Changes In Alanine Aminotransferase Levels Research Articles

A285 CHANGE IN ALT DURING MODIFIED OPTIFAST WEIGHT LOSS PROGRAM IN INDIVIDUALS AT RISK FOR NON-ALCOHOLIC FATTY LIVER DISEASE

Abstract Background Obesity is linked to various health complications, including diabetes, metabolic syndrome, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent cause of abnormally high alanine aminotransferase (ALT) levels. ALT is released at higher levels during hepatocellular injury and represents a simple, low cost and non-invasive method of assessing liver damage. There are conflicting data on ALT response to weight loss between men and women, with some evidence of transient increase in ALT levels in women. Purpose The aim of this study was to assess the impact of a dietary weight loss intervention with Optifast on ALT in patients with obesity who have baseline elevated ALT levels. Method This was a retrospective cohort study of Ontario adults who participated in a 26 week weight loss program, including 6 or 12 weeks of low-calorie liquid diet meal replacement with Optifast 900® (Nestlé, Canada), between 1992 and 2015. We included patients with elevated baseline ALT levels, defined by > 40 U/L, who had at least one follow-up ALT between week 15 and 26. We excluded patients with nonadherence to dietary intervention, established liver disease or using hepatotoxic drugs, excessive alcohol intake (>11U/wk for females and >14U/wk for males), and insufficient data to calculate FIB-4. The primary outcome was change in ALT levels, measured by normalization (post-intervention ALT < 40 U/L), percentage decrease and absolute decrease. Multiple linear regressions were obtained for the relationship between ALT changes and age, sex, body mass index (BMI) and FIB-4. All analyses were conducted in SPSS. P value of ≤0.05 was considered statistically significant. Result(s) 444 patients met study criteria. Mean age was 47.1 years +/- 10.9, 49 % of patients were female, and mean BMI was 43.5 kg/m2 +/- 7.9. All patients lost weight, with mean weight loss 27.3 kg +/- 11.5 and a mean 20.7% decrease from baseline weight. Mean ALT at baseline was 58.9 U/L +/- 25.4 and mean ALT post intervention was 32.3 U/L +/- 28.1 (p <0.01). 85.1% of patients had normalization of ALT. Mean % decrease in ALT was 41.9% and mean absolute decrease in ALT was 26.6 U/L +/- 25.4. Younger age and higher baseline FIB-4 were significantly associated with a larger decrease in ALT levels, while sex and initial BMI were not significantly associated with changes in ALT. Conclusion(s) In patients with obesity and baseline elevated ALT, dietary weight loss intervention with Optifast leads to ALT normalization in most patients, regardless of sex. Younger age at baseline and higher baseline FIB-4 are significantly associated with greater decrease in ALT. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared

S1208 Prevalence of Hepatitis B Virus (HBV) and Latent Tuberculosis Co-Infection and Risk of Drug-Induced Liver Injury Across Two Large HBV Cohorts in the United States

Introduction: Screening for hepatitis B virus (HBV) infection prior to starting tuberculosis (TB) treatment is important because HBV-TB co-infected patients have increased risk of drug-induced liver injury (DILI). However, there are limited real-world data on epidemiology of HBV-latent TB infection (LTBI) in the US. We evaluated prevalence and predictors of HBV-LTBI co-infection and DILI risk among two distinct US chronic HBV cohorts. Methods: Adults with chronic HBV from 2010–2020 were identified among the Chronic Hepatitis Cohort Study (CHeCS) and the Veterans Affairs national chronic HBV cohort (VA-HBV). HBV-LTBI co-infection was identified based on laboratory data (TB-Quantiferon), ICD-9/10 codes, and prescription data. DILI was identified based on established definitions that incorporated ICD-9/10 codes and changes in alanine aminotransferase levels following start of LTBI treatment. Results: Among 6,019 chronic HBV patients in the CHeCS cohort (44% female; 47% age 18-39y, 39% age 40-59y, 14% age >60y; 47% Asian, 20% non-Hispanic white (NHW), 14% African American (AA), 1% Hispanic; 3% HCV; 6% HIV), 9.1% were tested for TB, among which 7.7% had HBV-LTBI. Significantly higher odds of HBV-LTBI were observed in women vs. men (13% vs. 5%, OR 2.57, 95% CI 1.36-4.85 p< 0.01), but no other significant differences were observed. Among HBV-LTBI patients that received LTBI treatment, 28.6% developed DILI. Among 12,928 predominantly U.S.-born chronic HBV patients in the VA-HBV cohort (94% male; 6% age 18-39y, 30% age 40-59y, 65% age >60y; 10% Asian, 42% AA, 39% NHW, 2% Hispanic; 86% US-born; 15% HCV; 2.3% HIV), 14.7% were tested for TB, among which 14.5% had HBV-LTBI. Significantly higher odds of HBV-LTBI were observed in AA vs. NHW (15% vs. 12%, OR 1.70, 95% CI 1.18-2.43, p< 0.01) and in non-US born vs. US-born (25% vs. 13%, OR 2.13, 95% CI 1.34-4.00, p< 0.05). Among HBV-LTBI patients that received LTBI treatment, the proportion of patients that developed DILI was 3.6%. Conclusion: Among two large distinct US cohorts of chronic HBV patients, testing for LTBI was infrequent despite relatively high prevalence of HBV-LTBI. While nearly 30% of HBV-LTBI patients in the predominantly Asian and younger CHeCS cohort developed DILI, only 3.6% in the predominantly older, US born VA-HBV cohort developed DILI. Better understanding risk factors for DILI among HBV-LTBI patients can help guide clinicians to appropriately modify LTBI treatment to reduce DILI risk. Supported by ACG Clinical Research Award (Figure).Figure 1.: Prevalence of HBV-LTBI Co-Infection and Risk of DILI.

