Unmasked Adult-Onset Urea Cycle Disorders in the Critical Care Setting

The high-dose dexamethasone suppression test is a common and usually benign endocrine procedure. We report a patient with ornithine transcarbamylase deficiency (OTCD) who developed hyperammonemic encephalopathy after a high-dose dexamethasone suppression test.

A 46-year-old woman with a 1.3-cm right adrenal incidentaloma causing mild autonomous cortisol secretion underwent a high-dose dexamethasone suppression test for confirming adrenocorticotropic hormone independency. On the next day, she presented to the emergency room with confusion and somnolence. Her Glasgow Coma Scale score was 10 on arrival. The initial laboratory results showed ammonia, alanine transaminase, creatinine, and blood urea nitrogen levels of 289.51 (18.73-54.5) μg/dL, 21 (≤33) IU/L, 0.6 (0.6-1.1) mg/dL, and 13 (7-20) mg/dL, respectively. Electroencephalography showed triphasic morphology with no pathologies on brain imaging. Her husband told us that her brother and son had died in the neonatal period. On further review of medical records, we found that she was diagnosed as an OTCD carrier. We administered L-arginine, L-carnitine, rifaximin, and continuous renal replacement therapy. After 3 days, the serum ammonia level was 78.34 μg/dL with an increased Glasgow Coma Scale score of 15, and electroencephalography abnormalities disappeared.

Liver diseases and urea cycle disorders are the leading causes of hyperammonemia. This causes encephalopathy and death if the ammonia levels are too high. X-linked OTCD urea cycle disorder affects men more severely as they have only the carrier X chromosome. Glucocorticoids can exacerbate this disorder because they increase protein substrates converted to ammonia.

This case reminds that it may be particularly important to have a complete medical history when administering glucocorticoids.

Nonhepatic Hyperammonemic encephalopathy (NHAE) following Bariatric Surgery (BS), mainly Roux-en-Y Gastric Bypass (RYGB) and Biliopancreatic Diversion (BPD) is a potentially devastating condition if not diagnosed and managed promptly.

A literature review was performed using PRISMA guidelines. Eighteen studies and 3 conference abstracts with a total of 33 patients were included in this review.

Majority (28 patients, 84.8 %) had RYGB. Seven patients (21.2 %) had associated metabolic disorders. 60 % of patients presented with neurological symptoms or signs such as confusion, cognitive and/or psychomotor changes, and decreased reflexes. Two patients presented with status epilepticus. In 30 of the 33 patients an elevated serum ammonia levels was reported (90.9 %). The overall mortality was 39.3 %.

NHAE is a rare condition following bariatric surgery (in particular bypass procedures), carrying a high mortality rate. The signs and symptoms are predominantly neurological and may be mistaken for Wernicke's encephalopathy or other more common neurological conditions. Serum ammonia levels should be checked in those who present with these symptoms and signs. Prompt treatment might be life saving in patients with NHAE.

Hyperammonemia occurs frequently in the critically ill but is largely confined to patients with hepatic dysfunction or failure. Non-hepatic hyperammonemia (NHHA) is far less common but can be a harbinger of life-threatening diagnoses that warrant timely identification and, sometimes, empiric therapy to prevent seizures, status epilepticus, cerebral edema, coma and death; in children, permanent cognitive impairment can result. Subsets of patients are at particular risk for developing NHHA, including the organ transplant recipient. Unique etiologies include rare infections, such as with Ureaplasma species, and unmasked inborn errors of metabolism, like urea cycle disorders, must be considered in the critically ill. Early recognition and empiric therapy, including directed therapies towards these rare etiologies, is crucial to prevent catastrophic demise.

We review the etiologies of NHHA and highlight the first presentation of it associated with a concurrent Ureaplasma urealyticum and Mycoplasma hominis infection in a previously healthy individual with polytrauma. Based on this clinical review, a diagnostic and treatment algorithm to identify and manage NHHA is proposed.

Ornithine transcarbamylase deficiency is a rare X-linked genetic urea cycle disorder leading to episodes of acute hyperammonemia, adverse cognitive and neurological effects, hospitalizations, and in some cases death. DTX301, a non-replicating, recombinant self-complimentary adeno-associated virus vector serotype 8 (scAAV8)-encoding human ornithine transcarbamylase, is a promising gene therapy for ornithine transcarbamylase deficiency; however, the impact of sex and prophylactic immunosuppression on ornithine transcarbamylase gene therapy outcomes is not well characterized. This study sought to describe the impact of sex and immunosuppression in adult, sexually mature female and male cynomolgus macaques through day 140 after DTX301 administration. Four study groups (n = 3/group) were included: male non-immunosuppressed; male immunosuppressed; female non-immunosuppressed; and female immunosuppressed. DTX301 was well tolerated with and without immunosuppression; no notable differences were observed between female and male groups across outcome measures. Prednisolone-treated animals exhibited a trend toward greater vector genome and transgene expression, although the differences were not statistically significant. The hepatic interferon gene signature was significantly decreased in prednisolone-treated animals, and a significant inverse relationship was observed between interferon gene signature levels and hepatic vector DNA and transgene RNA. These observations were not sustained upon immunosuppression withdrawal. Further studies may determine whether the observed effect can be prolonged.

5-Fluorouracil (5-FU)-induced hyperammonaemic encephalopathy is a rare but serious 5-FU adverse drug reaction (ADR). Given the growing number of cancers treated with 5-FU and the paucity of data regarding this ADR, we performed a retrospective national survey to better characterise 5-FU-induced hyperammonaemic encephalopathy.

Since inception of the French pharmacovigilance database, we identified all patients who experienced 5-FU-induced hyperammonaemic encephalopathy. Variables regarding demographics, characteristics, management and outcome of patients were collected.

From 1986 to 2018, 30 patients were included. 5-FU-induced hyperammonaemic encephalopathy started 2 [1–4] days after 5-FU infusion onset. Most common neurological disorders were consciousness impairment, seizures and confusion. hyperammonaemia tended to be higher in patients with the lowest Glasgow score and admitted in intensive care unit (ICU) compared to non-ICU patients (250 [133–522] versus 139 [68–220] μmol/L respectively, p = NS). Dihydropyrimidine dehydrogenase deficiency was found in 27% of tested patients (n = 3/11). Encephalopathy-induced mortality was 17%, 57% of patients were admitted in ICU and 70% had a complete neurological recovery within 5 [2–10] days. A 5-FU rechallenge was considered in 14 (67%) patients with neurological recovery and a relapse was observed in 57% of them. No 5-FU-induced hyperammonaemic encephalopathy relapse was observed as long as 5-FU rechallenge was performed with decreased 5-FU dosage.

We report the largest cohort of 5-FU-induced hyperammonaemic encephalopathy cases so far. This ADR should be suspected and ammonaemia measured in all patients experiencing neurological disorders after 5-FU administration. In patients with complete neurological recovery, a 5-FU rechallenge could be cautiously considered.