Baseline In Alanine Aminotransferase Research Articles

Comparative effectiveness of sodium-glucose co-transporter-2 inhibitors and dipeptidyl peptidase-4 inhibitors on liver function in patients with type 2 diabetes in Japan: A real-world data analysis.

To compare the effects of sodium-glucose co-transporter-2 inhibitors (SGLT2is) versus dipeptidyl peptidase-4 inhibitors (DPP4is) on liver function in patients with type 2 diabetes (T2D) in Japan. This was a Japanese retrospective cohort study using the RWD Database (1 January 2015 to 24 September 2021). Patients newly treated with an SGLT2i or a DPP4i were matched 1:4 (SGLT2i:DPP4i) using propensity score. The primary endpoint was the change from baseline to 1 year after the index date in alanine aminotransferase (ALT). Secondary endpoints included change from baseline in various laboratory test results, including the Fibrosis-4 (FIB-4) index, aspartate aminotransferase, gamma-glutamyl transpeptidase (GGT), albumin and HbA1c. Endpoints were compared between treatment groups using Welch's t-test in the full population and in subgroups stratified by baseline characteristics. Baseline characteristics of 955 and 3063 matched patients newly treated with an SGLT2i and a DPP4i, respectively, were well balanced. Patients receiving an SGLT2i had significantly greater reductions in ALT, FIB-4 index and GGT and a significantly greater increase in albumin than patients receiving a DPP4i. A significantly greater change from baseline in ALT was observed in the SGLT2i group than in the DPP4i group among subgroups with lower baseline FIB-4 index and HbA1c. In this study, improvements in various measures, including ALT, the FIB-4 index, GGT and albumin, were observed with SGLT2is compared with DPP4is, suggesting that SGLT2is may provide hepatoprotective benefits, including the prevention of liver fibrosis, in patients with T2D in Japan.

Deucravacitinib in moderate to severe plaque psoriasis: liver transaminase results from the phase 3 POETYK PSO program

Introduction: Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, is approved by the US Food and Drug Administration for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. In the phase 3 POETYK PSO-1 and PSO-2 trials, deucravacitinib treatment did not result in clinically meaningful changes across multiple laboratory parameters, including liver transaminases and bilirubin. The current analysis assessed changes in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in the pooled POETYK PSO-1 and PSO-2 population over 16 weeks.
 Methods: In POETYK PSO-1 and PSO-2, patients with moderate to severe plaque psoriasis were randomized 1:2:1 to oral placebo, deucravacitinib 6 mg once daily, or apremilast 30 mg twice daily. Patients randomized to placebo crossed over to deucravacitinib at Week 16 in both trials. This analysis uses data from POETYK PSO-1 and PSO-2 pooled by treatment group from Weeks 0-16. ALT and AST were evaluated as mean levels over time, shifts from baseline in Common Terminology Criteria for Adverse Events (CTCAE version 5.0) severity grade, and fold-increase from upper limit of normal (ULN). Patient-level data were evaluated for those who experienced an elevation ≥3´ ULN for ALT or AST in the first 16 weeks of treatment.
 Results: The pooled POETYK PSO-1 and PSO-2 population included placebo (n=419), deucravacitinib (n=842), and apremilast (n=422). ALT and AST results were available for 413, 833, and 419 patients, respectively. Mean levels of ALT and AST did not change over 16 weeks in any treatment arm. Shifts upwards ≥2 CTCAE grades from baseline in ALT and AST over Weeks 0-16 occurred at a low frequency overall; rates were comparable in patients treated with deucravacitinib (ALT, 0.4%; AST, 0.5%), apremilast (ALT, 0.5%; AST, 0.5%), and placebo (both ALT and AST, 0%). In addition, ALT and AST elevations ≥3´ ULN were infrequent (ALT: placebo 1.2%, deucravacitinib 1.1%, apremilast 0.5%; AST: placebo 0.5%, deucravacitinib 1.6%, apremilast 0.7%). Almost all ALT or AST elevations ≥3´ the ULN between baseline and Week 16 were transient and/or could be traced to underlying liver conditions or concomitant medications.
 Conclusion: Treatment with deucravacitinib, apremilast, or placebo led to increases in ALT or AST levels from baseline over 16 weeks in a few patients; the increases that did occur were potentially related to underlying liver dysfunction, alcohol use, or use of concomitant medications.

A new glutamine synthetase index to evaluate hepatic lobular restoration in advanced fibrosis during anti-HBV therapy.

