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`INTERPRETATIONS
`
`Metabolic Medicine Unit, Great
`Ormond Street Hospital for
`Children with UCL Institute of
`Child Health, London, UK
`
`Correspondence to
`Dr Alexander Broomfi eld,
`Metabolic Medicine Unit, Great
`Ormond Street Hospital for
`Children with UCL Institute of
`Child Health, 34 Great Ormond
`Street, London WC1N 3JH, UK;
`Brooma@gosh.nhs.uk
`
`Received 14 April 2011
`Accepted 24 October 2011
`Published Online First
`18 November 2011
`
`How to use serum ammonia
`
`Alexander Broomfi eld, Stephanie Grunewald
`
`Abstract
`Hyperammonaemia is a potentially extremely
`important indicator of impairment in intermediate
`metabolism. However, lack of experience in
`sample handling and confusion about what
`level is signifi cant, can lead to its devaluation
`as a test. The aim of this article is to help the
`non-metabolic specialist to decide when it is
`appropriate to investigate for hyperammonaemia,
`to discuss potential investigatory pitfalls
`and to help in interpretation of results.
`
`Introduction
`When considering any key diagnostic
`metabolite in the investigation of suspected
`metabolic conditions, early and correct
`sampling are the main determinants of a
`successful diagnosis and can very often
`affect the outcome. Adequate perform-
`ance of any investigation is essential for
`both reliable and interpretable results.
`There are few better examples than that of
`plasma ammonia, an investigation that has
`been noted to be poorly performed even
`in specialised centres.1 2
`The aim of this study is to help the non-
`metabolic specialist to decide when it is
`appropriate to investigate for hyperam-
`monaemia (something unfortunately often
`investigated only after substantial delay),
`to discuss potential pitfalls and to help to
`interpret results. In addition, the authors
`provide some information on the inter-
`pretation of basic biochemical tests in the
`context of hyperammonaemia (table 1).
`However, as has been stated in previous
`studies in this series, there is no substitu-
`tion for close communication between the
`laboratory doing an investigation and the
`clinical team which is requesting it.
`
`Biochemical/physiological background
`Ammonia, a highly toxic intermediary
`metabolite, is formed during the catabolism
`of the nitrogen-containing amine groups of
`amino acids, as a normal part of biochemi-
`cal homoeostasis. At physiological pH,
`ammonia is mainly found as ammonium
`+), a small molecule (of molecular
`(NH4
`weight 18D), which can diffuse freely across
`
`the blood–brain barrier. To prevent ammo-
`nia accumulating, it is immediately incor-
`porated into glutamine and reconverted
`to ammonia in the liver.3 Here it is rapidly
`converted into urea by a series of reactions
`known as the urea cycle (figure 1). It is typ-
`ically a breakdown in the flux through this
`pathway that leads to hyperammonaemia,
`though general liver failure and the actions
`of urease-positive intestinal bacteria can
`also produce significant hyperammonae-
`mia.4 5The importance of normal ammonia
`homoeostasis can be from the deleterious
`pathological cascade that results when
`ammonia accumulates, with the central
`nervous system, being especially affected.
`Here, increased levels of ammonia result
`in both acute and chronic effects, such as
`osmotic effects due to glutamine accumula-
`tion, alterations in cerebral energy use and
`neurotransmission, impairment of axonal
`and dendritic growth and induction of neu-
`ronal apoptosis.3 6
`Inborn errors of metabolism (IEMs)
`that cause hyperammonaemia (table 2),
`without obvious liver failure, can be due
`to primary enzyme deficiencies of the urea
`cycle enzymes, due to defects in its sub-
`strate carriers, or because of secondary
`disruption of the urea cycle. Examples of
`secondary disruption are by the organic
`acidaemias such as propionic acidae-
`mia or methylmalonic acidaemia, where
`accumulating
`propionyl-coenzyme A
`competitively inhibits the production of
`N-acetylglutamate (the cofactor of car-
`bamylphosphate synthetase, CPS7, though
`there may be other contributing factors).8
`The mechanism behind the fatty acid oxi-
`dation defects leading to hyperammonae-
`mia is less clear but a possibility is that
`it is due to a generalised mitochondrial
`dysfunction resulting from a compensa-
`tory increase in ω-oxidation secondary to
`carnitine deficiency9 or due to deficiencies
`in acetyl CoA.10 Examples of transporter
`defects affecting the flux of urea cycle sub-
`strates into the cell cytoplasm or the mito-
`chondria are lysinuric protein intolerance
`and citrin deficiency, respectively.
