Gilles Pomier Layrargues

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction

BACKGROUND & AIMS Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction. METHODS Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats. RESULTS Mn content was significantly increased in frontal cortex (by 38%), occipital cortex (by 55%), pallidum (by 186%), putamen (by 66%), and caudate (by 54%) of cirrhotic patients compared with controls. Brain Mn content did not correlate with patient age, etiology of cirrhosis, or history of chronic hepatic encephalopathy. In cirrhotic and portacaval-shunted rats, Mn content was increased in pallidum (by 27% and 57%, respectively) and in caudate/putamen (by 57% and 67%, respectively) compared with control groups. Mn concentration in pallidum was significantly higher in portacaval-shunted rats than in cirrhotic rats. No significant changes in brain Mn concentrations were observed in rats with acute liver failure. CONCLUSIONS These findings suggest that brain Mn deposition results both from portal-systemic shunting and from liver dysfunction.

Amino Acid Changes in Autopsied Brain Tissue from Cirrhotic Patients with Hepatic Encephalopathy

Abstract: Brain tissue was obtained at autopsy from nine cirrhotic patients dying in hepatic coma and from an equal number of controls, free from neurological, psychiatric, or hepatic diseases, matched for age and time interval from death to freezing of dissected brain samples. Glutamine, glutamate, aspartame, and γ‐aminobutyric acid (GABA) levels were measured in homogenates of cerebral cortex (prefrontal and frontal), caudate nuclei, hypothalamus, cerebellum (cortex and vermis), and medulla oblongata as their O‐phthalaldehyde derivatives by HPLC using fluorescence detection. Glutamine concentrations were found to be elevated two‐ to fourfold in all brain structures, the largest increases being observed in prefrontal cortex and medulla oblongata. Glutamate levels were selectively decreased in prefrontal cortex (by 20%), caudate nuclei (by 27%), and cerebellar vermis (by 17%) from cirrhotic patients. On the other hand, GABA content of autopsied brain tissue from these patients was found to be within normal limits in all brain structures. It is suggested that such region‐selective reductions of glutamate may reflect loss of the amino acid from the releasable (neurotransmitter) pool. These findings may be of significance in the pathogenesis of hepatic encephalopathy resulting from chronic liver disease. Key Words: Hepatic encephalopathy—Hyperammonemia— Cerebral amino acids—Glutamine—Glutamate—γ‐Aminobutyric acid. Lavoie J. et al. Amino acid changes in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy.

Manganese toxicity, dopaminergic dysfunction and hepatic encephalopathy.

Patients with chronic liver disease manifest a high incidence (>75%) of pallidal signal hyperintensity on T1-weighted Magnetic Resonance Imaging (MRI), the intensity of which correlates with blood manganese levels and the presence of extrapyramidal symptoms. A major cause of pallidal hyperintensity on T1-weighted MRI is manganese deposition; chronic manganese intoxication in the absence of liver disease results in pallidal MR signal hyperintensity, in extrapyramidal symptoms and in selective effects on the dopaminergic neurotransmitter system in basal ganglia. Direct measurements in globus pallidus obtained at autopsy from patients with chronic liver disease who died in hepatic coma reveal 2 to 7-fold increases of pallidal manganese and a concomitant loss of dopamine D2 binding sites. Liver transplantation results in normalization of pallidal MR signals and of blood manganese levels. These findings suggest that (1) pallidal MR signal hyperintensity in patients with chronic liver disease is the result of manganese deposition and (2) alterations of dopaminergic function due to the toxic effects of manganese may contribute to the extrapyramidal symptoms in these patients.

Monoamines and metabolites in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Alterations in the metabolism of monoamine neurotransmitters have been proposed to be involved in the development of the hepatic encephalopathy (HE) associated with experimental and human liver failure. In order to evaluate this hypothesis, the monoamines and some of their metabolites were measured in homogenates of caudate nucleus (CAU), prefrontal (PFCo) and frontal cortex (FCo) dissected from brains obtained at autopsy from nine cirrhotic patients who had died in hepatic coma and an equal number of control subjects, free from neurological, psychiatric and hepatic disorders, matched for age and time interval from death to freezing of autopsied brain samples. Monoamine measurements were performed by high-performance liquid chromatography with ion-pairing and electrochemical detection after a simple extraction procedure. In all three regions investigated, concentrations of dopamine (DA) were unchanged in cirrhotic patients vs controls while its metabolites, 3-methoxytyramine (3-MT) and homovanillic acid (HVA) were selectively affected i.e.3-MT was found to be increased in CAU, while HVA levels were increased in FCo and CAU. DOPAC was also found to be unchanged in CAU. Noradrenaline (NA) levels were greatly increased in PFCo and FCo of cirrhotic patients but remained unchanged in CAU. No significant differences in the concentrations of either serotonin (5-HT) or of its precursor 5-hydroxytryptophan (5-HTP) were found in any of the three regions studied. However, 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, was increased in PFCo and CAU of cirrhotic patients. These findings show that selective alterations of catecholamine and 5-HT systems are involved in human HE and therefore, they may play an important role in the pathogenesis of certain neurological symptoms associated with this encephalopathy.

Selective loss of pallidal dopamine D2 receptor density in hepatic encephalopathy

The binding parameters of [3H]SCH 23390 and [3H]spiperone (radioligands for dopamine D1 and D2 receptors, respectively) were investigated in autopsied frontal cortex, caudate nucleus and globus pallidus/putamen of cirrhotic patients who died in hepatic coma as well as in age- and sex-matched controls. Specific [3H]SCH 23390 binding site densities were unchanged in all regions; in contrast, specific [3H]spiperone binding site density was decreased (by 44%, P < 0.001) in the globus pallidus/putamen of patients with HE. Decreased densities of pallidal D2 binding sites could relate to the motor dysfunctions commonly encountered in human HE.

