Critique 113: Metabolic and biochemical mechanisms by which alcohol consumption affects health — 11 June 2013

Whitfield JB, Heath AC, Madden PAF, Pergadia ML, Montgomery GW, Martin NG.  Metabolic and biochemical effects of low-to-moderate alcohol consumption. Alcohol Clin Exp Res 2013;37:575–586.

Authors’ Abstract

Background: Alcohol consumption has multiple biochemical consequences. Only a few of these are useful as diagnostic markers, but many reflect potentially harmful or beneficial effects of alcohol. Average consumption of 2 to 4 drinks per day is associated with lower overall or cardiovascular mortality risk than either lower or higher intake. We have analyzed the dose–response relationships between reported alcohol consumption and 17 biomarkers, with emphasis on intake of up to 3 drinks per day.

Methods: Biochemical tests were performed on serum from 8,396 study participants (3,750 men and 4,646 women, aged 51 ± 13 years, range 18 to 93) who had provided information on alcohol consumption in the week preceding blood collection.

Results: Gamma glutamyl transferase, alanine aminotransferase, aspartate aminotransferase, carbohydrate-deficient transferrin, urate, ferritin, and bilirubin showed little or no change with alcohol consumption below 2 to 3 drinks per day, but increased with higher intake. High-density lipoprotein cholesterol and albumin showed increasing results, and insulin showed decreasing results, across the entire range of alcohol use. Biphasic responses, where subjects reporting 1 to 2 drinks per day had lower results than those reporting either more or less alcohol use, occurred for triglycerides, glucose, C-reactive protein, alkaline phosphatase, and butyrylcholinesterase. Increasing alcohol use was associated with decreasing low-density lipoprotein cholesterol (LDL-C) in younger women, but higher LDL-C in older men.

Conclusions: Some markers show threshold relationships with alcohol, others show continuous ones, and a third group show biphasic or U-shaped relationships. Overall, the biochemical sequelae of low-to-moderate alcohol use are consistent with the epidemiological evidence on morbidity and mortality.

Forum Comments

The large majority of prospective epidemiologic studies have demonstrated a “J-shaped” or “U-shaped” relation between the consumption of alcohol and the risk of cardiovascular disease.  While the average amount of alcohol consumed is generally related to such risk, studies providing data on the pattern of drinking generally show an even greater reduction in the risk of cardiovascular disease at be associated with light-to-moderate drinking, especially the regular consumption of alcohol without binge drinking.

Numerous mechanisms for the beneficial effects of light drinking have been identified.  As well summarized by Brien et al (Effect of alcohol consumption on biological markers associated with risk of coronary heart disease: systematic review and meta-analysis of interventional studies. BMJ 2011;342:doi:10.1136/bmj.d636), mechanisms have been shown for alcohol’s effects on lipids, coagulation, inflammation, endothelial function, and other metabolic parameters.  Many studies have also shown that the polyphenols in wine have additional beneficial effects on risk of cardiovascular and other diseases.

The present paper describes the relation between reported alcohol consumption and a variety of metabolic and biochemical factors among a large number of subjects in a population-based study in Australia.  That study focused on genetic factors among twins and their families.  The main estimate of alcohol consumption was the reported total number of drinks in the preceding week from a retrospective alcohol diary collected at the time blood was drawn.  For most subjects, intake was also assessed from a telephone interview seeking an estimate of the average alcohol intake over the past year; the latter gave a lower estimated average alcohol intake, but essentially the same relation with metabolic and biochemical parameters as the alcohol diary.

The key findings of the study were a linear increase in HDL-cholesterol and a linear decrease in insulin levels with increasing amounts of alcohol.  For most other factors (including liver enzymes, triglycerides, blood glucose, and CRP), there was a “J-shaped” relation: lower values with light drinking and higher values with larger amounts of alcohol.  For most of these, there was a threshold value at which heavier drinking began to show adverse effects.  The lowest (most favorable) values varied by the measure: lowest triglycerides at about 1 to 2 drinks per day, lowest CRP at about 1 drink/day, lowest blood sugar and lowest alkaline phosphatase values at 1 to 3 drinks/day.

