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Saadatagah S, Larouche M, Naderian M, Nambi V, Brisson D, Kullo IJ, Duell PB, Michos ED, Shapiro MD, Watts GF, Gaudet D, Ballantyne CM. Recognition and management of persistent chylomicronemia: A joint expert clinical consensus by the National Lipid Association and the American Society for Preventive Cardiology. Am J Prev Cardiol 2025; 22:100978. [PMID: 40242365 PMCID: PMC12003024 DOI: 10.1016/j.ajpc.2025.100978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/18/2025] Open
Abstract
Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into four subtypes: 1) genetic FCS, 2) clinical FCS, 3) PC with "alarm" features, and 4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) post-heparin LPL activity <20 % of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apoC-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC specifically those with alarm features could help mitigate the risk of acute pancreatitis and other complications.
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Affiliation(s)
- Seyedmohammad Saadatagah
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, TX, USA
| | - Miriam Larouche
- Université de Montréal, Department of Medicine, Montreal, Canada
- ECOGENE-21, Chicoutimi, Canada
| | | | - Vijay Nambi
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
- Michael E. DeBakey Veterans Affairs Hospital, Houston, TX, USA
| | - Diane Brisson
- Université de Montréal, Department of Medicine, Montreal, Canada
- ECOGENE-21, Chicoutimi, Canada
| | - Iftikhar J. Kullo
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA
- Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA
| | - P Barton Duell
- Knight Cardiovascular Institute and Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland, OR, USA
| | - Erin D. Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Michael D. Shapiro
- Section of Cardiovascular Medicine, Center for Prevention of Cardiovascular Disease, Wake Forest University School of Medicine, Winston-Salem, NC, USA
| | - Gerald F. Watts
- Medical School, University of Western Australia, Perth, Australia
- Cardiometabolic Service, Departments of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia
| | - Daniel Gaudet
- Université de Montréal, Department of Medicine, Montreal, Canada
- ECOGENE-21, Chicoutimi, Canada
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Paquette M, Trinder M, Guay SP, Brunham LR, Baass A. Predictors of Cardiovascular Disease in Individuals With Dysbetalipoproteinemia: A Prospective Study in the UK Biobank. J Clin Endocrinol Metab 2025; 110:e1959-e1965. [PMID: 39243385 DOI: 10.1210/clinem/dgae618] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/23/2024] [Accepted: 09/05/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Dysbetalipoproteinemia (DBL) is a disorder of remnant cholesterol metabolism associated with a severe risk of atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE The objective of this study was to investigate the univariate and multivariate predictors of ASCVD in individuals with DBL. METHODS Data from 2699 individuals with ɛ2/ɛ2 genotypes from the UK Biobank were included in this study. DBL was defined as having an ɛ2ɛ2 genotype with evidence of dyslipidemia, defined as total cholesterol ≥ 200 mg/dL (5.2 mmol/L) and triglyceride ≥ 175 mg/dL (2.0 mmol/L) or lipid-lowering therapy use (n = 964). RESULTS Age, hypertension, waist circumference, and a polygenic risk score for coronary artery disease (PRSCAD) were independent predictors of ASCVD among individuals with DBL. Cumulative ASCVD-free survival was lower in the ɛ2/ɛ2 DBL group (84%) compared to the ɛ2/ɛ2 non-DBL group (94%) (P < .0001) and for DBL individuals with a PRSCAD ≥ median (79%) compared to those with a PRSCAD < median (89%) (P = .001). CONCLUSION We show in a large prospective cohort that a PRSCAD predicts the ASCVD risk among individuals with DBL. The findings of the present study highlight the need for better risk stratification in ɛ2/ɛ2 carriers to identify high-risk individuals who would need aggressive cardiovascular management despite their low apolipoprotein B value.
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Affiliation(s)
- Martine Paquette
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada
| | - Mark Trinder
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Simon-Pierre Guay
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada
- Department of Medicine, Division of Endocrinology, Université de Montréal, Montréal, QC H3T 1J4, Canada
| | - Liam R Brunham
- Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
- Department of Medicine, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada
| | - Alexis Baass
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC H2W 1R7, Canada
- Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, Montreal, QC H3G 2M1, Canada
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Paquette M, Guay SP, Baass A. Genetic determinants of pancreatitis risk in hypertriglyceridemia. Curr Opin Lipidol 2025; 36:55-60. [PMID: 39513935 DOI: 10.1097/mol.0000000000000962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
PURPOSE OF REVIEW In recent years, studies have shed light on the concept of risk heterogeneity among patients with severe hypertriglyceridemia (HTG). Several clinical risk factors for acute pancreatitis have been identified in this population, but the importance of different genetic factors above and beyond triglyceride concentration remains unclear. This review endeavours to summarize recent developments in this field. RECENT FINDINGS Recent studies suggest that the molecular basis of severe HTG (polygenic susceptibility vs. rare pathogenic variants) can modulate the risk of acute pancreatitis independently of triglyceride level. Furthermore, a pancreatitis polygenic risk score has been developed and validated using data from the largest GWAS meta-analysis of acute pancreatitis published to date. In patients with severe HTG, a high polygenic susceptibility for pancreatitis was associated with a three-fold increased risk of acute pancreatitis compared with those with a lower polygenic risk score. SUMMARY In the past months, there have been substantial advances in understanding the prediction of acute pancreatitis in patients with severe HTG. However, further efforts at developing risk-stratification strategies and predictive models may help identifying the patients who would benefit most from early and effective interventions to reduce the risk of pancreatitis, including treatment with APOC3 inhibitors.
