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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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Table of Contents

Executive Summary....................................................................................4Burden of Disease........................................................................................4Treatment Options.......................................................................................4

1. Introduction.........................................................................................51.1 Alcohol Addiction.................................................................................51.2 Alcoholic Liver Diseases......................................................................6

1.2.1 Alcoholic Fatty Liver...........................................................................61.2.2 Alcoholic Hepatitis..............................................................................61.2.3 Alcoholic Cirrhosis..............................................................................6

1.3 Diagnosis of Alcohol Abuse or Dependence........................................61.3.1 The DSM Criteria................................................................................71.3.2 ICD Criteria.........................................................................................7

2. What Are the Epidemiological Trends for Europe and the World........72.1 General................................................................................................7

2.1.1 Prevalence of Alcohol Abuse...............................................................82.1.2 Prevalence of ALD.............................................................................10

2.2 The European Burden of ALD............................................................102.3 Several Specific Epidemiologic Issues Exist with the Main Types of

Alcoholic Liver Disease......................................................................132.3.1 Immunomodulatory Effects of Alcohol..............................................132.3.2 ALD and the Elderly..........................................................................142.3.3 ALD and Women...............................................................................142.3.4 ALD and Genetics..............................................................................152.3.5 Diagnosis and Biochemical Markers.................................................162.3.6 Comorbidities Associated with Alcohol Abuse and Dependence.......17

3. What is the Control Strategy?............................................................173.1 Remediation of Alcohol Dependence.................................................173.2 Alcoholic Liver Disease (ALD)...........................................................18

3.2.1 Alcoholic Hepatitis (AH)....................................................................183.2.2 Alcoholic Cirrhosis...........................................................................19

3.3 Transplantation.................................................................................204. What is Known of the Affordability, Feasibility, and Sustainability of the Control Strategy?...............................................................................21

4.1 Economic Burden..............................................................................214.2 Feasibility of Control Strategy..........................................................22

5. Why Does the Disease Burden Persist?..............................................226. What Can Be Learnt from Past/Current Research into Pharmaceutical Interventions for this Condition?............................................................23

6.1 Dependence.......................................................................................236.2 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..........................................................................247.1.1 Opioid Antagonists............................................................................247.1.2 Serotonergics....................................................................................247.1.3 Dopaminergics..................................................................................247.1.4 Other Interventions...........................................................................25

7.2 Alcoholic Liver Disease.....................................................................257.3 “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...................................................................................298.1.1 European Sources of Funding for Alcoholic Liver Diseases: Selected Countries......................................................................................................298.1.2 United States Sources of Funding....................................................29

8.2 Private Sector Funding......................................................................309. 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....................................................................319.1.1 Basic Research..................................................................................319.1.2 Applied Research..............................................................................31

10. ...............................................................................................Conclusion32

Annex

Appendix

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Executive SummaryBurden 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 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 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.

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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.

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. IntroductionMany 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.

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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 LiverAlcoholic 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 HepatitisBetween 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 CirrhosisAlcoholic 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.

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1.3 Diagnosis of Alcohol Abuse or DependenceDiagnostic 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 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 CriteriaThe 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.

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2. What Are the Epidemiological Trends for Europe and the World2.1 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

2.1.1 Prevalence of Alcohol AbuseWith 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

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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). 2.1.2 Prevalence of ALDAlcoholic 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 non-alcoholic 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

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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 7-fold 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.

Alcoholic Use Disorders (as Percent of All DALYs by age group)

0.00%

2.00%

4.00%

6.00%

8.00%

10.00%

12.00%

14.00%

16.00%

18.00%

20.00%

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

EU15-MEU15-FEU10-MEU10-FWorld-MWorld-W

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.

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Liver Cirrhosis (Percent of All DALYs by age group)

0.00%

1.00%

2.00%

3.00%

4.00%

5.00%

6.00%

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

EU15-MEU15-WEU10-MEU10-WWorld-MWorld-W

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 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.

