Metabolic medicine

Learning objectives

By the end of this chapter the reader should:

Understand the biochemistry of metabolism, including urea cycle, Krebs cycle and fatty acid cycle
Understand the pathophysiology of metabolic disorders, e.g. electrolyte and acid–base disturbance, hyperammonaemia and hypoglycaemia
Know the genetic and environmental factors in the aetiology of metabolic disorders
Be aware of the metabolic disorders identified on neonatal screening
Understand the investigations that are used to diagnose metabolic disorders
Understand the principles of dietary and pharmacological treatment of metabolic diseases

Introduction

Intermediary metabolism is the term given to the biochemical reactions that degrade, synthesize or interconvert molecules within the cells. There are numerous metabolic pathways, which serve the following aims:

Generation of energy
Catabolism of organic molecules
Synthesis of cellular building blocks
Excretion of harmful substances.

These pathways require enzymes, which, if absent or deficient, can give rise to an inborn error of metabolism (IEM). This chapter describes the key metabolic pathways and links them with their associated diseases.

Acid–base disturbance

Definitions

The key terms are outlined in Table 29.1 .

Table 29.1

Acid–base definitions

Terminology	Definition
Acid	A proton or hydrogen ion donor. It can dissociate to yield H ⁺ and the corresponding base.
Anion gap (see Fig. 29.1 )	[Na ⁺ + K ⁺ ] − [Cl ⁻ + HCO ₃ ⁻ ]. Normal = 10 − 16 mmol/L. Reflects concentration of those anions not routinely measured, e.g. organic acids (see Question 29.1 ).
Base	A proton or hydrogen ion acceptor. Can accept H ⁺ to form corresponding undissociated acid.
Base excess	Measures the change in the concentration of a buffer base from the normal value. Normal range = +/− 2 mmol/L.
Buffer	Consists of a weak acid in the presence of its base. A buffer serves to minimize changes in H ⁺ concentration in response to the addition of an acid or base. Examples of buffers in: Plasma – bicarbonate, proteins, inorganic phosphate (Pi) Erythrocytes – haemoglobin, bicarbonate, Pi Kidneys – bicarbonate, Pi, ammonium
pH	The logarithm to the base 10 of the reciprocal of the hydrogen ion concentration. pH = −log [H ⁺ ]
pKa	The pH of a buffer at which half the acid molecules are undissociated and half are associated.

Biochemistry

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

Metabolic disturbances are compensated acutely by changes in ventilation and chronically by renal responses
Respiratory disturbances are compensated by renal responses.

Table 29.2

Acid–base disturbance

Abnormality	Primary disturbance	Effect on		Base excess	Compensatory response
		pH	pCO ₂
Respiratory acidosis	↑ pCO ₂	↓	↑	Negative	↑ [HCO ₃ ⁻ ]
Metabolic acidosis	↓ [HCO ₃ ⁻ ]	↓	N or ↓	Negative	↓ pCO ₂
Respiratory alkalosis	↓ pCO ₂	↑	N or ↓	Positive	↓ [HCO ₃ ⁻ ]
Metabolic alkalosis	↑ [HCO ₃ ⁻ ]	↑	N or ↑	Positive	↑ pCO ₂

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.

Table 29.3

Metabolic acidosis and anion gap

With normal anion gap	With raised anion gap
Intestinal loss of base, e.g. diarrhoea, fistulae Renal loss of base, e.g. renal tubular acidosis (RTA) types 1 and 2, pyelonephritis Carbonic anhydrase inhibitors	Diabetic ketoacidosis Renal failure Poisoning with: salicylate, methanol, propylene glycol, iron, isoniazid, ethylene glycol Inborn errors of metabolism, e.g. organic acidaemia, lactic acidosis

Fig. 29.1, Representation of the anion gap, an estimate of the osmolar difference between measured cations and anions.

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.

Question 29.1

A 6-day-old baby with tachypnoea

A 6-day-old 3 kg term baby boy, born after a normal pregnancy and delivery, presents with reduced feeding and tachypnoea (respiratory rate 80/minute) over the last 24 hours. On examination, he is encephalopathic.

