Although the diversity and complexity of inborn errors of metabolism in infants and children may seem overwhelming, keep in mind that making a definitive diagnosis is not as important as maintaining a high suspicion and that acute stabilization and management are relatively simple. As a group, these disorders involve enzyme deficiencies that lead to errors of metabolism resulting in the accumulation of various toxic biochemical products, which can cause dysfunction of multiple organ systems, especially the CNS. Although each individual type of inborn error of metabolism is extremely rare, as a group they are relatively common, with an incidence ranging from 1 in 1400 to 1 in 200,000 live births.13,14
Clinical manifestations of inborn errors of metabolism are a result of the accumulation of toxic metabolites and their effects on end-organs. Common symptoms and signs of inherited metabolic disorders include acute encephalopathy with or without metabolic acidosis and hypoglycemia (discussed earlier in "Hypoglycemia"). Because most metabolic toxins cross the placenta and are cleared by maternal enzymes, most newborns are asymptomatic and present after varying delays once enteral feeding begins. Hypoglycemia may be the primary presentation of some inherited disorders of metabolism and is discussed earlier (see "Hypoglycemia"). Jaundice and hepatic dysfunction can be seen in a number of inherited disorders such as galactosemia.16 Shock and cardiovascular collapse can occur with congenital adrenal insufficiency, but nonmetabolic conditions such as congenital heart disease and sepsis must be considered in the differential diagnosis of infants presenting in extremis. The discussion here is limited to conditions that typically present in early infancy with the potential for life-threatening consequences.
Most inborn errors of metabolism result from single-gene defects with a variety of inheritance patterns. The defects result in abnormal metabolism of protein, fat, carbohydrates, or other complex molecules. Affected proteins include enzymes, enzyme cofactors, and transport proteins. The result of these varied deficiencies is the accumulation of toxic substrates upstream of the impaired protein or of intermediates derived from alternate metabolic processes downstream. On the basis of metabolic and clinical manifestations, these disorders can often be grouped into those defects resulting in hyperammonemia, metabolic acidosis, hypoglycemia, or hyperbilirubinemia and liver dysfunction.16
Urea cycle defects, organic acidemias, and some fatty acid oxidation defects may result in the accumulation of ammonia, leading to encephalopathy.17 Examples of organic acidemias that present in the first 24 hours of life are glutaric acidemia and pyruvate carboxylase deficiency (which causes lactic acidemia). Urea cycle defects typically present after the first 24 hours of life and often lack associated metabolic acidosis. Examples are ornithine transcarbamylase deficiency, carbamyl phosphate synthetase deficiency, and citrullinemia. Ornithine transcarbamylase deficiency is X-linked in its inheritance, and therefore affects male infants.
Although organic acidemias can also lead to hyperammonemia, they are typically accompanied by metabolic acidosis. Examples are methylmalonic acidemia, propionic acidemia, and isovaleric acidemia. Defects in pyruvate metabolism, defects in enzymes of the respiratory chain, and mitochondrial disorders also result in metabolic acidosis, which is often independent of protein intake. These disorders result in lactic acidosis with normal urine organic acid levels and include pyruvate dehydrogenase deficiency.
Disorders of carbohydrate, lipid, or fatty acid metabolism include glycogen storage diseases and medium-chain acyl coenzyme A dehydrogenase deficiency. These disorders impair the ability to use or produce glucose, which leads to hypoglycemia, often in the setting of fasting or poor oral intake. Glycogen and lipid storage diseases usually present later in infancy or childhood with developmental delay, dysmorphic or progressively coarse features, and hepatomegaly. Fatty acid metabolism defects result in nonketotic hypoglycemia (see "Hypoglycemia" above), which is a distinguishing characteristic. Secondary carnitine deficiency is often seen in medium-chain acyl coenzyme A dehydrogenase deficiency.
Hyperbilirubinemia and liver dysfunction may be the presenting feature of inborn errors of metabolism such as galactosemia, tyrosinemia, or α1-antitrypsin deficiency. Galactosemia results from the deficiency of galactose-1-phosphate uridylyltransferase, which leads to an accumulation of galactose-1-phosphate and other metabolites that are toxic to the liver. In addition to hepatic dysfunction, these infants may develop hypoglycemia, hyperbilirubinemia, hemolysis, or overwhelming infection.
Many inborn errors of metabolism present with nonspecific symptoms, including irritability, lethargy, vomiting, and poor feeding; severe hypoglycemia or metabolic encephalopathy may present with seizures. A careful characterization of these symptoms, however, may point toward a metabolic disorder: poor feeding and lethargy may be more notable in the morning prior to the first feeding as a result of a relative period of fasting. Parents may note aversion to protein or carbohydrates. Diarrhea may accompany carbohydrate metabolism disorders or mitochondrial disease. Parents may report an abnormal body or urinary odor, although this is more commonly noted by clinicians. Abnormal odor is typical of isovaleric acidemia, glutaric acidemia, and maple syrup urine disease, which, as the name suggests, is accompanied by a characteristic sweet smell of the urine.
