Published online Dec 9, 2026. doi: 10.5409/wjcp.119970
Revised: February 26, 2026
Accepted: May 7, 2026
Published online: December 9, 2026
Processing time: 239 Days and 13.8 Hours
Protein-losing enteropathy (PLE) is a condition characterized by the abnormal loss of serum proteins into the intestinal lumen, and it is one of the most challenging complications in individuals with Fontan circulation. It affects approximately 5%-12% of Fontan patients and is associated with increased morbidity and mortality. As these patients age and milder or transient forms of PLE are more frequently recognized, its incidence is expected to rise. Although early detection and recent advances in treatment have improved quality of life, the risk of death remains significant. This review explores the pathogenesis of PLE in Fontan patients and discusses current management strategies. Treatment options are diverse and include medical therapies such as pulmonary vasodilators to reduce pulmonary vascular resistance, alpha-adrenergic agents to enhance lymphatic tone and promote lymphatic peristalsis and interventional procedures such as widening the fenestration to decongest the inferior vena cava. Additionally, lymphatic embo
Core Tip: Fontan-associated protein-losing enteropathy is a rare but life-threatening complication of Fontan circulation, driven by abnormal hemodynamics, lymphatic dysfunction, and intestinal barrier injury. This review synthesizes current understanding of protein-losing enteropathy pathophysiology and highlights contemporary management strategies, including nutritional optimization, targeted pharmacologic therapies, and emerging lymphatic interventions. Particular emphasis is placed on individualized, mechanism-based treatment and the evolving role of advanced imaging and interventional techniques. Improved recognition and multidisciplinary care have enhanced outcomes; however, refractory disease remains challenging, underscoring the need for novel therapeutic approaches.
- Citation: Al Atrash E, Zourob D, Alghfeli H, AbdelMassih A. Fontan-related protein-losing enteropathy: A comprehensive review of pathophysiology and current therapies. World J Clin Pediatr 2026; 15(4): 119970
- URL: https://www.wjgnet.com/2219-2808/full/v15/i4/119970.htm
- DOI: https://dx.doi.org/10.5409/wjcp.119970
For over half a century, the Fontan operation has served as a major milestone in the palliative surgical strategy of various single-ventricle congenital heart anomalies[1-3]. This surgical approach aims at separating the pulmonary and systemic circulations, with the primary objective of eliminating cyanosis and reducing the workload on the sole cardiac chamber. As new surgical techniques emerge, survival into adolescence and early childhood has improved[4]. Nevertheless, this comes at the expense of creating a unique circulatory physiology that is passively driven by abnormally elevated central venous pressure, subsequently creating chronic venous congestion and low cardiac output[1,3,5]. The neo-circulation, or what is known as the Fontan Paradox, a hemodynamic consequence of the Fontan procedure where the absence of a right ventricle causes high systemic venous pressure (needed to drive blood) to coexist with low pulmonary artery pressure (passive flow), is often complicated by protein-losing enteropathy (PLE). Prevalence varies across cohorts but is commonly cited in the 3%-18% range in the Fontan population, with an average onset of 3.5-5 years following the surgery[2,5]. The hallmark of PLE is excessive enteric protein loss, leading to profound hypoalbuminemia and ensuing generalized edematous state[2,3]. Beyond fluid overload, patients face significant secondary comorbidities, such as immunodeficiency, hypocalcemia, malnutrition, and growth failure[6,7]. Historically, PLE was associated with a dismal prognosis, with 5-year mortality rates approaching 50%. While modern multimodal care and earlier recognition have improved 5-year survival estimates to 88%-96% in some cohorts, the condition remains inherently life-threatening and difficult to manage[2,6,8-10]. Given these challenges, no single medical or surgical approach has proven universally successful, and cardiac transplantation remains the only definitive cure[2,10].
As we look forward, there is a compelling need for novel therapeutic modalities through a better understanding of the lymphatic and immune pathways involved in the pathophysiology[11].
Although described for decades, Fontan-associated PLE remains complex and heterogenous, reflecting an intricate interplay between hemodynamics, the lymphatic system, intestinal barrier, and inflammatory pathways (Figure 1)[11-13].
