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Many theories have been advanced to explain the encephalopathy associated with chronic liver disease and with the less common acute form. A major factor contributing to hepatic encephalopathy is hyperammonemia resulting from portacaval shunting and/or liver damage. However, an increasing number of causes of hyperammonemic encephalopathy have been discovered that present with the same clinical and laboratory features found in acute liver failure, but without liver failure. Here, we critically review the physiology, pathology, and biochemistry of ammonia (i.e., NH3 plus NH4+) and show how these elements interact to constitute a syndrome that clinicians refer to as hyperammonemic encephalopathy (i.e., acute liver failure, fulminant hepatic failure, chronic liver disease). Included will be a brief history of the status of ammonia and the centrality of the astrocyte in brain nitrogen metabolism. Ammonia is normally detoxified in the liver and extrahepatic tissues by conversion to urea and glutamine, respectively. In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte morphology and function. Mechanisms postulated to account for this toxicity will be examined with emphasis on the osmotic effects of excess glutamine (the osmotic gliopathy theory). Because hyperammonemia causes osmotic stress and encephalopathy in patients with normal or abnormal liver function alike, the term “hyperammonemic encephalopathy” can be broadly applied to encephalopathy resulting from liver disease and from various other diseases that produce hyperammonemia. Finally, the possibility that a brain glutamine synthetase inhibitor may be of therapeutic benefit, especially in the acute form of liver disease, is discussed.

This open-label, uncontrolled, 25-year study of treatment with sodium phenylacetate and sodium benzoate documents overall survival of 84% in historically lethal urea-cycle disorders characterized by acute hyperammonemic episodes. When episodes are promptly recognized and treated with this therapy, together with intravenous arginine hydrochloride and adequate calories to prevent catabolism, plus dialysis when necessary, plasma ammonium levels fall, markedly improving survival. This 25-year study of treatment with sodium phenylacetate and sodium benzoate documents overall survival of 84% in historically lethal urea-cycle disorders characterized by acute hyperammonemic episodes. Urea-cycle disorders are inborn errors of metabolism that are characterized by episodic, life-threatening hyperammonemia resulting from partial or complete inactivity of enzymes responsible for eliminating nitrogenous waste. Historically, mortality and morbidity have been very high, and survivors commonly have had devastating neurologic sequelae. 1 Initial efforts to remove accumulated ammonium in patients with hyperammonemic encephalopathy included lactulose therapy, 2 exchange transfusion, 3 , 4 peritoneal dialysis, 4 hemodialysis, 5 and supplementation with nitrogen-free analogues of essential amino acids. 6 These treatments prolonged survival in some patients, but the overall efficacy was disappointing — and mortality and morbidity remained high. Current therapeutic strategies include reducing the production of . . .

Ornithine transcarbamylase (ornithine carbamoyltransferase) deficiency is an X-linked disorder in which the synthesis of citrulline, and hence urea, from carbamoyl phosphate and ornithine is impaired. The consequences include hyperammonemia, hyperglutaminemia, hypoargininemia, hypocitrullinemia, and episodic encephalopathy that, if uncontrolled, results in brain injury and death. The most dramatic form of the disease occurs in newborn boys as catastrophic hyperammonemic encephalopathy; hemizygous males who survive the neonatal period have a poor neurologic outcome, with a high incidence of mental retardation, cerebral palsy, and seizures. 1 It is now apparent, however, that the disease may occur in males from the neonatal period through adulthood, . . .

