RESUMEN
BACKGROUND: Homozygous mutations in the APOA5 gene constitute a rare cause of monogenic hypertriglyceridemia, or familial chylomicronemia syndrome (FCS). We searched PubMed and identified 16 cases of homozygous mutations in the APOA5 gene. Severe hypertriglyceridemia related to monogenic mutations in triglyceride-regulating genes can cause recurrent acute pancreatitis. Standard therapeutic approaches for managing this condition typically include dietary interventions, fibrates, and omega-3-fatty acids. A novel therapeutic approach, antisense oligonucleotide volanesorsen is approved for use in patients with FCS. CASE PRESENTATION: We report a case of a 25-years old Afghani male presenting with acute pancreatitis due to severe hypertriglyceridemia up to 29.8 mmol/L caused by homozygosity in APOA5 (c.427delC, p.Arg143Alafs*57). A low-fat diet enriched with medium-chain TG (MCT) oil and fibrate therapy did not prevent recurrent relapses, and volanesorsen was initiated. Volanesorsen resulted in almost normalized triglyceride levels. No further relapses of acute pancreatitis occurred. Patient reported an improve life quality due to alleviated chronic abdominal pain and headaches. CONCLUSIONS: Our case reports a rare yet potentially life-threatening condition-monogenic hypertriglyceridemia-induced acute pancreatitis. The implementation of the antisense drug volanesorsen resulted in improved triglyceride levels, alleviated symptoms, and enhanced the quality of life.
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Apolipoproteína A-V , Homocigoto , Hipertrigliceridemia , Pancreatitis , Recurrencia , Humanos , Masculino , Adulto , Pancreatitis/genética , Apolipoproteína A-V/genética , Hipertrigliceridemia/genética , Mutación , Oligonucleótidos/uso terapéutico , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/complicaciones , Dieta con Restricción de Grasas , Triglicéridos/sangreRESUMEN
BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).
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Apolipoproteína C-III , Hiperlipoproteinemia Tipo I , Pancreatitis , Triglicéridos , Humanos , Pancreatitis/tratamiento farmacológico , Masculino , Femenino , Método Doble Ciego , Apolipoproteína C-III/sangre , Persona de Mediana Edad , Adulto , Triglicéridos/sangre , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/complicaciones , Enfermedad Aguda , Oligonucleótidos/uso terapéutico , Oligonucleótidos/efectos adversos , Anciano , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/sangre , Adulto JovenRESUMEN
BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.
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Predisposición Genética a la Enfermedad , Hipertrigliceridemia , Pancreatitis , Polimorfismo de Nucleótido Simple , Humanos , Pancreatitis/genética , Masculino , Femenino , Persona de Mediana Edad , Hipertrigliceridemia/genética , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/sangre , Factores de Riesgo , Adulto , Medición de Riesgo , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/diagnóstico , Índice de Severidad de la Enfermedad , Herencia Multifactorial , Triglicéridos/sangre , Fenotipo , Enfermedad Aguda , AncianoRESUMEN
BACKGROUND: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia associated with an increased risk of acute pancreatitis (AP). The risk of AP is heterogenous and is associated with increased level of triglycerides (TG) and presence of rare variants in TG metabolism-related genes. OBJECTIVE: To determine if the accumulation of common variants in pancreatitis susceptibility genes, measured with a weighted polygenic risk score (PRS), is associated with AP in MCS patients. METHODS: A total of 114 patients with MCS underwent genetic testing for eight single nucleotide polymorphisms (SNPs) in known pancreatitis susceptibility genes (ABCG8, CLDN2, CTRB1/2, CTRC, PRSS1, PRSS2, SPINK1 and TWIST2). A weighted PRS was calculated to account for the phenotypic effect of each SNP locus. RESULTS: A high pancreatitis-PRS score (≥ 0.44) was associated with a 2.94-fold increase risk of AP (p = 0.02) among patients with MCS. MCS patients with a high pancreatitis-PRS and a rare variant in TG metabolism-related gene have a 9.50-fold increase risk of AP (p = 0.001), compared to those with a low-PRS and no rare variant. A multivariate analysis including the presence of rare variants, the maximal TG values and a high pancreatitis-PRS explained 26% of the variability in AP in MCS patients. CONCLUSION: This study shows for the first time that the accumulation of common variants in pancreatitis susceptibility genes is associated with AP in MCS patients. Pancreatitis-PRS could help clinicians to identify MCS patients who may be at higher risk of AP and who may benefit from more aggressive treatment.