In the Fontan circulation, pulmonary blood flow is driven by passive venous return and a narrow pressure gradient, given the lack of a subpulmonary ventricle. This mechanistic failure spans over a spectrum and is the cornerstone of end-organ injury[4,14]. In many cohorts, PLE is more frequent in patients with unfavorable hemodynamics, including higher Fontan pressures, ventricular dysfunction, atrioventricular valve regurgitation, pulmonary artery-venous obstruction, and elevated pulmonary vascular resistance, all of which increase venous congestion and decrease effective forward flow[12-14]. From a microvascular perspective, sustained systemic venous hypertension increases intestinal capillary hydrostatic pressure and promotes interstitial fluid filtration. Therefore, in the setting of impaired lymphatic return, the intestine becomes vulnerable to edema, impaired mucosal perfusion, and barrier dysfunction that can facilitate protein leakage into the lumen[5].
A major body of clinical and radiographic evidence postulates lymphatic dysfunction as a major proximal driver of Fontan-PLE[2,11,13]. Elevated systemic venous pressure increases lymph formation and raises the outflow pressure into which the thoracic duct and central conducting lymphatics must drain, promoting lymphatic hypertension, dilation, and collateralization. Over time, abnormal lymphatic channels may decompress into third-space territories within the bowel wall, leading to luminal loss of protein[2,11,13,15,16]. The modern concept of Fontan-associated lymphatic disease frames PLE as a lymphatic flow disorder with distinct anatomic and flow patterns. Advanced lymphatic imaging, particularly dynamic contrast magnetic resonance lymphangiography has enabled visualization and localization of abnormal lymphatic flow, including enteric leak patterns relevant to PLE. Such imaging studies have reinforced a mechanistic model in which venous alongside lymphatic hypertension and abnormal central lymphatic anatomy interact to produce intestinal lymphangiectasia, mucosal edema, and direct lymph leakage[17,18].
Beyond hydrostatic congestion, the Fontan state may predispose to abnormal mesenteric hemodynamics and perfusion patterns. Low cardiac output and limited preload reduce splanchnic blood flow reserve, while venous congestion impairs arteriovenous gradients[4,14]. These changes can promote mucosal ischemia-reperfusion stress, epithelial injury, and altered absorptive and secretory functions. In children, who require adequate intestinal perfusion for growth and high nutritional demands, even modest chronic hypoperfusion may amplify susceptibility to malnutrition and inflammatory signaling, creating a self-reinforcing loop that worsens protein loss and edema[2,11,13].
A key downstream step in PLE is the failure of the intestinal barrier to restrict the translocation of macromolecules. In Fontan-PLE, barrier disruption is thought to involve both alterations in tight junctions and injury to the basement membrane, including heparan sulfate proteoglycans that contribute to barrier integrity[2,11,13]. Furthermore, research has demonstrated that heparan sulfate and syndecan-1 are critical for maintaining intestinal epithelial barrier function, and that loss or depletion can increase permeability to proteins[19,20]. In Fontan-PLE specifically, clinical observations have long pointed toward altered heparan sulfate expression in the intestinal epithelium as a plausible contributor, potentially interacting with venous and lymphatic hypertension to permit protein extravasation[2,11,13,19]. In addition, inflammatory mediators such as tumor necrosis factor alpha (TNF-α) have been implicated in barrier permeability pathways in PLE biology, with experimental data suggesting that heparan sulfate depletion can amplify TNF-α-associated permeability changes[21]. Collectively, these data support a model in which Fontan hemodynamic stress and lymphatic hypertension create mucosal edema and injury, while epithelial barrier alterations lower the threshold for protein leak.
Fontan-PLE is associated with systemic and intestinal inflammation, though causality is bidirectional: Lymphatic congestion and protein loss can trigger immune activation, while inflammation can worsen endothelial and epithelial permeability alongside lymphatic function. Contemporary reviews emphasize intestinal inflammation as a recurrent component of the heterogeneous pathogenesis[2,11,13]. Evidence of chronic inflammation, including altered TNF-α signaling and related inflammatory biomarkers, has been repeatedly demonstrated in those with PLE[22]. TNF-α contributes to barrier dysfunction by disrupting tight junction integrity, thereby linking inflammation to the basement membrane. This inflammatory milieu may contribute to endothelial activation, capillary leak, impaired lymphatic contractility, and further barrier compromise, all of which link hemodynamic stress to sustained mucosal permeability. Immune consequences of protein loss, like loss of immunoglobulins and lymphopenia, can predispose to infections. The consequence is further destabilization of Fontan hemodynamics and intensification of inflammatory cascades. In pediatrics, recurrent infections and nutritional compromise may be particularly impactful, and clinical trajectories often reflect episodes of decompensation where intercurrent illness precipitates worsening PLE[13,14].
