R E V I E W

Drug and Alcohol Review (July 2010), 29, 437–445

DOI: 10.1111/j.1465-3362.2009.00153.x

REVIEW

Alcohol as a risk factor for liver cirrhosis: A systematic review

and meta-analysis dar_153 437..445

JÜRGEN REHM1,2,3,4, BENJAMIN TAYLOR1,2, SATYA MOHAPATRA1, HYACINTH IRVING1,

DOLLY BALIUNAS1,2, JAYADEEP PATRA1 & MICHAEL ROERECKE1,2
1
Centre for Addiction and Mental Health,Toronto, Canada, 2Dalla Lana School of Public Health, University of Toronto,
Toronto, Canada, 3TU Dresden, Dresden, Germany, and 4Department of Psychiatry, University of Toronto,Toronto, Canada

Abstract
Introduction and Aims. Alcohol is an established risk factor for liver cirrhosis. It remains unclear, however, whether this
relationship follows a continuous dose–response pattern or has a threshold.Also, the influences of sex and end-point (i.e. mortality
vs. morbidity) on the association are not known. To address these questions and to provide a quantitative assessment of the
association between alcohol intake and risk of liver cirrhosis, we conducted a systematic review and meta-analysis of cohort and
case–control studies.Design and Methods. Studies were identified by a literature search of Ovid MEDLINE,EMBASE,Web
of Science, CINAHL, PsychINFO, ETOH and Google Scholar from January 1980 to January 2008 and by searching the
references of retrieved articles. Studies were included if quantifiable information on risk and related confidence intervals with
respect to at least three different levels of average alcohol intake were reported. Both categorical and continuous meta-analytic
techniques were used to model the dose–response relationship.Results. Seventeen studies met the inclusion criteria.We found some
indications for threshold effects.Alcohol consumption had a significantly larger impact on mortality of liver cirrhosis compared with
morbidity. Also, the same amount of average consumption was related to a higher risk of liver cirrhosis in women than in men.
Discussion and Conclusions. Overall, end-point was an important source of heterogeneity among study results.This result
has important implications not only for studies in which the burden of disease attributable to alcohol consumption is estimated, but
also for prevention. [Rehm J,Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, Roerecke M. Alcohol as a risk factor
for liver cirrhosis: A systematic review and meta-analysis. Drug Alcohol Rev 2010;29;437–445]

Key words: alcohol, liver cirrhosis, mortality, morbidity, meta-analysis.

2004 were as a result of liver cirrhosis [2]. Thus, it

Introduction
The causal impact of alcohol on liver disease and cir-
rhosis in particular has long been known. As early as in
1785, Benjamin Rush, in his famous Inquiry into the
Effects of Ardent Spirits upon the Human Body and Mind,
listed liver conditions as the second ‘usual’ disease con-
sequence of habitual drinking of spirits and compared
the effects of alcohol on the liver with the preying on
Prometheus’ liver by the vulture [1]. Liver cirrhosis is
the most important single fatal chronic disease condi-
tion caused by alcohol consumption globally, with
approximately 15% of all alcohol-attributable deaths in
comes as no surprise that liver cirrhosis has always been
included in standard alcohol-attributable disease lists
[3,4].
The empirical literature is likewise unequivocal—
several meta-analyses have assessed the association
between alcohol consumption and liver cirrhosis [5–8]
and all reached a general consensus that there is con-
vincing evidence that heavy alcohol consumption is
associated with increased risk of liver cirrhosis.
However, several questions remain. First is the exact
nature of the relationship, that is, whether there is a
continuous dose–response relationship or a threshold is

Jürgen Rehm PhD, Professor (CAMH—Centre for Addiction and Mental Health), Benjamin Taylor MSc, Research Analyst, Satya Mohapatra
PhD, Research Analyst, Hyacinth Irving MA, Research Method Specialist, Dolly Baliunas MSc, PhD Student, Jayadeep Patra PhD, Scientist,
Michael Roerecke MSc, PhD Student. Correspondence to Prof Dr Jürgen Rehm, Centre for Addiction and Mental Health, 33 Russell Street Room
2035, Toronto, ON, Canada M5S2S1. Tel: +416 5358501 ext. 6378; Fax: +416 2604156; E-mail: jtrehm@aol.com
Received 22 May 2009; accepted for publication 22 August 2009.

