Protein Losing Enteropathy After Fontan Operation: Glimpses of Clarity Through the Lifting Fog.

Fontan-associated protein losing enteropathy is a challenge to treat and is a major contributor to morbidity and mortality in patients with palliated single ventricle. Numerous strategies for management have been proposed, with confusion as to how best to stratify and implement care among the many treatments available. Medical management can be helpful in some, while novel lymphatic interventions hold potential for remission with good results. We review our institutional approach to protein losing enteropathy after Fontan operation and provide a suggested algorithm and pathway for effective care.

Proposal for Prevention or Alleviation of Protein/Lymph-Losing Enteropathy (PLE/LLE) After Fontan Circulation Treatment of Univentricular Hearts: Restoration of Lymph Balance With a "Lymphatic Right-to-Left Shunt."

In Fontan circulations created for univentricular hearts, systemic venous return is diverted to the lungs before returning to the heart. The Total Cavopulmonary Connection (TCPC) is often the preferred surgical procedure whereby a 4-way anastomosis is created with inflow from the superior vena cava (SVC) and inferior vena cava (IVC) and outflow to the right and left branches of the pulmonary artery. In this arrangement, the systemic venous pressure must be elevated sufficiently to perfuse the lungs passively without the normal boost of the right ventricle. Hence, unlike surgical corrections for other congenital heart conditions, the systemic venous pressures in a Fontan circuit must be elevated to make the circulation work. It is proposed here that the incidence of PLE/LLE is directly related to elevated venous and lymphatic pressures, which cause leakage of proteins/lymph into the gastrointestinal tract (GIT) and expulsion from the body. It is commonly held that elevated venous pressures are relatively better tolerated in the upper body, but much less so in the heptatosplanchnic circulation and the lower body. It is also well established that elevated venous pressure increases lymph formation, most of which is produced in the hepatosplanchnic region (liver and intestine). It is further argued here that the increase in lymph filling pressure arising from the higher lymph flow, in association with the backpressure exerted by elevated venous pressure at the main drainage point into the venous system, results in a substantial increase in pressure in the thoracic duct. This pressure is transmitted back to the intestinal lymphatics, causing dilatation with lacteal rupture and protein or bulk lymph leakage into the intestine. We propose in this paper a new approach, based on experimental evidence, to prevent and/or alleviate this condition by draining or redirecting the thoracic duct (or, alternatively, a more localized intestinal lymphatic vessel) into one of the pulmonary veins or the left atrium, which are typically at near-normal pressure in a Fontan circulation. This "lymphatic-venous right-to-left" shunt maneuver would significantly reduce the venous backpressure on the lymphatics as well as improve lymph circulation, resulting in a decrease in the intestinal lymphatic pressure and thereby prevent or alleviate protein/lymph loss, i.e. lymph balance would be restored. Moreover, the greatly facilitated lymphatic flow would encourage further capillary filtration to relieve excessive venous pressure in the hepatosplanchnic region and protect the liver and kidneys. This paper is intended as a discussion document for elicitation of comments on the soundness and viability of this proposal as well as on technical challenges and steps to explore and advance it.

The Fontan operation: the long-term outlook.

PURPOSE OF REVIEW: As perioperative survival following the Fontan procedure has improved and more patients are reaping the benefits of physiologic palliation, the costs of longstanding systemic venous hypertension and the functional limitations of a single ventricle are becoming clearer. Arrhythmias, heart failure, protein-losing enteropathy, hepatic cirrhosis, pulmonary hypertension, and ventricular dysfunction are common in late survivors and result in significant morbidity and mortality. Current research is focused on characterizing late morbidities and developing risk-prediction models for worse outcomes in long-term survivors. RECENT FINDINGS: Ten-year survival following the Fontan procedure is now 94-98%; however, estimated conditional survival in survivors aged above 18 years is 60% at 40 years of age. Atrial arrhythmias and heart failure are the leading causes of morbidity and mortality. Hypoplastic left heart syndrome, hepatic dysfunction, decreased exercise tolerance, lower quality of life, and markers of neurohormonal activation have been associated with worse outcome. Improvements in exercise tolerance are seen with selective pulmonary vasodilator therapy and exercise training. Heart transplant continues to be an effective therapy for end-stage Fontan failure, and reports of the use of traditional mechanical assist devices and the development of right heart assist devices in the setting of passive venous flow are ongoing. SUMMARY: Over a generation has passed since the Fontan procedure revolutionized the care of patients with a single ventricle. Data generated from retrospective and prospective observational studies in long-term survivors are identifying patients at risk.