Hepatic lobular architecture distortion is a deleterious turning point and a crucial histological feature of advanced liver fibrosis in chronic liver diseases. Regression of fibrosis has been documented in chronic hepatitis B (CHB) patients. However, whether lobular architecture could be restored following fibrosis regression after antiviral therapy is still unclear. Glutamine synthetase (GS) is generally expressed by perivenular hepatocytes around hepatic veins (HV). In this study, we defined abnormal lobular architecture (GSPT ) as GS expressing in the vicinity of portal tracts (PT), which denotes parenchymal extinction and lobular collapse. We defined normal lobular architecture (GSHV ) as GS positivity area not approximating PTs. Therefore, we propose a new GS-index, defined as the percentage of GSHV /(GSHV + GSPT ), to evaluate the extent of architectural disruption and restoration. We evaluated 43 CHB patients with advanced fibrosis (Ishak stage ≥4). Posttreatment liver biopsy was performed after 78 weeks of anti-HBV therapy. The median GS-index improved from 7% (interquartile range[IQR]: 0%-23%) at baseline to 36% (IQR: 20%-57%) at Week 78 (p < 0.001). Totals of 22 patients (51%) had significant GS-index improvement from 0% (IQR: 0%-13%) to 55% (IQR: 44%-81%), while the other half had almost no change between 17% (IQR: 0%-33%) to 20% (IQR: 12%-31%). When GS-index78w ≥ 50% was used to define hepatic lobular restoration, 37% of patients (16/43) achieved lobular restoration, with much improvement in alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels (median value of ∆/Baseline in ALT: restored vs. nonrestored was 79.1% vs. 48.8%, p = 0.018; median value of ∆/Baseline in AST: restored vs. nonrestored was 69.1% vs. 32.5%, p = 0.005). More importantly, lobular restoration correlated with fibrosis regression (median value of ∆/Baseline in Ishak stage: restored vs. nonrestored was 25.0% vs. 0%, p = 0.008). Therefore, in the era of antiviral therapy for CHB, restoration of hepatic lobular architecture is achievable in patients with advanced fibrosis. GS-index provides additional insight into fibrosis regression that goes beyond collagen degradation.

A219 AMINOTRANSFERASE IMPROVEMENTS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS ARE ASSOCIATED WITH FIBROSIS REGRESSION IN THE REGENERATE STUDY

Abstract Background The interim analysis of the REGENERATE study showed obeticholic acid (OCA) 25 mg treatment significantly improved liver histology in patients with nonalcoholic steatohepatitis (NASH) and fibrosis. Elevations in aminotransferases are associated with adverse liver-related outcomes in NASH. Aims Here, we evaluate the utility of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) as markers of treatment response to OCA in patients with NASH. Methods Changes in ALT (upper limit of normal [ULN] = 55 U/L) and AST (ULN = 34 U/L) were assessed systematically at 1, 3, 6, 12, and 18 months in 931 NASH patients with stage 2 or 3 fibrosis randomized 1:1:1 to placebo (PBO), OCA 10 mg, or OCA 25 mg in REGENERATE (intent-to-treat population). Least-square mean (LSM) and 95% confidence intervals (CIs) of percentage change from baseline in ALT and AST were analyzed using a mixed-effect repeated-measures model. Results Baseline characteristics were well-balanced across treatment arms: ALT 79±53 U/L; AST 58±36 U/L; 44% F2, 56% F3. Aminotransferase values were &amp;gt; ULN for ALT in 60% (7% &amp;gt; 3xULN), and for AST in 74% (9% &amp;gt; 3xULN) of patients. Rapid, progressive, and dose-dependent improvement in ALT and AST was seen across PBO, OCA 10 mg, and OCA 25 mg arms, which at Month 18 was: ALT LSM change (95% CI), respectively, -4.9% (-10.7–0.9), -23.2% (-28.9– -17.4) and -31.9% (-37.7– -26.1) and in AST, -8.7% (-12.1– -5.2), -13.4% (-16.8– -9.9), and -19.4 (-22.8– -15.9). ALT and AST LSM reductions in OCA arms vs PBO were seen regardless of patient ULN status at baseline. In all patients, ALT/AST reduction was associated with probability of fibrosis regression at Month 18, ranging from approximately 20%, 95% CI (14–27) to 45% (37–54) with any reduction in ALT (&amp;gt; 0%–100%) and between approximately 20%, 95% CI (25–38) to 43% (35–57) with any reduction in AST (&amp;gt; 0%–100%). Interestingly, even with increases of ≤ 40% in AST or ALT there was still a small probability of fibrosis regression (&amp;lt; 20%). Analysis of changes in ALT and AST in individual patients showed that more patients had improvements on OCA than PBO at Month 18 (FIG 1). Conclusions OCA resulted in consistent dose-dependent improvement of ALT and AST. Patients with reductions in ALT or AST were up to twice as likely to have fibrosis improvement than those whose ALT or AST increased. The REGENERATE study is ongoing and will continue through clinical outcomes for verification and description of clinical benefits of OCA in treatment of NASH. Funding Agencies None

