A Multidisciplinary Approach to Metabolic Liver Disease
March 27, 2019
Authors: Michael J. Jurczak, PhD, assistant professor of medicine, Division of Endocrinology and Metabolism, Maja Stefanovic-Racic, MD, PhD, assistant professor of medicine, Division of Endocrinology and Metabolism, director, EDM Fellowship Training Program, and Ramya Undamatla, MD, clinical fellow, Division of Endocrinology and Metabolism
Nonalcoholic Fatty Liver Disease — A Recent History
In the not too distant past, a diagnosis of fatty liver with inflammation, or steatohepatitis, unrelated to alcohol consumption, generally did not exist. Then in 1980, nonalcoholic steatohepatitis (NASH) was described for the first time, noting that the majority of patients with NASH were moderately obese and presented with obesity-associated diseases, such as type 2 diabetes (T2DM).1 Similarly, nonalcoholic fatty liver (NAFL), or the presence of liver fat greater than five percent without inflammation, has long been considered benign. However, over the last two decades NAFL gained recognition as a clinically relevant pathology that may portend the development of more serious liver disease, including NASH, cirrhosis, and hepato-cellular carcinoma.
NAFL and NASH now represent the early and late histological characteristics of a liver disease spectrum referred to as nonalcoholic fatty liver disease (NAFLD), which also encompasses fibrosis and cirrhosis. In 2005, the Pathology Committee of the NASH Clinical Research Network, which was established in 2002 by the National Institute of Diabetes and Digestive and Kidney Diseases, published a validated histological scoring system for NAFLD. Referred to as the NAFLD activity score or NAS, the system is comprised of four semi-quantitative features, including steatosis (scored 0–3), lobular inflammation (scored 0–2), hepatocellular ballooning (scored 0–2), and fibrosis (scored 0–4), as well as nine features documented as present or absent.2 The proposed NAS not only solidified key histological features that define NAFLD progression but, importantly, provided a standardized means of evaluating interventions to treat NAFLD and also paved the way for the more than 200 clinical trials for NAFLD treatments currently underway.
Nonalcoholic Fatty Liver Disease on the Rise
Over the past decade, NAFLD has emerged as the leading cause of chronic liver disease in the United States, with NASH now representing the second most common indication for liver transplant after chronic hepatitis C. The prevalence of NAFLD and NASH in the United States is currently estimated to be approximately 30 percent and five percent, respectively, and NASH is predicted to soon become the most common indication for liver transplant.3
Paralleling the increase in NAFLD is a rise in the prevalence of obesity and T2DM, which now afflicts as many as 93.3 million and 30.3 million Americans, respectively.4,5
There is a strong positive association among obesity, T2DM, and NAFLD, and greater than 70 percent of patients with T2DM have NAFLD.6,7
In fact, although age, ethnicity, sex, and a small number of genetic variations are associated with NAFLD, obesity and diabetes are the primary risk factors for developing the disease. The association of NAFLD with obesity and T2DM holds true not only for adults but also for children and adolescents for whom NAFLD prevalence in the United States is estimated at 11 percent, representing a doubling over the last decade.8
The exact sequence of events leading to NAFLD remains unclear, in part because the natural history of NAFLD appears variable. Approximately 30 percent of patients with NAFL will develop NASH and about 20 percent of patients with NASH will develop fibrosis. Understanding which patients with steatosis will progress to the more advanced stages of NAFLD is a major unmet clinical challenge. Currently, the first line of defense for treating patients with NASH is to prescribe lifestyle modifications, including dietary changes and exercise. Several studies have demonstrated that achieving weight loss of five to 10 percent is associated with improvement in histological features of NAFLD, and paired biopsy studies suggest that fibrosis regression can occur.9,10
There is currently no FDA-approved pharmacological treatment specifically for NAFLD, but the surge in activity in the pharmaceutical industry related to NAFLD and the large number of ongoing clinical trials suggests the first drug-based therapies may be on the horizon.
Nonalcoholic Fatty Liver Disease Pathogenesis — A Mitochondrial Component?