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Affiliation(s)
- Martine Paquette
- Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal
| | - Simon-Pierre Guay
- Division of Medical Genetics, Department of Pediatric, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke
| | - Alexis Baass
- Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal
- Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, Montreal, Québec, Canada
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Saadatagah S, Larouche M, Naderian M, Nambi V, Brisson D, Kullo IJ, Duell PB, Michos ED, Shapiro MD, Watts GF, Gaudet D, Ballantyne CM. Recognition and management of persistent chylomicronemia: A joint expert clinical consensus by the National Lipid Association and the American Society for Preventive Cardiology. J Clin Lipidol 2025:S1933-2874(25)00065-0. [PMID: 40360374 DOI: 10.1016/j.jacl.2025.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 05/15/2025]
Abstract
Extreme hypertriglyceridemia, defined as triglyceride (TG) levels ≥1000 mg/dL, is almost always indicative of chylomicronemia. The current diagnostic approach categorizes individuals with chylomicronemia into familial chylomicronemia syndrome (FCS; prevalence 1-10 per million), caused by the biallelic combination of pathogenic variants that impair the lipolytic action of lipoprotein lipase (LPL), or multifactorial chylomicronemia syndrome (MCS, 1 in 500). A pragmatic framework should emphasize the severity of the phenotype and the risk of complications. Therefore, we endorse the term "persistent chylomicronemia (PC)" defined as TG ≥1000 mg/dL in more than half of the measurements to encompass patients with the highest risk for pancreatitis, regardless of their genetic predisposition. We suggest classification of PC into 4 subtypes: (1) genetic FCS, (2) clinical FCS, (3) PC with "alarm" features, and (4) PC without alarm features. Although patients with FCS most likely have PC, the vast majority with PC do not have genetic FCS. Proposed alarm features are: (a) history of recurrent TG-induced acute pancreatitis, (b) recurrent hospitalizations for severe abdominal pain without another identified cause, (c) childhood pancreatitis, (d) family history of TG-induced pancreatitis, and/or (e) postheparin LPL activity <20% of normal value. Alarm features constitute the strongest risk factors for future acute pancreatitis risk. Patients with PC and alarm features have very high risk of pancreatitis, comparable to that in patients with FCS. Effective, innovative treatments for PC, like apolipoprotein C-III inhibitors, have been developed. Combined with lifestyle modifications, these agents markedly lower TG levels and risk of pancreatitis in the very-high-risk groups, irrespective of the monogenic etiology. Pragmatic definitions, education, and focus on patients with PC, specifically those with alarm features, could help mitigate the risk of acute pancreatitis and other complications.
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Affiliation(s)
- Seyedmohammad Saadatagah
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA (Drs Saadatagah, Nambi, and Ballantyne); Center for Translational Research on Inflammatory Diseases, Baylor College of Medicine, Houston, TX, USA (Dr Saadatagah)
| | - Miriam Larouche
- Department of Medicine, Université de Montréal, Montreal, Canada (Drs Larouche, Brisson, and Gaudet); ECOGENE-21, Chicoutimi, Canada (Drs Larouche, Brisson, and Gaudet)
| | - Mohammadreza Naderian
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA (Drs Naderian and Kullo)
| | - Vijay Nambi
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA (Drs Saadatagah, Nambi, and Ballantyne); Michael E. DeBakey Veterans Affairs Hospital, Houston, TX, USA (Dr Nambi)
| | - Diane Brisson
- Department of Medicine, Université de Montréal, Montreal, Canada (Drs Larouche, Brisson, and Gaudet); ECOGENE-21, Chicoutimi, Canada (Drs Larouche, Brisson, and Gaudet)
| | - Iftikhar J Kullo
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA (Drs Naderian and Kullo); Gonda Vascular Center, Mayo Clinic, Rochester, MN, USA (Dr Kullo)
| | - P Barton Duell
- Knight Cardiovascular Institute and Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland, OR, USA (Dr Duell)
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA (Dr Michos)
| | - Michael D Shapiro
- Section of Cardiovascular Medicine, Center for Prevention of Cardiovascular Disease, Wake Forest University School of Medicine, Winston-Salem, NC, USA (Dr Shapiro)
| | - Gerald F Watts
- Medical School, University of Western Australia, Perth, Australia (Dr Watts); Cardiometabolic Service, Departments of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia (Dr Watts)
| | - Daniel Gaudet
- Department of Medicine, Université de Montréal, Montreal, Canada (Drs Larouche, Brisson, and Gaudet); ECOGENE-21, Chicoutimi, Canada (Drs Larouche, Brisson, and Gaudet).
| | - Christie M Ballantyne
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA (Drs Saadatagah, Nambi, and Ballantyne).
