METABOLIC EMERGENCIES

DEBRA L. WEINER, MD, PhD

GOALS OF EMERGENCY THERAPY

Recognition and understanding of inborn errors of metabolism (IEMs) in the acutely ill child in the emergency department (ED) is critical for appropriate, and possibly lifesaving, management. Individually, metabolic diseases are rare, but collectively are common with over 5,000 identified. In the United States, the incidence is approximately 1 in every 1,000 to 1,500 newborns. Goals of emergency care are to recognize the possibility of IEM in the differential diagnosis of acutely ill, previously undiagnosed patients, and to identify, treat, and prevent acute metabolic derangements in patients with suspected or known IEMs, including the asymptomatic neonate with a positive newborn screening (NBS).

KEY POINTS

UNKNOWN SUSPECTED IEM

Goals of Treatment

Recognizing the possibility of an IEM is critical for optimal management of the child with unknown IEM. Immediate goals of treatment are to stabilize cardiopulmonary function, correct metabolic derangements, and avoid intake and/or endogenous production of potentially toxic substances. Early consultation with an IEM specialist, including prior to transport of a child being transported from an outside facility, is advised to guide treatment and collection of appropriate specimens for diagnosis.

CLINICAL PEARLS AND PITFALLS

• Recognition and treatment of a potential IEM does not require knowledge of specific IEMs but rather an understanding of the pathophysiology of categories of IEMs.

• Diseases involving the same metabolic pathways or organelle usually share similar features.

• Most IEMs with potential for acute decompensation present in neonates or infants, but may present in older children and adolescents.

• History, physical examination, and routine laboratory studies provide clues to when and which IEM should be considered. Most important in making the diagnosis of metabolic disease is a high index of suspicion.

• Any organ system can be affected depending on the IEM, manifestations are usually multiorgan. Physical examination is often normal.

• Acidosis, hypoglycemia, and/or hyperammonemia are laboratory hallmarks of IEM. Laboratory studies may be normalized by treatment, including intravenous fluids. Pretreatment samples should be sent for testing when possible.

• Prompt emergency treatment of physiologic decompensation, per PALS and APLS guidelines, metabolic derangements, as well of precipitant causes of decompensation and derangements is critical for optimizing outcome.

Current Understanding

IEMs are usually caused by single gene defects that result in abnormalities in protein, carbohydrate, fat, or complex molecule metabolism. Most are due to a defect in, or deficiency of, an enzyme, enzyme cofactor, or transport protein that results in a block in a metabolic pathway. Clinical effects are the consequence of toxic accumulations of substrates before the block or intermediates from alternative metabolic pathways and/or defects in energy production and utilization due to deficiency of products beyond the block. In the ED, evaluation and management of patients with undiagnosed suspected IEM is usually guided by the potential metabolic category of disease, and does not require a specific diagnosis. Categories of IEMs and their findings are detailed in Table 103.1. Patients with an organic acidemia, urea cycle defect, disorder of carbohydrate utilization or production, fatty acid oxidation defect, mitochondrial disorder, or peroxisomal disorder are at greatest risk of acute, life-threatening decompensation. Patients with congenital adrenal hyperplasia, detailed in Chapter 97 Endocrine Emergencies, may also present with acute critical decompensation.

TABLE 103.1

COMMON PRESENTATIONS OF INBORN ERRORS OF METABOLISM^a

Toxic accumulation of substances results from disorders of protein metabolism (i.e., aminoacidopathies, organic acidemias, urea cycle defects), carbohydrate intolerance, and lysosomal storage. Defects in energy production or utilization result from disorders of glycogenolysis and gluconeogenesis, fatty acid oxidation defects, and mitochondrial disorders. Peroxisomal disorders are a diverse group of IEMs caused by defects of single or multiple peroxisomal enzymes, or of peroxisomal biogenesis that result in toxic accumulations, energy deficiency, and/or defects in biosynthesis of complex molecules. Other categories include disorders of metal metabolism, purine, and pyrimidine biosynthesis (e.g., Lesch–Nyhan syndrome); cholesterol biosynthesis, heme, bile acid, and bilirubin metabolism, lipoprotein metabolism, and glycosylation.

