Idiopathic Hyperammonemia Following Rituximab for Rheumatoid Arthritis

Abstract

Introduction: Idiopathic hyperammonemia (IHA) is a syndrome of neurological changes with unexplained and often marked elevations in serum ammonia. We report a case of idiopathic hyperammonemia in a 53-year-old woman following rituximab use as a disease-modifying drug (DMARD) for rheumatoid arthritis. Case Presentation: A 53-year-old woman presented with somnolence and involuntary movements of her extremities for one week. There was no history of fevers, jaundice, or abdominal pain. She had severe steroid-dependent rheumatoid arthritis failing several DMARDs. Most recent therapies included rituximab, leflunomide and methotrexate. Physical exam findings included lethargy, fine tremor, myoclonic jerks, and joint swelling. Labs showed an initial serum ammonia level of 472 g/dL with normal liver function tests and creatinine. Viral serologies and imaging to rule out portal vein thrombosis were negative. A liver biopsy showed mixed micro vesicular and macro vesicular steatosis with no evidence of inflammation. Plasma and urine amino acid metabolite profile was negative for any occult urea cycle disorders, fatty acid oxidation defects, and branched chain aminoaciduria. Lactulose, rifaximin, and sodium phenyl acetate plus sodium benzoate failed to improve her ammonia levels. Protein restriction and dietary formula containing only branched chain amino acids were instituted to promote reduced muscle breakdown. Consistent control of her ammonia levels was achieved only with daily hemodialysis. Without HD, her serum ammonia levels rose to as high as 798 g/dL, and mental status worsened, requiring mechanical ventilation. She succumbed after a month of supportive care. Discussion: The diagnosis of idiopathic hyperammonemia is a diagnosis of exclusion; with acute onset of encephalopathy associated with elevated serum ammonia, with no hepatic dysfunction In our patient, all other causes of hyperammonemia were systematically excluded, as detailed above. Isolated reports of IHA with rituximab-based chemotherapy regimens have been reported. However, hyperammonemic encephalopathy has not been previously reported with use of rituximab as a DMARD; this is interesting to note, because the usual doses needed to treat rheumatoid arthritis are considerably lower than those used to treat malignancies. The probable cause, as described in case series, have been acquired urea cycle defect as the cause of hyperammonemia. Physicians should consider IHA in the differential of altered mental status in patients receiving rituximab as earlier recognition, and institution of early CVVHD has been reported to reduce mortality.