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National Advisory Council Meeting - September 17-18, 2008
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
Summary of the 119th Meeting
September 17–18, 2008
The National Advisory Council on Alcohol Abuse and Alcoholism convened for its 119th meeting at 5:30 p.m. on September 17, 2008, at the Fishers Lane Conference Center in Rockville, Maryland , in a closed session. Dr. Abraham Bautista presided over the closed review of grant applications. Dr. Ting-Kai Li, Director of the National Institute on Alcohol Abuse and Alcoholism (NIAAA), presided over the open session on September 18, 2008.
In accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C. and 10(d) of Public Law 92-463, the session on September 17, 2008, was closed to the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds.
Council Members Present:
Michael E. Charness, M.D.
Cheryl J. Stephens Cherpitel, M.P.H., Dr.P.H.
David W. Crabb, M.D.
Gen. Arthur T. Dean
Cindy L. Ehlers, Ph.D.
R. Adron Harris, Ph.D.
Deborah S. Hasin, Ph.D.
Joannes B. Hoek, Ph.D.
Vimal Kishore, Ph.D.
Lynell W. Klassen, M.D.
Mack C. Mitchell, Jr., M.D.
Peter M. Monti, Ph.D.
Larry I. Palmer, LL.B.
Chairperson: Ting-Kai Li, M.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Ralph W. Hingson, Sc.D., M.P.H., Robin I. Kawazoe, Howard Moss, M.D., Antonio Noronha, Ph.D., Kenneth R. Warren, Ph.D., Mark Willenbring, M.D., Samir Zakhari, Ph.D.
Other Attendees on September 18, 2008
Approximately 80 additional observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order of the Closed Session, September 17, 2008
Dr. Abraham Bautista called the closed session of the 119th meeting of the Council to order at 5:30 p.m. on Wednesday, September 17, 2008, for consideration of grant applications. He reviewed procedures and reminded Council members of regulations pertaining to conflict of interest and confidentiality. Members absented themselves from the discussion and evaluation of applications from their own institutions and in situations involving any real, apparent, or potential conflict of interest. The closed session adjourned at 7:00 p.m.
Call to Order and Introductions, September 18, 2008
Dr. Ting-Kai Li called the open session to order on September 18, 2008, at 8:50 a.m. and welcomed participants. Council members Victor Hesselbrock, Ph.D., and Hidekazu Tsukamoto, D.V.M., Ph.D., and e x-officio member Col. Joyce Adkins, M.P.H., Ph.D., were unable to attend. Dr. Li announced that John P. Allen, Ph.D., M.P.H., has joined the Council as an ex-officio member from the Department of Veterans Affairs. Dr. Allen was unable to attend. Members of NIAAA staff and the audience introduced themselves.
NIAAA Strategic Plan: Update
Dr. Kenneth Warren, NIAAA Deputy Director, described updates to NIAAA’s Strategic Plan, 2009–2014: Alcohol Across the Lifespan, acknowledging Dr. Susan Maier’s contributions to the effort. He explained that the plan, initially developed in 2006 as a rolling plan that accommodates annual updates, addresses the interaction of alcohol at discrete phases across the life span and highlights specific types of consequences. Cross-cutting themes include metabolism, genetics, epigenetics, diagnosis of alcohol use disorders (AUDs), and health services research. The plan focuses on opportunities for development of fiscally feasible new concepts, knowledge, and technologies. The previous update added a new chapter on childhood through age 10, expanded the chapter on alcohol and HIV, and integrated Extramural Advisory Board (EAB) reports on fetal alcohol syndrome and HIV/AIDS.
A significant new update incorporates opportunities related to new technologies and approaches to longitudinal studies, National Institute of Health’s (NIH) Gene Environment Initiative (GEI), gene expression with immortalized cell lines, health services research, and medications development. The updates address how research on risk factors and alcohol use can be exploited with new technologies for recording real-time events. These technologies facilitate modeling the interplay of developmental, biological, pharmacological, and environmental factors in the transition from alcohol use to dependence; offer potential to identify risk characteristics prior to alcohol exposure; and may suggest routes to pursue in looking for molecular mechanisms that underlie transitions, especially to alcohol dependence. The trans-NIH GEI initiative focuses on genetic analysis and new tools development to measure real-time exposures to alcohol and real-time physiology. Also in the GEI, such advances as the HapMap and Genome Wide Association Studies should aid in identification of genes known to be risk factors in alcohol use disorders, expand the number of identified genes, link genes and environmental factors, and develop models to explain alcohol dependence.
The updates include a recommendation that reference samples of a well-characterized set of lymphoblastoid cell lines be made readily available. In the area of health services research, the plan was updated with a recommendation to examine attitudes toward treatment barriers in order to focus on issues related to acceptance of services; seek and develop cost-effective disease management approaches and algorithms that are adaptive in nature and directed toward individualized care, and that address adherence and retention; focus on how best to measure outcomes and surrogate outcome measures; and measure quality in a multidimensional perspective. In medications development, NIAAA currently has 21 compounds under study at various stages ranging from pre-clinical through clinical testing.
