Diseases
Alcohol consumption is
a risk factor for many chronic diseases and conditions. The average volume of
alcohol consumed, consumption patterns, and quality of the alcoholic beverages
consumed likely have a causal impact on the mortality and morbidity related to
chronic diseases and conditions. Twenty-five chronic disease and condition
codes in the International Classification of Disease (ICD)-10 are entirely
attributable to alcohol, and alcohol plays a component-risk role in certain
cancers, other tumors, neuropsychiatric conditions, and numerous cardiovascular
and digestive diseases. Furthermore, alcohol has both beneficial and
detrimental impacts on diabetes, ischemic stroke, and ischemic heart disease,
depending on the overall volume of alcohol consumed, and, in the case of
ischemic diseases, consumption patterns. However, limitations exist to the
methods used to calculate the relative risks and alcohol-attributable
fractions. Furthermore, new studies and confounders may lead to additional
diseases being causally linked to alcohol consumption, or may disprove the
relationship between alcohol consumption and certain diseases that currently
are considered to be causally linked. These limitations do not affect the
conclusion that alcohol consumption significantly contributes to the burden of
chronic diseases and conditions globally, and that this burden should be a
target for intervention.
Alcohol has been a
part of human culture for all of recorded history, with almost all societies in
which alcohol is consumed experiencing net health and social problems (McGovern
2009; Tramacere et al. 2012b, c). With the industrialization of alcohol
production and the globalization of its marketing and promotion, alcohol
consumption and its related harms have increased worldwide (see Alcohol
Consumption Trends, in this issue). This has prompted the World Health
Organization (WHO) to pass multiple resolutions to address this issue over the
past few years, including the World Health Assembly’s Global Strategy to Reduce
the Harmful Use of Alcohol, which was passed in May 2010. Of growing concern
are noncommunicable chronic diseases and conditions that have been shown to
contribute substantially to the alcohol-attributable burden of disease (Rehm et
al. 2009). Specifically, in 2004 an estimated 35 million deaths and 603 million
disability-adjusted life-years (DALYs) lost were caused by chronic diseases and
conditions globally (WHO 2008); alcohol was responsible for 3.4 percent of the
deaths and 2.4 percent of DALYs caused by these conditions (Parry et al. 2011).
To address the burden of chronic diseases and conditions, the United Nation
(UN) General Assembly passed Resolution 64/265 in May of 2010, calling for
their prevention and control (UN 2010). This resolution is intended to garner
multisectoral commitment and facilitate action on a global scale to address the
fact that alcohol (together with tobacco, lack of exercise, and diet) plays a
significant role in chronic diseases and conditions. It is noteworthy that
cardiovascular diseases, cancers, and diabetes in particular have been
highlighted for targeted action (UN 2010) because alcohol is a risk factor for
many cardiovascular diseases and cancers and has both beneficial and
detrimental effects on diabetes and ischemic cardiovascular diseases,1
depending on the amount of alcohol consumed and the patterns of consumption.
1 Ischemic
cardiovascular diseases are those caused by a blockage of blood vessels,
resulting in a loss of blood supply to the tissue serviced by the affected
blood vessels.
Building on previous
reviews concerning alcohol and disease (Rehm et al. 2003a, 2009), this article
presents an up-to-date and in-depth overview of the relationship of alcohol
consumption and high-risk drinking patterns and the initiation/exacerbation and
treatment of various chronic diseases and conditions. It also assesses the
methods used to calculate the impact of alcohol consumption on chronic diseases
and conditions.
Alcohol Consumption As
a Risk Factor for Chronic Diseases and Conditions
Figure 1 presents a
conceptual model of the effects of alcohol consumption on morbidity and
mortality and of the influence of both societal and demographic factors on
alcohol consumption and alcohol-related harms resulting in chronic diseases and
conditions (adapted from Rehm et al. 2010a). According to this model, two
separate, but related, measures of alcohol consumption are responsible for most
of the causal impact of alcohol on the burden of chronic diseases and
conditions—overall volume of alcohol consumption and patterns of drinking. The
overall volume of alcohol consumption plays a role in all alcohol-related
diseases, whereas drinking patterns only affect ischemic cardiovascular
diseases. In addition to the overall volume and pattern of consumption, the
quality of the alcoholic beverages consumed also may influence mortality and
morbidity from chronic diseases and conditions. However, this pathway is of
less importance from a public health perspective (Lachenmeier and Rehm 2009;
Lachenmeier et al. 2007) because it has a much smaller impact than the other
two factors.
Figure 1 Causal model
of alcohol consumption, intermediate mechanisms, and long-term consequences, as
well as of the influence of societal and demographic factors on alcohol
consumption and alcohol-related harms resulting in chronic diseases and
conditions.
Figure 1 Causal model
of alcohol consumption, intermediate mechanisms, and long-term consequences, as
well as of the influence of societal and demographic factors on alcohol consumption
and alcohol-related harms resulting in chronic diseases and conditions.
The effects of overall
volume of alcohol consumed, consumption patterns, and quality of the alcoholic
beverages consumed on mortality and morbidity from chronic diseases and conditions
are mediated by three main mechanisms.
These include the
following:
The toxic and
beneficial biochemical effects of beverage alcohol (i.e., ethanol) and other
compounds found in alcoholic beverages;
The consequences of
intoxication; and
The consequences of
alcohol dependence.
These intermediate
mechanisms have been reviewed in more detail by Rehm and colleagues (2003a).
Chronic Diseases and
Conditions Related to Alcohol
Chronic Diseases and
Conditions Entirely Attributable to Alcohol
Of the chronic
diseases and conditions causally linked with alcohol consumption, many
categories have names indicating that alcohol is a necessary cause—that is,
that these particular diseases and conditions are 100 percent alcohol
attributable. Of these, alcohol use disorders (AUDs)—that is, alcohol
dependence and the harmful use of alcohol as defined by the International
Classification of Disease, Tenth Edition (ICD–10)—certainly are the most
important categories, but many other diseases and conditions also are entirely
attributable to alcohol (see table 1).
Table 1 Chronic
Diseases and Conditions That Are, by Definition, Alcohol Attributable (i.e.,
Require Alcohol Consumption As a Necessary Cause)
ICD–10
Code Disease
F10
Mental and behavioral
disorders attributed to the use of alcohol
F10.0
Acute intoxication
F10.1
Harmful use
F10.2
Dependence syndrome
F10.3
Withdrawal state
F10.4
Withdrawal state with
delirium
F10.5
Psychotic disorder
F10.6
Amnesic syndrome
F10.7
Residual and
late-onset psychotic disorder
F10.8
Other mental and
behavioral disorders
F10.9
Unspecified mental and
behavioral disorder
G31.2
Degeneration of
nervous system attributed to alcohol
G62.1
Alcoholic
polyneuropathy
G72.1
Alcoholic myopathy
I42.6
Alcoholic
cardiomyopathy
K29.2
Alcoholic gastritis
K70
Alcoholic liver
disease
K70.0
Alcoholic fatty liver
K70.1
Alcoholic hepatitis
K70.2
Alcoholic fibrosis and
sclerosis of liver
K70.3
Alcoholic cirrhosis of
liver
K70.4
Alcoholic hepatic
failure
K70.9
Alcoholic liver
disease, unspecified
K85.2
Alcohol-induced acute
pancreatitis
K86.0
Alcohol-induced
chronic pancreatitis
P04.3
Fetus and newborn
affected by maternal use of alcohol
Q86.0
Fetal alcohol syndrome
(dysmorphic)
Chronic Diseases and
Conditions for Which Alcohol Is a Component Cause
Alcohol is a component
cause for more than 200 other diseases and conditions with ICD–10 three-digit
codes—that is, alcohol consumption is not necessary for the diseases to develop
(Rehm et al. 2010a). For these conditions, alcohol shows a dose-response
relationship, where the risk of onset of or death from the disease or condition
depends on the total volume of alcohol consumed (Rehm et al. 2003a). Table 2
outlines these chronic diseases and conditions that are associated with alcohol
consumption and lists the source of the relative risk (RR) functions if the
chronic disease or condition is included as an alcohol-attributable harm in the
2005 Global Burden of Disease (GBD) Study.2 Several of these chronic diseases
and conditions are singled out for further discussion in the following sections
to highlight alcohol’s causative or protective role.
2 The GBD Study is a
project that aims to provide a consistent and comparative description of the
global burden of diseases and injuries and the risk factors that cause them.
Table 2 Chronic
Diseases and Conditions for Which Alcohol Consumption Is a Component Cause,
Identified by Various Meta-Analyses and Reviews and Listed in the 2005 Global
Burden of Disease (GBD) Study
No. of 2005 GBD
Code
Disease
ICD–10 Effect Level of Evidence
Meta-Analysis
Used if Included in the GBD Study
IIA
Malignant neoplasms
IIA1
Mouth cancer
C00–C08
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA2
Nasopharynx cancer and
other pharynx cancers
C09–C13
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA3
Esophagus cancer
C15
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA4
Stomach cancer
C16
Detrimental
Insufficient causal
evidence
IIA5
Colon and rectum
cancers
C18–C21
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA6
Liver cancer
C22
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA9
Larynx cancer
C32
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA10
Trachea, bronchus, and
lung cancers
C33–C34
Detrimental
Insufficient causal
evidence
IIA13
Breast cancer (women
only)
C50
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA16
Ovarian cancer
C56
Detrimental
Insufficient causal
evidence
IIA17
Prostate cancer
C61
Detrimental
Insufficient causal
evidence
IIA19
Kidney and other
urinary organ cancers
C64–C66, C68 (except
C68.9)
Beneficial (renal cell
carcinoma only)
Insufficient causal
evidence
IIA23
Hodgkins lymphoma
C81
Beneficial
Insufficient causal
evidence
IIA24
Non-Hodgkins lymphoma
C82–C85, C96
Beneficial
Insufficient causal
evidence
IIB
Other neoplasms
D00–D48 (except D09.9,
D37.9, D38.6, D39.9, D40.9, D41.9, 48.9)
Detrimental
Insufficient causal
evidence
IIC
Diabetes
E10–E13
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Baliunas et al. 2009)
IIE
Mental and behavioral
disorders
IIE1
Unipolar depressive
disorders
F32–F33, F34.1
Detrimental
Causally related
IIF
Neurological
conditions
IIF1
Alzheimer’s disease
and other dementias
F01–F03, G30–G31
Conflicting evidence
(mainly beneficial)
Insufficient causal
evidence
IIF3
Epilepsy
G40–G41
Detrimental
Causally related
(Samokhvalov et al.
