action of the urea cycle catalyzed by CPS, ammonia combines Metabolic disorders of ureagenesis can cause a Reye-like with adenosine triphosphate and bicarbonate to form carbasyndrome with potentially fatal hyperammonemia in children. myl phosphate. Carbamyl phosphate then reacts with orni-A mechanistically heterogeneous subset of these disorders thine to form citrulline in the first step of the actual urea shares the biochemical end-result of impaired mitochondrial synthesis in a reaction catalyzed by OTC. A deficiency in citrulline production. These include deficiencies of the mitoeither of these two enzymes will directly reduce mitochonchondrial enzymes, ornithine transcarbamylase (OTC) and drial citrulline production, and lead to impaired urea synthecarbamyl-phosphate synthase (CPS), as well as dibasic aminosis (Fig. 1). In contrast, impaired urea synthesis in dibasic acidurias hyperammonemia-hyperornithinemia-homocitrulaminoacidurias is the result of a functional deficiency in linuria (HHH) and lysinuric protein intolerance (LPI). In this citrulline production because of reduced mitochondrial ornireport, we present histopathology of the liver in 10 children thine levels. In hyperammonemia-hyperornithinemia-homowith defects of ureagenesis, including 6 with OTC deficiency, citrullinuria (HHH), the presumed defect is in the transport 3 with CPS deficiency, and 1 with HHH. The liver showed of cytoplasmic ornithine across the mitochondrial memdiffuse microvesicular steatosis, marked periportal nuclear branes ( Fig. 1). In lysinuric protein intolerance (LPI), the glycogen, and variable portal fibrosis with occasional delicate presumed defect is in the intestinal, hepatic, and renal transportal-to-portal bridging. Discrete aggregates of distended heport of ornithine and other dibasic amino acids. The defective patocytes with central nuclei and nonvacuolated clear cytointestinal absorption and reduced renal tubular reabsorption plasm were present in 5 of the 10 children, including two 2 of ornithine are thought to result in decreased plasma orni-OTC deficiency, 2 with CPS deficiency, and 1 with HHH.thine levels, which, in combination, with reduced hepatic Similar aggregates had been previously noted in the liver of some children with OTC deficiency or LPI, but their nature uptake, leads to reduced hepatocellular ornithine (Fig. 1). and diagnostic significance had so far remained unknown. Impaired citrulline production by any of the above mechaUsing special stains on frozen tissue sections and electron nisms can interfere with the catabolism of ammonia, causing microscopy, we show that the hepatocytes in these aggregates a Reye-like clinical syndrome with liver dysfunction and sehave little or no cytoplasmic neutral fat, but contain excessive vere, potentially fatal hyperammonemia in infancy or childfree cytoplasmic glycogen, morphologically mimicking a gly-hood. 1 cogen storage disease. In our experience, hepatocellular aggreHistopathology of the liver in CPS and OTC deficiencies gates of this nature do not occur in...
