Diagnostic Testing

When an IEM is suspected, it is often important to initiate treatment measures while an investigative workup is underway because a delay in therapy may affect the clinical outcome. Blood, urine, and cerebrospinal fluid (CSF) can be useful in the laboratory evaluation, and several laboratory studies are particularly helpful when an IEM is suspected in an ill child (Box 121-1). Serum electrolytes and blood gas analysis evaluate the acid-base status and anion gap. Ketone levels in urine, and sometimes blood, should be determined. Serum ammonia, lactate, and pyruvate, which can be tested in most hospitals, can also be informative, particularly in ill newborns. Metabolic laboratory studies such as plasma amino acids, plasma acylcarnitines, and urine organic acids, which provide important diagnostic information, must often be sent to specialized centers. Finally, one should consider other disease-specific testing, such as complete blood counts, to evaluate for bone marrow suppression in some organic acidurias. Molecular DNA testing and enzyme assays may require biopsy of specific tissues.

Key to interpretation of testing, some laboratories require special collection methods. For example, blood for ammonia for lactate levels should be drawn from a free-flowing vessel, transported to the laboratory on ice, and tested soon after collection or values may be falsely elevated. The metabolic workup is most appropriately performed in a focused, tiered fashion, starting with testing for the most likely and treatable disorders.

Special efforts are necessary to arrive at a diagnosis in patients suspected of having IEM who are dying or recently deceased because clear confirmation of an IEM greatly assists with genetic and reproductive counseling for families. In a dying patient, consider collection and freezing of urine and separated plasma as well as a skin biopsy to be stored in tissue culture medium at room temperature for isolation of skin fibroblasts. One may also consider a liver biopsy (frozen sample for enzyme assays and fresh tissue for electron microscopy).

Common Presentations

Although IEM have a broad range of manifestations, common presentations and laboratory findings can lead one to consider a metabolic disorder. Because IEM are individually rare, a practical, generalized approach to common presentations is valuable.

Hypoglycemia

In general, hypoglycemia can be induced by lack of adequate glucose intake, poor homeostatic controls, iatrogenic causes, infection, and inborn errors of glucose metabolism. The brain is particularly dependent on glucose for energy but can alternatively use ketone bodies. Symptoms of hypoglycemia include lethargy, sweating, pallor, seizures, and mental status changes. Central to determining a metabolic cause of hypoglycemia is its onset after a carbohydrate load. For example, whereas early postprandial symptoms are more likely to be related to hyperinsulinism and glycogenoses, defects in fatty acid oxidation, ketone body synthesis, gluconeogenesis, and other IEM tend to take longer to present with hypoglycemia (Figure 121-2). Diagnostic pathways to approach the metabolic differential diagnosis for hypoglycemia are useful (Figure 121-3). A focused evaluation for an IEM may include electrolytes, glucose level, urine ketones, urine-reducing substances, ammonia, lactate, urine organic acids, and plasma acylcarnitines. One should also consider evaluation for non-IEM causes of hypoglycemia such as infection, drugs or toxins, and abnormal counterregulatory hormone mechanisms.

Figure 121-2 Contributions to and factors influencing fasting glucose levels.

Figure 121-3 Diagnostic pathway for hypoglycemia.

Hyperammonemia

Ammonia is a product of protein metabolism that, in elevated levels, is toxic to the central nervous system (CNS), resulting in cerebral edema. Normally, ammonia is converted to urea in the liver via the urea cycle and is excreted in the urine. When the nitrogen load exceeds the clearance capacity of the liver, ammonia accumulates. The nitrogen load increases with dietary protein intake and endogenous protein breakdown, both of which can cause hyperammonemia in patients with primary or secondary urea cycle defects. Symptoms of hyperammonemia include vomiting, seizures, lethargy, coma, and hyperventilation associated with respiratory alkalosis. Nonspecific episodes of headache, vomiting, and mental status changes may be the only signs in later-onset cases. For extremely high ammonia levels, such as during neonatal presentations of urea cycle disorders (UCDs), dialysis to rapidly reduce the toxic levels may be necessary in addition to less invasive therapies. Nonmetabolic causes of hyperammonemia include sepsis; liver failure; use of medications such as valproate; and transient hyperammonemia of the newborn, a disorder associated with severe neonatal hyperammonemia that resolves perinatally, although residual neurologic sequelae may result. Classic metabolic causes of hyperammonemia include UCDs, organic acidurias, FAODs, hyperornithinemia-hyperammonemia-homocitrullinemia syndrome, pyruvate carboxylase deficiency, and hyperammonemia-hyperinsulinemia syndrome. Several of these disorders, including organic acidurias and FAODs, cause secondary urea cycle inhibition. Whereas hyperammonemia without metabolic acidosis and hypoglycemia is suggestive of UCD, an anion gap metabolic acidosis should arouse suspicion for an organic aciduria. Diagnostic pathways for biochemical causes of hyperammonemia are depicted in Figure 121-4.

Figure 121-4 Diagnostic pathway for hyperammonemia.

Treatment

In most IEM, long-term treatment goals focus on tight intake regulation of the offending substrate within the defective pathway, pharmacologic reduction of metabolite toxicity, and replacement of deficient metabolites. In some disorders, supplementation of cofactors to optimize residual enzyme activity, enzyme replacement, and tissue transplantation are also possible.

In disorders associated with hypoglycemia, hyperammonemia, and acidosis, patients may present critically ill or be at risk for rapid decompensation. Therefore, prompt management must be instituted to prevent long-term systemic sequelae. Oral intake of substrates or metabolites that are harmful in the disease must be restricted (e.g., protein restriction in UCDs). If hypoglycemia is detected, a bolus of intravenous (IV) glucose should be provided (often starting with 2-4 mL/kg of 10% dextrose). Continuous IV hydration with dextrose should be started with a glucose infusion rate of 6 to 9 mg/kg of dextrose per minute and further titrated to keep the patient euglycemic. This provides calories and an alternative safe energy source to reduce catabolism. An IV fluid rate of 1.5 to 2 times maintenance with 10% dextrose is often used, although alternative rates or concentrations may be required in the presence of fluid-restricted conditions such as heart disease. Furthermore, although dextrose administration is a primary therapy in most acute presentations of IEM, it is important to remember that it may be harmful in a few primary lactic acidosis syndromes (in which glucose is the harmful substrate).

In some situations, with the notable exception of FAODs, IV lipids are also used as an additional energy source to provide calories and decrease catabolism.

In addition to the critical provision of calories, other approaches, based on disease and presentation, are used. Management of metabolic acidosis may also require bicarbonate therapy. In UCDs, nitrogen scavenger therapy is given to reduce demand on the urea cycle. Dialysis may be necessary in some critically ill metabolic patients with very high levels of ammonia. Although other methods of dialysis have been used in the past, hemodialysis is currently the recommended standard. In acutely ill patients undergoing diet restriction, it is usually important to reintroduce the restricted substrate as the patient improves. For example, the essential amino acids required for normal metabolism can become deficient if a patient remains completely protein restricted for longer than 24 to 48 hours, increasing the risk for catabolism with breakdown of endogenous protein stores. After confirmation of a diagnosis, other disease-specific management goals exist, some of which are discussed below.