Archives: Summaries of Critiques:

(Presented below are summaries of critiques, by topic and inverse chronological order. For access to the full critique, go to Recent Reports on the Home Page and find the detailed report by date and number.)

Alcohol and Cardiovascular Disease

Critique 040. Lower risk of coronary heart disease from alcohol, even with heavy drinking. 27 April 2011

Reference: Le Strat Y, Gorwood P. Hazardous drinking is associated with a lower risk of coronary heart disease: Results from a national representative sample. Am J Addict 2011;20:257–263.

Using data from The 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions study (the NESARC study, n = 43,093), the authors of this paper conclude that alcohol may have cardioprotective effects not only in moderate drinkers, but also in individuals with patterns of use traditionally considered as “hazardous.” While such a finding has been shown in some population studies, there were questions by Forum reviewers as to the adequacy of the method for diagnosing coronary artery disease: self-report, with most subjects listing angina pectoris, a “soft” criterion for coronary disease.

In addition, the categories of drinking used in this study were very broad: rare or only occasional drinkers were combined with regular drinkers up to 7 or 14 drinks per week in the “moderate” category; the “hazardous” category included a broad range of drinkers, from a minimal increase over the recommended limits to very heavy drinkers. The pattern of drinking (especially the number of days per week that alcohol was consumed) was not reported, making it difficult to separate regular from heavy week-end drinkers. The effects of heavier drinking on other conditions (such as alcohol-related liver disease, mortality, etc.) were not included in this analysis.

It is physiologically possible that even hazardous use of alcohol, like moderate use, may well lead to cleaner arteries and therefore lower rates of coronary artery disease. If this is the case, an explanation for the increases in cardiovascular mortality reported for heavy drinkers in many studies may relate not directly to coronary artery disease, but to conditions such as cardiomyopathy or cardiac arrhythmias. However, the rates of accidents, suicide and other morbidity associated with hazardous alcohol use may well overcome any protective effects on coronary disease.

Critique 035. A review of the association of alcohol consumption with cardiovascular disease outcomes. 5 March 2011

Reference: Ronksley PE, Brien SE, Turner BJ, Mukamal KJ, Ghali WA. Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ 2011;342:d671; doi:10.1136/bmj.d671.

In an excellent summary, the authors of this paper have synthesized results from longitudinal cohort studies comparing alcohol drinkers with non-drinkers for the outcomes of overall mortality and mortality from cardiovascular disease (CVD), incident coronary heart disease (CHD), mortality from CHD, incident stroke, and mortality from stroke. They conclude that light to moderate alcohol consumption is associated with a reduced risk of multiple cardiovascular outcomes. Further, they suggest that current scientific data satisfy Hill criteria indicating causality, that alcohol intake is the cause of the lower risk of cardiovascular disease among moderate drinkers.

Forum members thought that this was a very well-done, comprehensive summary of a large number of studies on alcohol and cardiovascular disease. Some believed that two topics were not adequately discussed: (1) greater benefits from wine than from other beverages, a result seen in many studies, and (2) the importance of the pattern of drinking on the health effects of alcohol. However, Forum members welcomed the discussion in the paper as to causality and regarding future directions in research, with more emphasis into how physicians and individual patients might respond to encouragement to consume alcohol for its potentially beneficial effects on cardiovascular disease. Most believe that there is no substitute for balanced judgment by a knowledgeable, objective health professional when discussing alcohol intake, and this requires is a synthesis of common sense and the best available scientific facts as they apply to the individual.

Critique 034. A review of interventional studies in humans showing effects of alcohol on risk factors for cardiovascular disease 5 March 2011

Reference: Brien SE, Ronksley PE,Turner BJ, Mukamal KJ, Ghali WA. 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:d636; doi:10.1136/bmj.d636.

A summary paper on the effects of alcohol consumption on biologic mechanisms associated with coronary heart disease provides an excellent review of a large number of intervention studies in humans. Appropriate analyses were done and the results are presented in a very clear fashion, although there was little discussion of the separate, independent effects of alcohol and polyphenols on risk factors.

The trials the authors reviewed have demonstrated that the moderate intake of alcoholic beverages leads to increases in HDL-cholesterol, apolipoprotein A1, and adiponectin and decreases in fibrinogen, all factors associated with a lower risk of heart disease. The findings described in this paper strengthen the case for a causal link between alcohol intake and a reduced risk of coronary heart disease, suggesting that the lower risk of heart disease observed among moderate drinkers is caused by the alcoholic beverage itself, and not by other associated lifestyle factors.

Critique 033. Moderate-to-heavy alcohol intake may increase risk of atrial fibrillation.

12 February 2011

Reference: Kodama S, Saito K, Tanaka S, Horikawa C, Saito A, Heianza Y, Anasako Y, Nishigaki Y, Yachi Y, Iida KT, Ohashi Y, Yamada N, Sone H. Alcohol consumption and risk of atrial fibrillation. A meta-analysis. J Am Coll Cardiol 2011;57:427–436.

A number of well-done studies have shown an increase in the risk of atrial fibrillation to be associated with heavy alcohol intake or with alcoholism. Most previous studies suggest little if any increase in risk from light-to-moderate drinking. The present study was a meta-analysis based on 14 studies from Europe or North America. It showed an increase in risk with alcohol, but there were limited dose-response data to determine if there was a threshold above which the risk was increased. Overall, the scientific evidence from many studies suggests that at least heavy drinking may increase the risk of atrial fibrillation, although whether light-to-moderate intake increases the risk seems unlikely. Previous basic scientific data of mechanisms of atrial fibrillation have suggested that alcohol has little effect on this arrhythmia.

Critique026. Chinese study suggests that alcohol increases angiographically significant coronary artery disease. 8 December 2010

Reference: Zhou X, Li C, Xu W, Hong X, Chen J. Relation of alcohol consumption to angiographically proved coronary artery disease in Chinese men. Am J Cardiol 2010;106:1101–1103.

Among a large number of Chinese men presenting with chest pain or EKG changes, sequential subjects undergoing cardiac angiography were evaluated for obstructive coronary artery disease (CAD) lesions according to their reported recent alcohol intake. The study population consisted of 1,476 consecutive men 36 to 84 years of age; participants were categorized as nondrinkers, light drinkers, moderate drinkers, or heavy drinkers. Adjusted odds ratios for angiographically proved CAD for light, moderate, and heavy drinking were 1.16 (95% confidence interval 0.68 to 1.94), 1.78 (1.35 to 2.27), and 2.18 (1.46 to 3.25). Compared to non-drinking, adjusted odds ratios were 1.03 (0.54 to 1.87) for drinking 0 to 15 years, 1.61 (1.28 to 2.14) for 16 to 30 years, and 1.98 (1.23 to 3.05) for >30 years. The authors concluded that moderate-to-heavy alcohol consumption increased the risk of CAD in Chinese men. CAD risk tended to increase with an increase in frequency and duration of drinking.

This was a very select group of patients (those presenting with chest pain or EKG changes), and not typical of the Chinese population. No information was available on drinking patterns or on previous alcohol intake. Further, a recent large population-based study from mainland China showed that consumers of alcohol were less likely to develop coronary disease, results similar to those in most Western populations. It is not possible from the present study to say that the association of alcohol intake with CAD is different between Chinese and Western populations, as the present study gives results only for a very select group of patients.

The most important outcome regarding CAD is the occurrence of clinical events (myocardial infarction, cardiac death, etc.). The detection of such events requires long-term follow-up studies to be able to judge the overall effects of alcohol drinking on CAD.

Critique 025. Pattern of drinking and type of beverage affect the relation of alcohol intake to coronary heart disease 1 December 2010

Reference: Ruidavets J-B, Ducimetièere P, Evans A, Montaye M, Haas B, Bingham A, Yarnell J, Amouyel P, Arveiler D, Kee F, Bongard V, Ferrières J. Patterns of alcohol consumption and ischaemic heart disease in culturally divergent countries: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). BMJ 2010;341:c6077 doi:10.1136/bmj.c6077.

