Currently, only liver biopsy can provide a definitive diagnosis of NASH. As such, it is required for clinical trials evaluating novel therapies and the only means of accurately monitoring treatment efficacy and disease progression. However, this invasive procedure is risky, imperfect, and it is expensive, costing up to $3500 in the United States.1 Patients are often reluctant to undergo biopsy, and many physicians also try to avoid the procedure. As a result, a presumptive diagnosis of NASH is often made without biopsy. While NASH remains underdiagnosed and current treatment options limited the need for biopsy is less of an issue. However, as awareness of the disease grows and expensive novel drug treatments become available, biopsy could become a requirement for access to these new therapies.
And the lack of a non-invasive test has further impacts across the treatment landscape. Clinical trial enrolment can be challenging, treatment cannot be monitored easily, high-risk patients are not being identified, screening and monitoring programs are challenging to implement. Thankfully, academics, clinicians, regulators, and industry are coming together to seek more convenient means to diagnose NASH and monitor treatment effects. In Europe, the Liver Investigation: Testing Marker Utility in Steatohepatitis (LITMUS) group has been setup, with the Non-Invasive bioMarkers of metaBoLic diseasE (NIMBLE) group coming together in the United States. The overarching aim of both is to develop new biomarkers to assist with drug development, disease prevention, as well as diagnosis and monitoring. Some of the avenues being explored were presented at the recent Global NASH Congress in London.
Several talks focused on the utility and latest advances in imaging, but despite showing promise, no approach provide a simple, affordable, and accurate tool. Ultrasonography is widely available but can only accurately identify hepatic steatosis of >30%, whereas MRI-Proton density fat fraction can accurately quantify liver fat, its practical use is limited to research. Transient elastography and MR elastography can identify fibrosis but not if NASH is the cause. Moreover, MRIs are time consuming and relatively expensive. Nonetheless they may be of use in monitoring treatment effects in diagnosed patients. Overall, imaging tests are good at ruling out advanced fibrosis but more limited in terms of identifying NASH versus hepatic steatosis or identifying early fibrosis. Having said that, surveyed patients often stated a preference for imaging and a sense of empowerment coming with scan results.
The development of a simple blood diagnostic test along the lines of cholesterol levels and HbA1c for identifying dyslipidemia and diabetes, respectively, would be the holy grail. However, none of the biomarkers identified so far can accurately identify NASH or accurately measure fibrosis. Fibrosis is the key predictor of outcomes for patients with NASH. At present, there are numerous simple laboratory tests that can exclude advanced fibrosis. However, most are much better at ruling out than ruling in fibrosis, and some of the results can be indeterminant, meaning biopsy is required. Genfit, the company developing Phase III drug candidate elafibranor, are evaluating micro RNA as a means of identifying NASH patients and have established that MiR34a expression in increased in stressed hepatocytes. The company is using miR34a as part of a biomarker panel that could be predictive of disease progression. New drugs that come with a companion diagnostic or monitoring test could help build physician confidence in the new technologies as well as making life easier for busy practitioners.
Despite these advances, liver biopsy remains the best tool at present and this was emphasized, perhaps unsurprisingly, by the pathologists presenting at the meeting. Indeed, the case was made that rather than replacing biopsy, new non-invasive tests should be aiming to identify patients who would benefit from biopsy. The case was also put forward that biopsy is likely to remain the best diagnostic tool for some time yet. Obviously, progress is being made, but the critical step is still identifying the most at-risk patients – patients with NASH and advanced liver fibrosis. With the high prevalence of fatty liver in the general public, there needs to be a filter or specialist services could be overwhelmed with low-risk patients. Data from the Royal Free London hospital was presented showing the impact of a clinical pathways designed to help GPs identify those patients at risk of advanced fibrosis. Prior to implementation, less than 10% of referred by GPs were judged by consultants to have advanced fibrosis meaning the vast majority could have been managed by their GP. After introduction of a clinical pathway utilizing the Enhanced Liver Fibrosis (ELF) blood test, the proportion of patients judged to have advanced fibrosis after referral rose to more than 50%, representing an important saving of consultant effort and healthcare resources.
However, the biggest hurdle is still raising awareness of NASH as an important medical condition that needs to be considered. Non-invasive biomarkers are important but these tests will need to be developed, validated against biopsy, approved by regulators, and adopted by the majority of the medical community, all of which will take time. Educating the public and wider medical community about NASH and those most at risk and how to identify them will be critical first steps.
- Cleveland Clinic. Center for Continuing Education. Hepatitis C Management: The Role of Liver Biopsy in Hepatitis C (www.clevelandclinicmeded.com/online/monograph/hepc/page3.htm; accessed 12 March 2018).
For other highlights of the Global Engage NASH 2018 Congress, please check out my colleague Andrew Frost’s thoughts here.
For DRG’s assessment of the NASH market, please click here.