R e c o g n i z i n g a n d Ma n a g i n g a

Metabolic Crisis
Peter R. Baker II, MD

KEYWORDS
 Inborn error of metabolism  Hyperammonemia  Metabolic acidosis  Anion gap
 Lactate  Ketone  Catabolism  Sodium phenylbutyrate

KEY POINTS
 Metabolic emergencies can occur at any age, are gender non-specific, and if not recog-
nized and treated can result in permanent disability or death.
 Basic laboratories including blood gas, comprehensive metabolic panel, urine/plasma ke-
tones, and plasma lactate and ammonia can facilitate recognition at most medical
centers.
 Acute treatment includes providing calories (typically with dextrose) and detoxification
(with dialysis and some disease-specific therapies).
 Vitamin and nutritional interventions for specific disorders are useful in acute treatment, as
well as chronic management to avoid future metabolic emergencies.

INTRODUCTION

Inborn errors of metabolism (IEM) are genetic disorders involving biochemical path-
ways throughout the body. Categorically, there are subsets of these disorders that
cause acute intoxication, energy deficiency, and acidosis, resulting in a clinical meta-
bolic emergency.1 These conditions include urea cycle disorders (UCD), organic acid-
emias (OA), maple syrup urine disease (MSUD), fatty acid oxidation disorders (FAOD),
and primary lactic acidosis (PLA). There is great overlap in clinical presentation with
these disorders.2 They are characterized by an asymptomatic period (one day to
many years), followed by the onset of symptoms including vomiting, poor feeding
(particularly in neonates), lethargy, irritability, hallucinations, slurred speech, rapid
breathing, seizures, loss of consciousness, coma, and eventually death.3 These symp-
toms, as a broad group, are called symptoms of intoxication. In the absence of known
exogenous intoxicant ingestion, these symptoms should prompt the clinician to
consider an IEM in the differential diagnosis.1

University of Colorado, Children’s Hospital Colorado, 13123 East 16th Avenue, Box 300, Aurora,
CO 80045, USA
E-mail address: [email protected]

Pediatr Clin N Am 70 (2023) 979–993

https://doi.org/10.1016/j.pcl.2023.05.009 pediatric.theclinics.com
0031-3955/23/ª 2023 Elsevier Inc. All rights reserved.
980 Baker II

The onset of a metabolic emergency is precipitated by “metabolic stress.” This

can be due to an overwhelming amount of substrate in a blocked metabolic pathway
(eg, too much oral protein intake in a UCD). More commonly onset is precipitated by
catabolism, or the body’s mobilization of its own nutrients/substrates, for energy.
Catabolism can be caused by fasting (not eating/drinking calories), vomiting in the
setting of an infectious illness (losing calories), inadequate caloric intake for needs
(not eating/drinking enough calories during times of increased caloric needs), or
deficit of specific nutrients for prolonged periods of time (eg, withholding protein
for days).2,4 In these settings, the body naturally releases its own internal
energy stores of fatty acids (from adipose) and amino acids (typically from muscle),
which can overwhelm blocked pathways and result in the buildup of toxic
metabolites. Simultaneously, because of the primary metabolic block, the cell may
not be able to produce enough energy further resulting in cellular damage and/or
death.5
Episodes of metabolic stress and crisis can recur throughout the lifetime of the in-
dividual.6–11 Whether it is exogenous substrate overload or endogenous catabolism
that cause the metabolic emergency, recognizing the crisis and treating in a timely
manner can be the difference between an individual living without disease sequelae
or suffering life-altering end-organ damage. During crisis, in all of these disorders,
the central nervous system can suffer permanent damage to the cortex, white matter,
and/or basal ganglia, leading to irreversible sequelae including dystonia, epilepsy,
spasticity, paralysis, and/or intellectual disability (depending on which areas of the
brain are damaged). MSUD uniquely can present with a sweet odor (particularly in
the ear wax, and eventually in urine). MSUD is one of the few disorders that has a pro-
gressive prodrome of apnea, opisthotonos, and reflexive "bicycling" movements in the
first days of life.12 Other organs beyond the central nervous system can be affected as
well. The liver can be damaged in UCD, OA, and FAOD.13 Cardiomyopathy or rhabdo-
myolysis can be a presenting symptom in FAOD, particularly long-chain disorders.11 In
the most severe settings delayed treatment in any of these disorders can lead to
death.
Through current newborn screening, many of these conditions (but not all) can be
detected and managed within the first week of life. Sometimes, due to the severity
of the condition, diagnosis by newborn screen can come after the onset of symptoms
(day of life 2 or 3). In such cases, or in conditions that are missed by newborn
screening, a high index of suspicion needs to be maintained. This is especially true
in the neonatal intensive care unit, but holds true through every stage of life from
the pediatric clinic and emergency medicine, to internal medicine, obstetrics, and
the adult intensive care unit.6–11
Diagnosis of these IEM is accomplished through several mechanisms. Newborn
screen will detect many disorders and prompt further work-up. In disorders not
screened, patients may present symptomatically. In either case biochemical testing
of blood and urine, genetic testing, and enzymatic testing are helpful in diagnostic
confirmation. Once a diagnosis is confirmed, management can be targeted to the spe-
cific disease, and often includes diet modification, avoidance of fasting, vitamin and
nutritional supplements, and intervention to prevent an acute metabolic crisis from
occurring.
This article will outline easy and basic steps to detect, or at least raise suspicion for,
a metabolic emergency using basic laboratory tests available in most health care fa-
cilities. It details specialty testing that can be sent to support a metabolic diagnosis.
Finally, it discusses easy, rapid interventions that can mitigate damage and reverse
metabolic intoxication during an acute event.
 Metabolic Emergencies 981

