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Metabolic Diseases

• Introduction
• Patterns Of Presentation Of Metabolic Disease In The Neonate
• Metabolic acidosis
• Hypoglycaemia
• Cardiac disease
• Liver dysfunction
• Dysmorphism
• Fetal hydrops
• Approach To The Diagnosis Of Metabolic Disease
• Initial Management Of Suspected Metabolic Disease

Introduction

Whilst individually rare, as a group, metabolic diseases are a significant cause of illness in the neonate. Prior to delivery, a fetus is usually "protected" from any ill-effects of a metabolic disease by virtue of the function of the placenta in providing fuel and filtering toxic metabolites. Many metabolic diseases are thus unmasked in the first days of post-natal life. Their onset may initally be subtle, and the possibility of a metabolic disease must be considered in any infant with non-specific symptoms that are not explicable by another cause.

Patterns Of Presentation Of Metabolic Disease In The Neonate

The diverse nature of metabolic disease in the newborn is reflected in the modes by which metabolic abnormalities may present. These can be summarised as follows

Neurological presentation

• Symptom-free interval, then lethargy, poor feeding, followed by altered conscious state / seizures, culminating in coma. Typical of
  • organic acidoses (including maple syrup urine disease)
  • urea cycle disorders
• Severe neurological abnormality, without symptom-free interval
  • When characterized by encephalopathy, seizures and apnoea typical of
    • primary lactic acidoses
    • non-ketotic hyperglycinaemia
    • sulphite oxidase deficiency
    • pyridoxine dependency
      
  • If associated with profound hypotonia, dysmorphism and/or congenital anomalies
    • peroxisomal disorders
    • mitochondrial disease

Metabolic acidosis

Organic acidoses and primary lactic acidoses cause metabolic acidosis with increased anion gap. Whilst initially asymptomatic, as these diseases progress, neurological and circulatory abnormalities inevitably ensue.

Given that plasma lactate is now frequently measured in sick neonates, it is important to have a logical approach to high lactate levels. It is firstly necessary to consider whether the sample is adequate - capillary or venous lactate levels may be very high in the face of normal arterial lactate.

If arterial lactate is persistently high (> 3 mmol/L), the differential diagnosis is as follows

• Severe organ dysfunction leading to decrease tissue perfusion/oxygen delivery, or increased metabolic demand
  • perinatal asphyxia
  • congenital heart disease (duct-dependent lesions)
  • sepsis
  • untreated seizures
    
• Primary lactic acidoses
  • disorders of pyruvate metabolism
  • mitochondrial disorders
    
• Secondary lactic acidoses - other metabolic diseases may be associated with lactic acidosis, for example
  • fatty acid oxidation defects
  • organic acidoses
  • urea cycle defects
  • sulphite oxidase deficiency

  

Hypoglycaemia

Low blood glucose in a neonate most usually indicates either

• glycogen depletion +/- inadequate gluconeongenesis eg premature or SGA infant
• hyperinsulinism eg infant of a diabetic mother, Beckwith syndrome
• occasionally hypoglycaemia will be a manifestation of a metabolic disease eg fatty acid oxidation defect, glycogen storage disease

Cardiac disease

Cardiac failure and cardiomyopathy can occur in association with mitochondrial, lysosomal or fatty acid oxidation disorders.

Liver dysfunction

Persistent hyperbilirubinaemia (conjugated / unconjugated) may be indicative of a metabolic disease, in particular galactosaemia, but also hypothyroidism, tyrosinaemia, a1-antitrypsin deficiency, and others.

Dysmorphism

Metabolic diseases associated with dysmorphic features include

• peroxisomal disorders (Zellweger syndrome and others)
• disturbances of energy metabolism (eg pyruvate dehydrogenase deficiency)
• defects in cholesterol biosynthesis (eg Smith-Lemli-Opitz syndrome)
• storage disorders

Fetal hydrops

A number of metabolic diseases, all individually rare, can cause fetal hydrops.