Using cohort data from Belfast and France, investigators related weekly alcohol consumption, incidence of binge drinking (alcohol >50 g on at least one day a week), incidence of regular drinking (at least one day a week, and alcohol <50 g if on only one occasion), volume of alcohol intake, frequency of consumption, and types of beverage consumed to risk of coronary heart disease (CHD) events over a 10 year follow-up period. Overall, 60.5% of subjects from N. Ireland and 90.6% of French reported drinking alcohol at least once a week. Among drinkers, 12% of men in Belfast drank alcohol every day compared with 75% of men in France. Mean alcohol consumption was 22.1 g/ day in Belfast and 32.8 g/day in France. Binge drinkers comprised 9.4% and 0.5% of the Belfast and France samples, respectively.

Results showed that, after multivariate adjustment, the hazard ratio for hard coronary events compared with regular drinkers was 1.97 (95% CI 1.21 – 3.22) for binge drinkers, 2.03 (95% CI 1.41 – 2.94) for never drinkers, and 1.57 (95% CI 1.11 – 2.21) for former drinkers. The hazard ratio for hard coronary events in Belfast compared with in France was 1.76 (95% CI 1.37 to 2.67) before adjustment, and 1.09 (95% CI 0.79 to 1.50) after adjustment for alcohol patterns and wine drinking. Only wine drinking was associated with a lower risk of hard coronary events, irrespective of the country.

The authors conclude that regular and moderate alcohol intake throughout the week, the typical pattern in middle-aged men in France, is associated with a low risk of ischemic heart disease, whereas the binge drinking pattern more prevalent in Belfast confers a higher risk. While a strong inverse association between moderate alcohol consumption and cardiovascular disease has been demonstrated for decades, more recent research has emphasized the importance of the pattern of drinking (regular moderate versus episodic or binge drinking). Further, there continues to be debate about the potential greater effect of wine versus other beverages containing alcohol. This study shows that regular moderate drinking (especially of wine) is associated with lower risk of MI, but episodic or binge drinking (especially of beer or whiskey) increases the risk. Lifetime abstinence has a similar adverse relation to CHD as does episodic or binge drinking.

Critique 010. Should moderate alcohol consumption be advised following a heart attack? 30 June 2010

Reference: Carter MD, Lee JH, Buchanan DM, Peterson ED, Tang F, Reid KJ, Spertus JA, Valtos J, O’Keefe JH. Comparison of outcomes among moderate alcohol drinkers before acute myocardial infarction to effect of continued versus discontinuing alcohol intake after the infarct. Am J Cardiol 2010 (Published early online).

There has been considerable recent interest in the effects of alcohol consumption following an acute myocardial infarction (AMI). In an observational study among 325 subjects who were moderate drinkers prior to an AMI, 84% continued to drink and 16% quit. While most of the outcome measures showed no statistically significant effects between the two groups of patients, all outcomes showed a tendency towards better physical and mental health outcomes for persistent drinkers in comparison with those who quit drinking.

A key problem with this analysis, and with all observational epidemiologic studies on this topic, is that the reason that some subjects stopped drinking after having an AMI, while others continued to drink, is not known. Even though adjustments were made for many known related factors, there is always the possibility that subjects who stopped drinking were “sicker” in many ways than those who persisted in their alcohol consumption.

It may well require a randomized trial, in which some subjects having an AMI are randomly advised to continue to drink and others advised to stop drinking, to be able to determine reliably the effects on the clinical course of the persistence of alcohol intake following an AMI.

Critique 006. For patients who already have cardiovascular disease, continued moderate alcohol consumption may reduce their risk of death 2 June 2010

Reference: Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano G. Contemporary Reviews in Cardiovascular Medicine. Cardiovascular and overall mortality risk in relation to alcohol consumption in patients with cardiovascular disease. Circulation 2010;121;1951-1959.

This review paper in Circuation summarizes data from 8 epidemiologic studies of subjects with cardiovascular disease (CVD) as to their subsequent mortality (both CV and total-mortality) according to their alcohol consumption. Most studies showed significantly lower risk of both CV and total mortality for patients with CVD who were consumers of alcohol.

Despite these clear-cut findings, the authors were very cautious in their conclusions, focusing on the dangers of excessive drinking and not encouraging cardiovascular patients who do not drink to start regular drinking. They state that moderate consumers of alcohol who have CV disease should not be advised to stop drinking, but should be advised to not consume alcohol more heavily.

It is interesting that these authors published the meta-analysis upon which this review is largely based in the Journal of the American College of Cardiology earlier in 2010. In that paper, their conclusions were less restrained: “Cardiologists should be aware that regular, moderate alcohol consumption, in the context of a healthy lifestyle (increased physical activity, no smoking), dietary habits (decreased dietary fat intake, high consumption of fruit and vegetables), and adequate drug therapy, would put their patients at a level of cardiovascular or mortality risk substantially lower than either abstainers or heavy or binge drinkers.”

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Alcohol and Metabolic Diseases

Critique 024. Moderate alcohol consumption lowers risk of metabolic diseases in a population with high mean alcohol intake. 28 November 2010

Reference: Clerc O, Nanchen D, Cornuz J, Marques-Vidal P, Gmel G, Daeppen J-B, Paccaud F, Mooser V, Waeber G, Vollenweider P, Rodondi N. Alcohol drinking, the metabolic syndrome and diabetes in a population with high mean alcohol consumption. Diabet Med 2010;27:1241–1249.

A cross-sectional analysis of data from subjects in Switzerland related varying levels of alcohol intake to the presence of diabetes mellitus, the “metabolic syndrome,” and an index of insulin resistance (HOMA-IR). The strengths of this paper include being population-based and having a large number of subjects who reported that they consumed 14 or more drinks/week. Also, there was a good percentage (27%) of subjects reporting no alcohol intake during the one week of assessment used for classifying subjects. Another strength is the careful confirmation of drinking status with state-of-the-art laboratory tests. In multivariate analysis, the prevalence of the metabolic syndrome, diabetes and mean HOMA-IR decreased with low-risk drinking and increased with high-risk drinking. No differences were noted according to the type of beverage consumed.

This is a cross-sectional analysis, so a causative relation between alcohol intake and the metabolic outcomes cannot be assessed. Still, the data support much that has been shown in prospective studies. Several Forum members commented on potential problems when considering a number of physiologic conditions as the “metabolic syndrome” and focusing therapy on the syndrome; they believed that each metabolic factor should be evaluated and treated singly.

Critique 019. Both alcohol and caffeinated coffee intake are associated with lower risk of diabetes in African-American women. 27 September 2010

Reference: Boggs DA, Rosenberg L, Ruiz-Narvaez EA, Palmer JR. Coffee, tea, and alcohol intake in relation to risk of type 2 diabetes in African American women. Am J Clin Nutr 2010;92:960–966.

In a very large cohort of African-American women in the US, the association between the consumption of alcohol, tea, and coffee was related to the development of type 2 diabetes mellitus over a follow-up period averaging 12 years. Tea and decaffeinated coffee showed no relation with diabetes, but the intake of both caffeinated coffee and alcohol showed a significant inverse association.

This paper is particularly important because some previous studies have not shown a strong association between alcohol and the risk of cardiovascular disease among African-Americans. African-Americans, especially women, tend to drink little alcohol, yet are at markedly increased risk of diabetes. In the present study, the approximately 30% lower risk for moderate alcohol drinkers was about the same in these African-American women as has been found in many previous studies of whites.

Critique 003. Moderate alcohol consumption markedly reduces the risk of diabetes mellitus, even among subjects with otherwise very healthy lifestyles 17 May 2010

Reference: Joosten MM, Grobbee DE, van der A DL, Verschuren WWM, Hendriks HFJ, Beulens JWJ. Combined effect of alcohol consumption and lifestyle behaviors on risk of type 2 diabetes. Am J Clin Nutr 2010;91: 1777-1783.

In a very well-done analysis from a large Dutch population, it was shown that moderate drinking considerably lowers the risk of developing type 2 diabetes even among subjects who are otherwise following a healthy lifestyle (not obese, non-smokers, physically active, eating a healthy diet). Thus, it indicates that the effect of moderate drinking on lowering the risk of diabetes cannot be explained by other healthy lifestyle habits of such drinkers. Moderate drinking should be considered as a complement, and not as an alternative, to other healthy lifestyle habits that lower the risk of chronic diseases such as diabetes and coronary heart disease.