Obtain a dietary and developmental history. Frequent changes in formula due to vomiting or failure to thrive may indicate undiagnosed metabolic disease. Unexplained developmental delay may also be a clue to diagnosis. Take a thorough medical history. A history of recurrent hospitalizations with a response to IV fluids and glucose may suggest an underlying metabolic disorder. The maternal history taking should include questions about previous spontaneous abortions or miscarriages and the death of previous infants early in life. Maternal complications during pregnancy, such as acute fatty liver or HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), may be related to heterozygosity for fatty acid oxidation defects. The family history should include information about relatives with early cardiac disease, sudden infant death syndrome, neurologic disease, and liver disease with onset in childhood, all of which may signal inherited disorders of metabolism.
The physical examination begins with attention to the vital signs. Tachycardia is often present during acute metabolic crisis; congenital adrenal hyperplasia may cause hypotension. Hypothermia may accompany many metabolic diseases, particularly the urea cycle defects and organic acidemias. Tachypnea without increased work of breathing may be noted in patients with metabolic acidosis and may result in a respiratory alkalosis. Although the majority of inborn errors of metabolism that present in early infancy are not associated with other specific findings on physical examination, those that present later in childhood, such as glycogen storage disease, liposomal storage disease, and mucopolysaccharidoses, may manifest with hepatosplenomegaly, growth retardation, poor muscle tone, developmental delay, and coarse features.18 Some metabolic disorders have ocular findings, including cataracts (e.g., galactosemia) or dislocated lenses (e.g., homocystinuria). The GU examination is important when adrenal insufficiency is a consideration, because females with one specific defect may show signs of virilization (see "Congenital Adrenal Hyperplasia [Adrenal Insufficiency]" below). A complete head-to-toe physical examination should be performed, of course, despite the lack of characteristic findings in most inborn errors of metabolism presenting during infancy, in order to exclude alternative diagnoses, including sepsis and congenital heart disease.
Due to the rarity and diversity of these disorders, the aspects of their acute clinical presentations and management in the ED have yet to be well defined. A simplified, although not exhaustive, approach to inborn errors of metabolism is presented in the following sections and in Figure 144–2. The key laboratory studies that are most useful to the emergency physician in directing immediate management and suggesting potential diagnoses include bedside glucose level, urine ketone level, plasma ammonia concentration, basic metabolic screen, blood gas analysis, and plasma lactate level. These are discussed in more detail in the following sections. Additional clues may be provided by a CBC, liver function tests, and muscle function tests (lactate dehydrogenase, creatine kinase, and myoglobin levels) (Table 144–2). Definitive diagnosis often depends on plasma or serum levels of amino acids, acylcarnitine profile, and lactate and pyruvate levels, as well as urine test results for organic acids, acylglycines, and orotic acid, and potentially on results of cerebrospinal fluid studies, including tests for lactate, pyruvate, and organic and amino acids.16,18,19 A summary of laboratory evaluations for suspected metabolic disease and their utility and significance is provided in Table 144–2.
Additional Laboratory Tests in the Diagnosis of Metabolic Disease
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Additional Laboratory Tests in the Diagnosis of Metabolic Disease
|Test ||Result ||Diagnostic Implications |
|Liver function tests || |
Fatty acid oxidation disorders, mitochondrial disorders, urea cycle disorders
|CBC ||Pancytopenia ||Aminoacidopathy (propionic acidemia, isovaleric acidemia, methylmalonic acidemia) |
|Creatine kinase ||Elevated ||Mitochondrial disorders |
|Aldolase ||Elevated ||Fatty acid oxidation defects |
|Serum amino acids ||Abnormal quantitative results ||Aminoacidopathy, organic aciduria, urea cycle defect, mitochondrial disorder |
|Serum acylcarnitine ||Abnormal profile ||Organic acidurias, fatty acid oxidation defects, mitochondrial disorders, carnitine deficiency |
|Profile || || |
|Urine-reducing substances ||Positive test result is always abnormal ||Aminoacidopathy (tyrosinemia), carbohydrate intolerance disorders (galactosemia) |
|Urine organic acids ||Abnormal profile ||Aminoacidopathy, organic aciduria, fatty acid oxidation defects, mitochondrial disorders, peroxisomal disorders |
|Urine orotic acid ||Elevated ||Urea cycle defects (ornithine transcarbamylase deficiency) |
|Urine acylglycines ||Abnormal ||Aminoacidopathies, organic acidurias |
Approach to suspected metabolic disorders. CO2 = carbon dioxide.