Hepatic safety and tolerability of cipargamin (KAE609), in adult patients with Plasmodium falciparum malaria: a randomized, phase II, controlled, dose-escalation trial in sub-Saharan Africa

BackgroundThe novel anti-malarial cipargamin (KAE609) has potent, rapid activity against Plasmodium falciparum. Transient asymptomatic liver function test elevations were previously observed in cipargamin-treated subjects in two trials: one in malaria patients in Asia and one in volunteers with experimentally induced malaria. In this study, the hepatic safety of cipargamin given as single doses of 10 to 150 mg and 10 to 50 mg once daily for 3 days was assessed. Efficacy results, frequency of treatment-emerging mutations in the atp4 gene and pharmacokinetics have been published elsewhere. Further, the R561H mutation in the k13 gene, which confers artemisinin-resistance, was associated with delayed parasite clearance following treatment with artemether–lumefantrine in Rwanda in this study. This was also the first study with cipargamin to be conducted in patients in sub-Saharan Africa.MethodsThis was a Phase II, multicentre, randomized, open-label, dose-escalation trial in adults with uncomplicated falciparum malaria in five sub-Saharan countries, using artemether–lumefantrine as control. The primary endpoint was ≥ 2 Common Terminology Criteria for Adverse Events (CTCAE) Grade increase from baseline in alanine aminotransferase (ALT) or aspartate transaminase (AST) during the 4-week trial.ResultsOverall, 2/135 patients treated with cipargamin had ≥ 2 CTCAE Grade increases from baseline in ALT or AST compared to 2/51 artemether–lumefantrine patients, with no significant difference between any cipargamin treatment group and the control group. Cipargamin exposure was comparable to or higher than those in previous studies. Hepatic adverse events and general safety and tolerability were similar for all cipargamin doses and artemether–lumefantrine. Cipargamin was well tolerated with no safety concerns.ConclusionsThis active-controlled, dose escalation study was a detailed assessment of the hepatic safety of cipargamin, across a wide range of doses, in patients with uncomplicated falciparum malaria. Comparison with previous cipargamin trials requires caution as no clear conclusion can be drawn as to whether hepatic safety and potential immunity to malaria would differ with ethnicity, patient age and or geography. Previous concerns regarding hepatic safety may have been confounded by factors including malaria itself, whether natural or experimental infection, and should not limit the further development of cipargamin.Trial registration ClinicalTrials.gov number: NCT03334747 (7 Nov 2017), other study ID CKAE609A2202

Non-invasive evaluation of response to obeticholic acid in patients with NASH: Results from the REGENERATE study

Non-alcoholic steatohepatitis (NASH) is a chronic, progressive fibrotic liver disease that can lead to cirrhosis. While liver biopsy is considered the reference standard for the histologic diagnosis of NASH and staging of fibrosis, its use in clinical practice is limited. Non-invasive tests (NITs) are increasingly being used to identify and stage liver fibrosis in patients with NASH, and several can assess liver-related outcomes. We report changes in various NITs in patients treated with obeticholic acid (OCA) or placebo in the phase III REGENERATE study. Patients with NASH and fibrosis stage F2 or F3 (n= 931) were randomized (1:1:1) to receive placebo, OCA 10 mg, or OCA 25 mg once daily. Various NITs based on clinical chemistry and/or imaging were evaluated at baseline and throughout the study. Rapid, sustained reductions from baseline in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase levels, as well as in Fibrosis-4 (FIB-4), FibroTest, FibroMeter, and FibroScan-AST scores were observed in OCA-treated vs. placebo-treated patients. Reduction in liver stiffness by vibration-controlled transient elastography was observed in the OCA 25 mg group vs. the placebo group at Month 18. NIT changes were associated with shifts in histologic fibrosis stage. The greatest improvements were observed in patients with ≥1-stage fibrosis improvement; however, improvements in ALT, AST, FIB-4, and FibroTest were also observed in OCA-treated patients whose histologic fibrosis remained stable. Based on the REGENERATE Month 18 interim analysis, rapid and sustained improvements in various NITs were observed with OCA treatment. Dynamic changes in selected NITs separated histologic responders from non-responders. These results suggest that NITs may be useful in assessing histologic response to OCA therapy. CLINICALTRIALS. NCT02548351 LAY SUMMARY: Non-alcoholic steatohepatitis (NASH) is a chronic, progressive liver disease that can lead to cirrhosis. To diagnose and assess liver fibrosis (scarring) in patients with NASH, non-invasive tests (NITs) are increasingly being used rather than liver biopsy, which is invasive, expensive, and can be risky. In the REGENERATE study, which is evaluating the effects of obeticholic acid vs. placebo in patients with NASH, various NITs were also evaluated. This analysis shows that improvements in levels of certain blood components, as well as favorable results of ultrasound imaging and proprietary tests of liver function, were associated with improvements in liver fibrosis after treatment with obeticholic acid, suggesting that NITs may be useful alternatives to liver biopsy in assessing NASH patients' response to therapy.

