Intravenous and Oral Hyperammonemia Management

PHARMACOLOGY OF ACUTE CARE (J FANIKOS, SECTION EDITOR)

Intravenous and Oral Hyperammonemia Management

Abdulrahman Alshaya1 & John Fanikos1 & Elizabeth DeMaio1

# Springer Science+Business Media, LLC, part of Springer Nature 2018

AbstractPurpose of Review Hyperammonemia have significant morbidity and mortality. In this paper, we reviewed the latest research andevidence of both conventional and upcoming oral or intravenous treatments.Recent Findings New updates on the role of oral agents such as rifaximin, PEG, probiotics, glycerol phenylbutyrate, and zincsupplements in the management of both chronic hyperammonemia and overt hepatic encephalopathy have been discussed in thisreview. We discussed the recent findings on the role of branched-chain amino acids in patients with cirrhosis.Summary Rifaximin role has expanded as mono or combination therapy in patients with hepatic encephalopathy. Probiotics andzinc might play a role in the prevention of overt hepatic encephalopathy. Newer oral agents such as activated carbon seem to bepromising. Saline or albumin might play a role in diuretic-induced hyperammonemia but their role is yet to be determined. Moreresearch is needed for new interventions and treatment validation.

Keywords Ammonia . Hyperammonemia . Glutamine

AbbreviationsASL Argininosuccinic acid lyaseASS Argininosuccinate synthetaseATP Adenosine 5′-triphosphateBBB Blood-brain barrierBCAA Branch chain amino acidsCPS Carbamyl phosphate synthetaseCT Computed tomographyGI GastrointestinalICH Intracranial hemorrhageIEM Inborn error of metabolismIV IntravenousLOLA L-Ornithine-L-aspartateMRI Magnetic resonance imagingNAGS N-Acetyl glutamine synthetaseOTC Ornithine transcarbamylaseRRT Renal replacement therapyTPN Total parenteral nutrition

UCDs Urea cycle disordersUS Ultrasonography

Background

Ammonia is an important source of nitrogen and is requiredfor the biosynthesis of essential compounds such as aminoacids, the building blocks of protein structure [1]. Ammoniais produced by the gastrointestinal (GI) track, kidney, liver,muscle, brain, and is a by-product of protein digestion andbacterial metabolism [1, 2]. Within the kidney, ammonium isconcentrated in the medullary interstitium, where it is eitherreturned into the systemic circulation or used to facilitate pro-tons excretion in the urine; therefore, ammonia is crucial foracid-base homeostasis [3, 4]. The majority of ammonia iseither reutilized for amino acid synthesis or converted to theend product, urea. The remaining ammonia is released into theblood stream [1, 2]. Because unbound ammonia is extremelytoxic, especially to neurons, ammonia is rapidly converted tonontoxic urea by the urea cycle in the liver and excreted in theurine [1, 2, 4]. Blood ammonia is maintained at safe concen-trations below 50 μmol/L, as most ammonia produced in tis-sue is converted to glutamine [5]. Glutamine is utilized forenergy production by gut cells, which is metabolized to ala-nine, citrulline, and ammonia; hence, they are transported tothe liver via the bloodstream or excreted by the kidneys [6].

This article is part of the Topical Collection on Pharmacology of AcuteCare

* Abdulrahman [email protected]

1 Pharmacy Division, Brigham and Women’s Hospital, 75 FrancisStreet, Boston, MA 02115, USA

Current Emergency and Hospital Medicine Reportshttps://doi.org/10.1007/s40138-018-0174-5

http://crossmark.crossref.org/dialog/?doi=10.1007/s40138-018-0174-5&domain=pdf

mailto:[email protected]

High ammonia concentrations can be attributed to an increasein ammonia production via different triggers (e.g., seizures,gastrointestinal bleed, trauma or burn, infections, chemother-apy, steroids administration, and increased peripheral catabo-lism due to deficiency of essential amino acids) [7, 8].Moreover, hyperammonemia could be secondary to a de-crease in ammonia elimination (e.g., deficiency in essentialurea cycle enzymes, fatty acid oxidation defects, fulminanthepatic failure, trans-hepatic intrajugular portosystemic shunt,and valproate) [7, 8]. In the last few years, there has been anotable improvement in the recognition and treatment of ureacycle disorders (UCDs) [8]. Patients with UCDs can havepartial deficiency of any enzyme in the urea cycle and developsymptoms at any time in their life, usually as a result of in-creased catabolic stress [8]. Hyperammonemia severity variesfrom low-grade encephalopathy to hyperammonemic comawhich requires different pharmacological options with differ-ent routes of administration [9].

Pathophysiology

Main sources of ammonia are the colon and small intestine(through bacterial metabolism of proteins and urea, and deg-radation of glutamine) [10, 11]. In healthy human, the liver isprimarily responsible for ammonia metabolism [12]. Five con-secutive enzymatic reactions are essential to convert nitrogenwaste from protein intake and endogenous proteins catabolisminto urea; this process is known as “the urea cycle” [13]. Thepurpose of this cycle is to convert ammonia to more water-soluble molecule, urea, which could be excreted easilythrough the kidney [13]. For the urea cycle to be effective,the following enzymes are required: carbamyl phosphate syn-thetase (CPS), ornithine transcarbamylase (OTC),argininosuccinate synthetase (ASS), argininosuccinic acid ly-ase (ASL), and arginase (Fig. 1) [13, 14]. Urea cycle disordersare inherited deficiencies of enzymes or transporters that areessential for Krebs-Henseleit cycle [13, 14]. Therefore, thedeficiency of these enzymes will result in high ammonia con-centrations [14–16]. The prevalence of these disorders is esti-mated to be 1:8000–1:44,000 births for all UCDs collectively[14]. Deficiency of N-acetyl glutamine synthetase (NAGS),which is usually present in children, mimics CPS deficiencyand is present in children and adults. However, N-acetyl glu-tamine synthetase, and ASS deficiency, type II citrullinemia,also can be present only in adulthood [15, 16].

