Introduction
Hyperammonemia (HA) is a critical condition commonly encountered in adult patients. While 90% of cases are associated with liver disease, a smaller but significant portion comes from non-cirrhotic causes, with a study reporting as high as 76% of ICU patients [ 1 ]. As a neurotoxin, ammonia can trigger metabolic encephalopathy, with symptoms ranging from mild (anorexia, vomiting) to severe (altered mental status, seizures, coma) [ 2 ]. Untreated severe HA can cause irreversible brain damage in up to 5% of non-cirrhotic cases, with mortality rates as high as 64% in critically ill patients [ 3 ].
Therefore, timely recognition and intervention are essential to prevent permanent brain damage and improve survival [ 2 ]. The case report and following review of literature describe the pathophysiology of HA, evaluation through a practical diagnostic approach, and medical management including liver transplantation (LT) outcomes with a focus on adult-onset urea cycle disorders (UCDs). The CARE Checklist has been completed by the authors for this case report and is attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000553356 ).
Case Report
An 18-year-old female presented to the emergency department with a 1-week history of progressively worsening confusion, disorientation, and agitation, subsequently accompanied by abdominal pain, nausea, and dry heaving. Her past medical and family histories were unremarkable for chronic comorbidities. On presentation, vital signs were notable for tachycardia (heart rate 125 beats/minute) and hypotension (95/50 mm Hg); respiratory rate was 16 breaths/minute, and she was afebrile.
An initial complete blood count was unremarkable, as was her comprehensive metabolic panel. Arterial blood gas, however, was notable for a pH of 7.49, PaCO 2 of 30 mm Hg, PaO 2 of 90 mm Hg, and bicarbonate of 25 mmol/L. An ammonia level was subsequently checked and was elevated to 210 μg/dL. A computed tomography (CT) scan of the abdomen was unremarkable for any gross abnormalities.
Shortly after arrival, she experienced rapid neurological deterioration with loss of consciousness, necessitating endotracheal intubation for airway protection. Neurologic examination at that time demonstrated bruxism, extensor posturing of all extremities in response to central stimulation, and preserved brainstem reflexes. Non-contrast CT of the head revealed no acute intracranial abnormalities. Given concern for meningoencephalitis, empiric broad-spectrum antibiotic therapy was initiated, and the patient was transferred to the intensive care unit (ICU).
In the ICU, continuous electroencephalography demonstrated irregular, generalized low voltage slowing without epileptiform activity. Repeat serum ammonia was markedly elevated at 795 µg/dL. In the setting of worsening HA, urgent venous hemofiltration was initiated, and an intracranial pressure monitor was placed. Serum ammonia subsequently decreased to 87 µg/dL within 24 h. Brain magnetic resonance imaging revealed extensive areas of restricted diffusion with associated FLAIR hyperintensity involving the bilateral temporal lobes, as well as bilateral insular, frontal, and parietal cortical and subcortical regions ( Fig. 1 ).
Throughout hospital day 2, she received ongoing medical management for HA, including intravenous L-arginine at 30 g/day, glucose-electrolyte infusion supplemented with vitamins B1, B6, and B12, enteral lactulose 30 g/day, and levocarnitine 3,000 mg/day administered via nasogastric tube. Liver biochemistry and complete blood counts remained stable, with improvement in hemodynamics. By hospital day 3, the patient was able to follow commands and spontaneously open her eyes. Venous hemofiltration was discontinued, and she was successfully extubated later that day.
Plasma amino acid analysis obtained prior to initiation of L-arginine demonstrated decreased citrulline at 15 nmol/mL (reference range 17.1–42.6). Concurrent urine organic acid testing revealed mildly elevated uracil and markedly elevated orotic acid. These findings were diagnostic of late-onset ornithine transcarbamylase deficiency (OTCD). The patient was discharged on sodium benzoate therapy with recommendations for dietary protein restriction.