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Alcohol and Cognitive Function/Dementia

Critique 036. Alcohol consumption after age 75 associated with lower risk of developing dementia- 7 March 2011

Reference: Weyerer S, Schaufele M, Wiese B, Maier W, Tebarth F, van den Bussche H, Pentzek M, Bickel H, Luppa M, Riedel-Heller SG, for the German AgeCoDe Study Group (German Study on Ageing, Cognition and Dementia in Primary Care Patients). Current alcohol consumption and its relationship to incident dementia: results from a 3-year follow-up study among primary care attenders aged 75 years and older. Age and Ageing 2011; 0: 1–7; doi: 10.1093/ageing/afr007.

A population-based study of elderly Germans, aged 75 and older, evaluated the association between alcohol consumption and incident overall dementia and Alzheimer dementia over 3 years. There was good ascertainment of the development of dementia, even among subjects who died during follow up. Of 3,202 subjects free of dementia at baseline, 217 subjects met criteria of dementia during follow up. Subjects consuming alcohol had approximately 30% less overall dementia and 40% less Alzheimer dementia than did non-drinking subjects. Unlike many previous studies showing greater effects of wine on reducing risk of dementia, no significant differences were seen according to the type of alcoholic beverage consumed. Overall, these results are similar to several previous studies in the very elderly and suggest that moderate drinking is associated with less dementia, even among individuals aged 75 years and older.

Critique 014. Moderate drinking, especially of wine, is associated with better cognitive function. 13 August 2010

Reference: Arntzen KA, Schirmer H, Wilsgaard T, Mathiesen EB. Moderate wine consumption is associated with better cognitive test results: a 7 year follow up of 5033 subjects in the Tromsø Study. Acta Neurol Scandd 2010; Suppl 190:23-29.

A large prospective study of men and women in northern Norway reported that moderate wine consumption was independently associated with better performance on cognitive tests after 7 years of follow up. There was no consistent association between consumption of beer or spirits and cognitive test results. The authors also reported that abstinence was associated with significantly lower cognitive performance in women. As noted by the authors, in any observational study there is the possibility of residual confounding by other lifestyle habits affecting cognitive function, and the present study was not able to adjust for certain ones (e.g., diet, income, or profession) but did adjust for age, education, body mass index, depression, and cardiovascular disease and its major risk factors.

The results of this study support findings from a number of observational, prospective studies that have shown that the moderate consumption of alcohol, especially of wine, may have favorable effects on cognitive function. Such effects could relate to the presence in wine of a number of polyphenols and other substances that reduce the risk of cognitive decline with ageing. Mechanisms that have been suggested for such protection against cognitive dysfunction include effects on atherosclerosis, coagulation, inflammation, as well as direct neuroprotective effects.

Critique 008. Further evidence that moderate alcohol consumption may play a role in the prevention of Alzheimer’s Disease. 13 June 2010

Reference : García AM, Ramón-Bou N, Porta M. Isolated and joint effects of tobacco and alcohol consumption on risk of Alzheimer’s Disease. Journal of Alzheimer’s Disease 2010;20:577–586. (DOI 10.3233/JAD-2010-1399).

In a case-control study from Spain on the effects of smoking and alcohol use on the risk of Alzheimer’s Disease (AD), the authors found that the risk of AD was unaffected by any measure of tobacco consumption. On the other hand, alcohol consumers showed a 47% lower risk of developing AD than did never consumers, with effects mainly among women and among never smokers. No differences were noted by type of alcoholic beverage consumed. The authors conclude that mean daily total consumption of alcohol showed increasingly protective dose-response relationships in women.

The numbers in this analysis were rather small, and there is always the possibility of confounding by other lifestyle factors. Still, the study supports a number of previous epidemiologic studies showing a lower risk of developing AD for moderate consumers of alcohol.

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Alcohol and Cancer

Critique 039. The role that alcohol drinking may play in the risk of cancer. 17 April 2011

Reference: Schűtze M, Boeing H, Pischon T, et al, Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study. BMJ 2011; 342:d1584 doi: 10.1136/bmj.d1584 (Published 7 April 2011)

A large group of distinguished scientists have published a very detailed and rather complex paper describing the association between alcohol consumption and cancer. It is based on data from the EPIC study in Europe, with a mean follow up of 8.8 years for more than 300,000 subjects. The authors describe an increase in risk of many cancers from alcohol intake, but do not give data permitting the detection of a threshold of intake for an adverse effect on cancer risk. The investigators conclude that “In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits.”

Members of the Forum were concerned that the authors did not separate moderate consumption from heavy consumption for their main analyses, ignored the demonstrated benefits of moderate drinking on total mortality, and did not point out other environmental influences (such as smoking, diet, obesity, etc.) that often have much larger effects on the risk of many cancers than does alcohol consumption. The authors make statements such as alcohol has negative effects on total mortality that are not supported by the data presented in their paper, and are contradicted by most large-scale population-based studies. Overall, while this paper supports the well-known association between heavy drinking and an increased risk of upper aero-digestive and certain other cancers, it adds little information useful for the prevention of most types of cancer.

Critique 018. Alcohol consumption following diagnosis of early-stage breast cancer may increase risk of recurrence of cancer but not total mortality risk.

14 September 2010

Reference: Kwan ML, Kushi LH, Weltzien E, Tam EK, Castillo A, Sweeney C, Caan BJ. Alcohol consumption and breast cancer recurrence and survival among women with early-stage breast cancer: The Life After Cancer Epidemiology Study. J Clin Oncol 2010;28 (published ahead of print, 10.1200/JCO.2010.29.2730).

In the Life After Cancer Epidemiology (LACE) study, 1,897 participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited on average 2 years post-breast cancer diagnosis were evaluated for the association between alcohol intake and breast cancer recurrence and death. The women, who were generally light drinkers, were followed for an average of 7.4 years. The study reported an increase in risk of breast cancer recurrence and breast cancer death, but no effect on total mortality, to be associated with consumption of 3 to 4 or more drinks per week when compared with women not drinking following their cancer diagnosis.

Previous research has been mixed on this topic. Almost all large studies have shown no increase in all-cause mortality for women who drink moderately following a diagnosis of breast cancer (as does this study). As for recurrence of breast cancer, most have shown no increase in risk, although one previous study of women with estrogen-receptor + tumors found an increased risk of a primary cancer developing in the contralateral breast to be associated with alcohol intake of more than 7 drinks per week.

Because of conflicting results among studies on this topic, further research will be needed to determine the extent to which alcohol following a diagnosis of breast cancer may relate to subsequent disease and death.

Critique 016. Association of alcohol with breast cancer risk varies according to subtype of tumor. 29 August 2010

Reference Li CI, Chlebowski RT, Freiberg M, Johnson KC, Kuller L, Lane D, Lessin L, O’Sullivan MJ, Wactawski-Wende J, Yasmeen S, Prentice R. Alcohol consumption and risk of postmenopausal breast cancer by subtype: the Women’s Health Initiative Observational Study. J Natl Cancer Inst 2010 Aug 23. [Epub ahead of print].

Most studies show a slight increase in the risk of breast cancer for women who consume alcohol. The association is thought to relate to alcohol’s effects on hormones, and alcohol use tends to be more strongly associated with hormonally sensitive breast cancers than tumors not sensitive to hormones. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype. In the present study, follow-up data from 87,724 women in the Women’s Health Initiative Observational Study prospective cohort were evaluated for the relation of baseline alcohol consumption with subsequent breast cancer.

A total of 2,944 invasive breast cancer patients were diagnosed during follow up. In multivariable-adjusted analyses alcohol consumption was associated with an increase in the risk of lobular carcinoma (which makes up approximately 15-20% of breast cancers), but there was not a statistically significant association with the more-common ductal type of carcinoma. Hormone + cancers showed an association with alcohol intake, but not hormone – cancers. The findings support the importance of hormonal mechanisms in mediating the relation between alcohol use and breast cancer risk.

