Pediatr Nephrol
`DOI 10.1007/s00467-011-1838-5
`
`EDUCATIONAL REVIEW
`
`Hyperammonemia in review: pathophysiology, diagnosis,
`and treatment
`
`Ari Auron & Patrick D. Brophy
`
`Received: 23 September 2010 / Revised: 9 January 2011 / Accepted: 12 January 2011
`# IPNA 2011
`
`Abstract Ammonia is an important source of nitrogen and is
`required for amino acid synthesis. It is also necessary for
`normal acid base balance. When present in high concentra
`tions, ammonia is toxic. Endogenous ammonia intoxication
`can occur when there is impaired capacity of the body to
`excrete nitrogenous waste, as seen with congenital enzymatic
`deficiencies. A variety of environmental causes and medica
`tions may also lead to ammonia toxicity. Hyperammonemia
`refers to a clinical condition associated with elevated
`ammonia levels manifested by a variety of symptoms and
`signs, including significant central nervous system (CNS)
`abnormalities. Appropriate and timely management requires a
`solid understanding of the fundamental pathophysiology,
`differential diagnosis, and treatment approaches available.
`The following review discusses the etiology, pathogenesis,
`differential diagnosis, and treatment of hyperammonemia.
`
`Keywords Hyperammonemia . Dialysis . Urea cycle
`defects . Treatment . Pathophysiology
`
`Introduction
`
`Ammonia is an important source of nitrogen and is required
`for amino acid synthesis. Nitrogenous waste results from
`
`A. Auron
`Blank Memorial Hospital for Children,
`1200 Pleasant St,
`Des Moines, IA 50309, USA
`
`P. D. Brophy (*)
`Department of Pediatrics, Pediatric Nephrology, Dialysis &
`transplantation, University of Iowa Children’s Hospital,
`200 Hawkins Dr,
`Iowa City, IA 52242, USA
`e-mail: patrick-brophy@uiowa.edu
`
`the breakdown and catabolism of dietary and bodily proteins,
`respectively. In healthy individuals, amino acids that are not
`needed for protein synthesis are metabolized in various
`chemical pathways, with the rest of the nitrogen waste being
`converted to urea. Ammonia is important for normal animal
`acid base balance. During exercise, ammonia is produced in
`skeletal muscle from deamination of adenosine monophos
`phate and amino acid catabolism. In the brain, the latter
`processes plus the activity of glutamate dehydrogenase
`mediate ammonia production. After formation of ammonium
`from glutamine, α ketoglutarate, a byproduct, may be
`degraded to produce two molecules of bicarbonate, which
`are then available to buffer acids produced by dietary sources.
`Ammonium is excreted in the urine, resulting in net acid loss.
`The ammonia level generally remains low (<40 mmol/L) due
`to the fact that most ammonia produced in tissue is converted
`to glutamine. Glutamine is also excreted by the kidneys and
`utilized for energy production by gut cells, which convert the
`nitrogen byproduct into alanine, citrulline, and ammonia,
`which are transported to the liver via the bloodstream.
`Ammonia enters the urea cycle in hepatocytes or is ultimately
`converted to glutamine. [1 5]
`Ammonia is toxic when present in high concentrations.
`Endogenous ammonia intoxication can occur when there is
`impaired capacity of the body to excrete nitrogenous waste,
`as seen with congenital enzymatic deficiencies. Patients
`with urea cycle defects (UCD), organic acidemias, fatty
`acid oxidation defects, bypass of
`the major site of
`detoxification (liver) (such as that seen in cirrhosis), Reye
`syndrome, postchemotherapy, or exposure to various toxins
`and drugs can all present with elevations in ammonia.
