www.elsevier.com/locate/ypmed

Preventive Medicine 38 (2004) 613–619

A meta-analysis of alcohol consumption and the risk of 15 diseases

Giovanni Corrao, Ph.D.,a Vincenzo Bagnardi, Sc.D.,a

Antonella Zambon, Sc.D.,a and Carlo La Vecchia, M.D.b,c,*

aDipartimento di Statistica, Universita di Milano-Bicocca, Milan, Italyb Istituto di Statistica Medica e Biometria, Universita di Milano, Milan, Italy

c Istituto di Ricerche Farmacologiche ‘‘Mario Negri’’, Milan, Italy

Abstract

Background. To compare the strength of evidence provided by the epidemiological literature on the association between alcohol

consumption and the risk of 14 major alcohol-related neoplasms and non-neoplastic diseases, plus injuries.

Methods. A search of the epidemiological literature from 1966 to 1998 was performed by several bibliographic databases. Meta-

regression models were fitted considering fixed and random effect models and linear and nonlinear effects of alcohol intake. The effects of

some characteristics of the studies, including an index of their quality, were considered.

Results. Of the 561 initially reviewed studies, 156 were selected for meta-analysis because of their a priori defined higher quality,

including a total of 116,702 subjects. Strong trends in risk were observed for cancers of the oral cavity, esophagus and larynx, hypertension,

liver cirrhosis, chronic pancreatitis, and injuries and violence. Less strong direct relations were observed for cancers of the colon, rectum,

liver, and breast. For all these conditions, significant increased risks were also found for ethanol intake of 25 g per day. Threshold values were

observed for ischemic and hemorrhagic strokes. For coronary heart disease, a J-shaped relation was observed with a minimum relative risk of

0.80 at 20 g/day, a significant protective effect up to 72 g/day, and a significant increased risk at 89 g/day. No clear relation was observed for

gastroduodenal ulcer.

Conclusions. This meta-analysis shows no evidence of a threshold effect for both neoplasms and several non-neoplastic diseases. J-shaped

relations were observed only for coronary heart disease.

D 2004 The Institute For Cancer Prevention and Elsevier Inc. All rights reserved.

Keywords: Alcohol intake; Alcohol-related diseases; Meta-analysis

Introduction

Alcohol drinking is a major correlate of health and

disease, and it has been associated to cancer, cardiovascular

diseases, digestive tract conditions, accidents, and violence.

Although alcohol is not known to be carcinogenic in

animal experimentation, there is strong epidemiological

evidence that consumption of alcoholic beverages increases

the risk of cancers of the oral cavity and pharynx, esoph-

agus, and larynx [1,2]. The risks are essentially thought to

be related to ethanol content and appear to be linked to the

most commonly used alcoholic beverages in each popula-

tion. These risks tend to increase with the amount of ethanol

drunk, but it is still unclear whether there is any defined

0091-7435/$ - see front matter D 2004 The Institute For Cancer Prevention and

doi:10.1016/j.ypmed.2003.11.027

* Corresponding author. Istituto di Ricerche Farmacologiche ‘‘Mario

Negri’’, Via Eritrea 62, 20157 Milan, Italy. Fax: +39-02-3320-0231.

E-mail address: lavecchia@marionegri.it (C. La Vecchia).

threshold below which no effect is evident [1,2]. Alcohol

drinking is also associated with primary liver cancer, al-

though this relation is difficult to investigate in epidemio-

logical studies because most alcohol-related liver cancers

follow a cirrhotic degeneration, which leads to a reduction

of alcohol drinking [3].

Alcohol drinking has also been linked to cancers of the

large bowel in both sexes [2] and breast cancer in women

[4]. Although these associations are still open to discussion,

these are the two major causes of cancer death in developed

countries after lung cancer [5,6], and therefore even a

moderate excess risk may have important public health

implications. Furthermore, alcohol drinking is strongly

related to mortality from liver cirrhosis, chronic pancreatitis,

hypertension, stroke, accidents, and violence [7,8].

It has been suggested, in contrast, that moderate alcohol

consumption (i.e., <25 g/day) protects against coronary

heart disease [9]. A number of plausible mechanisms have

been formulated, including the relation between alcohol

Elsevier Inc. All rights reserved.