Discussion
Pathophysiology of HA: ammonia primarily originates from the gut via glutamine deamination, urea breakdown, nucleic acid degradation, and from microbes such as Escherichia coli and Bacteroides , and must be tightly regulated to avoid consequences like hepatic encephalopathy [ 4 ]. Smaller, but clinically relevant, sources of ammonia also include peripheral tissues (such as muscle) and the kidney, where ammonia participates in acid-base regulation. Ammonia is normally cleared by hepatocytes through the urea cycle, which maintains low ammonia levels [ 5 ]. The urea cycle and the key enzymes are illustrated in Figure 2 . When this balance is disrupted and ammonia production exceeds hepatic clearance or bypasses it, HA occurs. Under normal conditions, ammonia crosses the blood-brain barrier and is metabolized in astrocytes to glutamine [ 6 ]. However, in HA, excess ammonia leads to cerebral edema and disrupted neurotransmission [ 7 ]. Chronic exposure leads to astrocyte changes, oxidative stress, mitochondrial dysfunction, and blood-brain barrier disruption, leading to neurotoxicity [ 8 ]. Additionally, HA also impairs multi-organ function, such as the lungs and muscle, by impairing neutrophil function and promoting oxidative stress [ 9 , 10 ].
Non-cirrhotic causes of HA: while cirrhosis is the most recognized cause of HA, non-cirrhotic etiologies include reduced ammonia elimination, increased production, and drug-induced or congenital portosystemic shunting ( Table 1 ).
Table 1.
Non-cirrhotic causes of HA
| Mechanism of abnormality | Cause of HA |
| Acute liver failure or chronic liver disease | − Viral hepatitis − Drugs and toxins: tylenol toxicity, mushroom poisoning − Metabolic disorders, e.g., Wilson’s disease |
| Decreased ammonia elimination | Inborn errors of metabolism − UCDs − Organic acidurias (commonly presents during childhood) − Carnitine deficiency from defects in beta fatty acid oxidation (commonly presents during childhood) − Defects in pyruvate oxidation − Primary hepatic (hepato-cerebral) mitochondrial disorders |
| Portosystemic shunt − Congenital intrahepatic including abernathy malformation and extrahepatic portosystemic shunt − Portal vein thrombosis − Large hepatic hemangioma − Transhepatic intrajugular portosystemic shunt | |
| Distal renal tubular acidosis | |
| Surgery − Ureterosigmoidostomy − Roux-en-Y gastric bypass | |
| Drug-induced HA | − Valproic acid − Glycine − Carbamazepine − Ribavirin − Sulfadiazine − Pyrimethamine − Rifabutin − Salicylate |
| Increased ammonia production | Hemato-oncological disorders − Multiple myeloma − Leukemia − Fibrolamellar hepatocellular carcinoma − Bone marrow transplant − Organ transplantation (lung, liver) |
| Chemotherapeutic agents − Vincristine − Cytarabine − Etoposide − L-Asparaginase − Cyclophosphamide − 5-Fluorouracil | |
| Infections with urea-producing bacteria − P. mirabilis, Escherichia coli, Klebsiella species, Providencia rettgeri, Morganella morganii − Diphtheroids in patients with urinary tract abnormalities − Mycobacterium genavense − Herpes simplex virus − Systemic mycobacterial or mycoplasma infection in lung transplant patients | |
| Increased muscle catabolism − Seizures − Starvation/rapid weight loss − Gastric bypass − Trauma − Burns − Excessive exercise | |
| Miscellaneous causes | − Diets with high protein: total parenteral nutrition, atkins diet − Gastrointestinal bleeding (elevated ammonia production in the splanchnic circulation and the kidneys) − Medications affecting protein catabolism: intravenous or high-dose steroids |
| Often asymptomatic unless there underlying UCD |
Decreased Elimination of Ammonia
Causes of decreased elimination of ammonia include UCDs, such as carnitine deficiency, dibasic aminoaciduria, and pyruvate metabolism defects [ 11 ]. Partial enzyme deficiencies may remain clinically silent until metabolic stress unmasks them and can therefore present late in life, with acute cases triggered by infections, total parenteral nutrition, gastrointestinal bleeding, or medications [ 12 ].
