| 抄録 |
Hepatic Encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis with a major impact on survival, liver transplant priority and quality of life. The advent of modern molecular and neuroimaging techniques have provided new insights into pathophysiologic mechanisms in HE that include (1) Fluorodeoxyglucose-Positron Emission Tomographic (PET) evidence for a key role for the anterior cingulate cortex , a brain structure responsible for control of attention in early HE; and (2) Magnetic Resonance Imaging (MRI) evidence for manganese deposition in basal ganglia, leading to cirrhosis-related Parkinsonism and evidence for the presence of low-grade brain edema in the corticospinal tract in cirrhosis. To this, one might add new evidence for neuroinflammatory mechanisms (inflammation of the brain per se) in relation to HE, in both acute and chronic liver failure. This evidence consists of the increased expression of genes coding for the proinflammatory cytokines TNF alpha, IL-1 beta and IL-6, as well as the activation of microglia (a subclass of neuroglia that are responsible for immune responses in the brain) in both toxic and ischemic liver injury. Furthermore, evidence suggests that synergistic effects of ammonia with proinflammatory cytokines leads to the worsening of oxidative stress-related gene expression in the brain, and to the disruption of the blood-brain barrier in acute liver failure. Therapeutic management of HE in cirrhosis continues to evolve rapidly. For instance, dietary protein restriction is now indicated only in exceptional circumstances and then, for short periods of time. New strategies for the reduction of blood-borne ammonia in cirrhosis include the minimally-absorbed antibiotic rifaximin, as well as probiotics and acarbose. New studies recommend as well the continued use of non-absorbable disaccharides, branched-chain amino acids and ornithine aspartate. In addition, L-DOPA may be useful for the treatment of cirrhosis-related Parkinsonism. In the case of acute liver failure, experimental studies suggest beneficial effects originating from mild hypothermia, N-Acetyl cysteine, the TNF alpha-neutralizing molecule etanercept, and the tetracycline antibiotic minocycline; all of which appear to act, at least in part, by reduction of neuroinflammation. Translation of these findings to clinical practice will undoubtedly provide rational and effective additions to the strategies that are already currently available for the treatment of HE. (The author’s Research Unit is funded by The Canadian Institutes of Health Research). |
