National Institute on Alcohol Abuse and Alcoholism

FIVE YEAR

STRATEGIC PLAN

FY08-13

Alcohol Across the Lifespan

ALCOHOL ACROSS THE LIFESPAN

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U.S. Department of Health and Human Services

National Institutes of Health

National Institute on Alcohol Abuse and Alcoholism

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Table of Contents

Chapter I.
Overview

 

Chapter II.
Embryo and Fetus

 Chapter III.
Birth to Age Ten
 Chapter IV.
Youth and Adolescence
 Chapter V.
Young Adult
 
Chapter VI.
Midlife
Chapter VII.
Senior Adult

Mission and Vision of NIAAA

 

Background

 

Background

 

Definition of Youth and Adolescence

 Definition of Young Adult 

Drinking Patterns and Definitions

  
Epidemiology
  
Epidemiology
  
Epidemiology
  
Epidemiology
 
 
 

 

Prevalence of Alcohol Problems and Consequences

 Etiology  Etiology Biology  Biology  

Issues that Transcend Lifespan Perspective

 Prevention Prevention and Intervention Prevention Prevention and Treatment 

Alcohol Metabolism

 Treatment Opportunities Treatment  Opportunities 

Gene/Environment Interaction, Epigenetics

 Opportunities Outreach Opportunities Outreach 
Neurobiology Outreach   Outreach    
Diagnostic Criteria      Collaborations     
Alcohol Health Services Research         
 
          
 
          
 

NIAAA STRATEGIC PLAN

ALCOHOL ACROSS THE LIFESPAN

EXECUTIVE SUMMARY

Introduction

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the National Institutes of Health, U.S. Department of Health and Human Services, is the lead agency in this country for research on alcohol abuse, alcoholism, and other health effects of alcohol. This document, the NIAAA Strategic Plan for Research, 2008-2013 sets forth a fundamental organizing principle for alcohol research studies and describes research opportunities to deepen and broaden our understanding of alcohol use and alcohol use disorders.

Alcohol use disorders (AUD) is defined as alcohol abuse and alcohol dependence, and arise from drinking too much, too fast and/or too often. Alcohol Abuse is defined as a recurring pattern of high-risk drinking that creates problems for the drinker, for others, or for society. Adverse consequences can also arise from a single instance of hazardous alcohol use. Alcohol dependence, typically considered to be synonymous with alcoholism (alcohol addiction), is a complex disease characterized by persistent and intense alcohol-seeking, which results in a loss of control over drinking, a preoccupation with drinking, compulsion to drink or inability to stop, and the development of tolerance and dependence.

The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recently came to similar conclusions about the toll taken by excessive alcohol use. According to the CDC, excessive alcohol consumption is the number-three cause of preventable death in the United States. The WHO also ranks alcohol third among preventable risk factors for premature death in developed nations. In 2003, the worldwide prevalence of alcohol use disorders (AUD) was estimated at 1.7%, accounting for 1.4% of the total world disease burden in developed countries. In the United States, 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol use disorders. Only 7.1% of these individuals received any treatment for their AUD in the past year. Problems related to the excessive consumption of alcohol cost U.S. society an estimated $185 billion annually.

In addition to the adverse health effects that result directly from excessive alcohol consumption, other medical conditions often co-occur among individuals with excessive alcohol consumption. For example, alcohol abuse and dependence commonly occur in people who abuse other drugs, and in people with mood, anxiety, and personality disorders. An estimated 90% of cocaine addicts have alcohol problems and as many as 60% of patients at community mental health centers have alcohol and other drug abuse disorders. The high co-occurrence of alcohol and tobacco dependence poses special problems. An estimated 50% to 90% of alcohol dependent individuals are smokers who, in general, smoke heavily, become more addicted to nicotine and are less successful at quitting smoking than other smokers. This puts them at a much higher risk for certain cancers and cardiovascular diseases that develop more readily in the presence of both alcohol and nicotine.

Lifespan Perspective

Investigators traditionally have pursued solutions to the wide range of alcohol-related issues through studies of alcohol’s effects on biological systems, the genetic factors underlying these biological effects, and the environmental and cultural factors that influence alcohol use. This Plan applies a new organizing principle – the lifespan perspective – to these diverse areas of alcohol research. Scientists now recognize that human biology and behavior continues to change throughout life and changes occurring throughout the lifespan affect individuals' drinking patterns as well as the decisions they may make to change their drinking habits or to seek help for alcohol use problems. A lifespan perspective will allow researchers to identify how the emergence and progression of drinking behavior is influenced by changes in biology, psychology, and in exposure to social and environmental inputs over a person's lifetime, and vice versa. This approach should help researchers discover life stage- appropriate strategies for identifying, treating, and preventing alcohol use disorders.

Contributions to Alcohol Use and Alcohol Problems Across the Lifespan

Numerous factors influence the onset and continuation of alcohol use by an individual. The factors include the individual’s genetic makeup, the environments to which he or she is exposed and complex ways that genes interact with one another and with the environment. These same factors determine an individual's pattern of alcohol consumption and the risks for developing alcohol dependence (alcoholism).

Some of the first evidence of the importance of the lifespan perspective for understanding alcohol use disorders emerged less than ten years ago in an analysis of data derived from NIAAA’s National Longitudinal Alcohol Epidemiologic Study (NLAES). This analysis revealed that people who begin drinking at young ages have a significantly increased risk for developing alcoholism. This finding was confirmed by the recent National Epidemiologic Survey on Alcohol-Related Conditions (NESARC), which showed that young people who began drinking before age 15 are four times more likely to develop alcohol dependence during their lifetime than those who began drinking at age 21. This is true for individuals from families where a parent had a history of alcoholism and for individuals with no parental history of alcoholism. Therefore, while parental history clearly contributes to the risk for developing alcoholism, likely a reflection of genetic risk factors, early initiation of drinking is also an important predictor of risk for alcoholism. Researchers hypothesize that early exposure to alcohol may alter brain development in ways that increase an individual’s vulnerability to alcohol dependence. Some other biological factor, perhaps affecting personality, may also be responsible for both the early onset of drinking and the heightened risk for alcoholism.

Alcohol Policy and Public Health

A wide range of alcohol policies may affect alcohol consumption and other behaviors relating to alcohol, and can have important influences on public health outcomes. In the United States, laws, regulations, and jurisprudence address various aspects of alcohol use ranging from alcohol taxation to behaviors affected by alcohol, such as drinking and driving. Scientific research has identified a number of alcohol-related policies that have significant effects on public health outcomes. Examples of these include a reduction in the number of traffic fatalities (raising the minimum drinking age to 21, enforcing stricter drinking and driving penalties), a reduction in child abuse and sexually transmitted diseases (raising taxes on alcohol beverages), and enhancement of access to alcohol treatment programs (State-mandated provision in health care financing). In general, alcohol policies are designed to serve individuals at all levels of the lifespan through harm reduction and prevention of alcohol-related illness or injury.

Lifespan Perspective--Practical Implications

Understanding the interactions of alcohol with stages of life will enable us to address the prevention and treatment of alcohol problems in a life stage-appropriate manner. In particular, such an approach should lead to a better understanding of:
  • how alcohol perturbs development of the embryo and fetus, which may help reduce the impact of Fetal Alcohol Spectrum Disorders (FASD).
  • how genetic and environmental factors contribute to drinking initiation and the development of alcohol dependence, which will foster the rational design of prevention strategies that target specific risk factors at appropriate stages of the lifespan.
  • the factors that influence the common phenomenon of naturally “aging out” of alcohol dependence, to aid in the development of new therapeutic approaches and to help achieve behavioral change in alcoholism treatment.
  • how alcohol use produces functional and structural changes in the nervous system, which will aid in the development of behavioral and pharmacological therapies directed to specific molecular targets within the brain.
  • how the products of alcohol metabolism contribute to the development of alcohol-induced diseases of the liver, digestive system, lung, heart, brain, endocrine and immune system. Such knowledge could help develop better preventions and treatments for these disorders.

 

RESEARCH OPPORTUNTIES AND OUTREACH

The following is a brief outline of Research Opportunities and Outreach activities identified by NIAAA that will help guide the Institute’s research program and activities over the next 5 years.

Opportunities that Transcend the Lifespan Perspective

Several scientific issues have impact on all stages of life. While the manner by which they affect an individual may differ depending upon the person's stage of life, these issues are best considered from an overarching perspective and include: alcohol metabolism; genetic and environmental influences including epigenetics; neurobiological effects of alcohol; and improvements in the diagnostic recognition of alcohol use disorder.

Metabolism -- Individuals differ in how fast they metabolize alcohol and in the extent to which they are affected by a given dose of alcohol. These differences affect drinking behavior, the potential for the development of alcohol dependence, and the risk for developing alcohol-induced organ damage.

Alcohol and Gene/Environmental Interactions -- Neither genes nor environment alone can explain why any particular individual develops alcohol dependence. Rather, as a complex disorder, risk for alcohol dependence is a consequence of the interplay of multiple genes, multiple environmental factors, and the interaction of these genes and environmental factors. The alcohol field has benefited from the ability to model various aspects of alcohol consumption in animal models, but advances in our understanding of neurobehavioral aspects of drinking and its consequences requires the development of new models. The identification of a number of genes contributing to the vulnerability to alcohol dependence in human studies, coupled with technological advances including the ability to conduct genome-wide association studies, offer great promise to further define genetic risk factors and their interactions with environmental factors.