2010a)
IIH
Cardiovascular and
circulatory disease
IIH2
Hypertensive heart
disease
I11–I13
Detrimental (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Taylor et al. 2010)
IIH3
Ischemic heart disease
I20–I25
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Roerecke and Rehm
2010)
IIH4
Cerebrovascular
diseases
IIH4a
Ischemic stroke
I63–I67, I69.3
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Patra et al. 2010)
Specific Chronic
Diseases and Conditions Associated With Alcohol Consumption
Malignant Neoplasms
The relationship
between alcohol consumption and cancer already was suggested in the early 20th
century, when Lamy (1910) observed that patients with cancer either of the
esophagus or of the cardiac region were more likely to be alcoholics. The
accumulation of evidence supporting the relationship between ethanol and
cancers led the International Agency for Research on Cancer (IARC) to recognize
the cancer-inducing potential (i.e., carcinogenicity) of ethanol in animal
models and to conclude that alcoholic beverages are carcinogenic to humans
(IARC 2008). Specifically, the GBD study found that alcohol increased the risk
of cancers of the upper digestive track (i.e., mouth and oropharynx, esophagus,
and larynx), the lower digestive track (i.e., colon, rectum, and liver), and
the female breast (see figure 2). More up-to-date systematic reviews and
meta-analyses on alcohol consumption and the risk of developing cancer have
been published by Fedirko and colleagues (2011) for colorectal cancer, Islami
and colleagues (2011) for esophageal squamous cell carcinoma, Islami and
colleagues (2010) for laryngeal cancer, and Tramacere and colleagues (2010) and
Turati and colleagues (2010) for oral and pharyngeal cancers.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for cancer, with lifetime abstainers serving as the reference
group.
Figure 2 The
relationship between increasing amounts of average daily alcohol consumption and
the relative risk for cancer, with lifetime abstainers serving as the reference
group.
SOURCE: Lim et al.
2012.
A recent meta-analysis
also has indicated that alcohol consumption is significantly linked to an
increased risk of developing prostate cancer in a dose-dependent manner (Rota
et al. 2012); this observation is consistent with previous meta-analyses
concluding that alcohol consumption and the risk for prostate cancer are
significantly correlated (Dennis 2000; Fillmore et al. 2009). Additional research,
however, is required on the biological pathways to prove the role of alcohol
consumption in the development of this type of cancer.
Evidence also has
suggested that stomach cancer may be linked to ethanol consumption (Bagnardi et
al. 2001; Tramacere et al. 2012a); however, the findings have not been
unequivocal. Thus, two recent meta-analyses found no association between
alcohol drinking status (i.e., drinkers compared with non-drinkers) and risk of
gastric cardia adenocarcinoma (Tramacere et al. 2012a, d). However, one
meta-analysis did find an association between heavy alcohol consumption and the
risk of this type of cancer (Tramacere et al. 2012a).
For several types of
cancer investigators have found a nonsignificant positive association with alcohol
consumption, including endometrial (Bagnardi et al. 2001; Rota et al. 2012),
ovarian (Bagnardi et al. 2001), and pancreatic cancers (Bagnardi et al. 2001).
However, because the relationship at least between alcohol consumption and
endometrial and pancreatic cancer is modest (i.e., the point estimates of RR
are low, even at high levels of average daily alcohol consumption), additional
studies with large numbers of participants are needed to accurately assess the
relationship (Bagnardi et al. 2001). The relationship between alcohol
consumption and bladder and lung cancers is even less clear, with one
meta-analysis finding that alcohol significantly increases the risk for both
types of tumors (Bagnardi et al. 2001), whereas more recent meta-analyses have found
no significant association between alcohol consumption and the risk of bladder
cancer (Pelucchi et al. 2012) or the risk of lung cancer in individuals who had
never smoked (Bagnardi et al. 2001). These conflicting results may stem from
the studies in the more recent meta-analyses adjusting for smoking status when
assessing the risk relationship between alcohol and these cancers within
individual observational studies (Bagnardi et al. 2001; Pelucchi et al. 2012).
The biological
pathways by which alcohol increases the risk of developing cancer depends on
the targeted organ and are not yet fully understood. Factors that seem to play
a role include the specific variants of alcohol-metabolizing enzymes (i.e.,
alcohol dehydrogenase [ADH], aldehyde dehydrogenase [ALDH], and cytochrome P450
2E1) a person carries or the concentrations of estrogen as well as changes in
folate metabolism and DNA repair (Boffetta and Hashibe 2006). For example, a
deficiency in ALDH2 activity in people carrying a gene variant (i.e., allele)
called ALDH2 Lys487 contributes to an elevated risk of esophageal cancer from
alcohol consumption (Brooks et al. 2009). Because the ALDH2 Lys487 allele is
more prevalent in Asian populations (i.e., Japanese, Chinese, and Koreans) (Eng
et al. 2007), and ALDH2 is hypothesized to impact the risk associated with
alcohol for all cancers, studies should account for the presence of this allele
when assessing the risk relationship between alcohol consumption and the
development of any form of cancer.
However, it is
important to note that alcohol not only increases the risk of cancer but also
may lower the risk of certain types of cancer. For example, meta-analyses of
observational studies have found that alcohol significantly decreases the risk
of renal cell carcinoma (Bellocco et al. 2012; Song et al. 2012), Hodgkin’s
lymphoma (Tramacere et al. 2012c), and non-Hodgkin’s lymphoma (Tramacere et al.
2012b). Alcohol’s protective effect for renal cancer is thought to be mediated
by an increase in insulin sensitivity, because light to moderate alcohol
consumption has been associated with improved insulin sensitivity (Davies et
al. 2002; Facchini et al. 1994; Joosten et al. 2008). Insulin resistance may
play a key role in the development of renal cancer because people with
diabetes, which is characterized by insulin resistance, have an increased risk
of renal cancers (Joh et al. 2011; Lindblad et al. 1999). The mechanisms
underlying alcohol’s protective effect on the risk of developing Hodgkin’s
lymphoma and non-Hodgkin’s lymphoma currently are unknown (Tramacere et al.
2012b, c). Thus, these observed protective effects should be interpreted with
caution because the underlying biological mechanisms are not understood and
confounding factors and/or misclassification of abstainers within observational
studies may be responsible for these effects.
Diabetes
Research has found
that moderate alcohol consumption is associated with a reduced risk of type 2
diabetes3 (Baliunas et al. 2009). Because development of insulin resistance is
key in the pathogenesis of type 2 diabetes, it is thought that moderate alcohol
consumption protects against the disorder by increasing insulin sensitivity
(Hendriks 2007). Such an alcohol-related increase in insulin sensitivity has
been found in observational studies as well as in randomized controlled trials
(Davies et al. 2002; Kiechl et al. 1996; Lazarus et al. 1997; Mayer et al.
1993; Sierksma et al. 2004). Alternative explanations for the protective effect
of moderate alcohol consumption involve an increase in the levels of alcohol
metabolites, such as acetaldehyde and acetate (Sarkola et al. 2002); an
increase in high-density lipoprotein (HDL)4 (Rimm et al. 1999); and the
anti-inflammatory effects of alcohol consumption (Imhof et al. 2001). It is
important to note, however, that although there is reason to believe that
alcohol consumption is causally linked to reduced risk of type 2 diabetes, it
currently is unclear whether alcohol consumption itself is a protective factor
or if moderate drinking is a marker for healthy lifestyle choices that may
account for some of the observed protective effect.
3 There are two main
types of diabetes. Type 1 diabetes results from the body’s failure to produce
insulin, and patients therefore regularly must inject insulin. This type also
is known as juvenile diabetes because of its early onset, or
insulin-independent diabetes. Type 2 diabetes results from insulin resistance,
which develops when the cells fail to respond properly to insulin. It develops
with age and therefore also is referred to as adult-onset diabetes.
4 HDLs are certain
types of compounds consisting of both fat (i.e., lipid) and protein components
that are involved in cholesterol metabolism in the body. HDLs also are referred
to as “good cholesterol.”
Furthermore, the
effects of alcohol consumption on risk of diabetes are dose dependent (see
figure 3). Thus, in observational studies consumption of large amounts of
alcohol has been related to an increased risk of type 2 diabetes because higher
consumption levels may increase body weight, the concentrations of certain fats
(i.e., triglycerides) in the blood, and blood pressure (Wannamethee and Shaper
2003; Wannamethee et al. 2003).
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for diabetes and epilepsy, with lifetime abstainers serving as
the reference group.
Figure 3 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for diabetes and epilepsy, with lifetime abstainers
serving as the reference group.
SOURCE: Lim et al.
2012.
Neuropsychiatric
Conditions
One of the
neuropsychiatric conditions associated with alcohol consumption is epilepsy,
which is defined as an enduring predisposition for epileptic seizures and
requires the occurrence of at least one seizure for a diagnosis. Alcohol
consumption is associated with epilepsy, whereas alcohol withdrawal can cause
seizures but not epilepsy (Hillbom et al. 2003).5 Observational research has
found that a consistent dose-response relationship exists between alcohol
consumption and the risk of epilepsy (see figure 3). Multiple possible pathways
may underlie this relationship. In particular, alcohol consumption may have a
kindling effect, where repeated withdrawals from alcohol consumption by heavy
drinkers may lower the threshold for inducing an epileptic episode (Ballenger
and Post 1978). Alternatively, heavy alcohol consumption may increase the risk
of epilepsy by causing shrinkage of brain tissue (i.e., cerebral atrophy) (Dam
et al. 1985), cerebrovascular infarctions, lesions, head traumas, and changes
in neurotransmitter systems and ionic balances (Barclay et al. 2008; Dam et al.
1985; Freedland and McMicken 1993; Rathlev et al. 2006).
5 Seizures are excluded
from the 2005 GBD study definition of epilepsy.
Another
neuropsychiatric disorder considered to be causally linked to alcohol
consumption is unipolar depressive disorder. This association is supported by
the temporal order of the two conditions, consistency of the findings,
reversibility with abstinence, biological plausibility, and the identification
of a dose-response relationship. One study determined the risk of depressive
disorders to be increased two- to threefold in alcohol-dependent people (see
Rehm and colleagues [2003a] for an examination of the causal criteria). The
alcohol-attributable morbidity and mortality from unipolar depressive disorder
currently cannot be calculated because the relationship may be confounded by
several factors, including a genetic predisposition, environmental factors
(i.e., an underlying disorder or environmental exposure that may contribute to
both heavy alcohol use and depressive disorders), and potential self-medication
with alcohol by individuals with unipolar depressive disorders (Grant and
Pickering 1997; Rehm et al. 2004). Research findings suggest that all of these
pathways may play a role. The pathways for the association between alcohol and
unipolar depressive disorder in which alcohol does not play a causal role only
affect the measurement of the alcohol-based RR for unipolar depressive
disorder; however, they do not contradict the notion that alcohol is causally
related to the development of unipolar depressive disorder via other pathways.
This conclusion results from the observation that depressive symptoms increase
markedly during heavy-drinking occasions and disappear or lessen during periods
of abstinence (Rehm et al. 2003a).
Numerous studies also
have examined the association between alcohol and Alzheimer’s disease and
vascular dementia.6 These analyses generally have determined a beneficial
effect of alcohol, which has been attributed to alcohol’s ability to prevent
ischemic events in the circulatory system (Peters et al. 2008; Tyas 2001).
