Pathophysiology and Pharmacologic Modulation of Hepatic Fibrosis

Abstract

Most chronic liver disorders are accompanied morphologically by the deposition of fibrous tissue within the hepatic parenchyma. This fibrotic tissue compromises hepatic function and contributes significantly to hepatic failure. Fibrosis is a dynamic process associated with the continual deposition and resorption of connective tissue. Therapeutic strategies are emerging whereby this dynamic process can be modulated. Since collagen is the major component of the extracellular matrix deposited in hepatic fibrosis, most anti‐fibrotic therapies have been directed toward the control of collagen metabolism. After collagen genes are transcribed and translated into precursor procollagen proteins, a number of post‐translational modifications that ensure the deposition of structurally sound collagen within the extracellular matrix occur. A number of drugs can specifically modulate collagen biosynthesis at the transcriptional level or at various post‐translational stages. These anti‐fibrotic drugs include corticosteroids, azathioprine, penicillamine, colchicine, zinc, prostaglandins, cyclosporine, and interferons. The pharmacologic action of these drugs and the clinical role in veterinary and human fibrotic hepatopathies will be discussed.

Zinc and the Liver: An Active Interaction

“…Recent studies suggest that early-stage liver fibrosis is a reversible process and it is believed that understanding the mechanisms that contribute to liver fibrosis will prove helpful in designing more efficacious diagnostic and treatment strategies [74]. It has long been speculated that Zn has a protective effect against liver fibrosis [75,76]. Nevertheless, the antifibrotic properties of Zn have not been verified and recommendations for increased Zn intake in cirrhosis are based mostly on observations of reduced Zn levels in cirrhotic patients and on the beneficial effects of Zn supplementation on liver metabolism (Zn antioxidant properties).…”

The ubiquitous role of zinc in health and disease

“…Dietary zinc supplementation confers antifibrotic protection to the liver 143–145 . Antifibrotic therapy is aimed at modulating inflammation and balancing the synthesis and degradation of extracellular matrix and collagen 143 .…”

Potential of regenerative medicine techniques in canine hepatology

“…In addition, active inflammation and fibrosis may need to be resolved to obtain long-term success of regenerative treatments. The combined transplantation of immunomodulatory cells and HPCs with potential to repopulate the liver, could be highly interesting from this point of view (Leveille & Arias 1993).…”

“…Also on molecular level canine and human hepatitis are highly similar. Molecular characterization of canine hepatitis and parallel investigation with human liver diseases revealed that the cellular pathways of liver regeneration, and the cells and signals involved in liver fibrosis, are the same in man and dog (Leveille & Arias 1993;Gressner et al 2002;Spee et al 2005;Spee et al 2006;Spee et al 2007;Mortensen & Revhaug 2011). In human medicine, the development of new therapeutic strategies for liver disease has gained much attention.…”