NIAAA created transdisciplinary research teams to bridge programs across the divisions and eliminate silos. Since 2003, six EAB reviews have used materials developed by these teams resulting in several new initiatives. Following its 2007 staff retreat, NIAAA updated its team structures. Several teams that had been working on new areas transitioned into working groups that focus on the implementation of new concepts. For example, the former Research Resources and Technologies Team was reconstituted as the Informatics and Computation/Systems Biology Team, and the Underage Drinking Team has become a workgroup. New workgroups focus on biomarkers and fetal alcohol spectrum disorders (FASD). Formal structures for NIAAA Coordinating Committees on international research, health disparities, and HIV/AIDS offer increased visibility.
Discussion: To a question from Professor Palmer, Dr. Warren responded that NIAAA staff continue to work on HIV/AIDS and health disparity issues, and recruitment has begun to increase the membership of this coordinating committee. Dr. Kishore suggested that the plan’s focus in older adults on alcohol and drug interactions could apply across the life span. Dr. Warren concurred, noting that NIAAA would consider such an update for the next plan.
Concurrence: The Council unanimously accepted the strategic plan.
Extramural Advisory Board Report on Health Communications Programs and Research
Dr. Peter Monti, Director, Center for Alcohol and Addiction Studies, Brown University , and Co-chair, NIAAA Extramural Advisory Board (EAB), presented the EAB’s recommendations on NIAAA’s health communications programs and research. Although the EAB typically reviews NIAAA’s Extramural portfolio and develops recommendations for the field, the June 2008 meeting focused on the way NIAAA conducts its business. The themes of the review included NIAAA’s communications goals and approaches to disseminate meaningful research results to a global audience, information needs of the broad spectrum of NIAAA’s audience, and message development through multimedia solutions. NIAAA’s audiences include alcohol researchers, the medical/mental health/public health community, policy makers, liaison organizations and advocacy groups, and the lay public.
Dr. Monti presented the EAB’s recommendations:
1a. Develop a mission and vision statement to guide NIAAA communications that make NIAAA recognized as the definitive source for research, knowledge, and evidence-based information on alcohol and health.
b. Develop and emphasize brand and branding policy and tagline that incorporate mission and vision for products. Make NIAAA America’s alcohol information resource.
- Identify a key message (tied to a specific, change-related objective) for each of NIAAA’s most critical audiences, and then identify appropriate partners to amplify those messages and support a larger program for change. Inform to influence. Identify priority audiences such as middle and high school students and parents, young adults, military, college, and youth in the justice system (reduce risk of alcohol problems); professional groups (physicians, psychologists, social workers, primary care physicians [identify/refer and treat]); legal system (infuse evidence-based knowledge, partnerships); “Treatment Can Work” (accompanied by an effort to shift understanding of what treatment involves); the new face of alcohol dependence (i.e., the functional alcohol-dependent individual; policy makers).
- Explore partnerships: Government (Department of Defense and others); Federal agencies, professional and private groups; alcohol research centers and training programs; multicultural agencies (tribal entities; inner city agencies).
- Evaluate products and strategies. Implement a strategic plan/process that will:
· Update and redesign the Web site to achieve strategic goals; create a workgroup to examine use of social media; write a strategy that includes moving material to public space, including Wikipedia.
· Seek clearance from the Office of Management and Budget and initiate surveys; seek partners in the survey effort; focus on electronic and other new media.
· Evaluate other information sources; evaluate existing databases for secondary data, including novel, creative ways to measure impact; explore 1 percent set-aside funds for evaluation.
- Establish staff and grantee education (e.g., Research Society on Alcoholism [RSA]) to improve communications planning, interview skills, and consistency of messaging.
- Consider a call for communications and dissemination research (e.g., how to motivate a wider range of people to seek treatment, creative uses of secondary data sources for evaluation of communication efforts in the alcohol field).
Discussion: Dr. Charness stated that a Google search of “alcohol research” and “alcoholism” places NIAAA second on the results list. Echoed by Gen. Dean, he encouraged partnering with RSA and other organizations to couple NIAAA’s message with advocacy. Dr. Monti confirmed Dr. Kishore’s assumption that evaluations lead to changes related to findings. Given NIAAA’s global audience, Dr. Kishore inquired about plans to translate NIAAA materials. Dr. Monti stated that RSA’s current program includes a focus on globalization and the global burden of disease. Dr. Warren stated that NIAAA publishes virtually all materials disseminated to the public in English and Spanish, and groups in other countries have translated certain publications. Gen. Dean urged devising ways to penetrate and communicate with communities of color on both prevention and treatment. Dr. Hasin commented that limited research has produced little information on what Americans believe about alcohol, particularly by population subgroups, and asserted the need for research in this area to facilitate targeted information dissemination. Dr. Li emphasized the importance of creating change-related objectives for the Institute’s vision and mission. He observed that the Institute’s name does not convey its message, especially in the understanding of alcohol abuse and that term’s potential disappearance from the next DSM’s lexicon. He noted the importance of conveying to the public worldwide the Institute’s shift to a risk-reduction paradigm that transcends treating only the most severely chronic and relapsed individuals. He stated the importance of message consistency, asserted the field’s need for consistent definitions, including for standard drink and binge drinking, and urged NIAAA to persist in its leadership to promote the standard definitions established by the EAB. He acknowledged NIAAA’s valuable partnerships with RSA and the International Society for Biomedical Research on Alcoholism (ISBRA).
