Metabolomic profiling reveals novel biomarkers of alcohol intake and alcohol-induced liver injury in community-dwelling men (original) (raw)
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Alcohol-induced metabolomic differences in humans
Translational Psychiatry, 2013
Alcohol consumption is one of the world's major risk factors for disease development. But underlying mechanisms by which moderate-to-heavy alcohol intake causes damage are poorly understood and biomarkers are sub-optimal. Here, we investigated metabolite concentration differences in relation to alcohol intake in 2090 individuals of the KORA F4 and replicated results in 261 KORA F3 and up to 629 females of the TwinsUK adult bioresource. Using logistic regression analysis adjusted for age, body mass index, smoking, high-density lipoproteins and triglycerides, we identified 40/18 significant metabolites in males/females with P-values o3.8E À 04 (Bonferroni corrected) that differed in concentrations between moderate-to-heavy drinkers (MHD) and light drinkers (LD) in the KORA F4 study. We further identified specific profiles of the 10/5 metabolites in males/females that clearly separated LD from MHD in the KORA F4 cohort. For those metabolites, the respective area under the receiver operating characteristic curves were 0.812/0.679, respectively, thus providing moderate-to-high sensitivity and specificity for the discrimination of LD to MHD. A number of alcohol-related metabolites could be replicated in the KORA F3 and TwinsUK studies. Our data suggests that metabolomic profiles based on diacylphosphatidylcholines, lysophosphatidylcholines, ether lipids and sphingolipids form a new class of biomarkers for excess alcohol intake and have potential for future epidemiological and clinical studies.
Journal of Substance Abuse Treatment, 2017
Background: Alcohol use disorders (AUD) is a phase of alcohol misuse in which the drinker consumes excessive amount of alcohol and have a continuous urge to consume alcohol which may lead to various health complications. The current methods of alcohol use disorders diagnosis such as questionnaires and some biomarkers lack specificity and sensitivity. Metabolomics is a novel scientific field which may provide a novel method for the diagnosis of AUD by using a sensitive and specific technique such as nuclear magnetic resonance (NMR). Methods: A cross sectional study was conducted on three groups: individuals with alcohol use disorders (n = 30), social drinkers (n = 54) and alcohol-naive controls (n = 60). 1 H NMR-based metabolomics was used to obtain the metabolic profiles of plasma samples. Data were processed by multivariate principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) followed by univariate and multivariate logistic regressions to produce the best fit-model for discrimination between groups. Results: The OPLS-DA model was able to distinguish between the AUD group and the other groups with high sensitivity, specificity and accuracy of 64.29%, 98.17% and 91.24% respectively. The logistic regression model identified two biomarkers in plasma (propionic acid and acetic acid) as being significantly associated with alcohol use disorders. The reproducibility of all biomarkers was excellent (0.81-1.0). Conclusions: The applied plasma metabolomics technique was able to differentiate the metabolites between AUD and the other groups. These metabolites are potential novel biomarkers for diagnosis of alcohol use disorders.
What’s in Metabolomics for Alcoholic Liver Disease?
Journal of Gastrointestinal and Liver Diseases
Background & Aims: Current management of alcoholic liver disease (ALD), especially for alcoholic hepatitis (AH) is still driven by liver biopsy. Therefore, the identification of novel and accurate noninvasive biomarkers for the diagnosis and assessment of severity is important. Metabolomics, because it unravels changes closest to the phenotype, may represent the key for novel biomarkers. The aim of this study was to identify and characterize potential metabolomic biomarkers for diagnosis, staging and severity assessment of ALD.Methods: 30 consecutive ALD patients and 10 healthy controls were included in this proof-of-concept crosssectional study. Baseline assessment consisted in evaluation of Maddrey’s Discriminant Function, Model for End-Stage Liver Disease (MELD) and ABIC scores as well as ASH-Test (Fibromax) as a surrogate for the confirmatory diagnosis of AH in suggestive clinical and biologic settings. Additionally, SOP metabolomics and lipidomics were performed from serum samp...
Annals of Hepatology, 2019
Results. Results. Results. Results. The comparison of the metabolic profiles of patients with alcoholic hepatitis and decompensated cirrhosis showed marked differences between both groups. Importantly, metabolic differences were found among alcoholic hepatitis patients when subjects were stratified according to 90-day survival. Based on these findings, two non-invasive signatures were developed. The first one allowed an accurate non-invasive diagnosis of alcoholic hepatitis (AUROC 0.932; 95% CI 0.901-0.963). The second signature showed a good performance in the prognostic stratification of patients with alcoholic hepatitis (AUROC 0.963; 95% CI 0.895-1.000). Conclusions. Conclusions. Conclusions. Conclusions. Conclusions. Signatures based on metabolomics allowed an accurate non-invasive diagnosis and prognostic stratification of alcoholic hepatitis. The differences observed in the metabolic profile of the patients according to the presence and severity of alcoholic hepatitis are related with different mechanisms involved in the pathophysiology of alcoholic hepatitis such as peroxisomal activity, synthesis of inflammatory mediators or oxidation. This information could be useful for the development of novel targeted therapies.
