ISFAR member Erik Skovenborg’s comments on the newly published Canada’s Guidance on Alcohol and Health: Final Report (2023)

ISFAR member Erik Skovenborg’s comments on the newly published Canada’s Guidance on Alcohol and Health: Final Report (2023) Canada’s Guidance on Alcohol and Health: Final Report suggests that there should be a change in designation from ‘low risk consumption’ to that there is ‘no safe level of alcohol consumption’. The authors state that this comes from relatively recent research suggesting that for numerous health outcomes such as gastrointestinal diseases, cancers and injuries, there is no safe level of alcohol consumption. Further, the authors state that the evidence on alcohol consumption and cardiovascular diseases such as hypertension and haemorrhagic stroke, and indeed that any positive or protective effect of alcohol consumption on ischaemic heart disease (also known as coronary artery disease or coronary heart disease) is ‘more uncertain’ than previously estimated. This is a simplistic view predominantly taken on an association with the average amount of alcohol consumed, which fails to consider pattern of consumption. This is just one of many limitations listed, but not adequately addressed, in analyses and concluding comments. The methodology adopted in the report’s review of the literature is based on the use of multiple meta-analysis to calculate lifetime risk of death and disability. There were 12 primary conditions, diseases and injuries categories that were considered to be directly caused by alcohol consumption, also known as ‘casually related’. 1. Comments on selected studies The following comments by Forum member Erik Skovenborg critiques some of the very small number of papers (16) ‘selected’ for these meta-analyses by the authors according to their inhouse criteria. It is of considerable concern that some of the meta-analyses used were actually considered by the authors themselves to be of low to very low quality according to the criteria. 1.1 Cancer studies Five diverse studies were selected for the meta-analysis. Alcohol and cancer epidemiology has given little attention to the possible effect modification of drinking pattern on the association of alcohol consumption and cancer risk. Almost all studies included in the meta-analyses have investigated the effect of average consumption of alcohol over a certain period, without taking into account whether alcohol was consumed as regular intake of moderate amounts or as higher intakes on fewer occasions. Most often information on the level of alcohol consumption is based on weekly intake but expressed as a statistical artefact: grams of alcohol per day. Such an example is from Sun et al.’s meta-analysis on alcohol consumption and breast cancer, which states that “In our study using only cohort data, both total alcohol and wine intake and even light drinking were associated with increased risk of breast cancer. Its incidence was increased at the level of >1 g/day in total alcohol or wine, especially for postmenopausal breast cancer where the risk increased by 1.05% every 1 g/day.” Clearly the consumption of 1 g/day is an artefactual drinking pattern not observed in the real world. Further, the review of alcohol and breast cancer by Liu et al. (2015)2 identified three epidemiologic studies examining the relationship between binge drinking and breast cancer risk and found binge drinking related to increased risk of breast cancer in two prospective studies while a case-control study reported a nonsignificant increase in the risk for binge drinking. A recent report from the SUN cohort study focussed on Mediterranean alcohol-drinking patterns (MADP), namely moderation, preference for red wine, drinking with meals, and avoiding binge drinking, and all-cause mortality. Only one in five participants died of CVD while almost one in two died of cancer. The study results showed a decreased cancer mortality risk for participants with high adherence to MADP vs. participants with low adherence with only cancer deaths included, which actually was the equivalent of the cancer mortality risk of abstainers3. 1.2 Cardiovascular diseases (CVD) studies Four diverse papers were selected for the meta-analysis on five individual CVD. 1.2.1 Coronary Heart Disease (CHD) The Zhao et al. (2017)4 meta-analysis has Tim Stockwell as co-author and he is co-author of seven of the papers referenced in this meta-analysis. This meta-analysis did not observe a reduced CHD mortality in studies “of higher quality” with exclusion of studies with “systematic selection bias”. The methods used to select “higher quality studies” with “rigorous criteria” used by Stockwell et al. (2016)5 to explore the presence of misclassifying of former and occasional drinkers as abstainers and other potentially confounding study characteristics left only five “higher quality” studies for analysis and neither