`Delayed diagnosis or
`treatment of hyperammonemia,
`irrespective of the etiology, leads to neurologic damage
`and potentially a fatal outcome, and thus it becomes a
`medical emergency when present. [6]
`
`Page 1 of 16
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`Ammonia toxicity (pathogenesis)
`
`Hyperammonemia refers to a clinical condition character-
`ized by elevated serum ammonia levels and manifests with
`hypotonia, seizures, emesis, and abnormal neurologic
`changes (including stupor). It may also exert a diabetogenic
`effect mediated by ammonia inhibition of
`the insulin
`secretion induced by a glucose load [7]. Hyperammonemia
`can cause irreparable damage to the developing brain, with
`presenting symptoms such as posturing, cognitive impair-
`ment (mental retardation), seizures, and cerebral palsy. The
`total duration of hyperammonemic coma and maximum
`ammonia level (but not the rapidity of ammonia removal),
`is negatively correlated with the patient’s neurological
`outcome. This is concerning when ammonia levels at
`presentation exceed 300 mmol/L. If left untreated,
`the
`outcome can be fatal. [7, 8]
`
`Pathologic brain changes induced by hyperammonemia
`
`Deaths secondary to hyperammonemia reveal upon autop
`sia cadaverum brain edema, brainstem herniation, astrocyt-
`ic swelling, and white-matter damage [8]. Neuropathologic
`findings seen in children with hyperammonemia include
`ventriculomegaly, cerebral cortical atrophy, basal ganglia
`lesions, neuronal loss, gliosis, intracranial bleed, and areas
`of focal cortical necrosis and myelination deficiencies.
`Electroencephalogram (EEG) denotes slow delta-wave
`activity, consistent with a metabolic disturbance [9–19].
`The brains of neonates and infants with hyperammonemia
`demonstrate areas of cortical atrophy or gray/white matter
`hypodensities, which are remnants of lost neuronal fibers.
`There is also an increased number of oligodendroglia and
`microglia in striatum. [17]
`
`Amino acid disturbances in the brain
`
`Glutamine
`
`Glutamine synthesis mediated by the astrocytic enzyme
`glutamine synthetase is the major pathway for ammonia
`detoxification in the brain and cerebrospinal fluid. In
`conditions in which excess ammonia exists, brain osmoti-
`cally active glutamine concentrations increase, leading to
`astrocytic damage and swelling. Consequently, the astro-
`cyte promotes intercellular glutamate release, which
`decreases the glutamate intracellular pool and ultimately
`leads to cell death of the glutamatergic neurons [17, 20–22]
`
`Arginine
`
`Although arginine is an essential amino acid for the fetus
`and the neonate, they still synthesize part of it through
`
`Pediatr Nephrol
`
`intestinal expression of carbamyl phosphate synthetase −1
`(CPS), ornithine transcarbamylase (OTC), argininosucci-
`nate synthetase (AS), and argininosuccinase (AL). In the
`adult, arginine is synthesized through two pathways: in
`the intestine, CPS-1 and OTC synthesize citrulline; and
`AS and AL in the renal proximal
`tubules synthesize
`arginine from citrulline. Thus, patients with UCD (except
`Arginase deficiency I) have low serum arginine levels
`and need this amino acid to be replaced, although
`citrulline is a better replacement choice for patients with
`CPS-1 and OTC [17, 23]
`
`Alterations in neurotransmission systems
`
`Glutamatergic system
`
`An excess of extracellular glutamate accumulates in
`brain when the latter
`is exposed to ammonia. The
`mechanism involves astrocytic swelling, pH and calcium
`(Ca2+)-dependent
`release of glutamate by astrocytes,
`inhibition of glutamate uptake by astrocytes through
`inhibition of
`the glutamine aspartate transporter
`(GLAST), and excess depolarization of glutamatergic
`neurons. Excess extracellular glutamate secondary to
`ammonia exposure promotes toxic cellular hyperexcit-
`ability through activation of N-methyl-D-aspartate
`(NMDA) receptors and leads to alteration in nitric oxide
`(NO) metabolism, disturbances in sodium/potassium
`adenosine triphosphatase (Na+/K+−ATPase),
`(causing
`neuronal sodium/potassium influx), ATP shortage, mito-
`chondrial dysfunctions, free-radical accumulation, and
`oxidative stress, leading ultimately to cell death. Toxic
`stimulation of NMDA receptors can also be caused by
`quinolinic acid, which is an oxidation product of
`tryptophan acting on NMDA receptors and plays a role
`in the neurotoxicity seen in UCD patients (associated with
`death of spiny neurons in the striatum). Tryptophan and
`quinolinic acid concentration increases in brain and
`cerebrospinal
`fluid,
`respectively,
`in the presence of
`hyperammonemia. [17, 24–28]. In experimental animal
`models, as a protective cellular mechanism against excitotox-
`icity, a reduction in NMDA receptors is noted secondary to the
`increased release of glutamate. Nevertheless, in patients with
`UCD, despite the downregulation of NMDA receptors, there
`is still a certain degree of cellular toxicity that leads to cell
`death. Interestingly, prolonged cortical neuron survival has
`been reported to occur in hyperammonemic animals given the
`NMDA receptor antagonists MK-801 and 2-amino-5-phos-
`phonovaleric acid (APV) [29]. The glutamatergic stimuli
`secondary to prolonged brain exposure to ammonia can also
`affect activation of other neurotransmission systems, such as
`gamma-aminobutyric acidd (GABA) or benzodiazepine
`receptors [30]
`
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`Pediatr Nephrol
`
`Cholinergic system
`
`This system plays a key role in cognitive development.