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Fraction Total DALY burden per Age Group (EU15, EU10 Men)

0

0.1

0.2

0.3

0.4

0.5

0.6

0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

Alcohol use disorders Liver cirrhosis

EU15EU10

EU10EU15

Figure 3Source: World Health Organization Global Burden of Disease Database (2002)

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Fraction Total DALY burden per Age Group (EU15, EU10 Women)

0

0.1

0.2

0.3

0.4

0.5

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0-4 5-14 15-29 30-44 45-59 60-69 70-79 80+

Alcohol Use DisordersLiver Cirrhosis

EU10EU15

EU10EU15

Figure 4Source: 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

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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 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 ElderlyAlcohol 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 WomenThere is marked regional variability in the extent of gender differences with regard to alcohol-related 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 alcohol-attributable mortality is 18% in the former socialist countries of Eastern Europe (Europe C). 23

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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 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.

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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 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 MarkersThe 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

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http://mednet3.who.int/prioritymeds/report/append/alcohol_apx1.doc


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 5-hydroxytryptophol 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 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 DependenceThe 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.

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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 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

i 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.

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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 mechanismsin 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 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.

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.

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3.2.1.1 TNF-alphaImmune 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 TNF-alpha in suppressing liver injury 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 InjuryThere 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

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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 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-oxidantsHuman 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 ColchicineThis 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

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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 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 post-transplant 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.

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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 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 12- step 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

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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

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

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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

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 Dependence7.1.1 Opioid AntagonistsAn 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 placebo-controlled, 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

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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

1 Weiss F and. Porrino LJ, 2002. Behavioral Neurobiology of Alcohol Addiction: Recent Advances and Challenges The Journal of Neuroscience, 22):3332–33372 Grant KA and Lovinger DM . 1995, Cellular and behavioral neurobiology of alcohol: receptor-mediated neuronal processes. Clin Neurosci 3:155–164.3 Woodward JJ. 2000 . Ethanol and NMDA receptor signaling. Crit. Rev. Neurobiol 14:69–89.4 Morrow AL, VanDoren MJ, Penland SN, and Matthews DB . 2001 The role of GABAergic neuroactive steroids in ethanol action, tolerance and dependence. Brain Res Brain Res Rev 37:98–109.5 Lejoyeaux M. Solomon J and Ades J. 1998. Review : Benzodiazepine treatment for alcohol dependent patients Alcohol & Alcoholism 33: 563-575; Heinz A, Wilwer M & Mann K. 2003. Therapy and supportive care of alcoholics: guidelines for practitioners. Best Practice & Research in Clinical Gastroenterology, 17: 695-708; Koob GF. 2003. Alcoholism: allostasis and beyond, Alcoholism: Clinical & Experimental Research, 27: 232-243.6 Fuller RK, and -Sturmhöfel, S. 1999. Alcoholism Treatment in the United States Alcohol Research & Health Vol. 23: 69-77.7 Beckingham, IJ amd Ryder SD , 2001. ABC of diseases of liver, pancreas, and biliary system. Investigation of liver and biliary disease, MBJ 322: 33-36.8 Narayanan M, Gores GJ and Shah, VH. 2001. MDPathogenesis, Diagnosis, and Treatment of Alcoholic Liver Disease Mayo Clin Proc. 2001, 76: 1021-1029; Helander A. 2003. Biological markers in alcoholism, J> Neural Transmission S66: 15-32.9 Savolainen VT, Liesto K, Mannikko A, Penttila A, and Karhunen PJ. 1993. Alcohol consumption and alcoholic liver disease: evidence of a threshold level of effects of ethanol. Alcohol Clin Exp Res. 17:1112-1117.10 McCullough AJ. Alcoholic liver disease. In: Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s Diseases of the Liver. Vol 2. 8th ed. Philadelphia, Pa: Lippincott-Raven Publishers; 1999:941- 971.11 Friedman, SL. 2003. Liver fibrosis – from bench to bedside. Journal of Hepatology 38: S38–S53.12 Fattovich G, Giustina G, Degos F, Tremolada F, Diodati G, Almasio P, et al. 1997. Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients. Gastroenterology 112:463–472.13 Rehm, J,– Rehn, N., Roome R, Monteiro M, Gmelg G, Jernigan D., & Ulrich F. 2003. The Global Distribution of Average Volume of Alcohol Consumption and Patterns of Drinking. Eur Addict Res 9:147–156.14 Hibell B, Andersson B, Ahlström S, Balakireva O, Jarnasson T, Kokkevi A, et al: 2000. The 1999 ESPAD Report. Alcohol and Other Drug Use among Students in 30 European Countries. Stockholm, Pompidou Group, Council of Europe.