Clinical Considerations

Triage

IEM should be considered in any neonate or infant who is critically ill without known etiology.

Assessment

History. Poor feeding, frequent vomiting, failure to thrive, lethargy in the morning before feeding or with delayed feeding, and onset of symptoms with change in diet and/or unusual dietary preferences, particularly protein or carbohydrate aversion, are concerning for possible IEMs. Symptoms may be episodic in an otherwise apparently normal child. Physiologic stressors such as fasting, illness, trauma, or surgery may precipitate symptoms, especially if the stressor induces a catabolic state. Intercurrent infection may result in decompensation out of proportion to the illness. A history of multiple hospitalizations for lethargy and dehydration with improvement following IV fluids and glucose is common. Psychomotor developmental delay, especially with loss of milestones, is also concerning for an IEM.

Certain findings suggest particular categories of IEMs. Vomiting occurs with many IEMs but is a prominent feature of organic acidemias and urea cycle defects. Diarrhea is also a common feature of many IEMs, particularly disorders of carbohydrate intolerance and mitochondrial disorders. Lethargy progressing to coma is common with organic acidemias, urea cycle defects, fatty acid oxidation defects, and certain disorders of carbohydrate intolerance. IEM should also be considered in any child with unexpected, unexplained sudden death, even without other history suggestive of IEM. Most IEMs are autosomal recessive in their inheritance, but they may be X-linked, mitochondrial, or uncommonly autosomal dominant. A history of suggestive findings; death due to neurologic, cardiac, and/or hepatic dysfunction; sepsis; or unexplained neonatal or sudden infant deaths in siblings or maternal male relatives are also concerning. Maternal illness during pregnancy, particularly acute fatty liver of pregnancy or HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, may be due to maternal heterozygosity for a fatty acid oxidation defect, specifically 3-hydroxyacyl-CoA dehydrogenase deficiency. A negative family history does not rule out an IEM because most carriers have no clinical manifestations of disease. A negative NBS also does not exclude the possibility of an IEM. False-negative results occur, most commonly due to screening too soon after birth (especially within the first 24 hours), prematurity, neonatal illness, medications, transfusions, inadequate samples, and inappropriate sample handling. Results are often not available in the first several days of life, and in some states, parents have the option of not having their child tested.

Neonate. Most of the IEMs that are acutely life-threatening present during the neonatal period, usually as acute encephalopathy and/or hepatic disease. Among the most common life-threatening IEMs to present in the neonate are aminoacidopathies, organic acidemias, urea cycle defects, galactosemia, and hereditary fructose intolerance. Manifestations may include poor feeding, vomiting, diarrhea, dehydration, temperature instability, tachypnea or apnea, cyanosis, respiratory failure, bradycardia, poor perfusion, hiccups, jaundice, hepatomegaly, pseudoobstruction, irritability, lethargy, coma, seizures, involuntary movements (e.g., tremors, myoclonic jerks, boxing, pedaling), posturing (e.g., opisthotonus), and abnormal tone (e.g., hypertonia or central hypotonia). These same symptoms are also manifestations of sepsis, congenital viral infections, respiratory illness, cardiac disease, gastrointestinal obstruction, hepatic dysfunction, renal disease, central nervous system (CNS) problems, and drug withdrawal. In term infants who develop symptoms of sepsis without known risk for sepsis, metabolic disease may be nearly as common as sepsis. Sepsis may be the earliest recognized clinical manifestation of an IEM. Escherichia coli sepsis in galactosemia is the classic example. Other IEMs with increased risk of sepsis are the organic acidemias and glycogen storage disorders.

