Studies published between 1995 and 2022 consistently support liver transplantation as an effective therapeutic option for individuals with UCDs. Across pediatric and adult populations, excellent post-transplant outcomes have been reported, with one- and five-year patient survival rates exceeding 90% in multiple retrospective cohort studies, regardless of UCD subtype (F.5879, F.5917, F.6940, F.7168, F.7177, F.7178). Improved survival is largely attributed to sustained metabolic stability following transplantation, which reduces the risk of recurrent hyperammonemia and progressive neurological injury.

Several transplant approaches have been successfully utilized. Orthotopic liver transplantation remains the most common, while living donor transplantation, including the use of grafts from heterozygous carriers, has demonstrated comparable survival and metabolic outcomes and may facilitate earlier intervention when deceased donor organs are limited (F.5305, F.5830, F.5854, F.6638, F.7226, F.7240, F.7243, F.7318, F.7408). Auxiliary Partial Orthotopic Liver Transplantation (APOLT) has also been shown to improve metabolic control and alleviate protein restriction (F.5639, F.5860, F.6321, F.6467, F.7244, F.7450), though it carries a higher risk of postoperative complications, including rejection-associated hyperammonemia (F.6467, F.7239, F.7450, F.7451).

Beyond survival, case reports, case series, and cross-sectional studies demonstrate additional clinically meaningful benefits, including normalization of dietary protein intake (F.5007, F.5109, F.5305, F.5707, F.5785, F.5973, F.6016, F.6321, F.6467, F.7168, F.7180, F.7179, F.7240, F.7244, F.7408, F.7431, F.7711), the cessation of nitrogen scavenging medications (F.5305, F.5973, F.6321, F.6467, F.7168, F.7177, F.7240, F.7244, F.7431), and improved cognitive function (F.5109, F.5707, F.6976, F.7177).

Outcomes are strongly influenced by the timing of transplantation. Early transplant, ideally performed between three and 12 months of age, is associated with improved neurodevelopmental outcomes and reduced risk of irreversible neurological injury, particularly in neonatal-onset UCDs and those with lower peak ammonia concentrations at presentation (F.7178, F.7963).

Overall, liver transplantation is a recommended therapeutic intervention for preventing further neurological deterioration, achieving biochemical normalization, and normalizing dietary protein intake in various UCDs.

This topic was not included in the Delphi consensus process.

Published evidence describing nutritional assessment during pre-transplant evaluation in individuals with UCDs is limited. One retrospective review described a multidisciplinary pre-transplant assessment that included clinical nutrition expertise alongside abdominal surgery, biochemical genetics, developmental and behavioral specialists, and social work, with candidates also undergoing standardized pre-transplant laboratory evaluation in accordance with transplant requirements (F.7168). Although detailed nutrition-specific assessment parameters were not reported, inclusion of a registered dietitian within the pre-transplant evaluation framework is consistent with performing a nutritional assessment prior to transplantation.

Delphi 1 Results

There was unanimous agreement that, during transplant evaluation and prior to transplant, candidates should undergo nutrition evaluation, including dietary, anthropometric, and nutrition-focused laboratory assessment, performed by the metabolic and/or transplant dietitian.

As with any procedure requiring general anesthesia, liver transplantation places individuals with UCDs at increased risk for perioperative catabolism and acute hyperammonemia. Perioperative nutrition and metabolic management strategies to mitigate this risk have been described with similar approaches reported across successful liver transplants in children with CPS, OTC, CIT-I, and ASA.

To establish baseline metabolic status and inform perioperative management, one center obtained plasma ammonia, plasma amino acids, and liver function tests prior to surgery (F.7168). Fasting-related catabolism is commonly minimized using intravenous fluids containing 10% dextrose, with reports describing initiation approximately six hours before surgery (F.7168, F.7431) and continuation as a continuous infusion throughout the operative period (F.4551, F.5973, F.7168). Glucose infusion rates of 6-8 mg/kg/min have been reported to prevent catabolism and hyperammonemia (F.5973). Additional intraoperative metabolic support included intravenous lipid administration at 2 g/kg (F.7168). One clinical protocol also recommended initiating total parenteral nutrition at the onset of fasting, in coordination with the transplant dietitian (G.187). To further reduce the risk of hyperammonemia, nitrogen scavengers are typically administered (F.4551, F.5973, F.7431) along with intravenous L-arginine (F.7431).

Postoperatively, ammonia concentrations were monitored (F.7168, F.7226, F.7431), and intravenous dextrose and nitrogen scavengers were discontinued once graft function was established and ammonia concentrations normalized (F.5973). One center also measured plasma amino acids daily post-operatively for three days, then weekly until hospital discharge (F.7168).

In the context of liver transplantation, individuals have increased protein requirements to support anabolism, preserve lean body mass, and promote wound healing. The 2017 ASPEN guidelines recommend a minimum protein intake of 1.5 g/kg/day for critically ill infants and children, with higher intakes often required to achieve positive nitrogen balance, and selected populations may need 2.5-3.0 g/kg/day; these requirements exceed age-based DRIs (L.457). In one series of 23 patients with UCDs undergoing liver transplantation, parenteral amino acids were initiated postoperatively at 1.5-2.0 g/kg/day and continued until enteral nutrition was tolerated (F.7168).