Critique 015. Moderate drinking does not appear to increase risk of breast cancer among women with a BRCA gene mutation. 22 August 2010

Reference: Dennis J, Ghadirian P, Little J, et al: The Hereditary Breast Cancer Clinical Study Group. Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers. The Breast 2010; e-pub.

A large study was carried out to assess the effects of alcohol consumption on breast cancer risk among women with a BRCA1 or a BRCA2 gene mutation, both of which markedly increase the risk of breast cancer. Comparisons were made between women with a gene mutation who had developed invasive breast cancer matched with women with the same gene mutation who had not developed breast cancer. After a number of appropriate exclusions, there were 1,480 matched pairs with BRCA1 mutations and 445 pairs with BRCA2 mutations.

Data from the study support an earlier report suggesting no increase in breast cancer risk from alcohol intake for women with either gene mutation. In the previous study on this topic, a slight lowering of breast cancer risk was noted with light drinking among women with the BRCA2 mutation but not among those with the BRCA1 mutation. In the present study, a possible reduction in risk of breast cancer was seen for moderately drinking women with the BRCA1 mutation, but not the BRCA2 mutation. Further, in the present study, the reduction is risk of breast cancer was seen only for wine consumers. While one should not over-interpret epidemiologic data in the absence of identified biologic mechanisms, there have been a very large number of experimental studies showing that certain polyphenols present in wine actively impede the initiation and growth of cancer cells.

Overall, current scientific data suggest that alcohol in moderation does not increase the risk of breast cancer among women with a BRCA mutation, and wine may be somewhat protective. If this is indeed the case and given the high risk associated with these genetic mutations, it would be important to inform women with such a mutation that moderate alcohol does not appear to increase their risk of breast cancer.

Critique 001. Genetic effects on alcohol metabolism modify the relation of alcohol to breast cancer. 24 April 2010

Reference: Larsen SB, Vogel U, Christensen J, Hansen RD, Wallin H, Overvad K, Tjønneland A, Tolstrup I. Interaction between ADH1C Arg²⁷²Gln and alcohol intake in relation to breast cancer risk suggests that ethanol is the causal factor in alcohol related breast cancer. Cancer Letters, 2010, in press.

A study from Germany compared the association between alcohol and breast cancer risk according to genetic variations affecting levels of alcohol dehydrogenase, an enzyme that clears alcohol from the blood stream. The authors conclude that genetic factors associated with the slow clearance of alcohol are associated with increased risk of breast cancer for drinkers; an increase in cancer risk was not seen for drinkers with genetic factors leading to fast clearance of alcohol. Such a finding would suggest that alcohol itself is the cause of an increase in breast cancer risk among drinkers.

Unfortunately, some previous studies have shown the opposite, that an increase in breast cancer risk occurs only among women who have genes associated with fast, rather than slow, alcohol metabolism. Overall, current scientific data indicate that breast cancer’s relation to drinking is not resolved, remaining murky and conflicted, and perhaps overemphasized. This facet of that murkiness is itself also conflicted. As of now, it is unclear the degree to which genes affecting alcohol dehydrogenase modify the association between alcohol and the risk of breast cancer and other diseases.

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Alcohol and Liver Disease

Critique 028. Changes over time in relation of social class to mortality from cirrhosis. 9 January 2011

Reference: Crombie IK, Precious E. Changes in the social class gradient of cirrhosis mortality in England and Wales across the 20th century. Alcohol and Alcoholism 2011;46:80–82.

To explore the nature of the social class gradient of cirrhosis mortality in England and Wales across the 20^th century, data on male cirrhosis mortality by social class were obtained from the Registrar General’s Decennial Supplements for the years 1921–1991. This paper describes a dramatic change during the 20th century in the association between social class and mortality from liver cirrhosis. While deaths from cirrhosis were more common among higher social classes in the early part of the century, the pattern changed so that deaths from cirrhosis were much more common among the lower social classes by the end of the century.

Suggested reasons for the lower current rates among subjects at higher social class include different patterns of alcohol consumption, with regular moderate consumption (especially of wine with meals) becoming more common with higher social class subjects while binge drinking (especially of beer and spirits) remaining more common in lower social classes. However, a number of other factors may relate to the class differences in rates of hepatic cirrhosis, including a less healthy diet and greater rates of obesity (associated with hepatic fatty liver and cirrhosis) among lower social class subjects and social class differences in hepatitis rates. Further, certain medications, coffee consumption, and many other lifestyle factors are associated with hepatic cirrhosis. The actual reasons for the changes over time reported in this paper remain unclear.

Critique 013. Greater than moderate alcohol intake increases the risk of liver cirrhosis.

27 July 2010

Reference: Rehm J, Taylor B, Patra SM, Irving H, Baliunas D, Patra J, Roerecke M. Alcohol as a risk factor for liver cirrhosis: A systematic review and meta-analysis. Drug and Alcohol Review 2010,29,437–445. DOI: 10.1111/j.1465-3362.2009.00153.x.

A new meta-analysis shows that alcohol consumption is a strong factor in the development of cirrhosis of the liver. The study also supports the theory that there is a threshold of drinking above which the risk is increased, as some of their analyses suggest that the risk increases only with intake of more than 24 grams/day of alcohol for women (about 2 typical drinks by US standards) and 36 grams/day of alcohol for men (about 3 typical US drinks).

Despite some concerns about the approach used, our Forum agrees that the present meta-analysis supports previous studies indicating a strong role of heavy alcohol drinking in the development of cirrhosis. The differences found by the investigators between the effects of moderate alcohol intake on cirrhosis morbidity and on cirrhosis mortality are difficult to explain, but may relate to misclassification of alcohol intake (heavy drinkers reporting less alcohol), always a problem in observational studies of the effects of alcohol.

The results related to morbidity suggest that small amounts of alcohol are not associated with an increased risk of cirrhosis, and may be associated with lower risk of disease. Thus, the data provide evidence for a “threshold effect” of alcohol intake for the development of cirrhosis. Limited previous data are available suggesting that wine consumption may be associated with lower risk of cirrhosis than the intake of other beverages, but essentially all studies show heavy drinking of any type of beverage increases the risk.

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Effects of Alcohol Drinking on Other Diseases

Critique021 . Alcohol consumption affects risk of cataracts. 25 October 2010

Reference: Kanthan GL, Mitchell P, Burlutsky G, Wang JJ. Alcohol Consumption and the Long-Term Incidence of Cataract and Cataract Surgery: The Blue Mountains Study. Am J Ophthalmol 2010;150:434–440.

A population-based prospective study from Australia utilized repeated lens photographs over a period of 5 to 10 years to diagnose cataracts among more than 2,500 subjects. The investigators related the risk of their development, and the risk of cataract surgery, to the reported alcohol intake of subjects. Previous research has provided some biological mechanisms that make an association between alcohol and cataracts plausible.

Overall, the present study showed few statistically significant relations between alcohol and cataracts, although adjusted results suggested a “U-shaped” association between total alcohol intake and development of cataracts (a lower risk for moderate drinkers, higher risk for both abstainers and heavier drinkers). The U-shaped association with alcohol consumption was stronger for the risk of cataract surgery. These results are consistent with previous cohort studies. On inspection of the data presented, the potential reduction in risk of cataract was primarily for wine and beer. While some types of cataract may be reduced by moderate drinking, larger intake of alcohol may be associated with increased risk.

Critique 005. Alcohol in young women may increase their risk of benign breast disease.

27 May 2010

Reference: Berkey CS; Willett WC; Lindsay Frazier A; Rosner B; Colditz GA; Rockett RH; Helaine RM. Prospective study of adolescent alcohol consumption and risk of benign breast disease in young women. Pediatrics 2010;125:e1081-e1087.

Among more than 6,000 young women being followed in a longitudinal study, 67 confirmed cases of benign breast disease (BBD) were diagnosed. Alcohol consumption was reported on 57 women who developed BBD when they were 16 – 23 years of age, with all but 8 subjects being 18 or older when they reported alcohol intake, and no data were presented on potential exposures earlier following menarche. A significant increase in the risk of BBD was associated with alcohol intake, although many key factors that have been shown to relate to BBD were not reported in the paper. Hence, while the number of cases is small, and a number of potential risk factors are not included, this study suggests that BBD may be increased by alcohol consumption in young women.

