DEPARTMENT OF HEALTH AND HUMAN SERVICES
NATIONAL INSTITUTES OF HEALTH
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
150th Meeting of the
NATIONAL ADVISORY COUNCIL ON ALCOHOL ABUSE AND ALCOHOLISM
February 7, 2019
The National Advisory Council on Alcohol Abuse and Alcoholism (NIAAA) convened for its 150th meeting at 9:00 a.m. on Thursday, February 7, 2019, at NIAAA headquarters in Rockville, Maryland. The Council met in closed session from 9:00 a.m. to 9:26 a.m. for a presentation of the NIAAA Board of Scientific Counselors (AABSC) report and from 9:27 a.m. to 10:02 a.m. to review grant applications and cooperative agreements. Dr. Abraham Bautista, Director, Office of Extramural Activities, presided over the Council’s review session, which, in accordance with the provisions of Sections 552b(C)(6), Title 5, U.S.C., and 10(d) of Public Law 92-463, excluded the public for the review, discussion, and evaluation of individual applications for Federal grant-in-aid funds. The closed session recessed at 10:02 a.m.
Council Members Present:
Carmen Albizu-Garcia, M.D.
Louis E. Baxter, M.D.
Howard C. Becker, Ph.D.
Jill B. Becker, Ph.D.
Daniel J. Calac, M.D.
Tom B. Donaldson
Alex M. Dopico, M.D., Ph.D.
Tatiana M. Foroud, Ph.D.
Robert J. Hitzemann, Ph.D.
Constance M. Horgan, Sc.D.
Scott J. Russo, Ph.D.
Arun J. Sanyal, M.D.
Vijay H. Shah, M.D.
Frank A. Sloan, Ph.D.
Susan M. Smith, Ph.D.
Edith Vioni Sullivan, Ph.D.
Constance M. Weisner, D.R.P.H.
Karen Drexler, M.D.
Charles S. Milliken, M.D.
NIAAA Director and Chair: George F. Koob, Ph.D.
NIAAA Deputy Director: Patricia Powell, Ph.D.
Executive Secretary: Abraham P. Bautista, Ph.D.
Senior Staff: Vicky Buckley, M.B.A.; David Goldman, M.D.; Ralph Hingson, Sc.D., M.P.H.; M. Katherine Jung, Ph.D.; George Kunos, M.D., Ph.D.; Raye Litten, Ph.D.; Antonio Noronha, Ph.D.; and Bridget Williams-Simmons, Ph.D.
Other Attendees at the Open Session:
Approximately 65 observers attended the open session, including representatives from constituency groups, liaison organizations, NIAAA staff, and members of the general public.
Call to Order and Introductions
NIAAA Director George Koob, Ph.D., called the open session of the Council meeting to order at 10:02 a.m. on Thursday, February 7, 2019. He introduced three new Council members: Jill B. Becker, Ph.D.; Constance M. Horgan, Sc.D.; and Scott J. Russo, Ph.D. Council members and senior NIAAA staff introduced themselves.
Dr. Koob highlighted key recent NIAAA activities, referring to the written Director’s Report, which was distributed to Council members.
- Staff Transitions: Dr. Koob reported the death on November 18, 2018 of Ting-Kai Li, M.D., a renowned scientist who served as NIAAA’s director from 2002 to 2008. He welcomed new NIAAA staff members: Carlos Gomez, Administrative Officer, Administrative Services Branch; Kari Johnson, Ph.D., Research Fellow, Laboratory for Integrative Neuroscience (LIN); Andrew Kesner, Ph.D., Postdoctoral Fellow, LIN; Daniel Liput, Ph.D., Research Fellow, LIN; Aya Matsui, Ph.D., Research Fellow, Laboratory on the Neurobiology of Compulsive Behavior; Benson Stevens, Ph.D., Postdoctoral Fellow, Section on Human Psychopharmacology; Dominique Lorang-Leins, Ph.D., Program Director, Division of Neuroscience and Behavior (DNB); Jenica Patterson, Ph.D., Program Officer, DNB; Samara Toussaint, M.P.H., Program Analyst, Division of Epidemiology and Prevention Research (DEPR); and Pamela Wernett, Ph.D., Senior Health Policy Analyst, Science Policy Branch. Daniel Smyth, M.P.P., transferred to the Ethics and Management Analysis Branch as a Management Analyst from DEPR. Dr. Koob also recognized departing staff members: Shuly Babitz to the Maternal and Child Health Branch, Health Resources and Services Administration; Jennifer Hobin, Ph.D., to the National Institute on Drug Abuse (NIDA) as Deputy Director of the Office of Science Policy and Communications; and Katrina Possa Abrahao, Ph.D., to the Universidade Federal de São Paulo. Roz Breslow, Ph.D., Program Officer, and Marcia Scott, Ph.D., Health Scientist Administrator, retired from DEPR; Andrea Barnes, D.V.M., retired as Chief, Office of Laboratory Animal Science.
- Budget: NIAAA closed out the FY 2018 budget of $509.6 million, which funded 738 research project grants (RPGs); 253 competing awards; 175 other research grants; 20 research centers; 305 training positions; and $34.4 million for research and development contracts. For FY 2019, NIH received a total of $39.3 billion, which included general increases for Institutes and Centers (ICs); ongoing support for the Gabriella Miller Kids First Act pediatric research initiative; and allocations for research on opioids, the 21st Century Cures Act, the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, and research on influenza. NIAAA’s budget increased to $525.6 million for FY 2019.
- Success Rates: The 2018 RPG success rates were 26.7 percent for NIAAA and 20.2 percent for NIH.
- New Funding Opportunity Announcements (FOAs): New NIAAA FOAs include a Collaborative Study on the Genetics of Alcoholism (U10); Alcohol-HIV/AIDS Program Project (P01); Comprehensive Alcohol-HIV/AIDS Research Center (P60); Specialized Alcohol Research Centers Clinical Trial Optional (P50); Medications Development for the Treatment of Alcohol Use Disorder (U01); and Summer Research Education Experience Program (R25). There are currently over 40 NIH-wide FOAs with NIAAA participation, including 17 Helping to End Addiction Long-Term (HEAL) Initiative Requests for Applications (RFAs) and five BRAIN Initiative RFAs.
- Collaborative Research on Addiction (CRAN): The Adolescent Brain Cognitive Development (ABCD) Study completed its baseline recruitment of 11,874 participants (ages 9-10). Three NIH Notices were released in October describing an intent to publish limited-FOAs for renewal of the Coordinating Center, the Data Analysis and Informatics Center, and the Research Project Sites of the nationwide ABCD Consortium. ABCD data is uploaded to the National Institute on Mental Health Data Archive.
- Emerging Issues: Dr. Koob highlighted NIAAA’s response to the emerging issue of high intensity drinking, defined as alcohol intake at levels twice or more the threshold for binge drinking (i.e., more than four drinks for women/five drinks for men within a two-hour period). High intensity drinking is predictive of increased harm, e.g., visits to the emergency department. In October 2018, NIAAA convened a working group of external experts to better understand the social and cultural determinants of high-intensity drinking to inform the development of improved interventions. A meeting summary is available on the NIAAA website. Other emerging issues that are largely neglected include the sleep-alcohol use disorder, in which a two-way interaction between sleep disorders and alcohol use occurs, and the bi-directional relationship between pain and alcohol misuse.
- NIAAA Outreach: NIAAA and the Community Anti-Drug Coalitions of America (CADCA) co-sponsored a screening of the HBO documentary “Risky Drinking” in Washington, DC last September. NIAAA continues to be active in alcohol-related Twitter chats: In recognition of National Fetal Alcohol Spectrum Disorders (FASD) Awareness Day, NIAAA partnered with the National Organization on Fetal Alcohol Syndrome (NOFAS) in a September 2018 Twitter chat. In October 2018, NIAAA hosted an #AlcoholYouthChat with the American Society of Addiction Medicine (ASAM) on recognizing and preventing underage drinking. In January 2019, NIAAA participated in National Drugs and Alcohol Chat Day, an annual live online chat between high school students and NIH scientists.