Basic Laboratory Studies to Detect a Metabolic Crisis

While genetic testing is useful to confirm a diagnosis, it is not typically the first step in
diagnosing an IEM. If the individual has symptoms of intoxication there are several lab-
oratory studies that are available in almost any health care setting, and useful in
providing clues toward a diagnosis. Fig. 1 describes symptoms of intoxication, basic
initial laboratories to obtain, interpretation of these lab results in the most common dis-
orders, and next steps in metabolic work-up.
The most basic and often obtained study is the “comprehensive metabolic panel.”
Several elements can be helpful in a metabolic emergency. Plasma bicarbonate, com-
bined with venous or arterial blood gas, is useful in an acute intoxication event. In UCD
including ornithine transcarbamylase deficiency (OTC) and Citrullinemia Type 1 there
is a respiratory alkalosis.5 In other metabolic emergencies, anion gap metabolic
acidosis is detectable using these basic labs. Using plasma chloride, sodium, and
bicarbonate anion gap metabolic acidosis5 is seen in OA and PLA, due to over
production of ketones and/or lactate. In FAOD there may also be elevated in lactate
due to the secondary inhibition of pyruvate carboxylase. Elevations in either lactate
or plasma ketones resulting in anion gap metabolic acidosis are not unique to IEM,
but can be used as non-specific markers. Lactate is commonly elevated in severe
infection/sepsis, tissue necrosis, cardiac malformations, and in the setting of poor tis-
sue perfusion. In evaluating for these other conditions, considering an IEM would be
appropriate.
In a neonate, regardless of blood glucose, ketones should not be elevated to the
point of being detectable in the urine, or high enough to cause anion gap acidosis.14,15
While ketones are produced in neonates, and are important for supplying energy to the
central nervous system, elevation of urine ketones (easily detected using a bedside
urine dipstick or laboratory-based urinalysis) in a neonate (particularly in the first
week of life) is strongly suggestive of an OA.5,9

↔Urine ketones
↔ Lactate Urea Cycle Disorder:
↑↑ Ammonia Plasma Amino Acids
Respiratory Alkalosis