partially nor fully adjusted estimates indicated significantly decreased risk for low- and medium-volume drinkers although the estimated relative risks for all current drinkers were less than unity. The wide confidence intervals with loss of significance might be due to loss of power as a consequence of exclusion of many solid studies due to the arguments by the authors that only lifelong, complete abstainers are the rightful reference group for alcohol consumption with exclusion of abstainers that “almost never” had consumed a drink. Also, in the paper by Zhao et al. (2017) the authors question validity of observational studies of alcohol and health on multiple grounds. “For example, protective effects have been observed in numerous conditions other than CHD, including many for which a causal role seems implausible (e.g., asthma, the common cold, deafness, osteoporosis, arthritis, liver cirrhosis, and child neurocognition/behaviour.6,7 Thus, the Bradford–Hill criterion of effect “specificity” is not met, which raises the possibility that “moderate drinking” may be a marker for a range of protective lifestyle factors that may confound observed alcohol–CVD relationships.” Furthermore, the issue of confounding is indeed a problem for all observational research like studies of the protective effects of alcohol as well as the harmful effects of alcohol. The Final Report (page 23) states: “A total of 34 cause categories for alcohol-related diseases, conditions and injuries and more than 200 three-digit International Classification of Disease, version 10 (ICD-10-CA) codes were included in the modelling of alcohol-attributable deaths.” Like the example above, the Bradford–Hill criterion of effect “specificity” is not met, which raises the possibility that “binge drinking” and “heavy drinking” may be a marker for a range of harmful lifestyle factors that may confound observed alcohol–attributable disease relationships. 1.2.2 Hypertensive heart disease studies The term “hypertensive heart disease” refers to heart problems that occur because of high blood pressure that is present over a long time. This particular is not present in the paper by Liu et al. (2020)8 . Indeed, this paper is not focused on hypertensive heart disease but is a meta-analysis of race- and sex-specific association between alcohol consumption and hypertension or high blood pressure in 22 cohort studies. Concerning alcohol exposure, alcohol consumption was self-reported, and eight studies did not report the standard of a drink, and the amount of pure ethanol in these studies was transformed to grams by the criteria of one drink equivalent to 12 g. Heterogeneity among included articles was high. Furthermore, the mechanistic link between alcohol and hypertension is not yet clear and the observation of an increased relative risk of hypertension with drinking spirits than wine and beer statistically significant for 5.1-10 g/day consumption is not well understood. The association between alcohol intake and blood pressure was reported in average intake per day. Trevisan et al. (1987)9 found a higher prevalence of hypertension in Italian men and women consuming wine outside meals compared with drinkers of wine with meals , while a study of current drinkers from western New York found odds ratios for hypertension of 1.41 for drinking outside meals vs. 0.90 for daily drinking with food after adjustment for the amount of alcohol consumed.10 Recent results from the SUN Prospective Cohort Study also showed higher incidence of hypertension for drinkers with low adherence as compared to participants with high adherence to the Mediterranean Alcohol-Drinking Pattern, that is, regular, moderate intake of wine with meals, which had similar risk of hypertension as abstainers11. The alcohol-hypertension relationship among women observed, however, was J-shaped and compared with non-drinkers, 10 g/day ethanol consumption did not increase the relative risk of hypertension for women. With that significant result from the meta-analysis by Liu et al. (2020) in mind, the risk calculations by the mathematical model showing increased risk of hypertension from 1.2% with one average drink/week up to 7.7% with an average use of seven drinks/week, raise questions on the reliability of the mathematical risk modelling employed by the Canadian guideline authors. 