Epigenetics -- Metabolic and environmental factors can influence the manner in which genes are expressed through a process known as epigenetics. Epigenetics refers to stable alterations in the genome, sometimes heritable through cell division, that do not involve the DNA sequence itself. Epigenetic processes act as an additional source of biologic variation beyond that attributable to the genetic code. These processes involve the chemical modification of the constituents of the chromosome, the DNA molecules and the gene-regulating proteins known as histones, and may occur as a consequence of exposures to specific environmental substances and stimuli.

Neurobiology -- The brain, which is the primary target for alcohol-induced neurotoxic effects including alcohol dependence, continues to develop and mature from conception through birth into early adulthood. Alcohol consumption may affect the normal physiology of the central nervous system at any point throughout the lifespan, and those effects may differ depending on lifespan stage.

Diagnosis of Alcohol Use Disorders -- While the diagnostic criteria for alcohol dependence and alcohol abuse provided in current diagnostic schemes, including the DSM-IV and ICD-10, have contributed to improved case recognition and served researchers well over the past decade, research has begun to focus on developing quantitative representations of these criteria using statistical methods that provide differential severity weighting for individual AUD symptoms and allow for the inclusion of alcohol consumption variables. The development of quantitative criteria will lead to better understanding of the pathological stage of the disease for any given individual, provide the researcher an improved understanding of the etiology of alcohol dependence, and augment translational research to develop improved treatment approaches for the differing severity levels of alcohol dependence.

Alcohol Health Services Research--Alcohol health services research is a multidisciplinary field of applied research that seeks to improve the effectiveness, efficiency and equity of services designed to reduce the public health burden of alcohol use disorders across the lifespan. It does this by examining how social factors, financing systems, service environments, organizational structures and processes, health technologies, and personal beliefs and behaviors affect access to and utilization of healthcare, the quality and cost of healthcare, and in the end our health and well-being. Ultimately the goal of alcohol health services research is to identify ways to organize, manage, finance, and deliver high-quality care conistent with developmental needs of patients and their families.

Opportunities: Embryo and Fetus

The earliest stages of life are periods of great vulnerability to the adverse effects of alcohol. Embryonic and fetal development are characterized by rapid, but well-synchronized patterns of gene expression, including epigenetic imprinting, which makes the embryo/fetus particularly vulnerable to harm from alcohol, a known teratogen (an agent capable of causing physical birth defects). Alcohol's teratogenic effects were recognized over three decades ago, and it is now the leading known environmental teratogen. Alcohol may also damage neurological and behavioral development even in the absence of obvious physical birth defects. Alcohol-induced birth defects are known as fetal alcohol spectrum disorders (FASD). The severity of defects depends on the dose, pattern, and timing of in utero exposure to alcohol. Research in animal models has demonstrated that the potential for adverse effects increases with the maternal blood alcohol concentration (BAC). Research has also suggested that alcohol's causative role in FASD can be influenced by maternal hormones, nutrition, age, parity, years of drinking, and genetic factors. The most serious adverse consequence of prenatal alcohol exposure is fetal alcohol syndrome (FAS), a devastating developmental disorder characterized by craniofacial abnormalities, growth retardation, and nervous system impairments that may include mental retardation. Children and adults with FAS have irreversible neurobiological deficits that affect multiple systems, ranging from motor control to executive function.

Outreach: Embryo and Fetus

Opportunities: Birth to Age Ten

A number of significant research opportunities and directions exist for the birth to age ten years group. The first two are very high priority since there is little to no information in these areas. The third is also a very high priority as there is a need to better understand why drinking is a normative behavior among American adolescents and how drinking becomes so widespread among youth. The remaining opportunities represent areas where increased knowledge about known developmental pathways into alcohol use and AUDs will enhance prevention efforts with specific groups of youth at high risk.

In some cases, familial, neighborhood, and peer structures act in concert to encourage the development of early involvement with alcohol. Determine the degree to which these concurrent risk factors are synergistic for the development of risk.

 
Outreach: Birth to Age 10

Opportunities: Youth/Adolescence

The beginning of adolescence is demarcated biologically with the onset of puberty, and is understood to end when an individual assumes adult roles and responsibilities. Puberty consists of many biological processes that do not occur at the same chronological age and do not necessarily progress at the same pace or have the same pattern of unfolding in every individual. Importantly, brain development, marked by continuous generation of neurons and connections between neurons, and the refinement of communication among those neurons, continues during puberty and into the young adult ages. Drinking alcohol during this dynamic period of brain development may result in brain effects leading to an earlier onset of alcohol-induced specific diseases or to an earlier transition towards the development of alcohol use disorders. Very important to understanding alcohol use by youth from a developmental perspective is the fact that, over the past 100 years, the endocrine changes associated with puberty have been occurring at younger ages, while the attainment of adult roles such as starting a career, finding a partner, owning a home and becoming a parent are occurring much later. The result is the dramatic expansion of the period referred to as adolescence which prolongs the potential duration of one of the heaviest drinking periods of the lifespan and therefore may exacerbate the harmful effects on alcohol on development. In sum, adolescence is a period of dramatic biological change -- occurring in the context of equally dynamic socio-environmental change with regard to the adolescent's school, peer group, family, and social milieu. The majority (80%) of youth begin to drink by the end of high school, and some experience significant alcohol-related problems including the development of alcohol use disorders.

Outreach: Youth/Adolescence

Opportunities: Young Adult

Entry into young adulthood is defined by a variety of self-directed transitions that signal an individual's burgeoning independence from parental care. The pursuit of post-secondary education, enlisting in the military, and entering the workforce are a few such milestones, which traditionally have occurred when an individual is in his or her late teens or early twenties. Other events that traditionally mark this period include assuming large financial obligations, courtship, and marriage. In the U.S, most states have adopted age 18 as the legal age of majority – the point at which individuals assume responsibility for their own actions. However, from a developmental rather than a legal perspective, emerging or young adulthood now comprises an extended period of unsettled behavior for many individuals, as age of marriage and age of career initiation in the U.S., for example, have increased relative to historic norms. Compared to all other age groups, the prevalence of periodic heavy or high-risk drinking is greatest among young adults aged 18 to 24. Alcohol use disorders including alcohol dependence (alcoholism), also peak during this period. While most young adults transition out of harmful drinking behaviors, a minority will continue to drink heavily into the later stages of adulthood. These phenomena raise important research questions. For example, what factors allow some young adults to discontinue harmful drinking patterns, most often in the absence of formal alcoholism treatment? Why do others experience protracted alcohol problems well into their adulthood?

Outreach: Young Adult

Opportunities: Midlife

A broad spectrum of alcohol-related problems and issues becomes manifested during the adult period of life often referred to as midlife. At midlife, many of the pathological consequences of heavy alcohol use become most evident, and individuals with alcohol dependence are most likely to seek treatment of their alcoholism at this time.

Metabolism and Organ Injury

Alcohol and HIV/AIDS

Treatment and Behavioral Change

Medications Development

Outreach: Midlife
 

Opportunities: Senior Adult

Aging is associated with a variety of changes that place senior adults at special risk for alcohol-related health problems. Senior adults are known to differ in their physiological and behavioral responses to alcohol in a variety of social contexts, and their ability to develop tolerance to alcohol is greatly altered during the senior years. Drinking can aggravate a variety of pathological conditions in the senior adult including stroke, hypertension, neurodegeneration, memory loss, mood disorders, and cognitive or emotional dysfunction. As the percentage of persons in the senior age category is rapidly growing in the United States, improving knowledge about the effects of alcohol at this life stage is becoming increasingly important.

Outreach: Senior Adult

Top

 

CHAPTER I. OVERVIEW

The National Institute on Alcohol Abuse and Alcoholism (NIAAA), a component of the National Institutes of Health, U.S. Department of Health and Human Services, is the lead agency for U.S. research on alcohol abuse, alcoholism, and other health effects of alcohol. Its role is enunciated in the Institute Mission Statement:

A. Mission and Vision of NIAAA

The NIAAA Mission is to provide leadership in the national effort to reduce alcohol-related problems by:

The Institute's efforts to fulfill its mission are guided by the NIAAA Vision to support and promote, through research and education, the best science on alcohol and health for the benefit of all by:

This document, the NIAAA Strategic Plan for Research, 2008-2013, sets forth research opportunities to increase our understanding of why, how, and when people drink, as well as why and how some people develop alcohol use disorders (AUD). Throughout the years, investigators have pursued answers to these very questions through studies of alcohol’s effects on biological systems, the genetic factors underlying biology, and through the study of environmental and cultural factors. This Plan, however, proposes a significantly different direction for alcohol studies by applying the lifespan perspective -- the consideration of how the emergence and progression of drinking behavior is influenced by multiple changes (in biology, psychology, and in exposure to social and environmental inputs) over a person’s lifetime. These changes occurring throughout the lifespan affect the pattern of drinking (quantity and frequency) and the actions individuals may take to modify their drinking behavior or to seek help for an alcohol use disorder. Viewing alcohol use and alcohol problems through a lifespan perspective will provide knowledge that will, through early identification and intervention, significantly contribute to the ability to decrease the prevalence of alcoholism and other alcohol-related disorders, and to the treatment of these disorders.

