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BACKGROUND

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

FIGURE 85-1.

The urea cycle. The most common urea cycle defects are designated by starburst and abbreviated as follows: AL, argininosuccinic acid lyase; AR, arginase; AS, argininosuccinic acid synthetase; CPS, carbamoyl phosphate synthetase; OTC, ornithine transcarbamoylase. Note: Pharmacologic treatments used in the scavenger pathway are indicated by boxes with dotted lines.

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.

CLINICAL PRESENTATION

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

TABLE 85-1Symptoms Associated with Hyperammonemia

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 ...

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