+++
Disorders of
Fatty Acid Oxidation, Ketogenesis, and Ketone Body Utilization
++
A large number of diseases (discussed in detail in Chapter 150) result in impaired fatty acid oxidation.4 All
of these disorders are inherited as autosomal recessive traits.
Except for the most severe cases, children are well at baseline
but cannot tolerate periods of fasting or increased metabolic demand
(eg, fever, infection) when fatty acid oxidation would normally
be required. The impairment of fatty acid oxidation results in hypoketotic
hypoglycemia, acute liver dysfunction, rhabdomyolysis, and cardiac failure.
Hypoglycemia paired with inadequate ketogenesis impairs bioenergetics
in the central nervous system, leading to lethargy that can progress
rapidly to coma. Since lipolysis and fatty acid transport are not
impaired, fatty acids accumulate in hepatocytes, where they may
exert toxic effects in addition to impairing energy generation.
Hyperammonemia and lactic acidosis may occur due to secondary effects
on liver metabolism. The most common of the fatty acid oxidation
disorders, medium-chain acyl-CoA dehydrogenase (MCAD, see Chapter 150) deficiency, has an incidence
of approximately 1:10,000 and presents
with severe hypoglycemic episodes
characterized by nausea, lethargy, and potentially sudden death.4,5
++
There are also several diseases that impair production of ketone
bodies from the acetyl-CoA produced during fatty acid oxidation
(see Chapter 151) or that impair the utilization
of ketone bodies by extrahepatic tissues (the ketone utilization
disorders; see Chapter 152). Clinically, the
disorders of ketogenesis are similar to fatty acid oxidation defects,
with acute episodes of fasting-induced hypoglycemia and inappropriately
low ketones in the blood and urine. The ketone utilization defects present
with episodes of vomiting and profound ketoacidosis, typically with
normoglycemia.
++
The most important goal in acute management of these diseases
is to reverse the catabolic state as quickly as possible. This is
done most effectively by stimulating insulin release with a high
glucose infusion rate (6–8 mg/kg per minute).
Insulin and dextrose suppress lipolysis in the adipose tissue and
suppress fatty acid oxidation in the liver and elsewhere. These
actions curtail the supply of free fatty acids to the liver and
reduce the accumulation of partially oxidized intermediates in the β-oxidation
pathway. A 10% dextrose-based solution at 1.5 to 2 times
the estimated maintenance rate should be used initially. If central
access can be obtained, a higher dextrose concentration can be used
to limit the volume of the infusion. Insulin infusions are helpful
to augment endogenous insulin secretion in severely ill children.
These interventions also benefit acutely ill children who are normoglycemic,
because the increase in circulating free fatty acids may produce
symptoms of hepatotoxicity prior to the decrease in blood glucose.
For patients with these disorders requiring parenteral nutrition,
intralipid mixtures must be avoided.
++
During management of a metabolic decompensation, markers of metabolic
function (blood glucose, ammonia, liver function tests, CPK) should
be followed closely. Some acutely ill children will become hyperglycemic
after initiation of the dextrose infusion. In these children, it is
advisable to start an insulin infusion rather than to reduce the
glucose infusion rate. Cardiac function should also be monitored
closely given that defects in long-chain fatty acid oxidation are associated
with cardiomyopathy and cardiac failure. In this regard, obtaining
plasma carnitine levels may aid in therapy, because cardiac function improves
in children with carnitine transporter defects who receive carnitine
supplements. However, the benefit of carnitine therapy in other
fatty acid oxidation disorders is debatable, and there is concern
that it may be deleterious in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)
deficiency.6
++
When a disorder of fatty acid oxidation or ketone metabolism
is suspected but has not been confirmed, the plasma acylcarnitine
profile provides a diagnostic pattern in many of these disorders.
Urine organic acid analysis also provides helpful information. Measuring the
amino acids in plasma or urine is not helpful.
++
In children with urea cycle disorders (see Chapter 145)7, nitrogen imbalance occurs during periods
of inappropriately high protein intake or during periods of illness,
when inadequate caloric intake stimulates muscle proteolysis and
nitrogen overload. The events surrounding birth are particularly
dangerous, because they create metabolic challenges, including the
onset of fasting intervals between feeding and separation from the
maternal circulation, which had been clearing excess ammonia from
the fetal circulation. Thus, the classic presentation of a severe
urea cycle defect is a term neonate who experiences unexpected,
progressive lethargy within the first few days after birth. Importantly,
milder presentations have been reported in all the urea cycle disorders.
Thus, hyperammonemia must be excluded in older children presenting
with acute neurological symptoms or neurological decline of unclear
etiology. Late-onset urea cycle disorders have even presented in
teenagers with psychosis or recurrent headache and vomiting. The
most common disorder, ornithine transcarbamylase (OTC) deficiency,
is an X-linked trait with an apparent incidence of approximately
1:40,000. All other urea cycle disorders are inherited in an autosomal
recessive pattern.
