DOI: https://doi.org/10.22516/25007440.180 Review articles Colombian Guidelines for Diagnosis of Lipase Acid Deficiency Alfredo Santamaría Escobar,1 Carolina Baquero Montoya,2 Roberto García Bermejo,3 Adriana María Jaramillo Villegas,4 Armando Barrios,5 Mauricio Coll Barrios,6 Rodrigo de Vivero Camacho,7 Rocío del Pilar López Panqueva,8 William Márquez,9 Diana Victoria Mora Quintero,10 Omar Pérez Álvarez,11 Carolina Rivera Nieto,12 Evelyn Simancas Escalante,13 Giomar Sarmiento Marengo,14 Luis Carlos Ramírez Urrego,15 Patricia Ruiz Navas,16 Claudia Sánchez Franco,17 David Alfonso Suárez Zamora,18 Verónica Botero.19 1 Hospital Universitario San Vicente Fundación in Abstract Medellín, Colombia 2 Hospital Pablo Tobón Uribe in Medellín, Colombia Introduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads 3 Hospital Infantil Napoleón Franco Pareja, Universidad to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of del Sinú in Cartagena, Colombia onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical ma- 4 Clínicas Las Américas in Medellín, Antioquia, Colombia nifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes 5 Pediatric Gastroenterology Unit of Cesar in it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians Valledupar, Colombia recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was 6 Centro Médico Almirante Colón in Bogotá, Colombia 7 Pediatric Departament of the Hospital Infantil designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and Napoleón Franco Pareja and the Universidad de pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was Cartagena in Cartagena, Colombia conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate 8 Hospital Universitario Fundación Santa Fe de Bogotá and Universidad de los Andes in Bogotá Colombia suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: 9 Fundación Hospital de la Misericordia in Bogotá, This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek Colombia to optimize diagnosis for patients with this pathology. 10 Fundación Hospital de la Misericordia in Bogotá Colombia 11 Clínica la Misericordia in Barranquilla, Colombia Keywords 12 Fundación Cardio-Infantil in Bogotá, Colombia Acid lipase deficiency, cholesterol ester deposition disease, Wolman’s disease, dyslipidemia, hepatomegaly. 13 Hospital San Juan de Sahagún in Sahagún, Córdoba, Colombia 14 Hospital Universitario Fernando Troconis in Santa Marta, Magdalena, Colombia 15 Unidad Materno Infantil del Tolima at the Hospital Federico Lleras Acosta in Ibagué, Tolima, Colombia 16 Hospital Pablo Tobón Uribe in Medellín, Colombia 17 Fundación Hospital de la Misericordia in Bogotá, Colombia 18 Hospital Universitario Fundación Santa Fe de Bogotá in Bogotá Colombia 19 Fundación Valle del Lili in Cali, Colombia ......................................... Received: 04-04-17 Accepted: 06-10-17 INTRODUCTION criteria and autonomy but to be useful guides for clinical decision-making. This guide was the result of a consensus Guidelines and expert consensuses are documents that aim of 20 experts from several medical specialties. to help doctors evaluate the benefits and risks of diagnos- Each group of specialists conducted an exhaustive search tic and therapeutic procedures related to a specific patho- of the available evidence in the current medical literature logy. These documents are not intended to replace medical in PubMed and LILACS, the most frequently used search 358 © 2017 Asociaciones Colombianas de Gastroenterología, Endoscopia digestiva, Coloproctología y Hepatología engines. Then the group reviewed and synthesized the evi- This guide was developed by a committee of experts in dence which became the basis for the expert consensus. pediatrics, pediatric gastroenterology, pediatric endocri- Each group prepared a document on a related theme which nology, hepatology, pathology and genetics using nomi- was sent via e-mail to all the experts for their knowledge, nal group technique (NGT). Based on their experience analysis and contributions. The experts then presented and a wide literature review, the experts debated and dis- the best available evidence on the diagnostic criteria for cussed their different points of view to arrive at a list of LAL-D in each risk group at a face-to-face scientific con- recommendations representing their collective judgment. ference. This was followed by a debate in which each par- The objective was to propose guidelines that can be used ticipant was able to express her or his opinion. Once the in clinical