1.2.3 Atrial fibrillation (AF) studies The authors of the report have selected a prospective study and a dose-response meta-analysis of seven studies (7245 cases) from Larsson et al. (2014)12 for evaluation of the risk of AF associated with alcohol consumption. Compared with current drinkers of <1 drink/week (12 g alcohol/drink), there was a discernible increased AF risk for >21 drinks/week compared with 1 to 6 drinks/week, 7 to 14 drinks/week and 15 to 21 drinks/week. A subsequent 2017 meta-analysis with nine cohort studies (249,496 cases) found high levels of alcohol consumption was associated with an increased incident AF risk. Moderate levels of alcohol consumption were associated with a heightened AF risk in males but in not females, while light alcohol consumption of up to 1 standard drink per day, however, was not associated with AF development13. In addition, A recent 2022 meta-analysis that included a larger number of 16 cohort studies (305,433 cases), however, suggested a J-shaped relationship between alcohol consumption and incident AF. Up to 14 drinks/week seemed to decrease the risk for developing AF although because of the substantial heterogeneity observed, no robust conclusion can be drawn14 . Less is known, however, about drinking pattern and risk of AF. Binge drinking appears to increase risk. The PREDIMED study that assessed the Mediterranean alcohol-drinking pattern (241 incident cases of AF), however, did not find alcohol consumption associated to AF incidence among light and moderate drinkers, adherents to MADP or heavy drinkers compared with non-drinkers15. These additional studies all support that higher rather than light and moderate alcohol consumption is a risk for AF. 1.3 Digestive diseases – liver cirrhosis studies Only one paper was selected for the meta-analysis. In the 2019 UK Million Women Study, approximately half of the women reported usually drinking alcohol with meals. Their relative risk of liver cirrhosis was lower compared with the remainder who drank in a varied manner or predominantly not with meals. A lower relative risk was also found for wine-only drinkers compared with all other drinkers16. The effect modification of drinking with meals or drinking wine only has not been included, however, in the meta-analyses by Roerecke et al. (2019)17. 2. Additional issues on and limitations of the Final Report The following are comments relating to the limitations listed by the authors in section 3.2 of the report, that were effectively ignored in the overall analyses. 2.1 Underreporting The issue of underreporting is not appreciated by the guideline authors: “Although there is a hypothesis of a slight underestimation of alcohol use in medical epidemiology studies18, the direction of alcohol use measurement bias in cohort studies is unknown.” The analysis of a total of 1 876 046 participants in 40 cohort studies from 18 countries on alcohol use and all-cause mortality by Stockwell et al. (2018) found mean coverages of age 15+ per capita alcohol intake of 61.71% ranging from 29.19% for Russia and 55.35% for western European countries to 66.22% for the USA and 96.53% for Japan. To characterize those levels of underreporting as “a slight underestimation” is a nonchalant, not to say callous, dismissal of a serious methodological problem in observational epidemiology. The underreporting in survey data were corrected for total consumption in Canada (adult per capita consumption) using data from Statistics Canada, however, risk estimates are based on self-reported average weekly alcohol use, and the supposed underreporting in the cohort study data was not corrected for underreporting introducing a bias in the categorization of weekly alcohol use. “Measurement errors in surveys” is the title of the book by Biemer et al. (2004) and the conclusion of King in his study of different questionnaires for self-report of alcohol consumption in community surveys is the following: “the alcohol consumption questionnaire consistently resulted in the identification of a smaller percentage of drinkers and a lower reported frequency of alcohol intake”. “The difficulty of securing accurate consumption data has been recognized for many years: “In population samples, average alcohol consumption based on self-report data consistently underestimates documented sales of alcohol and the discrepancy apparently increases with the amount consumed. Despite this difficulty Péquinot et al. (1974) and Tuyns et al. (1977) attempted to establish the dose-specific risks of two alcohol-related diseases – liver cirrhosis and oesophageal cancer – through a careful case-control study. However, their results are open to questions because the average self-reported consumption of the control sample accounted for only about 50% of the average indicated by sales data to prevail in the population from which the sample was drawn.” 19 Klatsky et al. (2014) studied the role of underreporting in the moderate alcohol consumption and cancer association in a cohort of 127,176 persons. Persons reporting light to moderate drinking had increased cancer risk in this cohort, however, the increased risk of cancer was concentrated in the stratum suspected of underreporting. For example, among persons reporting 1-2 drinks/day risk of any cancer was 1.33 (1.21–1.45) among those suspected of underreporting, 0.98 (0.87–1.09) among those not suspected, and 1.20 (1.10–1.31) among those of unsure status. These disparities were similar for the alcohol-related composite and for breast cancer. 