However, studies of these associations have generated highly heterogeneous
results, and the design and statistical analyses of these studies make it
impossible to rule out the potential effects of confounding factors (Panza et
al. 2008; Peters et al. 2008).
6 Vascular dementia,
the second most common form of dementia after Alzheimer’s disease, is caused by
problems in the supply of blood to the brain. Its most common symptoms include
problems with thinking, concentration, and communication; depression and
anxiety; physical weakness or paralysis; memory problems; seizures; and periods
of severe confusion.
Cardiovascular and
Circulatory Diseases
Alcohol consumption
affects multiple aspects of the cardiovascular system, with both harmful and
protective effects. These include the following (figure 4):
Increased risk of
hypertension (at all consumption levels for men and at higher consumption
levels for women);
Increased risk of
disorders that are caused by abnormalities in the generation and disruption of
the electrical signals that coordinate the heart beat (i.e., conduction
disorders and other dysrhythmias);
Increased risk of
cardiovascular disease, such as stroked caused by blockage of blood vessels in
the brain (i.e., ischemic stroke) (at a higher volume of consumption) or
rupture of blood vessels (i.e., hemorrhagic stroke); and
Protective effects (at
lower levels of consumption) against hypertension in women and against ischemic
heart disease and ischemic stroke in both men and women.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for cardiovascular diseases (i.e., hypertension, conduction
disorders, and ischemic and hemorrhagic stroke), with lifetime abstainers
serving as the reference group. For both hypertension and hemorrhagic and
ischemic stroke, the relationship differs between men and women. Moreover, for
both ischemic and hemorrhagic stroke, the influence of alcohol consumption on
mortality is much greater than the influence on morbidity, at least in women. In
men, no such difference appears to exist.
Figure 4 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for cardiovascular diseases (i.e., hypertension,
conduction disorders, and ischemic and hemorrhagic stroke), with lifetime
abstainers serving as the reference group. For both hypertension and
hemorrhagic and ischemic stroke, the relationship differs between men and
women. Moreover, for both ischemic and hemorrhagic stroke, the influence of
alcohol consumption on mortality is much greater than the influence on
morbidity, at least in women. In men, no such difference appears to exist.
SOURCE: Lim et al.
2012.
The specific
biological pathways through which alcohol consumption interacts with the
cardiovascular system are not always clear, but several mechanisms have been
identified that may play a role. These include increased blood concentrations
of HDLs, effects on cellular signaling, decreased blood clot formation by
platelets, and increased blood clot dissolution through enzyme action (Zakhari
1997). More indirect effects also may play a role. For example, alcohol may
increase the risk of hypertension by enhancing the activity of the sympathetic
nervous system, which results in greater constriction of the blood vessels and
makes the heart contract more strongly. In addition, alcohol possibly decreases
the sensitivity of the body’s internal blood pressure sensors (i.e.,
baroreceptors), thereby diminishing its ability to regulate blood pressure.
Alcohol’s protective
effects against the risk of ischemic heart disease as well as against
hypertension in women is hypothesized to result from its ability to increase
HDL levels and/or reduce platelet aggregation on arterial walls. Differences in
the effects of alcohol in men and women may stem from differing drinking
patterns, with men more likely to engage in binge drinking, even at low average
levels of consumption. These heavy-drinking occasions may lead to an increased
risk of hypertension for men compared with women at similar alcohol consumption
levels (Rehm et al. 2003b).
Alcohol’s effect on
hypertension also contributes to the risk of hemorrhagic stroke (Taylor et al.
2009), with a hypothesized dose-response effect. The mortality and morbidity
from alcohol-attributable hemorrhagic stroke differ by sex (see figure 4). As
with hypertension, differences in drinking pattern between men and women most
likely are responsible for the differing RR functions for hemorrhagic stroke by
sex. Three possible explanations have been put forth to explain the effects of
drinking pattern on RR:
Heavy drinkers also
may have other comorbidities that may increase the probability of a fatal
hemorrhagic stroke.
Alcohol consumption
may worsen the disease course through biological mechanisms and by decreasing
compliance with medication regimens.
Alcohol’s effects on
morbidity may be underestimated because of a stigmatization of heavy alcohol
consumption in women, thereby potentially decreasing the probability that
female heavy drinkers will be treated for stroke.
Large cohort studies
and meta-analyses have shown that alcohol consumption leads to an increase in
the risk for conduction disorders and dysrhythmias (Samokhvalov et al. 2010b).
These effects are caused by changes in the electrical activity of the heart,
including direct toxic effects of alcohol on the heart (i.e., cardiotoxicity),
excessive activity of the sympathetic nervous system (i.e., hyperadrenergic
activity) during drinking and withdrawal, impairment of the parasympathetic nervous
system (i.e., of vagal tone), and increase of intra-atrial conduction time
(Balbão et al. 2009).
Alcohol interacts with
the ischemic system to decrease the risk of ischemic stroke and ischemic heart
disease at low levels of consumption; however, this protective effect is not
observed at higher levels of consumption. As mentioned above, alcohol exerts
these effects mainly by increasing levels of HDL, preventing blood clots, and
increasing the rate of breakdown of blood clots. However, binge drinking, even
by light to moderate drinkers, leads to an increased risk of ischemic events by
increasing the probability of clotting and abnormal contractions of the heart
chambers (i.e., ventricular fibrillation). As with hemorrhagic stroke, alcohol
has different effects on morbidity than on mortality related to ischemic events
(see figure 5). Thus, meta-analyses of alcohol consumption and the risk of
ischemic heart disease (Roerecke and Rehm 2012) and ischemic stroke (Taylor et
al. 2009) found a larger protective effect for morbidity than for mortality
related to these conditions. One possible explanation for this observation, in
addition to those listed above for hemorrhagic stroke, is that patients in the
morbidity studies may be younger at the time of the stroke than those in
mortality studies. Despite the increased risk for ischemic heart disease at
higher levels of alcohol consumption noted in observational studies (see
Roerecke and Rehm 2012 for the most up-to-date meta-analysis), there was not
enough evidence for a detrimental effect of alcohol consumption on ischemic
heart disease for it to be modeled in the 2005 GBD study.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for ischemic heart disease, with lifetime abstainers serving as
the reference group. Low to moderate alcohol consumption has a beneficial
effect on both mortality and morbidity from ischemic heart disease. However,
the specific effects depend on both the gender and the age of the drinker, with
the greatest beneficial effects of low-to-moderate consumption seen on
morbidity from ischemic heart disease in women ages 15 to 34.
Figure 5 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for ischemic heart disease, with lifetime abstainers
serving as the reference group. Low to moderate alcohol consumption has a
beneficial effect on both mortality and morbidity from ischemic heart disease.
However, the specific effects depend on both the gender and the age of the
drinker, with the greatest beneficial effects of low-to-moderate consumption
seen on morbidity from ischemic heart disease in women ages 15 to 34.
SOURCE: Lim et al.
2012.
Moreover, the
observational studies investigating the link between alcohol consumption and
ischemic events had several methodological flaws, and the RR functions for
ischemic events, especially ischemic heart disease, therefore are not well
defined. A meta-analysis conducted by Roerecke and Rehm (2012) observed a substantial
degree of heterogeneity among all consumption levels, pointing to a possible
confounding effect of heavy drinking. In addition, previous observational
studies have been limited by the inclusion of “sick quitters” in the reference
groups, who have an increased risk of ischemic events compared with lifetime
abstainers.
Digestive Diseases
Alcohol is associated
with various liver diseases and is most strongly related to fatty liver,
alcoholic hepatitis, and cirrhosis. The association between the risk of liver
cirrhosis and alcohol consumption has long been recognized (see figure 6). The
main biological mechanism contributing to this liver damage likely involves the
breakdown of ethanol in the liver through oxidative and nonoxidative pathways
that result in the production of free radicals, acetaldehyde, and fatty acid
ethyl esters, which then damage liver cells (Tuma and Casey 2003). Given the
same amount of alcohol consumption, alcohol increases the risk of mortality
from liver cirrhosis more steeply than the risk of morbidity because it worsens
the course of liver disease and has a detrimental effect on the immune system
(Rehm et al. 2010c).
Alcohol consumption
also has been linked to an increase in the risk for acute and chronic
pancreatitis. Specifically, heavy alcohol consumption (i.e., more than, on
average, 48 grams pure ethanol, or about two standard drinks, per day) leads to
a noticeably elevated risk of pancreatitis, whereas consumption below 48 grams
per day is associated with a small increase in risk of pancreatitis (see figure
6). Higher levels of alcohol consumption may affect the risk of pancreatitis
through the same pathways that cause liver damage, namely the formation of free
radicals, acetaldehyde, and fatty acid ethyl esters during the metabolism of
alcohol in damaged pancreatic acinar cells (Vonlaufen et al. 2007).
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for digestive diseases (i.e., liver cirrhosis and pancreatitis),
with lifetime abstainers serving as the reference group. For liver cirrhosis,
alcohol’s effects on mortality are greater than those on morbidity, and slight
differences exist between the effects in men and women.
Figure 6 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for digestive diseases (i.e., liver cirrhosis and
pancreatitis), with lifetime abstainers serving as the reference group. For
liver cirrhosis, alcohol’s effects on mortality are greater than those on
morbidity, and slight differences exist between the effects in men and women.
SOURCE: Lim et al.
2012.
Psoriasis
Psoriasis is a chronic
inflammatory skin disease caused by the body’s own immune system attacking
certain cells in the body (i.e., an autoimmune reaction). Although there is
insufficient biological evidence to indicate that alcohol is causally linked
with psoriasis, many observational studies have determined a detrimental impact
of drinking on psoriasis, especially in male patients. Alcohol is hypothesized
to induce immune dysfunction that results in relative immunosuppression. In
addition, alcohol may increase the production of inflammatory cytokines and
cell cycle activators, such as cyclin D1 and keratinocyte growth factor, that
could lead to excessive multiplication of skin cells (i.e., epidermal
hyperproliferation). Finally, alcohol may exacerbate disease progression by
interfering with compliance with treatment regimens (Gupta et al. 1993;
Zaghloul and Goodfield 2004).
Alcohol’s Effects on
Other Medication Regimens
Alcohol can affect
cognitive capacity, leading to impaired judgment and a decreasing ability to
remember important information, including when to take medications for other
conditions (Braithwaite et al. 2008; Hendershot et al. 2009; Parsons et al.
2008). Although the relationship between alcohol consumption and adherence to
treatment regimens mainly has been studied in regards to adherence to HIV
antiretroviral treatment (Braithwaite and Bryant 2010; Hendershot et al. 2009;
Neuman et al. 2012), research also has shown that alcohol consumption and
alcohol misuse impact adherence to medications for other chronic diseases, with
significant or almost-significant effects (Bates et al. 2010; Bryson et al.
2008; Coldham et al. 2002; Verdoux et al. 2000). Thus, for diseases or
conditions managed by pharmacotherapy, alcohol consumption likely is associated
with increased morbidity and even mortality (if nonadherence to the medication
could be fatal) if drinking results in nonadherence to medication regimens.
