• biochemical profile
• cholesterol
• Fontan circulation
• Fontan-associated liver disease
• liver stiffness
• univentricular heart

Summary: The Fontan procedure represents a cornerstone in the palliation of patients with functionally univentricular hearts (UVH), offering extended survival but at the cost of profound physiological changes. This surgical innovation bypasses the subpulmonary ventricle, establishing a passive flow of systemic venous blood to the pulmonary arteries. While this strategy achieves hemodynamic stability and relief from cyanosis, it imposes elevated central venous pressures and chronically reduced cardiac output, ultimately predisposing patients to a spectrum of cardiac and extracardiac complications. In particular, Fontan-associated liver disease (FALD) has recently attracted increasing interest due to its near-universal presence in long-term Fontan survivors; however, its diagnosis and management remain challenging. Moreover, data regarding the biochemical profile of these patients are still limited, particularly in relation to its potential association with hepatic involvement.
Aims: This study had several goals. We aimed to evaluate the biochemical profile of a cohort of patients with univentricular heart (UVH) physiology who had undergone Fontan palliation. In addition, we conducted further evaluations to assess the severity of Fontan-associated liver disease (FALD) within this population, to identify clinical, imaging and laboratory biomarkers potentially associated with FALD severity, and to explore their association with adverse cardiac outcomes.
Methods: Consecutive patients aged ≥10 years were enrolled from the multicenter “Multifon” study, a collaborative effort involving pediatric and adult cardiologists, hepatologists, and biologists. Surgical history and clinical data were abstracted from hospital records. All patients underwent a multimodality evaluation, including biochemical tests, hepatic imaging (ultrasound and FibroScan®), and cardiac assessments (echocardiography, cardiac MRI, cardiopulmonary exercise testing [CPET], and spirometry). Advanced liver involvement was evaluated using the VAST score, calculated by summing clinical findings (endoscopic or radiological signs of Varices, Ascites, Splenomegaly, and Thrombocytopenia [platelets <150,000/μL]). A control group of healthy individuals matched for age was also included for comparative biochemical analysis.
Results: Our study population included 78 consecutive Fontan patients (49 males [63%], mean age 27 ± 10 years) and 39 healthy controls (12 males [31%], mean age 28.3 ± 5.9 years). The most frequent diagnosis in the Fontan cohort was complex two-ventricle anatomy (28.5%). Compared to controls, Fontan patients showed a significantly lower platelet count (p < 0.001). Liver function testing revealed significantly higher transaminase levels (AST and ALT; p = 0.02 and p < 0.001, respectively). Notably, gamma-GT levels were markedly elevated, with 20 patients (30%) exceeding 73 U/L. Additionally, 44.4% of patients had vitamin D levels <20 ng/mL, and 72.2% were below 30 ng/mL. Total cholesterol, LDL cholesterol, and the cholesterol/HDL ratio were significantly lower in Fontan patients compared to controls. Moreover, 50 patients (71.4%) had total cholesterol levels below the 25th percentile (standardized for age and sex), and 34 patients (50%) were below the 10th percentile.
Median liver stiffness measurement (LSM), assessed via transient elastography, was 17.3 kPa (IQR: 13.5–24.5 kPa). A VAST score ≥2 was associated with higher LSM (p < 0.001), higher direct bilirubin levels (p = 0.019), and lower cholesterol levels (p = 0.045). ROC curve analysis identified an LSM cutoff of 20.8 kPa, with a sensitivity of 71% and specificity of 78% for detecting VAST ≥2 (AUC: 0.789, p < 0.001). Among patients on diuretic therapy, 50% had an LSM ≥20.8 kPa, compared to 24% of those not on diuretics.
Discussion: Our data suggest that LSM is a promising tool for evaluating and stratifying liver disease severity in Fontan patients. Higher LSM values were also associated with the use of diuretic therapy. Moreover, the cohort displayed low serum lipid levels and reduced 25-hydroxyvitamin D concentrations. Both higher LSM and lower cholesterol were associated with more advanced FALD. The association between hypocholesterolemia and liver disease severity calls for further, larger studies to confirm these findings and better understand lipid metabolism in this challenging population.
Conclusion: This thesis provides novel insights into the biochemical and hepatic phenotype of Fontan patients. It confirms that Fontan physiology results in a distinct and progressive systemic disorder affecting multiple organ systems beyond the heart. By identifying biochemical and imaging markers associated with FALD and adverse cardiac outcomes, this study contributes to improving risk stratification and clinical management in this complex and vulnerable population. Future research should aim to validate these findings in larger, prospective cohorts and develop tailored interventions to prevent disease progression and improve long-term quality of life.