Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Alcohol Use Disorders: Alcoholic Liver Diseases
and Alcohol Dependency
Opportunities to Address Pharmaceutical Gaps
By Warren Kaplan, Ph.D, JD, MPH
7 October 2004
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Table of Contents
Executive Summary ............................................................................................................................. 4
Burden of Disease .................................................................................................................... 4
Treatment Options .................................................................................................................. 4
1. Introduction .................................................................................................................................. 5
1.1 Alcohol Addiction ......................................................................................................... 5
1.2 Alcoholic Liver Diseases .............................................................................................. 6
1.2.1
1.2.2
1.2.3
1.3
Diagnosis of Alcohol Abuse or Dependence ............................................................. 6
1.3.1
1.3.2
2.
The DSM Criteria .......................................................................................................... 7
ICD Criteria ................................................................................................................... 7
What Are the Epidemiological Trends for Europe and the World ..................................... 7
2.1 General ............................................................................................................................ 7
2.1.1
2.1.2
2.2
2.3
Prevalence of Alcohol Abuse ...................................................................................... 8
Prevalence of ALD ...................................................................................................... 10
The European Burden of ALD ................................................................................... 10
Several Specific Epidemiologic Issues Exist with the Main Types of Alcoholic
Liver Disease ................................................................................................................ 13
2.3.1
2.3.2
2.3.3
2.3.4
2.3.5
2.3.6
3.
Alcoholic Fatty Liver .................................................................................................... 6
Alcoholic Hepatitis ....................................................................................................... 6
Alcoholic Cirrhosis ....................................................................................................... 6
Immunomodulatory Effects of Alcohol ................................................................... 13
ALD and the Elderly .................................................................................................. 14
ALD and Women ........................................................................................................ 14
ALD and Genetics ....................................................................................................... 15
Diagnosis and Biochemical Markers ........................................................................ 16
Comorbidities Associated with Alcohol Abuse and Dependence ....................... 17
What is the Control Strategy? .................................................................................................. 17
3.1 Remediation of Alcohol Dependence ....................................................................... 17
3.2 Alcoholic Liver Disease (ALD) .................................................................................. 18
3.2.1
3.2.2
Alcoholic Hepatitis (AH) ........................................................................................... 18
Alcoholic Cirrhosis .................................................................................................... 19
3.3 Transplantation ............................................................................................................ 20
4. What is Known of the Affordability, Feasibility, and Sustainability of the Control
Strategy? .............................................................................................................................................. 21
4.1 Economic Burden ........................................................................................................ 21
4.2 Feasibility of Control Strategy ................................................................................... 22
5. Why Does the Disease Burden Persist? ................................................................................. 22
6. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for
this Condition? ................................................................................................................................... 23
6.1 Dependence .................................................................................................................. 23
6.2 Liver Regeneration ...................................................................................................... 23
7. What is the Current “Pipeline” of Products that Are to Be Used for this Particular
Condition? .......................................................................................................................................... 24
7.1 Alcohol Dependence ................................................................................................... 24
7.1.1
7.1.2
7.1.3
7.1.4
7.2
7.3
Opioid Antagonists .................................................................................................... 24
Serotonergics ............................................................................................................... 24
Dopaminergics ............................................................................................................ 24
Other Interventions .................................................................................................... 25
Alcoholic Liver Disease ............................................................................................. 25
“Spillovers” from the Hepatitis C pipeline and Other Fibrotic Conditions ....... 28
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8. What is the Current Status of Institutions and Human Resources Available to Address
the Disease? ........................................................................................................................................ 29
8.1 Public Funding............................................................................................................. 29
8.1.1
8.1.2
9.
European Sources of Funding for Alcoholic Liver Diseases: Selected Countries29
United States Sources of Funding ............................................................................. 29
8.2 Private Sector Funding ............................................................................................... 30
Ways Forward from a Public Health Viewpoint with Regard to Public Funding ........ 31
9.1 Gaps between current research and potential research issues which could make
a difference. .................................................................................................................. 31
9.1.1
9.1.2
Basic Research ............................................................................................................. 31
Applied Research ........................................................................................................ 31
10. Conclusion .................................................................................................................................. 32
Annex
Appendix
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Executive Summary
Burden of Disease

In developed countries alcohol is one of the ten leading causes of disease and injury.
Worldwide, in 2000, alcohol caused about 3 per cent of all deaths (1.8 million) and about 4
per cent of ‘disability adjusted life years’ lost (DALYS) (58.3 million).

Globally, almost half of the global burden of alcohol-related mortality is due to alcoholrelated injuries, with 32% due to unintentional injuries and about 14% due to intentional
injuries. Malignant neoplasms (liver cancer and stomach cancer) are the next most important
category, accounting for about 20% of the overall alcohol-related mortality burden, followed
by cardiovascular disease (15%) and other non-communicable disease [mainly alcoholic liver
diseases (ALD)] such as liver cirrhosis –13% of all alcohol-attributable deaths

Alcoholic liver disease (ALD) is the commonest cause of cirrhosis in the Western world, and
ALD is currently one of the ten most common causes of death. Liver fibrosis caused by
alcohol abuse and its end stage, cirrhosis, represent enormous worldwide healthcare
problems. Patients with cirrhosis and superimposed alcoholic hepatitis have a 4-year
mortality of more than 60%.

As the onset of many types of liver disease is insidious, there is often a long time interval
(latent period) between disease occurrence and detection. Further, alcohol use lowers the
immune response. Infection is one of the most common causes of death in patients with
ALD, especially those with alcoholic hepatitis. Malnutrition, underlying liver cirrhosis, and
aggressive in-hospital medical procedures all contribute to the risk of infection.
Treatment Options

Overall, stopping drinking has been shown to improve the survival of patients with all
stages of ALD. This, this condition is eminently preventable. However, progress in
developing specific treatments for acute alcoholic hepatitis has been hampered by a poor
understanding of disease pathogenesis.

Many treatment modalities have been tried in patients with alcoholic hepatitis, however, few
have been consistently shown to have a beneficial effect and, accordingly, none have
achieved consensus status among practising hepatologists. Thus, current therapy still
focuses predominantly on supportive care.

Current treatments for alcoholic cirrhosis are severely limited. One can attempt to have
patients abstain from alcohol (where possible); eradicate existing viruses using interferon,
ribavirin, and lamivudine in viral hepatitis; and transplant the liver. The vast majority of
patients with ALD in clinical practice have advanced fibrosis or cirrhosis. No adjunctive
pharmacotherapies have been consistently shown to improve survival in more than one
randomized controlled trial, although some have shown promise.

Transplantation is a highly successful treatment, particularly for end stage cirrhosis, with a
75% five year survival rate. There is limited availability of organs, growing lists of patients
needing a transplant, issues of compatibility, and comorbid factors. Transplantation is also
costly with ongoing anti-rejection drug costs. Effective anti-fibrotic treatments are needed
urgently.

In light of the high burden of disease, there are very few medicines in clinical trials
specifically directed to reverse, inhibit or otherwise ameliorate alcoholic liver disease so
there is a large “gap” between basic and applied research.
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
There are many potential biological targets for anti-fibrotic therapies. Moreover, fibrosis of
the liver is a paradigm for other fibrotic conditions in other organs of the body.

There is little private-sector funding directed to alcoholic liver diseases. Public sector
funding may be insufficient as well, particularly when compared to the enormous economic
and social burdens placed on the healthcare system by ALD.
1.
Introduction
Many interacting issues are at work when dealing with alcohol abuse: the medical sequelae,
alcohol intoxication, alcohol tolerance, alcohol dependence, and alcohol withdrawal.1 From a
public health viewpoint, the diseases associated with alcohol abuse are preventable with
abstention and such behavioral modifications as may be necessary should be considered the
primary intervention. Nonetheless, for the present review, we focus on pharmacological
interventions for alcohol dependence and alcohol’s hepatotoxic effects, in particular the
spectrum of conditions known as alcoholic liver disease.2 3 4 5
1.1
Alcohol Addiction
Generally, the approaches currently used in the treatment of alcohol problems are based on
three sources of information: (1) the experiences of recovering alcoholics and the professional
staff treating them, (2) research on human behavior, and (3) studies of potential medications (i.e.,
pharmacological research. 6
The conditions that lead to excessive alcohol consumption in some individuals and not in others
are very complex as they involve interactions among genetic, psychosocial, environmental, and
neurobiological factors. Alcoholism is a multigenic disorder.1 The pharmacological effects of
ethanol that support alcohol reward and alcohol seeking behavior involve actions at multiple
receptors and neurochemical systems occurring throughout the body. Neuropharmacologic
studies in animals have provided evidence for specific neurochemical mechanisms in the brain
that are involved in alcohol dependence. There are many neurotransmitter systems that become
dysregulated during the development of alcohol dependence, including gamma(γ)aminobutryic acid (GABA), opioid peptides, glutamate, serotonin and dopamine systems. See
reference (5). Genetic studies on alcoholism are summarized in Appendix 6.14.1, below.
Briefly, Alcohol has two major actions on the brain: increasing neuronal inhibition mediated
through the inhibitory γ-aminobutyric acid (GABA), and other receptors. Prolonged alcohol use
down-regulates these receptors and decreases inhibitory neurotransmission. Prolonged alcohol
use inhibits excitatory neurotransmission by inhibiting both N-methyl-d-aspartate (NMDA)
and non-NMDA (e.g., α-amino-3-hydroxy-5-methisoxizole-4-propionic acid [AMPA]) receptors.
Cessation or reduction of alcohol use initiates an imbalance between the decreased
neuroinhibition and increased neuroexcitation. This causes the clinical manifestations of alcohol
withdrawal: e.g., tremors, hallucinations, insomnia, anxiety or agitation, and possibly seizures.
Alcohol also affects numerous other neurotransmitters.
Although about 30% of all alcohol-dependent patients are admitted to general hospitals, usually
to treat the alcohol-related physical diseases emphasized in this document, the alcohol
dependence itself is often ignored or not diagnosed. See Section 1.3.
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1.2
Alcoholic Liver Diseases
The spectrum of ALD ranges from fatty liver (steatosis), present in most, if not all heavy
drinkers, through steatohepatitis, fibrosis and ultimately cirrhosis.