++
Hyperammonemia is a medical emergency, because the likelihood
of permanent central nervous system damage increases the longer the
hyperammonemia persists. The pathophysiology of hyperammonia-associated
neurotoxicity is not completely understood. Neurological symptoms
during episodes of hyperammonemia include coma, seizures, cerebral
edema, and overstimulation of the brain-stem respiratory center.
The tests in Table 114-3 often allow the
physician to differentiate between the different categories of inborn
errors of metabolism that present with hyperammonemia. This is a
critically important issue, as the optimal management of hyperammonemia
differs according to the category of inborn error of metabolism.
In the urea cycle disorders, symptoms are typically confined to
the brain, so abnormalities in blood glucose, CPK, or liver function
tests suggest other disorders. Analysis of the blood-gas profile
is helpful, because urea cycle disorders classically present with
a respiratory alkalosis due to hyperammonemia-stimulated tachypnea,
while a metabolic acidosis usually indicates another disease, particularly one
of the branched-chain organic acidemias (although exceptions do
occur and a metabolic acidosis does not definitively exclude the
possibility of a urea cycle defect).
++
Acute management of hyperammonemia in decompensated urea cycle
disorders is focused on stabilizing cardiorespiratory function,
restoring nitrogen balance, and removing excess ammonia as rapidly
as possible. Because of the high potential for rapid neurological
dysfunction and injury in these patients, any hyperammonemic child
suspected of having a urea cycle disorder should immediately have
intravenous access established, with centrally placed catheters
if possible. Endotracheal intubation is recommended if there is
neurological involvement, especially when transport to another facility
is necessary.8 Any exposure to amino acids or protein
in the diet or intravenous fluids must be discontinued immediately.
Anabolism can be stimulated by using a high glucose infusion rate
(6–8 mg/kg per minute), with or without insulin.
This helps incorporate amino acids into cellular protein, limiting
the nitrogen load presented to the urea cycle. If fatty acid oxidation
disorders have been ruled out, intravenous lipid infusions can be
used as an additional source of calories to further suppress catabolism.
++
Disease specific management approaches to the various urea cycle
disorders are provided in Chapter 145.
+++
Branched-Chain Organic
Acidemias
++
The branched-chain organic acidemias (or acidurias; see Chapter 137) are disorders of oxidation of
leucine, isoleucine, or valine that result in the accumulation of
nonamino organic acids in the blood and urine.10 They
are inherited as autosomal recessive traits and together comprise
a large category of inborn errors of metabolism, with the most common diseases
being methylmalonic acidemia, propionic acidemia, isovaleric acidemia,
and 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency. Their presentation
and severity vary, but they share many similarities in the decompensated
state and in their management. In general, these conditions present
with a dramatic decompensating phenotype of emesis, dehydration,
and encephalopathy, often with evidence of multiorgan system involvement including
hepatic dysfunction, pancreatitis, acute renal insufficiency and
bone marrow suppression. Unusual odors may also be present in decompensated
children (“sweaty feet” in isovaleric acidemia
and “cat’s urine” in 3-methylcrotonyl-coenzyme
A carboxylase (3MCC) deficiency). Branched-chain organic acidemias
are complicated by complex effects on intermediary metabolism that
result in ketoacidosis, lactic acidosis, hyperammonemia, hypoglycemia,
and hyperglycinemia. The first episode of metabolic decompensation
may occur within the first week after birth, particularly for propionic
acidemia, methylmalonic acidemia, and isovaleric acidemia. Recurrent
episodes are prompted by fasting, infection, or increased intake
of branched-chain amino acids.
++
Maple syrup urine disease is also a defect in branched-chain
amino acid oxidation but differs from the others in that the amino
acids accumulate in addition to organic acids. Children with decompensated
maple syrup urine disease present with prominent neurological symptoms,
including cerebral edema, seizures, ataxia, and obtundation; involvement of
other organ systems is less common. Severe metabolic acidosis is
also less common than in other branched-chain organic acidemias.
++
If a branched-chain organic acidemia is suspected in an acutely
ill child, protein-containing foods should be discontinued immediately.
Testing the urine for ketones is a rapid and reliable indicator
of metabolic decompensation. Older children who can tolerate feeds
can be given sugary, protein-free drinks initially, but if emesis
occurs, intravenous access must be established in order to administer
dextrose. A solution of 10% dextrose or higher should be
used to obtain a glucose infusion rate of 6 to 8 mg/kg
per minute. If necessary, an insulin infusion can be used concurrently
to maintain a normal blood sugar. A modified amino acid formulation
lacking the branched-chain amino acids has been developed for use
in maple syrup urine disease and can be given to acutely ill children who
cannot tolerate enteral feeds. Severe metabolic acidosis may be
treated with intravenous sodium bicarbonate. Some children, particularly
those with severe metabolic acidosis or hyperammonemia, may require
hemodialysis to achieve rapid toxin removal. Specific therapies
include carnitine, which may become depleted due to conjugation
with organic acids, and enteral glycine in children with isovaleric
acidemia.