Fontan physiology commonly produces chronic hepatic congestion and progressive Fontan-associated liver disease[14]. While liver disease is not the sole cause of PLE, chronic venous hypertension can extend to the portal and mesenteric venous systems, potentially worsening intestinal congestion and lymph production. This presumed hepatic-portal-intestinal axis may therefore act as an important modifier of risk and severity, particularly in long-standing Fontan circulation.
Fontan-associated PLE is a severe and chronic complication observed in approximately 5%-12% of patients following Fontan palliation for single-ventricle congenital heart disease[2,12]. Excessive loss of serum proteins into the gastrointestinal lumen causes persistent hypoalbuminemia and a broad spectrum of systemic manifestations. Fontan-associated PLE usually develops months to several years after the Fontan operation, with a median onset of approximately five years, although considerable variability in timing has been reported[2,4,12]. Hypoalbuminemia underlies many of the clinical and biochemical abnormalities seen in affected patients[23,24]. Clinically, Fontan-associated PLE presents with manifestations of systemic venous congestion, malnutrition, and immune dysfunction. Peripheral edema, particularly involving the lower extremities, is the most frequent presenting feature and reflects the combined effects of hypoalbuminemia and venous hypertension[23-25]. Subtle periorbital or facial edema, often more apparent in the morning, may precede more generalized fluid accumulation. As the disease progresses, many patients develop ascites, leading to abdominal distension, bloating, and discomfort. Pleural and pericardial effusions are also common and may further compromise respiratory and cardiac function[4,8,26]. Gastrointestinal symptoms are variable and not universally present. Chronic or intermittent diarrhea may occur, although some patients exhibit significant hypoproteinemia in the absence of diarrhea, particularly in slowly progressive disease. When present, diarrhea is frequently associated with intestinal wall edema and malabsorption[24,26]. Lymphatic congestion within the bowel wall can impair fat absorption, resulting in steatorrhea, abdominal pain, and foul-smelling stools. Systemic consequences of Fontan-associated PLE are often profound. Patients commonly report extreme fatigue, malaise, and unintended weight loss. In pediatric populations, failure to thrive and impaired linear growth are prominent features and may serve as early indicators of disease severity[27]. Ongoing protein and micronutrient losses contribute to protein-energy malnutrition and exacerbate overall morbidity. Immune dysfunction is a hallmark of Fontan-associated PLE and results from gastrointestinal loss of immunoglobulins and lymphocytes[28,29]. This secondary immunodeficiency predisposes patients to recurrent infections and, in severe cases, life-threatening sepsis. Additionally, loss of coagulation factors may manifest as easy bruising or bleeding tendencies. Deficiencies of fat-soluble vitamins, particularly vitamin D, are common and may lead to osteopenia and reduced bone mineral density, further complicating long-term outcomes[8,26].
PLE, in most cases, can be suspected based on the patient’s history, physical findings, and clinical presentation[4,29]. The diagnosis can be established using stool-based tests or functional imaging studies when further confirmation is needed[29].
Measurement of alpha-1-antitrypsin (A1AT) in stool is a reliable method for identifying intestinal protein loss. A1AT is comparable in size to albumin, is not secreted or absorbed by the intestine, and is resistant to degradation, making it a sensitive marker of protein leakage[27]. Determination of A1AT clearance requires simultaneous measurement of serum A1AT levels and a 24-hour stool collection. Normal clearance values are less than 24 mL/24-hour, while significantly elevated values – particularly in patients with diarrhea – support the diagnosis of PLE[29]. A limitation of this test is that it does not identify the location of protein loss and may not detect gastric protein leakage[24,29].
Functional imaging techniques provide the advantage of localizing the site of protein loss. Among various radiotracers studied, technetium-99m-labeled human serum albumin is most commonly used and has demonstrated high sensitivity and specificity for detecting PLE, with no significant adverse effects reported[27].