Delphi 1 Results

There was strong or unanimous consensus for the following strategies during the perioperative period:

1. Consider collecting baseline ammonia or plasma amino acid concentrations (100%).
2. Individuals should be NPO for the minimum acceptable period (100%).
3. Individuals should receive adequate energy via continuous IV dextrose, and if indicated, lipid emulsion to minimize/prevent catabolism (92%). One respondent noted lipid emulsion in the perioperative period may increase the risk of pancreatitis, which had been observed in the respondent's metabolic patients who received lipid emulsion intraoperatively.
4. If fasted longer than 24 hours, individuals should receive parenteral amino acids to meet the protein dietary reference intake (DRI) for age (91%). One respondent clarified that, due to parenteral nutrition being more directly absorbed, the respondent aims for 80% of baseline protein or 80% of the protein DRI.

Agreement fell just short of consensus (79%) that ammonia should be monitored for the first 24 hours post-transplant and then discontinued if normal. Three respondents neither agreed nor disagreed, and two respondents disagreed.

There was strong agreement (92%) that individuals with a UCD should follow the same post-transplant protein goals for wound healing as non-UCD patients. For example, 2-3 g/kg/day for ages 0-2 years, 1.5-2 g/kg/day for ages 2-13 years, and 1.5 g/kg/day for ages 13-18 years (L.458), or as guided by institutional protocols.

Prior to liver transplantation, L-arginine and L-citrulline supplementation are used to support ureagenesis, prevent amino acid deficiencies, and reduce ammonia concentrations in individuals with UCDs. Following transplantation, the need for continued supplementation is less clear. Because several urea cycle enzymes have extrahepatic activity (F.6992), some individuals may experience persistently low plasma arginine or citrulline concentrations after transplant, prompting consideration of continued supplementation in certain cases (F.6480).

Low plasma arginine and/or citrulline concentrations after liver transplantation have been reported, with supplementation continued in some individuals based on biochemical findings. As the aim of supplementation is to ensure adequate arginine production, adjustments in dose of L-citrulline or L-arginine should be based on plasma arginine levels. L-citrulline supplementation has been used in individuals with CPS (F.7168, F.7179, F.7180) and OTC (F.7168, F.7179, F.7180), while L-arginine supplementation has been reported in individuals with OTC (F.7179), CIT-I (F.6992, F.7179, F.7180), and ASA (F.5785). In one retrospective cohort, L-arginine supplementation at 100 mg/kg/day, along with low-dose sodium benzoate and mild protein restriction, was used to manage recurrent hyperammonemia during the first year after transplantation in one of seven children with CIT-I (F.5973). Another study reported L-citrulline supplementation was required in only 20% of individuals with CPS (n=4) and 50% of those with OTC (n=8), with approximately half of the pre-transplant dose sufficient to maintain plasma citrulline concentrations (F.7168).

More recently, a registry-based analysis evaluated the impact of long-term L-citrulline and/or L-arginine supplementation following liver transplantation in 52 individuals with severe OTC, CIT-I, and ASA (L.459). Sixteen individuals received supplementation (doses not reported) and 36 did not, with follow-up periods ranging from four to six years. No significant differences were observed between groups in growth, cognitive outcomes, motor abnormalities, hospitalization rates, or plasma citrulline or arginine concentrations. The authors concluded that current post-transplant supplementation practices are not associated with measurable clinical or biochemical benefits, while noting the need for further prospective studies in larger cohorts (L.459).

Delphi 1 Results

There was no agreement (69%) about use of L-arginine and/or L-citrulline supplementation if plasma concentrations fall below the normal range following transplant. Five respondents neither agreed nor disagreed and two disagreed. One respondent commented that plasma citrulline often remains persistently low despite robust supplementation; therefore, the clinic supplements L-citrulline at a dose that maintains plasma arginine within normal limits.

For individuals receiving L-citrulline and/or L-arginine supplementation post-transplant, there was unanimous agreement that plasma amino acids should be measured at least annually.

Nominal Group

Nominal group experts unanimously agreed that post-transplant supplementation should be guided primarily by plasma arginine concentrations—given that arginine is a conditionally essential amino acid—with L-citrulline used for CPS and OTC and L-arginine for CIT-I and ASA in individuals with persistent deficiencies.

Across the literature, individuals with UCDs have been reported to successfully transition to an unrestricted diet following liver transplantation. This outcome has been described in individuals with CPS (F.5007, F.7168, F.7177, F.7179, F.7180, F.7240, F.7335, F.7408), OTC (F.6016, F.6321, F.7168, F.7177, F.7179, F.7180, F.7335), CIT-I (F.5109, F.5305, F.5707, F.5973, F.6467, F.7168, F.7177, F.7179, F.7180), ASA (F.5785, F.6687, F.7168), and ARG (F.7711, F.7179, F.7180). Although nutrition education and conseling may facilitate the transition to a healthy unrestricted diet, nutrition counseling was not specifically described in these reports.

Delphi 1 Results

There was strong consensus that most individuals can safely transition to an unrestricted diet following transplant (96%). Nearly all respondents agreed that this transition should be supported by nutrition counseling from a metabolic and/or transplant dietitian to ensure the diet remains nutritionally balanced (94%). Additionally, all respondents agreed upon the importance of long-term monitoring by a metabolic and/or transplant dietitian to assess growth, health maintenance, and overall nutritional status (100%).

Delphi 2 Results

There was consensus (87%) to provide individualized nutrition counseling, along with ongoing plasma amino acid monitoring, for approximately one year after transplant to support a safe transition to an unrestricted protein diet and ensure continued nutritional adequacy.

Nominal Group

Nominal group discussion emphasized that individuals undergoing liver transplantation for UCDs may experience challenges transitioning to an unrestricted protein diet due to longstanding dietary restriction and/or feeding challenges (including texture aversion in children). Participants also noted that continued engagement with the metabolic team during the early post-transplant period can be reassuring for families and may support both dietary adjustment and continuity of care during this transition.