Development of prediction model for alanine transaminase elevations during the first 6 months of conventional synthetic DMARD treatment.

Frequent laboratory monitoring is recommended for early identification of toxicity when initiating conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). We aimed at developing a risk prediction model to individualize laboratory testing at csDMARD initiation. We identified inflammatory joint disease patients (N = 1196) initiating a csDMARD in Turku University Hospital 2013-2019. Baseline and follow-up safety monitoring results were drawn from electronic health records. For rheumatoid arthritis patients, diagnoses and csDMARD initiation/cessation dates were manually confirmed. Primary endpoint was alanine transaminase (ALT) elevation of more than twice the upper limit of normal (ULN) within 6 months after treatment initiation. Computational models for predicting incident ALT elevations were developed using Lasso Cox proportional hazards regression with stable iterative variable selection (SIVS) and were internally validated against a randomly selected test cohort (1/3 of the data) that was not used for training the models. Primary endpoint was reached in 82 patients (6.9%). Among baseline variables, Lasso model with SIVS predicted subsequent ALT elevations of > 2 × ULN using higher ALT, csDMARD other than methotrexate or sulfasalazine and psoriatic arthritis diagnosis as important predictors, with a concordance index of 0.71 in the test cohort. Respectively, at first follow-up, in addition to baseline ALT and psoriatic arthritis diagnosis, also ALT change from baseline was identified as an important predictor resulting in a test concordance index of 0.72. Our computational model predicts ALT elevations after the first follow-up test with good accuracy and can help in optimizing individual testing frequency.

Association between serum ALT levels and incidence of new-onset diabetes in general population of Japanese: a longitudinal observational study (ISSA-CKD).

OBJECTIVE: We aimed to clarify the relationship between serum alanine transaminase (ALT) levels and incidence of new-onset diabetes in a Japanese general population. SETTING: Population-based retrospective cohort study using annual health check-up data for residents of Iki City, Nagasaki Prefecture, Japan. PARTICIPANTS: A total of 5330 Japanese individuals (≥30 years old) without diabetes at baseline were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: Serum ALT levels were determined using an enzymatic method and were classified into gender-specific quartile groups as follows: group 1 (3-16 U/L in men and 3-13 U/L in women), group 2 (17-21 U/L in men and 14-16 U/L in women), group 3 (22-29 U/L in men and 17-22 U/L in women) and group 4 (30-428 U/L in men and 23-268 U/L in women). The study outcome was the incidence of diabetes (fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, glycated haemoglobin ≥6.5% or use of glucose-lowering therapies). RESULTS: After an average follow-up period of 5.0 years, 279 individuals developed diabetes. The incidence rate of diabetes increased with elevation of serum ALT levels (0.7% per 100 person-years in group 1, 0.9% in group 2, 0.9% in group 3 and 1.7% in group 4) (p<0.001 for trend). This association was significant after adjustment for other risk factors including age, sex, obesity, hypertension, dyslipidaemia, smoking, current daily alcohol intake and regular exercise (p<0.001 for trend). Comparable associations were observed between men and women (p=0.459 for interaction). CONCLUSION: Serum ALT levels were associated with future development of diabetes in the general Japanese population.

Hepatitis E virus seroprevalence among employees in catering and public place industries in Nanjing, China.

This study aimed to assess the prevalence of anti-hepatitis E virus (HEV) immunoglobulin (Ig) M and elevated serum alanine aminotransferase (ALT) levels among employees in catering and public place industries. Blood samples were collected between January and December 2020 from 26,790 employees working in the Qinhuai district of Nanjing, China. Anti-HEV IgM in the serum samples was tested by the capture ELISA method and ALT was tested by the IFCC method. Samples positive for anti-HEV IgM or with ALT levels over 200 U/L were subjected to PCR screening of HEV RNA. The overall seroprevalence of anti-HEV IgM was 0.41%, and the seroprevalence was slightly higher in males (0.47%) than in females (0.37%); however, the difference was not substantial (p = 0.177). Seroprevalence of anti-HEV IgM increased with age, reaching its peak level after 48 years of age. The prevalence of elevated ALT levels was 4.24%, and males exhibited a higher prevalence than females (6.78% vs 2.65%, p < 0.001). Prevalence of elevated ALT levels differed in age groups and the 26-36-year-old group had the highest rate of elevated ALT levels. Employees with elevated ALT levels had a higher prevalence of positive anti-HEV IgM than those with normal ALT (0.57% vs 0.31%, p < 0.001). Positive HEV RNA was detected in one anti-HEV IgM-negative employee with ALT higher than 200 U/L. In our study, all the HEV RNA-positive and IgM-positive individuals are asymptomatic, and a combination of ALT tests, serological methods, and molecular methods is recommended to screen asymptomatic HEV carriers and reduce the risk of transmission.