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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

15 Jernigan DH. 2001. Global Status Report: Alcohol and Young People. Geneva, WHO.16 Rehn, N., Room, R. & Edwards, G. (2001) Alcohol in the European Region – consumption, harm and policies (Copenhagen, WHO Regional Office for Europe).17 Grant BF. Hartford TC. Dawson DA, Chou, P, DuFour, M, & Pickering R. 1994. Prevalence of DSM–IV alcohol abuse and dependence: United States, 1992. Alcohol Health & Research World 18:243–248.18 Lieber CS 1993. Alcoholic liver disease: a public health issue in need of a public health approach. Semin. Liver Disease 13: 105–107.19 Gutjahr E, Gmel G, & Rehm J. 2001. Relation between average alcohol consumption and disease: An overview. Eur Addict Res. 7:117–127.20 Ezzati M, Lopez AD, Rodgers A, Vander Horn S, Murray CJL, and the Comparative Risk Assessment Collaborating Group. 2002. Selected major risk factors and global and regional burden of disease. Lancet 360:1347–1360.21 Rehm J, Broome R, Monteiro M, Gmel G, Graham K, Rehn N, Sempos CT, Jernigan D. 2003. Alcohol as a Risk Factor for Global Burden of Disease, Eur. Addict . Res. 9:157–16422 Stewart, SF& Day CP. 2003 . Management of alcoholic liver disease. Journal of Hepatology, 38(Supp 1. 1) :S2-S13. 23 Alcohol Related Liver Disease Working Party, British Liver Trust, at http://www.britishlivertrust.org.uk, last accessed 6 June 2004. 24 Kim WR, Grown RS Jr, Terrault NA, El-Serag H. 2002. Burden of liver disease in the United States: Summary of a workshop , Hepatology 36: 227-242.25 Szabo, G. 1999, Consequences of Alcohol Consumption on Host Defense, Alcohol & Alcoholism, 34: 830-841.26 Baker, R.C. & Jerrells, TR. 1993. Recent developments in alcoholism: Immunological aspects. Recent Dev Alcohol 11:249–271.27 MacGregor RR & Louria DB. 1997. Alcohol and infection Curr Clin Top Infect Dis. 17:291–315.28 Centers for Disease Control and Prevention. Reported Tuberculosis in the United States:Surveillance Report 1996. Atlanta, GA: Division of Tuberculosis Prevention, National Center of Infectious Diseases, Centers for Disease Controland Prevention. 29 Friedman LN, Williams MT, Singh TP, & Frieden TR. 1996. Tuberculosis, AIDS, and death among substance abusers on welfare in New York City. N Engl J Med 334: 828–833.30 Cortese MM, Wolff M, Almeido-Hill J, Reid R, Ketcham J & Santosham M. 1992. High incidence rates of invasive pneumococcal disease in the White Mountain Apache population. Arch Intern Med 152:2277–2282.

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http://www.britishlivertrust.org.uk/