Concurrence : The Council unanimously concurred with the EAB’s recommendations.
Raynard S. Kington, M.D., Ph.D., Deputy Director, National Institutes of Health (NIH), formally announced Dr. Li’s intention to retire as NIAAA Director. He stated that Dr. Li’s accomplishments include NIAAA’s rolling strategic plan; continued success rates for grantees of 27–30% during a time of austerity budgets; review of the Extramural Program; oversight of the review of the Scientific Director; recruitment and retention of outstanding staff; ongoing contributions to NIH; and strong support for new investigators, multi- and interdisciplinary research, and innovation and creativity in measuring alcohol problems. Dr. Kington thanked Dr. Li for his contributions nationally and internationally to biomedical and behavioral research in the area of alcohol abuse and alcohol. Dr. Kington noted that Dr. Warren will serve as Acting Director and will initiate a search for the next Director of NIAAA. Attendees gave Dr. Li a standing ovation.
Dr. Li applauded the contributions of NIAAA staff, the Council, and the EAB. He asserted the importance of demonstrating to the research community NIAAA’s trustworthiness and the reliability of its messages, and acknowledged the high quality of new research and communications initiatives generated by the alcohol research community. He noted that during his tenure NIAAA has dramatically increased its transparency in grant awards and has leveled silos within and across Institutes.
Referring to the published “Director’s Report,” Dr. Li highlighted the following Institute activities:
§ Legislation, budget, and policy. Dr. Li reported that the President signed a supplemental appropriations bill that gave NIH an additional $150 million. Of that, NIAAA received $2.32 million, which permitted the Institute to achieve a 27% success rate. At the time of the Council meeting, the House and Senate were working on mark-ups for the FY 2009 budget.
§ Director’s activities. At a joint meeting of RSA and ISBRA in June, Dr. Li presented on “Harmful Drinking: Global Research Issues.” In September he lectured students in Japan on “Alcohol Research Now and the Future.” At a meeting called by the Office of National Drug Control and Prevention (ONDCP), Dr. Li spoke about training trainers to prepare the workforce to provide screening, brief intervention, referral and treatment (SBIRT) for alcohol and drugs. ONDCP recently persuaded Federal and other agencies to adopt CBT codes for reimbursement for SBIRT.
§ NIAAA staff and organization. Brenda Weis, Ph.D., joined NIAAA as Senior Advisor to the Director. Qi-Ying Liu, M.D., M.S., joined the Division of Neuroscience and Behavior as a Program Director.
§ Honors. NIH Director’s Awards went to Ms. Robin Kawazoe in recognition of her administrative management excellence and to Dr. George Kunos for his leadership of the Intramural Program and research on endocannabinoids. Recipients of a variety of group awards for service included Ms. Ann Bradley and Drs. Mark Willenbring, Antonio Noronha, Sam Zakhari, Mark Egli, Raye Litten, Bridget Grant, Patricia Powell, Vivian Faden, and Brenda Weis. Drs. Lisa Neuhold, Qi-Ying Liu, Lindsey Grandison, Peter Silverman, Thomas Greenwell, and Dennis Twombly were honored for their significant achievements related to the NIH Blueprint for Neuroscience.
§ Transdisciplinary research activities. The NIH Roadmap for Medical Research supports cross-cutting NIH programs to fill fundamental knowledge and technology gaps. NIAAA has been active in the development of several Roadmap initiatives; by having its grantees succeed in competing for Roadmap awards, NIAAA receives extra money from NIH’s Common Fund in support of alcohol research. Increasing numbers of staff have been involved in the creation and implementation of Roadmap initiatives; in 2008, NIAAA was the lead Institute in three of five major initiatives. Funding mechanisms will change in 2009. NIAAA also participates in the Blueprint, a collaborative project that provides tools, resources, and infrastructure, and that developing toolkits for diagnosis based on behavioral and neurological science. Three themes apply to alcohol: neurodegeneration, neurodevelopment, and neuroplasticity.
§ NIAAA research programs. Dr. Li described the types of research NIAAA undertakes, both by Extramural staff and grantees. He noted recent publications by Drs. Howard Moss and Vivian Faden, and highlighted such research topics as the influence of microRNA in development of alcohol tolerance, COGA’s longitudinal studies of predictors of problematic alcohol use in young adulthood, NESARC and NLAES data comparisons that show women’s disparity in use related to age at alcohol initiation, characterization of factors important across the drinking career, and the importance of smell as well as taste in animal studies.
§ Scientific meetings. Dr. Li stated that NIAAA has played an important role in organizing symposia and other panels. He noted that this practice has spawned controversy in the perception that NIAAA drives the program and determines priorities. Dr. Li asserted that no conflict of interest exists, but suggested that Dr. Monti, as president of RSA, discuss the issue with the organization’s board. Dr. Li noted that NIAAA pursues the research directions identified on its Web site.