`Cholinergic neurons loss, with decreased choline acetyl-
`transferase (ChAT) activity level, has been observed in
`animal models with hyperammonemia. [17, 31]
`
`Serotonergic system
`
`s e r o t o n i n ) a n d 5 -
`f o r
`Tr y p t o p h a n ( p r e c u r s o r
`hydroxyindoleacetic acid (5-HT) (metabolite of serotonin)
`are elevated in cerebrospinal fluid of children with UCD.
`Experimental hyperammonemic animal models demon-
`strate alterations in serotonergic activity through loss of 5-
`HT2 receptors and an increase in 5-HT1A receptors. These
`physiologic responses may play a role in anorexia and sleep
`disturbances noted in children with UCD [32–34]
`
`Cerebral energy deficit
`
`Hyperammonemic experimental animal models develop
`increased superoxide production and decreased activities
`of antioxidant enzymes in brain cells. Blockage of nitric
`oxide synthase by nitroarginine or NMDA receptor antag-
`onists prevent the latter changes, suggesting therefore that
`ammonia-induced oxidative stress is due to the increased
`nitric oxide formation as a consequence of NMDA receptor
`activation [34]. Indeed, excessive formation of nitric oxide
`seen with ammonia exposure impairs mitochondrial respi-
`ration, depletes ATP reserves, and increases free radicals
`and oxidative stress, which ultimately leads to neuron death
`[17, 26]. Creatine, too, plays a key role in cellular energy
`formation and is decreased in the brain cells of hyper-
`ammonemic animals due to altered creatine transport and
`synthesis. Acetyl-L-carnitine enhances restoration of ATP
`and phosphocreatine levels in ischemia and has been
`reported to enhance the recovery of cerebral energy deficits
`caused by hyperammonemia, thus having a neuroprotective
`effect (through restoration of cytochrome C oxidase activity
`and free-radical scavenging) [35–37]. Cotreatment with
`creatine (while there is exposure to ammonia) protects
`axonal growth, thereby suggesting a possible neuroprotec-
`tive role for this substance. [17, 38]
`
`regulated kinase (ERK)1/2, stress-activated protein kinase/c-
`Jun N-terminal kinase (SAPK/JNK), and p38 in astrocytes.
`Phosphorylation of ERK1/2 and p38 are responsible for
`ammonia-induced astrocyte swelling, and phosphorylation of
`SAPK/JNK and p38 are responsible for ammonia-induced
`inhibition of astrocytic uptake of glutamate. Adjunct treatment
`with CNTF has shown to induce protective effects on
`oligodendrocytes by reversing the demyelination induced by
`hyperammonemia [17, 39, 40]
`
`K+ and water channels
`
`Although the brain edema that develops in hyperammonemic
`patients with UCD has been thought to occur secondary to
`astrocytic swelling, recently, this has been challenged. In
`astrocytes of hyperammonemic animals, it has been noted that
`a reduction of proteins that regulate the K+ and water
`transport at the blood–brain barrier, including connexin 43,
`aquaporin 4 (aquaporins are membrane proteins that mediate
`water movement across the membrane), and the astrocytic
`inward-rectifying K+ channels Kir4.1 and Kir5.1, allows
`ammonia to easily permeate through the aquaporin channels.
`In the setting of hyperammonemia, downregulation of
`aquaporins occurs (reflecting a protective mechanism of
`astrocytes to prevent ammonia entering the cell), but
`simultaneously, the excretion of K+ and water is altered,
`and an increase in brain extracellular K+ and water develops,
`contributing to brain edema formation [41, 42].