`
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`INTERPRETATIONS
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`Table 1 Routine biochemical investigations and their meaning in the
`context of hyperammonaemia
`
`Investigation
`
`Meaning if hyperammonaemia present
`
`Blood gas
`
`Anion gap
`
`Glucose
`
`Lactate
`
`Hypo/hypercalcaemia
`
`Liver function test including
`clotting
`
`Urinary ketones
`
`
`
`A respiratory alkalosis is suggestive of a urea cycle disorder and
`results from initial over stimulation of central respiratory drive by
`ammonia which may be subtle.
`A metabolic acidosis should prompt the calculation of an anion gap
`but in the context of hyperammonaemia it is suggestive of severe
` cardiovascular compromise and/or an organic acidaemia.
`−+Cl−)=8–11. An increased anion gap is strongly
`(Na+)-(HCO3
` suggestive of an organic acidaemia
`While hypoglycaemia is a non-specifi c marker of disease it does
`raise the possibility of a fatty acid oxidation disorder and should
`prompt testing of both creatine kinase and urinary ketones.
`The later being absent/ unexpectedly low in fatty acid oxidation
`disorders and in the HIHA.
`Typically a manifestation of poor peripheral perfusion or sampling
`from a squeezed capillary sample, but raises the possibility of
`organic acidaemias due to secondary TCA cycle inhibition or a
`mitochondrial cytopathy
`A disturbance in calcium regulation is often found in organic
`acidaemias. This should also prompt an evaluation for pancreatitis,
`that is consider amylase and lipase, especially in older patients as
`this is a well-known complication of organic acidaemias.
`If abnormal, suspect a fatty acid oxidation disorder and a creatine
`kinase should be taken. However liver failure is a feature of many
` disorders resulting in liver dysfunction.
`The presence of ketones in the urine of a neonate is suggestive of
`an organic academia.14
`Their absence can suggest a fatty acid oxidation disorder or HIHA.
`
`HIHA, Hyperinsulinism hyperammonaemia syndrome; TCA, tricarboxylic acid.
`
`Technological background: how is ammonia
`measured?
`The majority of laboratories in the UK use a method
`based on the reductive amination of 2-oxoglutarate
`by glutamate dehydrogenase (GLDH). This reaction,
`as can be seen below, requires reduced nicotinamide
`adenine dinucleotide phosphate (NADPH) with the
`reduction in NAPDH being proportional to the plasma
`ammonia concentration:
`2-Oxoglutarate+NH3+NADPH
`↑↓GLDH
`Glutamate+NADP
`The importance of the NADPH is that the change in
`its concentration can be measured spectroscopically, as
`the decrease of absorbance at 340 nm (the wavelength
`of NADPH) reflects its oxidisation to NADP.11
`In smaller laboratories where the demand is limited,
`reflectance meters are often used, employing dry slide
`chemistry strips for whole blood ammonia. In this
`method the intensity of colour formed by the reaction
`between blood ammonia and bromocresol green or
`similar indicator reagent is measured. The advantages
`of this technique are that it is quick, cheap and accu-
`rate.12 However, it does have one very important dis-
`advantage, which is a cut-off range of 286 µmol/l.
`It is of the upmost importance that clinicians are
`aware of the techniques used in their laboratories,
`
`though the laboratory should also be feeding back that
`there is a possibility of the ammonia being substan-
`tially higher, if they are using reflectance meters.
`
`Indications and limitations
`In whom should hyperammonaemia be suspected?
`Plasma ammonia can be used both as part of diag-
`nostic investigations and for monitoring of efficacy of
`treatment. Diagnostically, while the key characteristic of
`hyperammonaemia is an unexplained acute or progres-
`sive encephalopathy,13 its clinical presentation is also
`determined by the age at presentation and the degree of
`hyperammonaemia. Whereas the neonatal presentation
`is very non-specific, with neonates usually rapidly dete-
`riorating, mimicking sepsis, the range of presentation in
`older children is more varied encompassing gastrointesti-
`nal symptoms, liver disease and psychiatric disturbances
`as well as classical encephalopathy. In both infants and
`older children the British Inherited Metabolic Disease
`Group (BIMDG) decreased consciousness level and the
`MetBionet investigation of developmental delay guide-
`lines are useful resources in help guiding non-specialists
`to appropriate investigations.
