With a broad research portfolio, the Hepatology Program’s investigations span scientific, clinical, and health services research. We study viral hepatitis, hepatocellular carcinoma, liver transplantation, fatty liver disease, alcoholic liver disease, drug induced liver injury, cirrhosis and its complications, Wilson disease, acute liver failure, and quality of care in liver diseases. Our faculty publish an average of 70 articles in peer-reviewed journals annually.
Our research efforts are funded by the National Institutes of Health, Veterans Health Administration, the Patient-Centered Outcomes Research Institute, and the American Association for the Study of Liver Diseases, as well as philanthropic, industry, and University of Michigan sources.
Several faculty head large, multicenter, clinical research networks funded by the National Institutes of Health, including those focused on acute liver failure, drug-induced liver injury, hepatitis B, and early diagnosis of hepatocellular carcinoma. We are also involved in many clinical studies supported by pharmaceutical companies that evaluate new therapies for various liver diseases, including hepatitis B and C, fatty liver disease, Wilson disease, portal hypertension complications, and hepatocellular carcinoma. The patients seen in any of the Hepatology Clinics who are potential candidates for new therapies and other research protocols are referred for participation in clinical studies.
Acute Liver Failure
Robert Fontana, MD
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.
Alcoholic Liver Disease
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. 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.
In a study published in 2018 in Hepatology, Dr. Jessica Mellinger and colleagues showed that, even among the privately insured who frequently have the best access to resources, rates of alcoholic cirrhosis had risen by over 40% in just seven years, with women and younger people experiencing even faster increases (Mellinger JL, et al. Hepatology 2018;68(3): 872–882). “While rates are rising,” said Dr. Mellinger, “we also found that these patients presented sicker, with more symptoms of cirrhosis, suggesting that they are being diagnosed later in their disease.”
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,” said Dr. Mellinger. “Seeing my patients succeed, often after having struggled for years to stop drinking, is among the most rewarding things I experience as a physician.”
Details coming soon.
Drug-Induced Liver Injury
Robert Fontana, MD
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.
At the AASLD 2018 meeting, Dr. Fontana participated in the Hepatotoxicity Special Interest Group program on herbal hepatotoxicity. At the meeting, Dr. Fontana reviewed the experience of the DILIN and other groups with an outbreak of untoward hepatotoxicity associated with the use of OxyELITE Pro. In addition, a summary of the experience with pembrolizumab hepatotoxicity seen at Michigan Medicine from 2012 to 2018 was presented by Dr. Fontana and the medical residents Dr. Russell Dolan and Dr. Irene Tsung.
Hepatocellular carcinoma, the most common primary cancer affecting the liver, and rising in incidence and mortality in the United States. The 46% increase in liver cancer deaths in the US from 1999-2016 was recently detailed in a publication from Michigan Hepatology by Drs. Elliot Tapper and Neehar Parikh (BMJ. 2018 Jul 18;362:k2817). The University of Michigan has several important research areas designed to address the rising tide of hepatocellular carcinoma.
One of the keys to improving survival in patients with hepatocellular carcinoma is to improve early detection. Dr. Neehar Parikh, the medical director of the Michigan Medicine Liver Tumor Program, has several NIH sponsored grants that fund projects that will discovering and validating novel markers for the early detection of liver cancer. Most recently, in the Fall of 2018 Drs. Anna Lok, Grace Su, and Thomas Wang, in the Division of Gastroenterology and Hepatology, were awarded a 5-year U01 for over $2 million dollars by the National to improve uptake of hepatocellular cancer screening and validate novel technologies to aid in the noninvasive diagnosis of liver cancer.
Once patients are diagnosed with liver cancer their prognosis is often uncertain, even for patients diagnosed at the same stage. We are interested in discovering better prognostic markers for liver cancer patients so that the best, most personalized treatment can be chosen. To accomplish this, we have an active biorepository of blood and tissue samples from patients diagnosed with liver cancer at our center. We are using these samples to discover and validate novel proteomic and genetic markers for prognosis that will aid in determining patient prognosis.
Treatment of Hepatocellular Carcinoma
Once patients are diagnosed with liver cancer, choice of the best treatments are paramount. Unfortunately, the treatment options are limited for many patients who present with liver cancer around the US. There are several novel treatments for hepatocellular carcinoma currently under investigation and our center has several open clinical trials for patients diagnosed with liver cancer. Our medical oncology team, which include Drs. Crysler, Sahai, and Zalupski, direct many of these open clinical trials which provide access to novel therapies for interested and eligible patients.
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.
Several faculty in the Liver Transplant Program at Michigan Medicine are active in policy development related to liver transplantation allocation. Dr. Pratima Sharma and colleagues showed that the risk of wait list mortality for high MELD patients (35-39) was similar to status 1 patients. This study and the LSAM analyses of distribution scheme with various cut off MELD scores by OPTN liver and intestine committee led to the implementation of Share 35 in June 2013. More recently, their study Serum sodium and survival benefit of liver transplantation found an important association of survival benefit of LT and serum sodium is seen in patient with MELD score > 11. This resulted in an important amendment in implementation of MELD-Na upgrade only for patients with MELD score > 11. This policy went into effect on January 11, 2016.