`
`Differential diagnosis of hyperammonemia
`
`Diagnostically, the presence of acidosis, ketosis, hypoglyce-
`mia, and low bicarbonate levels indicate that the root cause of
`hyperammonemia is probably due to an organic acidemia,
`systemic carnitine deficiency, Reye syndrome, toxins, drug
`effect, or liver disease. On the other hand, if there is normal
`lactate and no metabolic acidosis associated with the hyper-
`ammonemia, then UCD, dibasic aminoaciduria, or transient
`hyperammonemia of the newborn are more likely. The
`association of elevated liver enzymes with hyperammonemia
`is most consistent after insult from hepatotoxins, Reye
`syndrome, or carnitine deficiency [6] (Table 1).
`
`Cerebral exposure
`
`Urea cycle disorders
`
`Once the brain has been exposed to ammonia, intracerebral
`endogenous protective mechanisms that prevent or limit brain
`damage are triggered. Astrocytes express an injury-associated
`survival protein—ciliary neurotrophic factor (CNTF)—which
`is upregulated by ammonia through p38 mitogen-activated
`protein kinase (MAPK) activation. Ammonia activates a
`variety of kinase pathways including extracellular signal
`
`The urea cycle produces arginine by de novo synthesis. Six
`enzymatic reactions comprise the cycle, which occurs in the
`liver. The first three reactions are located intramitochond-
`rially and the rest are cytosolic. The enzymatic substrates
`are ammonia, bicarbonate, and aspartate. After each turn of
`the cycle, urea is formed from two atoms of nitrogen (see
`Fig. 1) [43]. Key enzymes in the urea cycle include CPS-1,
`
`Page 3 of 16
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`

`

`Table 1 Differential diagnosis of hyperammonemia
`
`Causes
`
`Disease
`
`Urea cycle disorders
`
`Organic acidemias
`
`Drug related causes
`
`Miscellaneous causes
`
`Argininosuccinic aciduria
`Citrullinemia
`Carbamyl Phosphate Synthetase (CPS)
`deficiency 1
`Ornithine transcarbamylase deficiency
`Argininemia
`Propionic acidemia
`Methylmalonic acidemia
`Isovaleric acidemia
`Maple syrup urine disease
`Dibasic aminoacidurias
`Type 1
`Type 2 (Lysinuric protein intolerance)
`Hyperammonemia hyperornithinemia
`homocitrullinuria
`Transient hyperammonemia of the
`newborn
`Salicylates
`Carbamazepine
`Valproic acid
`Topiramate
`Tranexamic acid
`Chemotherapeutic agents:
`Aspariginase 5 fluorouracil
`Rituximab
`Hypoglycin intoxication
`Pregnancy
`Distal Renal Tubular Acidosis (RTA)
`Carnitine transport defects
`Urinary tract dilatation
`Reye’s syndrome
`
`OTC, AS, AL, and arginase. There are cofactors necessary
`for optimal enzyme activity, the most clinically important
`of which is N-acetyl glutamate (NAG). In UCD, there is an
`increase in glutamine, which transports nitrogen groups to
`the liver for ammonia formation within hepatic mitochon-
`dria, and ammonium combines with bicarbonate in the
`presence of NAG to form carbamyl phosphate. If NAG is
`absent, hyperammonemia develops [1, 6]
`The presence of an enzymatic defect in the urea cycle
`results in arginine becoming an essential amino acid (except in
`arginase deficiency), and waste nitrogen accumulates mainly
`as ammonia and glutamine [6] Measurement of plasma amino
`acids aids in differentiating between the different urea cycle
`enzyme deficiencies. Citrulline is the product of CPS and
`OTC and the substrate for AS and AL, thus its value is of
`critical importance. In CPS and OTC deficiencies, plasma
`citrulline levels are low. These two defects are differentiated
`
`Pediatr Nephrol
`
`that orotic acid is elevated in OTC
`by the fact
`deficiency and absent
`in CPS deficiency.
`In AS
`(citrullinemia) and AL (argininosuccinic aciduria) defi-
`ciencies, plasma citrulline levels are increased (see
`Fig. 2). If the serum citrulline level
`is normal,
`then
`disorders such as argininemia, lysinuric protein intoler-
`ance, and the hyperammonemia-hyperornithinemia-
`homocitrullinuria syndrome should be considered [6]
`The prevalence of UCD is estimated at 1:8,200 in the
`USA. The overall incidence of defects presenting clinically
`is estimated at approximately 1 in 45,000 live births [1, 44].
`Each specific disorder is considered below.
