Veterans Affairs

Statins for treatment of hepatic encephalopathy

Reducing circulating bile acid concentration prevents neurological damage without causing liver damage

Medical & Biotechnology

Scientists at the U.S. Department of Veterans Affairs (VA) have recently identified methods and compositions for the treatment of hepatic encephalopathy. The patent pending technology is available via patent license agreement to companies that would make, use, or sell it commercially.

Hepatic encephalopathy (HE) is a serious neuro-psychiatric complication of both acute liver failure and chronic liver disease with the potential to affect quality of life, clinical management strategies, priority for liver transplantation. and patient survival. HE resulting from acute liver failure (Type A HE) causes altered mental states and cognitive disruptions that can progress to coma in hours or days. In the setting of cirrhosis, Type C HE develops slowly with many patients having altered sleep patterns and cognitive issues that can progress to more severe symptomology if there is no therapeutic intervention given.

Given the poor treatment options for the management of liver cirrhosis and the advances in the clinical diagnosis of cognitive symptoms, the prevalence of HE is increasing with an urgent need to develop effective treatment options for these patients. Veterans have a high risk of developing liver cirrhosis due, at least in part, to the high prevalence of alcohol and drug abuse. The prevalence of cirrhosis has been increasing in the Veteran Affairs Healthcare System (up 59% from 2001 to 2013) with over 1% of VA enrollees in 2013 presenting with cirrhosis. Cirrhosis and other liver diseases are among the most common reasons for both hospitalizations and mortality in this population, making liver disease a great challenge for the Veteran Affairs Healthcare System.

The increase of circulating bile acids has been identified as possible culprit contributing to the complex etiology of HE, although determining the specific mechanisms and downstream consequences of aberrant bile acid signaling in the brain has been elusive. Recently, VA researchers have discovered that aberrant bile acid signaling in the brain can contribute to the development of HE by dysregulating cholesterol homeostasis, resulting in increased neurosteroid synthesis. Thus, strategies to restrict aberrant bile acid signaling in the brain, or to prevent the accumulation of cholesterol, may prove to be viable therapeutic targets for the management of HE. As a result of the above, the researchers have proposed the use of cholesterol reducing agents – statins – for the treatment of HE. Preliminary research results appears to support this approach.

Method of action: During acute liver failure (ALF), the enterohepatic circulation becomes disrupted leading to bile acid accumulation in the blood stream. Increased serum bile acids induce permeability of the blood-brain barrier and can contribute to the development of hepatic encephalopathy (HE) following ALF. This occurs via activation of famesoid X receptor (FXR), which, in turn, upregulates transcription of small heterodimer partner (SHP) in neurons. The events downstream of FXR activation contributing to HE are unknown. However, in the liver FXR activation is known to decrease the expression of liver X receptor beta (LXRP). Highly expressed in neurons in the brain, LXRP has a role in regulation of Cyp46Al, an enzyme responsible for converting cholesterol to 24(S)-hydroxycholesterol-the main mechanism of cholesterol clearance in the brain. Thus it is believed that increased levels of cholesterol in the brain during ALF and HE result from bile acid-mediated activation of the FXR/SHP pathway and LXRP suppression leading to a dysregulation of cholesterol clearance.

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