- Success in Reducing Underage Drinking: NIAAA’s efforts to prevent underage drinking are succeeding; the percentage of teens who drank within the past 30 days has declined by one-third over the past ten years. However, about 35 percent of high school seniors continue to consume alcohol.
- Dissemination and Implementation of Evidence-Based Prevention Resources: In response to issues such as high intensity drinking, increased drinking among women, and underage drinking, coupled with a surprising lack of knowledge among the public about alcohol and its effects, NIAAA has made the dissemination of evidence-based prevention resources a priority. Dr. Koob and Elinore McCance-Katz, M.D., Ph.D., Assistant Secretary for Mental Health and Substance Use at the Substance Abuse and Mental Health Services Administration (SAMHSA), have agreed that SAMHSA will disseminate resources that NIAAA develops. Key resources currently in development include the Core Prevention Resource (CPR), an online resource that distills and synthesizes underage drinking preventive interventions into five prevention domains (i.e., individual, family, school, community, and policy). Preventive interventions for underage drinking shared via the CPR will be applicable to school and community settings, with a focus on effective school-based interventions. Also, in development is the Clinician’s Navigator, a resource for health professionals to help them build a “rolodex” of local high-quality treatment providers and to walk patients and family members through the existing Treatment Navigator. Finally, the NIAAA Clinical Core Resource (CCR) will address what clinicians need to know about alcohol, including its presentation in primary care; role in common co-occurring conditions; neuroscience; alcohol misuse across the lifespan; diagnostic criteria; recommended drinking limits; alcohol withdrawal syndrome; evidence-based therapies; stigma; and interactions with commonly used medications. The NIAAA CCR will also include suggestions for practice, e.g., how to start the conversation, and information about resources, such as Risky Drinking.
- NIAAA Research Highlights: Dr. Koob presented highlights of NIAAA-funded studies, including:
“Crystal Structure of the Human Cannabinoid Receptor CB2” was published in Cell (Epub 2019 Jan 10. doi: 10.1016/j.cell.2018.12.011) by X Li, T Hua, K Vemuri, JH Ho, Y Wu, L Wu, P Popov, O Benchama, N Zvonok, K Locke, L Qu, GW Han, MR Iyer, R Cinar, NJ Coffey, J Wang, M Wu, V Katritch, S Zhao, G, Kunos, LM Bohn, A Makriyannis, RC Stevens, and Z Liu. This study described the crystal structure of the antagonist-bound human CB2 cannabinoid receptor, a G-protein coupled receptor expressed in the immune system that has therapeutic potential for neuropathic pain, inflammation, and neurodegenerative disorders. The study provided insight into the activation mechanisms of the CB2 receptor that could facilitate design of novel therapeutic drugs targeting cannabinoid receptors.
“Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis and Inflammation in Mice” was published in Hepatology (Epub 2018 Sep 4. doi: 10.1002/hep.30249) by A Ambade, P Lowe, K Kodys, D Catalano, B Gyongyosi, Y Cho, A Iracheta Vellve, A Adejumo, B Saha, C Calenda, J Mehta, E Lefebvre, P Vig, and G Szabo. A prominent pathology of alcoholic hepatitis (AH) is liver infiltration by immune cells which requires chemokine receptors CCR2 and CCR5. This study tested a dual CCR2-CCR5 inhibitor, cenicriviroc (CVC), in a mouse model of alcohol-associated liver disease and found that CVC was highly effective in both preventing and reversing liver injury, including inflammation, fibrosis, and cell death, thus providing preclinical evidence that CVC might be clinically effective against AH.
“Bacteria Engineered to Produce IL-22 in Intestine Induce Expression of REG3g to Reduce Ethanol-Induced Liver Disease in Mice” was published in Gut (Epub 2018 Nov 17. doi: 10.1136/gutjnl-2018-317232) by T Hendrikx, Y Duan, Y Wang, J-H Oh, LM Alexander, W Huang, P Staerkel, SB Ho, B Gao, O Fiehn, P Emond, H Soko, J-P van Pijkeren, and B Schnabl. Alcohol misuse is linked to gut barrier dysfunction, increased intestinal permeability and changes in gut microbiota composition (dysbiosis) that contribute to alcohol-associated liver disease (ALD). This study identified the underlying mechanism of IL-22 and REG3g suppression in a mouse model of ALD and demonstrated that alcohol-induced liver damage can be reduced by introduction of bacteria engineered to produce IL-22.
“Adolescent Binge Ethanol-Induced Loss of Basal Forebrain Cholinergic Neurons and Neuroimmune Activation are Prevented by Exercise and Indomethacin” was published in PLoS One (2018 Oct 8; 13(10): e0204500. doi: 10.1371/journal.pone.0204500) by RP Vetreno and FT Crews. These researchers demonstrated that the loss of basal forebrain cholinergic neurons following adolescent alcohol exposure is accompanied by increased neuroimmune signaling and occurs independently of both sex and timing of adolescent alcohol exposure. In addition to identifying a neuroimmune mechanism for the cell loss, these experiments demonstrated that both exercise and the anti-inflammatory drug indomethacin can prevent alcohol-related cell loss. These findings identify factors that contribute to the adverse effects of adolescent binge drinking on cognitive functioning and suggest preclinical prevention approaches that may be translated to humans.
“Synaptic Adaptations in the Central Amygdala and Hypothalamic Paraventricular Nucleus Associated with Protracted Ethanol Abstinence in Male Rhesus Monkeys” was published in Neuropsychopharmacology (Epub 2018 Dec 5. doi: 10.1038/s41386-018-0290-7) by VA Jimenez, MA Herman, VC Cuzon Carlson, NA Walter, KA Grant, and M Roberto. Aberrant stress regulation contributes to relapse to heavy drinking following prolonged abstinence. This study observed changes in synaptic adaptations in amydalamic (increased GABA release) and hypothalamic (increased glutamate release) stress circuits during abstinence. These findings offer insights into the state of brain stress circuitry at a time when relapse is most likely to occur.
“Ghrelin Receptor Deletion Reduces Binge-Like Alcohol Drinking in Rats” was published in the Journal of Neuroendocrinology (Epub 2018 Nov 20. doi: 10.1111/jne.12663) by LJ Zallar, S Beurmann, BJ Tunstall, CM Fraser, GF Koob, LF Vendruscolo, and L Leggio. This study describes the use of a novel transgenic rat model lacking the ghrelin receptor, known as GHSR Knockout (GHSR KO), to examine drinking behavior in multiple experimental paradigms. GHSR KO rats consumed significantly less alcohol in both operant self-administration and binge-like drinking paradigms compared to wild-type rats that express GHSR. These results provide further support for the role of the ghrelin system in AUD and of the potential for GHSR as a novel target in the development of AUD medications.
“Neurofunctional Domains Derived from Deep Behavioral Phenotyping in Alcohol Use Disorder” was published in the American Journal of Psychiatry (Epub 2019 Jan 4. doi: 10.1176/appi.ajp.2018.18030357) by LE Kwako, ML Schwandt, VA Ramchandani, N Diazgranados, GF Koob, ND Volkow, C Blanco, and D Goldman. This study examined whether three key neurobiological domains that are critical to the addiction cycle (incentive salience, negative emotionality, and executive function) could be identified in a large, diverse clinical sample of individuals representing the spectrum of alcohol use disorder (AUD). Measures of addiction, personality, cognition, behavior, and exposure to early-life stress were collected. Using multiple indicators, multiple causes approach, the study confirmed the relevance of the three neurofunctional domains to AUD.
