Hepatic Encephalopathy in Cirrhosis: Pathology and Pathophysiology.

Neuropathology of hepatic encephalopathy (HE) in cirrhosis is primarily astroglial in nature characterized by Alzheimer type 2 astrocytosis together with activation of microglia indicative of neuroinflammation. Focal loss of neurons may also occur in the basal ganglia, thalamus and cerebellum. Pathophysiology of HE in cirrhosis is multifactorial, involving brain accumulation of ammonia and manganese, systemic and central inflammation, nutritional/metabolic factors and activation of the GABAergic neurotransmitter system. Neuroimaging and spectroscopic techniques reveal early deactivation of the anterior cingulate cortex in parallel with neuropsychological impairment. T1-weighted MR signal hyperintensities in basal ganglia resulting from manganese lead to a novel entity, 'Parkinsonism in cirrhosis'. Elucidation of the pathophysiological mechanisms has resulted in novel therapeutic approaches to HE aimed at reduction of brain ammonia, reduction of systemic and central inflammation, and reduction of GABAergic tone via the discovery of antagonists of the neurosteroid-modulatory site on the GABA receptor complex.

Hepatic encephalopathy in alcoholic cirrhosis.

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis in alcoholic patients that is characterized clinically by personality changes, sleep abnormalities, and impaired motor coordination, as well as cognitive dysfunction progressing to stupor and coma. Procedures used for diagnosis and grading of HE include neurologic assessment, electroencephalography, psychometric testing, and use of the critical flicker frequency test. Neuropathologically, HE in cirrhosis is principally a disorder of neuroglia characterized by Alzheimer type II astrocytosis and activation of microglia. However, thalamic and cerebellar neuronal pathologies have been noted as well as lesions to globus pallidus and substantia nigra, leading to a condition known as "parkinsonism in cirrhosis." Multiple mechanisms have been proposed to account for the pathogenesis of HE in cirrhosis, including the neurotoxic actions of ammonia and manganese (normally removed via the hepatobiliary route), impaired brain energy metabolism, central proinflammatory mechanisms, and alterations of both excitatory and inhibitory neurotransmission. Treatment of HE in cirrhosis continues to rely on ammonia-lowering strategies such as lactulose, antibiotics, probiotics and l-ornithine l-aspartate with nutritional management consisting of adequate (but not excessive) dietary protein and vitamin B1 supplements. l-DOPA may improve parkinsonian symptoms. Liver transplantation leads to recovery of central nervous system function in the majority of cases.

Metal toxicity, liver disease and neurodegeneration.

Hepatocerebral disorders are serious neuropsychiatric conditions that result from liver failure. These disorders are characterized neuropathologically by varying degrees of neuronal cell death in basal ganglia, cerebellum, and spinal cord, and include clinical entities such as Wilson's Disease, post-shunt myelopathy, hepatic encephalopathy, and acquired non-Wilsonian hepatocerebral degeneration. Morphologic changes to astrocytes (Alzheimer type II astrocytosis) are a major feature of hepatocerebral disorders. Neurological symptoms include Parkinsonism, cognitive dysfunction, and ataxia. Pathophysiologic mechanisms responsible for cerebral dysfunction and neuronal cell death in hepatocerebral disorders include ammonia toxicity and neurotoxic effects of metals such as copper, manganese, and iron. Molecular mechanisms of neurotoxicity include oxidative/nitrosative stress, glutamate (NMDA)-receptor-mediated excitotoxicity, and neuroinflammatory mechanisms. However, neuronal cell death in hepatocerebral disorders is limited by adaptive mechanisms that may include NMDA-receptor down-regulation, the synthesis of neuroprotective steroids and hypothermia. Management and treatment of hepatocerebral disorders include chelation therapy (Wilson's Disease), the use of ammonia-lowering agents (lactulose, antibiotics, ornithine aspartate) and liver transplantation.

Role of nutrition in the management of hepatic encephalopathy in end-stage liver failure.

Malnutrition is common in patients with end-stage liver failure and hepatic encephalopathy, and is considered a significant prognostic factor affecting quality of life, outcome, and survival. The liver plays a crucial role in the regulation of nutrition by trafficking the metabolism of nutrients, their distribution and appropriate use by the body. Nutritional consequences with the potential to cause nervous system dysfunction occur in liver failure, and many factors contribute to malnutrition in hepatic failure. Among them are inadequate dietary intake, malabsorption, increased protein losses, hypermetabolism, insulin resistance, gastrointestinal bleeding, ascites, inflammation/infection, and hyponatremia. Patients at risk of malnutrition are relatively difficult to identify since liver disease may interfere with biomarkers of malnutrition. The supplementation of the diet with amino acids, antioxidants, vitamins as well as probiotics in addition to meeting energy and protein requirements may improve nutritional status, liver function, and hepatic encephalopathy in patients with end-stage liver failure.

eNOS gene deletion restores blood-brain barrier integrity and attenuates neurodegeneration in the thiamine-deficient mouse brain.