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Predisposición Genética a la Enfermedad , Pancreatitis , Polimorfismo de Nucleótido Simple , Humanos , Pancreatitis/genética , Pancreatitis/complicaciones , Femenino , Masculino , Persona de Mediana Edad , Adulto , Herencia Multifactorial/genética , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/complicaciones , Enfermedad Aguda , Factores de Riesgo , Anciano , Puntuación de Riesgo GenéticoRESUMEN
BACKGROUND AND AIM: APO CII, one of several cofactors which regulate lipoprotein lipase enzyme activity, plays an essential role in lipid metabolism. Deficiency of APO CII is an ultra-rare autosomal recessive cause of familial chylomicronemia syndrome. We present the long-term clinical outcomes of 12 children with APO CII deficiency. METHODS AND RESULTS: The data of children with genetically confirmed APO CII deficiency were evaluated retrospectively. Twelve children (8 females) with a mean follow-up of 10.1 years (±3.9) were included. At diagnosis, the median age was 60 days (13 days-10 years). Initial clinical findings included lipemic serum (41.6%), abdominal pain (41.6%), and vomiting (16.6%). At presentation, the median triglyceride (TG) value was 4341 mg/dL (range 1277-14,110). All patients were treated with a restricted fat diet, medium-chain triglyceride (MCT), and omega-3-fatty acids. In addition, seven patients (58.3%) received fibrate. Fibrate was discontinued in two patients due to rhabdomyolysis and in one patient because of cholelithiasis. Seven (58.3%) patients experienced pancreatitis during the follow-up period. One female experienced recurrent pancreatitis and was treated with fresh frozen plasma (FFP). CONCLUSIONS: Apo CII deficiency is an ultra-rare autosomal recessive condition of hypertriglyceridemia associated with significant morbidity and mortality. Low-fat diet and MCT supplementation are the mainstays of therapy, while the benefit of TG-lowering agents are less well-defined.
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Biomarcadores , Hipertrigliceridemia , Triglicéridos , Humanos , Femenino , Masculino , Estudios Retrospectivos , Niño , Resultado del Tratamiento , Triglicéridos/sangre , Factores de Tiempo , Preescolar , Lactante , Biomarcadores/sangre , Hipertrigliceridemia/diagnóstico , Hipertrigliceridemia/terapia , Hipertrigliceridemia/sangre , Hipertrigliceridemia/complicaciones , Recién Nacido , Apolipoproteína C-II/genética , Apolipoproteína C-II/deficiencia , Apolipoproteína C-II/sangre , Dieta con Restricción de Grasas , Hipolipemiantes/uso terapéutico , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/terapia , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/complicaciones , Fenotipo , Factores de Edad , Ácidos Fíbricos/uso terapéutico , Predisposición Genética a la Enfermedad , Factores de RiesgoRESUMEN
PURPOSE OF REVIEW: The aim of this review was to understand the role of multifactorial chylomicronemia syndrome (MFCS) as a cause of severe hypertriglyceridemia; to distinguish it from other causes of severe hypertriglyceridemia; and to provide a rational approach to treatment. RECENT FINDINGS: There have been advances in understanding the genetic underpinning of MFCS, and a better appreciation as to how to differentiate it from the much rarer familial chylomicronemia syndrome, in which there are substantial differences in the approach to their treatment. New approaches to triglyceride lowering will help reduce the risk of pancreatitis, the major complication of MFCS. SUMMARY: MCSF is a condition in which plasma triglyceride levels are severely elevated, usually to due exacerbation of common genetic forms of hypertriglyceridemia by secondary causes of hypertriglyceridemia and/or triglyceride-raising drugs. Triglyceride-induced pancreatitis can be prevented by markedly reducing triglyceride levels by treating secondary causes and/or eliminating of triglyceride-raising drugs, and by using triglyceride-lowering drugs, especially fibrates. MFCS also increases cardiovascular disease risk, for which lifestyle measures and drugs are required.