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Bardey F, Rieck L, Spira D, März W, Binner P, Schwab S, Kleber ME, Danyel M, Barkowski R, Bobbert T, Spranger J, Steinhagen-Thiessen E, Demuth I, Kassner U. Clinical characterization and mutation spectrum of patients with hypertriglyceridemia in a German outpatient clinic. J Lipid Res 2024; 65:100589. [PMID: 38969064 PMCID: PMC11913797 DOI: 10.1016/j.jlr.2024.100589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Revised: 06/13/2024] [Accepted: 06/21/2024] [Indexed: 07/07/2024] Open
Abstract
BACKGROUND Severe hypertriglyceridemia (HTG) has predominantly multifactorial causes (MCS). Yet a small subset of patients have the monogenetic form (FCS). It remains a challenge to distinguish patients clinically, since decompensated MCS might mimic FCS´s severity. Aim of the current study was to determine clinical criteria that could sufficiently distinguish both forms as well as to apply the FCS score proposed by Moulin and colleagues. METHODS We retrospectively studied 72 patients who presented with severe HTG in our clinic during a time span of seven years and received genetic testing. We classified genetic variants (ACMG-criteria), followed by genetic categorization into MCS or FCS. Clinical data were gathered from the medical records and the FCS score was calculated for each patient. RESULTS Molecular genetic screening revealed eight FCS patients and 64 MCS patients. Altogether, we found 13 pathogenic variants of which four have not been described before. The FCS patients showed a significantly higher median triglyceride level compared to the MCS. The FCS score yielded a sensitivity of 75% and a specificity of 93.7% in our cohort, and significantly differentiated between the FCS and MCS group (p<0.001). CONCLUSIONS In our cohort we identified several variables that significantly differentiated FCS from MCS. The FCS score performed similar to the original study by Moulin, thereby further validating the discriminatory power of the FCS score in an independent cohort.
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Affiliation(s)
- Frieda Bardey
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Lorenz Rieck
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Dominik Spira
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Winfried März
- Synlab Academy, P5, 7, 68167 Mannheim, Germany; Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Auenbrugger Platz 15, 8036 Graz
| | - Priska Binner
- Synlab Center of Human Genetics, Harrlachweg 1, 68163 Mannheim, Germany
| | - Stefanie Schwab
- Synlab Center of Human Genetics, Harrlachweg 1, 68163 Mannheim, Germany
| | - Marcus E Kleber
- Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany; Synlab Center of Human Genetics, Harrlachweg 1, 68163 Mannheim, Germany
| | - Magdalena Danyel
- Berlin Institute of Health (BIH), Berlin, Germany; Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, Berlin, 13353, Germany
| | - Rasmus Barkowski
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Thomas Bobbert
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Joachim Spranger
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Elisabeth Steinhagen-Thiessen
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
| | - Ilja Demuth
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany; Charité - Universitätsmedizin Berlin, BCRT - Berlin Institute of Health Center for Regenerative Therapies, Berlin, Germany.
| | - Ursula Kassner
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Endocrinology and Metabolic Diseases (including Division of Lipid Metabolism), Augustenburger Platz 1, 13353 Berlin, Germany
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den Hollander B, Brands MM, Nijhuis IJM, Doude van Troostwijk LJAE, van Essen P, Hofsteenge GH, Koot BG, Müller AR, Tseng LA, Stroes ESG, van de Ven PM, Wiegman A, van Karnebeek CDM. Breaking the chains of lipoprotein lipase deficiency: A pediatric perspective on the efficacy and safety of Volanesorsen. Mol Genet Metab 2024; 142:108347. [PMID: 38401382 DOI: 10.1016/j.ymgme.2024.108347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 02/10/2024] [Accepted: 02/11/2024] [Indexed: 02/26/2024]
Abstract
RATIONALE Lipoprotein lipase (LPL) deficiency, a rare inherited metabolic disorder, is characterized by high triglyceride (TG) levels and life-threatening acute pancreatitis. Current treatment for pediatric patients involves a lifelong severely fat-restricted diet, posing adherence challenges. Volanesorsen, an EMA-approved RNA therapy for adults, effectively reduces TG levels by decreasing the production of apolipoprotein C-III. This 96-week observational open-label study explores Volanesorsen's safety and efficacy in a 13-year-old female with LPL deficiency. METHODS The patient, with a history of severe TG elevations, 53 hospital admissions, and life-threatening recurrent pancreatitis despite dietary restrictions, received weekly subcutaneous Volanesorsen injections. We designed a protocol for this investigator-initiated study, primarily focusing on changes in fasting TG levels and hospital admissions. RESULTS While the injections caused occasional pain and swelling, no other adverse events were observed. TG levels decreased during treatment, with more measurements below the pancreatitis risk threshold compared to pre-treatment. No hospital admissions occurred in the initial 14 months of treatment, contrasting with 21 admissions in the 96 weeks before. In the past 10 months, two pancreatitis episodes may have been linked to dietary noncompliance. Dietary restrictions were relaxed, increasing fat intake by 65% compared to baseline. While not fully reflected in the PedsQL, both parents and the patient narratively reported an improved quality of life. CONCLUSION This study demonstrates, for the first time, that Volanesorsen is tolerated in a pediatric patient with severe LPL deficiency and effectively lowers TG levels, preventing life-threatening complications. This warrants consideration for expanded access in this population.
