Nonalcoholic steatohepatitis (NASH), a chronic liver disease without an approved therapy, is associated with lipotoxicity and insulin resistance and is a major cause of cirrhosis and hepatocellular ...carcinoma. Aramchol, a partial inhibitor of hepatic stearoyl-CoA desaturase (SCD1) improved steatohepatitis and fibrosis in rodents and reduced steatosis in an early clinical trial. ARREST, a 52-week, double-blind, placebo-controlled, phase 2b trial randomized 247 patients with NASH (n = 101, n = 98 and n = 48 in the Aramchol 400 mg, 600 mg and placebo arms, respectively; NCT02279524 ). The primary end point was a decrease in hepatic triglycerides by magnetic resonance spectroscopy at 52 weeks with a dose of 600 mg of Aramchol. Key secondary end points included liver histology and alanine aminotransferase (ALT). Aramchol 600 mg produced a placebo-corrected decrease in liver triglycerides without meeting the prespecified significance (-3.1, 95% confidence interval (CI) -6.4 to 0.2, P = 0.066), precluding further formal statistical analysis. NASH resolution without worsening fibrosis was achieved in 16.7% (13 out of 78) of Aramchol 600 mg versus 5% (2 out of 40) of the placebo arm (odds ratio (OR) = 4.74, 95% CI = 0.99 to 22.7) and fibrosis improvement by ≥1 stage without worsening NASH in 29.5% versus 17.5% (OR = 1.88, 95% CI = 0.7 to 5.0), respectively. The placebo-corrected decrease in ALT for 600 mg was -29.1 IU l
(95% CI = -41.6 to -16.5). Early termination due to adverse events (AEs) was <5%, and Aramchol 600 and 400 mg were safe, well tolerated and without imbalance in serious or severe AEs between arms. Although the primary end point of a reduction in liver fat did not meet the prespecified significance level with Aramchol 600 mg, the observed safety and changes in liver histology and enzymes provide a rationale for SCD1 modulation as a promising therapy for NASH and fibrosis and are being evaluated in an ongoing phase 3 program.
Abstract Hepatitis C virus (HCV)-related end-stage liver disease represents the primary indication for liver transplantation in Western countries, but is associated with poor posttransplantation ...outcomes and a rapid progression of HCV-related disease. This article reviews the risk factors underlying this association and presents the current strategies used to manage HCV infections in transplant recipients.
We aimed to investigate HBx genetic elements correlated with hepatitis B virus (HBV) -related hepatocellular carcinoma (HCC) and their impact on (a) HBV replicative efficiency, (b) HBx binding to ...circular covalently closed DNA (cccDNA), (c) apoptosis and cell-cycle progression, and (d) HBx structural stability.
This study included 123 individuals chronically infected with HBV: 27 with HCC (77.9% (21/27) genotype D; 22.1% (6/27) genotype A) and 96 without HCC (75% (72/96) genotype D; 25.0% (24/96) genotype A). HepG2 cells were transfected by wild-type or mutated linear HBV genome to assess pre-genomic RNA (pgRNA) and core-associated HBV-DNA levels, HBx-binding onto cccDNA by chromatin immunoprecipitation-based quantitative assay, and rate of apoptosis and cell-cycle progression by cytofluorimetry.
F30V was the only HBx mutation correlated with HCC (18.5% (5/27) in HCC patients versus 1.0% (1/96) in non-HCC patients, p 0.002); a result confirmed by multivariate analysis. In vitro, F30V determined a 40% and 60% reduction in pgRNA and core-associated HBV-DNA compared with wild-type (p <0.05), in parallel with a significant decrease of HBx binding to cccDNA and decreased HBx stability. F30V also decreased the percentage of apoptotic cells compared with wild-type (14.8 ± 6.8% versus 19.1 ± 10.1%, p <0.01, without affecting cell-cycle progression) and increased the probability of HBx-Ser-31 being phosphorylated by PI3K-Akt kinase (known to promote anti-apoptotic activity).
F30V was closely correlated with HBV-induced HCC in vivo, reduced HBV replicative efficiency by affecting HBx-binding to cccDNA and increased anti-apoptotic HBx activity in vitro. This suggests that F30V (although hampering HBV's replicative capacity) may promote hepatocyte survival, so potentially allowing persistent production of viral progeny and initiating HBV-driven hepatocarcinogenesis. Investigation of viral genetic markers associated with HCC is crucial to identify those patients at higher risk of HCC, who hence deserve intensive liver monitoring and/or early anti-HBV therapy.
