The 40th anniversary of the National Institute on Alcoholism and Alcohol Abuse: The impact on liver disease

Authors

  • Gyongyi Szabo M.D., Ph.D.

    Corresponding author
    1. Professor of Medicine, Associate Dean for Clinical and Translational Sciences, Department of Medicine, University of Massachusetts Medical School, Worcester, MA
    • University of Massachusetts Medical School, Department of Medicine, LRB 215, 364 Plantation Street, Worcester, MA 01605
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    • fax: 508-856-4770


  • Potential conflict of interest: Nothing to report.

In 1970, Congress passed and President Richard M. Nixon signed the Comprehensive Alcohol Abuse and Alcoholism Prevention, Treatment, and Rehabilitation Act of 1970. With the passage of that law, the National Institute on Alcohol Abuse and Alcoholism (NIAAA) became the lead federal agency to address the problems associated with alcohol abuse and alcoholism. Over time, NIAAA has continued to evolve. Today's research portfolio casts a net over a wide range of studies, from epigenetics and neuroimaging to liver disease, health disparities, and personalized medicine. NIAAA continues to spark innovative approaches to research problems, to foster cooperation and collaboration with other agencies and programs, and to advance our understanding of alcohol and its effects.

Abbreviations:

HIV, human immunodeficiency virus; NAFLD, nonalcoholic fatty liver disease; NIAAA, National Institute on Alcohol Abuse and Alcoholism; NIH, U.S. National Institutes of Health.

Over the years, both intramural and extramural research supported by NIAAA excelled not only on the epidemiology, behavioral, and neurologic aspects of alcohol use but also on its end-organ effects with particular emphasis on the liver. For example, within the National Institutes of Health (NIH), NIAAA took the lead in supporting research to explore alcohol's effects on the liver. NIAAA liver research in fiscal year 2009 was $38,863,000, which is about 10.4% of the total extramural research budget. In addition, NIAAA spent $11,729,000 from the stimulus money (American Recovery and Reinvestment Act of 2009) on liver research. With these commitments, NIAAA is the primary source of extramural NIH funding for alcohol-related liver research. Although the liver research portfolio of the National Institute of Diabetes and Digestive and Kidney Diseases is six times larger than that of NIAAA, alcohol-related liver studies are supported primarily by NIAAA. As a result of this focus, seminal discoveries have been reached in alcohol-related liver research that have directly benefited patients, as well as other areas of investigation. To name a few:

  • The discovery of the concept that liver inflammation is the result of gut-derived pathogens in alcohol-related liver disease was seminal and affected the entire field of hepatology by unearthing a critical pathogenic mechanism common to liver diseases of any origin.

  • Similarly, the “multiple hit hypothesis” originally discovered in alcohol-related liver disease, has become the central element of the pathogenesis of nonalcoholic fatty liver disease (NAFLD).

  • Mitochondrial dysfunction, which was first discovered in alcoholic liver disease, applies to all various liver diseases.

  • Pioneering work in signal transduction pathways and nuclear receptors in alcoholic liver injury tremendously benefited research in NAFLD.

  • Alcohol research defined the global role of nutrition in liver disease, and paved the way for the use of some elements, such as zinc, in the treatment of liver diseases.

Research on alcohol metabolism and consequences laid the foundation to major discoveries in obesity and metabolic syndrome research, thus advancing the science in two research fields that are critical to public health. In addition, NIAAA is the only NIH institute that supports research on the combined effects of alcohol with other liver insults such as hepatitis B and C viral infections, and human immunodeficiency virus (HIV). It is the only institute that supports research linking the gut, liver, and the brain and addresses end-organ damage caused by alcohol and other liver insults.