We reviewed the natural history and differential diagnosis of ornithine transcarbamylase deficiency (an X-linked inborn error of urea synthesis) in 13 symptomatic female heterozygotes. The patients presented as early as the first week of life or as late as the sixth year. The most common symptoms before diagnosis were nonspecific: episodic extreme irritability (100 percent), episodic vomiting and lethargy (100 percent), protein avoidance (92 percent), ataxia (77 percent), Stage II coma (46 percent), delayed physical growth (38 percent), developmental delay (38 percent), and seizures (23 percent). Including the proband, 42 percent of the female members of the 13 families studied had symptoms. The median interval between the onset of major symptoms (vomiting and lethargy, seizures, and coma) and diagnosis was 16 months (range, 1 to 142). Five patients had IQ scores below 70 at the time of diagnosis. We suggest that careful evaluation of the family history, the dietary history, the episodic nature of the nonspecific symptoms, the response of these symptoms to the withdrawal of protein, and their frequent onset at the time of weaning from breast milk will permit early diagnosis and might thereby reduce the risk of death or neurologic impairment in female patients with partial ornithine transcarbamylase deficiency. (N Engl J Med 1986; 314:541–7.) ORNITHINE transcarbamylase deficiency (OTCD) is an inborn error of urea synthesis that is inherited as an X-linked trait 1 (Fig. 1). Although there have been advances in the treatment of urea-cycle enzymopathies since Russell's description of OTCD in 1962, 2 the prognosis remains poor for affected males. Unless treated, almost all hemizygotes die of hyperammonemic coma in the neonatal period, 3 and treated survivors are likely to be neurologically handicapped. 4 Females who carry the mutant gene present with a phenotype that may vary from apparent normality to the profound neurologic impairment observed in male hemizygotes. 6 , 7 This phenotypic variability reflects both genetic heterogeneity 8 , 9 and . . .

We studied 26 children with inborn errors of urea synthesis who survived neonatal hyperammonemic coma. There was a 92 per cent one-year survival rate associated with nitrogen-restriction therapy and stimulation of alternative pathways of waste nitrogen excretion. Seventy-nine per cent of the children had one or more developmental disabilities at 12 to 74 months of age; the mean IQ was 43±6. There was a significant negative linear correlation between duration of Stage III or IV neonatal hyperammonemic coma and IQ at 12 months (r = -0.72, P<0.001) but not between the peak ammonium level (351 to 1800 μM) and IQ. There was also a significant correlation between CT abnormalities and duration of hyperammonemic coma (r = 0.85, P<0.01) and between CT abnormalities and concurrent IQ (r = -0.75, P<0.02). These results suggest that prolonged neonatal hyperammonemic coma is associated with brain damage and impairment of intellectual function. This outcome may be prevented by early diagnosis and therapy. (N Engl J Med 1984; 310:1500–5.) INHERITED deficiencies of each of the five enzymes of the urea cycle have been described. The overall prevalence is estimated to be 1 in 30,000 live births. Unable to excrete waste nitrogen as urea, affected infants accumulate ammonia and other nitrogenous compounds. Children born with a complete deficiency of one of the urea-cycle enzymes (apart from arginase deficiency) appear normal during the first 24 hours of life, but by one week of age symptoms of hyperammonemia develop. These include feeding intolerance, vomiting, lethargy, respiratory distress, seizures, and coma. Previous therapy included modification of the quality and quantity of dietary nitrogen . . .

ORNITHINE carbamoyltransferase deficiency is an X-linked disorder of urea synthesis. Its clinical manifestations — lethargy, vomiting, coma, and cerebral edema — are related to hyperammonemia and hyperglutaminemia. Other laboratory findings include low plasma levels of arginine, citrulline, and urea. Orotic aciduria also occurs commonly during hyperammonemic episodes. 1 The phenotypic consequences of mutations at the ornithine carbamoyltransferase locus in children are well known; they are less well described in adults. In newborn boys, ornithine carbamoyltransferase deficiency is manifested by hyperammonemic coma that often leads to death or, in those who recover from coma, mental retardation and cerebral palsy. 1 Older boys may . . .

To the Editor: The otherwise excellent review of hypocapnia by Laffey and Kavanagh (July 4 issue) 1 was somewhat diminished by an oversimplified discussion of the effects of hypocapnia on the cerebral circulation. We would like to add two points. First, hypocapnia reduces cerebral blood flow but expands the plateau region of the cerebral autoregulatory curve, thereby improving cerebral autoregulation, the inherent ability of the cerebrovasculature to keep cerebral blood flow constant for a wide range of perfusion pressures. 2 As the authors rightly point out, increasing cerebral blood flow by whatever means may not always be in a patient's best interest, . . .