“Transancestral GWAS of Alcohol Dependence Reveals Common Genetic Underpinnings with Psychiatric Disorders” was published in Nature Neuroscience (2018 Dec; 21(12):1656-1669. doi: 10.1038/s41593-018-0275-1) by RK Walters, et al. In a large genome-wide association study of DSM-IV alcohol dependence (AD), investigators identified variants in the alcohol dehydrogenase (ADH1B) gene as a major contributor to risk for AD, in addition to identifying different protective variants in the same gene for individuals of European and African descent. This study also identified robust genetic correlation of AD with a variety of psychiatric outcomes. This correlation was strongest for aspects of negative mood.
“Drinking Risk Level Reductions Associated with Improvements in Physical Health and Quality of Life Among Individuals with Alcohol Use Disorder” was published in Alcoholism: Clinical and Experimental Research (2018 Dec; 42(12): 2453-2465. doi: 10.1111/acer.13897) by K Witkiewitz, HR Kranzler, KA Hallgren, SS O'Malley, DE Falk, RZ Litten, DS Hasin, KF Mann, and RF Anton. One- and two-level reductions in the World Health Organization (WHO) drinking risk levels have been proposed as alternatives to the Food and Drug Administration (FDA)-approved endpoints of abstinence and no heavy drinking days in clinical trials for alcohol use disorder (AUD). To examine the association between the reductions in WHO drinking risk levels and improved alcohol outcomes, a secondary data analysis was conducted using data from patients with AUD. One-and two-level reductions in WHO drinking risk levels were associated with improved physical health and quality of life, supporting the use of this outcome measure as a primary endpoint for AUD clinical trials.
“Acute Alcohol Intoxication Inhibits Bystander Intervention Behavior for Sexual Aggression Among Men with High Intent to Help” was published in Alcoholism: Clinical and Experimental Research (2019 Jan; 43(1):170-179. doi: 10.1111/acer.13920) by RM Leone and DJ Parrott. Bystander training programs are a form of primary prevention that aim to reduce sexual aggression, but they rarely focus on training bystanders to intervene effectively when intoxicated. This research evaluated the effects of intent to help strangers and acute alcohol intoxication on the likelihood and speed of sexual aggression intervention. Results indicated that intent to help strangers is associated with a decreased likelihood of sexual aggression intervention among intoxicated, but not sober, men. Programming efforts should begin accounting for the inhibiting effects of acute alcohol intoxication.
NIH Inclusion Report
Dr. Koob introduced Judith Arroyo, Ph.D., Coordinator, NIAAA Minority Health and Health Disparities, who presented aggregate data from the NIAAA Triennial Inclusion Report, Fiscal Years 2016-2018. Council members received a detailed print report on compliance regarding women and racial/ethnic minorities. Dr. Arroyo presented three tables of data. Table 1, Enrollment for All NIH-Defined Clinical Research by Sex/Gender, displayed a significant drop in female participation in 2018 (29,795) compared to 2016 (83,496) and 2017 (82,928). This was largely the result of four studies with high female enrollments that ended in 2018 (Correction ended in 2017), as well as a Veterans Administration (VA) study in 2018 that consisted primarily of men. To present the data in a less skewed manner, percentages were calculated for studies excluding those with an enrollment over 50,000 for all the tables. The results showed a more consistent pattern of female participation across the three years. Table 2, Enrollment for All NIH-Defined Clinical Research by Race, also reported raw numbers and percentages calculated when studies with more than 50,000 enrollees were excluded. Participation by different racial/ethnic groups across the three-year period was affected mostly by the beginning and end of specific studies. For example, AIAN decreased from 2017 to 2018 was due to the end of one study at a Tribal college, whereas and the number of African American enrollees increased sharply in 2018 due to the aforementioned VA study that reported large proportions of white and black veterans. Table 3 displayed Enrollment for All NIH-Defined Clinical Research by Ethnicity. Percentages calculated by excluding studies with enrollments over 50,000 showed that Hispanic/Latino participation stayed relatively stable, varying between 14.4 percent to 17.5 percent over the three-year period. The data did not allow for a break out of Hispanic ethnicity by race.
In summary, FY 2016-2018 enrollment data were influenced by large enrollment studies which skewed the enrollment distributions. These studies included surveys that did not collect sex/gender and race/ethnicity data and represented high percentages of the total enrollment (FY 2016 and FY 2017) and a VA study with a high proportion of African-American and White (not Hispanic) males that represented 75 percent of the total enrollment in FY 2018. When large studies were excluded, the enrollment distributions were mostly consistent from year-to-year. Changes in the inclusion system and reporting requirements may have also impacted the data. NIAAAA is working to better understand the impact of those changes. Finally, the data does not lend itself to disaggregating Hispanic enrollment by race.
Discussion: Constance Weisner, D.R.P.H., noted the many pragmatic randomized trials outside NIH that are representative of the clinical research system; she suggested that it is important to either broaden the definition of clinical studies or to evaluate participation in them in different ways. Dr. Arroyo responded that the definition of clinical trials has changed, so the number of participants is likely to increase. In addition, grantees are being asked to report Hispanic participants by race, so NIAAA will be able to report this information in the future. Arun Sanyal, M.D., inquired about the availability of data on the distribution of urban vs. rural participants, noting that their health status may be different. Dr. Arroyo said that urbanity is not one of the reporting requirements for compliance, although there is a coding system that addresses it. Dr. Weisner noted the instability of racial reporting, e.g., youngsters change how they define themselves racially over time. Dr. Arroyo concurred, noting that those who identify as Lesbian/Bisexual/Gay/Transgender (LBGT) also change how they report their identities over time.
Council Action: Council unanimously voted to accept the compliance report as is.
Women and Alcohol
Dr. Koob introduced Deidra Roach, M.D., Medical Project Officer who leads NIAAA’s efforts on women and alcohol. Dr. Roach represented the Interagency Work Group on Drinking and Drug Use in Women and Girls for this presentation, which she organized into five topics:
Epidemiology of Drinking Among Women: Guidelines for alcohol limits for men and women vary by source. NIAAA’s definition of binge drinking is to a blood alcohol concentration (BAC) of 0.08 gm percent. A 2016 meta-analysis of 68 studies found that the male/female gap in drinking and harmful effects of alcohol closed dramatically during the 20th century due to increases in women’s drinking. According to the 2017 National Survey on Drug Use and Health (NSDUH), over one-half (51.6 percent) of women consumed alcohol within the past month, 21.8 percent engaged in binge drinking, and 11.5 percent of pregnant women consumed alcohol. Four percent of women had an AUD within the past year, with 8.8 percent receiving specialty treatment. A 2015 study by NIAAA researchers reported an 8 percent increase in alcohol consumption between 2002-2012 among all cohorts of women 21 years of age and older; the steepest increase was among women 65 and older. Binge drinking among women 21 and older increased by 13 percent over the same period.
Risk Factors: Contributing to the rise in women’s drinking are changing cultural norms; increased availability due to increased manufacturing and distribution, as well as more disposable income; having a partner who drinks heavily; depression and anxiety; a history of childhood sexual or physical abuse; and intimate partner violence (IPV). Studies from WHO and elsewhere indicate that women with recent IPV are 1.8 times more likely to use alcohol, and twice as likely to engage in alcohol treatment. There is some evidence to suggest that women and girls are more motivated to drink for negative reinforcement, whereas men and boys are more likely to drink for positive reinforcement, suggesting that gender-specific prevention strategies may be needed. Researchers are currently investigating the hypothesis that differences in the brain’s wiring may be responsible for motivational differences: In boys, there is less inhibitory control, increased sensation-seeking and impulsivity, whereas for girls, stressful experiences and comorbid internalizing disorders may mediate substance use.
