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Hyperammonemia

Hyperammonemia is a metabolic disorder characterized by elevated levels of ammonia in the blood, which acts as a potent neurotoxin leading to severe neurological dysfunction.^[1]^[2] Normal serum ammonia concentrations are typically below 30-35 µmol/L in adults, with higher upper limits in newborns (around 80-90 µmol/L) and children (below 50 µmol/L after one month of age).^[1]^[2] The condition arises from either acquired or inherited causes that impair the body's ability to convert ammonia—a byproduct of protein metabolism primarily produced in the intestines and muscles—into urea for excretion via the liver's urea cycle.^[1] Acquired hyperammonemia most commonly results from liver dysfunction, such as cirrhosis or acute hepatic failure, accounting for about 90% of adult cases, as well as infections with urease-producing bacteria, drug toxicities (e.g., valproic acid), or conditions like Reye syndrome.^[1]^[2] Inherited forms stem from genetic defects in the urea cycle enzymes, with ornithine transcarbamylase deficiency being the most prevalent (incidence of 1 in 14,000 to 80,000 births, often X-linked), or from organic acidemias and other metabolic disorders.^[1]^[2] Pathophysiologically, excess ammonia crosses the blood-brain barrier, depleting glutamate and causing astrocyte swelling, which results in cerebral edema, increased intracranial pressure, and potential brain herniation if untreated.^[1]^[2] Clinical manifestations vary by onset and severity but often include nonspecific symptoms such as poor feeding, vomiting, irritability, lethargy, seizures, altered consciousness, and progression to coma, particularly in neonates with urea cycle disorders.^[1]^[2] Chronic or late-onset cases may present with developmental delays, intellectual impairment, ataxia, or behavioral issues.^[2] Diagnosis involves measuring plasma ammonia levels alongside supportive tests like arterial blood gases, serum amino acids, liver function panels, and neuroimaging to rule out complications like edema.^[1]^[2] Acute management focuses on rapid ammonia reduction through hemodialysis, protein restriction, and medications such as sodium phenylbutyrate or lactulose, while addressing underlying causes; liver transplantation may be required for severe inherited cases.^[1]^[2] Prognosis depends on the etiology and timeliness of intervention, with neonatal-onset urea cycle disorders carrying a 5-year survival rate of about 22% and frequent neurologic sequelae among survivors, whereas acquired forms like hepatic encephalopathy have one-year survival rates around 42%.^[1]^[2] Early recognition is critical to prevent irreversible brain damage.^[1]

Background

Definition

Hyperammonemia is a metabolic disturbance defined by excessively elevated blood ammonia levels, generally greater than 50 µmol/L in adults and greater than 100 µmol/L in neonates, which can result in neurotoxicity.^[1]^[3] Ammonia (NH₃) serves as a nitrogenous waste product generated primarily from the catabolism of amino acids and other nitrogen-containing compounds, and under normal conditions, it is detoxified in the liver via the urea cycle, where it is converted into urea for safe excretion in urine.^[4] Untreated hyperammonemia poses a life-threatening risk, potentially causing cerebral edema, seizures, coma, and death, particularly when ammonia concentrations surpass 200 µmol/L.^[1] The condition was first described in the 1960s in association with urea cycle disorders, marking the initial recognition of its clinical significance in inherited metabolic pathologies.^[5]

Normal Ammonia Metabolism

Ammonia is primarily produced in the body through the catabolism of proteins, where amino acids undergo deamination to release nitrogen as ammonia; this process is prominent during high-protein diets, starvation, or general protein breakdown.^[4] Additional sources include the action of gut bacteria, which produce ammonia via the breakdown of urea and proteins through urease activity, and cellular metabolism in tissues such as skeletal muscle and kidneys, where glutamine is deaminated by glutaminase to generate ammonia.^[6]^[7] The primary detoxification pathway for ammonia occurs in the liver via the urea cycle, a series of enzymatic reactions that convert ammonia into urea, a nontoxic compound excreted by the kidneys.^[4] This cycle, which spans the mitochondria and cytosol of hepatocytes, begins with the formation of carbamoyl phosphate from ammonia and bicarbonate, catalyzed by carbamoyl phosphate synthetase I (CPS1), the rate-limiting enzyme activated by N-acetylglutamate.^[4] Subsequent steps involve ornithine transcarbamylase (OTC) to form citrulline, argininosuccinate synthetase (ASS) incorporating aspartate to produce argininosuccinate, argininosuccinate lyase (ASL) cleaving it to arginine and fumarate, and finally arginase hydrolyzing arginine to yield urea and regenerate ornithine.^[4] Urea is then released into the bloodstream and filtered by the kidneys for urinary excretion, maintaining nitrogen balance.^[7] Minor pathways for ammonia handling include the synthesis of glutamine in peripheral tissues such as skeletal muscle and the brain, where glutamine synthetase combines ammonia with glutamate to form glutamine, which can be transported to the liver or kidneys for further processing.^[6] In the kidneys, glutamine serves as a substrate for ammoniagenesis, particularly during acid-base disturbances, allowing excretion of ammonia as ammonium ions to buffer excess protons.^[7] Under normal physiological conditions, blood ammonia levels are tightly regulated at less than 30-50 µmol/L in adults and less than 100 µmol/L in neonates to prevent toxicity.^[6]^[4]