In the setting of hyperammonemia, the kidney regulatesammonia levels by decreasing ammonia production and in-creasing its excretion the urine [3, 4]. Additionally, blood am-monia is transported to the muscle and cross the blood-brainbarrier (BBB) through either passive diffusion or mediatedtransport, thus the muscle and brain metabolize excess ammo-nia to glutamine [17, 18]. Physiologically, neuron cells

metabolize glutamine to glutamate, also astrocytes supportcontiguous neurons with adenosine 5′-triphosphate (ATP),glutamine, and cholesterol [19]. Glutamate, a neurotransmitterthat activates N-methyl D-aspartic acid (NMDA) receptors, isrecycled by astrocytes back to glutamine in the synapse [20](Fig. 2). The acute rise in ammonia level within the brainaffects the reciprocal relationship between neurons and astro-cytes negatively via excess glutamine production and hinder-ing ATP production; thus, an increase in the anaerobic metab-olism of pyruvate conversion to lactate is prominent [1, 19,20]. Astrocytes rapidly metabolize ammonia to glutamine;however, the acute rise in intracellular osmolarity causes as-trocyte swelling and loss [19, 20]. Subsequently, inflammato-ry cytokines, including tumor necrosis factor-α, interleukin-1,interleukin-6, and interferon, are released from the astrocytes[8, 19]. Ammonia, also, compromises astrocyte potassiumbuffering; hence increases the extracellular potassium concen-tration and induce neuronal overactivationwhich could lead toneurological dysfunction and seizures [21].

Astrocyte swelling prompts apoptosis, inflammatory cas-cades, and metabolic pathways that lead to cerebral edema,and loss of cerebral autoregulation [22]. Arterial ammonialevels in patients with hepatic failure correlate with glutaminelevels, which is a prognostic factor for the development ofintracranial hemorrhage (ICH) [23].

Toxic ammonia levels can be a serious complicationresulting from an acute liver failure secondary to acetamino-phen or valproic acid toxicities or other drug-inducedhyperammonemia (Table 1) [24, 28]. Moreover, chronic liverdiseases such as chronic hepatitis or most commonly livercirrhosis could lead to high ammonia concentrations and he-patic encephalopathy as well [29]. When patients with acuteliver failure develop hepatic encephalopathy, they are athigher risk of developing symptomatic cerebral edema withprogression into cerebral herniation. In contrary, symptomaticcerebral edema rarely occurs in patients with chronic liverdiseases who develop hepatic encephalopathy [29].

Proteus mirabilis, Klebsiella species, Escherichia coli,Providencia rettgeri, Morganella morganii, and diphtheroidsare urea-producing bacteria [30–32]. Infection can lead tononcirrhotic hyperammonemic encephalopathy [32].Systemic mycobacterium or mycoplasma infection as wellas herpes simplex virus infections in organ recipients and ne-onates have been described to increase ammonia concentra-tions in the blood [33–35]. The exact mechanism is assumedto be related to ammonium bypassing liver metabolism andminimal ammonium renal excretion [34, 35]. Physiologicstressors including upper respiratory tract illnesses, pneumo-nia, dietary changes, fever, and pregnancy can provokehyperammonemia in patients with UCDs [28, 36–39].Similarly, protein-rich total parenteral nutrition (TPN) hasbeen reported to unmask long-term asymptomatic UCDs[40]. High ammonia levels can occur with TPN containing

Curr Emerg Hosp Med Rep

only essential amino acids with impaired ammonia detoxifi-cation due to absence of ornithine [8, 40].

The incidence of hyperammonemia in hemato-oncologicaldisorders is unknown, but in previous retrospective reviewswas estimated to range from 0.5 to 2.4% [41, 42]. Althoughthe pathophysiology of hyperammonemia in these disease statesis still mysterious, it is thought to be caused by excess ammoniaproduction due to increased amino acid metabolism, and plasmacell infiltration in patients with multiple myeloma [43–45]. Inpatients with leukemia, idiopathic hyperammonemia has beendescribed hours to days after initiation of intensive regimen ofchemotherapy with higher risk of coma and death [46–48]. Fewcase reports also of severe hyperammonemia in bone marrowtransplant as well as heart-lung transplant patients and the mor-tality rate exceeds 75% in the reported cases [48, 49]. The com-plexity of etiology andmanagement of these disease statesmakesit difficult to assume that hyperammonemia is induced by a sin-gle mechanism; rather it is presumed to be multifactorial

including TPN, GI hemorrhage, sepsis, mucositis, andchemotherapy-induced hyperammonemia [50].

Ammonia metabolism is affected by body thermoregula-tion; particularly, hypothermia has been shown to decreasefree radicals production, astrocyte swelling and inflammationas well as improving cerebral blood flow and autoregulation[19, 20, 51]. In addition, hypothermia slows protein catabo-lism and ammonia production [19, 20].

Diagnostic Criteria

Typically, patients with hyperammonemia present with non-specific symptoms, for instance: loss of appetite, vomiting,lethargy, sleep disorders, ataxia, and seizures [52, 53].Psychiatric manifestations such as behavior abnormalities

Fig. 1 The urea cycle

Table 1 Drug-induced hyperammonemia [8, 24–27]

Cause Mechanism of inducing hyperammonemia

Glycine Stimulates ammonia production

Salicylates Reduce mitochondrial function in the hepatocytes

Valproate Increases propionic acid levels, which inhibit CPS

An overdose of valproate may cause significant hyperammonemia inhealthy patients, while therapeutic doses in patients with UCDs maycause hyperammonemic coma Abdulrahman. Case reports have also de-scribed hyperammonemia secondary to the use of carbamazepine, ribavi-rin, and sulfadiazine with pyrimethamine. Drugs associated with acuteliver failure such as acetaminophen, statins, and anti-tuberculous medica-tions might induce hyperammonemia

Fig. 2 Neuron-astrocyte glutamine: glutamate cycle


associated with hallucinations can also be seen in these pa-tients; manic episodes or psychosis usually presents in patientswith chronic hyperammonemia [53, 54].

Laboratory testing plays a major role in hyperammonemiadiagnosis [55, 56]. Venous and arterial blood samples are equallyaccepted for the measurement of ammonia levels [55, 56].Hyperammonemia is defined as plasma ammonia levels of >50 μmol/L in adults and > 100 μmol/L in newborns; however,a value of more than 100 μmol/L should prompt further investi-gation, especially in setting of normal liver function [57, 58].Levels between 250 and 500 μmol/L may necessitate on renalreplacement therapy (RRT), if no rapid drop of ammonia within3–6 h [59, 60]. Nonetheless, ammonia level value of >500 μmol/L would require an immediate intervention withRRT, if medical therapy did not result in proper response [59].In acute hyperammonemia, unlike chronic hyperammonemia,venous, arterial, and brain ammonia levels usually correlate ap-propriately. Seizures, cerebral edema, and herniation are uniqueto acute hyperammonemia and usually occur only when arterialammonia levels are > 200 μmol/L [20, 23].

Additionally, acid-base balance provides additional insightas metabolic acidosis increases the possibility of organicacidemia [61]. In contrast, respiratory alkalosis may be anindication of a urea cycle disorder [61]. Amino acid profiletriggers the evaluation for urine orotic acid, as orotic aciduriais suggestive to diagnose patients with OTC deficiency [59,62]. Negative results for amino acid profile and orotic acidcould indicate CPS or NAGS deficiencies [59, 63].