One of the most important clues to an IEM in the neonate is a history of deterioration after an initial period of apparent good health ranging from hours to weeks. For neonates with IEMs of protein metabolism and carbohydrate intolerance disorders, onset of symptoms occurs after there has been significant accumulation of toxic metabolites following the initiation of feeding. Onset of symptoms is usually between 2 and 5 days of life. Initial symptoms often are poor feeding, vomiting, irritability, and lethargy. In the neonatal period, jaundice occurs most commonly with tyrosinemia, galactosemia, and hereditary fructose intolerance. Progression to coma, multisystem organ failure, and death is usually rapid. Neonates with tyrosinemia may present with intracranial or pulmonary hemorrhage due to coagulopathy. Patients with organic acidemias may have recurrent or chronic subdural hemorrhages, sometimes mistakenly attributed to child abuse. Fatty acid oxidation disorders, particularly very long-chain acyl-CoA dehydrogenase deficiency, may present during the neonatal period. Many of the peroxisomal disorders and some of the mitochondrial and lysosomal disorders also present in the neonatal period; these infants are less likely to have coma as an early manifestation and are more likely to have dysmorphic features, brain abnormalities, skeletal malformations, cardiopulmonary compromise, organomegaly, hepatic dysfunction, myopathy, and/or severe generalized hypotonia, usually evident at birth. Intractable seizures due to pyridoxine or folic acid responsive disorders usually begin within the first few days of life.

Infant and young child (1 month to 5 years). Infants or children with potentially acute life-threatening IEMs (most commonly partial deficiency of the urea cycle enzyme ornithine transcarbamylase, fatty acid oxidation defects, disorders of carbohydrate intolerance, and disorders of gluconeogenesis and glycogenolysis) typically present during infancy with recurrent episodes of vomiting and lethargy, ataxia, seizures, or coma. Amino and organic acidopathies also present during infancy, usually with progressive neurologic deterioration. Lysosomal storage disorders, mitochondrial disorders, and peroxisomal disorders also become apparent in infancy and early childhood, usually presenting with dysmorphism or coarse features, organomegaly, myopathy, and/or neurodegeneration. More subtle and/or progressive findings in infants and children with IEMs include failure to thrive, chronic dermatoses, dilated or hypertrophic cardiomyopathy, liver dysfunction, hepatomegaly, pancreatitis, musculoskeletal weakness, hypotonia and/or cramping, impairments of hearing and vision, and developmental delay, sometimes with loss of milestones. With routine illnesses, children with IEMs may be more symptomatic, develop symptoms more quickly, or take longer than unaffected children to recover. Children with disorders of protein metabolism may present with dietary changes. Fructose intolerance often manifests between 4 and 8 months of age when fruits are introduced. Disorders with decreased tolerance for fasting, particularly fatty acid oxidation defects and defects of gluconeogenesis and glycogenolysis, often manifest when children have poor intake due to illness or surgery and when infants begin to have longer overnight fasts, commonly between 7 and 12 months of age. The length of fasting that produces symptoms may be less than 3 hours for disorders of glyconeogenesis and glycogenolysis, and 12 to 24 hours for fatty acid oxidation defects. When patients with these disorders present with vomiting, the severity of illness, particularly lethargy, is usually out of proportion to the duration of illness and the amount of vomiting. Ketotic hypoglycemia, commonly seen in children of ages 1 to 5 years, has been shown in some cases to be caused by fatty acid oxidation defects and, less commonly, aminoacidopathies or organic acidemias. It is now recognized that Reye syndrome–like conditions are often attributable to an IEM (most often a fatty acid oxidation defect, particularly medium-chain acyl-CoA dehydrogenase deficiency, or a urea cycle defect, particularly ornithine transcarbamylase deficiency). Mortality for those with a previously undiagnosed fatty acid oxidation defect can be 40% with the first clinical decompensation. IEMs also explain sudden infant death syndrome (SIDS) in approximately 5% to 10% of cases, most commonly fatty acid oxidation defects that cause cardiac arrest due to arrhythmia and/or cardiomyopathy; the most common of these is medium-chain fatty acyl-coA dehydrogenase deficiency. Other fatty acid oxidation defects, organic acidemias, and congenital adrenal hyperplasia account for most of the remainder of SIDS cases attributable to genetic defects.

