Síndrome de quilomicronemia familiar: experiencia pediátrica en Argentina / Familial chylomicronemia syndrome: pediatric experience in Argentina

El síndrome de quilomicronemia familiar (SQF) es unaenfermedad autosómica recesiva rara, con una prevalencia1:200 000 - 1:1 000 000, y se caracteriza por quilomicronemiaen ayunas y niveles muy elevados de triglicéridos (> 880 mg/dl). LPL es el gen más frecuentemente afectado, luego APOC2,GPIHBP1, APOA5 y LMF1; todos ellos comprometen la función de la lipoproteinlipasa endotelial. El SQF suele presentarseen la infancia con dolor abdominal recurrente, xantomaseruptivos, retraso del crecimiento, pancreatitis y, en ocasiones,asintomático. El tratamiento convencional es la restriccióndietética de grasas. Se muestra el resultado clínico de 20 pacientes pediátricoscon SQF reclutados de 4 hospitales en Argentina.

Familial chylomicronemia syndrome (FCS) is a rare autosomalrecessive disease, prevalence 1:200,000 - 1:1,000,000, andis characterized by fasting chylomicrons and very hightriglycerides > 880 mg/dl. LPL is the most frequentlyaffected gene, then APOC2, GPIHBP1, APOA5, LMF1, all ofthem compromising the function of lipoproteinlipase. FCScommonly presents in childhood with recurrent abdominalpain, eruptive xanthomas, failure to thrive, pancreatitis, andsometimes asymptomatic. The conventional treatment isdietetic fat restriction. The clinical outcome of 20 pediatric patients with FCS recruited from 4 hospitals in Argentina is reported.

Síndrome de quilomicronemia: aspectos genéticos y revisión de la literatura / Chylomicronemia syndrome: genetic aspects and literature review

Chylomicronemia syndrome is a metabolic condition characterized by severe hypertriglyceridemia and fasting chylomicronemia, secondary to an alteration in the ability to metabolize triglycerides. It can respond to different etiologies, the most frequent being multifactorial. Familial chylomicronemia syndrome, on the other hand, represents an infrequent cause of chylomicronemia syndrome, showing an autosomal recessive inheritance pattern. It's caused by pathogenic variants in genes related to chylomicron's metabolism, mainly LPL1 gene. One of the main associated risks is the occurrence of acute pancreatitis, which can also have a recurrent course. The primary therapy goal in patients with this condition is prevention of pancreatitis and related comorbidities. The treatment basis consists in reduce chylomicron formation by restriction of dietary fat, in association with physical activity and pharmacologic therapy. It is important to distinguish the etiology of chylomicronemia syndrome since it has repercussions in terms of response to treatment, complications, and recurrence risk. (AU)

Hipertrigliceridemia grave y síndrome de quilomicronemia familiar: una revisión de la literatura reciente / Severe hypertriglyceridemia and familial chylomicronemia syndrome: a review of recent literature

Resumen La hipertrigliceridemia (HTG) es un problema que se presenta con frecuencia en la práctica clínica. Su prevalencia en adultos es cercana al 10%. El espectro varía desde una predisposición que resulta en HTG solo en presencia de sobrepeso considerable o consumo excesivo de alcohol hasta mutaciones graves muy raras que pueden conducir a HTG grave en la infancia, incluso en ausencia de factores adicionales, como en el síndrome de quilomicronemia familiar (FCS, familial chylomicronemia syndrome). Este es un trastorno autosómico recesivo poco frecuente del metabolismo del quilomicrón que causa una importante elevación de los triglicéridos (>10 mmol/885 mg/dl). Esta condición está asociada con un riesgo significativo de pancreatitis aguda recurrente. La aproximación diagnóstica se logra mediante la caracterización fenotípica, y el hallazgo de la alteración genética ayuda a dar un diagnóstico más preciso. Además, se ha propuesto una puntuación clínica para el diagnóstico de FCS, pero necesita más validación. Las opciones de tratamiento disponibles para reducir los triglicéridos, como los fibratos y los ácidos grasos omega-3, no son eficaces en los pacientes con FCS. Actualmente, el único tratamiento sigue siendo una dieta de por vida muy baja en grasas, que reduce la formación de quilomicrones. Finalmente, los inhibidores de la apolipoproteína C-III están en desarrollo y podrían constituir opciones de tratamiento para estos pacientes. Considerando lo anterior, el objetivo de este artículo es realizar una revisión general sobre la HTG grave, con énfasis en el FCS, basados en la literatura disponible más reciente.