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Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Pancreatitis , Humanos , Hipertrigliceridemia/complicaciones , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Pancreatitis/complicaciones , Pancreatitis/tratamiento farmacológico , Triglicéridos , Ácidos Fíbricos/uso terapéuticoRESUMEN
Objective: Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations related to chylomicron metabolism. The objective of this study is to show the development and results of a screening program for FCS in Argentina. Materials and methods: A cross-sectional study was performed. All patients > 18 years with a triglyceride level ≥ 1,000 mg/dL in the period from January 1, 2017 to December 31, 2021 were included. The program was developed in three stages: (1) Review of electronic records and identification of suspected laboratory cases (triglyceride level ≥ 1,000 mg/dL); (2) Identification of suspected clinical cases (all suspected laboratory cases that had no relevant secondary factors) and application of the FCS score to define probable cases (score ≥ 10); (3) Perform genetic tests in probable cases. Results: Globally, 348 suspected laboratory cases (mean age of 49.9 years, 77.3% men) were included. The median triglycerides level was 1,309 mg/dL (interquartile range 1,175-1,607 mg/dL). In total, 231 patients were categorized as suspected clinical cases. After applying the FCS score, 3% of them were classified as "very likely FCS" (probable cases). Four variants of uncertain significance have been identified. No previously reported pathogenic variants were detected. Conclusion: This study shows a screening program for the detection of FCS. Although no patient was diagnosed with FCS, we believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.
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Hiperlipoproteinemia Tipo I , Masculino , Humanos , Persona de Mediana Edad , Femenino , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/genética , Hiperlipoproteinemia Tipo I/complicaciones , Estudios Transversales , Universidades , TriglicéridosRESUMEN
Acute pancreatitis is an often-overlooked cause of acute abdominal pain in children and adolescents. Severe hypertriglyceridaemia is an important cause of recurrent acute pancreatitis. Monogenic causes of hypertriglyceridaemia, such as familial chylomicronaemia caused by lipoprotein lipase deficiency, are more frequently encountered in children and adolescents, but remain rare. Polygenic hypertriglyceridaemia is more common, but may require a precipitant before manifesting. With the global increase in obesity and type 2 diabetes, secondary causes of hypertriglyceridaemia in children and adolescents are increasing. We report two cases of severe hypertriglyceridaemia and pancreatitis in adolescent females. Hypertriglyceridaemia improved markedly with restriction of dietary fat. An inhibitor to lipoprotein lipase was found to be the cause in one patient, while in the other limited genetic investigation excluded chylomicronaemia owing to deficiency of lipoprotein lipase, its activators and processing proteins.
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Diabetes Mellitus Tipo 2 , Hiperlipoproteinemia Tipo I , Hipertrigliceridemia , Pancreatitis , Enfermedad Aguda , Adolescente , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Humanos , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/genética , Hipertrigliceridemia/complicaciones , Hipertrigliceridemia/genética , Lipoproteína Lipasa/genética , Pancreatitis/etiología , SudáfricaRESUMEN
Genetic lipid disorders, ranging from common dyslipidemias such as familial hypercholesterolemia, lipoprotein (a), and familial combined hyperlipidemia to rare disorders including familial chylomicronemia syndrome and inherited hypoalphalipoproteinemias (ie, Tangier and fish eye diseases), affect millions of individuals in the United States and tens of millions around the world and are often undiagnosed in the general population. Clinicians should take into consideration the potential of inherited lipid disorders or syndromes when severe derangements in lipid parameters are observed. Patients' combined genotype and phenotype should be evaluated in conjunction with a host of environmental factors impacting their risk of atherosclerotic cardiovascular disease.