In terms of imaging, ultrasonography (US), abdominalcomputed tomography (CT), and neuroimaging via magneticresonance imaging (MRI) can all demonstrate portohepaticshunts [64]. Liver biopsy should be performed if an inbornerror of metabolism (IEM) is suspected [65]. Likewise, liverbiopsy is vital in excluding other reasons for hepatic cirrhosis[66]. Differential diagnosis includes seizure activity, metabol-ic and hepatic encephalopathy, diffuse hypoxic-ischemic inju-ry, and posterior reversible encephalopathy syndrome [67].

Treatment Options

The current pharmacological options to treat hyperammonemiatarget either the reduction of ammonia production or its absorp-tion in the GI, or the activation of ammonia elimination by up-regulating ureagenesis [8]. These pharmacological agents areavailable in different routes of administration such as oral andintravenous routes, which helps in the management of acute andchronic hyperammonemia [68].

(a) Oral Options

The first-line therapy for patients with hyperammonemiasecondary to hepatic encephalopathy is non-absorbable

disaccharides (e.g., lactulose which consists of the monosac-charides fructose and galactose) [68, 69]. Lactulose is metab-olized solely by β-galactosidase in the colon into lactic acid,formic acid, and acetic acid, causing acidification in the colon,thus inhibits the growth of urease-active bacteria [11](Table 2). Additionally, lactulose increases the osmotic pres-sure therefore accelerates the excretion of ammonia [11].Initially, lactulose syrup 25 mL every 1–2 h is recommendedwith titrated goal to a minimum of two bowel movements perday [68]. The downside for lactulose includes the challenge tocustomize the dosage to a certain clinical goal [68, 70]. Inaddition, lactulose has been reported to be associated withGI symptoms (e.g., abdominal cramping, bloating, and flatu-lence) and electrolyte imbalances [70, 71••]. Lactitol was non-inferior to lactulose in efficacy with less incidence of flatu-lence in a meta-analysis of several small studies [71••].Another meta-analysis questioned the clinical benefit oflactulose despite the widespread use of non-absorbable disac-charides in the current practice [72]. Moreover, the findings ofRahimi and colleagues in a randomized clinical trial demon-strated the superior effect of a polyethylene glycol 3350-electrolyte over lactulose on clinical and neuropsychologicalhepatic encephalopathy symptoms [73]. It is important to no-tice the therapeutic benefit in the outpatient setting may not becomparable to that in a clinical trial because of low adherencein lactulose therapy [74, 75].

Several antibiotics have been studied in the management ofhyperammonemia including neomycin, metronidazole, andrifaximin [68, 70, 76]. Urease-producing bacteria in the GIhave early been identified as an important source of ammoniaproduction in the body, thus using empiric antibacterial ther-apy to manage hyperammonemia seems intuitive [30–32].The aminoglycoside neomycin was used in the treatment ofacute hepatic encephalopathy episodes; however, its clinicaluse has diminished because of its unfavorable adverse reactionprofile including ototoxicity, neurotoxicity, and nephrotoxici-ty [70]. Despite its low oral bioavailability (3%), significantsystemic exposure and toxicities have been observed in cir-rhotic patients [77]. Doses of 6 g per day compared to placeboin a double blinded randomized trial found no significant dif-ference in treatment failures time or to resolution of hepaticencephalopathy [77]. Additionally, small trials have evaluatedmetronidazole and suggested minimal benefit but the risk ofneurotoxicity discouraged its use as mainstay therapy [78, 79].Oral vancomycin may be used as alternative treatments forpatients with chronic liver disease; however, limited safetyand efficacy data preclude the routine use of vancomycin forthis indication [80].

Rifaximin is a semi-synthetic derivative of rifampicin [81].It has become a very attractive choice of antibiotic in thetreatment of hyperammonemia because of its safety, efficacy,and tolerability [82–88]. It works locally in the GI track as aresult of the addition of a non-absorbable pyridoimidazole


ring [82]. However, generic rifaximin formulations exhibiteddifferent crystal polymorphs than the alpha form which haveresulted in altered bioavailability [89]. It was designed to havenegligible bioavailability while retaining its activity to crossthe cell wall of Gram-negative bacteria [90]. Rifaximin is abroad-spectrum antibiotic that has wide coverage against

Gram-positive and Gram-negative aerobic and anaerobic bac-teria [90, 91]. It inhibits RNA synthesis by binding to the βsubunit of the bacterial DNA-dependent RNA polymeraseenzyme [91]. In 2010, the food and drug administration(FDA) in the USA approved rifaximin for the secondary pre-vention of overt hepatic encephalopathy in adult patients. Thecurrent practice now is to add it to lactulose in refractoryhepatic encephalopathy [68, 70, 92]. Doses of 1200 mg/daywere studied as both monotherapy and combination therapyand compared to non-absorbable disaccharides, and none ofthese studies showed rifaximin superiority in patients withovert hepatic encephalopathy grade I-III [87, 92–94]. Onerandomized clinical trial was conducted by Sharma et al. com-paring combination of rifaximin with lactulose to lactulosewith placebo in patients with severe hepatic encephalopathy(80% were grade III-IVand 70% were Child Class C) [87]. InSharma’s study, the combination of rifaximin and lactulosegroup had higher proportion of complete reversal of hepaticencephalopathy, shorter hospital length of stay, and better sur-vival outcomes [87]. The finding of this study needs to beevaluated in a larger scale to validate their results. Twometa-analyses supported the use of rifaximin and further ob-served favorable effects on mortality and full recovery fromhepatic encephalopathy [75, 95].

In patients with UCDs, sodium benzoate and sodiumphenylacetate are the backbone drugs in treatment plan [96].Sodium benzoate reduces glycine metabolism in the liver, kid-ney, and brain. Benzoate integrates with coenzyme A (CoA) toform benzoyl-CoA in hepatic mitochondria [96–98]. Then,benzoyl-CoA transfers the benzoyl moiety of the CoA ester toglycine and yields hippurate [96, 97]. This process hampers thedegradation of glycine in the liver, kidney, and brain [96–98].Sodium phenylacetate and sodium phenylbutyrate are oxidizedto phenylacetate, which conjugates with glutamine in the liverand then is excreted renally as a phenylacetylglutamine [99,100•]. In addition, it prevents glutamine-stimulated ammoniaproduction [100•]. A combination of sodium benzoate and sodi-um phenylacetate decreases plasma ammonia levels and contrib-utes in lowering the percentage of mortality in acutehyperammonemic UCD patients with an acceptable adverse ef-fects profile consisting of headache, nausea, and impairedmentalstatus [101]. The oral administration of sodium phenylacetatemight cause complications to patients with history of hyperten-sion derived from exceeding daily sodium uptake [100•, 101,102•]. In addition, oral treatment with sodium phenylbutyrate(Buphenyl®) can be challenging as the salty (sodium) and bitter(phenylbutyrate) taste could lead to aversive reactions [103]. Ataste-masked granulate, Pheburane®, has been developed toovercome this problem and shown to be bioequivalent to thecomparator compound Buphenyl® [104].