Impact of Sex, Race,
and Age on the Association of Alcohol Consumption With Chronic Diseases
Given the same amount
of alcohol consumed, men and women can have differing morbidity and mortality
from alcohol-related chronic disease and conditions. These differences may be
related to the pharmacokinetics of alcohol in men and women. Women generally
have a lower body water content than men with the same body weight, causing
women to reach higher blood alcohol concentrations than men after drinking an
equivalent amount of alcohol (Frezza et al. 1990; Taylor et al. 1996).
Moreover, women appear to eliminate alcohol from the blood faster than do men,
possibly because they have a higher liver volume per unit body mass (Kwo et al.
1998; Lieber 2000). In addition to these pharmacokinetic factors, hormonal
differences also may play a role because at least in the case of liver disease,
alcohol-attributable harm is modified by estrogen. However, hormonal influences
on alcohol-related risks are not yet fully understood (Eagon 2010).
As noted previously, a
deficiency of the ALDH2 enzyme in people carrying the ALDH2 Lys487 allele
contributes to an elevated risk of cancer from alcohol consumption. Because
alcohol metabolism also plays a role in many other chronic diseases, the ALDH2
Lys487 allele also may increase the risk for digestive diseases. The
heterogeneity of risk caused by this allele, which is more prevalent in Asian
populations, may lead to incorrect measurements of the risk for cancer and digestive
disease outcomes in countries with a small Asian population, and will lead to
incorrect results if the RRs from these countries are applied to Asian
populations (Lewis and Smith 2005; Oze et al. 2011).
Because the pathology
of alcohol-related ischemic heart disease is affected by the age of the drinker
(Lazebnik et al. 2011), differences also may exist in the risk of ischemic
heart disease in different age groups. Preliminary research assessing this
issue across multiple studies has found that the association between alcohol
consumption and the resulting risk for ischemic heart disease does indeed
differ by age (see figure 5). However, no meta-analyses to date have
investigated the effects of alcohol consumption on the risk of morbidity and
mortality in different age groups for other chronic diseases and conditions.
Accordingly, research is needed to assess if the varying relationship between
alcohol consumption and ischemic heart disease in different age groups results
from biological differences in pathology or from differences in drinking
patterns. Additionally, research is needed to assess if age modifies the risk
relationships between alcohol and other diseases.
Estimating the
Alcohol-Attributable Fractions of Chronic Diseases and Conditions
When assessing the
risk of chronic diseases and conditions that are related to alcohol consumption
in some, but not all, cases, one of the variables frequently analyzed is the
alcohol-attributable fraction (AAF)—that is, the proportion of cases that can
be attributed to the patient’s alcohol consumption. Because alcohol consumption
can be modeled using a continuous distribution (Kehoe et al. 2012; Rehm et al.
2010b), the calculation of the alcohol-attributable burden of disease uses a
continuous RR function.7 Thus, the AAFs for chronic diseases and conditions can
be calculated using the following formula:
AAF=P[sub abs] +P[sub
form]RR[sub form]+ integral[sup max]over[sub +0]P(x)RR(x)dx-1 divided by P[sub
abs] +P[sub form]RR[sub form]+ integral[sup max]over[sub +0]P(x)RR(x)dx
In this formula, Pabs
represents the prevalence of the disease among lifetime abstainers, Pform is
the prevalence among former drinkers, RRform is the relative risk for former
drinkers, P(x) is the prevalence among current drinkers with an average daily
alcohol consumption of x, and RR(x) is the relative risk for current drinkers
with an average daily alcohol consumption of x. These AAFs vary greatly
depending on alcohol exposure levels. (For examples of AAFs and information on
the calculation of the 95 percent confidence intervals for chronic diseases and
conditions see Gmel and colleagues [2011]).
7 The exception to
this approach is tuberculosis because only data on categorical alcohol exposure
risks are available.
Limitations of RR
Functions for Chronic Diseases and Conditions
The chronic disease RR
functions outlined in figures 2 to 6 are derived from the most up-to-date and
rigorous meta-analyses in which the risk of a disease (i.e., for mortality and,
where possible, morbidity) was provided by alcohol consumption as a continuous
function (for more details on the meta-analysis methods used in each study, see
the original articles cited in table 2). However, the RR functions and the
relationship between alcohol consumption and the risk of chronic diseases and
conditions are biased by multiple factors. First, the RRs can be limited by
poor measurement of alcohol exposure, outcomes, and confounders. Research on
alcohol consumption patterns and disease is scarce, and only few studies have
investigated the effects of drinking patterns on chronic diseases and
conditions. Thus, the chronic disease and condition RRs presented in this
article may be confounded by drinking patterns, which are correlated to overall
volume of alcohol consumption. Additionally, the volume of alcohol consumed
generally is poorly measured, with many medical epidemiology studies measuring
alcohol consumption only at baseline. As a result, these analyses do not
include measures of the volume of alcohol consumed during the medically
relevant time period, which may encompass several years. For example, in the
case of cancer, the cumulative effects of alcohol may take many years before an
outcome is observed. Likewise, many of the larger cohort studies only use
single-item, semi-quantitative food questionnaires that measure either
frequency or volume of consumption.
Second, medical
epidemiology studies typically suffer from poorly defined reference groups
(Rehm et al. 2008). Thus, such studies typically only measure alcohol consumption
at one point or during one time period in a participant’s life and classify,
for example, all people who do not consume alcohol during the reference period
as abstainers, even though it is essential to separate ex-drinkers, lifetime
abstainers, and very light drinkers. As a result, these measurements of alcohol
consumption may lead to incorrect risk estimates because the groups of
nondrinkers in these studies have heterogeneous risks for diseases (Shaper and
Wannamethee 1998). The potential significance of this issue is underscored by
previous research indicating that more than 50 percent of those participants
who identified themselves as lifetime abstainers in medical epidemiology
studies also had reported lifetime drinking in previous surveys (Rehm et al.
2008).
Third, chronic disease
and condition outcomes in medical epidemiology studies also frequently are
poorly measured, most often by means of self-reporting. Additionally, other
confounding factors, such as relevant, non-substance use–related confounders,
often are not controlled for.
Fourth, RR estimates
for chronic diseases and conditions resulting from alcohol consumption
frequently are hampered by weak study designs that base estimates of
alcohol-related risks on nonexperimental designs (i.e., case-control and cohort
studies). These study designs are limited by factors that cannot be controlled
for and which may lead to incorrect results. For example, experimental studies
on the effects of antioxidants have failed to confirm the protective effects of
such agents found in observational studies (Bjelakovic et al. 2008).
Furthermore, the sampling methodology of many of the cohort studies that were
used in the meta-analyses for the above-presented RRs is problematic,
especially when studying the effects of alcohol consumption. Many of the
cohorts in these studies were from high-income countries and were chosen based
on maximizing follow-up rates. Although the chosen cohorts exhibited variation
in average daily alcohol consumption, little variation was observed in drinking
patterns and other potential moderating lifestyle factors.
The overall effect of
these limitations on the RRs and AAFs, and on the estimated burden of mortality
and morbidity calculated using these RRs, currently is unclear. In order to
investigate the effect of these biases, studies should be undertaken that
combine better exposure measures of alcohol consumption with state-of-the-art
outcome measures in countries at all levels of economic development. These
studies are important, not only for understanding the etiology of
alcohol-related chronic diseases and conditions, but also for formulating
prevention measures (Stockwell et al. 1997).
Limitations of AAFs
for Chronic Diseases and Conditions
In most studies
assessing AAFs for chronic diseases and conditions, the AAF for an outcome is
calculated as if the health consequences of alcohol consumption are immediate.
Indeed, for most chronic diseases and conditions, including even diseases such
as cirrhosis, a large degree of the effects caused by changes in alcohol
consumption can be seen immediately at the population level (Holmes et al.
2011; Leon et al. 1997; Zatonski et al. 2010; for a general discussion see
Norström and Skog 2001; Skog 1988). For cancer, however, the situation is different.
The effects of alcohol consumption on the risk of cancer only can be seen after
years, and often as long as two decades. Nevertheless, for the purpose of
illustrating the entire alcohol-attributable burden of disease it is important
to include cancer deaths, because they account for a substantial burden. For
example, a recent large study found that in Europe 1 in 10 cancers in men and 1
in 33 cancers in women were alcohol related (Schütze et al. 2011). Therefore,
in the interpretation of alcohol’s effect on mortality and burden of disease in
this article, the assumption that there has been uniform exposure to alcohol
for at least the previous two decades must be kept in mind.
Another limitation to
calculating the burden of chronic diseases and conditions attributable to
alcohol consumption is the use of mainly unadjusted RRs to determine the AAFs.
The RR formulas were developed for risks and were adjusted only for age (see
Flegal et al. 2006; Korn and Graubard 1999; Rockhill and Newman 1998), although
many other socio-demographic factors are linked with both alcohol consumption
and alcohol-related harms (see figure 1). However, two arguments can be made to
justify the use of mainly unadjusted RR formulas in the 2005 GBD study. First,
in risk analysis studies (Ezzati et al. 2004) almost all of the underlying
studies of the different risk factors only report unadjusted risks. Relying on
adjusted risks would severely bias the estimated risk functions because only a
small proportion of generally older studies could be included. Second, most of
the analyses of alcohol and the risk of chronic diseases and conditions show no
marked differences after adjustment (see Rehm et al. 2010b). However, the need
for adjustment to the RRs may change when other dimensions of alcohol
consumption, such as irregular heavy-drinking occasions, are considered with
respect to ischemic heart disease.
Conclusions
There are limitations
to the current ability to estimate the burden of chronic diseases and
conditions attributable to alcohol consumption. The comparative risk assessment
study within the GBD study only can determine this burden based on current
knowledge of alcohol consumption and risk and mortality patterns at a global
level. More detailed, country-specific estimates often are limited by the
validity of the available consumption and mortality data. As more studies are
published, it is likely that new confounders will be discovered for some of the
relationships between alcohol consumption and various chronic diseases and conditions.
The results from such new studies then may be used in meta-analyses of the
effect of alcohol in diseases where alcohol only plays a small role, such as
bladder, endometrial, and ovarian cancer. New studies also may lead to the
recognition of a causal link between alcohol consumption and other diseases.
Furthermore, new confounders and new studies may disprove the relationship
between alcohol consumption and certain diseases that currently are considered
to be causally linked.
Although there are limitations
to the current methodology used to estimate the alcohol-attributable burden of
chronic diseases and conditions, the limitations discussed in this article do
not affect the overall conclusion that alcohol consumption is related to a
considerable number of chronic diseases and conditions and contributes to a
substantial amount of the global burden of chronic diseases and conditions.