1.2.1
Alcoholic Fatty Liver
Alcoholic fatty liver is predominantly an asymptomatic condition that develops in response to a
short duration (a few days) of alcohol abuse. Patients with fatty liver are asymptomatic so that
they rarely present with liver related problems. Fatty liver is reversible with abstention but it is
a risk factor for progression to fibrosis and cirrhosis in those patients who continue drinking. 7
1.2.2
Alcoholic Hepatitis
Between 20- 40% of persistent heavy drinkers will develop more serious liver disease. In some of
these patients, they will get alcoholic hepatitis (AH) while others will present with complications
of portal hypertension, and other conditions. People with advanced alcoholic liver disease
(ALD) can also be asymptomatic and may even have normal liver blood tests. 8 The level of
alcohol consumption necessary for the development of these advanced forms of alcoholic liver
disease is probably 80 g of alcohol per day, the equivalent to 6 to 8 drinks daily for several
years.9
Alcoholic hepatitis and is usually accompanied by fatigue, anorexia, and weight loss, and other
non-specific symptoms, such as nausea and vomiting. Severe alcoholic hepatitis may be
evidenced by gastrointestinal (GI) bleeding, and ascites. Other findings depend on the severity
of liver insult and may include jaundice and other conditions.
1.2.3
Alcoholic Cirrhosis
Alcoholic cirrhosis may occur at any time before, during , after, or independent of a bout of
alcoholic hepatitis. Liver fibrosis and cirrhosis (clinically distinct conditions but, unless
specifically mentioned, they are used interchangeably in this report) represent a continuous
disease spectrum characterized by an increase in total liver collagen and other matrix proteins
which disrupt the architecture of the liver and impair liver function. 10 Fibrosis results from
sustained wound healing in the liver in response to chronic or iterative injury. The wound
healing response is an integral part of the overall process of inflammation and repair: it is
dynamic and has the potential to resolve without scarring. 8 The clinical history of alcoholic
cirrhosis is similar to that of alcoholic hepatitis, and symptoms are similar to those observed
with other forms of endstage liver disease.10 At present, there are few interventions available to
alter the underlying fibrotic process in many patients with liver disease, although data from
clinical and laboratory based research show that cirrhosis may be reversible.
About 40% of patients with cirrhosis are asymptomatic and may remain so for more than a
decade, but progressive deterioration is inevitable once complications develop. 11 In such
patients there is a 50% 5-year mortality, with approximately 70% of these deaths directly
attributable to liver disease. 12 In asymptomatic individuals, cirrhosis may be first suggested
during routine examination or diagnosed at autopsy, although biopsy is still required to
establish the diagnosis postmortem (see below). Cirrhosis affects hundreds of millions of
patients worldwide. It is the most common non-neoplastic cause of death among the
hepatobiliary and digestive diseases.
1.3
Diagnosis of Alcohol Abuse or Dependence
Diagnostic criteria for alcohol abuse and dependence reflect the consensus of researchers as to
precisely which patterns of behavior or physiological characteristics constitute symptoms of
these conditions . Diagnostic criteria allow clinicians to plan treatment and monitor treatment
progress; make communication possible between clinicians and researchers; enable public health
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
planners to ensure the availability of treatment facilities; help health care insurers to decide
whether treatment will be reimbursed; and allow patients access to medical insurance coverage .
Diagnostic criteria for alcohol abuse and dependence have evolved over time. Current USA
standards are the American Psychiatric Association's Diagnostic and Statistical Manual of
Mental Disorders, Fourth Edition (DSM-IV) (American Psychiatric Association. Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition. Washington, D.C.: the Association, 1994).
The criteria found in the World Health Organization's International Classification of Diseases,
Tenth Revision (ICD-10) are not often used in the USA (World Health Organization. The ICD-10
Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic
Guidelines, Tenth Revision. Geneva: World Health Organization, 1992).
1.3.1
The DSM Criteria
Researchers and clinicians in the United States usually rely on the DSM diagnostic criteria,
found in the Diagnostic and Statistical Manual of Mental Disorders, currently in its Fourth
Edition (DSM-IV). DSM-IV, like its predecessors, includes nonoverlapping criteria for
dependence and abuse. However, in a departure from earlier editions, DSM-IV provides for the
subtyping of dependence based on the presence or absence of tolerance and withdrawal. The
criteria for abuse in DSM-IV were expanded to include drinking despite recurrent social,
interpersonal, and legal problems as a result of alcohol use. In addition, DSM-IV highlights the
fact that symptoms of certain disorders, such as anxiety or depression, may be related to an
individual's use of alcohol or other drugs.
1.3.2
ICD Criteria
The World Health Organization develops diagnostic criteria for the purpose of compiling
worldwide statistics on all causes of death and illness, including those related to alcohol abuse
or dependence. The ICD defines alcohol dependence in a way that is similar to the DSM. The
diagnosis focuses on an interrelated cluster of psychological symptoms, such as craving,
physiological signs ( such as tolerance and withdrawal) and behavioral indicators such as the
use of alcohol to relieve withdrawal discomfort. However, in a departure from the DSM, rather
than include the category "alcohol abuse," ICD-10 includes the concept of "harmful use." This
category was created so that health problems related to alcohol and other drug use would not be
underreported. Harmful use implies alcohol use that causes either physical or mental damage in
the absence of dependence. Some differences between the two major diagnostic criteria still
exist, but they have been revised by consensus as to how alcohol abuse and dependence are best
characterized for clinical purposes.
2.
What Are the Epidemiological Trends for Europe and the World
2.1
General
Accurate estimates for the incidence and prevalence of alcohol-induced liver disease are difficult
to obtain, because many individuals with alcohol-induced liver disease are asymptomatic and
national surveys may not bother to not ask questions detailed enough to allow classification by
specific causes of liver disease. Thus, there are significant gaps in our current understanding of
the epidemiology and burden of liver disease at the population level. This is partly because of
the fact that many investigations in hepatology are conducted at referral centers and are based
on selected patients. As most liver diseases have a substantial latency period during which
patients have mild asymptomatic liver disease, studies based on referral patients only recognize
patients with the most severe or advanced disease and fail to obtain information on the entire
spectrum of disease. Population-based data are especially important for those diseases whose
prevalence is on the rise.8
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2.1.1
Prevalence of Alcohol Abuse
With the exception of Islamic regions, alcohol is ubiquitous in the modern world. 13 It seems
possible that the role of alcohol as a major factor in the burden of disease will increase in the
future. Two trends are relevant. The average volume of drinking is expected to increase in most
populous regions of the world (Southeast Asia, including India and China). Alcohol is also
linked to conditions also predicted to increase (e.g., accidents and injuries, cardiovascular
disease).15 Second, there are some indications that relatively healthful patterns of drinking are
deteriorating in young people, particularly in Europe. 14 Globalization seems to lead to
converging patterns of drinking around the world, and not necessarily to convergence to the
most favorable patterns (i.e., regular light to moderate drinking with meals). It is arguable
that the deterioration of the favorable pattern in young people in Europe has been linked to
aggressive marketing to the youth market. 15 Drinking is being promoted as a lifestyle in
association with recreation.
Specifically, within the European Region of the World Health Organization (WHO), alcohol
consumption is responsible for increasing the risk of liver cirrhosis, certain cancers, raised blood
pressure, stroke and congenital malformations.16 Furthermore, alcohol consumption increases
the risk of many family, work and social problems. For instance, in the European Region of the
WHO, between 40 and 60 per cent of all deaths from intentional and unintentional injuries are
estimated to be attributable to alcohol consumption. 18 Drinking alcohol is in Europe a severe
social and public health problem.
With regard to the United States, more than a decade ago the 1992 National Longitudinal
Alcohol Epidemiologic Survey, a national household survey, found that a remarkable 7.5
percent of the U.S. population (about 14 million Americans) abuse and/or are dependent on
alcohol.17 More than 700,000 people receive alcoholism treatment on any given day in the
United States.6
Indeed, most prevalence studies have been carried out in North America, 6 so that the results
may not be generalisable to other cultures. Rates of alcohol use disorders also vary depending
on the diagnostic criteria used. Community-based studies have estimated the prevalence of
alcohol misuse or dependence as 2-4%, with much higher rates of 17% (men) and 7% (women)
when looser criteria such as excessive alcohol consumption are used.18 For hospital based
studies, the same difficulties exist as the definitions for alcohol use disorders are not clearly
specified in many studies.
Notwithstanding the above, what is known is that the average volume of alcohol consumption
and patterns of drinking are not related to each other. 15 There is a marked variation between
geographic regions (based on World Health Organization subregions ) on both dimensions. The
average volume of drinking is highest in established market economies in Western Europe and
the former Socialist economies in the Eastern part of Europe and in North America, and lowest
in the Eastern Mediterranean region and parts of Southeast Asia including India. 15 Patterns are
most detrimental to health in the former Socialist economies in the Eastern part of Europe, in
Central and South America and parts of Africa. Overall, exposure to alcohol around the world
varies considerably between regions, the overall exposure by volume is quite high and patterns
are relatively detrimental. 15
Alcohol is one of the major risk factors for burden of disease in established market economies. 19
20 21 Tables 1 and 2 are taken directly from ref (21)
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In developed countries, alcohol is one of the ten leading causes of disease and injury.
Worldwide, alcohol causes 3.27 per cent of deaths (1.8 million) and 4 per cent of ‘disability
adjusted life years’ lost (DALYS) (58.3 million). This varies with age, as seen in Figures 1 and 2.
In developed countries, alcohol is responsible for 9.2 per cent of the total disease burden. 21 In
terms of alcohol- related mortality, almost half of the global burden (46%; see Table 1) is related
to alcohol-related injuries, with 32% due to unintentional injuries and about 14% due to
intentional injuries. Malignant neoplasms (liver cancer and stomach cancer) are the next most
important category, accounting for about 20% of the overall alcohol-related mortality burden,
followed by cardiovascular disease (15%) and other non-communicable disease (mainly ALD
such as liver cirrhosis –13% of all alcohol-attributable deaths). 21
The biggest shift of relative impact of disease categories for DALYs compared to mortality can
be found with respect to neuropsychiatric diseases. Neuropsychiatric diseases are often
disabling, but not lethal, and this is reflected in the markedly higher proportion of overall
disease burden caused by this category, compared to alcohol attributable mortality (38% of
alcohol-attributable DALYs; 6% of alcohol-attributable mortality; see Table 2).