Dr. Li stated that NIAAA participates in a number of international symposia, including the recent Third International Symposium on Alcoholic Liver and Pancreatic Disease and Cirrhosis in Spain . For the 2010 ISBRA meeting in France, NIAAA will continue its tradition of grant support to enable U.S. investigators, especially young investigators, to attend.
What is ahead. Dr. Kathleen A. Grant will present the Mark Keller Honorary Lecture on her studies of monkeys that display binge drinking.
Discussion. Dr. Harris expressed the alcohol research field’s appreciation for Dr. Li’s contributions and leadership.
Hepatic Fibrosis: The New Frontier in Chronic Liver Disease from Alcohol
Scott Friedman, M.D., Fishberg Professor of Medicine and Chief, Division of Liver Diseases, Mount Sinai School of Medicine, stated that hepatic fibrosis represents the liver’s wound-healing response to chronic injuries, including, for example, hepatitis viruses, inherited metabolic disorders, cholestatic disorders, immune disorders, and alcohol. Researchers have hoped that identification of the key sources of scarring might uncover mechanisms relevant to many, if not all, forms of chronic liver disease. The liver’s regenerative capacity leads hepatologists typically to see chronic inflammatory disease that takes 10 to 50 years until it culminates in cirrhosis, the end-stage fibrotic state. Cirrhotic patients acquire the risk of hepatocellular carcinoma, the third most common cause of cancer mortality worldwide. This form of cancer develops on a substrate of chronic liver disease, including among patients with alcoholic cirrhosis. Liver transplantation is an option, but not the ultimate answer, for the more than 300 million patients with chronic hepatitis viruses worldwide or for patients who drink to excess. Dr. Friedman noted that the variability of progression offers a hint about genetic determinants of response to injury that are as relevant to alcohol as to viruses.
Dr. Friedman discussed clinical challenges, including the need for better markers of fibrosis stage and activity, better predictors of whose disease will progress, better models of liver injury and fibrosis, and a proof-of-concept anti-fibrotic trial. He explained that the highly invasive liver biopsy covers less than 1/50,000th of the total volume of the liver and is prone to sampling variability, highlighting an urgent search for sensitive, specific markers that respond quickly to changes in fibrogenic activity and that are tested rigorously and validated in an unbiased manner. Pharmaceutical companies have developed anti-fibrotic drugs and an array of targets, but the lack of robust, standardized endpoints is the limiting factor. Dr. Friedman noted the need for biomarkers (not surrogates) in blood or through imaging that monitor the cellular biology of the liver’s response to injury and assess improvement. Some available serum markers offer an integrated readout, but are not sufficiently developed for individual management. The medical field currently relies on biopsy scoring systems that do not account for the nonlinear development of scar content or the fact that rates of fibrosis and fibrogenesis are different. Dr. Friedman stated that progress in diagnostics depends on assessment of scarring and a determination that a therapy attenuates the process. Researchers are currently looking at imaging methods that might use labeled ligand to identify receptors expressed in a zone of fibrogenesis. Patients with hepatitis C have markedly variable fibrosis progressions. Alcohol is probably the single most important external factor that determines whether or not hepatitis C progresses, and some genetic and environmental factors apply—but no correlation exists between viral load or genotype and fibrosis progression. Researchers are investigating whether single nucleotide polymorphisms (SNPs) may correlate with risk of fibrosis progression and have determined the importance also of the host immune phenotype on fibrosis progression (and on the aftermath of liver transplantation).
In order to predict whose fibrosis will progress, researchers hope to identify genetic markers and then to conduct clinical trials to validate the markers to optimize stratification, shorten the duration of clinical trials, and extend genetic studies to all ethnicities. In this effort, equal stratification of genetic risk in the placebo and treatment groups is critical to understand the efficacy of treatments. Information about risk of disease can be gleaned by defining genetic individuality using SNPs related to slow or rapid progression. Dr. Friedman stated that one company has conducted a comprehensive approach to identifying risk genes that predict whether a patient with any chronic liver disease is likely to progress. In one study particularly relevant to alcohol that used a whole genome scanning approach, toll-like receptors recognize structural components unique to a variety of microorganisms and signal and activate inflammatory responses. Two well-known SNPs correlate with slower fibrosis progression. One potential pathway is that cells that harbor this genetic variant are cells that are less fibrogenic and less responsive to liver injury; Dr. Friedman has shown how the gene variant affects the biology. He suggested that such studies offer the potential to predict disease progression and refine therapy. This approach has uncovered new genes mechanistically linked to pathogenesis, and liver fibrosis SNPs may be correlated with fibrosis progression in other organs, including kidney, lung, and pancreas, which may lead to information about progression to end-stage disease.
In discussing the need for better models of liver diseases, Dr. Friedman noted that rodent models are time consuming, expensive, and not faithful to human disease, and cited the need for models that are genetically tractable and rapid. He shared data developed with zebrafish (Salder-Edepli). Development of the transparent zebrafish takes just 5 days; these vertebrates produce 10–500 embryos per clutch, are inexpensive to care for, are amenable to screens for mutants by chemical or genetic agents, and have biology more faithful to humans than drosophila. Many critical pathways in the human liver are present in zebrafish, which contract acute alcoholic liver disease. When dilute alcohol is added to the water, zebrafish metabolize ethanol and develop abnormalities that include steatosis of the liver.