Therefore, alcohol consumption should be considered in developing intervention
strategies aimed at reducing the burden of chronic diseasesDiseases
Alcohol consumption is
a risk factor for many chronic diseases and conditions. The average volume of
alcohol consumed, consumption patterns, and quality of the alcoholic beverages
consumed likely have a causal impact on the mortality and morbidity related to
chronic diseases and conditions. Twenty-five chronic disease and condition
codes in the International Classification of Disease (ICD)-10 are entirely
attributable to alcohol, and alcohol plays a component-risk role in certain
cancers, other tumors, neuropsychiatric conditions, and numerous cardiovascular
and digestive diseases. Furthermore, alcohol has both beneficial and
detrimental impacts on diabetes, ischemic stroke, and ischemic heart disease,
depending on the overall volume of alcohol consumed, and, in the case of
ischemic diseases, consumption patterns. However, limitations exist to the
methods used to calculate the relative risks and alcohol-attributable
fractions. Furthermore, new studies and confounders may lead to additional
diseases being causally linked to alcohol consumption, or may disprove the
relationship between alcohol consumption and certain diseases that currently
are considered to be causally linked. These limitations do not affect the
conclusion that alcohol consumption significantly contributes to the burden of
chronic diseases and conditions globally, and that this burden should be a
target for intervention.
Alcohol has been a
part of human culture for all of recorded history, with almost all societies in
which alcohol is consumed experiencing net health and social problems (McGovern
2009; Tramacere et al. 2012b, c). With the industrialization of alcohol
production and the globalization of its marketing and promotion, alcohol
consumption and its related harms have increased worldwide (see Alcohol
Consumption Trends, in this issue). This has prompted the World Health
Organization (WHO) to pass multiple resolutions to address this issue over the
past few years, including the World Health Assembly’s Global Strategy to Reduce
the Harmful Use of Alcohol, which was passed in May 2010. Of growing concern
are noncommunicable chronic diseases and conditions that have been shown to
contribute substantially to the alcohol-attributable burden of disease (Rehm et
al. 2009). Specifically, in 2004 an estimated 35 million deaths and 603 million
disability-adjusted life-years (DALYs) lost were caused by chronic diseases and
conditions globally (WHO 2008); alcohol was responsible for 3.4 percent of the
deaths and 2.4 percent of DALYs caused by these conditions (Parry et al. 2011).
To address the burden of chronic diseases and conditions, the United Nation
(UN) General Assembly passed Resolution 64/265 in May of 2010, calling for
their prevention and control (UN 2010). This resolution is intended to garner
multisectoral commitment and facilitate action on a global scale to address the
fact that alcohol (together with tobacco, lack of exercise, and diet) plays a
significant role in chronic diseases and conditions. It is noteworthy that
cardiovascular diseases, cancers, and diabetes in particular have been
highlighted for targeted action (UN 2010) because alcohol is a risk factor for
many cardiovascular diseases and cancers and has both beneficial and
detrimental effects on diabetes and ischemic cardiovascular diseases,1
depending on the amount of alcohol consumed and the patterns of consumption.
1 Ischemic
cardiovascular diseases are those caused by a blockage of blood vessels,
resulting in a loss of blood supply to the tissue serviced by the affected
blood vessels.
Building on previous
reviews concerning alcohol and disease (Rehm et al. 2003a, 2009), this article
presents an up-to-date and in-depth overview of the relationship of alcohol
consumption and high-risk drinking patterns and the initiation/exacerbation and
treatment of various chronic diseases and conditions. It also assesses the
methods used to calculate the impact of alcohol consumption on chronic diseases
and conditions.
Alcohol Consumption As
a Risk Factor for Chronic Diseases and Conditions
Figure 1 presents a
conceptual model of the effects of alcohol consumption on morbidity and
mortality and of the influence of both societal and demographic factors on
alcohol consumption and alcohol-related harms resulting in chronic diseases and
conditions (adapted from Rehm et al. 2010a). According to this model, two
separate, but related, measures of alcohol consumption are responsible for most
of the causal impact of alcohol on the burden of chronic diseases and
conditions—overall volume of alcohol consumption and patterns of drinking. The
overall volume of alcohol consumption plays a role in all alcohol-related
diseases, whereas drinking patterns only affect ischemic cardiovascular
diseases. In addition to the overall volume and pattern of consumption, the
quality of the alcoholic beverages consumed also may influence mortality and
morbidity from chronic diseases and conditions. However, this pathway is of
less importance from a public health perspective (Lachenmeier and Rehm 2009;
Lachenmeier et al. 2007) because it has a much smaller impact than the other
two factors.
Figure 1 Causal model
of alcohol consumption, intermediate mechanisms, and long-term consequences, as
well as of the influence of societal and demographic factors on alcohol
consumption and alcohol-related harms resulting in chronic diseases and
conditions.
Figure 1 Causal model
of alcohol consumption, intermediate mechanisms, and long-term consequences, as
well as of the influence of societal and demographic factors on alcohol consumption
and alcohol-related harms resulting in chronic diseases and conditions.
The effects of overall
volume of alcohol consumed, consumption patterns, and quality of the alcoholic
beverages consumed on mortality and morbidity from chronic diseases and conditions
are mediated by three main mechanisms.
These include the
following:
The toxic and
beneficial biochemical effects of beverage alcohol (i.e., ethanol) and other
compounds found in alcoholic beverages;
The consequences of
intoxication; and
The consequences of
alcohol dependence.
These intermediate
mechanisms have been reviewed in more detail by Rehm and colleagues (2003a).
Chronic Diseases and
Conditions Related to Alcohol
Chronic Diseases and
Conditions Entirely Attributable to Alcohol
Of the chronic
diseases and conditions causally linked with alcohol consumption, many
categories have names indicating that alcohol is a necessary cause—that is,
that these particular diseases and conditions are 100 percent alcohol
attributable. Of these, alcohol use disorders (AUDs)—that is, alcohol
dependence and the harmful use of alcohol as defined by the International
Classification of Disease, Tenth Edition (ICD–10)—certainly are the most
important categories, but many other diseases and conditions also are entirely
attributable to alcohol (see table 1).
Table 1 Chronic
Diseases and Conditions That Are, by Definition, Alcohol Attributable (i.e.,
Require Alcohol Consumption As a Necessary Cause)
ICD–10
Code Disease
F10
Mental and behavioral
disorders attributed to the use of alcohol
F10.0
Acute intoxication
F10.1
Harmful use
F10.2
Dependence syndrome
F10.3
Withdrawal state
F10.4
Withdrawal state with
delirium
F10.5
Psychotic disorder
F10.6
Amnesic syndrome
F10.7
Residual and
late-onset psychotic disorder
F10.8
Other mental and
behavioral disorders
F10.9
Unspecified mental and
behavioral disorder
G31.2
Degeneration of
nervous system attributed to alcohol
G62.1
Alcoholic
polyneuropathy
G72.1
Alcoholic myopathy
I42.6
Alcoholic
cardiomyopathy
K29.2
Alcoholic gastritis
K70
Alcoholic liver
disease
K70.0
Alcoholic fatty liver
K70.1
Alcoholic hepatitis
K70.2
Alcoholic fibrosis and
sclerosis of liver
K70.3
Alcoholic cirrhosis of
liver
K70.4
Alcoholic hepatic
failure
K70.9
Alcoholic liver
disease, unspecified
K85.2
Alcohol-induced acute
pancreatitis
K86.0
Alcohol-induced
chronic pancreatitis
P04.3
Fetus and newborn
affected by maternal use of alcohol
Q86.0
Fetal alcohol syndrome
(dysmorphic)
Chronic Diseases and
Conditions for Which Alcohol Is a Component Cause
Alcohol is a component
cause for more than 200 other diseases and conditions with ICD–10 three-digit
codes—that is, alcohol consumption is not necessary for the diseases to develop
(Rehm et al. 2010a). For these conditions, alcohol shows a dose-response
relationship, where the risk of onset of or death from the disease or condition
depends on the total volume of alcohol consumed (Rehm et al. 2003a). Table 2
outlines these chronic diseases and conditions that are associated with alcohol
consumption and lists the source of the relative risk (RR) functions if the
chronic disease or condition is included as an alcohol-attributable harm in the
2005 Global Burden of Disease (GBD) Study.2 Several of these chronic diseases
and conditions are singled out for further discussion in the following sections
to highlight alcohol’s causative or protective role.
2 The GBD Study is a
project that aims to provide a consistent and comparative description of the
global burden of diseases and injuries and the risk factors that cause them.
Table 2 Chronic
Diseases and Conditions for Which Alcohol Consumption Is a Component Cause,
Identified by Various Meta-Analyses and Reviews and Listed in the 2005 Global
Burden of Disease (GBD) Study
No. of 2005 GBD
Code
Disease
ICD–10 Effect Level of Evidence
Meta-Analysis
Used if Included in the GBD Study
IIA
Malignant neoplasms
IIA1
Mouth cancer
C00–C08
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA2
Nasopharynx cancer and
other pharynx cancers
C09–C13
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA3
Esophagus cancer
C15
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA4
Stomach cancer
C16
Detrimental
Insufficient causal
evidence
IIA5
Colon and rectum
cancers
C18–C21
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA6
Liver cancer
C22
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA9
Larynx cancer
C32
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA10
Trachea, bronchus, and
lung cancers
C33–C34
Detrimental
Insufficient causal
evidence
IIA13
Breast cancer (women
only)
C50
Detrimental
Causally related
International Agency
for Research on Cancer 2008 (based on relative risks from Corrao et al. 2004)
IIA16
Ovarian cancer
C56
Detrimental
Insufficient causal
evidence
IIA17
Prostate cancer
C61
Detrimental
Insufficient causal
evidence
IIA19
Kidney and other
urinary organ cancers
C64–C66, C68 (except
C68.9)
Beneficial (renal cell
carcinoma only)
Insufficient causal
evidence
IIA23
Hodgkins lymphoma
C81
Beneficial
Insufficient causal
evidence
IIA24
Non-Hodgkins lymphoma
C82–C85, C96
Beneficial
Insufficient causal
evidence
IIB
Other neoplasms
D00–D48 (except D09.9,
D37.9, D38.6, D39.9, D40.9, D41.9, 48.9)
Detrimental
Insufficient causal
evidence
IIC
Diabetes
E10–E13
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Baliunas et al. 2009)
IIE
Mental and behavioral
disorders
IIE1
Unipolar depressive
disorders
F32–F33, F34.1
Detrimental
Causally related
IIF
Neurological
conditions
IIF1
Alzheimer’s disease
and other dementias
F01–F03, G30–G31
Conflicting evidence
(mainly beneficial)
Insufficient causal
evidence
IIF3
Epilepsy
G40–G41
Detrimental
Causally related
(Samokhvalov et al.
