Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis

November 6, 2009

Hepatology

Early View (Articles online in advance of print)

Published Online: 13 Oct 2009

Liver Failure/Cirrhosis/Portal Hypertenstion

Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in

cirrhosis

Debbie L. Shawcross *, Shabnam S. Shabbir§, J. §, Robin D.

Institute of Liver Studies, King's College London School of Medicine at King's

College Hospital, King's College Hospital, London, UK

email: Debbie L. Shawcross (debbie.shawcross@...)

*Correspondence to Debbie L. Shawcross, Institute of Liver Studies, King's

College London School of Medicine at King's College Hospital, 3rd Floor Cheyne

Wing, King's College Hospital, Denmark Hill, London SE5 9RS, UK

Potential conflict of interest: Nothing to report.

fax: (44)-020-3299-3167.

§These authors contributed equally to this work.

Funded by:

5-year UK Department of Health HEFCE Clinical Senior Lectureship

Young Investigator Award (2008) from the Intensive Care Society

Abstract

Hepatic encephalopathy (HE) constitutes a neuropsychiatric syndrome which

remains a major clinical problem in patients with cirrhosis. In the severest

form of HE, cirrhotic patients may develop varying degrees of confusion and

coma. Ammonia has been regarded as the key precipitating factor in HE, and

astrocytes have been the most commonly affected cells neuropathologically.

Although the evidence base supporting a pivotal role of ammonia is robust, in

everyday clinical practice a consistent correlation between the concentration of

ammonia in the blood and the manifest symptoms of HE is not observed. More

recently the synergistic role of inflammation and infection in modulating the

cerebral effects of ammonia has been shown to be important. Furthermore, it has

been recognized that infection impairs brain function both in the presence and

absence of liver disease. Thus it could be postulated that in the presence of

ammonia, the brain is sensitized to a systemic inflammatory stimulus and is able

to elicit an inflammatory response involving both proinflammatory and

neurotransmitter pathways. Ammonia is not only directly toxic to astrocytes but

induces neutrophil dysfunction with the release of reactive oxygen species,

which contribute to oxidative stress and systemic inflammation. This may further

exacerbate the cerebral effects of ammonia and potentially reduce the capacity

of the neutrophil to fight microbial attack, thus inducing a vicious circle.

This evidence supports the neutrophil in addition to ammonia as being culpable

in the pathogenesis of HE, making the neutrophil a target for future

anti-inflammatory therapeutic strategies in addition to ammonia lowering

therapies. (HEPATOLOGY 2010.)

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Received: 11 August 2009; Accepted: 1 October 2009

Digital Object Identifier (DOI)

10.1002/hep.23367

November 6, 2009