Noninvasive Testing Using Magnetic Resonance Imaging Techniques as Outcomes in Nonalcoholic Steatohepatitis Clinical Trials: How Full Is the Glass?

Nonalcoholic steatohepatitis (NASH) has become the most common cause of chronic liver disease in the United States and the European Union, the leading cause of liver transplant in women, and the second leading cause of transplant in men.(1,2) NASH is the advanced form of nonalcoholic fatty liver disease (NAFLD), the dominant feature of which is steatosis.(3) In NASH, steatosis is accompanied by inflammation and hepatocyte injury in the form of ballooning, which can lead to fibrosis. Patients with NASH with stage 2 fibrosis (F2) or higher have worse clinical outcomes than those with no or mild fibrosis. The association of poorer prognosis with fibrosis has led to a shift from emphasis on treating the entire NASH spectrum to focusing on NASH with at least F2 fibrosis. F2 fibrosis has also become the main criterion for entry into phase 3 clinical trials of NASH.(3) Emphasis on fibrosis in NASH also is a feature of a recent white paper from the U.S. Food and Drug Administration in which the approval of NASH drugs has required meeting two main histologic outcomes from phase 3 trials: either resolution of NASH without worsening fibrosis or improvement of fibrosis by one stage without worsening of NASH (Fig. 1).(3) On the other hand, early phase trials, especially phase 2a trials, have adopted changes in noninvasive tests, especially in magnetic resonance imaging–proton density fat fraction (MRI-PDFF) as primary outcome, and liver enzymes, inflammatory and fibrosis biomarkers, and magnetic resonance elastography (MRE) changes as secondary outcomes(4) MRI techniques have rapidly become the preferred methods for evaluating NASH because of the invasive nature and poor patient acceptance of liver biopsy and increasingly evident advantages of MRI. MRI can accurately assess the degree of steatosis and fibrosis (cross-sectional); show dynamic changes within a relatively short time (which support the proofof-concept of action of many agents, especially those that target steatosis); and potentially detect changes in steatosis at a minimum and possibly also of steatohepatitis and fibrosis (the last by using MRE). They are also accurate in patients who are overly obese.(5) Abbreviations: 2D/3D, two/three-dimensional; AUROC, area under the receiver operating characteristic curve; F2, f ibrosis stage 2; MRE, magnetic resonance elastography; MRI-PDFF, magnetic resonance imaging–proton density fat fraction; NAS, nonalcoholic fatty liver disease activity score; NASH, nonalcoholic steatohepatitis.