Health Impacts: For adolescent girls, cognitive impairments resulting from alcohol use affect school performance. Girls who consume alcohol have a three times greater risk for sexual victimization, i.e., unplanned, unsafe sex. Initiating drinking before the age of 14 carries up to a seven times greater risk for AUD. Drunk driving is a leading cause of teen deaths. Young women in their 20s and 30s are at greater risk for sexual and other violent assaults, as well as for unplanned and unsafe sex. They are also at greater risk for motor vehicle accidents and more likely to experience the onset of long-term health problems, such as an increased cancer risk. Furthermore, these young women in their prime child-bearing and child-rearing years are those who are drinking the most heavily. The prevalence of drinking among women 65 and older is also increasing; stigma in this age group may be a barrier to seeking treatment. Alcohol problems in older women are often overlooked and untreated, but may be an important factor in depression, sleeping problems, poor appetite, heart failure, and frequent falls. Further, medications can interact harmfully with alcohol. Gender differences in the health impacts of alcohol include women and girls having higher mortality and morbidity from heavy drinking than men; telescoping, i.e., alcohol-related health problems occur sooner and progress more quickly in women with all vital organs affected; and an increased risk for breast cancer. Gender differences are also apparent in patients with Alcoholic Liver Disease (ALD): Women with ALD have a more rapid progression to fibrosis. There has been a roughly 35 percent increase in death rates for alcohol-related cirrhosis for men and women between 2000-2015, driven largely by an 85 percent increase for white women compared to 32 percent for white men.
Treatment: Treatment works for both genders, but, overall, fewer than 10 percent of women and men access treatment. Women do as well as men in mixed gender treatment, but are more successful in women-only treatment settings; women in women-only treatment were 2.3 times less likely to report substance use and 2.5 times less likely to report criminal activity than women in mixed gender treatment. Women in women-only residential treatment were likely to spend significantly more days in treatment and twice as likely to complete treatment, compared to those in mixed gender programs. In response to the challenge of how to help women access evidence-based treatment, the Interagency Work Group on Drinking and Drug Use in Women and Girls proposed a Multi-Institute Implementation Science Initiative. Phase I would be devoted to strategic planning based on operations research to predict the best mix of prevention and treatment evidence-based interventions (EBIs) for women in different target communities. Phase II would address implementation and ongoing evaluation of statistically modeled, tailored EBI service bundles for women in different target communities. Phase III would consist of the development and dissemination of an online resource to share the resulting evidence-based continuums of care with communities nationwide.
NIAAA Response: NIAAA is analyzing its portfolio in terms of women’s health research to identify gaps. The Interagency Work Group is holding quarterly webinars on harmful substance use among women and girls, and has developed a white paper on the topic. The goal for 2019 is to use the white paper as the basis for a special journal issue on harmful substance use among women. The Interagency Work Group has also submitted a virtual issue of Alcohol Clinical and Experimental Research that is currently under review.
Discussion: Howard Becker, Ph.D., inquired about the use of the term “telescoping,” stating that it originally was used to explain the earlier onset of alcohol use in women, but that Dr. Roach’s presentation referred to greater volume of alcohol. Dr. Roach replied that the term encompasses both quantity and a shorter timeline from onset to progression. Dr. Russo asked if there is state-by-state variation in access to treatment and if one stands out as a model. Dr. Roach responded that she didn’t have that data but is aware of disparities across states. Louis Baxter, M.D., commented that he has observed more young women drinking because they now have the freedom to do so. Dr. Roach said that cultural norms have shifted dramatically over the past 50 years, making it more acceptable for women to drink. She also noted that alcohol is marketed more heavily to women. Dr. Jill Becker cited a new report on women’s health that documented an increase in death among women across all causes, noting that it’s a larger problem than just alcohol, although alcohol is part of the picture. Dr. Roach commented that mental health issues play a large role in women’s alcohol use. Dr. Koob concluded the discussion by stating that the issue of women and alcohol continues to be a high priority area for NIAAA.
NIAAA Diversity Workgroup Report
Dr. Koob introduced Daniel Calac, M.D., Chair of the NCAA Working Group on Diversity and Health Disparities in the Biomedical Workforce, who updated Council on the Working Group’s progress. Dr. Calac reviewed Dr. Koob’s charge to the Group: to support programs that guide young people into the alcohol research field and help retain them, while recognizing differences across settings. He reviewed key aspects of the Working Group’s discussions, including a focus on mentors rather than mentees; conceptualizing an outfacing website, such as the National Research Mentoring Network (NRMN)’s site; developing an online toolkit for mentors and mentees; and promoting an acceptable mentor brand. Dr. Calac also briefly reviewed exemplary programs to support a diverse pool of biomedical researchers at the undergraduate, graduate, postdoctoral, investigator, and institutional levels.
Dr. Calac presented the Workgroup’s initial recommendations: Focus on mentoring, rather than mentees; track the outcome data of NIH diversity supplements; identify and share data with high visibility partners like the National Science Foundation (NSF) and Building Infrastructure Leading to Diversity (BUILD) initiative from the National Institute of General Medical Sciences (NIGMS); brand mentoring initiatives; use social media to disseminate information about what a good mentor is and how to mentor; develop a distinguished lecture concept model; establish models to incentivize mentors; and promote NIAAA activities at the Annual Biomedical Research Conference for Minority Students (ABRCMS), Society for Advancement of Chicanos/Hispanics and Native Americans in Science (SACNAS) or other minority undergraduate research conferences to grantees and their students
Discussion: Susan Smith, Ph.D., asked about the emphasis on mentoring rather than mentees. Dr. Calac responded that most initiatives have been 90 percent mentee-oriented and only 10 percent mentor-oriented. The Working Group’s conversation focused on how to support mentors who usually work on a volunteer basis without any incentive, such as points toward tenure. Dr Koob interjected that the field gives awards for great mentors at national meetings, but acknowledged this may not happen at the university level. Dr. Sanyal noted that the National Center for Advancing Translational Sciences (NCATS) does a lot of work on mentoring and wondered if there is a way to leverage what is being done at NIH. Every Clinical and Translational Sciences Awards (CTSA) program, for example, is developing a mentorship program. Dr. Koob emphasized that the goal is to use mentoring as a way to increase diversity in the workforce. Dr. Sanyal replied that CTSA is doing that. Dr. Smith observed that the University of Wisconsin-Madison’s molecular sciences program emphasized mentoring women and minorities, and the program developed helpful resources. Patricia Powell, Ph.D., commented that she was impressed by mentoring support approaches that went beyond just teaching how to mentor, to changing how the faculty looked at mentees, resulting in a complete culture shift at the institution. Dr. Koob reiterated that this initiative is of great interest to NIAAA and encouraged Council members to provide input to him.
Concept Clearance/Future Meeting Dates
Dr. Koob noted that all programs must now be vetted through Council. Abraham Bautista, Ph.D., reviewed five (5) NIAAA programs and/or initiatives, as follows: 1) the Alcohol Research Center Program that provides leadership in fostering interdisciplinary, collaborative research on topics relevant to the Institute’s mission; 2) Neurobiology of Adolescent Drinking in Adulthood (NADIA) that seeks to elucidate persistent changes in complex brain function-behavior relationships following adolescent alcohol exposure; 3) the NIAAA intramural/extramural collaborative program that provides an opportunity for NIAAA intramural scientists and extramural scientists to engage in collaborative research; 4) NIAAA medications development for the treatment of AUD that involves both a contract organization to provide support functions and multiple clinical sites; and 5) Alcohol and Opioid use Disorders and Chronic Pain, which seeks to identify the neurobiological and neurobehavioral mechanisms linking alcohol abuse, opioid use disorder and chronic pain in order to provide insight into effective treatment and prevention strategies. He noted that NIAAA plans to publish, RFA (Request for Applications), RFP (Request for Proposals) and PAR (Program Announcement-with specific Review criteria) using applicable contract and grant mechanisms, including the cooperative agreements.
Council Action: Council voted unanimously to approve both the concepts and the funding mechanisms that may remain active for the next five years.
