Removal of inhibitors of brain Na+, K+-ATPase by hemoperfusion in fulminant hepatic failure.

Serum from patients with fulminant hepatic failure inhibits rat brain Na+, K+-ATPase activity in vitro. The effect of hemoperfusion on the level of inhibition was investigated with both resin and charcoal columns in clinical use. In the patient perfusions, the mean inhibitory activity of serum fell from 34.7 +/- 1.6 (SE) to 20.9 +/- 1.5% compared with pooled control serum when a resin column was used for the first time and from 26.9 +/- 2.2 to 20.4 +/- 1.7% with charcoal hemoperfusion, a statistically significant (p less than 0.01) removal in both groups. Column chromatography on Sephadex G-25 of material eluted from the resin column post-hemoperfusion and of serum ultrafiltrates before and after in vitro adsorption with charcoal showed considerable overlap in the profile of the substances removed, but with some peaks removed by only one adsorbent. Combinations of resin and charcoal in one hemoperfusion should remove a wider range of potentially toxic substances.

Inhibition of partially purified rat brain Na+, K+-dependent ATPase by bile acids, phenolic acids and endotoxin.

Sera from patients with fulminant hepatic failure (FHF) has previously been shown to contain substance(s) which inhibit leucocyte ouabain-sensitive sodium efflux and rat brain Na+, K+-dependent ATPase in vitro. Similar effects in the patients could be an important mechanism in the development of encephalopathy and cerebral oedema. In previous studies, bilirubin, free fatty acids and mercaptans have been shown to inhibit Na+, K+-ATPase in vitro. The present report is concerned with the effects of a number of other potentially toxic substances present in the serum of patients with FHF. Chenodeoxycholic acid, p-hydroxyphenyllactic acid, p-hydroxyphenylpyruvic acid and endotoxin caused 30-45% inhibition of partially purified rat brain Na+, K+-ATPase at concentrations known to occur in the serum of patients with FHF. At low concentrations the inhibitory effects of these substances were additive, but at higher concentrations a maximum level of inhibition was reached. These further substances are likely, therefore, to be of importance in the disturbances of brain function found in FHF.

Inhibition of rat brain Na+,K+-ATPase activity by serum from patients with fulminant hepatic failure.

Among the toxins accumulating in the circulation of patients with fulminant hepatic failure (FHF) are substances which inhibit leucocyte ouabain-sensitive sodium transport. A similar inhibition of brain Na+,K+-ATPase could lead to both coma and cerebral edema found in these patients which are associated with high mortality. In this study, we have investigated the effect of sera from FHF on normal rat brain Na+,K+-ATPase activity in vitro. Serum from patients with FHF significantly decreased the ouabain-sensitive Na+,K+-ATPase activity (13.58 +/- S.D. 2.60 mumoles Pi mg protein-1 hr-1) in the rat brain membrane preparation in vitro as compared to normal serum (20.33 +/- 3.24 mumoles Pi mg protein-1 hr-1, p less than 0.001). A final serum dilution of 1 in 40 was required to abolish the inhibition of Na+,K+-ATPase activity. Cerebrospinal fluid obtained at postmortem from FHF patients also contained the inhibitory substances. Serum from patients in coma due to decompensated chronic liver disease inhibited the Na+,K+-ATPase activity (17.25 +/- 1.37 mumoles Pi mg protein-1 hr-1), but this was less marked than with FHF serum. Hence, the inhibition of brain Na+,K+-ATPase by substances accumulating in the serum in FHF may be important in the pathogenesis of hepatic coma.