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

Abstract

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.

Behavioral and biochemical characterization of rats treated chronically with thioacetamide: proposal of an animal model for hepatic encephalopathy associated with cirrhosis

“…In HE patients, dysfunction of the liver results in disturbances of amino acid metabolisms and subsequent elevation of plasma and brain contents of aromatic amino acids such as Trp and Tyr (Bergeron et al, 1989). The elevation of these aromatic amino acids leads to increased synthesis of 5HT, DA, and NA in the brain (Cascino et al, 1982;Bernardini and Fischer, 1982;Fanelli et al, 1986).…”

Tryptophan metabolism in alcoholism

“…It would, however, be unwise to extrapolate this to the situation in man, given that some subjects experience 'late' withdrawal and clinically some behavioural disorders secondary to alcohol dependence, which may have biochemical correlates; for example depression can take up to 4 weeks after withdrawal to resolve. There is also the possibility that pathological changes associated with long-term alcohol dependence, for example liver cirrhosis, may exert permanent effects on Trp disposition (for example, see Rössle et al 1986;Bergeron et al 1989). Accordingly, the Trp metabolic status of human alcoholism should best be studied in long-term abstinence and in subjects not afflicted with overt organ damage, or, preferably, in offspring of adults with a family history of alcoholism before their exposure to alcohol.…”

Portal-Systemic Encephalopathy in Emergency Treatment of Cirrhosis and Bleeding Esophageal Varices

“…This increase in MAO-A gene expression was found to be associated with increased activities of the enzyme and increased densities of catalytic sites on the enzyme protein (Mousseau et al, 1997). Moreover, studies of the same brain extracts revealed increased concentrations of homovanillic andhydroxyindoleacetic acids, the final metabolites of dopamine and serotonin, respectively (Bergeron et al, 1989). Increased concentrations of 5-hydroxyindoleacetic acid were also reported in cerebrospinal fluid from patients (Young & Lai, 1980) and experimental animals (Bergeron et al, 1995) with chronic liver failure.…”

“…Studies in autopsied brain tissue from cirrhotic patients (Bergeron et al, 1989) and from rats with PCS (Bergeron et al, 1995) reveal several-fold increases in concentration of the dopamine metabolite homovanillic acid, a finding that could result from increased activities of monoamine oxidase reported in the same material (Mousseau et al, 1997). In another study, densities of the postsynaptic dopamine D 2 receptor were significantly reduced in pallidum/putamen from cirrhotic patients (Mousseau et al, 1993) a finding that could have resulted from manganese deposition in the brains of these patients .…”