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 double-blind 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 31 Esposito AL. 1984. Community-acquired bacteremic pneumococcal pneumonia: Effect of age on manifestations and outcome. Arch Intern Med 144: 945–948.32 Kuo CH, Changchien CS, Yang CY, Sheen IS & Liaw YF. 1991. Bacteremia in patients with cirrhosis of the liver. Liver 11:334–339.33 Koff RS & Dienstag JL. 1995. Extra hepatic manifestations of hepatitis C and the association with alcoholic liver disease. Seminars in Liver Disease 15:101-109. 34 Rosman AS, Paronetto F, Galvin K, Williams RJ, & Lieber CS. 1993. Hepatitis C virus antibody in alcoholic patients: Association with the presence of portal and/or lobular hepatitis. Arch Intern Med. 153: 965-969.35 Ostapowicz G, Watson KJR, Locarnini SA, & Desmond PV. 1998. Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hematology 27:1730-173536 Corrao G & Arico S. 1998. Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hematology 27:914-919.37 O’Connell H, Chin A-V, Cunningham C, Lawlor B. 2003. Alcohol use disorders in elderly people—redefining an age old problem in old age BMJ 327:664–667.38 Johnson I. 2000. Alcohol problems in old age: a review of recent epidemiological research. Int J Geriatr Psychiatry 15:575-81.39 Reid MC & Anderson PA. 1997. Geriatric substance use disorders. Med Clin North Am 81:999-1016.40 Curtis JR, Geller G, Stokes EJ, Levine DM, & Moore RD. 1989. Characteristics, diagnosis, and treatment of alcoholism in elderly patients. J Am Geriatr Soc 37:310-316.41 Williams R & Horm J. 1977. Association of cancer sites with tobacco and alcohol consumption and socioeconomic status of patients: Interview study from the Third National Cancer Survey. J Natl Cancer Inst 58:525–547.42 Holman C, English D, Milne E, & Winter E. 1996. Meta-analysis of alcohol and all-cause mortality: A validation of NHMRC recommendations. Med J Aust 164:141–145.43 Smith-Warner S, Spiegelman D, Yaun S, van den Brandt P, Folsom A, Goldbohm A, Graham S, Holmberg L, Howe G, Marshall J, Miller A, Potter J, Speizer F, Willett W, Wolk A, & Hunter D. 1998. Alcohol and breast cancer. JAMA 279:535–540.44 Katsouyanni K, Trichopoulos A, Stuver S, Vassilaros S, Papadiamantis Y, Bournas N, Skarpov N, Mueller N & Trichopoulos D. 1994. Ethanol and breast cancer: An association that may be both confounded and causal. Int J Cancer 58:356–361.45 Roth H & Levy P. 1995. Alcohol and breast cancer response. J Clin Epidemiol 48:498–500.46 Becker U, Deis A, Sorensen TI, Gronbaek M, Borch-Johnsen K, Muller CF, Schnohr, P, & Jensen G. 1996. Prediction of risk of liver disease by alcohol intake, sex and age: A prospective population study. Hepatology 23:1025–1029.

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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. 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 47 Arthur MJ., Lee A & Wright R. 1994. Sex differences in the metabolism of ethanol and acetaldehyde in normal subjects. Clin Sci 67:397–401. 48 Loft S, Olesen KL, & Dossing M. 1987. Increased susceptibility to liver disease in relation to alcohol consumption in women. Scand J Gastroenterology ;22:1251-1256.49 Tsuang MT, Lyons MJ, Eisen SA, Goldberg J True W, Lin N, Meyer JM, et al. 1996. Genetic influences on DSM-III-R drug abuse and dependence: a study of 3,372 twin pairs. Am J Med Genet. 67:473–477.50 Schuckit MA & Smith TL. 1996. An 8-year follow-up of 450 sons of alcoholic and control subjects. Arch Gen Psychiatry. 53:202–10.51 Monzoni A, Masutti F, Saccoccio G, Bellentani S, Tiribelli C & Giacca M. 2001. Genetic determinants of ethanol-induced liver damage. Mol Med. 7:255–262.52 Jarvelainen HA, Orpana A, Perola M, Savolainen VT, Karhunen PJ & Lindros KO. 2001. Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease Hepatology 33:1148–53.53 Rosenberg W, Becka BA , Voelker M, Arthur MJP. 2000. Automated assays of serum markers of liver fibrosis predict histological hepatic fibrosis. Hepatology 32:183A.54 Anni, H., et al, 2003. Alcoholism: Clinical and Experimental Research 27:1613-1621. 55 Fuller RK & Gordis E. 2004. Does disulfiram have a role in alcoholism treatment today? Addiction. 99: 21-24; Rezvani AH, Overstreet DH, Mason GA, Janowsky D, Hamedi M, Clark E., & Yang Y. 2000. Combination pharmacotherapy: A mixture of Small Doses of Naltrexone, Fluoxetine and a thyrotropin-releasiong hormone reduces alcohol intake in three strains of alcohol preferring rats. Alcohol & Alcoholism Vol. 35, No. 1, pp. 76–83, 200056 Volpicelli, J R., Alterman, A I., Hayashida, M. & O’Brien C P . 1992. Naltrexone in the treatment of alcohol dependence. Archives of General Psychiatry 49, 876–880. 57 Pucilowski, O., Rezvani, A H. & Janowsky, D.S. 1992. Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor, GOE 5438. Psychopharmacology 107, 447–452.58 Hodge C A., Haraguchi M., Erickson H L. & Samson H H. 1993. Ventral tegmental microinjections of quinpirole decreaseethanol and sucrose-reinforced responding. Alcoholism: Clinical and Experimental Research 17, 370–375.59 Hodge C A., Samson, H H., Lewis R S. & Erickson, H L. 1993. Specific decreases in ethanol — but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205–930. Alcohol 10: 191–196.60 Rezvani AH & Janowsky, D S. 1990. Decrease of alcohol consumption by verapamil in alcohol preferring rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry 14, 623–631.