The observations that obesity is strongly associated with NAFLD and that body weight loss can prevent or reverse NAFLD progression provide some clues as to the pathophysiology of the disease, where exposure of the liver to energy excess, particularly fatty acids, is a key feature. Increased hepatic fatty acid exposure may derive from multiple sources, including dietary excess, increased rates of adipose tissue lipolysis, and hepatic de novo lipogenesis. The liver possesses multiple mechanisms to cope with fatty acid oversupply, such as esterification to triglyceride for hepatocellular storage or export as triglyceride-rich lipoproteins, and increased rates of mitochondrial oxidation. While the liver may be able to compensate for overexposure to metabolic stress in the short term, observations in patients with established obesity, T2DM, or NAFLD suggest that this compensation fails over time. This decompensation eventually leads to dysfunction in many of these pathways, particularly mitochondrial respiration, thereby contributing to NASH pathogenesis. For example, a recent first-of-its-kind human study in which liver biopsies were collected from healthy patients, obese patients with and without NAFL, and obese patients with NAFL and NASH demonstrated distinct changes in mitochondrial function that occurred in response to obesity and were subsequently lost after the onset of NASH.11
More specifically, mitochondrial respiration was increased despite no change in mitochondrial mass in obese subjects with and without NAFL compared with controls, whereas mitochondrial respiration was reduced despite increased mitochondrial mass in patients with NASH compared with the lean and obese groups. Another interesting observation within this study was that mitochondrial respiratory control, a measure of mitochondrial electron transport chain efficiency, was reduced in obese patients with and without fatty liver or NASH. These observations suggest that energy excess, which is common in obesity, increases the metabolic load placed on hepatic mitochondria, inducing adaptations to buffer this load, which eventually fail. Mitochondrial function and mass are in part maintained by balancing the production of new mitochondria through mitochondrial biogenesis and removal of damaged mitochondria through a recently described process called mitophagy. Mitophagy is an essential cellular mitochondrial quality control process that regulates selective removal of damaged mitochondria from the cell, preventing abnormal mitochondrial function. Rates of mitophagy in the liver recently were reported to be reduced in a preclinical animal model of obesity-associated NAFL,12 raising the possibility that defective hepatic mitophagy contributes to obesity-associated NAFL and the subsequent pathogenesis of NAFLD.
Nonalcoholic Fatty Liver Disease and Mitophagy
At the University of Pittsburgh Division of Endocrinology, investigators in the laboratory of Michael Jurczak, PhD, are investigating the patho-genesis of NAFLD, and more specifically, the role of mitophagy in NAFLD, as well as other diseases.13,14
Dr. Jurczak, in collaboration with clinical endocrinology fellow Ramya Undamatla, MD, are currently testing the hypothesis that reduced hepatic mitophagy is a specific feature of NAFLD that marks the transition from benign steatosis to NASH. While previous work in this area demonstrated that reduced mitophagy is associated with NAFL, these will be some of the first studies to determine the cause and effect relationship of liver fat content and changes in mitophagy flux. These studies are made possible in part by the recent development of genetic tools for monitoring rates of mitophagy in preclinical animal models12
and directly modulating rates of mitophagy in the liver. If this hypothesis is confirmed, enhancing mitochondrial quality control by augmenting mitophagy in the liver could represent a novel target for NAFLD treatment. This new mode of therapy could conceivably complement current strategies undergoing testing in clinical trials that include targeting metabolic stress, inflammation and cell death, and fibrosis,9
each of which touch upon distinct aspects of mitochondrial function and signaling. This research is but one of many research projects addressing metabolic/fatty liver disease being conducted in the Division of Endocrinology and Metabolism at the University of Pittsburgh.15–19
Nonalcoholic Fatty Liver Disease at UPMC
With the expanding epidemic of NAFLD and other complications of obesity, it is more necessary than ever to promote multidisciplinary collaborative approaches to understanding and treating metabolic liver disease. To achieve this goal, the Division of Endocrinology at the University of Pittsburgh contributes to both clinical and basic research efforts in this area. The Divisions of Endocrinology and Gastro-enterology, Hepatology and Nutrition have a multidisciplinary NAFLD clinic, led by Maja Stefanovic-Racic, MD, and Jaideep Behari, MD, respectively. This clinic provides comprehensive expertise in hepatology, as well as endocrinology, diabetes, metabolism, nutrition, lipidology, and obesity. In addition to the above clinical collaboration, the Pittsburgh Liver Research Center (PLRC) (http://www.livercenter.pitt.edu/) promotes collaboration between clinicians and researchers to improve the clinical care of patients with liver disease through innovative research into the fundamental mechanisms underlying these disorders. Led by Paul Monga, MD, from the Department of Pathology, and Ramon Bataller, MD, PhD, from the Division of Gastroenterology, Hepatology and Nutrition, the PLRC provides pilot grant funding to support innovative new projects related to liver disease, including the above-described project being conducted in Dr. Jurczak’s laboratory. Together, these activities provide a rich environment for research, education, and clinical care to address NAFLD and other metabolic disorders.
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