The need for non-invasive diagnosis and monitoring of NASH
Posted 29th October 2018 by Jane Williams
Nonalcoholic steatohepatitis (NASH) is a chronic liver disease and is increasing in prevalence as an etiology for end-stage liver disease and also hepatocellular carcinoma. NASH is often a silent disease and many patients have undiagnosed NASH for several years without experiencing any symptoms.
Currently NASH can only be diagnosed by histological assessment of liver biopsy, therefore it is difficult to obtain an accurate estimate of NASH prevalence. NASH prevalence in the adult population of developed countries has been estimated as high as 12%, the number may be underestimated due to the asymptomatic nature of the disease and the lack of non-invasive diagnosis tools. There is currently no approved therapy for NASH, though many investigative drugs are being developed.
A key component of the assessment of NASH is the determination of the extent of liver fibrosis, which has been linked to the risk of mortality and liver-related clinical outcomes. NASH patients with fibrosis stage 2 or greater determined by histology from liver biopsy, especially those with advanced fibrosis (stage 3–4), are at increased risk of death. A major barrier to identify this subset of patients is the need for a liver biopsy to define the presence of NASH with moderate-advanced fibrosis (stage 2–3). Liver biopsies are invasive and occasionally associated with severe morbidity.
Moreover, interpretation of liver biopsy sections is limited by sampling variability and both intra- and inter-observer variability in assessment. These carry the potential harm to patients and are also a barrier to recruitment to clinical trials, thus hamper the development of therapies. There is an urgent need to develop non-invasive tools for the assessment of the liver fibrosis in those with suspected NASH.
Few non-invasive biomarkers indirectly associated with fibrosis stages in NASH, such as FIB-4 score (calculated from aspartate aminotransferase (AST)/Alanine aminotransferase (ALT), platelet, age), AST/ALT ratio and NAFLD Fibrosis Score (NFS), have been extensively studied. However these biomarkers do not directly measure the underlying pathophysiology in the liver. Recently, there has been growing interest in interrogating the biomarkers that directly reflect the process of fibrogenesis and fibrolysis to fully understand the dynamic nature of fibrosis. We have recently reported that collagen III formation biomarker PRO-C3 levels in the serum are significantly higher in patients with advanced fibrosis (stage 3–4) than those with fibrosis stage 0–2.
Furthermore, in a small longitudinal study cohort with paired biopsies, mean PRO-C3 increased with worsening of fibrosis and decreased with fibrosis improvement/regression. The results suggest that PRO-C3 may be a potentially useful biomarker in identifying patients with advanced fibrosis and active fibrogenesis, as well as in assessing changes in fibrosis over time. PRO-C3 may be used to monitor disease progression and therapeutic response. It is worthy of further evaluation to confirm its diagnostic value and clinical utility.
What is driving the fibrogenesis/fibrosis in the liver? NASH starts with chronic fat accumulation in the liver which then triggers cell injury and inflammation, possibly by lipotoxicity, oxidative stress, metabolic dysfunction or gut microbiome. Fibrosis results from the overreaction of the liver to the chronic injury.
How do we monitor the injuries? Can we identify serum biomarkers that reflect the mechanisms driving the disease progression? The histology based fibrosis classification is static and does not tell us whether the disease is progressing, stable or on the way for regression. Can we classify patients (progression, stable and regression) based on the mechanistic biomarkers measuring multi-pathways involved in the disease pathophysiology? To initially approach these questions, we explored novel biomarkers that are correlated with fibrosis stages in NASH patients using metabolomics and proteomics analysis. A number of metabolic and protein biomarkers are identified. These biomarkers reflect hormonal and metabolic changes, inflammation, cell stress response and tissue remodeling, and demonstrate the complexity of NASH pathogenesis.
I will present some of the data we have recently generated at the Global NASH Congress. Combination of these biomarkers may help us in identifying patients with high risk of progression and those who need treatment, and may also help us to monitor the treatment response to therapies addressing different disease mechanisms. Further research and clinical validation are warranted for these novel biomarkers for NASH fibrosis, especially whether these biomarkers can predict clinical outcome.
Yi Luo is Clinical Biomarker and Translational Medicine Lead in Innovative Medicine Development at Bristol-Myers Squibb. She will present “Circulating biomarkers for fibrosis in NASH: collagen biomarkers and beyond” at the Global NASH Congress.
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