Robert Fontana, MD, an expert in severe acute liver injury, currently co-chairs two large National Institutes of Health (NIH) research networks, including the Acute Liver Failure Study Group. Patients with acute liver failure (ALF) and drug-induced liver injury have access to the latest therapies to improve their likelihood of survival. The U-M Hepatology Program was a key contributor to a study that demonstrated improved transplant-free survival in ALF patients who received IV N-acetylcysteine compared to placebo. Studies using a non-invasive breath test to identify those who will recover with supportive care as soon as possible are currently underway. In addition, studies have been completed assessing the safety and efficacy of an IV medication that can lower blood ammonia levels.

More recently, Dr. Fontana has been involved in other ALF studies that explore the role of hepatitis E virus infection in patients with acute liver injury, and the use of rotational thromboelastography to identify ALF patients who are at increased risk of bleeding.

Alcohol use is skyrocketing in the US, and with it, alcoholic liver disease rates have been rising. Michigan hepatology researchers have been making strides in defining the extent of the alcoholic liver disease epidemic and identifying solutions. Dr. Jessica Mellinger, along with Dr. Scott Winder in psychiatry and Dr. Anne Fernandez in psychology, founded the Michigan Alcohol Improvement Network (MAIN), a clinical and research collaborative dedicated to improving the lives of those with alcohol use and liver disease through improvements in clinic care and advances in research.

These rising rates of alcoholic liver disease also produce higher mortality. Dr. Elliot Tapper and Dr. Neehar Parikh published a groundbreaking study showing that deaths from alcoholic cirrhosis had risen dramatically over a 16-year period and that, in young people ages 25–34, the increase in cirrhosis mortality was driven entirely by alcohol-related liver disease.

Improving mortality and preventing poor health outcomes in alcohol-related liver disease is key, and one major way of improving outcomes is by helping patients stop alcohol use. Dr. Mellinger and Dr. Scott Winder, who specializes in transplant psychiatry and alcohol-related liver disease, have continued exploring ways to help patients connect with alcohol use treatment. Access to alcohol use treatment is low in patients with alcoholic liver disease, but in those who do not yet have symptoms of cirrhosis, the risk of developing symptoms was lower at one year in those who engaged in alcohol use treatment, compared to those who do not (Mellinger JL, et al ACER 2018 (accepted)).

Following on from this work, in a qualitative study where patients with alcoholic liver disease were interviewed, Dr. Mellinger and Dr. Winder found that patients frequently had misconceptions about the need for alcohol use treatment and its effectiveness, misconceptions that are barriers to obtaining needed treatment (Mellinger JL, Winder GS, et al Journal of Substance Abuse Treatment 2018;91:20–27). Dr. Mellinger and the Michigan Alcohol Improvement Network (MAIN) team continue to work to develop novel ways to help ALD patients stop drinking, whether on their own, or by engaging in alcohol use treatment. To that end, Dr. Mellinger and her MAIN colleagues formed one of the first multidisciplinary alcohol-related liver disease clinics in the nation, bringing expert hepatology, addiction psychiatry and psychology, social work, and nutrition care into a single clinic.

One of the most important things we can do as hepatologists is help our patients stop drinking. Seeing my patients succeed, often after having struggled for years to stop drinking, is among the most rewarding things I experience as a physician.”

- Dr. Mellinger, Assistant Professor of Internal Medicine and Psychiatry

Robert Fontana, MD, is recognized as an international authority in drug-induced liver injury (DILI). As the co-chair of the Drug-Induced Liver Injury Network (DILIN) funded by the NIDDK for the past 15 years, Dr. Fontana has published important papers on the etiology and outcomes of DILI both in children and adults from the Unites States.