`
`Argininosuccinic aciduria: argininosuccinase deficiency 1
`
`The genetic deficiency responsible for this disorder is
`located on chromosome 7-q11.2. The diagnosis is suspected
`by observing hyperammonemia without acidosis in the
`presence of increased AL levels in plasma and urine.
`Plasma citrulline is also elevated. Measuring AL activity in
`erythrocytes or fibroblasts confirms the diagnosis. Distin-
`guishing clinical
`features include mental
`retardation,
`trichorrhexis nodosa (fragile hair with a nodular appear-
`ance), and an erythematous maculopapular skin rash. The
`latter two are associated with arginine deficiency and
`disappear with arginine supplementation. Liver involve-
`ment is characterized by hepatomegaly and elevated trans-
`aminases, and the associated histopathology displays
`enlarged hepatocytes and fibrosis [6, 45]
`
`Citrullinemia: argininosuccinate synthetase deficiency
`
`The genetic deficiency responsible for this disorder is
`located on chromosome 9q34. Common findings include
`hyperammonemia and low serum urea nitrogen and
`arginine levels, but
`the pathognomonic finding is a
`markedly elevated plasma citrulline level in the absence
`of AS. Affected individuals are able to partially incorporate
`the waste nitrogen into urea-cycle intermediates, which
`makes treatment easier [6, 45]
`
`Carbamyl phosphate synthetase (CPS) deficiency 1
`
`This represents the most severe form of UCD, with early
`development of hyperammonemia in the neonatal period,
`although it can also become apparent in adolescence. The
`genetic deficiency responsible for this disorder is located on
`chromosome 2q35. Biochemical findings in this entity
`include recurrent hyperammonemia, absent citrulline, and
`low levels of arginine, urea nitrogen, and urinary orotic
`acid. Diagnosis is confirmed by demonstrating <10%
`normal CPS activity in hepatic, rectal, or duodenal tissue
`[6, 45, 46].
`
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`

`Pediatr Nephrol
`
`Fig. 1 Urea cycle pathway. Black arrows indicate primary pathway.
`Yellow arrows show alternative pathways used to eliminate nitrogen in
`patients with urea cycle defects. Enzymes are in blue. CPS
`carbamoylphosphate synthetase, OTC ornithine transcarbamoylase,
`
`AS argininosuccinate synthetase, AL argininosuccinate lyase, ARG
`arginase, NAGS N acetylglutamate synthase. Reproduced with
`permission from Walters and Brophy [43]
`
`Ornithine transcarbamylase deficiency
`
`and elevated urinary orotic acid. Liver biopsy helps confirm
`the diagnosis [1, 45, 47, 48]
`
`This represents the most common urea cycle enzyme
`defect, with an incidence of 1 in 14,000, and is the only
`one inherited as a sex-linked trait. OTC catalyzes the
`reaction of ornithine and carbamoyl phosphate to produce
`the amino acid citrulline. The OTC gene is located on the
`short arm of
`the X chromosome at Xp21, which is
`expressed specifically in the liver and gut. Around 350
`pathological mutations have been reported, and in approx-
`imately 80% of patients, a mutation is found. In girls in
`whom there is partial expression of the X-linked OTC
`deficiency disorder, mild symptoms can be seen. Only 15%
`of female carriers are symptomatic, and most asymptomatic
`carriers have a normal IQ score. Biochemical diagnostic
`findings include hyperammonemia, absent serum citrulline,
`
`Argininemia: arginase deficiency 1
`
`Afflicted patients do not develop symptoms in infancy.
`Children develop toe walking as a characteristic feature,
`which progresses to spastic diplegia. Finding elevated
`serum arginine, urine orotic acid, and ammonia levels
`makes the diagnosis.