2010a)
IIH
Cardiovascular and
circulatory disease
IIH2
Hypertensive heart
disease
I11–I13
Detrimental (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Taylor et al. 2010)
IIH3
Ischemic heart disease
I20–I25
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Roerecke and Rehm
2010)
IIH4
Cerebrovascular
diseases
IIH4a
Ischemic stroke
I63–I67, I69.3
Beneficial (however,
this depends on drinking patterns and volume of consumption)
Causally related
(Patra et al. 2010)
Specific Chronic
Diseases and Conditions Associated With Alcohol Consumption
Malignant Neoplasms
The relationship
between alcohol consumption and cancer already was suggested in the early 20th
century, when Lamy (1910) observed that patients with cancer either of the
esophagus or of the cardiac region were more likely to be alcoholics. The
accumulation of evidence supporting the relationship between ethanol and
cancers led the International Agency for Research on Cancer (IARC) to recognize
the cancer-inducing potential (i.e., carcinogenicity) of ethanol in animal
models and to conclude that alcoholic beverages are carcinogenic to humans
(IARC 2008). Specifically, the GBD study found that alcohol increased the risk
of cancers of the upper digestive track (i.e., mouth and oropharynx, esophagus,
and larynx), the lower digestive track (i.e., colon, rectum, and liver), and
the female breast (see figure 2). More up-to-date systematic reviews and
meta-analyses on alcohol consumption and the risk of developing cancer have
been published by Fedirko and colleagues (2011) for colorectal cancer, Islami
and colleagues (2011) for esophageal squamous cell carcinoma, Islami and
colleagues (2010) for laryngeal cancer, and Tramacere and colleagues (2010) and
Turati and colleagues (2010) for oral and pharyngeal cancers.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for cancer, with lifetime abstainers serving as the reference
group.
Figure 2 The
relationship between increasing amounts of average daily alcohol consumption and
the relative risk for cancer, with lifetime abstainers serving as the reference
group.
SOURCE: Lim et al.
2012.
A recent meta-analysis
also has indicated that alcohol consumption is significantly linked to an
increased risk of developing prostate cancer in a dose-dependent manner (Rota
et al. 2012); this observation is consistent with previous meta-analyses
concluding that alcohol consumption and the risk for prostate cancer are
significantly correlated (Dennis 2000; Fillmore et al. 2009). Additional research,
however, is required on the biological pathways to prove the role of alcohol
consumption in the development of this type of cancer.
Evidence also has
suggested that stomach cancer may be linked to ethanol consumption (Bagnardi et
al. 2001; Tramacere et al. 2012a); however, the findings have not been
unequivocal. Thus, two recent meta-analyses found no association between
alcohol drinking status (i.e., drinkers compared with non-drinkers) and risk of
gastric cardia adenocarcinoma (Tramacere et al. 2012a, d). However, one
meta-analysis did find an association between heavy alcohol consumption and the
risk of this type of cancer (Tramacere et al. 2012a).
For several types of
cancer investigators have found a nonsignificant positive association with alcohol
consumption, including endometrial (Bagnardi et al. 2001; Rota et al. 2012),
ovarian (Bagnardi et al. 2001), and pancreatic cancers (Bagnardi et al. 2001).
However, because the relationship at least between alcohol consumption and
endometrial and pancreatic cancer is modest (i.e., the point estimates of RR
are low, even at high levels of average daily alcohol consumption), additional
studies with large numbers of participants are needed to accurately assess the
relationship (Bagnardi et al. 2001). The relationship between alcohol
consumption and bladder and lung cancers is even less clear, with one
meta-analysis finding that alcohol significantly increases the risk for both
types of tumors (Bagnardi et al. 2001), whereas more recent meta-analyses have found
no significant association between alcohol consumption and the risk of bladder
cancer (Pelucchi et al. 2012) or the risk of lung cancer in individuals who had
never smoked (Bagnardi et al. 2001). These conflicting results may stem from
the studies in the more recent meta-analyses adjusting for smoking status when
assessing the risk relationship between alcohol and these cancers within
individual observational studies (Bagnardi et al. 2001; Pelucchi et al. 2012).
The biological
pathways by which alcohol increases the risk of developing cancer depends on
the targeted organ and are not yet fully understood. Factors that seem to play
a role include the specific variants of alcohol-metabolizing enzymes (i.e.,
alcohol dehydrogenase [ADH], aldehyde dehydrogenase [ALDH], and cytochrome P450
2E1) a person carries or the concentrations of estrogen as well as changes in
folate metabolism and DNA repair (Boffetta and Hashibe 2006). For example, a
deficiency in ALDH2 activity in people carrying a gene variant (i.e., allele)
called ALDH2 Lys487 contributes to an elevated risk of esophageal cancer from
alcohol consumption (Brooks et al. 2009). Because the ALDH2 Lys487 allele is
more prevalent in Asian populations (i.e., Japanese, Chinese, and Koreans) (Eng
et al. 2007), and ALDH2 is hypothesized to impact the risk associated with
alcohol for all cancers, studies should account for the presence of this allele
when assessing the risk relationship between alcohol consumption and the
development of any form of cancer.
However, it is
important to note that alcohol not only increases the risk of cancer but also
may lower the risk of certain types of cancer. For example, meta-analyses of
observational studies have found that alcohol significantly decreases the risk
of renal cell carcinoma (Bellocco et al. 2012; Song et al. 2012), Hodgkin’s
lymphoma (Tramacere et al. 2012c), and non-Hodgkin’s lymphoma (Tramacere et al.
2012b). Alcohol’s protective effect for renal cancer is thought to be mediated
by an increase in insulin sensitivity, because light to moderate alcohol
consumption has been associated with improved insulin sensitivity (Davies et
al. 2002; Facchini et al. 1994; Joosten et al. 2008). Insulin resistance may
play a key role in the development of renal cancer because people with
diabetes, which is characterized by insulin resistance, have an increased risk
of renal cancers (Joh et al. 2011; Lindblad et al. 1999). The mechanisms
underlying alcohol’s protective effect on the risk of developing Hodgkin’s
lymphoma and non-Hodgkin’s lymphoma currently are unknown (Tramacere et al.
2012b, c). Thus, these observed protective effects should be interpreted with
caution because the underlying biological mechanisms are not understood and
confounding factors and/or misclassification of abstainers within observational
studies may be responsible for these effects.
Diabetes
Research has found
that moderate alcohol consumption is associated with a reduced risk of type 2
diabetes3 (Baliunas et al. 2009). Because development of insulin resistance is
key in the pathogenesis of type 2 diabetes, it is thought that moderate alcohol
consumption protects against the disorder by increasing insulin sensitivity
(Hendriks 2007). Such an alcohol-related increase in insulin sensitivity has
been found in observational studies as well as in randomized controlled trials
(Davies et al. 2002; Kiechl et al. 1996; Lazarus et al. 1997; Mayer et al.
1993; Sierksma et al. 2004). Alternative explanations for the protective effect
of moderate alcohol consumption involve an increase in the levels of alcohol
metabolites, such as acetaldehyde and acetate (Sarkola et al. 2002); an
increase in high-density lipoprotein (HDL)4 (Rimm et al. 1999); and the
anti-inflammatory effects of alcohol consumption (Imhof et al. 2001). It is
important to note, however, that although there is reason to believe that
alcohol consumption is causally linked to reduced risk of type 2 diabetes, it
currently is unclear whether alcohol consumption itself is a protective factor
or if moderate drinking is a marker for healthy lifestyle choices that may
account for some of the observed protective effect.
3 There are two main
types of diabetes. Type 1 diabetes results from the body’s failure to produce
insulin, and patients therefore regularly must inject insulin. This type also
is known as juvenile diabetes because of its early onset, or
insulin-independent diabetes. Type 2 diabetes results from insulin resistance,
which develops when the cells fail to respond properly to insulin. It develops
with age and therefore also is referred to as adult-onset diabetes.
4 HDLs are certain
types of compounds consisting of both fat (i.e., lipid) and protein components
that are involved in cholesterol metabolism in the body. HDLs also are referred
to as “good cholesterol.”
Furthermore, the
effects of alcohol consumption on risk of diabetes are dose dependent (see
figure 3). Thus, in observational studies consumption of large amounts of
alcohol has been related to an increased risk of type 2 diabetes because higher
consumption levels may increase body weight, the concentrations of certain fats
(i.e., triglycerides) in the blood, and blood pressure (Wannamethee and Shaper
2003; Wannamethee et al. 2003).
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for diabetes and epilepsy, with lifetime abstainers serving as
the reference group.
Figure 3 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for diabetes and epilepsy, with lifetime abstainers
serving as the reference group.
SOURCE: Lim et al.
2012.
Neuropsychiatric
Conditions
One of the
neuropsychiatric conditions associated with alcohol consumption is epilepsy,
which is defined as an enduring predisposition for epileptic seizures and
requires the occurrence of at least one seizure for a diagnosis. Alcohol
consumption is associated with epilepsy, whereas alcohol withdrawal can cause
seizures but not epilepsy (Hillbom et al. 2003).5 Observational research has
found that a consistent dose-response relationship exists between alcohol
consumption and the risk of epilepsy (see figure 3). Multiple possible pathways
may underlie this relationship. In particular, alcohol consumption may have a
kindling effect, where repeated withdrawals from alcohol consumption by heavy
drinkers may lower the threshold for inducing an epileptic episode (Ballenger
and Post 1978). Alternatively, heavy alcohol consumption may increase the risk
of epilepsy by causing shrinkage of brain tissue (i.e., cerebral atrophy) (Dam
et al. 1985), cerebrovascular infarctions, lesions, head traumas, and changes
in neurotransmitter systems and ionic balances (Barclay et al. 2008; Dam et al.
1985; Freedland and McMicken 1993; Rathlev et al. 2006).
5 Seizures are excluded
from the 2005 GBD study definition of epilepsy.
Another
neuropsychiatric disorder considered to be causally linked to alcohol
consumption is unipolar depressive disorder. This association is supported by
the temporal order of the two conditions, consistency of the findings,
reversibility with abstinence, biological plausibility, and the identification
of a dose-response relationship. One study determined the risk of depressive
disorders to be increased two- to threefold in alcohol-dependent people (see
Rehm and colleagues [2003a] for an examination of the causal criteria). The
alcohol-attributable morbidity and mortality from unipolar depressive disorder
currently cannot be calculated because the relationship may be confounded by
several factors, including a genetic predisposition, environmental factors
(i.e., an underlying disorder or environmental exposure that may contribute to
both heavy alcohol use and depressive disorders), and potential self-medication
with alcohol by individuals with unipolar depressive disorders (Grant and
Pickering 1997; Rehm et al. 2004). Research findings suggest that all of these
pathways may play a role. The pathways for the association between alcohol and
unipolar depressive disorder in which alcohol does not play a causal role only
affect the measurement of the alcohol-based RR for unipolar depressive
disorder; however, they do not contradict the notion that alcohol is causally
related to the development of unipolar depressive disorder via other pathways.
This conclusion results from the observation that depressive symptoms increase
markedly during heavy-drinking occasions and disappear or lessen during periods
of abstinence (Rehm et al. 2003a).
Numerous studies also
have examined the association between alcohol and Alzheimer’s disease and
vascular dementia.6 These analyses generally have determined a beneficial
effect of alcohol, which has been attributed to alcohol’s ability to prevent
ischemic events in the circulatory system (Peters et al. 2008; Tyas 2001).
