Metabolic emergencies

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10.1 Metabolic emergencies

Drago Bratkovic, Peter Francis

Essentials

1 Inborn errors of metabolism are individually rare but as a group are not uncommon.

2 The possibility of an inborn error of metabolism needs to be considered in any child with unexplained hypoglycaemia, acidosis, altered conscious state, neurological presentation or vomiting.

3 Prompt recognition is important to allow appropriate therapy and to avoid further decompensation.

4 Precise identification of the defect in the ED is not generally important as long as appropriate initial therapy is commenced and this usually consists of dextrose.

Introduction

Inborn errors of metabolism are a diverse group of disorders that result from a defect or absence of an enzyme or transport system. The presenting symptoms and signs are equally diverse; however, there are a number of common features that can alert the clinician to their presence. This chapter will concentrate on those metabolic conditions that present acutely to the emergency department (ED), but will also touch on those with more chronic presentations which could easily go unrecognised.

The majority of patients presenting with acute metabolic conditions to the emergency department will have already been diagnosed, particularly given the advent of extended newborn screening (see end of chapter). However, not all conditions can be screened for and some can be missed by screening, thus children and, indeed, adults can still present acutely with an undiagnosed metabolic condition.

Physiology and pathogenesis

The process by which living matter is built up (anabolism) or broken down (catabolism) is termed metabolism. Strictly speaking, an inborn error of metabolism (IEM) is an inherited defect in a metabolic pathway or enzyme. Generally, there is a defect in an enzyme that catalyses the conversion of one organic compound to another. However, not all defects in metabolic pathways give rise to pathology. Figure 10.1.1 shows that compound A is converted to B. If the enzyme that catalyses the reaction is not present or is functioning poorly, this can affect the body in any one of the following ways.

There is accumulation of A, which is toxic – example: phenylketonuria.

There is a deficiency of B, which results in cellular dysfunction – example: Smith–Lemli–Opitz syndrome, a disorder of cholesterol biosynthesis.

Excess A is converted to C via an alternate pathway which is toxic – example: tyrosinaemia type 1.

Excess A results in accumulation of metabolite E earlier in the pathway, which is toxic – example: maple syrup urine disease.

Excess A is excreted by reacting/conjugating with D, which results in deficiency of D – example: carnitine deficiency in fatty acid oxidation defects.

Fig. 10.1.1 Pathogenic mechanisms in IEM; refer to text for a full explanation.

The pathology seen in an IEM can result from any of the processes outlined in Figure 10.1.1, but in fact most IEM are the result of more than one mechanism. Genetic defects can also occur in the support processes of metabolic pathways such as transport proteins, enzyme chaperones and enzyme complex assembly proteins, which result in the block of a metabolic process and thus pathology.

Clinical features

The clinical features and presentations of IEM are many and varied due to the diverse nature of the enzymes and processes affected; however, Table 10.1.1 shows that there are a number of common features that should alert the clinician to the possibility of an IEM.

IEM group Common presenting features Glycogen storage disorders,e.g. GSD III, IV, VI, VII and IX Hypoglycaemia, rhabdomyolysis, cardiomyopathy, hepatomegaly Aminoacidopathies and organic acidaemia, e.g. maple syrup urine disease (MSUD) Vomiting, acidosis, encephalopathy Urea cycle defects, e.g. ornithine transcarbamylase deficiency (OTC) Vomiting, encephalopathy, hyperammonaemia, respiratory alkalosis Disorders of gluconeogenesis, e.g. glycogen storage disease type I Lactic acidosis and hypoglycaemia Fatty acid oxidation defects,e.g. medium chain acyl-CoA dehydrogenase deficiency (MCAD) Hypoketotic hypoglycaemia, encephalopathy and rhabdomyolysis Mitochondrial respiratory chain defects, e.g. Leigh disease, MELAS Lactic acidosis, seizures, stroke-like events Disorders of ketone production and utilisation, e.g. ketolytic defect Severe ketoacidosis, hypoglycaemia

Table 10.1.2 can be used as a guide to identifying an IEM in the ED:

Table 10.1.2 Guide to identifying an IEM in the ED
Clinical features	Biochemical features
Overwhelming illness in the neonatal period Recurrent vomiting Coma or encephalopathy Apnoea and/or seizures Failure to thrive or malnutrition Presence of an unusual odour Not responding to usual treatment Unusual odour FH of neonatal or infant death, SIDS or acute life threatening event (ALTE)	Acute acidosis (with raised anion gap) Hypoglycaemia Lactic acidosis (normal perfusion) Ketoacidosis Acute hepatic dysfunction Coagulopathy

An IEM should be considered if there is both a clinical and a biochemical feature from each of the lists; however, considering an IEM should never take the place of the work up and treatment for more common causes of the above presentations, the most important being sepsis.

IEM are broken down into a number of groups of conditions, all of which affect a common metabolic pathway. The groups of IEM that are likely to present to the ED are outlined in Table 10.1.1, including the common presenting features of each.

Investigation

The metabolic markers of many IEM are present only at the time of presentation and may disappear with treatment. Thus, the timing of investigations is extremely important; if done incorrectly they could result in an incorrect or no diagnosis, with risky provocation testing, such as fasting or loading studies being the only option.

The following investigations are a good starting point when considering an IEM. They are all standard laboratory investigations with rapid turn-around times and are thus likely to be available to the physician in the emergency department.

Blood acid–base, ammonia, urea, creatinine, electrolytes, liver function tests, laboratory glucose, lactate and calculated anion gap ([Na + K] – [C1 + HCO₃]). Urine ketone dipstick (will only detect acetoacetate).

