Skip to main content

Strategic Plan 2017-2021

National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Goal 1: Basic Science

Identify Mechanisms of Alcohol Action, Alcohol-Related Pathology, and Recovery

Image of brain

Basic research is the foundation for medical advancement, and it is integral to NIAAA’s mission to reduce the public health burden associated with alcohol misuse. Through research, great strides have been made in understanding the mechanisms by which alcohol exerts its effects on human health and behavior. Breakthroughs in neuroscience have revolutionized our understanding of alcohol use disorder (AUD) and demonstrated that it is a chronic brain disease with the potential for recovery and recurrence. As individuals progress from initial alcohol use to misuse to AUD, changes occur in brain structure and function that drive the transition from occasional, controlled alcohol use to chronic, compulsive drinking. Sophisticated new tools and techniques are enabling researchers to identify these changes with a precision never before possible. Basic research across the biomedical sciences is opening new avenues of investigation for understanding the biological and behavioral mechanisms through which these conditions develop. Studies are beginning to reveal the complex interactions between organ systems, including the gut, liver, and brain, and the immune and endocrine systems. This work indicates that the neurobiological changes induced by alcohol misuse may not be due entirely to the direct actions of alcohol on the brain, but that they may be mediated, in part, by interactions with peripheral systems.

A major focus of NIAAA’s work is to generate a more thorough understanding of these processes and to translate this information into innovative interventions for AUD and co-occurring mental health conditions. NIAAA is also committed to defining the mechanisms by which alcohol and its byproducts exert their effects on the body, including how patterns of alcohol consumption interact with genetic and environmental factors to influence health and the development and progression of alcohol-related pathology. NIAAA will continue to support a robust portfolio of basic biological and behavioral alcohol research and identify opportunities to apply the knowledge gained through this work into effective interventions for preventing and treating disease.

To advance these goals, NIAAA will pursue the following objectives:

Objective 1a: Identify mechanisms underlying alcohol use disorder and co-occurring mental health conditions 

AUD is characterized by a three-stage cycle: a loss of control in limiting alcohol intake (binge/intoxication stage), the experience of a negative emotional state in the absence of alcohol (withdrawal/negative affect stage), and a compulsion to seek out and consume alcohol (preoccupation/anticipation stage).17 (See “The Three Stages of the Alcohol Use Disorder Cycle.”) These stages are largely mediated by distinct but interacting neurobiological circuits involved in the experience of reward and habit formation (the basal ganglia), stress (the extended amygdala), and executive function (the prefrontal cortex).18 NIAAA supports preclinical and clinical research to examine: how alcohol-induced changes in these circuits contribute to AUD; how they relate to the cognitive, behavioral, and emotional phenotypes observed in individuals with AUD and co-occurring psychiatric conditions such as post-traumatic stress disorder and other substance use disorders (SUDs); and how they may be modified during treatment and recovery.

The role of the neuroimmune system in AUD is an important area of focus. Human and animal studies have revealed a link between alcohol consumption and altered neuroimmune function. Characterizing the pathways by which neuroimmune signaling contributes to functional changes in the brain associated with alcohol misuse could provide a new framework for understanding the development of AUD and lead to the identification of novel molecular targets for treating this disorder.

Studies investigating the effects of low-dose alcohol (i.e., less than 10 mM) on the brain also are of interest. Relatively low concentrations of alcohol are known to adversely affect aspects of cognitive function and behavior, yet little is known about how low-dose alcohol affects brain function, including what molecular and cellular targets mediate its initial rewarding effects. Elucidating how the brain responds to low-dose alcohol will provide a window into the brain changes that occur in the progression from alcohol use to misuse to AUD and into the neurobiological mechanisms underlying resilience or vulnerability to the disorder.

A major challenge to preventing and treating AUD lies in its heterogeneity. While the mechanisms underlying each stage of the AUD cycle are similar across individuals, there is variation in how people progress through the cycle and in the extent and nature of the disruptions to relevant brain circuits. For example, whereas some people with AUD may have trouble moderating their drinking because of heightened sensitivity to stress, others may drink due to an inability to experience pleasure from once-rewarding experiences, deficits in cognitive function that lead to poor decision-making, or some combination of these or other factors. Developing a better understanding of the neurobiological and behavioral phenotypes associated with AUD, including those relevant to the mental health conditions with which AUD frequently co-occurs, will facilitate the development of precision medicine–based approaches to preventing and treating these disorders.