Abstract Hypertriglyceridemia (HTG) is a problem that occurs frequently in clinical practice. Its prevalence in adults is close to 10% and it varies between regions. The spectrum ranges from a disposition that results in HTG only in the presence of considerable overweight and/or excessive alcohol consumption to very rare serious mutations that can lead to severe HTG in childhood, even in the absence of additional factors such as familial chylomicronemia syndrome (FCS). This is a rare autosomal recessive disorder of chylomicron metabolism that causes a severe elevation in triglyceride levels (>10 mmol/885 mg/dL). This condition is associated with a significant risk of recurrent acute pancreatitis. Because this is a genetic condition, the optimal diagnostic strategy remains the genetic test. In addition, a clinical score for the diagnosis of FCS has been proposed but it needs further validation. Available treatment options to lower triglycerides, such as fibrates or omega-3 fatty acids, are not effective in patients with FCS. Currently, the cornerstone of treatment remains a very low-fat, lifetime diet that reduces chylomicron formation. Finally, apolipoprotein C-3 inhibitors are under development and may eventually be treatment options for these patients. The objective of this article is to carry out a general review of severe HTG, with an emphasis on FCS and based on the most recent available literature.

Familial chylomicronemia syndrome-induced acute necrotizing pancreatitis during pregnancy

Abstract Acute pancreatitis is a rare condition in pregnancy, associated with a high mortality rate. Hypertriglyceridemia represents its second most common cause.We present the case of a 38-year-old woman in the 24th week of gestation with a history of hypertriglyceridemia and recurrent episodes of pancreatitis. She was admitted to our hospital with acute pancreatitis due to severe hypertriglyceridemia. She was stabilized and treated with fibrates. Despite her favorable clinical course, she developed a second episode of acute pancreatitis complicated by multi-organ dysfunction and pancreatic necrosis, requiring a necrosectomy. The pregnancy was ended by cesarean section, after which three plasmapheresis sessions were performed. She is currently asymptomatic with stable triglyceride levels. Acute pancreatitis due to hypertriglyceridemia represents a diagnostic and therapeutic challenge in pregnant women, associated with serious maternal and fetal complications. When primary hypertriglyceridemia is suspected, such as familial chylomicronemia syndrome, the most important objective is preventing the onset of pancreatitis.

Quilomicronemia familiar / Familial chylomicronemia

Resumen La quilomicronemia familiar es una condición en que una mutación genética altera la capacidad de metabolizar los triglicéridos que viajan en las lipoproteínas, causando elevación extrema de triglicéridos plasmáticos y complicaciones asociadas. La complicación más frecuente es la pancreatitis, que puede llevar a falla multiorgánica o insuficiencia pancreática. La quilomicronemia familiar también afecta la calidad de vida, las relaciones sociales y el desarrollo profesional. El gen más frecuentemente afectado en la quilomicronemia familiar es el de lipoproteína lipasa-1 (LPL), enzima que hidroliza triglicéridos circulantes para su captación tisular. Mutaciones en genes (como APOC2, APOAV, LMF-1, GPIHBP-1) que codifican para proteínas que regulan la maduración, transporte o polimerización de lipoproteína lipasa-1, también pueden estar involucradas. Sin embargo, en cerca del 30% de los pacientes no se encuentra la variante causal. La quilomicronemia familiar debe sospecharse en casos de hipertrigliceridemia extrema, resistente al tratamiento convencional, o que se acompaña de xantomas eruptivos, lipemia retinalis o dolor abdominal. La disponibilidad de escalas de riesgo y pruebas genéticas deben promover la detección oportuna. La nutrición se basa en una dieta muy baja en grasa con adecuada suplencia de vitaminas liposolubles y ácidos grasos esenciales, además de evitar el consumo de alcohol. Si bien el tratamiento farmacológico incluye fibratos y ácidos grasos omega 3, el enfoque actual privilegia agentes biotecnológicos dirigidos a los defectos moleculares propios de la enfermedad. Ello incluye un oligonucleótido antisentido dirigido contra apoC-III (volanesorsen), un anticuerpo monoclonal contra la proteína similar a angiopoietina tipo 3 (evinacumab), y otros compuestos en desarrollo.

