title: Metabolic alkalosis as driving force for urea synthesis in liver disease: pathogenetic model and therapeutic implications.
abstract: Despite a marked reduction of the urea cycle capacity, patients with well-compensated chronic liver disease excrete near-normal amounts of urea. Compensation of the urea cycle defect apparently occurs through the activation of liver glutaminase, as suggested by an inverse relationship between the in vitro ureagenic capacity and the flux through glutaminase in liver tissue from patients with a normal, fatty, or cirrhotic liver. In these patients, the flux through glutaminase, as determined in vitro, increases in parallel with the plasma bicarbonate level and plasma pH determined in vivo. In view of this and results from previous studies, the following hypothesis is suggested: The decrease of urea cycle enzyme activities in liver cirrhosis produces metabolic alkalosis due to an impaired bicarbonate elimination. Alkalosis in turn activates and stabilizes hepatic glutaminase and accordingly mitochondrial ammonia provision for carbamoylphosphate synthetase. This results in a compensatory stimulation of the urea cycle flux in the cirrhotic patient to near-normal rates, despite the marked reduction of urea cycle enzyme activity. Accordingly, alkalosis is an important driving force for urea synthesis in the cirrhotic patient. With respect to clinical medicine, attention must be paid to acid-base disturbances in the hyperammonemic patient.
authors.affiliation: Medizinische Universitätsklinik Freiburg.
authors.forename: D
authors.initials: D
authors.lastname: Häussinger
authors.forename: R
authors.initials: R
authors.lastname: Steeb
authors.forename: W
authors.initials: W
authors.lastname: Gerok
mesh_terms: D000471:Alkalosis / Q000378:metabolism*; D001639:Bicarbonates / Q000378:metabolism; D004789:Enzyme Activation; D005234:Fatty Liver / Q000378:metabolism*; D005972:Glutaminase / Q000378:metabolism; D006801:Humans; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism*; D014508:Urea / Q000378:metabolism*
chemical_list: D001639:Bicarbonates; D014508:Urea; D005972:Glutaminase