Glycerol phenylbutyrate is a prodrug that converts tophenylbutyrate (PBA) via pancreatic lipase. PBA is metabolizedthrough β-oxidation to phenylacetate (PAA), which is

Table 2 Oral treatment options [11, 68–70, 71••, 72, 73–99, 100•, 101,102•, 103 –107, 108–132]

Drug Mechanism ofaction

Adverseevents

Specialconsideration

Lactulose Intestinalacidificati-on,catharsis,andsuppressionof intestinalbacteria

Abdominalcramping,bloating,flatulence,electrolyteimbalances

Taper dose perresponse

Polyethylene glycol Osmoticlaxative

Bloating,flatulence,anddiarrhea

Taper dose perresponse

Rifaximin Suppressionof intestinalbacteria

Nausea,bloating,diarrhea

Antibioticresistance,high cost

Metronidazole Suppressionof intestinalbacteria

Ototoxicity,neurotoxic-ity

None

Neomycin Suppressionof intestinalbacteria

Ototoxicity,neurotoxic-itynephrotoxi-city

None

Sodium phenylbutyrate Glutamineelimination

Complicationfor patientswithhyperten-sion

Buphenyl® isavailable intablet,powder andPheburan-e® isgranulate

L-Ornithine-L-aspartate Urea cycleandglutaminesynthaseactivation

Severestomachcrampinganddiarrhea

None

Carglumic acid Restoration ofNAGSfunction

Chills, bodyaches, flusymptoms,sores in themouth andthroat

Can be giventhroughnasogastrictube

Zinc salts Restoration ofOTCfunction

Nausea,vomiting,anddiarrhea

None

L-Carnitine Activate ureacycleenzymes

Nausea,vomiting,anddiarrhea

Urine, breath,and sweatmay have afishy odor


conjugated with glutamine in the liver and the kidney to formphenylacetylglutamine (PAGN), which is easily excreted renally[105]. Glycerol phenylbutyrate might be an attractive option forpatients with hyperammonemia secondary to hepatic encepha-lopathy with history of hypertension [105–107]. A recent studyshowed promising results for glycerol phenylbutyrate in hepaticcirrhotic patients admitted to the ICU for overt hepatic encepha-lopathy [106].

L-ornithine-L-aspartate (LOLA) is available in oral andintravenous (IV) dosage forms [107]. It stimulates OTC andCPS, and is a substrate for the formation of urea [108]. Inaddition, LOLA stimulates glutamine synthesis in the skeletalmuscle which lowers ammonia level consequently [108].LOLA (doses 9–18 g per day split into several doses) wasshown to be beneficial in improving the quality of life andreducing ammonia levels in patients with chronichyperammonemic hepatic encephalopathy; however, it is stillyet to prove its role in acute settings [109–112]. LOLA isavailable in an intravenous form as an IV infusion (over 4 h,20–30 g per day) for 5 to 7 days [109–112]. Moreover, intra-venous LOLA is recommended as an alternative or add-ontherapy for patients who do not respond to the conventionaltherapy [111]. On a meta-analysis that was published in 2008,LOLAwas shown to be effective in patients with grade I and IIovert hepatic encephalopathy [113].

Carglumic acid or (N-carbamoyl-L-glutamic acid) is a syn-thetic analogue that replaces N-acetylglutamate [114]. It actsas an allosteric activator of CPS, reactivates the geneticallyimpaired urea cycle, and lowers systemic ammonia [107,114]. Carbaglu® is an FDA-approved orphan drug for theadjunctive therapy of acute and maintenance treatment ofchronic hyperammonemia due to NAGS deficiency [57].Nevertheless, carglumic acid seems to be effective againsthyperammonemia induced by valproic acid, which inhibitsN-acetylglutamate synthetase [115]. A recent case reported asuccessful treatment with carglumic acid for the managementof ASS in a patient with citrullinemia type 1 [116].

Probiotics are mono or mixed cultures of live microbialorganisms in a defined number [117]. They work via promot-ing the growth of non-urease-producing bacteria in cirrhoticpatients [118]. Furthermore, they restore the large-intestinalmicrobial balance in liver cirrhosis patients [117, 118].Probiotics have shown to decrease plasma levels of ammonia(on average by 7 μmol/L after 3 months) in patients withchronic hepatic encephalopathy [119]. However, a recentmeta-analysis of studies with high risk of systematic errorsfound an improved recovery, which may decrease the risk ofdeveloping high plasma ammonia concentration, overt hepaticencephalopathy, and quality of life but no clear benefit onsurvival rates [120]. VSL#3 is an oral probiotic that is formu-lated as capsules without enteric coating [107, 121]. Eachcapsule contains ca. 110 billion live freeze-dried bacteria thatare constituents of the normal GI flora (Lactobacillus and

Bifidobacterium strains, and Streptococcus thermophiles) inhealthy humans [107, 121]. In two-phase II/III randomizedcontrolled trials, VSL#3 was shown to decrease arterial am-monia levels, improve symptoms, and lower the risk of hepat-ic encephalopathy in patients with low and high grade hepaticencephalopathy episodes compared to placebo [121, 122].

Zinc plays a major role in ammonia reduction in two path-ways in the liver and the skeletal muscles [123]. Ammonia isconverted to urea by OTC in the liver and glutamine synthesisin the skeletal muscle; both pathways are affected by zincdeficiency [124]. Five randomized clinical trials with hetero-geneous findings in the effect of zinc supplementation onchronic hyperammonemia [124–128]. The most recent oneby Katayama and colleagues looked in zinc supplementationfor 3 months in patients with hyperammonemia secondary toliver cirrhosis [128]. Doses of 50–150 mg/day of elementalzinc was shown to be safe and effective for the management ofhyperammonemia in liver cirrhosis [124–128]. However, theoutcome of Katayama and colleague’s study should beinterpreted carefully as they included small number of patients[128].

