Obeticholic Acid and Fibrates in Primary Biliary Cholangitis: Comparative Effects in a Multicentric Observational Study.

INTRODUCTION: Obeticholic acid (OCA) and fibrates therapy results in biochemical improvement in placebo-controlled trials in patients with primary biliary cholangitis and insufficient response to ursodeoxycholic acid. There is scarce information outside of clinical trials. Therefore, we have assessed the effectiveness and adverse events of these treatments. METHODS: Data from patients included in the ColHai registry treated with OCA, fibrates, or both were recorded during a year, as well as adverse events and treatment discontinuation. RESULTS: Eighty-six patients were treated with OCA, 250 with fibrates (81% bezafibrate; 19% fenofibrate), and 15 with OCA plus fibrates. OCA group had baseline significantly higher alkaline phosphatase (ALP) (P = 0.01) and lower platelets (P = 0.03) than fibrates. Both treatments significantly decreased ALP, gamma-glutamyl transferase (GGT), and transaminases and improved Globe score. Albumin and immunoglobulin type M improved in the fibrates group. ALP decrease was higher under fibrates, whereas alanine aminotransferase decline was higher under OCA. Although baseline transaminases and GGT were higher in patients with OCA plus fibrates, significant ALP, GGT, alanine aminotransferase, and Globe score improvement were observed during triple therapy. Adverse events were reported in 14.7% of patients (21.3% OCA; 17.6% fenofibrate; 10.7% bezafibrate), mainly pruritus (10.1% with OCA). Discontinuation was more frequent in fenofibrate treatment mainly because of intolerance or adverse events. DISCUSSION: Second-line therapy with OCA or fibrates improves hepatic biochemistry and the GLOBE score in primary biliary cholangitis patients with suboptimal response to ursodeoxycholic acid. Simultaneous treatment with OCA and fibrates improved ALP as well.

Real-world evidence of the effectiveness of ombitasvir-paritaprevir/r ± dasabuvir ± ribavirin in patients monoinfected with chronic hepatitis C or coinfected with human immunodeficiency virus-1 in Spain.

AIM: We describe the effectiveness and safety of the interferon-free regimen ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin (OBV/PTV/r ± DSV ± RBV) in a nationwide representative sample of the hepatitis C virus (HCV) monoinfected and human immunodeficiency virus-1/hepatitis C virus (HIV/HCV) coinfected population in Spain. MATERIAL AND METHODS: Data were collected from patients infected with HCV genotypes 1 or 4, with or without HIV-1 coinfection, treated with OBV/PTV/r ± DSV ± RBV at 61 Spanish sites within the initial implementation year of the first government-driven "National HCV plan." Effectiveness was assessed by sustained virologic response at post-treatment week 12 (SVR12) and compared between monoinfected and coinfected patients using a non-inferiority margin of 5% and a 90% confidence interval (CI). Sociodemographic and clinical characteristics or patients and adverse events (AEs) were also recorded. RESULTS: Overall, 2,408 patients were included in the intention-to-treat analysis: 386 (16%) were patients with HIV/HCV. Patient selection reflected the real distribution of patients treated in each participating region in Spain. From the total population, 96.6% (95% CI, 95.8-97.3%) achieved SVR12. Noninferiority of SVR12 in coinfected patients was met, with a difference between monoinfected and coinfected patients of -2.2% (90% CI, -4.5% - 0.2%). Only genotype 4 was associated with non-response to OBV/PTV/r ± DSV ± RBV treatment (p<0.001) in the multivariate analysis. Overall, 286 patients (11.9%) presented AEs potentially related to OBV/PTV/r ± DSV, whereas 347 (29.0%) presented AEs potentially related to ribavirin and 61 (5.1%) interrupted ribavirin. CONCLUSIONS: Our results confirm that OBV/PTV/r ± DSV ± RBV is effective and generally well tolerated in a representative sample of the HCV monoinfected and HCV/HIV coinfected population in Spain within the experience of a national strategic plan to tackle HCV.

Effect of neoadjuvant chemotherapy in hepatic steatosis.

UNLABELLED: Chemotherapy drugs often produce side effects in the liver. In recent years, there has been speculation about the ability to produce hepatic steatosis in patients treated with 5-fluorouracil and oxaliplatin. This prospective study examines whether these drugs can produce steatosis in patients with neoadjuvant treatment who were operated on for liver tumors. PURPOSE: Our objective was to assess the effect of neoadjuvant chemotherapy (NAC) on the development of hepatic steatosis in the healthy liver. PATIENTS AND METHODS: This was a prospective study based on 32 patients divided into two groups. The presence of steatosis was assessed using a histological score (Kleiner classification) and a biochemical method (Folch method) for patients from both groups. RESULTS: A total of 14 patients (44%) had hepatic steatosis and half of these were in each group. The steatosis was moderate to severe (grades 2-3) in 4 patients (13%), 2 in each group. The mean levels of triglycerides in the liver were 33.38 and 29.94 mg/g in group I and group II, respectively, with the difference not being statistically significant. CONCLUSIONS: Almost half of the patients treated with NAC for liver neoplasia developed steatosis. Nevertheless, NAC does not seem to increase the risk of hepatic steatosis.

Pravastatin inhibits cell proliferation and increased MAT1A expression in hepatocarcinoma cells and in vivo models.