EDP-305 in patients with NASH: A phase II double-blind placebo-controlled dose-ranging study

EDP-305 is an oral farnesoid X receptor (FXR) agonist under development for the treatment of non-alcoholic steatohepatitis (NASH). Herein, we aimed to assess the efficacy, safety and tolerability of EDP-305 in patients with fibrotic NASH. In this double-blind phase II study, patients with fibrotic NASH (without cirrhosis), diagnosed by historical biopsy or phenotypically, were randomized to EDP-305 1 mg, EDP-305 2.5 mg, or placebo, for 12 weeks. The primary endpoint was mean change in alanine aminotransferase (ALT) from baseline to Week 12, and the key secondary endpoint was mean change in liver fat content from baseline to Week12. Between January 2018 and July 2019, 134 patients were randomized and 132 were evaluated. At Week 12, the least squares mean reductions from baseline in ALT for patients receiving 2.5 mg EDP-305 and 1 mg EDP-305 were -27.9 U/L (95% CI 0.03 to 24.9; p= 0.049) and -21.7 U/L (-5.8 to 18.3: p= 0.304), respectively, compared to -15.4 U/L for those receiving placebo. Absolute liver fat reduction was -7.1% (2.0-7.5; p= 0.0009) with 2.5 mg EDP-305, -3.3% with EDP-305 1 mg, and -2.4% with placebo. The most common (≥5%) adverse events were pruritus, nausea, vomiting, diarrhea, headache, and dizziness. Pruritus occurred in 50.9%, 9.1%, and 4.2% of patients in the 2.5 mg, 1 mg, and placebo groups, respectively, and led to study drug discontinuation in 20.8% of patients in the 2.5 mg group and 1.8% in the 1 mg group. EDP-305 reduced ALT levels and liver fat content, providing support for a longer-term trial assessing histological endpoints in patients with NASH. CLINICALTRIALS. NCT03421431 LAY SUMMARY: Non-alcoholic fatty liver disease is a chronic hepatic disease that can progress to non-alcoholic steatohepatitis (NASH), which is associated with an increased risk of cirrhosis and liver cancer. Results from this phase II study support continued development of EDP-305, an oral farnesoid X receptor agonist, for the treatment of patients with NASH.

Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme

To evaluate the effects of dulaglutide vs placebo on liver and glycaemic/metabolic measurements in a population with Type 2 diabetes and in a subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis. A total of 1499 participants from AWARD-1, AWARD-5, AWARD-8 and AWARD-9 clinical trials were included in this analysis (dulaglutide 1.5 mg, n=971 and placebo, n=528). Thresholds of alanine aminotransferase levels ≥30 IU/l in men and ≥19 IU/l in women were used to determine the subgroup who had non-alcoholic fatty liver/non-alcoholic steatohepatitis. Objectives included changes from baseline to 6 months in: (1) alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels in the overall population and (2) alanine aminotransferase, aspartate transaminase, gamma-glutamyl transpeptidase and glycaemic/metabolic measurements (e.g. HbA1c , fasting serum glucose, body weight, lipids and homeostatic model assessment) in the non-alcoholic fatty liver/non-alcoholic steatohepatitis subgroup. In the overall population at 6 months, dulaglutide significantly reduced alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels vs placebo [least squares mean treatment differences: -1.7 IU/l (95% CI -2.8, -0.6), P=0.003; -1.1 IU/l (95% CI -2.1, -0.1), P=0.037; -6.6 IU/l (95% CI -12.4, -0.8), P=0.025, respectively]. In the subgroup with non-alcoholic fatty liver/non-alcoholic steatohepatitis (alanine aminotransferase levels greater than or equal to the upper limit of normal), mean baseline liver enzyme values were 38.0 IU/l, 27.8 IU/l and 43.9 IU/l for alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase, respectively. In this population, more pronounced reductions from baseline in alanine aminotransferase were observed with dulaglutide vs placebo (-8.8 IU/l vs -6.7 IU/l). In the subgroup of people with alanine aminotransferase levels less than the upper limit of normal, changes from baseline in alanine aminotransferase did not significantly differ between treatment groups (0.0 IU/l vs 0.7 IU/l). Once-weekly dulaglutide improved alanine aminotransferase, aspartate transaminase and gamma-glutamyl transpeptidase levels compared with placebo in a pattern consistent with liver fat reductions. Our results add further weight to the notion that glucagon-like peptide-1 receptor agonists may provide benefit in lowering liver fat in addition to their other metabolic actions.