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2.1.2
Prevalence of ALD
Alcoholic liver disease (ALD) is the commonest cause of cirrhosis in the Western world, and
ALD is currently one of the ten most common causes of death. 20 Liver fibrosis and its end stage,
cirrhosis, represent enormous worldwide healthcare problems. In the United Kingdom, more
than two thirds of the 4000 people who died of cirrhosis in 1999 were under 65, and the
incidence of cirrhosis related death is increasing. Patients with cirrhosis and superimposed
alcoholic hepatitis have a 4-year mortality of more than 60%. 22
Worldwide, the common causes of liver fibrosis and cirrhosis include hepatitis B and hepatitis C
and alcohol. Other causes include immune mediated damage, genetic abnormalities, and nonalcoholic hepatitis, which is associated with obesity and diabetes Type 2. Changing patterns of
alcohol consumption in the West and the increasing rates of obesity and diabetes mean that
advances in preventing and treating viral liver infections may be offset by an increasing burden
of fibrosis and cirrhosis related to alcohol and non-alcoholic abuse. 21
2.2
The European Burden of ALD
Alcohol causes nearly 1 in 10 of all ill-health and premature deaths in Europe. 21 The World
Health Organization’s Global Burden of Disease Study finds that alcohol is the third most
important risk factor, after smoking and raised blood pressure, for European ill-health and
premature death.20 Alcohol is more important than high cholesterol levels and obesity, three
times more important than diabetes and five times more important than asthma. This level of
alcohol-related death, disease and disability is much higher in men than women and is highest
in Europe and the Americas, where it ranges from 8%-18% for males and 2%-4% for females. 21
There is an immense impact of alcohol on liver disease in the UK. 23 It is estimated that 8% of
men and 3% of women are "problem drinkers" in the UK. Many more people drink excessive
amounts of alcohol, but are not addicted. The result is a growing increase in the number of
people developing fibrosis of the liver, cirrhosis and in later stages liver failure and possibly
liver cancer. At least half of all clinical presentations of liver disease in the UK are is alcohol
related Between 1996 and 2000 inclusive, alcoholic cirrhosis was the primary indication for
liver transplantation (468 transplants; total 3400 all-cause), at an estimated cost of £23.5 million
for the transplants alone.
In the UK, the trend in cirrhosis is rising while the trend is declining in the rest of the EU. This is
further exacerbated by the hepatitis C epidemic, where progression of liver disease is accelerated
by alcohol, similarly in all other liver disease. "Large rises in death rates from chronic liver
disease and cirrhosis have occurred in most age groups. In 45-54 year olds, there has been a
greater than 4-fold increase amongst men since the early 1970s and a 3-fold increase in women.
In 35-44 year olds, the rise has been even larger: an 8-fold increase in men and approaching a 7fold increase in women.23
Figure 1 shows the burden of alcoholic use disorders as a percent of the total DALY burden (all
acute and chronic conditions) across various age groups and European regions. This burden
peaks between the ages 15-44 at a remarkable 14-18% of all DALYs for men in Europe. The
burden for European women in this age group is much less but is generally in the range of the
global values. Over all age groups and both sexes, the EU15 countries have higher disease
burdens than the EU10 countries.
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Alcoholic Use Disorders (as Percent of All DALYs by
age group)
20.00%
18.00%
16.00%
14.00%
EU15-M
EU15-F
EU10-M
EU10-F
World-M
World-W
12.00%
10.00%
8.00%
6.00%
4.00%
2.00%
0.00%
0-4
5-14
15-29
30-44
45-59
60-69
70-79
80+
Source: World Health Organization Global Burden of Disease Database (2002)
Figure 2 shows the burden of liver cirrhosis as a percent of the total DALY burden (all acute and
chronic conditions) across various age group and regions. This burden peaks between the ages
45-59 at about 4-5% of all DALYs for men in Europe. The burden for European women in this
age group is much less but is generally in the range of the global values. Over all age groups and
both sexes, the EU10 countries have higher liver cirrhosis disease burdens than the EU15
countries, a situation reversed from that of alcohol abuse disorders.
Liver Cirrhosis (Percent of All DALYs by age group)
6.00%
5.00%
EU15-M
EU15-W
EU10-M
EU10-W
World-M
World-W
4.00%
3.00%
2.00%
1.00%
0.00%
0-4
5-14
15-29 30-44 45-59 60-69 70-79
80+
Source: World Health Organization Global Burden of Disease Database (2002)
The peak in distribution of disease burden for liver cirrhosis precedes that for alcohol abuse
disorders by about 20 years. Although liver cirrhosis can be caused by infective agents (e.g.,
viral hepatitis), the time lag is not unreasonable under the hypothesis that the liver cirrhosis is in
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
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large part the result of the earlier alcohol abuse. Figures 3 and 4 are frequency plots of the
fraction of total DALYs attributed to each age group for the particular geographic area. Thus, in
Figure 3, we see that about 40% of the total alcohol abuse and liver cirrhosis DALY burden for
men in the EU15 can be attributed to the 15-29 year and 45-59 year age groups, respectively. In
Figure 4, we see the same trends for European women.
Fraction Total DALY burden per Age Group (EU15,
EU10 Men)
0.6
Liver cirrhosis
Alcohol use disorders
0.5
0.4
EU15
EU10
0.3
0.2
EU10
EU15
0.1
0
0-4
5-14
15-29
30-44
45-59
60-69
Figure 3
Source: World Health Organization Global Burden of Disease Database (2002)
6.14-12
70-79
80+
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Fraction Total DALY burden per Age Group (EU15,
EU10 Women)
0.6
Liver Cirrhosis
0.5
Alcohol Use Disorders
0.4
0.3
0.2
EU10
EU15
EU10
EU15
0.1
0
0-4
5-14
15-29
30-44
45-59
60-69
70-79
80+
Figure 4
Source: World Health Organization Global Burden of Disease Database (2002)
2.3
Several Specific Epidemiologic Issues Exist with the Main Types of Alcoholic
Liver Disease
Disease frequency may be measured either by the pool of existing cases (prevalence) or by the
occurrence of new cases (incidence). As the onset of many types of liver disease is insidious,
there is often a long time interval (latent period) between disease occurrence and detection. 11
Further, many patients with liver disease remain asymptomatic until their livers fail. Thus, it is
very difficult, if not impossible, to accurately ascertain incidence rates of liver disease. While
estimating prevalence may in general be more feasible than incidence rates, many epidemiologic
investigations are conducted based on referral patients, which may not represent the true
disease prevalence in entire populations. 24 Population-based studies of liver disease are
necessary for accurate information on the burden of disease and the contribution of specific
etiologies of liver disease to this burden.
2.3.1
Immunomodulatory Effects of Alcohol
There is an increased susceptibility to infections in alcohol related diseases. 25 As a result,
infection is one of the most common causes of death in patients with ALD, especially those with
alcoholic hepatitis. Malnutrition, underlying liver cirrhosis, and aggressive in-hospital medical
procedures all contribute to the risk of infection. 8 Alcoholic liver disease and liver failure may
even have a component of autoimmunity, in which the immune system turns on the body’s own
tissues. A number of reviews provide an overview of current knowledge concerning alcohol’s
effects on the human immune system. 26 27
Several important infectious diseases that are highlighted in other sections of this Report are also
implicated in alcohol-related immunocompromised individuals. The incidence and severity of
pulmonary tuberculosis (TB) is greater in alcoholics than in nonalcoholics. 29 In the overall
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
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population, 16 percent of TB patients are alcohol abusers; the percentage ranges up to more than
35 percent in some marginalized populations. 28 Significantly, long-term studies of drug and
alcohol abusers who were followed for many years showed that these individuals had TB
incidence rates from 15 to 200 times (!) the rates for reference populations. 29 In recent years, the
incidence of TB has been increased by the presence of human immunodeficiency virus (HIV) in
drug and alcohol abusers. However, even after this added risk is taken into account, it is still
clear that drug and alcohol abusers have increased rates of illness and death from TB. 30
Alcohol abusers are more susceptible than nonabusers to septicemia, urinary tract infections ,
bacterial peritonitislung abscess, empyema (an accumulation of pus in the chest), spontaneous
bacterial peritonitis, diphtheria, cellulitis, and meningitis. 29 30 31 32 It is clear that the increased
incidence of infectious diseases in alcohol abusers represents a significant toll of individual
suffering and of medical expense to society. The risk of untreatable infections in alcohol abusers
will also increase as antimicrobial resistance increases.
Most important , however, is the association of alcoholic liver disease with hepatitis C. Fully 25%
of all patients with alcoholic liver disease have also markers of HCV infection, even in the
absence of risk factors such as intravenous drug abuse. 33 34 Alcohol may favor the acquisition,
replication, or persistence of the virus so alcohol consumption is clearly a risk factor for the
progression of liver disease caused by HCV. 35 HCV infection multiplies the alcohol-associated
risk of cirrhosis. 36
2.3.2
ALD and the Elderly
Alcohol use disorders in elderly people are common and associated with considerable
morbidity.37 The ageing of populations worldwide means that the absolute number of older
people with alcohol use disorders is on the increase even though the prevalence of alcohol use
disorders in elderly people is generally lower than in younger people. Rates, however, may be
underestimated because of under-detection and misdiagnosis. 38 Age related changes in body
composition means that equivalent amounts of alcohol produce higher blood alcohol
concentrations in older people. 39 Even so, elderly people have been shown to be at least as
likely to benefit from treatment as younger people. 40 Alcohol use disorders in elderly people
may prove to be a silent epidemic, yet media attention and public health initiatives related to
alcohol use disorders tend to focus almost exclusively on younger populations. 41
2.3.3
ALD and Women
There is marked regional variability in the extent of gender differences with regard to alcoholrelated morbidity and mortality. Female alcohol-attributable mortality ranges from a negative
value (more deaths prevented than caused) in established market economies of Western Europe
(Europe A), North America (Americas A) and the Western Pacific Region (Western Pacific A) to
more than 5% of all female deaths being attributable to alcohol in the former socialist countries
of Eastern Europe around Russia (WHO Region Europe C). 23 For comparison, female alcoholattributable mortality is 18% in the former socialist countries of Eastern Europe (Europe C). 23
The differences among regions reflect the differences in the overall relationship between average
volume of alcohol consumption and mortality generally. For DALY burdens, males have a far
greater alcohol related DALY burden than females. See Figures 1-4, above. It should be noted
that for disease burden there is no region where alcohol has an overall beneficial impact on
either gender. 23
The relationship between breast cancer risk and alcohol intake was first noted in the 1970’s
among women participating in the third National Cancer Survey. 41 Meta-analysis of case
control studies (not randomized trials) have found that women who drank three or more
alcoholic beverages per day (or 40 grams of alcohol, with about 13 grams in a standard drink)
had a 69 percent higher risk of getting breast cancer compared with nondrinkers. 42 A separate
6.14-14
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
analysis of six prospective cohort studies showed that those who had two to four drinks per day
(30 to 60 grams of alcohol) had a 41 percent greater risk of getting breast cancer than those who
did not drink. 43 Remarkably, over a range of one to six drinks per day, the relationship of
alcohol to breast cancer was linear.