Increased Ammonia Production
Increased ammonia production occurs in hemato-oncological disorders, organ transplantation, infections, and states of heightened catabolism or protein load. For example, in multiple myeloma, excess ammonia may result from increased amino acid metabolism, impaired urea metabolism, and liver infiltration causing portosystemic shunting [ 13 ]. External stressors such as chemotherapy or viral illness can also trigger HA through mechanisms such as protein breakdown, low arginine levels, and parenteral nutrition [ 14 ].
Drug-Induced HA
Medication-induced HA occurs when drugs disrupt the urea cycle or increase renal ammonia release. A common culprit is valproic acid, where valproate-induced HA occurs in 35–45% of patients and is thought to contribute to HA by inhibiting astrocyte glutamate uptake and, via its metabolic by-products, increasing propionic acid and inhibiting carbamoyl phosphate synthetase I (CPS I) [ 15 – 17 ]. Other drugs, such as carbamazepine, sulfadiazine, and ribavirin, among others, may similarly unmask HA ( Table 1 ).
Congenital Portosystemic Shunting
Congenital portosystemic shunts (CPS) arise from abnormal development of the vitello-umbilical venous plexus [ 18 ]. While CPS can be asymptomatic, complications of CPS include encephalopathy, portal hypertension, liver tumors, and high-output heart failure as they divert portal blood into the systemic circulation. HA in this group may present as encephalopathy, cognitive impairment, speech delays, behavioral issues, and learning difficulties [ 19 ].
Practical Approach to Evaluation of a Patient with HA
Step 1: Detailed History, Clinical Presentation, and Physical Examination
Given its diverse etiologies, HA can present nonspecifically, making a thorough history and careful physical examination essential. Symptoms range from mild (headache, nausea) to severe (seizures, coma, psychosis) and may fluctuate with diet, stress, or infection. Although the neurological manifestations of HA are similar regardless of etiology, certain clinical features may help distinguish non-cirrhotic HA from hepatic encephalopathy associated with decompensated cirrhosis. Patients with adult-onset UCDs frequently present with acute or rapidly progressive encephalopathy, behavioral or psychiatric disturbances, seizures, and respiratory alkalosis despite normal liver biochemistry. In contrast, HA in decompensated cirrhosis typically occurs in the setting of established chronic liver disease, portal hypertension, and other manifestations of hepatic decompensation [ 7 , 14 ].
Step 2: Ensure Appropriate Ammonia Sample Collection and Processing
Diagnosis should begin with testing. Serum ammonia can be measured from arterial or venous blood, but careful specimen handling is essential to avoid false elevations from cell contact or anaerobic metabolism [ 20 ]. Improper specimen handling can result in pseudo-HA and potentially lead to unnecessary diagnostic testing or treatment. To minimize pre-analytical error, blood samples should be placed immediately in an ice slurry after collection and transported rapidly to the laboratory for prompt processing, ideally within 30 min. Delays in transport, prolonged cellular contact, hemolysis, inadequate cooling, or improper storage conditions may result in falsely elevated ammonia concentrations and should be considered when interpreting unexpected results. Additionally, patients should be fasting and rested as feeding or exercise can also raise ammonia levels.
Step 3: Laboratory Findings
Ammonia measurement is rarely used in the management of cirrhosis; however, in a case of altered mental status without chronic liver disease, measuring ammonia levels may be critical. If serum ammonia levels exceed 100 µmol/L (175 µg/dL) in adolescents and adults without a history of liver failure, additional investigations are warranted [ 21 ]. Evaluation should include CBC, arterial blood gases, lactate, glucose, electrolytes, and amino acids (shown in Fig. 3 ) [ 21 ].
Acid-base status can provide important diagnostic clues. Acidosis suggests organic acidurias; respiratory alkalosis may indicate UCDs; if acid-base status is normal, serum and urine amino acids should be checked. If inconclusive, elevated urine orotic acid identifies OTCD while normal results suggest CPS or N-acetyl glutamine synthetase deficiency. An algorithm for diagnosis of UCDs is shown in Figure 3 .