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Aterosclerosis , Enfermedades Cardiovasculares , Dislipidemias , Hiperlipoproteinemia Tipo I , Aterosclerosis/diagnóstico , Aterosclerosis/epidemiología , Aterosclerosis/genética , Enfermedades Cardiovasculares/complicaciones , Dislipidemias/epidemiología , Dislipidemias/genética , Humanos , Hiperlipoproteinemia Tipo I/complicaciones , Lípidos , Factores de Riesgo , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVES: We aimed to compare plasmapheresis and medical apheresis as lipid-lowering therapies in children with familial lipoprotein lipase (LPL) deficiency. METHODS: The data of 13 patients who were followed up after a diagnosis of LPL deficiency were retrospectively analyzed. Plasma triglyceride, cholesterol, amylase, and lipase values and complications were recorded before and after each patient underwent plasmapheresis or medical apheresis. RESULTS: The mean follow-up period of the patients was 99.64 ± 52.92 months in the medical apheresis group and 118 ± 16.97 months in the plasmapheresis group. While the mean triglyceride level before plasmapheresis was 1,875.38 ± 547.46 mg/dL, it was 617 ± 228.28 mg/dL after plasmapheresis. While the mean triglyceride level before medical apheresis was 1,756.86 ± 749.27 mg/dL, it was found to be 623.03 ± 51.36 mg/dL after medical apheresis. Triglyceride levels were decreased by 59.62% with medical apheresis and 65.57% with plasmapheresis. The cost of treatment for medical apheresis was found to be lower compared to plasmapheresis 296.93 ± 29.94 Turkish lira (USD 43.34 ± 4.01) vs. 3,845.42 ± 156.17 Turkish lira (USD 561.37 ± 20.93; p<0.001). CONCLUSIONS: Although there is no standardized strategy for the acute treatment of hypertriglyceridemia due to LPL deficiency, medical apheresis is a safe and effective treatment with a low risk of side effects. Unlike plasmapheresis, medical apheresis can be performed in any center, which is another important advantage of the procedure.
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Eliminación de Componentes Sanguíneos/métodos , Hiperlipoproteinemia Tipo I/complicaciones , Hipertrigliceridemia/terapia , Plasmaféresis/métodos , Triglicéridos/sangre , Eliminación de Componentes Sanguíneos/economía , Niño , Preescolar , Femenino , Costos de la Atención en Salud , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hipertrigliceridemia/sangre , Hipertrigliceridemia/etiología , Lactante , Recién Nacido , Masculino , Plasmaféresis/economía , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Primary chylomicronemia (PCM) is a rare and intractable disease characterized by marked accumulation of chylomicrons in plasma. The levels of plasma triglycerides (TGs) typically range from 1,000 - 15,000 mg/dL or higher.PCM is caused by defects in the lipoprotein lipase (LPL) pathway due to genetic mutations, autoantibodies, or unidentified causes. The monogenic type is typically inherited as an autosomal recessive trait with loss-of-function mutations in LPL pathway genes (LPL, LMF1, GPIHBP1, APOC2, and APOA5). Secondary/environmental factors (diabetes, alcohol intake, pregnancy, etc.) often exacerbate hypertriglyceridemia (HTG). The signs, symptoms, and complications of chylomicronemia include eruptive xanthomas, lipemia retinalis, hepatosplenomegaly, and acute pancreatitis with onset as early as in infancy. Acute pancreatitis can be fatal and recurrent episodes of abdominal pain may lead to dietary fat intolerance and failure to thrive.The main goal of treatment is to prevent acute pancreatitis by reducing plasma TG levels to at least less than 500-1,000 mg/dL. However, current TG-lowering medications are generally ineffective for PCM. The only other treatment options are modulation of secondary/environmental factors. Most patients need strict dietary fat restriction, which is often difficult to maintain and likely affects their quality of life.Timely diagnosis is critical for the best prognosis with currently available management, but PCM is often misdiagnosed and undertreated. The aim of this review is firstly to summarize the pathogenesis, signs, symptoms, diagnosis, and management of PCM, and secondly to propose simple diagnostic criteria that can be readily translated into general clinical practice to improve the diagnostic rate of PCM. In fact, these criteria are currently used to define eligibility to receive social support from the Japanese government for PCM as a rare and intractable disease.Nevertheless, further research to unravel the molecular pathogenesis and develop effective therapeutic modalities is warranted. Nationwide registry research on PCM is currently ongoing in Japan with the aim of better understanding the disease burden as well as the unmet needs of this life-threatening disease with poor therapeutic options.
