Acute liver failure (ALF) due to Wilson disease (WD) is invariably fatal without emergency liver transplantation. Therefore, rapid diagnosis of WD should aid prompt transplant listing. To identify the best method for diagnosis of ALF due to WD (ALF-WD), data and serum were collected from 140 ALF patients (16 with WD), 29 with other chronic liver diseases and 17 with treated chronic WD. Ceruloplasmin (Cp) was measured by both oxidase activity and nephelometry and serum copper levels by atomic absorption spectroscopy. In patients with ALF, a serum Cp <20 mg/dL by the oxidase method provided a diagnostic sensitivity of 21% and specificity of 84% while, by nephelometry, a sensitivity of 56% and specificity of 63%. Serum copper levels exceeded 200 g/dL in all ALF-WD patients measured (13/16), but were also elevated in non-WD ALF. An alkaline phosphatase (AP) to total bilirubin (TB) ratio <4 yielded a sensitivity of 94%, specificity of 96%, and a likelihood ratio of 23 for diagnosing fulminant WD. In addition, an AST:ALT ratio > 2.2 yielded a sensitivity of 94%, a specificity of 86%, and a likelihood ratio of 7 for diagnosing fulminant WD. Combining the tests provided a diagnostic sensitivity and specificity of 100%. In conclusion, conventional WD testing utilizing serum ceruloplasmin and/or serum copper levels are less sensitive and specific in identifying patients with ALF-WD than other available tests. More readily available laboratory tests including alkaline phosphatase, bilirubin and serum aminotransferases by contrast provides the most rapid and accurate method for diagnosis of ALF due to WD.

In the current Model for End-Stage Liver Disease allocation system, patients are at risk of suffering repeated episodes of hepatic encephalopathy (HE) while waiting for an orthotopic liver transplantation (OLT); the posttransplantation impact of these episodes has not been well explored. We evaluated the cognitive function and quality of life in a group of OLT recipients (n ϭ 25) who had suffered from overt HE prior to their procedure (HE-PreLT group) and compared their performance to that of a similar group of patients (n ϭ 14) without overt HE (No HE-PreLT group) as well as to controls. Patients were selected from a cohort of 280 patients who underwent OLT during this period; the presence of clinical confounders excluded many of the remaining subjects. Demographic and clinical characteristics were balanced among groups. At an average of 18 months after OLT, we administered 2 neuropsychological batteries [Psychometric Hepatic Encephalopathy Score (PHES) test battery and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS)]; a pyschophysiological test (critical flicker frequency); and the SF-36 quality of life score. The HE-PreLT group scored below controls in 5 of 6 cognitive domains tested by RBANS, 3 of 6 PHES subtests, as well as the critical flicker frequency test. The No HE-PreLT group scored below the controls in 1 of the 6 cognitive domains tested by RBANS. The more severe neurocognitive abnormalities seen in the HE-PreLT group did not appear to affect quality of life, as lower values than normative data were only found in 1 of the 8 SF-36 scales. In conclusion, neurocognitive abnormalities were more severe in liver transplant recipients that had suffered from overt HE prior to OLT. Prospective studies of neurocognitive function pre-OLT and post-OLT are needed to fully determine the impact of such abnormalities. Liver Transpl 15:184-192, 2009.

