Objective: To evaluate the effect of moderate alcohol consumption on the acute phase proteins C-reactive protein and fibrinogen.
Design: Randomized, diet-controlled, cross-over study.
Setting: The study was performed at TNO Nutrition and Food Research, Zeist, The Netherlands.
Subjects: Ten middle-aged men and 10 postmenopausal women, all apparently healthy, non-smoking and moderate alcohol drinkers, were included. One women dropped out because of a treatment-unrelated cause. The remaining 19 subjects finished the experiment successfully.
Interventions: Men consumed four glasses and women consumed three glasses of beer or no-alcohol beer (control) with evening dinner during two successive periods of 3 weeks. The total diet was supplied to the subjects and had essentially the same composition during these 6 weeks. Before each treatment there was a 1 week washout period to compensate for possible carry-over effects.
Results: Plasma C-reactive protein and fibrinogen levels were decreased by 35% (P=0.02) and 12.4% (P≤0.001), respectively, after 3 weeks' consumption of beer, as compared to no-alcohol beer consumption.
Conclusions: Moderate alcohol consumption significantly decreased plasma C-reactive protein and fibrinogen levels. An anti-inflammatory action of alcohol may help explain the link between moderate alcohol consumption and lower cardiovascular disease risk.
Sponsorship: Dutch Foundation for Alcohol Research (SAR).
Coronary heart disease (CHD) is the leading cause of death in the developed world. Atherosclerosis, which damages the coronary arteries, is the primary disease mechanism of CHD. Atherosclerosis is clearly multifactorial, and it is now recognized that inflammation within the lesions contributes considerably to the initiation and progression. C-reactive protein (CRP), a marker for systemic inflammation, predicts cardiovascular events among apparently healthy men and women. Even modest elevations of the concentration of CRP were strongly predictive (Kuller et al, 1996; Mendall et al, 1996; Ridker et al, 1997,1998, 2000; Strandberg & Tilvis 2000; Tracy et al, 1997). Recently, two epidemiological studies showed that moderate alcohol consumption is associated with decreased CRP concentrations (Imhof et al, 2001; Koenig et al, 1999). The aim of the present study was to further investigate the effect of moderate alcohol consumption on CRP in a randomized, diet-controlled, cross-over study. Fibrinogen was evaluated as positive control, because it is a liver protein with an acute phase behavior, and it is known to decrease after moderate alcohol consumption (Dimmitt et al, 1998; Hendriks & Van der Gaag, 1998; Pellegrini et al, 1996). Moreover, elevation of fibrinogen is a well-recognized risk marker for coronary events (Iacoviello et al, 1998).
Ten middle-aged men (45–64 y) and 10 postmenopausal women (49–62 y), all non-smoking, were recruited from the pool of volunteers of TNO Nutrition and Food Research and through an advertisement in a local newspaper. The protocol was carefully explained to the volunteers and their written informed consent was obtained. Subjects were eligible if they fulfilled the following inclusion criteria: consumption of ≤28 alcohol-containing beverages per week for men and ≤21 for women, body mass index (BMI) between 21 and 31 kg/m2 and no family history of alcoholism. Subjects were healthy as indicated by the values of the pre-study laboratory tests, which were all within the normal range. In addition, they were healthy as indicated by their medical history and a physical examination by the medical investigator. Medication use based on prescription by a physician was an exclusion criterion. During the study volunteers were only allowed to use paracetamol as painkiller. Aspirin was not allowed as it might have an anti-inflammatory effect (Ridker et al, 1997). The postmenopausal women had not had menses for at least a year, were not ovariectomized and did not use hormone replacement therapy. Blood concentrations of follicle-stimulating hormone (FSH) and estradiol were >40 IU/l and <70 pg/ml, respectively. One postmenopausal woman dropped out because of a treatment-unrelated cause. The remaining 19 subjects finished the experiment successfully. Characteristics of the study population are given in Table 1.
The subjects entered a randomized cross-over trial consisting of two periods of 3 weeks. Five men and five women were randomly allocated to the sequence beer (Amstel Bier, Amsterdam, The Netherlands; 5 vol% alcohol) followed by no-alcohol beer (Amstel Malt Bier, Amsterdam, The Netherlands; <0.1 vol% alcohol). The other half of the subjects consumed no-alcohol beer first followed by beer. In this way, any systematic bias due to the beverage order or to drift of variables over time was eliminated (Snedecor & Cochran, 1980). Both the participants and staff were unblinded to the treatment sequence.
