An 80% dysfunction rate at 2 years limits the use of transjugular intrahepatic portosystemic shunts (TIPS) in the treatment of complications of portal hypertension. The use of covered stents could improve shunt patency; however, long-term effect and safety remain unknown. Eighty patients randomized to be treated by TIPS either with a covered stent (Group 1) or an uncovered prosthesis (Group 2) were followed-up for 2 years. Doppler US was performed every 3 months. Angiography and portosystemic pressure gradient measurement were performed every 6 months or whenever dysfunction was suspected. Actuarial rates of primary patency in Groups 1 and 2 were 76% and 36% respectively (P=0.001). Clinical relapse occurred in four patients (10%) in Group 1 and 12 (29%) in Group 2 (P<0.05). Actuarial rates of being free of encephalopathy were 67% in Group 1 and 51% in Group 2 (P<0.05). Probability of survival was 58% and 45% at 2 years, respectively, in Groups 1 and 2 (NS). The mean Child-Pugh score improved only in Group 1 (from 8.1+/-1.6 to 7+/-2.2 at 2 years -P<0.05). We also compared the Doppler-US parameters between patent and dysfunctioning shunts. In patent shunts, the mean velocity within the portal vein was significantly higher but the performance of Doppler-US was not accurate enough to predict shunt dysfunction. In conclusion, the improvement in TIPS patency by using covered prostheses is maintained over time with a decreased risk of encephalopathy, while the risk of death was not increased.

There is substantial clinical and experimental evidence to suggest that ammonia toxicity is a major factor in the pathogenesis of hepatic encephalopathy associated with subacute and chronic liver disease. Ammonia levels in patients with severe liver disease are frequently found to be elevated both in blood and cerebrospinal fluid (csf). Hepatic encephalopathy results in neuropathological damage of a similar nature (Alzheimer type II astrocytosis) to that found in patients with congenital hyperammonemia resulting from inherited defects of urea cycle enzymes. Following portocaval anastomosis in the rat, blood ammonia concentration is increased 2-fold, and brain ammonia is found to be increased 2-3-fold. Administration of ammonia salts or resins to rats with a portocaval anastomosis results in coma and in Alzheimer type II astrocytosis. Since the CNS is devoid of effective urea cycle activity, ammonia removal by brain relies on glutamine formation. Cerebrospinal fluid and brain glutamine are found to be significantly elevated in cirrhotic patients with encephalopathy and in rats following portocaval anastomosis. In both cases, glutamine is found to be elevated in a region-dependent manner. Several mechanisms have been proposed to explain the neurotoxic action of ammonia. Such mechanisms include: Modification of blood-brain barrier transport; alterations of cerebral energy metabolism; direct actions on the neuronal membrane; and decreased synthesis of releasable glutamate, resulting in impaired glutamatergic neurotransmission.

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.

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, aspartate, and gamma-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.

Peripheral-type benzodiazepine receptors were evaluated using the specific ligand [3H]-PK 11195 in brain homogenates from nine cirrhotic patients who died in hepatic coma and from an equal number of age-matched control subjects. Histopathological studies showed evidence of severe Alzheimer type II astrocytosis in the brains of all cirrhotic patients. Saturation-binding assays revealed a single saturable binding site for [3H]-PK 11195 in brain, with affinities in the 2- to 3-nmol/L range. Diazepam was found to be a relatively potent inhibitor of 3H-PK 11195 binding (IC50 = 253 nmol/L), whereas the central benzodiazepine antagonist Ro 15-1788 displaced 3H-PK 11195 binding with low affinity (IC50 greater than 40 mumols/L). Densities of [3H]-PK 11195 binding sites were found to be increased by 48% (p less than 0.01) and 25% (p less than 0.05) in frontal cortex and caudate nuclei, respectively, from cirrhotic patients. Densities of [3H]-PK 11195 binding sites in frontal cortex from two nonencephalopathic cirrhotic patients were not significantly different from control values. No concomitant changes of affinities of these binding sites were observed. Because it has been suggested that peripheral-type benzodiazepine receptors may be localized on mitochondrial membranes and may therefore be involved in cerebral oxidative metabolism, the alterations observed in this study could be of pathophysiological significance in 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.

No abstract

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.