Fontan surgery failure: risk factors and experience in a Colombian reference centre.

BACKGROUND: The Fontan procedure is considered one of the most remarkable achievements in paediatric cardiology and cardiac surgery. Its final anatomical objective is a venous return through the superior and inferior vena cava. The complications inherent to this procedure and subsequent failure are its limitations. OBJECTIVE: To describe the clinical and haemodynamic characteristics of patients with Fontan failure and define the risk factors associated with it, with its short- and long-term outcomes during a 21-year observation period. METHODS: This is a retrospective follow-up study in which 15 patients diagnosed with Fontan failure in the single-ventricle programme of a high-complexity hospital in Medellín, Colombia, between 2001 and 2022 were included. RESULTS: One hundred and eight patients were identified in whom the Fontan procedure was performed, and 17 met the failure criteria. 82.4% were men, with a median age of 4.3 years. Ebstein's anomaly was the most common diagnosis, 29.4%. All patients underwent Fontan with an extracardiac tube following the procedure. According to the type of failure, 58.8% of patients presented protein-losing enteropathy and 17.6% plastic bronchitis. During follow-up, 5.9% of patients died. CONCLUSION: Fontan surgery in our centre is an option for patients with univentricular physiology. The correct selection of the patient is essential to mitigate failure risks.

Protein-losing enteropathy secondary to graft-versus-host disease.

Protein-losing enteropathy is a gastrointestinal complication of Graft versus host disease. The clinical presentation can be similar to that of multiple pathologies and represents a diagnostic challenge for clinicians. We report a 23-year-old man with a history of acute lymphoid leukemia that required allogeneic hematopoietic stem cell transplantation that came to evaluation due to anasarca. We report a 23-year-old man with a history of acute lymphoid leukemia who required allogeneic hematopoietic stem cell transplantation and came to evaluation due to anasarca.

Donor-specific antibodies after heart transplantation for Fontan-associated protein-losing enteropathy.

BACKGROUND: Despite ubiquitous exposure to sensitizing events, most Fontan PLE patients have low panel reactive antibodies (PRA). To assess whether they are at risk for donor-specific antibody (DSA) memory response following heart transplantation (HT) when their PLE resolves, DSA profiles, incidence of rejection, and graft outcomes in Fontan recipients with and without PLE were compared. METHODS: Patient characteristics, appearance of newly detected DSA (nDSA), and graft outcomes were compared between patients with and without PLE using Wilcoxon rank-sum and Chi-squared tests. DSA burden was quantified using titers and time to nDSA, incidence of rejection, and graft outcomes were compared using Kaplan-Meier curves and the log-rank test. RESULTS: Characteristics of patients with and without PLE were similar. Lymphocyte and albumin levels were lower in the PLE group, and flow PRA were comparable. Graft failure, CAV, and ACR were similar between the two groups, but AMR occurred more frequently in the PLE group (p = .03). Nearly 50% of PLE patients experienced class II nDSA by 1-year post-HT, compared to 30% of non-PLE patients, but this difference was statistically not significant. Antibody burden did not differ between groups. CONCLUSIONS: In this cohort, PLE was associated with AMR within the first-year post-HT, despite no significant difference in nDSA. Small patient numbers limited statistical comparison of nDSA in this cohort. PLE may be a risk factor for AMR post-HT, and the possibility of a clinically important DSA memory response remains. Larger studies are necessary to better understand these preliminary findings.

The Fontan immunophenotype and post-transplant outcomes in children: A multi-institutional study.

BACKGROUND: Patients after Fontan palliation represent a growing pediatric population requiring heart transplant (HTx) and often have lymphopenia (L) and/or hypogammaglobinemia that may be exacerbated by protein-losing enteropathy (PLE, P). The post-HTx effects of this altered immune phenotype are not well studied. METHODS: In this study of the Pediatric Heart Transplant Society Registry, 106 Fontan patients who underwent HTx between 2005 and 2018 were analyzed. The impact of lymphopenia and PLE on graft survival, infection, rejection, and malignancy was analyzed at 1 and 5 years post-HTx. RESULTS: The following combinations of lymphopenia and PLE were noted: +L+P, n = 37; +L-P, n = 23; -L+P, n = 10; and -L-P, n = 36. Graft survival between the groups was similar within the first year after transplant (+L+P: 86%, +L-P: 86%, -L+P: 87%, -L-P: 89%, p = .9). Freedom from first infection post-HTx was greatest among -L-P patients compared to patients with either PLE, lymphopenia, or both; with a 22.1% infection incidence in the -L-P group and 41.4% in all others. These patients had a significantly lower infection rate in the first year after HTx (+L+P: 1.03, +L-P: 1, -L+P: 1.3, -L-P: 0.3 infections/year, p < .001) and were similar to a non-single ventricle CHD control group (0.4 infections/year). Neither freedom from rejection nor freedom from malignancy 1 and 5 years post-HTx, differed among the groups. CONCLUSIONS: Fontan patients with altered immunophenotype, with lymphopenia and/or PLE, are at increased risk of infection post-HTx, although have similar early survival and freedom from rejection and malignancy. These data may encourage alternative immunosuppression strategies and enhanced monitoring for this growing subset of patients.