Pathophysiology

Urea Cycle Role

The urea cycle operates primarily within hepatocytes of the liver, with its enzymes predominantly expressed in the periportal zone to facilitate efficient ammonia detoxification near the portal vein where ammonia influx is highest.^[8] This localization ensures that nitrogenous waste from intestinal amino acid metabolism is rapidly processed before entering systemic circulation. The cycle integrates mitochondrial and cytosolic reactions, converting toxic ammonia derived from protein catabolism into non-toxic urea for excretion by the kidneys.^[4] The urea cycle proceeds through five enzymatic steps, starting in the mitochondria and completing in the cytosol. In the first mitochondrial step, ammonia reacts with carbon dioxide and two molecules of ATP to form carbamoyl phosphate, catalyzed by the rate-limiting enzyme carbamoyl phosphate synthetase I (CPS1). Carbamoyl phosphate then combines with ornithine in the second mitochondrial reaction, driven by ornithine transcarbamylase (OTC), to produce citrulline, which is transported to the cytosol. There, citrulline reacts with aspartate and two ATP equivalents to form argininosuccinate via argininosuccinate synthetase (ASS). Argininosuccinate is subsequently cleaved by argininosuccinate lyase (ASL) into arginine and fumarate, with the fumarate entering the citric acid cycle. Finally, arginase hydrolyzes arginine into urea and ornithine, regenerating ornithine for the cycle's continuation.^[4] Each full cycle incorporates two nitrogen atoms—one from ammonia and one from aspartate—into one molecule of urea./02:Unit_II-Bioenergetics_and_Metabolism/18:Nitrogen-_Amino_Acid_Catabolism/18.03:Nitrogen_Excretion_and_the_Urea_Cycle) The process is energetically demanding, requiring the hydrolysis of four high-energy phosphate bonds from ATP per urea molecule synthesized: two ATP in the CPS1 reaction and two ATP equivalents in the ASS step (where ATP is converted to AMP and pyrophosphate, necessitating additional energy for regeneration)./02:Unit_II-Bioenergetics_and_Metabolism/18:Nitrogen-_Amino_Acid_Catabolism/18.03:Nitrogen_Excretion_and_the_Urea_Cycle) Regulation occurs mainly at the CPS1 level through allosteric activation by N-acetylglutamate (NAG), which is synthesized by N-acetylglutamate synthase (NAGS) in response to arginine levels, thereby linking cycle activity to substrate availability and overall nitrogen load.^[9] Defects in any urea cycle enzyme or transporter impair this pathway, causing ammonia to accumulate proximal to the block, while overload from excessive ammonia production—such as during high-protein diets that increase amino acid breakdown or catabolic states like starvation, infection, or trauma that accelerate endogenous protein degradation—can overwhelm even a functional cycle, leading to hyperammonemia.^[4]

Neurotoxic Effects

Ammonia, being a small, uncharged molecule, readily diffuses across the blood-brain barrier, allowing elevated blood levels to penetrate the central nervous system and initiate neurotoxic processes.^[10] Once in the brain, ammonia is primarily detoxified in astrocytes through the action of glutamine synthetase, which catalyzes the conversion of glutamate and ammonia into glutamine. This reaction is as follows:

\text{glutamate} + \text{NH}_4^+ + \text{ATP} \rightarrow \text{glutamine} + \text{ADP} + \text{P}_\text{i}

In hyperammonemia, the excessive ammonia influx overwhelms this pathway, leading to overproduction of glutamine within astrocytes.^[11] The accumulation of glutamine acts as an osmotic agent, drawing water into astrocytes and causing cellular swelling, which contributes to cytotoxic cerebral edema. This astrocyte swelling disrupts the extracellular space and can exacerbate overall brain volume increase, impairing neuronal function.^[11] Furthermore, the glutamine synthesis process depletes intracellular glutamate pools, reducing the availability of this key excitatory neurotransmitter, while promoting the conversion of glutamine to gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, in neurons. This imbalance shifts neurotransmission toward inhibition, underlying the development of encephalopathy.^[12]^[13] Secondary effects of hyperammonemia amplify neurotoxicity, including the induction of oxidative stress through reactive oxygen species generation and mitochondrial dysfunction, which leads to energy failure in neurons by impairing ATP production.^[14] Cerebral edema from astrocyte swelling can also elevate intracranial pressure, further compromising cerebral perfusion and exacerbating neuronal injury.^[1] Ammonia levels exceeding 200 µmol/L typically precipitate acute neurotoxic crises, marking a critical threshold for severe brain involvement.^[15]

Causes

Primary Causes

Primary causes of hyperammonemia encompass congenital genetic defects that intrinsically impair ammonia detoxification, primarily through enzyme deficiencies in the urea cycle or related metabolic pathways.^[16] These inherited disorders disrupt the conversion of toxic ammonia into urea for excretion, leading to its accumulation in the blood.^[16] The most prevalent urea cycle disorder is ornithine transcarbamylase (OTC) deficiency, an X-linked condition caused by mutations in the OTC gene located at Xp11.4.^[17] It has an estimated prevalence of 1 in 14,000 to 1 in 80,000 live births, with neonatal onset typically severe in hemizygous males due to complete enzyme absence.^[17] Heterozygous females may exhibit variable expressivity, ranging from asymptomatic to late-onset hyperammonemic episodes triggered by protein loads or stressors.^[17] Other urea cycle disorders include carbamoyl phosphate synthetase 1 (CPS1) deficiency, an autosomal recessive condition with a prevalence of approximately 1 in 1,300,000, often presenting as a severe neonatal form characterized by profound hyperammonemia shortly after birth.^[16] Argininosuccinate synthetase (ASS) deficiency, also known as citrullinemia type I, is autosomal recessive with an incidence of about 1 in 250,000 and features elevated citrulline levels alongside hyperammonemia in neonatal or later-onset cases.^[16] Argininosuccinate lyase (ASL) deficiency, or argininosuccinic aciduria, is similarly autosomal recessive (incidence 1 in 218,750) and involves accumulation of argininosuccinic acid, contributing to both acute hyperammonemia and chronic neurotoxicity.^[16] Arginase deficiency, termed hyperargininemia, is autosomal recessive (incidence 1 in 950,000) and generally milder, with progressive spastic diplegia rather than acute neonatal crises.^[16] Beyond urea cycle enzymes, additional primary genetic etiologies include certain organic acidemias, such as propionic acidemia and methylmalonic acidemia, which are autosomal recessive disorders of branched-chain amino acid metabolism that secondarily inhibit the urea cycle through toxic intermediates, resulting in hyperammonemia during metabolic decompensation.^[18] Lysinuric protein intolerance, caused by biallelic mutations in the SLC7A7 gene, represents another primary defect; this autosomal recessive transport disorder impairs dibasic amino acid uptake, leading to urea cycle dysfunction and postprandial hyperammonemia.^[19] Genetic inheritance patterns for these disorders are predominantly autosomal recessive, except for the X-linked OTC deficiency, with mutations typically involving missense, nonsense, or frameshift variants that reduce enzyme activity.^[16] Newborn screening programs, implemented in various regions since the early 2000s, enable early detection of some urea cycle disorders through tandem mass spectrometry analysis of amino acids like citrulline and arginine, facilitating prompt intervention to prevent irreversible brain damage.^[16]

