CASE REPORT |
https://doi.org/10.5005/jp-journals-11006-0075 |
Noncirrhotic Multifactorial Hyperammonemia: Unmasking an Adult-onset Partial Urea Cycle Disorder
1–4Department of Critical Care Medicine, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India
Corresponding Author: Paramita Basu, Department of Critical Care Medicine, Apollo Multispeciality Hospitals, Kolkata, West Bengal, India, Phone: +91 7059207605, e-mail: basuparamita10@gmail.com
ABSTRACT
Aim and background: Urea cycle disorder (UCD) is a metabolic disturbance and can be a harbinger of life-threatening hyperammonemic encephalopathy. We report a case of adult-onset partial urea cycle defect precipitated by septic shock and status epilepticus and its successful treatment with continuous renal replacement therapy, adaptive nutrition, nitrogen scavengers, and gut decontamination.
Case description: A 37-year-old woman with known seizure disorder presented with status epilepticus, urosepsis, and septic shock due to Enterococcus faecalis infection. Her two other sisters died from an unknown neuropsychiatric illness in early childhood. She was initially treated with invasive mechanical ventilation, vasopressor support, intravenous antibiotics, and antiepileptic drugs. After stabilization of hemodynamics and control of visible seizures, her mental status was not improving despite the sedation hold. Further workup revealed high ammonia, respiratory alkalosis, triphasic waveform on the electroencephalogram, normal liver function and sonologic evidence of cerebral edema. Urinary analysis for amino acids and organic acids was noncontributory. A partial defect in the urea cycle was suspected and she was successfully treated with continuous renal replacement therapy and other available adjunctive treatments to a favorable outcome.
Conclusion: In patients who present with noncirrhotic hyperammonemic encephalopathy and have had one or multiple stressors, a diagnosis of UCD should be suspected to optimize early management and improve prognosis.
How to cite this article: Banerjee R, Basu P, Choudhary S, et al. Noncirrhotic Multifactorial Hyperammonemia: Unmasking an Adult-onset Partial Urea Cycle Disorder. Indian J Crit Care Case Rep 2023;2(5):145–147.
Source of support: Nil
Conflict of interest: None
Patient consent statement: The author(s) have obtained written informed consent from the patient for publication of the case report details and related images.
Keywords: Case report, Cerebral edema, Continuous renal replacement therapy, Noncirrhotic hyperammonemic encephalopathy, Status epilepticus, Urea cycle disorder
INTRODUCTION
Urea cycle disorder (UCD) is a metabolic disturbance that presents, rarely, for the first time in adulthood. It is often underrecognized and underreported because of diverse phenotypic presentation. In the intensive care setting, diagnosis of hyperammonemic encephalopathy from adult-onset UCD is challenging as patients are already critically ill from other reasons. Subsequent delays in treatment put patients at risk of fatal cerebral edema. Mortality rises as ammonia level increases >200 µmol/L, with a marked worsening at >500 µmol/L and again at >1000 µmol/L.1 Timely identification of the underlying etiology combined with expedited therapy may be life-saving. We report a case of acute severe noncirrhotic hyperammonemic encephalopathy associated with septic shock and status epilepticus in the setting of a previously undiagnosed partial UCD.
CASE DESCRIPTION
A 37-year-old lady with a known seizure disorder (well controlled on per oral levetiracetam) presented with status epilepticus and rapid decline in mental status. She had no other comorbidities and there was no history of addiction or substance abuse. She was managed with intubation and mechanical ventilation, intravenous benzodiazepine, fosphenytoin, and a loading dose of levetiracetam. Her oxygen requirement was minimal and she was hypotensive on presentation, requiring vasopressor support. In view of suspected meningoencephalitis and sepsis, broad-spectrum intravenous antibiotics along with acyclovir were initiated. Laboratory workup revealed an elevated white blood cell count and C-reactive protein along with pyuria. All other investigations, including cerebrospinal fluid analysis, toxicology screening, and neuroimaging, were unremarkable. After 24 hours, there were no visible seizures, but her sensorium was not improving despite the sedation holiday. On further workup, she had respiratory alkalosis without any hyperlactatemia, anion gap, or metabolic acidosis, had a very high arterial ammonia level (356 µmol/L) and triphasic waveform in the electroencephalogram. Her phenytoin levels were adequate and she was normoglycemic. The liver appeared normal in ultrasonography and except for hydrocortisone used in the context of septic shock, no other culprit drug can be found. Urine culture revealed growth of Enterococcus faecalis and antimicrobials were adjusted accordingly. Sonologic measurement of optic nerve sheath diameter (ONSD) (Fig. 1) at the bedside was suggestive of raised intracranial pressure (ONSD of >6 mm bilaterally) and effectively treated with intravenous mannitol boluses. At this point, upon further questioning, relatives gave a history of two other sisters dying from unknown neuropsychiatric illnesses in early childhood. Urine analysis with gas chromatography and mass spectrometry was sent for the unmasking of any adult-onset inborn errors of metabolism. But, it was noncontributory, and a partial urea cycle defect was suspected. However, enzymatic assay and molecular genetic testing [deoxyribonucleic acid (DNA) sequence analysis] could not be done due to logistic reasons.