© 2010 Australasian Professional Society on Alcohol and other Drugs

438 J. Rehm et al.
not clear. Results from the classic study of Lelbach and
the meta-analyses by Corrao et al. [5–7,9] suggest a
continuous curve of increasing risk of liver cirrhosis
with increasing volume of alcohol consumption without
any evident threshold. Corrao et al. found a significant
increase in the risk of liver cirrhosis at 25 g of pure
alcohol per day compared with abstainers and overall a
monotonic, almost exponential increase of relative risks
(RR) for the range of consumption considered [6]. On
the other hand, a Danish group [10] concluded, that
there was a threshold seen at a consumption level of
greater than five drinks (60 g of pure alcohol) on
average per day. People drinking that heavily had a
27-fold increased mortality from alcoholic cirrhosis in
men and a 35-fold increased mortality from alcoholic
cirrhosis in women compared with the Danish general
population. However, there was no further dose–
response relationship and no additional risk for drink-
ing a much higher volume than 60 g day-1.
The second unanswered question concerns the influ-
ence of sex on the association between alcohol con-
sumption and risk of liver cirrhosis. With the exception
of one meta-analysis by Corrao et al. [5], previous
meta-analyses have presented their findings mainly
undifferentiated by sex. English et al. [8], for example,
found more than a ninefold increase in the risk of liver
cirrhosis for more drinking more than 40 g of pure
alcohol in both sexes compared with abstainers, indi-
cating no gender difference in RR for heavy consump-
tion categories. Nevertheless, they did state different
risks for men and women drinking between 20 and 40 g
of pure alcohol per day.
The third question is whether the risk of liver cirrho-
sis varies by the end-point under consideration, that is,
morbidity versus mortality. In the meta-analyses by
Corrao et al. [5–7] there was a high degree of hetero-
geneity among the studies, possibly indicating that the
end-point was an important source of variation among
study results. However, to our knowledge, no system-
atic analysis has been conducted to investigate this
question. However, there are biological reasons why
liver cirrhosis mortality should be more strongly
affected by drinking alcohol (compared with morbid-
ity). Alcohol drinking, especially heavy consumption,
has been shown to worsen existing liver disease consid-
erably and to have detrimental effects on the immune
system, thus negatively affecting the course of existing
liver disease and increasing the chance of death
[11–15].
In the present study, we aimed to address these three
unanswered questions and to quantify the risk of liver
cirrhosis associated with increasing alcohol consump-
tion based on an updated systematic review and meta-
analysis of observational studies. The search for the last
meta-analysis published in 2004 [6] was conducted
© 2010 Australasian Professional Society on Alcohol and other Drugs
more than 10 years ago, and we included seven studies
not previously included in the former study. In particu-
lar, we wanted to test for a threshold effect by conduct-
ing a meta-analysis on all study results with less than
12 g and between 12 and 24 g of pure alcohol per day
and quantify the alcohol–liver cirrhosis relationship by
sex and by end-point. The results will not only be used
in the Comparative Risk Assessment for alcohol within
the Global Burden of Disease 2005 Study [16], but also
will have implications for public health measures, such
as guidelines for low risk drinking.
Methods
Case definition
Liver cirrhosis is a chronic disease of the liver charac-
terised by the replacement of normal tissue with fibrous
tissue and the loss of functional liver cells. Cirrhosis
results from permanent damage or scarring of the liver
that leads to a blockage of blood flow through the liver
and prevents normal metabolic and regulatory pro-
cesses. Cirrhosis can also lead to an inability of the liver
to perform its biochemical functions (http://www.liver.
ca/Liver_Disease/Adult_Liver_Diseases/Cirrhosis_of_
the_Liver.aspx; accessed 11 November 2008). Only
studies with clinical defined assessment of morbidity
and death certificates for mortality were included (i.e.
no, self-reports). Depending on the different periods in
which the data were collected, several different revisions
of the International Classification of Diseases (ICD)
were used to define liver cirrhosis. The codes used for
potential inclusion were: 581 in ICD7 and 571 in ICD8
and ICD9, and K70, K74 in ICD10. We found no
studies based on ICD10.
Literature search
We performed a literature search for studies in humans
of the association between alcohol consumption and
liver cirrhosis in multiple electronic bibliographic data-
bases from January 1980 to January 2008, including:
Ovid MEDLINE, EMBASE, Web of Science,
CINAHL, PsychINFO, ETOH and Google Scholar.
The search was conducted using any combination of
the key words: alcohol, alcohol consumption, alcohol
intake, heavy drinking, liver diseases and liver cirrhosis.
In addition, we manually reviewed the content pages of
the major epidemiological journals and the reference
lists of relevant and review articles. No language restric-
tions were imposed.
Inclusion and exclusion criteria
Studies were included in the meta-analysis if: (i) they
had a case–control or cohort design, that is, a stronger