↑Urine ketones
Organic Acidemia:
↑Lactate
Plasma Acylcarni ne
↑Ammonia
Profile
Anion Gap Acidosis
Urine Organic Acids
Acute Intoxica on Symptoms: Comprehensive Metabolic Panel
Encephalopathy/Seizures Venous Blood Gas ↑ Urine ketones
Maple Syrup Urine
Vomi ng/poor feeding Urinalysis ↔ Lactate
Disease:
Hallucina ons/Confusion Lactate ↔ Ammonia
Plasma Amino Acids
Dyscoordina on/Ataxia Ammonia Anion Gap Acidosisa
Urine Organic Acids
↓Urine ketonesa
↑ Lactatea Fa y Acid Oxida on
↑ Ammoniaa Disorder:
Anion Gap Acidosisa Plasma Acylcarni ne
Profile
↑ Urine ketonesa
Primary Lac c Acidosis:
↑↑ Lactate
Urine Organic Acids
↑ Ammoniaa
Plasma Amino Acids
Anion Gap Acidosis

Fig. 1. Flow diagram describing the interpretation of basic, widely available laboratory find-
ings in the setting of a metabolic emergency. The presence of symptoms of acute intoxica-
tion should prompt obtaining these labs. Findings should prompt further investigation
using specialty biochemical labs to aid in the diagnosis of the inborn error of metabolism.
a
Variable based on age and/or severity.
982 Baker II

In a non-neonatal healthy individual, ketones should be elevated in the setting of low

blood glucose and/or prolonged fasting, and result in anion gap metabolic acidosis.
This is termed physiologic ketosis and is necessary for the brain and heart to operate
in starvation. A lack of elevation (hypoketosis) during fasting and hypoglycemia may
indicate a FAOD.5 Blood glucose can be, but is not always, low in acutely presenting
IEM.5 Particularly profound (blood glucose <20 mg/dL) or refractory hypoglycemia can
be indicative of a metabolic disorder.
Elevated transaminases (alanine aminotransferase and aspartate aminotransferase)
are markers of hepatocellular damage. This can be present in FAOD, OA, UCD, and
PLA.5 Hepatic synthetic dysfunction (evident by elevated low albumin and high INR)
may be present. This degree of hepatic dysfunction can be seen particularly in UCD
and FAOD.5 Combined hepatopathy and encephalopathy (Reye-like presentation)
should raise concern for an intoxicating IEM as well.16 In long-chain FAOD, elevations
in transaminases may also originate from the muscle and be a sign of rhabdomyoly-
sis.17 In this case, creatinine kinase (CK) would be elevated as well.
One final and relatively ubiquitous laboratory analysis is plasma ammonia. Hyper-
ammonemia is one of the primary intoxicating metabolites in most IEM with an acute
phenotype, including in UCD, OA, FAOD, and even in some PLA.5 Whether it is the pri-
mary driver of intoxication in all of these disorders is controversial and confounded by
energy deficits to vital organs such as the brain and liver, metabolic acidosis, and
derangement of other bioactive compounds including organic and amino acids.
High plasma ammonia (>60–100 mM) should raise concern for an IEM, especially in
the setting of intoxication symptoms and the other aforementioned laboratory abnor-
malities. There are many other etiologies of hyperammonemia including primary liver
failure/insufficiency, vascular malformations, toxin or drug exposure, neoplasm, and
urease-producing infection, to name a few. Care should be taken to investigate
such etiologies concomitantly with IEM.
There are several other caveats regarding hyperammonemia. First, in a neonate,
normal ammonia can be up to 100 to 125 mM. In older children and adults, these levels
would be considered moderately elevated, so keeping the age of the patient in mind is
important. Although most laboratories report ammonia in units of “micromol/L” (micro-
molar, mM), some laboratories use mg/dL. With a conversion factor of w0.6 from mg/dL
to micromol/L (eg, 170 mg/dL 5 100 mM) care should be taken to clarify units and refer-
ence range when considering whether an individual is hyperammonemic. Finally, and
very importantly, blood ammonia levels can be falsely elevated and dependent on how
a sample is drawn and handled. If it is drawn with a tourniquet, drawn under strain or
pressure, sampled by heal/capillary blood, allowed to sit at room temperature, or
allowed to sit for prolonged period before processing in the lab, elevated values
should be viewed with caution.18 Ammonia should be drawn through a free-flowing
line, without a tourniquet, placed on ice immediately, and processed in the lab as
soon as possible (ideally within 30–40 minutes).