G. Corrao et al. / Preventive Medicine 38 (2004) 613–619614

drinking and cholesterol, high density lipoprotein, apolipo-

proteins, fibrinolysis, coagulation factors, and blood pres-

sure, but none has as yet been firmly established [10].

It has also been suggested that the protection is specific,

or greater, for selected types of alcoholic beverages, such as

red wine (due to phenolic compounds, flavonoids or tannin)

[11,12]. Independently of the population studied, and hence

of the most frequent type of alcohol beverages, however,

most studies found reduced risk of cardiovascular diseases in

moderate drinkers compared with nondrinkers [8,9,13–16].

Several comprehensive reviews are available on the effect

of alcohol on disease [1,17–23]. To evaluate the global

effect of alcohol on a population level, a more accurate

quantification of its effects and of its dose–risk relation on

various diseases is nonetheless required. This paper thus also

includes an original analysis of risks for moderate doses,

which are of specific interest for medical practice.

Methods

The following 15 conditions considered to be alcohol-

related were included in the meta-analysis: malignant neo-

plasms of the oral cavity and pharynx, of the esophagus, of

the colon, of the rectum, of the liver, of the larynx, and of the

breast, essential hypertension, coronary heart disease, hem-

orrhagic stroke, ischemic stroke, gastroduodenal ulcer, liver

cirrhosis, chronic pancreatitis, and injuries and violence. The

methods of this work are described in details elsewhere

[18,19].

Articles included in the meta-analysis were found through

a search of the literature published from 1966 to 1998. The

search was based on several bibliographic databases (MED-

DLINE, Current Contents, EMBASE CAB Abstracts, and

Core Biomedical Collection) supplemented by attention to

all references in the selected articles. Completeness was

verified by a hand search on the most relevant journals of

epidemiology and medicine and by comparing our search

with that of general reviews and meta-analyses published on

this issue [17,20–23].

For each of the above-reported conditions, the search

process involved combining the keywords ‘‘alcohol con-

sumption’’, ‘‘relative risk’’, and the specific ‘‘conditions’’.

These keywords were exploded in the search, thus to include

all the articles investigating the same issue, but reporting the

same term in different forms (i.e., ‘‘alcohol consumption’’ or

‘‘alcohol intake’’, ‘‘relative risk’’ or ‘‘risk ratio’’ or ‘‘odds

ratio’’, ‘‘cancer’’ or ‘‘malignant neoplasm’’ or ‘‘neoplasia’’,

‘‘cerebrovascular disease’’ or ‘‘stroke’’).

Each publication identified by this process was reviewed

and included in the analysis if the following criteria were

met: (i) case-control or cohort study published as an original

article; (ii) findings expressed as odds ratio or relative risk

(RR) considering at least three levels of alcohol consump-

tion; (iii) papers reporting the number of cases and noncases

and the estimates of the odds ratios or RR for each exposure

level. When the results of a study were published more than

once, only the most recent and complete article was included

in the analysis.

Two readers, blinded to the authors’ names and affilia-

tions and to the results pertaining to alcohol consumption,

independently determined the eligibility of each paper. The

same readers evaluated several characteristics of each study

and scored the quality of the studies according to criteria

elsewhere reported [18,19]. Questions related to the study

design (nine items), data collection methods for alcohol

consumption (four questions), and data analysis (two items).

The quality score for a study was obtained by adding up the

points given for individual questions. The readers also

evaluated whether each study reported RR adjusted for major

known risk factors (e.g., gender and age for all the con-

ditions, smoking for upper aerodigestive tract cancers, breast

cancer and stroke, hepatitis virus infections for liver cancer

and cirrhosis, hormonal and reproductive factors for breast

cancer, etc.. . .). Discrepancies between readers in the choice

to include an article and in quality score assignment were

resolved in conference.

Pooled estimates of the effect of alcohol consumption on

the risk of each investigated condition were based on a four-

step procedure. In the first step, several weighed least

squares regression models were fitted by prepooling the

results of all studies included, taking into account the

correlation between estimates within each study [24]. A

family of second-degree models was generated by power

transformation of the exposure variable, and the best-fitting

model was chosen to summarize the relation of interest [25].

Depending on both the magnitude and the sign of the

estimated parameters, the resulting function was able to

identify J-, U-, or L-shaped curves, and to accommodate

relations asymptotically tending towards a RR value for high

exposure levels.