In all cases of hypoglycaemia the following additional investigations are recommended and need to be collected before the hypoglycaemia is treated. Most tertiary paediatric emergency departments will have a hypoglycaemia investigation kit for use in this situation.


Blood	insulin, cortisol, growth hormone, adrenocorticotropic hormone (ACTH), free fatty acids (FFA), ketones (beta-hydroxy-butyrate and acetoacetate), acylcarnitine profile (collect a newborn screening card; NBS or Guthrie card).
Urine	organic and amino acids.

Once the results of the initial investigations are available, a possible diagnosis and further investigations may be suggested, depending on the profile (Table 10.1.3 and Figure 10.1.2). However, if this not helpful, all of the following second line investigations should be performed:

Table 10.1.3 Biochemical profiles of the different IEM

Fig. 10.1.2 Clinical approach to the child with a suspected metabolic disorder.


Blood	plasma amino acids, plasma ketones, acylcarnitine profile, creatine kinase, urate.
Urine	organic and amino acids.

Many of these investigations can take days for a result, and it is suggested that all suspected metabolic cases be discussed with a metabolic physician, so a treatment plan can be developed to keep the child stable while awaiting further results. The single most useful investigation in the suspected IEM work up is the urine organic and amino acids, which in some centres is referred to as the ‘metabolic urine screen’. This can be performed even on a small non-sterile urine sample; however, for technical reasons most laboratories will not perform the test if there is faecal contamination.

Management

The management of a child suspected of having an acute presentation of an IEM has three primary goals:

Correction of altered homeostasis.

Reduction of toxic compound production.

Removal or enhancement of excretion of toxic compounds.

Correction of altered homeostasis

Hypoglycaemia and metabolic acidosis are the two most common biochemical abnormalities seen in IEM.

Hypoglycaemia should always be corrected immediately with an initial infusion of 5 mL kg⁻¹ of 10% dextrose. This should be followed with an infusion of 10% dextrose at maintenance rates, equating to 5–6 mg kg⁻¹ min⁻¹ of glucose, and will be enough to meet basal endogenous glucose needs, however, to suppress catabolism higher rates of up to 10 mg kg⁻¹ min⁻¹ of glucose may be required. The requirement of infusion rates of dextrose higher than this suggests hyperinsulinism.

Persistent metabolic or lactic acidosis can be problematic; however, the management strategies outlined later in this section will help reduce acidosis as the patient recovers; occasionally sodium bicarbonate may be required; however, the effect of the associated sodium load needs to be considered and may make other clinical problems such a cerebral oedema worse.

Reduction of toxic compound production

This is generally achieved through dietary means and varies with the metabolic condition. A feature common to all dietary interventions in the acutely unwell patient with an IEM is the provision of increased calories. Many of the IEM are in catabolic pathways, and thus measures that help suppress catabolism, such as increased caloric intake, help reduce the production of toxic compounds.

The source of calories will vary depending on the condition (carbohydrate vs. fat vs. protein); however, in the acute emergency setting, extra calories from glucose are considered safe and preferable in the majority of IEM. However, protein-containing calories, which include all regular infant formulas, should be avoided in the undiagnosed IEM patient, given that most children presenting acutely with IEM are in pathways of amino acid degradation. Fat sources such as MCT oil or intralipid are a dense source of calories; however, they should only be used when a fatty acid oxidation disorder has been excluded.

Thus in the suspected IEM, dextrose at a high rate of between 5 and 10 mg kg⁻¹ min⁻¹ is the safest and best option while awaiting results and discussion with a metabolic clinician.

Removal/enhancement of excretion of toxic compounds

There are a number of pathways through which toxic metabolites are removed from the body in IEM. Renal excretion, usually conjugated to carnitine is a common pathway, but in some conditions there is no excretory pathway and the only treatment option is haemofiltration or dialysis. This is particularly the case in organic acidaemias such a maple syrup urine disease in order to remove the neurotoxic amino acid, leucine, and in the urea cycle disorders to help remove ammonia.

In the acute presentation of IEM, prompt institution of appropriate management is essential to achieve a good outcome for the patient; previously diagnosed patients should have a care plan for acute presentations, and in some centres pre-made supplements and formulas available for use. Thus, patients with a known IEM should always be seen promptly (ATS 2) and those with a suspected IEM should be discussed with a metabolic physician when the suspicion is first raised.

Chronic presentations

There are a number of IEM that do not present with acute symptoms, but in a progressive degenerative manner, frequently multisystemic. The early symptoms and signs in these conditions can be common presentations or incidental findings in the ED (Table 10.1.4). Appreciation of their significance can allow for early diagnosis and in a growing number of conditions an improved outcome for the patient, through innovative new therapies such as enzyme replacement therapy (ERT) and, in the future, gene and stem cell therapy.

Sign Disorder(s) Test Recurrent abdominal hernia, especially umbilical MPS, oligosaccharidoses Urine MPS screen
Oligosaccharides Spinal deformity in infant or toddler MPS, oligosaccharidoses Urine MPS screen
Oligosaccharides Recurrent otitis media MPS, oligosaccharidoses Urine MPS screen
Oligosaccharides Persistent nasal discharge MPS, oligosaccharidoses Urine MPS screen
Oligosaccharides Recurrent pain attacks, particularly with fevers Fabry disease Lysosomal enzymes Recurrent or bilateral avascular necrosis of the femoral head Gaucher disease Lysosomal enzymes Hepatospelenomegaly Any lysosomal storage disorder including MPS Lysosomal enzymes
Urine MPS screen Interstitial lung disease Niemann-Pick disease Lysosomal enzymes

MPS = mucopolysaccharidoses.