After confirming the diagnosis, evaluation should focus on identifying the underlying cause[29]. Stool studies are useful for excluding infectious etiologies, while serologic testing may reveal immune-mediated disorders. Cardiac assessment, including electrocardiography and echocardiography, may be necessary in selected patients[4,29]. Cross-sectional imaging, such as computed tomography or magnetic resonance imaging can help identify the extent of intestinal involvement[17,26]. Endoscopy allows direct visualization of mucosal abnormalities and tissue sampling for histologic confirmation. In suspected intestinal lymphangiectasia, a high-fat meal before endoscopy enhances lymphatic visualization, by stimulating lymphatic flow, making dilated lymphatics more prominent[25]. Capsule endoscopy offers a noninvasive option for evaluating small-bowel pathology and is safe for use in children older than 1.5 years[28].
PLE is a challenging clinical syndrome that requires a comprehensive and individualized treatment approach. PLE represents a manifestation of diverse underlying conditions rather than a single disease entity; therefore, management is primarily directed toward reducing intestinal protein loss, correcting nutritional and metabolic consequences, and treating the underlying disorder[3,4,6]. Advances in nutritional therapy, pharmacologic agents, lymphatic interventions, and targeted disease-specific treatments have significantly improved outcomes in certain patient groups. This review addresses the current strategies for the treatment and management of PLE[2,3].
The cornerstone of PLE management is identification and treatment of the underlying cause, along with supportive measures aimed at reducing protein loss and restoring nutritional and immunologic balance[3,4]. Because PLE represents a common final pathway of multiple disease processes, no single treatment approach is universally effective.
Management goals include: (1) Reducing of gastrointestinal protein loss; (2) Maintenance of adequate serum albumin and oncotic pressure; (3) Optimization of nutritional status and growth; (4) Prevention of complications such as infections, thrombosis, and micronutrient deficiencies; and (5) Improvement in functional status and quality of life[6,8,27].
Nutritional therapy should be initiated early, as it is essential in all forms of PLE[26]. Probiotics and gut-barrier–stabilizing supplements and medium-chain triglycerides (MCTs), while not pharmacologic drugs, are often adjunctively used to reduce intestinal lymphatic load. Patients with PLE require increased protein intake to compensate for ongoing enteric losses, up to 3 g/kg/day and 1.5-3 g/kg/day for children and adults, respectively[26]. Protein supplementation may be delivered orally, enterally, or parenterally in severe or refractory cases. A low-fat diet supplemented with MCTs is particularly beneficial for lymphatic forms of PLE[26]. Reduction of long-chain triglycerides lowers intestinal lymph flow and protein leakage, whereas MCTs provide an alternative energy source that is absorbed directly into the portal circulation[26]. Micronutrient deficiencies are common in PLE and require routine monitoring and supplementation of fat-soluble vitamins (A, D, E, K), iron, zinc, calcium, magnesium, and trace elements. Routine monitoring and supplementation using water-miscible preparations are recommended to optimize absorption. Dosage should be tailored to the degree of deficiency and individual patient factor with close monitoring to prevent toxicity[8,26].
Drug-based therapy for Fontan-related PLE aims to counteract the complex interplay of elevated central venous pressures, impaired lymphatic drainage, mucosal inflammation, and endothelial dysfunction that collectively promote enteric protein loss[3,4,6]. Because PLE arises from a spectrum of hemodynamic, inflammatory, and lymphatic abnormalities, no single medication is universally effective; rather, patients often require multidrug regimens tailored to the predominant underlying mechanism driving their disease. Therapeutic strategies, therefore, focus on reducing systemic venous and lymphatic pressures, improving ventricular performance and pulmonary blood flow, stabilizing the intestinal barrier, and attenuating chronic intestinal inflammation[2,3,6]. Drug therapy is frequently initiated before invasive lymphatic or surgical interventions, and even when not curative, medical optimization often stabilizes patients sufficiently to allow further targeted management[2,6].
Optimization of hemodynamics remains one of the foundational pillars of therapy[2,3]. Diuretics, including loop diuretics and spironolactone, are commonly employed to reduce volume overload, ascites, and peripheral edema, thereby alleviating some of the downstream lymphatic congestion that contributes to protein leakage. Although diuretics rarely reverse PLE, symptomatic benefit is consistent, particularly when combined with agents that improve ventricular function or reduce afterload[2]. Angiotensin-converting enzyme inhibitors and β-blockers are used selectively in the presence of ventricular dysfunction; however, caution is essential, as excessive reduction in preload may compromise the Fontan circulation[3,6]. The goal is meticulous hemodynamic titration to maintain adequate forward flow while reducing venous pressures that drive intestinal lymphatic engorgement[3].