To better understand mechanisms underlying AUD and co-occurring mental health conditions, including other SUDs, NIAAA will support preclinical and clinical research to:

  • Elucidate mechanisms mediating each of the three stages of the AUD cycle.
  • Identify mechanisms that confer resistance to AUD and those that influence recovery and relapse.
  • Study how alcohol affects neural circuits involved in reward, emotional regulation, behavioral control, sleep, and decision-making; assess whether these effects can be remediated by modulating relevant neural pathways.
  • Identify and classify neurobiological and behavioral phenotypes of AUD, including those relevant to co-occurring mental health conditions, and the mechanisms underlying them.
  • Examine how mechanisms of learning, memory, and other cognitive functions contribute to the development and maintenance of AUD and co-occurring mental health conditions.
  • Identify mechanisms through which stress contributes to the development and maintenance of AUD and co-occurring mental health conditions, and identify stress-related biomarkers predictive of relapse.
  • Investigate mechanisms through which neuroimmune factors contribute to the development and maintenance of AUD.
  • Define molecular targets and neuropathways that mediate the effects of low-dose alcohol (i.e., 10 mM and below) on the brain.
  • Encourage the application of computational and “big data” approaches to integrate data on alcohol’s effects on the brain across multiple studies and levels of investigation.

Objective 1b: Identify genomic and nongenomic factors associated with resilience and vulnerability to alcohol misuse, alcohol use disorder, and co-occurring mental health conditions 

Whereas the research strategies outlined in Objective 1a are aimed at developing a more thorough understanding of the mechanisms underlying AUD and co-occurring mental health conditions, the strategies outlined in Objective 1b are expected to further elucidate factors that predispose individuals to, or protect them from, these conditions. Over the past several decades, NIAAA has supported a number of large studies to examine the role that genetics play in the development of AUD and the mechanisms through which genes exert their effects. Studies of twins, adopted siblings, and individuals from families with an extensive history of AUD have established that genetic factors account for about half a person’s risk of developing AUD.19

The genes most strongly implicated in AUD and best characterized are those that code for enzymes involved in the metabolism of alcohol. Other gene variants are thought to influence drinking by affecting the activity of neurotransmitters associated with alcohol use or with impulsivity, reward deficits, stress, or cognitive function, which contribute to alcohol misuse. Still other variants are linked to AUD treatment responses. Environmental factors, such as exposure to childhood trauma and peer and parental influences, also affect AUD risk and resilience; epigenetic changes in gene expression due to environmental influences likely play a role as well. Continued research in this area, facilitated by advances in genomics and large-scale data collection, aggregation, and analysis, offers promise for defining factors associated with AUD risk and resilience and for guiding treatment.

The developmental stage at which an individual begins drinking and at which he or she is exposed to certain risk and protective factors has a profound influence on the development of alcohol-related problems. Adolescence is the stage of life during which most people begin drinking, and it is also a time of considerable social, psychological, and physiological change. The brain, particularly the frontal cortex, continues to develop throughout adolescence and does not fully mature until early adulthood. Adolescent alcohol exposure can impair brain development, compromise short- and long-term cognitive functioning, and increase the likelihood of developing alcohol-related problems during adolescence and later in life. Furthering our understanding of alcohol’s effects on the developing brain—as well as how differences in brain structure and function prior to alcohol initiation contribute to later alcohol misuse and AUD—is a high priority for NIAAA. (See “Advancing Research on Alcohol and the Adolescent Brain.”)

An increase in pubertal hormones is a prominent feature of adolescence that shapes adolescent brain development, including sexual differentiation of the brain. Although patterns of alcohol use are similar between boys and girls in early adolescence, sex differences in alcohol use emerge by adulthood, when men tend to drink more than women. Notably, however, the gap between men’s and women’s drinking patterns has been narrowing. In animal models, individual differences in alcohol-seeking and drinking, as well as in associated behaviors, such as novelty seeking, depression and anxiety, stress reactivity, and cognition, develop during the transition to adulthood. The extent to which sex contributes to these effects and to the broader neurobiological and behavioral changes associated with alcohol misuse, and the mechanisms through which sex exerts its effects, are important areas of investigation with implications for developing sex- and age-appropriate interventions.