++
In some children with branched-chain organic acidemias, activity
of the dysfunctional enzyme can be improved with large doses of
vitamin cofactors (see Chapter 137). A trial of the relevant cofactor
should be considered in children presenting with an initial episode
of decompensation. More importantly, like the branched-chain organic
acidemias, the multiple carboxylase deficiencies (biotinidase deficiency
and holocarboxylase synthetase deficiency) present with neurological
dysfunction, metabolic acidosis, and accumulation of lactate and
intermediates of amino acid oxidation.11,12 Biotin
therapy is highly effective in biotinidase deficiency and in many
cases of holocarboxylase synthetase deficiency. Thus, these two
disorders should be ruled out in children with organic acidemias
in whom the specific diagnosis is unclear.
++
Most of the branched-chain organic acidemias are diagnosed by
newborn screening programs that perform acylcarnitine profiling by
tandem mass spectrometry. In children in whom a diagnosis has not
been firmly established, the clinician should obtain urine organic
acids and a quantitative plasma acylcarnitine profile. Plasma amino
acids should also be measured if maple syrup urine disease is suspected.
+++
Primary Lactic Acidosis
Syndromes
++
The primary lactic acidosis syndromes (also known as congenital
lactic acidosis syndromes) are a large category of inborn
errors of metabolism caused by impaired oxidation of pyruvate leading
to excessive accumulation of lactic acid and metabolic acidosis.13 They are
discussed here because they are a major cause of severe metabolic
dysfunction in newborn babies and older children. However, unlike
the diseases previously covered, there are generally no specific
therapies for these conditions, and care is largely supportive.14 For
the purposes of this chapter, primary lactic acidosis syndromes
include pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency,
deficiencies of enzymes of the tricarboxylic acid cycle, and mitochondrial
defects (see Chapter 159). Patients with primary lactic
acidosis syndromes generally have prominent neurological abnormalities,
which predominate in pyruvate dehydrogenase deficiency, pyruvate
carboxylase deficiency, and most defects of the tricarboxylic acid
cycle. Mitochondrial disorders are notoriously pleiotropic, but
central nervous system involvement is common.15 The
complex phenotypes of these patients reflect the combined effects of
acidosis, compromised cellular bioenergetics, enhanced reactive
oxygen species generation, and interference with other aspects of intermediary
metabolism.
++
Severe lactic acidosis in newborns is usually due to ischemia
(sepsis, cardiac dysfunction), anemia or hypoxemia. When those causes
have been ruled out and tissue perfusion is adequate, the persistence
of plasma lactate greater than 2 mmol/L should raise suspicion
of a primary lactic acidosis syndrome. While acute illnesses can
exacerbate lactic acidosis in primary lactic acidosis syndromes,
these diseases generally do not follow a pattern of episodic acute
decompensations with interim periods of metabolic stability. Rather,
the children tend to have developmental delay, failure to thrive,
and chronic elevations of lactate, sometimes requiring bicarbonate
therapy. During periods of illness, the emphasis should be on supportive
cardiorespiratory management and hydration, because impaired tissue
perfusion will increase lactate production. Base deficits, if severe, should
be carefully replaced. One important consideration in these diseases
is that lactate is largely derived from glucose metabolism. Therefore,
unless the child is hypoglycemic, dextrose should be administered
carefully with a goal glucose infusion rate of only 3 to 4 mg/kg
per minute. The physician must be able to distinguish a likely primary
lactic acidosis syndrome from other inborn errors of metabolism
in which elevated lactate is a secondary feature (eg, fatty acid
oxidation disorders), where high glucose infusion rates are needed in
acutely ill patients. In children with primary lactic acidosis syndromes
who require dextrose infusions, the lactate levels should be monitored
to guard against exacerbating the acidosis.
++
Other metabolic abnormalities observed in primary lactic acidosis
syndromes include hyperammonemia in pyruvate carboxylase deficiency
and prominent ketosis in pyruvate carboxylase deficiency and mitochondrial
defects. Renal tubular dysfunction also occurs in pyruvate carboxylase
deficiency and mitochondrial defects and can result in bicarbonate wasting
that further complicates the acidosis.
++
There are very few treatment options for these disorders, both
for acute and chronic management. In pyruvate dehydrogenase deficiency,
high-fat, low-carbohydrate (“ketogenic”) diets
have led to biochemical and perhaps clinical improvements in some
children.16,17 In addition, a small fraction of
children presenting with mitochondrial defects have a deficiency
in coenzyme Q biosynthesis and respond to pharmacological doses
of this cofactor.18 Therefore, a trial of coenzyme
Q seems justified in children with primary lactic acidosis syndromes
of unknown etiology. Establishing a specific diagnosis in children
with primary lactic acidosis syndromes is difficult and usually
involves a combination of biochemical, enzymatic, and molecular
testing. However, a simple test that may provide useful information
is to measure plasma lactate and pyruvate concurrently. An elevated
lactate with a normal lactate-to-pyruvate ratio (10–20)
is usually due to pyruvate dehydrogenase deficiency.