Randomized placebo-controlled trial of losartan for pediatric NAFLD.

Background and AimsTo date, no pharmacotherapy exists for pediatric NAFLD. Losartan, an angiotensin II receptor blocker, has been proposed as a treatment due to its antifibrotic effects.Approach and ResultsThe Nonalcoholic Steatohepatitis Clinical Research Network conducted a multicenter, double‐masked, placebo‐controlled, randomized clinical trial in children with histologically confirmed NAFLD at 10 sites (September 2018 to April 2020). Inclusion criteria were age 8–17 years, histologic NAFLD activity score ≥ 3, and serum alanine aminotransferase (ALT) ≥ 50 U/l. Children received 100 mg of losartan or placebo orally once daily for 24 weeks. The primary outcome was change in ALT levels from baseline to 24 weeks, and the preset sample size was n = 110. Treatment effects were assessed using linear regression of change in treatment group adjusted for baseline value. Eighty‐three participants (81% male, 80% Hispanic) were randomized to losartan (n = 43) or placebo (n = 40). During an enrollment pause, necessitated by the 2019 coronavirus pandemic, an unplanned interim analysis showed low probability (7%) of significant group difference. The Data and Safety Monitoring Board recommended early study termination.Baseline characteristics were similar between groups. The 24‐week change in ALT did not differ significantly between losartan versus placebo groups (adjusted mean difference: 1.1 U/l; 95% CI = −30.6, 32.7; p = 0.95), although alkaline phosphatase decreased significantly in the losartan group (adjusted mean difference: −23.4 U/l; 95% CI = −41.5, −5.3; p = 0.01). Systolic blood pressure decreased in the losartan group but increased in placebo (adjusted mean difference: −7.5 mm Hg; 95% CI = −12.2, −2.8; p = 0.002). Compliance by pill counts and numbers and types of adverse events did not differ by group.ConclusionsLosartan did not significantly reduce ALT in children with NAFLD when compared with placebo.

803-P: The Association between Empagliflozin and Changes in Alanine Aminotransferase Levels: Data from the Association of British Clinical Diabetologists (ABCD) Audit Programme

Background: Nonalcoholic fatty liver disease (NAFLD) commonly co-exists with type 2 diabetes. Alanine aminotransferase (ALT) levels are known to correlate, to some degree, with liver inflammation. Methods: All data submitted to the ABCD nationwide empagliflozin audit programme were included if they had relevant baseline and follow-up data and were then stratified by baseline ALT for two analyses: 1) using gender-specific reference ranges; 2) by normal ( Results: 6510 datasets were included with mean(±SD) age 60.0yrs(±10.4), 61.2% male, BMI 34.2kg/m2(±6.5), HbA1c 9.3%(±1.6) and weight 98.4kg(±21.23). For the entire population, median ALT changed by -4 U/L (95% CI -4, -4; P Conclusion: Our data demonstrate changes in ALT associated with empagliflozin use. Decreases of a significantly greater magnitude are noted in those with raised ALT at baseline. Empaglifozin may provide benefit in NAFLD. Disclosure T. S. J. Crabtree: Other Relationship; Self; Novo Nordisk, Sanofi. J. Elliott: Advisory Panel; Self; Abbott, Speaker’s Bureau; Self; Abbott, Dexcom, Inc., Insulet Corporation, Novo Nordisk. A. Bickerton: None. I. W. Gallen: None. K. Dhatariya: Speaker’s Bureau; Self; Novo Nordisk. M. L. Cull: None. A. Evans: None. S. M. Phillips: None. R. E. Ryder: Other Relationship; Self; Novo Nordisk. Funding Boehringer Ingelheim

Changes in alanine aminotransferase levels after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in HIV-positive people without viral hepatitis in the Swiss HIV Cohort Study.

