Current therapies and novel approaches for biliary diseases

Abstract

Chronic liver diseases that inevitably lead to hepatic fibrosis, cirrhosis and/or hepatocellular carcinoma have become a major cause of illness and death worldwide. Among them, cholangiopathies or cholestatic liver diseases comprise a large group of conditions in which injury is primarily focused on the biliary system. These include congenital diseases (such as biliary atresia and cystic fibrosis), acquired diseases (such as primary sclerosing cholangitis and primary biliary cirrhosis), and those that arise from secondary damage to the biliary tree from obstruction, cholangitis or ischaemia. These conditions are associated with a specific pattern of chronic liver injury centered on damaged bile ducts that drive the development of peribiliary fibrosis and, ultimately, biliary cirrhosis and liver failure. For most, there is no established medical therapy and, hence, these diseases remain one of the most important indications for liver transplantation. As a result, there is a major need to develop new therapies that can prevent the development of chronic biliary injury and fibrosis. This mini-review briefly discusses the pathophysiology of liver fibrosis and its progression to cirrhosis. We make a special emphasis on biliary fibrosis and current therapeutic options, such as angiotensin converting enzyme-2 (known as ACE2) over-expression in the diseased liver as a novel potential therapy to treat this condition.

Keywords: Angiotensin converting enzyme-2; Biliary fibrosis; Chronic liver disease; Current therapies for biliary fibrosis; Gene therapy.

Figure 1

Mast cell infiltration and its role in biliary fibrosis. HSC: Hepatic stellate cell; ECM: Extracellular matrix; IBDM: Intrahepatic bile duct mass; TGF-β1: Transforming growth factor-beta 1.

Figure 2

A bile duct consists of cholangiocytes in normal liver (A) and ductular reaction with reactive ductular cells in biliary diseases (B) (arrows indicate bile ducts).

Figure 3

Hepatic ACE2 gene expression and fibrosis in a short-term model of biliary fibrosis with rAAV2/8-ACE2 therapy. ACE2 gene expression was significantly increased in ACE2-treated mice with biliary fibrosis compared to BDL mice injected with a control human serum albumin vector (rAAV2/8-HSA). rAAV2/8-ACE2 gene therapy markedly reduced the liver fibrosis in BDL mice compared to mice injected with rAAV2/8-HSA.