Enteropatía perdedora de proteínas en pacientes con corazón univentricular / Protein-losing enteropathy found in patients with univentricular heart

Introducción: la enteropatía perdedora de proteínas puede aparecer en la evolución de los pacientes con corazón univentricular que sobreviven a la derivación cavopulmonar total. Una vez que se diagnostica, la mortalidad es alta. Objetivo: identificar los posibles factores de riesgo de esta complicación. Métodos: se realizó un estudio de cohorte prospectivo de la evolución en 74 pacientes con derivación cavopulmonar total, intervenidos en el Cardiocentro Pediátrico William Soler, desde enero de 1992 hasta enero de 2011. Resultados: el tiempo promedio de evolución fue de 8 años. Sufrió enteropatía perdedora de proteínas 8,1 por ciento de los pacientes. Se presentó con mayor frecuencia en los operados con la técnica intratrial, en los operados con más de 6 años de edad, y en quienes sufrieron derrames pleurales persistentes en el posoperatorio inmediato. Se encontró relación significativa entre la enteropatía y la disfunción ventricular posoperatoria, con RR= 11,45 (IC: 95 por ciento: 2,37 a 55,16). El análisis multivariado identificó a la disfunción ventricular como factor de riesgo. Conclusión: la detección de disfunción ventricular en la evolución del paciente con derivación cavopulmonar debe orientar el tratamiento, en aras de evitar la aparición de enteropatía perdedora de proteínas(AU)

Introduction: protein-losing enteropathy may occur in the progression of patients with univentricular heart, who survived total cavopulmonary shunt. Once diagnosed, the mortality rate of the condition is high. Objective: to identify the possible risk factor of this complication. Methods: a prospective cohort study of the progression of 74 patients with total cavopulmonary shunt was conducted from January 1992 through January 2011. They had been operated on at William Soler pediatric cardiac center. Results: the average time of progression was 8 years. In this group, 8.1 percent of patients suffered protein-losing enteropathy that was more frequently seen in patients operated on by the intraatrial technique, aged over 6 years and in those suffering persistent pleural effusion in the immediate postoperative period. Significant statistical relation was found between enteropathy and postoperative ventricular dysfunction with RR= 11.45 (CI: 95 percent: 2.37 to 55.16). The multivariate analysis showed that the ventricular dysfunction was a risk factor. Conclusions: Detection of the ventricular dysfunction in the progression of a patient with cavopulmonary shunt should guide the treatment to avoid occurrence of protein-losing enteropathy(AU)

Enteropatía perdedora de proteínas en pacientes con corazón univentricular / Protein-losing enteropathy found in patients with univentricular heart

INTRODU: la enteropatía perdedora de proteínas puede aparecer en la evolución de los pacientes con corazón univentricular que sobreviven a la derivación cavopulmonar total. Una vez que se diagnostica, la mortalidad es alta. OBJETIVO: identificar los posibles factores de riesgo de esta complicación. MÉTODOS: se realizó un estudio de cohorte prospectivo de la evolución en 74 pacientes con derivación cavopulmonar total, intervenidos en el Cardiocentro Pediátrico "William Soler", desde enero de 1992 hasta enero de 2011. RESULTADOS: el tiempo promedio de evolución fue de 8 años. Sufrió enteropatía perdedora de proteínas 8,1 % de los pacientes. Se presentó con mayor frecuencia en los operados con la técnica intratrial, en los operados con más de 6 años de edad, y en quienes sufrieron derrames pleurales persistentes en el posoperatorio inmediato. Se encontró relación significativa entre la enteropatía y la disfunción ventricular posoperatoria, con RR= 11,45 (IC: 95 %: 2,37 a 55,16). El análisis multivariado identificó a la disfunción ventricular como factor de riesgo. CONCLUSIÓN: la detección de disfunción ventricular en la evolución del paciente con derivación cavopulmonar debe orientar el tratamiento, en aras de evitar la aparición de enteropatía perdedora de proteínas.

