Introduction: liver transplantation (LT) is a rising treatment option in several Inherited Metabolic Diseases (IMD). Plasma citrulline, a non-protein amino acid synthesized by small bowel enterocytes, has been explored as a potential biomarker of intestinal function and enterocyte mass. The study aims to determine whether citrulline levels could represent an indicator of intestinal function’s after LT.
Methods: 44 IMD patients who underwent LT from 2013 to 2024 were retrospectively included in the study. As a standard protocol, plasma aminoacid levels (including citrulline) were systematically analyzed after LT at different points (LT, 1-2, 3-7, 8-14, 15-30 post-operative days). Patients were divided in three diagnostic groups Argininosuccinic Aciduria (ASA, 9 pts), Organic Aciduria [OAs (MMA & PA), 22 pts], and Maple Syrup Urine Disease (MSUD, 13 pts). 
Results: Prior to LT, citrulline levels were in the expected ranges for the specific metabolic defect. After LT, citrulline levels sharply declined within the first 48 hours, followed by a progressive raise to pre-LT values within the first 4 weeks post-LT (p < 0.05). As expected, ASA patients exhibited significantly higher citrulline levels at any study time compared to other IMD groups (p < 0.05). In ASA patients, the median plasma citrulline at LT was 185 μmol/l (144-240), falling to 77 μmol/l (65-85) in the first two days after LT, and then returning to 120 μmol/l (104-137) one month after LT. Patients with MSUD and OAs showed normal median citrulline levels prior to LT [26 μmol/l (18-30) and 28 μmol/l (20-34), respectively] with a rapid reduction immediately after LT [12 μmol/l (9-20) and 10 μmol/l (8-13), respectively], followed by a return to pre-LT levels after one month in MSUD [22 μmol/l (15-28)], with a less pronounced rise in OAs [14 μmol/l (10-22)]. Higher early post-LT citrulline levels correlated with a shorter duration of parenteral nutrition (p <0.05). Resumption of bowel movements occurred at a median time of 5.5 days post-LT, which corresponded to a rise in plasma citrulline levels. None of the patients had surgical or medical intestinal complications.
Conclusions: The study showed that, regardless of the disease category, plasma citrulline levels present an early reduction after LT, followed a progressive increase once resuming bowel movements, thus providing the proof of principle that longitudinal monitoring of plasma citrulline may represent a non-invasive marker of post-LT enterocyte function.