What are the triggers of acute hyperammonemic events in UCD?
Peter McGuire, MS, MD
National Human Genome Research Institute National Institutes of Health
Data was analyzed from the Longitudinal Study of UCD (Urea Cycle Disorders Consortium). The analysis sought to characterize acute hyperammonemic episodes in terms of types of triggers and utilization of medical resources. A total of 128 patients with UCD experienced 413 hyperammonemic (HA) events. Most patients experienced between 1-3 (65%) and 4-6 (23%) HA events since the study inception, averaging less than 1 HA event per year. The most common trigger was an infectious process (33%). Data revealed that 24% of infections were due to upper/lower respiratory tract infections. Increased illness was seen with infectious triggers, resulting in increased hospitalization rates, longer hospital stays (+2.0 days) and increased use of intravenous ammonia scavengers (+45-52%).
Summary: Infection is the most common trigger of acute HA in patients with urea cycle disorders and is associated with indicators of increased illness. These results support the notion that infectious triggers of acute HA are a distinct clinical entity and may require a different approach to treatment.
Is there unrecognized acute liver failure and hepatocellular injury in OTCD?
Renata Gallager, MD, PhD
Children's Hospital of Colorado
Acute liver failure and hepatocellular injury may be under-recognized in ornithine transcarbamylase deficiency (OTCD). Hepatocellular injury and liver failure have been reported occasionally in patients with a UCD, but there has been no systematic study of the prevalence of hepatic injury or dysfunction in UCDs. Charts were reviewed at two centers to assess the proportion of 71 individuals with OTCD who had evidence of acute liver failure (INR > 2.0), liver dysfunction (INR 1.5-1.99), or hepatocellular injury (AST/ALT> 250 IU/L). 57% of the 49 patients with symptomatic OTCD had liver involvement: 29% met the criteria above for acute liver failure, 20% had liver dysfunction, and 8% had isolated hepatocellular injury. The proportion with acute liver failure was greatest in those with more severe OTCD, including neonates with markedly elevated ammonia levels (> 1,000 µmol/L). Some patients with severe liver involvement (INR > 2.0 and AST/ALT > 1,000 IU/L) had only moderate hyperammonemia (100 - 400 µmol/L). Acute liver failure was the initial presenting symptom of OTCD in at least 3 of 49 symptomatic OTCD patients.
Summary: We conclude that episodes of hepatocellular injury, liver dysfunction, and acute liver failure occur in a high proportion of individuals with symptomatic OTCD. The more severely affected OTCD patients had a higher likelihood of acute liver failure. We suggest that the diagnosis of a UCD should be considered in unexplained acute liver failure, dysfunction or hepatocellular injury.
IQ scores after liver transplant of children who presented with UCD in the neonatal period or under 2 years of age.
Philippe Campeau, MD, FCCMG
Baylor College of Medicine
In this analysis, 42 of 66 patients were transplanted before 2 years of age (suggesting neonatal onset disease). In the last two years, 8 patients were transplanted and 7 of these patients were younger than 2 years of age, suggesting transplant was occurring earlier.
7 infants with neonatal-onset CPS1 deficiency were transplanted on average at 1 year of age. One additional patient presented at 32 years and was transplanted at 34 years. Formal psychological testing after transplantation was available for 3 of these patients. Results of their latest evaluations showed that after transplantation their IQ/DQ scores in the average range (IQ 85-115) up to 10 years after transplantation.
27 male iinfants with neonatal-onset OTC deficiencyths) (neonatal onset) of age were transplanted on average at 1 year of age. Formal psychological testing after transplantation was available for 19 of them. Results on their latest evaluations showed IQ/DQ scores with an average of 78 (+/-19) at 5 years of age, 3 years after transplantation.
6 female children with OTC deficiency presenting on average at 17 months of age were transplanted on average at 6 years of age (+/- 8 years). Formal psychological testing after transplantation was available for 5 of them. Results on their latest evaluations showed IQ/DQ scores ion average were 87 (+/-23) at 14 years of age, 7 years after transplantation.
10 infants with neonatal-onset ASL deficiency were transplanted on average at 5 years of age. Formal psychological testing after transplantation was available for 7 of them. Results on their latest evaluations showed IQ/DQ scores in the mild range of intellectual disability (IQ 55-70) at 12 years of age, 5 years after transplantation.
13 patients with neonatal-onset ASS1 deficiency (citrullinemia) were transplanted on average at 2 years of age. Formal psychological testing after transplantation was available for 8 of them. Results on their latest evaluations showed IQ/DQ scores with an average of 87 (+/-14) at 6 years of age, 4 years after transplantation.
The lowest post-transplantation IQ/DQ scores were found in neonatal onset ASL patients and then in male neonatal onset OTC patients.
After liver transplantation, there were 5 HA events reported on 2 subjects (both neonatal OTC males). There were 4 events for 1 patient and 1 event for the other. The other 64 patients had no further hyperammonemia after transplantation.
Summary: These results suggest that liver transplantation appears to be curative for OTC and CPS1 deficiencies. Transplantation for ASL and citrullinemia appears to be curative for hyperammonemia, but patients remain on arginine supplementation. Intellectual outcomes are mainly good. However, the study did not look at mortality and morbidity associated with liver transplantation.
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