Secondary Causes

Secondary causes of hyperammonemia encompass acquired conditions that impair ammonia detoxification or increase its production, distinguishing them from primary genetic defects in the urea cycle.^[1] These extrinsic factors are often reversible upon addressing the underlying issue and predominate in adults, with approximately 90% of cases linked to chronic liver disease such as cirrhosis.^[1] Hepatic causes primarily involve liver dysfunction that hinders urea cycle activity. Acute liver failure, for instance, can arise from acetaminophen overdose, leading to rapid elevations in ammonia levels due to hepatocyte necrosis.^[20] Chronic conditions like cirrhosis, often resulting from alcohol abuse or viral hepatitis, account for the majority of adult presentations by progressively reducing hepatic capacity for ammonia clearance.^[1] Hepatitis, particularly chronic forms from hepatitis B or C viruses, contributes to hyperammonemia through ongoing inflammation and fibrosis.^[1] Reye syndrome, a rare but severe pediatric condition associated with aspirin use during viral illnesses like influenza or varicella, features mitochondrial dysfunction in the liver, resulting in hyperammonemia alongside elevated transaminases and hepatomegaly.^[1] Non-hepatic causes stem from increased ammonia generation outside the liver. Urease-producing bacterial infections, such as those caused by Proteus mirabilis in urinary tract infections, Escherichia coli, Klebsiella, or Helicobacter pylori in the gastrointestinal tract, hydrolyze urea into ammonia, elevating systemic levels.^[1]^[21] Gastrointestinal hemorrhage heightens ammonia production by providing a large protein load for bacterial breakdown in the gut.^[1] Total parenteral nutrition, especially with high amino acid content, can overwhelm detoxification pathways and precipitate hyperammonemia.^[1] Iatrogenic factors include medications and procedural interventions that disrupt ammonia metabolism. Valproic acid, an anticonvulsant, inhibits carnitine-dependent fatty acid transport and glutamate uptake, fostering ammonia accumulation.^[1] Asparaginase, used in chemotherapy for leukemia, depletes glutamine and asparagine, indirectly impairing urea cycle function.^[22] Portosystemic shunts, whether congenital or surgically created, divert portal blood away from the liver, bypassing ammonia-processing hepatocytes.^[1] Transient hyperammonemia occurs in specific vulnerable populations. In premature newborns, immature urea cycle enzymes lead to temporary elevations that typically resolve with hepatic maturation.^[1] Post-surgical scenarios, such as after lung transplantation, may induce acute hyperammonemia due to stress, ischemia-reperfusion injury, or immunosuppressive drugs.^[1] Risk factors exacerbate susceptibility in individuals with marginal liver function. A high-protein diet increases intestinal ammonia production from amino acid deamination, potentially unmasking latent impairments.^[1] Renal failure impairs urinary excretion of ammonia as ammonium ions, compounding hepatic overload.^[1]

Clinical Presentation

Acute Symptoms

Acute hyperammonemia typically presents with a rapid onset, often within 24 to 72 hours after birth in neonates with urea cycle disorders, or acutely in decompensated older children and adults, frequently triggered by infections, increased protein intake, or catabolic stress such as fasting or illness.^[1]^[23]^[24] Early signs are nonspecific and include poor feeding, vomiting, irritability, lethargy, and occasionally hypothermia, mimicking conditions like sepsis.^[23]^[24]^[25] As ammonia levels elevate, usually exceeding 100-150 µmol/L in neonates or 200 µmol/L in adults, symptoms progress to more severe neurological involvement, such as altered mental status progressing from confusion and disorientation to stupor and coma, along with seizures and hyperventilation that induces respiratory alkalosis due to direct stimulation of the respiratory center by ammonia.^[1]^[23]^[24] In neonates, the acute presentation is particularly fulminant, featuring prominent hypotonia, apnea, and grunting respirations, with ammonia concentrations surpassing 1000 µmol/L associated with rapid clinical deterioration, cerebral edema, and mortality rates exceeding 50% if untreated.^[23]^[26] Systemic manifestations, including hepatomegaly and dehydration, may accompany the crisis in some cases, particularly those linked to specific urea cycle enzyme deficiencies, though the dominant features remain neurological.^[23]^[1]