Pulmonary vasodilators represent an increasingly utilized category in the medical management of PLE, particularly given their capacity to improve transpulmonary flow and reduce Fontan pressures. Sildenafil and tadalafil, through phosphodiesterase-5 inhibition, lower pulmonary vascular resistance and enhance pulmonary blood flow, leading to improved cardiac output and reduced systemic venous congestion[2,6]. Select patients demonstrate meaningful improvements in exercise tolerance, ascites, and even serum albumin levels following pulmonary vasodilator therapy. Endothelin receptor antagonists, such as bosentan, have also been explored, though clinical experience is more limited[2]. These therapies are particularly beneficial in patients with elevated pulmonary vascular resistance or borderline Fontan hemodynamics and may serve as a bridge to more definitive interventions[2,4]. However, responses remain heterogeneous, underscoring the need for careful patient selection and hemodynamic assessment before initiation[2,3].
Budesonide has emerged as one of the most effective pharmacologic therapies for Fontan-related PLE. Its high first-pass hepatic metabolism allows potent local anti-inflammatory effects on the intestinal mucosa with minimal systemic toxicity[2-4]. Many patients experience significant increases in serum albumin, reductions in stool α-1 antitrypsin, and improvement in gastrointestinal symptoms[3,4]. The dramatic response seen in some individuals highlights the contribution of mucosal inflammation and immune-mediated epithelial injury to PLE pathogenesis. Systemic corticosteroids may be reserved for acute exacerbations, although long-term toxicity limits their use[3]. Additional immunomodulatory therapies – including sirolimus, which may attenuate lymphatic proliferation and immune activation, and mycophenolate mofetil – have been used in refractory cases, but evidence remains limited to small case series[3,6].
Heparin has unique properties beyond anticoagulation that make it a valuable adjunct in selected patients. It may stabilize endothelial tight junctions, reduce enteric capillary leak, and modulate lymphatic flow[19,20]. While some patients experience marked improvement, relapse upon therapy withdrawal is frequent, and bleeding risk must be carefully balanced[1,4]. Octreotide, a somatostatin analogue, reduces splanchnic blood flow and intestinal lymphatic production[1,4]. It has shown efficacy in both acute exacerbations and chronic settings, particularly in patients with prominent lymphatic dysfunction. Its use is often limited by gastrointestinal side effects, gallstones, and variable long-term response[4]. Newer therapeutic concepts target VEGF-C/VEGFR-3 pathways, endothelial nitric oxide signaling, and lymphatic contractility, though these remain experimental[9].
Albumin infusion remains a supportive but frequently necessary therapy, particularly in patients with severe hypoalbuminemia, anasarca, or impaired intestinal absorption of oral medications[8,26]. When combined with diuretics, albumin can transiently improve intravascular oncotic pressure and enhance diuresis, though the therapeutic window is often short. Electrolyte replacement, vitamin supplementation, and anticoagulation in patients with thrombotic risk factors are additional supportive components of care[8,26]. Despite the breadth of available drug options, medical therapy alone rarely offers sustained remission for all patients; nevertheless, it plays a crucial role in symptom stabilization, improving nutritional status, and identifying responders who may avoid more invasive treatments. In refractory cases, transcatheter lymphatic interventions, Fontan revision, or heart transplantation may ultimately be required, but pharmacologic therapy remains the essential first step in a structured, multidisciplinary approach to Fontan-related PLE[2,6,28].
Recent advances in lymphatic imaging, such as dynamic contrast-enhanced magnetic resonance lymphangiography and intranodal lymphangiography, have significantly enhanced the ability to identify abnormal lymphatic channels and pinpoint sites of leakage[10,11,17]. This has paved the way for highly targeted interventional procedures, including percutaneous lymphatic embolization and thoracic duct rerouting, which can effectively reduce protein loss in selected patients with well-defined lymphatic leaks. These minimally invasive approaches represent a shift from conventional, nonspecific management toward precision therapy based on individual lymphatic anatomy and pathophysiology[9-11].