Abstract Familial chylomicronemia is a disease in which a genetic mutation affects the ability of the organism to metabolize triglycerides bound to lipoproteins, causing extremely high plasma triglycerides and associated consequences. The most frequent complication is acute pancreatitis, which may lead to multiorganic failure or pancreatic insufficiency. Familial chylomicronemia also exerts a profound negative impact on quality of life, social relationships and professional development. The gene most frequently affected is lipoprotein lipase-1 gene (LPL), the enzyme in charge of hydrolyzing circulating triglycerides for tissue uptake. Mutations in other genes regulating maturation, transport or polymerization (eg. APOC2, APOAV, LMF-1, GPIHBP-1) of lipoprotein lipase-1, may also be involved. However, in about 30% of patients the causal variant is not identified. Familial chylomicronemia should be suspected in patients with severe hypertriglyceridemia with poor response to conventional treatment, or accompanied by eruptive xanthomas, lipemia retinalis or abdominal pain. The availability of risk scores and genetic tests should facilitate its opportune detection and management. Nutritional therapy is based on a very-low-fat diet with adequate supply of lipid-soluble vitamins and essential fatty acids, plus avoidance of alcohol consumption. Current pharmacological treatment may include fibrates and omega-3 fatty acids but prioritizes biotechnological agents targeting the molecular disturbances of the disease. These include an antisense oligonucleotide against apoC-III (volanesorsen), a monoclonal antibody against angiopoietin-like protein-3 (evinacumab), and other agents currently in development.

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.

Guía colombiana para el diagnóstico de la deficiencia de lipasa ácida / Colombian Guidelines for Diagnosis of Lipase Acid Deficiency

Resumen Introducción: la deficiencia de lipasa ácida lisosomal (LAL-D) es una entidad de herencia autosómica recesiva que lleva a la acumulación de esteres de colesterol y triglicéridos en el hígado, bazo y otros órganos. La edad de inicio y la tasa de progresión son muy variables, lo que posiblemente sea explicado por las mutaciones presentes en el gen LIPA. Las manifestaciones clínicas son las mismas que para otras patologías hepáticas, cardiovasculares y metabólicas, lo que hace difícil reconocerla en la práctica clínica. Objetivo: proveer una guía que permita a los clínicos reconocer los principales grupos de riesgo en los cuales se debe sospechar de LAL-D y mejorar su diagnóstico. Metodología: este documento se diseñó como un consenso de expertos en el cual participaron médicos especialistas en gastroenterología, hepatología, endocrinología, genética, patología y pediatría. Se realizó una revisión de la literatura acerca de las manifestaciones clínicas y de las herramientas para el diagnóstico de LAL-D y se siguió la metodología de técnica de grupo nominal. Resultados: se generaron algoritmos diagnósticos por consenso para cada uno de los grupos de riesgo, que facilitaran la sospecha y el diagnóstico de LAL-D. Conclusiones: esta guía propone algoritmos para el diagnóstico de LAL-D con base en el consenso clínico, que buscan optimizar la ruta diagnóstica en los pacientes con dicha patología.