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Affiliation(s)
- Bibiche den Hollander
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands; United for Metabolic Diseases, the Netherlands
| | - Marion M Brands
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands; United for Metabolic Diseases, the Netherlands
| | - Ilse J M Nijhuis
- Wilhelmina Hospital Assen, Department of Pediatrics, Europaweg-Zuid 1, Assen, the Netherlands
| | | | - Peter van Essen
- Radboud University Medical Center, Department of Pediatrics, Amalia Children's Hospital, Geert Grooteplein Zuid 10, Nijmegen, the Netherlands
| | - Geesje H Hofsteenge
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Nutrition & Dietetics, Meibergdreef 9, Amsterdam, the Netherlands
| | - Bart G Koot
- Amsterdam UMC location University of Amsterdam, Department of Paediatric Gastroenterology and Nutrition, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
| | - Annelieke R Müller
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands
| | - Laura A Tseng
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands; University Medical Center Rotterdam, Department of Pediatrics, Sophia Children's Hospital, Dr. Molewaterplein 40, Rotterdam, the Netherlands
| | - Erik S G Stroes
- Amsterdam UMC location University of Amsterdam, Department of Vascular Medicine, Meibergdraaf 9, Amsterdam, the Netherlands
| | - Peter M van de Ven
- University Medical Centre Utrecht, Department of Data Science and Biostatistics, Julius Center for Health Sciences and Primary Care, Heidelberglaan 100, Utrecht, Netherlands
| | - Albert Wiegman
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands
| | - Clara D M van Karnebeek
- Amsterdam UMC location University of Amsterdam, Department of Pediatrics, Emma Children's Hospital, Amsterdam Gastroenterology Endocrinology Metabolism, Meibergdreef 9, Amsterdam, the Netherlands; Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, the Netherlands; United for Metabolic Diseases, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Human Genetics, Amsterdam Reproduction and Development, Meibergdreef 9, Amsterdam, the Netherlands.
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Mangeshkar S, Nazarenko N, Varrias D, Spanos M, Borkowski P, Alhuarrat MAD, Li W, Kishore P, Faillace RT. A Case of Type V Hyperlipoproteinemia Resistant to Insulin Treatment. Cureus 2023; 15:e41424. [PMID: 37546045 PMCID: PMC10403339 DOI: 10.7759/cureus.41424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2023] [Indexed: 08/08/2023] Open
Abstract
Type V hyperlipoproteinemia or multifactorial chylomicronemia syndrome is a rare lipid disorder triggered mainly by uncontrolled diabetes, obesity, poor diet, or particular medications. It is associated with an increased risk of acute pancreatitis and accelerated coronary artery disease which may manifest in younger age groups. We present a case of a 42-year-old male who presented to the emergency department (ED) complaining of a non-healing hand injury. Upon laboratory workup, the patient was found to have an elevated total cholesterol (TC) of 1129 mg/dL, very low levels of high-density lipoprotein (HDL) and triglycerides (TG) > 4000 mg/dL with an inability to calculate low-density lipoprotein (LDL). Lipoprotein electrophoresis revealed an actual TG level of > 7000 mg/dL, increased chylomicrons, normal B and pre-B-lipoproteins, and increased L-lipoproteins with an elevated Apolipoprotein B. Despite these derangements, the patient did not exhibit any abdominal complaints, demonstrating a normal lipase level. The physical exam was indicative of bilateral arcus senilis and obesity. Insulin drip was initiated along with intravenous (IV) hydration and it required 12 days to bring triglycerides down to less than 1000 mg/dL. The total cholesterol was also seen to be down trending to around 500 mg/dL and the HDL improved to 22 mg/dL. We present this case as a unique presentation of asymptomatic chylomicronemia resistant to insulin treatment with an elevated ApoB but with no evidence of pancreatitis or coronary artery disease.