This overview describes the origins of the lifespan perspective, highlights the complexity of alcohol issues in health, and provides a view to why solutions to these problems cannot be approached from any single discipline but must be approached in a multidisciplinary and transdisciplinary manner. Further, the findings at any investigative level (molecular, cellular, animal model, human laboratory, human clinical to community) must be translated to other levels and eventually to clinical practice in the world environment. Transdisciplinary and translational research over the course of the next decade will be aided by the intellectual and technical developments arising from the NIH Roadmap and the NIH Neuroscience Blueprint, and their potential application to address health issues related to alcohol use has been integrated into this Plan.

B. Drinking Patterns and their Definitions

An understanding of the drinking patterns that exist in the population, as well as the alcohol-use disorders that arise from drinking too much, too fast and/or too often, is important for identifying targets for future research pursuits.

Alcohol Abuse and Alcohol Dependence are two clinical disorders characterized by either a persistent pattern of inappropriate alcohol use or of adverse consequences. Alcohol dependence is typically considered to be synonymous with alcoholism. Alcohol abuse and alcohol dependence may be defined as shown in Tables I-1 and I-2. A proposal has recently been made to use the term addiction to specify the behavioral, CNS neuroadaptive responses to chronic alcohol exposure vis a vis loss of control, preoccupation with drinking and compulsion to drink, as distinct from the physiological dependence symptoms of tolerance and withdrawal.

Table I-1. Harmful or Hazardous Alcohol Use (Alcohol Abuse)

A recurring pattern of high-risk drinking that result in adverse outcomes, including:

* Personal problems: memory and cognition; job, family, friends, and other significant relationships; health and organ damage
* Problems to others: injury and death; violence and crime (property damage, assault, homicide)
* Problems for society: underage drinking; health care costs; economic productivity
* Use in hazardous situations

 

Table I-2. Alcohol Dependence (Alcoholism)

A complex disease characterized by a persistent and progressive pattern of abnormally intense alcohol-seeking behavior that, over time, results in:

* loss of control over drinking
* a preoccupation with drinking
* compulsion to drink/unable to stop
* the development of tolerance or dependence

 

While recurrent or persistent harmful or hazardous alcohol use results in adverse consequences in the long-term situation, adverse consequences can occur in individuals who may have used alcohol in a harmful or hazardous manner on only one occasion. These adverse consequences include alcohol-related traffic crashes, drownings, and alcohol poisonings, among many others.

Drinking in a manner that will cause intoxication clearly poses risks to the drinker. A term frequently used to describe this pattern is binge drinking. Different definitions often have been used for this pattern of drinking. To provide clarification, the National Advisory Council on Alcohol Abuse and Alcoholism (NAC) in 2004 developed a standard definition for binge drinking as a pattern of drinking alcohol that brings the blood alcohol concentration to 0.08 gram percent (the legal limit for drinking and driving in all states) or above. The NAC further noted that for a typical adult male, this BAC level may be obtained after the consumption of 5 drinks in a 2 hour period, and for females, 4 drinks in the same period. The Council definition of binge drinking and recommendations are provided in Table I-3.

Table I-3. Definition of Binge Drinking

 

A "binge" is a pattern of drinking alcohol that brings blood alcohol concentration

(BAC) to 0.08 gram percent or above. For the typical adult, this pattern corresponds to consuming 5 or more drinks (male), or 4 or more drinks (female), in about 2 hours. Binge drinking is clearly dangerous for the drinker and for society.

* In the above definition, a "drink" refers to one serving of 12 g of absolute alcohol (e.g., one 12-oz. Beer, one 5-oz. glass of Wine, or one 1.5-oz. Shot of distilled spirits).
* Binge drinking is distinct from "risky" drinking (reaching a peak BAC between .05 gram percent and .08 gram percent) and a "bender" (2 or more days of sustained heavy drinking).
* For some individuals (e.g., seniors or people taking other drugs or certain medications), the number of drinks needed to reach a binge level BAC is different than for the "typical adult".
* People with risk factors for the development of alcoholism have increased risk with any level of alcohol consumption, even that below a "risky" level.
* For pregnant women, any drinking presents risk to the fetus.

* Drinking by persons under the age of 21 is illegal.

Source: NIAAA, National Advisory Council, February, 2004

Binge drinking is common across most life stages. Fifty percent of college students who drink engage in binge drinking, and twenty percent do so twice or more every three weeks. More than two-thirds of binge drinking episodes in the U.S. occur among adults age 26 and older, and half of all binge drinking episodes occur among people who otherwise drink moderately.

The NIAAA also provided a definition of moderate drinking as this term has been used in many different ways. Moderate drinking is defined by the NIAAA as consuming up to two drinks per day for men and one drink per day for either women or senior adults. While moderate drinking is considered to offer some benefits to some individuals, drinking at this level poses real risks for others. For example, women who are pregnant or considering pregnancy, persons driving or operating heavy machinery, and those taking one or more of the more than 150 medications that interact with alcohol should not drink even moderately. Persons with a high vulnerability to develop alcohol dependence may be encouraged to refrain from alcohol use.

The National Epidemiological Survey on Alcohol and Related Conditions (NESARC) study completed its first wave of data collection, which involved recording the responses to questions posed to over 43,000 individuals about alcohol and other drug use, abuse and dependence, and their associated disabilities. These data were used to develop extremely valuable information relating quantity and frequency of alcohol use to the risk of developing alcohol abuse and alcoholism. These data have been used to establish the following cut points for risk drinking, which mirrors the definition for moderate drinking: Exceeding 2 drinks per day for men, 1 drink for women, and 14 drinks per week for men and 7 drinks per week for women. The NESARC data revealed that, compared with individuals who adhere to the weekly and daily limits, those who exceed only the weekly limits have an 8-fold increase in risk for developing alcohol abuse and a 12-fold increase in risk for becoming alcohol dependent at some point in their lives (Table I-4). Exceeding daily limits once a week or more increases risk for alcohol abuse by 30-fold, and for dependence by 80-fold. Exceeding both weekly and daily limits increases the risk of alcohol dependence by more than 200-fold.

Table I-4. U.S. Adult Drinking Patterns and Risks 2001-2002: Odds Ratios
Adult Drinking Patterns and Risks
Source: NIAAA 2001-2002 NESARC data

C. Prevalence of Alcohol Problems and Their Consequences

How extensive are the health problems arising from inappropriate alcohol use and what are those problems? Excessive, long-term alcohol consumption can cause a variety of adverse health effects, including alcoholic liver disease, alcoholic pancreatitis, brain damage, and cardiomyopathy and compromised immune and endocrine functions. Excessive drinking is also associated with an increased risk for cancers of the esophagus, liver, and larynx, irregular heartbeats, and can exacerbate the health consequences of infection with hepatitis C, HIV and other infectious agents. Alcohol consumption can also alter neuronal function, resulting in cognitive deficits, and in neuroadaptations that contribute to the behavioral changes observed with alcoholism (tolerance, sensitization, loss of control, dependence, withdrawal, and relapse).

Epidemiologic data inform us of the problems associated with alcohol consumption and, when collected over time, allow us to track our progress in addressing these problems. The U.S. Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recently came to similar conclusions about the toll taken by alcohol misuse. According to the CDC, excessive alcohol consumption is the number-three cause of preventable death in the United States. The WHO also ranks alcohol third among preventable risk factors for premature death in developed nations. The extent of the alcohol use disorders problem in the U.S. and worldwide is summarized in Table I-5.

Table I-5. Extent of the Alcohol Use Disorder Problem

Globally:

* In 2003, the prevalence of alcohol use disorders was estimated at 1.7%, accounting for 1.4% of the total world disease burden in developed countries

United States:
* 18 million Americans (8.5% of the population age 18 and older) suffer from alcohol abuse or dependence. Only 7.1% of these individuals received any treatment for their alcohol problems in the past year.
* Alcohol problems cost U.S. society an estimated $185 billion annually

* Alcohol was the third leading cause of death in the US in 2003 (an estimated 85,000 deaths)

Source: World Health Organization, 2003

Alcohol also contributes significantly to mortality from a wide-range of acute and chronic injuries and diseases (see Table I-6). In the U.S. in 2001, 75,766 deaths were attributable to alcohol, 40,933 deaths were attributable to acute conditions primarily unintentional injuries such as motor vehicle injuries, and fall injuries, and intentional injuries such as homicide and suicide, and 34,883 deaths were attributable to chronic conditions especially alcoholic liver disease and liver cirrhosis. Because alcohol attributable deaths resulting from acute conditions occur earlier in the life span than chronic alcohol attributable deaths, they account for nearly twice as many years of productive life lost (e.g., 1,491,317) compared with chronic alcohol attributable deaths (e.g., 788,005). Recently, the NIAAA Extramural Advisory Board (EAB; a working sub-group of the NIAAA National Advisory Council) recommended that researchers could improve the estimation of alcohol-attributable factors (AAF) for morbidity and mortality by better characterizing the relationship between patterns of drinking (e.g., binge-drinking) and a variety of outcomes, and by incorporating relevant indicators of drinking (e.g., medical examiner data).