Improvements in Liver Enzymes with Empagliflozin in the EMPA-REG OUTCOME Trial

Empagliflozin (EMPA) reduces weight and HbA1c in patients with T2DM, but it is not known if it leads to reductions in elevated liver enzymes reflective of liver fat. We investigated the effect of EMPA on liver transaminases in the EMPA-REG OUTCOME trial. Patients with T2DM and established CV disease were randomized to receive EMPA 10 mg, EMPA 25 mg, or placebo (PBO) in addition to standard of care. Changes from baseline in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assessed in all treated patients (N=7020) and in tertiles by baseline ALT or AST. In the EMPA group, ALT decreased from baseline to week 28 and then remained stable. In the PBO group, ALT declined steadily to a lesser extent. Reductions in ALT were greatest in the highest tertile of baseline ALT (tertile 3). In the lowest tertile, changes in ALT were similar between EMPA and PBO. AST decreased from baseline to week 28 and then remained stable with EMPA; there were no relevant changes with PBO. Changes from baseline in AST were generally similar between EMPA and PBO at weeks 28 and 164 in the second and third tertiles, but were greater with EMPA than PBO in the highest tertile by baseline AST. Similar patterns were observed in analysis of pooled Phase III trial data and a trial of EMPA vs. glimepiride. In conclusion, EMPA reduced ALT and AST vs. PBO in the EMPA-REG OUTCOME trial, with greater reductions in ALT than AST, in a pattern consistent with a reduction in liver fat. Table. Changes in ALT and AST in the EMPA-REG OUTCOME trial.ALT (U/L)AST (U/L)Week 28PBOEMPAPBOEMPAAll patientsChange from baseline-0.73 (0.25)-2.96 (0.18)-0.31 (0.20)-1.32 (0.14)Difference vs PBO-2.22 (-2.83, -1.62)***-1.01 (-1.48, -0.54)***Tertile 1Change from baseline1.57 (0.51)1.51 (0.36)1.88 (0.38)1.72 (0.27)Difference vs PBO-0.06 (-1.27, 1.15)-0.16 (-1.08. 0.75)Tertile 2Change from baseline0.29 (0.51)-1.15 (0.35)0.70 (0.36)-0.03 (0.26)Difference vs PBO-1.45 (-2.65, -0.24)*-0.73 (-1.61, 0.14)Tertile 3Change from baseline-3.96 (0.48)-8.33 (0.35)-3.15 (0.34)-4.69 (0.24)Difference vs PBO-4.36 (-5.51, -3.21)***-1.53 (-2.35, -0.72)***Week 164All patientsChange from baseline-1.80 (0.36)-3.(0.25)-0.51 (0.33)-1.17 (0.23)Difference vs PBO-1.26 (-2.12, -0.40)**-0.66 (-1.45, 0.13)Tertile 1Change from baseline2.46 (0.72)2.32 (0.49)2.69 (0.67)2.51 (0.45)Difference vs PBO-0.13 (-1.84, 1.58)-0.18 (-1.75, 1.39)Tertile 2Change from baseline0.04 (0.71)-0.86 (0.48)1.17 (0.61)0.73 (0.42)Difference vs PBO-0.91 (-2.59, 0.77)-0.44 (-1.88, 1.00)Tertile 3Change from baseline-7.33 (0.65)-9.54 (0.46)-4.51 (0.57)-5.50 (0.39)Difference vs PBO-2.22 (-3.78, -0.66)**-0.99 (-2.34, 0.36)Mixed model repeated measures analysis in patients treated with ≥1 dose of study drug based on observed cases. Changes from baseline are adjusted mean (standard error). Differences vs PBO are adjusted mean (95% confidence interval). Tertile 3 indicates the highest tertile by baseline value. All patients: N=2333 for PBO; N=4686 for EMPA. *p&amp;lt;0.05; **p&amp;lt;0.01; ***p&amp;lt;0.001 Disclosure N. Sattar: Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Novo Nordisk A/S, Eli Lilly and Company. Research Support; Self; Boehringer Ingelheim GmbH. Advisory Panel; Self; Amgen Inc.. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Mitsubishi Tanabe Pharma Corporation, Medscape, Sanofi-Aventis Deutschland GmbH. D.H. Fitchett: Advisory Panel; Self; Boehringer Ingelheim GmbH, Eli Lilly and Company. Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Amgen Inc., Sanofi. S. Hantel: Employee; Self; Boehringer Ingelheim GmbH. J.T. George: Employee; Self; Boehringer Ingelheim GmbH. B. Zinman: Consultant; Self; Novo Nordisk A/S, Boehringer Ingelheim Pharmaceuticals, Inc., AstraZeneca, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi, Merck &amp; Co., Inc., Abbott.