level of control than with a cross-sectional study; (ii)
hazard ratios, RR or odds ratios and their 95% confi-
dence intervals (CIs) (or information allowing us to
compute them) were reported; (iii) the end-point was
liver cirrhosis morbidity and/or mortality as defined
above; (iv) three or more categories of alcohol con-
sumption were reported, one of them being abstention;
and (v) clinical assessment of morbidity and mortality
(the latter via death certificates). Studies were excluded
if: they were not published as full reports, such as
conference abstracts and letters to editors; a cross-
sectional design was used; a continuous measure or
only two categories of alcohol consumption were
included. If multiple published reports from the same
study cohort were available, the one with the most
comprehensive data on alcohol consumption was
included.
Data extraction
Information from the identified studies was indepen-
dently extracted by two investigators. A third investiga-
tor extracted data from a random sample of 15 articles
to assess inter-rater reliability of the process. Of the 710
data points extracted for the reliability, 95.6% agree-
ment was obtained. Using a standardised spreadsheet,
the following data were extracted from each study: title,
authors, year of publication, year of study, sample size,
country, region, ethnicity, age, sex, end-points, adjust-
ments, design of the study baseline, methods of inter-
view, time period of alcohol consumption, number of
beverages, patterns of drinking and the RR with corre-
sponding 95% CIs for each category of alcohol con-
sumption. Throughout this paper, the term RR is used
to describe risk estimates, including odds ratios, RRs or
hazard ratios. If a study only reported RRs relative to
current abstention, the RR and its 95% CI was adjusted
to lifetime abstention. To do this, all studies reporting
RRs of former drinkers compared with lifetime abstain-
ers were grouped together, and a pooled RR for former
drinkers was estimated. In addition, the ratio of former
drinkers to lifetime abstainers in this pooled estimate
was calculated. For those studies reporting only current
abstention, the proportion of lifetime abstainers and
former drinkers was estimated based on the ratio of
former drinkers previously calculated and the RRs in
each article were adjusted based on the pooled RR.This
was done to avoid the ‘sick-quitter effect’ [17], a situa-
tion where previously heavy drinkers who have stopped
drinking because of health reasons confound the true
RR for abstainers, thus artificially increasing lifetime
abstainers’ risk for liver cirrhosis.
If studies only reported results for both sexes com-
bined, the same results were applied to both female and
male datasets. Similarly, if combined results were
Alcohol and liver cirrhosis 439
reported for mortality and morbidity studies, the same
results were applied to both mortality and morbidity
datasets. Sensitivity analyses were conducted to check if
this procedure resulted in biased results compared with
restricting the analyses to ‘pure’ categories, and exclud-
ing studies with ‘mixed’ categories.
Standardisation of alcohol consumption
Information on alcohol consumption was extracted and,
if not already presented as such, converted to grams per
day based on the type of alcohol and the size of a
standard drink in the study’s country of origin. In cases
where the standard drink was not 12 g of pure alcohol,
we used the International Monitoring Guide for Moni-
toring Alcohol Consumption and Related Harm [18]
and another overview http://www.icap.org/PolicyTools/
ICAPBlueBook/BlueBookModules/20StandardDrinks/
tabid/161/Default.aspx, last accessed 13 August 2009)
to obtain the country-specific standard drink size.When
ranges of alcohol were given to define a category, the
midpoint was taken. In cases where no upper bound for
the highest category existed, 75% of the width of the
previous category’s range was added to the lower bound
and this measure was used. This procedure had already
been used in previous meta-analyses [19,20].
Statistical analysis
The dose–response relationship was assessed with
random effects meta-regression models. We used the
method proposed by Greenland et al. [21,22] to back-
calculate and pool study-specific trend estimates. We
completed several meta-analyses. In the first, alcohol
consumption was first modelled as a continuous vari-
able using the fractional polynomial method [23] to
demonstrate the relationship between alcohol con-
sumption and the logarithmised RR of liver cirrhosis.
Only first-degree fractional polynomials with powers of
-2, -1, -0.5, 0, 0.5, 1, 2 and 3 were evaluated as a
monotonic dose–response relationship between alcohol
consumption and risk of liver cirrhosis was assumed on
biological grounds.
Fractional polynomial models are potentially
unstable at both tails [24]. Because we were interested
in examining whether a threshold exists, that is, a level
of alcohol consumption under which the risk of liver
cirrhosis was not increased, the potential instability of
fractional polynomial models in the left tail was of
concern. Therefore, we also did a second meta-analysis
in which we modelled alcohol intake using the catego-
ries: 0 (reference group), >0–12, >12–24, >24–36, >36–
48, >48–60 and >60 g day-1. We assigned the level of
alcohol consumption from each study to these catego-
ries based on the calculated midpoint of alcohol
© 2010 Australasian Professional Society on Alcohol and other Drugs
440 J. Rehm et al.