INTRODUCTION: protein-losing enteropathy may occur in the progression of patients with univentricular heart, who survived total cavopulmonary shunt. Once diagnosed, the mortality rate of the condition is high. ONJECTIVE: to identify the possible risk factor of this complication. METHODS: a prospective cohort study of the progression of 74 patients with total cavopulmonary shunt was conducted from January 1992 through January 2011. They had been operated on at "William Soler" pediatric cardiac center. RESULTS: the average time of progression was 8 years. In this group, 8.1 % of patients suffered protein-losing enteropathy that was more frequently seen in patients operated on by the intraatrial technique, aged over 6 years and in those suffering persistent pleural effusion in the immediate postoperative period. Significant statistical relation was found between enteropathy and postoperative ventricular dysfunction with RR= 11.45 (CI: 95 %: 2.37 to 55.16). The multivariate analysis showed that the ventricular dysfunction was a risk factor. CONCLUSIONS: Detection of the ventricular dysfunction in the progression of a patient with cavopulmonary shunt should guide the treatment to avoid occurrence of protein-losing enteropathy.

MALT lymphoma of the small bowel with protein-losing enteropathy.

Mucosa-associated lymphoid tissue (MALT) lymphoma usually arises from chronic inflammation. We herein report a case of small intestinal MALT lymphoma with protein-losing enteropathy (PLE). A 73-year-old woman presented with lower leg edema and severe hypoalbuminemia. She had a medical history of pylorus-preserving pancreaticoduodenectomy with Billroth II reconstruction. Oral and anal route double-balloon enteroscopies revealed irregular nodular mucosal lesions with erosion extending from the jejunum to terminal ileum. Histopathological evaluation of the biopsied mucosa showed proliferation of small-to-medium-sized lambda light chain-restricted B cells. Plasmacytic differentiation and lymphoepithelial lesions were present, leading to the diagnosis of MALT lymphoma. Tc-99m albumin scintigraphy indicated tracer exudation in the small bowel, suggesting the presence of PLE. Combination immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen improved both MALT lymphoma and PLE, whereas rituximab monotherapy was not successful. This case is considered to be common type of MALT lymphoma at an uncommon site and is distinct from immunoproliferative small intestinal disease (IPSID). To our knowledge, this is the first case of non-IPSID-type small intestinal MALT lymphoma complicated by PLE. Gastrointestinal reconstruction may be responsible for underlying chronic inflammation via small intestinal bacterial overgrowth.

Octreotide in Hennekam syndrome-associated intestinal lymphangiectasia.

A number of disorders have been described to cause protein losing enteropathy (PLE) in children. Primary intestinal lymphangiectasia (PIL) is one mechanism leading to PLE. Few syndromes are associated with PIL; Hennekam syndrome (HS) is one of them. The principal treatment for PIL is a high protein, low fat diet with medium chain triglycerides supplementation. Supportive therapy includes albumin infusion. Few publications have supported the use of octreotide to diminish protein loss and minimize hypoalbuminemia seen in PIL. There are no publications on the treatment of PIL with octreotide in patients with HS. We report two children with HS and PLE in which we used octreotide to decrease intestinal protein loss. In one patient, octreotide increased serum albumin to an acceptable level without further need for albumin infusions. The other patient responded more dramatically with near normal serum albumin levels and cessation of albumin infusions. In achieving a good response to octreotide in both patients, we add to the publications supporting the use of octreotide in PIL and suggest that octreotide should be tried in patients with PIL secondary to HS. To the best of our knowledge, this is the first case report on the use of octreotide in HS-associated PIL.

[Protein-losing enteropathy: a cause of hypoalbuminaemia in patients with systemic lupus erythematosus]. / Enteraler Proteinverlust als Ursache einer schweren Hypoalbuminämie bei systemischem Lupus erythematodes.

Lupus nephritis is the most common cause of extended edema and hypoalbuminemia in patients with systemic lupus erythematosus (SLE). However, the same immune complex mechanisms which lead to renal protein loss can also be active in the gastrointestinal tract, resulting in severe hypoproteinemia through enteral protein loss. The case of a young female patient with otherwise mild SLE and severe hypoproteinemia through bowel manifestation of the disease is presented here. No gastrointestinal symptoms such as diarrhoea were present, but immunohistology of the smaller and larger bowel showed severe immunocomplex disease with focus on the submucosa and the basal membrane. Other causes of hypoproteinemia were excluded. Treatment with prednisolone and azathioprine led to fast and durable resolution of symptoms.