In the second step, with the aim of testing the hypothesis

that the qualitative characteristics of the studies may modify

the effect of alcohol, several meta-regression models were

fitted [26]. Models included as covariate: (i) the term(s) of

alcohol consumption identified in the first step of the

analysis; (ii) the interaction term between alcohol intake

and a covariate describing a qualitative characteristic of the

study. The qualitative characteristics were the quality score,

the availability of adjusted RR, and the study design.

In the third step, with the aim of yielding more reliable

functions, studies with higher quality score (the cut-off was

placed differently for each condition, considering studies

with a score equal or above the condition-specific median

value), those conducted with a cohort design or those

reporting estimates adjusted for relevant covariates, were

selected only if one or more of these qualitative character-

istics resulted as significant effect modifiers.

Pooled RR and the corresponding 95% confidence inter-

vals (CI) were derived from the parameters of the meta-

regression models described above and by the corresponding

standard errors. For each condition, RR was modelled to

G. Corrao et al. / Preventive Medicine 38 (2004) 613–619 615

obtain an estimate of the risk associated to specific doses of

alcohol with respect to nondrinkers (model-based RR).

Finally, in the fourth step, the consistency of the model-

based RR was evaluated with reference studies reporting

relative risks for light consumption (V25 g/day). Pooled RR

and the corresponding 95% CI were estimated as simple

average of the reported RR weighed for the inverse of the

corresponding variance [27]. A test of homogeneity of the

RR across studies was provided by the Q statistics [27], and

random effects models were used when there was evidence

of significant heterogeneity [28].

Results

A total of 561 studies were retrieved. Of these, 240 were

included in the analysis (because they gave information on

number of subjects, on RRs for more than two levels of

alcohol consumption, and were not included in subsequent

reports), and 156 were selected for final analysis because of

their higher quality, and the results refer therefore to 156

studies. Of the selected studies, 148 reported adjusted

estimates for the main risk covariates of interest, 99 were

case-control, and 57 cohort studies, including a total of

116,702 cases of the 15 conditions considered.

Table 1

Selection process and main characteristics of the studies selected for the meta-an

Condition History of studies selection Study design

Retrievedb Includedc Selectedd Case-control Coh

Neoplastic conditions (cancer site)

Oral cavity and pharynx 58 24 15 14 1

Esophagus 51 28 14 13 1

Larynx 38 20 20 20 0

Colon 16 16 12 4

Rectum }49 14 6 4 2

Liver 43 19 10 8 2

Breast 72 48 29 24 5

Non neoplastic conditions

Essential hypertension 11 3 2 0 2

Coronary heart disease 196 51 28 0 28

Ischemic stroke 7 6 3 3

Hemorrhagic stroke }56 9 9 6 3

Gastroduodenal ulcer 9 3 2 1 1

Liver cirrhosis 27 15 9 6 3

Chronic pancreatitis 4 2 2 2 0

Injures and violence 34 18 12 1 11

Total 561 240 156 99 57

Model-based pooled relative risks and corresponding 95% confidence interval foa Pooled relative risk and corresponding 95% confidence interval (CI) directly ob

alcohol drinkers.b All the 561 case-control or cohort studies published as original articles were firsc Causes of exclusion were: only two alcohol categories were reported; number o

characterize exposure in terms of grams of alcohol per day; the article considere

included in meta-analysis.d Criteria for selection were: high quality score (malignant neoplasm of oral cavi

disease, and liver cirrhosis); reporting estimates adjusted for the main risk indicato

ulcer, and injures and adverse effects); or performed with a prospective cohort de

The main characteristics of the studies selected for meta-

analysis are given in Table 1, together with the model-based

pooled RR and 95% CI for 25, 50, and 100 g/day of alcohol

intake. Direct trends in risk were observed for cancers of the

oral cavity and pharynx, esophagus, and larynx. Direct

relations were also observed for cancers of the colon, rectum,

and liver, as well as for breast cancer. Among non-neoplastic

conditions, strong direct trends in risk were derived for

hypertension, liver cirrhosis, chronic pancreatitis, and inju-

ries and violence. For all these conditions, significant in-

creased risks were found starting from the lowest dose of

alcohol considered (25 g/day, corresponding to about two

drinks per day). Significant increased risks were found only

at 100 g/day for coronary heart disease and ischemic stroke,

and at 50 g/day for hemorrhagic stroke. A significant

protective action was observed at 25–50 g/day for coronary

heart disease. No clear relation was observed for gastrodu-

odenal ulcer.