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. The RRI calculator can be used as a clinical tool that risk stratify patients at the time of LT to personalize immunosuppression.
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.
Non-Alcoholic Fatty Liver Disease (NAFLD)
Elizabeth Speliotes, MD, PhD, MPH
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.
Dr. Speliotes’ studies provide new insights into the pathophysiology of these disorders and identify new targets for therapy. (Nature, 2015; Feb 12;518(7538):197-206; PLoS Genetics, 2011; Mar;7(3):e1001324.
Hari Conjeevaram, MD, MSc
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.
Monica Tincopa, MD, MSc
Given that lifestyle interventions, healthy eating, and regular physical activity, are the mainstay of therapy for NAFLD, Monica Tincopa, MD, MSc is investigating ways to optimize these behaviors for patients. She has worked closely with the University of Michigan Metabolic Fitness program to investigate the benefits of structured lifestyle programs for patients with NAFLD. This work demonstrated the multiple positive benefits from an overall metabolic and liver-related standpoint for patients who complete the program, particularly among those who are able to achieve at least 5% weight loss. Dr. Tincopa has also collaborated with University of Michigan Endocrinology and Bariatric Surgery to investigate the benefits and long term outcomes of bariatric surgery in NAFLD and non-alcoholic steatohepatitis (NASH). This multidisciplinary research effort has highlighted the important role of bariatric surgery as an effective treatment option for patients with severe obesity, particularly in terms of high rates of resolution of NASH. Given the significant public health burden of NAFLD, Dr. Tincopa established a dedicated NAFLD clinic that focuses on lifestyle interventions, multidisciplinary treatment of NAFLD including on site dietitians, and incorporation of clinical research trials including multiple pharmacologic agents.
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.
In a landmark study of hepatitis C, published in 2012, Dr. Anna Lok and colleagues showed it was possible to achieve a sustained virologic response in patients infected with genotype 1 of the virus using a combination of all-oral, direct-acting antiviral agents (DAAs), rather than the standard therapy, ribavirin and interferon (New England Journal of Medicine, 2012; 366:216-224).
“It was a small, proof-of-concept study,” said Dr. Lok, “but showing that what all our patients had been hoping for (a cure without having to take injections for a year that make them sick) can happen was astounding. An editorial accompanying that article was aptly titled ‘A Watershed Moment in the Treatment of Hepatitis C.’”
Dr. Lok is continuing 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.
But the breakthrough can only benefit patients if treatment is initiated early; therefore, improved screening is critical. Dr. Lok and Dr. Tincopa recently conducted a pilot study using the Michigan Medicine electronic medical records system to identify patients born between 1945 and 1965 – a generation with a much higher prevalence of infection – who have not yet been screened. The system alerts patients’ primary care physicians and links to an order set and educational materials. The pilot improved screening rates sevenfold and has been rolled out to primary care providers throughout Michigan Medicine.
Continuing along the spectrum, Dr. Lok developed a noninvasive way to stage liver damage that results from hepatitis C infection. This alternative to liver biopsy assesses fibrosis and cirrhosis using two measures obtained from a simple blood test: platelet count and aspartate aminotransferase (AST) (Hepatology, 2003;38(2):518-26). The AST-to-platelet ratio index (APRI), has been adopted by the U.S. Centers for Disease Control and Prevention and the World Health Organization as a simple and accurate method to assess the stage of liver damage, not only for those with hepatitis C but also for individuals with hepatitis B.
To assess the likelihood of progression to advanced liver disease in patients, Dr. Lok also partnered with colleagues to use advanced statistical methods to develop dynamic predictive models. In addition to baseline data, the models incorporate longitudinal patient information. Risk calculations adjust as the individual’s course of disease changes.
“My patients continue to guide me toward the research questions we need to be asking and to persevere when we hit roadblocks. Seeing my own patients and knowing patients all over the world get better as a result of the knowledge we’ve gained from our work is the biggest reward a researcher can ever ask for.” - Anna Lok, MD
Dr. Robert Fontana has also recently participated in a study using the APRI to identify patients without cirrhosis who may benefit from a shorter duration of DAA therapy. This work, which will be presented as a poster at the AASLD meeting in 2018, demonstrated a 100% clearance rate in non-cirrhotic HCV patients with genotype 1 to 6 infection who received an 8-week course of glecaprevir/pibretenasvir. “These data demonstrate that the APRI can help identify patients with a low likelihood of cirrhosis who may benefit from a shorter duration of treatment and lead to more patients worldwide being able to access these therapies in a cost-effective and efficient manner”.
Details coming soon.
Click on a faculty name below to view their publications:
- Anna Lok, MD, FACP
- Frederick K. Askari, MD, PhD
- Graham F. Brady, MD
- Hari S. Conjeevaram, MD, MS
- Robert J. Fontana, MD
- Hellan K. Kwon, MD
- Jessica L. Mellinger, MD, MSc
- Neehar Parikh, MD
- Nataliya Razumilava, MD
- Pratima Sharma, MD, MS
- Elizabeth K. Speliotes, MD, PhD, MPH
- Grace L. Su, MD
- Andrew W. Tai, MD, PhD
- Elliot B. Tapper, MD
- Monica Tincopa, MD, MSc