Dr. Bautista announced upcoming meeting dates. In 2019, the Council will meet on May 14 and September 12; the CRAN Council will meet in 2019 on May 15. Council meetings in 2020 will be held on February 6, May 12, and September 10; the CRAN Council will meet in 2020 on May 13. In 2021, the Council will meet on February 4, May 11, and September 9; the CRAN Council will meet on May 12, 2021.
Council broke for lunch at 12:19 p.m. and reconvened at 1:06 p.m. for the afternoon session.
Council Member Presentation: Challenges and Opportunities in the Development of Therapeutics for Alcoholic Hepatitis
Dr. Koob introduced Dr. Sanyal to discuss challenges and opportunities in the development of medications for ALD. Dr. Sanyal reported there has been a steady increase in mortality due to ALD between 2007-2016, accompanied by a steep increase in alcohol consumption over the same time period. However, there are no drugs currently approved for liver disease due to alcohol. To gain FDA approval of new drugs, a patient-centered framework is required, i.e., the goal of therapeutics is to improve how the patient feels, functions, or survives. Thus, the first step in drug development is to understand the natural course of the disease and associated clinically meaningful outcomes. In the case of ALD, the current paradigm is that heavy sustained alcohol consumption may lead to either the development of fatty liver and/or steatohepatitis with the individual having no immediate liver-related clinical outcomes or to acute AH. Acute alcoholic hepatitis is a clinical syndrome characterized by development of jaundice hepatomegaly in a patient with a history of heavy alcohol use. It can progress to multiorgan failure and death in the short-term, progress to cirrhosis or resolve completely. The short term prognosis is linked to the severity of the liver injury whereas the long-term outcomes are related to recidivism. Both clinically inapparent liver disease identifiable only by invasive testing as well as alcoholic hepatitis may lead to cirrhosis of the liver, decompensation and, ultimately, death. One challenge is to select the population along this disease progression continuum as the best target for therapeutics because much is still unknown, including the proportion of heavy drinkers who ultimately develop AH and the proportion of those who progress to cirrhosis; the time course of progression; and possible confounders other than alcohol consumption. Thus, it is difficult to risk-stratify the patient population and to identify clinically meaningful endpoints (e.g., reduced progression to cirrhosis). Therefore, the core information needed to design therapeutic studies is missing. What is needed is a redefinition of the natural history of ALD to identify biomarkers and describe disease progression.
There is substantial debate about how to define the ALD study population with two major schools of thought. In Europe, AH is considered a severe form of steatohepatitis, and a histological approach relying on liver biopsies is used. In the United States, in contrast, AH is considered a distinct clinical syndrome superimposed on the background of heavy drinking, and not simply a more severe form of alcoholic steatohepatitis. Inflammation itself does not predict mortality; instead, there may be different molecular pathways in different patients driving the clinical course. Clinical features are better at predicting progression and disease. Thus, the AH research network in the United States has chosen the clinical approach.
The progression of AH has three paths: complete resolution, partial resolution, and progression to cirrhosis. In the first 30 days after hospital admission, most patients are dying of other organ failure. Between 30-90 days, sepsis starts playing an important role in mortality. After 90 days, the outcome depends on whether the patient maintains the original insult.
The drug development paradigm indicates a clear pathway for the development of therapeutics. For the early phases (1 and 2A) with a focus on dosing, safety, and proof of concepts, studies in the U.S. are implemented with low risk populations to gain evidence of efficacy and safety. The downside, however, is that it remains unknown if the drug under development works in the population that it will eventually target, safety data cannot be generated, and the pharmacokinetics (PK) of the drug in the ultimate population of interest remains unknown. Is a placebo-controlled trial necessary? Dr. Sanyal suggests that the approach that’s been used successfully with hepatitis C in which the natural history is modeled can be just as effective, i.e., if the drug out-performs that natural history twice as well, one can assume the drug works. This is a strong argument for developing very robust models of the natural disease. Therefore, if NIAAA wants to accelerate therapeutic development, the natural history approach is the best course of action.
Further, there is a changing pattern of AH outcomes over the past few years as the population ages and develops different risk factors. For example, between 2001-2011, increases were documented for GI bleed, hepatic encephalopathy, hepatorenal syndrome, sepsis, and pancreatitis. The question, therefore, becomes: Is mortality the best endpoint for clinical trials? All-cause mortality is reasonable if the population is homogeneous in terms of the drivers of mortality and there is a single primary driver of death. But this is not the case in decompensated AH. Typically, other organs become involved, and death results from multi-organ failure. Commonly, it is the development of sepsis that leads to death and these are the patients who are excluded from all the treatment trials which typically use corticosteroids and immunosuppression as treatments. Dr. Sanyal and his colleagues are starting a pilot study using high-dose Vitamin C treatment, leveraging off a recently-completed Phase 2 trial in sepsis by the Critical Care Group, which had positive mortality benefits. If it works, this will be the first treatment for AH patients with sepsis, i.e., those who have the greatest risk of dying.
In terms of sepsis, the entire approach to date has focused on attacking immune activation and inflammation in alcoholic steatohepatitis. As patients progress, they come immuno-suppressed, so one can hypothesize that one reason why people on steroids develop sepsis or don’t do well is that their disease status is too far advanced. The field needs good biomarkers to understand when people are in the inflamed state and when they are actually severely immune-suppressed. That could change the course of treatment. There is a need for improved risk prediction, primary prevention, biomarkers for early detection, optimized medication strategies, and secondary prevention.
Clinically meaningful measures need to be measurable, objective, sensitive to change, and clinically meaningful. They may include factors such as sepsis, development of multi-organ dysfunction, days in hospital, need for escalation of care, and/or an increase in the Sequential Organ Failure Assessment (SOFA) score. There is also a need to integrate medical treatment with the approach to abstinence to ensure the best outcomes. One study found that the odds ratio for one-year mortality among those who are abstinent at 90 days is 1:00 but rises to 2:99 for those who resume drinking at previous levels. The SOFA score include changes in bilirubin and platelet counts which are universally abnormal in alcoholic hepatitis and may not be very useful in this setting.
Regarding liver transplants, Dr. Sanyal noted the expense and risk of transplants, as well as limits on the number of organs available. Typically, when patients come in to start drug treatment, providers try to stratify their risk and determine if the patient is likely to improve. Those with a low mortality risk are best assigned to medical treatment, while there is no need to waste an organ on those at high risk. Transplants are best suited for those at intermediate mortality risk, if the recidivism risk is acceptable. Many centers are beginning to do transplants for AH. Dr. Sanyal predicts there will eventually be a backlash against this trend if a great many people die after receiving a transplant.
Clinical trials for cirrhosis due to AUD must be considered in the context of when the intervention is planned. There are many stages of cirrhosis, from development to end-stage liver disease. A simple score called the Model of End-Stage Liver Disease (MELD) score is used to determine prognosis. When the MELD score crosses 15, the patient is often considered for a liver transplant. Understanding where the patient with alcohol-induced cirrhosis is in the disease progression is important because that information predicts what happens next, again pointing to the importance of identifying endpoints for trials. Furthermore, the potential risk factors for recidivism and analysis of other factors than may affect transplant outcomes need to be evaluated in greater detail to inform general policies towards acceptance of patients with alcohol induced cirrhosis with high MELD scores for transplant listing. Some of the factors include ongoing alcohol consumption and consumption of other recreational drugs, underlying psycho-pathological factors, social factors and status of other end-organs such as the heart which can also be affected by alcohol.
In addition, future trials must incorporate patient-reported outcomes and caregiver-related outcomes. Providers tend to underestimate the impact of someone with a severe disease on caregiver burnout, and how burnout affects the patient’s outcomes. There is a need to understand this more clearly.