The authors conclude that “The pattern of potentially beneficial effects of alcohol on HDL-C and insulin increasing progressively as consumption increases, whereas the negative effects show thresholds, is consistent with net U- or J-shaped effects of alcohol on health.”    

Specific comments by Forum members:  Reviewer Puddey considered this to be “a very informative paper, from a well characterised and sizeable cohort, on the potential pathophysiological links between alcohol and either reduced or increased risk of disease. Potential confounding by smoking and obesity is described and has been controlled for in the regression analyses.” 

Forum members noted especially the very high percentage of subjects who met DMS-IV criteria for lifetime alcohol dependence (31.5% of men and 15.9% of women).  On the baseline questionnaire, most of these subjects reported a high number of drinks in the preceding week; however, such subjects also made up 25.3% of male and 11.3% of females who currently reported no alcohol consumption.  As stated by Forum member Lanzmann-Petithory, “Either this population is non-representative, or Australia has a serious problem of alcoholism.”

Forum member Ellison stated: “Given the high frequency of abuse, it is somewhat surprising that most factors were influenced favorably by light drinking.  The findings from this study provide support for the epidemiologic results typically found: less cardiovascular disease for light drinking and, in some studies, increased cardiovascular risk for heavier drinkers, those whose consumption exceeds a certain threshold of intake.”

Forum reviewers Waterhouse, Lanzmann-Petithory, and others were disappointed that the authors did not comment on the effects of the pattern of drinking, even though they collected daily consumption data.  Further, the authors do not show whether or not there was a relationship between beverage of choice and DSM-IV AD positive rating. That would be most interesting, as prior work by a number of investigators has shown less alcohol abuse among consumers of wine when compared with drinkers of other beverages.

Reviewer Skovenborg stated: “Overall, the metabolic and biochemical responses to alcohol consumption are consistent with previous studies and also consistent with the epidemiological evidence on morbidity and mortality. No big surprises here.  An analysis of the potential effects of a binge drinking pattern versus a regular, steady drinking pattern on the metabolic and biochemical responses to alcohol consumption would have been interesting.”  He added: “The markers of liver dysfunction related to alcohol showed little change with alcohol consumption below 2 to 3 drinks per day, confirming their value as markers of heavy consumption.”  He, and others, also commented on the very high percentage of subjects with a lifetime history of alcohol dependency, much higher than in other populations.  “I wonder whether the study participants are representative of the general population of Australia and whether the external validity of the study results is damaged by the large percentages of alcohol-dependant participants.”

Forum reviewer Van Velden and his associates previously carried out a clinical trial of the effects of wine and brandy, finding that both types of beverage markedly increased HDL-cholesterol, regardless of the presence or absence of the E4 allele of the Apolipoprotein E polymorphism.  In their studies, genetic factors modified the relation with triglycerides.  Van Velden states: “The problem with most epidemiological observations is that it is presumed that everybody will react the same to a nutritional intervention. With our knowledge of nutrigenetics, we know now that this is not the case. The mild increase in triglyceride concentrations observed with alcohol in some population studies may be relate mainly to people with an HFE mutation-positive abnormality, whereas subjects without this abnormality show little effect.”