Older child, adolescent, or adult (older than 5 years). In the older child, adolescent, or even adult, undiagnosed metabolic disease should be considered in individuals with subtle neurologic or psychiatric abnormalities. Many will have had long-term manifestations believed to be due to other causes. Most typically, these individuals are diagnosed as having birth injury, behavioral problems, attention deficit hyperactivity disorder, psychiatric disorders, or atypical forms of medical diseases such as multiple sclerosis, migraines, epilepsy, or stroke. The more common findings include mild to profound developmental delay, autism, and learning disabilities. Manifestations may be intermittent, precipitated by the stress of illness or by dietary changes or fast, especially as teens take more control over their own diet, or may be progressive. Most IEMs diagnosed in this age group are not immediately life-threatening. However, even a patient with a late-onset, presumably milder, form of an IEM may die with a first metabolic crisis. An example is partial ornithine transcarbamylase deficiency, which can manifest at this time as a life-threatening encephalopathy. This is seen particularly in adolescent females with a history of protein aversion, migraine-like headaches, vomiting, abdominal pain, lethargy, and behavioral problems, particularly following protein ingestion. Fatty acid oxidation defects may also present at this time with sudden death or life-threatening cardiac arrhythmia, hypoketotic hypoglycemia, and/or rhabdomyolysis. Glycogen storage disorders that manifest as exercise intolerance, muscle weakness, cramping, and/or rhabdomyolysis often present in adolescents because of their greater participation in sports during these years. Some mitochondrial disorders present during adolescence or adulthood with loss of vision and/or hearing, cardiac dysfunction, myopathy, neurologic degeneration, and endocrine disturbances. Stroke or stroke-like episodes with or without encephalopathy may occur with aminoacidopathies, in particular homocystinuria, urea cycle defects, organic acidemias, disorders of carbohydrate metabolism, and mitochondrial disorders, most notably mitochondrial encephalomyopathy, lactic acidosis, stroke-like episodes (MELAS). Disorders in which psychiatric disturbances may be the initial presenting manifestation include homocystinuria; urea cycle defects, especially partial ornithine transcarbamylase deficiency; lysosomal storage disorders; peroxisomal disorders; and Wilson disease, a disorder of copper metabolism. Patients with phenylketonuria who are no longer on a low-protein diet may also manifest psychiatric symptoms.

Physical Examination. Clinical manifestations of IEMs vary from those of acute life-threatening decompensation to subacute progressive degenerative disease (Table 103.1). Nearly all IEMs have several variants that differ in age of clinical onset and severity. Clinical manifestations may even vary among family members. Life-threatening diseases tend to present clinically during the neonatal period or infancy, whereas those with intermittent decompensation or insidious onset and slow progression tend to become apparent later.

IEMs can affect any organ system, and often affect multiple organ systems, and therefore should be considered in patients who present with altered level of consciousness, encephalopathy, cardiac failure, hepatic failure, skeletal muscle myopathy, weakness and/or cramping, and/or neuropsychiatric disturbance. Physical examination may be normal, have subtle and/or nonspecific findings, or have findings that provide more specific diagnostic information (Table 103.2). Findings tend to be related to abnormal anatomic proportion (i.e., size and shape), rather than to major structural defects and usually become more pronounced over time. Patients tend to have characteristic facies, short stature, organomegaly, and/or musculoskeletal abnormalities. IEMs within each major category are listed in Table 103.3. Features of specific IEMs can be found in texts referenced at the end of this chapter and on various web sites, including the National Center for Biotechnology Information’s “Online Mendelian Inheritance in Man” web site (http://www.ncbi.nlm.nih.gov/omim).

Laboratory Findings. In the patient with potentially life-threatening symptoms, evaluation for possible IEM should be initiated immediately.