Controversy remains over the interpretation of these studies as the effect is modest in magnitude
and is not restricted to one type of alcoholic beverage. The risk is most pronounced at high
intakes of alcohol. Increased exposure to estrogens and androgens with alcohol consumption is
one plausible—but unconfirmed— biological mechanism to explain alcohol’s effect on breast
cancer risk. 44 45
The mechanisms for the differential impact of alcohol on heart disease and mortality and on
neurologic function in women and men are also still unclear. There remain possibilities at every
level of alcohol processing: its metabolism by enzymes in the stomach and liver, its absorption
into the bloodstream, and its actions on the physiology of end organs—that might explain
mechanisms that could contribute to gender related differences in the health consequences of
drinking. 49 Adverse effects have been observed at levels of consumption that many would
regard as low- between 7 to 13 drinks per week. 46 It is important that research be aimed at
identifying why women are so vulnerable to alcohol
For any given level of alcohol intake, women have an increased susceptibility to alcoholic liver
disease.47 48 Table 3, is reproduced directly as Table 1 from reference (8). However, the
threshold of alcohol necessary for the development of advanced alcoholic liver disease varies
substantially among individuals, and factors other than absolute alcohol consumption clearly
have an important role in determining who will develop alcoholic liver disease and who will
not. These observations highlight the role of genetic factors that may predispose specific persons
to greater propensity toward alcohol-induced liver toxicity.
2.3.4
ALD and Genetics
Alcoholism and alcohol-induced liver disease are partly genetic diseases. There is much
information on alcohol dependence per se with regard to the biological mechanism of action;
heritability studies; animal studies, and linkage and association studies. While the present
review is not intended to be exhaustive, the potential new gene candidates for alcohol
6.14-15
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
dependence is an important area of study. Appendix 6.14.1 summarizes some of the most
important studies in the field.
One study has identified a stronger genetic component for male dependence on alcohol than for
arterial hypertension. 49 Sons of alcohol-dependent fathers tend to be more tolerant to alcohol
and to have fewer hangovers, a fact which renders alcohol more pleasurable to them. 50 The C2–
promoter allele of the gene coding for the cytochrome 450CYP2E1 shows a significantly different
distribution in heavy drinkers. This C2–allele, which leads to higher production of the
cytochrome protein, is present in 6% of healthy heavy drinkers, in 19% of heavy drinkers with
alcoholic liver disease and in 33% of heavy drinkers with cirrhosis. 51 Similarly, two identical
sections of the alcohol dehydrogenase gene (one on each chromosome) is found in 7% of healthy
heavy drinkers and 31% in heavy drinkers with ALD. 53 A change in a region of the DNA
encoding human CD14 protein, has been linked to the development of fibrosis in alcoholic liver
disease. 52 Specific genetic polymorphisms have been detected in patients with alcoholic liver
disease, most notably mutations in the tumor necrosis factor (TNF) promoter. 53
2.3.5
Diagnosis and Biochemical Markers
The major clinical assessment necessary for diagnosing alcoholic liver disease is determining
whether the patient is abusing alcohol but this is not always easy. Alcoholic patients and even
their family members often minimize or conceal alcohol use. Because of the inherent difficulties
in obtaining a reliable history of alcohol use, various biochemical markers have been evaluated
for their ability to detect surreptitious alcohol abuse. A comprehensive marker for alcohol
dependence has not been identified although a series of successful markers exist for determining
drinking status. Traditional serologic markers of alcohol abuse are based on liver injury and
include elevations in aspartate aminotransferase (AST) and alanine aminotransferase (ALT)
levels, and elevated AST/ALT ratios. 8 These tests have diminished sensitivity and specificity,
generally less than 70%. Other tests have been evaluated. Measuring urinary 5hydroxytryptophol or ethyl glucuronide are more sensitive than measuring blood or breath
ethanol. Carbohydrate-deficient serum transferrin protein is a more specific marker for
identifying excessive alcohol consumption and monitoring abstinence. 8
Although hepatitis C virus (HCV) is a leading risk factor for liver fibrosis, there is no standard
laboratory serum analyses, imaging tests or virologic assays that currently can distinguish those
with hepatitis C, or any other condition, who are at risk for progressive fibrosis. 11 Thus,
increasing numbers of patients will require assessment of fibrosis, exposing them to the potential
risks, inconvenience and cost of liver biopsy and its interpretation. If a non-invasive assay were
developed that reliably excludes the possibility of significant fibrosis, then such patients may not
require treatment with antiviral therapies, and, moreover, could be followed regularly to
confirm lack of fibrosis progression. Increasing evidence that advanced fibrosis may be
reversible, such that more frequent and refined analysis may render even severe disease
amenable to therapy. The expectation that as antifibrotic therapies are developed, there will be a
need for early and regular monitoring of response in order to establish effectiveness and
optimize dosing.11
Clinical assessment of interventions also relies on serial liver biopsies. Liver biopsy remains
associated with a (small) morbidity and mortality and is prone to sampling error. It may not be
an appropriate way of monitoring in a dynamic situation like a clinical trial. A panel of serum
fibrosis markers has been developed which can be used to predict the stage of fibrosis and
monitor disease progression or resolution without repeated liver biopsies. 53
Acetaldehyde is a toxic product of the metabolism of alcohol. Acetaldehyde will form a
conjugate, both in vitro and in vivo, with the compound cysteinylglycine. Cysteinylglycine is
derived from an antioxidant that plays a role in protecting the liver from alcohol-induced injury.
The significance of the present finding is two-fold: first, the conjugation of acetaldehyde and
6.14-16
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
cysteinylglycine may act as a means of scavenging the potentially toxic acetaldehyde; and
second, the conjugate could potentially serve as a marker of alcohol consumption. 54
2.3.6
Comorbidities Associated with Alcohol Abuse and Dependence
The term "comorbidity" refers to the presence of any two or more illnesses in the same person.
With respect to treatment, persons exhibiting comorbid alcohol-related and medical or
psychiatric disorders often fall through the cracks of the health care system because of
administrative distinctions among addiction, medical, and mental health-related services.
Patients are often forced to choose between clinical settings, often resulting in neglect of one
condition. Alcoholism and other disorders might be related in a number of ways, including the
following: 1) Alcoholism and a second disorder can co-occur, either sequentially or
simultaneously, by coincidence. 2) Alcoholism can cause various medical and psychiatric
conditions or increase their severity. 3) Comorbid disorders might cause alcoholism or increase
its severity. 4) Both alcoholism and the comorbid disorder may be caused, separately, by some
third condition. 5) Alcohol use or alcohol withdrawal can produce symptoms that mimic those
of an independent psychiatric disorder.
Aside from the liver conditions that we focus on in this report, other medical conditions are
associated with excessive alcohol use. i Alcohol-induced heart damage appears to increase with
lifetime dose of alcohol. Alcohol can damage the brain in many ways and the most serious effect
is Korsakoff's syndrome, characterized in part by an inability to remember recent events or to
learn new information. The incidence of alcohol-related brain damage is approximately 10
percent of adult dementias in the United States. Milder attention and memory deficits may
improve gradually with abstinence. Alcoholics are far more likely to also have a diagnosis of
antisocial personality disorder, drug abuse, mania, and schizophrenia as compared with
nonalcoholics. Eating disorders are also associated with alcoholism. Between 33 and 83 percent
of bulimics may have a first-degree relative suffering from alcohol abuse or alcoholism. Studies
indicate that approximately 10 to 30 percent of alcoholics have panic disorder, and about 20
percent of persons with anxiety disorders abuse alcohol. Among alcoholics entering treatment,
about two-thirds have symptoms that resemble anxiety disorders. Alcoholics are 35 times more
likely than nonalcoholics to also use cocaine. Similar odds ratios for other types of drugs are:
sedatives, 17.0 times; opioids, 13.0 times; hallucinogens, 12.0; stimulants, 11.0; and marijuana
and related drugs, 6.0. Surveys of both clinical and nonclinical populations indicate that at least
90 percent of alcoholics are nicotine dependent.
3.
What is the Control Strategy?
