Biomarkers of alcohol consumption and related liver disease.

Abstract Alcohol abuse is a major cause of abnormal liver function throughout the world. While measurements of liver enzyme activities (GGT, ALT, AST) are important screening tools for detecting liver disease, due to lack of ethanol-specificity and inconsistencies regarding the definitions of significant alcohol consumption, several other blood tests are usually needed to exclude competing and co-existing causes of abnormal liver function. Information on the specific role of ethanol consumption behind hepatotoxicity may be obtained through measurements of blood ethanol and its specific metabolites (ethyl glucuronide, phosphatidylethanol, protein-acetaldehyde condensates and associated autoimmune responses). Recent studies have indicated that being overweight is another increasingly common cause of abnormal liver enzyme levels and adiposity may also increase the impact of ethanol consumption on liver pathology. Interestingly, increased liver enzyme activities in circulation may reflect not only hepatic function but can also serve as indicators of general health and the status of oxidative stress in vivo. ALT and GGT activities predict insulin resistance, metabolic syndrome, mortality from coronary heart diseases and even mortality from all causes. If the upper reference limits for liver enzyme activities were defined based on the data obtained from normal weight abstainers, the clinical value of liver enzyme measurements as screening tools and in patient follow-up could be significantly improved.

Evaluation of reference intervals for biomarkers sensitive to alcohol consumption, excess body weight and oxidative stress.

BACKGROUND: Unexplained liver enzyme activities are often found in health screening programs and constitute an increasingly common cause for referral to specialized clinics. Recent studies have indicated that both excess body weight and alcohol consumption may lead to metabolic aberrations which are readily reflected in the activities of liver enzymes in circulation. MATERIALS AND METHODS: We compared various laboratory markers and their upper normal limits in relation to information on alcohol consumption and BMI in a large population of apparently healthy individuals collected from Nordic countries. RESULTS: Based on the data obtained from normal weight abstainers (BMI 19-25 kg/m(2)) the upper normal limits in men should be 50 U/L for ALT, and 45 U/L (<40 years) and 70 U/L (>or=40 years) for GGT, while the current recommendations are 70 U/L, 80 U/L, and 115 U/L, respectively. Already in comparisons between normal weight abstainers and corresponding moderate drinkers notable impacts (+14% - +74%) on upper limits for these analytes were seen, which further grew when adiposity occurred together with alcohol drinking (+75% - +186%, BMI >or=27 kg/m(2)). In addition to liver enzymes, similar changes were also found for uric acid. CONCLUSIONS: Alcohol consumption and excess body weight even in apparently healthy individuals have a significant influence on liver enzyme activities, which may be due to a cumulative oxidative stress burden. The metabolic changes induced by adiposity or ethanol intake should be considered in the definition of normal ranges for all laboratory parameters sensitive to oxidative stress.

Gender-dependent impacts of body mass index and moderate alcohol consumption on serum uric acid--an index of oxidant stress status?

Uric acid seems to be causally involved in a variety of medical disorders involving oxidative stress. Although alcohol abuse and obesity are known to increase serum uric acid, the interactions between moderate drinking, adiposity, and uric acid metabolism have remained poorly understood. We examined serum uric acid concentrations from 2062 apparently healthy volunteers (970 men, 1092 women) reporting either no alcohol (abstainers) or <40 g of ethanol consumption per day (moderate drinkers). The study population was further classified according to BMI as follows: <19 (underweight), 19-25 (normal weight), 25-30 (overweight), and >30 (obese). Serum uric acid concentrations in male moderate drinkers were significantly higher, and in females they were lower, than in the corresponding groups of abstainers. In the BMI-based subgroups, the highest concentrations were found in those who were overweight or obese. Significant two-factor interactions occurred between gender and drinking status (p<0.001) and between gender and BMI (p<0.02). Serum uric acid also correlated with indices of hepatocellular health (GGT, ALT, AST). The data indicate distinct gender-dependent impacts of alcohol consumption and BMI on serum uric acid. These findings should be applicable to the assessment of oxidative stress status and associated morbidity in alcohol consumers and individuals with excess body weight.

IgA immune responses against acetaldehyde adducts and biomarkers of alcohol consumption in patients with IgA glomerulonephritis.

