Chapter 114. Acute Metabolic Dysfunction

Inborn errors of metabolism are genetic diseases caused by mutations in metabolic enzymes, nutrient transporters, and related genes. Because metabolism is the foundation of basic processes such as energy homeostasis, fuel storage, and growth, it is not surprising that many inborn errors of metabolism present with severe, multisystem failure culminating in shock, cardiorespiratory collapse, and coma. Therefore, inborn error of metabolism is a crucial category of diseases in pediatric emergency medicine and critical care. Their pathophysiology involves a combination of disturbances emanating from the dysfunctional metabolic pathway, including failure to produce energy and required metabolites, accumulation of toxic intermediates, and complex effects on global metabolism due to sequestration of cofactors.

Inborn errors of metabolism are by definition chronic diseases, which may present with acute, life-threatening metabolic dysfunction1 (Table 114-1). Many of these “decompensating” metabolic conditions can be stabilized with rather straightforward interventions if the clinician recognizes the presence of an inborn error of metabolism and takes appropriate action. The difficulty and danger in decompensated inborn errors of metabolism is that their relatively low incidence and nonspecific symptoms at presentation may not trigger suspicion of a metabolic disorder. However, a few simple analytical considerations will prompt the astute clinician to recognize an inborn error of metabolism in an acutely ill child. First, such children often have clues within their clinical presentations that can be elicited by asking questions like the ones in Table 114-2. If these questions suggest the possibility of an inborn error of metabolism, the clinician should ensure that several metabolic screening laboratory studies (Table 114-3) are performed to add supporting clinical information and to guide presumptive management and specialized diagnostic testing.

Regardless of a patient’s clinical history, inborn error of metabolism should be considered in all newborn babies with serious unexplained illnesses, because many of the diseases discussed in this chapter can cause a severe sepsislike syndrome in the neonatal period. Recent improvements in expanded newborn screening programs have made it possible to diagnose many inborn errors of metabolism within the first week of life, thereby reducing the uncertainty when acute metabolic dysfunction occurs or preventing it altogether.2 Accordingly, it is vital that the treating physician retrieve the results of the sick child’s newborn screen when the underlying diagnosis is not known.

In this chapter, we focus on straightforward treatment paradigms aimed at recognizing and reversing metabolic emergencies caused by the disorders listed in Table 114-1. Further discussion of the presentations of inborn errors of metabolism at various ages, and with different symptom complexes, as well as initial management is found in Chapter 134. Specific disorders are discussed in detail in the remainder of Section 11. In general, the goals of managing children with acute metabolic dysfunction are to

1. 1. Stabilize cardiorespiratory function.

   2. Determine the category of metabolic dysfunction (fatty acid oxidation, urea cycle, etc).

   3. Eliminate the offending agent.

   4. Promote anabolic metabolism.

   5. Remove toxins (eg ammonia, organic acids).

   6. Arrange specialized diagnostic testing.

One further consideration is that many children with inborn errors of metabolism do not survive their first episode of metabolic decompensation. Because these are genetic diseases, accurate counseling about recurrence risk is of the utmost importance for the family and depends on establishing a definitive diagnosis in the affected child. This may require procuring fresh tissues for enzymatic analysis after death.3 In critically ill children who do not respond to initial efforts to reverse metabolic dysfunction, it is recommended that a pathologist be consulted to plan for the possibility of rapid tissue harvest immediately after death.

Disorders of Fatty Acid Oxidation, Ketogenesis, and Ketone Body Utilization

A large number of diseases (discussed in detail in Chapter 150) result in impaired fatty acid oxidation.4 All of these disorders are inherited as autosomal recessive traits. Except for the most severe cases, children are well at baseline but cannot tolerate periods of fasting or increased metabolic demand (eg, fever, infection) when fatty acid oxidation would normally be required. The impairment of fatty acid oxidation results in hypoketotic hypoglycemia, acute liver dysfunction, rhabdomyolysis, and cardiac failure. Hypoglycemia paired with inadequate ketogenesis impairs bioenergetics in the central nervous system, leading to lethargy that can progress rapidly to coma. Since lipolysis and fatty acid transport are not impaired, fatty acids accumulate in hepatocytes, where they may exert toxic effects in addition to impairing energy generation. Hyperammonemia and lactic acidosis may occur due to secondary effects on liver metabolism. The most common of the fatty acid oxidation disorders, medium-chain acyl-CoA dehydrogenase (MCAD, see Chapter 150) deficiency, has an incidence of approximately 1:10,000 and presents with severe hypoglycemic episodes characterized by nausea, lethargy, and potentially sudden death.4,5