3.1
Remediation of Alcohol Dependence
Remediation of alcohol dependence has been the primary control strategy but it remains a
great challenge for many reasons. Disulfiram (antabuse), an inhibitor of acetaldehyde
dehydrogenase, has been used for many years in the management of alcohol-dependent
For earlier reviews see the following references: Urbano-Marquez A.; Estruch, R.; Navarro-Lopez, F.; Grau,
J.M.; Mont, L.; & Rubin, E. The effects of alcoholism on skeletal and cardiac muscle. New England Journal of
Medicine 320(7):409-415, 1989; Berman, M.O. Severe brain dysfunction: Alcoholic Korsakoff's syndrome. Alcohol
Health & Research World 14(2):120-129, 1990; DeSoto, C.B.; O'Donnell, W.E.; & amp; DeSoto, J.L. Long-term
recovery in alcoholics. Alcoholism: Clinical and Experimental Research 13(5): 693-697, 1989; Kaye WH,
Gwirtsman, H.E.; George, S.R.; Weiss, S.R.; & Jimerson, D.C. Relationship of mood alterations to bingeing
behaviour in bulimia. British Journal of Psychiatry 149:479-485, 1986; Ross HE, Glaser, F.B.; & Germanson, T. The
prevalence of psychiatric disorders in patients with alcohol and other drug problems. Archives of General
Psychiatry 45:1023-1031, 1988; Helzer JE & Pryzbeck, T.R. The co-occurrence of alcoholism with other psychiatric
disorders in the general population and its impact on treatment. Journal of Studies on Alcohol 49(3):219-224, 1988;
Bobo JK. Nicotine dependence and alcoholism epidemiology and treatment. Journal of Psychoactive Drugs
21(3):323-329, 1989.
i
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
patients. It induces an adverse reaction to alcohol intake characterised by nausea. In general, the
consensus appears to be that disulfiram is not a very effective therapy for most alcoholics. 55
It has been known for many years that useful pharmacological agents in humans and animal
models include the opioid receptor antagonists naloxone and naltrexone, 56 calcium channel
blockers, 57 dopaminergic agents,58 serotonin antagonists, 59 serotonin uptake inhibitors, 60 and
GABA-altering drugs. 61
Naltrexone has been approved by FDA as an adjunct to psychosocial treatment for alcoholism.
In light of the extensive research into the neurochemical basis for alcohol addiction, it is curious
that more approved interventions are not available. Perhaps this is because alcohol-seeking
behavior is complex and involves several neurotransmitter systems, so perhaps a range of
medications can modify drinking behaviour. Naltrexone is a ß-endorphin antagonist and has
been extensively studied for alcohol dependence since the early 1990s. The use of targeted
naltrexone therapy combined with brief psychotherapeutic management may become an
important strategy for reducing excessive alcohol use.
Acamprosate (calcium acetylhomotaurine)—a structural analogue of GABA—has been used in
Europe for almost 20 years and has consistently been found to be significantly better than
placebo in reducing both drinking frequency and cumulative drinking days. The drug is thought
to restore glutamatergic-mediated inhibitory and excitatory neurotransmission in the nucleus
accumbens (NA). The majority of acamprosate studies have reported positive effects over
placebo for abstinence, relapse, and percentage of nondrinking days.
The FDA in May 2002 rejected acamprosate for use in the US. The drug is being tested in
combination with naltrexone in the Combining Medications and Behavioral Interventions Study
(COMBINE)ii, a large, double-blind, multisite study . Substantial evidence suggests continued
evaluation of acamprosate.
3.2
Alcoholic Liver Disease (ALD)
3.2.1
Alcoholic Hepatitis (AH)
Cessation or a marked reduction in alcohol intake has been shown to improve the survival of
patients with all stages of ALD. 62 63 Thus, measures to establish and maintain abstinence are a
critical component of the management of patients with ALD. As an alternative, or preferably
as an addition, to psychological therapies, some patients may derive benefit from
pharmacological therapy. Some patients with AH can progress to cirrhosis even with
abstention, 66 and patients with coexisting AH and cirrhosis have a worse long-term survival
than patients with cirrhosis only. 64 This suggests the need for longer-term treatment trials in
patients with AH.
Progress in developing specific treatments for acute AH has been hampered by a poor
understanding of disease pathogenesis. Animal models suggest that AH occurs as a result of
oxidative stress and cytokine release. 65 66 However, evidence for these mechanisms
in humans is either absent or, at best, indirect.
After more than 12 randomized controlled clinical trials and meta-analyses on this topic,
consensus is lacking regarding the use of corticosteroids. 67 68 Although several similarly
designed, well-conducted studies showed that corticosteroids reduced mortality in patients with
alcoholic hepatitis, 69 a large study 45 failed to show a survival benefit of corticosteroids in
ii
Combine Study Research Group. Testing combined pharmacotherapies and behavioral interventions for alcohol
dependence (the COMBINE study): a pilot feasibility study. Alcohol Clin Exp Res. 2003;27:1123-1131.
6.14-18
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
patients with moderate and severe alcoholic hepatitis. 70 Thus, the efficacy of corticosteroids is
controversial. Two potential side effects of steroids used in medium/high dose include poor
wound healing and increased susceptibility to infection. This highlights the need for
alternative therapies for AH.
3.2.1.1 TNF-alpha
Immune cells from patients with AH produce tumor necrosis factor alpha (TNFa) and at higher
levels than controls and serum levels are high on admission to hospital and correlate with
mortality.71 Experimental evidence suggests that TNFa and other cytokine pathways signaling
cell death are critical in initiating and/or perpetuating alcohol-induced liver injury.72 TNFa may
have a critical role in the pathogenesis of liver injury associated with alcoholic hepatitis. 73 As a
result, investigators have studied the role of antibodies to TNFinjury caused by chronic exposure to alcohol in experimental animal models. 74 The anti- TNFa
antibody, infliximab, binds to TNFa and blocks its biological effects. To date, we were unable to
find randomised controlled trials of infliximab in patients with AH. 75 Large randomized
controlled studies are required to determine which patients benefit most from treatment, the
important adverse effects and the optimal duration of therapy.
3.2.1.2 Oxidative Stress and Hepatocyte Membrane Injury
There is some evidence implicating oxidative stress as a key mechanism in alcohol-mediated
hepatotoxicity. Reactive oxygen containing species are the superoxide anion, hydrogen
peroxide and hydroxyl and hydroxyethyl radicals, the latter arising during ethanol
metabolism.76 Several recent trials using antioxidant supplementation in AH have shown no
survival benefit. Specifically, to reduce hepatic oxygen consumption, investigators have
examined the role of propylthiouracil in patients with alcoholic hepatitis. Although a
randomized controlled trial showed clinical benefit, follow- up studies have been inconclusive.77
Propylthiouracil is also hepatotoxic so the drug remains experimental.
The first randomized controlled trial of pentoxiphylline was reported in 2000 in AH and led to a
40% reduction in mortality compared to placebo. 78 Pentoxiphylline reduces TNFa gene
transcription and, accordingly, to reduced levels of important downstream TNFa effectors
including other pro-inflammatory cytokines.81 Comparisons should be made with steroids and
placebo (in patients in whom steroids are contraindicated) and trials of pentoxiphylline in
combination with steroids in order to find the most efficacious treatment.
3.2.1.3 Liver Dialysis
A further experimental therapy that may benefit patients with AH is liver dialysis, although it is
marketed under the name “molecular adsorbents recycling system” (MARS). The primary aim of
this treatment is to support impaired liver function while the liver recovers or the patient
undergoes liver transplantation. It may, therefore, have a role in patients with AH either alone
or in combination with other pharmacological therapies. The principal of the MARS procedure is
to dialyse blood against an albumin solution aimed at removing albumin-bound toxins
including bilirubin and bile salts. To date, only small series of patients with AH have been
treated with this procedure. 79 However, clinical improvement has been reported in these cases
and further randomized trials are important.
In summary, many treatment modalities have been tried in patients with AH, however, few
have been consistently shown to have a beneficial effect and, accordingly, none have achieved
consensus status among practising hepatologists. Opportunities exist for comparative clinical
trials, possibly with a combination of agents. Current therapy still focuses predominantly on
supportive care.
3.2.2
Alcoholic Cirrhosis
Current treatments for cirrhosis are limited. One can remove underlying injurious stimulus
(where possible); eradicate existing viruses using interferon, ribavirin, and lamivudine in viral
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
hepatitis; and transplant the liver. The high mortality of severe AH is coupled with the
relatively young age of many of the patients and this makes it an important area for therapeutic
trials. However, the vast majority of patients with ALD in clinical practice have advanced
fibrosis or cirrhosis. Unfortunately, as with AH, no adjunctive pharmacotherapies have been
consistently shown to improve survival in more than one randomized controlled trial, although
some have shown promise Table 4 is reproduced directly from Table 4 of reference (24).
3.2.2.1 Anti-oxidants
Human trials have evaluated the drug silymarin, which is the active component of the herb
milk-thistle and has potent antioxidant properties. 80 Results are conflicting.
Evaluation of S-adenosyl-L-methionine (SAMe) acts as both an antioxidant and maintains cell
membrane fluidity. It has been evaluated in patients with alcoholic cirrhosis. Using death or
liver transplantation as a combined end-point, there was a significant beneficial effect of SAMe
treatment in patients with cirrhosis. 81
3.2.2.2 Propylthiouracil (PTU)
This compound may improve the long-term survival of patients with alcoholic cirrhosis. There
has, however, been only one trial reported thus far. 82 PTU has not been widely adopted by the
liver community.
3.2.2.3 Colchicine
This anti-inflammatory drug has been evaluated in the treatment of patients with alcohol and
non-alcohol-related cirrhosis because of its anti-fibrotic effects.83 To date, clinical results have
been conflicting. A recent meta-analysis has also reviewed 14 randomised controlled trials and
found no benefit of colchicine treatment on mortality or liver histology. 84
3.3
Transplantation
Transplantation is a highly successful treatment, particularly for end stage cirrhosis, with a 75%
five year survival rate. But limited availability of organs, growing lists of patients needing a
transplant, cost, issues of compatibility, and comorbid factors mean that not everyone is eligible
for transplantation. As a result, effective antifibrotic treatments are needed urgently. (See below)
Alcoholic liver disease is currently the second most common indication for liver transplantation
in the United States. Patients who undergo transplantation because of alcoholic liver disease
have excellent survival rates. 85 At present, most transplant centers require patients to have 6
6.14-20
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
months of abstinence and appropriate addiction treatment before they can undergo liver
transplantation. Patients with active alcoholic hepatitis are not candidates for liver
transplantation because of their lack of demonstrated abstinence and high perioperative
mortality. Most studies suggest that alcohol relapse after transplantation occurs in 15% to 30% of
patients. 86
Transplantation for ALD remains controversial, principally due to concerns over the risk of posttransplant recidivism and its effect on outcome and public opinion at a time of increasing donor
shortage. This issue is coupled with a perception that these patients are more likely to have
contraindications to transplantation - due either to non-liver complications of alcohol abuse or to
a lack of self-care. This may contribute to reluctance of many centers to offer transplantation to
patients with ALD.89 There is no evidence that patients with ALD have a higher frequency of
post-operative complications compared to patients transplanted for other indications. 87 The
improvement in quality of life following transplantation also compares favorably with other
indications in the short-term, although not after 3 years follow-up.88 The reason for this decline is
unclear but does not seem to be related to a return to problem drinking. 24 Studies that have
considered any alcohol use after transplantation as a ‘relapse’ have reported recidivism rates as
high as 49% 89 while those that have restricted the definition to heavy or problem drinking have
reported lower rates of 10–15%. 90
Beyond 5 years, patients transplanted for alcohol-induced liver cirrhosis are doing less well.