Nutrients, 2018
Identifying the metabolites associated with alcohol consumption may provide insights into the metabolic pathways through which alcohol may affect human health. We studied associations of alcohol consumption with circulating concentrations of 123 metabolites among 2974 healthy participants from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Alcohol consumption at recruitment was self-reported through dietary questionnaires. Metabolite concentrations were measured by tandem mass spectrometry (BIOCRATES AbsoluteIDQTM p180 kit). Data were randomly divided into discovery (2/3) and replication (1/3) sets. Multivariable linear regression models were used to evaluate confounder-adjusted associations of alcohol consumption with metabolite concentrations. Metabolites significantly related to alcohol intake in the discovery set (FDR -value < 0.05) were further tested in the replication set (Bonferroni-corrected -value < 0.05). Of the 72 metabolites signifi...
Non-oxidative ethanol metabolites as a measure of alcohol intake
Clinica Chimica Acta, 2013
Recent alcohol intake can be monitored by the measurement of indirect biomarkers. Elevated levels of liver enzymes (i.e. gamma-glutamyl transferase (GGT), alanine amino transferase (ALT) and aspartate amino transferase (AST)) in blood are commonly used in clinical practice as an indicator of alcohol-induced liver damage. With the exception of carbohydrate-deficient transferrin (CDT), the specificity of indirect markers is only moderate because many cases of elevated levels are unrelated to alcohol consumption. Because of their intermediate half-life and tendency to accumulate in hair, non-oxidative ethanol metabolites can be used as markers with an intermediate timeframe between ethanol measurements and GGT and CDT with regard to recent alcohol consumption occurring between hours to 1 week. Additionally, these biomarkers offer a high ethanol-specificity in combination with approximately a twofold higher sensitivity in comparison with indirect alcohol markers. In case of forensic use of direct ethanol metabolites, caution has to be taken in interpretation and pre-analytical pitfalls should be considered.
Scientific Reports, 2018
Metabolomics studies of diseases associated with chronic alcohol consumption provide compelling evidence of several perturbed metabolic pathways. Moreover, the holistic approach of such studies gives insights into the pathophysiological risk factors associated with chronic alcohol-induced disability, morbidity and mortality. Here, we report on a GC-MS-based organic acid profiling study on acute alcohol consumption. Our investigation-involving 12 healthy, moderate-drinking young mensimulated a single binge drinking event, and indicated its metabolic consequences. We generated timedependent data that predicted the metabolic pathophysiology of the alcohol intervention. Multivariate statistical modelling was applied to the longitudinal data of 120 biologically relevant organic acids, of which 13 provided statistical evidence of the alcohol effect. The known alcohol-induced increased NADH:NAD + ratio in the cytosol of hepatocytes contributed to the global dysregulation of several metabolic reactions of glycolysis, ketogenesis, the Krebs cycle and gluconeogenesis. The significant presence of 2-hydroxyisobutyric acid supports the emerging paradigm that this compound is an important endogenous metabolite. Its metabolic origin remains elusive, but recent evidence indicated 2-hydroxyisobutyrylation as a novel regulatory modifier of histones. Metabolomics has thus opened an avenue for further research on the reprogramming of metabolic pathways and epigenetic networks in relation to the severe effects of alcohol consumption. Notwithstanding the encyclopaedic information on alcoholism, the WHO asserts that alcohol remains one of the world's leading risk factors for disability, morbidity and mortality-5.9% of all deaths worldwide are attributable to alcohol consumption, exceeding those from HIV/AIDS (2.8%), violence (0.9%) or tuberculosis (1.7%) 1. The tenth edition of the International Classification of Diseases lists at least 25 chronic conditions that are entirely attributable to alcohol; alcohol is also a risk factor in certain cancers, some tumours, numerous cardiovascular and digestive diseases, and many neuropsychiatric conditions 2. Brain image studies have revealed changes in brain structure during the progression from adolescence to adulthood 3,4 , a critical period characterized by increased brain connectivity and maturation of brain neural circuits. These changes are highly susceptible to the effects of exogenous substances, which likely include alcohol 5-7 , making children and adolescents especially vulnerable to alcohol-related harm 8. It was reported from a recent survey that approximately 50% of children (aged 11-14 years) in the UK have consumed alcohol, and 33% of adolescents (15-16 years) admitted to having experienced at least one episode of acute alcohol intoxication in the month preceding the survey 9 .
Metabolomics in alcohol research and drug development
Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism, 2008
Developers of new medications need to describe and predict the functional attributes of test compounds administered to cells, animals, and humans. Today, researchers increasingly appreciate the role that intermediary products (i.e., metabolites) generated in the course of various metabolic pathways play in both health and disease states and how their analysis can support development of new medications. Advances in analytical and computational techniques have facilitated the rise of new and powerful tools for measuring metabolic and biochemical pathways in such complex systems. Metabolomics--a systems biology approach to characterizing metabolites produced in biochemical pathways--is contributing to many studies of disease progression and treatment, although it has not yet been extensively applied in research on metabolic perturbations associated with alcohol abuse. However, numerous metabolomic approaches may contribute to alcohol-related research, as illustrated by studies on alcoh...