BACKGROUND: Statins may have therapeutic effects on hepatocarcinoma (HCC). This type of disorder is the most common malignant primary tumour in the liver. Our objective was to determine whether pravastatin had a therapeutic effect in vitro and in vivo models. METHOD: We design in vitro and in vivo model. In vitro we used PLC and determine cell proliferation. In vivo, we used and animal model to determined, PCNA and MAT1A expression and transaminases levels. RESULTS: We found that pravastatin decreases cell proliferation in vitro (cell proliferation in pravastatin group was 82%, in sorafenib group 51% and in combined group 40%) and in vivo (in pravastatin group 80%, in sorafenib group 76.4% and in combined group 72.72%). The MAT1A levels, was significantly higher in Pravastatin group (D 62%, P 94%, S 71%, P + S 91%). The transaminases levels, decreased significantly in Pravastatin group (GOT and GPT levels D 619.5 U/L; 271 U/L) (P 117.5 U/L; 43.5 U/L) (S 147 U/L; 59 U/L) (P + S 142 U/L; 59 U/L). CONCLUSION: The combination of pravastatin + sorafenib were more effective than Sorafenib alone.

Accurate fat fraction quantification by multiecho gradient-recalled-echo magnetic resonance at 1.5T in rats with nonalcoholic fatty liver disease.

AIM: To assess the diagnostic accuracy of a new reconstruction technique for gradient-recalled-echo magnetic resonance (MR) sequences that provides a full decomposition of the water and fat content inside a voxel for nonalcoholic fatty liver disease (NAFLD) in rats. MATERIAL AND METHODS: Rats were randomized into two groups. A control group (n = 10) was given free access to regular dry rat chow for 4 weeks. The steatosis (n = 40) group was given free access to feed and water 4 days per week, and fasted for the remaining 3 days for 4 weeks. All rats were killed at 4 weeks and assessed for fatty infiltration and biochemical method. RESULTS: The average fat content using the gold standard method was 2.65 g (2.20-3.05) of fat/100g liver for the control group and 4.14 g (1.95-8.60) of fat/100g of liver for the overfed group (p<0.05). The average fat-fraction obtained from the MR was 0.016 (0.01-0.02) for the control group and 0.057 (0.00-0.18) for the overfed group. The Pearson correlation coefficient between the samples was r(2) = 0.87. CONCLUSION: Multi-echo MR is a good technique to quantify liver fat in rats.

Inflammatory mediators of hepatic steatosis.

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming a world-wide public health problem. NAFLD represents a spectrum of disease ranging from "simple steatosis", which is considered relatively benign, to nonalcoholic steatohepatitis and to NAFLD-associated cirrhosis and end-stage liver disease. The etiology of NAFLD and its progression is complex and remains incompletely understood. The progression of the disease involves many factors. Apart from the two hits, the accumulation of TG and the development of fibrosis and necroinflammatory processes, exit numerous molecules associated with these two hits. Among them we can highlight the pro-inflammatory molecules and adiponectins. This review focuses on the growing evidence from both experimental and human studies suggesting a central role of cytokines in the pathogenesis of NAFLD. We review the role of cytokines as key regulators of insulin sensitivity and hepatic lipid overloading, liver injury and inflammation, and fibrosis with an emphasis on potential therapeutic implications.

Biochemical determination of lipid content in hepatic steatosis by the Soxtec method.

AIM: To establish a quantitative method to measure the amount of lipids. METHODS: The livers of 53 male Wistar rats (225 g) with different degrees of hepatic steatosis were studied. This model of hepatic steatosis was based on a high carbohydrate, fat-free modified diet. Biopsies were classified into four grades depending on fat accumulation, using the Kleiner and Brunt classification. Total fat was studied by the Soxtec method (Soxtec 2050 Auto Fat Extraction System), and agreement between both assays was assessed by calculating the kappa coefficient. RESULTS: According to the histological classification, 38% of rats presented grade 0, 21% grade 1, 22% grade 2 and 20% grade 3. The amount of fat per 100 g tissue was 2.60 +/- 0.64 g for grade 0, 3.87 +/- 1.59 g for grade 1, 5.82 +/- 1.37 g for grade 2 and 8.68 +/- 2.30 g for grade 3. Statistically significant differences were found between the mean values for each of the histological grades (P < 0.05). The correlation for the quantification of fat in the liver between both assays was moderate (kappa = 0.60). CONCLUSION: The biochemical quantification of fat in liver tissue by the Soxtec method was correlated with the histological classification, although the agreement between the two tests was only moderate.

Colorectal cancer prognosis twenty years later.

AIM: To evaluate changes in colorectal cancer (CRC) survival over the last 20 years. METHODS: We compared two groups of consecutive CRC patients that were prospectively recruited: Group I included 1990 patients diagnosed between 1980 and 1994. Group II included 871 patients diagnosed in 2001. RESULTS: The average follow up time was 21 mo (1-229) for Group I and 50 mo (1-73.4) for Group II. Overall median survival was significantly longer in Group II than in Group I (73 mo vs 25 mo, P < 0.001) and the difference was significant for all tumor stages. Post surgical mortality was 8% for Group Iand 2% for Group II (P < 0.001). Only 17% of GroupI patients received chemotherapy compared with 50% of Group II patients (P < 0.001). CONCLUSION: Survival in colorectal cancer patients has doubled over the past 20 years. This increase seems to be partly due to the generalization in the administration of chemotherapy and to the decrease of post surgical mortality.