L-Carnitine has been reported to lower hyperammonemiavia the activation of urea cycle enzymes and interaction withglutamate receptors, and scavenging of free radicals [129,130]. It was shown to be beneficial in reducing ammonialevels in valproate-induced hyperammonemia [131]. In pa-tients with mild and severe hepatic encephalopathy, acetyl-L-carnitine was observed to lower ammonia levels and im-prove hepatic encephalopathy symptoms [132]. In acute casesof hyperammonemia with unknown reasons, the administra-tion of L-carnitine, biotin, and hydroxycobalamin intrave-nously should be considered, because deficiencies in theseessential micronutrients of the vitamin B family may increaseblood ammonia levels [59].

(b) Intravenous Options:

A combination of sodium benzoate/sodium phenylacetate(Ammunol®) may be used in an acute hyperammonemia; thiscombination act as a nitrogen scavenger to provide an alter-native method of nitrogen metabolism [133] (Table 3).Ammonul®, contains 10% sodium benzoate and 10% sodiumphenylacetate, is currently approved as adjuvant therapy forthe management of hyperammonemia and associated enceph-alopathy in patients with UCDs [101]. It should be adminis-tered only through a central venous catheter and must be di-luted in 10% dextrose before infusion to prevent proteinbreakdown [101, 133]. Data for this combination in improv-ing survival and ammonia levels are driven from pediatricpopulation, with few case reports of successful treatment inadults [101, 134, 135].

L-Ornithine phenylacetate is a combination that activatesthe urea cycle and glutamine synthetase (through L-Ornithine)


and lowers ammoniagenic amino acids such as glutamine andglycine via conjugation (through phenyacetate) [136, 137]. Ina phase I study in cirrhotic patients with an episode of upperGI bleeding in the preceding 24 h L-Ornithine phenylacetatewas administered intravenously as a continuous infusion(maximum daily dose of 10 g) [137]. Average plasma ammo-nia decreased by 50% from the initial levels after the first 36 h,and it remained in that range during the infusion [137].

L-Arginine is a product of the urea cycle and an essential aminoacid in all UCDs, except ARG deficiency [59]. L-Arginine admin-istration leads to the excretion of nitrogen as L-citrulline, an inter-mediate product of the urea cycle [57, 59]. Moreover, L-argininelowers ammonia levels through excreting nitrogen asargininosuccinate in ASS and ASL deficiency [57, 59, 138•,139]. In NAGS, CPS, ornithine, andOTCdeficiencies, the admin-istration of L-citrulline restores L-arginine levels [57, 59, 60].

Patients with cirrhosis have altered amino acid profile with adecrease in branch chain amino acids (BCAA) [140]. TheBCAAs(valine, leucine, and isoleucine) are a source of glutamate, whichhelps to metabolize ammonia via glutamine synthesis in skeletalmuscle [140, 141]. BCAAs catalyze the transfer of the aminegroup of a BCAA to alpha-ketoglutarate to form a branched-

chain alpha-keto acid and a glutamate [141]. Hence, glutaminesynthetase transforms glutamate to glutamine [142]. The currentrecommendation by the American Society for Parenteral andEnteral Nutrition (ASPN) for protein intake is 0.6–0.8 g/kg/dayin patients with liver cirrhosis patients with acute encephalopathy[143]. Furthermore, BCAAs stimulate hepatic protein synthesis,inhibit protein degradation, and fuel oxidative energy productionin skeletal muscles [144, 145]. Split doses BCAA lowered plasmaammonia in hepatic encephalopathy patients, which had a benefi-cial effect on clinical hepatic encephalopathymanifestations but noimpact on survival [144]. A meta-analysis discussed the capacityof BCAA to improve the mental state of hepatic encephalopathypatients significantly [95]. In addition, a recent Cochrane reviewreinforced the beneficial effect of BCAA administration on theprognosis of patients with liver cirrhosis [147].

Dehydration reduces ammonia excretion renally, especiallyin hyperammonemia precipitated by overuse of diuretics [107,148]. Intravenous volume expansion using albumin or normalsaline decreased blood ammonia levels in diuretic-inducedhepatic encephalopathy, possibly via enhanced urinary ammo-nia excretion [148–150].

Activated carbon microparticles and glutaminase inhibitorsmight be promising pharmacological treatment approaches forthe management of hyperammonemia [151, 152]. Activated car-bon microparticles have been studied in patients with low-gradehepatic encephalopathy; however, no clinical endpoints benefitswere not met despite a reduction in plasma ammonia [151].Metformin, antidiabetic biguanide agent, has glutaminase-inhibiting activity and protects against hepatic encephalopathyin diabetic patients with cirrhosis; however, it has not been in-vestigated in hyperammonemia management [152]. Promisingnon-pharmacological interventions such as dialysis, gene thera-py, cell therapy, and bioartificial liver support systems have beenstudied. [107, 141, 153–156].

Conclusion

Patients with toxic ammonia levels have significant morbidityand mortality, and can be caused by multiple mechanisms suchas UCDs, liver failure, physiological stressors, and drug-induced hyperammonemia. Identifying the most likely reasonsof hyperammonemia is essential to tailor a patient-specific reg-imen and to optimize medical management. A challenging as-pect of acute and chronic UCD treatments is the paucity of thesedisorders, which complicates having strong evidence-based as-sessment for thei r safe ty and eff icacy. Chronichyperammonemia may be managed via oral route by non-absorbable disaccharides such as lactulose, polyethylene gly-col, antibiotics, or other available options. Finally, acute man-agement of hyperammonemia is still challenging regardless ofthe pathophysiology, and an effective medical pharmacothera-py consensus is yet to be determined clinically.

Table 3 Intravenous treatment options [101, 133–137, 138•, 139,140–145, 146•, 147, 148–150]

Mechanism ofaction

Adverse events Specialconsideration

Sodiumbenzoate andsodiumphenylacetate(Ammonul®)

Glycine andglutamineelimination

Abdominalcramping,bloating,flatulence,electrolyteimbalances

Should be giventhrough centralline

Must be dilutedwith steriledextroseinjection, 10%at > 25 mL/kgbeforeadministration

Dose is differentbased on thespecific UCDtype

Arginine Partialrestoration ofUC activity

Hyperchloremicmetabolicalkalosis,hypokalemia,elevated BUNflatulence,and diarrhea

Dose is differentbased on thespecific UCDtype

Branched-chainamino acids

Decreaseglutaminedegradation,increaseglutamineelimination

Fatigue and lossofcoordination

Increase of bloodammonia if notusedappropriately

Albumin normalsaline

Volumeexpansion

Hypernatremia,volumeoverload

None


Funding None.

Compliance with Ethical Standards

Conflict of Interest The authors declare that they have no conflict ofinterest.

Human and Animal Rights and Informed Consent This article does notcontain any studies with human or animal subjects performed by any ofthe authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major Importance

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4. Olde Damink SW, Dejong CH, Deutz NE, et al. Kidney plays amajor role in ammonia homeostasis after portasystemic shuntingin patients with cirrhosis. Am J Physiol Gastrointest Liver Physiol.2006;291:G189–94.