Chronic Symptoms

In survivors of neonatal hyperammonemic crises due to urea cycle disorders (UCDs), chronic manifestations often include intellectual disability and developmental delays, affecting approximately 40-60% of survivors with cognitive impairments persisting into later life.^[27]^[28] These delays encompass broad neurodevelopmental deficits, such as impaired motor skills and language acquisition, stemming from recurrent or sustained exposure to elevated ammonia levels that disrupt brain maturation. Behavioral issues are prevalent in chronic UCDs, manifesting as attention deficits, hyperactivity, self-injurious behaviors, and autism-like traits, including social withdrawal and repetitive actions, which may lead to misdiagnosis as primary psychiatric conditions.^[29] Executive function impairments, such as difficulties with working memory and planning, further compound these challenges, particularly in late-onset forms like ornithine transcarbamylase deficiency (OTCD).^[29] Protein aversion and intolerance emerge as hallmarks of genetic UCDs, where affected individuals self-restrict dietary protein to avoid exacerbating ammonia buildup, often resulting in nutritional deficiencies.^[30] Recurrent episodes in partially managed or untreated chronic hyperammonemia include episodic ataxia, characterized by intermittent gait instability and dysmetria, alongside failure to thrive due to poor appetite and vomiting.^[23] Growth impairment is a common sequela in pediatric genetic forms, with suboptimal linear growth and weight gain attributed to chronic metabolic stress and protein restriction.^[23] In adults with chronic UCDs, persistent symptoms often resemble mild hepatic encephalopathy, featuring subtle confusion, altered mental status, and sleep pattern inversion, such as daytime somnolence and nocturnal insomnia.^[30] Asterixis, or flapping tremor, may occur during recurrent encephalopathic episodes, alongside behavioral disturbances like irritability and mild cognitive fog, necessitating ongoing dietary management to mitigate protein intolerance.^[6] Chronic hyperammonemia in acquired causes, such as liver cirrhosis, typically presents as hepatic encephalopathy with graded severity: minimal encephalopathy (subtle cognitive changes), or overt stages involving confusion, disorientation, asterixis, and in advanced cases, stupor or coma, often fluctuating with triggers like gastrointestinal bleeding or infection.^[1]^[31]

Diagnosis

Laboratory Evaluation

Laboratory evaluation is essential for confirming hyperammonemia and distinguishing primary urea cycle disorders from secondary causes, guiding urgent management in suspected cases.^[1] Immediate testing is critical, as delays can exacerbate neurological damage, with blood samples collected without tourniquet use to avoid artifactual elevations and transported on ice for analysis within 30-60 minutes.^[24] Plasma ammonia concentration is the cornerstone of diagnosis, measured via arterial blood for accuracy, though properly handled venous samples are acceptable. Normal levels vary by age: typically below 30-35 µmol/L in adults, below 50 µmol/L in children older than one month, and up to 80-90 µmol/L (or 100 µmol/L in some references) in newborns during the first days of life; levels exceeding 200 µmol/L in the context of clinical symptoms are diagnostic of significant hyperammonemia and correlate with encephalopathy.^[1]^[32] Quantitative plasma amino acid profiling reveals characteristic patterns in urea cycle defects, such as elevated glutamine and alanine with low citrulline in ornithine transcarbamylase (OTC) deficiency, or elevated argininosuccinic acid in argininosuccinate lyase deficiency. Urine orotic acid measurement is particularly useful, as elevations indicate OTC deficiency or other proximal urea cycle enzyme defects due to carbamoyl phosphate shunting into pyrimidine synthesis.^[1]^[24] Additional laboratory tests support etiology assessment, including liver function tests like serum ALT, AST, and bilirubin to evaluate hepatic involvement in secondary hyperammonemia, and arterial blood gas analysis often showing respiratory alkalosis from hyperventilation. Acylcarnitine profiling and urine organic acids help rule out organic acidemias or fatty acid oxidation disorders as mimics.^[24] For primary causes, confirmatory enzyme assays on liver biopsy, fibroblasts, or erythrocytes (e.g., OTC activity) and genetic testing, such as targeted sequencing of the OTC gene, are performed once stabilized, with molecular analysis identifying mutations in up to 80% of OTC deficiency cases.^[1]^[32]

Imaging and Differential Diagnosis

In acute hyperammonemia, computed tomography (CT) scans of the brain may reveal cerebral edema, particularly in severe cases with ammonia levels exceeding four times the normal range, manifesting as effacement of sulci, ventricular compression, or herniation signs.^[33] Magnetic resonance imaging (MRI) is more sensitive for detecting early changes, showing symmetrical signal abnormalities in the insular and cingulate cortices with restricted diffusion on diffusion-weighted imaging, indicative of cytotoxic edema in acute encephalopathy.^[34] In chronic hyperammonemia, such as in urea cycle disorders, MRI often demonstrates delayed myelination in the white matter, particularly in neonates or long-term survivors, alongside potential atrophy or gliosis.^[35] Electroencephalography (EEG) plays a key role in assessing encephalopathy, frequently showing triphasic waves—high-amplitude, sharply contoured waves with a characteristic morphology—in hyperammonemic states, especially those linked to hepatic encephalopathy or urea cycle defects.^[36] These waves reflect metabolic toxic effects and may coexist with generalized slowing or burst suppression patterns.^[37] In neonates or during acute episodes, continuous EEG monitoring is essential to detect subclinical seizures or non-convulsive status epilepticus, which occur in up to 50% of cases with elevated ammonia and glutamine.^[38] Advanced imaging techniques provide further diagnostic insights. Proton magnetic resonance spectroscopy (MRS) can identify elevated glutamine and glutamate peaks in the brain, reflecting osmotic dysregulation during hyperammonemia, often with reduced myoinositol as a compensatory response.^[39] For secondary hyperammonemia due to liver dysfunction, abdominal ultrasound evaluates for cirrhosis, revealing nodular liver contours, increased echogenicity, or portal hypertension signs like splenomegaly and ascites.^[40] Newborn screening for urea cycle disorders, which predispose to hyperammonemia, employs tandem mass spectrometry on dried blood spots to detect elevated amino acids such as citrulline or argininosuccinate, enabling presymptomatic intervention in certain defects like argininosuccinate synthetase or lyase deficiencies. However, it has limited sensitivity for ornithine transcarbamylase deficiency due to low citrulline levels; some expanded programs include additional markers like glutamine for proximal defects, though screening for OTC is available in only a limited number of regions as of 2025.^[41]^[42] Differential diagnosis of hyperammonemic encephalopathy requires excluding mimics such as sepsis, which can precipitate or simulate symptoms through systemic inflammation and metabolic derangement.^[1] Other considerations include metabolic acidosis from organic acidemias, drug toxicities like valproate-induced hyperammonemia, and non-convulsive status epilepticus, which may present with altered mental status and EEG abnormalities overlapping those of ammonia toxicity.^[43] Imaging and EEG help distinguish these by identifying specific patterns absent in pure infectious or toxic etiologies.^[38]