In summary, there are many challenges but also many opportunities. There are ten clinical trials on AH currently registered and over 200 for non-alcoholic fatty liver disease. There is a need for a clear regulatory path, natural history of the disease, better-defined study populations with respect to disease drivers and clinical profile, better prediction biomarkers, and development of appropriate study endpoints. These are opportunities for NIAAA to address that will lead to more clinical trials.
Discussion: Carmen Albizu-Garcia, M.D., asked about recommendations to drink coffee and eat dark chocolate to retard the progression of liver disease. Dr. Sanyal responded that most of the evidence for coffee is epidemiological and the effect size is not enough to recommend coffee as a primary therapeutic approach. Chocolate is a double-edged sword because it reduces portal pressures, but also contains a lot of calories and fat. Again, the effect size is quite modest. Dr. Koob inquired about the kind of prospective studies that would be most useful, and what kinds of biological samples would be required, e.g., would collecting blood samples be sufficient? Dr. Sanyal commented that researchers can trace the progression of disease from the mid-point to the end of life for cohorts with advanced disease; what would be helpful is to follow heavy drinkers to the mid-point, e.g., magnetic resonance imaging (MRI)-based studies to look at the heart, pancreas, and liver. There are also MR technologies now that can measure different compartments of the body and produce an integrated readout of sarcopenia, obesity, and organ status that would allow construction of a comprehensive model. One would need to follow about 1000-2000 patients for 5-10 years because it takes time for outcomes to develop. The best way to do this is with systematic MRI assessment and additional blood work occurring every six months or annually. Clinic visits would need to be coupled with a bi-monthly phone call to monitor alcohol consumption and outcomes. Dr. Koob asked if this could be done with the NIH-sponsored All of Us study sample, which includes a group followed for AUD. Dr. Sanyal responded affirmatively if there’s blood work collected on these patients for screening and a subset invited in for an MRI-based sub-study. Dr. Koob asked, given 200 trials for non-alcoholic hepatitis, if a treatment that works for non-alcoholic hepatitis would also work for AH. Dr. Sanyal responded negatively because the biology of the two conditions is very different. Robert Hitzemann, Ph.D., asked if Dr. Sanyal is advocating Phase 1 trials, noting Phase 2 trials require normal controls. Dr. Sanyal responded that European researchers only want to study the normal population; he concurred that normal controls would be included in Phase 2 trials. David Goldman, M.D., inquired about the number of likely AH transplants and how that would fit into the entire landscape of liver transplants. Dr. Sanyal replied that the Journal of the American Medical Association (JAMA) reported that alcoholic-related liver transplants are the fastest-growing category of liver transplants. Dr. Goldman mentioned that clear rules, such as the six-month abstinence rule, are needed. Dr. Sanyal replied that there is no scientific evidence in support of the six-month abstinence rule. Providers don’t know who is going to do well following a transplant. In the United States, centers have different criteria for transplants, and surgeons are resistant to changing their views. Bad outcomes at one or two centers will garner media attention that will make it difficult for those in need to obtain a transplant. Dr. Koob commented that the issue of transplants is one that Council should revisit; there is an argument that a transplant also cures the AUD if there is appropriate support provided.
Council Member Presentation: Therapeutic Opportunities for Alcoholic Hepatitis: Clinical and Pre-Clinical Studies
Dr. Koob introduced Vijay Shah, M.D., to discuss clinical and pre-clinical studies supporting the development of therapeutics for AH. Dr. Shah described the current treatment algorithm for AH: For those with mild disease, alcohol abstinence is prescribed. Those with more severe disease are considered for pharmacological therapies, primarily corticosteroids. If they don’t respond well, then they’re considered for a transplant. There are now trials spanning each stage of disease severity.
Alcohol is toxic to liver and to the gut. Gut toxicity increases gut permeability, leading to bacterial products that eventually activate the immune system and stimulate liver injury and inflammation. Alcohol also has direct toxic effects on the liver and stimulates the death of the hepatocytes. The death signals of the hepatocytes lead to immune cell activation and the recruitment of neutrophils.
Among consortia studying these issues with NIAAA funding is the Translational Research and Evolving Alcoholic hepatitis Treatment (TREAT) Consortium, comprised of the Mayo Clinic, Indiana University (IU), and Virginia Commonwealth University (VCU), currently in its last cycle of support. It has conducted three trials, including one on bovine colostrum examining the effects on the gut, one on Interleukin 22 (IL-22) focused on injury and regeneration, and one on obeticholic acid that addressed anti-oxidant effects on inflammation.
The IL-22 study was spearheaded by the Mayo Clinic. IL-22 is made from blood cells. It promotes hepatocyte regeneration and reduces fibrosis. The trial used F-652, a recombinant fusion protein consisting of IL-22 in a dose-ranging study using different doses of the compound and different disease severity, as measured by MELD scores. There was no control arm. Nonetheless, results (not yet published) indicated an improvement in MELD score at both Day 28 and Day 42. The results of these trials have set the stage for a randomized, placebo-controlled pilot trial to determine the efficacy of IL-22 (F-652) in patients with AH to begin later this year or early next year with a total of 48 subjects. The aims of the pilot are to determine the efficacy and confirm the safety of IL-22 agonist (F-652) in AH patients with a MELD score of 11-20 and those with a MELD score of 21-28 as demonstrated by improved MELD scores at 90 days. These studies are also looking to advance biology to understand how IL-22 works and how alcohol activates the caspases, i.e., molecules that execute the death cell pathway. The stress of the hepatocytes results in the release of exosomes (small vesicles) with disease-specific cargo; these exosomes hold promise as biomarkers for the disease. The researchers have also identified white blood cells that make IL-22 and are currently seeking to identify the pathways by which IL-22 can protect hepatocytes from alcohol-induced cell death.
Data is not yet available from the trial conducted at VCU on bovine colostrum. It addressed issues related to gut products and gut permeability as well as changes in the bacteria that reside in the gut in response to chronic alcohol consumption. The study neutralized these bacterial products through bovine colostrum to see if it could reduce liver injury. The third trial, conducted at Indiana, addressed obeticholic acid (OCA). However, the drug was put on hold by the FDA after several studies indicated it was being prescribed at doses that were too high, and the Indiana trial was stopped.
In the last funding cycle, there was a consolidation of various consortia who will now all be part of a single new network known as AlcHepNet. The signature trial that AlcHepNet is carrying out is addressing the inflammazone pathway, which is how an injured cell is able to lead to recruitment of neutrophils and cause inflammation. Both injured cells as well as bacteria are able to stimulate the inflammazone response. It is possible that if this pathway were blocked, it might reduce inflammation and subsequent liver fibrosis. Anakinra is an IL-1 receptor antagonist that shows promise of providing an important signal for recruiting neutrophils, and the Consortium has selected this compound as worthy of further study. Another trial will evaluate granulocyte colony stimulating factor (G-CSF), a compound that stimulates liver regeneration. The exact mechanism is unknown, but it’s thought to recruit bone marrow cells that may, in turn, lead to hepatocyte regeneration. Most positive studies have been from India, with one negative study from Europe. AlcHepNet would like to de-risk this approach by using two drugs, which requires a larger sample size to demonstrate effects. Institutional Review Board (IRB) approval has been obtained for a prospective, multicenter, observational study of patients with AH and suitable controls that will serve as the foundation for conducting future studies. Patients will then be enrolled in a Phase 2B efficacy trial of G-CSF versus Anakinra (plus zinc) versus standard medical therapy (Prednisolone) in patients with severe AH conducted across eight clinical centers and coordinated by two Data Coordinating Centers (DCCs). The primary endpoint will be mortality at Day 90..