We previously demonstrated an association between tenofovir disoproxil fumarate (TDF) and chronic liver enzyme elevation in the D:A:D study. The objective of the study was to assess changes in alanine aminotransferase (ALT) levels after switching from TDF to tenofovir alafenamide (TAF). We included Swiss HIV Cohort Study participants who switched from TDF to TAF withtwo or more ALT values in the 24months before andtwo or more values in the 24months after replacing TDF with TAF. Individuals with replicating viral hepatitis were excluded. Uni- and multivariable linear mixed models were used to explore changes in ALT values associated with switching from TDF to TAF, and to assess potential modifying effects. A total of 1712 participants were included, contributing 6169 ALT values before and 5482 after switching. Median (interquartile range, IQR) age was 50(42-57) years, and 75% were male. Median (IQR) ALT was 28(22-38) U/L before and 24 (19-32) U/L after replacing TDF with TAF. ALT values decreased by 3.7 U/L (95% confidence interval: 3.2-4.2) after the switch. The median drop was larger in patients with chronic ALT elevation (defined astwo or more elevated values for≥6months) compared with patients with normal ALT values (17.8 vs. 3.3 U/L, P<0.001). We did not identify any major effect modifications of the ALT change with any of the potential variables studied. Replacing TDF with TAF in HIV-monoinfected people led to a significant decrease in ALT values. Findings were not significantly affected by known risk factors for hepatotoxicity.

Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: A single-arm, pilot study.

Dyslipidemia (DL) is commonly associated with non-alcoholic fatty liver disease (NAFLD). Pemafibrate, a selective peroxisome proliferator activated receptor α modulator (SPPARMα), has been shown to improve liver function among patients with DL. The aim of this single-arm prospective study is to evaluate the efficacy of pemafibrate in NAFLD patients with DL. Twenty NAFLD patients with DL who received pemafibrate (0.1mg) twice a day for 12weeks were prospectively enrolled in this study. The primary end-point was change in serum alanine aminotransferase (ALT) levels from baseline to week 12. Serum ALT levels decreased from 75.1IU/L at baseline to 43.6IU/L at week 12 (P = 0.001). Significant improvements in triglyceride, high-density lipoprotein cholesterol, total fatty acid, saturated fatty acid (SFA), and unsaturated fatty acid were also noted. The serum level of remnant-like protein cholesterol, SFA, and polyunsaturated/saturated fatty acid ratio (PUFA/SFA ratio) at baseline were correlated with change in ALT level (r = -0.53, r = -0.57, and r = 0.46, respectively). Change in PUFA and change in PUFA/SFA ratio were negatively correlated with change in ALT level (r = -0.49 and r = -0.53). No hepatic or renal adverse events were reported. Selective peroxisome proliferator activated receptor α could be a promising novel agent for treatment of NAFLD patients with DL by regulating fatty acid composition. A further long-term large-scale trial is warranted to confirm the efficacy of SPPARMα on NAFLD with DL.

Improved liver function in patients with cirrhosis due to chronic hepatitis C virus who achieve sustained virologic response is not accompanied by increased liver volume.

BackgroundSerum albumin level improves in patients with chronic hepatitis C virus (HCV) infection who achieve sustained virologic response (SVR) with antiviral therapy. However, it remains controversial whether liver volume increases along with SVR.MethodsPatients with chronic HCV infection with a history of hepatocellular carcinoma (HCC) who achieved SVR with anti-HCV treatment from March 2003 to November 2017 were enrolled. Patients were followed up with periodic computed tomography (CT) scans to detect HCC recurrence. Patients who underwent treatment for HCC recurrence within 1 year after initiation of anti-HCV treatment were excluded. Laboratory data, including alanine aminotransferase (ALT) level, serum albumin level, and platelet count, were collected at baseline and timepoints after treatment initiation. Liver volume was evaluated at baseline and 24 and 48 weeks after treatment initiation using a CT volume analyzer. A linear mixed-effects model was applied to analyze the chronologic change in liver volume. The correlations between changes in ALT level, albumin level, and liver volume were also evaluated.ResultsOf 108 enrolled patients, 78 had cirrhosis. Serum albumin level continued to increase through 48 weeks after treatment initiation. A significant increase in liver volume was observed only in patients without cirrhosis (P = 0.005). There was a significant correlation between ALT level decrease and albumin level increase (P = 0.018).ConclusionsImproved liver albumin production with SVR was contributed by improved liver cell function rather than increased liver volume in patients with cirrhosis.

Efficacy and safety of PERIOdontal treatment versus usual care for Nonalcoholic liver disease: protocol of the PERION multicenter, two-arm, open-label, randomized trial

BackgroundWe report the first protocol for a multicenter, randomized comparison study to compare the efficacies of periodontal scaling and root-planing treatment against that of tooth-brushing treatment for nonalcoholic fatty liver disease (NAFLD) (PERION: PERIOdontal treatment for NAFLD). Nonalcoholic steatohepatitis (NASH) is an advanced form of NAFLD, which can progress to cirrhosis and hepatocellular carcinoma. Increased endotoxemia is associated with the progression of NAFLD. Periodontal bacteria possess endotoxins; Porphyromonas gingivalis is well-known as a major pathogenic bacterium in periodontitis, and serum antibody levels for P. gingivalis are high in patients with periodontitis. Several reports have indicated that P. gingivalis is related to NAFLD. This study aims to investigate the effect of periodontal treatment for liver damage, P. gingivalis infection, and endotoxemia on patients with NAFLD.MethodsWe will include adult patients (20–85 years old) with NAFLD, alanine aminotransferase (ALT) ≥ 40 IU/L, and equivalent steatosis grade ≥ 1 (target sample size, n = 40 patients; planned number of patients with outcome data, n = 32). Participants will be randomly assigned to one of two groups: a scaling and root-planing group or tooth-brushing as the usual group. The primary outcome will be the change in ALT levels from baseline to 12 weeks; the key secondary outcome will be the change in the serum immunoglobulin G (IgG) antibody titer for P. gingivalis at 12 weeks.DiscussionThis study should determine whether periodontal treatment decreases liver damage, P. gingivalis infection, and endotoxemia in patients with NAFLD.Trial registrationUniversity Hospital Medical Information Network (UMIN) Clinical Trials Registry, ID: UMIN000022079.