Fatty liver in hepatitis C patients post-sustained virological response with direct-acting antivirals.

AIMTo determine steatosis and fibrosis prevalence in hepatitis C patients after a sustained virological response achieved with direct-acting antivirals.METHODSTransient elastography with controlled attenuation parameter (CAP) was used to assess hepatic steatosis post-sustained virological response (SVR); the CAP technology was not available in the United States at study initiation. Liver stiffness/fibrosis was measured before and 47 wk after treatment completion. Patients with genotype 3 and patients with cirrhosis were excluded.RESULTSOne hundred and one patients were included in the study. Post-SVR there were decreases from baseline in alanine aminotransferase (ALT) (63.1 to 17.8 U/L), aspartate aminotransferase (51.8 to 21.5 U/L) and fibrosis score (7.4 to 6.1 kPa) (P < 0.05). Post-SVR, 48 patients (47.5%) had steatosis on CAP; of these, 6.25% had advanced fibrosis. Patients with steatosis had higher body mass index (29.0 vs 26.1 kg/m2), glucose (107.8 vs 96.6 mg/dL), ALT (20.4 vs 15.3 mg/dL), CAP score (296.3 vs 212.4 dB/m) and fibrosis score (7.0 vs 5.3 kPa); P < 0.05. Interestingly, compared to baseline, both patients with and without steatosis had change in fibrosis score post-SVR (7.7 kPa vs 7.0 kPa and 7.0 kPa vs 5.3 kPa); alternatively, (P < 0.05) and therefore patients with steatosis continued to have clinically significant stiffness (≥ 7 kPa).CONCLUSIONFatty liver is very common in hepatitis C virus (HCV) patients post-SVR. These patients continue to have elevated mean fibrosis score (≥ 7 kPa) compared to those without fatty liver; some have advanced fibrosis. Long term follow up is needed to assess steatosis and fibrosis in HCV patients post-SVR.

Efficacy of a Standardized Extract of Prunus mume in Liver Protection and Redox Homeostasis: A Randomized, Double-Blind, Placebo-Controlled Study.

The antioxidant, anti-inflammatory and hepatoprotective effects of Prunus mume (PM) have previously been demonstrated. This double-blind, placebo-controlled study was designed to evaluate the influence of two doses of a food supplement, made of 150 mg of a standardized PM extract on liver transaminases, lipid profile, glycemia, neopterin and reduced and oxidized thiols in plasma and erythrocytes, during a 3-month treatment period, in healthy subjects with transaminases levels between 20 and 40 UI/L. Forty-five subjects (56.0 ± 11.6 years) were enrolled. The results showed a beneficial and statistically significant effect versus placebo of PM extract on liver function, with a decrease versus baseline in alanine aminotransferase (47%), aspartate aminotransferase (7%), gamma-glutamyl transpeptidase (15%) and glycemia (11%). The lipid profile modification was also positive with an increase versus baseline in HDL cholesterol (13%), and a decrease in LDL/HDL ratio (12%) and triglycerides (8%). The antioxidant action of PM translated into a decrease in oxidized glutathione, reduced/oxidized cysteine-glycine, oxidized cysteine (intracellular pro-oxidant) and neopterin (inflammation biomarker), was associated with an increase in reduced glutathione. These results are in favor of the use of a standardized extract of P. mume for the support of liver health and prevention of common metabolic and inflammation-based diseases. Copyright © 2016 John Wiley & Sons, Ltd.