Four glasses of each beverage for men and three glasses of each beverage for women were consumed daily during the meal. During the beer period, alcohol intake equaled 40 and 30 g a day for men and women, respectively. To exclude any dietary confounding, the total diet was supplied. They consumed all foods at home, except for evening dinner, which was served at TNO Nutrition and Food Research, together with the beer or no-alcohol beer. Subjects were not allowed to eat or drink anything but the foods supplied, except for tap water and coffee (limited amount of creamer was supplied) and they were asked to maintain their habitual physical activity pattern. There was a 1 week washout period (no alcohol or no-alcohol beer) before each treatment to compensate for possible carry-over effects.
We considered the energy provided by alcohol to be 19.6 kJ (4.7 kcal) per gram, assuming the net utilizable energy content of alcohol is 70% of the theoretically present 28 kJ (7 kcal) per gram (Rumpler et al, 1996; Westerterp, 1996). Taking this into account, no-alcohol beer contained approximately 90 kJ/100 ml (22 kcal/100 ml), and alcoholic beer contained approximately 130 kJ/100 ml (31 kcal/ 100 ml). The source of energy in no-alcohol beer was almost 100% carbohydrates, in alcoholic beer approximately 40 energy percent (en%) was derived from carbohydrates and 60 en% from alcohol. The diets, including beer or no-alcohol beer, were comparable so that the macronutrient composition and total energy were the same during the beer and no-alcohol beer period. The macronutrient composition of the diet was based on the most recent national Dutch food consumption survey of 1998 (Anonymous, 1998). Diets during the beer and no-alcohol beer period consisted of approximately 17 en% protein, 39 en% fat and 44 en% carbohydrate, for both males and females. Daily energy requirement was estimated for each subject according to Schofield (1985).
The diet was provided in seven different levels of energy intake per day, 7, 8, 9, 10, 11, 12 and 13 MJ (1.7, 1.9, 2.2, 2.4, 2.6, 2.9 and 3.1 Mcal), depending on the body weight of the subject. Body weight was determined every 3 or 4 days. When a subject's body weight deviated more than 1.5 kg from his or her weight at the first experimental day, energy supply was adjusted (±1 MJ (0.24 Mcal)), without changing the macronutrient composition, in order to maintain body weight. Compliance with the protocol, physical adverse events and medicine use was checked by a daily questionnaire.
The study was performed according to the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) Guideline for Good Clinical Practice (Anonymous, 1995), complied with the Declaration of Helsinki, and was approved by the independent Medical Ethical Committee of TNO Nutrition and Food Research.
Blood collection and sample preparation
Blood was taken from the intermedian cubital vein and collected in ice-chilled tubes containing CTAD and in tubes containing gel and clot activator (Becton Dickinson, Vacutainer Systems). To obtain plasma and serum, the blood was centrifuged for 15 min at 2000 g and 4°C, between 15 and 30 min after collection. All aliquots were stored at −80°C until analysis.
Blood alcohol concentrations (BAC)s were measured enzymatically (Roche Diagnostics GmbH, Mannheim, Germany) in serum samples collected at 1 h after dinner on the last evening of each of the two experimental periods.
At the end of each of the two experimental periods fasting blood samples were collected in the morning. In plasma, CRP was measured in one batch with a sensitive sandwich enzyme-immunoassay (intra-assay variation 5.2%) using polyclonal antibodies (Dako, Copenhagen, Denmark) as decribed by De Maat et al (1996), with a sensitivity of >0.1 mg/l. Plasma fibrinogen levels were determined according to the method of Von Clauss (1957) (intra-assay variation 4%). Serum triglycerides and HDL-cholesterol were determined using enzymatic methods (Roche Diagnostics GmbH). Activities of the liver enzymes asparagine aminotransferase (ASAT), alanine aminotransferase (ALAT) and γ-glutamyltransferase (GGT) were determined in serum using commercially available testkits (Roche Diagnostics GmbH). Staff conducting the laboratory analyses were blind to the group assignments.
Data were analyzed using the SAS statistical software package (SAS/STAT Version 6, SAS Institute, Cary, NC, USA). The outcome measures were tested for normality. Treatment effects were assessed by analysis of variance, by use of general linear modeling, using as factors gender, beverage, and gender in combination with beverage. To test for carry-over effects the factor treatment order was also used in this model. Differences within men and women were also examined. Correlation coefficients (Pearson's or Spearman's) were computed to assess associations between changes in outcome measures.
No important deviations in consumption of the supplied foods and drinks occurred during the study and average body weight did not differ between beer and no-alcohol beer treatment periods (data not shown). Physical adverse events included some minor headaches and common colds mainly (data not shown). Medication was rarely used and no medicine was taken at least 24 h before blood sampling (data not shown).