They die from cardiorespiratory problems and from tumours. The relative rate of cancers 5 years
after liver transplantation for alcohol-induced liver disease is 25% for oesophageal cancers and
4% for lung cancers.90 The frequency of oropharyngeal cancers after liver transplantation in
patients with alcohol-induced liver disease was 17% compared with 0% in patients transplanted
for other indications. 90 Organ shortage is a significant problem and the decision to be an organ
donor remains voluntary in most European countries. A recent UK study demonstrated that,
when compared to other patient groups, the general public, primary care physicians and even
gastroenterologists, all place patients with ALD well down their list of patients most deserving a
liver transplant. 91 The perception that patients with ALD have played a significant role in their
disease and the widely held belief that, ‘once a drinker always a drinker’ seem likely to be the
most important factors contributing to this negative view of ALD patients. Transplantation for
alcoholic liver disease will remain a complex issue.
4.
What is Known of the Affordability, Feasibility, and
Sustainability of the Control Strategy?
4.1
Economic Burden
Alcohol significantly affects the lives of many people in Europe through profits from alcohol
production and trade as well as employment, salaries or other revenues to distillery and
brewery workers, to wine farmers, to waiters and shopkeepers, and to producers of raw
materials and other equipment to the alcohol industry and trade. For instance, it has been
estimated that in 1990 the production and trade of alcoholic beverages provided directly or
indirectly employment to nearly three million people or to about 2.0 per cent of the civilian
employment in the 12 member states of the European Communities (EC). 15 In 1992, the top six
alcohol exporting countries were France, the United Kingdom, Italy, Germany, Spain and the
Netherlands. 15 Alcohol consumption is also socially and culturally deeply embedded in the
daily lives of most Europeans.
The precise estimation of the cost of alcohol abuse and its medical consequences as ALD is the
subject of methodological debate, as the many costs related to alcohol abuse and ALD can not be
measured directly. Indirect costs of liver disease, namely economic loss as a result of premature
death, illness, and disability associated with liver disease, are substantial, as liver disease tends
6.14-21
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
to affect people in their most productive phase of life. It has been calculated that the cost of
alcoholism in Europe, in terms of lost production and cost of medical services, represents
between 2% and 6% of Gross National Product, depending on the country. 15 In the United
States, the total economic burden (direct and indirect costs) imposed by alcohol abuse as a
proportion of total health care expenditure is a remarkable 16.6 percent. 92
4.2
Feasibility of Control Strategy
Detoxification, with or without pharmacotherapy, is the first step of treatment. The major
behavioral approaches currently used in alcoholism treatment include cognitive-behavioral
therapy, motivational enhancement therapy, and Alcoholics Anonymous (AA) or related 12step programs. 6 Clinical studies, have compared the effectiveness of these approaches. Overall,
most studies detect no significant differences among the three treatments in patient outcome,
although certain treatment methodologies may be most appropriate for patients with certain
characteristics. 6 Pharmacotherapy with aversive or anti-craving medications may supplement
behavioral treatment approaches. Prevention requires concerted effort with regard to diet,
lifestyle, diagnosis, costs and access. 6
Cure of alcohol dependence is not possible at present as it requires intensive basic and applied
research into the genetic and metabolic mechanisms.
The overall picture of alcohol as causing considerable global burden of disease will continue
going forward, if the current levels and patterns of alcohol consumption remain stable.
Nonetheless, most of the disease burden attributable to alcohol could be prevented
immediately. It has been asserted that, if alcohol disappeared in the next year, all acute
alcohol-related disease consequences would disappear completely (40% of the overall disease
burden- See Table 1), as well as marked portion of chronic disease. Of course, the total
disappearance of alcohol is not realistic. Thus, although there is no justification for the
alcohol related disease burden continuing to stay at this high level, actually altering this
burden is problematic. The moderate consumption patterns of, for example, Southern Europe,
seems to have been the result of long cultural formations, which are not easily transposed
into other cultures. 93
5.
Why Does the Disease Burden Persist?
The burden persists for the following reasons: 1. The difficulty in changing large scale alcohol
consumption patterns; 2. The lack of effective therapies; 3. The high mortality rate of patients
with alcoholic hepatitis and alcoholic cirrhosis; 4. No accurate, accessible, available and
acceptable test that can predict such susceptibility, which weakens any primary and secondary
prevention initiatives we may wish to undertake.
Overall volume of drinking plays a major role in the extent of alcohol problems, both at
individual and at population levels. 23 It may be possible to imagine a population with a net
gain in health from drinking – a population with a low per capita consumption, with alcohol
consumed frequently but only in small amounts – but no such national population has been
identified in the real world. On the basis of patterns of consumption in real national populations,
an increase in the volume of drinking will result in net losses in terms of years of life lost to
death and disability.
By and large, the policy options which are politically easiest to implement in young people
(alcohol education, alcohol public information campaigns, providing alternatives to drinking)
have not been shown to be very successful. 94
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
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There are also limitations in our knowledge about the distribution of exposure, especially with
respect to pattern of drinking in regions other than established market economies. In addition,
there are limitations in our knowledge regarding the establishing causal relationships between
alcohol consumption and various disease categories.
6.
What Can Be Learnt from Past/Current Research into
Pharmaceutical Interventions for this Condition?
6.1
Dependence
Advances in neurobiology support the development of medications to treat alcoholism by
modifying the activity of specific chemical messengers (i.e., neurotransmitters) in the brain.
These include opioid antagonists, specific glutamate antagonists, selective serotonin reuptake
inhibitors and dopamine antagonists, 5HT3 receptor antagonists.
The practical effectiveness of these, and any pharmacological intervention, may be compromised
by poor patient compliance and other factors. It is important to investigate whether use of
specific medications in combination can further enhance their effectiveness. Additional research is
needed to determine how medications interact with different psychosocial factors and
treatments.
However, many of these compounds, in addition to reducing alcohol intake, may suppress
appetite or have other undesirable effects. Thus, the development of suitable medications with
greater selectivity toward excessive alcohol intake remains a major goal. Understanding the
neurobiological basis of the actions of these interventions in human alcoholics, perhaps with
new imaging technologies is also important.
The high mortality of severe AH, highlights the need for better therapy and our increased
understanding of the precise mechanisms of ethanol-induced liver injury and there are now
several promising therapeutic modalities. In contrast, little progress has been made towards the
development of specific pharmacotherapy for advanced fibrosis and cirrhosis. Potential reasons
for the lack of progress in cirrhosis thus far include: (a) a lack of a clear understanding of disease
pathogenesis; (b) problems with compliance in long-term treatment trials; and (c) the
confounding effect of drinking behavior during the duration of the trial. As a result, at present
the management of patients with advanced fibrotic ALD is directed primarily at preventing and
treating the complications of portal hypertension, liver failure and hepatocellular carcinoma and
deciding if and when to consider patients for orthotopic liver transplantation. 24
In short, no safe and effective liver anti-fibrotic therapies are on the world market due in large
part of the inability of most drugs to inhibit excessive fibrosis in the liver without
simultaneously affecting the production of beneficial and needed fibrotic mechanisms in other
parts of the body. Novel therapies to inhibit and reverse fibrosis remain the ultimate goal to treat
liver cirrhosis.
6.2
Liver Regeneration
Alcoholic hepatitis is characterized by death and injury of hepatocytes so that it seems rational
to develop therapies to stimulate proliferation of hepatocyte mass. This concept has been
examined in patients with alcoholic hepatitis by treating them with insulin and glucagons,
which is thought to stimulate liver regeneration. 95 However, the results have been discouraging,
and cases of severe hypoglycemia have dimmed enthusiasm for this approach. In advanced liver
disease such as cirrhosis, the liver is unable to regenerate itself enough. Researchers are looking
at various means, including use of adult bone, blood or liver stem cells and growth control
proteins (e.g., cyclins, cyclin-dependent kinases) to stimulate growth. 96
6.14-23
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
The number and kind of presently-used therapeutic interventions (See Tables above) is
significant in that there is a gap between these few interventions and the large amount of
basic research into potential targets for ALD.
7.
What is the Current “Pipeline” of Products that Are to Be Used
for this Particular Condition?
7.1
Alcohol Dependence
7.1.1
Opioid Antagonists
An oral form of the antagonist nalmefene (an injectable, marketed as Revex® for reversing the
effects of opioid anesthetics) has been shown to increase abstinence in a preliminary placebocontrolled, double-blind study of 105 alcoholics. 97 Nalmefene is also less likely than naltrexone
to produce the adverse side effect of liver damage. Consequently, large-scale clinical trials of
nalmefene in alcoholic populations would be important but we found none in the USA database.
Further animal and human studies are needed. Nalmefene has a longer half-life (about eight to
12 hours) and possesses a greater protein binding ability than naltrexone. The dose and optimal
duration of therapy for nalmefene have not yet been established.
7.1.2
Serotonergics
Selective serotonin reuptake inhibitors (SSRIs): Serotonin 5-HT1A receptors may be associated
with alcohol consumption and the development of tolerance, 5-HT2 receptors have been found
to contribute to reward, and 5-HT3 receptors are linked to the development of reinforcement. 98
Results of clinical trials using SSRIs have been mixed as most double-blind, placebo-controlled
studies using SSRIs have not reduced drinking or any other measures of alcohol dependency.
