Schleiger A, Ovroutski S, Peters B, Schubert S, Photiadis J, Berger F, Kramer P. Cardiol Young. 2020 May;30(5):698-709. doi: 10.1017/S1047951120000864. Epub 2020 May 4.PMID: 32364090
- Protein-losing enteropathy (PLE) occurred in 30 out of 439 (6.8%) Fontan patients managed at a single institution during the study period of 1986-2019, and it developed at the median of 2.9 years after Fontan operation.
- Cardiopulmonary perturbations in the form of unilateral diaphragmatic paralysis or central PA stenosis or Fontan pathway obstruction or bradyarrhythmia were present at manifestation or during the disease in 25 of 30 patients (83%).
- The factors significantly associated with the development of PLE in this cohort were bradyarrhythmia, phrenic nerve palsy, and stenosis within the Fontan pathway. Patency of Fontan fenestration was associated with decreased odds of PLE.
- The treatment strategies were varied, including surgical management of phrenic palsy with diaphragm plication, pacemaker implantation for bradyarrhythmia, and percutaneous cath interventions aimed at relieving the Fontan pathway obstruction. Medical therapies were predominantly a combination of pulmonary vasodilator therapy and anti-inflammatory therapy with budesonide and diuretics and heart failure therapy. Between all the treatment strategies, stable remission, defined as regression of symptoms and elevated serum albumin levels >3.5g/dl over 12 months, was seen among 15 patients (50%) at the time of the study.
- The somatic growth and physical development was significantly delayed in Fontan patients associated with PLE than non-PLE cohort as compared by z-scores for height and body weight. The sexual development was also delayed but not statistically significant.
- The mortality in this cohort was 33.3% and occurred after a median of 7.2 years from the onset of the disease. The survival estimates declined from 96.1% at five years to 70.5 % at 10 and 50.1% at 20 years.
- Nonsurvivors had lower serum albumin and total protein levels, higher pulmonary artery pressure, and impaired ventricular function, at last follow-up compared to survivors. Lack of indications for surgical or cath-based interventions and failure to respond to medical treatment with no significant improvement or remission within 6-12 months should prompt cardiac transplantation evaluation.
Commentary from Dr. Venugopal Amula (Salt Lake City UT), section editor of Pediatric Cardiology Journal Watch: Protein Losing Enteropathy is an infrequent but critical complication that limits survival in Fontan patients – the exact pathophysiological mechanism of which remains unknown. This current report by A. Schleiger et al. is a retrospective, observational study of Fontan patients followed up at a single institution between 1986 and 2019. The authors identified a cohort of 439 patients, of which 327 were operated in their institution. They retrospectively applied a proposed universal diagnostic definition of protein-losing enteropathy in Fontan patients and identified 30 patients with the disease condition. PLE was defined by the criteria of the combination of persistent diarrhea or recurring edema or pleural effusions or ascites, decreased serum albumin levels, and total serum protein levels and confirmation of intestinal protein loss with increased fecal alpha antitrypsin levels.
Demographic, clinical, laboratory, and echocardiographic data were abstracted from institutional medical records. Surgical and hemodynamic data detailing the Fontan surgery was also retrieved. Standard descriptive statistics were applied survival, and freedom from PLE was assessed using Kaplan Meier Survival analysis.
The PLE patients had a long median follow up of 13.1 years. The long follow up helped them chronicle the anthropometric, clinical, hemodynamic, and laboratory parameters of these patients since the onset of PLE. Extracardiac total cavopulmonary connection was a common type of Fontan modification in 20 of 30 patients, and 60% had a single left ventricle. Patents who eventually developed PLE had significantly prolonged ICU and hospital lengths of stay, however ventricular morphology was unrelated to disease manifestation.
Around 80% of patients had cardiopulmonary perturbations that were heterogeneous, ranging from diaphragm paralysis, obstruction of Fontan pathway, bradyarrhythmia, and central PA stenosis. Significant risk factors associated with PLE were phrenic nerve palsy, bradyarrhythmia, and Fontan pathway obstruction.
The treatment strategies for PLE were analyzed in detail and involved surgical and catheter-based interventions for those indicated. Medical therapy was targeted towards pulmonary vasodilation, anti-inflammatory therapy with budesonide, diuretic, and heart failure therapy. Surgical indications were discrete such as phrenic nerve palsy and PM placement for bradyarrhythmias. A total of 64 percutaneous catheter-based procedures were performed in 25 patients directed towards relieving Fontan pathway obstruction.
Overall, 15 patients were in remission at the time of study with surgical or interventional or medical or combination of therapies.
During the follow up there was a progressive decline in ventricular function, although the degree of Av valve regurgitation did not change. One-third of the patients died after a median interval of 7.2 years, with an estimated ten-year survival of 70.5% and 20-year survival of 50.1%. Overall, four patients were listed for transplant with two patients receiving it while two died on the waiting list. Among those transplanted, one died in the postoperative period.
Although the authors evaluated a large cohort of patients with a reasonable long follow up period, the study is limited by being a single institutional experience. It may not apply to other centers with different populations and variations in surgical and postoperative management strategies. The extended study period lends itself to era effect on disease manifestation with improved current era surgical and anesthetic techniques. Significant advances in the understanding of the abdominal lymphatic system and drainage in the setting of central venous congestion have occurred recently and are paramount to the latest interventions of redirecting lymphatic drainage to prevent and treat PLE.