No abstract

Two mechanisms may account for brain edema in fulminant hepatic failure: the osmotic effects of brain glutamine, a product of ammonia detoxification, and a change of cerebral blood flow (CBF). We have shown brain edema, a marked increase in brain glutamine, and a selective rise in CBF in rats after portacaval anastomosis receiving an ammonia infusion. In this study, we inhibited the activity of glutamine synthetase with methionine-sulfoximine (MSO) and examined ammonia levels, brain water and CBF. A major complication of fulminant hepatic failure (FHF) is the development of brain edema and intracranial hypertension, a leading cause of death in this syndrome. 1 The pathogenesis of the increase in brain water in the setting of a failing liver remains controversial. Over a decade of research in this area, 2 main theories have emerged. In the first, the accumulation of glutamine in glial cells would account for the development of brain edema. 2 Glutamine is the product of detoxification of ammonia, a reaction localized to astrocytes in view of the selective localization of glutamine synthetase to this cell. 3 Glial swelling is a prominent neuropathological feature of experimental 4 and human FHF. 5 Inhibition of glutamine synthesis with methionine-sulfoximine (MSO) prevents the development of ammonia-induced brain edema in normal rats, 6 decreases astrocyte swelling, 7 and ameliorates brain edema in rats after portacaval anastomosis receiving an ammonia infusion. 8 A second view emphasizes a pathogenic role for disturbances in the cerebral circulation. 9 A high cerebral blood flow (CBF) is noted in patients with FHF who develop brain edema. 10,11 In addition, failure of cerebrovascular autoregulation to changes in arterial pressure is also prominent in these subjects. 12 The possibility that this increase in CBF may be linked to brain edema is further supported by reports of selective abnormalities of the blood-brain barrier, a controversial observation in experimental models of FHF. 13,14 The rat after portacaval anastomosis receiving a continuous intravenous ammonia infusion is a well-standardized, controlled paradigm of brain edema, in which cerebral swelling occurs in the absence of acute liver failure. In this preparation, we have recently reported the simultaneous presence of a marked increase in brain glutamine and a selective 3-fold increase in cerebral perfusion at the time of an increase in brain water and intracranial pressure. 15 Furthermore, mild hypothermia (35°C, 33°C) prevented the development of brain edema in spite of a similar increase in brain glutamine as the normothermic animals. The main effect of hypothermia was to prevent the rise in CBF seen in the edematous, normothermic rats.If MSO ameliorates brain edema in this model by inhibiting glutamine synthesis and hypothermia also prevents brain swelling by normalizing CBF, it is of interest to determine the effects of MSO on cerebral perfusion. Normalization of CBF with MSO would suggest that the 2 postulated mechanisms of brain edema may in fac...

and mechanisms that lead to the decrease of cerebral myoBrain myo-inositol, an organic osmolyte, is decreased inositol are poorly understood. in cirrhotic patients with hepatic encephalopathy but myo-Inositol is a six-carbon polyol that participates in the appears unchanged in fulminant hepatic failure. An ossynthesis of intracellular signaling compounds of the phosmoregulatory response to the increase in brain glutaphatidylinositol group 5 and is a main organic osmolyte in mine may explain the decrease in brain myo-inositol; if the regulatory volume response to osmotic stress. 6 Besides this is the case, organic osmolytes may account for difhepatic encephalopathy, a decrease in brain myo-inositol has ferences in the development of brain edema seen in been noted in affective disorders 7 and in chronic hyponaacute or chronic liver failure. The response of myo-inositremia. 8 In the latter, the decrease of myo-inositol is accompatol and nine other organic osmolytes to the increase in nied by a reduction of other organic osmolytes, including glubrain glutamine at different time intervals after portacatamine, as part of the process of cellular regulatory volume val anastomosis (PCA) in the rat was studied. Organic decrease. This response is elicited by the osmotic gradient osmolytes were measured in brain tissue and cerebrobetween the intracellular and extracellular compartments. spinal fluid. Water in cerebral cortex was measured after During regulatory volume decrease, brain cells lose inorganic ammonia infusion with the gravimetric method. Six ions as well as organic osmolytes, such as amino acids, meweeks after PCA, despite an increase in brain glutamine thylamines, and inositols, to avoid cell swelling. ), the content of total organic osmo-vere neurophysiological consequences, the unique physical lytes did not increase (PCA, 44.1 { 3; sham, 43 { 4) be-and chemical properties of organic osmolytes allow cells to cause of a decrease of other osmolytes (myo-inositol, 54%; withstand large changes in their concentration without detriurea, 39%; taurine, 33%; and glutamate, 8%). Brain myo-mental effects to cellular structure and function.6 In hyponainositol was lower at 3 weeks (3.4 { 0.5 kg wt 01 ) than at tremia, up to one fourth of the osmotic response is dependent 1 day after PCA (4.7 { 0.5 kg wt 01). An ammonia infusion on organic osmolytes. 10 resulted in brain edema at both time points. In conclu-In hepatic encephalopathy, the decrease in brain myo-inosion, the reduction in brain myo-inositol in PCA rats is sitol could occur as a compensatory response to the osmotic accompanied by the decrease of other organic osmo-gradient induced by the accumulation of glutamine in astrolytes, supporting the view that changes in myo-inositol cytes. If this is the case, other organic osmolytes should also reflect an osmoregulatory response. The decrease in decrease in response to the increase in glutamine. In patients brain myo-inositol is more marked as time elapses after with fulminant hepatic failure (FHF), the accumulation o...