Emerging therapeutics for chronic hepatitis B.

Hepatitis B is a global health problem. Patients with chronic hepatitis B (CHB) carry a significant risk to eventually develop cirrhotic liver disease. Recent therapeutic advances against CHB offer excellent potential for long-term suppression of hepatitis B virus (HBV) replication during antiviral therapy, and occasionally a durable remission off medication. Selection of appropriate patients for antiviral therapy depends on identification of HBV replication and an elevated alanine aminotransferase level or histologic liver injury. Pegylated interferon alpha offers potent immunomodulatory and antiviral activity with the potential for durability, but also with adverse effects and significant cost. The nucleoside or nucleotide analogs, lamivudine, adefovir, and entecavir, suppress HBV replication and are extremely well-tolerated, but long-term or even lifelong therapy is required. Most experience has been gained with lamivudine, but viral resistance occurs frequently. Newer analogs appear to be relatively free of this problem. Approaches using a combination of agents have promise, but have yet to be proven superior to individual drugs alone.

Recent developments in the pathophysiology of cholestasis.

The past decade has brought tremendous growth in the under-standing of the pathophysiologic mechanisms involved in cholestasis, both at the genetic and acquired levels. The discovery and characterization of an array of hepatobiliary transport proteins, the nuclear receptors that regulate them, and the potential clinical implications of these defective, altered, or variably expressed proteins are the key elements of our current understanding of cholestasis. It is hoped that future studies will enhance therapeutic options and the ability to care for patients with cholestatic disorders.

Gastrointestinal disorders of the critically ill. Cholestasis of sepsis.

Cholestasis of sepsis is a form of hepatocellular cholestasis that occurs as a result of sepsis. Usually, prior to the development of cholestasis, the manifestations of sepsis dominate the clinical picture. The occurrence of cholestasis is without direct bacterial involvement of the biliary system and appears to be mediated systemically by pro-inflammatory cytokines. These cytokines are released in response to the vigorous inflammatory reaction mediated by endotoxinaemia and bacterial wall lipopolysaccharides. The principal cytokines involved are the pro-inflammatory tumour necrosis factor-alpha (TNF-alpha), interleukin (IL) 1-beta and IL-6. Interplay between these cytokines and a series of hepatocyte membrane transporters appears to result in the cholestasis. Management principles focus upon the control of sepsis.

Metabolic liver disease in the young adult.

This chapter describes the gene mutations, phenotypes, diagnosis and therapy of the common metabolic liver diseases in young adulthood: haemochromatosis, Wilson disease, alpha(1)-anti-trypsin deficiency and cystic fibrosis. The remarkable variability of the phenotypical expression of the mutated genotypes makes screening recommendations and the establishment of prognosis for these liver disorders in young adults problematical. The diagnosis and therapy of the young adult with metabolic liver disease is discussed, with an emphasis on maintaining quality-of-life and balancing the importance of early intervention with the stigmatization of the diagnosis of potentially life-threatening liver disease. There is a critical need for the development of biochemical markers that would predict the risk of expression of clinical phenotypes and prognosis.