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Alcohol Drinking and Mortality

Critique 017. Moderate alcohol intake is associated with a lower risk of total mortality than are either abstinence or heavy drinking. 5 September 2010

Reference: Holahan CJ, Schutte KK, Brennan PL, Holahan CK, Moos BS, Moos RH. Late-Life Alcohol Consumption and 20-Year Mortality. Alcoholism: Clinical and Experimental Research 2010;34:in press, November 2010.

In a study based on data from 1,824 predominantly Caucasian Americans from the Western part of the United States, alcohol consumption at baseline was related to mortality risk during a 20-year follow-up period. Subjects were recruited into a longitudinal project that has examined late-life patterns of alcohol consumption and drinking problems. Lifetime abstainers were not included in the study, which focused on stress and coping processes among problem drinkers and non-problem drinkers. The sample at baseline included only subjects aged 55 to 65 years who had had outpatient contact with a health care facility in the previous 3 years.

The database at baseline included information on daily alcohol consumption, sociodemographic factors, former problem drinking status, health factors, and social-behavioral factors. Subjects who were not lifetime abstainers but did not report drinking at the time of the baseline examination were classified as “abstainers.” Data on potential changes in alcohol consumption during the course of the study were not collected. Death during follow up was confirmed primarily by death certificate.

The key results of the paper are that even when adjusting for sociodemographic factors, former problem drinking status, health factors, and social-behavioral factors, moderate drinking was associated with considerably lower risk of all-cause mortality. In comparison with “moderate drinkers” (subjects reporting up to 3 drinks/day), abstainers had 51% higher mortality risk and heavy drinkers had 45% higher risk. The study supports most previous scientific studies showing that moderate drinking, in comparison with both abstinence and heavy drinking, is associated with lower risk of total mortality.

Critique 012. Moderate drinking in the elderly is associated with lower total mortality. 23 July 2010

Reference: McCaul KA, Almeida OP, Hankey GJ, Jamrozik K, Byles JE, Flicker L. Alcohol use and mortality in older men and women. Addiction 2010. On-line prior to publication: doi:10.1111/j.1360-0443.2010.02972.x

The effects of alcohol consumption in the elderly may be modified by a decreased ability to metabolize alcohol, an altered volume of distribution due to reduced lean body mass and total body water, and an increased prevalence of co-morbid conditions. These factors make this study of the net effects of drinking among a large number of community-dwelling elderly men and women especially important.

In large prospective studies from Australia of men aged 60-79 and women aged 70-75 years of age, men consuming up to 4 drinks/day and women up to 2 drinks/day had considerably lower risk of dying (total mortality) than did non-drinkers. For subjects reporting 1-2 drinks/day, their total mortality risk was about 20-30% lower than that of abstainers.

While the authors concluded that not consuming alcohol on 1 or 2 days per week was associated with better outcomes, this conclusion is not in accordance with their own data. The benefit of one or two “alcohol-free” days per week has never been substantiated with solid evidence from any large epidemiological study.

Our Forum review concludes that in terms of total mortality risk, recommendations for very low levels of drinking among the elderly may be overly restrictive, as this study showed lower total mortality for up to 4 drinks/day for elderly men and 2 drinks/day for elderly women. Further, this study does not provide support for the conclusion that mortality is lower for people who have 1 or 2 “alcohol-free” days per week.

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Patterns of Drinking/Associated Lifestyle Factors

Critique 028. Changes over time in relation of social class to mortality from cirrhosis.

9 January 2011

Reference: Crombie IK, Precious E. Changes in the social class gradient of cirrhosis mortality in England and Wales across the 20th century. Alcohol and Alcoholism 2011;46:80–82.

Critique025. Pattern of drinking and type of beverage affect the relation of alcohol intake to coronary heart disease. 1 December 2010

Critique 022. Alcohol consumption decreases with the development of disease.

21 November 2010

Reference: Liang W, Chikritzhs T. Reduction in alcohol consumption and health status. Addiction 2010; in press (doi:10.1111/j.1360-0443.2010.03164.x).

In a cross-sectional study from the 2004 and 2007 Australian National Drug Strategy Household (NDSH) surveys, respondents were questioned about their current and past drinking, the presence of formal diagnosis for specific diseases (heart disease, type 2 diabetes, hypertension, cancer, anxiety, depression) and self-perceived general health status. The sample sizes for the 2004 and 2007 NDSH surveys were 24,109 and 23,356, respectively.

The authors report that respondents with a diagnosis of diabetes, hypertension, or anxiety were more likely to have reduced or stopped alcohol consumption in the past 12 months. The likelihood of having reduced or ceased alcohol consumption in the past 12 months increased as perceived general health status declined from excellent to poor (although the authors do not point out that lifetime abstainers were more likely than moderate drinkers to report less than excellent health status).

The authors conclude that the experience of ill health is associated with subsequent reduction or cessation of alcohol consumption (“sick quitters), which is consistent with most prospective epidemiologic studies. The authors also conclude that this may at least partly underlie the observed ‘J-shaped’ function relating alcohol consumption to premature mortality. On the other hand, most modern epidemiologic studies are careful not to include “sick quitters” within the non-drinking category, and relate health effects of drinkers with those of lifetime abstainers. Further, prospective studies in which alcohol intake is assessed at different times (rather than having “changes” based only on recall at one point in time, as was done in this study) usually indicate that subjects who decrease their intake are more likely to subsequently develop adverse health outcomes, especially related to cardiovascular disease, than those who continue moderate drinking.

Critique 017. Moderate alcohol intake is associated with a lower risk of total mortality than are either abstinence or heavy drinking. 5 September 2010

Critique 007. People may change to a “healthier” pattern of drinking as they age.

9 June 2010

Reference : Molander RC, Yonker JA, Krahn DD. Age-related changes in drinking patterns from mid- to older age: results from the Wisconsin Longitudinal Study. Alcoholism: Clinical and Experimental Research 2010;34 (Published early online 7 May 2010).

In a prospective longitudinal study of a cohort of Americans in the “Baby Boomer” generation, subjects’ drinking habits were assessed at two points, when they were approximately 53 years of age and again when they were approximately 64 years of age. As the subjects got older, they began to consume fewer drinks per occasion but to consume alcohol more frequently; the net effect was little change in total alcohol intake for women but a slight increase for men.

In most epidemiologic studies, regular moderate drinking is the pattern associated with lower risk of many chronic diseases; hence, the described change in drinking pattern in this study (smaller amounts on more frequent occasions) can be considered a “healthy” change. Most long-term observational studies show a decrease in total alcohol intake with ageing, although reasons for such are poorly understood.

This paper emphasizes the importance of knowing the pattern of drinking, and not just the total number of drinks consumed over a week, when evaluating the impact of alcohol consumption on health and disease.

Critique 004. Moderate alcohol consumption is associated with other healthy lifestyle factors. 24 May 2010

Reference: Hansel B, Thomas F, Pannier B, Bean K, Kontush A, Chapman MJ, Guize L, Bruckert E. Relationship between alcohol intake, health and social status and cardiovascular risk factors in the urban Paris-Ile-De-France Cohort: is the cardioprotective action of alcohol a myth? European J Clin Nutrition, advance online publication, doi:10:1038/ejcn.2010.61.

An analysis based on a very large number of subjects in France demonstrates, as have most other studies, that moderate consumers of alcohol have many associated healthy lifestyle habits: lower levels of body mass index, blood glucose, heart rate, stress and depression scores; higher subjective health status, HDL-cholesterol values, levels of physical activity and social status. The authors suggest that alcohol is not related causally to any of these factors, and that the other lifestyle factors, not alcohol consumption, are the reason that moderate drinkers have less cardiovascular disease. They chose a very narrow group of citations from the literature to support this contention.

The authors ignore a large number of well-conducted prospective epidemiologic studies showing that moderate drinkers are at lower risk over time of developing certain risk factors. Further, the authors of this paper ignore an immense basic science literature that suggests that alcohol is an important factor in the development of biological risk factors, atherosclerosis, and cardiovascular disease. Further, they do not describe a number of studies that have shown specifically that moderate drinking is associated with less cardiovascular disease and diabetes among subjects who are otherwise very healthy (non-smokers, not obese, physically active, and on a healthy diet).