Recognizing Acute Hepatitis C in Hemodialysis Patients

Dear Sir, Hepatitis C virus (HCV) infection is common in hemodialysis patients and the relatively lower alanine aminotransferase (ALT) values in acute [1] and chronic hepatitis C infections [2, 3] of these patients make the diagnosis more difficult. Acute hepatitis C in hemodialysis patients can be treated by interferon (IFN) therapy [4], although the response rates are lower than in patients with normal renal function [5]. Lampe et al. [6] emphasized the role of recognizing acute HCV infection in hemodialysis patients by comparing the ALT level to the patient’s ALT baseline values. A 53-year-old male was under hemodialysis for 10 years due to hypertensive nephropathy. Hemodialysis was applied 3 times weekly and the serology of HCV and hepatitis B virus (HBV) and biochemistry were checked monthly. When his ALT level was measured as 29 U/l, which seemed significantly higher than his previous measurements (4, 5, 7, 4, and 6 IU/l, respectively), HCV and HBV serology was repeated. Although antiHCV remained negative and anti-HBs was positive, his ALT level was serially checked. Within 1 month, his ALT level increased to 114 U/l and anti-HCV was detected as positive. He remained symptomless. HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) was measured as 7,130 IU/l and the genotype study remained an indeterminate result. HCV RNA studies obtained 2 weeks apart gave comparable results of 5,150 and 6,120 IU/l. His ALT level increased to a maximum level of 155 U/l and then tended to decrease (Fig. 1). He was initiated with pegylated IFN alpha-2a 135 lg weekly. The study of Lemos et al. [7] emphasized the role of monitoring ALT for recognizing acute HCV infection, since the patients are almost always asymptomatic, as in our case. They observed ALT elevation in all patients and the median peak ALT was 4.79 the upper limit of normal (range: 1.1–47.4). The median interval between ALT elevation and anti-HCV seroconversion was 1 month. What is the upper limit of normal of ALT in hemodialysis patients? Espinosa et al. [1] reported the upper limit for ALT in hepatitis-free hemodialysis patients as 27 IU/l. The sensitivity of a mean ALT value C27 IU/l in the diagnosis of HCV viremia was 50% and the specificity was 100%. They reported the positive predictive value of this test in the diagnosis of hepatitis C viremia as 100% and concluded that a high ALT level can constitute an excellent tool in predicting viremia in hemodialysis patients, once other causes of liver disease have been excluded. In two studies including 19 and 32 patients with acute hepatitis C under hemodialysis, the peak median ALT levels of the patients were 345 IU/l (range: 24–1,473) [8] and 169 IU/l (range: 22–325), respectively. Another study used the definition of acute HCV infection as ‘‘a rise of twice the normal or more of serum ALT level compared to baseline in addition to a positive serum anti-HCV antibody’’ [4]. To conclude, recognizing acute HCV infection is critical, since treatment can prevent progressive liver damage by a considerable part. The ALT levels are not expected to increase by several times, so any increase compared to his/ her ‘‘normal’’ values should be considered as a warning. R. Ozaras (&) M. Yilmaz B. Mete A. Demirel Department of Infectious Diseases, Cerrahpasa Medical Faculty, University of Istanbul, Aksaray, Istanbul 34303, Turkey e-mail: rozaras@yahoo.com

The effects of exogenous l-carnitine on lipid peroxidation and tissue damage in an experimental warm hepatic ischemia-reperfusion injury model

Background: l-Carnitine is the essential endogenous factor for the transport of long-chain fatty acids from the cytoplasm to within the mitochondrion where the β-oxidation process takes place. l-Carnitine is a superoxide scavenger and an antioxidant that possesses an anti-ischemic action and a stabilizing effect on cell membranes. It may be of help in liver ischemia reperfusion injury. Results regarding the effects of l-carnitine on liver ischemia and reperfusion injury are few and conflicting. Objective: The aim of this study was to investigate the efficacy of exogenous l-carnitine on lipid peroxidation and protecting liver at different stages of experimental total warm hepatic ischemia-reperfusion (TWHIR) procedure in rats. Methods: This experimental study in healthy, weanling, male Wistar rats (weighing 180–200 g) was conducted at the Experimental Animal Research Laboratory of the Faculty of Medicine of Mersin University, Mersin, Turkey. Rats were randomly divided into 5 groups: (A) Control group; (B) TWHIR procedure only; (C) l-carnitine administered 2 hours before the TWHIR procedure; (D) l-carnitine administered just before the TWHIR procedure; and (E) l-carnitine administered after total warm hepatic ischemia but just before the reperfusion procedure. Total warm hepatic ischemia (via the Pringle maneuver) and reperfusion were performed for 45 and 30 minutes, respectively. l-Carnitine (200 mg/kg) was administered intravenously. At the end of each procedure a blood sample was drawn and total hepatectomy was performed following reperfusion. Malondialdehyde (MDA) and myeloperoxidase (MPO) levels of both plasma and liver tissue, total antioxidant capacity (TAOC), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in plasma, and histopathologic examination were analyzed to assess lipid peroxidation and damage in liver tissue. Results: Thirty-four rats (mean [SD]age, 59.26 [1.2]days; mean [SD] weight, 194.1 [5.1] g) were used in the study. There was a significant difference observed between groups A (n = 5) and B (n = 5) for all evaluation parameters. The TWHIR procedure performed in group B was associated with significant increases versus baseline in ALT, AST, MDA, and MPO in plasma, and MDA and MPO in liver tissue, but a significant decrease of TAOC in plasma. ALT, AST, serum and liver MDA, and MPO levels of group B were significantly higher than all groups administered l-carnitine. l-Carnitine administration between total warm hepatic ischemia and reperfusion was associated with a significant attenuation in all parameters. The liver MDA levels of groups C (n = 8) and D (n = 8) were significantly lower than that of group E (n = 8) (mean [SD]: C, 16.53 [3.32] and D, 18.28 [1.67] vs E, 23.05 [3.52]; P = 0.001 and P = 0.016, respectively). The mean (SD) liver MPO level of group C (1.09 [0.16]) was significantly lower than that of groups D (2.12 [0.25]) and E (2.11 [0.28]) (both, P = 0.001). The TAOC of group B (0.77 [0.12]) was significantly lower than that of groups C (1.34 [0.19]) and D (1.08 [0.20]) ( P = 0.001 and P = 0.015, respectively). The TAOC of group C was significantly higher than that of the other l-carnitine groups (E, 0.94 [0.13]) ( P = 0.023 vs group D; and P = 0.001 vs group E). Histopathologic scores of groups A, C, and E were significantly lower than that of group B, but the difference between groups B and D was not statistically significant. Conclusions: In this experimental study, administration of exogenous l-carnitine was associated with significantly decreased lipid peroxidation in plasma and liver tissue when administered prior to a TWHIR procedure. In addition, l-carnitine seemed to be more effective with regard to decreasing lipid peroxidation in liver tissue when administered before warm hepatic ischemia. l-Carnitine was associated with significantly decreased leukocyte sequestration in plasma and liver tissue. A significant increase in TAOC was associated with l-carnitine administered prior to ischemia. These observations suggest that l-carnitine might have a protective effect against ischemia-reperfusion injury in rat liver tissue.