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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

61 McBride W J., Murphy J M., Lumeng L & Li T.-K. (1990. Serotonin, dopamine and GABA involvement in alcohol drinking ofselectively bred rats. Alcohol 7, 199–205. 62 Alexander JF, et al. 1971. Natural history of alcoholic hepatitis. Am J. Gastroenterol. 56:515–525.63 Pares A, et al. 1986. Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage. J Hepatol 2:33–42.64 Orrego H, et al. 1987. Prognosis of alcoholic cirrhosis in the presence and absence of alcoholic hepatitis. Gastroenterology 92:208–214.65 Stewart S, et al. 2001. Alcoholic liver disease: new insights into mechanisms and preventative strategies. Trends Mol Med 7:408–413.66 Tsukamoto H & Lu SC. 2001. Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 15:1335–1349.67 Imperiale TF & McCullough AJ. 1990. Do corticosteroids reduce mortality from alcoholic hepatitis? a meta-analysis of the randomized trials. Ann Intern Med. ;113:299-307.68 Christensen E & Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables.Gut. 37:113-118.69 Carithers RL Jr, Herlong HF, Diehl AM, et al. 1989. Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial. Ann Intern Med. 110:685-69070 Mendenhall CL, Anderson S, Garcia-Pont P, et al. 1985. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med. 311:1464-1470.71 McClain CJ, Barve S, Barve S, Deaciuc I, & Hill DB. 1998. Tumor necrosis factor and alcoholic liver disease. Alcohol Clin Exp Res. 2(5, suppl):248S-252S.72 Faubion WA, & Gores GJ. 1999. Death receptors in liver biology and pathobiology. Hepatolog 29:1 ??73 Felver ME, Mezey E, McGuire M, et al. 1990. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis. Alcohol Clin Exp Res. 14:255-259.74 Iimuro Y, Gallucci RM, Luster MI, Kono H, & Thurman RG. 1997. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology. 26:1530-1537.75 Iimuro Y, Gallucci RM, Luster MI, Kono H, & Thurman RG. 1997. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat. Hepatology 26:1530-1537.

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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 cirrhosis106 (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

