Ammonia and the neutrophil in the pathogenesis of hepatic encephalopathy in cirrhosis.
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.
Shawcross
Debbie L
DL
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. debbie.shawcross@kcl.ac.uk
Shabbir
Shabnam S
SS
Taylor
Nicholas J
NJ
Hughes
Robin D
RD
D000641:Ammonia / Q000009:adverse effects*; D000818:Animals; D006501:Hepatic Encephalopathy / Q000821:virology*; D006801:Humans; D008103:Liver Cirrhosis / Q000150:complications*; D009504:Neutrophils / Q000502:physiology*
D000641:Ammonia