There are also several diseases that impair production of ketone bodies from the acetyl-CoA produced during fatty acid oxidation (see Chapter 151) or that impair the utilization of ketone bodies by extrahepatic tissues (the ketone utilization disorders; see Chapter 152). Clinically, the disorders of ketogenesis are similar to fatty acid oxidation defects, with acute episodes of fasting-induced hypoglycemia and inappropriately low ketones in the blood and urine. The ketone utilization defects present with episodes of vomiting and profound ketoacidosis, typically with normoglycemia.

The most important goal in acute management of these diseases is to reverse the catabolic state as quickly as possible. This is done most effectively by stimulating insulin release with a high glucose infusion rate (6–8 mg/kg per minute). Insulin and dextrose suppress lipolysis in the adipose tissue and suppress fatty acid oxidation in the liver and elsewhere. These actions curtail the supply of free fatty acids to the liver and reduce the accumulation of partially oxidized intermediates in the β-oxidation pathway. A 10% dextrose-based solution at 1.5 to 2 times the estimated maintenance rate should be used initially. If central access can be obtained, a higher dextrose concentration can be used to limit the volume of the infusion. Insulin infusions are helpful to augment endogenous insulin secretion in severely ill children. These interventions also benefit acutely ill children who are normoglycemic, because the increase in circulating free fatty acids may produce symptoms of hepatotoxicity prior to the decrease in blood glucose. For patients with these disorders requiring parenteral nutrition, intralipid mixtures must be avoided.

During management of a metabolic decompensation, markers of metabolic function (blood glucose, ammonia, liver function tests, CPK) should be followed closely. Some acutely ill children will become hyperglycemic after initiation of the dextrose infusion. In these children, it is advisable to start an insulin infusion rather than to reduce the glucose infusion rate. Cardiac function should also be monitored closely given that defects in long-chain fatty acid oxidation are associated with cardiomyopathy and cardiac failure. In this regard, obtaining plasma carnitine levels may aid in therapy, because cardiac function improves in children with carnitine transporter defects who receive carnitine supplements. However, the benefit of carnitine therapy in other fatty acid oxidation disorders is debatable, and there is concern that it may be deleterious in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency.6

When a disorder of fatty acid oxidation or ketone metabolism is suspected but has not been confirmed, the plasma acylcarnitine profile provides a diagnostic pattern in many of these disorders. Urine organic acid analysis also provides helpful information. Measuring the amino acids in plasma or urine is not helpful.

Urea Cycle Defects

In children with urea cycle disorders (see Chapter 145)7, nitrogen imbalance occurs during periods of inappropriately high protein intake or during periods of illness, when inadequate caloric intake stimulates muscle proteolysis and nitrogen overload. The events surrounding birth are particularly dangerous, because they create metabolic challenges, including the onset of fasting intervals between feeding and separation from the maternal circulation, which had been clearing excess ammonia from the fetal circulation. Thus, the classic presentation of a severe urea cycle defect is a term neonate who experiences unexpected, progressive lethargy within the first few days after birth. Importantly, milder presentations have been reported in all the urea cycle disorders. Thus, hyperammonemia must be excluded in older children presenting with acute neurological symptoms or neurological decline of unclear etiology. Late-onset urea cycle disorders have even presented in teenagers with psychosis or recurrent headache and vomiting. The most common disorder, ornithine transcarbamylase (OTC) deficiency, is an X-linked trait with an apparent incidence of approximately 1:40,000. All other urea cycle disorders are inherited in an autosomal recessive pattern.

Hyperammonemia is a medical emergency, because the likelihood of permanent central nervous system damage increases the longer the hyperammonemia persists. The pathophysiology of hyperammonia-associated neurotoxicity is not completely understood. Neurological symptoms during episodes of hyperammonemia include coma, seizures, cerebral edema, and overstimulation of the brain-stem respiratory center. The tests in Table 114-3 often allow the physician to differentiate between the different categories of inborn errors of metabolism that present with hyperammonemia. This is a critically important issue, as the optimal management of hyperammonemia differs according to the category of inborn error of metabolism. In the urea cycle disorders, symptoms are typically confined to the brain, so abnormalities in blood glucose, CPK, or liver function tests suggest other disorders. Analysis of the blood-gas profile is helpful, because urea cycle disorders classically present with a respiratory alkalosis due to hyperammonemia-stimulated tachypnea, while a metabolic acidosis usually indicates another disease, particularly one of the branched-chain organic acidemias (although exceptions do occur and a metabolic acidosis does not definitively exclude the possibility of a urea cycle defect).