`
`Organic acidemias
`
`This group of autosomally recessive inherited disorders
`results from enzyme deficiencies in amino acid degra-
`dation pathways. Most of
`the disorders are due to
`
`Page 5 of 16
`
`

`

`Fig. 2 Etiology of hyperammo
`nemia. Urea cycle defects:
`ornithine transcarbamylase
`(OTC); carbamyl phosphate
`synthetase (CPS);
`argininosuccinate synthetase
`(ASS); transient
`hyperammonemia of the
`newborn (THN). Reproduced
`with permission from Walters
`and Brophy [43]
`
`Pediatr Nephrol
`
`Hyperammonemia
`
`Blood pH and
`HCO3
`
`Acidosis
`
`Urine Organic
`Acids
`
`Organic
`Acidemias
`
`Low
`
`Low or Absent
`
`Increased
`
`Citrulline
`
`Normal or Slightly
`Increased
`
`Argininosuccinic
`Acid
`
`No
`Acidosis
`
`Plasma Amino
`Acids
`
`Significantly
`Increased
`
`Citullinemia
`
`CPS
`
`OTC
`
`Normal
`
`Increased
`
`THN
`
`ASS
`
`defective metabolism of branched-chain amino acids
`(leucine,
`isoleucine, and valine),
`tyrosine, homocys-
`teine, methionine, threonine, lysine, hydroxylysine, and
`tryptophan. This results
`in the accumulation and
`excretion of non-amino (organic) acids in plasma and
`urine. Hallmark findings in organic acid disorders
`include high anion gap metabolic acidosis, ketoacidosis
`(due to the accumulation of lactate and organic acids),
`and pancytopenia. Hyperammonemia is seen and is
`caused by accumulation of coenzyme A (CoA) deriva-
`tives, which inhibit carbamyl phosphate synthetase
`activity [6].
`
`Propionic acidemia
`
`The defect responsible for this disorder is in the enzyme
`propionyl-CoA carboxylase, which converts propionyl CoA
`to D-methylmalonyl CoA. Consequently, plasma ammoni-
`um, propionate, and glycine levels are elevated. The
`diagnosis is confirmed by measuring propionyl-CoA
`carboxylase activity in leukocytes or skin fibroblasts [6].
`
`Methylmalonic acidemia
`
`This disorder results from the inability to convert methyl-
`malonyl CoA to succinyl CoA. Patients develop metabolic
`ketoacidosis, hypoglycemia, hyperglycinemia, pancytope-
`nia, and hyperammonemia. There is also increased urinary
`excretion of methylmalonic acid [6].
`
`Isovaleric acidemia
`
`This entity results from a defect in leucine metabolism
`whereby isovaleryl CoA cannot be dehydrogenated to 3-
`methylcrotonyl CoA. This is characterized by a strong body
`odor resembling “sweaty feet.” Diagnostic features include
`elevated serum ammonia, isovaleric acid, and hypocarniti-
`nemia [6].
`
`Maple syrup urine disease
`
`Maple syrup urine disease is characterized by maple syrup
`odor noted in the urine and elevated serum branched-chain
`amino acid concentrations (leucine, isoleucine, and valine)
`during the first 24 h of life. Hyperammonemia contributes
`to neurologic deterioration. Glutamate levels are decreased,
`with consequent decrease in urea synthesis [15].
`
`Dibasic aminoacidurias
`
`recessive
`Lysinuric protein intolerance This autosomal
`condition is characterized by lysinuria and inadequate urea
`formation with development of hyperammonemia. The
`primary defect resides in renal tubular, intestinal, epithelial,
`and hepatic dibasic amino acid transport mechanisms. This
`results in a drop of available serum levels of ornithine,
`lysine, and arginine, leading eventually to hyperammone-
`mia. There are concomitant increases in urinary excretion
`of lysine, ornithine, arginine, and citrulline [49].
`
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`

`Pediatr Nephrol
`
`Hyperammonemia hyperornithinemia homocitrullinuria
`
`recessive condition results from low
`This autosomal
`ornithine transport into abnormal mitochondria, resulting
`in decreased flow through OTC. Consequently, plasma
`ornithine levels rise with an associated increase in excretion
`of homocitrulline in the urine and hyperammonemia [6].
`
`Transient hyperammonemia of the newborn
`
`This disorder may be found in infants with a history of
`perinatal asphyxia, and symptoms can develop before the
`infant is 24 h of age. It presents in two forms: asymptom-
`atic and symptomatic. The former is self-limited and is
`thought to occur secondary to a transient deficiency of one
`of the urea cycle enzymes, a renal
`transport defect of
`arginine or ornithine, or a deficient synthesis of ornithine.
`All of these presumably are related to developmental
`immaturity.
`In the second form (unknown etiology),
`patients present with respiratory distress,
`lethargy, and
`coma. In both forms, plasma amino acids show elevated
`glutamine and alanine levels. The neurologic outcome in
`these patients can range from normal intellectual capacity to
`profound mental retardation and seizures [6].