Surgical interventions, such as segmental intestinal resection or lymphatic diversion procedures, are generally reserved for patients with localized intestinal involvement who remain refractory to optimized medical and interventional therapies. In these cases, careful patient selection is critical to minimize morbidity and optimize outcomes[2,3].
For patients with end-stage cardiac disease complicated by PLE, cardiac transplantation remains the definitive and potentially curative therapy. Transplantation addresses the underlying hemodynamic derangements contributing to lymphatic congestion and protein loss, offering the best long-term prognosis when other therapies fail[5,7,28,30].
Long-term management requires regular monitoring of nutritional status, serum proteins, immunoglobulin levels, and micronutrients. Ongoing surveillance for infections, thromboembolism, and bone disease is essential. A multidisciplinary follow-up approach involving gastroenterology, cardiology, nutrition, and immunology is recommended[6,8,26].
In conclusion, PLE remains a significant and complex complication in patients with Fontan circulation, posing substantial challenges in management and prognosis. Despite advances in early detection, medical therapies, and interventional techniques. PLE continues to carry considerable morbidity and mortality risks[2,4,5]. Current treatment strategies focus on a multifaceted approach that includes hemodynamic optimization, nutritional support, targeted pharmacologic interventions, and innovative lymphatic procedures[2,3,6]. Long-term, multidisciplinary care is essential to monitor and address the diverse systemic effects of PLE and to improve patient quality of life. Future directions lie in deepening our understanding of the underlying lymphatic and immune mechanisms to develop novel, more effective therapies, with the ultimate goal of reducing reliance on cardiac transplantation as the definitive cure shifting the paradigm from palliation toward targeted, pathophysiology-driven interventions to improve outcomes and potentially delay the need for transplantation[6,8,9,18].
| 1. | Johnson JN, Driscoll DJ, O'Leary PW. Protein-losing enteropathy and the Fontan operation. Nutr Clin Pract. 2012;27:375-384. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 51] [Cited by in RCA: 59] [Article Influence: 4.2] [Reference Citation Analysis (0)] |
| 2. | Alsaied T, Lubert AM, Goldberg DJ, Schumacher K, Rathod R, Katz DA, Opotowsky AR, Jenkins M, Smith C, Rychik J, Amdani S, Lanford L, Cetta F, Kreutzer C, Feingold B, Goldstein BH. Protein losing enteropathy after the Fontan operation. Int J Cardiol Congenit Heart Dis. 2022;7:100338. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 8] [Cited by in RCA: 15] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 3. | Mazza GA, Gribaudo E, Agnoletti G. The pathophysiology and complications of Fontan circulation. Acta Biomed. 2021;92:e2021260. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 31] [Reference Citation Analysis (0)] |
| 4. | Rychik J, Atz AM, Celermajer DS, Deal BJ, Gatzoulis MA, Gewillig MH, Hsia TY, Hsu DT, Kovacs AH, McCrindle BW, Newburger JW, Pike NA, Rodefeld M, Rosenthal DN, Schumacher KR, Marino BS, Stout K, Veldtman G, Younoszai AK, d'Udekem Y; American Heart Association Council on Cardiovascular Disease in the Young and Council on Cardiovascular and Stroke Nursing. Evaluation and Management of the Child and Adult With Fontan Circulation: A Scientific Statement From the American Heart Association. Circulation. 2019;140:e234-e284. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 365] [Cited by in RCA: 734] [Article Influence: 104.9] [Reference Citation Analysis (0)] |
| 5. | Conway J, Tunuguntla H. Impact of disease process on post-transplant outcomes: Protein-losing enteropathy in Fontan patients. J Heart Lung Transplant. 2019;38:3-4. [RCA] [PubMed] [DOI] [Full Text] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |
| 6. | Al Balushi A, Mackie AS. Protein-Losing Enteropathy Following Fontan Palliation. Can J Cardiol. 2019;35:1857-1860. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 13] [Cited by in RCA: 25] [Article Influence: 3.6] [Reference Citation Analysis (0)] |