Table 1. Characteristics of the included studies (starting with earliest study)

Author Country Sex Study design n cases Total sample size End-point

Blackwelder et al. (1980) [29] USA Male Cohort 16 7 888 Mortality

Klatsky et al. (1981) [30] USA Both Cohort 51 8 060 Mortality
Gordon and Kannel (1984) [31] USA Both Cohort 25 4 747 Mortality
Kono et al. (1986) [32] Japan Male Cohort 40 4 639 Mortality
Gordon and Doyle (1987) [33] USA Male Cohort 15 1 762 Mortality
Garfinkel et al. (1988) [34] USA Female Cohort 568 548 185 Mortality
Boffetta and Garfinkel (1990) [35] USA Male Cohort 611 239 462 Mortality
Corrao et al. (1991) [36] Italy Both Case–control 184 369 Morbidity
Corrao et al. (1993) [37] Italy Both Case–control 320 640 Morbidity
Fuchs et al. (1995) [38] USA Female Cohort 52 85 709 Mortality
Becker et al. (1996) [39] Denmark Both Cohort 124 13 236 Both
Bellentani et al. (1997) [40] Italy Both Cohort 35 6 442 Morbidity
Corrao et al. (1997) [41] Italy Both Case–control 462 1 113 Morbidity
Thun et al. (1997) [42] USA Both Cohort 446 457 423 Mortality
Yuan et al. (1997) [43] China Male Cohort 35 18 244 Mortality
Becker et al. (2002) [44] Denmark Both Cohort 292 30 630 Both
Klatsky et al. (2003) [45] USA Both Cohort 108 49 338 Mortality

consumption. Dummy variables were generated, and

they were included in the categorical meta-analysis to
assess the possibility of threshold effects across alcohol
consumption categories.
Statistical heterogeneity among studies was assessed
using both the Cochrane Q-test and the I2 statistic [25].
We assessed publication bias using the tests of Egger
et al. [26] and Begg and Mazumdar [27]. All statistical
analyses were completed for women and men sepa-
rately using the GLST procedure in stata Version 10.1
(StataCorp LP, College Station, Texas, USA) [28].

Results
Characteristics of the included studies
We identified 17 studies that met the inclusion criteria
outlined in Figure 1. Table 1 summarises the charac-
teristics of the included studies. The majority of studies
were conducted in the USA (n = 9), followed by Italy
(n = 4) and Denmark (n = 2). China and Japan each
contributed one study. Of the 17 studies, seven
[31,37,39,41,42,44,45] reported liver cirrhosis end-
points separately for women and men. Only two studies
[34,38] reported data for women only, while five
studies [29,32,33,35,43] included men only. Three
studies [30,36,40] reported undifferentiated by sex.
Collectively, the 17 studies provided 12 datasets for
women and 15 datasets for men for a total of 1477 887
individuals with 3384 cases of liver cirrhosis.

Assessing publication bias

Among women, the Begg and Mazumdar’s [27]
Figure 1. Flow diagram describing selection of articles. (P = 0.837) and Egger et al.’s [26] tests (P = 0.215)
© 2010 Australasian Professional Society on Alcohol and other Drugs
 Alcohol and liver cirrhosis 441

suggested no significant asymmetry of the funnel plot,

indicating no evidence of substantial publication bias. A
similar finding was also observed among men. The
Begg and Mazumdar’s and Egger et al.’s values were
0.767 and 0.196, respectively.