Injuries are the leading cause of death in the U.S. from ages 1-44, and alcohol is the leading contributor to those injury deaths. It should be noted that many people who die from alcohol attributable injury deaths are persons other than the drinker. For example, 40% of people who die in crashes involving drinking drivers are persons other than the drinking driver e.g. passengers in the same vehicle, passengers in vehicles struck by the drinking driver, bicyclists and pedestrians. Further, many homicide victims are fatally injured by persons who had been drinking. This underscores the need to identify, through rigorous research programs, policies that protect individuals from their own excessive drinking, as well as from the potential harms excessive drinking may cause society. One manner in which to get some indication of how policies affect excessive alcohol consumption leading to harm would be to undertake systematic studies of key alcohol and other relevant public policies and their outcomes (Recommendation of the NIAAA EAB, August 2006).

Table I-6. Number of deaths and years of potential life lost (YPLLs) attributable to the harmful effects of excessive alcohol use for selected conditions, by cause and sex – United States, 2001

 
Deaths
YPLLs
 
CauseMaleFemaleTotalMaleFemale Total
Chronic conditions
     
Acute pancreatitis

370

364 7347,1386,05413,192
Acute cardiomyopathy
443
5649910,1951,552 11,747
Alcohol-induced chronic Pancreatitis

224

71
295
6,2092,1358,344
Alcoholic liver disease8,9273,27412,201221,36994,952
316,321
Chronic pancreatitis
126
106
232
2,606
1,952
4,560
Esophageal cancer
394
53
447
6,213
788
7,000
Liver cancer
518
172
690
8,640
2,633
11,273
Liver cirrhosis, unspecified3,9172,802 6,71980,61654,528135,144
Oropharyngeal cancer
303
57
360
5,280
889
6,169

Total

24,448 10,28534,883549,396239,619788,005

Acute conditions

      
Alcohol poisoning
253
78
331
8,798
2,952
11,750
Homicide5,963
1,692
7,655262,37971,543333,922
Motor vehicle 10,674
3,000
13,674442,943136,558579,501
Suicide
5,617
1,352
6,969186,56849,297235,865
Falls
2,500
2,206
4,766
41,627
24, 288
65, 914
Total Acute Conditions30,30910,53440,9331,131,028350,2891,491,397

Total

54,94720,91875,7661,679,414599,9082,279,322

Source: Adapted from the table in Alcohol-Attributable Deaths and Years of Potential Life Lost --- United States, 2001 MMWR September 24, 2004, 53;866-870.

Co-Morbid Conditions

In addition to the many adverse health effects that result directly from alcohol misuse, co-morbid conditions often present further complications for individuals with alcohol abuse problems. Alcohol abuse and dependence commonly occur in individuals who suffer from mood, anxiety, and personality disorders as well as the effects of other drugs of abuse, (see Table I-7). For example, an estimated 90% of cocaine addicts have alcohol problems. It also has been estimated that as many as 60% of patients presenting at community mental health centers have co-morbid alcohol and other drug abuse disorders. Patients suffering from both disorders often have poorer treatment outcomes and are more likely to drop out of treatment. Unfortunately, effective pharmacological and behavioral treatments have yet to be established for the various conditions of co-morbid AUD and other drug abuse disorders.

The high co-morbidity between alcohol and tobacco dependence poses special problems. Fifty to ninety percent of alcoholics smoke, a rate that is three times higher than among the population as a whole. Alcoholics smoke heavily, are more addicted to nicotine and are less successful at quitting smoking, which puts them at a greatly increased risk for the synergistic effects of alcohol and nicotine on the development of certain cancers and cardiovascular diseases. According to one study, more individuals with alcoholism die from smoking-related diseases than alcohol-related diseases. Furthermore, there is experimental evidence that smoking may lead to a reduction in blood alcohol concentration for a given amount of alcohol consumed, thus leading to an increased use of alcohol to achieve the same pleasurable feelings from alcohol ingestion. Thus, smoking increases the amount of alcohol consumed and subsequently the risks for short-term and long-term adverse effects from the increased consumption of alcohol, including the perpetual cycle of use leading to dependence on both substances. Finally, there is evidence to suggest that the brain pathways that underlie the pleasurable feelings derived from alcohol consumption and smoking are thought to be the same, thus accounting for the increase in use of both substances, which suggests that treatment programs to reduce or cease alcohol consumption should also address cessation of smoking. There are some data indicating that treating one use disorder without treating the other concurrently leads to a higher relapse rate for either substance.

Table I-7. Odds of Current (past 12-month) DSM-IV Alcohol Dependence Co-Occurring with Selected Psychiatric Conditions and Other Drug Dependencies Odds of Current (past 12-month) DSM-IV Alcohol Dependence Co-Occurring with Selected Psychiatric Conditions and Other Drug Dependencies

 

 

 

 

 

 

 

 

 

 

 

Source: NIAAA 2001-2002 NESARC data

Contributions to Alcohol Use and Alcohol Problems Across the Lifespan

The initiation and continuation of alcohol use by an individual is influenced by numerous factors, chiefly the individual's genetic makeup, the environments to which he or she is exposed, and complex mechanisms through which genes interact with one another and with the environment. These same factors determine an individual's pattern of alcohol consumption and the risks for developing alcohol dependence (alcoholism) or other alcohol use disorders.

More than three decades of research has firmly established that genes account for more than half of the risk for alcoholism and environmental factors account for the remainder. This statement, however, belies the true complexity of the mechanisms underlying the risk for, and protection against, alcohol abuse and alcohol dependence. As with many other complex diseases, there is no single genetic or environmental factor that can fully account for the risk of alcoholism. The development of such complex behavioral and other medical disorders likely depends upon the specific genetic factors interacting with one another, the interaction of multiple environmental risk factors, and the interaction of genetic and environmental factors.

Research has also revealed that neither genetic nor environmental factors are static. That is, the emergence and progression of drinking behavior and of drinking consequences is influenced by multiple ongoing changes in biology, physiological and psychological development, and environment that occur over the course of a person's life. These observations are in accord with a broader recognition that human development continues throughout life, rather than stopping after adulthood is reached. A full understanding of the development of drinking behaviors and disorders, therefore, requires a lifespan context, in which the central concept is that the influence of alcohol on biology and behavior is dynamic and changes as an individual moves from childhood into adolescence and through the various stages of adulthood. This conceptual framework is depicted schematically in Figure I-1.

Figure I-1. Alcohol Across the Lifespan

Alcohol Across the Lifespan

Some of the first evidence of the importance of the lifespan perspective for understanding alcohol use disorders emerged less than ten years ago in an analysis of data derived from NIAAA’s National Longitudinal Alcohol Epidemiologic Study (NLAES). This analysis indicated that persons who begin drinking at younger ages have a significantly increased risk for the development of alcoholism. This finding was replicated in the recent NESARC study, as shown in Figure I-2. These data show that young people who begin drinking before age 15 were four times more likely to develop alcohol dependence during their lifetime than those who begin drinking at age 21. This is true for individuals from families where a parent had a history of alcoholism (Parental History Positive) and for individuals with no parental history of alcoholism (Parental History Negative). Therefore, while parental history clearly contributes to the risk for developing alcoholism, likely a reflection of genetic risk factors, early initiation of drinking is also an important predictor of risk for the eventual development of alcoholism.

Figure I-2. Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Parental History of Alcoholism

Prevalence of Lifetime Alcohol Dependence by Age of First Alcohol Use and Parental History of Alcoholism

Source: NIAAA 1991-1992 NLAES data (left panel) and NIAAA 2001-2002 NESARC data (right panel)

What is the mechanism by which exposure to alcohol in youth or adolescence increases the risk for alcoholism? Early exposure to alcohol may alter neurodevelopment through one or more mechanisms to cause increased vulnerability to alcohol dependence. Alternatively, it is possible that some other biological factor, perhaps affecting personality, is responsible for both the early onset of drinking and the heightened risk for alcoholism. As research continues, new findings will help to establish how, and the extent to which each of these two potential mechanisms contribute to the development of alcohol problems. That knowledge will arise from research on brain development in general, as well as from research directed specifically to alcohol-related issues. For example, research on human brain development has revealed that the brain continues to develop through adolescence and into young adulthood. Research also has shown that adolescents in treatment for alcohol dependence have reductions in the size of a brain region known as the hippocampus. Taken together, these two findings provide support for the hypothesis that early alcohol exposure perturbs and thereby alters early brain development which contributes to later vulnerabilities for alcoholism and other disorders.

What is the prevalence of alcohol problems in other phases across the lifespan? As Table I-8 shows, the prevalence of alcohol abuse and alcohol dependence within the past year varies with age. The highest previous year prevalence of alcohol dependence is found among the young adult population (defined as 18-29 years of age), particularly between the ages of 18 through 24. As has been noted, problems with alcohol use disorders are also very significant in the adolescent population, aged 12-17 years (further discussed in Chapter IV). From its peak in the young adult years, the prevalence of past year alcohol dependence declines with increasing age (adolescence, young adult, midlife defined as 30-59 years of age, and senior), falling below one percent among senior adults (defined as 60 years of age and older). According to these data, at any time point, the percentage of individuals who received treatment for their alcohol use disorder is quite small relative the numbers experiencing alcohol problems (also see Figure I-5).