Investigations:

Blood:

Full blood count	mild pancytopenia
Sodium	136 mmol/L
Potassium	3.6 mmol/L
Chloride	110 mmol/L
Lactate	8 mmol/L (1–2.8)
Ammonia	60 µmol/L (normal <100)
C-reactive protein	6 mg/L

Blood gas:

pH 7.29

pCO ₂ 2.0 kPa (15 mmHg)

pO ₂ 13 kPa (98 mmHg)

Bicarbonate 10 mmol/L

Base excess −18 mmol/L

Which of the following is the most likely diagnosis? Select ONE answer only.

A.
Group B streptococcal septicaemia
B.
Hypoxic–ischaemic encephalopathy
C.
Organic acid disorder
D.
Surfactant protein B deficiency
E.
Urea cycle defect

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.

Key points – organic acid disorders

Methylmalonic and propionic acidaemia are the most common organic acidaemias
Can cause pancytopenia because of effects on the bone marrow at times of decompensation
pH can be maintained with hyperventilation
A lactate of 8 mmol/L would not by itself generate such a large anion gap
To calculate a half correction (using this case as an example):

\begin{matrix} \frac{Base deficit \times weight (kg) \times 0.3}{2} \\ = \frac{18 \times 3 \times 0.3}{2} \\ = 8.1 {mmol NaHCO}_{3}^{-} \end{matrix}

$\begin{matrix} \frac{Base deficit \times weight (kg) \times 0.3}{2} \\ = \frac{18 \times 3 \times 0.3}{2} \\ = 8.1 {mmol NaHCO}_{3}^{-} \end{matrix}$

Table 29.4

Causes of a raised lactate

Metabolic	Non-metabolic
Respiratory chain disorder Pyruvate dehydrogenase deficiency Pyruvate carboxylase deficiency Disorders of gluconeogenesis Glycogen storage disorders Organic acidaemia Fatty acid oxidation disorder	Hypoxic–ischaemic encephalopathy Severe illness Cardiac disease Sampling artefact

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:

Nitrogen produced from amino acid metabolism
Glutamate by the action of glutamate dehydrogenase
Glutamine by the action of glutaminase.
Alanine and glutamine produced by muscle turnover
Urease-positive gut bacteria
Ingested protein not utilized in biochemical processes

The urea cycle

The urea cycle (see Fig. 29.2 ) consists of six enzymes, with each full cycle disposing of two nitrogen atoms: one from ammonia and one from aspartate. The cycle progresses as:

N -acetylglutamate forms from the condensation of glutamate with acetyl-CoA catalysed by N -acetylglutamate synthetase
Condensation of ammonia with bicarbonate forms carbamoyl phosphate catalysed by carbamoyl phosphate synthetase. The latter is only active in the presence of N -acetylglutamate.
Carbamoyl phosphate condenses with ornithine to form citrulline
Citrulline is transferred into the cytoplasm and combines with aspartate to form argininosuccinate, catalysed by argininosuccinate synthase.
Argininosuccinate lyase cleaves argininosuccinate to arginine
Arginine is hydrolysed to urea, which is excreted in urine. Each urea molecule contains two nitrogen atoms and one carbon atom. Ornithine is transported back into the mitochondrion by the ornithine transporter.

Ammonia is also buffered by the conversion of glutamate to glutamine via the action of glutamine synthetase. At times of hyperammonaemia, the glutamine concentration increases and thus can be used as an indicator of insufficient urea synthesis and is indicative of longer term metabolic control.

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.

Table 29.5

Differential diagnosis of hyperammonaemia

Inborn errors of metabolism	Acquired
Urea cycle disorder Organic acidaemia Fatty acid oxidation disorders Pyruvate carboxylase deficiency Ornithine aminotransferase deficiency HHH syndrome (hyperammonaemia, hyperornithinaemia, homocitrullinuria)	Transient hyperammonaemia of newborn Severe illness Herpes simplex infection Cardiac disease Medications (sodium valproate, asparaginase) Reye-like illness Liver disease Porto-systemic shunts Artefactual from poor sampling

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.