Dr. Friedman discussed the mechanisms of fibrosis in rodent models and humans related to the hepatic stellate cell, which multiplies in response to injury and makes profound changes in surrounding cells. Liver failure results from hepatocytes unable to preserve their differentiated function because they are bathed in a micro environment hostile to their preservation and replication. The stellate cell is emerging as a major inflammatory regulator within the liver. A number of newly uncovered pathways represent targets for anti-fibrotic therapy. This therapy has a potential role to attenuate fibrotic progression, thereby reducing the risk of hepatocellular carcinoma and eliminating the need for transplantation.
The final challenge is a proof-of-concept trial for anti-fibrotic therapies. The pharmaceutical industry loses interest when drugs fail; trials are viewed as too costly and long; without positive trials, skepticism increases about treating fibrosis; and better antiviral therapies for hepatitis B and C have diminished enthusiasm for anti-fibrotics. Dr. Friedman asserts the need for anti-fibrotics to reverse the disease and render it more responsive to disease-specific therapies. Emerging therapies for hepatic fibrosis include reducing primary disease with antivirals, stopping alcohol ingestion, and perhaps anti-oxidants; turning off early stellate cell activation; inhibiting the properties of activated stellate cells; stimulating stellate cell apoptosis; and degrading the “scar” mix.
Future advances projected over the next few years include the use of improved genetic markers of disease risk in individuals who drink to excess; better noninvasive markers of injury and fibrosis, including small molecule mimetics and hepatocyte growth factor; regenerative therapies for liver failure; continued refinements in therapies for viral hepatitis and for alcoholic and nonalcoholic steatohepatitis; improved management of metabolic syndrome and obesity; use of long-term anti-fibrotics, alone or in combination, as a chronic therapy and complement to other disease therapies; and earlier diagnosis and more cures of hepatocellular carcinoma. Dr. Friedman ended his talk by acknowledging NIAAA’s support for this work.
Discussion: In response to Dr. Harris’s question, Dr. Friedman stated that hepatic stellate cells, Kupffer cells, and epithelial cells are affected by toll-like receptors 4 (TLR4). Dr. Friedman plans to study the response of single-nucleotide polymorphism’s (SNP) expressing Kupffer cells. SNPs may have competing activities, depending on which cell expresses the TLR4. Dr. Moss inquired about characteristics of an ideal approach for a marker for fibrosis. Dr. Friedman stated that research is emphasizing both circulating biomarkers and imaging. Regarding imaging, for example, platelet-derived growth factor (PDGF) receptors are expressed only when stellate cells are activated; in the injured liver, binding activity for labeled PDGF ligand should be proportionate to the massive activated stellate cells. Other markers, a host of extracellular matrix molecules, may be activation specific for cell type. Serum markers pose a greater challenge because such markers must be fibrosis or fibrogenesis specific, but also released and liberated; there may be combinations of cytokines or cell surface receptors that are shed or cleaved and that circulate; it remains unknown whether the amount found in the serum correlates with activity present in the liver. In response to a question from Dr. Li, Dr. Friedman stated that he expects genetic markers for progression to be found to differ among ethnic groups. Sample sets in Asians and African Americans show SNPs represented to different extents, leading one to envision customized SNP sets related to the ethnicity of the patient. Dr. Klassen inquired whether national databases are being pursued. Dr. Friedman stated that the original datasets were derived from several institutions with tissue banks, populated by more than 1,000 patients based on biopsy results. One company is seeking to work with the repository of the National Institute of Diabetes and Digestive and Kidney Diseases. He stated that the American Association for the Study of Liver Diseases has advocated for national databanks and clinical trials networks. Dr. Friedman suggested that resources from companies that see profit opportunities are essential in an era of tight research budgets.
Cell Biology of Adaptation to Alcohol: More Questions Than Answers
Dr. Jan B. Hoek, Department of Pathology, Anatomy, and Cell Biology, Thomas Jefferson University , described intracellular processes that provide an integrated picture of cell functions or subcellular structures, such as cell signaling, repair, proliferation, death and mitochondrial functions and dynamics. He also presented how such processes are affected by prolonged alcohol treatment; and how to characterize changes in a cells’ functional state as a result of adaptation to alcohol. The cell aims to maintain homeostasis in the face of a variable extracellular environment by means of cell signaling machinery embedded in a system of positive and negative feedback loops that promote a return to the stable homeostatic state. With a persistent or potentially damaging external or internal challenge, cells change their makeup to maintain homeostasis, at least in part mediated by epigenetic regulation, and change is minimized to maintain robust cell function.