76 Kono H, Rusyn I, Yin M, et al. 2000. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J ClinInvest. 106:867-872.77 Halle P, Pare P, Kaptein E, Kanel G, Redeker AG, & Reynolds TB. 1982. Double-blind, controlled trial of propylthiouracil in patients with severe acute alcoholic hepatitis. Gastroenterology. 82(5, pt 1):925-931.78 Akriviadis E, Botla R, Briggs W, Han S, Reynolds T, & Shakil O. 2000. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology. 119:1637-1648.79 Heemann U, et al. 2002. Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study. Hepatology 36:949–958.80 Carini R, et al. 1992. Lipid peroxidation and irreversible damage in the rat hepatocyte model. Protection by the silybin–phospholipid complex IdB 1016. Biochem Pharmacol. 43:2111–2115.81 Mato JM, et al. 1999. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol 30:1081–1089.82 Orrego H, et al. 1987. Long-term treatment of alcoholic liver disease with propylthiouracil. N Engl J Med 317:1421–1427.83 Kershenobich D, et al. 1998. Colchicine in the treatment of cirrhosis of the liver. N Engl J Med 318:1709–1713.84 Rambaldi A & Gluud C. 2001. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis. Cochrane Database Syst Rev 3.85 Starzl TE, et al. 1988. Orthotopic liver transplantation for alcoholic cirrhosis. J Am Med Assoc 260:2542–2544.86 Belle SH, et al. 1997. Liver transplantation for alcoholic liver disease in the United States: 1988 to 1995. Liver Transpl Surg 3:212–219.87 Wiesner RH, et al. 1997. Liver transplantation for end-stage alcoholic liver disease: an assessment of outcomes. Liver Transpl Surg 3:231–239.88 Bird GL, et al. 1990. Liver transplantation in patients with alcoholic cirrhosis: selection criteria and rates of survival and relapse. BrMed J 301:15–17.89 Gerhardt TC, et al. 1996. Alcohol use following liver transplantation for alcoholic cirrhosis. Transplant Proc 62:1060–1063.90 Pageaux GP, et al. 1999. Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism. Gut 45:421–426.91 Neuberger J, et al. 1998. Assessing priorities for allocation of donor liver grafts: survey of public and clinicians. Br Med J 317:172–175.

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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

92 Heffler S, Levit K, Smith S, Smith C, Cowan C, Lazenby H, & Freeland M. 2001. Health spending growth up In 1999: fastergrowth expected in the future. Health Affairs. 20:193-202.93 Room R: 1992. The impossible dream? Routes to reducing alcohol problems in a temperance culture. J Subst Abuse 4:91–106.94 Foxcroft DR, Ireland D, Lister-Sharp DJ, Lowe G, & Breen R. 2003. Longer-term primary prevention for alcohol misuse in young people: A systematic review. Addiction 98:397–41195 Diehl AM. 1998. Alcohol and liver regeneration. Clin Liver Dis. 2 723-738.96 Alison MR. 2003. Liver regeneration with reference to stem cells. Sem. Cell & Dev. Biol. 13: 385-387.. 97 Mason BJ et al. 1999. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch. Gen. Psy. 56: 719-724.98 Lovinger D. Serotonin's role in alcohol's effects on the brain. 1997. Alcohol Health and Res World. 21:114-120.99 Cornelius JR, Salloum IM, et al. 1997. Fluoxetine in depressed alcoholics. A double-blind placebo controlled trial. Arch Gen Psychiatry. 54:700-705.100 Johnson BA, Roache J, et al. 2000. Ondansetron for reduction of drinking among biologically predisposed patients: a randomized controlled trial. JAMA. 284:963-971; Kranzler HR, Pierucci-Lagha A, et al. 2003. Effects of ondansetron in early- versus late-onset alcoholics: a prospective, open-label study. Alcohol Clin Exp Res. 27:1150-1155.101 Fawcett J, Kravitz HM, et al. 2000. Pharmacological treatments for alcoholism: revisiting lithium and considering buspirone. Alcohol Clin Exp Res. 24:666-674.102 Modell JG, Mountz JM, et al. Effect of haloperidol on measures of craving and impaired control in alcoholic subjects. 1993. Alcohol Clin Exp Res. 17:234-240; Shaw GK, Waller S, et al. 1994. Tiapride in the prevention of relapse in recently detoxified alcoholics. Br J Psychiatry.1994;165:515-523; Hutchinson K, Swift R, et al. 1998. Effects of olanzapine on cue induced craving in moderate to heavy social drinkers. Alcohol Clin Exp Res. 22: 662A; Drake RE, Xie H, et al. 2000. The effects of clozapine on alcohol and drug use disorders among patients with schizophrenia. Schizophr Bull.26:441-449.103 Johnson BA, Ait-Doud N, et al. 2003. Oral topiramate for treatment of alcohol dependence: a randomised controlled trial. Lancet. 361:1677-1685.104 Johnson BA, Ait-Doud N, Prihoda, TJ. 2000. Combining ondansetron and naltrexone effectively treats biologically predisposed alcoholics: from hypothesis to preliminary clinical evidence. Alcohol Clin Exp Res. 24:737-742.105 National Institute on Alcohol and Alcohol Abuse http://www.niaaa.gov, last accessed 12 May 2004. 106 Iredale JPO. 2003. Science, medicine, and the future Cirrhosis: new research provides a basis for rational and targeted treatments . BMJ 327:143-147.