Management

Acute Interventions

Acute interventions for hyperammonemia aim to rapidly reduce elevated ammonia levels, mitigate cerebral edema, and stabilize the patient during life-threatening crises, typically triggered by metabolic decompensation. These measures are initiated immediately upon confirmation of hyperammonemia, with the goal of lowering plasma ammonia to below 100 µmol/L within hours to prevent irreversible neurological damage.^[44] Treatment is most urgent in neonates and children, where ammonia levels exceeding 500 µmol/L warrant extracorporeal removal techniques.^[45] The gold standard for severe hyperammonemia involves extracorporeal dialysis, such as hemodialysis or continuous venovenous hemofiltration (CVVH), particularly when plasma ammonia surpasses 500 µmol/L or fails to respond to initial medical therapy within 4 hours. Hemodialysis can achieve a 50% reduction in ammonia levels within 1-2 hours and up to 75% within 3-4 hours, with typical clearance rates removing substantial amounts per session, though exact volumes vary by patient size and modality. CVVH is preferred in hemodynamically unstable patients, offering continuous clearance with blood flow rates of 10-20 mL/min and dialysate rates exceeding 1,000 mL/h in neonates, effectively lowering levels from extremes like 881 µmol/L to 367 µmol/L in 2 hours. These interventions must be started promptly, often within hours of presentation, to interrupt the cycle of encephalopathy and edema.^[45]^[44] Pharmacologic ammonia scavenging with intravenous sodium phenylacetate and sodium benzoate (as Ammonul) is a cornerstone adjunctive therapy, administered as a loading dose varying by weight—for patients <20 kg, 250 mg/kg each over 90-120 minutes; for >20 kg, 5.5 g/m² each—in patients with suspected urea cycle disorders (UCDs), followed by the same dose as maintenance over 24 hours.^[46]^[44] These agents conjugate with glycine to form hippurate and with glutamine to form phenylacetylglutamine, respectively, facilitating alternative nitrogen excretion via the kidneys and bypassing the urea cycle. This is typically initiated when ammonia levels are above 150-200 µmol/L but deferred until levels drop to 3-4 times the upper reference range if extracorporeal methods are imminent. Arginine hydrochloride is co-administered to support the cycle: 200 mg/kg loading dose for carbamoyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC) deficiencies; 600 mg/kg for argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) deficiencies (except arginase deficiency).^[46]^[44] Supportive care is essential to halt endogenous protein catabolism and address complications. Protein intake is immediately halted, replaced by intravenous 10% glucose at 4.8-6 mL/kg/h (providing 8-10 mg/kg/min) plus lipids (1-3 g/kg/day) to maintain anabolism and prevent hypoglycemia. Electrolyte imbalances, such as hypokalemia or acidosis, are corrected aggressively, while cerebral edema is managed with mannitol (0.5-1 g/kg IV) or hypertonic saline (3% NaCl boluses) to reduce intracranial pressure. In cases of respiratory failure or deep coma, endotracheal intubation and mechanical ventilation are required to secure the airway and control hypercapnia, which exacerbates encephalopathy.^[44]^[45]^[47] All interventions follow a tight timeline: monitoring plasma ammonia every 2-4 hours, with dialysis preparation overlapping medical therapy to achieve targets within the first 24 hours. Once stabilized (ammonia <100 µmol/L), gradual reintroduction of nutrition occurs, but acute phase focuses solely on rapid detoxification and hemodynamic support.^[45]

Chronic Therapies

Chronic therapies for hyperammonemia focus on sustaining metabolic control, averting crises, and enhancing long-term health in patients with urea cycle disorders (UCDs). These approaches are tailored to the underlying defect and patient age, emphasizing nitrogen restriction and augmentation of residual urea cycle function.^[48] Dietary management forms the foundation of chronic care, typically involving a low-protein intake of 0.5-1 g/kg/day to minimize ammonia generation from amino acid catabolism, while incorporating supplements of essential amino acids, trace elements, and vitamins to maintain nutritional balance and prevent growth impairment.^[49] For defects proximal to argininosuccinate synthetase, such as ornithine transcarbamylase (OTC) deficiency, citrulline supplementation (typically 0.1-0.2 g/kg/day) is preferred to provide substrate for the urea cycle without accumulating citrulline; arginine (0.1-0.3 g/kg/day) is used for distal defects like argininosuccinate lyase deficiency to support argininosuccinate formation.^[50] These regimens require close collaboration with metabolic dietitians to ensure caloric adequacy and monitor for deficiencies.^[51] Pharmacologic interventions include ammonia-scavenging agents to facilitate alternative nitrogen excretion pathways. Sodium phenylbutyrate (Buphenyl), administered orally at 250-500 mg/kg/day for patients <20 kg or 5.5-12.4 g/m²/day for >20 kg in divided doses, conjugates glutamine to phenylacetylglutamine, which is renally excreted, thereby reducing plasma ammonia by up to 30-50% in stable UCD patients and allowing modest increases in dietary protein tolerance.^[52]^[53] For carbamoyl phosphate synthetase 1 (CPS1) deficiency, carglumic acid (100-250 mg/kg/day) acts as an analog of N-acetylglutamate to allosterically activate CPS1, restoring urea cycle flux and normalizing ammonia levels in responsive cases without the need for dialysis.^[54] To curb enteric ammonia production, nonabsorbable antibiotics like rifaximin (e.g., 550 mg twice daily in adults or weight-based in children) or neomycin (500-1000 mg/day in adults, adjusted for pediatrics) are prescribed intermittently or chronically, targeting urease-producing gut bacteria and lowering postprandial ammonia rises by 20-40% in UCD patients with recurrent elevations.^[55]^[56] Liver transplantation serves as a curative modality for severe UCDs, replacing the defective hepatic enzyme capacity and achieving complete metabolic correction; in pediatric cases, 5- and 10-year patient survival exceeds 90%, with graft survival around 85-90% in experienced centers.^[57] Routine monitoring is essential, encompassing monthly plasma ammonia and amino acid profiling to titrate therapies, alongside annual neurodevelopmental assessments to detect subclinical impairments and adjust interventions accordingly.^[58] As of 2025, investigational gene therapies for OTC deficiency, including adeno-associated virus (AAV) vectors such as Ultragenyx's DTX301 (phase 3 trial) and iECURE's ECUR-506 (phase 1/2 with initial patient data demonstrating safety, functional OTC restoration, and ammonia reduction), have shown promising results in clinical trials.^[59]^[60]^[61]

