New Approaches for Alcohol-related Liver Disease

August 25, 2021

The research and clinical teams working with Ramon Bataller, MD, PhD, focus on alcohol-related liver disease (ALD), one of the main causes of advanced liver disease in the United States. ALD includes a wide range of clinical syndromes that range from simple hepatic steatosis (fat accumulation) to progressive steatohepatitis (inflammation), leading to fibrosis and ultimately cirrhosis with its associated complications. A particularly severe form of ALD, alcoholic hepatitis (AH), presents with jaundice and progressive liver failure in patients with heavy alcohol intake. The three-month mortality for AH can be as high as 40%.

ALD is the main cause of liver-related hospitalization at UPMC and remains a significant clinical challenge. In contrast with recent viral hepatitis treatment advances, few improvements for the treatment of ALD are available. For instance, AH therapy remains largely unchanged since the introduction of prednisolone in 1978 and, subsequently, pentoxifylline in 2000, with a recent landmark study (Steroids or Pentoxifylline for Alcoholic Hepatitis) showing no benefit to treatment beyond 30 days.1 Moreover, few studies have investigated the impact of alcohol abuse relapse after an episode of AH. In Barcelona and during his time with UNC-Chapel Hill, Dr. Bataller developed a multidisciplinary care team to manage patients with ALD. Most notably, an addiction counselor saw clinic patients in conjunction with a hepatologist to expedite and facilitate access to motivational and drug therapy for the underlying alcohol problem. These programs were successful because the root cause of disease — alcohol use disorder — was addressed with equal weight by both addiction professionals and physicians. Stopping drinking is the best strategy to get better and even reverse ALD. 

To replicate this success at UPMC, Dr. Bataller started a multidisciplinary clinic to treat patients with ALD and AH, which includes addiction support integrated with medical care. The key to preventing alcohol-related morbidity and mortality relies on the timely detection of high risk alcohol use and early recognition of substance abuse complications. Noninvasive Fibroscan® technology helps with early identification of progressive liver disease and is available in the primary care and addiction treatment center settings to diagnose patients with advanced fibrosis. We expect that early detection will be followed by lifestyle modifications to halt the progression of decompensated liver disease.

Despite maximal medical treatment, many AH patients face exceedingly high short term mortality. Dr. Bataller’s clinical team has developed a protocol for early liver transplantation in selected patients with AH who fail to respond to medical therapy. Suitable transplant candidates presenting within their index episode of AH are identified using criteria that select for insight into their substance abuse behavior as well as low likelihood of relapse following transplant. Additionally, strong social support and commitment to ongoing substance abuse treatment are imperative. Ultimately, UPMC will be one of just a few transplant centers in the country to offer select patients with alcohol-related disease this life-saving transplant treatment option, including live donation. 

To complement ALD and AH clinical work, the Bataller research lab performs clinical, translational, and epidemiological studies in the field of ALD. From a clinical and epidemiological research standpoint, Dr. Bataller’s group recently used the WHO 2014 Global Status Report (www.who.int) to show that 60% of cirrhosis in North America and Europe is attributable to alcohol. Interestingly, the percentage of heavy drinkers in these countries determines the burden of alcoholic cirrhosis (i.e., rather than the per capita consumption).2 Other worldwide epidemiological studies are investigating the prevalence of alcohol abuse and alcoholic cirrhosis as well, and are studying the impact of various alcohol policies, the impact of cold weather and sunlight hours, and the role of economic and social inequality. In fact, Dr. Bataller’s former multidisciplinary team from Barcelona reported recently on a follow-up study from a large patient cohort that survived an episode of AH.3 In this Spanish study, two simple prognostic factors of increased alcohol relapse were identified, including an age younger than 48 years and failed prior alcohol rehabilitation attempts. 