Table I-8. Percentage of U.S. Adults 18 and Over with Past-year Alcohol Abuse or Dependence and Percentage of Those with Past-year Abuse or Dependence Who Received Alcohol Treatment, by Type of Treatment

Past-year disorder

Type of treatment

Age group

Abuse

Dependence

Any treatment

12-Step only

Other only

12-Step and other

All ages

4.7 (0.2)

3.8 (0.1)

7.1 (0.5)

1.1 (0.2)

2.7 (0.3)

3.4 (0.4)

Young Adult

18-29

7.0 (0.4)

9.2 (0.4)

5.9 (0.7)

1.3 (0.4)

2.3 (0.4)

2.3 (0.5)

18-24

6.7 (0.5)

11.6 (0.6)

6.4 (0.9)

1.4 (0.5)

2.8 (0.6)

2.2 (0.6)

25-29

7.3 (0.6)

5.7 (0.4)

4.9 (1.2)

1.0 (0.5)

1.2 (0.5)

2.7 (0.9)

Midlife

30-59

5.0 (0.2)

3.0 (0.2)

8.5 (0.7)

0.8 (0.2)

3.1 (0.5)

4.5 (0.6)

30-44

6.0 (0.3)

3.8 (0.2)

8.9 (1.0)

0.7 (0.2)

3.2 (0.7)

5.0 (0.8)

45-59

3.9 (0.3)

2.0 (0.2)

7.5 (1.2)

1.0 (0.4)

3.0 (0.8)

3.5 (0.8)

Senior

60+

1.4 (0.1)

0.5 (0.1)

3.4 (1.3)

1.9 (1.1)

0.8 (0.6)

0.6 (0.4)

Source: NIAAA 2001-2002 NESARC data

Figure I-3 looks at the history of alcohol abuse and alcohol dependence from a cumulative life-time perspective. The figure shows the cumulative conditional probability that an individual at a given age would have at some point in their life met the diagnostic criteria for DSM-IV alcohol abuse or dependence. As seen from the figure, by age 30 these probabilities were 10% and 17% respectively for dependence and abuse. By age 60 they are 14% and 20% respectively.

 

Figure I-3. Cumulative Probability of Onset of DSM-IV Alcohol Abuse or Alcohol Dependence by Age

Cumulative Probability of Onset of DSM-IV Alcohol Abuse or Alcohol Dependence by Age

Source: Substance Abuse and Mental Health Services Administration (SAMHSA) 2002 National Survey on Drug Use and Health (NSDUH) data (ages 12-17) and NIAAA 2001-2002 NESARC data (ages 18-60+)

Figure I-4 examines this same data from NESARC, looking at the past-year status of drinking by the interval since the individual first met the diagnostic criteria for alcohol dependence. Less than 10% of the individuals interviewed met the criteria for past-year alcohol dependence 20 years or more after initially meeting dependence criteria. Of those individuals who initially met diagnostic dependence criteria less than 5 years previously, 65% still met the criteria for dependence. As the figure shows, over 30% of individuals who initially met dependence criteria 20 or more years previously were abstinent in the past year, but in this time-frame category, as well as the other time frames since dependence onset, some individuals in the past year were in partial remission (some but not all dependence or abuse symptoms), asymptomatic risk drinkers, or low risk drinkers (less than 5 drinks on any occasion or 14 drinks per week).

 

Figure I-4. Past-year Alcohol Use Status by Interval Since Onset of Dependence

Past-year Alcohol Use Status by Interval Since Onset of Dependence
Source: NIAAA 2001-2002 NESARC data

 

Figure I-5. History of Prior Interventions in Prior to Past Year Alcohol Dependence Subjects

History of Prior Interventions in Prior to Past Year Alcohol Dependence Subjects
Source: NIAAA 2001-2002 NESARC data

 

The changes in drinking status over time shown in Figure 1-4, coupled with the finding that 24.4% of individuals who had prior to the past year (PPY) alcohol dependence recovered without the benefit of alcohol dependence treatment (Figure I-5) provides evidence that some individuals may "age-out" or experience natural recovery from the disorder.

Alcohol-Related Policy and Public Health Outcome

A wide range of public policies may affect alcohol consumption and other behaviors relating to alcohol, and therefore can have important influences on public health outcomes. In the United States, laws, regulations, and jurisprudence address (1) alcoholic beverage production, packaging, transportation, marketing, taxation, sales, and consumption, (2) financing and delivery of alcohol-related treatment and preventive services, and (3) behaviors that may be affected by alcohol, such as driving and boating. In many of these topic areas, policies are established by governments at all levels (Federal, State, county, and municipal).

Scientific research has identified a number of alcohol-related policies that have significant effects on public health outcomes. Among the policies with the best evidence of effectiveness is the minimum legal drinking age of 21, which has been shown to reduce consumption and traffic crash deaths among youth 16-21. This policy may also have other benefits, as studies have shown that deferring the initiation of drinking reduces both the risk and severity of subsequent alcohol use disorders. Although every state now sets the minimum age for possession and purchase of alcoholic beverages at 21, there is still substantial variation in states' policies toward underage drinking. Many states afford significant exceptions to the laws against possession and consumption (e.g., except for in a private residence, or only in a public place).

Policies addressing drinking and driving have been shown to reduce traffic fatalities. Every State has now established a law against driving with a blood alcohol concentration (BAC) of .08 or above. All States have also adopted so-called "zero tolerance" laws that set BAC limits for drivers under the age of 21 at no more than .02 percent. These laws, combined with a variety of other policies designed to deter driving after drinking, have helped reduce rates of alcohol-related traffic fatalities in the United States by 50% since 1982.

Alcoholic beverage taxes are another policy for which there is strong evidence of effectiveness. Although tax rates are most often established for fiscal rather than public health purposes, a number of studies have found significant relationships between higher taxes on alcoholic beverages and lower rates of traffic crash fatalities or drunk driving, particularly among younger drivers or during nighttime hours. Other research has found associations between higher alcoholic beverage taxes and lower rates of some types of violent crime, reduced incidence of physical child abuse committed by women, and lower rates of sexually transmitted diseases and liver cirrhosis mortality, as well as with increases in college graduation rates.

Public policies affecting the delivery and financing of alcohol-related treatment and preventive services may have important effects on access to treatment services. Most states now require health insurers to cover treatment for alcoholism, and a number of other states require such coverage to be offered but not necessarily included in every insurance contract. However, no Federal laws require coverage for alcoholism treatment, and Federal law exempts many large employers from state laws with such requirements. As a result, many insurance policies may not include coverage for alcoholism treatment.

Many states have laws, known as "Uniform Accident and Sickness Policy Provision Laws," or UPPL, that permit health insurers to deny payment for losses that are the result of the insured person being intoxicated. Researchers have suggested that these policies create a disincentive for health care providers in emergency and primary care settings to screen for alcohol problems, with the result that fewer individuals in need of treatment for alcohol problems are referred to treatment just when such referrals might be most effective. While studies have not yet established the true effects of UPPL provisions on treatment referrals, a few states have recently enacted laws that prohibit exclusion of insurance benefits on the basis of intoxication.

Because of the complexity of alcohol-related public policies, researchers face a challenge in identifying how specific policy measures may affect health outcomes. The Alcohol Policy Information System (APIS), developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA), provides reliable, detailed, and comparable information on alcohol-related public policies in the United States at both the state and Federal levels. The APIS Web site ( http://alcoholpolicy.niaaa.nih.gov ) provides public access to detailed information on a wide variety of alcohol-related public policies. Intended primarily as a tool for researchers, APIS features compilations and analyses of alcohol-related statutes and regulations designed to simplify the process of ascertaining the state of the law for studies on the effects and effectiveness of alcohol-related policies.

D. Issues that Transcend the Lifespan Perspective

There are six issues that provide significant background perspectives necessary for the accurate interpretation of previous results and the formulation of research hypotheses with respect to alcohol use across the lifespan. These issues are alcohol metabolism, alcohol and gene/environment interactions, the neurobiology of alcohol, the diagnostic criteria for alcohol abuse and dependence, span. alcohol health services research, and social, legal and ethical issues of alcohol research. They are presented in this overview as they transcend the full lifespan.

D.1. Alcohol Metabolism

Individuals differ in how fast they metabolize alcohol (pharmacokinetics) and in the extent to which they are affected by a given dose of alcohol (pharmacodynamics). These individual differences affect drinking behavior, the potential for the development of alcohol dependence, and the risk for developing alcohol-induced organ damage. These individual differences in females also contribute to the extent that alcohol metabolism affects the fetus during development. Therefore, understanding these differences will provide important information about alcohol’s health effects throughout the lifespan.

The major pathway for the metabolism of alcohol is found in the liver and involves the enzyme alcohol dehydrogenase (ADH) (see Figure I-6). Alcohol is metabolized to acetaldehyde, a highly reactive and potentially toxic molecule. In most circumstances, acetaldehyde is rapidly metabolized by another enzyme, aldehyde dehydrogenase (ALDH) to acetate. Because of the rapid enzymatic conversion of acetaldehyde to acetate, the concentration of acetaldehyde in the cell is typically a thousand-fold lower than that of alcohol, and the eventual product of this pathway, acetate. Both alcohol and acetate are found at millimolar levels following drinking, while acetaldehyde is found at micromolar concentrations. [The legal intoxicating blood alcohol level in all states in the U.S. is 80 mg%, which is 17.4 mM. The normal baseline level for acetaldehyde in humans is 9 µM, or 40 µg%. After alcohol ingestion, the acetaldehyde level in most individuals will increase to 20-30 µM, or 90-- 130 µg%. Metabolism of a dose of alcohol achieving a blood alcohol concentration of 80 mg% may result in elevation of tissue acetate levels to 2mM] When the level of acetaldehyde increases, an individual may experience very dysphoric feelings and the potential for toxic reactions with various cellular components increases. Men and women differ with respect to the rate of alcohol metabolism based primarily on differences in total water body content, and potentially changes associated with the menstrual cycle. The extent of difference in alcohol metabolism between pregnant and non-pregnant women is not well studied, although it has clear implication for the amount and duration of alcohol available to the fetus during pregnancy.