Genetic variation and elevated liver enzymes during childhood, adolescence and early adulthood.

BACKGROUND: Genetic factors influence the risk of fatty liver disease (FLD) in adults. The aim of this study was to test if, and when, genetic risk factors known to affect FLD in adults begin to exert their deleterious effects during childhood, adolescence and early adulthood. METHODS: We included up to 4018 British children and adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort. Three genetic variants known to associate robustly with FLD in adults (PNPLA3 rs738409, TM6SF2 rs58542926 and HSD17B13 rs72613567) were tested for association with plasma levels of alanine transaminase (ALT) and aspartate transaminase (AST) during childhood (mean age: 9.9 years), early adolescence (15.5 years), late adolescence (17.8 years), and early adulthood (24.5 years). We also tested the associations of a 17-variant score and whole-genome polygenic risk scores (PRS) derived from associations in adults with plasma ALT and AST at the same four time points. Associations with elastography-derived liver steatosis and fibrosis were tested in early adulthood. RESULTS: Genetic risk factors for FLD (individually, combined into a 3-variant score, a 17-variant score and as a genome-wide PRS), were associated with higher liver enzymes, beginning in childhood and throughout adolescence and early adulthood. The ALT-increasing effects of the genetic risk variants became larger with increasing age. The ALT-PRS was associated with liver steatosis in early adulthood. No genetic associations with fibrosis were observed. CONCLUSIONS: Genetic factors that promote FLD in adults associate with elevated liver enzymes already during childhood, and their effects get amplified with increasing age.

Abnormal alanine aminotransferase levels in patients with moderate or severe ovarian hyperstimulation result in an increased risk of obstetric complications.

OBJECTIVES: To explore the effect of abnormally elevated serum alanine aminotransferase (ALT) on pregnancy outcomes in patients with moderate and severe ovarian hyperstimulation syndrome (OHSS) at disease onset. METHODS: This was a single-center retrospective cohort study conducted between January 1, 2014 and October 31, 2021. A total of 3550 fresh in vitro fertilization/intracytoplasmic sperm injection embryo transfer cycles were included, using Golan's three-degree, five-level classification to diagnose patients with OHSS. According to the patient's ALT level after diagnosis of OHSS, 123 (3.46%) patients with moderate-to-severe OHSS were divided into two groups. A control group included 3427 (96.54%) non-OHSS patients, and 91 (2.56%) abnormal ALT patients were matched with the control group for propensity scores. RESULTS: There was no difference in baseline data between the abnormal ALT and matched control groups. The incidence of obstetric complications was significantly higher in the abnormal ALT group than in the matched control group (P < 0.05). After adjusting for confounding factors, the incidence of obstetric complications in the abnormal ALT group was still higher than that in the normal ALT group (P < 0.05). CONCLUSION: In patients with moderate and severe OHSS, higher ALT levels resulted in an increased risk of obstetric and neonatal complications.

Prevalence of nonalcoholic fatty liver disease and the related risk factors among healthy adults: A cross-sectional study in Chongqing, China.