However, there is good evidence that fluoxetine may reduce heavy drinking in depressed
alcoholics. 99
Serotonin 5-HT3 antagonists: Ondansetron, an anti-emetic, may be a treatment for the same
biologically predisposed subtype (type B) that does not respond to SSRIs. Ondansetron, which
has functionally opposite effects to SSRIs, blocks serotonin. While further evidence is needed,
early studies suggest ondansetron could provide important adjunctive treatment for a particular
alcoholic subgroup. In one study, the early-onset alcoholics taking a subtherapeutic dosage of 4
mg/kg twice daily of ondansetron reported a lower cumulative percentage of drinking days than
placebo, again suggesting the existence of subtypes of alcoholics. Another mode of
administration, such as using an oral solution, has also demonstrated value in the treatment of
early-onset alcoholic patients. 100
Serotonin agonists: Buspirone is primarily a 5-HT1A partial agonist that exhibits anxiolytic
properties. Interpretations of the results of trials using buspirone have been inconclusive due to
preexisting mood and anxiety disorders. In an attempt to control for these disorders, a doubleblind placebo-controlled trial comparing buspirone and lithium to placebo was performed but
the results suggested that neither lithium nor buspirone was superior to placebo. 101
7.1.3
Dopaminergics
Haloperidol, tiapride, olanzapine, and clozapine have all demonstrated various degrees of
usefulness in reducing alcohol consumption or increasing abstinence. 102 To date, the use of
these drugs has been limited by their side-effect profiles (eg, haloperidol and tiapride by
neurological movement disorders, olanzapine by weight gain, and clozapine by
agranulocytosis). Dopamine's importance in the addiction process suggests a need for further
studies using dopamine antagonist medications with more modest side-effect profiles.
6.14-24
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
7.1.4
Other Interventions
Topiramate is an FDA-approved antiepileptic thought to have multiple mechanisms of action,
including enhanced GABA(A) inhibition. In a double-blind placebo-controlled trial, patients
taking topiramate reported having significantly fewer drinks per day and per drinking day,
significantly fewer drinking days, significantly more days of abstinence, and significantly less
craving than the placebo arm. 103 Coadministration with other medications such as naltrexone
and/or acamprosate, ondansetron, or SSRIs may produce enhanced efficacy outcomes,
particularly for various subtypes of alcoholic patients.
Naltrexone has been administered with ondansetron in early-onset alcoholic patients. In an
eight-week, double-blind, placebo-controlled trial, the combination was found to significantly
reduce drinks per day and per drinking day and had a positive effect on the percentage of days
abstinent compared to placebo. 104 In late-onset alcoholics, evidence suggests that sertraline may
provide some reduction in alcohol use. Furthermore, certain drugs may be more effective at
particular points of the dependence cycle, such as topiramate for abstinence initiation. 105
7.2
Alcoholic Liver Disease
There are a large number of potential interventions that might be used to modulate the course of
fibrosis in alcoholic liver disease, particularly in the latter states of hepatitis and cirrhosis 106 (See
Table 6).
Table 6: Possible therapeutic interventions in liver fibrosis in progressive or established fibrosis
based on laboratory/academic research and animal models.
Inflammation
 Removal of injurious agent
 Interleukin-10—anti-inflammatory effect
 Tumour necrosis factor _ inhibitors—anti-inflammatory effect
 Antioxidants—suppress fibrotic response to oxidative damage
Stellate cell activation
 Interferon gamma (or interferon alfa)—inhibits activation of hepatic stellate cells
 Hepatocyte growth factor—inhibits activation of hepatic stellate cells
 Peroxisome proliferator-activated receptor ligand—reduces activation of hepatic stellate
cells
Perpetuation of stellate cell activation
 Transforming growth factor -1 antagonists—reduce matrix synthesis and enhance matrix
degradation
 Platelet derived growth factor antagonists—reduce proliferation of hepatic stellate cells
 Nitric oxide—inhibits proliferation of hepatic stellate cells
 Angiotensin-converting-enzyme inhibitors—inhibit proliferation of hepatic stellate cells
Inhibitors of Stellate cell secretion of collagen rich matrix
 Angiotensin converting enzyme inhibitors—reduce fibrosis
 Polyhydroxylase inhibitors—reduce experimental fibrosis
 Interferon gamma—reduces fibrosis
 Endothelin receptor antagonists—reduce fibrosis and portal hypertension
To enhance or initiate resolution of fibrosis
Stellate cell apoptosis
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency


Gilotoxin—causes apoptosis of hepatic stellate cells
Nerve growth factor—causes apoptosis of hepatic stellate cells
Degradation of collagen rich matrix
 Metalloproteinases—enhance activity of metalloproteinases
 Tissue inhibitor of matrix (TIMP) antagonists—enhance activity of metalloproteinases
 Transforming growth factor _-1 antagonists—downregulate TIMPs and increases activity
f metalloproteinases
 Relaxin—downregulates TIMPs and increases activity of metalloproteinases
There seems to be a mismatch between the potential targets for ALD (particularly in its latter
stages as evidence by Table 6) and the actual number of compounds tested in the regulatory
system (Table 7) as inferred from information on clinical trials. Clinical trial information
probably provides a reasonably up to date and reliable source in this regard. We reviewed
information on 2004 US clinical trials on the NIH website 107 devoted to clinical trials using the
search term “alcoholic liver disease”, “liver fibrosis”, or “cirrhosis”. We found are no industrysponsored clinical trials for interventions designed to eliminate alcohol dependence in this
database (Annex 6.14.1). We also repeated the search using another clinical trials database,
which includes some UK trials (www.controlled-trials.com) and found similar results. We note
the presence of a new EU clinical trials database (www.eudract.emea.eu.int ) which came into
force on 1 May 2004 wherein all clinical trials on medicinal products for human use that takes
place in the 25 EU states must be registered. However, the information submitted will be
confidential and only national and EU regulatory authorities as well as the EC will be able to
find out what trials are going on.
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Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
Table 7 : Clinical trials related to alcoholic liver disease, liver fibrosis, alcoholic hepatitis,
cirrhosis, fibrosis
Condition
Sponsor
Phase
Treatment
NIDDK
II
Pirfenidone
Pulmonary
fibrosis
Lung
scleroderma
NHLBIb
II and III
Oral bosentan
NHLBI
III
Childhood
hepatic cirrhosis
Systemic
Sclerosis
NCRR
Cyclophosphami
de
azathioprine
Colchicine
Kidney fibrosis
Nonalcoholic
Steatohepatitis
(NASH)
c
Genzyme/
Cambridge
Antibody
Technologies
NIDDK
I
I and II
Anti TGF beta 1
monoclonal
antibody
II
metformin
Methrotrexate/ur
sodiol vs,
methotrexate/colc
hicine
Interferon
gamma 1b
Primary biliary
cirrhosis
NCRR and
NIDDK
III
Liver Fibrosis
InterMune
II
Primary biliary
cirrhosis
NIDDK
III
Primary biliary
fibrosis
NASH
NIDDK
NIDDK
OTHERS
Idiopathic
pulmonary
fibrosis
NOTES
Patients
with
glomerulosclerosis
Trial Sitesa
1 state (25)
International
1 state (15)
4 states
NASH
associated
with
diabetes
1 state (30)
2 states (405)d
In HCV
patients
only
(500)
11 states
I
Ursodiol/methotr
exate vs.
methotrexate
budesonide
II
Pioglitazone
(60) d
(50)
North America
InterMune
III
InterMune
II
InterMune
I and II
Interferon
gamma
and EU (600)
Pirfenidone
Kidney disease in
diabetics
Pirfenidone
(120)
a. Proposed or actual enrollment (in parenthesis).
b. National Health, Lung, and Blood Institute
c. National Center for Research Resources
d. Several different phase I, II or III trials combined
Treatment will remain a challenging task, however, and thus far no drugs are approved as
liver antifibrotic agents in humans. 24 Therapies will need to be well tolerated over decades,
with good targeting to liver and few adverse effects on other tissues. The liver offers a unique
6.14-27
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
advantage as a target for orally administrated agents, since those with efficient liver “ extraction
“ will have, in principle, agents targeted directly to the liver since systemic distribution will be
minimized. Combination therapies may prove synergistic rather than additive, but agents must
first be tested individually to establish safety and ‘proof-of-principle’.
It is uncertain whether antifibrotic therapies will require intermittent or continuous
administration.24 Testing of antifibrotic agents in clinical trials presents unique challenges, since
efficacy cannot be simply assessed by a serum test such as viral load, and, moreover, a clinical
benefit may only be apparent after a prolonged period of treatment. In contrast, for example,
trials of antiviral medications for HCV, can obtain evidence of efficacy within weeks or months
by a simple blood test assessing viral load. Additionally, there are no established serum markers
that can substitute for obtaining tissue, obligating investigators to perform percutaneous liver
biopsies at the onset and completion of therapy, which limits attractiveness to patients. 24
7.3
“Spillovers” from the Hepatitis C pipeline and Other Fibrotic Conditions
Possibly for these reasons, the contrast between the “liver fibrosis” pipeline and the drug
pipeline directed to liver diseases resulting from chronic hepatitis infections is telling. The
medical need and the potential market for a liver-specific anti-fibrotic agent will be large and
this appears to be driven in large part by the market for hepatitis, not alcoholic liver disease.
Most of the impetus for developing useful anti-fibrotic therapies for ALD could, in principle,
be developed as “spillover” from research into chronic hepatitic C.
Nearly 200 million people worldwide are affected by HCV infection and although antivirals are
generally effective, we emphasize that there are no approved therapeutic interventions to delay
or reverse liver fibrosis associated with HCV. iii Drugs for the treatment of chronic HCV
infection are estimated at present to cost $4 billion per year and the HCV market is expected to
rise.108 We note that as of early 2003, there were 29 compounds either in preclinical development
or in clinical trials for hepatitis.109 The overall annual market for anti-fibrotic drugs (excluding
those used to treat liver fibrosis caused by HCV as well as ALD) could easily be in excess of the
existing several billion dollar hepatitis C market . We have not, however, investigated the public
and private markets for these other, non-liver fibrotic conditions (e.g., cystic fibrosis,
sarcoidosis, idiopathic pulmonary fibrosis, scleroderma).