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Affiliation(s)
- Shaunak Mangeshkar
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
| | - Natalia Nazarenko
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
| | - Dimitrios Varrias
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
| | - Michail Spanos
- Cardiovascular Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, USA
| | - Pawel Borkowski
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
| | - Majd Al Deen Alhuarrat
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
| | - Weijia Li
- Cardiology, AdventHealth Orlando, Orlando, USA
| | | | - Robert T Faillace
- Internal Medicine, Albert Einstein College of Medicine, Jacobi Medical Center, New York, USA
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De Villers-Lacasse A, Paquette M, Baass A, Bernard S. Non-alcoholic fatty liver disease in patients with chylomicronemia syndromes. J Clin Lipidol 2023; 17:475-482. [PMID: 37258405 DOI: 10.1016/j.jacl.2023.05.096] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 05/05/2023] [Accepted: 05/16/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Chylomicronemia syndrome is a form of severe hypertriglyceridemia (HTG) caused by the familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS). Non-alcoholic fatty liver disease (NAFLD) has been associated with components of the metabolic syndrome and is more prevalent in subjects with elevated triglycerides. OBJECTIVE The primary objective was to compare the prevalence of hepatic steatosis assessed by conventional imaging between HTG groups (FSC, MCS and moderate HTG (mHTG)). The secondary objective was to determine the difference in the prevalence of liver fibrosis. METHODS This cross-sectional observational study was performed on adult patients from the lipid clinic of the Montreal Clinical Research Institute (IRCM). We retrospectively reviewed the imaging reports available in the patients' files for signs of NAFLD. We also used the FIB-4 index as a surrogate marker of liver fibrosis. RESULTS We reviewed the medical files of 300 patients; 22 with FCS, 82 with MCS and 196 with mHTG. There was significantly more hepatic steatosis in the MCS group compared to the mHTG and FCS groups (79%, 66% and 43% respectively p=0.02). There was a significantly higher prevalence of subjects within the "unlikely fibrosis" category in the mHTG group (91%) compared to the MCS (84%) and FCS groups (59%), p=0.0004. CONCLUSION We found that the prevalence of hepatic steatosis was 3-, 2.5-, and 2-fold higher in MCS, mHTG and FCS patients than in the general population. This suggests that patients with elevated triglycerides, regardless of the underlying etiology, are at higher risk of hepatic steatosis and NAFLD.
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Affiliation(s)
- Ariane De Villers-Lacasse
- Department of Medicine, Division of Endocrinology, University of Montreal, Montreal (Québec, Canada)
| | - Martine Paquette
- Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal (Québec, Canada)
| | - Alexis Baass
- Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal (Québec, Canada); Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, Montreal (Québec, Canada)
| | - Sophie Bernard
- Department of Medicine, Division of Endocrinology, University of Montreal, Montreal (Québec, Canada); Genetic Dyslipidemias Clinic of the Montreal Clinical Research Institute, Montreal (Québec, Canada); Research Centre of the Centre Hospitalier Universitaire de Montréal (CRCHUM), Montreal, (Québec, Canada).
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9
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Yu F, Teng Y, Li J, Yang S, Zhang Z, He Y, Yang H, Ding CF, Zhou P. Effects of a Ganoderma lucidum Proteoglycan on Type 2 Diabetic Rats and the Recovery of Rat Pancreatic Islets. ACS OMEGA 2023; 8:17304-17316. [PMID: 37214729 PMCID: PMC10193549 DOI: 10.1021/acsomega.3c02200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/02/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023]
Abstract
Type 2 diabetes (T2D) results from both insulin resistance and pancreatic β-cell dysfunction. A natural proteoglycan extracted from Ganoderma lucidum, namely, FYGL, has been demonstrated to be capable of ameliorating insulin resistance in previous work. In this work, a T2D rat model induced by streptozocin (STZ) and a high-fat diet was used to investigate the effects of FYGL on pancreatic functions, and the transcriptomics of the rat pancreas was used to investigate the biological processes (BP) and signal pathways influenced by FYGL on the gene basis. Furthermore, the results of transcriptomics were verified both by histopathological analyses and protein expression. The studies showed that FYGL positively regulated T2D-related BP and signaling pathways and recovered the pancreatic function, therefore ameliorating hyperglycemia and hyperlipidemia in vivo. Importantly, the recovery of the pancreatic function suggested a crucial strategy to radically treat T2D.
