PATHOPHYSIOLOGY

Ammonia, the nitrogen-containing waste product of protein metabolism, is extremely toxic at high concentrations. Under normal circumstances, blood ammonia is cleared rapidly by the urea cycle, a biochemical pathway of hepatocytes that converts ammonia into water-soluble urea, which can then be excreted in urine (Figure 85-1). This system keeps ammonia levels under 100 μM/L in neonates and generally 20 to 60 μM/L in infants and older children. Elevated blood ammonia levels (hyperammonemia) trigger a variety of neurotoxic consequences that result in aberrant neurotransmitter levels and cerebral edema, causing severe and potentially irreversible injury to the central nervous system.¹

Hyperammonemia occurs during periods of “nitrogen imbalance,” when nitrogen load exceeds the capacity for clearance. Nitrogen load is proportional to circulating amino acid levels, which are the result of both dietary protein intake and breakdown of endogenous protein (e.g. from muscle). Nitrogen clearance depends primarily on the ability of the liver to perform the urea cycle. Therefore, diseases that drastically increase nitrogen load or compromise liver function can result in hyperammonemia. Restoring nitrogen balance is the main goal in treating hyperammonemia. The urea cycle defects (UCDs) are an important category of diseases that present with severe hyperammonemia and are the main focus of this chapter.

Symptoms associated with hyperammonemia reflect primarily ammonia’s neurotoxicity; therefore, hyperammonemia should be considered in patients with unexplained changes in mental status, encephalopathy, or signs of increased intracranial pressure (Table 85-1). A recent longitudinal study revealed that children usually present with neurologic findings (80%) and/or gastrointestinal complaints (33%) such as vomiting and poor feeding. In addition, this study found that 66% of patients with UCDs presented beyond the neonatal period.²

The typical presentation of hyperammonemia in neonates with UCDs is an unremarkable term-gestation newborn who is well for the first few days of life. However, normal increased protein intake leads to nitrogen imbalance and hyperammonemia in these children, usually within the first week of life. A retrospective analysis of 74 infants with ornithine transcarbamoylase (OTC) deficiency, the most common UCD, demonstrated a mean onset of illness at 63 hours of life, with a range of 12 to 240 hours.³ In neonates, symptoms of hyperammonemia may be impossible to distinguish from those of sepsis: decreased activity, poor feeding, encephalopathy, and seizure. An important distinguishing characteristic is that neonates with hyperammonemia may have a respiratory alkalosis (average pH 7.5, with a PCO₂ of 24) because ammonia stimulates hyperventilation.³ Furthermore, these children usually fail to improve after fluid resuscitation and antimicrobial therapy; instead, neurologic symptoms may progress to coma. In such cases, a UCD should be strongly suspected.

In older children, hyperammonemia may be even harder to identify because symptoms are either nonspecific (cyclic vomiting, headache, poor appetite) or easily confused with more common problems such as drug abuse or primary psychiatric disease (acute mental status changes, frank psychosis). A complete dietary history is important since children with UCD will often self-restrict protein intake by refusing or limiting high-protein foods such as meat and cheese.

Children with most types of UCDs have a lifetime risk of hyperammonemic episodes, which usually occur when a new nitrogen imbalance is introduced. This may be caused by increased dietary protein intake or catabolic stress–induced muscle protein turnover, which occurs during prolonged fasting, fever, or increased exercise. Blood ammonia levels can increase rapidly during these periods, and prompt treatment is critical. Similarly, children with mild forms of UCDs may not suffer an initial hyperammonemic crisis until an illness during infancy or even later in childhood or adolescence, when nitrogen imbalance causes acute mental status changes or other signs of hyperammonemia. In such patients, a thorough history may reveal the cause of the imbalance, such as a sudden increase in dietary protein intake or a dramatic increase in exercise.

Although numerous inborn errors of metabolism present in the neonatal period, it is important to remember that many cases of hyperammonemia are due to acquired problems (Table 85-2). Hyperammonemic neonates should be carefully evaluated for treatable problems, especially infection with either bacterial pathogens or herpes simplex virus. In addition, liver function should be evaluated, because hyperammonemia is a complication of liver failure from a variety of causes. Transient hyperammonemia of the newborn (THAN), a phenomenon that generally occurs in premature infants with pulmonary disease, may present similar to UCDs, causing ammonia levels to rise high enough to induce coma.^4,5 The precise biochemical defect responsible for THAN is not known, and symptoms tend to resolve after initial treatment, often without neurologic sequelae. These children do not have recurrences and tolerate normal amounts of dietary protein.

Metabolic causes of hyperammonemia include diseases that compromise the urea cycle either directly (e.g. UCDs) or indirectly through hepatic toxicity (Table 85-2). Although a definitive diagnosis of these disorders usually requires metabolic testing, a reasonable differential diagnosis can be established based on the results of common screening tests. For example, the presence of hypoglycemia is more consistent with fatty acid oxidation defects or defects in carbohydrate utilization (e.g. galactosemia, hereditary fructose intolerance) rather than UCD. Although hyperammonemia in UCD can be associated with respiratory alkalosis, the absence of respiratory alkalosis does not rule out a UCD. The presence of metabolic acidosis should raise suspicion for an organic acidemia or a primary lactic acidosis syndrome, such as pyruvate carboxylase deficiency. In nearly all states, newborn screening programs provide diagnostic information within the first week of life that can rule in or rule out many inborn errors associated with hyperammonemia. In these instances, a prompt call to the newborn screening laboratory may allow the physician to establish a tentative diagnosis and proceed with a logical round of confirmatory tests and presumptive treatment.