Hepatic encephalopathy: An approach to its multiple pathophysiological features

Abstract

Hepatic encephalopathy (HE) is a neuropsychiatric complex syndrome, ranging from subtle behavioral abnormalities to deep coma and death. Hepatic encephalopathy emerges as the major complication of acute or chronic liver failure. Multiplicity of factors are involved in its pathophysiology, such as central and neuromuscular neurotransmission disorder, alterations in sleep patterns and cognition, changes in energy metabolism leading to cell injury, an oxidative/nitrosative state and a neuroinflammatory condition. Moreover, in acute HE, a condition of imminent threat of death is present due to a deleterious astrocyte swelling. In chronic HE, changes in calcium signaling, mitochondrial membrane potential and long term potential expression, N-methyl-D-aspartate-cGMP and peripheral benzodiazepine receptors alterations, and changes in the mRNA and protein expression and redistribution in the cerebral blood flow can be observed. The main molecule indicated as responsible for all these changes in HE is ammonia. There is no doubt that ammonia, a neurotoxic molecule, triggers or at least facilitates most of these changes. Ammonia plasma levels are increased two-to three-fold in patients with mild to moderate cirrhotic HE and up to ten-fold in patients with acute liver failure. Hepatic and inter-organ trafficking of ammonia and its metabolite, glutamine (GLN), lead to hyperammonemic conditions. Removal of hepatic ammonia is a differentiated work that includes the hepatocyte, through the urea cycle, converting ammonia into GLN via glutamine synthetase. Under pathological conditions, such as liver damage or liver blood by-pass, the ammonia plasma level starts to rise and the risk of HE developing is high. Knowledge of the pathophysiology of HE is rapidly ex-HE is rapidly ex-HE is rapidly expanding and identification of focally localized triggers has led the development of new possibilities for HE to be considered. This editorial will focus on issues where, to the best of our knowledge, more research is needed in order to clarify, at least partially, controversial topics.

Modern view on hepatic encephalopathy: basic terms and concepts of pathogenesis

“…In animals experiments with the administration of an inhibitor of astrocytic GlnS the severity of edema was significantly decreased [27]. It is also supposed the active participation of glutamine in the mechanisms of oxidative and nitrosative stress, which are of great importance in the pathobiochemical cascade reactions in brain in conditions of hyperammonemia [15]. On the other hand, in studies carried out on rat model of portocaval anastomoses with additional administration of ammonium acetate, it is shown that when using methionine sulphoximine, an inhibitor of glutamine synthetase, the drug does not completely arrested cerebral edema, indicating that the osmotic properties of glutamine only partially explain the mechanisms of edema development in conditions of hyperammonemia [28].…”

“…Despite more than 200 years (since 1765, when Giovanni Battista Morgagni was the first to describe a case of liver cirrhosis with HE) studying of the problem and numerous attempts to formulate a common pathogenetic concept of HE, to date there is no holistic view on the factors of etiopathogenesis and accordingly there is no single approach to managing such patients [15]. Data on the morphogenesis of HE in the current literature are of limited character and are presented in form of single studies of predominantly experimental character.…”

“…Quite poor described pathomorphological changes in the brain tissue do not allow convincing clinic-morphological comparisons; however, it is fairly clear that in the pathogenesis of HE the main conditions are decrease in the detoxification function of the liver and/or portosystemic discharge of blood with the entry of intestinal and/or liver origin pathogenic factors in the brain tissue. In general, the HE is considered as the final result of the accumulation of a number of neurotoxic substances in the brain, the most actively considering ammonia, mercaptans, short chain fatty acids, false neurotransmitters (tyramine, betaphenylethanolamine, octopamine), gamma-aminobutyric acid (GABA), manganese [15].…”

“…At the World Congress of Gastroenterology in 1998, 2002 the HE classification was elaborated, according to which it was classified according to 4 characteristics [13,15]:…”

Cerebral hemodynamic and metabolic changes in fulminant hepatic failure

“…This is an uncommon, but not rare, condition with approximately 2,000 cases annually in the United States and a mortality rate ranging from 50% to 90%, despite intensive care therapy 1,2 . Cerebral edema leading to intracranial hypertension complicates approximately 50% to 80% of patients with severe FHF (grade III or IV coma), in whom it is the leading cause of death 2,3,4 . Brain edema in FHF patients is a relatively recent concept.…”