Dose–response meta-analyses and potential

threshold effects
A total of eight first-degree fractional polynomial
models were examined separately for women and men.
Among women, the best first-degree model with power
(0.5) and function b1x0.5 fitted the data significantly
better than the linear model with a deviance decrease of
76.12. For men, the linear model (P = 1) and function
b1x1 fitted the data best. However, the goodness-of-fit
test suggested that marked heterogeneity was still
present in the models for both women [Q = 200.59,
P ⱕ 0.001, I2 = 72%, 95% CI (63%, 78%)] and men
[Q = 305.22, P ⱕ 0.001, I2 = 78%, 95% CI (72%,
82%)].
To assess whether the heterogeneity of study results
might be as a result of differences in the study’s end-
point (mortality or morbidity), we created an interaction
(product) term between the type of end-point under
consideration (1 for mortality and 0 for morbidity) and
the dose variable, and we included it in the model for
each sex.The interaction term was significant for women Figure 2. Relative risk and meta-regression curve of liver
(X2 = 7.89, d.f. = 1, P = 0.005) and for men (X2 = cirrhosis associated with alcohol consumption by sex and end-point.
17.06, d.f. = 1, P ⱕ 0.001), suggesting that the effect of
alcohol consumption on the risk of liver cirrhosis was bidity as the end-point. For all levels of consumption
different in mortality compared with morbidity studies. and for both genders the RR for mortality was signifi-
Figure 2 displays the results of these analyses for cantly higher than the RR for morbidity.
both sexes. Results indicate that, for both sexes, there With respect to sex differences, results in Table 2
was a continuous dose–response relationship between revealed that women had higher RRs than men for the
alcohol consumption and risk of liver cirrhosis in both same amount of drinking in both mortality and mor-
mortality and morbidity studies. However, the effect of bidity studies. Whereas in mortality studies the RR for
alcohol consumption was greater for mortality in com- five drinks per day for women was 14.7 (95% CI 11.0,
parison with morbidity studies for both sexes. In mor- 19.6), for men the RR was 7.0 (95% CI 5.8, 8.5). In
tality studies, compared with women who were lifetime morbidity studies, the differences between the sexes
abstainers, the RRs of liver cirrhosis were 4.9 (95% CI were not as pronounced as they were in mortality
4.0, 6.2) and 12.5 (95% CI 8.8, 17.7) for those who studies (Table 2).
consumed 24 and 60 g of alcohol per day, respectively. There were, however, some noteworthy differences in
In morbidity studies, relative to women who were life- the results displayed in Figure 2 and Table 2. For
time abstainers, those who consumed 24 and 60 g of women in morbidity studies, one to two drinks daily
alcohol per day had RRs of 3.2 (95% CI 2.6, 3.9) and had virtually the identical risk as lifetime abstention
6.2 (95% CI 4.4, 8.7). Although less pronounced, a [RR = 1.0, 95% CI (0.5, 1.9), P = 0.981], while two to
similar pattern of effect was observed among men. three drinks was the lowest category associated with a
Table 2 presents the results of the second assessment significantly higher risk [RR = 2.4, 95% CI (1.8, 3.2),
of the association between the risk of liver cirrhosis and P ⱕ 0.001]. Among men in mortality studies, a similar
alcohol consumption, with consumption modelled in dose threshold was observed. Another difference of
categories. The results were similar to those reported in note was that, relative to lifetime abstainers, men who
Figure 2 in that alcohol consumption had a greater consumed one to two drinks per day in morbidity
impact on the risk of liver cirrhosis in studies that had studies had lower risk of liver cirrhosis (RR = 0.3, 95%
mortality as compared with those that reported mor- CI 0.2, 0.4).
© 2010 Australasian Professional Society on Alcohol and other Drugs
442 J. Rehm et al.