Abstract Introduction: Lysosomal acid lipase deficiency (LAL-D) is an inherited autosomal recessive entity that leads to the accumulation of cholesterol and triglyceride esters in the liver, spleen and other organs. The age of onset and rate of progression vary greatly, possibly explained by mutations of the LIPA gene. Clinical manifestations are the same as those of other hepatic, cardiovascular and metabolic pathologies which makes it difficult to recognize in clinical practice. Objective: The objectives of these guidelines is to help clinicians recognize the major groups at risk for LAL-D and to improve its diagnosis. Methodology: This document was designed as a consensus of experts in gastroenterology, hepatology, endocrinology, genetics, pathology and pediatrics. A review of the literature regarding clinical manifestations and tools for diagnosis of LAL-D was conducted and the nominal group technique was followed. Results: Diagnostic algorithms which facilitate suspicion and diagnosis of LAL-D were generated by consensus for each of the risk groups. Conclusions: This guide proposes algorithms for the diagnosis of LAL-D based on clinical consensus. The algorithms seek to optimize diagnosis for patients with this pathology.

Homozygous LPL p.Gly188Glu Mutation in a Mexican Girl With Lipoprotein Lipase Deficiency

No abstract available.

Homozygous LPL p.Gly188Glu Mutation in a Mexican Girl With Lipoprotein Lipase Deficiency

No abstract available.

Lipoprotein lipase gene-deficient mice with hypertriglyceridaemia associated with acute pancreatitis

ABSTRACT PURPOSE: To investigate the severity of pancreatitis in lipoprotein lipase (LPL)-deficient hypertriglyceridaemic (HTG) heterozygous mice and to establish an experimental animal model for HTG pancreatitis study. METHODS: LPL-deficient HTG heterozygous mice were rescued by somatic gene transfer and mated with wild-type mice. The plasma amylase, triglyceride, and pathologic changes in the pancreas of the LPL-deficient HTG heterozygous mice were compared with those of wild-type mice to assess the severity of pancreatitis. In addition, acute pancreatitis (AP) was induced by caerulein (50 µg/kg) for further assessment. RESULTS: The levels of plasma amylase and triglyceride were significantly higher in the LPL-deficient HTG heterozygous mice. According to the pancreatic histopathologic scores, the LPL-deficient HTG heterozygous mice showed more severe pathologic damage than the wild-type mice. CONCLUSIONS: Lipoprotein lipase deficient heterozygous mice developed severe caerulein-induced pancreatitis. In addition, their high triglyceride levels were stable. Therefore, LPL-deficient HTG heterozygous mice are a useful experimental model for studying HTG pancreatitis.

Etiology, clinical spectrum and outcome of metabolic liver diseases in children

To determine the etiology, clinical spectrum and outcome of metabolic liver diseases [MLD] in children admitted in a tertiary care hospital of Eastern India. An observational study. Paediatric Liver Clinic and Paediatrics Inpatient Department of Nilratan Sircar Medical College and Hospital, Kolkata, Eastern India, from April 2009 to March 2011. All children aged 0 - 12 years having characteristic clinical features along with diagnostic hallmark of any MLDs were included in this study and data were collected on a pre-designed proforma. After appropriate management and discharge, all patients were followed-up for next 6 months. Fifty one children with mean age 4.34 +/- 3.78 years [range 2 days - 12 years], male: female ratio 1.55:1, were studied. The etiologies were Wilson's disease [33.33%, n = 17]; glycogen storage disorder [23.53%, n = 12]; galactosemia [19.61%, n = 10]; non-alcoholic fatty liver disease [11.76%, n = 6]; Gaucher disease [5.88%, n = 3]; mucopolysaccharidoses [3.92%, n = 2] and familial hyperlipoproteinemia type-I [1.96%, n = 1]. Jaundice [n = 24] and hepatomegaly [n = 47], was the commonest symptom and sign respectively. Of the 17 non-responders, most were Wilson's disease [n = 7] cases. There was statistical difference in outcome with respect to INR > 1.3 at diagnosis [p = 0.026]. High index of suspicion, early detection and screening, simple dietary modification and cost effective drugs along with good compliance are sufficient to treat and even prevent evolution of most causes of the MLDs

