• Key words. Ammonia metabolism;
  • glutamine metabolism;
  • liver;
  • cirrhosis.

Abstract Ammonia and glutamine metabolism was studied in slices from normal, fatty and cirrhotic human livers. The liver disease was evaluated by histological examination. With respect to ammonia removal, urea and glutamine synthesis in human liver represent low and high affinity systems with k0·5(NH4+) values of 3·6 and 0·11 mM, respectively. Compared with normal control livers, cirrhotic livers showed a decreased glutamine synthesis from NH4Cl by about 80%. The same was true for urea synthesis. Conversely, flux through hepatic glutaminase was increased in cirrhosis 4–6-fold. These changes in hepatic glutamine and ammonia metabolism were observed regardless of whether reference was made to liver wet weight, DNA or protein content. Acetazolamide inhibited urea synthesis in cirrhotic liver slices by about 50%, indicating that mitochondrial carbonic anhydrase is required for urea synthesis also in cirrhosis. There was a significant correlation between the in-vitro determined capacity for urea synthesis from NH4Cl and the in-vivo determined plasma bicarbonate concentration. The data suggest that (i) pathogenesis of hyperammonaemia in chronic liver disease involves the impairment of the perivenous ammonia scavenger cells capable of glutamine synthesis; (ii) the increased flux through glutaminase observed in cirrhosis increases the ammonia input into the urea cycle and acts as a compensatory mechanism for maintenance of a life-compatible urea cycle flux despite the decreased urea cycle enzyme activities; (iii) intramitochondrial bicarbonate provision for carbamoylphosphate synthetase by carbonic anhydrase may become rate-controlling also in liver cirrhosis; and (iv) hyperbicarbonataemia in chronic liver disease may, amongst other effects, be due to an impaired hepatic HCO3- removal by urea synthesis, in line with the concept of a role of the liver in systemic acid–base homeostasis.