Fig. 1: Optic nerve sheath diameter (ONSD)
She was treated with lactulose and rifaximin for gut decontamination. Protein intake was stopped for 48 hours and reintroduced after the ammonia level was below 100 µmol/L. Nutrition was maintained through intravenous dextrose and lipid formulations with concomitant insulin infusion for glycemic control. Intravenous L-carnitine and oral sodium benzoate were also on board without much improvement. Due to profound and refractory hyperammonemia, continuous venovenous hemodiafiltration (CVVHDF) was initiated on an urgent basis. The ammonia level was reduced but did not normalize (232 µmol/L). She again underwent sustained low-efficiency dialysis (SLED) for 4 more days until her ammonia level came to below 90 µmol/L. She gradually became alert and conversant without any focal neurological deficit and was extubated successfully. Antibiotics continued for a total of 8 days. She was maintained on a low-protein diet and oral antiepileptic drugs. She continued to improve clinically and was discharged with her premorbid baseline functional status. She was advised to do molecular genetic testing (required for definitive diagnosis) and to follow up with a specialist dietetic and metabolic center for further guidance.
DISCUSSION
Disorders involving the urea cycle (Fig. 2) represent an important cause of noncirrhotic hyperammonemia and can occur due to either complete or partial deficiency of enzymes. It is composed of five primary enzymes, one cofactor, and two transport molecules across the mitochondrial membrane. Genetic mutations causing a complete deficiency of enzymes will lead to disruption of urea synthesis and result in the accumulation of ammonia and other metabolic intermediaries, depending on where the pathway is blocked. It is commonly diagnosed in the neonatal or early childhood years, and the main effect is usually an accumulation of the substrate and/or a decrease of the product for the affected step in the cycle. However, in partial deficiency, enzyme activities may vary, and it may take decades before encountering environmental stress strong enough to overwhelm this marginal ureagenesis capacity. Usually, there is a history of similar past episodes (not present in our case), and the hyperammonemia is mild. But in the presence of one or more stressors, ammonia elevation can be profound, necessitating urgent treatment. Thus, UCD should be considered at any age in hyperammonemic patients during physiological stress and catabolism like septic shock and status epilepticus in our patient.
Fig. 2: Urea cycle; ARG, arginase; ASL, arginosuccinate lyase; ASS, arginosuccinate synthase; CPSI, Carbamoyl phosphate synthetase I; OTC, ornithine carbamoyltransferase
Workup for noncirrhotic hyperammonemia includes measuring blood levels (with levels >150 µmol/L, patients typically are encephalopathic), serum electrolytes, glucose, lactate, and checking urinary ketones along with arterial pH and carbon dioxide tension. Respiratory alkalosis in the absence of metabolic acidosis and in the context of normoglycaemia, normal anion gap,2 normal lactate and low urea level may be an indicator of UCD. Since the point at which hyperammonemic episodes will occur depends on the genetically determined baseline capacity of the cycle, normal urine analysis for organic aciduria could not comprehensively rule out a partial UCD in the context of extensive catabolism like our patient. A targeted diagnostic evaluation involving DNA sequence analysis would have been confirmatory but could not be conducted due to the dearth of logistic support. However, a combination of family history, clinical context and basic metabolic workup, along with rapid clinical improvement on treatment indirectly pointed towards the unmasking of previously undiagnosed partial UCD.
Treatment of hyperammonemia associated with UCD can be acute or extended. It is initiated as soon as UCD is suspected and is usually concurrent with the diagnostic process. A multipronged therapy involving ammonia removal by extracorporeal detoxification and/or pharmacological scavengers like sodium benzoate, reversal of catabolism by adaptive nutrition and control of stressors, use of urea cycle stimulators and substrates like L-carnitine and L-arginine and gut decontamination by lactulose and rifaximin is often tried along with referral for a specialist dietetic and metabolic guidance. Finally, liver transplant is an option for recurrent hyperammonemia resistant to conventional therapy,3 but it is associated with significant morbidity. Since the duration and severity of hyperammonemia strongly correlate with brain damage4,6 and reduction of ammonia to nontoxic concentrations are slow by other therapies, currently, the first choice of treatment is to initiate extracorporeal detoxification as early as possible7,9 (often before precise metabolic diagnosis) to reverse encephalopathy and prevent cerebral edema and death. Ammonia is like urea in diffusive clearance, and because it is a gas, its rapid removal is not associated with osmotic problems like dialysis disequilibrium syndrome. Considering the hemodynamic instability and possibility of rebound hyperammonemia, we applied CVVHDF followed by SLED in our patient. Sodium benzoate was used concurrently for a possible synergistic effect.10 Catabolic burden was reduced by control of sepsis and status epilepticus. Rifaximin, lactulose, and L-carnitine were also initiated for their possible beneficial actions. Protein intake was stopped for 48 hours and reintroduced only after the ammonia level was <100 µmol/L. This avoided essential amino acid deficiency and endogenous protein catabolism. Calorie intake was maintained through intravenous dextrose and lipids. Owing to the possibility of an ongoing septic process, we did not use L-arginine.
Long-term management focuses on dietary modification, avoiding triggering events with monitoring of ammonia levels and use of emergency regimes in the presence of known stressors. A detailed written day-to-day plan, including when and how to contact the hospital should be provided, and periodic follow-up in a specialist center is recommended.
CONCLUSION
Unmasking of an asymptomatic underlying UCD should be considered in the differential diagnosis of patients who have had the presence of one or more stressors and present with encephalopathy, hyperammonemia, and intact liver function. It is a therapeutic emergency that requires a high index of suspicion. Timely intervention using extracorporeal detoxification as the primary modality of treatment is crucial to avoid catastrophic demise. The final diagnosis can be made after the resolution of the initial crisis and needs close collaboration with a metabolic disorder specialist.
ORCID
Rupak Banerjee https://orcid.org/0009-0001-5218-3721
Paramita Basu https://orcid.org/0009-0000-5792-6128
Samyogita Choudhary https://orcid.org/0000-0001-7682-7440
Chandrashish Chakravarty https://orcid.org/0000-0002-4768-1195
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