Gestational hyperlipidemia and acute pancreatitis with underlying partial lipoprotein lipase deficiency and apolipoprotein E3/E2 genotype

We report the case of a patient who experienced extreme recurrent gestational hyperlipidemia. She was diagnosed with partial lipoprotein lipase (LPL) deficiency but without an associated LPL gene mutation in the presence of the apolipoprotein E3/2 genotype. This is the first reported case of extreme gestational hyperlipidemia with a partial LPL deficiency in the absence of an LPL gene mutation and the apolipoprotein E 3/2 genotype. She was managed with strict dietary control and medicated with omega-3 acid ethyl esters. A patient with extreme hyperlipidemia that is limited to the gestational period should be considered partially LPL-deficient. Extreme instances of hyperlipidemia increase the risk of acute pancreatitis, and the effect of parturition on declining plasma lipid levels can be immediate and dramatic. Therefore, decisions regarding the timing and route of delivery with extreme gestational hyperlipidemia are critical and should be made carefully.

A Case of Lipoprotein Lipase Deficiency inan Infant with Recurrent Pancreatitis / 대한소아소화기영양학회지

Familial chylomicronemia syndrome is a rare disorder characterized by severe hypertriglyceridemia and fasting chylomicronemia. Causes of the syndrome include lipoprotein lipase (LPL) deficiency, apolipoprotein C-II deficiency, or the presence of inhibitors to LPL. We managed a 3-month-old girl who had recurrent acute pancreatitis caused by chylomicronemia. We report the first case of familial chylomicronemia in Korea caused by LPL deficiency in an infant with recurrent acute pancreatitis.

Familial chylomicronemia in a nine months old infant

Familial Chylomicronemia syndrome is a rare disorder of lipoprotein metabolism due to familial lipoprotein lipase or apolipoprotein C-II deficiency or the presence of inhibitors to lipoprotein lipase. It manifests as eruptive xanthomas, acute pancreatitis, and lipaemic plasma due to marked elevation of triglyceride and chylomicrons levels. We report a rare case of familial Chylomicronemia in a 9-month-old infant, who was diagnosed after his plasma was incidentally found to be milky. Lipid profile showed familial Chylomicronemia [Type 1 Hyperlipidemia]. The infant was started on a low fat diet and advised a regular follow-up

Encephalopathy in type I hyperlipidemia.

Familial chylomicronemia syndrome is a group of rare genetic disorders characterized by deficient activity of an enzyme lipoprotein lipase or apo-protein C-II deficiency. In this paper we present an infant with massive hyperchylomicronemia and severe pancreatitis. Exchange transfusion for controlling hypertriglyceridemia and pancreatitis led to an increase in hyperviscosity which resulted in encephalopathy.

Familial chylomicronemia syndrome.

Familial chylomicronemia syndrome is a group of rare genetic disorders characterized by deficient activity of an enzyme lipoprotein lipase or apo-protein C-II deficiency. Incidence is 1 out of 1,000,000. Alternative names to this syndrome are Type I hyper lipoproteinemia and familial lipoprotein lipase deficiency.

Hiperlipoproteinemia tipo I / Type I hyperlipoproteinemia

Se presenta el caso clínico de una paciente portadora de una hiperlipoproteinemia tipo I controlada durante 5 años. Se describe las características clínicas y de laboratorio de esta enfermedad así como la respuesta al tratamiento dietético que es fundamental en la evolución de esta alteración metabólica tan poco frecuente

Proteinose lipóide palpebral: doença de Urbach-Wiethe / Eyelid lipoid proteinosis: Urbach-Wiethe disease

Relata-se o caso de proteinose lipóide (doença de Urbach-Wiethe) no qual a única manifestaçäo clínica, possivelmente inicial, foi a presença de numerosos nódulos translucentes dispostos ao nível dos bordos palpebrais em ambos os olhos. Comentam-se os aspectos clínicos e histopatológicos desta rara genodermatose