Prognosis

Outcomes by Type

Hyperammonemia outcomes vary significantly by type, with primary forms stemming from urea cycle enzyme deficiencies and secondary forms arising from underlying conditions like liver disease. In primary urea cycle disorders, neonatal-onset cases exhibit poorer prognosis, with 5-year survival rates of about 22-30%, largely due to severe initial hyperammonemic crises and limited therapeutic response in early life.^[1]^[62] Late-onset primary cases, often presenting as partial defects, demonstrate substantially better survival, achieving 90-100% long-term rates with appropriate management as of 2025, reflecting milder enzymatic impairments and fewer acute decompensations.^[63]^[62] Among survivors of primary disorders, approximately 50% experience intellectual disability, particularly those with neonatal presentation, underscoring the neurotoxic impact of recurrent hyperammonemia.^[64] Secondary hyperammonemia, commonly associated with hepatic encephalopathy in liver dysfunction, carries a 1-year survival rate of 42% and a 3-year rate of 23%, influenced by the severity of the underlying hepatic pathology.^[65] Outcomes improve when a reversible cause, such as acute infection or medication toxicity, is identified and addressed promptly, compared to irreversible chronic liver failure.^[1] Acute presentations in both primary and secondary types generally yield worse immediate survival than chronic forms, where ongoing monitoring allows for preventive interventions. As of 2025, overall survival for primary UCDs has improved to 93%, driven by newborn screening and advances in management.^[62] Early diagnosis profoundly enhances outcomes across types; for instance, newborn screening for primary urea cycle disorders facilitates presymptomatic treatment, reducing early mortality risks through avoidance of initial catastrophic episodes.^[41] In the long term, patients with partial primary defects often achieve near-normal cognition when adhering to lifelong therapy, including dietary restriction and ammonia scavengers, highlighting the value of sustained metabolic control.^[66] As of 2023, liver transplantation in eligible pediatric cases of primary urea cycle disorders has elevated survival to 95% at one year post-procedure, offering near-normalization of urea cycle function and markedly improved quality of life; recent data indicate 97% 1-year survival in metabolic disease transplants.^[67]^[68]

Long-term Complications

Hyperammonemia, particularly when resulting from urea cycle disorders (UCDs), can lead to permanent neurological damage due to repeated episodes of cerebral edema and astrocyte swelling, manifesting as intellectual disability, cognitive impairments, and motor deficits in survivors.^[16] Seizure disorders, including epilepsy, affect 20-30% of survivors, often emerging as a long-term sequela of neonatal or early-onset hyperammonemic crises.^[16] Spasticity is also prevalent, progressing to severe forms such as spastic paraparesis or quadriplegia in disorders like arginase 1 deficiency and hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome.^[69] In certain primary UCDs, such as argininosuccinate lyase deficiency, chronic liver involvement can progress to fibrosis and cirrhosis, leading to sustained hepatic dysfunction.^[69] Portal hypertension may develop as a complication of this progression, contributing to further multi-organ strain and requiring vigilant monitoring in affected individuals.^[69] Metabolic disturbances from recurrent hyperammonemia and the demands of chronic low-protein dietary therapy often result in growth stunting, with failure to thrive observed in conditions like arginase deficiency and citrin deficiency.^[16] Osteoporosis can emerge as a consequence of prolonged nutritional restrictions and metabolic imbalances, exacerbating skeletal fragility over time.^[16] Psychological sequelae are significant in genetic forms of UCDs, with adolescents frequently experiencing anxiety and depression alongside attention-deficit/hyperactivity disorder and behaviors resembling autism spectrum disorder.^[16] These issues stem from cumulative neurotoxic effects and the psychosocial burden of lifelong management. Untreated hyperammonemia carries high mortality risks from recurrent crises, with an estimated 10-20% annual incidence of severe hyperammonemic episodes leading to encephalopathy or death in affected individuals.^[16] Liver transplantation, while curative for the urea cycle defect, introduces complications such as hepatic artery thrombosis, chylothorax, and immunosuppression-related issues, occurring in a subset of pediatric cases.^[70] Emerging therapies, including advanced nitrogen scavengers and investigational gene therapies, may further improve long-term prognosis as of 2025.^[71]