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Affiliation(s)
- Fanzhen Yu
- State
Key Laboratory of Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433, China
| | - Yilong Teng
- State
Key Laboratory of Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433, China
| | - Jiaqi Li
- State
Key Laboratory of Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433, China
| | - Shutong Yang
- Department
of Chemistry, Fudan University, Shanghai 200433, China
| | - Zeng Zhang
- Yueyang
Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China
| | - Yanming He
- Yueyang
Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China
| | - Hongjie Yang
- Yueyang
Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, P. R. China
| | - Chuan-Fan Ding
- Zhejiang
Provincial Key Laboratory of Advanced Mass Spectrometry and Molecular
Analysis, Institute of Mass Spectrometry, School of Material Science and Chemical Engineering, Ningbo University, Ningbo, Zhejiang 315211, China
| | - Ping Zhou
- State
Key Laboratory of Molecular Engineering of Polymers, Department of
Macromolecular Science, Fudan University, Shanghai 200433, China
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10
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Izar MCDO, Santos Filho RDD, Assad MHV, Chagas ACP, Toledo Júnior ADO, Nogueira ACC, Souto ACCF, Lottenberg AMP, Chacra APM, Ferreira CEDS, Lourenço CM, Valerio CM, Cintra DE, Fonseca FAH, Campana GA, Bianco HT, Lima JGD, Castelo MHCG, Scartezini M, Moretti MA, Barreto NSF, Maia RE, Montenegro Junior RM, Alves RJ, Figueiredo RMM, Fock RA, Martinez TLDR. Brazilian Position Statement for Familial Chylomicronemia Syndrome - 2023. Arq Bras Cardiol 2023; 120:e20230203. [PMID: 37075362 PMCID: PMC10348387 DOI: 10.36660/abc.20230203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/07/2023] Open
Affiliation(s)
| | | | | | | | | | | | | | - Ana Maria Pitta Lottenberg
- Laboratório de Lípides (LIM 10) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP - Brasil
- Hospital Israelita Albert Einstein (HIAE), São Paulo, SP - Brasil
| | - Ana Paula Marte Chacra
- Instituto do Coração (Incor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP - Brasil
| | | | | | - Cynthia Melissa Valerio
- Instituto Estadual de Diabetes e Endocrinologia Luiz Capriglione (IEDE-RJ), Rio de Janeiro, RJ - Brasil
| | | | | | | | | | - Josivan Gomes de Lima
- Hospital Universitário Onofre Lopes da Universidade Federal do Rio Grande do Norte (UFRN), Natal, RN - Brasil
| | | | | | - Miguel Antonio Moretti
- Instituto do Coração (Incor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP), São Paulo, SP - Brasil
| | | | | | - Renan Magalhães Montenegro Junior
- Complexo Hospitalar da Universidade Federal do Ceará (UFCE), Empresa Brasileira de Serviços Hospitalares (EBSERH), Fortaleza, CE - Brasil
| | - Renato Jorge Alves
- Hospital Santa Casa de Misericórdia de São Paulo, São Paulo, SP - Brasil
| | - Roberta Marcondes Machado Figueiredo
- Hospital Israelita Albert Einstein (HIAE), São Paulo, SP - Brasil
- Faculdade Israelita de Ciências da Saúde Albert Einstein (FICSAE), São Paulo, SP - Brasil
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11
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Yang QY, Zhao Q, Hu JW. Incidence and clinical treatment of hypertriglyceridemic acute pancreatitis: A few issues. World J Clin Cases 2023; 11:479-481. [PMID: 36686359 PMCID: PMC9850974 DOI: 10.12998/wjcc.v11.i2.479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 11/16/2022] [Accepted: 01/03/2023] [Indexed: 01/12/2023] Open
Abstract
Hypertriglyceridemia is a well-recognized etiology of acute pancreatitis, and the incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) has increased in frequency worldwide in response to lifestyle changes. It is crucial to identify hypertriglyceridemia as the cause of pancreatitis and initiate appropriate treatment. Insulin treatment produces effective lowering of triglycerides, but in our opinion, non-diabetic patients with HTG-AP require separate consideration to avoid hypoglycemia.
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Affiliation(s)
- Qun-Ying Yang
- Department of Gastroenterology, Dongyang People's Hospital, Dongyang 322100, Zhejiang Province, China
| | - Qian Zhao
- Department of Gastroenterology, Dongyang People's Hospital, Dongyang 322100, Zhejiang Province, China
| | - Jian-Wen Hu
- Department of Gastroenterology, Dongyang People's Hospital, Dongyang 322100, Zhejiang Province, China
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12
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Paquette M, Bernard S, Baass A. Dysbetalipoproteinemia Is Associated With Increased Risk of Coronary and Peripheral Vascular Disease. J Clin Endocrinol Metab 2022; 108:184-190. [PMID: 36056815 DOI: 10.1210/clinem/dgac503] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 08/12/2022] [Indexed: 02/03/2023]
Abstract
CONTEXT Dysbetalipoproteinemia (DBL) is a disorder in which remnant lipoproteins accumulate in the plasma due to a genetic apolipoprotein E dysfunction in conjunction with the presence of secondary metabolic factors. An increased risk of both coronary and peripheral vascular disease (PVD) has been observed in these patients in retrospective studies. OBJECTIVE The primary objective was to compare the incidence of atherosclerotic cardiovascular disease (ASCVD) and PVD in a cohort of patients with DBL compared with normolipidemic controls. As a secondary objective, the incidence of ASCVD and PVD was compared between patients with DBL and patients with familial hypercholesterolemia (FH). METHODS A total of 221 patients with DBL, 725 patients with FH, and 1481 normolipidemic controls were included in the study. The data were obtained by review of medical records. RESULTS In patients with DBL, there was an overall excess risk of PVD (hazard ratio [HR] 13.58, 95% CI 4.76-38.75) and ASCVD (HR 3.55, 95% CI 2.17-5.83) (P < .0001) when compared with normolipidemic controls. When compared with patients with FH, an increased risk of PVD (HR 3.89, 95% CI 1.20-12.55, P = .02) was observed in patients with DBL. CONCLUSION We demonstrated that the risks of ASCVD and PVD in DBL are >3-fold and >13-fold higher, respectively, than normolipidemic controls. Furthermore, the risk of PVD is ∼4-fold higher in DBL than in FH. Adequate screening of DBL is imperative to improve the clinical care of these patients by preventing the development of ASCVD.