Studies have shown that chronic alcohol feeding increases the cell’s capacity to respond to tumor necrosis factor- α (TNF‑α) that results in apoptosis or programmed cell death; for example, evidence indicates that cell signaling pathways in chronically ethanol-fed rats are at least partly responsible for enhanced responsiveness of hepatic parenchymal cells to pro-inflammatory cytokines, such as TNF. TNF at low concentrations is not cytotoxic. However, the combination of low TNF concentration and ethanol through a novel pathway dependent on endoplasmic reticulum-localized caspases-4 and -12, causes the activation of lipogenic transcription factor, SREBP-1 to induce the synthesis of lipogenic enzymes and triglycerides. This mechanism may lead to the development of hepatic steatosis, which is likely to contribute to enhanced liver injury in chronic alcoholics. (Pastorino and Shulga, 2008, J. Biol. Chem. 283:25638-25649).
Dr. Hoek explained that chronic alcohol treatment results in gross morphological abnormalities in mitochondria that are evident in the liver and other tissues—but similar abnormalities occur in cells that do not metabolize ethanol. Morphological changes may reflect mitochondrial dynamics concerning distribution of mitochondria to sites of energy demand, formation and disruption of the mitochondrial reticular network in fusion and fission, disposal of defective mitochondria, and mitochondrial biogenesis.
The distribution of mitochondria in many cells follows the microtubular network, of particular importance in neuronal cells where mitochondria traffic through the axons is mediated by cytoskeletal interactions. Mitochondria bind to the cytoskeletal tracts by means of the motor protein kinesin and a newly identified adaptor protein Milton and receptor protein Miro. Hajnoczky shows new evidence that reactive oxygen species influence this interaction of mitochondria with the kinesin molecule and are critical for identification of that process. Dr. Hoek explained that as the mitochondria move along the microtubules, they constantly undergo fusion and fission. Although the connection between transport and fusion and fission is not yet understood, a number of mitochondrial components are known. Fusion is mediated by the proteins OPA1 and Mfn, while fission requires the proteins Fis1 and Drp1 to separate mitochondria into different components. The defects in proteins are associated with differences in mitochondrial appearance in the cell and are disease associated.
Dr. Hoek summarized the research findings, noting that prolonged exposure to ethanol causes disruption of mitochondrial morphology in both hepatocytes and H9c2 cells, but that this effect does not appear to require its metabolism. Ethanol inhibits mitochondrial fusion processes and motility by targeting mitochondrial fusion-fission proteins, mitochondrial channels involved in volume regulation and signaling mechanisms, such as Ca2+, kinases, and reactive oxygen species. Dr. Hoek observed that open questions remain: Does the inhibition of mitochondrial dynamics contribute to cell injury by ethanol? If so, it would result in impaired regulation of the balance of energy supply and demand, impaired regulation of mitochondrial function in apoptosis, and impaired disposal of defective mitochondria. Can methods be developed to study mitochondrial dynamics in intact tissue or in vivo? Imaging processes are under consideration.
Dr. Hoek expressed appreciation for NIAAA’s support and his interactions with Council members. Dr. Li noted that NIAAA considers research on mitochondrial functions to be a high priority.
Treatment of Alcoholic Hepatitis: What We Have Learned from Clinical Trials
Dr. Mack C. Mitchell, Jr., Johns Hopkins Bayview Medical Center, stated that clinical trials have produced less information than has basic science about alcoholic hepatitis, and most patients with alcoholic liver disease are treated with old approaches. He explained that three major conditions are associated with heavy alcohol consumption and alcoholic liver disease: cirrhosis, fatty liver, and alcoholic hepatitis—an inflammatory condition in the liver that is the focus of most treatment strategies.
The few prospective studies conducted have revealed little about the relationship between alcohol consumption and the development of liver disease (Zakhari & Li, Hepatology, 2007). Studies have reported increased risk for alcoholic liver injury with heavy, sustained consumption, but only a small minority of heavy drinkers develops serious injury, underscoring the need to understand more about those individuals. Studies of consumption patterns show that drinking only at mealtime is associated with lower risk, and extreme degrees of binge drinking increase risk of alcoholic liver injury. Studies also have shown that women are more susceptible than men to liver injury from alcohol, even considering their lower body mass, but the increased risk is not understood. Black Americans and Hispanics have slightly higher odds of developing advanced liver injury, and patients with chronic hepatitis C who drink heavily have a greater risk of fibrosis.
Dr. Mitchell defined alcoholic hepatitis as a necrotizing, inflammatory condition of the liver due solely to alcohol. Its clinical symptoms include jaundice, enlargement, nausea and anorexia, fever, and abdominal pain. A variety of biomarkers that assist in diagnosis are expected to be useful in future clinical trials. It has been possible to identify persons who histologically would have the lesion associated with alcoholic hepatitis, which is characterized by an accumulation of fat within the liver cells and condensation of eosinophilic material. Ballooning degeneration of liver cells and inflammation have been associated with the progression of alcoholic liver disease beyond fatty liver to cirrhosis. Several older studies show that the presence of this histological entity increases the chance of developing cirrhosis over 10 years.
Cirrhosis is a leading cause of death, especially among individuals under age 50. Mortality ranges from 5 to 60 percent within 1 month of diagnosis, from hepatorenal dysfunction, infection, or gastrointestinal bleeding; spontaneous hepatic encephalopathy is associated with poor prognosis. Certain laboratory parameters that project diagnosis and prognosis, including prothrombin time, serum bilirubin, and serum creatinine, are more useful than clinical detection.
