Novel biomarkers represent a promising means to improve diagnosis of nonalcoholic steatohepatitis (NASH). Currently, a definitive diagnosis requires a liver biopsy, a surgical procedure with many limitations. There are a variety of biomarkers that can assess liver status, but they do not always distinguish between patients with NASH and those with other disorders. Advanced imaging techniques, while useful for evaluating some liver features, can be impractical and costly.
The ultimate goal is to find noninvasive biomarkers that clearly show if the patient has steatohepatitis or liver fibrosis associated with nonalcoholic fatty liver disease (NAFLD). Recent studies suggest that nuclear magnetic resonance (NMR) spectroscopy, microRNA tests and genotyping may prove to be useful tools. Incorporating additional biomarkers into clinical trials can give biopharmaceutical companies an early indication of whether a compound is efficacious - and provide the confidence to move forward to the next phase of clinical testing.
As a technique that is invasive, fairly qualitative and associated with risks, a liver biopsy is not ideal for NASH diagnosis. In addition, biopsies are performed on only a small section of the liver, which may not capture areas of inflammation or fibrosis. Depending on where the sample is obtained, results can vary. It is difficult to take the sample from the same place in every patient, as well as to take a large enough sample to be completely reliable.
Multiple noninvasive biomarkers and panels (combination of biomarkers) have been tested, aiming to differentiate fatty liver from NASH and to identify liver fibrosis. For instance, NASH FibroSure® and enhanced liver fibrosis (ELF) are two commonly used panels to test for liver fibrosis. FibroSure incorporates measurements of 10 biomolecules, such as liver enzymes and triglycerides, as well as clinical parameters such as age and weight. ELF assesses three matrix turnover proteins and combines them into a score for liver fibrosis severity. The three proteins in the ELF score are the only direct measures of fibrosis. Although they may reflect extrahepatic fibrosis, these proteins combine for a score that has been useful in clinical trials for showing improvement after treatment.
These tests provide useful information but still leave room for improvement. For instance, FibroSure is not very good at determining whether a patient has NASH or simply fatty liver. ELF can identify patients with hepatitis C or liver fibrosis but does not perform as well with NASH diagnosis.
Several novel biomarkers for NASH are emerging but still require clinical validation:
NMR spectroscopy. This technique can be used to quantify the number and size of lipoprotein particles, and data suggest that certain lipoprotein features are linked to NASH. Markers include lipoprotein particle subclasses and a lipoprotein insulin resistance score, which offer a cost-efficient way to assess insulin resistance in large clinical trials. Measuring the weighted average size of very low-density lipoprotein (VLDL) particles or the number of small VLDL particles may enhance panels such as the FibroSure scores for NASH and liver fibrosis, respectively.
MicroRNA. MicroRNAs are a promising biomarker because they are relatively stable in serum and plasma, easy to obtain and easy to detect. The liver releases these small RNA molecules as signaling molecules. Specific circulating microRNAs have been linked to hepatic carcinoma, hepatitis B, hepatitis C and drug-induced injury. Research suggests that certain microRNAs are associated with NASH.
Given that sets of microRNAs for different diseases overlap with each other, more work is needed to determine which panels are the most sensitive. In the meantime, pharmaceutical companies are starting to use microRNAs as an exploratory endpoint for possible retrospective analysis.
Genotyping. Researchers have found some genes associated with NASH. Specifically, a variant of the gene PNPLA3 is linked to higher probability of developing nonalcoholic fatty liver disease. Approximately one-quarter of people carry this variant, but the proportion is higher in certain populations.
By genotyping patients, pharmaceutical companies can enrich their studies for people who are more likely to develop NASH. Retrospective analysis also could reveal whether patients with a certain variant responded better to the drug. If the compound works only in people with the higher-risk variant, for instance, companies could offer a companion diagnostic to determine if that drug should be prescribed.
With a strong background in advancing NASH treatments, we are partnering with several academic sites to generate clinical validation data on novel noninvasive biomarkers for NASH. As a CRO that works from preclinical through post development, our study of NASH biomarkers begins as early as the discovery phase. Our liver disease experts can offer guidance on using biomarkers to make clinical decisions and draw on experience with NMR spectroscopy, microRNA technology, genotyping and companion diagnostics to transform results in your NASH program.