`
`Newborns
`In the neonatal period, given the limited clinical reper-
`toire of response in the newborn, the initial symptoms
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`Table 2 Causes of hyperammonaemia
`
`Artefact
`
`Haemolysis/specimen contamination/ delayed
`separation
`
`IEM resulting in direct
` inhibition of the urea cycle
`
`Urea cycle disorders
`
`Organic acidaemias
`
`Fatty acid oxidation
`disorders
`Other mainly
`
`Hepatic dysfunction
`
`Prehepatic
`
`
`
`hepatic
`Post hepatic
`
`Primary enzyme defects:
`N-acetylglutamate synthetase defi ciency;
`carbomylphosphate synthase defi ciency;
`ornithine transcarbamylase defi ciency;
`argininosuccinate synthase defi ciency;
`argininosuccinate lyase defi ciency;
` arginase defi ciency.
`Transporter defects:
`citrin defi ciency; hyperornithinaemia
`hyperammmonaemia homocitrullinuria
`(HHH); lysinuric protein intolerance.
`Propionic acidaemia; methylmalonic
` acidaemia; isovaleric acidaemia.
`Especially CPT1/LCHAD/VLCAD/glutaric
`aciduria type II.
`Ornithine aminotransferase defi ciency
`(OAT); hyperinsulinism hyperammonaemia.
`Abernathey malformation; Budd–Chiari
`syndrome.
`Any cause of hepatic failure.
`Biliary atresia.
`
`CPT1, carnitine palmitoyltransferase-1 (CPT-1) defi ciency; IEM, inborn errors of metabolism;
`LCHAD, long chain 3-hydroxyacyl-CoA dehdrogenase defi ciency; VLCAD, very long chain
`acyl-CoA dehydrogenase defi ciency.
`
`often mimic sepsis with lethargy, irritability, tempera-
`ture instability and feeding difficulties. As the ammonia
`level increases, respiratory distress, vomiting, altera-
`tion in tone, convulsions and apnoeas become more
`prominent.13 The rate of this decline is dependent on
`the nature of the underlying defect and its severity:
`the early manifesting urea cycle disorders (UCDs) and
`organic acidaemias often present between 12 and 72 h
`of age after an initial symptom-free period.14 However,
`hyperammonaemia can present at any age and the
`length of the classical symptom-free period may be
`absent or so short that it is not obvious. It is also to be
`noted that a respiratory alkalosis should always raise
`suspicion for hyperammonaemia though again it may
`be subtle. However, very often, the hyperammonae-
`mic sick neonate presents with an apparent metabolic
`acidosis, secondary to a concurrent impairment in car-
`diovascular stability.
`It seems sensible to target any neonate with pro-
`found encephalopathy or a pattern of presentation
`that does not fit with the presumed diagnosis: for
`example, patients with suspected hypoxic–ischaemic
`encephalopathy with normal Apgar scores or those
`with suspected sepsis but normal inflammatory mark-
`ers and negative cultures.15 Although hyperammo-
`naemia is a relatively rare cause of neonatal illness,
`it should not be missed, given that it is reversible and
`can have detrimental effects on the long-term progno-
`sis of affected individuals. Therefore, the authors feel
`that ammonia should be investigated in any neonate
`with unexplained non-specific systemic illness with
`
`neurological impairment. This is while fully accept-
`ing that occasionally the ammonia will have to be
`repeated to differentiate between false positives and
`those truly affected.
`
`Infants and older children
`In infants and older children the symptoms can be
`less acute, with some children showing a pattern of
`chronic failure to thrive, anorexia, lethargy and/or
`poor global development. Presentation can also be
`episodic, with neurological manifestations varying
`from mild behavioural disturbances and headaches to
`more severe symptoms such as ataxia, hemiplegia and
`convulsions16: One common clue often elicited in the
`history, is a self-restricted diet with the avoidance of
`high protein foods such as meat, cheese and fish.17 The
`severity of the symptoms is a reflection of the underly-
`ing disorder and the degree of catabolic stress: a good
`example is a previously well woman presenting post-
`partum with encephalopathy, a well recognised pres-
`entation of an ornithine trancarbamylase carrier where
`the protein load secondary to uterine involution may
`result in hyperammonaemia.18
`Because of the broad variation of clinical presenta-
`tions, decision towards testing for hyperammonaemia
`needs to be decided by the individual case. However in
`the authors’ opinion, plasma ammonia testing should
`be considered in any patient with recurrent neuro-
`logical symptomatology or a degree of neurological
`impairment, out of keeping with their clinical history
`or in the absence of other explanations.