 

Figure I-6. Alcohol Metabolism in the Liver

Alcohol Metabolism in the Liver

Source: Figure created by Brenda Hewitt

There are a number of variants of the ADH and ALDH enzymes, and the differences in the profile of the variants present can influence an individual's drinking behavior. The various functional variants of ADH and ALDH are shown in Table I-9.

Table I-9. Human ADH and ALDH Isozymes

Class

Nomenclature

Km (mM)

Vmax(min-1)

Alcohol

Dehydrogenase (ADH)

I

ADH1A

4.0

30

ADH1B*1

0.05

4

ADH1B*2

0.9

350

ADH1B*3

40.0

300

ADH1C*1

1.0

90

ADH1C*2

0.6

40

II

ADH4

30.0

20

III

ADH5

10

IV

ADH7

Aldehyde

?

?

a

ALDH2*1

3

 
ALDH2*2
~300--

Source: ADH: Km and Vmax values from Hurley et al., 2002; ALDH Vmax: Yin & Li (pp. 227-247), In Sun et al., Molecular Mechanisms of Alcohol: Neurobiology and Metabolism, Humana Press, 1989; ALDH Km: Mizoi et al., 1994.

Most of the alcohol consumed by humans is metabolized by the Class I and Class II ADH enzymes (Table I-9). While only one functional form of the Class II ADH isknown, the Class I ADHs exist in a number of polymorphic forms, and differences in individual Class I ADHs contribute to variation in the alcohol metabolic rate (Table I-9). Of particular importance are the three known functional variants of ADH1B. The ADH1B*2, found in the majority of Asians and 25 percent of people of Jewish ancestry, and the ADH1B*3, found in some African Americans, oxidize alcohol at a faster rate thanthe ADH1B*1 variant which predominates in most European Americans. Two functional forms of the ADH1C gene also exist (ADH1C*1 and ADH1C*2). The Class I ADH enzymes are found primarily in the liver in the cytosol compartment of the cell.

There are other enzyme pathways that can metabolize alcohol to acetaldehyde, including cytochrome P450 and catalase (Figure I-7). The cytochrome P450 isozyme CYP2E1 is the form which is predominantly involved in alcohol oxidation. It is present in an internal cellular structure known as the endoplasmic reticulum and particularly comeinto play after chronic, heavy, alcohol exposure. Alcohol metabolism by CYP2E1 also produces highly reactive oxygen species (ROS) with the potential to cause tissue damage. Unlike most Class I ADH enzymes that are primarily found in the liver, CYP2is found in a number of tissues and organs including liver, brain, heart, lung, and the neutrophils and macrophages of the immune system. Therefore, the generation of acetaldehyde and ROS within these tissues poses risks for injury to these systems. The enzyme catalase (Figure I-7), located in the intracellular structure known as the peroxisome, is also capable of oxidizing alcohol in the presence of a hydrogen per(H2O2)-generating system. However, catalase appears to be a minor pathway for alcohol metabolism.

 

Figure I-7. Minor Oxidative Pathways of Alcohol Metabolism

 

Minor Oxidative Pathways of Alcohol Metabolism

Source: Figure created by Dr. Ting-Kai Li and Dr. Samir Zakhari.

The acetaldehyde that is produced from alcohol oxidation through any of these enzyme systems is typically metabolized rapidly to acetate. ALDH catalyzes the oxidation of many aldehydes, and under conditions of ethanol exposure, ALDH enzymes specifically convert acetaldehyde to acetate. Genetic polymorphisms in the ALDH genes have been linked to decreased risk of alcoholism and increased risk of alcohol-induced cancers. A variant of the mitochondrial aldehyde dehydrogenase enzyme (ALDH2*2) is found in about 50 percent of Taiwanese, Han Chinese, and Japanese populations. The enzyme expressed by ALDH2*2 is virtually inactive. Consequently, individuals with one, and particularly two copies of this allele show elevations in acetaldehyde after consuming alcohol (see Figure I-8). Individuals with both ADH1B*2 and ALDH2*2 genes have been shown to have virtually complete protection against developing alcoholism, presumably due to the adverse effects of elevated acetaldehyde. This allelic combination is curiously absent in Native American Indian populations, who have a high prevalence of alcoholism, suggesting that other combinations of ADH and ALDH genes may confer various forms of protection or susceptibility to alcohol use disorders.

Figure I-8. Blood Acetaldehyde Concentrations of Han Chinese Men with Different ALDH2 Allelotypes (0.2 g/kg ethanol)

Blood Acetaldehyde Concentrations of Han Chinese Men with Different ALDH2 Allelotypes (0.2 g/kg ethanol)

Source: Chen et al. Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism. Am J Hum Genet 65:795-807, 1999

Most of the acetate arising from ethanol metabolism departs the liver via the circulatory system and is eventually metabolized to carbon dioxide (CO2) and water by way of the tricarboxylic acid cycle (TCA) in heart, skeletal muscle, brain, and liver. Further, acetate itself is not an inert product; in addition to being a metabolic source of energy, it can increase portal blood flow in the liver, and potentially in other organs, and contributes to the biosynthesis of adenosine which has its own effects on cortical and coronary blood flow in response to need.

The oxidation of alcohol through ADH, and acetaldehyde through ALDH, is accompanied by the conversion of the co-enzyme nicotinamide-adenine dinucleotide (NAD+) to its reduced form NADH (Figure I-7). When sufficiently large amounts of alcohol are consumed, alcohol metabolism can change the reductive-oxidative state of the cell (redox state), expressed as the ratio of NAD+/NADH. The change in the NAD+/NADH ratio, in turn, can affect a number of metabolic pathways within the cell. Further, the NADH generated through alcohol and acetaldehyde oxidation is subsequently re-oxidized to NAD+ through the mitochondrial electron transport chain, a process that involves the generation of the energy intermediate ATP. Enzymes within the electron transport chain also have the potential to generate ROS. In a cellular environment low on antioxidant defense mechanisms (e.g., glutathione), such as occurs after heavy alcohol exposure, these ROS have the potential to disrupt developmental processes and to cause tissue damage.

In addition to the oxidative pathways of alcohol presented above, alcohol can also be non-oxidatively metabolized by at least two pathways. One leads to the formation of fatty acid ethyl esters (FAEE) and the other to phosphatidyl-ethanol. Both oxidative and non-oxidative pathways of alcohol metabolism are inter-related, and may result in tissue injury throughout the lifespan.

Opportunities for Research in Alcohol Metabolism Across the Lifespan

D.2. Alcohol and Gene/Environment Interaction, Epigenetics
Neither genes nor environment alone can explain why any particular individual develops alcohol dependence. Rather, as a complex disorder, risk for the development of alcohol dependence will be a consequence of the interplay of multiple genes, potentially multiple environmental factors, and the interaction of these genes and the environmental factors. Similarly, it is not likely that any single mechanism of gene-environmental interaction will explain all vulnerability to alcohol dependence. While in the past decade investigators have sought to define both genes and environmental factors underlying risk, this effort had been limited due to a lack of powerful technologies and methodologies that could be applied to the genetic study of complex disorders such as alcoholism. In recent years, advanced technologies such as single nucleotide polymorphisms (SNPs) and haplotype maps have enabled scientists to identify genes associated with these disorders. Although a few genes, such as GABRA2, ADH, ALDH, CHRM2, OPRM1 and NPY, have been linked to alcohol dependence and its related disorders, it is apparent that more genes will be rapidly identified. A number of candidate genes in animals and humans are presented in Table I-10.

 

Table I-10. Genes Contributing to Alcohol-Related Behaviors in both Rodents and Humans

Table I-10. Genes Contributing to Alcohol-Related Behaviors in both Rodents and Humans

 

The search for both genetic and environmental risk factors includes both human population genetics investigation, as well as studies involving animal models. Specifically, selected animal strains are used to model the endo- and intermediate phenotypes (see Table I-11) involved in the development of human alcohol dependence. While animal models of alcohol tolerance and alcohol preference have been developed in the past, refinement of current models is still required in order for them to more closely parallel those features of the clinical syndrome phenotype, including modeling such contributing traits as anxiety, propensity for relapse, and obsessive-compulsive behaviors such as craving.

Table I-11. Definition of Endophenotype, Intermediate Phenotype, and Clinical Syndrome Phenotype

Endophenotype: innate or biological host factors that may predispose an organism to alcohol dependence (e.g., temperament, gene expression, electrophysiology, developmental biology)

Intermediate phenotype: host factors interact with environmental factors to facilitate the development of alcohol dependence (e.g., sensitivity, tolerance, reward)

Clinical Syndrome Phenotype: the transition from voluntary to nonvoluntary, obsession with and compulsion to use alcohol

 

Epigenetics

One additional route by which alcohol may affect the development of alcohol disorders, from alcohol dependence to organ disease is through epigenetics, which refers to stable alterations in the genome, sometimes heritable through cell division, that do not involve permanent changes to the DNA sequence itself. Epigenetic processes act as an additional source of biologic variation beyond that attributable to the genetic code. These processes involve the chemical modification of the constituents of the chromosome, the DNA molecules and the gene-regulating proteins known as histones, and may occur as a consequence of exposures to specific environmental substances and stimuli. Alcohol and its metabolites could be important environmental factors contributing to epigenetic processes. For example, alcohol has been shown to cause acetylation at specific histone sites in the rat chromosome, resulting in increased expression of the ADH gene. Further, alcohol has the ability to alter the normal biochemical pathways by which DNA and histones might be modified in response to other events occurring in the environment. For example, alcohol can interfere in the metabolic pathways leading to the biosynthesis of the intermediates required to modify DNA, by altering biosynthetic pathways involving folate, and inhibiting the synthesis of a “methyl donor” known as S-adenosyl methionine (see Figure VI-1 in Chapter VI).

