EDITORIAL Dopamine in the pathogenesis of minimal hepatic encephalopathy: a new player? Rahul Rai • Radha K. Dhiman Received: 9 May 2013 / Accepted: 13 July 2013 Ó Asian Pacific Association for the Study of the Liver 2013 Keywords Minimal hepatic encephalopathy Á Hepatic encephalopathy Á Cirrhosis Á Neurotransmitter Abbreviations CM Calmodulin cGMP Cyclic guanosine monophosphate HE Hepatic encephalopathy HRQOL Health-related quality of life MHE Minimal hepatic encephalopathy NMDAR N-methyl-D-aspartate receptor NOS Nitrous oxide synthetase NO Nitric oxide sGC Soluble guanyl cyclase SNAP S-nitroso-N-acetylpenicillamine Minimal hepatic encephalopathy (MHE) is the mildest form in the spectrum of hepatic encephalopathy (HE). It is characterized by subtle motor and cognitive deficits that cannot be detected by standard neuro-psychological examination. Various evaluation tools for the diagnosis of MHE include neuropsychological and computerized tests, short neuropsychological and computerized test batteries and neurophysiological tests [1]. The burden and impact of MHE are significant. The prevalence of MHE has been reported to vary between 22 and 74 % in patients with cirrhosis of the liver [1]. MHE impairs daily functioning and health-related quality of life (HRQOL), is associated with an increased number of traffic violations and accidents, predicts the development of overt HE and is also associated with poor survival [1, 2]. For the last 6 decades, hyperammonemia, due to liver dysfunction with resultant decreased detoxification of nitrogenous compounds and the presence of porto-systemic shunts in cirrhosis, has been the dominant explanation for the pathogenesis of HE, and its central role remains unchallenged to this day [3]. Ammonia readily crosses the blood-brain barrier and leads to increased glutamine syn- thesis in astrocytes, leading to their swelling and low-grade cerebral edema [4, 5]. Recently, however, evidence has emerged highlighting the role of other concurrent factors in the development of HE, such as inflammation and oxida- tive and nitrosative stress. Some degree of cerebral edema occurs in all patients with HE, including those with MHE, and astrocyte swelling plays a key role in its pathogenesis. The precise molecular mechanisms that cause these chan- ges in the brain are, however, yet to be elucidated [5, 6]. Hyperammonemia may cause cognitive and motor alterations seen in patients with HE by various direct and indirect mechanisms. One of them is alteration of different steps of glutamatergic neurotransmission. Glutamate is the main excitatory neurotransmitter and modulates learning and memory. It controls release of cGMP through the post- synaptic N-methyl-D-aspartate (NMDA) receptor and glu- tamate-NO (nitric oxide)-cyclic guanosine monophosphate (cGMP) pathway [7]. In MHE there is defective learning and memory that is related to attention and visual per- ception deficits [8]. Chronic hyperammonemia, with or without liver failure, impairs the glutamate-nitric oxide- cGMP pathway function in the brain and reduces extra- cellular cGMP, as well as the ability of rats to learn a Y maze conditional discrimination task [7]. In a study in rat Editorial to Qichuan Zhuge et al, Dopamine from cirrhotic liver contributes to the impaired learning and memory ability of hippocampus in minimal hepatic encephalopathy R. Rai Á R. K. Dhiman (&) Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India e-mail: rkpsdhiman@hotmail.com 123 Hepatol Int (2013) 7:795–797 DOI 10.1007/s12072-013-9465-9