Liver fibrosis is a paradigm for wound healing in other tissues in the body such as the lung and
kidney as it involves analogous cells and cell mediators. Thus, there is a large “research gap”
between academic research into fibrotic conditions and translation into clinical, and even
pre-clinical research into anti-fibrotic interventions to treat alcoholic liver disease. Whatever
“spillover’ effects exist between anti-fibrotic interventions for hepatitis and anti-fibrotic
interventions for ALD remain hidden to us.
The anti-viral agent interferon, may reverse fibrosis in hepatitis infection. See Dufour J-FJ & Kaplan MM. 2004.
The Antifibrotic effect of Interferon alpha in the treatment of chronic hepatitis C: An unanticipated but important
endpoint, at The Hepatitis Assocation, at http://www.hepcassoc.org, last accessed 8 May 2004.
iii
6.14-28
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
8.
What is the Current Status of Institutions and Human Resources
Available to Address the Disease?
8.1
Public Funding
Overall, there is an imbalance between the severity and magnitude of alcoholic liver diseases
and the amount of money spent on research.
8.1.1
European Sources of Funding for Alcoholic Liver Diseases: Selected Countries
8.1.1.1 United Kingdom
The level of research into the epidemiology, aetiology and treatment of alcoholic liver disease is
not consistent with funding for research in the EU overall and in the US. Much of the research
currently undertaken deals with addictions and is psychosocial in nature, which although very
relevant is not the totality of requirement. The UK Medical Council on Alcohol has a large
clinical trial on psycho-social interventions. Basic research on alcoholic liver disease and fibrosis
is being funded by the Wellcome Trust.
There are several UK clinical trials devoted to various fibrotic conditions, none of them are for
liver fibrosis. The National Health Service has a Phase II clinical trial directed to use of
Combivir® for treating primary biliary cirrhosis, the UK Cancer Research Center has a trial on
use of pentoxiphylline and alpha-tocopherol to treat radiation-induced fibrosis.
The UK counterpart of the National Institutes of Health, the Medical Research Council (MRC) is
sponsoring a clinical trial on use of steroids to treat pulmonary fibrosis. We note the MRC has a
research collaboration with the Japanese company Teijin to find novel drug targets for kidney
and lung fibrosis, although this has been operative for several years without an apparent “hit”
and liver fibrosis in apparently not specifically included in the research.
The Foundation for Liver Research (based in the Royal Free & Union College, London) is
supporting development of the above identified liver dialysis (MARS) technology at a level of
about $4 million USD.
8.1.1.2 European Union
Within the EU for 2004, the following areas of work have been identified as “priority areas”:
health determinants: tobacco; alcohol; drugs; nutrition and physical activity; sexual and
reproductive health; mental health; injury prevention; environmental health determinants;
socioeconomic determinants of health; health promotion in particular settings; training in public
health; disease prevention, in particular cardiovascular diseases, cancer and diabetes. The
financial envelope of the public health program for the period 2003-2008 is € 312 million. The
budget available for 2004 is about € 61 million. Thus, it appears that the EU has made alcohol
research a priority in terms of Public Health but how this is to be implemented, and whether
pharmacological interventions are part of this priority is far less clear.
The Health and Consumer Protection Directorate of the EC has funded several alcohol-related
projects funded under its Health Promotion Program- all directed to psychosocial interventions.
Other initiatives are of interest in this regard as well. The WHO supports an Alcohol Control
Databank (European Alcohol Information System. The database is designed primarily to tract
alcohol policies and their implementation.
8.1.2
United States Sources of Funding
The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is the lead U.S. governmental
agency at the NIH for alcohol use and abuse. The NIAAA received about $400 million USD last
6.14-29
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
year. The NIAAA is supporting over a dozen clinical protocols with regard to alcohol abuse and
its sequelae (See Table 7). Its extramural programs include one with Germany (who is
contributing €9 million for three years) on a project dealing with addiction research, but not
therapeutic interventions. In comparison to the total appropriations package for other NIH
research centers, the individual share to the NIAAA is small (Figure 5). The 2004 NIAAA
appropriation is about 4% of the estimated ALD economic burden in the United States ($9 billion
USD in 1998) but a trivial fraction of the direct and indirect economic costs from alcohol abuse.
In contrast, the appropriated funding for diabetes research by the federal agency responsible for
this (NIDDK) is about 1.5% of the annual U.S. diabetes economic burden, and that for cancer
research (NCI) is about 2.5% of the average annual direct and indirect cost of cancer . 110 Unlike
ALD, however, both cancer and diabetes are much better represented in the development
pipeline and do not suffer from apparent neglect by the private sector.
Figure 5
Annual Appropriations for Selected NIH Institutes
4,500,000
National Cancer Institute
4,000,000
National Heart Lung and Blood InstituteI
Approriation (USD)
3,500,000
National Institute of Diabetes,Digestive and
Kidney Diseases
3,000,000
NIAAA
2,500,000
2,000,000
1,500,000
1,000,000
500,000
0
1
2
3
4
5
6
7
8
9
10
11
Year (1=1995)
8.2
Private Sector Funding
We have no information on EU private sector funding for alcoholic liver diseases.
With regard to the U.S., in the short term at least there appears to be a shortage of U.S. private
research funding specifically directed to alcoholic liver diseases.
Maxim Pharmaceuticals is a small biotechnology company that is developing histamine
dihydrochloride (Ceplene(TM)) to prevent alcohol-induced damage in rodents. According to
their website (http://www.maxim.com) this compound has been tested in “ … 17 completed or
ongoing clinical trials in 20 countries, including four Phase 3 clinical trials …” . We can only
infer that these trials are not directed to alcoholic liver disease as this compound has not been
found on the U.S. clinical trials database (www.clinicaltrials.gov) . Maxim and the National
Cancer Institute are, however, engaged in trials for histamine dihydrochloride to treat metastatic
kidney cancer and liver cancer.
InterMune- This company in in clinical trials with a formulation of interferon gamma-1b for
HCV patients with liver fibrosis but not in alcoholic patients with liver fibrosis. Its compound
6.14-30
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
pirfenidone ( 5-methyl-1-phenyl-2 (1H) pyridine)) has received Orphan Drug approval for
pulmonary fibrosis (http://www.corporate-ir.net/ireye/ir.html).
Biomedicines Pharmaceuticals- This company in-licenses technology and has licensed omega –
interferon from Boehringer Ingelheim to test in hepatitis and fibrosis/cirrhosis.
Cambridge Antibody Technologies- This large, publicly traded company has an anti-TNF alpha
monoclonal antibody in U.S. clinical trials.
FibroGen- This is a privately held company with monoclonal antibody used to treat pulmonary
fibrosis which blocks a fibrotic protein (connective tissue growth factor). It is unclear if this
antibody has proceeded beyond Phase I trials.
9.
Ways Forward from a Public Health Viewpoint with Regard to
Public Funding
9.1
Gaps between current research and potential research issues which could
make a difference.
Gaps in Basic and Applied Research
9.1.1
Basic Research
The burden of alcohol-related mortality and morbidity is due to alcohol-related injuries,
malignant cancers, cardiovascular disease and alcoholic liver diseases. Liver fibrosis caused by
alcohol abuse in developed countries alcohol is one of the ten leading causes of disease and
injury. Thirteen percent of all alcohol-attributable deaths are due to alcoholic liver disease.
Stopping drinking has been shown to improve the survival of patients with all stages of ALD.
Many kinds of treatment have been tried in patients with alcoholic hepatitis but few are
consistently beneficial. Current treatments for alcoholic cirrhosis are severely limited. Effective
antifibrotic treatments are needed urgently. There is need for:


New therapeutic interventions for liver fibrosis
New biochemical markers and diagnostics for the variety of alcoholic liver diseases
Transplantation is a highly successful treatment, particularly for end stage cirrhosis, with a 75%
five year survival rate. There is limited availability of organs, growing lists of patients needing a
transplant, issues of compatibility, and co-morbid factors. Alcoholic hepatitis leads to death and
injury of liver cells so research has been directed to stimulating proliferation of hepatocytes.
Results have been discouraging. Researchers are looking at various means, including use of
adult bone, blood or liver stem cells and growth control proteins (e.g., cyclins, cyclin-dependent
kinases) to stimulate growth. There is need for:


9.1.2
More basic research into liver regeneration using stem cells
More basic research into the co-morbidities of alcoholic liver disease (TB, infections,
HCV) and effect of alcohol use on treatment efficacy
Applied Research
The distinction between the “alcoholic liver fibrosis” pipeline and the pipeline directed to liver
diseases resulting from chronic hepatitis infections is telling. The medical need and the potential
market for a liver-specific anti-fibrotic agent will be large and this appears to be driven in large
part by the market for hepatitis, not alcoholic liver disease. Most of the impetus for developing
useful anti-fibrotic therapies for ALD could, in principle, be developed as “spillover” from
research into chronic hepatitic C. Nearly 200 million people worldwide are affected by HCV
6.14-31
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
but, just as in alcohol-derived liver disease, there are no approved therapeutic interventions to
delay or reverse liver fibrosis associated with HCV. There is a need for:



10.
Closing the gap between the targets for anti-fibrotic therapies and the actual number of
anti-fibrotic interventions. Public funding should be directed to translating this basic
research into the clinic and to improve the inefficiencies in going from animal models to
humans.
Encouraging information “spillover” from research on hepatitis-induced liver fibrosis,
lung and biliary fibrosis to research on alcohol-induced liver fibrosis.
Public funds to support clinical trials specifically on ALD
Conclusion
This review highlights the importance of preventing ALD and particularly AH and cirrhosis.
This can be done through a variety of public policy measures, including regulatory, financial
and educational approaches. This is a long-term approach. Due to the strong cultural affinity for
alcohol in Europe, dealing with the sequelae of alcohol abuse will continue to be a significant
challenge. The burden of disease is substantial, the health service costs are increasing and the
therapeutic options are lacking. Liver transplantation, a very expensive treatment option, has
disappointing long term outcomes. There is a need for basic and applied research on all aspects
of this problem. Moreover, blaming the ALD patient for behavior which induced their disease
will not change the reality that these patients consume substantial health service resources and
need more effective treatments.
6.14-32
Chapter 6.14: Alcohol Use Disorders: Alcoholic Liver Diseases and
Alcohol Dependency
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