Background: Epidemiological characteristics of nonalcoholic fatty liver disease (NAFLD) in Chongqing, a west-central city of China, remain unclear. The objective of this study was to investigate the prevalence of NAFLD and the related risk factors among healthy adults for physical examination in Chongqing. Methods: A total of 110,626 subjects were enrolled in the present study. Each of the participants underwent physical examination, laboratory measurements, and abdominal ultrasonography. The chi-square test was employed to compare differences in the NAFLD prevalence, and logistic regression analysis was used to estimate the odds ratio for risk factors of NAFLD. Results: The prevalence of NAFLD in individuals in the population of Chongqing was 28.5%, and the prevalence in men (38.1%) was significantly higher than that in women (13.6%) (OR = 2.44; 95% CI: 2.31-2.58). NAFLD was more common in men aged 51-60 years and women over 60 years. Approximately 79.1% of the people with obesity and 52.1% of the people with central obesity had NAFLD. The prevalence of NAFLD in people with hypertension and cholelithiasis was 48.9 and 38.4%, respectively. Logistic regression showed that gender, age, body max index (BMI), central obesity, hypertension, impaired fasting glucose/diabetes mellitus (DM), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), hyperuricemia (HUA), alanine transaminase (ALT), and cholelithiasis were independently associated with the presence of NAFLD. Conclusion: The prevalence of NAFLD among healthy adults in Chongqing was high. To improve the prevention and management of NAFLD, special attention should be paid to the factors associated with the presence of NAFLD, including higher BMI, higher waist circumference, higher blood glucose, hypertension, hypertriglyceridemia, hyperuricemia, cholelithiasis, and elevated ALT.

Extremely Low Activity of Serum Alanine Aminotransferase Is Associated with Long-Term Overall-Cause Mortality in the Elderly Patients Undergoing Percutaneous Coronary Intervention after Acute Coronary Syndrome.

Background and Objectives: Recent studies revealed that the extremely low activity of serum alanine aminotransferase (ALT) is associated with frailty and contributes to increased mortality after acute physical stress. We aimed to investigate whether the extremely low activity of serum ALT (<10 U/L) at the time of diagnosis can be used to predict overall-cause mortality in elderly patients that underwent percutaneous coronary intervention (PCI) after acute coronary syndrome (ACS) diagnosis. Materials and Methods: A retrospective medical record review was performed on 1597 patients diagnosed with ACS who underwent PCI at a single university hospital from February 2014 to March 2020. The associations between the extremely low activity of serum ALT and mortality were assessed using a stepwise Cox regression (forward: conditional). Results: A total of 210 elderly patients were analyzed in this study. The number of deaths was 64 (30.5%), the mean survival time was 25.0 ± 18.9 months, and the mean age was 76.9 ± 7.6 years. The mean door-to-PCI time was 74.0 ± 20.9 min. The results of stepwise Cox regression analysis showed that the extremely low activity of serum ALT (adjusted hazard ratio: 5.157, 95% confidence interval: 3.001-8.862, p < 0.001) was the independent risk factor for long-term overall-cause mortality in the elderly who underwent PCI after ACS diagnosis. Conclusions: The extremely low activity of serum ALT at ACS diagnosis is a significant risk factor for increased long-term overall-cause mortality in the elderly who underwent PCI after ACS diagnosis. It is noteworthy that a simple laboratory test at the time of diagnosis was found to be a significant risk factor for mortality.

Nomogram for evaluating obvious liver inflammation in treatment-naïve HBeAg positive chronic hepatitis B virus infection patients with normal ALT.

The purpose of this study was to develop an effective and non-invasive nomogram for evaluating liver obvious inflammation in untreated HBeAg positive patients with chronic hepatitis B virus (HBV) infection. A nomogram was established on a model cohort of 292 treatment-naïve HBeAg positive patients with normal alanine aminotransferase (ALT ≤40 U/L) at Beijing Ditan Hospital from January 2008 to March 2018. Then the nomogram was prospectively validated in a cohort of 88 patients from July 2019 to May 2021. Calibration curves and Concordance index were used to evaluate the accuracy of prediction and identification performance of the model. In untreated HBeAg positive chronic hepatitis B virus infection patients with normal ALT, the formula for predicting liver inflammation was Logit (P) =-0.91-0.41×log10 (qHBeAg)+0.11×AST-0.01×PLT. The nomogram had C-index of 0.751 (95% CI, 0.688-0.815), indicating a good consistency between prediction and real observation on the model cohort. The validation cohort confirmed its good performance. In this study, liver inflammation nomograms based on HBeAg, AST, and PLT were established and verified in treatment-naïve HBeAg positive chronic HBV patients with normal ALT.