Table 2. Relative risk (95% CI) of liver cirrhosis associated with alcohol consumption derived from the random effects categorical models
by sex and end-point

Mortality Morbidity

Alcohol consumption Interaction

(pure alcohol g day-1) RR P-value (95% CI) RR P-value (95% CI) P-valuea

Women
>0–12b 1.9 0.013 (1.1, 3.1) 0.4 0.105 (0.1, 1.2) 0.023
>12–24b 5.6 <0.001 (4.5, 6.9) 1.0 0.981 (0.5, 1.9) <0.001
>24–36b 7.7 <0.001 (6.3, 9.5) 2.4 <0.001 (1.8, 3.2) <0.001
>36–48b 10.1 <0.001 (7.5, 13.5) 1.9 <0.001 (1.4, 2.6) <0.001
>48–60b 14.7 <0.001 (11.0, 19.6) 5.9 <0.001 (3.7, 9.3) 0.001
>60b 22.7 <0.001 (17.2, 30.1) 6.1 <0.001 (4.6, 8.0) <0.001
Men
>0–12c 1.0 0.991 (0.6, 1.6) 0.3 0.026 (0.1, 0.9) 0.05
>12–24c 1.6 <0.001 (1.4, 2.0) 0.3 <0.001 (0.2, 0.4) <0.001
>24–36c 2.8 <0.001 (2.3, 3.4) 0.7 0.029 (0.5, 1.0) <0.001
>36–48c 5.6 <0.001 (4.5, 7.0) 2.0 <0.001 (1.5, 2.7) <0.001
>48–60c 7.0 <0.001 (5.8, 8.5) 2.3 <0.001 (1.7, 3.2) <0.001
>60c 14 <0.001 (11.7, 16.7) 5.0 <0.001 (3.9, 6.4) <0.001

a
The interaction terms measures the significance of a difference in RR for morbidity versus mortality. bWomen who were lifetime
abstainers were the reference group. cMen who were lifetime abstainers were the reference group. CI, confidence interval; RR,
Relative risk.

Sensitivity analyses did reveal a very similar pattern
for the pure categories in comparison with mixed cat-
egories. This was not surprising, as we found marked
differences between the two sexes and by type of end-
point, even though the procedure of adding studies that
did not report disaggregated results to both categories
involved leads to an attenuation of results.
Discussion
Our meta-analyses confirmed the close dose–response
relationships between average amount of alcohol con-
sumed and risk of liver cirrhosis. With respect of a
threshold, using the categorical approach, light to mod-
erate drinking up to two drinks among women and men
was not associated with a significant increase in risk of
liver cirrhosis morbidity. However, all consumption cat-
egories over two drinks a day in the categorical analyses
were significantly associated with a higher risk for
women, as well as all consumption categories over three
drinks for men. For mortality in women, already one
drink per day on average was associated with a signifi-
cantly elevated risk, and the risks increased with
increasing volume of alcohol consumption. Thus, for
women in mortality studies, the data were more con-
sistent with a continuous risk increase without thresh-
old (see also [46,47]) for potential mechanisms and a
further discussion). For men, a very low threshold
could not be discounted, even though the same under-
lying biological processes apply.
© 2010 Australasian Professional Society on Alcohol and other Drugs
The lack of difference between abstainers and
drinking up to 12 g of pure alcohol per day may be
explained by the fact that light occasional drinkers,
where we would not expect any biological effect, were
classified as drinkers. This again underlines the plea to
decide about comparison groups for alcohol con-
sumption based on biological reasoning; combining
lifetime abstainers with people, who had very light
and infrequent drinking episodes, where no biological
effects on the liver could be possible, should be the
norm [48–50]. Considering all these points, the
results point into the direction of a threshold for mor-
bidity, but not mortality.
What does this mean for public health? Obviously
where liver cirrhosis is concerned, no alcohol con-
sumption can be recommended, although consump-
tion of small doses up to two drinks per day may not
confer an increased risk for morbidity. Once there are
any signs of liver problems, no matter from what
cause, people should abstain as the higher RRs for any
kind of consumption associated with mortality clearly
indicate, and as there may be interactions with drugs
taken in association with liver problems (e.g. [51].).
Additionally, these results cannot be seen as separate
from the individual studies from which they come—
although together they are more compelling, these
point estimates and associated CIs should be inter-
preted in the context of the strength and limitations of
the work they come from, and of the merits of meta-
analysis generally.