20 2.2 Drinking pattern Despite the comprehensive efforts of tailoring drinking thresholds to the health risks in a number of meta-analyses, the relative risks (RRs) and measures of alcohol exposure used in the model have numerous limitations. The first and most important limitation is that drinking patterns were not considered in the analyses. Heavy episodic drinking (HED), often called binge drinking and often defined as the intake of 60 g or more of ethanol on one occasion, is reported by more than one in three drinkers. Drinking patterns are key for understanding injury risks, and for understanding the possible protective effects of alcohol consumption. Among moderate drinkers, HED increases the risk of ischaemic diseases, which are a major contributor to alcohol-attributable diseases in middle-aged (aged 40–59 years) and older (≥ 60 years) adults. Thus, the J-shaped curve indicating a protective effect of moderate alcohol use on ischaemic heart disease, vanishes when considering HED. 21 Individuals with alcohol poisonings or heavy self-reported overall consumption combined with a binge drinking habit have a marked 3- to 6-year loss in healthy longevity. 22 In a cluster analysis study of data from a subset of the 1990 Ontario Health Survey, clusters were found with generally higher social class indicators and health status and drinking patterns which did not include drinking to excess. Clusters were also found for which high-volume drinking occasions correspond with poor health status and high levels of risk factors for chronic disease. The confounding effects of these patterns in epidemiological studies of binge drinking are often not recognized nor adjusted for. 23 A UK telephone survey also found current binge drinking associated with deprivation independently of total consumption. Deprived drinkers are more likely than affluent counterparts to consume alcohol as part of a suite of health challenging behaviours including smoking, excess weight and poor diet/exercise. Together these can have multiplicative effects on risks of wholly (e.g., alcoholic liver disease) and partly (e.g., cancers) alcohol-related conditions. 24 According to the report: “Binge drinking, usually defined as consuming five standard drinks or more for men or four standard drinks or more for women is a common yet dangerous pattern of consumption that results in legal impairment (a BAC > 0.08%) for most persons, and is significantly associated with a range of alcohol-related health and social problems.” Two important factors are missing in this explanation of binge drinking, namely, the timing of alcohol consumption and whether you drink on an empty stomach or with a meal. o Timing: Using Widmark’s formula, a 68 kg man would reach a blood alcohol concentration (BAC) of approximately 0.095 if he consumed five 12-oz beers in 1 h, assuming he had an empty stomach. A 59 kg woman under those same conditions would reach a peak BAC of about 0.142. However, if the same 68 kg male consumed 5 drinks over 5 h, he may never reach a BAC greater than 0.03. Even 3 h can be enough time to keep BACs less than 0.05. A study of drinkers returning from visiting bars in Tijuana (the average time spent in Tijuana was 4.0 and 3.8 h for men and women, respectively), provided both BAC and the self-reported number of drinks consumed. Fifty-eight men reported consuming exactly five drinks and 90 women reported consuming four drinks. Their mean BACs were 0.06 and 0.05, respectively. A calculation showed that it would take 8.2 drinks for men and 6.7 drinks for women to predict a BAC of 0.08. 25 o Empty stomach vs. drinking with a meal: In a two-part crossover study, ten healthy men drank a moderate dose of ethanol (0.80 g/kg) in the morning after an overnight fast or immediately after breakfast. All subjects felt less intoxicated when alcohol was ingested after breakfast compared with drinking on an empty stomach. The peak BAC was 0.067 (+/- 0.0095) after ethanol and food compared with 0.104 (+/- 0.0165) when the drinking occurred after an overnight fast. The time required to metabolize the dose of ethanol was approximately two hours shorter after the subjects had eaten breakfast. These results suggest that food in the stomach before drinking not only leads to a lowering of the peak BAC and diminishes the feelings of intoxication, but also boosts the rate of ethanol metabolism. A food-induced increase in the rate of disposal of ethanol was also confirmed when subjects ate a meal five hours after drinking, that is, when the post-absorptive phase of ethanol metabolism was well established. The mean rate of disappearance of alcohol from blood was increased by between 36 and 50%. 