Protein-losing enteropathy: integrating a new disease paradigm into recommendations for prevention and treatment.

Protein-losing enteropathy is a relatively uncommon complication of Fontan procedures for palliation of complex congenital cardiac disease. However, the relative infrequency of protein-losing enteropathy belies the tremendous medical, psychosocial and financial burdens it places upon afflicted patients, their families and the healthcare system that supports them. Unfortunately, because of the complexity and rarity of this disease process, the pathogenesis and pathophysiology of protein-losing enteropathy remain poorly understood, and attempts at treatment seldom yield long-term success. The most comprehensive analyses of protein-losing enteropathy in this patient population are now over a decade old, and re-evaluation of the prevalence and progress in treatment of this disease is needed. This report describes a single institution experience with the evaluation, management, and treatment of protein-losing enteropathy in patients with congenital cardiac disease in the current era, follows with a comprehensive review of protein-losing enteropathy, focused upon what is known and not known about the pathophysiology of protein-losing enteropathy in this patient population, and concludes with suggestions for prevention and treatment.

Late surgical fenestration for complications after the Fontan operation.

BACKGROUND: Significant morbidity after Fontan operation results in either takedown, heart transplantation, or death. Initial creation of a fenestration results in less morbidity and mortality; however, the role of late creation of a fenestration in aiding patients manifesting morbidity after an initial nonfenestrated Fontan operation is unclear. METHODS AND RESULTS: We reviewed our experience with late creation of a surgical fenestration in 9 patients (5.2 +/- 3.1 years old) exhibiting chronic effusions (n = 4) or protein-losing enteropathy (PLE) (n = 5) after lateral tunnel-type Fontan operation. Patients with effusions had creation via coronary punch of two or three 3-mm defects; patients with PLE had creation of a large, 5-mm defect. One child with effusions and multisystem organ failure before fenestration died 7 weeks after surgery secondary to low cardiac output; the other 3 had resolution of effusions within 4 to 6 weeks. Of the 5 with PLE, 3 had normalization of serum proteins and resolution of symptoms at 2 to 6 weeks. The 2 failures had arterial saturations > 89% after surgery. Follow-up was from 25 to 30 months. Spontaneous closure of defects occurred in all 3 with effusions. No return of symptoms was noted in 2; however, the third reaccumulated effusions and has undergone refenestration with a large defect. All 3 patients with PLE have remained asymptomatic with patency of the fenestration (4 to 5 mm on echocardiography) and arterial saturation < or = 85% for > 2 years. CONCLUSIONS: Late surgical creation of fenestration results in resolution of morbidity after Fontan operation. Improvement is related to the degree of right-to-left shunt created.

Pharmacological protection of NSAID-induced intestinal permeability in the rat: effect of tempo and metronidazole as potential free radical scavengers.

Recently, NSAID-induced changes in both the structure and function of the distal intestine have been found to occur more frequently and with greater toxicological significance than previously thought. We have previously validated a suitable animal model to evaluate intestinal permeability changes using orally administered 51Cr-EDTA that correlates with intestinal ulceration. In this study we investigated the suitability of metronidazole and the nitroxide stable free radical scavenger (tempo) as protective agents against NSAID-induced intestinal permeability. Male Sprague-Dawley rats were dosed with two doses of metronidazole (50 mg/kg, 12 and 1 h pre-NSAID) or a single 100 mg/kg dose of tempo 1 h prior to NSAIDs. The urinary excretion of the orally administered marker 51Cr-EDTA was measured. Both tempo and metronidazole dramatically reduced indomethacin (20 mg/kg) and flurbiprofen (10 mg/kg)-induced intestinal permeability. All the animals exposed to indomethacin alone died within 48-96 h and presented with histological evidence of drug-induced enteropathy, ulceration and frank peritonitis. Protection by tempo and metronidazole suggests that free radicals and/or bacteria may be important mediators in the pathogenesis of intestinal mucosal damage induced by NSAIDs. Nitric oxide donor compounds used concomitantly with NSAIDs may protect gastrointestinal tract.