However, studies of these associations have generated highly heterogeneous
results, and the design and statistical analyses of these studies make it
impossible to rule out the potential effects of confounding factors (Panza et
al. 2008; Peters et al. 2008).
6 Vascular dementia,
the second most common form of dementia after Alzheimer’s disease, is caused by
problems in the supply of blood to the brain. Its most common symptoms include
problems with thinking, concentration, and communication; depression and
anxiety; physical weakness or paralysis; memory problems; seizures; and periods
of severe confusion.
Cardiovascular and
Circulatory Diseases
Alcohol consumption
affects multiple aspects of the cardiovascular system, with both harmful and
protective effects. These include the following (figure 4):
Increased risk of
hypertension (at all consumption levels for men and at higher consumption
levels for women);
Increased risk of
disorders that are caused by abnormalities in the generation and disruption of
the electrical signals that coordinate the heart beat (i.e., conduction
disorders and other dysrhythmias);
Increased risk of
cardiovascular disease, such as stroked caused by blockage of blood vessels in
the brain (i.e., ischemic stroke) (at a higher volume of consumption) or
rupture of blood vessels (i.e., hemorrhagic stroke); and
Protective effects (at
lower levels of consumption) against hypertension in women and against ischemic
heart disease and ischemic stroke in both men and women.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for cardiovascular diseases (i.e., hypertension, conduction
disorders, and ischemic and hemorrhagic stroke), with lifetime abstainers
serving as the reference group. For both hypertension and hemorrhagic and
ischemic stroke, the relationship differs between men and women. Moreover, for
both ischemic and hemorrhagic stroke, the influence of alcohol consumption on
mortality is much greater than the influence on morbidity, at least in women. In
men, no such difference appears to exist.
Figure 4 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for cardiovascular diseases (i.e., hypertension,
conduction disorders, and ischemic and hemorrhagic stroke), with lifetime
abstainers serving as the reference group. For both hypertension and
hemorrhagic and ischemic stroke, the relationship differs between men and
women. Moreover, for both ischemic and hemorrhagic stroke, the influence of
alcohol consumption on mortality is much greater than the influence on
morbidity, at least in women. In men, no such difference appears to exist.
SOURCE: Lim et al.
2012.
The specific
biological pathways through which alcohol consumption interacts with the
cardiovascular system are not always clear, but several mechanisms have been
identified that may play a role. These include increased blood concentrations
of HDLs, effects on cellular signaling, decreased blood clot formation by
platelets, and increased blood clot dissolution through enzyme action (Zakhari
1997). More indirect effects also may play a role. For example, alcohol may
increase the risk of hypertension by enhancing the activity of the sympathetic
nervous system, which results in greater constriction of the blood vessels and
makes the heart contract more strongly. In addition, alcohol possibly decreases
the sensitivity of the body’s internal blood pressure sensors (i.e.,
baroreceptors), thereby diminishing its ability to regulate blood pressure.
Alcohol’s protective
effects against the risk of ischemic heart disease as well as against
hypertension in women is hypothesized to result from its ability to increase
HDL levels and/or reduce platelet aggregation on arterial walls. Differences in
the effects of alcohol in men and women may stem from differing drinking
patterns, with men more likely to engage in binge drinking, even at low average
levels of consumption. These heavy-drinking occasions may lead to an increased
risk of hypertension for men compared with women at similar alcohol consumption
levels (Rehm et al. 2003b).
Alcohol’s effect on
hypertension also contributes to the risk of hemorrhagic stroke (Taylor et al.
2009), with a hypothesized dose-response effect. The mortality and morbidity
from alcohol-attributable hemorrhagic stroke differ by sex (see figure 4). As
with hypertension, differences in drinking pattern between men and women most
likely are responsible for the differing RR functions for hemorrhagic stroke by
sex. Three possible explanations have been put forth to explain the effects of
drinking pattern on RR:
Heavy drinkers also
may have other comorbidities that may increase the probability of a fatal
hemorrhagic stroke.
Alcohol consumption
may worsen the disease course through biological mechanisms and by decreasing
compliance with medication regimens.
Alcohol’s effects on
morbidity may be underestimated because of a stigmatization of heavy alcohol
consumption in women, thereby potentially decreasing the probability that
female heavy drinkers will be treated for stroke.
Large cohort studies
and meta-analyses have shown that alcohol consumption leads to an increase in
the risk for conduction disorders and dysrhythmias (Samokhvalov et al. 2010b).
These effects are caused by changes in the electrical activity of the heart,
including direct toxic effects of alcohol on the heart (i.e., cardiotoxicity),
excessive activity of the sympathetic nervous system (i.e., hyperadrenergic
activity) during drinking and withdrawal, impairment of the parasympathetic nervous
system (i.e., of vagal tone), and increase of intra-atrial conduction time
(Balbão et al. 2009).
Alcohol interacts with
the ischemic system to decrease the risk of ischemic stroke and ischemic heart
disease at low levels of consumption; however, this protective effect is not
observed at higher levels of consumption. As mentioned above, alcohol exerts
these effects mainly by increasing levels of HDL, preventing blood clots, and
increasing the rate of breakdown of blood clots. However, binge drinking, even
by light to moderate drinkers, leads to an increased risk of ischemic events by
increasing the probability of clotting and abnormal contractions of the heart
chambers (i.e., ventricular fibrillation). As with hemorrhagic stroke, alcohol
has different effects on morbidity than on mortality related to ischemic events
(see figure 5). Thus, meta-analyses of alcohol consumption and the risk of
ischemic heart disease (Roerecke and Rehm 2012) and ischemic stroke (Taylor et
al. 2009) found a larger protective effect for morbidity than for mortality
related to these conditions. One possible explanation for this observation, in
addition to those listed above for hemorrhagic stroke, is that patients in the
morbidity studies may be younger at the time of the stroke than those in
mortality studies. Despite the increased risk for ischemic heart disease at
higher levels of alcohol consumption noted in observational studies (see
Roerecke and Rehm 2012 for the most up-to-date meta-analysis), there was not
enough evidence for a detrimental effect of alcohol consumption on ischemic
heart disease for it to be modeled in the 2005 GBD study.
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for ischemic heart disease, with lifetime abstainers serving as
the reference group. Low to moderate alcohol consumption has a beneficial
effect on both mortality and morbidity from ischemic heart disease. However,
the specific effects depend on both the gender and the age of the drinker, with
the greatest beneficial effects of low-to-moderate consumption seen on
morbidity from ischemic heart disease in women ages 15 to 34.
Figure 5 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for ischemic heart disease, with lifetime abstainers
serving as the reference group. Low to moderate alcohol consumption has a
beneficial effect on both mortality and morbidity from ischemic heart disease.
However, the specific effects depend on both the gender and the age of the
drinker, with the greatest beneficial effects of low-to-moderate consumption
seen on morbidity from ischemic heart disease in women ages 15 to 34.
SOURCE: Lim et al.
2012.
Moreover, the
observational studies investigating the link between alcohol consumption and
ischemic events had several methodological flaws, and the RR functions for
ischemic events, especially ischemic heart disease, therefore are not well
defined. A meta-analysis conducted by Roerecke and Rehm (2012) observed a substantial
degree of heterogeneity among all consumption levels, pointing to a possible
confounding effect of heavy drinking. In addition, previous observational
studies have been limited by the inclusion of “sick quitters” in the reference
groups, who have an increased risk of ischemic events compared with lifetime
abstainers.
Digestive Diseases
Alcohol is associated
with various liver diseases and is most strongly related to fatty liver,
alcoholic hepatitis, and cirrhosis. The association between the risk of liver
cirrhosis and alcohol consumption has long been recognized (see figure 6). The
main biological mechanism contributing to this liver damage likely involves the
breakdown of ethanol in the liver through oxidative and nonoxidative pathways
that result in the production of free radicals, acetaldehyde, and fatty acid
ethyl esters, which then damage liver cells (Tuma and Casey 2003). Given the
same amount of alcohol consumption, alcohol increases the risk of mortality
from liver cirrhosis more steeply than the risk of morbidity because it worsens
the course of liver disease and has a detrimental effect on the immune system
(Rehm et al. 2010c).
Alcohol consumption
also has been linked to an increase in the risk for acute and chronic
pancreatitis. Specifically, heavy alcohol consumption (i.e., more than, on
average, 48 grams pure ethanol, or about two standard drinks, per day) leads to
a noticeably elevated risk of pancreatitis, whereas consumption below 48 grams
per day is associated with a small increase in risk of pancreatitis (see figure
6). Higher levels of alcohol consumption may affect the risk of pancreatitis
through the same pathways that cause liver damage, namely the formation of free
radicals, acetaldehyde, and fatty acid ethyl esters during the metabolism of
alcohol in damaged pancreatic acinar cells (Vonlaufen et al. 2007).
The relationship
between increasing amounts of average daily alcohol consumption and the
relative risk for digestive diseases (i.e., liver cirrhosis and pancreatitis),
with lifetime abstainers serving as the reference group. For liver cirrhosis,
alcohol’s effects on mortality are greater than those on morbidity, and slight
differences exist between the effects in men and women.
Figure 6 The
relationship between increasing amounts of average daily alcohol consumption
and the relative risk for digestive diseases (i.e., liver cirrhosis and
pancreatitis), with lifetime abstainers serving as the reference group. For
liver cirrhosis, alcohol’s effects on mortality are greater than those on
morbidity, and slight differences exist between the effects in men and women.
SOURCE: Lim et al.
2012.
Psoriasis
Psoriasis is a chronic
inflammatory skin disease caused by the body’s own immune system attacking
certain cells in the body (i.e., an autoimmune reaction). Although there is
insufficient biological evidence to indicate that alcohol is causally linked
with psoriasis, many observational studies have determined a detrimental impact
of drinking on psoriasis, especially in male patients. Alcohol is hypothesized
to induce immune dysfunction that results in relative immunosuppression. In
addition, alcohol may increase the production of inflammatory cytokines and
cell cycle activators, such as cyclin D1 and keratinocyte growth factor, that
could lead to excessive multiplication of skin cells (i.e., epidermal
hyperproliferation). Finally, alcohol may exacerbate disease progression by
interfering with compliance with treatment regimens (Gupta et al. 1993;
Zaghloul and Goodfield 2004).
Alcohol’s Effects on
Other Medication Regimens
Alcohol can affect
cognitive capacity, leading to impaired judgment and a decreasing ability to
remember important information, including when to take medications for other
conditions (Braithwaite et al. 2008; Hendershot et al. 2009; Parsons et al.
2008). Although the relationship between alcohol consumption and adherence to
treatment regimens mainly has been studied in regards to adherence to HIV
antiretroviral treatment (Braithwaite and Bryant 2010; Hendershot et al. 2009;
Neuman et al. 2012), research also has shown that alcohol consumption and
alcohol misuse impact adherence to medications for other chronic diseases, with
significant or almost-significant effects (Bates et al. 2010; Bryson et al.
