Noninvasive Diagnosis of NASH and Liver Fibrosis Within the Spectrum of NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the United States, affecting an estimated 70 million Americans. The histologic spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and eventually cirrhosis. Patients with NASH and significant fibrosis seen on liver biopsy have an increased risk for liver-related morbidity and mortality compared to patients with simple steatosis. Due to the high prevalence of NAFLD, there has been an urgent need to develop reliable noninvasive markers and tests that can accurately predict the presence of advanced disease without the need for liver biopsy. These tests can be divided into 2 groups: those that predict the presence of NASH (such as markers of hepatocyte apoptosis, oxidative stress, and inflammation, as well as predictive models based on clinical variables) and those that predict the presence of fibrosis (such as simple and complex predictive models). This paper provides an overview of various noninvasive methods for detecting NAFLD and suggests a diagnostic algorithm that can be used in clinical practice.

Keywords: Nonalcoholic ratty liver disease; apoptosis; fibrosis; liver biopsy; nonalcoholic steatohepatitis; noninvasive markers; oxidative stress.

Figure 1

Mechanistic pathways leading to disease progression from simple steatosis to nonalcoholic steatohepatitis (NASH) and advanced fibrosis. Hepatocytes loaded with lipids, mainly in the form of triglycerides, are more susceptible to multiple secondary hits that can lead to progression to NASH, which occurs via mechanisms including hepatocyte apoptosis, oxidative stress, and liver inflammation. This progression can result in the activation of quiescent hepatic stellate cells (HSC), subsequently leading to liver fibrosis. Noninvasive markers of NASH and fibrosis have been developed based on these pathways. ALT=alanine aminotransferase; AST=aspartate aminotransferase; BARD=body mass index, AST/ALT ratio, and diabetes score; CK18=cytokeratin 18; ELF=Enhanced Liver Fibrosis panel; NFS=nonalcoholic fatty liver disease fibrosis score; ROS=reactive oxygen species; sFas=soluble Fas.

Figure 2

A proposed conservative approach for diagnosing significant fibrosis and nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD). The algorithm starts by applying noninvasive tests that can predict the presence of significant fibrosis (NAFLD fibrosis score [NFS] or FIB4). Patients with indeterminate or high values should undergo a liver biopsy to confirm the presence of significant fibrosis and should be assessed for cirrhosis. Those with values below the lower cutoff level should proceed to noninvasive testing for NASH. Those with high values for cytokeratin 18 (CK18) or a positive NASHTest result should undergo a liver biopsy to confirm their NASH diagnosis, and they should receive therapy for NASH. Those with low values can be reassured, and lifestyle modifications (including weight loss and exercise) can be recommended. This approach is conservative because it calls for liver biopsy in patients with high or indeterminate values to confirm the presence of significant fibrosis or NASH. It should be noted that some of these tests are not commercially available; therefore, all of the recommendations may not be feasible.