e., they had portal hypertension) and, upon follow-up, HVPG was more predictive of clinical decompensation than histological fibrosis staging. Simple histologic features may also

have important prognostic implications in cirrhotic liver biopsies. For example, the thickness of fibrous septa correlates with HVPG and is an independent predictor of both clinically significant portal hypertension (i.e., HVPG > 10 mmHg)20 and clinical decompensation.21 Moreover, digital image analysis of septal thickness, but not total fibrosis area, predicts cirrhosis decompensation.22 Studies performed in the past two decades have identified several attractive targets for antifibrotic treatment. These include the major cellular sources of scar, most notably activated hepatic stellate cells and Wnt antagonist portal myofibroblasts, as well as key cytokines such as platelet-derived growth factor and transforming growth factor beta.23 The roles of bone marrow–derived cells and those arising from epithelial-mesenchymal mTOR inhibitor transition are still under evaluation, but it is unlikely that these sources of fibrogenic cells provide a major contribution to

hepatic extracellular matrix in chronic human liver disease. Cellular sources of proteases that degrade scar and the pathways that regulate them are better understood. Moreover, a more nuanced understanding of distinctive pathogenic features of fibrosis at different stages and from different etiologies means that fibrosis may be customized according to its duration and underlying cause. Cirrhosis in experimental models and human disease may be reversible.24 Following withdrawal of an injurious stimulus, see more a dense micronodular cirrhosis can undergo remodeling to a more attenuated, macronodular pattern. However, some septa will persist, likely representing those laid down early in the injury and are

therefore the most “mature” (i.e., cross-linked). Moreover, in experimental models, such mature scars may be the site of neoangiogenesis. Such angiogenesis is already present in chronic inflammatory liver diseases25 concurrent with the fibrogenic process and may also play a role in the pathogenesis of portal hypertension.26 The effectiveness of therapeutic angiogenic inhibitors in not only improving fibrosis, but also in reducing portal pressure, is suggested by data from animal models but has not been established in humans.27 Although there are no data linking septal remodeling to portal pressure changes, recent work correlating increased portal hypertension with smaller nodule size and septal thickening suggests that reversal of these events might lower portal pressure.20 These rodent models and human studies throw into relief the inadequacy of a simple one stage classification, because although the micronodular and remodeled attenuated macronodular cirrhosis are very different, they are both defined by the same original pathologic description: “cirrhosis”.