Analysis of serum microRNA-122 in a randomized controlled trial of N-acetylcysteine for treatment of antituberculosis drug-induced liver injury.

AIM: Serum microRNA-122 (miR-122) is a novel biomarker for drug-induced liver injury, with good sensitivity in the early diagnosis of paracetamol-induced liver injury. We describe miR-122 concentrations in participants with antituberculosis drug-induced liver injury (AT-DILI). We explored the relationship between miR-122 and alanine aminotransferase (ALT) concentrations and the effect of N-acetylcysteine (NAC) on miR-122 concentrations. METHODS: We included participants from a randomized placebo-controlled trial of intravenous NAC in AT-DILI. ALT and miR-122 concentrations were quantified before and after infusion of NAC/placebo. We assessed correlations between ALT and miR-122 concentrations and described changes in ALT and miR-122 concentrations between sampling occasions. RESULTS: We included 45 participants; mean age (± standard deviation) 38 (±10) years, 58% female and 91% HIV positive. The median (interquartile range) time between pre- and post-infusion biomarker specimens was 68 h (47-77 h). The median pre-infusion ALT and miR-122 concentrations were 420 U/L (238-580) and 0.58 pM (0.18-1.47), respectively. Pre-infusion ALT and miR-122 concentrations were correlated (Spearman's ρ = .54, P = .0001). Median fold-changes in ALT and miR-122 concentrations between sampling were 0.56 (0.43-0.69) and 0.75 (0.23-1.53), respectively, and were similar in the NAC and placebo groups (P = .40 and P = .68 respectively). CONCLUSIONS: miR-122 concentrations in our participants with AT-DILI were considerably higher than previously reported in healthy volunteers and in patients on antituberculosis therapy without liver injury. We did not detect an effect of NAC on miR-122 concentrations. Further research is needed to determine the utility of miR-122 in the diagnosis and management of AT-DILI.

A noninvasive model discriminating significant histological changes in treatment-naive chronic hepatitis B patients with normal ALT.

BACKGROUND: Traditionally part of chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) are recommended to antiviral therapy referring to liver biopsy. However, liver biopsy is an invasive method with various potential complications. A noninvasive model was established in the study to evaluate liver histology and to identify the need of antiviral therapy. METHODS: A total of 614 liver biopsied CHB patients with ALT less than upper limit of normal from 2 centers were retrospectively analyzed. They were divided into a training cohort and a validation cohort. A noninvasive model to predict the significant liver histological changes was established and validated. RESULTS: The results of analysis showed that ALT, Age, platelet (PLT) and liver stiffness (LS) were independent risk factors for significant liver injury. The model was established based on the 4 indexes, with the area under the curve of 0.85 and 0.87 in training cohort and validation cohort. Meanwhile, 2 cut-off scores were selected. By applying the low cut-off score (- 0.207), patients without significant liver injury could be identified with high accuracy, with negative predictive value of 72.7% and 73.7% in training and validation cohorts. By applying the high cut-off score (0.537), the presence of significant liver injury could be diagnosed with high accuracy, with positive predictive value of 90.3% and 88.8% in the training and validation cohorts. By applying the model, liver biopsy would have been avoided in 87.6% (538/614) patients, with correct prediction in 87.9% (473/538). CONCLUSION: The novel noninvasive model composed of ALT, Age, PLT, LS can correctly assess liver histology in CHB patient with normal ALT, which helps to determine the need of antiviral therapy without liver biopsy.

Dietary Supplement Intake is Associated with Healthier Lifestyle Behaviors in College Students Attending a Regional University in the Southeast: A Cross-Sectional Study.

