Focal glycogenosis of the liver in disorders of ureagenesis: its occurrence and diagnostic significance.

Metabolic disorders of ureagenesis can cause a Reye-like syndrome with potentially fatal hyperammonemia in children. A mechanistically heterogeneous subset of these disorders shares the biochemical end-result of impaired mitochondrial citrulline production. These include deficiencies of the mitochondrial enzymes, ornithine transcarbamylase (OTC) and carbamyl-phosphate synthase (CPS), as well as dibasic aminoacidurias hyperammonemia-hyperornithinemia-homocitrullinuria (HHH) and lysinuric protein intolerance (LPI). In this report, we present histopathology of the liver in 10 children with defects of ureagenesis, including 6 with OTC deficiency, 3 with CPS deficiency, and 1 with HHH. The liver showed diffuse microvesicular steatosis, marked periportal nuclear glycogen, and variable portal fibrosis with occasional delicate portal-to-portal bridging. Discrete aggregates of distended hepatocytes with central nuclei and nonvacuolated clear cytoplasm were present in 5 of the 10 children, including two 2 OTC deficiency, 2 with CPS deficiency, and 1 with HHH. Similar aggregates had been previously noted in the liver of some children with OTC deficiency or LPI, but their nature and diagnostic significance had so far remained unknown. Using special stains on frozen tissue sections and electron microscopy, we show that the hepatocytes in these aggregates have little or no cytoplasmic neutral fat, but contain excessive free cytoplasmic glycogen, morphologically mimicking a glycogen storage disease. In our experience, hepatocellular aggregates of this nature do not occur in Reye syndrome or in any of its metabolic mimics other than the subset of defects listed above. Identification of these aggregates on liver biopsy can potentially narrow the differential diagnosis of a Reye-like syndrome with diffuse hepatocellular steatosis.