References

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Jul 30, 2014 · This review covers aspects of protein metabolism and the control of the two major molecules involved in renal nitrogen excretion: urea and ammonia.
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Modelling urea cycle disorders using iPSCs - Nature
Sep 26, 2022 · The urea cycle pathway is fully expressed in the liver (Fig. 1), precisely in periportal hepatocytes following a specific metabolic zonation.
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CPS1: Looking at an Ancient Enzyme in a Modern Light - PMC
CPS1 catalyzes the first step of the urea cycle by condensing ammonia with bicarbonate, generating carbamoyl phosphate that is eventually incorporated into urea ...
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Alterations of Blood Brain Barrier Function in Hyperammonemia
Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy.
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Astrocyte glutamine synthetase: Importance in hyperammonemic ...
In the brain, glutamine synthesis is largely confined to astrocytes, and it is generally accepted that in hyperammonemia excess glutamine compromises astrocyte ...
[11]
Disturbance of the Glutamate-Glutamine Cycle, Secondary to ...
Jan 26, 2021 · Cognitive and motor alterations in hyperammonemia may be caused by a deregulation of the glutamate-glutamine cycle, particularly in astrocytes, ...
[12]
Hepatic encephalopathy as a result of ammonia-induced increase in ...
Nov 19, 2024 · We propose that the hyperammonemia via astrocytic glutamine synthetase causes an increased γ-aminobutyric acid (GABA) mediated neuro-inhibition.
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Ammonia-induced mitochondrial dysfunction and energy ...
Ammonia negatively affects several key enzymes that are responsible for energy metabolism in mitochondria [11]. Hence, the targeting of bioenergetics failure ...Missing: secondary pressure
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Threshold for toxicity from hyperammonemia in critically ill children
Peak ammonemia ≥200 μmol/L within the first 48 h was an independent risk factor for mortality, with greater risk found in liver failure than in urea cycle ...
[15]
Urea Cycle Disorders Overview - GeneReviews® - NCBI Bookshelf
Apr 29, 2003 · Respiratory alkalosis with hyperammonemia is highly suggestive of an underlying urea cycle disorder. Metabolic acidosis with a wide anion gap ...Genetic Causes of Urea Cycle... · Evaluation Strategies to... · Genetic Counseling
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Ornithine Transcarbamylase Deficiency - GeneReviews - NCBI - NIH
Aug 29, 2013 · An early estimated prevalence of OTC deficiency was 1:14,000 live births [Brusilow & Maestri 1996]. However, other surveys of incidence of OTC ...
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Hyperammonaemia in classic organic acidaemias - PubMed Central
Dec 6, 2018 · This article describes the three OAs most likely to result in hyperammonaemia during acute metabolic decompensation: propionic acidaemia (PA; ...
[18]
Update on Lysinuric Protein Intolerance, a Multi-faceted Disease ...
Jan 5, 2017 · Lysinuric protein intolerance (LPI) is a rare metabolic disease resulting from recessive-inherited mutations in the SLC7A7 gene encoding the cationic amino- ...
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Acetaminophen Toxicity - StatPearls - NCBI Bookshelf
Apr 10, 2025 · More pronounced symptoms, including jaundice, confusion, hyperammonemia, abnormal aminotransferases, and bleeding diathesis, along with ...
[20]
Effect of H pylori infection and its eradication on hyperammo-nemia ...
Recently, it has been suggested H pylori contributes to hyperammonemia in cirrhotic patients and bacterium eradication decreases blood ammonia concentration.
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Asparaginase-associated hyperammonemia - Haematologica
Apr 24, 2025 · In patients with hyperammonemia due to causes other than asparaginase treatment, such as inborn errors of metabolism, liver failure or sepsis, ...
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Hyperammonemia Clinical Presentation: History, Physical, Causes
Sep 28, 2021 · Patients present with symptoms and signs of cerebral and hepatic dysfunction—vomiting, altered level of consciousness, seizures, cerebral edema, ...History · Physical · CausesMissing: definition | Show results with:definition
[23]
Guidelines for acute management of hyperammonemia in the ...
Acute hyperammonemia is defined as elevated plasma ammonia levels associated with muscular hypotonia, seizures, vomiting, and impaired consciousness.1 The ...
[24]
What are the symptoms - National Urea Cycle Disorders Foundation
... hyperammonemia in these infants. Refusal to Feed. Vomiting. Irritability progressing to lethargy and somnolence. Hypothermia. Seizures. Hyperventilation leading ...Missing: acute | Show results with:acute
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Neonatal factors related to survival and intellectual and ...
Ammonia (NH3) levels are key to acute management [1,14], as the survival rate is <50% for peak NH3 > 1000 μmol/L [12,21,32]. The relationship between the degree ...<|control11|><|separator|>
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What are the symptoms - National Urea Cycle Disorders Foundation
Hyperammonemia in the Emergency Department · Protein aversion · Loss of appetite · Sleep disorders · Psychiatric or behavioral disorders · Trichorrhexis nodosa (due ...
[29]
Recommendations for the Diagnosis and Therapeutic Management ...
Jul 2, 2022 · Hyperammonaemia is a metabolic derangement that may cause severe neurological damage and even death due to cerebral oedema, further complicating ...
[30]
Acute Hyperammonemic Encephalopathy in Adults: Imaging Findings
Patients with acute hyperammonemic encephalopathy present with progressive drowsiness, seizures, and coma due to primary toxic effects of ammonia on the brain ...
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MRI Findings in Acute Hyperammonemic Encephalopathy - NIH
Jan 30, 2020 · Symmetrical extensive cortical signal abnormalities, typically involving the insular and cingulate cortices, often showing restricted diffusion, ...
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Magnetic resonance imaging findings and neurodevelopmental ...
Aug 19, 2013 · Urea-cycle defects (UCDs) result in hyperammonemia and the accumulation of glutamine and various toxic metabolites. Neonatal-onset UCDs are ...
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EEG Triphasic Waves - StatPearls - NCBI Bookshelf
They are non-specific, high amplitude, sharply contoured waves with a unique morphology. They were believed to be pathognomonic of hepatic encephalopathy.
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Hyperammonemic Encephalopathy due to Underlying Ornithine ...
Electroencephalogram (EEG) showed generalized triphasic waves with diffuse slowing, indicating a metabolic toxic encephalopathy [Figure 1]. Magnetic resonance ...
