Eficacia y seguridad de la fórmula nutricional con bajo contenido lipídico y alto contenido de triglicéridos de cadena media para el tratamiento de pacientes menores de 18 años con linfangiectasia intestinal primaria / Efficacy and safety of nutritional formula with low lipid content and high content of medium chain triglycerides for the treatment of patients under 18 years of age with primary intestinal lymphangiectasia

ANTECEDENTES: En el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, aprobada mediante Resolución de Institución de Evaluación de Tecnologías en Salud e Investigación N° 111-IETSI-ESSALUD-2021, se ha elaborado el presente dictamen, el que expone la evaluación de tecnología acerca de la eficacia y seguridad de la fórmula nutricional con bajo contenido lipídico y alto contenido de triglicéridos de cadena media (TCM) para el tratamiento de pacientes menores de 18 años con linfangiectasia intestinal primaria (LIP). Así, el Dr. Marco Morales Acosta, médico especialista en pediatría del Hospital Nacional Edgardo Rebagliati Martins perteneciente a la Red Prestacional Rebagliati, siguiendo la Directiva N° 003-IETSI-ESSALUD-2016, envía al Instituto de Evaluación de Tecnologías en Salud e Investigación - IETSI la solicitud de uso, por fuera del petitorio, del producto fórmula nutricional con bajo contenido lipídico y alto contenido de TCM. ASPECTOS GENERALES: La linfangiectasia intestinal primaria (LIP) es una condición causada por una deformidad congénita del sistema linfático del intestino delgado; la cual se caracteriza por la dilatación (local o difusa) de los vasos linfáticos de la mucosa y submucosa del intestino delgado (Suresh et al., 2009; Vignes & Bellanger, 2008; Waldmann et al., 1961). Esta dilatación de vasos linfáticos conduciría a la fuga de la linfa hacia el intestino delgado (enteropatía perdedora de proteínas); ocasionando hipoproteinemia, hipogammaglobulinemia, hipoalbuminemia, linfopenia; los que, a su vez, conducen a edema, pérdida de peso, entre otros (Abramowsky et al., 1989; Vignes & Bellanger, 2008). Aunque también se ha sugerido que el paso de la linfa hacia el lumen del intestino delgado podría deberse a una ruptura directa de los vasos linfáticos a través de la mucosa (Waldmann et al., 1961). La LIP es una enfermedad infrecuente que suele presentarse en menores de 3 años; aunque también se han reportado casos en la adultez (Freeman & Nimmo, 2011; Vignes & Bellanger, 2008). A la fecha, la prevalencia e incidencia mundial de LIP sigue siendo desconocida. En el Perú, solo se ha identificado un reporte de caso publicado en el año 2019 (Usnayo et al., 2019). Los médicos especialistas en pediatría del Servicio de Nutrición Pediátrica del Hospital Nacional Edgardo Rebagliati Martins reportan que en los últimos 10 años han atendido a tres pacientes con LIP. METODOLOGÍA: Se llevó a cabo una búsqueda bibliográfica exhaustiva con el objetivo de identificar la mejor evidencia sobre la eficacia y seguridad la fórmula nutricional con bajo contenido lipídico y alto contenido de TCM para el tratamiento de pacientes menores de 18 años con LIP. La búsqueda bibliográfica se realizó en las bases de datos PubMed, The Cochrane Library y LILACS. Asimismo, se realizó una búsqueda manual dentro de las páginas web pertenecientes a grupos que realizan evaluación de tecnologías sanitárias y guías de práctica clínica (GPC) incluyendo el National Institute for Health and Care Excellence (NICE), Canadian Agency for Drugs and Technologies in Health (CADTH), Scottish Medicines Consortium (SMC), Scottish Intercollegiate Guidelines Network (SIGN), Institute for Clinical and Economic Review (ICER), Instituto de Calidad y Eficiencia en la Atención de la Salud (IQWiG, por sus siglas en alemán), Agency for Healthcare Research and Quality (AHRQ), Guidelines International Network (GIN), National Health and Medical Research Council (NHMRC), Haute Autorité de Santé (HAS), International HTA Database, la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA), la Organización Mundial de la Salud (OMS), el Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI) y la Agencia de Evaluación de Tecnologías Sanitarias del País Vasco. Asimismo, se realizó una búsqueda de GPC de las principales sociedades o instituciones especializadas en enfermedades raras como la National Organization for Rare Disorders (NORD) y Orphanet. Finalmente, se realizó una búsqueda en la página web de registro de ensayos clínicos (EC) www.clinicaltrials.gov, para identificar EC en curso o que no hayan sido publicados aún. RESULTADOS: Luego de la búsqueda bibliográfica, realizada hasta el 25 de setiembre del 2021, se incluyeron tres estudios. El primero fue un estudio observacional que comparó tres dietas en pacientes con linfangiectasia intestinal (Aoyagi et al., 2005). El segundo fue un estudio observacional que realizó un análisis pre-post de una dieta alta en proteínas (1.5 ­ 3.0 g/Kg/día) y baja en lípidos (15 ­ 20 % del total de calorías); de los cuales el 60 % fueron TCM, en pacientes menores de 18 años con LIP (Prasad et al., 2019). El tercer estudio fue una revisión de evidencia científica en la cual se compararon los reportes de pacientes tratados con TCM y pacientes que recibieron otros tratamientos (Desai et al., 2009). Adicionalmente, se incluyó una ETS realizada por el Ministerio de Sanidad, Servicios Sociales e Igualdad de España (Güemes et al., 2013). CONCLUSIÓN: Por lo expuesto, el Instituto de Evaluación de Tecnologías en Salud e Investigación 9.~ aprueba el uso de la fórmula nutricional con bajo contenido lipídico (25 % del requerimiento calórico) y alto contenido de TCM (mayor o igual al 56 %) para el tratamiento de los pacientes con LIP, como producto farmacéutico no incluido en el Petitorio Farmacológico de EsSalud, según lo establecido en el Anexo N° 1. La vigencia del presente dictamen preliminar es de un año a partir de la fecha de publicación. Así, la continuación de dicha aprobación estará sujeta a la evaluación de los resultados obtenidos y de mayor evidencia que pueda surgir en el tiempo.