BACKGROUND: The pathogenesis of IgA glomerulonephritis (IgAGN) involves intense deposition of IgAs within the glomerulus. Although previous studies have shown that heavy drinking frequently leads to the generation of IgA antibodies against neo-antigens induced by ethanol metabolites and tissue deposition of IgAs, the associations between alcohol consumption, IgA immune responses, and kidney disease have not been examined. METHODS: A total of 158 IgAGN patients (96 men, 62 women) were classified as abstainers (n = 38), moderate drinkers (n = 114), and heavy drinkers (n = 6) based on self-reported alcohol consumption. The reference population included 143 individuals (99 men, 44 women) who were either apparently healthy abstainers (n = 31), moderate drinkers (n = 43), or heavy drinkers devoid of liver disease (n = 69). The assessments included various biomarkers of alcohol consumption: carbohydrate-deficient transferrin (CDT), glutamyl transferase, gamma-CDT (combination of GGR and CDT), mean corpuscular volume (MCV), tests for liver and kidney function, serum immunoglobulin A (IgA), and specific IgA antibodies against acetaldehyde-protein adducts. RESULTS: In male IgAGN patients, drinking status was significantly associated with MCV, p < 0.001; CDT, p < 0.01; and gamma -CDT, p < 0.05. In the reference population, all biomarkers and anti-adduct IgA levels were found to vary according to drinking status. In IgAGN patients, anti-adduct IgA levels were elevated in 63% of the cases but the titers did not associate with self-reported ethanol intake. CONCLUSIONS: These data indicate high levels of IgA antibodies against acetaldehyde-derived antigens in IgAGN patients, which may hamper the use of the immune responses as markers of alcohol consumption among such patients. Future studies on the pathogenic and prognostic significance of anti-adduct immune responses in IgAGN patients are warranted.

Biomarkers of liver status in heavy drinkers, moderate drinkers and abstainers.

AIMS: Although a wide variety of biomarkers reflecting liver status are known to be influenced by excessive ethanol consumption, the dose-response relationships between ethanol intake and marker changes have remained less understood. METHODS: Serum gamma-glutamyltransferase (GGT), aspartate aminotransferase (AST), alanine aminotransferase (ALT) activities, and ferritin and albumin protein concentrations were compared in a large population of heavy drinkers (105 men, 28 women), moderate drinkers (781 men, 723 women) and abstainers (252 men, 433 women), who were devoid of apparent liver disease. RESULTS: In heavy drinkers, serum GGT, AST, ALT, ferritin and albumin were all significantly higher than in moderate drinkers or abstainers (P < 0.001 for all comparisons). The highest incidences of elevated values were found for GGT (62%) followed by AST (53%), ALT (39%), ferritin (34%) and albumin (20%). Serum GGT (P < 0.001), ALT (P < 0.01) and ferritin (P < 0.05) in moderate drinkers were also higher than the levels observed in abstainers. When the study population was further divided into subgroups according to gender, significant differences between moderate drinkers and abstainers in GGT and ALT were noted in men whereas not in women. CONCLUSIONS: The data demonstrate that biomarkers of alcohol abuse and liver function may respond to even rather low levels of ethanol intake in a gender-dependent manner, which should be implicated in studies on the early-phase interactions of ethanol and the liver and in the definition of normal ranges for such biomarkers.

Effect of moderate alcohol consumption on liver enzymes increases with increasing body mass index.

BACKGROUND: Although both ethanol consumption and overweight alter the activities of hepatic enzymes in circulation, the differentiation of an alcohol or nonalcohol basis for such changes remains problematic. The magnitude of alterations occurring among moderate drinkers has remained obscure. OBJECTIVE: We examined the links between moderate ethanol consumption, body mass index (BMI; in kg/m(2)), and liver enzymes. DESIGN: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyltransferase (GGT) were recorded from 2,164 apparently healthy participants (1,028 men, 1,136 women) reporting either no alcohol (abstainers) or <40 g ethanol consumption per day (moderate drinkers). The study population was further classified according to BMI as follows: <19 (underweight), > or =19 and <25 (normal weight), > or =25 and <30 (overweight), and > or =30 (obese). RESULTS: Serum ALT (P < 0.05) and GGT (P < 0.001) but not AST (P = 0.805) activities in moderate drinkers were higher than those in abstainers. For all enzymes, a significant main effect was observed of increasing BMI, which was more striking in moderate drinkers than in abstainers. Tests of between-subjects effects indicated significant interactions with sex and drinking status, although not with sex and BMI. CONCLUSIONS: The effect of moderate alcohol consumption on liver enzymes increases with increasing BMI. These findings should be considered in the clinical assessment of overweight alcohol consumers and in the definition of normal ranges for liver enzymes. These results may also help to develop new approaches for examining patients with fatty liver induced by either ethanol or adiposity.