Metabolic Diseases in Acidotic Newborns

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DESCRIPTION

  • High anion gap metabolic acidosis is a common acute presentation of an inborn error of metabolism (IEM). Acidosis can also be seen as a result of hypoperfusion, congenital heart disease, sepsis, liver failure, toxic ingestion, and diabetic ketoacidosis (DKA).
  • In general, IEMs are defects of protein, fat, or carbohydrate metabolism or of the mitochondrial respiratory chain that result in either toxic accumulations and/or deficiencies of substrates necessary for energy production.
  • IEMs should be considered early in a child with metabolic acidosis in order to provide appropriate treatment prior to the development of neurologic and other sequelae of these disorders.
ALERT

Infants with IEMs are at increased risk for decompensation and acute presentation in cases of infection, fever, fasting, or other causes of catabolism.

ETIOLOGY

Multifactorial. Primary metabolic disease is typically due to a genetic defect that causes a block in metabolism resulting in buildup of toxic intermediates or absence/reduction of necessary downstream products.

RISK FACTORS

Genetics

  • The majority of IEMs are autosomal recessive.
  • X-linked IEMs include pyruvate dehydrogenase deficiency, ornithine transcarbamylase (X-linked), glycerol kinase deficiency, and phosphorylase kinase deficiency.
  • Primary mitochondrial disorders can be either maternally inherited (if defect is in the mitochondrial genome) or X-linked, autosomal dominant, or autosomal recessive (if defect is in nuclear genome).

GENERAL PREVENTION

  • Avoid propofol if possible (anecdotal increase in pancreatitis).
  • Avoid prolonged fasting or nutritional deprivation.
  • Avoid use of systemic steroids whenever possible (steroids may increase the metabolic demands).

PATHOPHYSIOLOGY

  • Metabolic acidosis (pH <7.30, Pco 2 <30 mm Hg, HCO3 <15 mEq/L) is the biochemical imbalance that results from:
    • Excessive production of hydrogen ions, such as in many IEMs due to accumulation of one or more of the following:
      • Organic acids
      • Lactate
      • Ketones
    • Inadequate excretion of hydrogen ions, such as in renal tubular acidosis (also with genetic etiologies)
    • Increased loss of bicarbonate, such as in congenital diarrheal syndromes (also with genetic etiologies)
  • Metabolic acidosis is often a downstream effect of the primary metabolic abnormality. A block in normal metabolism can result in dysfunction of the mitochondrial respiratory chain, buildup of toxic intermediates, disordered or reduced energy production, buildup of waste nitrogen in the form of ammonia and specific amino acids, and through conjugation of the acids with carnitine, lead to carnitine depletion.
  • These events can lead to multiorgan dysfunction including the following:
    • Central nervous system (CNS) toxicity: edema, neurologic effects of hypoglycemia, toxic encephalopathy
    • Cardiac: arrhythmias, left ventricular noncompaction, cardiomyopathy
    • Liver: hepatosplenomegaly, elevation of liver function tests, prolonged hyperbilirubinemia
    • Hematologic: bone marrow suppression
    • Renal: proximal tubule dysfunction, kidney failure (typically later onset)

COMMONLY ASSOCIATED CONDITIONS

  • Maternal hypertension, elevated liver enzymes, low platelets (HELLP), fatty liver of pregnancy, preeclampsia: associated with specific fetal disorders of fatty acid oxidation
  • Metabolic stroke: stroke affecting the basal ganglia (not ischemic or hemorrhagic in character)

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