BEDSIDE GLUCOSE AND URINE KETONE LEVELS
Hypoglycemia may be a feature of several inborn errors of metabolism, including glycogen storage disease, fatty acid oxidation disorders, and disorders of gluconeogenesis. Some organic acidemias may also be associated with hypoglycemia. Hypoglycemia in the absence of urinary ketones suggests a fatty acid oxidation defect, and hypoglycemia with urinary ketones can be seen in organic acidemias.
PLASMA AMMONIA CONCENTRATION
Ammonia is formed during the deamination of amino acids and excreted as urea in the urine. Urea is produced in the hepatocyte mitochondria and cytosol through the metabolic process known as the urea cycle. Normal neonatal ammonia concentrations are <65 micromoles/L, but may be two to three times this in stressed or nonfasting newborns and infants. Levels >200 micromoles/L suggest metabolic disease and are the hallmark of urea cycle disorders. Hyperammonemia detected in the first 24 hours of life may be seen with pyruvate carboxylase deficiency, whereas hyperammonemia associated with urea cycle defects usually presents after protein feeding has begun and may reach ammonia concentrations well above 400 micromoles/L. The severe hyperammonemia of urea cycle disorders may stimulate central hyperventilation, resulting in respiratory alkalosis. Secondary causes of more modest hyperammonemia include mitochondrial, respiratory chain, or fatty acid oxidation defects, which are often associated with metabolic and/or lactic acidosis.
BLOOD GAS ANALYSIS AND BASIC METABOLIC PANEL
Evaluation of acid-base status is best achieved through analysis of blood gas samples and serum electrolyte levels. Serum lactate levels (discussed below in "Plasma Lactate Level") provide additional information. The anion gap (sodium – [chloride + bicarbonate]) is usually <15 mEq/L but increases with excess acid production. Organic acidemias are associated with significant anion gap acidosis, often higher than 30 to 50 mEq/L. Other inborn errors of metabolism associated with metabolic acidosis include respiratory chain disorders, disorders of pyruvate metabolism, and some glycogen storage diseases. In comparison with organic acidemias, these conditions typically include significant accumulation of lactic acid, which helps distinguish them from organic acidemia.15,16,18
Lactate is produced from pyruvate, and lactic acidosis is a common feature of severe illnesses ranging from sepsis to hypoxia from pulmonary or cardiac disease or hypovolemic shock. Dehydration often accompanies metabolic disease and may produce some degree of lactic acidosis in any critically ill neonate with a metabolic disorder; however, subtracting the plasma lactate from the anion gap can aid in distinguishing between primary lactic acidosis resulting from mitochondrial disorders, fatty acid oxidation defects, and some glycogen storage disease (normal anion gap after subtraction of lactate), and secondary metabolic causes such as organic acidemias (elevated anion gap after subtraction of lactate).16
Despite the diverse etiology and complexity of inborn errors of metabolism, ED resuscitation and stabilization are relatively simple. Neonates, infants, and children presenting in metabolic crisis, regardless of cause, show some combination of dehydration, metabolic acidosis, and encephalopathy, which must be immediately addressed. Therefore, the goals of treatment are to improve circulatory status by restoring circulatory volume, provide energy substrate to halt catabolism, remove the inciting metabolic substrate (formula or breast milk), and help eliminate toxic metabolites.20,21,22
As with any critically ill patient, attending to the ABCDs (airway, breathing, circulation, disability [neurologic status]) is the first step. Apnea, hypoventilation, and hypoxia are treated with positive-pressure ventilation or endotracheal intubation and administration of oxygen. Take care when paralyzing the infant in metabolic crisis, because metabolic acidosis can be worsened by respiratory acidosis if insufficient ventilation is provided. Restore circulation with crystalloid boluses, typically 10 to 20 mL/kg in the neonate and 20 mL/kg in the infant, with frequent reassessment and further fluid administration as clinically indicated. (Because congenital heart disease can present similarly to metabolic crisis, careful reevaluation after each fluid bolus is essential.) Even a patient who is not in shock may benefit from a bolus of normal saline followed by double the usual level of maintenance fluids with dextrose, because aggressive hydration promotes urine output with increased clearing of toxic metabolites (e.g., organic acids, ammonia), whereas dextrose provides a substrate for metabolism. Avoid hypotonic fluids because they may increase the risk of cerebral edema, particularly in hyperammonemic states. Assess neurologic status before definitive airway management. The cause of altered mental status (hypoglycemia or hyperammonemia) must be determined and may be reversible but is difficult to assess in the paralyzed or sedated patient (see below).