Specialty Laboratories and Diagnostic Confirmation of an Intoxicating Inborn

Errors of Metabolism
Specialty biochemical tests are processed and interpreted in a Clinical Biochemical
Laboratory. Most health care centers around the United States do not have a Clinical
Biochemical Laboratory available on site. Most clinicians send samples to a regional
academic or commercial center, usually once a biochemical genetics specialist is
involved. Still, understanding what types of tests are sent to and processed by such
laboratories, and their utility in diagnosing intoxicating IEM is important in understand-
ing the overall evaluation for the presence of an IEM. Unless there is a laboratory that
 Metabolic Emergencies 983

can process these samples on-site, real-time decision-making based on results dur-
ing an acute metabolic crisis is not possible. Results that return in 24 to 48 hours may
have some utility in acute management, but largely these tests are sent to support
diagnostic testing rather than to guide treatment. They are also used in some cases
to optimize nutritional management in the more chronic, outpatient clinical setting.
There are 3 main specialty biochemical tests that are ordered when assessing for
the etiology of acute metabolic crisis: plasma amino acids, urine organic acids, and
plasma acylcarnitines, also known as the plasma acylcarnitine profile. Plasma amino
acids can help in the evaluation of UCD, OA, MSUD, and PLA. In UCD glutamine is
elevated as a result of hyperammonemia; alanine and/or glycine may be elevated as
well.19 Depending on the type of UCD other amino acids are variably affected. Citrul-
line is low in proximal UCD such as OTC Deficiency, and it is elevated in distal UCD
including Citrullinemia Type 119. Citrulline may also be elevated in the PLA, pyruvate
carboxylase deficiency. Arginine can be high (Arginase Deficiency) or low (Citrulline-
mia Type 1) depending on which enzyme in the urea cycle is affected.19 The amino
acid pattern alone may be diagnostic of a UCD. In OA, amino acids are not specific
for any single condition, but generally glycine is high and glutamine is low compared
to the reference range.9,20 In MSUD, the branched chain amino acids leucine, isoleu-
cine, and valine are elevated, as well as the pathognomonic elevation of alloisoleu-
cine.21 Finally, alanine is typically elevated in chronic lactic acidosis, and thus can
be useful in diagnosing PLA.22
Urine organic acids are helpful in diagnosing most of these metabolic conditions.
The primary use of UOA is in diagnosing and distinguishing types of OA. Specific pat-
terns will be present for methylmalonic acidemia (MMA), propionic acidemia (PA), and
isovaleric acidemia (IVA) that are diagnostic for each condition.23 MSUD has variable
elevations in alpha-ketoacids, as well as ketones (acetoacetate and beta-hydroxybu-
tyrate).12 FAO may have non-specific elevations in dicarboxylic acids. In MCAD defi-
ciency the presence of hexanoylglycine can be diagnostic. UCD (specifically OTC
deficiency) will have orotic acid and uracil that is detectable in a UOA sample.9 PLA,
as expected, demonstrates elevated lactate, but plasma concentrations are typically
higher (above 6–10 mM), and more refractory to treatment than other etiologies.
Finally, the plasma acylcarnitine profile is useful in detecting OA and FAOD. In OA,
there will be elevations of C3 (propionylcarnitine) acylcarnitine for MMA and PA, and
C5 (isovalerylcarnitine) in IVA.24 Specific acylcarnitine patterns can be seen in, and
are diagnostic for medium-chain (C8, octanoylcarnitine), very long-chain (C14:1,
myristoylcarnitine), and long-chain hydroxy (C16-OH, hydroxy-palmitoylcarnitine)
acyl-coA dehydrogenase deficiencies. Carnitine Palmitoyl Transferase type 1 (CPT1)
typically has high free carnitine and low long-chain species (eg, C18, stearoylcarni-
tine), while Carnitine Acylcarnitine Translocase (CACT) deficiency and Carnitine
Palmitoyl Transferase type 2 (CPT2) deficiency have low free carnitine and elevated
long-chain species (eg, C18).24 Ketone-related acylcarnitines (C2, acetylcarnitine
and C4-OH, hydroxy-butyrylcarnitine) are low in these disorders.
Besides biochemical testing, the confirmation of an IEM, and potentially under-
standing the severity, requires molecular testing (gene sequencing) and/or enzymatic
testing. Alternatively, the use of genomic sequencing including rapid whole exome, or
rapid/ultra-rapid whole genome sequencing, can achieve a diagnosis within days, and
is now often preferred over single gene and panel testing that may take weeks. The
former can be obtained using blood, saliva, or buccal swab, and there are many com-
mercial laboratories that offer single gene or gene panel testing. The decision
regarding what test to get is guided by biochemical pattern and clinical features. Enzy-
matic testing is more rarely done. It often requires skin fibroblasts obtained from a
984 Baker II

