Regression of Liver Fibrosis: Evidence and Challenges
Liver fibrosis is a chronic wound-healing process that involves an imbalance between fibrogenesis and fibrolysis. Historically, fibrosis, compensated cirrhosis, and decompensated cirrhosis were considered a sequential and irreversible process. However, recent advancements in anti-viral therapy for chronic hepatitis B (CHB) and hepatitis C (CHC) have demonstrated that effective and long-term viral suppression can lead to fibrosis regression in many patients. This article systematically reviews the evidence of fibrosis regression based on histology, liver stiffness, and serum biomarkers, while addressing clinically relevant challenges.
Introduction
Liver fibrosis results from chronic liver injury and is characterized by the excessive accumulation of extracellular matrix components. Traditionally, fibrosis and cirrhosis were deemed irreversible, but emerging evidence suggests that fibrosis can regress after the removal of underlying liver injuries. This reversal has become a critical endpoint in evaluating treatment responses, particularly in clinical trials for new anti-fibrotic drugs and therapies for non-alcoholic fatty liver disease (NAFLD).
Evidence-Based Histological Assessment
Liver biopsy remains the gold standard for assessing fibrosis regression. Several studies have used paired liver biopsies before and after treatment to evaluate fibrosis regression in various liver diseases. For instance, 51% to 88% of patients with HBV-related liver fibrosis achieved regression after long-term suppression of HBV replication. Similarly, fibrosis induced by HCV infection regressed after viral eradication. Regression has also been observed in non-viral liver diseases, such as alcoholic fatty liver disease, NAFLD, autoimmune hepatitis, and hemochromatosis, following effective treatment.
Traditional histological staging systems, such as the Ishak and METAVIR scores, define fibrosis regression as at least a one-stage decrease in fibrosis. However, these systems may not capture all regressive features. The “hepatic repair complex” (HRC), proposed by Wanless et al., includes eight parameters that describe regressive histological features, such as thin/delicate septa with few inflammatory cells. Recently, the “Beijing Classification” introduced the P-I-R score (predominantly regressive, indeterminate, and predominantly progressive), which provides additional insights into fibrosis quality by evaluating the balance between progressing and regressing septa.
Quantitative methods, such as collagen proportionate area (CPA) and qFibrosis, have further confirmed fibrosis regression by measuring collagen content and fibrous septa width. These techniques have demonstrated significant reductions in collagen and fibrosis in patients achieving sustained virological response (SVR) after HCV treatment.
Non-Invasive Assessment in Fibrosis Regression
While liver biopsy is the gold standard, it is invasive, expensive, and prone to sampling errors. Non-invasive methods, such as liver stiffness measurements and serum biomarkers, have emerged as alternatives for assessing fibrosis regression.
Liver Stiffness Measurement
Liver stiffness, measured by transient elastography (TE), is a feasible and repeatable method for monitoring fibrosis improvement. Longitudinal studies have shown significant reductions in liver stiffness in patients with CHB and CHC after anti-viral therapy. Liver stiffness decreases rapidly in parallel with alanine aminotransferase (ALT) levels during the first six months of treatment, followed by a slower decline after inflammation remission. The early steep reduction in liver stiffness may predict histological reversibility of fibrosis.
However, reductions in liver stiffness can also result from inflammation remission rather than fibrosis regression. Studies have shown that the proportion of patients with significant liver stiffness reduction does not always correlate with histological fibrosis regression. Therefore, liver stiffness changes should be interpreted cautiously, considering the impact of ALT normalization.
Serum Biomarkers
Serum biomarkers, such as the aspartate aminotransferase-to-platelet ratio index (APRI) and fibrosis index based on four factors (FIB-4), are commonly used to assess fibrosis in HCV patients. However, these markers are less effective for monitoring fibrosis improvement in CHB patients undergoing anti-viral therapy. Reductions in APRI and FIB-4 are often associated with inflammation remission rather than fibrosis regression.
Platelet count alone has been used to monitor fibrosis improvement, with increases in platelet count correlating with fibrosis regression in HCV and HBV patients. Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) is a novel glycobiomarker that can identify early fibrosis stages and monitor fibrosis changes in CHB patients. Decreases in WFA+-M2BP levels have been associated with fibrosis regression in patients on interferon-based therapy.
Challenges in Fibrosis Regression
Restoration of Distorted Lobular Architecture
Advanced fibrosis and cirrhosis are characterized by the loss of normal lobular metabolic zonation and the formation of neovessels along fibrous septa. Studies have shown that metabolic zonation can be restored in HCV-related cirrhosis after achieving SVR. However, data on the restoration of lobular architecture after fibrosis regression are limited.
Impact on Clinical Outcomes
Viral suppression in HBV and HCV infections is associated with fibrosis regression and improved clinical outcomes, such as reduced incidence of hepatocellular carcinoma (HCC) and decompensations. However, the long-term prognostic benefits of fibrosis regression remain unclear. Some studies suggest that fibrosis regression may translate into clinical benefits, but more direct evidence is needed.
Re-Compensation in Decompensated Cirrhosis
Some patients with decompensated cirrhosis may achieve “re-compensation” after effective treatment, meaning decompensated complications do not recur for a long period. This phenomenon has been observed in patients with alcoholic and viral-related decompensations, but the definition and stability of re-compensation require further investigation.
Conclusion
Compelling clinical and histological evidence supports the reversibility of liver fibrosis and even cirrhosis after the eradication of liver injuries. Liver biopsy remains the gold standard for assessing fibrosis regression, while non-invasive methods, such as liver stiffness measurements and serum biomarkers, offer valuable insights but must be interpreted with caution due to confounding factors like inflammation remission. Further research is needed to elucidate the long-term benefits of fibrosis regression and its impact on clinical outcomes.
doi.org/10.1097/CM9.0000000000000835
Was this helpful?
0 / 0