Linfangiectasia intestinal em adulto: relato de caso / Intestinal lymphangiectasia in an adult: case report

Resumo A linfangiectasia intestinal consiste em um grupo de doenças raras caracterizadas pela dilatação dos canais linfáticos. A fisiopatologia compreende a obstrução da drenagem linfática do intestino delgado com dilatação secundária dos vasos linfáticos mucosos, submucosos ou subserosos, que distorcem a arquitetura das vilosidades e conduzem à perda de linfa para a luz intestinal, levando à má absorção. Os vasos linfáticos afetados localizam-se primariamente no intestino delgado, que é atingido em extensão variável. A sua etiologia é ainda desconhecida. O relato a seguir apresenta um raro caso de linfangiectasia intestinal em paciente adulto.

Abstract Intestinal lymphangiectasia is a group of rare diseases characterized by dilation of lymphatic channels. Its pathophysiology comprises obstruction of small bowel lymphatic drainage with secondary dilation of mucosal, submucosal, or subserous lymphatic vessels, distorting villous architecture and causing loss of lymph into the intestinal lumen, leading to malabsorption. The affected lymphatic vessels are primarily located in the small intestine, which is affected to a varying extent. Its etiology is still unknown. The following report presents a rare case of intestinal lymphangiectasia in an adult patient.

Hennekam syndrome: an uncommon cause of chylous ascites and intestinal lymphangiectasia in the tropics.

Paediatric chylous ascites in tropics is commonly caused by infections and trauma. We describe the clinical characteristics of an uncommon inherited cause of chylous ascites, Hennekam syndrome, treated by nutritional modification.

Exacerbation of primary intestinal lymphangiectasia during late pregnancy and recovery after delivery: A case report and literature review.

RATIONALE: Primary intestinal lymphangiectasia (PIL) is a rare disease characterized by dilated intestinal lacteals resulting in lymph leakage into the small bowel lumen. Main clinical features include intermittent diarrhea, hypoproteinemia. Scattered case reports suggested that PIL is compatible to pregnancy, but with increased complications. PATIENT CONCERNS: A 34-year-old woman with endoscopically diagnosed PIL presented to antenatal our clinic at 10 weeks into gestation. She reported strict adherence to low-fat/high-protein diet with medium-chain triglycerides (MCTs) supplementation. She was general well except for moderate edema and hypoalbuminemia. At 33 weeks, she developed diarrhea, nausea, and vomiting, with decreased fetal movements. One week later, she had an asthma attack. Nonstress test showed frequent variable deceleration. DIAGNOSES: The diagnosis of PIL was established endoscopically 8 years earlier. INTERVENTIONS: Hypoalbuminemia was corrected with intravenous albumin administration. She also received corticosteroid therapy to promote fetal lung maturation in anticipation to early termination of the pregnancy. OUTCOMES: A cesarean section was carried out at 34 weeks due to fetal distress. The baby girl was apparently healthy: weighing 2160 g, with an Apgar score of 9 at both 1 and 5 minutes. Symptoms dissipated rapidly after the delivery. The last follow-up visit at 15 months was unremarkable for both the mother and infant. LESSONS: PIL could be compatible with pregnancy, but requires strict adherence to dietary treatment, proper management of the symptoms (e.g., hypoalbuminemia), particularly during late gestation.

