Urea cycle disorders and indications for liver transplantation

Abstract

Urea cycle disorders (UCD) are inborn errors of metabolism caused by deficiency of enzymes required to convert nitrogen from ammonia into urea. Current paradigms of treatment focus on dietary manipulations, ammonia scavenger drugs, and liver transplantation. The aim of this study was to describe the characteristics and indication of liver transplantation in UCD in a tertiary hospital. We performed a retrospective study of children with UCD seen in the period 2000-2021. Data was collected on clinical onset, hyperammonemia severity, evolution and liver transplantation. There were 33 patients in the study period, whose diagnosis were: ornithine transcarbamylase (OTC, n = 20, 10 females), argininosuccinate synthetase (ASS, n = 6), carbamylphosphate synthetase 1 (CPS1, n = 4), argininosuccinate lyase (ASL, n = 2) and N-acetylglutamate synthetase (NAGS, n = 1) deficiency. Thirty one were detected because of clinical symptoms (45% with neonatal onset). The other 2 were diagnosed being presymptomatic, by neonatal/family screening. Neonatal forms (n = 14) were more severe, all of them presented during the first week of life as severe hyperammonemia (mean peak 1,152 µmol/L). Seven patients died (6 at debut) and all survivors received transplantation. There was no mortality among the late forms. Of the 27 patients who did not die in the neonatal period, 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation. The transplant's metabolic success was accompanied by neurologic sequelae in 69%, but there was no progression of brain damage. Decision of continuous medical treatment in 11 patients appeared to be related with preserved neurodevelopment and fewer metabolic crises.

Keywords: hepatology; hyperammonemia; inborn errors of metabolism; liver transplant; urea cycle disorders.

Figure 1

Characteristics of patients diagnosed with a UCD at La Paz University Hospital between January 2000 and December 2021.

Figure 2

Pictures (A–C) show the liver explant histology of a patient diagnosed with OTC (ornithine transcarbamylase deficiency). (A) Preserves hepatic architecture. Patchy clear hepatocytes with no zonal distribution. Haematoxylin&Eosin, 20×. (B) There is no significant fibrosis. Masson's Trichrome, 20×. (C) Hydropic/glycogenated hepatocytes (*) admixed with macrovesicular steatotic patches (+). Around the central veins, sinusoidal aggregated neutrophils can be seen (surgical hepatitis, arrowhead). Haematoxylin&Eosin, 20×. Pictures (D–F) belong to a patient diagnosed with ASL (argininosuccinate lyase deficiency). (D) Micronodular liver architecture with both complete and incomplete septae. Haematoxylin&Eosin, 20×. (E) Both portal to portal and portal to central septae can be seen. Masson's Trichrome, 20×. (F) Hepatocytes are uniformly swollen, wih clear cytoplasm and prominent cell membrane. Masson's Trichrome, 20×.

Figure 3

Neurodevelopmental outcomes—correlation with mean ammonium level and UCD type. Severe neurological impairment was considered in those patients diagnosed with epilepsy and cerebral palsy categorized with Gross Motor Function Classification System (GMFCS) level 5. Mild neurological impairment was described in those with motor, speech or global delay. Normal neurodevelopment included normal motor and intellectual status. The correlation with UCD type, neurological outcome, and mean ammonium level at diagnosis showed that the maximum ammonium level at onset was higher (>500 µmol/L) in those with neurological damage including mild and severe. Orange boxes show the peak of ammonium level in neurological outcome related with the UCD type. (A) Schematic box plots for neurological outcome show the distribution of the ammonium values within each group. The x mark shows mean on each category with its respective range: Normal 251,6 (123–361); Mild 606 (312–1420); Severe 713.5 (488–939) µmol/L) (B).