The corresponding RR functions, with 95% CI, are

plotted in Fig. 1. Most functions were linear on a logarithmic

scale, except for diseases more strongly related to alcohol

(oral and pharyngeal cancer and liver cirrhosis), with flatten

curves at higher doses, and for cardiovascular diseases with

evidence of J-shaped relations. For ischemic and hemorrhag-

ic strokes, the nadirs were reached at 15 and 3 g/day,

alysis

No. of RR (and 95% CI) for selected doses of alcohol intakea

ortcases

25 g/day 50 g/day 100 g/day

4507 1.86 (1.76–1.96) 3.11 (2.85–3.39) 6.45 (5.76–7.24)

3233 1.39 (1.36–1.42) 1.93 (1.85–2.00) 3.59 (3.34–3.87)

3789 1.43 (1.38–1.48) 2.02 (1.89–2.16) 3.86 (3.42–4.35)

5360 1.05 (1.01–1.09) 1.10 (1.03–1.18) 1.21 (1.05–1.39)

1420 1.09 (1.08–1.12) 1.19 (1.14–1.24) 1.42 (1.30–1.55)

1321 1.19 (1.12–1.27) 1.40 (1.25–1.56) 1.81 (1.50–2.19)

32,175 1.25 (1.20–1.29) 1.55 (1.44–1.67) 2.41 (2.07–2.80)

5801 1.43 (1.33–1.53) 2.04 (1.77–2.35) 4.15 (3.13–5.52)

49,640 0.81 (0.79–0.83) 0.87 (0.84–0.90) 1.13 (1.06–1.21)

893 0.90 (0.75–1.07) 1.17 (0.97–1.44) 4.37 (2.28–8.37)

1192 1.19 (0.97–1.49) 1.82 (1.46–2.28) 4.70 (3.35–6.59)

425 0.98 (0.77–1.25) 0.97 (0.59–1.57) 0.93 (0.35–2.45)

2202 2.90 (2.71–3.09) 7.13 (6.35–8.00) 26.52 (22.26–31.59)

247 1.34 (1.16–1.54) 1.78 (1.34–2.36) 3.19 (1.82–5.59)

4501 1.12 (1.06–1.18) 1.26 (1.13–1.40) 1.58 (1.27–1.95)

116,706 – – –

r selected doses of alcohol consumption are also reported.

tained from the coefficients of the meta-regression model; reference: non-

tly retrieved. A study may include information on more than one condition.

f cases or noncases were not reported; article reported insufficient data to

d only partial results subsequently reported in complete form in an article

ty, of rectum, of liver, and of breast, essential hypertension, coronary heart

rs (malignant neoplasm of esophagus, ischemic stroke, gastric and duodenal

sign (coronary heart disease).

Fig. 1. Relative risk functions and corresponding 95% confidence intervals describing the dose-response relationship between alcohol consumption and the risk of 15 alcohol-related conditions obtained by fitting

meta-regression models.

G.Corra

oet

al./Preven

tiveMedicin

e38(2004)613–619

616

Fig. 3. Comparison between model-based and point-based relative risks and corres

25 g/day.

Fig. 2. Relative risk function and corresponding 95% confidence intervals

describing the dose-response relationship between alcohol consumption and

the risk of coronary heart disease.

G. Corrao et al. / Preventive Medicine 38 (2004) 613–619 617

respectively, but no evidence of significant protective effect

was observed. Significant increased risks were obtained

starting from 53 to 28 g/day, respectively. The RR function

of coronary heart disease is also plotted in Fig. 2. The

minimum (RR = 0.80) was reached at 20 g/day, a significant

protective effect was observed up to 72 g/day, while a

significant increased risk was obtained starting from 89

g/day (RR = 1.05).