Table 29.6

Diagnosis of urea cycle disorders

Enzyme	Disorder	Plasma amino acid concentrations relative to reference range					Urine orotic acid
		Alanine	Glutamine	Citrulline	ASA	Arginine
NAGS	NAGS def	↑	↑				Normal
CPS	CPS def	↑	↑	↓		↓	Normal
OTC	OTC def	↑	↑	↓		↓	↑↑↑
ASS	Citrullinaemia	↑	↑	↑↑		↓	↑
ASL	ASA def	↑	↑		↑	↓	↑
Arginase	Arginase def				↑		↑

ASA, argininosuccinic aciduria; ASL, argininosuccinate lyase; ASS, argininosuccinate synthetase; CPS, carbamoyl phosphate sythetase; def, deficiency; NAGS, N -acetylglutamate synthetase; OTC, ornithine transcarbamylase.

Management

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

Acute:

Stop feeds and commence 10% dextrose to reduce nitrogen load on the cycle
Commence intravenous ammonia scavenging medications (see Principles of pharmacological treatment , below)
Commence intravenous arginine to replenish the urea cycle
Transfer to specialist centre in preparation for haemofiltration

Chronic:

Low protein diet to reduce nitrogen load on the cycle
Ammonia scavenging medications to aid excretion of excess nitrogen
Arginine (except in arginase deficiency) to replace arginine not produced by the urea cycle

Question 29.2

A 5-day-old baby with drowsiness and poor feeding

A 5-day-old baby girl is born at term after a normal pregnancy and delivery. She presents with a 24-hour history of increasing sleepiness and poor feeding. On examination, she is encephalopathic with an irritable cry.

Investigations:

Blood:

Haemoglobin	136 g/L
White cell count	10.0 × 10 ⁹ /L
Platelets	360 × 10 ⁹ /L
CRP	10 mg/L
Glucose	4.0 mmol/L
Ammonia	875 µmol/L (<100)
Lactate	5 mmol/L (1–2.8)
Urea and electrolytes	normal
Liver function tests	normal
Calcium, phosphate, ALP	normal

Blood gas:

pH 7.5

pCO ₂ 2.5 kPa

pO ₂ 11.3 kPa

Base excess −5 mmol/L

Bicarbonate 22 mmol/L

Which of the following is the most likely diagnosis? Select ONE answer only.

A.
Hyperinsulinaemia of the newborn
B.
Intrapartum hypoxia
C.
Pyridoxine dependency
D.
Septicaemia
E.
Urea cycle defect

Answer 29.2

E. Urea cycle defect.

A urea cycle defect is the most likely because of the elevated lactate level and the extremely high ammonia. Hyperinsulinaemia is possible but ruled out by the normal blood glucose. Intrapartum hypoxia would have presented earlier with seizures and possibly renal failure. Pyridoxine dependency would result in intractable seizures. Septicaemia is unlikely with the virtually normal blood count.

Intravenous sodium benzoate and sodium phenylbutyrate are commenced. She is transferred to the paediatric intensive care unit (PICU) for haemofiltration. Ammonia normalizes over 6 hours. While on PICU she suffers a seizure. Investigations: High plasma citrulline and absent urine orotic acid suggest citrullinaemia, subsequently confirmed with mutation analysis. She subsequently recovers and is discharged on a low protein diet, sodium benzoate and arginine.

Key points – urea cycle defects

Ammonia is a respiratory stimulant and can cause respiratory alkalosis
Seizures can be seen in the acute phase due to cerebral oedema secondary to the effects of hyperammonaemia
Early referral to PICU for haemofiltration is essential
High ammonia levels (>1000 µmol/L) are associated with poor prognosis in terms of survival and long-term neurological outcome

Glucose and glycogen metabolism

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pH	7.29
pCO ₂	2.0 kPa (15 mmHg)
pO ₂	13 kPa (98 mmHg)
Bicarbonate	10 mmol/L
Base excess	−18 mmol/L

pH	7.5
pCO ₂	2.5 kPa
pO ₂	11.3 kPa
Base excess	−5 mmol/L
Bicarbonate	22 mmol/L

Learning objectives

Introduction

Acid–base disturbance

Definitions

Biochemistry

Clinical

Presentation

Diagnosis

Management

Lactic acidosis

A 6-day-old baby with tachypnoea

The urea cycle and hyperammonaemia

Biochemistry

Ammonia

The urea cycle

Clinical

Presentation

Diagnosis

Management

A 5-day-old baby with drowsiness and poor feeding

Glucose and glycogen metabolism

You're Reading a Preview

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