Effects of sodium-glucose co-transporter-2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi-institutional cohort study.

Clinical trials have indicated that sodium-glucose co-transporter-2 (SGLT2) inhibitors have a favourable effect on serum alanine aminotransferase (ALT) levels in people with type 2 diabetes (T2D), but supporting evidence from real-world studies is lacking. We identified patients with T2D who initiated SGLT2 inhibitors during the period 2016 to 2017 from Chang Gung Research Database, which covers 1.3 million individuals from seven hospitals (6% of the Taiwan population). We classified patients by baseline ALT level and evaluated changes in ALT values from baseline to 1 year after initiation of SGLT2 inhibitors. We identified 11 690 new users of SGLT2 inhibitors with a mean (SD) age of 59.3 (11.8) years. The mean (SD) glycated haemoglobin and ALT levels were 8.9 (1.7)% and 34.7 (28.9) U/L at baseline, respectively. The mean change in ALT levels was -5.0 U/L (95% confidence interval [CI] -6.4, -3.5) 1 year after initiation of SGLT2 inhibitors. In patients with ALT levels ≤1× the upper limit of normal (ULN), the change in ALT levels was 1.6 U/L (95% CI -0.1, 3.4), while in those with ALT levels >1× ULN, the change in ALT levels was -26.5 U/L (95% CI -28.6, -24.3). The higher the baseline ALT level, the greater the decline after SGLT2 inhibitor treatment. Our findings suggest the initiation of SGLT2 inhibitors for T2D management could improve serum ALT levels in clinical practice, particularly in patients with especially high ALT levels.

Effects of Melatonin on Metabolic Abnormalities in HIV Patients Treated with Antiretroviral Drugs

Aims: Highly Active Antiretroviral Therapy (HAART) is the current care standard for treating patients with HIV/AIDS. Although HAART has is the only regimen potent enough to decrease viral load, adverse events may limit its efficacy. Metabolic disorders are common in patients treated with HAART. Melatonin (N-acetyl-5-methoxytryptamine) was initially thought to be exclusively of pineal origin but recent studies have shown that melatonin synthesis may occur in several cells and organs. Melatonin has been shown to have a variety of functions and research during the last decade has proven the indole to be a direct free radical scavenger and indirect antioxidant. Due to these activities and possibly others that remain to be defined, melatonin has been shown to reduce toxicity and increase the efficacy of a large number of drugs. This study evaluated the effects of melatonin supplementation (6mg / day / 30 days) in AIDS patients using antiretroviral therapy (HAART).&#x0D; Methodology: Current study was carried out in a double-blind, placebo-controlled and completely randomized design. AIDS patients who had metabolic alterations were selected. Patients were divided into two groups: Group I (HAART) consisted of patients receiving placebo once a day in the evening. Group II (HAART+ Melatonin) comprised patients who received the melatonin (6 mg) once a day in the evening for one month. Clinical and laboratorial evaluation was performed before and after 30 days. Clinical evaluation was performed to assess the patients´ overall clinical state. Patients were instructed to report any complications. Laboratorial evaluation was performed. Glucose levels were determined by glucose oxidase method and ELISA (Genway Biotechnology, USA), respectively, following manufacturer’s instructions. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were performed by the kinetic colorimetric method; triglycerides, total cholesterol and creatinine were performed by enzymatic colorimetric method, both provided by Gold Analisa Diagnóstica Ltda. &#x0D; Results: Sixty patients who had some metabolic abnormalities (glucose levels above 100.0 mg/dL or total cholesterol above 200 mg/dL or triglycerides above 200 mg/dL) participated in the study. All had been using HAART therapy for at least five years, with an average 15-year infection period. Patient´s age ranged between 35 and 49 years, with a mean of 43.7 years. Fasting glucose was significantly lower in subjects in Group I treated with melatonin when compared with subjects included in the control group not treated with melatonin after one month of treatment. Levels of blood glucose were 23% lower in patients who used melatonin, with reference rates after one month of treatment. Current study revealed that 40% (12/30) of the patients had changes in AST liver enzymes (&gt; 38 U/I), 30% (9/30) had changes in ALT levels (&gt; 38 U/I) and 30% (9/30) had GGT levels (&gt; 40 U/I). Results obtained after the use of melatonin suggest melatonin activity on the liver. Significant differences between groups in plasma cholesterol indicate that melatonin exerted better improvement of blood lipid composition. Melatonin would lower cholesterol in liver and decrease plasma cholesterol. Above all, melatonin could decrease oxidative stress and improve dyslipidemia.&#x0D; Conclusion: Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efficacy of the drugs, its use may be important and significant as a combination therapy with HAART. Current study which investigated the effect of melatonin associated with antiretroviral treatment demonstrated beneficent effects on metabolic abnormalities in AIDS patients.