Strengths and limitations
Strengths of the present study included the modelling
of alcohol consumption as both a continuous and a
categorical variable. A similar pattern of associations
obtained from the two methods further strengthens our
findings. Our evaluation of the association between
alcohol consumption and risk of liver cirrhosis sepa-
rately for each sex and by end-point also were strengths
of our study. As a meta-analysis of published studies, we
are exposed to potential publication bias. However, the
results from our tests of publication bias suggested that
there was no evidence of this effect.
The study also has a number of limitations that must
be discussed. We restricted ourselves to quantify effects
of average volume of alcohol consumption and did not
investigate other dimensions of alcohol intake usually
summarised under the topic of patterns of drinking,
such as drinking over time, binge drinking or beverage
preference.
With respect to drinking over time, there had been a
tradition of integrating this variable either directly or
indirectly by computing indices, such as average
amount of drinking per drinking year (e.g. [52,53].The
results of this approach are quite similar to our
approach, where we implicitly assume for cohort
studies, that level of drinking at baseline is an indicator
for drinking over time.
We had intended to address the issue of binge drink-
ing and beverage preference quantitatively and system-
atically in our review; however, the lack of such
information in the studies that were included in our
meta-analysis precluded us from doing so. With respect
to pattern of drinking, it has been shown in recent
studies that continuous drinking rather than binge
drinking seem to be associated with the development of
cirrhosis in persons with alcohol use disorders [54,55].
On the other hand, in a follow up of a large general
populations survey of the USA [56], it was found that
one or two heavy drinking occasions per week were
associated with a significantly increased risk for liver
disease, even after controlling for volume of drinking.
Concerning beverage type, some studies have found
that the incidence of liver cirrhosis and resulting mor-
tality were related to beverage type [44,57]. Conversely,
Pelletier et al. [58] found no such relationship between
the type of alcoholic beverage and the occurrence of
liver cirrhosis. Further studies on the impact of binge
drinking are certainly necessary.
Finally, there are few studies on light to moderate
drinking and liver cirrhosis morbidity as an end-point.
Our analyses showed a protective effect of drinking up
to two standard drinks of alcohol per day, albeit with no
biological pathway. We need more data on regular light
drinking and liver cirrhosis morbidity with valid assess-
Alcohol and liver cirrhosis 443
ment of former drinking separately from lifetime
abstention to decide about whether our current results
can be corroborated by other studies.
Conclusions
Overall, the end-point was an important source of het-
erogeneity among study results. Alcohol consumption
had a significantly greater impact on the risk of liver
cirrhosis in studies that had mortality compared with
those studies that had morbidity as the end-point. This
was an important result with respect to studies where
burden of disease attributable to alcohol consumption
is estimated [2,59]. Up to now, despite some compel-
ling arguments for separating effects on mortality
versus effects on morbidity (i.e. Single et al. [60]), to
our knowledge no study has systematically estimated
these important differential effects. Theoretically, as
indicated above, we expected a larger RR for mortality
than for morbidity based on the biology of disease, and
this hypothesis was confirmed. The same reasoning
would apply for other chronic and infectious disease
end-points of alcohol, as well as to other substance-
related risk factors that have effects on the immune
system, such as tobacco or illegal drugs [61,62]. The
current practice in epidemiology tends to derive RR
from both end-points combined without testing for
potential differences. This approach should be aban-
doned for a systematic exploration of differential effects
of risk factors on morbidity versus mortality. Also,
potential threshold effects of alcohol consumption on
liver cirrhosis morbidity were suggested for men and
women, a first for this disease. Future research on this
piece of the puzzle is warranted as it has broad potential
public health and health policy impacts.
Acknowledgements
NIAAA (contract # HHSN267200700041C ‘Alcohol-
and Drug-Attributable Burden of Disease and Injury in
the US’ to the first author) and the Global Burden of
Disease and Injury 2005 Project provided financial
and/or technical support for this study. In addition,
support to Centre for Addiction and Mental Health for
salary of scientists and infrastructure has been provided
by the Ontario Ministry of Health and Long Term
Care. The views expressed do not necessarily reflect
those of the Ministry of Health and Long Term Care.
We would like to thank the core group of the Compara-
tive Risk Assessment for alcohol within the Global
Burden of Disease 2005 Study for their support and
comments on the general methodology and on an
earlier version of this paper: Drs G. Borges, G. Gmel,
K. Graham, B. Grant, Ch. Parry, V. Poznyak and
R. Room.
© 2010 Australasian Professional Society on Alcohol and other Drugs
444 J. Rehm et al.
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