The relationship between intake of dietary supplements and biomarkers such as insulin and insulin-like growth factor has not been well explored. The primary aim of this cross-sectional study was to investigate the associations between supplement intake and biological and lifestyle factors. We hypothesized that dietary supplement intake was associated with healthier lifestyle behaviors. College students attending a Southeast university were recruited between January 2018 and April 2019. Blood samples were collected to measure insulin, insulin-like growth factor 1 (IGF-1) and alanine aminotransferase (ALT). Statistical tests employed were linear regression and analysis of variance. Ninety-eight participants completed the study and 91% reported taking at least one supplement, while 5.1% reported taking 9+ supplements once per week. There were no differences in levels of insulin, IGF-1 and ALT by levels of dietary supplement intake. Although there were no differences in HEI-2015 score among the groups, those who consumed five or more supplements met a higher percentage of the recommended intake for fruits, performed aerobic exercise for longer duration, and had lower body fat percentage compared to participants who consumed two or less supplements at least once per week. These findings are consistent with previous studies and suggest that dietary supplement intake is highly prevalent in college students, and it may be related to healthy lifestyle behaviors. Future studies should employ mixed methodology to examine reasons by which college students consume dietary supplements and to assess perceived and direct health benefits associated with consumption.

[Effect of forsythiaside A against CCl_4-induced liver fibrosis in mice and its mechanism].

This study aims to investigate the efficacy of forsythiaside A(FTA) against CCl_4-induced liver fibrosis and the mechanism. Specifically, activities of serum alanine/aspartate aminotransferase(ALT/AST) and hydroxyproline(HYP) level in liver were detected, and pathological morphology of liver was observed based on hematoxylin-eosin(HE) staining, Masson's trichrome staining, and Sirius red staining of liver. On this basis, the effect of FTA on liver fibrosis was evaluated. The mRNA expression of actin alpha 2/α-smooth muscle actin(Acta2/α-SMA), transforming growth factor ß(Tgfß), collagen Ⅰ alpha 1(Col1 a1), and collagen Ⅲ alpha 1(Col3 a1) in liver tissue and hepatic stellate cells(HSC) was determined by qPCR, and the protein expression of α-SMA in liver tissue and HSC was measured by Western blot to assess the inhibition of FTA on HSC activation. The protein expression of α-SMA, vi-mentin(Vim), vascular endothelial cadherin(Ve-cadherin), and platelet endothelial cell adhesion molecule-1(PECAM-1/CD31) was measured by Western blot to evaluate the reverse of endothelial-mesenchymal transition(EMT) by FTA. The efficacy of FTA in relieving CCl_4-induced liver fibrosis was evidenced by the alleviation of hepatocyte necrosis, liver inflammation, and hepatic collagen deposition. FTA decreased the mRNA expression of Acta2, Tgfß, Col1 a1, and Col3 a1 and protein expression of α-SMA both in vivo and in vitro. FTA reversed the increase of α-SMA and Vim and the decrease of CD31 and Ve-cadherin in livers from mice treated with CCl_4. Therefore, FTA alleviated CCl_4-induced liver fibrosis in mice via suppressing HSC activation and reversing EMT.

Incidence and Pattern of Aminotransferase Elevation During Anti-Hypertensive Therapy With Angiotensin-II Receptor Blockers.

BACKGROUND: Angiotensin type II receptor blockers (ARBs) are the most widely used anti-hypertensive drugs. This study aimed to elucidate the likelihood and pattern of ARB-induced liver injury in a hospital-based cohort. METHODS: Data of patients receiving fimasartan (n = 5,543), candesartan (n = 6,406), valsartan (n = 6,040), and losartan (n = 9,126) were retrieved from the clinical data warehouse of two tertiary hospitals. Patients with alanine aminotransferase (ALT) levels > 5 times the upper normal limit were assessed according to the Roussel Uclaf Causality Assessment Method (RUCAM). RESULTS: A total of 27,115 patients were enrolled, including 14,630 (54.0%) men, with a mean age of 64.6 years (standard deviation, 13.6). During 31,717 person-years of ARB therapy, serum ALT levels > 120 IU/L were found in 558 (2.1%) person-years, and levels > 200 IU/L were found in 155 (0.6%) person-years. The incidence of ALT elevation > 120 IU/L per 106 cumulative defined daily doses was 6.6, 3.6, 3.9, and 4.0 in the fimasartan, candesartan, valsartan, and losartan groups, respectively (P = 0.002). An ALT level > 200 IU/L with RUCAM score ≥ 6 was found in 20 patients, suggesting probable drug-induced liver injury for 11 (0.2%) patients receiving fimasartan, five (0.1%) receiving candesartan, four (0.1%) receiving valsartan, and none receiving losartan (P < 0.001). CONCLUSION: Approximately 2% of patients receiving ARB therapy had significant ALT elevation (4.24/106 cumulative defined daily doses [cDDDs]), which was associated with probable ARB-related liver injury in 0.07% of patients (0.15/106 cDDDs). Elevation of ALT was more commonly associated with fimasartan than the other ARBs. Clinicians should be aware of the possibility of ARB-related ALT elevation in patients with unexplained chronic abnormal ALT.

