Not So Rare: Errors of Metabolism During the Neonatal Period

Sandra A. Banta-Wright, MN, RNC, NNP; Robert D. Steiner, MD

Disclosures

NAINR. 2003;3(4) 

In This Article

Metabolic Acidosis

Metabolic acidosis is defined as a low pH (<7.35) due to an excess of acid (H+)oradeficit of base (HCO3-). This occurs when there is an increased production of fixed or nonvolatile acids with a simultaneous decrease in the buffering capacity. The anion gap should be calculated to elucidate whether the metabolic acidosis is caused by an accumulation of organic acids or a decrease in bicarbonate. This is important in establishing the diagnosis of suspected EM. The anion gap is calculated by Sodium – (Chloride + Bicarbonate).[13] Hyperchloremic acidosis is a hallmark of metabolic acidosis due to bicarbonate wasting and usually occurs in newborns with intestinal or renal disorders. When the anion gap is increased (≥16) with a normal chloride level, the acidosis is from excess acid production.

Metabolic acidosis is a common finding in the sick newborn. In some cases, the metabolic acidosis is acute, severe, and life threatening, as in shock. In other cases, the acidosis is mild, but persistent and, in still others, may be intermittent. The most common approach to metabolic acidosis in neonates is to correct the acidosis by administering bicarbonate. Metabolic acidosis caused by EM presenting acutely in the neonatal period, almost without exception, will not respond to bicarbonate, except transiently. The effective treatment of acidosis in EM is correction of the cause of the acidosis, such as decreasing the endogenous overproduction of specific acids.

Several categories of EM may present with metabolic acidosis and an increased anion gap ( Table 3 ). A simplified flowchart for the evaluation of a newborn with metabolic acidosis and an increased anion gap is presented in Fig 2. The largest group associated with metabolic acidosis during the neonatal period is organic acidemias.[14] In addition, this situation occurs also with some amino acid disorders. Other disorders, such as defects in pyruvate metabolism or in the respiratory chain, may present with metabolic acidosis and an elevated lactate during the neonatal period, but these may not always have an increased anion gap.[15] However, these newborns will often not have specific diagnostic elevations of organic acids on urine organic acid analysis. A lactate/pyruvate ratio less than 25 suggests pyruvate dehydrogenase deficiency (PDH) or other disorders of pyruvate metabolism, whereas a ratio greater than 25 suggests a respiratory chain defect.[16,17,18,19,20] In addition, fatty acid oxidation disorders, such as medium-chain acyl-CoA dehydrogenase deficiency (MCADD), may present with metabolic acidosis and hypoglycemia.[21]

Simplified flowchart of the evaluation of a newborn with metabolic acidosis and an increased anion gap. HMG, 3-hydroxy-3-methylglutaryl-CoA lyase deficiency; IVA, isovaleric acidemia; LCHADD, long chain 3-chydroxyacyl-CoA dehydrogenase deficiency; MSD, Maple syrup disease; MCADD, medium chain acyl-CoA dehydrogenase deficiency; MMA, methylmalonic acidemia; MADD, multiple acyl-CoA dehydrogenased deficiency (GAII, glutaric acidemia, type II); PEPCK, phosphoenolpyruvate carbosykinase deficiency; PPA, propionic acidemia; PCD, pyruvate carboxylase deficiency; VLCADD, very long chain acyl-CoA dehydrogenase deficiency. Adapted with permission from Ward JC. Inborn errors of metabolism of acute onset in infancy. Pediatr Rev 11:205-216, 1990.

The organic acidemias, such as methylmalonic acidemia (MMA), propionic acidemia (PPA), and isovaleric acidemia (IVA), form the most common category to be considered in the evaluation of metabolic acidosis.[22,23,24,25] All three disorders are the result of defects in branched chain amino acid metabolism, affecting the catabolism of isoleucine (ILE), leucine (LEU), and valine (VAL). All disorders are autosomal recessive. These three disorders are almost clinically indistinguishable from one another when they present in the neonatal period. The clinical finding is a healthy newborn at birth who becomes rapidly ill after the first day of life. Clinical signs include ketoacidosis, poor feeding, vomiting, dehydration, hypotonia, lethargy, tachypnea/hyperpea, seizures, coma, and an unusual odor ( Table 4 ). The main laboratory diagnostic tool is urinary organic acid analysis. The urine organic acid analysis will reveal the specific elevated urinary organic acids.[26] In addition, ketonuria will be present. When associated with metabolic acidosis, particularly in the neonatal period, ketonuria is almost always pathognomic of an error of metabolism. The plasma lactate is often elevated in organic acidemias as a result of secondary interference with coenzyme A (CoA) metabolism. Notably, neutropenia and thrombocytopenia are common and mimic neonatal sepsis. Hyperammonemia is common, but is not usually as impressive in organic acid disorders as in urea cycle defects. There will be an increased acylcarnitine-to-free carnitine ratio, which is accompanied by abnormal patterns of blood acylcarnitines.[27,28]

The management of a newborn with a presumed diagnosis of an organic acidemia is to first stabilize the newborn. Within 24 to 48 hours, the results of quantitative amino acid and organic acid analysis should be available. If the laboratory cannot provide results in this time frame, alternative arrangements with another laboratory should be pursued. Treatment at this time is directed toward the removal of the accumulating metabolites, such as ammonia or organic acid intermediates, with hemodialysis.[29] If a center is unable to provide hemodialysis to a newborn, transfer should be strongly considered. Exchange transfusions, peritoneal dialysis, or hemofiltration are less efficient than hemodialysis in managing these disorders.[30] Insulin can be used to augment the anabolic state.[31] Carnitine is used to remove toxic metabolites during the acute phase.[32,33,34] During an acute illness, intravenous carnitine is preferred either as a continuous drip or in six divided daily doses over oral administration. After the newborn has been stabilized, oral feedings should be reinitiated. A wide range of specialty formulas are available that restrict certain amino acids.[35] The assistance of a dietitian with experience in managing EM and the metabolic specialist is vital. Efforts to reduce the endogenous production of toxic metabolites may include antibiotic suppression of gut flora that produce metabolites that enter the newborn's bloodstream, such as the long-term use of metronidazole in the treatment of methylmalonic and propionic acidemias.[36] In addition, specific vitamins, such as hydroxocobalamin, may be provided as cofactors for certain enzyme deficiencies. Several abnormalities in the reduction of cobalamin result in impaired methylmalonly-CoA mutase (MMM) activity in MMA. Some newborns with decreased MMM activity will respond to pharmacologic doses of hydroxocobalamin with enhancement of enzyme activity and increased tolerance of ILE, methionine (MET), threonine (THR), and VAL.[37,38] The success in the acute management of the organic acidemias has led to improved survival and outcome. The long-term prognosis varies widely for different disorders and within disorders due to the genetic heterogeneity.

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