Effect of a Low Free Sugar Diet vs Usual Diet on Nonalcoholic Fatty Liver Disease in Adolescent Boys

Pediatric guidelines for the management of nonalcoholic fatty liver disease (NAFLD) recommend a healthy diet as treatment. Reduction of sugary foods and beverages is a plausible but unproven treatment. To determine the effects of a diet low in free sugars (those sugars added to foods and beverages and occurring naturally in fruit juices) in adolescent boys with NAFLD. An open-label, 8-week randomized clinical trial of adolescent boys aged 11 to 16 years with histologically diagnosed NAFLD and evidence of active disease (hepatic steatosis >10% and alanine aminotransferase level ≥45 U/L) randomized 1:1 to an intervention diet group or usual diet group at 2 US academic clinical research centers from August 2015 to July 2017; final date of follow-up was September 2017. The intervention diet consisted of individualized menu planning and provision of study meals for the entire household to restrict free sugar intake to less than 3% of daily calories for 8 weeks. Twice-weekly telephone calls assessed diet adherence. Usual diet participants consumed their regular diet. The primary outcome was change in hepatic steatosis estimated by magnetic resonance imaging proton density fat fraction measurement between baseline and 8 weeks. The minimal clinically important difference was assumed to be 4%. There were 12 secondary outcomes, including change in alanine aminotransferase level and diet adherence. Forty adolescent boys were randomly assigned to either the intervention diet group or the usual diet group (20 per group; mean [SD] age, 13.0 [1.9] years; most were Hispanic [95%]) and all completed the trial. The mean decrease in hepatic steatosis from baseline to week 8 was significantly greater for the intervention diet group (25% to 17%) vs the usual diet group (21% to 20%) and the adjusted week 8 mean difference was -6.23% (95% CI, -9.45% to -3.02%; P < .001). Of the 12 prespecified secondary outcomes, 7 were null and 5 were statistically significant including alanine aminotransferase level and diet adherence. The geometric mean decrease in alanine aminotransferase level from baseline to 8 weeks was significantly greater for the intervention diet group (103 U/L to 61 U/L) vs the usual diet group (82 U/L to 75 U/L) and the adjusted ratio of the geometric means at week 8 was 0.65 U/L (95% CI, 0.53 to 0.81 U/L; P < .001). Adherence to the diet was high in the intervention diet group (18 of 20 reported intake of <3% of calories from free sugar during the intervention). There were no adverse events related to participation in the study. In this study of adolescent boys with NAFLD, 8 weeks of provision of a diet low in free sugar content compared with usual diet resulted in significant improvement in hepatic steatosis. However, these findings should be considered preliminary and further research is required to assess long-term and clinical outcomes. ClinicalTrials.gov Identifier: NCT02513121.

Melatonin reduces toxicity induced by HAART in mice and HIV patients

Aims: Highly Active Antiretroviral Therapy (HAART) is the current care standard for treating patients with HIV/AIDS. Although HAART has is the only regimen potent enough to decrease viral load, adverse events may limit its efficacy. HAART-associated major toxic effects: neuropathy, myopathy, pancreatitis, hepatic steatosis, lactic acidosis and lipoatrophy, metabolic complications (insulin resistance and hyperlipidemia).Melatonin (N-acetyl-5-methoxytryptamine), the neuro-hormone synthetized during the night, has seen an unexpected extension of its functional implications toward type 2 diabetes development, sleep disturbances and depression. Melatonin has been shown to reduce the toxicity and increase the efficacy of a large number of drugs. Objective: This study evaluated the effects of melatonin supplementation (6mg / day / 30 days) in mice treated with antiretroviral therapy and AIDS patients using antiretroviral therapy (HAART). Material and Methods: For animal experiments mice were divided into experimental groups with 12 animals each: (I) animals treated with antiretroviral therapy for 15 days, (II) animals untreated animals treated with antiretroviral therapy and melatonin 6 mg/kg/day for 15 days, (III) untreated animals. Body weight, water intake and ration, excretion products and behavior were clinically assessed before and after treatment; further, serum cholesterol, triglycerides, hepatic enzymes (AST, ALT, GGT), creatinine, were evaluated by specific methods. For patient evaluation the study was carried out in a double-blind, placebo-controlled and completely randomized design. AIDS patients who had metabolic alterations were selected. Patients were divided into two groups: Group I (HAART) consisted of patients receiving placebo once a day in the evening. Group II (HAART+ Melatonin) comprised patients who received the melatonin (6 mg) once a day in the evening for one month. Clinical, emotional and laboratorial evaluation was performed before and after 30 days. Clinical evaluation was performed to assess the patients´ overall clinical state. Patients were instructed to report any complications. Laboratorial evaluation was performed. Glucose levels were determined by glucose oxidase method and ELISA (Genway Biotechnology, USA), respectively, following manufacturer’s instructions. Plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and gamma glutamyl transferase (GGT) were performed by the kinetic colorimetric method; triglycerides, total cholesterol and creatinine were performed by enzymatic colorimetric method, both provided by Gold Analisa Diagnóstica Ltda. Results: Animals treated with antiretroviral therapy and melatonin (II) had higher body weight gain, less hepatomegaly, less anxiety, lower levels of triglycerides, cholesterol and hepatic enzymes when compared to animals treated with antiretroviral therapy. Current study revealed that 40% (12/30) of the patients had changes in AST liver enzymes (> 38 U/I), 30% (9/30) had changes in ALT levels (> 38 U/I) and 30% (9/30) had GGT levels (> 40 U/I). Results obtained after the use of melatonin suggest melatonin activity on the liver. Significant differences between groups in plasma cholesterol indicate that melatonin exerted better improvement of blood lipid composition. Melatonin would lower cholesterol in liver and decrease plasma cholesterol. Above all, melatonin could decrease oxidative stress and improve dyslipidemia. Conclusion: Considering the low toxicity of melatonin and its ability to reduce the side effects and increase the efficacy of the drugs, its use may be important and significant as a combination therapy with HAART. Current study which investigated the effect of melatonin associated with antiretroviral treatment demonstrated that melatonin reduces toxicity induced by HAART. Melatonin improves metabolic abnormalities and emotional disturbs in animals and patients.