Step 4: Cross-Sectional Imaging and Biopsy
Abdominal imaging, such as ultrasound, CT abdomen/CT angiogram, and MRI, is key for detecting portosystemic shunts and non-cirrhotic portal hypertension. MRI of the brain also offers diagnostic value during episodes of HA encephalopathy, even when ammonia levels are not significantly elevated [ 22 ]. Brain matter changes typically include bilateral symmetric signal-intensity abnormalities with restricted diffusion involving the insular cortex and cingulate gyrus [ 22 ].
Liver biopsy helps rule out cirrhosis and other liver disorders (e.g., primary biliary cirrhosis, schistosomiasis). However, it is rarely needed, except when rapid diagnosis or inconclusive genetic testing requires histology. At this stage, if structural and secondary causes are excluded, inherited metabolic disorders should be considered. Although several inborn errors of metabolism can cause HA, this review focuses specifically on common adult-onset UCDs.
Step 5: Determining the Specific Type and Genetic Cause of a Suspected Inborn Error of Metabolism
UCDs : UCDs are a group of inborn errors of metabolism caused by deficiencies in enzymes essential for ureagenesis, leading to ammonia buildup. The prevalence of UCDs is estimated to be about 1 in 35,000 births in the USA across all ethnicities [ 23 ]. As UCDs can manifest with neuropsychiatric features, they can also mimic drug intoxication or encephalitis. The next section will focus on adult-onset UCDs outlining diagnosis, management, and outcomes, emphasizing LT [ 24 ].
OTCD : OTCD is an X-linked disorder, which impairs conversion of ornithine and carbamoyl phosphate to citrulline, the second step of the urea cycle. Its estimated incidence is 1:56,500 [ 25 ]. Complete OTCD presents in newborns with severe, sometimes fatal symptoms, progressing quickly from anorexia to HA-related neurologic signs [ 26 ]. Late-onset OTCD in older children and adults has a highly variable presentation, including lethargy and anorexia; during stressful events, it may also manifest as erratic behavior and delirium [ 27 ]. Diagnosis relies on plasma amino acids, urine organic acids, and genetic testing.
Citrin deficiency (CD) : CD or type II citrullinemia (CTN2) is an autosomal recessive disorder caused by a defect in citrin, which disrupts transfer of cytosolic NADH-reducing equivalent into the mitochondria [ 28 ]. Its estimated incidence is 1:100,000–1:230,000 in Japan, but global incidence is unknown [ 29 ]. In neonates, CD presents with cholestasis, hypoglycemia, and fatty liver; in older children, it presents as FTTDCD (failure to thrive and dyslipidemia caused by CD), characterized by poor growth and a preference for protein and fat with avoidance of carbohydrates [ 28 ]. It usually presents in adolescence or adulthood (20–50 years) with recurrent HA and neuropsychiatric symptoms, though neonatal or childhood forms exist [ 28 ]. In adults, CD may cause hepatocellular carcinoma.
Citrullinemia type I (CTLN1): CTLN1 is an autosomal recessive UCD caused by a gene encoding arginosuccinate synthetase, a rate-limiting enzyme in the urea cycle [ 30 ]. Its estimated incidence is 1:250,000 [ 31 ]. The classic homozygous form causes neonatal hypercitrullinemia, HA, and orotic aciduria, potentially leading to encephalopathy and death if untreated [ 30 ]. Adult-onset CTLN1 is a milder form, which can present with more subtle neurological findings such as intense headache, ataxia, lethargy, and scotomas [ 32 ]. Early recognition and management through a low-protein, high-carbohydrate, high-fat diet improves prognosis, while untreated HA can be fatal or cause permanent disability [ 33 ].
Carbamoyl phosphate synthetase 1 deficiency (CPSD) : CPSD is a rare autosomal recessive UCD (approx. incidence 1:150,000–300,000) due to mutations in the CPS1 gene, which affects the first step in the urea cycle [ 34 ]. Neonatal CPSD is often lethal, while adult-onset forms may be mild or asymptomatic until HA occurs [ 35 ]. Neonatal-onset CPSD shows absent/trace plasma citrulline, while later-onset CSPD shows low to low-normal citrulline levels, elevated plasma glutamine, and normal-to-low urine orotic acid. Genetic testing can confirm diagnosis.