The median BAC at 1 h after dinner with alcoholic beer was 10.0 mmol/l. The median BAC in men and women was 11.0 and 9.4 mmol/l, respectively.
Plasma CRP levels
No carry-over effects were seen. Plasma CRP distribution was skewed. Log transformation resulted in normalization of the distribution. Statistical analyses were performed on the natural logarithm of this variable and median values are presented. Plasma CRP concentrations were significantly decreased by 35% (P=0.02) after 3 weeks' consumption of beer as compared to no-alcohol beer consumption (Table 2 and Figure 1). Both in men and women separately a trend was seen to decreased plasma CRP levels after beer consumption, which however was only significant in women (Table 2). Plasma CRP levels after beer consumption showed a significant positive correlation with plasma CRP levels after no-alcohol beer consumption (Spearman's r=0.79, P≤0.001). The decrease in plasma CRP levels after beer consumption was larger for subjects with higher concentrations of plasma CRP levels after the no-alcohol beer period (Figure 1).
Plasma fibrinogen levels
Plasma fibrinogen levels were significantly decreased by 12.4% (P≤0.001) after beer consumption (Table 2 and Figure 2). In both men and women the decrease in plasma fibrinogen after beer consumption as compared to no-alcohol beer consumption was significant (Table 2).
Serum HDL-cholesterol and triglyceride levels
After 3 weeks' daily beer consumption serum HDL-cholesterol concentrations were significantly increased by 11% (P≤0.001), as compared to no-alcohol beer consumption (Table 2). The decrease in CRP after moderate alcohol consumption was not correlated with the increase in HDL-cholesterol (Pearson's r=−0.19, P=0.45). Serum triglyceride levels were not affected (Table 2).
Alcohol did not affect activities of the liver enzymes ALAT and ASAT. There was a slight increase in GGT after 3 weeks' consumption of beer as compared to no-alcohol beer consumption (Table 2), which was not correlated with the decrease in CRP (Spearman's r=−0.007, P=0.98). In women only both GGT and ALAT activities were slightly increased (Table 2). These increases in liver enzyme activity were not correlated with the decrease in CRP (Pearson's r=0.52, P=0.16 and Spearman's r=0.02, P=0.96, respectively).
The inverse association between moderate drinking and CHD mortality is well established. The benefits of alcohol appear to focus on three major physiological systems. First, increases in HDL-cholesterol levels (Hendriks et al, 1998; Van der Gaag et al, 1999), with associated increases in paraoxonase activity (Van der Gaag et al, 1999) and cholesterol efflux (Van der Gaag MS et al, 2001). Second, alcohol may stimulate fibrinolysis (Hendriks et al, 1994) and decrease coagulation (Dimmitt et al, 1998). The third system might be a decrease in inflammatory processes (Imhof et al, 2001; Koenig et al, 1999). The present study showed that a moderate dose of alcohol with evening dinner decreased plasma CRP and fibrinogen concentrations in healthy middle-aged men and postmenopausal women already within 3 weeks. Observations from prior studies support the hypothesis that CRP is a highly sensitive marker of systemic (micro)-inflammation (atherosclerosis), tissue damage and infection. Upon stimulation its plasma concentration can increase up to 1000-fold (Koenig & Wanner, 1999). About 90% of apparently healthy individuals have plasma CRP concentrations <3 mg/l and 99% have plasma concentrations <10 mg/l (Pepys, 1996). The plasma CRP levels in this study were not higher than 5 mg/l, therefore we assume that inflammation, tissue damage or infection could not have influenced the results.
The decrease in plasma CRP level may contribute to reduction of CHD risk in moderate drinkers. A greater plasma CRP decrease in subjects with high plasma CRP concentrations may explain why plasma CRP did not significantly change in men. Men had overall lower plasma CRP levels as compared to postmenopausal women, which is in agreement with other studies (Gram et al, 2000; Harris et al, 1999). Excluding the ‘outlier’ (a male volunteer in whom plasma CRP concentration after the no alcohol beer period was 3.34 mg/l and after the beer period 0.66 mg/l), did not change the conclusions. The decrease in plasma CRP concentration after moderate alcohol intake was still significant (P=0.02).
Mezzano et al (2001) did not observe a change in plasma CRP levels in an intervention study with a Mediterranean or high-fat diet combined with moderate red wine intake. However, the study had a completely different design with young male students, who had low plasma CRP levels. Also the amount of alcohol consumed was lower as compared to our study (23.2 vs 40/30 g/day).