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Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/terapia , Dolor Abdominal/etiología , Animales , Manejo de la Enfermedad , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/complicaciones , Pancreatitis/etiología , Pronóstico , Triglicéridos/sangreRESUMEN
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.
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Humanos , Femenino , Embarazo , Adulto , Complicaciones del Embarazo/diagnóstico , Diagnóstico Prenatal , Pancreatitis Aguda Necrotizante/diagnóstico , Hiperlipoproteinemia Tipo I/diagnóstico , Complicaciones del Embarazo/diagnóstico por imagen , APACHE , Pancreatitis Aguda Necrotizante/complicaciones , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Diagnóstico Diferencial , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/diagnóstico por imagenRESUMEN
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.
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Hiperlipoproteinemia Tipo I/diagnóstico , Pancreatitis Aguda Necrotizante/diagnóstico , Complicaciones del Embarazo/diagnóstico , Diagnóstico Prenatal , APACHE , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/diagnóstico por imagen , Pancreatitis Aguda Necrotizante/complicaciones , Pancreatitis Aguda Necrotizante/diagnóstico por imagen , Embarazo , Complicaciones del Embarazo/diagnóstico por imagenRESUMEN
The chylomicronemia syndrome is characterized by severe hypertriglyceridemia and fasting chylomicronemia and predisposes affected individuals to acute pancreatitis. When due to very rare monogenic mutations in the genes encoding the enzyme, lipoprotein lipase, or its regulators, APOC2, APOA5, GPIHBP1, and LMF1, it is referred to as the familial chylomicronemia syndrome. Much more frequently, the chylomicronemia syndrome results from a cluster of minor genetic variants causing polygenic hypertriglyceridemia, which is exacerbated by conditions or medications which increase triglyceride levels beyond the saturation point of triglyceride removal systems. This situation is termed the multifactorial chylomicronemia syndrome. These aggravating factors include common conditions such as uncontrolled diabetes, overweight and obesity, alcohol excess, chronic kidney disease and pregnancy and several medications, including diuretics, non-selective beta blockers, estrogenic compounds, corticosteroids, protease inhibitors, immunosuppressives, antipsychotics, antidepressants, retinoids, L-asparaginase, and propofol. A third uncommon cause of the chylomicronemia syndrome is familial forms of partial lipodystrophy. Development of pancreatitis is the most feared complication of the chylomicronemia syndrome, but the risk of cardiovascular disease as well as non-alcoholic steatohepatitis is also increased. Treatment consists of dietary fat restriction and weight reduction combined with the use of triglyceride lowering medications such as fibrates, omega 3 fatty acids and niacin. Effective management of aggravating factors such as improving diabetes control, discontinuing alcohol and replacing or reducing the dose of medications that raise triglyceride levels is essential. Importantly, many if not most cases of the chylomicronemia syndrome can be prevented by effective identification of polygenic hypertriglyceridemia in people with conditions that increase its likelihood or before starting medications that may increase triglyceride levels. Several new pharmacotherapeutic agents are being tested that are likely to considerably improve treatment of hypertriglyceridemia in people at risk.