Cholestasis in alcoholic hepatitis has been associated with both sepsis and endotoxemia. Recent information on jaundice shows a probable interaction between pneumococcal infection, and the infection’s toxins, superimposed on the background of fatty liver due to alcohol, as modeled in basic science. Septic patients with cholestasis show slight increases in AST, ALT, and alkaline phosphatase, similar to alcoholic hepatitis. When jaundice is persistent, the mortality rate is high; liver biopsies show the same type of Kupffer cell hyperplasia as in alcoholic liver disease—neutrophilic sinusoidal infiltrate, and mild periportal inflammation. Underlying liver disease appears to be the common factor; when infection is superimposed on nonalcoholic hepatitis, the chances of dying due to infection are greater. Patients without underlying liver disease rarely become jaundiced, even during overwhelming sepsis. Several studies over the years have found a relationship between high levels of plasma endotoxin and interleukins associated with inflammatory responses.
Goals in treatment of alcoholic hepatitis include prevention of further liver injury, improved short- and long-term mortality rates, stabilization for 6 or more months for consideration for liver transplantation, and preventing certain specific complications, such as hepatorenal syndrome.
Dr. Mitchell discussed the efficacy of specific therapies. Abstinence is the best treatment for alcoholic hepatitis and all other forms of the disease; considerable evidence shows that moderate drinkers with cirrhosis do not fare as well. Next steps in treatment are to consider altering the pathophysiology by addressing mechanisms of injury or by selecting a subgroup of patients for whom treatment is indicated because they are too ill and would die despite interventions, or they would not improve on their own with abstinence. Treatments shown ineffective have included propythiouracil, colchicine, milk thistle, vitamin E, anabolic steroids, and antioxidants. Thirteen randomized controlled trials and several meta-analyses support corticosteroid treatment of severe alcoholic hepatitis, and the American College of Gastroenterology considers steroids to be the best treatment for severe alcoholic hepatitis. But steroids seem to offer little long-term benefit, in part because some subjects may have returned to drinking. All the studies that show the benefit of steroids have focused on severely ill patients and excluded other serious conditions. Recent studies have required liver biopsy to verify diagnoses, but new biomarkers may prove useful in eliminating the need for biopsy in future studies. Studies of intravenous nutritional therapy for alcoholic hepatitis show no difference in mortality, but enteral nutrition shows some improvement in survival compared to standard therapy. Anti-inflammatory therapy for alcoholic hepatitis has derived from studies that showed that survival rates were better among patients with alcoholic hepatitis with no measurable levels of TNF. Recent randomized studies with Infliximab and Etanercept have not confirmed earlier studies of their effectiveness; both earlier studies were discontinued. This therapy may not work because blocked TNF reduces the liver’s ability to regenerate. A study of Pentoxifylline, which reduces production of TNF through a cyclase dependent mechanism, showed improved survival due to decrease in death from hepatorenal syndrome. Although recent studies have failed to confirm initial findings, an NIAAA RCT is pending analysis. Costly liver transplantation is not ideal for everyone with serious alcoholic liver injury.
Dr. Mitchell concluded that though many clinical features of alcoholic liver disease suggest a role for endotoxin as a stimulus for inflammation, insufficient data describe the mechanism. A select group of patients benefit from anti-inflammatory therapy with steroids, but optimal duration and dosage are unclear. Assessment of severity is needed to select a subgroup of patients who might benefit, along with monitoring the response, to see if it is possible to predict who will benefit in order to limit side effects and improve outcomes. Combining treatments, such as enteral nutrition and anti-inflammatory therapy, may produce progress, but many studies are difficult to conduct because of the heterogeneity of the population and lack of accurate measures of hepatic function. In addition, questions arise about whether clinically severe alcoholic hepatitis is the same as histological alcoholic hepatitis, and whether severe alcoholic hepatitis is the correct disease to study—or if study is warranted of other aspects of alcoholic livery injury. Dr. Mitchell stated that while multicenter studies will be required, funding is problematic because pharmaceutical companies have no interest in treating alcoholics. He suggested that future studies investigate how long steroid therapy should be used and whether combining therapies may be the best mechanism for long-term success.
Discussion: Dr. Ehlers inquired whether an age curve is indicative of morbidity and mortality. Dr. Mitchell stated that for individuals under age 50, alcoholic cirrhosis is a greater cause of mortality. In older populations, heart disease and cancer are greater causes of death. Dr. Li inquired about studies on the role of anti-estrogen or progesterone therapy and whether endotoxins and antibiotics might be used to reduce women’s greater susceptibility. Dr. Mitchell replied that anti-estrogen therapy has not been investigated, but women are more likely to respond to steroids than men. Antibiotic therapy has been tried, but with broad-spectrum antibiotics, all subjects contract fungal disease. Dr. Harris inquired about the prospects for delivering gene therapy to the liver to knock down toll receptors. Dr. Mitchell stated that many people hope that in the future targeted delivery of medications to the liver will increase the probability of success. Problems with TNF require demonstration of high effectiveness before entering human studies. To Dr. Monti’s question about the insurance industry’s response to transplants, Dr. Mitchell stated that transplantation is now considered an acceptable treatment for end-stage liver disease, regardless of cause, if the subject has no heart injury, but patients encounter financial problems due to lifetime caps on coverage for anti-rejection drugs. To Dr. Zakhari’s question, Dr. Mitchell responded that small, uncontrolled trials have been conducted with probiotics that are focused more on nonalcoholic than alcoholic liver disease. Probiotics may reduce portal vein endotoxemia, which may precipitate alcoholic hepatitis.