There is no doubt that confounding by associated lifestyle factors can play a role in the lower risk of chronic diseases among moderate drinkers, who tend to also have other healthy behaviors. However, there is now a large body of scientific evidence that indicates that alcohol is an important factor in the lower rates of such diseases; current scientific data do not support the conclusions of the authors of this paper.

Critique 003. Moderate alcohol consumption markedly reduces the risk of diabetes mellitus, even among subjects with otherwise very healthy lifestyles. 17 May 2010

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Genetic Factors Related to Alcohol Use

Critique 037. Genes found to relate to level of alcohol consumption among Asians.

27 March 2011

Reference: Baik I, Cho NH, Kim SH, Han B-G, Shin C. Genome-wide association studies identify genetic loci related to alcohol consumption in Korean men. Am J Clin Nutr 2011;93:809–816.

Accompanying Editorial: Agrawal A, Freedman ND, Bierut LJ. Genome-wide association studies of alcohol intake—a promising cocktail? Am J Clin Nutr 2011;93:681–683.

In a study of 1,721 Korean male drinkers aged 40–69 y in an urban population–based cohort, and another sample of 1,113 male drinkers from an independent rural cohort, information on average daily alcohol consumption was collected and DNA samples were collected for genotyping. In a genome-wide association (GWA) study, 12 single-nucleotide polymorphisms (SNPs) on chromosome 12q24 had genome-wide significant associations with alcohol consumption. These polymorphisms were closely related to genes that determine levels of ALDH, low levels of which relate to flushing after even small amounts of alcohol. Such enzymes are much more common among Asians than among westerners. Further, associations were tested only with the weekly amount of alcohol consumed, not the pattern of drinking; hence, these findings are not direct measures of alcoholism.

The editorial by Freedman et al states “epidemiologic literature suggests that those who begin drinking at an early age may be at greater risk for a maladaptive and more genetically pronounced form of alcohol consumption, and other environmental milieus affect the risk of alcoholism.” It will be important to investigate the interplay of genes and environmental factors when seeking the determinants of alcohol abuse. Despite the findings of this study, our understanding of factors associated with alcoholism remains very limited.

Critique 001. Genetic effects on alcohol metabolism modify the relation of alcohol to breast cancer. 24 April 2010

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Wine Polyphenols and Health

Critique 031. Wine polyphenols have a variety of beneficial effects on health

30 January 2011

Reference: Rodrigo R, Miranda A, Vergara L. Modulation of endogenous antioxidant system by wine polyphenols in human disease. Clin Chim Acta 2011;412:410-424.

Much of the protection against cardiovascular disease attributed to wine intake may relate not only to the alcohol in wine, but to its polyphenolic constituents. This review article summarizes research into the chemistry, bioavailability, metabolism and excretion of polyphenols as well as mechanisms of their action. As stated by the authors, “These protective effects could be due to one or many components of the complex mixture of bioavailable and bioactive compounds present in red wine including ethanol, resveratrol, flavonols, flavan-3-ols, anthocyanins, phenolic acids as well as their metabolites formed either in the tissues or in the colon by the microflora.” The authors describe their cardioprotective effects, effects on vascular function and atherosclerosis, anti-platelet effects, effects on myocardial ischemia, and anti cancer and anti-diabetic effects.

The authors conclude that “Polyphenols are the most abundant antioxidants in the diet and are widespread constituents of wine, fruits and vegetables.” Their review provides an extensive scientific literature on polyphenols in wine; it suggests multiple mechanisms by which such substances may have beneficial effects on health.

Critique 030. Young rats given red wine polyphenols show less deterioration in endothelial function with ageing. 30 January 2011

Reference: Dal-Ros S, Zoll J, Lang AL, Auger C, Keller N, Bronner C, Geny B, Schini-Kerth VB. Chronic intake of red wine polyphenols by young rats prevents aging-induced endothelial dysfunction and decline in physical performance: Role of NADPH oxidase. Biochem Biophys Res Commun 2011;404:743-749.

The gradual decrease in endothelial function over time is a key factor in the development of diseases associated with ageing, especially cardiovascular disease (CVD). Many epidemiologic studies suggest greater protection against CVD from wine than from other beverages containing alcohol, with at least one factor being the polyphenols in red wine (RWPs).

The present study in rats found that the administration of red wine polyphenols protected against ageing-induced endothelial dysfunction. As stated by the authors: “The present findings indicate that regular intake of RWPs in the drinking water starting at young age (16 week-old) prevented the aging-related endothelial dysfunction most likely by reducing the excessive oxidative stress in the arterial wall.” They further suggest an important role of NADPH oxidase and possibly also the angiotensin system in the abnormal vascular response in aging. Their study showed that, “RWPs intake had also a physiological beneficial effect since it improved the physical exercise capacity of old rats.”

Forum members thought that this was an excellent paper, as it begins to delve into mechanisms by which polyphenols improve health. A mechanism is addressed and results are consistent with the working hypothesis of a specific interaction between polyphenols and peculiar enzymes. There is a satisfying agreement between basic mechanisms and pathophysiology. Some scientists believe that interventions to improve endothelial function (such as the consumption of red wine or other sources of polyphenols) should begin earlier in life to slow down the endothelial dysfunction that occurs with ageing. This study in rats tends to support such a belief.

Critique 027. Effects of resveratrol and quercetin on inflammation and insulin resistance 20 December 2010

Reference: Chuang C-C, Martinez K, Xie G, Kennedy A, Bumrungpert A, Overman A, Jia W, McIntosh MK. Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-a–mediated inflammation and insulin resistance in primary human adipocytes. Am J Clin Nutr 2010;92:1511–1521.

A study was carried out to examine the extent to which quercetin and trans-resveratrol (RSV) prevented inflammation or insulin resistance in primary cultures of human adipocytes treated with tumor necrosis factor-a (TNF-a)—an inflammatory cytokine elevated in the plasma and adipose tissue of obese, diabetic individuals. Cultures of human adipocytes were pretreated with quercetin and trans-RSV followed by treatment with TNF-a. Subsequently, gene and protein markers of inflammation and insulin resistance were measured. The authors report that quercetin, and to a lesser extent trans-RSV, attenuated the TNF-a–induced expression of inflammatory genes such as interleukin (IL)-6, IL-1b, IL-8, and monocyte chemoattractant protein-1 (MCP-1) and the secretion of IL-6, IL-8, and MCP-1.

Forum members were concerned about certain aspects of the study, especially the extrapolation of in vitro results to in vivo situations. The in vitro conditions the authors describe are minimally representative of an in vivo condition. In vivo, after consumption of quercetin or resveratrol, these compounds undergo extensive metabolism, leading to glucuronidated, sulphated or methylated compounds. In a previous study, quercetin 3-glucoside was transformed to 3,4-dihydroxyphenylacetic acid, acetate and butyrate in cells from human gut; only 3′-methylquercetin has been detected in human plasma, present at a concentration of 0.1 to 0.2 µM after 3 h. The authors of the current paper are using concentrations up to 60 µM, concentrations which have not been found in vivo.

There were also concerns with the work on cell uptake of quercetin and resveratrol. Primary adipocytes were incubated with the polyphenols, but it is not clear whether or not the concentrations used were subtoxic. Our current knowledge is limited about local concentration of the molecules we are studying in subcellular compartments, their interaction with alternative targets, and eventually their transformation into products that could be more or less active on a given specific pathway. The real difficult and important issue is the identification of a reasonable convergence — if not agreement — between data originating from extremely distant approaches. In this case, the notion that metabolic diseases are related to a homeostatic imbalance in adipose tissue, linked to a different redox status, linked to activation of specific pathways, and that different redox sensitive polyphenols do have a protective effect, encompasses the evidence produced by extremely distant approaches.

From a clinical point of view, the role of phytochemicals acting as antioxidants and anti-inflammatory agents could be extremely important in inflammation-associated chronic conditions such as cardiovascular disease, diabetes, and cancer. Quercetin and resveratrol may indeed play an important role in this regard, and need to be investigated further to establish the clinical importance of natural dietary compounds in the prevention of chronic degenerative conditions.