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11. Patil D, Westaby D, Mahida Y, et al. Comparative modes of actionof lactitol and lactulose in the treatment of hepatic encephalopathy.Gut. 1987;28:255–9.

12. Wright G, Noiret L, Olde Damink SW, Jalan R. Interorgan ammo-nia metabolism in liver failure: the basis of current and futuretherapies. Liver Int. 2011;31:163–75.

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20. Vaquero J, Chung C, Cahill ME, Blei AT. Pathogenesis of hepaticencephalopathy in acute liver failure. Semin Liver Dis. 2003;23:259–69.

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22. Hertz L, Kala G. Energy metabolism in brain cells: effects ofelevated ammonia concentrations. Metab Brain Dis. 2007;22(3–4):199–218.

23. Clemmesen JO, Larsen FS, Kondrup J, et al. Cerebral herniationin patients with acute liver failure is correlated with arterial am-monia concentration. Hepatology. 1999;29(3):648–53.

24. Kulick SK, Kramer DA. Hyperammonemia secondary to valproicacid as a cause of lethargy in a postictal patient. Ann Emerg Med.1993;22:610–2.

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26. Bertrand P, Faro A, Cantwell P, Tzakis A. Intravenous ribavirinand hyperammonemia in an immunocompromised patient infect-ed with adenovirus. Pharmacotherapy. 2000;20:1216–20.

27. Sekas G, Paul HS. Hyperammonemia and carnitine deficiency in apatient receiving sulfadiazine and pyrimethamine. Am J Med.1993;95:112–3.

28. Ishikawa F, Nakamuta M, Kato M, et al. Reversibility of serumNH3 level in a case of sudden onset and rapidly progressive caseof type 2 citrullinemia. Intern Med. 2000;39:925–9.

29. Solga S. Probiotics can treat hepatic encephalopathy. MedHypotheses. 2003;61:307–13.

30. Samtoy B, DeBeukelaer MM. Ammonia encephalopathy second-ary to urinary tract infection with Proteus mirabilis. Pediatrics.1980;65:294–7.

31. Cheang HK, Rangecroft L, Plant ND, Morris AAM.Hyperammonaemia due toKlebsiella infection in a neuropathic blad-der. Pediatr Nephrol. 1998;12:658–9.

32. Kaveggia FF, Thompson JS, Schafer EC, Fischer JL, Taylor RJ.Hyperammonemic encephalopathy in urinary diversion with urea-splitting urinary tract infection. Arch Intern Med. 1990;150:2389–92.

33. Nurmohamed S,WeeninkA,MoeniralamH, et al. Hyperammonemiain generalized Mycobacterium genavense infection after renal trans-plantation. Am J Transplant. 2007;7(3):722–3.

34. WylamME, Kennedy CC, Hernandez NM. Fatal hyperammonaemiacaused byMycoplasma hominis. Lancet. 2013;382(9908):1956.

35. Barnes PM, Wheldon DB, Eggerding C, Marshall WC, LeonardJV. Hyperammonaemia and disseminated herpes simplex infec-tion in the neonatal period. Lancet. 1982;1:1362–3.

36. LoWD, Sloan HR, Sotos JF, Klinger RJ. Late clinical presentationof partial carbamyl phosphate synthetase I deficiency. Am J DisChild. 1993;147:267–9.

37. Finkelstein JE, Hauser ER, Leonard CO, Brusilow SW. Late-onsetornithine transcarbamylase deficiency in male patients. J Pediatr.1990;117:897–902.

38. Schimanski U, Krieger D, Horn M, Stremmel W, Wermuth B,Theilmann L. A novel two-nucleotide deletion in the ornithinetranscarbamylase gene causing fatal hyperammonia in early preg-nancy. Hepatology. 1996;24:1413–5.


39. Arn PH, Hauser ER, Thomas GH, Herman G, Hess D, BrusilowSW. Hyperammonemia in women with a mutation at the ornithinecarbamoyltransferase locus: a cause of postpartum coma. N Engl JMed. 1990;322:1652–5.

40. Felig DM, Brusilow SW, Boyer JL. Hyperammonemic coma dueto parenteral nutrition in a woman with heterozygous ornithinetranscarbamylase deficiency. Gastroenterology. 1995;109:282–4.

41. Davies SM, Szabo E, Wagner JE, Ramsay NK, Weisdorf DJ.Idiopathic hyperammonemia: a frequently lethal complication ofbone marrow transplantation. Bone Marrow Transplant. 1996;17:1119–25.

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43. Matsuzaki H, Uchiba M, Yoshimura K, Yoshida M, Akahoshi Y,Okazaki K, et al. Hyperammonemia in multiple myeloma. ActaHaematol. 1990;84:130–4.

44. Kwan L, Wang C, Levitt L. Hyperammonemic encephalopathy inmultiple myeloma. N Engl J Med. 2002;346:1674–5.

45. Takimoto Y, Imanaka F, Hayashi Y, Morioka S. A patient withammon i a - p r o du c i ng mu l t i p l e mye l oma s how i nghyperammonemic encephalopathy. Leukemia. 1996;10:918–9.

46. Ho AY, Mijovic A, Pagliuca A, Mufti GJ. Idiopathichyperammonaemia syndrome following allogeneic peripheralblood progenitor cell transplantation (allo-PBPCT). BoneMarrow Transplant. 1997;20:1007–8.

47. Liaw CC, Liaw SJ, Wang CH, Chiu MC, Huang JS. Transienthyperammonemia related to chemotherapy with continuous infu-sion of high-dose 5-fluorouracil. Anti-Cancer Drugs. 1993;4:311–5.

48. Espinos J, Rifon J, Perez-Calvo J, et al. Idiopathic hyperammonemiafollowing high-dose chemotherapy. Bone Marrow Transplant.2006;37:899.

49. Lichtenstein GR, Yang YX, Nunes FA, Lewis JD, Tuchman M,Tino G, et al. Fatal hyperammonemia after orthotopic lung trans-plantation. Ann Intern Med. 2000;132:283–7.

50. del Rosario M, Werlin SL, Lauer SJ. Hyperammonemic encepha-lopathy after chemotherapy: survival after treatment with sodiumbenzoate and sodium phenylacetate. J Clin Gastroenterol.1997;25:682–4.

51. Vaquero J, Blei AT. Mild hypothermia for acute liver failure: areview of mechanisms of action. J Clin Gastroenterol. 2005;39:S147–57.

52. Salvi S, Santorelli FM, Bertini E, Boldrini R, Meli C, Donati A,et al. Clinical and molecular findings in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome. Neurology.2001;57:911–4.