Relationship between Body Mass Index and Serum Alanine Transaminase Concentration in Obese Female.

The serum Alanine Transaminase (ALT) activity has been regarded as a reliable and sensitive marker of liver disease. In the context of obesity ALT may also be a good indicator of overall health. Obesity has been reported as a risk factor associated with elevation of ALT, which is a surrogate marker of Non-alcoholic fatty liver disease (NAFLD). Elevated ALT may correlate with the severity of NAFLD in obese female. This study was done to evaluate the changes of serum ALT in obese female age ranged 30-60 years in comparison to normal healthy female of same age. At the same time we can know the relationship between body mass index and serum ALT concentration in obese female. This analytical cross-sectional study was carried out in the Department of Physiology, Mymensingh Medical College, Mymensingh, Bangladesh from January 2020 to December 2020. A total number of 100 female subjects were included in this study. Among them fifty (50) normal healthy female were taken as control group (Group I) and fifty (50) obese female were taken as study group (Group II). The level of serum ALT was determined by Ultra violet (UV) method. Data were expressed as mean±SD and statistical significance of difference among the group was calculated by unpaired Student's 't' test. Pearson's correlation coefficient test was done to find the correlation of serum ALT with BMI by using SPSS (version 21.0). During interpretation of results, p values of <0.001 were considered as statistically highly significant. In this study, serum level of ALT was significantly higher (p<0.001) in obese female compared to those of healthy control female. In addition, there is a positive correlation of serum ALT with BMI. From the results of the present study, it can be concluded that, elevated ALT was significantly associated with high BMI as well as with other feature of NAFLD.

Association between alanine aminotransferase as surrogate of fatty liver disease and physical activity and sedentary time in adolescents with obesity.

To compare patterns of sedentary (SED) time (more sedentary, SED + vs less sedentary, SED-), moderate to vigorous physical activity (MVPA) time (more active, MVPA + vs less active, MVPA-), and combinations of behaviors (SED-/MVPA + , SED-/MVPA-, SED + /MVPA + , SED + /MVPA-) regarding nonalcoholic fatty liver diseases (NAFLD) markers. This cross-sectional study included 134 subjects (13.4 ± 2.2 years, body mass index (BMI) 98.9 ± 0.7 percentile, 48.5% females) who underwent 24-h/7-day accelerometry, anthropometric, and biochemical markers (alanine aminotransferase (ALT) as first criterion, and aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), AST/ALT ratio as secondary criteria). A subgroup of 39 patients underwent magnetic resonance imaging-liver fat content (MRI-LFC). Hepatic health was better in SED- (lower ALT, GGT, and MRI-LFC (p < 0.05), higher AST/ALT (p < 0.01)) vs SED + and in MVPA + (lower ALT (p < 0.05), higher AST/ALT (p < 0.01)) vs MVPA- groups after adjustment for age, gender, and Tanner stages. SED-/MVPA + group had the best hepatic health. SED-/MVPA- group had lower ALT and GGT and higher AST/ALT (p < 0.05) in comparison with SED + /MVPA + group independently of BMI. SED time was positively associated with biochemical (high ALT, low AST/ALT ratio) and imaging (high MRI-LFC) markers independently of MVPA. MVPA time was associated with biochemical markers (low ALT, high AST/ALT) but these associations were no longer significant after adjustment for SED time. CONCLUSION: Lower SED time is associated with better hepatic health independently of MVPA. Reducing SED time might be a first step in the management of pediatric obesity NAFLD when increasing MVPA is not possible. WHAT IS KNOWN: • MVPA and SED times are associated with cardiometabolic risks in youths with obesity. • The relationships between NAFLD markers and concomitant MVPA and SED times have not been studied in this population. WHAT IS NEW: • Low SED time is associated with healthier liver enzyme profiles and LFC independent of MVPA. • While low SED/high MVPA is the more desirable pattern, low SED/low MVPA pattern would have healthier liver enzyme profile compared with high MVPA/high SED, independent of BMI, suggesting that reducing SED time irrespective of MVPA is needed to optimize liver health.