Diagnostic Evaluation of UCDs
In the US, newborn screening includes tandem mass spectrometry to diagnose argininosuccinate lyase deficiency and citrullinemia type I/argininosuccinate synthase deficiency, which are both rare UCDs. Additional UCDs included in newborn screening panels vary by state. Diagnosis combines clinical presentation, family history, biochemical testing, and molecular genetic confirmation. Plasma ammonia should be checked in adults with unexplained acute encephalopathy as levels >150 µmol/L with normal anion gap and glucose strongly suggest a UCD and warrant further amino acid and organic acid testing [ 23 ]. Enzyme assays are additional options but are invasive and less reliable, making molecular genetic testing the definitive diagnostic tool [ 29 ]. Diagnostic algorithm for UCDs is shown in Figure 3 .
Management of UCD
There are three mainstays in medical treatment of UCD: nitrogen scavenger therapy, dietary protein restriction, and essential amino acid supplementation with L-citrulline or L-arginine. The only known “curative therapy” is LT, although it does not correct all metabolic abnormalities and has significant long-term complications.
UCD management including early HA detection, treatment adherence, and drug tolerability requires a multidisciplinary team of intensivists, geneticists, genetic counselors, dieticians, neuropsychologists, metabolic physicians, hepatologists, nephrologists, and transplant surgeons [ 36 ]. Earlier interventions improve survival, whereas delayed, lack of, or noncompliant treatment shows poor cognitive outcomes [ 37 ].
Treatment of Acute Presentation
Acute HA management focuses on lowering ammonia, preventing complications, and avoiding triggers. Milder cases are treated with nitrogen scavengers. If ineffective, hemodialysis is started with a target ammonia level <150 µmol/L [ 38 ]. Other treatments for HA are based on the specific enzyme deficiency; for example, patients with carbamoyl phosphate synthetase I deficiency (CPS-1) receive carglumic acid [ 39 ]. Extracorporeal membrane oxygenation is indicated for severe cases with encephalopathy and coma. Protein is restricted for 12–24 h, and transition from parenteral to enteral nutrition is made if the patient is clinically stable.
Intravenous nitrogen-scavenging therapy with sodium benzoate, sodium phenylbutyrate, and glycerol triphenyl butyrate promotes nitrogen ( Table 2 ). Therapy continues until HA resolves and enteral nutrition resumes. Depending on the specific type of UCD, replacement of deficient intermediates may be necessary.
Table 2.
Dose recommendations for acute and chronic management of UCDs
UCD: Urea cycle disorder, OTCD: Ornithine transcarbamylase deficiency, CPSD: Carbamoyl phosphate synthetase 1 deficiency, CD: Citrin deficiency.
| UCD | Acute management | |||||
| Nitrogen scavengers – sodium PBA/phenylacetate (to be given IV in 10% glucose) | Nitrogen scavengers – sodium benzoate (to be given IV in 10% glucose) | L-arginine hydrochloride (to be given IV in 10% glucose) | ||||
| OTCD/CPSD | 250 mg/kg bolus (90–120 min), maintenance: 250–500 mg/kg/day (if >20 kg body weight, 5.5 g/m 2 /day) | 250 mg/kg as a bolus in 90–100 min, then maintenance 250–500 mg/kg/day (if >20 kg body weight, 5.5 g/m 2 /day) | 250–400 mg/kg bolus (90–120 min), maintenance 250 mg/kg/day | |||
| Type 1 citrullinemia | 250 mg/kg bolus (90–120 min), maintenance: 250–500 mg/kg/day (if >20 kg body weight, 5.5 g/m 2 /day) | 250 mg/kg as a bolus in 90–100 min, then maintenance 250–500 mg/kg/day (if >20 kg body weight, 5.5 g/m 2 /day) | 250–400 mg/kg bolus (90–120 min), maintenance 250 mg/kg/day | |||
| CD | – | – | – | |||
| UCD | Maintenance therapy | |||||
| L-arginine (hydrochloride or free base) | L-citrulline | Sodium benzoate | Sodium PBA | Dietary therapy | Sodium pyruvate | |
| OTCD/CPSD | <20 kg: 100–200 mg/kg/day | ≥25 kg: 3.8 g/m 2 /day | ≤250 mg/kg/day, max: 12 g/day | <20 kg: ≤250 mg/kg/day | Protein intake at recommended dietary allowance | – |