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Affiliation(s)
- Martine Paquette
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC, Canada
| | - Sophie Bernard
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC, Canada
- Department of Medicine, Division of Endocrinology, Université de Montreal, Montreal, QC, Canada
| | - Alexis Baass
- Lipids, Nutrition, and Cardiovascular Prevention Clinic of the Montreal Clinical Research Institute, Montreal, QC, Canada
- Department of Medicine, Divisions of Experimental Medicine and Medical Biochemistry, McGill University, Montreal, QC, Canada
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13
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Abstract
PURPOSE OF REVIEW This review will briefly revise the evidence concerning the pharmacological inhibition of Apolipoprotein CIII (ApoCIII) in patients with hypertriglyceridemia. RECENT FINDINGS ApoCIII is a plasma apolipoprotein playing a major role in the metabolism of triglyceride-rich lipoproteins, namely chylomicrons and very-low-density lipoproteins as well as in the pathological processes involved in atherosclerosis. Therefore, ApoCIII is a potential new target for reducing plasma levels of TRLs and, thereby, cardiovascular risk. In recent years, there have been extensive preclinical and clinical pharmacological studies aimed at testing drugs directed against ApoCIII. SUMMARY In this review, firstly we will summarize the molecular function of ApoCIII in lipoprotein metabolism. Then, we will examine the lipid-lowering potential of the pharmacological inhibition of ApoCIII based on the results of clinical trial employing Volansesorsen, the first approved antisense therapeutic oligonucleotide against ApoCIII mRNA. The future perspectives for ApoCIII inhibition will be also revised.
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Affiliation(s)
- Daniele Tramontano
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
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14
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Paquette M, Bernard S. The Evolving Story of Multifactorial Chylomicronemia Syndrome. Front Cardiovasc Med 2022; 9:886266. [PMID: 35498015 PMCID: PMC9046927 DOI: 10.3389/fcvm.2022.886266] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 03/24/2022] [Indexed: 11/13/2022] Open
Abstract
Multifactorial chylomicronemia syndrome (MCS or type V hyperlipoproteinemia) is the most frequent cause of severe hypertriglyceridemia and is associated with an increased risk of acute pancreatitis, cardiovascular disease, and non-alcoholic steatohepatitis. The estimated prevalence of MCS in the North American population is 1:600–1:250 and is increasing due to the increasing prevalence of obesity, metabolic syndrome, and type 2 diabetes. Differentiating between familial chylomicronemia syndrome and MCS is crucial due to their very different treatments. In recent years, several cohort studies have helped to differentiate these two conditions, and recent evidence suggests that MCS itself is a heterogeneous condition. This mini-review will summarize recent literature on MCS, with a specific focus on the genetic determinants of the metabolic risk and the latest developments concerning the pharmacological and non-pharmacological treatment options for these patients. Possible research directions in this field will also be discussed.