Consideration of the June 2008 Minutes and Future Meeting Dates
Council members voted unanimously to approve the minutes of the Council meeting of June 4–5, 2008. Dr. Abraham Bautista announced that upcoming Council meetings will convene on February 4–5, 2009, June 10–11, 2009, September 16–17, 2009; February 3–4, 2010, June 9–10, 2010, September 15–16, 2010; February 16–17, 2011; June 8–9, 2011; and September 14–15, 2011.
Council Round Table
Prompted by a question from Dr. Crabb, Dr. Faden described NIAAA’s response to the Amethyst Initiative, a proposal by 120 college presidents to lower the legal drinking age to 18. NIAAA’s Web site has posted two general, factual statements, one of which focuses on college drinking; SAMHSA has placed a link to both statements on its Web site. NIAAA does not take a position on legal drinking age, but policy makers can use the information to make informed decisions. Gen. Dean stated that, working with NIAAA, he developed and sent a letter on behalf of the Council of Anti-Drug Coalitions of America (CADCA) to the college presidents explaining the way in which communities work to address the issue and their concerns about the Amethyst approach. Eleven presidents responded that their intention was to create dialogue, not to lower the legal drinking age. Gen. Dean observed that a significant consequence of lowering the drinking age might be to shift the problem to high school principals. He also noted that many college-age students understand the consequences of drinking and are abstaining. Dr. Ehlers commended the NIAAA message. She suggested clarification of the statement regarding minimum legal age by country and incorporation of NESARC data. Dr. Li noted a provocative article by Cloud, who asserts that U.S. children should learn to drink as they do in France and Italy, but France’s INSERM reports that binge drinking in France has led to consideration of raising that country’s legal drinking age to 21. Dr. Ehlers noted that the San Francisco Family Study found a statistically significant higher rate of alcohol dependence in a group that started drinking between ages 18 and 21 than those who started drinking after age 21. She suggested that using the same methodology, NESARC data would show the same results. Dr. Hasin stated that analysis would be possible; Dr. Li added that it would be possible for NLAES data as well. In response to Dr. Mitchell’s question about activities related to the Amethyst letter, Gen. Dean stated that Columbia University’s National Center on Addiction and Substance Abuse will host a policy panel in October. Dr. Li pointed out that there are approximately 3,500 college presidents; only 120 signed the Amethyst letter. Dr. Hasin noted the risk that a member of Congress might propose legislation to lower the drinking age. Dr. Faden responded that some States have proposed legislation, but Dr. Hingson stated that this unlikely action would risk Federal withholding of highway funds; opposition remains considerable on Capitol Hill. Mr. Palmer noted, however, that grassroots efforts have resulted in removing Federal legislation that then enabled Kentucky to rescind a mandate for motorcycle helmets.
Liaison Representative Reports and Public Comment
Ms. Mimi Fleury, President, Community of Concern, an organization of parents, students, and schools working together to educate parents to keep youth alcohol and other drug free, recognized Dr. Li for his vision of NIAAA as the premier source of science in America relating to alcohol and addiction. This posture has enabled her organization to construct a prevention initiative with science as the cornerstone. She commended Dr. Li’s emphasis on community outreach, translating science into lay terms, and creating NIAAA’s underage drinking team.
Dr. Erin Frey, National Organization for Fetal Alcohol Syndrome (NOFAS), a liaison organization with NIAAA, stated that HRSA has awarded NOFAS funding for its community health center FASD prevention project. The project trains doctors and nurses to screen women, using the NIAAA-developed AUDIT-C. She noted continuing support on Capitol Hill for FASD, and thanked NIAAA for ongoing support.
Mr. Martin Kerrigan, Acting Chairperson, Maryland State Traumatic Brain Injury Advisory Board, called attention to the relationship between brain injury (both traumatic and acquired) and significantly higher rates of substance abuse in a population typically ignored. He noted, for example, that 36–51% of traumatic brain injuries (TBI) occur when individuals are above the common legal limit for intoxication, while 75% of persons with TBI had consumed some alcohol at the time of injury. He asserted that rehabilitation efforts must include prevention, early intervention, and treatment of substance abuse. Alcohol and drug abuse are risk factors for poor outcomes following TBI and reflect both physiological and biological vulnerability. With an increase in survivors of war injuries and better medical care, the substance abuse needs of more survivors who return to society must be addressed.
Mr. David Wallace, Director, National Center for DWI Courts, stated that this new initiative of the National Association of Drug Court Professionals deals with high-risk drinking drivers. He stated that he looks forward to disseminating NIAAA’s information to providers.
Dr. Li adjourned the meeting at 1:58 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Kenneth Warren, Ph.D.
Abraham P. Bautista, Ph.D.
Prepared: February 2009