biopsy. Some studies are optimized for leukocytes, which is less invasive. Due to
maintenance cost, disease rarity, and improved molecular testing, many enzymatic
assays are no longer clinically available.

TREATMENT OF METABOLIC CRISIS: STOP THE PRECURSOR, REVERSE CATABOLISM,

AND START DETOXIFICATION

There are 3 major principles to the general treatment of a metabolic crisis/emergency.

The application of these principles to each categorical disorder can be found in
Table 1. First, any offending precursors need to be stopped. In UCD, OA, and
MSUD, this is protein. In FAOD it is fat, however it is not clear whether this is acutely
harmful.25 In emergency fluid management FAOD are the only group of conditions in
which lipids should be withheld for caloric repletion. Of note, in UCD and OA protein
should not be held for too long (no longer than 24 hours), because withholding protein
alone can induce protein catabolism of muscle. After w24 hours a small amount of
protein (eg, 0.8 mg/kg/d (d)) should be reintroduced enterally or parenterally.26 In
MSUD parenteral amino acid mixtures free of leucine are used.27
Second, because the emergency is typically being triggered by metabolic stress
which induces catabolism, catabolism must be stopped. As above, catabolism occurs
with prolonged fasting, vomiting, and/or infection. Often these all occur at once. In
some instances, catabolism can be triggered by a medication such as steroids. To
reverse/treat catabolism, dextrose with appropriate electrolytes should be adminis-
tered. Typically, D10 in normal saline given at 1.5 times the maintenance rate is
used. This provides roughly 8 to 10 gm/kg/min glucose.26 It is important to maintain
relatively high glucose infusion rates. If blood glucose begins to climb (>80–110 mg/
dL), it is preferable to not lower the GIR, but rather to begin insulin to facilitate intracel-
lular transport of glucose.26 Intralipid can be added to the anabolic regimen if the pa-
tient does not have a FAOD. Typically, 2-3 g/kg/d of 20% lipid emulsion is sufficient.26
In adults we may only use 1 g/kg/d based on tolerance and dietary needs. Very rarely
are dextrose or lipids contraindicated. Lipids should theoretically not be given in
FAOD. In PLA-like pyruvate dehydrogenase (PDH) deficiency, excess dextrose can
exacerbate lactic acidosis by overwhelming glycolysis, therefore a w4:1 lipid-to-
carbohydrate ratio parenteral nutrition has been suggested.26 Chronically, use of a
ketogenic diet may be beneficial. Generally, the use of less dextrose and more lipid
is less effective in other PLA such as mitochondrial respiratory chain disorders.
Here, adequate caloric support with a careful balance of dextrose and lipid is
optimal.26 Dextrose is contraindicated in Citrullinemia Type II, where protein and lipids
are the preferred regimen, and dextrose can exacerbate a hyperammonemic crisis.28
Finally, when possible, detoxification should be started to decrease levels of the
intoxicating chemical. Typically, this is ammonia, but may also be organic acids
and/or lactate. In UCD sodium phenylbutyrate and sodium benzoate can be used in
hyperammonemia.29–31 These ammonia “scavengers” bind glutamine and glycine to
generate phenylacetyl glutamate and hippuric acid, respectively. These chemicals
can be excreted in urine. As the major reservoirs of ammonia in the blood, binding
glutamine and glycine is a highly effective way of bringing the bodies circulating
ammonia levels down.31 They are administered with arginine.9,32 Any of these can
be given enterally through a gastric or nasogastric tube.29 Ideally, however, these
are given intravenously using the formulation Ammonul.31 Use of this drug may be
limited by cost and/or availability.
Arguably, Ammonul should not be used in OA.30 While the sodium benzoate compo-
nent could be effective to lower glycine (which is often elevated), there is not an
Table 1
Disorders that can cause a metabolic emergency/crisis (and some examples of these disorders), followed by the primary clinical features, specialty
biochemical testing, and management points