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Hiperlipoproteinemia Tipo I/complicaciones , Hipertrigliceridemia/etiología , Pancreatitis/etiología , Humanos , Hipertrigliceridemia/patología , Pancreatitis/patologíaRESUMEN
PURPOSE OF REVIEW: Familial chylomicronemia syndrome (FCS) is a rare recessive genetic disorder often underdiagnosed with potentially severe clinical consequences. In this review, we describe the clinical and biological characteristics of the disease together with its main complication, i.e., acute pancreatitis. We focused the paper on new diagnostic tools, progress in understanding the role of two key proteins (apolipoprotein CIII (apo CIII) and angiopoietin-like3 (ANGPTL-3)), and new therapeutic options. RECENT FINDINGS: Recently, a new diagnostic tool has been proposed by European experts to help identify these patients. This tool with two recently identified parameters (low LDL and low body mass index) can help identify patients who should be genetically tested or who may have the disease when genetic testing is not available. FCS is caused by homozygous or compound heterozygous mutations of lipoprotein lipase, apolipoprotein C-II, apolipoprotein A-V, glycosylphosphatidylinositol anchored high-density lipoprotein-binding protein 1, and lipase maturation factor. Two proteins have been identified as important player in the metabolism of triglyceride-rich lipoprotein and its regulation. These two proteins are therapeutic target. Antisense oligonucleotide targeting apo CIII has been shown to significantly decrease triglyceride levels even in FCS and is the first available treatment for these patients. Further development might identify new compounds with reduced risk to develop severe thrombocytopenia. ANGPTL-3 inhibitors have not yet been tested in FCS patients but exert significant hypotriglyceridemic effect in the more frequent and less severe polygenic forms. Beyond these two new targets, microsomal triglyceride transfer protein (MTTP) inhibitors could also be part of the armamentarium, if on-going trials confirm their efficacy. New clinical tools and simple criteria can help select patients with possible FCS and identify patients who should have a genetic testing. Identifying patients with FCS is a major issue since these patients have a high risk to suffer severe episodes of acute pancreatitis and may now benefit from new therapeutic options including antisense oligonucleotide targeting apo CIII.
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Proteínas Similares a la Angiopoyetina/antagonistas & inhibidores , Índice de Masa Corporal , Proteínas Portadoras/antagonistas & inhibidores , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Lipoproteínas LDL/sangre , Oligonucleótidos Antisentido/uso terapéutico , Proteína 3 Similar a la Angiopoyetina , Animales , Apolipoproteína A-V/genética , Apolipoproteína C-III/genética , Pruebas Genéticas/métodos , Humanos , Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/genética , Lipoproteína Lipasa/genética , Mutación , Pancreatitis/tratamiento farmacológico , Pancreatitis/etiología , Receptores de Lipoproteína/genética , Resultado del TratamientoRESUMEN
Aims: Familial chylomicronemia syndrome (FCS) is a rare genetic disorder with no currently approved therapies. Treatments are in development, and cost-utility analyses will be needed to examine their value. These models will require health state utilities representing FCS. Therefore, the purpose of this study was to estimate utilities for FCS and an associated episode of acute pancreatitis (AP).Methods: Because it is not feasible to gather a large enough sample of patients with this extremely rare condition to complete standardized preference-based measures, vignette-based methods were used to estimate utilities. In time trade-off interviews, general population participants in the UK and Canada valued health state vignettes drafted based on literature review, clinician input, and interviews with patients. Four health states described variations of FCS. A fifth health state, describing AP, was added to one of the other health states to evaluate its impact on utility.Results: A total of 308 participants provided utility data (208 UK; 100 Canada). Mean utilities for FCS health states ranged from 0.46 to 0.83, with higher triglycerides, more severe symptoms, and a history of AP associated with lower utility values. The disutility (i.e. utility decrease) of AP ranged from -0.17 to -0.25, with variations depending on the health state to which it was added. Utility means were similar in the UK and Canada.Conclusions: The vignette-based approach is useful for estimating utilities of a rare disease. The health state utilities derived in this study would be useful in models examining cost-effectiveness of treatments for FCS.