Polycythemia as an Uncommon Finding in 2 Children, One With Systemic Capillary Leak Syndrome and the Other With Protein-losing Enteropathy Caused by CD55 Deficiency.

We report 2 children with distinct causes of polycythemia, 1 from systemic capillary leak syndrome (SCLS) and the other from protein-losing enteropathy (PLE) caused by CD55 deficiency. There is only a single case series about polycythemia in children with SCLS, but none on polycythemia in children with PLE. We present a 10-year-old girl with hypoalbuminemia, polycythemia, and edema who died as a result of an SCLS attack and a 1-year-old girl with PLE who was successfully treated with eculizumab. Our experience suggests that hematologists should be alert for SCLS and PLE in children with relative polycythemia.

The prognostic role of liver volumetry in Fontan patients.

BACKGROUND AND HYPOTHESES: High venous pressures and associated hepatic congestion are important drivers for Fontan-associated liver disease. The prognostic significance of hepatomegaly as a marker of congestion however is not well defined and is further explored in this research study. METHODS: Fontan patients who have had liver ultrasound scans were identified from the Prince Sultan Cardiac Centre Fontan Database and had their anatomic, surgical, clinical histories abstracted from the electronic medical records following institutional ethics approval. Liver volumes were determined retrospectively from reviewing individual US images, and these, divided into tertiles, were analysed in the context of the predefined endpoints of (i) Primary - death or heart or liver transplantation, or (ii) Secondary - combined endpoint of death, transplantation, arrhythmia, or protein-losing enteropathy. RESULTS: Mean indexed liver volumes for the entire cohort (n = 199) were 1065.1 ± 312.1 ml/m2, range 387 to 2071 ml/m2. Patients with the largest liver volumes (highest tertile) were less likely to have a functioning fenestration compared to those in the lowest tertile 44% versus 56% p = 0.016 and experienced the highest burden of mortality and heart or heart-liver transplantation, p = 0.016, and were more likely to reach the composite endpoint of death, protein-losing enteropathy, arrhythmia, or transplantation, p = 0.010. Liver volumes had an overall predictive accuracy for the combined outcome of 61% (CI 53%, 67%, p = 0.009). CONCLUSIONS: Liver volumetry may serve as a potentially important congestion biomarker for adverse outcomes after the Fontan operation.

Protein-losing Enteropathy as a Complication and/or Differential Diagnosis of Common Variable Immunodeficiency.

As protein-losing enteropathy (PLE) can lead to hypogammaglobulinemia and lymphopenia, and since common variable immunodeficiency (CVID) is associated with digestive complications, we wondered if (1) PLE could occur during CVID and (2) specific features could help determine whether a patient with antibody deficiency has CVID, PLE, or both. Eligible patients were thus classified in 3 groups: CVID + PLE (n = 8), CVID-only (= 19), and PLE-only (n = 13). PLE was diagnosed using fecal clearance of α1-antitrypsin or 111In-labeled albumin. Immunoglobulin (Ig) A, G, and M, naive/memory B and T cell subsets were compared between each group. CVID + PLE patients had multiple causes of PLE: duodenal villous atrophy (5/8), nodular follicular hyperplasia (4/8), inflammatory bowel disease-like (4/8), portal hypertension (4/8), giardiasis (3/8), and pernicious anemia (1/8). Compared to the CVID-only group, CVID + PLE patients had similar serum Ig levels, B cell subset counts, but lower naive T cell proportion and IgG replacement efficiency index. Compared to the CVID-only group, PLE-only patients did not develop infections but had higher serum levels of IgG (p = 0.03), IgA (p < 0.0001), and switched memory B cells (p = 0.001); and decreased naive T cells (CD4+: p = 0.005; CD8+: p < 0.0001). Compared to the PLE-only group, CVID + PLE patients had higher infection rates (p = 0.0003), and lower serum Ig (especially IgA: p < 0.001) and switched memory B cells levels. In conclusion, PLE can occur during CVID and requires higher IgG replacement therapy dosage. PLE can also mimic CVID and is associated with milder immunological abnormalities, notably mildly decreased to normal serum IgA and switched memory B cell levels.