26 The favourable profile of wine is often typified by drinking it slowly while socialising over dinner. In contrast, the less favourable profile of beer and spirits conjures up images of binge drinking pints of lager on an empty stomach. Here is an example: a woman (bodyweight 55 kg) who consumes 2 drinks (26.9 g alcohol) within an hour on an empty stomach resulting in a BAC of 0.088 which actually reflects binge drinking. Her sister (also 55 kg bodyweight) drinks a small glass of wine (10 g alcohol) with her meal every day (7 x 10 = 70 g alcohol/week) resulting in a BAC of 0.012 due to the effect modification of food in the stomach. Which sister has the healthier drinking pattern? The authors neither includes advice about drinking with food nor suggest timing of the low risk 2 drinks/week. 2.3 Mendelian randomisation (MR) Plausible and robust J-shaped relations between light to moderate alcohol consumption and the risk of CHD, CVD mortality and all-cause mortality has been found in a large number of epidemiological studies. Among the potential mechanisms underlying the proposed protective effects are higher levels of high density lipoprotein cholesterol (HDL), lacking the protein coding gene apolipoprotein C3 associated with the breakdown of lipoproteins, reduced platelet aggregability, increased level of endothelial cell fibrinolysis, increased insulin sensitivity and decreased inflammation. 27 A 2020 review of the extent of the methodological problems in studies of the J-shaped curve included a discussion of the possibility that the J-shaped curve is an artefact created by reverse causality and residual confounding and a look at the issue of possible effect modification of drinking pattern and type of alcohol. The review concluded that measurement errors like potential biases and residual confounding probably do not overcome the J-shaped alcohol-CDH-association observed in most epidemiologic studies, however, the existence of a J-shaped curve is challenged by some degree of uncertainty. Accordingly, the need for large-scale randomized trials to clarify the causal relation and to give greater insight into the health effects of population-wide alcohol consumption has been argued 28. A review of methodology for MR and a description of its early application to judging health effects of alcohol was done and a recommended approach of combining MR results with those from observational and experimental studies was suggested. Among several limitations of the MR study are the lack of ability to account for drinking patterns, the low precision in the analyses of outcomes with few cases and the inability to investigate potential U-shaped or J-shaped associations precluding specific quantitative statements about the relative harm of moderate drinking versus heavy drinking29. Scientific evidence now indicates that the combination of results from MR, observational data, animal studies, and human clinical trials, when considered together, offer the best opportunity to determine the overall effects of alcohol on health30 . Furthermore, concerning MR studies of alcohol and cancer, the causal role of alcohol consumption for site-specific cancers is uncertain, as available evidence originates from observational studies which are susceptible to confounding and reverse causation bias. A MR study in UK Biobank and international genetic consortia participants data found genetically predicted alcohol consumption statistically significantly positively associated with lung cancer but not with any other site-specific cancer or overall cancer31 . 2.4 Misclassification of abstainers In the study of alcohol consumption and survival in the Italian rural cohorts of the Seven Countries Study, since there were only 38 non-drinkers among the 1536 inhabitants in the two small Italian villages under study (Crevalcore and Montegiorgio), they could not act as the reference category and were included in the category of occasional drinkers consuming ≤ 1 drink/day. This effectively means that there was: • No selection bias: the study consisted of all male 1536 subjects aged 40-59 years, resident in two small Italian villages. • Reference category: occasional drinkers consuming ≤ 1 drink/day. • No sick quitters: 30 years of follow-up from baseline and only 8% of these middle-aged men were unemployed or retired. • Data on alcohol consumption: no underreporting among the rural cohorts where consumption of wine with meals has been a tradition for centuries. Data on heavy consumption verified in local wine shops and among relatives. • Confounders: small risk of confounding among participants living in small villages with very similar living conditions and similar dietary pattern. • Consumption categories: cut points at 4, 7 and 10 drinks of wine/day where 4 drinks/day is considered as moderate consumption and 10+ drinks/day as heavy consumption. • Drinking pattern: regular consumption of red wine with meals and no binge drinking. Concerning longest survival, the study observed the following: Age-adjusted: 21.6 ± 0.4 years for men drinking 