2008; Coldham et al. 2002; Verdoux et al. 2000). Thus, for diseases or
conditions managed by pharmacotherapy, alcohol consumption likely is associated
with increased morbidity and even mortality (if nonadherence to the medication
could be fatal) if drinking results in nonadherence to medication regimens.
Impact of Sex, Race,
and Age on the Association of Alcohol Consumption With Chronic Diseases
Given the same amount
of alcohol consumed, men and women can have differing morbidity and mortality
from alcohol-related chronic disease and conditions. These differences may be
related to the pharmacokinetics of alcohol in men and women. Women generally
have a lower body water content than men with the same body weight, causing
women to reach higher blood alcohol concentrations than men after drinking an
equivalent amount of alcohol (Frezza et al. 1990; Taylor et al. 1996).
Moreover, women appear to eliminate alcohol from the blood faster than do men,
possibly because they have a higher liver volume per unit body mass (Kwo et al.
1998; Lieber 2000). In addition to these pharmacokinetic factors, hormonal
differences also may play a role because at least in the case of liver disease,
alcohol-attributable harm is modified by estrogen. However, hormonal influences
on alcohol-related risks are not yet fully understood (Eagon 2010).
As noted previously, a
deficiency of the ALDH2 enzyme in people carrying the ALDH2 Lys487 allele
contributes to an elevated risk of cancer from alcohol consumption. Because
alcohol metabolism also plays a role in many other chronic diseases, the ALDH2
Lys487 allele also may increase the risk for digestive diseases. The
heterogeneity of risk caused by this allele, which is more prevalent in Asian
populations, may lead to incorrect measurements of the risk for cancer and digestive
disease outcomes in countries with a small Asian population, and will lead to
incorrect results if the RRs from these countries are applied to Asian
populations (Lewis and Smith 2005; Oze et al. 2011).
Because the pathology
of alcohol-related ischemic heart disease is affected by the age of the drinker
(Lazebnik et al. 2011), differences also may exist in the risk of ischemic
heart disease in different age groups. Preliminary research assessing this
issue across multiple studies has found that the association between alcohol
consumption and the resulting risk for ischemic heart disease does indeed
differ by age (see figure 5). However, no meta-analyses to date have
investigated the effects of alcohol consumption on the risk of morbidity and
mortality in different age groups for other chronic diseases and conditions.
Accordingly, research is needed to assess if the varying relationship between
alcohol consumption and ischemic heart disease in different age groups results
from biological differences in pathology or from differences in drinking
patterns. Additionally, research is needed to assess if age modifies the risk
relationships between alcohol and other diseases.
Estimating the
Alcohol-Attributable Fractions of Chronic Diseases and Conditions
When assessing the
risk of chronic diseases and conditions that are related to alcohol consumption
in some, but not all, cases, one of the variables frequently analyzed is the
alcohol-attributable fraction (AAF)—that is, the proportion of cases that can
be attributed to the patient’s alcohol consumption. Because alcohol consumption
can be modeled using a continuous distribution (Kehoe et al. 2012; Rehm et al.
2010b), the calculation of the alcohol-attributable burden of disease uses a
continuous RR function.7 Thus, the AAFs for chronic diseases and conditions can
be calculated using the following formula:
AAF=P[sub abs] +P[sub
form]RR[sub form]+ integral[sup max]over[sub +0]P(x)RR(x)dx-1 divided by P[sub
abs] +P[sub form]RR[sub form]+ integral[sup max]over[sub +0]P(x)RR(x)dx
In this formula, Pabs
represents the prevalence of the disease among lifetime abstainers, Pform is
the prevalence among former drinkers, RRform is the relative risk for former
drinkers, P(x) is the prevalence among current drinkers with an average daily
alcohol consumption of x, and RR(x) is the relative risk for current drinkers
with an average daily alcohol consumption of x. These AAFs vary greatly
depending on alcohol exposure levels. (For examples of AAFs and information on
the calculation of the 95 percent confidence intervals for chronic diseases and
conditions see Gmel and colleagues [2011]).
7 The exception to
this approach is tuberculosis because only data on categorical alcohol exposure
risks are available.
Limitations of RR
Functions for Chronic Diseases and Conditions
The chronic disease RR
functions outlined in figures 2 to 6 are derived from the most up-to-date and
rigorous meta-analyses in which the risk of a disease (i.e., for mortality and,
where possible, morbidity) was provided by alcohol consumption as a continuous
function (for more details on the meta-analysis methods used in each study, see
the original articles cited in table 2). However, the RR functions and the
relationship between alcohol consumption and the risk of chronic diseases and
conditions are biased by multiple factors. First, the RRs can be limited by
poor measurement of alcohol exposure, outcomes, and confounders. Research on
alcohol consumption patterns and disease is scarce, and only few studies have
investigated the effects of drinking patterns on chronic diseases and
conditions. Thus, the chronic disease and condition RRs presented in this
article may be confounded by drinking patterns, which are correlated to overall
volume of alcohol consumption. Additionally, the volume of alcohol consumed
generally is poorly measured, with many medical epidemiology studies measuring
alcohol consumption only at baseline. As a result, these analyses do not
include measures of the volume of alcohol consumed during the medically
relevant time period, which may encompass several years. For example, in the
case of cancer, the cumulative effects of alcohol may take many years before an
outcome is observed. Likewise, many of the larger cohort studies only use
single-item, semi-quantitative food questionnaires that measure either
frequency or volume of consumption.
Second, medical
epidemiology studies typically suffer from poorly defined reference groups
(Rehm et al. 2008). Thus, such studies typically only measure alcohol consumption
at one point or during one time period in a participant’s life and classify,
for example, all people who do not consume alcohol during the reference period
as abstainers, even though it is essential to separate ex-drinkers, lifetime
abstainers, and very light drinkers. As a result, these measurements of alcohol
consumption may lead to incorrect risk estimates because the groups of
nondrinkers in these studies have heterogeneous risks for diseases (Shaper and
Wannamethee 1998). The potential significance of this issue is underscored by
previous research indicating that more than 50 percent of those participants
who identified themselves as lifetime abstainers in medical epidemiology
studies also had reported lifetime drinking in previous surveys (Rehm et al.
2008).
Third, chronic disease
and condition outcomes in medical epidemiology studies also frequently are
poorly measured, most often by means of self-reporting. Additionally, other
confounding factors, such as relevant, non-substance use–related confounders,
often are not controlled for.
Fourth, RR estimates
for chronic diseases and conditions resulting from alcohol consumption
frequently are hampered by weak study designs that base estimates of
alcohol-related risks on nonexperimental designs (i.e., case-control and cohort
studies). These study designs are limited by factors that cannot be controlled
for and which may lead to incorrect results. For example, experimental studies
on the effects of antioxidants have failed to confirm the protective effects of
such agents found in observational studies (Bjelakovic et al. 2008).
Furthermore, the sampling methodology of many of the cohort studies that were
used in the meta-analyses for the above-presented RRs is problematic,
especially when studying the effects of alcohol consumption. Many of the
cohorts in these studies were from high-income countries and were chosen based
on maximizing follow-up rates. Although the chosen cohorts exhibited variation
in average daily alcohol consumption, little variation was observed in drinking
patterns and other potential moderating lifestyle factors.
The overall effect of
these limitations on the RRs and AAFs, and on the estimated burden of mortality
and morbidity calculated using these RRs, currently is unclear. In order to
investigate the effect of these biases, studies should be undertaken that
combine better exposure measures of alcohol consumption with state-of-the-art
outcome measures in countries at all levels of economic development. These
studies are important, not only for understanding the etiology of
alcohol-related chronic diseases and conditions, but also for formulating
prevention measures (Stockwell et al. 1997).
Limitations of AAFs
for Chronic Diseases and Conditions
In most studies
assessing AAFs for chronic diseases and conditions, the AAF for an outcome is
calculated as if the health consequences of alcohol consumption are immediate.
Indeed, for most chronic diseases and conditions, including even diseases such
as cirrhosis, a large degree of the effects caused by changes in alcohol
consumption can be seen immediately at the population level (Holmes et al.
2011; Leon et al. 1997; Zatonski et al. 2010; for a general discussion see
Norström and Skog 2001; Skog 1988). For cancer, however, the situation is different.
The effects of alcohol consumption on the risk of cancer only can be seen after
years, and often as long as two decades. Nevertheless, for the purpose of
illustrating the entire alcohol-attributable burden of disease it is important
to include cancer deaths, because they account for a substantial burden. For
example, a recent large study found that in Europe 1 in 10 cancers in men and 1
in 33 cancers in women were alcohol related (Schütze et al. 2011). Therefore,
in the interpretation of alcohol’s effect on mortality and burden of disease in
this article, the assumption that there has been uniform exposure to alcohol
for at least the previous two decades must be kept in mind.
Another limitation to
calculating the burden of chronic diseases and conditions attributable to
alcohol consumption is the use of mainly unadjusted RRs to determine the AAFs.
The RR formulas were developed for risks and were adjusted only for age (see
Flegal et al. 2006; Korn and Graubard 1999; Rockhill and Newman 1998), although
many other socio-demographic factors are linked with both alcohol consumption
and alcohol-related harms (see figure 1). However, two arguments can be made to
justify the use of mainly unadjusted RR formulas in the 2005 GBD study. First,
in risk analysis studies (Ezzati et al. 2004) almost all of the underlying
studies of the different risk factors only report unadjusted risks. Relying on
adjusted risks would severely bias the estimated risk functions because only a
small proportion of generally older studies could be included. Second, most of
the analyses of alcohol and the risk of chronic diseases and conditions show no
marked differences after adjustment (see Rehm et al. 2010b). However, the need
for adjustment to the RRs may change when other dimensions of alcohol
consumption, such as irregular heavy-drinking occasions, are considered with
respect to ischemic heart disease.
Conclusions
There are limitations
to the current ability to estimate the burden of chronic diseases and
conditions attributable to alcohol consumption. The comparative risk assessment
study within the GBD study only can determine this burden based on current
knowledge of alcohol consumption and risk and mortality patterns at a global
level. More detailed, country-specific estimates often are limited by the
validity of the available consumption and mortality data. As more studies are
published, it is likely that new confounders will be discovered for some of the
relationships between alcohol consumption and various chronic diseases and conditions.
The results from such new studies then may be used in meta-analyses of the
effect of alcohol in diseases where alcohol only plays a small role, such as
bladder, endometrial, and ovarian cancer. New studies also may lead to the
recognition of a causal link between alcohol consumption and other diseases.
Furthermore, new confounders and new studies may disprove the relationship
between alcohol consumption and certain diseases that currently are considered
to be causally linked.
Although there are limitations
to the current methodology used to estimate the alcohol-attributable burden of
chronic diseases and conditions, the limitations discussed in this article do
not affect the overall conclusion that alcohol consumption is related to a
considerable number of chronic diseases and conditions and contributes to a
substantial amount of the global burden of chronic diseases and conditions.
Therefore, alcohol consumption should be considered in developing intervention
strategies aimed at reducing the burden of chronic diseases and conditions.
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