To identify additional factors associated with resilience and vulnerability to alcohol misuse, AUD, and co-occurring conditions, NIAAA will support studies that:

  • Capitalize on advances in genomics and studies of twins, adopted siblings, individuals from families with a high density of AUD, and participants in AUD treatment studies to identify additional gene variants, noncoding genomic elements, and gene networks associated with alcohol misuse, AUD, and co-occurring disorders.
  • Examine the impact of AUD candidate genes on alcohol-related neurobiological and behavioral phenotypes, including factors such as temperament and behavioral control that interact with the environment to affect alcohol-related outcomes.
  • Examine whether sex affects the development of AUD and co-occurring mental health conditions and the mechanisms through which these effects may occur.
  • Identify the neurobiological mechanisms that convey risk and resilience for alcohol misuse and AUD.
  • Use structural and functional brain imaging to examine the effects of adolescent alcohol use on brain structure and function into adulthood and the mechanisms underlying these effects.
  • Use computational and “big data” approaches to integrate data from multiple studies using different tools and techniques (e.g., genetics, epigenetics, and imaging).

Objective 1c: Identify mechanisms through which alcohol affects health and disease across the lifespan 

Chronic and binge alcohol consumption have wide-ranging, adverse effects on human health. Alcohol is a toxin that can damage tissues and organs directly and indirectly through its metabolic byproducts such as acetaldehyde. Alcohol-metabolizing enzymes have been extensively studied, and researchers have identified multiple pathways through which metabolic byproducts contribute to tissue damage. Further elucidating the genetic-, epigenetic-, cellular-, organ-, and systems-level mechanisms through which these effects occur would provide new opportunities to prevent and treat alcohol-related diseases. The prenatal stage of development is characterized by dynamic and highly orchestrated developmental changes that are especially vulnerable to perturbation by alcohol. Alcohol exposure during embryonic and fetal development is a leading preventable cause of birth defects and can result in fetal alcohol spectrum disorders (FASD). (See “Fetal Alcohol Spectrum Disorders.”) Individuals with FASD may experience damage to the brain and other organs, growth retardation, facial abnormalities, and a range of neurobiological deficits that can result in physical, cognitive, behavioral, and social challenges throughout a person’s life. While research on FASD has historically focused on the neurobiological deficits associated with the condition, the research community has become increasingly aware that prenatal alcohol exposure has wide-ranging effects on other organ systems, including the kidneys, circulatory system, and immune system.

The deficits observed in people with FASD and the severity of those deficits depend on the dose, pattern, and timing of prenatal alcohol exposure. In addition, FASD can be influenced by maternal hormones, nutrition, age, number of previous pregnancies, years of drinking, and genetic factors. Alcohol exerts its injurious effects through multiple mechanisms. These include alterations in gene expression patterns, cellular responses to growth factors, and cell death; impairments in the molecular mechanisms involved in moving brain cells to their correct locations during development; and cell damage from chemically reactive molecules.

To further characterize the biological mechanisms involved in the development of FASD, NIAAA will support research to:

  • Investigate the diverse neurobehavioral consequences of prenatal alcohol exposure in individuals with FASD in relation to the activities of daily living, including its effects on sensory, motor, cognitive, and emotional function.
  • Further characterize neural mechanisms through which prenatal alcohol exposure adversely affects neurodevelopment and sensory, motor, cognitive, and emotional function.
  • Identify when, and at which doses of alcohol exposure, these neural mechanisms are activated during prenatal development and how they contribute to the diverse phenotypes associated with FASD.
  • Identify biological and environmental factors that impact susceptibility to FASD and contribute to diverse phenotypes associated with it.
  • Examine biological mechanisms by which prenatal alcohol exposure contributes to other chronic diseases and health conditions later in life.