The mechanism causing moderate alcohol consumption to reduce CRP levels needs further investigation. The mechanism may involve nuclear factor (NF)-κB (Blanco-Colio et al, 2000). NF-κB is a redox-sensitive transcription factor which activates genes involved in the immune, inflammatory, or acute-phase response, such as cytokines interleukin 6 (Ridker et al, 2000) and tumor necrosis factor α (Mendall et al, 1996), which regulate CRP production by the liver.
In our study different amounts of alcohol for men and women were introduced (40 vs 30 g, respectively), as women generally have a lower body weight, a lower percentage of body water and a slower metabolism of alcohol. In previous studies we have seen that peak levels of BACs were achieved 1 h after dinner with alcoholic beverage, thereafter BACs were decreasing (Pikaar et al, 1988; Wedel et al, 1991). Therefore, in the present study BACs were obtained only at 1 h after dinner. The BACs were close to 10.85 mmol/l (0.5 g/l), the Dutch legal limit for drinking and driving. Similar BACs have been observed in our previous studies using the same amount of alcohol with the evening meal (Hendriks et al, 1994; Van der Gaag et al, 1999). Thus the observed effects on outcome measures occurred after relatively low BACs. Although higher BACs occurred at 1 h after dinner in men as compared to women, effects on plasma CRP levels were lower in men as compared to women.
Elevated fibrinogen in the circulation is an independent risk marker for vascular diseases (Iacoviello et al, 1998). The observed decrease in plasma fibrinogen levels after moderate alcohol consumption is in agreement with results of previous studies (Dimmitt et al, 1998; Hendriks & Van der Gaag, 1998; Pellegrini et al, 1996).
Moderate alcohol consumption increased serum HDL-cholesterol concentrations significantly, but did not affect serum triglyceride levels. These findings were also observed in our earlier studies (Hendriks et al, 1998; Van der Gaag et al, 1999).
In many investigations alcohol is supplied in the fasting state. We supplied the beverages with evening dinner, as this better represents a habitual pattern of moderate alcohol intake in The Netherlands. Since the study had a balanced cross-over design and was diet-controlled, the observed effects cannot be attributed to confounding such as carry-over, variation between individuals and diet.
Beer was chosen because we wanted to investigate a commonly consumed alcoholic beverage. No-alcohol beer of the same brand was chosen as control beverage. This no-alcohol beer is produced in the same way as the alcohol-containing beer, but at the end of the production process the alcohol is taken out.
Potential confounding variables in this study could have been physical adverse events and medication. Physical adverse events included some minor headaches and common colds. Medication was rarely used and no medicine was taken at least 24 h before blood sampling. The effect of the specific medication used had worn off by that time. These minor physical adverse events and rarely used medication could not have influenced the results. In addition, the plasma CRP levels in this study were not above the level for inflammation, tissue damage or infection.
Liver enzymes were considered as possible confounders because the liver is the sole determinant of plasma CRP concentration. In women only both GGT and ALAT activities were slightly increased after beer consumption as compared to no-alcohol beer consumption. These changes were not considered clinically significant, as these changes were all within the normal values for GGT and ALAT (GGT between 7 and 32 U/l and ALAT between 10 and 35 U/l; Roche Diagnostics GmbH). Besides that, the increase in liver enzyme activity after alcohol consumption could not explain the observed decrease in plasma CRP, because there was no correlation.
BMI could also have confounded the results, as higher BMI is associated with higher CRP concentrations (Ford, 1999; Visser et al, 1999). However, there was no significant BMI effect nor an interaction between BMI and treatment in our study (P=0.13 and P=0.99, respectively). A previous study suggested that HDL has anti-inflammatory properties (Strandberg et al, 2000). Thus HDL-cholesterol could be a confounding factor in CRP changes. However, in our study there was no correlation between the decrease in plasma CRP levels with the increase in serum HDL-cholesterol concentrations after moderate alcohol consumption.
In conclusion, moderate alcohol consumption significantly decreased plasma CRP and fibrinogen levels. An anti-inflammatory action of alcohol may help explain the link between moderate alcohol consumption and lower cardiovascular disease risk. Our findings are in agreement with epidemiological data (Imhof et al, 2001; Koenig et al, 1999). Alcohol consumption is a life-style factor, which in clinical and epidemiological studies may affect the association between CRP and CHD, and may therefore be considered as a possible confounder.
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We acknowledge all those involved in the conduct of the study and thank the volunteers for their enthusiastic participation.
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Sierksma, A., van der Gaag, M., Kluft, C. et al. Moderate alcohol consumption reduces plasma C-reactive protein and fibrinogen levels; a randomized, diet-controlled intervention study. Eur J Clin Nutr 56, 1130–1136 (2002). https://doi.org/10.1038/sj.ejcn.1601459
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