Metabolic medicine


Chapter 29

Metabolic medicine



Elisabeth Jameson


Learning objectives




Acid–base disturbance


Definitions


The key terms are outlined in Table 29.1.




Biochemistry


Acid–base balance is essential for correct cellular functioning. Blood gas measurement can identify the primary disturbance (Table 29.2). In general:




In the case of metabolic acidosis, calculation of the anion gap will determine if there is the presence of an unmeasured anion such as an organic acid, e.g. methylmalonic or propionic acid (Table 29.3 and Fig. 29.1). Acidosis with a normal anion gap is often associated with hyperchloraemia because the loss of base is buffered by an increase and/or retention of chloride.





Clinical


Metabolic acidosis is a common finding. In the majority of cases, it reflects severe illness rather than an inborn error of metabolism (IEM). The latter should be considered if the acidosis is out of keeping with the clinical picture, is persistent despite standard management and there is no identifiable acid present, e.g. lactate or ketones.



Presentation


Metabolic acidosis is typically non-specific in presentation. Signs may include a reduced conscious level, vomiting or those associated with the underlying aetiology, e.g. non-blanching rash in the case of meningococcal sepsis. Many patients will display an increased respiratory rate, Kussmaul respiration, reflecting the compensatory hyperventilation that occurs to promote removal of carbon dioxide.



Diagnosis


The blood gas is key to identifying the primary disturbance in acid–base balance. In addition to calculating the anion gap, ketones and lactate should be measured as potential causes of acidosis. When investigating for an IEM, urine organic acids and plasma amino acids and acylcarnitines are required. It is important to measure an ammonia level as this can be elevated in an organic acidaemia due to the metabolites inhibiting the urea cycle.



Management


The underlying aetiology, when known, should be treated. If acidosis is severe, normalization of acid–base balance can be achieved with administration of sodium bicarbonate.



Lactic acidosis


Normal plasma lactate is <2 mmol/L. A raised level has a wide differential (Table 29.4). In terms of IEM, mitochondrial disorders are classically associated with a raised lactate, with levels often fluctuating. When considering the possibility of mitochondrial disease, measuring cerebral spinal fluid for a raised level can be helpful. However, a normal lactate does not exclude a mitochondrial disorder.




Answer 29.1


C. Organic acid disorder.


There is a marked anion gap. The anion gap = (136 + 3.6) − (110 + 10) = 31.6 mmol/L.


In this patient, the gas normalizes with intravenous 10% dextrose and two half corrections of sodium bicarbonate. Further investigations: urine organic acid analysis reveals methylmalonic acidaemia (MMA).


Group B streptococcal septicaemia is possible, but is more likely to present with shock and a much more abnormal blood count, including low or high white blood cell count and thrombocytopenia. The low CRP in spite of being ill for 24 hours is also against this diagnosis. Hypoxic–ischaemic encephalopathy would present before 6 days. Surfactant protein B deficiency would present with increasing respiratory distress from birth. A urea cycle defect is possible, but the ammonia level is normal for a neonate.



The urea cycle and hyperammonaemia


Biochemistry


Ammonia

Ammonia is a highly neurotoxic chemical detoxified by the urea cycle (Fig. 29.2), which principally occurs in the liver. Ammonia is formed from:




Clinical


Hyperammonaemia (normal plasma ammonia levels are <100 µmol/L in neonates and <50 µmol/L thereafter) has a wide differential (Table 29.5). Urgent measurement of ammonia should therefore take place in any baby, child or adult presenting with unexplained encephalopathy or illness. The urea cycle disorders (UCD) arise due to deficiency of one of the six main urea cycle enzymes.



Presentation


The classic presentation is the term baby who becomes increasingly sleepy and encephalopathic on day 3–5 of life with poor feeding and vomiting (see Question 29.2). Ammonia levels can rise rapidly. Urgent investigation is required to clarify the diagnosis and guide management.


The urea cycle disorders are inherited in an autosomal recessive manner, except for ornithine trans­carbamylase (OTC) deficiency, which is X-linked (see Genetics of metabolic disorders, below). Male infants are severely affected and many do not survive the neonatal period. Female carriers have a varied phenotype; the majority remain asymptomatic but approximately 15% will require treatment.


Diagnosis


Diagnosis of urea cycle disorders (Table 29.6) is based upon plasma amino acid analysis and the presence or absence of urine orotic acid, which is produced when carbamoyl phosphate passes into the pyrimidine pathway. The absence of orotic acid in a urea cycle disorder implies N-acetylglutamate synthetase (NAGS) or carbamoyl phosphate synthetase (CPS) deficiency. Orotic acid is classically very elevated in OTC because of the accumulation of intracellular carbamoyl phosphate. The remaining defects are associated with a much smaller or negligible amount of orotic aciduria.



Management


This can be thought of in terms of acute and long term.


Acute:



Chronic:




Jun 15, 2016 | Posted by in PEDIATRICS | Comments Off on Metabolic medicine

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