New perspectives for the treatment of cholestasis: Lessons from basic science applied clinically

Abstract

Cholestasis is a clinical syndrome that results from the disturbances in the formation of bile, a unique and vital property of the liver. The causes of cholestasis are broad and range from rare genetic diseases and disruption of the normal development of the bile excretory anatomy, to progressive, ultimately fatal diseases such as primary biliary cirrhosis and sclerosing cholangitis(1). Cholestasis may also develop from mechanical obstructions in the extrahepatic bile ducts or during the course of viral hepatitis or the administration of certain drugs and hormones. Whatever the cause, the syndrome is manifested by the hepatic retention of products normally excreted into bile, in particular bile salts. As the process progresses with time, jaundice and hypercholesterolemia may follow. The syndrome is almost always characterized by an elevation in serum alkaline phosphatase and if progressive, fibrosis, cirrhosis and clinical signs of liver failure ultimately develop. During the past decade, as the molecular basis of bile formation has been clarified, the pathogenesis of many cholestatic disorders has also evolved resulting in the following paradigm. Determinants of bile secretion undergo an adaptive response during cholestasis which tend to minimize hepatic injury. This adaptation occurs by: (a) limiting hepatic uptake of bile acids and other organic solutes, (b) reducing bile acid synthesis, (c) accelerating bile acid detoxification and (d) up-regulating alternative pathways for excretion of bile salts and other solutes in liver, kidney and intestine Much of this information has resulted from the study of animal models of cholestasis, which with some exceptions have been confirmed in patients with cholestasis (1–3). The molecular basis of this process, which underlies current efforts to intervene clinically, has resulted from 3 fundamental developments: 1) The cloning of transporters that are the determinants of hepatobiliary secretion (greatly advanced by the completion of the human genome project) (1). 2) The discovery that mutations in some of these transporters result in cholestatic liver disease in patients (thereby providing “proof of principle” for their function (4) and 3) The evolving field of nuclear receptors which now enable a partial understanding of how these critical transporter and metabolism genes are transcriptionally regulated (5;6) (Fig 1). Fig 1 Drugs that regulate hepatic bile acid and other organic solute uptake, synthesis, detoxification and secretion. The figure illustrates their action as nuclear receptor ligands that inhibit or stimulate transcription of key transporters and enzymes in ... It is obvious that were these adaptive responses more robust, progressive cholestatic liver diseases might not occur or at least might become more protracted over time. Therefore the central question is whether therapy can be devised that might augment these potentially beneficial adaptive responses in expression of transporters and metabolic pathways? This commentary reviews the molecular basis of bile formation and the adaptive responses that are known to occur in cholestatic liver injury. It follows with a summary of current as well as possible future therapies for jaundice and cholestasis that are mediated by nuclear receptor ligands.