week 57; patients in the other study were followed every 4 weeks up to week 120. Results: In total, 53 and 85 patients were randomized to placebo in the trials. Baseline alanine aminotransferase (ALT) was greater than the laboratory upper limit of normal (ULN) in 53% and 49% of participants, aspartate aminotransferase (AST) was > ULN in 49% and 59%, alkaline phosphatase was > ULN in 36% and 27%, and bilirubin was >ULN in 13% and 19%. During follow-up, ALT increased to 2× baseline in 8% and 15%, AST increased to 2× baseline in 6% and 21%, and bilirubin increased to 2× baseline in 9% and 18%. Alkaline phosphatase did not increase to 2× baseline for any patient. The maximum ALT was 3× ULN in 9% and 12%. ALT increased to 3× baseline in three patients and to 5× ULN in two patients. No patients had elevations consistent with Hy's law. The maximum ALT for patients with abnormal baseline values was higher [median 48 U/L (range 34-299) and 56 U/L (47-85)] than for those with normal baseline values [median 26.5 U/L (range 18-33) and 29 U/L (25.5-30.5)] in both studies, respectively, with p < 0.001. Conclusion: Spontaneous liver enzyme abnormalities are common in patients with NASH cirrhosis in clinical trials, and these abnormalities rarely met criteria for DILI suspicion. Further work to better define these abnormalities and continued vigilance to detect DILI in this population is needed

The SWELLS survey. II. Breaking the disk-halo degeneracy in the spiral galaxy gravitational lens SDSS J2141-0001

The degeneracy among the disk, bulge and halo contributions to galaxy rotation curves prevents an understanding of the distribution of baryons and dark matter in disk galaxies. In an attempt to break this degeneracy, we present an analysis of the spiral galaxy strong gravitational lens SDSS J2141-0001, discovered as part of the SLACS survey. We present new Hubble Space Telescope multicolor imaging, gas and stellar kinematics data derived from long-slit spectroscopy, and K-band LGS adaptive optics imaging, both from the Keck telescopes. We model the galaxy as a sum of concentric axisymmetric bulge, disk and halo components and infer the contribution of each component, using information from gravitational lensing and gas kinematics. This analysis yields a best-fitting total (disk plus bulge) stellar mass of log_{10}(Mstar/Msun) = 10.99(+0.11,-0.25). The photometric data combined with stellar population synthesis models yield log_{10}(Mstar/Msun) = 10.97\pm0.07, and 11.21\pm0.07 for the Chabrier and Salpeter IMFs, respectively. Accounting for the expected gas fraction of \simeq 20% reduces the lensing plus kinematics stellar mass by 0.10\pm0.05 dex, resulting in a Bayes factor of 11.9 in favor of a Chabrier IMF. The dark matter halo is roughly spherical, with minor to major axis ratio q_{halo}=0.91(+0.15,-0.13). The dark matter halo has a maximum circular velocity of V_{max}=276(+17,-18) km/s, and a central density parameter of log_{10}\Delta_{V/2}=5.9(+0.9,-0.5). This is higher than predicted for uncontracted dark matter haloes in LCDM cosmologies, log_{10}\Delta_{V/2}=5.2, suggesting that either the halo has contracted in response to galaxy formation, or that the halo has a higher than average concentration. At 2.2 disk scale lengths the dark matter fraction is f_{DM}=0.55(+0.20,-0.15), suggesting that SDSS J2141-0001 is sub-maximal.Comment: 24 pages, 20 figures, accepted to MNRAS, minor change

Effects of Belapectin, an Inhibitor of Galectin-3, in Patients With Nonalcoholic Steatohepatitis With Cirrhosis and Portal Hypertension

Background & Aims Increased levels of galectin 3 have been associated with nonalcoholic steatohepatitis (NASH) and contribute to toxin-induced liver fibrosis in mice. GR-MD-02 (belapectin) is an inhibitor of galectin 3 that reduces liver fibrosis and portal hypertension in rats and was safe and well tolerated in phase 1 studies. We performed a phase 2b, randomized trial of the safety and efficacy of GR-MD-02 in patients with NASH, cirrhosis, and portal hypertension. Methods Patients with NASH, cirrhosis, and portal hypertension (hepatic venous pressure gradient [HVPG] ≥ 6 mm Hg) from 36 centers were randomly assigned, in a double-blind manner, to groups that received biweekly infusions of belapectin 2 mg/kg (n = 54), 8 mg/kg (n = 54), or placebo (n = 54) for 52 weeks. The primary endpoint was change in HVPG (Δ HVPG) at the end of the 52-week period compared with baseline. Secondary endpoints included changes in liver histology and development of liver-related outcomes. Results We found no significant difference in ΔHVPG between the 2 mg/kg belapectin group and placebo group (–0.28 mm HG vs 0.10 mm HG, P = 1.0) or between the 8 mg/kg belapectin and placebo group (–0.25 mm HG vs 0.10 mm HG, P = 1.0). Belapectin had no significant effect on fibrosis or nonalcoholic fatty liver disease activity score, and liver-related outcomes did not differ significantly among groups. In an analysis of a subgroup of patients without esophageal varices at baseline (n = 81), 2 mg/kg belapectin was associated with a reduction in HVPG at 52 weeks compared with baseline (P = .02) and reduced development of new varices (P = .03). Belapectin (2 mg/kg) was well tolerated and produced no safety signals. Conclusions In a phase 2b study of 162 patients with NASH, cirrhosis, and portal hypertension, 1 year of biweekly infusion of belapectin was safe but not associated with significant reduction in HVPG or fibrosis compared with placebo. However, in a subgroup analysis of patients without esophageal varices, 2 mg/kg belapectin did reduce HVPG and development of varices