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The utility of EEG monitoring in neonates with hyperammonemia ...
Seizures occur frequently in neonates with hyperammonemia; most can be detected only with continuous EEG. Seizures may occur when ammonia and glutamine ...
[36]
Multimodal imaging in urea cycle-related neurological disease
Feb 15, 2020 · MR spectroscopy demonstrated that glutamine was elevated during hyperammonemia with myoinositol reduction, reflecting osmotic buffering.
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Non-cirrhotic hyperammonaemia: are we missing the diagnosis?
Mar 30, 2020 · The presence of porto-systemic shunts should also be worked up via ultrasound Doppler of the liver. Ammonia-lowering agents are also started ...
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Considering Proximal Urea Cycle Disorders in Expanded Newborn ...
Oct 8, 2020 · Proximal urea cycle disorders (PUCDs) have adverse outcomes such as intellectual disability and death, which may benefit from newborn screening (NBS).
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Automated tandem mass spectrometry for mass newborn screening ...
Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism.
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Hyperammonemia: What Urea-lly Need to Know: Case Report of ...
Aug 28, 2016 · In absence of hepatic dysfunction, hyperammonemia can be caused by increased ammonia production or decreased ammonia excretion. Aggressive ...Missing: definition | Show results with:definition
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Suggested guidelines for the diagnosis and management of urea ...
May 29, 2012 · Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the ...
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Consensus guidelines for management of hyperammonaemia in ...
Apr 8, 2020 · Toxic levels of ammonia can be due to either a primary or a secondary deficiency of the urea cycle. Congenital deficiency of any of the six ...
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[PDF] Ammonul - accessdata.fda.gov
On admission to the hospital, patients with hyperammonemia or a potential urea cycle disorder (UCD) were treated with a bolus dose of 0.25 g/kg (or 5.5 g/m2) ...
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Acute pediatric hyperammonemia: current diagnosis and ...
Sep 12, 2018 · The most common causes of hyperammonemia in children are severe liver failure and inherited metabolic diseases.
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Long-Term Management of Patients with Mild Urea Cycle Disorders ...
Dec 20, 2023 · The therapy should be based on a low-protein diet and nitrogen scavengers. The long-term follow-up is based on growth and nutritional assessment ...
[46]
Nutrient Intake and Nutritional Status in Adult Patients with Inherited ...
Oct 29, 2020 · Low-protein diets (LPDs) are the main treatment for urea cycle disorders (UCDs) and organic acidemias (OAs). In most cases, LPDs start in ...
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Citrulline in the management of patients with urea cycle disorders
Jul 21, 2023 · The results also suggest that citrulline supplementation may be more effective than arginine supplementation at increasing plasma arginine ...
[48]
Primary Hyperammonaemia: Current Diagnostic and Therapeutic ...
Long-term management consists of a low-protein diet supplement with essential amino acids, trace elements and vitamins and the use of nitrogen scavenging drugs.
[49]
Profile of sodium phenylbutyrate granules for the treatment of urea ...
Sep 6, 2017 · Among the ammonia-scavenging drugs, sodium phenylbutyrate is a well-known long-term treatment of urea-cycle disorders. It has been used ...
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Therapeutic effect of N-carbamylglutamate in CPS1 deficiency - PMC
Jul 8, 2020 · Hyperammonemia associated with UCDs, including CPS1D, compromises cognitive status and is life-threatening. The extent of developmental delay is ...
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The Pharmabiotic Approach to Treat Hyperammonemia - PMC
Jan 28, 2018 · Liver malfunctions cause hyperammonemia that leads to central nervous system (CNS) dysfunctions, such as brain edema, convulsions, and coma. The ...
[52]
Urea cycle disorders and indications for liver transplantation - PMC
Pediatric LT now has 5- and 10-year survival rates that are significantly above 90%. As the morbidity and mortality risks of LT have gradually declined, and ...
[53]
Suggested guidelines for the diagnosis and management of urea ...
May 29, 2012 · This mainstay of long-term management is based upon minimising the nitrogen load on the urea cycle.<|separator|>
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Gene therapy for urea cycle defects: An update from historical ...
Apr 18, 2023 · We provide an update about the state of the art of gene therapy technologies for UCDs and the current advantages and pitfalls driving future directions for ...
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A longitudinal study of urea cycle disorders - PMC - NIH
Aug 10, 2014 · Despite aggressive treatment with hemodialysis, the five year survival of these newborns was about 50% (pre-2002) [1]. In our initial (1980s) ...
[56]
Comparing Treatment Options for Urea Cycle Disorders - NCBI - NIH
Patients with neonatal-onset UCDs all require chronic therapy with both stringent protein restriction and high doses of ammonia scavengers, but they may ...<|control11|><|separator|>
[57]
Intellectual, Adaptive, and Behavioral Functioning in Children ... - NIH
Inborn errors of urea synthesis lead to an accumulation of ammonia in blood and brain, and result in high rates of mortality and neurodevelopmental disability.
[58]
Prognostic significance of hepatic encephalopathy in patients with ...
Results: During follow-up (12+/-17 months), 82 (74%) patients died. The survival probability was 42% at 1 year of follow-up and 23% at 3 years.
[59]
Patient prognosis in hepatic encephalopathy - Hepa Merz
Survival after first acute HE episode is estimated to be 42% at 1 year, 27% at 2 years, and 23% at 3 years. Patients who go into a coma have about an 80% ...
[60]
Impact of diagnosis and therapy on cognitive function in urea cycle ...
The major aim of this study was to evaluate the impact of diagnostic and therapeutic interventions on cognitive outcomes in UCDs.Missing: partial | Show results with:partial
[61]
Urea cycle disorders and indications for liver transplantation - PubMed
Mar 3, 2023 · Of the 27 patients who did not die in the neonatal period, 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance ...
[62]
Hepatic Manifestations of Urea Cycle Disorders - PMC - NIH
Arginine and citrulline supplementation replenishes deficient urea cycle substrates. Importantly, arginine supplementation is contraindicated in arginase ...
[63]
Pediatric Liver Transplantation as Definitive Therapy for Urea Cycle ...
Postoperative complications included hepatic artery thrombosis (n=1), chylothorax (n=1), and bowel perforation (n=1).