Identifying nonalcoholic fatty liver disease patients with active fibrosis by measuring extracellular matrix remodeling rates in tissue and blood

Abstract

Excess collagen synthesis (fibrogenesis) in the liver plays a causal role in the progression of nonalcoholic fatty liver disease (NAFLD). Methods are needed to identify patients with more rapidly progressing disease and to demonstrate early response to treatment. We describe here a novel method to quantify hepatic fibrogenesis flux rates both directly in liver tissue and noninvasively in blood. Twenty‐one patients with suspected NAFLD ingested heavy water (2H2O, 50‐mL aliquots) two to three times daily for 3‐5 weeks prior to a clinically indicated liver biopsy. Liver collagen fractional synthesis rate (FSR) and plasma lumican FSR were measured based on 2H labeling using tandem mass spectrometry. Patients were classified by histology for fibrosis stage (F0‐F4) and as having nonalcoholic fatty liver or nonalcoholic steatohepatitis (NASH). Magnetic resonance elastography measurements of liver stiffness were also performed. Hepatic collagen FSR in NAFLD increased with advancing disease stage (e.g., higher in NASH than nonalcoholic fatty liver, positive correlation with fibrosis score and liver stiffness) and correlated with hemoglobin A1C. In addition, plasma lumican FSR demonstrated a significant correlation with hepatic collagen FSR. Conclusion: Using a well‐characterized cohort of patients with biopsy‐proven NAFLD, this study demonstrates that hepatic scar in NASH is actively remodeled even in advanced fibrosis, a disease that is generally regarded as static and slowly progressive. Moreover, hepatic collagen FSR correlates with established risks for fibrotic disease progression in NASH, and plasma lumican FSR correlates with hepatic collagen FSR, suggesting applications as direct or surrogate markers, respectively, of hepatic fibrogenesis in humans. (Hepatology 2017;65:78‐88).

Gut Microbiome-Based Metagenomic Signature for Non-invasive Detection of Advanced Fibrosis in Human Nonalcoholic Fatty Liver Disease

“…(Angulo et al, 2015; Dulai et al, 2017; Ekstedt et al, 2015; Younossi et al, 2015) Early identification of the presence of advanced fibrosis using non-invasive modalities is a major unmet need in the field. (Decaris et al, 2016; Dulai et al, 2016)…”

Diagnostic modalities for nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and associated fibrosis

“…Serological markers for the evaluation of liver fibrosis (LF) may be divided into “indirect” markers (that reflect alterations in hepatic function, but not collagen turnover, e.g., ALT, AST, and platelet levels) and “direct” markers (that directly measure aspects of extracellular matrix (ECM) deposition and/or turnover) . Furthermore, novel kinetic biomarkers using deuterated water‐based approaches are emerging to assess dynamic changes in the fractional synthesis rate of collagen turnover in the liver in patients with NAFLD …”

“…Interpatient variation in NAFLD progression risk is, at least in part, determined by genetic modifiers that influence individual response to environmental (diet, lifestyle) factors . Mounting evidence indicates that epigenetic factors, such as differential DNA methylation and circulating cell‐free DNA methylation signatures in plasma, may potentially stratify patients with NAFLD into mild versus severe fibrosis . miRNA is another genetic marker that appears to be relatively stable and can be detected in plasma following release from injured tissue and may serve as another disease biomarker .…”

Dual‐photon microscopy‐based quantitation of fibrosis‐related parameters (q‐FP) to model disease progression in steatohepatitis

“…This has fueled efforts to identify all aspects of the disease noninvasively. Several circulating and imaging‐based fibrosis markers are currently in development along with kinetic markers of fibrogenesis . The current development path for such noninvasive methods are based on traditional histological assessment as the gold standard.…”