Critique 023. Evidence that PPAR-gamma is a mechanism for the effects of wine polyphenolics on cardiovascular risk. 27 November 2010

Reference: Zoechling A, Liebner F, Jungbauer A. Red wine: A source of potent ligands for peroxisome proliferator-activated receptor γ. Food & Function, Journal of the Royal Society of Chemistry, in press. DOI: 10.1039/c0fo00086h.

It is important that biological mechanisms are identified for the observed inverse relation between the moderate consumption of wine and cardiovascular disease shown in most epidemiologic studies. A paper by Zoechling et al is an elegant example of the needed effort to provide a biochemical mechanism for the biological effects of wine. Data on binding of different wine component were produced and this result is interpreted in light of epidemiological evidence.

It would have been appropriate to provide evidence also for the actual shift of gene expression primed by the same wine component in a cell or animal model. In this respect, results must be rated appropriate but still as preliminary; a ligand could have different effects. Further, biological evidence is not provided to support the contention that these polyphenols act through the PPAR-gamma receptor. The sort of evidence that should have been provided is a comparison with rosiglitazone in a cell population known to respond to PPAR-gamma agonists (e.g. adipocytes).

Further, the analytical data does not describe the amounts of any of the “active” substances. So while there is a lot of discussion of the active components, it is not possible to compare any wine’s “activity” with the amount of the key substances. Lacking such a comparison, it is very hard to conclude that these substances are in fact the responsible factors in the observed activity. Nevertheless, this paper provides important data on potential mechanisms by which the constituents of wine and certain other beverages may act to reduce the risk of cardiovascular disease.

Critique 014. Moderate drinking, especially of wine, is associated with better cognitive function 13 August 2010

Critique 002. Red wine, but not other types of alcohol, improve endothelial function in a randomized trial 26 April 2010

Reference: Huang PH, Chen YH, Tsai HY, Chen JS, Wu TC, Lin FY, Sata M, Chen JW, Lin SJ. Intake of red wine increases the number and functional capacity of circulating endothelial progenitor cells by enhancing nitric oxide bioavailability. Arteriosclerosis Thrombosis and Vascular Biology 2010;30:869-877.

The healthy state of cells that form the lining of arteries, assessed by indices of endothelial function, is a key factor associated with preventing the development and progression of atherosclerosis and coronary heart disease. In a randomized trial among healthy young adults, the daily consumption of about 3 ounces of red wine for three weeks led to significant improvement in endothelial function. Such improvements were not seen with the consumption of water, or of beer or vodka containing similar amounts of alcohol.

Further, in a series of in-vitro studies, the authors showed very similar effects from red wine and from a high concentration of resveratrol (but not from beer or ethanol) on factors associated with improved endothelial function. The study supports many epidemiologic and animal experiments suggesting that certain non-alcoholic constituents of red wine have additional beneficial effects on cardiovascular risk over those of just the alcohol itself.

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Alcohol Drinking During Pregnancy

Critique 020. New data on effects of alcohol during pregnancy. 12 October 2010

Reference: Kelly YJ, Sacker A, Gray R, Kelly J, Wolke D, Head J, Quigley MA. Light drinking during pregnancy: still no increased risk for socioemotional difficulties or cognitive deficits at 5 years of age? J Epidemiol Community Health 2010; doi:10.1136/jech.2009.103002.

A very large population-based observational study from the UK found that at the age of 5 years, the children of women who reported light (no more than 1-2 units of alcohol per week or per occasion) drinking did not show any evidence of impairment on testing for behavioral and emotional problems or cognitive ability. There was a tendency for the male children of women reporting “heavy/binge” drinking during pregnancy (7 or more units per week or 6 or more units per occasion) to have poorer behavioral scores, but the effects were less clear among female offspring.

Scientific data continue to indicate that higher intake of alcohol during pregnancy may adversely affect the fetus, and could lead to very severe developmental or other problems in the child. However, most recent publications (as does this one) show little or no effects of occasional or light drinking by the mother during pregnancy. They also demonstrate how socio-economic, education, and other lifestyle factors of the mother may have large effects on the health of the fetus and child; these must be considered when evaluating the potential effects of alcohol during pregnancy.

Overall, current scientific data indicate that while drinking during pregnancy should not be encouraged, there is little evidence to suggest that an occasional drink or light drinking by the mother is associated with harm. Heavy drinking, however, may be associated with serious developmental defects in the fetus.

Addendum: After the above critique was prepared, a new paper has been published on the topic by O’Leary et al (O’Leary CM, Nassar N, Kurinczuk JJ, de Klerk N, Geelhoed E, Elliott EJ, Bower C. Prenatal Alcohol Exposure and Risk of Birth Defects Pediatrics 2010;126;e843-e850; DOI: 10.1542/peds.2010-0256). Overall, the results of that study are similar to those of the study by Kelly et al, with no increase in risk of birth defects in children born of women reporting low or moderate drinking during pregnancy but with an increased risk of defects among children of women reporting heavy drinking.

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Recommendations Regarding Drinking / Alcohol Policy

Critique 038. Effects of a large reduction in alcohol prices on mortality in Finland.

7 April 2011

Reference: Herttua K, Mäkelä P, Martikainen P. An evaluation of the impact of a large reduction in alcohol prices on alcohol-related and all-cause mortality: time series analysis of a population-based natural experiment. Int J Epidemiol 2011;40:441-454; doi:10.1093/ije/dyp336.

Time series intervention analysis modeling was applied to the monthly aggregations of deaths in Finland for the period 1996–2006 to assess the impact of a reduction in alcohol prices in 2004. The authors report that alcohol-related deaths increased in men aged 40–49 years, and in men and women aged 50–69 years: the mean rate of alcohol-related mortality increased by 17%, 14%, and 40%, respectively, which implies 2.5, 2.9 and 1.6 additional monthly deaths per 100,000 person-years following the price reduction. In contrast to alcohol-related mortality, CVD and all-cause mortality decreased among men and women in the highest age category. The changes were consistent with 19 and 25 fewer monthly deaths per 100,000 person-years for CVD and 42 and 69 fewer monthly deaths for all-cause mortality.

Forum members agreed that both potentially harmful and beneficial effects resulting from changes in alcohol intake should be considered when estimating population effects. They were unsure whether all of the reported effects in the elderly should be attributed to changes in alcohol intake, as decreases in CVD and all-cause mortality rates were occurring prior to the change in alcohol intake.

Critique 032. Comments on alcohol in newly released Dietary Guidelines for Americans, 2010. 9 February 2011

Reference: www.cnpp.usda.gov/Publications/DietaryGuidelines/2010/PolicyDoc/Chapter3.pdf

The United States has released new Dietary Guidelines for Amercans, 2010. While the Key Recommendations regarding alcohol remain similar to those of earlier guidelines, there were some changes in the text that reflect increasing scientific data indicating potential health benefits of moderate drinking. The key recommendation is as follows:

“If alcohol is consumed, it should be consumed in moderation—up to one drink per day for women and two drinks per day for men—and only by adults of legal drinking age.”

Within the main body of the guidelines, comments on alcohol include the following:

“The consumption of alcohol can have beneficial or harmful effects, depending on the amount consumed, age, and other characteristics of the person consuming the alcohol. Alcohol consumption may have beneficial effects when consumed in moderation. Strong evidence from observational studies has shown that moderate alcohol consumption is associated with a lower risk of cardiovascular disease. Moderate alcohol consumption also is associated with reduced risk of all-cause mortality among middle-aged and older adults and may help to keep cognitive function intact with age. However, it is not recommended that anyone begin drinking or drink more frequently on the basis of potential health benefits because moderate alcohol intake also is associated with increased risk of breast cancer, violence, drowning, and injuries from falls and motor vehicle crashes.”

Critique029. Differing opinions on the message to the public regarding alcohol consumption. 16 January 2011

References:

1. Maurizio Ponz de Leon. What should we advise about alcohol consumption? Intern Emerg Med, DOI 10.1007/s11739-010-0487-1.