Recently, Dr. Fontana has published papers demonstrating an increased susceptibility to minocycline and terbinafine hepatotoxicity among patients with unique HLA genotypes. These observations may improve the ability to more rapidly diagnose patients with idiosyncratic DILI. Other studies have reported an alarming increase in the incidence of liver injury attributed to a variety of herbal and dietary supplements. The DILIN is currently developing a prospective clinical trial for patients with severe acute DILI and also has a companion study exploring novel diagnostic and prognostic biomarkers. To learn more, visit the DILIN website.

The Liver Transplant Program at Michigan Medicine is a leader in the conditioning of donor organs from high-risk donors. A clinical trial with 10 other transplant sites is ongoing using a portable normothermic extracorporeal perfusion device, the Organox System, which has shown great promise in Europe.

If successful, this novel approach could enable us to substantially expand the donor supply and provide transplants to more patients."

- Robert Fontana, MD, Medical Director of the U-M Liver Transplant Program

Dr. Fontana is also involved in the implementation of protocols to expand the use of anti-HCV + donor livers and kidneys into recipients with HCV infection as well as those without pre-existing HCV via the use of potent Direct acting antiviral agents post-transplant

Dr. Fontana is also the Co-PI of Acute Liver Failure Study Group. This consortium of 13 major medical centers has played an important role in moving the field forward in improving outcomes and demonstrating the safety and efficacy of IV N-acetylcysteine to patients with non-acetaminophen related ALF. Other ongoing studies are exploring the use of Rotational Thromboelastography (ROTEM) in ALF patients as well as the deployment of a radiolabeled methacetin breath test to identify patients who may recover without a transplant.

Dr. Pratima Sharma was also the first to show that MELD-based allocation policy was associated with increased risk of new onset end stage renal disease. She and colleagues further constructed and validated a renal-risk index (RRI) that would predict the future risk of post-LT End Stage Renal Disease (ESRD). RRI model included 14 recipient factors independently associated (p<.05) with post-LT ESRD.

Dr. Christopher Sonnenday, Surgical Director for the liver transplant program, and Dr. Englesbe spearheaded the work on sarcopenia and frailty among liver transplant candidates and recipients. Now they are actively working towards incorporating their work in the Prehab Program for liver transplant candidates. Research protocols offering the latest treatments for patients with hepatitis C, alcoholic hepatitis and cholangiocarcinoma are also ongoing. Other studies include efforts led by Dr. Monica Tincopa regarding the optimal means of assessing cardiac risk prior to and after liver transplantation. Finally, Michigan Medicine has been a leader in the use of radiation therapy and other neo-adjuvant treatments for the management of liver cancer such as Y-90, which have led to improved outcomes and more patients becoming eligible for transplant.

Elizabeth Speliotes, MD, PhD, MPH utilized human population-based and functional genetic studies to show that the genetic etiology of obesity and nonalcoholic fatty liver disease (NAFLD) are influenced by genes in the nervous system, in adipose tissue, and in the liver. Her laboratory found that genes play a role in neuronal processes, energy expenditure, and eating behavior, and they predispose to development of overall obesity, whereas pathways that affect lipid and glucose metabolism predispose to development of NAFLD.

Hari Conjeevaram, MD, MSc is looking at the role of the microbiome in non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH), a condition increasing in prevalence globally. He is also looking into the role of fecal microbiome transplantation (FMT) in the management of NASH. Part of this work is currently in collaboration with investigators at the All India Institute of Medical Sciences (AIIMS) in New Delhi, India, where there has been a rise in the prevalence of NAFLD, and where the pathophysiology, including the role of diet, might differ from that seen in Americans.

Hepatitis C Research

Our groundbreaking research into hepatitis C led to new all-oral drug regimens, with significantly reduced side effects and more than 95% cure rates for most patients with hepatitis C.

Dr. Lok continues her efforts to investigate new combinations of DAAs for patients who failed earlier DAAs, as well as the impact of DAA therapy on patient-reported outcomes. She and Dr. Fontana are also studying the long-term outcome of patients who achieved sustained virologic response, particularly those who had cirrhosis prior to a cure.