Hyperammonemia Secondary to an Acquired Urea Cycle Disorder in a Patient With Metastatic Hepatocellular Carcinoma: 2264

INTRODUCTION: Urea cycle disorders are rare but critically important to consider in the differential diagnosis of hyperammonemia. Delayed treatment may result in disastrous neurologic consequences. CASE DESCRIPTION/METHODS: A 45-year-old woman with past history of gastric sleeve, no known liver disease, and biopsy-proven hepatocellular carcinoma (HCC) with peritoneal metastases on sorafenib presented with acute onset confusion and seizures. She was found to have severe hyperammonemia to 331 µMol/L. Labs were also notable for normal urine organic acids and low plasma citrulline (Table 1). She started on emergent dialysis as well as levetiracetam, lactulose, rifaximin, citrulline, and a low protein diet; sorafenib was discontinued. Her ammonia levels and mentation gradually improved over 3 days. She underwent genetic testing for 14 genes associated with primary urea cycle defects and further testing for another 72 genes associated with secondary hyperammonemia, all of which were negative. DISCUSSION: Urea cycle disorders (UCDs), whether genetic or acquired, can lead to life-threatening hyperammonemia. While classically seen in children, an increasing number of late-onset genetic UCDs have been reported. Ornithine transcarbamylase (OTC) deficiency in particular is X-linked and late-onset, and mild forms are more common than in other genetic UCDs. Individuals may also develop acquired urea cycle defects, with symptoms and lab results consistent with the genetic forms but without an identifiable mutation, as seen in this patient. Acquired UCDs have been reported secondary to tyrosine kinase inhibitors such as sorafenib, and a few cases described in untreated fibrolamellar-type HCC (Table 2). Whether these are primary acquired deficiencies in the setting of hypermetabolic states, as seen in advanced tumors, or an unmasking of an underlying genetic predisposition remains unknown. Further, this patient’s bariatric surgery could have resulted in nutritional deficiencies, revealing an occult UCD. Regardless of etiology, treatment for UCDs includes aggressive ammonia control with nitrogen scavengers, amino acid supplements, and appropriate dietary protein intake. Suspected offending agents should be stopped immediately and emergent hemodialysis initiated if hyperammonemia does not improve with conservative measures. Empiric therapy should be initiated even without confirmation of the diagnosis, as prolonged exposure to high ammonia can lead to irreversible neurological ramifications.