Acute management of hyperammonemia in decompensated urea cycle disorders is focused on stabilizing cardiorespiratory function, restoring nitrogen balance, and removing excess ammonia as rapidly as possible. Because of the high potential for rapid neurological dysfunction and injury in these patients, any hyperammonemic child suspected of having a urea cycle disorder should immediately have intravenous access established, with centrally placed catheters if possible. Endotracheal intubation is recommended if there is neurological involvement, especially when transport to another facility is necessary.8 Any exposure to amino acids or protein in the diet or intravenous fluids must be discontinued immediately. Anabolism can be stimulated by using a high glucose infusion rate (6–8 mg/kg per minute), with or without insulin. This helps incorporate amino acids into cellular protein, limiting the nitrogen load presented to the urea cycle. If fatty acid oxidation disorders have been ruled out, intravenous lipid infusions can be used as an additional source of calories to further suppress catabolism.

Disease specific management approaches to the various urea cycle disorders are provided in Chapter 145.

Branched-Chain Organic Acidemias

The branched-chain organic acidemias (or acidurias; see Chapter 137) are disorders of oxidation of leucine, isoleucine, or valine that result in the accumulation of nonamino organic acids in the blood and urine.10 They are inherited as autosomal recessive traits and together comprise a large category of inborn errors of metabolism, with the most common diseases being methylmalonic acidemia, propionic acidemia, isovaleric acidemia, and 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency. Their presentation and severity vary, but they share many similarities in the decompensated state and in their management. In general, these conditions present with a dramatic decompensating phenotype of emesis, dehydration, and encephalopathy, often with evidence of multiorgan system involvement including hepatic dysfunction, pancreatitis, acute renal insufficiency and bone marrow suppression. Unusual odors may also be present in decompensated children (“sweaty feet” in isovaleric acidemia and “cat’s urine” in 3-methylcrotonyl-coenzyme A carboxylase (3MCC) deficiency). Branched-chain organic acidemias are complicated by complex effects on intermediary metabolism that result in ketoacidosis, lactic acidosis, hyperammonemia, hypoglycemia, and hyperglycinemia. The first episode of metabolic decompensation may occur within the first week after birth, particularly for propionic acidemia, methylmalonic acidemia, and isovaleric acidemia. Recurrent episodes are prompted by fasting, infection, or increased intake of branched-chain amino acids.

Maple syrup urine disease is also a defect in branched-chain amino acid oxidation but differs from the others in that the amino acids accumulate in addition to organic acids. Children with decompensated maple syrup urine disease present with prominent neurological symptoms, including cerebral edema, seizures, ataxia, and obtundation; involvement of other organ systems is less common. Severe metabolic acidosis is also less common than in other branched-chain organic acidemias.

If a branched-chain organic acidemia is suspected in an acutely ill child, protein-containing foods should be discontinued immediately. Testing the urine for ketones is a rapid and reliable indicator of metabolic decompensation. Older children who can tolerate feeds can be given sugary, protein-free drinks initially, but if emesis occurs, intravenous access must be established in order to administer dextrose. A solution of 10% dextrose or higher should be used to obtain a glucose infusion rate of 6 to 8 mg/kg per minute. If necessary, an insulin infusion can be used concurrently to maintain a normal blood sugar. A modified amino acid formulation lacking the branched-chain amino acids has been developed for use in maple syrup urine disease and can be given to acutely ill children who cannot tolerate enteral feeds. Severe metabolic acidosis may be treated with intravenous sodium bicarbonate. Some children, particularly those with severe metabolic acidosis or hyperammonemia, may require hemodialysis to achieve rapid toxin removal. Specific therapies include carnitine, which may become depleted due to conjugation with organic acids, and enteral glycine in children with isovaleric acidemia.