Primary Biochemical
Disorder Examples Main Clinical Features Test Primary Treatments Vitamins/Supplements
Urea Cycle N-Acetylglutamate Respiratory alkylosis Plasma Amino Acids Dextrose, Lipid Arginine or citrulline in
Synthase (NAGS) Hyperammonemia Withhold/reduce OTC deficiency
Deficiency Ornithine Liver dysfunction Protein
Transcarbamylase Ammonia Scavengers
(OTC) Deficiency Carglumic acid
Citrullinemia Type 1 Hemodialysis
Organic Acidemias Methylmalonic Anion gap metaoblic Urine Organic Acids Dextrose, Lipid Levocarnitine
Acidemia (MMA) acidosis Plasma Acylcarnitine Withhold/reduce Hydroxocobalamin
Propionic Acidemia (PA) Ketoacidosis Profile Protein (some forms of MMA)
Isovaleric Acidemia Lactic acidosis Carglumic Acid Glycine(IVA)
(IVA) Hyperammonemia Hemodialysis Biotin (some forms of
Liver dysfunction PA)
Amino Acidopathy Maple Syrup Urine Ketoacidosis Plasma Amino Acids Dextrose, Lipid Isoleucine and valine
Disease (MSUD) Sweet odor (ear wax) Urine Withhold/reduce supplmentation
Spasticity, bicycling, Organic Acids Leucine Thaimine (some forms
opisthotonos Supplement Isoleucine of MSUD)
and Valine
Hemodialysis
Fatty acid oxidation Medium-Chain Acyl- Anion gap metaoblic Plasma Acylcarnitine Dextrose Levocarnitine used in

Metabolic Emergencies
CoA Dehydrogenase acidosis Profile MCADD and MADD
(MCAD) Deficiency Hypoketotic Low doses and with
Multiple Acyl-CoA Hypoglycemia caution in VLCADD
Dehydrogenase Lactic acidosis Triheptanoin used in
Deficiency (MADD) Hyperammonemia long chain disorders
Long-Chain Disorders Liver dysfunction
Very Long Chain Acyl- Cardiomyopathy (LC
CoA Dehydrogenase only)

(continued on next page)

985
 986
Baker II
Table 1
(continued )
Primary Biochemical
Disorder Examples Main Clinical Features Test Primary Treatments Vitamins/Supplements
(VLCAD) Deficiency Rhabdomyolysis (LC
Carnitine-Acyl-Carnitine only)
Translocase (CACT)
Deficiency
Carnitine Palitoyl
Transferase Type 2
(CPT2) Deficiency
Long Chain Hydroxy
Acyl-CoA
Dehdrogenase
(LCHAD) Deficiency
Primary lactic acidosis Pyruvate Anion gap metaoblic Plasma lactate and Dextrose, Lipid (use of Thiamine (PDH)
Dehydrogenase (PDH) acidosis pyruvate each varies per Ketogenic Diet (PDH)
Deficiency Lactic acidosis Plasma Amino Acids condition)
Pyruvate Carboxylase Liver dysfunction Urine Organic Acids Hemodialysis
(PC) Deficiency
Mitochondrial
Respiratory Chain
Disorders
 Metabolic Emergencies 987