53. Lemay JF, Lambert MA, Mitchell GA, Vanasse M, Valle D,Arbour JF, et al. Hyperammonemia-hyperornithinemia-homocitrullinuria syndrome: neurologic, ophthalmologic, andneuropsychologic examination of six patients. J Pediatr.1992;121:725–30.

54. Smith W, Kishnani PS, Lee B, Singh RH, Rhead WJ, SnidermanKing L, et al. Urea cycle disorders: clinical presentation outsidethe newborn period. Crit Care Clin. 2005;21:S9–S17.

55. Blanco Vela CI, Bosques Padilla FJ. Determination of ammoniaconcentrations in cirrhosis patients-still confusing after all theseyears? Ann Hepatol. 2011;10(Suppl 2):S60–5.

56. Ong JP, Aggarwal A, Krieger D, Easley KA, Karafa MT, vanLente F, et al. Correlation between ammonia levels and the sever-ity of hepatic encephalopathy. Am J Med. 2003;114(3):188–93.

57. Haberle J. Clinical and biochemical aspects of primary and sec-ondary hyperammonemic disorders. Arch Biochem Biophys.2013;536(2):101–8.

58. Colombo JP, Peheim E, Kretschmer R, Dauwalder H,Sidiropoulos D. Plasma ammonia concentrations in newbornsand children. Clin Chim Acta. 1984;138(3):283–91.

59. Häberle J, Boddaert N, Burlina A, et al. Suggested guidelines forthe diagnosis and management of urea cycle disorders. Orphanet JRare Dis. 2012;7:32.

60. Alfadhel M, Mutairi FA, Makhseed N. Guidelines for acute man-agement hyperammonemia in the Middle East region. Ther ClinRisk Manag. 2016;12:479–87.

61. Naylor EW, Chace DH. Automated tandemmass spectrometry formass newborn screening for disorders in fatty acid, organic acid,and amino acid metabolism. J Child Neurol. 1999;14(Suppl 1):S4–8.

62. Wraith JE. Ornithine carbamoyltransferase deficiency. Arch DisChild. 2001;84:84–8.

63. Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycledisorders. J Pediatr. 2001;138:S21–9.

64. Watanabe A. Portal-systemic encephalopathy in non-cirrhotic pa-tients: classification of clinical types, diagnosis and treatment. JGastroenterol Hepatol. 2000;15(9):969–79.

65. Laish I, Ben AZ. Noncirrhotic hyperammonaemic encephalopa-thy. Liver Int. 2011;31(9):1259–70.

66. Upadhyay R, Bleck TP, Busl KM. Hyperammonemia: what urea-lly need to know: case report of severe noncirrhotichyperammonemic encephalopathy and review of the literature.Case Rep Med. 2016;2016:8512721.

67. U-King-Im JM, Yu E, Bartlett E, Soobrah R, Kucharczyk W.Acute hyperammonemic encephalopathy in adults: imaging find-ings. AJNR Am J Neuroradiol. 2011;32(2):413–8.

68. Vilstrup H, Amodio P, Bajaj J, Cordoba J, Ferenci P, Mullen KD,et al. Hepatic encephalopathy in chronic liver disease: 2014Practice Guideline by the American Association for the Study ofLiver Diseases and the European Association for the Study of theLiver. Hepatology. 2014;60(2):715–35.

69. Als-Nielsen B, Gluud LL, Gluud C. Nonabsorbable disaccharidesfor hepatic encephalopathy. Cochrane Database Syst Rev. 2004;2:CD003044.

70. Leise MD, Poterucha JJ, Kamath PS, Kim WR. Management ofhepatic encephalopathy in the hospital. Mayo Clin Proc. 2014;89:241–53.

71.•• Gluud LL, VilstrupH,MorganMY.Non-absorbable disaccharidesversus placebo/no intervention and lactulose versus lactitol for theprevention and treatment of hepatic encephalopathy in people withcirrhosis. Cochrane Database Syst Rev. 2016; (5):CD003044.This was a meta-analysis for 38 randomized clinical trials thatwere selected based on GRADE criteria. Th authors com-pared non-absorbable disaccharides versus placebo/no inter-vention and lactulose versus lactitol for the prevention andtreatment of hepatic encephalopathy in people with cirrhosis.Random-effects meta-analysis showed a beneficial effect ofnon-absorbable disaccharides on mortality, hepatic encepha-lopathy compared to placebo. In addition, non-absorbable di-saccharides can help to reduce serious adverse events associ-ated with the underlying liver disease including liver failure,hepatorenal syndrome, and variceal bleeding.

72. Als-Nielsen B, Gluud LL, Gluud C. Non-absorbable disaccharidesfor hepatic encephalopathy: systematic review of randomised tri-als. BMJ. 2004;328(7447):1046.

73. Rahimi RS, Singal AG, Cuthbert JA, Rockey DC. Lactulose vspolyethylene glycol 3350—electrolyte solution for treatment ofovert hepatic encephalopathy: the HELP randomized clinical trial.JAMA Intern Med. 2014;174(11):1727–33.

74. Gupta T, Rathi S, Dhiman RK. Managing encephalopathy in theoutpatient setting. Euroasian J Hepato-Gastroenterol. 2017;7(1):48–54.


75. Kimer N, Krag A, Gluud LL. Safety, efficacy, and patient accept-ability of rifaximin for hepatic encephalopathy. Patient PreferAdherence. 2014;8:331–8.

76. Atterbury CE, Maddrey WC, Conn HO. Neomycin-sorbitol andlactulose in the treatment of acute portal-systemic encephalopathy.A controlled, double-blind clinical trial. Am J Dig Dis.1978;23(5):398–406.

77. Last PM, Sherlock S. Systemic absorption of orally administeredneomycin in liver disease. N Engl J Med. 1960;262:385–9.

78. Kim KH, Choi JW, Lee JY, Kim TD, Paek JH, Lee EJ, et al. Twocases of metronidazole-induced encephalopathy. Korean JGastroenterol. 2005;45(3):195–200.

79. Uhl MD, Riely CA. Metronidazole in treating portosystemic en-cephalopathy. Ann Intern Med. 1996;124:455.

80. Tarao K, Ikeda T, Hayashi K, Sakurai A, Okada T, Ito T, et al.Successful use of vancomycin hydrochloride in the treatment oflactulose resistant chronic hepatic encephalopathy. Gut.1990;31(6):702–6.

81. Lester W. Rifampin: a semisynthetic derivative of rifamycin—aprototype for the future. Annu Rev Microbiol. 1972;26:85–102.