`
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`Box 1 Factors infl uencing serum ammonia levels
`
`▶
`
`▶
`
`▶
`
`▶
`
` Primary diagnosis, its severity and nature of the underlying
`defect. A patient with arginase defi ciency will tend to manifest
`a lower level of hyperammonaemia than a patient with citrulli-
`naemia. However, even within a particular disorder, the extent
`of hyperammonaemia is variable. This variability normally
`refl ects the severity of underlying enzymatic impairment, with
`the disorders that present in the neonatal period tending to be
`more severe than those that present later in life.
` Amount of protein and energy the patient has been receiving
`in the diet prior to presentation. Inadequate dietary energy or
`protein provision has the potential to push the patient into a
`catabolic state. Inadequate provision of essential amino acids
`and energy drives deamination of the patients’ muscle pro-
`tein and increases fl ux through the urea cycle. The converse
`is also unfortunately true where excessive protein load, for
`example, a high protein intake can result in excessive strain
`on the compromised pathway. Thus, one of the key principles
`of long-term treatment is the provision of a safe dietary pro-
`tein minimum to meet the individual’s needs but minimising
`the fl ux through the urea cycle. Protein intake should be dis-
`continued, when patients are acutely unwell and adequate
`calorie intake should be provided by carbohydrates. Total
`protein exclusion beyond 48 h will, however, result in catabo-
`lism and thus increase fl ux through the urea cycle.
` Patient’s medication may also have a profound effect on the
`level of ammonia; for example, sodium valporate seems to
`act by reducing the amount of N-acetylglutamate, causing a
`secondary inhibition of carbamylphosphate synthetase, and
`therefore should be avoided.
` Level of muscle activity. This is the basis of exercise provoca-
`tion testing where high-intensity exercise results in ammonia
`production from the purine nucleotide breakdown, while in pro-
`longed submaximal exercise, ammonia production comes from
`the breakdown of branched chain amino acids. However. given
`that provocation testing traditionally requires 2 min of vigorous
`ischaemic exercise, this is not routinely of practical signifi cant.
`
`Patients with known IEM and risk of hyperammonaemia
`In any patient with an urea cycle defect, repeated
`ammonia levels are one of the key determinants of the
`efficacy of long-term treatment of the low-protein diet
`and ammonia scavenger drugs, sodium benzoate and
`sodium phenylbuturate.
`Additionally, ammonia levels should be among the
`initial investigations in any circumstances of suspected
`metabolic decompensation in any patient with an
`increased risk of hyperammonaemia (table 2). Children
`might have already become symptomatic, before an
`appreciable change in plasma ammonia is detectable.
`In these situations, careful observation and discussion
`of patients with the local metabolic team is warranted
`even in the face of normal ammonia levels.
`The importance of the evaluation of potential hyper-
`ammonaemia cannot be overstated in these patients, as
`hyperammonaemia is a treatable medical emergency.
`The basic concepts of therapy are based on the imme-
`diate elimination of protein (reducing flux of toxic
`
`INTERPRETATIONS
`
`metabolites), provision of high carbohydrates to stop
`catabolism/promote anabolism and the use of ammo-
`nia scavenger drugs.
`
`What is a signifi cant level of hyperammonaemia
`and when is it diagnostically relevant?
`The normal values for ammonia probably do not vary
`greatly with age of patient. Factors influencing serum
`ammonia levels are outlined in box 1.In term neonates
`typical plasma values are less that 65 µmol/l.19 However,
`any sick neonate, even those without a primary meta-
`bolic disorder may have much higher values.20 Given
`ammonia’s capacity to rise with generalised illness,
`particularly in the neonatal period and the difficulties
`of sampling, ammonia values of >150 µmol/l in sick
`premature neonates, >100 µmol/l in term neonates
`and >40 µmol/l in older infants and children should
`be considered as potentially worth investigating.21 22
`The current advice from The BIMDG is that ammo-
`nia measurement must be repeated immediately in
`children with levels >150 µmol/l and in neonates with
`levels >200 µmol/l.23
`Although historically it has been felt that the degree of
`hyperammonaemia and its rapidity of increase might be a
`guide towards underlying diagnosis, practically the value
`of the ammonia is not often diagnostically useful. While
`values of greater than 200 µmol/L are usually consid-
`ered to be suggestive of a potential metabolic disorder,2
`very high levels might primarily raise the suspicion for a
`UCD. However, overwhelming hyperammonaemia can
`also be seen in organic acidaemias especially in propi-
`onic aciduria,24 and even sepsis can result in ammonia
`levels of >700 µmol/l.25 High ammonia levels are much
`less commonly seen in fatty acid oxidation disorder.