At the Mayo Clinic, the Mayo Alcoholic Liver Disease Translational and Treatment Team (MALT) has undertaken a number of AlcHepNet studies. One is examining the release of extracellular vesicles following alcohol-induced injury to the hepatocytes as potential biomarkers. IL-1 receptor antagonist will be the target for the next trial. There is also exciting data emerging from imaging studies and various ways to use non-invasive imaging as a biomarker. High-throughput technologies using histone modifications with techniques to look at sequencing of mRNA and chromatin immunoprecipitation-sequencing (ChIPseq) can be conducted. Researchers are also looking at the variety of genes that are up-regulated and down-regulated in patients with AH, and their correspondence with activation of histone proteins that lead the DNA to be active or inactive. Pathway analyses currently possible include granulocyte adhesion, i.e., neutrophil recruitment, as well as IL-17. There are a number of chemokines that are mediating the recruitment of neutrophils that can now be identified from the analysis of these large datasets; these chemokines are all treatable by drug therapies. One example of Mayo’s work is with the CSCL 1 Super Enhancer (SE) identified from the ChiPseq. It may be that multiple chemokines can be targeted simultaneously if they are all regulated by the same SE. Mayo is also developing compounds to target the molecules that bind to the SE and activate it. In another area, Mayo is examining the alcohol-related release of vesicles from injured hepatocytes that may contain molecules that lead to the inflammatory response and recruitment of neutrophils and macrophages. Prior studies have shown that AH patients have more of these vesicles. From the AlcHepNet data, it’s becoming apparent that the number of vesicles corresponds to the MELD scores and that mortality can be predicted from the number of these vesicles, so they may have potential as biomarkers.
Dr. Shah concluded by noting that ALD has had few trials compared to its mortality rate. However, many more trials have started in the past ten years and he is optimistic about progress in treating the disease and bringing new researchers into the field.
Discussion: Dr. Koob observed that the field would benefit if the people who treat AUD interacted with the people who treat liver disease. He inquired if the extracellular vesicles could be candidates to be markers for recovery from AUD. Dr. Shah responded that even heavy drinkers have more vesicles, but less than those with severe injury, so it may be gradation that could be useful. George Kunos, M.D., asked if it is possible to design a prospective study with a large number of people who were biopsied and verified to have AH that would detail patients’ vesicle/cytokine/enhancer profiles, follow them for a few years to find out how many and which of them develop acute AH, and then analyze any difference in this exosome profile to see if a marker stands out as a biomarker to predict future acute hepatitis. Dr. Shah considered that a great idea. He explained that what researchers are trying to do now is synchronize these vesicle collections with existing trials such that patients in the trials who are receiving different therapies will have their vesicles measured in order to correlate the data to answer different questions, such as the relationship with alcohol consumption and response to drugs. Dr. Russo noted that G-CSF enhances the addictive properties of drugs. He asked if abstinence was followed in the studies cited by Dr. Shah and if it might be the explanatory variable about why some were positive and others negative. He also asked if it would make sense, given the addiction-enhancing nature of G-CSF, to develop drugs that cannot cross the blood-brain barrier. Dr. Shah agreed, noting that the studies conducted to date have been short-term and may not have addressed issues like recidivism. The first step is to see if a new drug has any beneficial effect on the liver. Dr. Goldman asked how dynamic the exosome release is and what the half-life of these exosomes is. He also inquired if researchers are able to identify their cell of origin. Dr. Shah responded that the release is very dynamic; he does not know the half-life figure. He noted that cell-of-origin researchers are now trying to track markers in pre-clinical studies; many seem to be coming out of blood cells, like platelets and neutrophils, but they also think a significant number come from hepatocytes in response to injury. Dr. Baxter asked if there was any data about the recovery status of patients who relapsed. Dr. Shah replied that what is known is that recidivism typically occurs around 90 days because the patient can’t drink in the hospital. Between 30-90 days is when providers start losing patients. Dr. Koob stated that this discussion will continue in future Council meetings.
Council Member Presentation: Nutrient-Alcohol Interactions in Fetal Alcohol Spectrum Disorders: A (Largely) Undiscovered Country
Dr. Koob Introduced Dr. Smith who presented her work on nutrient-alcohol interactions in FASD, specifically the question: Does maternal iron status affect FASD vulnerability? How does it interact with prenatal alcohol exposure (PAE)? Factors that substantiate the importance of this topic include the fact that those with ALD often have iron overload because alcohol suppresses the expression of a peptide hormone called hepcidin, which regulates iron uptake. Twenty-two percent of child-bearing-age women in the U.S. are iron deficient; smoking, diabetes, and intrauterine growth restriction (IUGR) all impair placental iron transport to the fetus. Finally, there are many parallels between gestational iron deficiency and prenatal alcohol exposure. Iron is essential for brain development and function, including energy metabolism, myelination and the formation of white matter, and neurotransmitter metabolism. Iron deficiency (ID) affects IQ, motor performance, hyperactivity, and conduct disorder. Iron adequacy in later life does not reverse damage from earlier deficiency. Infants obtain Iron during the third trimester of pregnancy, which is the period of brain growth spurt, and is sensitive to alcohol’s neurotoxicity.
Dr. Smith reviewed the findings from three studies from her laboratory that used rat models to address the interaction between maternal iron status and PAE. In each study, animals were fed either an iron-sufficient (IS) or ID diet through gestation and lactation; at weaning, all animals were fed an iron-fortified diet.
Iron Deficiency (ID)-Prenatal Alcohol Exposure (PAE) Recapitulates the Severe End of FASD. In a study led by Echoleah Rufer, Ph.D., looking at the growth-spurt period, post-natal measurement found that iron-deficient mothers had low iron stores but were not anemic. Their offspring, on the other hand, were anemic at birth and replete at adolescence. Thus, the iron-deficient mothers were unable to meet their offspring’s iron needs. Deficits in several areas were also observed: The offspring of ID mothers experienced reduced body weight; in contrast to the females, the male offspring of the ID-PAE mothers had stunted growth due to an interaction between iron deficiency and alcohol. Neuroanatomical deficits were also observed. In the offspring of ID-PAE mothers, there was a significant interaction that reduced the myelin content in cerebellar Lobules I and VIa. This suggests that white matter deficits observed in FASD may be attributed in part to poor maternal iron status during alcohol exposure. The study also provided evidence of an impact on associative learning as a further interaction between ID and PAE; specifically, eyeblink classical conditioning (ECC) was delayed in the offspring and the effect became increasingly profound as the quantity of alcohol increased. If iron status was improved and alcohol intake reduced, learning performance also improved. Finally, the study showed similar impairment effects on trace ECC learning (hippocampal-dependent), fear conditioning (cerebellar-& hippocampal-dependent); and reduced hippocampal & cerebellar interpositus nucleus (IPN) neuronal cellularity.
How do Iron-Status and Alcohol Interact? In a study of gestational alcohol exposure led by Shane Heubner, Ph.D., animals were mated and then fed an iron-sufficient or iron-deficient diet. On gestational days 13.5-19.5, dams received either 5.0 g ethanol/kg body weight (PAE) or isocaloric maltodextrin by daily gavage. Tissue was collected for analysis on gestational day 20.5. The results showed that PAE caused fetal anemia, with significantly reduced red cell counts, hematocrit, and hemoglobin. Fetal brain iron deficiency was also observed, but not fetal liver iron deficiency. This is because iron crosses the placenta, reaching the liver but not the brain. In fact, PAE prevents the fetus from adapting to poor iron status; the fetal liver hoards the iron it receives. There was no difference in other minerals. Thus, data show that PAE causes functional iron deficiency in the fetus.
Why Doesn’t the Fetus Respond to its Alcohol-induced Iron Deficiency? The key factor appears to be hepcidin, a protein that acts as the master regulator of iron’s entry into the body’s circulation. Its job is to reduce circulating iron and it drives iron into liver stores. In adult alcoholics, alcohol suppresses hepcidin. The Huebner study revealed that PAE stimulates hepcidin production, thus reducing circulating iron and driving iron into storage in the liver. Alcohol alone caused a three-fold increase in hepcidin production in fetal liver, and even under iron deficiency, it’s still elevated. It should have been silenced, but it was not. A similar pattern was seen in the dams, but to a lesser degree. Why did this occur? There are two major pathways which drive expression of the HAMP gene, which encodes hepcidin. In one, IL-6 interacts with its receptor to stimulate JAK/STAT signaling to drive HAMP expression; the other pathway involves BMP6 /SMAD signals to also drive HAMP. In a study led by Nipun Saini, Ph.D., and Kaylee Helfrich (in preparation), Dr. Smith’s team discovered that the IL-6 pathway appears to be the one responsible for the increase in hepcidin expression.