Further comments from Forum member Skovenborg: “I agree with the comments of other Forum members about beverage-specific effects, and would add some data from our lab suggesting the importance of distinguishing wine from other alcoholic beverages and the importance of genetic polymorphisms in regulating biochemical markers of alcohol consumption.  We carried out a randomized clinical trial in conjuction with investigators in Barcelona and found that both wine and gin showed anti-inflammatory effects by reducing plasma fibrinogen and IL-1alpha levels. However, wine had the additional effect of decreasing hs-CRP, as well as monocyte and endothelial adhesion molecules (Estruch et a al. Different effects of red wine and gin consumption on inflammatory biomarkers of atherosclerosis: a prospective randomized crossover trial. Effects of wine on inflammatory markers.  Atherosclerosis. 2004,175:117-23).   Further, we found that compared to gin intervention, wine intake reduced plasma SOD activity and MDA levels; lag phase time of LDL oxidation analysis also increased 11.0 min (CI, 1.2-20.8; P=0.032) after wine, compared to gin, whereas no differences were observed between the two interventions in oxidation rate of LDL particles. Peroxide concentration in LDL particles also decreased after wine, as did plasma oxidized LDL concentrations (Estruch et al, Moderate consumption of red wine, but not gin, decreases erythrocyte superoxide dismutase activity: a randomised cross-over trial.  Nutr Metab Cardiovasc Dis 2011; 21:46-53).

Forum Summary

A large study from Australia, that included a high percentage of current or former alcohol abusers, related alcohol consumption with a variety of metabolic and biologic parameters that relate to health.  Included were markers of lipid function, inflammation, glucose metabolism, and liver function.  As expected, there was a linear increase in HDL-cholesterol with increasing alcohol intake; somewhat surprisingly, there was a linear decrease in insulin levels with increasing alcohol consumption (which may relate to the typical finding of a significantly lower risk of diabetes mellitus among moderate drinkers).  Essentially all of the other factors showed a “J-shaped” or “U-shaped” relation with alcohol: a decrease with small to moderate amounts of alcohol and an increase with larger intake. 

In their association with alcohol, the lowest (most favorable) values of parameters varied by the measure: lowest triglycerides at about 1 to 2 drinks per day, lowest CRP at about 1 drink/day, lowest blood sugar and lowest alkaline phosphatase values at 1 to 3 drinks/day.  Adverse effects on liver enzymes, blood glucose, and inflammatory markers showed a threshold level of intake that varied somewhat by marker.  For example, reported non-drinkers had higher values of CRP, triglycerides, and alkaline phosphatase; among drinkers, significant increases were seen only in consumers of 40 or more drinks/week.  Unfortunately, the investigators did not report on the pattern of drinking, which usually shows preferable results from regular, moderate intake of alcohol with no binge drinking.        

The key findings of the study can be summarized as favorable effects of moderate alcohol intake on HDL-cholesterol and insulin levels, and for most other factors (including liver enzymes, triglycerides, blood glucose, and the inflammatory marker CRP), a “J-shaped” relation: lower values with light drinking and higher values with larger amounts of alcohol.  For most of these, there was either no effect or a favorable effect until alcohol intake exceeded a “threshold value,” at which heavier drinking began to show adverse effects.

Forum reviewers agreed with the conclusion of the authors: “The pattern of potentially beneficial effects of alcohol on HDL-C and insulin increasing progressively as consumption increases, whereas the negative effects show thresholds, is consistent with net U- or J-shaped effects of alcohol on health.”  While actual health outcomes were not evaluated in this study, overall it provides strong support for the results of most prospective epidemiologic studies that show lower rates of cardiovascular and other diseases among light-to-moderate drinkers than among abstainers or heavy drinkers.   

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Comments on this critique by the International Scientific Forum on Alcohol Research were provided by the following members:

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy

R. Curtis Ellison, MD, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France

Ian Puddey, MD, Dean, Faculty of Medicine, Dentistry & Health Sciences, University of Western Australia, Nedlands, Australia

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Gordon Troup, MSc, DSc, School of Physics, Monash University, Victoria, Australia

David Vauzour, PhD, Senior Research Associate, Department of Nutrition, Norwich Medical School, University of East Anglia, Norwich, UK

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Andrew L. Waterhouse, PhD, Marvin Sands Professor, Department of Viticulture and Enology, University of California, Davis; Davis, CA, USA