How the Multifactorial Nature of NASH May Affect Treatment

It is no surprise to me that socioeconomic changes promoting a sedentary lifestyle and broadening access to high-calorie dietary intake are creating an increasingly obesogenic environment and leading to an increase in metabolic syndrome. As hepatologists, the hepatic manifestation of metabolic syndrome─nonalcoholic fatty liver disease (NAFLD)─is hitting close to home. NAFLD is now the most prevalent cause of chronic liver disease in the Western world, and its metabolic aspect is difficult to ignore.

As I will explain at an upcoming symposium in Boston, we are now hitting the ground running as we continue to advance our understanding of this disease.

NAFLD is the accumulation of fat within hepatocytes, which can occur with no evidence of inflammation or hepatocyte injury. Later stages of NAFLD are characterized by lobular inflammation and hepatocyte ballooning, which reflect the immune response to liver injury and cellular damage, and can be accompanied by activation of hepatic stellate cells and, ultimately, fibrogenesis. The presence of inflammation and ballooning in NAFLD represents nonalcoholic steatohepatitis (NASH).

Those with NASH can regress, smolder in a steady state of indolent disease activity, or progress to fibrosis and cirrhosis. The presence of hepatic fibrosis is the primary predictor for liver-related and all-cause morbidity and mortality in patients with NAFLD. However, among patients with NAFLD, discerning those patients with NASH and NASH-related hepatic fibrosis is challenging. Liver biopsy is the current “gold standard” for differentiating patients with NASH but is impractical for population-based screening.

Treatment Progress
Currently, there are no FDA-approved therapies for NASH. However, obeticholic acid, an FXR receptor agonist, has been granted a Breakthrough Therapy designation by the FDA—which expedites the review of promising treatments for serious conditions—and had positive phase III trial results presented this year. Many other potential NASH drugs with novel targets are in phase II and III clinical trials.

In anticipation of new therapies for the treatment of NASH, the development of noninvasive biomarkers for diagnosis, staging, and monitoring of NAFLD disease activity is a priority and remains an unmet clinical need.

Is Combination Therapy the Answer?
Genetic, epigenetic, and environmental risk factors, in addition to concomitant medical conditions and associated medications, all contribute to the variable natural history and the heterogeneity of NAFLD. Diagnosis and treatment of NAFLD/NASH will therefore need to be tailored to a clinical and/or histologic phenotype and include both the drivers of disease as well as the severity of liver injury. As such, combination therapies including antimetabolic, antiinflammatory, and antifibrotic therapies will likely be the treatment paradigm of the future.

Although the field of drug development for NAFLD/NASH has been challenged by complex disease pathobiology, by lack of highly sensitive and specific biomarkers, and by a placebo response rate that sets a higher bar of efficacy for developmental therapies, there has been incremental progress made that I believe will translate into effective therapies in the near future.

Your Thoughts?
What progress in the development of treatment strategies for NASH do you think will translate to effective future therapies? Please tell us your thoughts in the comment box below. Then join me and my colleagues Paul Y. Kwo, MD, and Oluwaseun Falade-Nwulia, MBBS, MPH, for a CME/MOC-certified symposium in Boston, where we will discuss these and other topics related to advances in liver health. If you can’t be there in person, you can register to attend a live simulcast.