In 1975, Charles Lieber and colleagues published seminal findings showing that alcohol itself is the primary cause for the higher prevalence of liver disease seen in patients suffering from alcoholism, rather than dietary deficiencies and malnutrition that often accompany alcoholism.1, 2 Their new paradigm challenged previously held theories that alcohol was not a major cause of liver damage, and opened the platform for several decades of new studies on the direct effects of alcohol and its metabolism in the liver. Since those early studies, clinical and experimental evidence continued to show a connection between high amounts of alcohol consumption and liver disease. Subsequent investigations revealed that different cell types are affected by alcohol, not only hepatocytes, but also the liver resident macrophages, Kupffer cells, as well as stellate cells whose functions are altered in the alcoholic liver.2-4 The discovery of tumor necrosis factor and inflammatory cytokines in the early 1980s paved the way for identification of the role of inflammation in alcoholic liver disease.5, 6 Studies in the late 1980s from Ronald Thurman's group demonstrated that Kupffer cell elimination can attenuate alcohol-induced liver injury in animal models and demonstrated a role for lipopolysaccharide endotoxin in alcoholic liver disease.7, 8 The concept emanating from alcohol research that gut-derived endotoxin or other microbial products contribute to liver diseases is now widely accepted and has been shown to play a role in various liver diseases and in viral infections.

NIAAA-supported research on the effects of alcohol and its metabolites on the molecular mechanisms of hepatocyte injury and fatty liver played a central role in the understanding of NAFLD. The multiple-hit hypothesis accepted in NAFLD has been initiated by studies involving alcohol-induced liver injury. Discoveries in different alcohol-related molecular pathways including peroxisome proliferator-activated receptors, reactive oxygen species, mitochondrial electron transport, and cytochrome P450 benefited the general understanding on how the liver responds to insults and danger signals (reviewed in Nath and Szabo,9 and Mandrekar and Szabo10). As a result of such NIAAA-supported discoveries, scientists now have a better understanding of the interaction of alcohol with other insults to the liver.

One of the strategies of NIAAA has been to support research to discover the synergistic biological effects and health consequences of alcohol use in patients with coexisting diseases. For example, although the comorbidity of alcohol use and hepatitis C virus infection is a well-established risk factor for poor liver outcome, little is known about the mechanisms or specific therapeutic strategies in these patients. Research supported by NIAAA has now started to provide evidence for the combined effects of alcohol and hepatitis C virus on oxidative stress in hepatocytes and the components of the decreased antiviral immunity. The combined effects of alcohol and other coexisting diseases, especially HIV, is still a clinical dilemma where more intense basic, translational, and clinical research is needed to study the effects of highly active antiretroviral therapy, HIV, and alcohol on the liver.

Today, the Division of Metabolism and Health Effects of NIAAA has a rich portfolio to support research on the effects of alcohol, not only on the liver but also on other end-organs such as the gut and pancreas. Research support from NIAAA extends to scientists in basic research as well as translational and clinical investigators, using the traditional research project grants (R01), small research grants (R03), exploratory/developmental grants (R21), and resource-related research projects (R24). In addition, NIAAA strongly supports young investigators through the National Research Service Award for predoctoral (F30 for M.D./Ph.D. or F31 for Ph.D.) and postdoctoral (F32) fellowship programs. Furthermore, NIAAA offers research career programs (K01, K02) that support young investigators to K05 grants to enable established investigators in their role as mentors supporting the development of the next generation of scientists engaged in alcohol and liver research, clinical investigator award (K08), mentored patient-oriented research career development award (K23), and career transition award (K99/R00). Furthermore, NIAAA supports research program projects (P01), center grants (P20, P30, P50, P60), cooperative agreements (U01), small business technology transfer (STTR) grants (R41, R42), small business innovation research (SBIR) grants (R43, R44), institutional training programs (T32), and national and international meeting grants (R13). In addition to the broad range of extramural grant support, several research groups within the Division of Intramural Clinical and Biological Research contribute to liver research areas such as molecular mechanisms of liver damage and therapeutic modification of fatty liver disease with state-of-the-art novel discoveries such as endocannabinoid receptor CB1 antagonists. Most recent studies with NIAAA support research on epigenetic modulation related to alcohol use on the liver at the level of histone acetylation, DNA methylation, and microRNAs. The recent availability of genome-wide analysis and single-nucleotide polymorphism in combination with systems biology approaches will lead to new discoveries in alcohol research. The contribution of NIAAA to liver-related basic, clinical, and translational research will remain the heartbeat of present and future research of alcoholic liver disease and other comorbid liver diseases modified by alcohol use. Congratulations to NIAAA on 40 years of major contributions to discoveries in the liver!