intravenous form available in the United States. Sodium phenylbutyrate is not typically
used in OA mainly because glutamine is not elevated,9,30 it is low. Giving phenylbuty-
rate could exacerbate hypoglutaminemia.33 Further, both components (benzoate and
phenylbutyrate) can acidify the mitochondrial matrix, potentially exacerbating
dysfunction. A different medication, carglumic acid (N-carbamylglutamate), tradition-
ally used for hyperammonemia in the UCD N-acetylglutamate Synthase (NAGS) Defi-
ciency, is now approved for OA.29,34–36 The mechanism of hyperammonemia in OA is
the inhibition of the synthesis of N-acetylglutamate, a cofactor for the first step in the
urea cycle. Carglumic acid replaces the cofactor and allows the urea cycle to function
properly.
The most efficient and effective means of detoxification of ammonia in OA, as well
as in UCD in which the ammonia is greater than w300 to 400 micromol/L, is hemodi-
alysis.37 This is superior to peritoneal dialysis and continuous renal replacement ther-
apy (CRRT),38 although the latter two therapies could be used if hemodialysis is not
possible (particularly due to neonatal size, fragility, access, or on site availability).39,40
Dialysis is also the preferred means of treating hyperammonemia in acute liver failure.
In this setting the enzymes that allow sodium benzoate and sodium phenylbutyrate to
work are dysfunctional, rendering these medications much less efficacious. Therefore,
the use of them separately or as Ammonul is not proven effective in acute liver
failure.41
In PLA, FAOD, and OA, lactate, ketones, and some organic acids can contribute to
anion gap metabolic acidosis. In most of these disorders, simply reversing catabolism
can mitigate the acidosis. Bicarbonate can be used as the blood pH decreases. In se-
vere crises the preferred method of detoxification, as with hyperammonemia, is
dialysis.42,43

Nutritional Supplements and Cofactors

The principles above broadly cover most IEM in the setting of metabolic crisis. Vita-
mins and nutritional supplements specific to groups of disorders should be considered
to help mitigate metabolic derangements. With a variety of mechanisms (depending
on the supplement and the disorder), these can be used in acute crisis situations to
regain metabolic control. Frequently they are used on a more chronic basis to maintain
control and avoid episodes of crisis in the setting of illness, fasting, or other metabolic
stressors.
Levocarnitine is used in treating most OA, both to prevent secondary depletion but
also as a detoxifying agent. Particularly, PA, MMA, IVA, and even glutaric acidemia
type 1 (GA1, a cerebral organic acidemia) respond well to higher doses of intravenous
carnitine (100–400 mg/kg/d) in times of illness.44–47 In general, carnitine allows for the
excretion of toxic organic acid species via conversion from an acyl-CoA molecule (not
excretable, trapped within the mitochondria) to an acyl-carnitine molecule (can
escape the mitochondria and excretable in urine).47 Further, the conjugation of an
overproduced acyl group (again, usually bound as an acyl-CoA) with carnitine allows
the intracellular CoA pool to be available for energy production within the mitochon-
dria.48 Both mechanisms are thought to mitigate cellular damage in crisis. High doses
(>100–200 mg/kg/d) should not be given orally as they could produce adverse effects
of gastrointestinal upset, production of trimethylamine, and diarrhea.49,50 In FAOD,
carnitine can be given in medium-chain acyl CoA dehydrogenase deficiency (MCADD)
to replete stores depleted by the over-production of medium-chain fatty acyl-CoAs.
Some practices will do this only if plasma carnitine levels are low. Some do it empir-
ically in illness. In longer chain disorders (particularly VLCADD) it has been postulated
that higher doses of intravenous carnitine are arrhythmogenic. While this is not
988 Baker II

supported by rigorous study to date, it is a practice cautiously and generally observed