practice for identification of patients with this discussion points were analyzed. Consensus was defined as pathology in Colombia. agreement of more than 80% of the members. Once con- sensus was reached, a report was issued with the recom- PHYSIOPATHOLOGY mendations and the design of algorithms that defined the path for the diagnosis of this pathology for the risk groups LAL-D originates in mutations of the LIPA gene located at under consideration. This was the responsibility of the con- 10q23.2. It has 10 exons and an approximate length of 45 sensus coordinators. This document was then provided to kilobases (kb). (1) This entity is autosomal recessive inhe- all participants and consensus was reached. ritance whose most common defect is associated with a LAL-D (OMIM 278000) is an autosomal recessive mutation at the site of exon 8 (c.894G> A) which is known disease caused by mutations in the LIPA gene that dras- as E8SJM. This mutation is present in about half of the affec- tically reduce the activity of the lysosomal acid lipase ted patients, (12) To date, more than 40 mutations which enzyme (LAL, EC 3.1.1.13). (1) This enzyme is responsi- lead to alterations of the enzyme’s function and which are ble for breaking down cholesterol esters and triglycerides, related to this pathology have been described. (2) The most so dysfunction leads to their accumulation in the liver, drastic ones are nonsense and frameshift mutations which spleen, macrophages and other organs. (2) The disease are usually associated with severely affected patients, while is characterized by microvesicular steatosis that produces cases in children and adults are associated with mutations liver failure, elevation of serum transaminases, accelerated whose effects on the protein are not as dramatic. (13) atherosclerosis and premature death. (3) Infantile presen- The LAL enzyme plays a key role in the metabolism of tation was described in 1956, and this disease was histo- lipids since it is responsible for hydrolysis of cholesterol rically called Wolman’s disease. (4) It is characterized by esters and triglycerides within lysosomes. (14) The action of vomiting, diarrhea, failure to thrive and hepatosplenome- this enzyme generates free cholesterol which is involved in galy (HSM) with rapid deterioration of liver functioning negative regulation of LDL receptors, in the inhibition of the and death at an average age of 3.7 months. (5) The late 3-hydroxy-3-methylglutaryl-coenzyme A reductase which onset form was known as cholesterol ester deposit disease is a rate controlling enzyme, and in the stimulation of acyl- and was first described in 1963. (6) It has a broad clinical coenzyme A (CoA):cholesterol acyltransferase (ACAT). spectrum and can occur in infants, children or adults. (7) Congenital deficiencies of this enzyme lead to lysosomal It is usually underdiagnosed and presents with liver com- accumulation of cholesterol and triglyceride esters and to promise, elevated transaminases and elevated serum levels failure of the LDL receptor pathway. Therefore, in addition of LDL (low density lipoprotein) cholesterol and triglyce- to this massive lysosomal accumulation of cholesterol esters, rides with normal or low levels of HDL cholesterol (high there is a systemic increase in synthesis of cholesterol. (15) density lipoprotein). Early death is due to hepatic insuffi- ciency or accelerated atherosclerosis secondary to chronic CLINICAL PICTURE hyperlipidemia. (2) Incidence has been estimated from genetic studies at Acid lipase deficiencies have a wide range of phenotypic 1/40,000 while the approximate incidence of the most presentations which manifest in very early childhood, in severe forms is 1/500,000. (8, 9, 10) Given its nonspecific later childhood or in later stages of life. clinical presentation and the relatively low number of publis- hed cases, it is believed that this entity has a high index of Presentation in Infants underdiagnoses. (11) For this reason, these guidelines have been developers to offer health-care personnel a series of LAL-D usually manifests with the most acute symptoms recommendations to guide themselves in developing suspi- when it manifests in the first days of life. Gastrointestinal cion of LAL-D and the ability to correctly diagnose it. symptoms include vomiting, diarrhea, steatorrhea, and Colombian Guidelines for Diagnosis of Lipase Acid Deficiency 359 abdominal distension secondary to hepatosplenomegaly. total lipase activity with lipase activity in the presence In