As the primary site of alcohol metabolism, the liver is particularly vulnerable to damage from drinking. Alcohol misuse can lead to alcoholic liver disease (ALD), a serious and potentially fatal disease that includes steatosis (fatty liver), alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. (See “Alcoholic Liver Disease.”) It is not clear why some people progress from fatty liver to more severe forms of ALD, but factors such as gender, body mass, genes, diet, race and ethnicity, and smoking status are thought to play a role. AH, which has a mortality rate of more than 50 percent within the first 60 days of diagnosis in severe cases,20 is a particularly important area of focus for NIAAA. Activation of liver immune mechanisms, alcohol and lipid metabolism, oxidative stress, and the production of reactive oxygen species are all known to contribute to AH (see “Pathogenesis of Alcoholic Liver Disease”); however, the complexity of the liver and a lack of animal models that reflect the severity of human disease and relevant pathological endpoints have made it challenging to develop a comprehensive understanding of disease pathogenesis. NIAAA will continue to support research on ALD, including through translational research consortia aimed at improving our understanding of the mechanisms underlying AH and translating this knowledge into novel therapies.

The gastrointestinal system is the primary site at which alcohol is absorbed into the blood stream, and accumulating evidence indicates that processes occurring in this system contribute to alcohol’s adverse effects on other organs, including the liver and brain. A single episode of binge drinking can increase intestinal permeability, causing bacterial toxins to escape into the blood stream and induce inflammation in peripheral organs. Chronic alcohol misuse can also affect the composition of the microbiome, exacerbating the problem. Inflammation is implicated in much of the downstream organ damage associated with alcohol misuse, including liver damage, and it is emerging as an important factor in the development of many other diseases, including AUD.

Nutrition is a factor in some alcohol-related diseases. Individuals with severe AUD may consume a significant portion of their daily calories from alcohol, depriving their bodies of essential nutrients. Drinking to excess can impair absorption and digestion of nutrients from food, as well as the liver’s ability to use them. Nutrition also plays a role in preventing and treating cardiovascular and liver diseases, two potential consequences of alcohol misuse, and it is an important factor in FASD.

Although considerable progress has been made toward understanding the effects of alcohol on human health and disease, the complex mechanisms through which alcohol exerts its effects are not fully understood. Moreover, while considerable attention has been focused on the adverse health effects of alcohol, some studies have found benefits associated with moderate alcohol consumption, particularly for cardiovascular disease. NIAAA encourages research that integrates genetic-, molecular-, cellular-, and systems-level approaches to investigating how alcohol affects tissue and organ function, how one dysregulated physiological system may perturb others, as well as the common and unique aspects of alcohol-induced pathology at multiple organ sites.

To identify new pathways for preventing, diagnosing, and treating alcohol-related disease, NIAAA will support research to:

  • Identify physiological mechanisms through which alcohol contributes to chronic diseases and conditions, including ALD, pancreatitis, cancer, neurodegeneration, and cardiovascular disease; through which moderate alcohol consumption may protect against disease; and through which alcohol interacts with biological and environmental factors to affect health and disease states.
  • Support a prospective clinical trial to examine the effects of moderate alcohol use on health outcomes.
  • Further elucidate mechanisms by which alcohol affects interactions among the gut, liver, and brain, including through changes in the composition of gut microbiota and its metabolomes, increased intestinal permeability, and inflammation.
  • Develop and validate new animal models to explore mechanisms by which genetics, sex, nutrition, drinking patterns, aging, and obesity contribute to ALD.
  • Identify new endogenous stem cell populations in organs susceptible to alcohol damage, and use new and existing stem cell lines to develop alcohol-related disease models.
  • Identify new molecular targets for treating ALD by conducting functional studies of the physiology dysregulated in AH, cirrhosis, and hepatocellular carcinoma and determining the association of these physiological changes with disease severity and mortality.

Extraordinary progress has been made in preventing and treating human immunodeficiency virus (HIV) and improving the lives of the millions of people affected by it. Nonetheless, HIV remains a serious public health concern. Approximately 40,000 people are diagnosed with HIV infection each year in the United States alone;21 worldwide the number is considerably higher. In the United States, a substantial proportion of people living with HIV consume alcohol, and the prevalence of unhealthy alcohol use in this group ranges from 8 to 42 percent.22 As noted above, chronic drinking facilitates HIV infection, accelerates disease progression, and hastens the death of those who have progressed to AIDS, but the mechanisms for these interactions are not well understood. Alcohol may interfere with the metabolism of medications to treat HIV, an effect that could account for the increased frequency of adverse medical events and increased mortality among HIV-infected individuals who take antiretroviral medications and drink. In addition, little is known about how alcohol affects the effectiveness of medications taken to prevent HIV infection (i.e., pre-exposure prophylaxis). Alcohol can exacerbate HIV-associated comorbid conditions such as tuberculosis and hepatitis C virus, and it has been linked to the development of other diseases in HIV-infected individuals. People with HIV and hepatitis C virus are especially likely to develop liver disease if they drink, and alcohol has been identified as a key factor in increased liver mortality among people with HIV. Alcohol also contributes to age-related medical problems including cardiovascular dysfunction, peripheral neuropathies, and neurocognitive impairments in HIV-positive individuals.