`
`Drug related causes
`
`Salicylate Salicylate overdose can lead to a Reye-like
`clinical presentation,
`including emesis, anorexia, fever,
`hyperventilation, irritability, and hallucinations. In the early
`phase, there is respiratory alkalosis, with later development
`of metabolic acidosis associated with hypoglycemia, hyper-
`ammonemia, elevated serum salicylate levels, and hepato-
`toxicity. The pathogenesis involves mitochondrial
`dysfunction and uncoupling of oxidative phosphorylation
`[6].
`
`Carbamazepine Asterixis and hyperammonemia are un-
`common complications associated with carbamazepine use.
`The mechanism by which hyperammonemia develops is
`unknown, and treatment
`for
`the latter
`is simply to
`discontinue the anticonvulsant [50–52].
`
`Valproic acid Valproic acid use has been associated with
`the induction of hyperammonemic encephalopathy through
`astrocytic edema, renal tubular interference with glutamine
`synthesis, and/or
`increased renal glutaminase activity
`(resulting in enhanced ammoniagenesis). Valproic acid
`depends on carnitine for its metabolism and can deplete
`the latter. Hyperammonemia has been prevented by
`providing supplemental carnitine [53–55]. Once the
`valproic-acid-induced hyperammonemic encephalopathy
`has been identified, discontinuation of the drug results in
`
`recovery after a few days, with normalization of serum
`ammonia levels. In patients with inborn errors of metabo-
`lism who are having seizures, valproate should be avoided,
`as it can worsen the hyperammonemia [56].
`
`Topiramate Topiramate in combination with valproic acid
`has been associated with the development of hyperammo-
`nemia [57] The toxic effects of topiramate may relate to its
`ability to inhibit carbonic anhydrase, which in turn affects
`gamma-aminobutyric-acid-gated chloride ion conductance
`at the GABA A receptor and through its effect on the
`hepatic availability of bicarbonate (HCO3), which is also a
`substrate for carbamoylphosphate synthesis [53, 58]. In
`addition, topiramate inhibits glutamine synthetase activity
`in the brain, leading to toxic levels of ammonia [55].
`
`Tranexamic acid This is an antifibrinolytic agent that has
`been associated with the development of hyperammonemia
`seen as cause or result of convulsions caused by the
`medication [59].
`
`Chemotherapy Hyperammonemic coma has been described
`postinduction chemotherapy for acute myeloid leukemia. It
`has also been described in patients with multiple myeloma
`(as abnormal plasma-cell clones may produce ammonia) in
`those receiving chemotherapy with asparaginase, 5-
`fluorouracil
`(transient hyperammonemia), and in those
`receiving rituximab. The pathogenic mechanism is thought
`to be related to an acquired deficiency of glutamine
`synthetase of unknown cause. [60–65]
`
`Miscellaneous causes of hyperammonemia
`
`Hypoglycin (Jamaican vomiting sickness) This is caused by
`a toxin present in the unripe ackee fruit. The Jamaican
`vomiting sickness, which has a high mortality rate (up to
`50%), is characterized by vomiting, lethargy, hallucinations,
`coma, hypoglycemia, hyperammonemia, and abnormal
`liver enzymes, which occur when this unripe fruit
`is
`ingested [6].
`
`Pregnancy Hyperammonemic presentation occurs mostly
`during puerperium, but it has also been reported during
`pregnancy in patients with OTC and CPS deficiencies.
`During pregnancy,
`the healthy fetus can metabolize
`ammonia, whereas after delivery, this metabolic process is
`absent and ammonia accumulates in the mother. In addition,
`tissue breakdown occurs with postdelivery uterine involu-
`tion, adding more waste nitrogen products to the urea cycle
`[66–68].
`
`Distal renal tubular acidosis (RTA) Most renal production
`of ammonia occurs in the S1 and S2 segments of the
`
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`proximal renal tubule. The renal ammonia production and
`tubular reabsorption are stimulated by chronic metabolic
`acidosis and potassium depletion. Distal renal
`tubular
`acidosis (RTA) has been reported in association with
`hyperammonemia and should be considered in the differ-
`ential diagnosis in infants with distal RTA who are
`hypokalemic [69–71].
