Blood Pressure Drug Losartan Associated with Liver Fibrosis Regression in Small Study

By Liz Highleyman

Over years or decades, chronic viral hepatitis and a variety of other causes can cause fibrosis, or accumulation of fibrous scar tissue produced by support cells in the liver. Fibrosis may progress to cirrhosis and end-stage liver failure, and may trigger hepatocellular carcinoma. While antiviral therapy can slow or halt liver disease progression, there is currently no treatment that can reliably reverse or "cure" advanced fibrosis.

Fiona Oakley and colleagues from the U.K. sought to better understand the pathways underlying fibrosis and its potential for reversal. Results of their study were published in the June 2009 issue of Gastroenterology.

A transcription factor called nuclear factor kappa-B (NFkB) promotes survival of myofibroblasts (cells that produce collagen and other scar material) and promotes fibrogenesis through mechanisms that are poorly understood, the authors noted as background.

In a laboratory study using rat and human liver tissue, the researchers investigated the activity of 2 natural cytokines -- angiotensin II and IkB kinase (IKK) -- that regulate NFkB activity, and their role in promoting fibrosis. They also conducted a small clinical trial to assess whether losartan (Cozaar), an angiotensin-converting enzyme (ACE) inhibitor that interferes with the activity of angiotensin II, might reduce liver fibrosis.

In the laboratory study, the authors demonstrated that ACE and IKK inhibitors led to regression of fibrosis in diseased rodent livers. When accumulation of new fibrotic tissue is halted, existing scar tissue is not replaced after it naturally deteriorates, resulting in reduced fibrosis.

The open-label clinical trial included 14 chronic hepatitis C patients with advanced liver fibrosis (Metavir stage F2 or higher) but no history of decompensation. Participants received 50 mg/day losartan for 18 months.

Tests of paired pre- and post-treatment biopsy samples revealed that half the patients initially had high levels of NFkB, but these fell after losartan administration. Furthermore, treatment with losartan led to a reduction of fibrotic tissue build-up in these participants.

"This early stage trial has shown that we can shrink liver scarring in some patients and shows promise for a treatment that could make a huge difference to the lives of thousands of people," said coauthor Derek Mann of Newcastle University. He noted that biopsies might enable clinicians to predict which individuals might benefit from losartan or similar therapies.

The investigators plan to conduct further research involving patients with liver disease due to non-viral causes such as heavy alcohol use, genetic factors, and autoimmune diseases.

Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK; University of Southampton, Southampton, UK; Institut Clínic de Malalties Digestives i Metabòliques, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; University of Queensland, School of Medicine, Princess Alexandra Hospital, Queensland, Australia; Laboratory of Molecular and Cellular Biology, University of Crete Medical School, Crete, Greece.

6/19/09

References

F Oakley, V Teoh, G Ching, and others. Phosphorylation of RelA at Ser536 to Promote Myofibroblast Survival and Liver Fibrosis. Gastroenterology 136(7). 2334-2344.e1. June 2009.

M Pinzani. Unraveling the spider web of hepatic stellate cell apoptosis. Gastroenterology 136(7). 2061-2063. June 2009.