Considering the serious adverse consequences associated with alcohol misuse by people with HIV, NIAAA will support research to:

  • Determine how current and past alcohol use in the context of HIV infection and other co-infections affects development and progression of organ and tissue injury with a focus on the gut, liver, lung, and brain, and translate these findings into strategies for limiting alcohol-related organ and tissue injury in HIV-positive individuals.
  • Improve understanding of how alcohol affects disease progression and tissue and organ injury in HIV-positive individuals taking antiretroviral medications.
  • Identify and model mechanisms through which alcohol contributes to infectious and noninfectious diseases and mental health conditions among HIV-positive individuals, as well as to frailty among HIV-infected older adults.
  • Elucidate how the interaction of HIV, HIV medications, and alcohol affects brain development and function, and identify neurobiological mechanisms underlying the persistence of neuronal injury and dysfunction in HIV-infected individuals with varying patterns of viral suppression and immune competence.


The Three Stages of the Alcohol Use Disorder Cycle 

Alcohol use disorder (AUD) is characterized by a three-stage cycle involving a loss of control over alcohol intake (binge/intoxication stage), the experience of a negative emotional state in the absence of alcohol (withdrawal/negative affect stage), and a compulsion to seek out and consume alcohol (preoccupation/anticipation stage). There may be variation in how people progress through the cycle, the intensity with which they experience each of the stages, and the nature of the disruptions to the underlying neurobiological circuits.

three stages of alcoholic use disorder cycle

The binge/intoxication stage primarily involves the nucleus accumbens and the striatum, two structures within the brain’s basal ganglia. The nucleus accumbens mediates the rewarding, or pleasurable, effects of alcohol. Repeated activation of this reward system by alcohol can trigger changes in the striatum, an area of the brain responsible for habit formation, and lead to the development of compulsive alcohol seeking. The stimuli present when people drink—including people, places, and even their own internal mood states—can become associated with the rewarding effects of alcohol, and over time these cues may acquire the ability to activate the brain’s reward centers even in the absence of alcohol. This associative learning process, a phenomenon called facilitation of incentive salience, helps explain the intense desire for alcohol and compulsive alcohol seeking that occurs when some people addicted to alcohol are exposed to cues they have come to associate with drinking.

During the withdrawal/negative affect stage, the absence of alcohol leaves the reward neurotransmitter systems in a deficit state, activates stress neurotransmitters in the brain’s extended amygdala, and dysregulates the activity of neurotransmitters that counter stress. These effects contribute to the feelings of unease, anxiety, and irritability that typically accompany alcohol withdrawal. Repeated cycles of alcohol use and withdrawal also disrupt the activity of neurotransmitters in the brain’s reward systems and sensitize anti-reward stress systems, making it more difficult for people suffering from AUD to experience the pleasures of daily living. The combination of loss of function in reward systems (i.e., reward deficit), heightened activation of brain stress systems (i.e., stress surfeit), and conditional responding to environmental stimuli associated with the rewarding effects of alcohol (i.e., incentive salience) drive the motivation to drink and are key elements of relapse during the preoccupation/anticipation stage of AUD.

The prefrontal cortex—an area of the brain responsible for executive function, including the ability to organize thoughts and activities, prioritize tasks, manage time, and make decisions—plays a key role in the preoccupation/anticipation stage of AUD. The prefrontal cortex can be divided into two opposing systems: a “go” system that drives impulsive behavior and habitual responding, and a “no-go” system that inhibits these responses and exerts control over activation of brain stress systems, putting the brakes on compulsive behavior. Too much activity in the go system, or too little activity in the no-go system, can lead to binge drinking, as well as increased responsiveness to alcohol-associated cues and heightened stress reactivity, both of which can increase alcohol craving and lead to relapse.