4-7 drinks/day; Smoking-adjusted: 22.4 ± 0.5 years for non-smokers drinking 4-7 drinks/day; and Physical activity-adjusted: 32.4 ± 0.7 years for hard workers drinking 1-4 drinks/day. The results of this study of Italian men followed for total mortality from 1965 to 1995 clearly showed that men aged 45-64 at entry, drinking about 5 glasses of red wine per day had a longer life expectancy than occasional (< 12 g alcohol/day) and heavy drinkers (> 120 g/day). The results are difficult to understand in view of the statement: “less consumption means less risk of harm from alcohol” from the report. The results of this study also show that about two years of life are gained by moderate drinkers both in comparison with occasional and heavy drinkers, but the same period of two years is lost by smokers compared to non-smokers. 32 2.5 Confounding Data on associations of alcohol use with disease and death from cohort studies that are subject to confounding like all other observational studies. For example, confounding undoubtedly introduces biases into estimates of moderate drinking because moderate drinkers probably have many protective moderate habits. 33 The question whether the decrease in risk of IHD and type 2 diabetes associated with regular, moderate intake of alcohol among middle-aged and older adults is due to biological effects of alcohol or to what degree part of the risk reduction is a consequence of confounding by protective, moderate habits can only be answered by a problematic, hard to do, randomized controlled trial. As no answers from a randomized controlled trial are currently expected, let’s take a look at a study where five protective moderate habits are taken account of in the study protocol and final analysis: Using data from the Nurses’ Health Study (1980–2014; n=78 865) and the Health Professionals Follow-up Study (1986–2014, n=44 354), the authors defined five low-risk lifestyle factors as never smoking, body mass index of 18.5 to 24.9 kg/m2, ≥30 min/day of moderate to vigorous physical activity, moderate alcohol consumption (5 to 15 g/day for women and 5 to 30 g/day for men), and a high diet quality score (upper 40%), and estimated hazard ratios for the association of total lifestyle score (0–5 scale) with mortality. For those who adopted all five low risk factors, they projected a life expectancy at age 50 years of 43.1 years for women and 37.6 years for men. The projected life expectancy at age 50 years was on average 14.0 years longer among female Americans with five low risk factors compared with those with nil low-risk factors; for men, the difference was 12.2 years. Further, in a sensitivity analysis using a low-risk score without moderate alcohol consumption, the projected life expectancy at age 50 years was on average 11.4 years longer among female Americans with four low-risk factors compared with those with nil low-risk factors; for men, the difference was 10.0 years. The Nurses’ Health Study also showed that men and women who had such healthy lives were 82% less likely to die of CVD and 65% less likely to die of cancer compared with those with the least healthy lifestyles, over the roughly 30 years of the study. Adding moderate consumption of alcohol to the other four low risk factors extended the projected life expectancy at age 50 years with 2.6 years for women and 12.2 years for men similar to the extra two years for the wine-drinking Italian men. 34 3. Concluding comments on the guidance Forum member Skovenborg muses that maybe there is no such thing as a “One-Size-Fits-All” approach in advice of drinking.35 Population-level initiatives, such as recommending drinking limits, can only go so far, after which individual level approaches are needed. An open and honest dialogue about alcohol consumption should include factors such as age, sex, drinking pattern and the importance of drinking with a meal. An example of drinking advice with age in mind has been suggested by the GBD 2020 Alcohol Collaborators – for people aged 40 years and older without any underlying health conditions, drinking a small amount of alcohol may provide some benefits, such as reducing the risk of ischaemic heart disease, stroke and diabetes. In general, for individuals aged 40–64 years in 2020, safe alcohol consumption levels ranged from about half a 10 g standard drink/day (5. 27 g alcohol/day for males and 5.62 g for females) to almost two 10 g standard drinks/day (16.9 g alcohol/day for males and 18.2 g for females). For individuals over 65 years, the risks of health loss from alcohol consumption were reached after consuming a little more than three 10 g standard drinks/day (31.9 g alcohol/day for males and 35.1 g for females) 36. ccsa.ca/canadas-guidance-alcohol-and-health-final-report Liu Y, et al. (2015) Links between alcohol consumption and breast cancer: a look at the evidence. 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