To conclude on a positive note, Dr. Smith reviewed evidence that prescribing iron fortification (IF) during pregnancy counteracts alcohol-induced fetal iron deficiency. IF normalizes maternal-fetal cytokines and fetal hematology, as well as normalizes hepcidin, and improves fetal iron status.
The implications of this research are: Maternal iron status is a crucial variable affecting FASD. Iron deficiency magnifies key FASD characteristics, including growth, learning, white matter, and neural losses. Dietary iron fortification normalizes fetal hepcidin, anemia, and brain iron. PAE increases fetal iron requirements, driven by inflammation and elevated hepcidin. Maternal iron status under-reports fetal iron status (fetal anemia; brain is iron deficient). The critical period is perinatal; post-weaning iron does not rescue the fetus. Strategies to enhance maternal/fetal iron status may reduce FASD severity and vulnerability, e.g., studies suggest micronutrient supplements improve FASD outcomes, iron deficiency exacerbates growth deficits. It can’t be assumed that alcohol has the same impact in pregnancy as it does in the non-pregnancy state, so more studies on FASD and nutrition are needed.
Discussion: Dr. Koob asked how iron interacts with other substances like choline that have been implicated in FASD. Dr. Smith responded that choline and iron are known to interact, but has not been studied in the context of PAE. There is likely to be a similar impact for about ten different micro-nutrients. In future work, the mechanistic linkages among PAE and nutrients need to be established. Further, researchers have not yet looked at behavioral outcomes after iron fortification. Dr. Jill Becker inquired about what iron and alcohol are doing at the level of the placenta. Dr. Smith replied that iron is getting across and there is increased cytokine production in the placenta; one of her post-doctoral students has found that, based on the placental cytokine profiles, she can project about 35% of fetal weight reductions that occur in response to alcohol. Dr. Milliken asked if iron fortification should begin in the second trimester. Dr. Smith stated that one limitation of the study reported here is that the researchers started iron fortification before pregnancy. There’s a new trial that will compare the effectiveness of intramuscular and oral forms of iron fortification. NIAAA Program Director Gary Murray, Ph.D., inquired about the dose of iron fortification. Dr. Smith replied that an intake that was five-fold above the standard dose for rats succeeded in attenuating PAE’s effects here, and her team is evaluating other forms because they have lesser side effects. She also noted that there are other public health strategies for improving iron status in pregnant women.
Dr. Koob asked Council members to send him questions or comments by email.
Ex-Officio Reports/Public Comments
VA: Karen Drexler, M.D., reported that the VA’s National Substance Abuse Disorder Program is updating its policy to include an annual screening for adverse alcohol use and tracking it with metrics. Currently, over 90 percent of veterans have an annual screen using the Alcohol Use Disorders Identification Test (AUDIT-C). Eighty percent receive a brief intervention or referral to treatment. The VA Office of the Inspector General has asked the program to work on improving that number. The VA partners with the Department of Defense (DoD) to develop evidence-based clinical practice guidelines, including recommendations for specific medications and psycho-social interventions. The VA has all the FDA-approved medications for AUD on its national formulary and has a nationwide quality improvement initiative called the Psychotropic Drug Safety Initiative. Now in Phase III, the Initiative is asking each VA healthcare system to select one of two quality improvement initiatives: increase medication prescribing for either AUD or opioids. More systems have chosen to address AUD than opioids, and 19 systems are doing both. This has resulted in increases in clinical prescribing for AUD. Because the VA is risk screening over 90 percent of its members, it is probably making the diagnosis more often than other healthcare systems. Over a quarter of patients are receiving the indicated medications when they come for treatment. The VA partners with pharmacy benefits managers and deploy clinical pharmacists who are academic detailers engaged in a data-driven process to educate individual providers about how they’re doing compared to their peers and one-on-one coaching. This Initiative will continue next year.
Discussion: Dr. Koob commented with satisfaction about seeing research-based recommendations translated into practice at the VA. Dr. Howard Becker asked which medications were used and if they were prescribed equally across all hospitals. Dr. Drexler responded that it varies by facility. The most common medication prescribed is oral naltrexone, although other drugs are also approved. Dr. Becker inquired if gabapentin is used for management of detox. Dr. Drexler said that many facilities use this drug for detox, but it gets a lesser endorsement than other drugs in the VA-DoD clinical practice guidelines and its use is therefore not tracked. Dr. Koob inquired about where patients are referred, i.e., within or outside the VA? Dr. Drexler replied that that’s changing rapidly with the Choice Act and the Mission Act aimed at making treatment more accessible. VA physicians can refer outside the VA if the needed services can’t be offered in a timely fashion. Dr. Koob wondered if the NIAAA Treatment Navigator would be helpful. Dr. Drexler responded enthusiastically, noting that the VA’s treatment navigation is a work in progress. Raye Litten, Ph.D., inquired about follow-up after a patient receives naltrexone. Dr. Drexler explained that the VA has a Measurement-based Care Initiative. For substance use disorders (SUDs), it encourages the Brief Addiction Monitor (BAM) which can be self- or provider-administered and is included in the VA EHR, allowing its data fields to be tracked. Thus, the approach is to assess at admission and at least one more time within the next 90 days.
DoD: Dr. Milliken reported that DoD also does annual screening using Audit-C. In addition, any patient at a military behavioral health clinic gets an Audit C and the BAM. Follow-up data is collected via an automated self-administered record that can plot out trends over time. The problem with screening in the military is that current regulations require that as soon as someone admits to an alcohol problem, the provider is supposed to call his or her commander, which initiates a series of potentially negative effects on career, security clearance, etc. This has been an ongoing challenge because it renders useless the evidence-based guidelines on problematic alcohol use. The Army’s addiction program has been transferred back from the Installation Management Command (IMCOM), a non-medical branch of the Arm, to the medical service. Under its approach, alcohol counselors are part of the medical system and embedded in the behavioral health clinics to allow more coordinated care and documentation in the EHR. Presently on the Secretary of the Army’s desk is a bill that ensures that alcohol diagnosis and treatment remains private between the patient and the provider; this would allow for more early intervention. Currently, DoD is consolidating Army, Air Force, and Navy medical care into one big operation. There is currently capacity within the system to care for all active service members. One fear is that too many services will be contracted out to non-military providers who do not understand the military culture. If that starts to happen, Dr. Milliken may ask for Council’s help in explaining why some services need to remain within the military system.
Discussion: Dr. Weisner commented that she was glad to learn that DoD is continuing to work on the culture issue. She was part of the Institute of Medicine (IOM) study on Substance Use Disorders in the U.S. Armed Forces (2012). One of the most striking experiences was listening to focus groups of those who had served in Afghanistan who described the life and death consequences of soldiers drinking or using drugs, and their desire for suboxone to be made available to military members. She was pleased to hear that progress had been made in moving the addiction program back into medical hands. Dr. Milliken said that the IOM report was instrumental in moving discussion of the transition back to medical care forward. Dr. Koob commented that the topic of health services is worth a Council presentation. Dr. Milliken commented that linking NIAAA’s proposed clinician core resource to continuing education will make it more marketable since travel funds for education are no longer available.
Public Comment: Diana, professional community liaison for AA, commented that AA has a professional community page on its website with resources for professionals and future professionals, as well as a “find a meeting” app for individuals to locate an AA meeting near them.
The meeting adjourned at 3:10 p.m.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.