Contemporary Provider Management Practices and Attitudes Toward Referral for Advanced Heart Failure Therapies in Fontan Patients Across North America.

BACKGROUND: To date, no reports have described clinicians' management practices for patients with Fontan circulatory failure or their understanding of risk factors for mortality and transplant outcomes in these patients. METHODS AND RESULTS: A cross-sectional survey of caregivers across North America was conducted from February to September 2020. Responses were compared by primary specialty (heart failure/transplant vs non-heart failure/transplant), years of experience (early, mid, and late career), and Fontan center volume (low, medium, and high). Of 400 responses, the majority were from general cardiologists (111, 28%) followed by heart failure/transplant specialists (93, 23%). Although most agreed that patients with Fontan physiology will have signs/symptoms of heart failure (369 [93%]) and eventuate in heart transplant (286 [72%]), many disagreed (180 [45%]) that routine evaluation by a transplant cardiologist is needed without symptoms. Transplant providers were more likely than non-transplant providers to suggest referral for manifestations of Fontan circulatory failure such as protein-losing enteropathy, plastic bronchitis, liver fibrosis/cirrhosis, and worsening valve regurgitation. Non-transplant providers were more likely to suggest that protein-losing enteropathy, plastic bronchitis, and Fontan-associated liver disease lead to inferior outcomes after transplantation. Early career and transplant providers more favorably viewed ventricular assist device use for Fontan patients failing traditional heart failure therapy (P < .05 for all). CONCLUSIONS: There is significant variation in the management of Fontan patients, including heterogeneous timing of referral of such patients to the heart failure/transplant team, which may have implications for future outcomes.

Dynamic Contrast Magnetic Resonance Lymphangiography Localizes Lymphatic Leak to the Duodenum in Protein-Losing Enteropathy.

OBJECTIVES: Protein-losing enteropathy (PLE) is a disorder of intestinal lymphatic flow resulting in leakage of protein-rich lymph into the gut lumen. Our primary aim was to report the imaging findings of dynamic contrast magnetic resonance lymphangiography (DCMRL) in patients with PLE. Our secondary objective was to use these imaging findings to characterize lymphatic phenotypes. METHODS: Single-center retrospective cohort study of patients with PLE unrelated to single-ventricle circulation who underwent DCMRL. We report imaging findings of intranodal (IN), intrahepatic (IH), and intramesenteric (IM) access points for DCMRL. RESULTS: Nineteen patients 0.3-58 years of age (median 1.2 years) underwent 29 DCMRL studies. Primary intestinal lymphangiectasia (PIL) was the most common referring diagnosis (42%). Other etiologies included constrictive pericarditis, thoracic insufficiency syndrome, and genetic disorders. IN-DCMRL demonstrated a normal central lymphatic system in all patients with an intact thoracic duct and localized duodenal leak in one patient (1/19, 5%). IH-DCMRL detected a duodenal leak in 12 of 17 (71%), and IM-DCMRL detected duodenal leak in 5 of 6 (83%). Independent of etiology, lymphatic leak was only visualized in the duodenum. CONCLUSIONS: In patients with PLE, imaging via DCMRL reveals that leak is localized to the duodenum regardless of etiology. Comprehensive imaging evaluation with three access points can provide detailed information about the site of duodenal leak.

Protein-losing enteropathy recurrence after pediatric heart transplantation: Multicenter case series.

BACKGROUND: Protein-losing enteropathy (PLE) is a devastating complication of the Fontan circulation. Although orthotopic heart transplantation (HTx) typically results in resolution of PLE symptoms, isolated cases of PLE relapse have been described after HTx. METHODS: Patients with Fontan-related PLE who had undergone HTx at participating centers and experienced relapse of PLE during follow-up were retrospectively identified. Available data related to pre- and post-HTx characteristics and PLE events were collected. RESULTS: Eight patients from four different centers were identified. Median time from Fontan procedure to the development of PLE was 8 years, and median age at HTx was 17 years (range 7.7-21). In all patients, PLE resolved at a median time of 1 month after HTx (0.3-5). PLE recurrences occurred at a median time of 7.5 months after HTx (2-132). Each occurrence was associated with one or more significant clinical events; most commonly cellular- or antibody-mediated rejection; and less commonly graft dysfunction, infection, thrombosis, and posttransplant lymphoproliferative disease. PLE recurrences resolved after the successful treatment of the concomitant event, after a median time of 2 months in seven cases, while persisted and recurred in one patient in association with atypical mycobacterium infection and subsequent PTLD onset and relapses. Six patients were alive during follow-up at a median time of 4 years (1.3-22.5) after HTx. CONCLUSIONS: This is the largest series of PLE recurrence after HTx. All cases were associated with one or more concomitant and significant clinical events. PLE typically resolved after resolution of the inciting clinical event.