Metabolic acidosis during metabolic crisis can arise from dehydration, which may respond to fluid administration, or from the underlying metabolic defect. The ongoing production of acidic metabolites may necessitate the administration of sodium bicarbonate; however, treatment may be associated with side effects, including sodium overload, cerebral edema, and cardiac dysfunction. A conservative approach is to treat a blood pH of <7.0 with 0.5 mEq/kg/h.13,20
All patients in metabolic crisis should be kept NPO to remove potential inciting metabolic substrates (protein, carbohydrates, fats), and adequate dextrose should be provided for anabolic substrate. Dextrose 10% is usually preferred and should be administered at twice the usual maintenance rates.
ELIMINATE TOXIC METABOLITES
Elimination of toxic metabolites is the next step. Hyperammonemia, as seen in urea cycle defects and some organic acidemias, is the most common cause of metabolic encephalopathy in infants. Ammonia levels of <500 micromoles/L should be treated with a combination of sodium phenylacetate and sodium benzoate (Ammonul®): 250 milligrams/kg in 10% dextrose is administered through a central venous line (or intraosseous line) over 90 minutes followed by 250 milligrams/kg/d as a continuous infusion. Arginine, 210 milligrams/kg IV/IO in 10% dextrose over 90 minutes followed by 210 milligrams/kg/d continuous infusion, should also be provided (Figure 144–3). Empiric therapy with arginine with or without sodium benzoate can reduce ammonia levels drastically. Early aggressive treatment may eliminate the need for hemodialysis for excessive ammonia removal. Additional therapy may include empiric carnitine, 400 milligrams IV/IO, which combines with organic acids to form acylcarnitines that are readily excreted from urine (Figure 144–4), although no prospective trials have been performed.23 Reduction in acyl coenzyme A levels eliminates their inhibitory effect on the urea cycle, resulting in reduced serum ammonia levels.17,21
Combined role of carnitine and arginine in metabolic crisis in inborn errors of metabolism. Acetyl CoA = acetyl coenzyme A; AL = argininosuccinate lyase; ASS = argininosuccinate synthase; CPS = carbamoyl phosphate synthetase; NAGS = N-acetylglutamate synthase; OTC = ornithine transcarbamylase.
Role of carnitine in metabolic crisis in inborn errors of metabolism. Acyl CoA = acyl coenzyme A.
For hyperammonemia of >400 to 600 micromoles/L, consider dialysis. For infants with seizures, empiric administration of pyridoxine, 100 milligrams IV/IO, for pyridoxine-dependent metabolic disease can be tried. If this is ineffective, folinic acid, 2.5 milligrams IV/IO, or biotin, 10 milligrams by nasogastric tube, can be considered.13 A summary of second-tier therapies for specific suspected inborn errors of metabolism is provided in Table 144–3.
Specific Therapies for Inborn Errors of Metabolism
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Specific Therapies for Inborn Errors of Metabolism
|Inborn Error of Metabolism ||Drug ||Dosage |
|Urea cycle defects || |
Arginine HCl 10%
Sodium benzoate and/or phenylacetate
210 milligrams/kg IV/IO over 90 min
250 milligrams/kg IV/IO continuous infusion over 24 h
|Organic acidemias ||Carnitine ||400 milligrams IV/IO or PO |
|Fatty acid oxidation defects ||Biotin ||10 milligrams IV/IO or PO |
|Pyridoxine-dependent seizures ||Pyridoxine ||100 milligrams IV/IO |
|Maple syrup urine disease, primary lactic acidosis ||Thiamine ||25–100 milligrams IV/IO |
During metabolic crisis, the accumulation of various organic acids can suppress granulopoietic stem cells and thereby cause bone marrow suppression of all cell lines. This leads to an immunocompromised state with an increased incidence of sepsis due to unusual organisms. The incidence is 15% to 30% per 100 episodes. Therefore it is essential to rule out sepsis in all patients with metabolic crisis. Chronic anemia and thrombocytopenia may accompany a number of inborn errors of metabolism and may be exaggerated during metabolic crisis. Give empiric broad-spectrum antibiotics such as ceftazidime, 50 milligrams/kg IV.
Hyperammonemia is a specific risk factor for cerebral edema, especially when hypotonic solutions are administered during therapy. Cerebral edema is a clinical diagnosis and should be suspected when laboratory parameters improve but altered mental status continues. Treatment for cerebral edema is mannitol (0.5 gram/kg IV/IO) and avoidance of hypo-/hyperventilation. Do not give steroids because steroids exacerbate hyperammonemia.
DISPOSITION AND FOLLOW-UP
All patients in metabolic crisis should be admitted to the hospital or transferred to a tertiary care children's hospital where metabolic specialists are available to help with definitive diagnosis and dietary management. Patients with severe metabolic abnormalities requiring hemodialysis require intensive care.