Regression of Liver Fibrosis: From Myth to Reality

Mechanisms of Fibrogenesis

Fibrosis represents the histologically evident end result of the wound healing response of the liver, which attempts to repair tissue damage caused by chronic injury. Whereas acute liver damage may be rectified by cellular regeneration and an appropriate inflammatory response without significant tissue remodeling or extracellular matrix (ECM) deposition, these mechanisms are eventually overwhelmed by persistent and continuing injury so that the balance between matrix deposition and degradation shifts toward excessive matrix deposition, resulting in a fibrous scar.

Changes in ECM during the fibrotic process are both quantitative and qualitative, with accumulation skewed towards deposition of ECM rich in fibrillary collagens, predominantly collagens I and III. The accumulation of ECM itself elicits positive feedback pathways that further amplify fibrosis and have a significant effect on liver cell regeneration and the microvasculature, both of which are critical to the development of progressive liver damage that eventually culminates in cirrhosis. Vascular abnormalities in cirrhosis include obliteration of afferent and efferent venules and formation of microscopic portosystemic/arteriovenous shunts. The sinusoids are also altered because they lose fenestrations and acquire a basement membrane, changes that are referred to as sinusoidal capillarization. Therefore cirrhosis is not simply “a lot of fibrosis but is also the presence of profound structural, especially vascular, alterations. These alterations are central to the development of portal hypertension and its complications.

The process of fibrogenesis involves both parenchymal and nonparenchymal liver cells, as well as infiltrating immune cells. Chronic hepatocyte death is a critical step, inducing inflammatory and profibrogenic pathways, which cause activation and proliferation of myofibroblasts (MFs). Hepatic stellate cells (HSCs), the resident perisinusoidal cells that store vitamin A, can differentiate into MFs and are the major source of ECM in chronic liver diseases. Following liver injury, a complex network of autocrine/paracrine fibrogenic signals promotes HSC transdifferentiation to a MF phenotype. This results in the gradual loss of retinoids and expression of fibrogenic genes like vimentin, collagen α1, and α−smooth muscle actin (α-SMA). Early studies demonstrate that an expansion of α−SMA expressing activated HSCs is a risk factor for the development of cirrhosis in posttransplant recurrent viral hepatitis. Autophagy seems to be critical for HSC activation because its inhibition suppresses HSC activation and proliferation. Another established component of the HSC activation pathway is oxidative stress, a common feature of chronic liver disease. Indeed, reactive oxygen species released from stressed and damaged hepatocytes and other cells provide paracrine initiation signals to HSCs. Recent studies suggest that Kupffer cells contribute to the establishment of a profibrotic microenvironment. During fibrosis progression, the inflammatory response triggers the recruitment of macrophages into the liver, where they produce cytokines and chemokines inducing the transition of HSCs to ECM-producing MFs.

Evidence from both animal and human studies indicates that MFs, may also derive from portal-periportal fibroblasts and from bone marrow cells. Portal fibroblasts undergo MF differentiation primarily in cholestatic liver injuries. A further fibrogenic mechanism is epithelial to mesenchymal transition, by which fully differentiated epithelial cells undergo phenotypic transition to fully differentiated mesenchymal cells (fibroblasts or myofibroblasts). This process may lead to the generation of reactive cholangiocytes and peribiliary fibrosis. A pathologic feature known as ductular reaction, which contains hepatic progenitor cells, activated HSCs and ECM, is increasingly linked to fibrosis progression in liver injury models and human diseases. Hepatic MFs are also the principal source of tissue inhibitors of metalloproteinases (TIMPs), which inhibit the matrix-degrading enzymes metalloproteinases (MMPs). MMPs are potentially capable of breaking down a variety of ECM components, including fibrillar collagens. Inhibition of MMPs by TIMPs thus prevents scar degradation.

Morphologic Patterns of Fibrosis

Although different causes of chronic liver injury share similar fibrogenic mechanisms, the morphologic pattern of fibrosis is related to the underlying disease because it reflects the topographic distribution of liver damage and variable contribution of different cell types. In biliary diseases, fibrosis deposition begins in portal-periportal tracts, leading progressively to cirrhosis through the formation of portal-portal septa. Studies suggested a prominent role for portal fibroblasts in the setting of biliary disorders, in particular in early disease stages. In chronic viral hepatitis, different mechanisms contribute to disrupting tissue architecture. These include interface hepatitis (responsible for portal/periportal fibrosis and portal to portal septa) and more extensive necroinflammatory lesions (ie, portal-central bridging necrosis), leading to the onset of portal-central vein fibrous septa. Portal to central vein septa are critical to the development of abnormal arteriovenous anastomoses. In both alcoholic and nonalcoholic steatohepatitis, fibrosis begins around central veins (ie, the site of early cell damage and inflammation). It manifests as pericellular (perisinusoidal) fibrosis, with collagen fibers distributed along the sinusoids and around single or small groups of hepatocytes (“chicken-wire” fibrosis). Fibrosis later extends to portal tracts as well as between perivenular areas. This leads to the formation of fibrous bridges, which are often accompanied by ductular reaction. Recognizing this variability in morphogenesis of fibrosis/cirrhosis is critical to histologic assessment of fibrosis progression and regression. Finally, because fibrosis develops and progresses differently, different scoring systems have been developed for different causes of chronic liver disease.