| >20 kg: 2.5–6 g/m 2 /day | OR | >20 kg: 5 g/m 2 /day | ||||
| Max: 6 g/day | 200 mg/kg/day (max: 6 g/day) | Max: 12 g/day | ||||
| Type 1 citrullinemia | <20 kg: 100–300 mg/kg/day | – | – | – | Low-protein, l-carnitine 100 mg/kg/day divided in 3–4 doses | – |
| >20 kg: 2.5–6 g/m 2 /day | ||||||
| Max: 8 g/day | ||||||
| CD | 5–10 g/day | – | | | Low calorie/carb and high protein diet; MCT oil administration | 0.1–0.3 g/kg/day |
Long-Term Management
Long-term UCD management aims to maintain stable ammonia levels by avoiding triggers (stress, illness, surgery, corticosteroids) and using lifelong protein restriction, amino acid supplementation (arginine/citrulline), and nitrogen scavengers ( Table 2 ) [ 14 ]. While there are several reports of chronic use of nitrogen-scavenging drugs, UCD-specific therapies are preferred. Orthotopic LT is the only proven curative option for refractory UCD as it restores hepatic ureagenesis and prevents recurrent HA crises. However, LT cannot reverse pre-existing neurological injury caused by prior HA episodes and therefore should not be viewed as a means of recovering lost neurological function. Additionally, LT carries risks of perioperative morbidity, mortality, and lifelong immunosuppression [ 40 ]. Neurological outcomes after LT are largely determined by the extent of neurological injury present before transplantation, underscoring the importance of prompt diagnosis and treatment of HA. Emerging gene therapies have also been explored for OTCD [ 41 ]. In particular, liver-directed adeno-associated virus-based gene transfer has demonstrated promising results in preclinical studies and early clinical trials by restoring OTC enzyme activity and improving ammonia metabolism [ 42 , 43 ]. Although these therapies have the potential to provide long-term metabolic correction, additional studies are needed to establish their durability, safety, and long-term clinical efficacy.
Comparing Outcomes of LT and Medical Management for UCDs
LT is curative for UCDs in patients with recurrent crises, failed medical therapy, or poor dietary adherence by restoring metabolic stability and eliminating the need for protein restriction or scavengers [ 44 ]. Late-onset UCDs show 1- and 5-year post-liver transplant survival rates of 100% and 90–97%, respectively [ 45 , 46 ]. However, LT carries surgical risks, requires lifelong immunosuppression, and does not reverse existing neurological damage. Despite this, quality of life generally improves after transplantation [ 47 ]. Although no randomized control trials directly compare medical management with LT for UCD treatment, existing evidence indicates that timely medical management can achieve outcomes comparable to LT with similar quality of life, survival rates, and neuropsychological development [ 29 , 36 ].
Conclusion
Our case describes an 18-year-old female with rapid clinical deterioration due to HA, which was ultimately diagnosed as late-onset OTD. As illustrated by this case, mental status and encephalopathy are medical emergencies, particularly when etiology is unclear. Thus, obtaining an ammonia level through correct blood sampling and transportation techniques is crucial. If HA occurs without liver disease, UCD identification and ruling out CPS is crucial for optimal management.
Statement of Ethics
Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient for publication of this case report and any accompanying images and can be provided on request.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
This study was not supported by any sponsor or funder.
Author Contributions
Z.N., A.A., and S.Y.K.: writing – original draft. O.T.S., K.R., and S.N.L.: conceptualization, supervision, and review and editing of writing.
Data Availability Statement
The data that support the findings of this study are not publicly available due to patient confidentiality but are available from the corresponding author upon reasonable request.
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