Effect of ipragliflozin on liver function in Japanese type 2 diabetes mellitus patients: a subgroup analysis of the STELLA-LONG TERM study (3-month interim results).

This subgroup analysis of STELLA-LONG TERM, an ongoing 3-year post-marketing surveillance study on the long-term efficacy and safety of ipragliflozin, assessed the effect of ipragliflozin on liver function in type 2 diabetes mellitus (T2DM) patients. Patients were divided according to baseline liver function (normal [male: ALT ≤30, female: ALT ≤20], abnormal [male: ALT ≥31, female: ALT ≥21]). We evaluated changes in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyltransferase (γ-GTP), alkaline phosphatase (ALP), and fatty liver index (FLI) at 3 months of treatment; the proportion of patients with abnormal liver function whose liver function normalized after 3 months of treatment; and correlations between changes in ALT levels and efficacy variables/laboratory values. Liver function was normal in 2,570 and abnormal in 3,239 patients. Only patients with abnormal liver function showed a statistically/clinically significant decrease in AST, ALT, γ-GTP, and ALP levels at 3 months (all p < 0.05 vs. baseline). The FLI significantly decreased from 63.2677 ± 26.4363 (baseline) to 56.7137 ± 27.6484 (3 months) (p < 0.05) in the overall patient population. Liver function normalized in 20.5% (543/2,648) of patients with abnormal liver function. There was no obvious correlation between changes in ALT and changes in efficacy/laboratory parameters. Liver function improved after 3-month treatment with ipragliflozin in T2DM patients with abnormal liver function.

Identification of Specific MicroRNA Biomarkers in Early Stages of Hepatocellular Injury, Cholestasis, and Steatosis in Rats.

Recently, studies on circulating microRNAs (miRNAs) as potential biomarkers of drug-induced liver injury (DILI) have received increasing attention. It has been demonstrated that miR-122 and miR-192, which are liver enriched, could be potential biomarkers of DILI; however, these miRNAs cannot discern types of injuries. In the present study, we comprehensively analyzed time-dependent plasma miRNA profiles in rats with drug- or chemical-induced hepatocellular injury, cholestasis, and steatosis with high-throughput miRNA sequencing. To enable the comparison of miRNA expression levels between DILI models with different severity and peak time of injuries, the stages of injury were defined as early, middle, and late, according to cluster patterns of miRNA expression profiles. Through differential analysis, we characterized miRNAs that were specifically up- or down-regulated in each DILI model. Several miRNAs were dramatically changed earlier than traditional biomarkers such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST). For example, in an acetaminophen (APAP)-induced hepatocellular injury model, plasma let-7b-5p was up-regulated as early as 3 h after dosing, whereas a significant change in ALT level was observed at 12 h. We then focused on the DILI type-specific miRNAs in plasma that were up-regulated at the early stage of injury. RT-qPCR analysis validated that let-7b-5p and miR-1-3p for hepatocellular injury, miR-143-3p and miR-218a-5p for cholestasis, and miR-320-3p for steatosis models showed significant increases in the early stage of the injuries. The present study suggests the utility of miRNAs as specific biomarkers for the early detection of DILI.

After successful hepatitis C virus antiviral therapy: It looks that normal alanine aminotransferase level is not the normal.

