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Hyperammonemia in the Acute Catabolic State

Education and Research Strategies
  • Primary Categories:
    • Clinical- Pediatric
  • Secondary Categories:
    • Clinical- Pediatric
Introduction
Non-hepatic hyperammonemic encephalopathy (NHHE), although rare is usually associated with a poor prognosis. While commonly seen in urea cycle defects and advanced liver disease, several other processes can lead to symptomatic hyperammonemia. Here we present two cases where, ammonia created by protein catabolism overwhelms the urea cycle leading to hyperammonemic metabolic encephalopathy.

Case Presentation
Our first case is an 8-year-old female with Lennox-Gastaut syndrome, chronic lung disease, and GJ-tube dependance admitted to the pediatric intensive care unit for evaluation of altered mental status secondary to hyperammonemia with respiratory failure in the setting of urosepsis. Our second case is a 6-year-old female with TUBB3 genetic mutation, refractory epilepsy, and global developmental delay transferred from an outside hospital in the setting of altered mental status secondary to hyperammonemia in the setting of bacterial pneumonia and urosepsis.

Diagnostic Workup
Our first patient demonstrated an initial ammonia level of 340 ug/dL. Further biochemical screening labs were consistent with urine organic acids and acylcarnitine profile showing multiple nonspecific elevations in a non-diagnostic pattern. Urinary orotic acid were unremarkable. Plasma carnitine levels and plasma aminoacids were low. CT head revealed diffuse cerebral edema and MR spectroscopy revealed concomitant glutamine/glutamate peak consistent with hyperammonemic encephalopathy. Electroencephalogram was consistent with epileptiform discharges in the left hemisphere and severe diffuse encephalopathy. Urine culture was found to be positive for Escherichia coli. Rapid genome sent was otherwise unremarkable.

Our second patient developed septic shock with progression to multiorgan failure with need for vasopressor support. Initial ammonia level was noted to be 240 ug/dL with mild transaminitis. Her metabolic screening labs for hyperammonemia was unremarkable except for deficiency of most amino acids and severe carnitine deficiency which is reflective of chronic poor nutritional status. Plasma amino acids pattern of decreased arginine and citruline with elevated glutamine could be suggestive of urea cycle defect but urine organic acids results were negative ruling out any metabolic pathway deficiency. CT scan of the head revealed diffuse cerebral edema consistent with hyperammonemia. Her infectious workup revealed enterococcus in the urine culture and pseudomonas in the endotracheal aspirate. Our patient likely progressed to probable infection triggered secondary hemophagocytic lymphohistiocytosis with elevated ferritin to 2,830 ng/mL and worsening liver enzymes and synthetic liver function with PT/INR at 20.7 secs/ 1.83. Her ammonia now peaked at 460 ug/dL. Whole exome sequencing was within normal limits.

Treatment and Management
After elaborate and extensive workup, and negative metabolic tests, the cause for hyperammonemia was likely secondary to chronic malnutrition resulting in severe muscle protein catabolism during episodes of acute illness. Both patients were on a pea protein diet which was inadequate to meet the body’s protein energy requirements during periods of stress. Both patients’ hyperammonemia responded adequately to intravenous scavengers including sodium phenylacetate and sodium benzoate and the levels normalized prior to discharge.

Outcome and Follow-Up
Our first case, required readmissions for hyperammonemia until the changes in diet were addressed. Gradual reintroduction of high protein diet enterally with an animal protein based formula mitigated further admissions to the intensive care unit. Our second patient progressed to multiorgan failure and was pronounced deceased during the current admission. 

Discussion
Ammonia is a byproduct of protein metabolism and is normally detoxified in the liver via the urea cycle. Hypercatabolic states (as in this patient with poor protein intake) cause increases in protein breakdown leading to excessive ammonia production which can overwhelm the liver’s conversion ability. The reintroduction of adequate nutrition readily fixes this imbalance.

Conclusion
These cases highlight how alternative causes of hyperammonemic encephalopathy may be missed or delayed in the absence of a metabolic condition or advanced liver disease. 

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