Initial laboratory findings in the acutely ill patient that may suggest an IEM include serum electrolytes, blood gas, and lactate that detect electrolyte imbalances, an increased anion gap, and/or acid–base status abnormalities; blood urea nitrogen (BUN) and creatinine levels that reveal impaired renal function; total and direct bilirubin, aspartate transaminase (AST) and alanine transaminase (ALT) transaminases, prothrombin time (PT), partial thromboplastin time (PTT), and/or ammonia that indicate hepatic dysfunction or failure; hypoglycemia, particularly with low or absent urine ketones, that suggests inability to appropriately metabolize fatty acids or carbohydrates; or urine-reducing substances that suggest carbohydrate intolerance (Table 103.4). A complete metabolic screen may also reveal abnormalities in uric acid, calcium, phosphate, and/or magnesium. In addition to these studies, patients with history or physical examination suggestive of myopathy should have lactate dehydrogenase, aldolase, creatinine phosphokinase, and urine myoglobin measured as part of their initial screen. Although not diagnostic, IEM can lead to abnormalities of any cell line on CBC.

If a metabolic disease is suspected, consultation with an IEM specialist may be helpful in guiding further laboratory evaluation and assisting with appropriate collection and processing of specimens. Blood should be collected and, based on results of initial studies, sent for plasma amino acids and acylcarnitine profile, which reflect fatty acid oxidation and organic acid, and, indirectly, amino acid metabolisms (Table 103.5). In neonates younger than or at 14 days of age, blood on NBS filter paper can be used for tandem mass spectrometry and should be considered not only if tandem mass spectrometry was not initially performed but also if the initial screen was negative. Urine should be collected for potential analysis of organic acids, acylglycine, and/or orotic acid. Additional blood and urine for possible further testing should be obtained and stored. Cerebrospinal fluid (CSF), if obtained, should be collected at the same time as plasma and immediately frozen and stored for possible further testing for neurometabolic disorders, most commonly nonketotic hyperglycinemia, disorders of serine biosynthesis, and/or neurotransmitter disorders. Measurement of lactate and pyruvate in the acute setting may be difficult to interpret, particularly in the patient with hypoxia, poor perfusion, seizure, and/or sepsis. Plasma-free fatty acids, ketones, endocrine studies, and disease-specific tests may also be appropriate. Laboratory abnormalities are often transient, particularly if fluids and/or glucose are administered; therefore, normal values do not rule out an IEM. It is critical to obtain pretreatment specimens, if possible. If pretreatment specimens were not obtained, as is often the case because many IEMs are first suspected based on results of routine laboratory studies, discarded pretreatment samples are likely to be more informative than those collected after therapy. Collection of samples during acute illness is usually preferred to provocative testing by metabolic challenge performed when the child is otherwise well because this method may not yield diagnostic specimens and may be dangerous.

TABLE 103.2

CLINICAL AND LABORATORY FINDINGS OF INBORN ERRORS OF METABOLISM

The confirmatory specific diagnosis of most IEMs requires additional specialized tests for detection of abnormal metabolites or abnormal concentrations of metabolites in plasma, urine, and/or CSF; histochemical light and/or electron microscopic evaluation of affected tissues; and chromosome, DNA, and/or enzyme analysis in red blood cells, leukocytes, skin fibroblasts, and/or tissues from affected organs.

In the child who has died, it is still extremely important to attempt to diagnose an IEM because of the possibility that asymptomatic family members are affected or future children are at risk. Routine autopsy is usually not informative for the definitive diagnosis of IEM but may rule out other causes of death and offer clues. IEMs can be diagnosed in the child who has just died, by collecting the appropriate specimens (Table 103.6). Most IEMs can be categorized based on findings of initial laboratory evaluations. Nearly all patients with IEMs that present as acute life-threatening disease will have hypoglycemia, metabolic acidosis, and/or hyperammonemia. These initial findings will guide immediate treatment and further evaluation. Important exceptions are nonketotic hyperglycinemia (usually presents within 48 hours of birth with lethargy, coma, seizures, hypotonia, spasticity, hiccups, and apnea) and pyridoxine deficiency and folinic acid–responsive disorders (which present with intractable seizures with or without encephalopathy as neonate).

TABLE 103.3

SPECIFIC INBORN ERRORS OF METABOLISM BY CATEGORY^a

TABLE 103.4

INITIAL LABORATORY STUDIES^a

Hypoglycemia.

Related posts:

Ataxia Cyanosis Pain: Earache Oligomenorrhea Tachycardia Pain: Chest

Stay updated, free articles. Join our Telegram channel

Join