Cirrhosis

Pathogenesis

The hepatic stellate cell, also referred to as the Ito cell or lipocyte, is the primary storage site for retinoids and is critical to the process of hepatic fibrogenesis. On stimulation by inflammation or other noxious factors, stellate cells become contractile and are activated, demonstrating features of myofibroblasts and releasing cytokines and other inflammatory mediators. Subsequently, a deposition of extracellular matrix results in fibrosis, development of scar tissue, vascular obstruction, and sinusoidal hypertension, followed by portal hypertension and eventually hepatic failure. This dynamic process may be accelerated by the addition of hepatotoxins (e.g., alcohol, drugs) or may be decelerated by the reduction of hepatic necroinflammation through immunomodulator therapy (e.g., corticosteroids) or elimination of the inciting agent (e.g., direct antivirals for hepatitis B or C infection).

Other cells, such as fibroblasts, are also involved in the development of hepatic fibrosis. Over time, this process can result in the development of widespread scar tissue throughout the liver and ultimately leads to established cirrhosis. Cytokines that play a key role in stellate cell proliferation and activation include transforming growth factor-β, interleukins, hepatocyte growth factor, and platelet-derived growth factor. These cytokines have multiple effects; some are fibrogenetic, whereas others may promote fibrinolysis. Some are primarily proinflammatory, and others are antiinflammatory.

The progression to cirrhosis in a patient with chronic liver injury is characterized by increased deposition of extracellular matrix, ongoing inflammation, and an imbalance in favor of fibrogenetic rather than fibrinolytic pathways. The current research to identify the key mediators responsible for hepatic fibrogenesis is the first step in the development of novel antifibrotic therapies potentially capable of halting or even reversing the process leading to cirrhosis.