Transaminitis prevalence among HIV-infected adults eligible for tuberculosis preventive therapy.

OBJECTIVE: To assess the prevalence of severe transaminitis precluding tuberculosis (TB) preventive therapy (TPT) initiation for people with HIV (PWH) in a high TB/HIV burden setting. DESIGN/METHODS: We conducted a secondary analysis of data from a prospective cohort study of PWH with pre-antiretroviral therapy (ART) CD4 + counts 350 cells/µl or less undergoing systematic TB screening from two HIV clinics in Uganda. For this analysis, we excluded patients with culture-confirmed TB and patients without aspartate transaminase (AST) or alanine transaminase (ALT) levels measured within three months of enrollment. We compared the proportion of patients with any transaminitis (AST or ALT greater than one times the upper limit of normal ULN) and severe transaminitis (AST or ALT >3 times ULN) for patients screening negative for TB by symptoms and for those screening negative by C-reactive protein (CRP). We also assessed the proportion of patients with transaminitis by self-reported alcohol consumption. RESULTS: Among 313 participants [158 (50%) women, median age 34 years (IQR 27-40)], 75 (24%) had any transaminitis and six (2%) had severe transaminitis. Of 32 of 313 (10%) who screened negative for TB by symptoms, none had severe transaminitis. In contrast, six-times more PWH screened negative for TB by CRP (194 of 313; 62%), of whom only four (2.1%) had severe transaminitis. Differences in the proportion with any and severe transaminitis according to alcohol consumption were not statistically significant. CONCLUSION: Prevalence of severe transaminitis was low among PWH without culture-confirmed TB in this setting, and is therefore, unlikely to be a major barrier to scaling-up TPT.

Personalized-Inherent Variability in a Time-Dependent Immune Response: A Look into the Fifth Dimension in Biology.

INTRODUCTION: Individualized response to the immune triggers influences the course of immune-mediated diseases and the response to immunotherapies. Both inter- and intra-subject variations occur in time-dependent dynamics of biological systems. The present study aimed to establish a model for inherent personalized-time-dependent variability in response to immune triggers. METHODS: Male C57BL/6 mice were administered concanavalin A (ConA) and followed every 2 h for 10 h and at 24 h for serum alanine aminotransferase (ALT) levels. RESULTS: A marked intragroup variability was noted for both the timing of the effect of ConA, the magnitude of the increase in ALT levels, and the time to peak. While in some mice, a peak level was achieved, whereas a continuous increase in liver damage was noted in others. Four mice died at different time points during the study irrespective of their liver damage, further supporting the individualized-based response to the trigger. CONCLUSIONS: This feasibility study established a model for determining the personalized-inherent variability in a time-dependent response to the immune triggers. These results highlight the importance of considering both the time and the wide range of individualized variability in immune responses while designing personalized-based immunotherapies.

Gender Difference in Liver Enzymes in Newly Defined Subgroups of Diabetes Revealed by a Data-Driven Cluster Analysis.

BACKGROUND: Recently, a newly proposed data-driven approach for classifying diabetes has challenged the status quo of the classification of adult-onset patients with diabetes. This study investigated the association between liver injury and diabetes, classified by data-driven cluster analysis, as liver injury is a significant risk factor for diabetes. METHODS: We enrolled 822 adult patients with newly diagnosed diabetes. Two-step cluster analysis was performed using six parameters, including age at diagnosis, body mass index, hemoglobin A1C, homoeostatic assessment model 2 estimates about insulin resistance (HOAM2-IR) and beta-cell function (HOMA2-B), and glutamic acid decarboxylase antibodies (GADA) positivity. Patients were allocated into five clusters. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity were compared as indicators of liver injury among clusters. RESULTS: Serum ALT and AST activities were significantly different among clusters (P=0.002), even among those without GADA positivity (P=0.004). Patients with severe insulin-resistant diabetes (SIRD) and mild obesity-related diabetes (MOD) had a more severe liver injury. Gender dimorphism was also found for serum ALT and AST activities among subgroups. Female patients had better liver function than males with SIRD and MOD. CONCLUSIONS: We verified the feasibility of a newly proposed diabetes classification system and found robust and significant relationship and gender differences between serum ALT and AST activities and diabetes in some specific subgroups. Our findings indicate that more attention should be paid to diabetes subgroups when studying risk factors, indicators, or treatment in diabetic research.