Normal serum alanine aminotransferase (ALT) levels differ with age, gender, and body mass index. Adjusting the upper limits of normal (ULN) for ALT needs further research in different populations. Aim of this work was to monitor the effect of successful chronic hepatitis C (CHC) treatment on the ALT levels in patients with normal pretreatment ALT. Data of 1160 CHC patients with persistent pretreatment normal liver enzymes were retrospectively analyzed. Treatment response to direct acting antiviral agents (DAAs) therapy was recorded. Changes in ALT levels before and after treatment were analyzed by patients' demographic, laboratory, and radiologic characteristics. Areas under the receiver operating characteristic curve (AUROC) of ALT after treatment were used to generate a new ALT ULN. Males were 568 (49%) and females 592 (51%) with a mean age of 50.7years. After treatment, mean (±SD) of ALT levels significantly decreased from (26.3±7.8) to (19.1±10.9). This reduction was more significant in interferon-free than interferon-based regimens. ROC curve analyses suggested a new ALT ULN cut off (26.4IU/L) in the treated patients (sensitivity=78.6%, specificity=83.8%, AUROC=0.89. This cutoff dropped to 14.7IU/L in cirrhotic patients (sensitivity=77.4%, specificity=44.7%, AUROC=0.612). The identified cutoffs were 16.3IU/L (sensitivity=66.7%, specificity=47.5%, AUROC=0.499) and 15.5IU/L (sensitivity=76.5%, specificity=51.3%, AUROC=0.576) in males and females, respectively. The current ALT ULN needs readjustment to identify new normal cutoffs in CHC patients. Posttreatment cutoffs differ according to gender, pretreatment liver affection, and treatment regimen.

Effects of canagliflozin, an SGLT2 inhibitor, on hepatic function in Japanese patients with type 2 diabetes mellitus: pooled and subgroup analyses of clinical trials

BackgroundWe aimed to investigate the efficacy of canagliflozin (based on its effect on liver function and blood glucose levels) and its safety in high alanine aminotransferase (ALT) patients (ALT >30 U/L).MethodsThis post hoc analysis of canagliflozin in type 2 diabetes mellitus (T2DM) patients was divided into Study 1 (pooled analysis of 12- and 24-week placebo-controlled, monotherapy studies) and Study 2 (52-week monotherapy/combination therapy study). The canagliflozin 100 mg group data were compared with placebo or baseline ALT subgroup (baseline ALT >30 or ≤30 U/L) data. The primary endpoint was change in ALT level from baseline. Secondary endpoints were changes in efficacy-related parameters. Adverse events (AEs) were evaluated.ResultsThe mean ALT change at 12 weeks was −10.3 ± 11.7 and −3.2 ± 17.6 U/L in the canagliflozin vs. placebo group in the high ALT subgroup (P = 0.0206); no significant difference was shown in the low ALT subgroup (Study 1). In both ALT subgroups, glycosylated hemoglobin (HbA1c) and body weight were significantly reduced in the canagliflozin vs. placebo group (all P < 0.0001). The mean change in ALT at 52 weeks was −16.0 ± 18.8 U/L in the high ALT subgroup (P < 0.0001, Study 2). The incidence of AEs or serious AEs in the high ALT subgroup in the canagliflozin group was similar to that in the placebo group (Study 1) or low ALT subgroup (Studies 1 and 2).ConclusionsIn T2DM patients with impaired liver function, canagliflozin may improve liver function, reduce HbA1c and body weight, and be well tolerated.

Simple Resistance Exercise for 24 Weeks Decreases Alanine Aminotransferase Levels in Patients with Non-Alcoholic Fatty Liver Disease.

Exercise therapy is effective and recommended for non-alcoholic fatty liver disease (NAFLD) based on the efficacy of hepatic fat reduction. However, the efficacies of exercise therapy are based on short-term intervention. Moreover, no reports have examined whether significant reductions in serum levels of alanine aminotransferase (ALT) are achieved with exercise therapy in patients with NAFLD. The aim of this study is to assess the effects of simple resistance exercise for 24 weeks in NAFLD. 59 patients with NAFLD were assigned to a resistance exercise group ( n =28) or a control group ( n =31). The resistance exercise group performed 2 exercises (push-ups and squats) 3 times a week on nonconsecutive days for a trial periods of 24 weeks. Patients in the control group proceeded with regular physical activities under a restricted diet throughout the study. The effects of exercise were compared between groups after 24 weeks. Mean ALT level, homeostasis model assessment-estimated insulin resistance index and hepatic steatosis grade were all decreased in the resistance exercise group. Changes in ALT levels correlated negatively with changes in muscle:body weight ratio in the exercise group. These data demonstrate that 24 weeks of simple resistance exercise comprising squats and push-ups represents an effective treatment for NAFLD.

Weight loss results in significant improvements in quality of life for patients with nonalcoholic fatty liver disease: A prospective cohort study.