`However, similar lower levels of ammonia are seen early
`into decompensation in patients’ diagnosed with UCDs
`and organic acidaemias.
`One important situation where the level of ammo-
`nia may be helpful is with the diagnosis is of transient
`hyperammonaemia of the newborn (THAN), a condi-
`tion caused by failure of closure of the ductus venous
`and lack of filtration of the ammonia from the blood:
`here, the levels of ammonia are extremely high within
`the first 24 h of life (often >1500 µmol/l). These levels
`when coupled with the history of a sick premature,
`often slightly growth-restricted neonate, are strongly
`suggestive of the diagnosis.26 Given the relatively high
`survival and good neurological outcomes of THAN
`with aggressive treatment, this is an important differ-
`ential to consider; however it is still crucial to perform
`a full differential investigation.
`
`Does the degree of hyperammonaemia give a
`guide to prognosis?
`Both survival rates and neurological outcome are
`affected by the duration and the degree of hyperam-
`monaemia. Enns et al, investigating neonatal hyper-
`ammonaemia secondary to UCD, found that survival
`was related to peak ammonia level. This study showed
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`Figure 1 The urea cycle and primary urea cycle defects. Enzymes: 1, ornithine transcarbamylase; 2, argininosuccinate synthetase;
`3, argininosuccinate lyase; 4, arginase; 5, N-acetylglutamate synthetase and 6, carbamyl phosphate synthetase. Transporters: 7,
`citrin (mitochondrial aspartate-glutamate carrier) and 8, mitochondrial ornithine transporter cause of HHH, hyperammonaemia–
`hyperornithaemia–homocitrullinuria.
`
`that those patients whose maximal ammonia level was
`<500 µmol/l had a 94% survival rate but this fell to
`only 38% in those with ammonia levels >1000 µmol/
`l.27 Bachmann, in a study looking at neurological
`outcome in 88 patients with UCDs, reported that no
`patient whose peak ammonia had been >480 µmol/l
`had a normal neurological outcome. However, it is
`to be noted that for the most part this study predated
`the regular use of ammonia scavenger drugs and
`modern intensive care unit practices.28 Other studies
`have indicated that the duration of the encephalo-
`pathic coma is a better predictor of overall neurologi-
`cal outcome with increasingly poor results are seen
`with comas lasting greater than 48 h.29 Finally, the
`underlying cause of the hyperammonaemia has also
`been seen to be a determinant of outcome.30
`
`The meaning of routine biochemistry in the
`context of hyperammonaemia
`Although it is beyond the scope of this study to
`review all biochemical changes associated with
`
`hyperammonaemia, table 1 relates to changes in
`other routinely available biochemical investigations.
`These should be taken in any child being evaluated
`for potential hyperammonaemia where the diagnosis
`is uncertain.
`
`Limitations
`The challenge in ammonia testing is the large number
`of false positives that are generated by poor sampling
`and handling of specimens, most commonly due to a
`delay in transit to the laboratory. This has been shown
`to reduce the positive predictive value of ammonia
`down to as less as 60%.1 The recommendations from
`the UK National Metabolic Biochemistry Network
`state that ammonia should be measured as a free-
`flowing venous sample, with the avoidance of capil-
`lary samples, often difficult in a neonate, and should
`arrive at laboratory within 15 min, ideally on ice.22
`The reasons for these suggestions are that haemolysis
`secondary to capillary sampling results in increased
`interference in spectroscopic assay.11 31 The rapid
`
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`transit to the laboratory is essential, since ammonia
`is constantly being generated, by both continued red
`blood cell metabolism and the deamination of amino
`acids, particularly glutamine.32 While these are bio-
`logical process dependent on the degree of enzymatic
`activity, cooling with ice does not in itself prevent
`sample deterioration whose major cause is prolonged
`transit time or other delays in processing. The preven-
`tion of potential delay of transport or processing of
`the sample needs to be avoided, hence clinical staff
`should inform the laboratory early of an impending
`sample, documenting the time of sample collection.
`It is also here where the ice may help, as its presence
`maintains the focus of the teams involved that delayed
`processing is detrimental.
