In animal models of early liver injury, the accumulation of extracellular matrix as a result of the activation of stellate cells is offset by a proportional increase in the degradation of matrix through the action of so-called interstitial collagenases. In animal models, as liver injury resolves, activated stellate cells are cleared by apoptosis, and the expression of TIMPs decreases, allowing active enzymes to resorb extracellular matrix. Although these observations in animals need to be validated in humans, they point to the potential for exploiting the factors that regulate collagenase activity in order to develop effective antifibrotic therapies. This growing body of clinical and scientific evidence suggests that extensive fibrosis or cirrhosis in patients with well-preserved liver function should no longer be considered untreatable. Both current and future therapies have the potential for preventing the progression of disease and facilitating endogenous mechanisms that lead to the degradation of extracellular matrix and the regression of fibrosis.
Several issues remain to be addressed, however.
Liver fibrosis does not develop at the same rate in all patients, and responses to treatment vary. Furthermore, the possible roles of treatment strategies designed to reverse fibrosis should be analyzed critically. As an example, long-term therapy with interferon alfa may improve fibrosis in patients with chronic hepatitis C, even in the absence of a virologic response. This finding might justify the use of long-term interferon alfa therapy, under certain circumstances, in patients without virologic responses to treatment. The report by Hammel et al. should spur efforts to develop new treatments for patients with extensive liver fibrosis or cirrhosis.