The steatocrit test as a guide in the prevention of cow's-milk enteropathy following acute infectious enteritis.

This study was designed to evaluate the following in infants with acute enteritis (AE): the influence of different types of milk on the evolution of the acute phase of the diarrhea and whether the degree of steatorrhea during the acute phase might be a risk factor for developing cow's milk enteropathy (CME). We studied 90 infants with AE, divided into three groups and refed differently after the acute episode: group A was refed using a semielemental formula; group B was refed using a milk containing soy proteins and vegetable oils; and group C was refed using a common cow's-milk formula. Patients with pathological steatocrit values on hospitalization were randomly assigned to groups A and B; patients with normal steatocrit values were placed in group C. After 4 weeks, the patients included in groups A and B were challenged with cow's milk and their reactions were recorded. During the acute phase of the disease, we noticed a longer persistence of diarrhea in group A than in groups B (p less than 0.01) and C (p less than 0.0025). In addition, the number of evacuations per day and steatocrit values were higher in group A than in groups B or C, but these differences were not statistically significant. After 4 weeks, the patients in groups A and B were challenged with cow's milk, and eight of 60 patients had positive reactions; intestinal biopsy confirmed the diagnosis of CME. The mean age of these eight patients was 40.3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

New surgical method to prevent pelvic radiation enteropathy.

Pelvic radiation doses exceeding 4,000-4,500 cGy are known to be associated with acute and chronic radiation enteropathy. This same radiation dose is, at the same time, only moderately effective in the elimination of microscopic malignancy, let alone gross clinical disease. Numerous medical and surgical attempts to minimize this complication have been uniformly unsuccessful. With the availability of a new synthetic, absorbable, polyglycolic acid mesh, an intestinal sling surgical procedure has been devised to exclude the small bowel from the pelvis and subsequent radiation fields. Twenty-five patients have been treated by this new technique with only one complication presenting as a fungal infection. Small-bowel barium contrast studies in 16 patients referred for postoperative radiation demonstrated 13 satisfactory exclusions of the small bowel from the translateral pelvic irradiation field. In 16 evaluable patients, three had unsatisfactory exclusion two of which were due to technical error. This has permitted high-dose (5,500-6,500 cGy) radiotherapy to the critical treatment volume without posttreatment complication. Mean follow-up time is 14.8 months. Several patients have been reexplored demonstrating complete absorption of the mesh without fibrinous adhesions or other foreign body reaction. It is concluded that this new technique of small bowel exclusion will permit the routine delivery of much higher doses of radiation in patients requiring improved local-regional control of their pelvic cancers and without morbidity from radiation-associated small bowel injury.

Is faecal alpha 1-antitrypsin excretion a reliable screening test for protein-losing enteropathy?

Estimation of alpha 1-antitrypsin in random faecal samples has been suggested as a reliable index of intestinal protein loss. There was a poor correlation between faecal alpha 1-antitrypsin concentrations and simultaneously measured faecal loss of 51Cr-albumin in twenty adults with suspected protein-losing enteropathy. This indicates that faecal alpha 1-antitrypsin estimation may not be a valid screening test for protein-losing enteropathy.

Prevention and suppression by azathioprine of venom-induced protein-losing gastropathy in dogs.

Irrigation of the dog's oxyntic glandular mucosa contained in a chronically prepared, vagally denervated, separated pouch of the dog's stomach with a solution (0.5 mg ml-1) of lyophilized venom of the hooded cobra (Naja naja) increases the permeability of the mucosa. If irrigation with venom solution is repeated at weekly intervals, the mucosa responds with increasing plasma-shedding which reaches a peak of 1-2 ml min-1 from roughly 60 cm2 of mucosa in 4-6 weeks. Plasma shedding in response to irrigation with venom gradually declines, leaving a permanent residual response of different magnitude in different dogs. Giving naive dogs the immunosuppressant azathioprine by mouth in a dose of 5 mg kg-1 day-1, beginning 1 week before the first irrigation with venom solution and continuing for 4 weeks, postpones the plasma-shedding response until the sixth or seventh week of venom irrigation. The plasma-shedding response is wholly or partially suppressed by further administration of azathioprine by mouth in a dose of 3.3 mg kg-1 day-1. These data support the hypothesis that the plasma-shedding response to repeated venom irrigation involves the immune system of the stomach.