Looking Into the Crystal Ball: Predicting the Future Challenges of Fibrotic NASH Treatment

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common form of chronic liver disease worldwide, and its aggressive form of nonalcoholic steatohepatitis (NASH) is becoming a leading cause for end-stage liver disease and liver transplantation in the United States. In patients with NASH, the presence of advanced fibrosis is considered the most important prognostic factor in predicting liver-related morbidity and mortality. Unfortunately, there are no US Food and Drug Administration (FDA)-approved medications to treat patients with NASH-induced advanced fibrosis. However, the field of drug development to treat NASH and fibrosis has witnessed major advances over the past 5 years with several medications in phase III trials. Results from some of these trials are expected in 2019 with potential FDA approval in 2020. Clinicians who treat patients with NAFLD are likely to face several challenges over the next few years related to identifying patients with advanced fibrosis who may derive most benefit from pharmacologic treatment, the requirement for liver biopsy to assess histologic severity and response to treatment, and the urgent need to validate noninvasive tests to replace liver biopsy-to determine treatment initiation, response, futility, and the need for combination therapy with multiple drugs. Conclusion: In this review, we aim to dissect each of these challenges and attempt to provide suggested solutions while fully realizing that knowledge gaps still exist where future research is likely to provide urgently needed answers.

Figure 1

Summary of future challenges in the management of fibrotic NASH treatment.

Figure 2

Primary care physicians’ algorithm for the identification of patients with NAFLD and advanced fibrosis. Screening for NAFLD with ALT and ultrasonography should be considered in high‐risk patients, such as those with metabolic syndrome and type 2 diabetes or MetS. In patients with NAFLD, the presence of advanced fibrosis can be determined by the NFS or FIB‐4 index. For patients with indeterminate or discordant results, an advanced serologic or imaging test can be ordered, such as the ELF test and VCTE, respectively.

Figure 3

Proposed algorithm to determine treatment response to fibrotic NASH medications. We use the ELF test as an example of serologic tests and the VCTE as an example of imaging studies. More data are needed before this algorithm can be adopted in clinical practice.