ANCA-associated vasculitis with protein-losing enteropathy is characterized by hypocomplementemia.

Protein-losing enteropathy (PLE) has been reported to be associated with various systemic autoimmune diseases. However, reports regarding PLE in ANCA-associated vasculitis (AAV) patients are limited. We herein aimed to describe the clinical characteristics of AAV with PLE. We conducted a retrospective chart review of patients who were diagnosed with AAV and who began treatment at the University of Tokyo Hospital between June 2003 and June 2020. Among 68 AAV patients, there were four patients (5.9%) with PLE, consisting of two patients with MPA, one patient with GPA, and one patient with EGPA. Clinical courses were described, and their data were compared with AAV patients without PLE. Demographic characteristics, disease activity, and the pattern of organ involvement were similar between patients with PLE and without PLE. Patients with PLE had hypocomplementemia more frequently than the patients without PLE (CH50 75.0% vs 1.8%, p < 0.001, C3 50.0% vs 1.8%, p = 0.01, C4 75.0% vs 3.5%, p = 0.001). Although hypoalbuminemia improved with immunosuppressive therapy for AAV, the improvement in hypoalbuminemia was slow in most cases. We also performed a systematic review on PLE associated with vasculitis. Thirteen reports were included, and Henoch-Schonlein Purpura patients with PLE also tended to have hypocomplementemia. In conclusion, PLE is a rare complication of AAV and complement system may associate with the mechanism of PLE.

Primary intestinal lymphangiectasia: a rare disease as a cause of protein-losing enteropathy.

Primary intestinal lymphangiectasia is a rare disorder associated with protein-losing enteropathy. The main manifestations are those resulting from hypoalbuminemia. Diagnosis requires the typical endoscopic image of intestinal lymphangiectasia and increased 24-hour fecal alpha-1-antitrypsin clearance. Treatment is basically dietary.

[CD5-positive diffuse large B-cell lymphoma with gastrointestinal infiltration presenting with protein-losing enteropathy].

Protein-losing enteropathy is rarely associated with malignant lymphoma. This report describes the case of a 67-year-old man with diffuse large B-cell lymphoma (DLBCL) and concomitant protein-losing enteropathy who was admitted to our hospital for evaluation of watery diarrhea, edema, and abdominal fullness. On admission, the patient reported a history of weight gain. Subsequent examination showed ascites, hepatosplenomegaly, and hypoalbuminemia. Notably, 99mTc-labeled human serum albumin scintigraphy revealed protein loss from the intestine, and the patient was diagnosed with protein-losing enteropathy. Endoscopy revealed erosive and edematous hyperplasia of the gastric-colonic mucosa, and histopathological evaluation of a biopsy specimen showed proliferation of CD20+ and CD5+ tumor cells. Thus, the diagnosis of DLBCL was histopathologically confirmed. Lymphomatous infiltration of the bone marrow was observed; however, no lymphadenopathy was detected. Based on these findings, the patient was diagnosed with protein-losing enteropathy associated with gastrointestinal infiltration of CD5+ DLBCL. Hypoalbuminemia and diarrhea improved following the initiation of R-CHOP regimen. The DLBCL showed a favorable response to treatment, and gastrointestinal lesions and hepatosplenomegaly improved, along with the resolution of protein-losing enteropathy.

Growth in Children with a Fontan Circulation.

OBJECTIVE: To evaluate growth in a population of patients with Fontan circulation. STUDY DESIGN: We performed a cross-sectional evaluation of patients followed in our multidisciplinary Fontan clinic from January 2011 through August 2015. We reviewed the historical data, anthropometry, clinical, and laboratory studies and performed bivariate and multivariate analysis of factors associated with height z score. RESULTS: Patients (n = 210) were included in the study at median age 11.07 years (8.3, 14.73 years) (43% female); 138 (65%) had a dominant right systemic ventricle and 92 (44%) hypoplastic left heart syndrome. Median age at completion of Fontan circulation was 31 months (7.6, 135.8 months). Median height z score was -0.58 (-1.75, 0.26). Twenty-five (12%) had current or past history of protein-losing enteropathy (PLE). Median height z score for those with current or past history of PLE was -2.1 (-2.46, 1.24). Multivariate analysis revealed positive associations between height z score and body mass index z score, time since Fontan, mid-parental height, dominant systemic ventricle type, and serum alkaline phosphatase. Height correlated negatively with known genetic syndrome, PLE, use of stimulant or oral steroid medication. CONCLUSIONS: Children with Fontan circulation have mild deficits in height, with greater deficits in those with PLE. Height z score improves with time postsurgery. Improving weight, leading to improved body mass index, may be a modifiable factor that improves growth in those who are underweight. Biochemical markers may be helpful screening tests for high-risk groups in whom to intensify interventions.

