DEFINITION OF REVERSIBILITY OF LIVER FIBROSIS

1. DEFINITION OF REVERSIBILITY OF LIVER FIBROSIS DIANA ALCANTARA-PAYAWAL, MD Cardinal Santos Medical Center Fatima Medical University Center University of Santo Tomas

2. NATURAL HISTORY OF CHRONIC LIVER DISEASE HEPATIC VENOUS PRESSURE GRADIENT (HVPG) mmHg

3. Chronic liver injury leads to progressive fibrosis which ultimately develops to cirrhosis leading to portal hypertension , liver failure and hepatocellular carcinoma Fibrosis is a dynamic bidirectional process which is potentially reversible.

4. CIRRHOSIS is progression of stages of increasing severity and non-reversibility Stages accordingly to D Amico et al, J of Hepatology 2006

5. The Role of the Hepatic Stellate cell in FIBROGENESIS • Initiation is provoked by soluble stimuli that include oxidant stress signals, apoptotic bodies, LPS and paracrine stimuli from neighboring cell types including hepatic macrophages (Kupffer cells), sinusoidal endothelium, and hepatocytes. • Perpetuation includes pecificphenotypic changes like proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling

6. ROLE OF EXTRACELLULAR MATRIX IN FIBROGENESIS • scar-associated macrophages and stellate cells are sources of interstitial collagenases. • decreased TIMP-1 fosters apoptosis of fibrogenicmyofibroblasts.

7. HEPATIC STELLATE CELL ACTIVATION- CENTRAL EVENT IN LIVER FIBROSIS • Normal Liver Activated HSC with fibrosis Friedman SL and Arthur, science and Medicine 2002

8. Reversal of cirrhosis is a complete restoration of normal architecture after the establishment of cirrhosis Regression of fibrosis or cirrhosis, indicating that the fibrosis content is less than earlier, without quantifying the extent of regression or suggesting that the histology has returned completely to normal. IREDALE , JCI, 2007

9. RESOLUTION OF FIBROSIS Role of hepatic macrophages in matrix degradation through increased production of MMP-13 Clearance of stellate cells by apoptosis Cross-linking of collagen by tissue transglutaminase is an importanctdeterminnt of fibrosis reversibility

10. Determinants of Reversibility • Duration of injury and fibrosis • More rapid onset more likely to regress • Extent and type of cellularity of the scar • More cells more sources of proteases • Cross-linking of the scar • More cross-linking more insoluble • Thickness of the fibrotic bands • Thicker septa more inaccessible to proteases • Balance of proteases (MMOs) and inhibitos (TIMPs) • High TIMP levels impede regression • Other factors • Genetic determinants of regression • Underlying etiology`

11. Recommendations: • Hepatic Stellate Cells (HSC) is the primary source of extracellular matrix (ECM) in normal and fibrotic liver and undegoes phenotypic activation in chronic liver diseases with the acquisition of fibrogenic properties . (Grade A, Level 1a) • The activation and proliferation of hepatic myofibroblasts is a key mechanism in development of liver cirrhosis (Grade A, Level 1a) • “Regression” of fibrosis or cirrhosis indicates that the fibrosis content is less than earlier, without quantifying the extent of regression or suggesting that the histology has returned completely to normal.(Grade A, Level 1a) • Fibrosis regression is not synonymous with cirrhosis reversal (Grade A, Level 1a). • Histological evaluation through liver biopsy is considered as the reference standard for liver fibrosis regression (Grade A, Level 1a); combining non-invasive methodologies may represent ways to complement traditional/morphometric histopathological findings.(Grade B, Level 2b) • Clinical outcomes of patients may be a considered a reliable determinant of regression of disease and histological assessment and/or combined non-invasive methodology is a surrogate marker for clinical outcome.(Grade B, Level 2A) 1. Hepatic fibrosis as assessed by tissue pathology can regress especially after specific treatment (1a). 2. There is not enough evidence to suggest that cirrhosis is reversible; however, remodeling can occur (3a). 3. Fibrosis regression is not synonymous with cirrhosis reversal (1a). 4. Liver architecture may not return to normal even after specific treatment (1a). 5. Hepatic function may not return to normal even after specific treatment (3a). 6. Vascular shunts when established do not reverse even after specific treatment (2a).