Approach To The Diagnosis Of Metabolic Disease

History and clinical information

Perinatal information that should be sought includes

• a history of previous pregnancy losses
• consanguinity
• any problems during the pregnancy

Detailed clinical examination should be performed, focussing in particular on the cardiorespiratory and neurological status of the infant, supplemented by imaging and metabolic testing as appropriate.

"Screening tests" for metabolic disease

• odour of baby and urine (but most babies with malodorous urine do not have metabolic disease)
• blood glucose
• serum ammonia
• acid-base status
• anion gap ([Na⁺ + K⁺] - [Cl^- + HCO3^-], normal < 12 mmol)
• lactate - arterial sample
• liver function tests
• urinary reducing substances (Clinitest). Remember that glucose is a reducing substance, so if the Clinitest is positive, check the urine specifically for glucose using a glucose oxidase strip
• urinary ketones
• urine metabolic screen. A sample of 5-10 mL of freshly-collected urine is needed for this test; the sample can be frozen prior to analysis if necessary. As much clinical information as possible should be included on the request card to assist in the interpretation of the results

In only a few cases will the results of the above "screening" tests pinpoint the exact metabolic defect. They will, however, identify infants with a high likelihood of having a metabolic disease, in whom further tests would be performed as appropriate. The details of these tests is beyond the scope of this work, see reference 2 for details.

Initial Management Of Suspected Metabolic Disease

If a metabolic disease is suspected, it is highly recommended that the case be discussed with a physician conversant with the management of metabolic disease in the neonate. Where the index of suspicion is high, or the infant is significantly unwell, transfer to a tertiary centre should be arranged, with interim treatment measures commenced as outlined below.

General measures

Infants with metabolic disease frequently require vigorous supportive measures to stabilise their physiological state. Examples of commonly encountered problems, and the appropriate responses are

• profound encephalopathy or apnoea - mechanical ventilation
• circulatory failure - intravascular volume expansion, inotrope therapy
• seizures- anticonvulsant therapy

Specific therapy

In addition to general supportive measures, in some cases specific treatment should be instituted as soon as a metabolic disease is recognised. Examples of the reponse in specific situations are

• any case where metabolic disease appears likely - cease oral feeds and administer 10% dextrose / electrolytes (milk is the source of toxic metabolites in many metabolic diseases). Give dextrose at an infusion rate of at least 5 mg/kg/min (=3 mL/kg/hr of 10% dextrose). Many metabolic diseases are aggravated by tissue catabolism; a higher rate of dextrose infusion may be required beyond 24 hours
• hyperammonaemia - sodium benzoate (250 mg/kg loading dose over 1-2 hrs, infusion of 250 mg/kg/24 hrs). This is an interim measure to clear waste nitrogen; resolution of hyper-ammonaemic coma usually requires haemodialysis
• hypoglycaemia - dextrose infusion to maintain euglycaemia (may need to use a dextrose concentration > 10%, ideally through an umblicial venous catheter)
• metabolic acidosis - correct pH using sodium bicarbonate. The formula for "half-correction" of a metabolic acidosis is
  • amount of HCO₃^- to infuse (in mEq) = (base deficit x weight) / 4
  • repeated NaHCO₃ corrections may be required, in which case beware of hypernatraemia
• suspected organic acidosis/fatty acid oxidation defect - give carnitine 100 mg/kg/day in 4 divided doses until the results of metabolic tests are at hand

For details of further acute management, and the ongoing care of infants with metabolic disease, the interested reader is referred to reference 2.

References

Chakrapani A, Cleary MA, Wraith JE. Detection of inborn errors of metabolism in the newborn. Arch Dis Child 2001; 84: F205-10.

Hoffman GF, Nyhan WL, Zschocke J, Kahler SG, Mayatepek E. Inherited metabolic diseases. Philadelphia: Lippincott Williams & Wilkins, 2002

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