Molecular Signature Predicts Progression of Early-stage Liver Fibrosis

There's an urgent need to prevent the progression of liver fibrosis before it reaches an advanced stage when treatment is costly and provides a limited survival benefit. Unfortunately, the slow progression to cirrhosis, typically two to three decades, has made it practically impossible to confirm the benefit of anti-fibrotic therapies in clinical trials.

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Now, Raymond T. Chung, MD, vice chief of the Division of Gastroenterology and director of the Hepatology and Liver Center at Massachusetts General Hospital; Shijia Zhu, PhD, and Yujin Hoshida, MD, PhD, of the University of Texas Southwestern Medical Center; and colleagues have defined a molecular signature that classifies the risk of long-term fibrosis progression while patients are at an early stage of chronic liver disease. They describe both tissue- and serum-based applications of the biomarker in Gastroenterology.

Definition and Initial Testing of the FPS

The researchers defined what they dubbed the Fibrosis Progression Signature (FPS) by integrating transcriptomics expression data shared by 421 patients with chronic hepatitis C (HCV) or non-alcoholic steatohepatitis (NASH). Liver biopsy samples had been obtained from these patients when they had no or minimal fibrosis, and for all of them, the time to progression was known.

The FPS was then tested in the same patients with HCV, some of whom had HIV infection or were immunosuppressed, conditions that accelerate fibrosis progression:

• Of 43 patients with HCV (including 25 co-infected with HIV), the FPS predicted a high risk of fibrosis progression in 11, and five of them (45%) had actually had progression within five years
• Of 38 patients who had undergone liver transplantation for HCV-related cirrhosis, the FPS predicted a high risk of post-transplant progression in 11, and 10 of them (91%) had actually had progression within five years

Validation of the FPS

The team validated the FPS in an independent cohort of 78 patients with NASH. When used to profile liver biopsy tissue samples, the FPS classified 19% of patients as being at high risk, 56% at intermediate risk and 24% at low risk.

A follow-up biopsy was performed a median of 2.4 years later. A high-risk FPS at baseline was associated with:

• Progression of fibrosis by ≥1 stage, the primary endpoint—adjusted OR (aOR), 10.93; P=0.04; area under the receiver operating curve (AUROC), 0.86
• No regression of fibrosis—aOR, 13.66; 95% CI, 1.28–145.29; AUROC, 0.89

Furthermore, changes in FPS over the course of follow-up reflected changes in fibrotic, steatotic and inflammatory features.

Non-invasive Prediction

Realizing a requirement for biopsy samples would limit the appeal of the FPS, the researchers translated it into a serum protein–based surrogate biomarker they call the Fibrosis Progression Secretome (FPSec). They tested FPSec using serum samples from 79 patients with various liver diseases who had developed cirrhosis:

• There was significant correlation between risk predictions based on the FPS and the FPSec (P<0.001)
• High-risk FPSec (n=62, 51%) was significantly associated with the incidence of hepatic decompensation (HR, 3.94; 95% CI, 1.59–9.78)

Looking Ahead

The researchers also present evidence that ex vivo assessment of liver tissue using the FPS can identify targets for potential anti-fibrotic drugs as well as novel combination regimens. The FPS could also guide enrollment in trials of antifibrotics and serve as a surrogate endpoint to gauge the benefit of the therapies within a normal timeframe.

FPS-based risk status could change over time, though, whether spontaneously or in response to lifestyle or therapeutic interventions. FPSec would enable a more detailed time-series analysis to understand how the molecular risk of fibrosis progression evolves over the natural history of various liver diseases.

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