Abstract Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism due to intracellular enzyme deficiency resulting in abnormal storage of glycogen in tissues. GSD ...represents an indication for liver transplantation (OLT) when medical treatment fails to control the metabolic dysfunction and/or there is an high risk of malignant transformation of hepatocellular adenomas (HCA). Herein we have reported two cases of GSD, type Ia and type VI, which were both associated with rapidly growing HCA, and underwent OLT because of suspect changes in their radiological features. Final histological findings in the explanted liver showed the presence of hepatocellular carcinoma (HCC) in both cases. In GSD type Ia and VI, OLT is considered to be the treatment of choice when a liver neoplasm is suspected. While the association of HCC with GSD type Ia is well known, this is the first case of HCC in GSD type VI so far reported to the best of our knowledge.
Early graft dysfunction develops in up to 10-50% of liver transplanted patients and is related to the number of risk factors which identify marginal livers. Marginal livers are defined by the ...presence of af least one of the following risk factors: (1) donor aged > 50 years; (2) donor with hemodynamic instability or with a residence time in ICU greater than 5 days; (3) donor with hypersodiemia; (4) donor with HCV or HBV infection; and (5) donor with macrovescicular steatosis present in > 25% of hepatocytes. The presence of steatosis involving less than 25% of hepatocytes is not considered sufficient to identify a marginal donor, although it may be associated with some risk of early or late graft failure. The reason is that the steatotic liver is characterized by a decreased tolerance to ischemia/reperfusion. It has been observed that the accumulation of fat in the hepatocytes and the increased cell volume cause an impairment of liver microcirculation. Steatosis is associated with decreased capability of ATP production and storage, with increased lipid peroxidation, and with increased release of tumor necrosis factor-a which is believed to be responsible of the lung damage possibly occurring after transplant. The assessment of the type and extent of steatosis requires liver biopsy, not usually indicated in healthy individual. In the transplant setting a precise assessment of steatosis is the prominent reason for performing a liver biopsy of the donor liver.
Data on the occurrence of sardine (Sardina pilchardus) eggs from 42 national ichthyoplankton surveys along the European Atlantic coast were collated in order to describe the spawning habitat and ...spawning distribution of sardine in recent decades (1985-2005). A modification of existing spawning habitat characterisation techniques and a newly developed method to compare the probability of egg presence across surveys carried out with different sampling gears were used. Results showed that sardine spawning off the Atlantic European coast is mainly restricted to the shelf area, with the main geographical range being between the Strait of Gibraltar (the southern limit of data available for this analysis) and the middle part of the Armorican shelf (latitude around 47.5 super(o) North), and along a temperature range of 12-17 super(o)C. Spawning grounds within these limits show a nearly continuous geographical distribution, covering a large proportion of the shelf of the Iberian peninsula and adjacent waters, except for: (1) a persistent gap at the north west corner of the Iberian peninsula, (2) a small secondary break at the Spanish-French border in the inner part of the Bay of Biscay and (3) at the south west corner of the peninsula where there is a narrowing of the shelf width. These discontinuities were used to separate spawning into four nuclei and to describe the changes in spawning distribution in the time series. The relative importance of each nucleus and the degree of separation between adjacent nuclei varies between years, with the exception of the permanent gap at the northwest corner of the Iberian peninsula, which is persistent throughout the time series. Year to year changes in the proportion of the potential spawning habitat in which spawning actually occurred, changing from around 60% before the mid 1990s to around 40% thereafter, and did not show any relationship with spawning stock biomass. Evolution of potential habitat occupation over the Armorican shelf shows larger variability than that observed in the Iberian peninsula, with percentages of occupation ranging from around 30% up to nearly 80% of the shelf in recent years (within the limitations of the relatively sparse data for this region).
The present study investigated the larval fish dispersal along an estuarine-ocean gradient to explore connectivity between ocean and estuaries. During spring 2009, a combined ocean-estuarine survey ...was conducted along the Lima estuarine salinity gradient and in two transects off the adjacent coast (northwestern Iberian Peninsula), until the 100 m isobaths. Salinity, total particulate matter, particulate organic matter, total dissolved carbon, and dissolved organic carbon reached higher values at the ocean, and chlorophyll a and nutrients increased at the estuary. From the total 56 taxa identified, 14 were present along the gradient, including estuarine species (ES), marine stragglers (MS), and migrants (MM). Canonical correspondence analysis showed that species were separated along the gradient according to their ecological functional classification. MM associated with high salinity were separated from ES correlated with lower salinities and high chlorophyll a concentrations of inner estuary. Flounder (Platichthys flesus) showed a typical spatial gradient of MM, with abundance increasing from the ocean towards inner estuary. The dispersal of larvae along the Lima estuarine-ocean gradient was indicative of connectivity between habitats, emphasizing the need to consider this feature in management plans, mainly for species exploited by commercial fisheries.
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