The neuroadaptations that underlie AUD may persist long after a person stops drinking, contributing to the chronic nature of this disease.

Advancing Research on Alcohol and the Adolescent Brain 

Group of adolescent kids

NIAAA has made a major commitment to research aimed at advancing our understanding of alcohol’s effects on the developing brain and how differences in brain structure and function prior to alcohol initiation contribute to later alcohol misuse and alcohol use disorder.

In 2012, NIAAA launched the National Consortium on Alcohol and Neurodevelopment in Adolescence (NCANDA), a nationally representative, accelerated longitudinal study evaluating brain structure and function in more than 800 youth before and after they start to drink. NCANDA has provided important insights into the adverse effects of alcohol on the adolescent brain. It has also laid the methodological foundation for the ongoing Adolescent Brain Cognitive Development (ABCD) Study, the largest long-term study of brain development and child health in the United States.

More than 11,000 9- to 10-year-olds will be recruited to the ABCD Study. Using advanced brain imaging and neuropsychological and behavioral assessments, researchers will track the biological and behavioral development of participating youth over a 10-year period, with the goal of collecting data before and after they start to use alcohol or other addictive substances.

The ABCD Study will yield an unprecedented amount of information about normal adolescent brain development and how it is affected by substance use and other childhood experiences, such as sleeping patterns and sports, social media, and video game engagement. The study is also expected to illuminate neurobiological, cognitive, and behavioral precursors of substance misuse and could ultimately inform preventive and treatment interventions.

Complementing NCANDA and ABCD, NIAAA’s Neurobiology of Adolescent Drinking in Adulthood initiative is enabling investigators to examine, in animal models, the molecular-, cellular-, and circuit-level mechanisms by which adolescent drinking affects brain structure and function in the short and long term, and how the changes observed during this critical period persist into adulthood.

Fetal Alcohol Spectrum Disorders 

4D ultrasound of fetus

Prenatal alcohol exposure occurs when the embryo or fetus is exposed to alcohol. Alcohol can disrupt prenatal development at any stage during pregnancy—including at the earliest stages, often before a woman knows that she is pregnant. Fetal alcohol spectrum disorders (FASD) is an umbrella term for a range of physical, cognitive, and behavioral abnormalities caused by prenatal alcohol exposure. The medical disorders labeled as FASD include the following:

Fetal Alcohol Syndrome (FAS): FAS is characterized by structural or functional central nervous system (CNS) abnormalities, growth deficits, skeletal abnormalities, and facial anomalies, which may include narrow eye openings, a smooth area between the lip and the nose, and a thin upper lip.

Partial Fetal Alcohol Syndrome (pFAS): pFAS is characterized by some, but not all, of the features of FAS. For example, individuals with pFAS may not experience growth deficits.

Alcohol-Related Neurodevelopmental Disorder (ARND): Individuals with ARND do not exhibit the full range of physical deficits that characterize FAS or pFAS; they do have the CNS, cognitive, and behavioral deficits.

Alcohol-Related Birth Defects (ARBD): ARBD is characterized by physical abnormalities, such as heart, kidney, and skeletal problems. ARBD is rarely seen alone but rather as a secondary disorder accompanying other forms of FASD.

Neurobehavioral Disorder Associated with Prenatal Alcohol Exposure (ND-PAE): ND-PAE is defined only by cognitive and behavioral features and is characterized specifically by impairments in neurocognition, self-regulation, and adaptive functioning.

Pathogenesis of Alcoholic Liver Disease 

chart of alcohol lover disease including alcohol hepatitis
Figure adapted and modified from Haber et al.
Pathogenesis and management of alcoholic hepatitis.
J Gastroenterol Hepatol. 2003;18:1332–1344.