`It is to be noted that all these problems will cause
`a rise in ammonia and while it is the authors’ view
`that investigation of hyperammonaemia is still a vastly
`underperformed investigation, it should be noted
`that ammonia levels within the normal range do not
`need repeating unless the clinical status of the patient
`alters.
`Finally, hyperammonaemia is not a diagnosis in itself
`and while it is indicative of a degree of metabolic dys-
`function, more specialised investigations are required
`to establish the correct diagnosis. These must include
`evaluation of plasma and urinary amino acids, urine
`organic acids and plasma acylcarnitines, though the
`full range of these investigations should be discussed
`with the local metabolic centre.
`
`Future research
`The information gathered from measurement of
`plasma ammonia is limited, and it is an incomplete
`reflection of the intraglial and intraneuronal chemi-
`cal changes experienced by patients. Increasingly, it is
`these downstream cascades initiated by hyperammo-
`naemia that are the focus of research.6 Areas of investi-
`gation include the reduction of N-methyl-D-aspartate
`(NMDA) receptor-mediated excitotoxicity, caused by
`increased levels of glutamate, with NMDA receptor
`agonists having been shown to improve cortical neuro-
`nal survival in animal models. Nitric oxide production
`secondary to NMDA activation is another potential
`target for reduction of toxicity. Other potential treat-
`ments address the energy deficiencies that seem to
`occur in neurons and glial cells exposed to hyperam-
`monaemia. Examples of the later include the use of
`creatine to prevent the secondary creatine deficiencies
`and the use of acetyl-L-carnitine, which appears to
`increase the ATP and phosphocreatine levels.
`These are all exciting areas of research and raise
`the potential of improving the neurological outcome
`of patients. However, to date, the most important
`aspects to prevention of hyperammonaemia continue
`to be clinical awareness and willingness to perform of
`plasma ammonia testing.
`
`Quiz
`
`QUESTION 1
`Which one of the following is unlikely to cause an ammonia of
`500 μmol/l
`a) Ornithine transcarbamylase defi ciency
`b) Delayed processing of a sample
`c) Urine infection with urease-positive organisms
`d) A struggling neonate
`e) Propionic acidaemia
`QUESTION 2
`Which of the following statements is untrue?
`a) Most ammonia checkers have a maximum upper limit of
`286 μmol/l
`b) A respiratory alkalosis is an early sign of hyperammonaemia
`c) Portal systemic shunting is a recognised cause of
`hyperammonaemia in the newborn period
`d) Ammonia sampling can be adequately performed by
`capillary sampling
`e) There is an overall 94% survival rate in neonates whose
`maximal ammonia is <500 μmol/l
`QUESTION 3
`True or false
`a) Liver cirrhosis is a known complication of a urea cycle
`disorder
`b) Typical neonatal values for ammonia are 65 μmol/l
`c) Haemolysis increases the rate of ammonia production
`d) Cerebral oedema is the major cause of neonatal mortality in
`urea cycle disorders
`e) The citrin transporter transports aspartate into the
`mitochondria
`Answers to the quiz are on page 80
`
` ■
`
` ■
`
` ■
`
`Clinical bottom line
`Hyperammonaemia is a medical emergency and a delay
` ■
`in treatment may have profound consequences.
`Testing for ammonia should be considered in all
`patients with unexplained or unusual neurological
`symptoms, especially in neonates whose clinical
`history does not match the severity of their illness
`and or whose illness is unexplained.
`Care must be taken to ensure the laboratory receive
`an adequate sample.
`Ammonia results should be interpreted in light of
`both the clinical symptomatology and the routine
`biochemistry available, though definitive diagnosis
`requires specialised investigations.
`Acknowledgements The authors would like to
`acknowledge Dr JH Walter Royal Manchester
`Children’s Hospital, Oxford Road, Manchester,
`M13 9WL, for use of figure 1.
`Competing interests None.
`Provenance and peer review Commissioned;
`externally peer reviewed.
`The reference list is published online only
`at http://ep.bmj.com/content/97/2
`
`Arch Dis Child Educ Pract Ed 2012;97:72–77. doi:10.1136/archdischild-2011-300194
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`How to use serum ammonia
`Alexander Broomfield and Stephanie Grunewald
`
`
`
` 2012 97: 72-77 originally published onlineArch Dis Child Educ Pract Ed
`November 18, 2011
`doi: 10.1136/archdischild-2011-300194
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