Nutritional therapy and effect assessment of infants with primary intestinal lymphangiectasia: Case reports.

RATIONALE: Intestinal lymphangiectasia (IL) is a rare enteropathy involving the expansion and rupture of intestinal lymphatic channels. Although several reports have studied cases of primary IL (PIL), this condition is very rare, and is even less commonly encountered in infants. This study aimed to investigate the nutritional therapy and effect assessment of chylous reflux disorder caused by PIL in infants. PATIENT CONCERNS: Infantile patients were enrolled in the Affiliated Beijing Shijitan Hospital of the Capital Medical University between January 2012 and March 2014. The minimum age of onset was 4 months and the maximum age of onset was 16 months, with an average age of 4.9 months. DIAGNOSES: All children were inpatient who had been diagnosed with chylous reflux syndrome (chylothorax and/or chylic abdomen) caused by PIL. INTERVENTIONS: Retrospective analysis and individualized nutrition therapy of these cases were carried out. Finally, nutritional therapy and prognosis of PIL were assessed and summarized. OUTCOMES: All the children survived, showed improvement in the serum total protein, albumin, and HGB levels after nutritional therapy. After comprehensive nutritional therapy, we were able to achieve diarrhea control for all the 9 patients, and after treatment, the children passed soft, yellow stools 1 to 2 times/d. After treatment, the height and weight of all patients increased to within the normal ranges of the World Health Organization standard chart. The mean serum albumin level reached 41.3 g/L. All nutrition-related indicators were found to have significant improvement compared with the baseline levels. LESSONS: The results revealed that nutritional therapy for the 9 children with PIL was effective, and it may be able to improve the clinical syndromes and symptoms of children with PIL and promote recovery.

Primary Intestinal Lymphangiectasia Manifested as Unusual Edemas and Effusions: A Case Report.

Primary intestinal lymphangiectasia (PIL) is a rare disorder of unknown etiology characterized by diffuse or localized dilation and eventual rupture of the enteric lymphatic vessels in mucosa, submucosa, and/or subserosa. Lymph, rich in all kinds of proteins and lymphocytes, leaks into the gastrointestinal tract via the affected lymphatic vessels causing hypoproteinemia and lymphopenia. The main symptom is variable degrees of pitting edemas of bilateral lower limbs. But edemas of any other parts of body, and mild serous effusions may also occur sometimes. PIL occurs in conjunction with a right hemifacial edema, a right upper limb lymphedema, asymmetric bilateral calves edemas, and a unilateral massive pleural effusion seems never to be reported before. In addition, increased enteric protein loss that may cause severe hypoproteinemia usually get overlooked, and the lymphatic system disorders always put the diagnoses in a dilemma.We described a case of a 17-year-old Chinese girl with a history of gradually progressive swellings of right-sided face, right upper limb, and bilateral calves since 3 to 4 months of age. A right-sided massive pleural effusion, a moderate pericardial effusion, and a mild ascites have been proved unchanged by a series of computerized tomography (CT) scans since 5 years ago. The diagnosis of PIL was finally confirmed by severe hypoproteinemia, endoscopic changes, and histology of jejunum biopsy. Further lymphoscintigraphy and lymphangiography also identified lymph leakage in her bowel and several abnormal lymphatic vessels. A high-protein, low-fat diet supplemented with medium-chain triglycerides (MCT) showed some benefit.This case suggested that PIL was a rare but important etiology of hypoproteinemia, effusions, and edemas. PIL, effusions, and lymphedema can be the features of multisegmental generalized lymphatic dysplasia. In addition, both lymphoscintigraphy and intranodal lymphangiography could be considered when lymphatic system disorders are suspected.

Intestinal lymphangiectasia in children. A favorable response to dietary modifications.

Intestinal lymphangiectasia (IL) is a rare disease characterized by dilatation of intestinal lymphatics. It can be classified as primary or secondary according to the underlying etiology. The clinical presentations of IL are pitting edema, chylous ascites, pleural effusion, acute appendicitis, diarrhea, lymphocytopenia, malabsorption, and intestinal obstruction. The diagnosis is made by intestinal endoscopy and biopsies. Dietary modification is the mainstay in the management of IL with a variable response. Here we report 2 patients with IL in Bahrain who showed positive response to dietary modification.