2. Augusto Di Castelnuovo, Simona Costanzo, Maria Benedetta Donati, Licia Iacoviello, Giovanni de Gaetano. What should we advise about alcohol consumption? Reply letter by A. Di Castelnuovo. Intern Emerg Med, DOI 10.1007/s11739-010-0502-6.

3. Ramon Estruch • Rosa Ma Lamuela-Raventos. What should we advise about alcohol consumption: reply letter by R. Estruch. Intern Emerg Med; DOI 10.1007/s11739-010-0503-5.

A Letter to the Editor entitled “What should we advise about alcohol consumption?” was recently published by Maurizio Ponz de Leon in Intern Emerg Med.¹ Dr. de Leon argues that the message of health benefits of moderate drinking “seems to me hazardous and extremely dangerous to diffuse in the general population.” His reasons included (1) many people may be unable to distinguish between low–moderate and high consumption of wine, beer or spirits, and alcohol metabolism may differ remarkably from one subject to another; (2) alcohol remains a frequent cause of car crash, and governments (in almost all western countries) try to convince or force people to abstain from drinking before driving; and (3) to consider alcohol as a medication whose consumption may contribute to improved health is another source of concern. Dr. de Leon asks: “Are we truly at the point of prescribing alcohol consumption in order to reduce the risk of stroke and coronary damage?” He concluded that “more studies are needed before we can give sensible recommendations on alcohol consumption to the general population.”

The de Leon editorial has prompted considerable response from other scientists, including further Letters to the Editor of the journal by Di Castelnuovo, Costanzo, Donati, Iacoviello, and de Gaetano,² and by Estruch and Lamuela-Raventos.³ In addition, the original editorial has stimulated considerable debate among members of the International Scientific Forum on Alcohol Research. Among key arguments presented by the Forum members, all experts in scientific research on alcohol, are that messages to the public should not be “paternalistic” (we will tell you what is best for you since you are not smart enough to understand the facts), and that guidelines must always be based on sound, balanced scientific data rather than on uninformed opinion. Forum members emphasized that there are certain people who should not drink at all (including former abusers of drugs or alcohol, people with certain medical conditions, children and adolescents, and people with religious or moral proscriptions against alcohol), and there can never be a general recommendation for everybody to consume alcohol. On the other hand, physicians should not withhold from their patients and the public scientifically sound and balanced data on alcohol and health. And the data are extremely strong supporting a role for moderate alcohol intake, for appropriate adults, for the reduction in risk of coronary artery disease and other diseases of ageing.

Several Forum members pointed out that it was unfortunate that the journal had chosen to publish the original letter that castigates alcohol from an author with good scientific credentials, but little to no apparent research expertise in the subject of alcohol and health. Many Forum members disagreed with the statement of de Leon that “Many people may be unable to distinguish between low–moderate and high consumption of wine, beer or spirits.” A leading scientist dealing with this subject for decades, Dr. Arthur Klatsky, has written: “Most people know very well what the difference is between light to moderate drinking and binge or excessive drinking. While some patients may rationalize their heavy drinking because of its purported health effects, I have yet to find someone who had developed alcohol abuse because of messages about the health effects of moderate drinking.” Medical practitioners, in his view, “have a ‘solemn duty’ to tell the truth about alcohol consumption, as they understand it, to all of their patients.”

While pointing out that certain individuals will not benefit from the consumption of alcohol (and it should definitely not be encouraged in people with former abuse or other contraindications to alcohol use), several Forum members believed that it would be unethical for physicians to withhold from middle-aged or elderly subjects at risk of cardiovascular disease information on the potential benefits of light-to-moderate drinking.

Critique 011. A Review of the Proposed New US Dietary Guidelines. 14 July 2010

Reference: The draft of the proposed new Dietary Guidelines is available at http://www.cnpp.usda.gov/DGAs2010-DGACReport.htm.

Members of our International Scientific Forum on Alcohol Research have submitted a detailed review of the draft recently circulated by the United States Department of Agriculture for proposed new US Dietary Guidelines for 2010. In general, Forum members were very pleased with the alcohol recommendations in the proposal, finding them interesting, balanced, and accurate. Many commented that, rather than just focusing on warnings against heavy drinking, the new Guidelines appear to take into account the large amount of recent epidemiologic and experimental data that support many potential beneficial health effects of moderate drinking.

Among specific recommendations from the Forum were the following:

■ A stronger statement is needed of the effects of light-to-moderate drinking on total mortality, in that recent prospective studies show a considerably lower of risk of death for moderate drinkers.

■ Additional emphasis is needed on the reduced risk of developing diabetes for moderate drinkers, and the much lower risk of cardiovascular disease among diabetics who consume some alcohol.

■ Further information should be presented on the consistent scientific data showing that women who drink moderately are at reduced, not increased, risk of weight gain in adult life.

There were a number of topics not discussed in the draft Guidelines that members of the Forum thought deserved consideration for inclusion.

■ Recent reports have consistently shown that among people who have already had a myocardial infarction or other cardiovascular event, moderate drinking is associated with a reduced risk of further cardiovascular events and death.

■ More emphasis in the Guidelines should be put on the pattern of drinking (regular moderate rather than occasional binge drinking) and also on the much lower blood alcohol levels after drinking when the beverage is consumed with food, rather than on an empty stomach.

■ It was also suggested to the Guidelines Committee that the beneficial effects on cardiovascular risk of polyphenols and other substances in wine and certain beers, in addition to alcohol, be discussed more adequately.

There were also some suggestions from THE FORUM regarding future research needs in the field.

■ The Forum strongly supports the need for further research on the risks and benefits of light-to-moderate alcohol consumption, rather than focusing research only on alcohol abuse.

■ The Forum proposed emphasis on future research dealing with targeting recommendations for groups of people according to age, gender, other behaviors, etc., although there was some disagreement among Forum members as to whether or not moderate drinking has strong health effects in the young and not just in middle-aged and older adults.

■ The Forum considers moderate drinking, unless contraindicated by certain conditions (e.g, former abuse, some types of severe liver disease), to be an important aspect of a healthy lifestyle. It should be a complement, not an alternative, to other lifestyle factors such as not smoking, getting exercise, eating a healthy diet, and avoiding obesity.

Critique 010. Should moderate alcohol consumption be advised following a heart attack? 30 June 2010

Reference: Carter MD, Lee JH, Buchanan DM, Peterson ED, Tang F, Reid KJ, Spertus JA, Valtos J, O’Keefe JH. Comparison of outcomes among moderate alcohol drinkers before acute myocardial infarction to effect of continued versus discontinuing alcohol intake after the infarct. Am J Cardiol 2010 (Published early online).

Critique 009 Should moderate alcohol consumption be advised for its health effects?

25 June 2010

Reference: Clinical Crossroads: Conferences with patients and doctors. A 42-year-old man considering whether to drink alcohol for his health. Kenneth J. Mukamal, MD, MPH, Discussant. JAMA 2010;303:2065-2073. (doi:10.1001/jama.2010.550)

A report from a conference that took place at the Medicine Grand Rounds at Beth Israel Deaconess Medical Center, Boston, Massachusetts, on January 15, 2009 has recently been published in the Journal of the American Medical Association, JAMA. It provides a discussion by an epidemiologist with a broad knowledge in the field in response to a theoretical question, as from a middle-aged patient, as to the advisability of consuming some alcohol “for his health.”

The paper provides an excellent discussion of a theoretical question about drinking and health. It focuses on the potential risks and benefits associated with moderate drinking for a middle-aged male patient. Most members of the International Scientific Forum on Alcohol Research were pleased with the discussion of the topic. It was noted how uncommon it is that such knowledgeable, detailed, and mostly objective data appear in the mainstream medical literature. It was thought to be “readable, informative and thoughtful.”

The Forum critique points out a number of topics that were covered incompletely in the paper, including inadequate information on the importance of the pattern of drinking: moderate regular consumption versus binge drinking. Further, there was a notable lack of information on the beneficial effects on many pathophysiologic processes of polyphenols and other non-alcohol substances present in wine and certain other foods and beverages. Overall, it was believed that the paper provided important information for physicians who may be discussing alcohol consumption with their patients.

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