Primary lab goals in the basic science and translational research realms are focused on identification of primary determinants of alcohol abuse, noninvasive assessment of advanced fibrosis, and new treatments for AH patients. For example, the Bataller lab has classified several scoring systems using both clinical and histologic criteria to predict short-term survival in AH (ABIC and AHHS scores) and has identified the systemic inflammatory response syndrome as a key driver of multi-organ failure and death.4-6 The Bataller team is also seeking to identify new therapeutic targets for AH. In addition to several molecular drivers (i.e., CXC chemokines, Fn14, osteopontin, and p90RSK), they found that AH is characterized by poor hepatic regeneration and inefficient ductular reaction.7,8 Moreover, we identified that a protein called HNF4a, that is key for the liver cells to work normally, to be an important factor leading to liver failure in these patients.9 Work is ongoing to identify the molecular drivers of hepatocellular failure in AH, potentially leading to a new family of targeted therapies. 

After the discovery of effective all-oral therapies for hepatitis C, we are now entering a new era in hepatology in which most liver disease will be caused by ALD and nonalcoholic fatty liver disease or its combination. UPMC aims to lead this new era by offering a multidisciplinary treatment approach and by fostering continued research to serve these growing patient populations.

References

1. Thursz MR, Richardson P, Allison M, Austin A, Bowers M, Day CP, Downs N, Gleeson D, MacGilchrist A, Grant A, Hood S. Prednisolone or pentoxifylline for alcoholic hepatitis. New Engl J Med. 2015; 372: 1619-28

2. Stein E, Cruz-Lemini M, Altamirano J, Ndugga N, Couper D, Abraldes JG, Bataller R. Heavy daily alcohol intake at the population level predicts the weight of alcohol in cirrhosis burden worldwide. J Hepatol. 2016; 65: 998-1005. 

3. Altamirano J, Lopez-Pelayo H, Michelena J, Jones PD, Ortega L, Gines P, Caballería J, Gual A, Bataller R, Lligoña A. Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: prediction and impact on long-term survival. Hepatology. 2017 (in press).

4. Domínguez M, Rincón D, González-Abraldes J, Miquel R, Colmenero J, Bellot P, García-Pagán JC, Fernández-Caspistrán R, Moreno M, Bañares R, Arroyo V, Caballería J, Ginès P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008; 103: 2747-56. 

5. Altamirano J, Miquel R, Katoonizadeh A, Abraldes JG, Duarte-Rojo A, Louvet A, Agustin S, Mookerjee RP, Michelena J, Smyrk TC, Buob M, Leteurtre E, Rincon D, Ruiz P, García-Pagán JC, Guerrero-Marquez G, Jones PD, Barritt IV AS, Arroyo V, Bruguera M, Bañares R, Ginès P, Caballería J, Roskams T, Nevens F, Jalan R, Mathurin P, Shah VH, Bataller R. A histologic scoring system for prognosis of patients with alcoholic hepatitis. Gastroenterology. 2014; 146: 1231-9.

6. Michelena J, Altamirano J, Abraldes JG, Affò S, Morales-Ibanez O, Sancho-Bru P, Dominguez M, García-Pagán JC, Fernández J, Arroyo V, Gines P, Louvet A, Mathurin P, Mehal WZ, Caballería J, Bataller R. Systemic inflammatory response and serum lipopolysaccharide levels predict multiorgan failure and death in alcoholic hepatitis. Hepatology. 2015; 62: 762-72. 

7. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011; 141: 1572-85. 

8. Sancho-Bru P, Altamirano J, Rodrigo-Torres D, Coll M, Millán C, José Lozano J, Miquel R, Arroyo V, Caballería J, Ginès P, Bataller R. Liver progenitor cell markers correlate with liver damage and predict short-term mortality in patients with alcoholic hepatitis. Hepatology. 2012; 55: 1931-41.

9. Argemi J, Latasa MU, Atkinson SR, Blokhin IO, Massey M, Gue JP, Cabezas J, Lozano JJ, Van Booven D, Bell A, Cao S, Vernetti LA, Arab JP, Ventura-Cots M, Edmunds LR, Fondevilla C, Starkel P, Dubuquoy L, Louvet A, Odena G, Gomez JL,  Aragon T, Altamirano J, Caballeria J, Jurzak MJ, Taylor DL, Berasain C, Wahlestedt C, Monga ST, Morgan MY, Sancho-Bru P, Mathurin P, Furuya S, Lackner C, Rusyn I, Shah VH, Thursz MR, Mann J, Avila MA, Bataller R. Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis. Nat Commun. 2019; 10:3126.