Chronic liver disease: current concepts of disease mechanisms

Optimal management of chronic liver disease requires an understanding of aetiological factors or conditions initiating and sustaining tissue damage. Injury may derive initially from toxin or xenobiotic exposure (direct, biotransformation adducts, hypersensitivity responses or immune-mediated mechanisms), infectious organisms, inborn errors of metabolism, or pathological accumulations of transition metals (iron or copper), endotoxins or membranocytolytic bile acids. Secondarily, cells and mediators associated with inflammation, pathological expression of major histocompatibility foci on hepatocytes and biliary epithelia, aberrant initiation of apoptosis, modification of the extracellular matrix, and depletion of natural antioxidants can each play pivotal roles. Cholestatic liver injury derived from extrahepatic mechanical obstruction or intrahepatic cholestasis (many causes) can induce membrane damage subsequent to accumulation of membranocytolytic bile acids, copper retention, and membrane peroxidation. This paper reviews contemporary issues of chronic hepatocellular injury and hepatic fibrosis with the aim of broadening the clinical perspective of treatment strategies.