# Fontan associated protein-losing enteropathy is linked to distinct metabolic and hepatic alterations

## TL;DR

Fontan patients with protein-losing enteropathy show unique metabolic changes involving lipids, bile acids, and hormone activation.

## Contribution

Identifies a distinct metabolic and hepatic signature in Fontan patients with protein-losing enteropathy using targeted serum metabolomics.

## Key findings

- Fontan patients with PLE show increased cholesterol, triacylglycerols, and phosphatidylcholine species compared to those without PLE.
- Bile acid derivatives like taurodeoxycholic acid are lower in PLE patients and correlate with renin and phosphatidylcholine levels.
- Hypoalbuminemia and hypogammaglobulinemia in PLE are linked to activation of the renin-angiotensin-aldosterone system and vasopressin.

## Abstract

The univentricular Fontan circulation is associated with long-term multiorgan complications, including protein-losing enteropathy (PLE). While hemodynamic and lymphatic contributors to PLE have been described, its systemic metabolic signature remains incompletely characterized. We aimed to identify PLE-associated alterations in circulating metabolites using targeted serum metabolomics. Targeted serum metabolomic profiling was performed by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using the AbsoluteIDQ p180 kit. Forty-nine individuals were included: Fontan patients with PLE (FPLE, n = 10), Fontan patients without PLE (F, n = 30), and clinically stable biventricular controls (C, n = 9). Data were analyzed using MetaboAnalyst v6.0, including multivariate modeling (PLS-DA), univariate statistics with false discovery rate correction, correlation analyses, and receiver operating characteristic (ROC) analyses. Compared with controls, Fontan patients without PLE showed reduced concentrations of cholesterol, triacylglycerols, and several phosphatidylcholine (PC) species, whereas Fontan patients with PLE demonstrated relative increases in these lipid classes. Among 90 quantified PCs, 11 showed a consistent gradient with the lowest concentrations in F and the highest in FPLE. FPLE was further characterized by marked hypoalbuminemia and hypogammaglobulinemia, accompanied by elevated renin, aldosterone, and copeptin levels, indicating pronounced renal–neurohormonal activation of the renin-angiotensin-aldosterone system (RAAS) and vasopressin. Bile acid derivatives, including taurodeoxycholic acid and glycodeoxycholic acid, tended to be lower in FPLE and showed group-specific associations with both renin and selected PC species. Exploratory ROC-based screening identified the immunoglobulin G (IgG)-to-aldosterone and the albumin-to-PC ae C40:3 ratios as the most informative biomarker combinations distinguishing FPLE from non-PLE Fontan patients. These findings are exploratory and hypothesis-generating and require validation in independent cohorts. Fontan patients with PLE show a distinct metabolic phenotype integrating protein loss, lipid alterations, bile acid perturbations, and activation of the renin–angiotensin–aldosterone system. These findings suggest that metabolic and renal–neurohormonal pathways extend beyond lymphatic dysfunction in PLE and identify candidate biomarker patterns for further investigation rather than established diagnostic tools. Further studies are required to clarify causality, mechanistic links, and clinical generalizability.

The online version contains supplementary material available at 10.1038/s41598-026-37974-1.