Optical assay using B-doped core-shell Fe@BC nanozyme for determination of alanine aminotransferase.

B-doped core-shell Fe@BC nanozyme was synthesized. The peroxidase (POD) like activity of Fe@BC nanozyme was studied and utilized for detecting the activity of alanine aminotransferase (ALT). In the presence of ALT as well as ALT co-substrates L-alanine and α-ketoglutarate, L-glutamate is generated. The following catalytic oxidation of L-glutamate by glutamate oxidase leads to the generation of H2O2. The POD-like activity of Fe@BC can oxidize 3,3',5,5'-tetramethylbenzidine (TMB) to oxTMB in the presence of H2O2, generating a blue-colored compound. Through the detection of the amount of H2O2 generated, ALT activity can be determined through measuring the absorbance intensity variation at 450 nm. The limit of detection of the assay is 4 U/L, with a linear range from 10 to 1000 U/L. For human serum samples, the ALT levels determined by our assay are comparable to those determined by the hospital with a correlation coefficient of 0.991, demonstrating the reliability of our assay results.

Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A.

BACKGROUND: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus 5 (AAV5)-based gene-therapy vector containing a coagulation factor VIII complementary DNA driven by a liver-selective promoter. The efficacy and safety of the therapy were previously evaluated in men with severe hemophilia A in a phase 1-2 dose-escalation study. METHODS: We conducted an open-label, single-group, multicenter, phase 3 study to evaluate the efficacy and safety of valoctocogene roxaparvovec in men with severe hemophilia A, defined as a factor VIII level of 1 IU per deciliter or lower. Participants who were at least 18 years of age and did not have preexisting anti-AAV5 antibodies or a history of development of factor VIII inhibitors and who had been receiving prophylaxis with factor VIII concentrate received a single infusion of 6×1013 vector genomes of valoctocogene roxaparvovec per kilogram of body weight. The primary end point was the change from baseline in factor VIII activity (measured with a chromogenic substrate assay) during weeks 49 through 52 after infusion. Secondary end points included the change in annualized factor VIII concentrate use and bleeding rates. Safety was assessed as adverse events and laboratory test results. RESULTS: Overall, 134 participants received an infusion and completed more than 51 weeks of follow-up. Among the 132 human immunodeficiency virus-negative participants, the mean factor VIII activity level at weeks 49 through 52 had increased by 41.9 IU per deciliter (95% confidence interval [CI], 34.1 to 49.7; P<0.001; median change, 22.9 IU per deciliter; interquartile range, 10.9 to 61.3). Among the 112 participants enrolled from a prospective noninterventional study, the mean annualized rates of factor VIII concentrate use and treated bleeding after week 4 had decreased after infusion by 98.6% and 83.8%, respectively (P<0.001 for both comparisons). All the participants had at least one adverse event; 22 of 134 (16.4%) reported serious adverse events. Elevations in alanine aminotransferase levels occurred in 115 of 134 participants (85.8%) and were managed with immune suppressants. The other most common adverse events were headache (38.1%), nausea (37.3%), and elevations in aspartate aminotransferase levels (35.1%). No development of factor VIII inhibitors or thrombosis occurred in any of the participants. CONCLUSIONS: In patients with severe hemophilia A, valoctocogene roxaparvovec treatment provided endogenous factor VIII production and significantly reduced bleeding and factor VIII concentrate use relative to factor VIII prophylaxis. (Funded by BioMarin Pharmaceutical; GENEr8-1 ClinicalTrials.gov number, NCT03370913.).