82. Marchi E, Montecchi L, Venturini AP, et al. 4-Deoxypyrido[1′,2′:1,2]imidazo[5,4-c]rifamycin SV derivatives. A new series ofsemisynthetic rifamycins with high antibacterial activity and lowgastroenteric absorption. J Med Chem. 1985;28(7):960–3.

83. Bucci L, Palmieri GC. Double-blind, double-dummy comparisonbetween treatment with rifaximin and lactulose in patients withmedium to severe degree hepatic encephalopathy. Curr Med ResOpin. 1993;13(2):109–18.

84. Pedretti G, Calzetti C, Missale G, et al. Rifaximin versus neomy-cin on hyperammoniemia in chronic portal systemic encephalop-athy of cirrhotics. A double-blind, randomized trial. Ital JGastroenterol. 1991;23(4):175–8.

85. Mas A, Rodés J, Sunyer L, Rodrigo L, Planas R, Vargas V, et al.Comparison of rifaximin and lactitol in the treatment of acutehepatic encephalopathy: results of a randomized, double-blind,double-dummy, controlled clinical trial. J Hepatol. 2003;38(1):51–8.

86. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB,et al. Rifaximin treatment in hepatic encephalopathy. N Engl JMed. 2010;362(12):1071–81.

87. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, SarinSK. A randomized, double-blind, controlled trial comparingrifaximin plus lactulose with lactulose alone in treatment of overthepatic encephalopathy. Am J Gastroenterol. 2013;108(9):1458–63.

88. Kimer N, Krag A, Møller S, Bendtsen F, Gluud LL. Systematicreview with meta-analysis: the effects of rifaximin in hepatic en-cephalopathy. Aliment Pharmacol Ther. 2014;40(2):123–32.

89. Blandizzi C, Viscomi GC, Marzo A, Scarpignato C. Is genericrifaximin still a poorly absorbed antibiotic? A comparison ofbranded and generic formulations in healthy volunteers.Pharmacol Res. 2014;85:39–44.

90. Huang DB, DuPont HL. Rifaximin—a novel antimicrobial forenteric infections. J Inf Secur. 2005;50(2):97–106.

91. Descombe JJ, Dubourg D, Picard M, Palazzini E. Pharmacokineticstudy of rifaximin after oral administration in healthy volunteers. Int JClin Pharmacol Res. 1994;14(2):51–6.

92. Ahire K, Sonawale A. Comparison of rifaximin plus lactulosewith the lactulose alone for the treatment of hepatic encephalopa-thy. J Assoc Physicians India. 2017;65(8):42–6.

93. Williams R, James OF,Warnes TW. Evaluation of the efficacy andsafety of rifaximin in the treatment of hepatic encephalopathy: adouble-blind, randomized, dose-finding multi-centre study. Eur JGastroenterol Hepatol. 2000;12(2):203–8.

94. Paik YH, Lee KS, Han KH, Song KH, Kim MH, Moon BS, et al.Comparison of rifaximin and lactulose for the treatment of hepatic

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95. Zhu GQ, Shi KQ, Huang S, Wang LR, Lin YQ, Huang GQ, et al.Systematic review with network meta-analysis: the comparativeeffectiveness and safety of interventions in patients with overthepatic encephalopathy. Aliment Pharmacol Ther. 2015;41(7):624–35.

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98. Webster LT, Siddiqui UA, Lucas SV, Strong JM, Mieyal JJ.Identification of separate Acyl-CoA:Glycine and Acyl-CoA:L-glutamine N-acyltransferase activities in mitochondrial fractionsfrom liver of rhesus monkey and man. J Biol Chem. 1976;251:3352–8.

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101. Enns GM, Berry SA, Berry GT, Rhead WJ, Brusilow SW,Hamosh A. Survival after treatment with phenylacetate and ben-zoate for urea-cycle disorders. N Engl J Med. 2007;356:2282–92.

102.• Pena-Quintana L, Llarena M, Reyes-Suarez D, Aldamiz-EchevarriaL. Profile of sodiumphenylbutyrate granules for the treatment of urea-cycle disorders: patient perspectives. Patient Prefer Adherence.2017;11:1489–96. Authors discussed recently developed taste-masked formulation of sodium phenylbutyrate granules was de-signed to overcome the considerable issues that taste has on ad-herence to therapy. Analysis for the most recent studies showedimproved compliance, efficacy, and safety with this new product.

103. Newmark HL, Young CW. Butyrate and phenylacetate as differ-entiating agents: practical problems and opportunities. J CellBiochem Suppl. 1995;22:247–53.

104. Guffon N, Kibleur Y, Copalu W, Tissen C, Breitkreutz J.Developing a new formulation of sodium phenylbutyrate. ArchDis Child. 2012;97(12):1081–5.

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106. Weiss N, Tripon S, Lodey M, et al. Treating hepatic encephalop-athy in cirrhotic patients admitted to ICU with sodiumphenylbutyrate (PB): a preliminary study. Fundam ClinPharmacol. 2018;32(2):209–15. This is a prospective matchedcontrol data that aimed to assess the benefits of sodium PB incirrhotic patients admitted to ICU for overt HE. The authorsassessed the following outcomes: ammonia levels decrease,neurological improvement, and survival. They have foundthat sodium PB could be effective in reducing ammonia levelsas well as in improving neurological status and ICU survival.

107. Matoori S, Leroux JC. Recent advances in the treatment ofhyperammonemia. Adv Drug Deliv Rev. 2015;90:55–68.

108. Rose C, Michalak A, Pannunzio P, Therrien G, Quack G, KircheisG, et al. L-ornithine-L-aspartate in experimental portal-systemicencephalopathy: therapeutic efficacy and mechanism of action.Metab Brain Dis. 1998;13(2):147–57.


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114. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments inthe treatment of hyperammonemia: emerging use of carglumicacid. Int J Gen Med. 2011;4:21–8.

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129. Malaguarnera M. Acetyl-L-carnitine in hepatic encephalopathy.Metab Brain Dis. 2013;28(2):193–9.

130. Rebouche CJ. Kinetics, pharmacokinetics, and regulation of L-carnitine and acetyl-L-carnitine metabolism. Ann N YAcad Sci.2004;1033:30–41.

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132. Jiang Q, Jiang G, Shi KQ, Cai H, Wang YX, Zheng MH. Oralacetyl-L-carnitine treatment in hepatic encephalopathy: view ofevidence-based medicine. Ann Hepatol. 2013;12(5):803–9.

133. Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symp-toms, frequency and mortality of 260 patients with urea cycle disor-ders from a 21-year, multicentre study of acute hyperammonaemicepisodes. Acta Paediatr. 2008;97(10):1420–5.

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Intravenous and Oral Hyperammonemia Management