| 7. | Schumacher KR, Yu S, Butts R, Castleberry C, Chen S, Edens E, Godown J, Johnson J, Kemna M, Lin K, Lowery R, Simpson K, West S, Wilmot I, Gossett JG. Fontan-associated protein-losing enteropathy and post‒heart transplant outcomes: A multicenter study. J Heart Lung Transplant. 2019;38:17-25. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 28] [Cited by in RCA: 53] [Article Influence: 6.6] [Reference Citation Analysis (0)] |
| 8. | Alkofair B, Alruwaili A, Gai J, Harahsheh AS. Impact of protein-losing enteropathy in children who underwent the Fontan operation. Cardiol Young. 2020;30:1273-1280. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 1] [Cited by in RCA: 3] [Article Influence: 0.5] [Reference Citation Analysis (0)] |
| 9. | Ostrow AM, Freeze H, Rychik J. Protein-losing enteropathy after fontan operation: investigations into possible pathophysiologic mechanisms. Ann Thorac Surg. 2006;82:695-700. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 130] [Cited by in RCA: 119] [Article Influence: 6.0] [Reference Citation Analysis (0)] |
| 10. | Schleiger A, Ovroutski S, Peters B, Schubert S, Photiadis J, Berger F, Kramer P. Treatment strategies for protein-losing enteropathy in Fontan-palliated patients. Cardiol Young. 2020;30:698-709. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 15] [Cited by in RCA: 26] [Article Influence: 4.3] [Reference Citation Analysis (1)] |
| 11. | Barracano R, Merola A, Fusco F, Scognamiglio G, Sarubbi B. Protein-losing enteropathy in Fontan circulation: Pathophysiology, outcome and treatment options of a complex condition. Int J Cardiol Congenit Heart Dis. 2022;7:100322. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 8] [Cited by in RCA: 13] [Article Influence: 3.3] [Reference Citation Analysis (0)] |
| 12. | Mertens L, Hagler DJ, Sauer U, Somerville J, Gewillig M. Protein-losing enteropathy after the Fontan operation: an international multicenter study. PLE study group. J Thorac Cardiovasc Surg. 1998;115:1063-1073. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 385] [Cited by in RCA: 359] [Article Influence: 12.8] [Reference Citation Analysis (0)] |
| 13. | Lee JY. Protein-Losing Enteropathy: A Big Challenge in Fontan Circulation. Korean Circ J. 2022;52:621-622. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 3] [Reference Citation Analysis (0)] |
| 14. | Veldtman GR, Webb GD. Improved survival in Fontan-associated protein-losing enteropathy. J Am Coll Cardiol. 2014;64:63-65. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 7] [Cited by in RCA: 7] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 15. | RochéRodríguez M, DiNardo JA. The Lymphatic System in the Fontan Patient-Pathophysiology, Imaging, and Interventions: What the Anesthesiologist Should Know. J Cardiothorac Vasc Anesth. 2022;36:2669-2678. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 21] [Article Influence: 4.2] [Reference Citation Analysis (0)] |
| 16. | Mackie AS, Veldtman GR, Thorup L, Hjortdal VE, Dori Y. Plastic Bronchitis and Protein-Losing Enteropathy in the Fontan Patient: Evolving Understanding and Emerging Therapies. Can J Cardiol. 2022;38:988-1001. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 26] [Article Influence: 6.5] [Reference Citation Analysis (0)] |
| 17. | Brownell JN, Biko DM, Mamula P, Krishnamurthy G, Escobar F, Srinivasan A, Laje P, Piccoli DA, Pinto E, Smith CL, Dori Y. Dynamic Contrast Magnetic Resonance Lymphangiography Localizes Lymphatic Leak to the Duodenum in Protein-Losing Enteropathy. J Pediatr Gastroenterol Nutr. 2022;74:38-45. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 15] [Article Influence: 3.8] [Reference Citation Analysis (0)] |
| 18. | Lemley BA, Biko DM, Dewitt AG, Glatz AC, Goldberg DJ, Saravanan M, O'Byrne ML, Pinto E, Ravishankar C, Rome JJ, Smith CL, Dori Y. Intrahepatic Dynamic Contrast-Enhanced Magnetic Resonance Lymphangiography: Potential Imaging Signature for Protein-Losing Enteropathy in Congenital Heart Disease. J Am Heart Assoc. 2021;10:e021542. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 19] [Cited by in RCA: 24] [Article Influence: 4.8] [Reference Citation Analysis (0)] |