In some children with branched-chain organic acidemias, activity of the dysfunctional enzyme can be improved with large doses of vitamin cofactors (see Chapter 137). A trial of the relevant cofactor should be considered in children presenting with an initial episode of decompensation. More importantly, like the branched-chain organic acidemias, the multiple carboxylase deficiencies (biotinidase deficiency and holocarboxylase synthetase deficiency) present with neurological dysfunction, metabolic acidosis, and accumulation of lactate and intermediates of amino acid oxidation.11,12 Biotin therapy is highly effective in biotinidase deficiency and in many cases of holocarboxylase synthetase deficiency. Thus, these two disorders should be ruled out in children with organic acidemias in whom the specific diagnosis is unclear.

Most of the branched-chain organic acidemias are diagnosed by newborn screening programs that perform acylcarnitine profiling by tandem mass spectrometry. In children in whom a diagnosis has not been firmly established, the clinician should obtain urine organic acids and a quantitative plasma acylcarnitine profile. Plasma amino acids should also be measured if maple syrup urine disease is suspected.

Primary Lactic Acidosis Syndromes

The primary lactic acidosis syndromes (also known as congenital lactic acidosis syndromes) are a large category of inborn errors of metabolism caused by impaired oxidation of pyruvate leading to excessive accumulation of lactic acid and metabolic acidosis.13 They are discussed here because they are a major cause of severe metabolic dysfunction in newborn babies and older children. However, unlike the diseases previously covered, there are generally no specific therapies for these conditions, and care is largely supportive.14 For the purposes of this chapter, primary lactic acidosis syndromes include pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, deficiencies of enzymes of the tricarboxylic acid cycle, and mitochondrial defects (see Chapter 159). Patients with primary lactic acidosis syndromes generally have prominent neurological abnormalities, which predominate in pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, and most defects of the tricarboxylic acid cycle. Mitochondrial disorders are notoriously pleiotropic, but central nervous system involvement is common.15 The complex phenotypes of these patients reflect the combined effects of acidosis, compromised cellular bioenergetics, enhanced reactive oxygen species generation, and interference with other aspects of intermediary metabolism.

Severe lactic acidosis in newborns is usually due to ischemia (sepsis, cardiac dysfunction), anemia or hypoxemia. When those causes have been ruled out and tissue perfusion is adequate, the persistence of plasma lactate greater than 2 mmol/L should raise suspicion of a primary lactic acidosis syndrome. While acute illnesses can exacerbate lactic acidosis in primary lactic acidosis syndromes, these diseases generally do not follow a pattern of episodic acute decompensations with interim periods of metabolic stability. Rather, the children tend to have developmental delay, failure to thrive, and chronic elevations of lactate, sometimes requiring bicarbonate therapy. During periods of illness, the emphasis should be on supportive cardiorespiratory management and hydration, because impaired tissue perfusion will increase lactate production. Base deficits, if severe, should be carefully replaced. One important consideration in these diseases is that lactate is largely derived from glucose metabolism. Therefore, unless the child is hypoglycemic, dextrose should be administered carefully with a goal glucose infusion rate of only 3 to 4 mg/kg per minute. The physician must be able to distinguish a likely primary lactic acidosis syndrome from other inborn errors of metabolism in which elevated lactate is a secondary feature (eg, fatty acid oxidation disorders), where high glucose infusion rates are needed in acutely ill patients. In children with primary lactic acidosis syndromes who require dextrose infusions, the lactate levels should be monitored to guard against exacerbating the acidosis.

Other metabolic abnormalities observed in primary lactic acidosis syndromes include hyperammonemia in pyruvate carboxylase deficiency and prominent ketosis in pyruvate carboxylase deficiency and mitochondrial defects. Renal tubular dysfunction also occurs in pyruvate carboxylase deficiency and mitochondrial defects and can result in bicarbonate wasting that further complicates the acidosis.

There are very few treatment options for these disorders, both for acute and chronic management. In pyruvate dehydrogenase deficiency, high-fat, low-carbohydrate (“ketogenic”) diets have led to biochemical and perhaps clinical improvements in some children.16,17 In addition, a small fraction of children presenting with mitochondrial defects have a deficiency in coenzyme Q biosynthesis and respond to pharmacological doses of this cofactor.18 Therefore, a trial of coenzyme Q seems justified in children with primary lactic acidosis syndromes of unknown etiology. Establishing a specific diagnosis in children with primary lactic acidosis syndromes is difficult and usually involves a combination of biochemical, enzymatic, and molecular testing. However, a simple test that may provide useful information is to measure plasma lactate and pyruvate concurrently. An elevated lactate with a normal lactate-to-pyruvate ratio (10–20) is usually due to pyruvate dehydrogenase deficiency.