Wernicke's encephalopathy is a cerebral disorder caused by thiamine (vitamin B(1)) deficiency (TD). Neuropathologic consequences of TD include region-selective neuronal cell loss and blood-brain barrier (BBB) breakdown. Early increased expression of the endothelial isoform of nitric oxide synthase (eNOS) occurs selectively in vulnerable brain regions in TD. We hypothesize that region-selective eNOS induction in TD leads to altered expression of tight junction proteins and BBB breakdown. In order to address this issue, TD was induced in C57BL/6 wild-type (WT) and eNOS(-/-) mice by feeding a thiamine-deficient diet and treatment with the thiamine antagonist pyrithiamine. Pair-fed control mice were fed the same diet with additional thiamine. In medial thalamus of TD-WT mice (vulnerable area), increased heme oxygenase-1 and S-nitrosocysteine immunostaining was observed in vessel walls, compared to pair-fed control-WT mice. Concomitant increases in IgG extravasation, decreases in expression of the tight junction proteins occludin, zona occludens-1 and zona occludens-2, and up-regulation of matrix metalloproteinase-9 in endothelial cells were observed in the medial thalamus of TD-WT mice. eNOS gene deletion restored these BBB alterations, suggesting that eNOS-derived nitric oxide is a major factor leading to cerebrovascular alterations in TD. However, eNOS gene deletion only partially attenuated TD-related neuronal cell loss, suggesting the presence of mechanisms additional to BBB disruption in the pathogenesis of these changes.

Thiamine deficiency-related brain dysfunction in chronic liver failure.

End-stage chronic liver failure results in thiamine deficiency caused principally by depletion of liver thiamine stores. Chronic liver failure also leads to increased brain ammonia concentrations. Both ammonia and thiamine deficiency result in decreased activity of alpha-ketoglutarate dehydrogenase, a rate-limiting tricarboxylic acid cycle enzyme. Loss of enzyme activity results in a mitochondrial oxidative deficit in brain and consequent increases in brain lactate, oxidative/nitrosative stress, cellular energy impairment and release of proinflammatory cytokines, all of which have been described in brain in end-stage chronic liver failure. Synergistic effects of ammonia exposure and thiamine deficiency could explain the diencephalic and cerebellar symptomatology described in patients with "hepatic encephalopathy". Unsuspected brain lesions due to thiamine deficiency could explain the incomplete resolution of neuropsychiatric symptoms following the use of ammonia-lowering agents or liver transplantation in patients with end-stage chronic liver failure. These findings underscore the need for prompt, effective thiamine supplementation in all patients with chronic liver failure.

Impaired oxidation of branched-chain amino acids in the medial thalamus of thiamine-deficient rats.

Thiamine, in its diphosphate form, is a required cofactor for enzymes of glucose metabolism and branched-chain alpha-ketoacid dehydrogenase (BCKDH). Although metabolic impairments in glucose metabolism have been found to occur in selectively vulnerable brain regions of the thiamine-deficient (TD) brain, the effects of thiamine deficiency on BCKDH have not been studied. BCKDH activity was assayed radiochemically in brain extracts of vulnerable (medial thalamus; MT) versus non-vulnerable (frontal cortex; FC) brain regions of rats made TD by administration of the central thiamine antagonist, pyrithiamine. A significant regional variation in BCKDH within the TD rat brain was noted, with a higher capacity for branched-chain amino acid oxidation in FC compared to MT: BCKDH activity was significantly reduced in MT of TD rats, resulting in selective accumulation of BCAAs in this brain region. Leucine concentrations were elevated over fivefold in the MT of symptomatic TD rats, compared with pair-fed control (PFC) rats. Impaired branched-chain ketoacid metabolism in rats may contribute to the neuronal dysfunction and ultimate thalamic neuronal cell death observed in thiamine deficiency.

Glucose loading precipitates focal lactic acidosis in the vulnerable medial thalamus of thiamine-deficient rats.

Glucose loading in thiamine-deficient patients is known to precipitate Wernicke's Encephalopathy; however, the mechanisms responsible have not been fully elucidated. Lactate accumulation occurs in brains of thiamine-deficient rats. In order to determine whether glucose loading in thiamine-deficient rats causes selective lactic acidosis in vulnerable brain structures, cerebral pH was measured autoradiographically using 14-labeled 5,5-dimethyloxazolidine-2, 4-dione ([(14)C]DMO) in the medial thalamus, a vulnerable brain region, versus cerebral cortex, a brain region that is spared in thiamine deficiency. Following administration of a glucose load, regional lactate levels and de novo lactate synthesis measured by (1)H-(13)C-NMR spectroscopy, increased significantly to 21.86 +/- 3.04 mumol/g (wet weight) in the medial thalamus (p < 0.001) and pH in this brain region was decreased significantly from 7.08 +/- 0.04 to 6.87 +/- 0.05 (p < 0.001). No such changes were observed in cerebral cortex following a glucose load. These results demonstrate that the increased production and accumulation of brain lactate result in acidosis following glucose loading in thiamine deficiency. Alterations of brain pH could contribute to the pathogenesis of thalamic neuronal damage and consequent cerebral dysfunction in Wernicke's Encephalopathy.