`
`Carnitine transport defects Carnitine transport enzyme
`defects manifest with hypoglycemia, lethargy, and poten-
`tially a Reye-like syndrome (hepatomegaly, elevated trans-
`aminases, and ammonia). Carnitine plays a key role as
`cofactor in fatty-acid metabolism and its deficiency can
`lead to abnormal fatty-acid oxidation, leading to develop-
`ment of hyperammonemia and encephalopathy. In primary
`systemic carnitine deficiency, an autosomal
`recessive
`condition, the organic cation transporter gene OCTN2 is
`mutated, resulting in hypocarnitinemia secondary to re-
`duced renal tubular reabsorption of carnitine. Patients with
`this often present with hyperammonemia, encephalopathy,
`hypoglycemia, and myopathies [72].
`
`Urinary tract dilatation Proteus is a bacteria that charac-
`teristically produces an alkaline urine pH due to the
`hydrolysis of urea to ammonia by the bacterial urease.
`Children with massively dilated urinary tracts whose
`urinary tract is infected/colonized by this bacterium may
`develop hyperammonemia [73].
`
`Reye syndrome Reye syndrome is a disease of unknown
`etiology associated with hyperammonemia. Viruses (espe-
`cially influenza B and varicella),
`toxins/drugs (valproic
`acid, salicylate, aflatoxin, pesticides, and bacillus cereus),
`and a genetic component (increased risk of occurrence in
`siblings) have been implicated as causal factors. The key
`physiologic findings noted are a consequence of hepatic
`mitochondrial
`injury (swelling and death) caused by
`inhibition of the mitochondrial respiratory chain. Abnormal
`findings include acute encephalopathy, hyperammonemia,
`lactic acidosis, hypoglycemia, elevated liver enzymes,
`fatty-liver infiltration, and increased intracranial pressure
`[6, 74].
`
`Clinical symptoms of hyperammonemia
`
`Symptomatology varies with patient age and ammonium
`level and may include, among the most common findings:
`hypotonia, vomiting,
`lethargy, seizures, coma, ataxia,
`anorexia, abnormal behavior patterns, dysarthria, weakness,
`liver enlargement, and dementia. Most patients with UCD
`present during the neonatal period with nonspecific
`symptoms (poor feeding, vomiting, somnolence, irritability,
`tachypnea, and lethargy).
`
`Pediatr Nephrol
`
`Hepatic encephalopathy
`
`Acute and chronic hepatic encephalopathy (HE), in which
`hyperammonemia plays a pivotal role, can be seen as a
`complication of acute (i.e., drug toxicity,
`infections) and
`chronic liver disease. Swelling of astrocytes can lead to
`increased intracranial hypertension, cerebral edema, brain-
`stem herniation, and death. Chemical abnormalities include a
`generalized aminoacidemia (except for branched-chain amino
`acid levels, which are normal), hypoglycemia, hypovolemia,
`electrolyte disturbances, and hyperammonemia. Once the
`latter is reduced to normal levels, then clinical manifestations
`of hepatic encephalopathy reverse [22].
`
`Hyperammonemia treatment
`
`Toxin removal, enzyme induction, and anabolism are the
`main goals of emergency treatment. Normal patient growth
`and development should be the main goal of long-term
`treatment. Given the correlation between the duration of
`hyperammonemic coma and prospective neurocognitive
`function, it is imperative to institute treatment for hyper-
`ammonemia as soon as possible to prevent
`further
`neurological damage (even prior to a definitive diagnosis
`being made). The infant/child neurologic status should be
`examined carefully to assess response to treatment and,
`simultaneously,
`to ascertain the degree of neurological
`impairment that has occurred as sequelae from the primary
`disease. Overall, the treatment approach is similar, irre-
`spective of diagnosis. Dialysis should be immediately
`available and started if there is no response to conventional
`treatment (perhaps even at the same time).
`Treatment for acute hyperammonemia should be started
`with the goal of decreasing serum ammonia rapidly by
`reducing the production of nitrogenous waste (achieved by
`discontinuing protein intake, for no more than 48 h) and
`providing a hypercaloric glucose-based solution to enhance
`anabolism [75]. Supportive treatment and correction of
`hydration, nutritional status, mineral (calcium, potassium),
`and electrolyte imbalances should be addressed. In patients
`with UCD, bacterial sepsis can lead to a fatal outcome due
`to catabolism, thus, antibiotic coverage should be consid-
`ered even as prophylaxis, as patients often undergo multiple
`invasive procedures (such as line placement