Everolimus for Primary Intestinal Lymphangiectasia With Protein-Losing Enteropathy.

Primary intestinal lymphangiectasia (PIL), also known as Waldmann's disease, is an exudative enteropathy resulting from morphologic abnormalities in the intestinal lymphatics. In this article, we describe a 12-year-old boy with PIL that led to protein-losing enteropathy characterized by diarrhea, hypoalbuminemia associated with edema (serum albumin level: 1.0 g/dL), and hypogammaglobulinemia (serum IgG level: 144 mg/dL). Severe hypoalbuminemia, electrolyte abnormalities, and tetany persisted despite a low-fat diet and propranolol. Everolimus (1.6 mg/m(2)/day) was added to his treatment as an antiangiogenic agent. With everolimus treatment, the patient's diarrhea resolved and replacement therapy for hypoproteinemia was less frequent. Hematologic and scintigraphy findings also improved (serum albumin level: 2.5 g/dL). There were no adverse reactions during the 12-month follow-up. To the best of our knowledge, this is the first report of everolimus use in a patient with PIL.

Primary intestinal lymphangiectasia with generalized warts.

Primary intestinal lymphangiectasia (PIL) is a rare protein-losing enteropathy with lymphatic leakage into the small intestine. Dilated lymphatics in the small intestinal wall and mesentery are observed in this disease. Laboratory tests of PIL patients revealed hypoalbuminemia, lymphocytopenia, hypogammaglobulinemia and increased stool α-1 antitrypsin clearance. Cell-mediated immunodeficiency is also present in PIL patients because of loss of lymphocytes. As a result, the patients are vulnerable to chronic viral infection and lymphoma. However, cases of PIL with chronic viral infection, such as human papilloma virus-induced warts, are rarely reported. We report a rare case of PIL with generalized warts in a 36-year-old male patient. PIL was diagnosed by capsule endoscopy and colonoscopic biopsy with histological tissue confirmation. Generalized warts were observed on the head, chest, abdomen, back, anus, and upper and lower extremities, including the hands and feet of the patient.

[Protein-losing enteropathy due to intestinal lymphangiectasis: a rare disease. Report of two cases]. / Enteropatía perdedora de proteínas por linfangiectasia intestinal: una enfermedad rara. Presentación de 2 casos.

Congenital intestinal lymphangiectasis (LIP) is a protein-losing enteropathy that appears sporadically in children. It begins with edema due to hypoproteinemia and hypoalbuminemia, and in some cases with ascites, immunodeficience and hypocalcemic tetania. The purpose of this report is to present two patients with LIP which appeared during the first year of life. The diagnosis was certificated by upper gastrointestinal videoendoscopy and histological findings. Both patients were treated with a new formula containing mean chain triglycerides with an adequate response, not obtained before with a common semielemental formula.

The clinical efficacy of dietary fat restriction in treatment of dogs with intestinal lymphangiectasia.

BACKGROUND: Intestinal lymphangiectasia (IL), a type of protein-losing enteropathy (PLE), is a dilatation of lymphatic vessels within the gastrointestinal tract. Dietary fat restriction previously has been proposed as an effective treatment for dogs with PLE, but limited objective clinical data are available on the efficacy of this treatment. HYPOTHESIS/OBJECTIVES: To investigate the clinical efficacy of dietary fat restriction in dogs with IL that were unresponsive to prednisolone treatment or showed relapse of clinical signs and hypoalbuminemia when the prednisolone dosage was decreased. ANIMALS: Twenty-four dogs with IL. METHODS: Retrospective study. Body weight, clinical activity score, and hematologic and biochemical variables were compared before and 1 and 2 months after treatment. Furthermore, the data were compared between the group fed only an ultra low-fat (ULF) diet and the group fed ULF and a low-fat (LF) diet. RESULTS: Nineteen of 24 (79%) dogs responded satisfactorily to dietary fat restriction, and the prednisolone dosage could be decreased. Clinical activity score was significantly decreased after dietary treatment compared with before treatment. In addition, albumin (ALB), total protein (TP), and blood urea nitrogen (BUN) concentration were significantly increased after dietary fat restriction. At 2 months posttreatment, the ALB concentrations in the ULF group were significantly higher than that of the ULF + LF group. CONCLUSIONS AND CLINICAL IMPORTANCE: Dietary fat restriction appears to be an effective treatment in dogs with IL that are unresponsive to prednisolone treatment or that have recurrent clinical signs and hypoalbuminemia when the dosage of prednisolone is decreased.