Asunto(s)
Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/fisiopatología , Pancreatitis/etiología , Prioridad del Paciente , Absentismo , Canadá , Análisis Costo-Beneficio , Femenino , Estado de Salud , Humanos , Hiperlipoproteinemia Tipo I/psicología , Entrevistas como Asunto , Masculino , Persona de Mediana Edad , Calidad de Vida , Enfermedades Raras , Triglicéridos/sangre , Reino UnidoRESUMEN
Familial chylomicronemia is caused by deficiency of lipoprotein lipase or its co-activators. Here, we report an infant with apolipoprotein C-II (APOC2) deficiency, who developed acute pancreatitis 37 days after birth. He presented as abdominal sepsis with fever, irritability and abdominal distention. Amylase levels were low, but lipase levels and imaging findings were consistent with acute pancreatitis. He had severe hypertriglyceridemia (1091 mg/dl). Keeping him nil orally for two days resulted in rapid decrease in triglyceride levels and resolution of the clinical findings. APOC2 gene sequencing revealed a homozygous splice-site mutation (c.55+1G>C). To the best of our knowledge, this patient is not only the youngest reported patient with APOC2 deficiency, but also the youngest such patient who developed pancreatitis. Although he had a severe presentation, invasive methods to treat hypertriglyceridemia were not necessary. We emphasize that clinical findings and amylase levels are not reliable to diagnose pancreatitis in this age group.
Asunto(s)
Hiperlipoproteinemia Tipo I/complicaciones , Hiperlipoproteinemia Tipo I/genética , Pancreatitis/etiología , Predisposición Genética a la Enfermedad , Humanos , Lactante , Masculino , Mutación , Pancreatitis/terapiaRESUMEN
Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder of chylomicron metabolism causing severe elevation of triglyceride (TG) levels (>10 mmol L-1 ). This condition is associated with a significant risk of recurrent acute pancreatitis (AP). AP caused by hypertriglyceridaemia (HTG) has been associated with a worse prognosis and higher mortality rates compared to pancreatitis of other aetiology. Despite its association with poor quality of life and increased lifelong risk of HTG-AP, few healthcare providers are familiar with FCS. Because this condition is under-recognized, the majority of FCS patients are diagnosed after age 20 often after consulting several physicians. Although other forms of severe HTG such as multifactorial chylomicronemia have been associated with high atherosclerotic cardiovascular disease (ASCVD) risk and metabolic abnormalities, ASCVD and metabolic syndrome are not usually observed in FCS patients. Because FCS is a genetic condition, the optimal diagnosis strategy remains genetic testing. The presence of bi-allelic pathogenic mutations in LPL, APOC2, GPIHBP1, APOA5 or LMF1 genes confirms the diagnosis. However, some cases of FCS caused by autoantibodies against LPL or GPIHBP1 proteins have also been reported. Furthermore, a clinical score for the diagnosis of FCS has been proposed but needs further validation. Available treatment options to lower triglycerides such as fibrates or omega-3 fatty acids are not efficacious in FCS patients. Currently, the cornerstone of treatment remains a lifelong very low-fat diet, which prevents the formation of chylomicrons. Finally, inhibitors of apo C-III and ANGPTL3 are in development and may eventually constitute additional treatment options for FCS patients.
Asunto(s)
Hiperlipoproteinemia Tipo I/complicaciones , Hipertrigliceridemia/etiología , Enfermedad Aguda , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Pancreatitis/etiologíaRESUMEN
Familial Chylomicronemia Syndrome (FCS) is a rare autosomal recessive lipid disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis. Because the disorder is often misdiagnosed or not diagnosed and because traditional triglyceride lowering medications are often ineffective, the disease leads to a tremendous physical, social and emotional burden on afflicted patients and their caretakers. Mutations in 5 different genes have been implicated in the development of FCS, all of which have an effect on the activity of lipoprotein lipase. Lipoprotein lipase(LPL) is responsible for removing triglycerides from chylomicrons and other triglyceride rich lipoproteins in the circulation, breaking them down into free fatty acids for use as energy. Patients with FCS have loss of function of their LPL leading to severely elevated chylomicrons in the circulation and hence, severe hypertriglyceridemia. The principle treatment for FCS is to reduce chylomicron formation in the gut by placing the patient on an extremely low fat diet. New medications in development hold significant promise for improving the quality of life for FCS patients.