Neurotransmitter dysfunction in Hepatic Encephalopathy: New approaches andnew findings

Hepatic Encephalopathy (HE) is a serious neuropsychiatric condition of both acute and chronic liver failure. Acute liver failure is characterized by r apid evolution of HE and by brain edema. Portal-Systemic encephalopathy (PS E) is particularly prevalent following treatment of portal hypertension or ascites by the TIPS procedure. Available evidence currently suggests that n eurotransmission changes rather than brain energy failure are the primary c ause of HE. Recent studies both in autopsied brain tissue from HE patients as well as in experimental animal models of HE reveal that liver failure re sults in altered expression of several genes coding for proteins having key roles in the control of neuronal excitability. Such alterations include de creased expression of the glutamate transporter GLT-1, and increased expres sion of monoamine oxidase (MAO-A isoform), the "peripheral-type" benzodiaze pine receptor (PTBR) as well as constitutive neuronal nitric oxide synthase (nNOS). Such changes result in altered protein expression and in increased extracellular brain glutamate, increased degradation of monoamine neurotra nsmitters, increased synthesis of neurosteroids with inhibitory properties, and increased production of nitric oxide (respectively) in brain in chroni c liver failure. In the case of GLT-1, PTBR, and nNOS, alterations in expre ssion result from exposure to ammonia and/or manganese, two neurotoxic agen ts shown previously to be increased in brain in liver failure.