Ornithine carbamoyltransferase is an X-linked mitochondrial enzyme expressed in hepatocytes and enterocytes. A deficiency of this enzyme results in central nervous system dysfunction, which may be fatal in newborn boys. Milder forms are seen in older boys and girls and in adults. Establishing the carrier status of women at risk for ornithine carbamoyltransferase deficiency is important for determining reproductive and medical risks for affected women. We report a test to establish the carrier status of women at risk for ornithine carbamoyltransferase deficiency. This test relies on the allopurinol-induced accumulation of orotidine, whose synthesis is stimulated by carbamoyl phosphate, a substrate that accumulates in ornithine carbamoyltransferase deficiency. We used anion-exchange, high-performance liquid chromatography to measure urinary orotidine and orotic acid excretion after the administration of a 300-mg oral dose of allopurinol in 24 women who were obligate heterozygotes, 13 who were probable heterozygotes, 15 mothers of affected boys from monoplex families (families with only one affected member), 12 mothers of affected girls from monoplex families, and 25 normal, unrelated women who were not carriers. Urinary orotidine excretion was increased 3 SD or more above the mean value for the normal women in 95.8 percent of the obligate heterozygotes, 84.6 percent of the probable heterozygotes, 73.3 percent of the mothers of affected boys in monoplex families, and 33.3 percent of the mothers of affected girls in monoplex families, thus establishing that these women were carriers of a mutant ornithine carbamoyltransferase allele. The presence of allopurinol-induced orotic aciduria was not as sensitive or specific an indicator of carrier status as the presence of orotidinuria. We conclude that measurement of urinary orotidine excretion after the administration of allopurinol is a simple and reliable test for the identification of women who are heterozygous for ornithine carbamoyltransferase deficiency. (N Engl J Med 1990; 322:1641–5.) ORNITHINE carbamoyltransferase is a mitochondrial-matrix enzyme encoded on the X chromosome and expressed in the liver and small intestine. It catalyzes the synthesis of citrulline from carbamoyl phosphate and ornithine. A deficiency of this enzyme results in a disease whose major clinical manifestations — lethargy, vomiting, coma, and cerebral edema — are related in an as yet unexplained way to hyperammonemia. 1 The phenotypic consequences of mutations at the ornithine carbamoyltransferase locus vary. In males, it is most commonly expressed as hyperammonemic coma leading to death in the neonatal period; those who recover from coma have mental retardation and cerebral palsy. . . .

Although normal plasma ammonium levels can be maintained in children with inborn errors of ureagenesis, these children are vulnerable to episodic hyperammonemia often resulting in coma and death. To treat such episodes, we designed a therapeutic protocol that included prompt recognition of hyperammonemia, therapy with intravenous sodium benzoate, sodium phenylacetate, and arginine, and nitrogen-free intravenous alimentation. Dialysis was performed if the hyperammonemia was unresponsive to drug therapy. Twelve episodes of hyperammonemia in seven children deficient in carbamyl phosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase were treated; one patient died and the others recovered. In two patients measurement of the distribution of urinary nitrogen revealed that hippurate nitrogen and phenylacetylglutamine nitrogen together accounted for 60 per cent of \"effective\" urinary waste nitrogen. Successful therapy of episodic hyperammonemia plays an important part in the long-term management of disorders of the urea cycle. (N Engl J Med 1984; 310:1630–4.) INFANTS with inborn errors of ureagenesis maintain normal plasma levels of ammonium and may have normal growth and development. Therapy relies on restriction of nitrogen intake, an abundant energy supply, activation of alternative pathways for waste-nitrogen excretion, and dietary supplementation with arginine. The rationale, details, and results of long-term therapy have been reported previously. 1 2 3 The maintenance therapy of carbamyl phosphate synthetase and ornithine transcarbamylase deficiency has recently been modified; sodium phenylacetate has been added, and citrulline has been substituted for arginine. Sodium phenylacetate has also been added to the treatment of argininosuccinic acid synthetase deficiency. Despite long-term therapy, all such . . .