Efficacy and safety profile of fenofibrate-coated microgranules 130 mg, with and without food, in patients with hypertriglyceridemia and the metabolic syndrome: An 8-week, randomized, double-blind, placebo-controlled study

Background:The limited bioavailability of certain fenofibrate formulations necessitates administration with food, raising concerns about efficacy and compliance. There is a need for new formulations that have improved bioavailability and eliminate the requirement for administration with food. Objective:The aim of this study was to assess the food-related efficacy of a new formulation of micronized fenofibrate coated on inert microgranules (FF-μG) for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome. Methods:This was a randomized, double-blind, placebo-controlled, double-dummy, parallel-group study in patients who had fasting triglyceride (TG) concentrations ≥300 mg/dL and <1000 mg/dL and met National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome. A 6-week washout and diet lead-in period was followed by an 8-week treatment period. Eligible patients were randomized to receive either FF-μG 130 mg with food, FF-μG 130 mg without food, or placebo every day for 8 weeks. The primary end point was the mean percent change in TG levels from baseline to the end of treatment; changes in other lipid end points were also assessed. Safety profiles were assessed based on adverse-event reports, changes in clinical laboratory values and vital signs (including electrocardiography), and the findings of physical examinations. Results:One hundred forty-six patients took part in the study: 54 received FF-μG 130 mg with food, 42 received FF-μG 130 mg without food, and 50 received placebo. The groups were similar in terms of mean age (56 years), sex (59.5%–63.0% men; 37.0%–40.5% women), race (83.3%–100% white), mean body weight (92 kg), mean height (172 cm), mean fasting baseline TG concentrations (480 mg/dL), and other components of the metabolic syndrome. The 2 FF-μG groups (with and without food) showed similar improvements in the dyslipidemia associated with the metabolic syndrome: TG levels decreased a mean of 36.7% and 36.6%, respectively (P < 0.001 vs placebo). The overall frequency of adverse events was similar in the 2 FF-μG groups and did not differ significantly from placebo (63.0%, 61.9%, and 52.0%, respectively). Gastrointestinal disturbances (eg, diarrhea, dyspepsia) occurred more frequently in the 2 FF-μG groups compared with the placebo group (31.5%, 26.2%, and 12.0%; P = NS). Significant increases from baseline in alanine aminotransferase were seen in both FF-μG groups (mean [SEM], 3.77 [2.60] and 11.69 [7.42] U/L, respectively; P ≤ 0.05 vs placebo); however, these increases were considered clinically significant in only 5 cases, none of them requiring discontinuation of study drug. Conclusions:This study found no inequivalence in the TG-lowering effects of the 2 fenofibrate regimens compared with placebo. Both regimens were well tolerated. Thus, FF-μG 130 mg administered without regard to meals appears to be efficacious and well tolerated for the treatment of hypertriglyceridemia in patients exhibiting the metabolic syndrome.