Recent insights into the pathogenesis of hepatic encephalopathy and treatments

Abstract

Hepatic encephalopathy (HE) encompasses a spectrum of neuropsychiatric disorders related to liver failure. The development of HE can have a profound impact on mortality as well as quality of life for patients and carers. Ammonia is central in the disease process contributing to alteration in neurotransmission, oxidative stress, and cerebral edema and astrocyte swelling in acute liver failure. Inflammation in the presence of ammonia coactively worsens HE. Inflammation can result from hyperammonemic responses, endotoxemia, innate immune dysfunction or concurrent infection. This review summarizes the current processes implicated in the pathogenesis of HE, as well as current and potential treatments. Treatments currently focus on reducing inflammation and/or blood ammonia levels and provide varying degrees of success. Optimization of current treatments and initial testing of novel therapies will provide the basis of improvement of care in the near future.

Keywords::

• acute liver failure
• ammonia
• astrocyte
• cerebral edema
• cirrhosis
• hepatic encephalopathy
• inflammation
• treatments

Financial & competing interests disclosure

D Shawcross has participated in Advisory Boards, consultancy and paid lectures for Norgine, makers of rifaximin alpha. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Hepatic encephalopathy (HE) is a spectrum of neuropsychiatric disorders ranging from subtle cognitive changes through to coma.

• HE is a multisystem disease with dysfunction/compensation seen in the gastrointestinal tract, immune system, central nervous system, kidneys and cardiovascular system.

• High blood ammonia levels, along with systemic or neuroinflammation is the key to the pathogenesis of the disease.

• Circulating ammonia is able to reach the brain. Astrocytes play an important role in protecting the brain from ammonia.

• Ammonia induces changes in neurotransmission, may induce neuroinflammation and induce endogenous production of neurosteroids.

• Disturbances in the immune system in patients with HE leads to a state of immunodeficiency. This makes patients more susceptible to infection, and SIRS is frequently seen in HE patients. This worsens inflammation, HE and prognosis.

• Treatments for HE currently focus on reducing the blood ammonia level, reducing inflammation, or both.

• Current treatments are suboptimal across the spectrum of HE; the only definitive treatment for patients with acute liver failure and severe HE is a liver transplantation. Treatment failure of minimal and chronic HE results in poor quality of life for patients and carers, and worsens prognosis.

Notes