Fig. 3 compares model-based and point-based (i.e., based

on studies providing direct information on intake <25 g/day)

pooled RR for light alcohol intake. Chronic pancreatitis was

not considered because no studies reported RR for light

intake. Owing to the smaller number of studies included and

to the weaker statistical assumptions, point-based RR

showed wider CI than model-based estimates. Consistent

and significant increased RRs were observed for cancers of

the oral cavity and pharynx, esophagus, larynx, colon, liver,

and breast, hypertension, liver cirrhosis, and injuries and

ponding 95% confidence intervals associated with alcohol intake lower than

G. Corrao et al. / Preventive Medicine 38 (2004) 613–619618

violence. The RR was above unit—though nonsignificant-

ly—for rectal cancer, too. The protective action of low dose

of alcohol on the risk of coronary heart disease was also

confirmed. Ischemic and hemorrhagic stroke, and gastrodu-

odenal ulcer were not associated to moderate alcohol intake

according to both analyses. The point-based RRs were

homogeneous across studies for all conditions, except inju-

ries and violence.

Discussion

This work has some of the limitations, but also most

strengths, of meta-analyses of published studies. Thus, bias

towards selective publications of studies showing inverse

relations with moderate levels of alcohol drinking was

apparent for coronary heart disease and is likely to have

occurred—in various directions—for other diseases, includ-

ing esophageal and laryngeal cancer, too. The overall pooled

estimates may be systematically influenced by the study

characteristics. We used three approaches to control for this.

Firstly, because an important part of the heterogeneity was

explained by the quality of the studies, we only used data

from a selection of 156 studies meeting a priori-defined

quality criteria. Secondly, we investigated reasons for het-

erogeneity. At least two of these, that is, geographic area and

gender, may reflect real effect modification due to different

patterns of drinking in southern Europe as compared to

northern Europe and the United States, as well as potential

differences in alcohol metabolism in women and men

[18,19]. Thirdly, because for some diseases a large amount

of unexplained heterogeneity remained even after these

controls, random effect models were used to derive pooled

RR estimates at moderate intake. With such an approach,

heterogeneous estimates still remained only for injuries and

violence. This finding is likely attributable to the broad

spectrum of conditions included in this category (e.g., road

injuries, suicides, homicides, accidental falls, etc.. . .).It is possible that alcohol drinking has been systemati-

cally underreported in several studies, mostly for specific

conditions, such as liver cirrhosis or accidents and violence.

Consequently, all the RRs would be underestimated in case

of selective underreporting by cases. Further, although this

meta-analysis included a total of more than 116,000 cases,

absolute numbers were relatively limited for some diseases

(i.e., gastroduodenal ulcer) or levels of alcohol drinking

(i.e., high levels for breast cancer in women). Exclusion of

cross-sectional studies has also substantially limited the

information available on hypertension [18]. Finally, the

estimates may be grossly biased for some of the diseases

considered, including liver cancer, due to preexisting cir-

rhosis and consequent reduced alcohol consumption [3,29].

These limitations notwithstanding, this meta-analysis still

include most published information on alcohol and disease,

and consequently provide the most accurate estimates of risk

for most common conditions considered to be alcohol-

related. Some of the findings from this meta-analysis are

innovative and of specific relevance, including the absence

of a threshold effect for any of the seven cancer sites

considered from both model-based and point-based RR,

and the apparently stronger association for oral and pharyn-

geal as compared to esophageal or laryngeal cancer across

subsequent levels of alcohol drinking. The absence of

evidence of association with gastroduodenal ulcer is of

interest, although it may be due to decreased alcohol drink-

ing following symptoms of the disease. The strong associ-

ations for hypertension and, mostly, for liver cirrhosis are

also of interest for a more accurate quantification of the dose-

risk relation and of the consequent public health relevance.

Of even greater importance is the definition of a risk

function between alcohol drinking and coronary heart dis-

ease, based on data from almost 50,000 cases, and providing

an estimate of a 20% risk reduction for 20 g/day of alcohol,

and an RR below unity until 70 to 80 g/day, but significantly

above unity more than 90 g/day. Finally, there was evidence

of a threshold effect for both ischemic and hemorrhagic

stroke.

These figures will therefore assist in any risk or benefit

assessment for alcohol drinking on an individual basis and a

population level. To put these findings in a context of

absolute risk, the baseline incidence of various diseases in

the population and the individual’s age should be taken into

account.

Acknowledgments

Supports for this study came from the Italian Ministry of

Health, the Italian Ministry of the University and Scientific

and Technologic Research, COFIN 2003, and the Italian

Association for Research on Cancer.

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