Related to such metabolic alterations, alcohol may influence epigenetic processes in ways opposite to that necessary for normal functioning, and in the case of the fetus, to that required for normal development. Epigenetic events also may contribute to the development of alcohol tolerance and sensitization, obsessive-compulsive drinking, craving, cognitive effects of chronic drinking and organ damage associated with heavy drinking.

Cellular Phenotypes/Immortalized Cell Lines

Recent advances in rapid molecular biology techniques coupled with the sequencing of the human genome, and the genomes from select animal model systems, has provided the opportunity to identify the complex relationships that inter-connect genotype and phenotype underlying the progression 'from sequence to function.' A thorough understanding of biological systems requires a complete assessment of not only gene-gene interactions, but protein-protein interactions, post-translational modifications, and metabolic effects. One approach to understanding these complex interactions involves the phenotypic characterization of immortalized cell lines (of known genetic background) from organ systems of interest following the application of a manipulation, such as alcohol exposure under conditions within the physiological range of normal and binge human alcohol consumption. Gene targeting experiments can further elucidate the molecular signals in temporal sequence by perturbation of the cell line through knockdown/inactivation or over-expression of genes in isolation combined with microarray techniques that allow expression of phenotypic changes in the response to alcohol exposure.

Opportunities for Exploring Alcohol and Gene/Environment Interaction, and Epigenetics Across the Lifespan
There are many opportunities to explore the effects of alcohol exposure on the interaction of genes and environment across the lifespan, even though the effects of heavy alcohol consumption may differ significantly given the age of exposure, and with respect to alcohol's direct or indirect effects.
D.3. Neurobiology of Alcohol

Since the brain is a significant target for alcohol-induced toxic effects, and the brain undergoes development and maturation continuously from conception to birth and into adulthood, the effects of alcohol on neurobiology and neural processes in general are observed throughout life. Therefore, at any point in the lifespan, alcohol consumption may affect the normal physiology of the CNS, which makes the topic of alcohol's detrimental effects on the brains of any age of importance for comprehensive examination.

Alcohol has complex pharmacodynamic effects on the body, primarily through its interactions with the brain within the central nervous system (CNS). Alcohol's pharmacologic effects typically begin with mild stimulation, followed by CNS depression as shown in Figure I-9. Disinhibition and anxiolysis may also be experienced in the early phase following alcohol ingestion. As is noted in Figure I-9, as breath alcohol concentration (BrAC) increases, the likelihood and severity of functional impairments increases, ranging from impaired motor function to respiratory depression and death.

 

Figure I-9 Pharmacodynamics of Ethanol on the Central Nervous System

 

Pharmacodynamics of Ethanol on the Central Nervous System

Among the physiological or behavioral consequences of chronic alcohol use, that is, drinking too much, too fast and/or too often, are the disorders of alcohol abuse, and alcohol dependence. However, there are other pathologic consequences to both the CNS and the peripheral nervous system (PNS) that can arise from drinking over long periods of time. These usually do not clinically manifest themselves until the midlife period. Alcohol neurotoxicity can result from heavy alcohol consumption beginning as early as adolescence, which may be critical to understanding why certain individuals drink excessively and what biological factors continue to prompt them to drink. Furthermore, alcohol neurotoxicity affects the fetus with long-term consequences. Therefore, a discussion of alcohol's effect on the brain involves all ages of individuals.

Alcohol's effect on the brain can have immediate, direct, and wide-ranging ramifications, from effects on normal physiology (patterns of sleep-wake, thermoregulation), to effects on basic motor functions (balance, gait, coordination), to effects on thoughts and emotions (cognition). Of particular interest are physical or chemical alterations in the brain that may cause changes in cognition leading to a variety of responses that manifest as, for example, the decision to start or stop drinking alcohol or the decision to seek help for an AUD. The adaptations that occur in the development of alcohol dependence occur within the CNS as well. Therefore, it is important to explore the effects of alcohol on the brain at many levels, from cellular and molecular biology to cognitive effects, using the range of techniques and methods of neuroscience. Some relevant research topics that may advance the knowledge about the effects of alcohol on brain include an examination of synaptic protein adaptation, the differential temporal vulnerability (differences across the lifespan) of various brain regions and neuronal cell types to long-term consequences of alcohol-induced toxicity, changes in frontal lobe function associated with alcohol-induced cognitive alterations, impairments of neuroimmune and neuroendocrine function that predispose individuals to organ damage, and neuronal plasticity. These areas can be approached from a variety of perspectives in both clinical (human) and experimental (animal models) settings using imaging and functional imaging, electroencephalography, and cellular and molecular biology techniques.

Recommendations of the NIAAA Extramural Advisory Board (EAB) "Mechanisms of Alcohol Addiction ( MAAIT II)"
  • Learning and tolerance mechanisms. Explore learning, cognitive and tolerance mechanisms that facilitate or inhibit the escalation of drinking (within and across drinking bouts) in human and animal paradigms, and identify actions in relevant molecular and neural systems supporting these mechanisms.
  • Endophenotypes (risk and genetics). Identify physiological, temperamental, and cognitive traits and responses to alcohol associated with risk for or protection from developing alcohol dependence and study mechanistically-based hypotheses in animal and human laboratory paradigms.
  • Adolescent to adult transitions. Study alcohol's actions upon and interactions with genetic, physiological, hormonal, temperamental, neurocognitive, and social-affective factors associated with transitions into adolescence and adulthood that establish drinking patterns leading to uncontrolled drinking and examine the role of gender and early life events on this trajectory.
  • Epigenetics. Determine the mechanisms and examine the role of epigenetic modifications in the etiology or progression of alcoholism and alcohol-relevant behaviors, examining the influence of alcohol exposure at various life-stages and interactions with stressors and other internal and external moderators.

More detail on the recommendations made by the NIAAA EAB can be found at: http://www.niaaa.nih.gov/ResearchInformation/ExtramuralResearch/AdvisoryCouncil/

 

Opportunities for Examination of the Neurobiology of Alcohol Across the Lifespan

The central nervous system is a major target for adaptive, as well as toxic effects of alcohol across the lifespan, e.g., alterations in developing neurons, changes in neurotransmitter systems that alter neuronal function. Therefore, there is a wealth of information to be gained from researching the basics of the neurobiology of alcohol across various ages of subjects and experimental systems.

Since the early 1900s, numerous definitions of AUDs have been proposed. Currently, in the United States, the clinical standard used for defining and diagnosing AUDs is the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV).

Definitions of alcohol abuse (see Table I-1) and dependence (see Table I-2) appearing in the DSM-IV both describe maladaptive patterns of alcohol use leading to clinically significant impairment or distress.

DSM-IV alcohol abuse requires at least one of the following four symptoms to occur within a 12-month period:
DSM-IV alcohol dependence requires that at least three of the following seven criteria be met in a 12-month period:

Several issues have been raised concerning the applicability of the DSM-IV diagnostic definitions. With regard to dependence, the categorical nature of the diagnosis has been criticized as failing to represent the degree of severity inherent in the phenomenon. Each diagnostic symptom criterion carries equal weight in the classification, when clearly some criteria subsume symptoms that are more severe or disabling than others. The DSM-IV dependence diagnosis has also been questioned due to the absence of alcohol consumption measures, especially those consumption measures related to excessive drinking that have been found to increase individuals' risks for a variety of physical and psychiatric disorders. To address these issues, research has begun to focus on developing quantitative representations of AUD diagnostic criteria using statistical methods that provide differential severity weighting for individual AUD symptoms and allow for the inclusion of alcohol consumption variables (Saha et al., 2007).

Figure I-10. Severity of Alcohol Use Disorder: Comparison of Frequency of Risk Drinking (5+/4+) with Average Daily Ethanol Intake

 

Severity of Alcohol Use Disorder: Comparison of Frequency of Risk Drinking (5+/4+) with Average Daily Ethanol Intake

Source: Dawson, D. Laboratory of Epidemiology and Biometry, NIAAA, 2007.

 

As part of this effort, the relationship of average daily volume of alcohol consumption to severity of AUD, as well as the relationship between risk drinking and AUD was analyzed from the NESARC data. As seen in Figure 1-10, the increase in severity of AUD is non-linear with respect to average daily alcohol consumption or the frequency of risk or binge drinking, but rather increases at a greater than linear. One interesting observation is that the severity of AUD attained is about the same for individuals who engage in risk drinking once a month (5 drinks per occasion for males/4 drinks per occasion for females) as it is for individuals whose overall average daily alcohol consumption is 1 standard drink per day (30 drinks per month) (the blue bars in the two graphs in Figure 1-10).