Abdominal Imaging of Children and Young Adults With Fontan Circulation: Pathophysiology and Surveillance.

OBJECTIVE. The Fontan procedure has significantly improved the survival in children with a functional single ventricle, but it is associated with chronically elevated systemic venous pressure that leads to multisystemic complications. Imaging plays an important role in assessing these complications and guiding management. The pathophysiology, imaging modalities, and current surveillance recommendations are discussed and illustrated. CONCLUSION. Significant improvement in survival of patients with Fontan circulation is associated with ongoing cardiac and extracardiac comorbidities and multisystemic complications. The liver and intestines are particularly vulnerable to damage. In addition, this patient population has been shown to be at increased risk of certain malignancies such as hepatocellular carcinoma and neuroendocrine tumors. Familiarity with imaging findings of Fontan-associated liver disease and other abdominal complications of the Fontan circulation is essential for radiologists because we are likely to encounter these patients in our general practice.

Primary intestinal lymphangiectasia presenting as limb hemihyperplasia: a case report and literature review.

BACKGROUND: Primary intestinal lymphangiectasia is an exceedingly rare disorder. Epidemiology is unknown. It usually presents with lower extremity swelling, diarrhea, ascites, and protein-losing enteropathy. Since the pathogenesis of edema is usually due to hypoalbuminemia; both extremities are typically involved. The edema can rarely be due to abnormal lymphatic circulation, causing lymphedema, which usually involves both extremities as well. Diagnosis is made by the constellation of clinical, biochemical, endoscopic, and histological findings. Treatment involves dietary modification, to reduce lymphatic dilation in response to dietary fat. Other pharmacologic (e.g., octreotide) and replacement measures may be indicated as well. The most serious long-term complication is intestinal lymphoma. Herein is a case of Primary intestinal lymphangiectasia presenting with unilateral lower limb swelling. CASE PRESENTATION: A 4-year-old boy presents with left foot swelling since the age of 4 months, in addition to intermittent diarrhea, and abdominal swelling. The foot swelling had been evaluated by different health care professionals in the past, and was mislabeled as either cellulitis, or congenital hemihyperplasia. Physical examination revealed mild ascites, and a non-pitting foot edema with a positive Stemmer's sign (lymphedema). Blood work revealed hypoalbuminemia (albumin 2 g/dl), and hypogammaglobulinemia. Endoscopy showed dilated lacteals throughout the duodenum. Histopathologic examination revealed massively dilated lamina propria lymphatics in the duodenal biopsies. The patient was diagnosed with primary intestinal lymphangiectasia. He was treated with high-protein and low-fat diet, and supplemental formula high in medium chain triglycerides. On follow-up, the patient's diarrhea completely resolved, and his ascites and edema improved significantly. CONCLUSIONS: The presence of unilateral lower limb edema should not preclude the diagnosis of systemic disorders, and a high index of suspicion is required in atypical presentations. A good knowledge about Primary intestinal lymphangiectasia manifestations, and physical examination skills to differentiate edema or lymphedema from tissue overgrowth can significantly aid in the diagnosis.

Novel Case Report: A Previously Reported, but Pathophysiologically Unexplained, Association Between Collagenous Colitis and Protein-Losing Enteropathy May Be Explained by an Undetected Link with Collagenous Duodenitis.

Collagenous colitis (CC) is associated with non-bloody, watery diarrhea, which is pathophysiologically reasonable because normal colonic absorption (or excretion) of water and electrolytes can be blocked by the abnormally thick collagen layer in CC. However, CC has also been associated with six previous cases of protein-losing enteropathy (PLE), with no pathophysiologic explanation. The colon does not normally absorb (or excrete) amino acids/proteins, which is primarily the function of the small bowel. Collagenous duodenitis (CD) has not been associated with PLE. This work reports a novel case of CD (and CC) associated with PLE; a pathophysiologically reasonable mechanism for CD causing PLE (by the thick collagen layer of CD blocking normal intestinal amino acid absorption); and a novel association of PLE with severe COVID-19 infection (attributed to relative immunosuppression from hypoproteinemia, hypoalbuminemia, hypogammaglobulinemia, and malnutrition from PLE).