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and associated with decreased quality of life (QOL). The currently available treatment is weight loss through lifestyle modification. However, longitudinal QOL data are lacking on whether weight loss improves QOL. We prospectively enrolled 151 patients with NAFLD from 2009 to 2014. All patients received a liver biopsy, lifestyle assessment, blood tests, and QOL tools, including the Chronic Liver Disease Questionnaire (CLDQ), a validated health-related quality of life measurement. All patients were followed with a repeat CLDQ at 6 months. The cohort included 91 (60%) men, ages 51.5 ± 12.6 years, 46 (30%) of whom were diabetic. Thirty (21%) had advanced fibrosis or cirrhosis and 67 (47%) had a NAFLD Activity Score >4. Overall, 47 (31%) patients achieved at least a 5% reduction in weight. The cohort's median baseline total CLDQ value was 5.6 (interquartile range: 4.8-6.2). Those who achieved at least a 5% reduction in weight had a 0.45 (95% confidence interval [CI]: 0.24-0.66; P < 0.0001) point improvement in the total CLDQ, compared to 0.003 (95% CI: -0.12-0.12; P = 0.95) in those who did not. Nondiabetic patients with nonalcoholic steatohepatitis and without advanced fibrosis are most likely to achieve QOL benefits from weight loss. For every decrement in body mass index (BMI), there was a corresponding increase of 0.09 (95% CI: 0.03-0.16) points in the CLDQ scale (P = 0.005), adjusting for histology, diabetes, sex, age, and change in alanine aminotransferase level and change in FIB-4 index. A decrease by 5 points in BMI leads to a 10% adjusted improvement in QOL. Patients with NAFLD can experience significant improvements in QOL that appear specific to weight loss and not biochemical improvements.

Vitamin E and changes in serum alanine aminotransferase levels in patients with non‐alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a common cause of serum alanine aminotransferase (ALT) elevations and chronic liver disease, but it is unclear how well ALT elevations reflect the liver injury. To assess how well changes in ALT elevations reflect improvements in liver histology in response to vitamin E therapy. The vitamin E and placebo arms of the Pioglitazone vs. Vitamin E vs. Placebo in Non-alcoholic Steatohepatitis (PIVENS) trial were reassessed for associations among changes in ALT levels, body weight and liver histology. An ALT response was defined as a decrease to ≤40 U/L and by ≥30% of baseline. Liver biopsies taken before and after treatment were scored for non-alcoholic fatty liver disease activity (NAS) and fibrosis. ALT responses were more frequent among vitamin E (48%) than placebo (16%) recipients (P < 0.001). Among vitamin E recipients, ALT responses were associated with decreases in NAS (P < 0.001), but not fibrosis scores (P = 0.34), whereas among placebo recipients, ALT responses were associated with significant decreases in both (P < 0.05). Weight loss (≥2 kg) was also associated with ALT response (P < 0.001), improvements in NAS (P < 0.001) and fibrosis (P < 0.02), but vitamin E had an added effect both with and without weight loss. Weight gain (≥2 kg) was associated with lack of ALT response and worsening NAS and fibrosis scores in patients not on vitamin E. Decrease of ALT levels to normal in patients with NASH is usually associated with improved histological activity. Management should stress the value of weight loss and strongly discourage weight gain. Vitamin E can improve both ALT levels and histology with and without weight loss. NCT00063622.

Effect of Silymarin (Milk Thistle) on Liver Disease in Patients With Chronic Hepatitis C Unsuccessfully Treated With Interferon Therapy

The botanical product silymarin, an extract of milk thistle, is commonly used by patients to treat chronic liver disease, despite scant and conflicting evidence of its efficacy. To determine the effect of silymarin on liver disease activity in patients with chronic hepatitis C virus (HCV) infection unsuccessfully treated with interferon-based therapy. Multicenter, double-blind, placebo-controlled trial conducted at 4 medical centers in the United States. Participants included 154 persons with chronic HCV infection and serum alanine aminotransferase (ALT) levels of 65 U/L or greater who were previously unsuccessfully treated with interferon-based therapy. Enrollment began in May 2008 and was completed in May 2010, with the last follow-up visit completed in March 2011. Participants were randomly assigned to receive 420-mg silymarin, 700-mg silymarin, or matching placebo administered 3 times per day for 24 weeks. The primary outcome measure was serum ALT level of 45 U/L or less (considered within the normal range) or less than 65 U/L, provided this was at least a 50% decline from baseline values. Secondary outcomes included changes in ALT levels, HCV RNA levels, and quality-of-life measures. After 24 weeks of treatment, only 2 participants in each treatment group (P ≥ .99) met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin). The mean decline in serum ALT activity at the end of treatment did not differ significantly (P = .75) across the 3 treatment groups (mean decline, -4.3 [95% CI, -17.3 to 8.7] U/L for placebo, -14.4 [95% CI, -41.6 to 12.7] U/L for 420-mg silymarin, -11.3 [95% CI, -27.9 to 5.4] U/L for 700-mg silymarin); there likewise were no significant differences in HCV RNA levels (mean change, 0.07 [95% CI, -0.05 to 0.18] log10 IU/mL for placebo, -0.03 [95% CI, -0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, -0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P = .54) or quality-of-life measures. The adverse event profile of silymarin was comparable with that of placebo. Higher than customary doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy. clinicaltrials.gov Identifier: NCT00680342.