in biochemical genetics.
Vitamins can be very helpful in some conditions, in initial crisis-like presentations as
well as long term. Hydroxocobalamin (a potent high dose form of vitamin B12) is
invaluable in treating inborn errors of cobalamin metabolism that result in elevated
MMA and/or homocysteine.51–54 Subcutaneous hydroxocobalamin, formulated to
be given intravenously in the setting of cyanide poisoning in house fires,55,56 is given
daily to reduce MMA and/or homocysteine levels and gain metabolic control, and to
maintain lower levels of MMA chronically to avoid/delay onset of chronic renal dis-
ease.52 This form of cobalamin is more efficacious than cyanocobalamin,57 and it is
very safe in the relatively small doses given in cobalamin defects.54,56 It should be
given immediately if there is a suspected OA.44,52 Some forms of PA and PLA (pyru-
vate carboxylase deficiency) are responsive to Biotin.44 Riboflavin (vitamin B2) can
be given in the acute management and maintenance management of multiple acyl-
CoA dehydrogenase deficiency, and in some rare responsive forms of GA1.58–61
Thiamin (thiamine; vitamin B1) can be given in some forms of PLA (PDH deficiency)
as well as responsive forms of MSUD.12
Amino acid supplementation may be given during acute crises, but also chronically
for conditions such as IVA (glycine),47 OTC deficiency (arginine intravenously or oral
citrulline),32 and MSUD (isoleucine and valine).12 In IVA, glycine is given along with lev-
ocarnitine because of its ability to bind with isovaleryl- and 3-hydroxyisovaleryl-CoA,
making these excretable and further detoxifying.47 In OTC deficiency, arginine and/or
citrulline act to replenish urea cycle intermediates in crisis. Additionally, citrulline has
an added benefit of scavenging extra ammonia into the urea cycle, downstream of the
enzymatic block, by incorporating the amine group of aspartate into urea.32 In MSUD,
as leucine is being withheld in acute crises, isoleucine and valine are given to both
replete these essential amino acids as well as to help block the transport of cytotoxic
leucine across the blood brain barrier, via competition at the LAT1 cation
transporter.62
In disorders of long-chain fat metabolism, the administration of medium-chain fats
(in the form of medium-chain triglycerides, typically composed of 3 molecules of
octanoate (C8) on a glycerol backbone) has been used to supplement long-chain fat
restriction to treat and prevent acute episodes of rhabdomyolysis as well as sub-
acutely treat cardiomyopathy.63,64 The efficacy of MCT supplementation has been
recently challenged, in favor of a synthetic molecule, triheptanoin. This is a molecule
composed of 3 heptanoate (C7) moieties on a glycerol backbone. Using an odd chain
fatty acid with both 2- and 3-carbon catabolites, C7 better provides energy to
the tricarboxylic acid cycle (TCA) cycle. Head-to-head studies have demonstrated
the superiority of triheptanoin for treating cardiomyopathy. It is promising also in the
long-term prevention of hospitalizations due to rhabdomyolysis as well.65,66

SUMMARY

While individually rare, taken together, metabolic crisis from an IEM is a relatively com-
mon phenomenon, which, if not detected and treated immediately, could result in per-
manent disability or death. An initial/presenting episode can occur in the first few days
of life, in the elderly, or anytime in between. Newborn screening has allowed us to
detect many, but by no means all, of these conditions before they present acutely.
Therefore, a high index of suspicion is required. Suspicion can be easily and quickly
substantiated with some basic, widely available labs including urinalysis (ketones),
comprehensive metabolic panel, plasma lactate and ammonia, and venous/arterial
 Metabolic Emergencies 989

blood gas. The diagnosis can be confirmed as empiric treatment is being implemented
using more sophisticated specialty biochemical labs as well as genetic testing. Safe,
empiric treatment includes removing offending substrates, stopping catabolism by
giving calories (dextrose and in most cases lipids), and in the setting of hyperammo-
nemia and/or metabolic acidosis, starting a treatment that removes toxins. While there
are disease-specific means of doing this, the most effective across nearly all acutely
presenting disorders is dialysis. Finally, fine-tuning therapy with supplements of vita-
mins/cofactors, amino acids, and/or lipid nutritional supplements can be key in main-
taining metabolic stability well beyond discharge. Supportive management in illness
and avoidance of triggers is important in the chronic management and prevention of
metabolic crises across the lifespan.

CLINICS CARE POINTS

 Obatain basic laboratory studies.

 Begin parenteral nutrition (typically glucose to begin).
 Apply specific interventions (vitamins, detoxificants, other nutritional supplements) as labs
direct toward a more specific diagnosis.

DISCLOSURE

The author has nothing to disclose.

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