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http://www.niaaa.gov/


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 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 industry-sponsored 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.

107 NIH clinical trials website, at http://www.clinicaltrials.gov, last accessed 3 June 2004.6.14-35

http://www.eudract.emea.eu.int/

http://www.controlled-trials.com/

http://mednet3.who.int/prioritymeds/report/annexes/alcohol_anx.doc

http://www.clinicaltrials.gov/


Table 7 : Clinical trials related to alcoholic liver disease, liver fibrosis, alcoholic hepatitis, cirrhosis, fibrosis

Condition Sponsor Phase Treatment NOTES Trial Sitesa

Kidney fibrosis NIDDK II Pirfenidone Patients with glomerulo-sclerosis

1 state (25)

Pulmonary fibrosis

NHLBIb II and III Oral bosentan International

Lung scleroderma

NHLBI III Cyclophosphamideazathioprine

Childhood hepatic cirrhosis

NCRR c I Colchicine 1 state (15)

Systemic Sclerosis

Genzyme/Cambridge Antibody Technologies

I and II Anti TGF beta 1 monoclonal antibody

4 states

NonalcoholicSteatohepatitis(NASH)

NIDDK II metformin NASH associated with diabetes

1 state (30)

Primary biliary cirrhosis

NCRR and NIDDK

III Methrotrexate/ursodiol vs, methotrexate/colchicine

2 states (405)d

Liver Fibrosis InterMune II Interferon gamma 1b

In HCV patients only

(500)

Primary biliary cirrhosis

NIDDK III Ursodiol/methotrexate vs. methotrexate

11 states

Primary biliary fibrosis

NIDDK I budesonide (50)

NASH

OTHERSIdiopathic pulmonary fibrosis

Kidney disease in diabetics

NIDDK

InterMune

InterMune

InterMune

II

III

II

I and II

Pioglitazone

Interferon gamma

Pirfenidone

Pirfenidone

(60) d

North America

and EU (600)

(120)

a. Proposed or actual enrollment (in parenthesis).b. National Health, Lung, and Blood Institutec. National Center for Research Resourcesd. Several different phase I, II or III trials combined

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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 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).

iii 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. 108 LaBonte, J and DeVasher C., 2004. Hepatitis C Virus, Decision Resources Market report, at http://www.dresources.com, last accessed 8 June 2004. 109 Pawlotsky J-M & McHutchinson JG. 2004. Hepatitis C. Development of new drugs and clinical trials: Promises and pitfalls, Hepatology 39: 554-567.

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http://www.dresources.com/

http://www.hepcassoc.org/


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.

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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 UnionWithin 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

6.14-39


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 FundingThe 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 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

8.2 Private Sector Funding

We have no information on EU private sector funding for alcoholic liver diseases.

110 United States Cancer Statistics, available at http://www.cdc.gov, last accessed 10 May 2004.

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http://www.cdc.gov/


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 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 Research9.1.1 Basic ResearchThe 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

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http://www.corporate-ir.net/ireye/ir.html

http://www.corporate-ir.net/ireye/ir.html

http://www.clnicaltrials.gov/

http://www.maxim.com/


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:

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 efficacy9.1.2 Applied ResearchThe 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 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:

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

10. ConclusionThis 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.

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