Activities of neuronal and astrocytic marker enzymes in autopsied brain tissue from patients with hepatic encephalopathy

Activities of the γ-aminobutyric acid (GABA) and cholinergic nerve-terminal marker enzymes glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) as well as the astrocytic enzyme glutamine synthetase (GS) were measured in homogenates of dissected brain tissue obtained at autopsy from nine cirrhotic patients dying in hepatic encephalopathy and an equal number of control subjects matched for age, agonal status, and time interval from death to freezing of autopsied material. GAD activities varied as a function of agonal status in control samples, confirming a previous report, but were unchanged in brain tissue from cirrhotic patients, suggesting no loss of integrity of presynaptic GABA nerve terminals in this disease. On the other hand, GS activities were selectively decreased by 25% (P < 0.01) in caudate nuclei of cirrhotic patients, reflecting, no doubt, the severe astrocytosis consistently observed in this brain structure. CAT activities, expressed per milligram of protein, were found to be increased by 30% (P < 0.01) in the prefrontal cortex of cirrhotic patients. Whether such changes result from a relative increase in CAT as a consequence of losses of astrocytic protein or reflect altered cholinergic function in hepatic encephalopathy associated with chronic liver disease awaits further study.

Increased activities of MAOA and MAOB in autopsied brain tissue from cirrhotic patients with hepatic encephalopathy

Using radioenzymatic assays, activities of MAOA and MAOB were measured in autopsied brain tissue from cirrhotic patients who died in hepatic coma and in material from an equal number of age-matched subjects who were free from hepatic, neurological or psychiatric disorders. Activities of both MAOA and MAOB were significantly increased in frontal cortex and caudate nucleus, two brain regions shown previously to be the site of functional and morphological alterations of astrocytes and increased concentrations of the acid metabolites of dopamine and serotonin. These findings suggest that increased monoamine metabolism and subsequent modifications of monoaminergic synaptic function could contribute to the pathogenesis of hepatic encephalopathy.

Accumulation of manganese and copper in pallidum of cirrhotic patients: role in the pathogenesis of hepatic encephalopathy?

Concentrations of zinc, copper and manganese were measured by atomic absorption spectrometry in samples of globus pallidus obtained at autopsy from 9 patients with chronic liver disease and an equal number of age-matched controls. Manganese concentrations were significantly increased several fold (p<0.01) in globus pallidus of liver disease patients accompanied by smaller but significant 2-fold increases of copper. Zinc concentrations, on the other hand, were within normal limits. Increased pallidal manganese offers a cogent explanation for the observed T1-weighted MRI signal hyperintensity in pallidum of cirrhotic patients. Increased copper content in brain suggests the existence of common pathophysiologic mechanisms in inherited (Wilson Disease) and acquired hepatocerebral disorders.

Portal vein blood flow measurements using pulsed doppler and electromagnetic flowmetry in dogs: A comparative study

Comparative measurements of portal vein blood flow were performed at laparatomy in anesthetized dogs using either a pulsed Doppler echo system or electromagnetic flowmeters. Three hundred four simultaneous determinations were obtained under baseline conditions and during vasopressin and glucagon infusions. In each dog, serial triplicate measurements were taken within 10 min of each other. In all the cases, flow changes induced by vasoactive drugs followed the same direction regardless of the method used. Portal vein blood flow as measured by electromagnetic flowmetry ranged from 85 to 1570 ml/min. Portal vein blood flow values obtained with Doppler and electromagnetic flowmeters were not significantly different (609 +/- 335 vs. 600 +/- 370 ml/min; p = NS) and were highly correlated (r = 0.918, p less than 0.001). The difference between values obtained by the two techniques was -3 +/- 159 ml/min or -1.0% +/- 21.2% (mean +/- SD). This difference was not influenced by the portal vein diameter but increased slightly as a function of the angle of insonation. When considering the mean of triplicate measurements, we also found a highly significant correlation between data obtained by the two techniques (r = 0.934, p less than 0.001; n = 63). The mean difference was 11 ml/min, but limits of agreement between these methods were -267 and +239 ml/min. This relative discrepancy was explained by a coefficient of variation higher in Doppler measurements than in electromagnetic measurements (10.9% vs. 5.9%). These data demonstrate that under our experimental conditions, Doppler flowmetry is probably not an ideal method to measure absolute portal vein blood flow values, and that more sophisticated equipment is needed to improve its reproducibility and accuracy. In humans, however, this method might be a useful tool to assess the direction of portal flow changes in the same individual.

Cost-Effectiveness of Proton-Pump Inhibition Before Endoscopy in Upper Gastrointestinal Bleeding

BACKGROUND & AIMS Randomized trials suggest high-dose proton-pump inhibitors (PPIs) administered before gastroscopy in suspected upper gastrointestinal bleeding downstage bleeding ulcer stigmata. We assessed the cost-effectiveness of this approach. METHODS A decision model compared high-dose IVPPI initiated while awaiting endoscopy with IVPPI administration on the basis of endoscopic findings. IVPPIs were given to all patients undergoing endoscopic hemostasis for 72 hours thereafter. Once the IV regimen was completed or for patients with low-risk endoscopic lesions, an oral daily PPI was given for the remainder of the time horizon (30 days after endoscopy). The unit of effectiveness was the proportion of patients without rebleeding, representing the denominator of the cost-effectiveness ratio (cost per no rebleeding). Probabilities and costs were derived from the literature and national databases. RESULTS IVPPIs before endoscopy were both slightly more costly and effective than after gastroscopy in the U.S. and Canadian settings, with cost-effectiveness ratios of US