Another important issue related to the current DSM-IV formulation of alcohol abuse and dependence concerns the relevance of some of the criterion items to certain subgroups of the population. For example, some researchers have questioned the applicability of DSM-IV symptom items to females, a result of the historical definitions of diagnostic criteria based on clinical samples that have been composed largely of middle-aged males. The need to determine if differential case identification for AUDs exists for males versus females will be paramount for future prevention and intervention efforts. Biases attributable to language, differences in response tendencies (e.g., trait desirability, social approval, or acquiescence), or cultural expectations and experiences can also lead to differential reliability and validity of the AUD diagnoses across race-ethnic subgroups of the U.S. population.

Further, questions have been raised about the applicability of specific diagnostic symptom items across the lifespan, particularly among youth, young adults, and the elderly. Whether some symptoms of AUDs may be more relevant to different stages of the life course is an important research question. Given the relationship between early-onset drinking and the increased risk of developing an AUD, identifying criterion symptom items specific to youth and young adults will be critical to prevention and intervention efforts. Similarly, identifying AUD symptoms of greatest relevance in the elderly can increase our ability to recognize serious alcohol problems among this important subgroup of the population, which is projected to increase dramatically over the next 10 years.

Opportunities Related to the Diagnostic Criteria for Alcohol Abuse and Dependence

D.5. Alcohol Health Services Research Across the Lifespan

Alcohol health services research is a multidisciplinary field of applied research that seeks to improve the effectiveness, efficiency and equity of services designed to reduce the public health burden of alcohol use disorders across the lifespan. It does this by examining how social factors, financing systems, service environments, organizational structures and processes, health technologies, and personal beliefs and behaviors affect access to and utilization of healthcare, the quality and cost of healthcare, and in the end our health and well-being. Ultimately the goal of alcohol health services research is to identify ways to organize, manage, finance, and deliver high-quality care consistent with developmental needs of patients and their families.

Opportunities Related to Alcohol Health Research Services Across the Lifespan
D.5. Ethical, Legal and Social Issues in Alcohol Research

The consumption of alcohol, more than any other substance, is governed by a variety of complex social and legal conditions. The complexity around alcohol consumption by humans adds important ethical, social, and legal issues (ELSI) to alcohol research. Each researcher using human or animal subjects must ensure that the research is being conducted in an ethical manner. NIAAA recognizes that adequate consideration of ethical, legal and social issues in alcohol research requires that the home institution provide support and guidance for the researchers as they carry out their research programs. NIAAA continues to approach this challenge though such activities as:

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CHAPTER II. The Embryo and Fetus

A. Background

The earliest stages of life, in particular, embryonic and fetal development, are periods of great vulnerability to the adverse effects of alcohol. A known teratogen (an agent capable of causing physical birth defects), alcohol may also damage neurological and behavioral development even in the absence of obvious physical birth defects. Alcohol's teratogenic effects were recognized over three decades ago, and it is now the leading known environmental teratogen.

Ranging from mild to severe, alcohol-induced birth defects are known as fetal alcohol spectrum disorders (FASD). The severity of defects depends on the dose, pattern, and timing of in utero exposure to alcohol. Research in animal models has demonstrated that the potential for adverse effects increases with the maternal blood alcohol concentration (BAC). As such, the peak dose, as measured by BAC, is a more important determinant of harm than is the total dose consumed.

The most serious adverse consequence of prenatal alcohol exposure is fetal alcohol syndrome (FAS), a devastating developmental disorder characterized by craniofacial abnormalities, growth retardation, and nervous system impairments that may include mental retardation. Children and adults with FAS have irreversible neurobiological deficits that affect multiple systems, ranging from motor control to executive function. Consequently, many secondary disabilities may occur, such as learning disabilities, attention disorders, failure in school, poor social skills, delinquent or criminal behavior, psychiatric co-morbidities, and premature and/or promiscuous sexual activity. Prenatal alcohol exposure itself may be a risk factor for subsequent alcohol and other drug use disorders later in life. The disabilities of FAS are life-long and place heavy emotional and financial burdens on individuals, families, and society.

Another fetal alcohol spectrum disorder is partial FAS, which includes the facial and neurodevelopmental deficits of FAS but not the growth deficits. Other FASD outcomes include alcohol-related birth defects (ARBD), where physical attributes of FAS are seen in the absence of the full syndrome, and alcohol-related neurodevelopmental disorder (ARND) in which neurobehavioral deficits are consistent with FAS, but the facial or physical features of FAS are absent.

By virtue of the lifelong learning and neurobehavioral deficits that characterize FAS and other types of FASD, many consider the central nervous system to be most critically affected by prenatal alcohol exposure. Imaging and neurobehavioral research in individuals with FAS and FASD reveals that some brain regions appear to be most sensitive to prenatal alcohol while other areas apparently are spared adverse effects. Particularly vulnerable regions include the frontal cortex, hippocampus, corpus callosum, and components of the cerebellum, including the anterior cerebellar vermis. Obviously, the extent of damage to any brain area may be related to the timing of alcohol exposure relative to the rapid development or neurogenesis of a particular brain region, and the stage of embryonic development.

Epidemiological studies have revealed other adverse outcomes of prenatal alcohol exposure, including an increase in the risk for spontaneous abortion, pre-term delivery, stillbirth, and sudden infant death syndrome (SIDS).

B. Epidemiology

Despite alcohol's potent teratogenicity, only a small proportion of women who drink heavily give birth to children with FAS. The prevalence of FAS and FASD are presented in Table II-1 for selected countries. In the U.S., the prevalence of FAS has been estimated at 0.5-2.0 cases per 1000 births, with FASD projected to occur at several times that prevalence (10 per 1000 births). In some parts of the world the rate of FAS is far greater than in the U.S. This is particularly true in countries where alcohol consumption during pregnancy is more common than in the U.S. For example, in parts of South Africa, where farm wages once were paid in part, with alcohol, a heavy drinking culture is quite prevalent among the mixed ancestry farm workers. The incidence of FAS in this region exceeds 60 cases per 1000 individuals.

Table II-1. Prevalence of FASD, FAS and Associated Disorders (FAE, ARND, ARBD) by Country (per 1000 cases)
Country
Fetal Alcohol Spectrum Disorders
Fetal Alcohol Syndrome
Canada
25 -- 46^
10.3^
France
6.0 (FAS and ARBD)
1.2 -- 2.9
Italy
20 -40
3.7 - 7.04
South Africa
-----
65-74*
Sweden
3.3 (FAS and ARBD)
1.7
United States
10
0.5 -- 2.0
Source: Canada: Habbick et al., 1996, Williams et al., 1999, Boland et al., 1998; South Africa: Viljoen et al., 2005; Italy: May et al., 2006; Sweden, France, and the United States: IOM Report, 1996.
Fetal Alcohol Spectrum Disorders include FAS, ARND, ARBD and FAE.
*Western Cape Province, Republic of South Africa
^ Among Aboriginal populations in Northern British Columbia and Yukon territory
Given that alcohol consumption is the prime factor responsible for FASD, the extent of drinking in pregnancy is an important epidemiological question. Despite a number of prevention efforts, including point of sale warning signs and bottle labeling, surveillance data indicate that 10% of pregnant women drink some alcohol and 2% are binge drinking. More than 12% of women who are not using contraception and are at risk of becoming pregnant are drinking at levels that exceed 7 drinks per week or 4 or more drinks per occasion.

 

C. Etiology

Research has shown that, in the development of FASD, alcohol's causative effect can be influenced by a number of maternal factors, including hormone status (e.g., thyroid hormones), nutrition, age, parity, and drinking history.

Research shows that genetic factors influence adverse pregnancy outcome in both humans and animal models. Animal research has also shown that the genetic profiles of the mother and the fetus are important for determining the potential for risk of physical birth defects, prenatal mortality, learning and other neurobehavioral deficits in the offspring. In humans, the presence of a specific variant of the alcohol dehydrogenase gene, ADH1B*2, in either the mother or child, has been shown to decrease risk for FAS. Other studies have shown that the presence of the ADH1B*3 variant decreases risk for neurodevelopmental deficits associated with ARBD. Both of these ADH variants have kinetic properties that make them more efficient at oxidizing alcohol to acetaldehyde, a noxious intermediate metabolite, suggesting that elevated acetaldehyde levels may contribute to decreased alcohol consumption to lessen the risk FAS and FASD.

Recommendations of the NIAAA Extramural Advisory Board (EAB) "Fetal Alcohol Spectrum Disorders Research"
  • To define full range of FASD/prenatal alcohol phenotypes and endophenotypes across the lifespan using advanced methods, technologies and applications -- integrative biology/systems biology and database approaches.
  • Develop and validate biomarkers to assess the exposure and insult to the mother and the fetus.
  • Conduct analyses of pre- and postnatal nutritional, genetic, epigenetic and environmental factors to determine risk or protective factors and co-morbidities (e.g., diabetes, tobacco and other drugs) that may alter susceptibility and natural history of fetal alcohol spectrum disorders.
  • Study the safety and efficacy of interventions (e.g., nutritional, pharmacological, neurobehavioral, and environmental) during periconceptional, pregnancy, and lactational periods.
  • Elucidate biological mechanisms that contribute to ethanol teratogenesis in a range of experimental models and in humans, including mechanistic links to biomarkers and treatment.

Detailed information regarding these EAB recommendations can be found at: http://www.niaaa.nih.gov/ResearchInformation/ExtramuralResearch/AdvisoryCouncil/