| 19. | Bode L, Salvestrini C, Park PW, Li JP, Esko JD, Yamaguchi Y, Murch S, Freeze HH. Heparan sulfate and syndecan-1 are essential in maintaining murine and human intestinal epithelial barrier function. J Clin Invest. 2008;118:229-238. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 105] [Cited by in RCA: 115] [Article Influence: 6.4] [Reference Citation Analysis (0)] |
| 20. | Westphal V, Murch S, Kim S, Srikrishna G, Winchester B, Day R, Freeze HH. Reduced heparan sulfate accumulation in enterocytes contributes to protein-losing enteropathy in a congenital disorder of glycosylation. Am J Pathol. 2000;157:1917-1925. [PubMed] [DOI] [Full Text] |
| 21. | Bode L, Eklund EA, Murch S, Freeze HH. Heparan sulfate depletion amplifies TNF-alpha-induced protein leakage in an in vitro model of protein-losing enteropathy. Am J Physiol Gastrointest Liver Physiol. 2005;288:G1015-G1023. [PubMed] [DOI] [Full Text] |
| 22. | Manning LN, Schumacher KR, Friedland-Little JM, Yu S, Lowery R, Goldstein BH, Charpie JR. Impact of Protein-Losing Enteropathy on Inflammatory Biomarkers and Vascular Dysfunction in Fontan Circulation. Am J Cardiol. 2021;155:128-134. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 2] [Cited by in RCA: 9] [Article Influence: 1.8] [Reference Citation Analysis (0)] |
| 23. | Blackstone MM, Mittal MK. The edematous toddler: a case of pediatric Ménétrier disease. Pediatr Emerg Care. 2008;24:682-684. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 23] [Cited by in RCA: 17] [Article Influence: 0.9] [Reference Citation Analysis (0)] |
| 24. | Ozen A, Lenardo MJ. Protein-Losing Enteropathy. N Engl J Med. 2023;389:733-748. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 60] [Cited by in RCA: 56] [Article Influence: 18.7] [Reference Citation Analysis (1)] |
| 25. | Chehade M, Magid MS, Mofidi S, Nowak-Wegrzyn A, Sampson HA, Sicherer SH. Allergic eosinophilic gastroenteritis with protein-losing enteropathy: intestinal pathology, clinical course, and long-term follow-up. J Pediatr Gastroenterol Nutr. 2006;42:516-521. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 97] [Cited by in RCA: 95] [Article Influence: 4.8] [Reference Citation Analysis (5)] |
| 26. | Schwartz LK, Semrad CE. Protein-Losing Gastroenteropathy. In: Talley NJ, Kane SV, Wallace MB, editors. Practical Gastroenterology and Hepatology: Small and Large Intestine and Pancreas. Hoboken: John Wiley & Sons, 2010. [DOI] [Full Text] |
| 27. | Seok JW, Kim S, Lee SH, Kim IJ, Kim YK. Protein-losing enteropathy detected on Tc-99m HSA and Tc-99m MDP scintigraphy. Clin Nucl Med. 2002;27:431-433. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 16] [Cited by in RCA: 14] [Article Influence: 0.6] [Reference Citation Analysis (0)] |
| 28. | Fritscher-Ravens A, Scherbakov P, Bufler P, Torroni F, Ruuska T, Nuutinen H, Thomson M, Tabbers M, Milla P. The feasibility of wireless capsule endoscopy in detecting small intestinal pathology in children under the age of 8 years: a multicentre European study. Gut. 2009;58:1467-1472. [RCA] [PubMed] [DOI] [Full Text] [Cited by in Crossref: 110] [Cited by in RCA: 84] [Article Influence: 4.9] [Reference Citation Analysis (4)] |
| 29. | Braamskamp MJ, Dolman KM, Tabbers MM. Clinical practice. Protein-losing enteropathy in children. Eur J Pediatr. 2010;169:1179-1185. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in Crossref: 95] [Cited by in RCA: 124] [Article Influence: 7.8] [Reference Citation Analysis (33)] |
| 30. | Goret N, Lambe C, Ecochard-Dugelay E, Fabre A, Dabadie A, Comte A, Rebeuh J, Poinsot P, Chaillou E, Clouzeau H, Sabard A, Dubern B, Willot S. Clinical presentation, treatment, and outcome of children with primary intestinal lymphangiectasia: A national retrospective study. J Pediatr Gastroenterol Nutr. 2026;82:398-406. [RCA] [PubMed] [DOI] [Full Text] [Full Text (PDF)] [Cited by in RCA: 1] [Reference Citation Analysis (0)] |