Repeated exposure to alcohol contributes to liver damage through several parallel processes. Alcohol exposure increases gut permeability, leading to leakage of microbes and microbial products, including lipopolysaccharides, into the liver and into circulation. These and other bacterial products trigger the activation of Kupffer cells (resident liver macrophages) to produce the pro-inflammatory cytokines interleukin 8 (IL8), interleukin 6 (IL6), interleukin 1 (IL1), and tumor necrosis factor alpha (TNFα). A sustained inflammatory state damages the host tissue. In parallel, alcohol is metabolized in the liver by the enzymes alcohol dehydrogenase (ADH) and cytochrome P450 oxidase 2E1 (CYP2E1), leading to the production of acetaldehyde and the reduced form of nicotinamide adenine dinucleotide (NADH). The altered balance between NADH and the oxidized form of nicotinamide adenine dinucleotide (NAD) results in oxidative stress that also damages host tissue. Excess acetaldehyde leads to the formation of protein adducts that contribute to inflammation and DNA adducts that interfere with DNA synthesis. Pro-inflammat ory cytokines, acetaldehyde, and oxidative stress activate hepatic stellate cells, a specialized cell population whose activation triggers fibrosis. Chronic inflammation caused by excessive alcohol intake leads to chronic liver injury and impairs tissue repair. Progenitor cells normally support liver repair and regeneration. However, aberrant activation of progenitor cells by alcohol interferes with the liver’s capacity to repair damage and further promotes fibrosis by hepatic stellate cell stimulation.

Forms of Alcoholic Liver Disease 

Alcoholic liver disease (ALD) comprises a broad spectrum of liver disease, which can include asymptomatic fatty liver, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. A particularly severe form of ALD, with an especially high mortality rate, is alcoholic hepatitis. ALD development is not necessarily linear; the main determinants of its progression are still the subject of debate in the alcohol research community. What is clear is that there are multiple stages of ALD varying in severity. The images below show human liver tissue in various healthy and diseased states

Healthy Liver

Healthy Liver

The liver helps digest food, store energy, and break down (or metabolize) and remove toxins from the body. It is the chief organ responsible for metabolizing alcohol and is especially vulnerable to alcohol-related injury.


Alcoholic Steatosis (Fatty Liver Disease)

Alcoholic Steatosis (Fatty Liver Disease)

It has been estimated that up to 90 percent of patients with heavy alcohol intake have alcoholic steatosis, or fatty liver, which is the least serious form of ALD and clinically asymptomatic. Abstaining from drinking will reverse this damage.


Alcoholic Steatohepatitis

Alcoholic Steatohepatitis*

Alcoholic steatohepatitis is a histological representation of an inflammatory condition in the liver caused by continued drinking and characterized by fat accumulation in the hepatocytes, neutrophil infiltration, and cellular damage.


Alcoholic Hepatitis

Alcoholic Hepatitis*†

Alcoholic hepatitis is a severe and acute form of ALD defined clinically and characterized clinically by rapid elevation in serum bilirubin levels, jaundice, and liver-related complications after prolonged, heavy alcohol use. Many alcoholic hepatitis patients also have underlying severe fibrosis or cirrhosis.




Liver fibrosis is characterized by an accumulation of fibrous connective tissue around cells in the liver, forming a chicken-wire pattern. Fibrosis distorts normal liver architecture and function.




The most severe form of fibrosis is cirrhosis, or scarring of the liver.23 Cirrhosis increases risk of ALD complications such as abdominal fluid accumulation, bleeding in the gastrointestinal tract, loss of brain function, kidney failure, and bacterial infections. Several longitudinal studies indicate that 11–18 percent of patients with alcoholic fatty liver who continue to drink develop cirrhosis over a period of 4–13 years.

Hepatocellular Carcinoma

Hepatocellular Carcinoma

A large cross-sectional study shows that 10 percent of patients with alcoholic cirrhosis have hepatocellular carcinoma (HCC), or malignant liver cancer, whereas longitudinal studies suggest that patients with alcoholic cirrhosis have a rate of developing HCC at 0.2–1.8 incidence per year per 100 persons.24 The risk remains even after cirrhosis patients have stopped drinking.

*The alcoholic liver disease field has yet to reach consensus on the terms alcoholic hepatitis and alcoholic steatohepatitis.

†The thresholds for amount and duration of alcohol use causing alcoholic hepatitis are not known, although a pattern of drinking more than three drinks per day for women and four drinks per day for men for more than five years is typical.

All images provided courtesy of Drs. Vijay Shah, Dhanpat Jain, and Taofic Mounajjed, except the alcoholic hepatitis image, which was provided courtesy of Drs. John Woosley and Ramon Bataller.

Looking for U.S. government information and services?