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Affiliation(s)
- Martine Paquette
- Genetic Dyslipidemias Clinic, Montreal Clinical Research Institute, Montreal, QC, Canada
| | - Sophie Bernard
- Genetic Dyslipidemias Clinic, Montreal Clinical Research Institute, Montreal, QC, Canada
- Division of Endocrinology, Department of Medicine, Université de Montréal, Montreal, QC, Canada
- *Correspondence: Sophie Bernard
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15
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Volanesorsen: A New Era in the Treatment of Severe Hypertriglyceridemia. J Clin Med 2022; 11:jcm11040982. [PMID: 35207255 PMCID: PMC8880470 DOI: 10.3390/jcm11040982] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 11/20/2022] Open
Abstract
Introduction: Familial chylomicronemia syndrome (FCS) is a rare inherited disease, mainly due to lipoprotein lipase (LPL) gene mutations, leading to lipid abnormalities. Volanesorsen, a second-generation 2′-O-methoxyethyl (2′-MOE) chimeric antisense therapeutic oligonucleotide, can decrease plasma apolipoprotein C3 and triglycerides (TG) levels through LPL-independent pathways. The European Medicines Agency has approved volanesorsen as an adjunct to diet in adult FCS patients with an inadequate response to TG-lowering therapy. Areas covered: Available clinical data on volanesorsen efficacy and safety are presented. Furthermore, we discuss the yearly treatment with volanesorsen of a 21-year-old female FCS patient with LPL mutation. Volanesorsen was well-tolerated and decreased patient’s TG levels (from >5000 mg/dL (56 mmol/L) to 350–500 mg/dL (4–5.6 mmol/L)) at 12 months. Lipoprotein apheresis (LA) was stopped and there were no episodes of pancreatitis or abdominal pain. Expert opinion: Severe hypertriglyceridemia can potentially be fatal. Until recently, there was no specific treatment for FCS, apart from hypotriglyceridemic diet, fibrates, omega-3 fatty acids, and LA sessions. Therefore, volanesorsen represents a promising therapeutic solution for these patients. The main side effect of volanesorsen therapy is thrombocytopenia, which should be monitored and treated accordingly. Increasing evidence will further elucidate the clinical implications of volanesorsen use in daily practice.
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16
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Both low-fat and low-carbohydrate diets reduce triglyceride concentration in subjects with multifactorial chylomicronemia syndrome: a randomized crossover study. Nutr Res 2022; 101:43-52. [DOI: 10.1016/j.nutres.2022.02.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 02/02/2022] [Accepted: 02/10/2022] [Indexed: 12/19/2022]
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17
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Wang M, Zhou Y, He X, Deng C, Liu X, Li J, Zhou L, Li Y, Zhang Y, Liu H, Li L. Two novel mutations of the LPL gene in two Chinese family cases with familial chylomicronemia syndrome. Clin Chim Acta 2021; 521:264-271. [PMID: 34324844 DOI: 10.1016/j.cca.2021.07.022] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 07/23/2021] [Accepted: 07/23/2021] [Indexed: 10/20/2022]
Abstract
The aim of this study was to investigate the clinical features and genetic causes of two family cases with familial chylomicronemia syndrome (FCS). Clinical manifestations of proband 1 and her families, and also proband 2 showed severe hypertriglyceridemia, especially the triglycerides levels of two probands were extremely high. Gene sequencing results showed that the LPL genes in each of the two probands had a new mutation site. For the proband 1, a compound heterozygous mutation at c.429 (c.429 + 1G > T) was detected in the LPL gene, which was splicing mutation and inherited from her mother. Homozygous mutation was detected in the LPL gene of proband 2, the nucleotide mutation at c.802 (c.802C > T) exhibited missense mutation, his parents and brother had a heterozygous mutation at the same site. It was confirmed that the conservative lipoprotein lipase superfamily domain changed an amino acid from histidine to tyrosine at p. 268 (p. His268Tyr). Flow cytometry confirmed the deficient expression of LPL protein in two families. These results indicated that the mutation in LPL gene might be the cause of familial chylomicronemia syndrome.
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Affiliation(s)
- Mingying Wang
- Department of Gastroenterology, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Yuantao Zhou
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Xiaoli He
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Chengjun Deng
- Department of Gastroenterology, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Xiaoning Liu
- Department of Pharmacy, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Juan Li
- Department of Gastroenterology, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Lin Zhou
- Department of Nutrition, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Ying Li
- Department of Gastroenterology, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Yu Zhang
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Haifeng Liu
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming 650228, Yunnan, China
| | - Li Li
- Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children's Major Disease Research, Yunnan Medical Center for Pediatric Diseases, Yunnan Institute of Pediatrics, Kunming Children's Hospital, Kunming 650228, Yunnan, China.
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18
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Okazaki H, Gotoda T, Ogura M, Ishibashi S, Inagaki K, Daida H, Hayashi T, Hori M, Masuda D, Matsuki K, Yokoyama S, Harada-Shiba M. Current Diagnosis and Management of Primary Chylomicronemia. J Atheroscler Thromb 2021; 28:883-904. [PMID: 33980761 PMCID: PMC8532063 DOI: 10.5551/jat.rv17054] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
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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Affiliation(s)
- Hiroaki Okazaki
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo
| | - Takanari Gotoda
- Department of Metabolic Biochemistry, Faculty of Medicine, Kyorin University
| | - Masatsune Ogura
- Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute
| | - Shun Ishibashi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University
| | - Kyoko Inagaki
- Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, Nippon Medical School
| | - Hiroyuki Daida
- Faculty of Health Science, Juntendo University, Juntendo University Graduate School of Medicine
| | - Toshio Hayashi
- School of Health Sciences, Nagoya University Graduate School of Medicine
| | - Mika Hori
- Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University
| | - Daisaku Masuda
- Department of Cardiology, Health Care Center, Rinku Innovation Center for Wellness Care and Activities (RICWA), Rinku General Medical Center
| | - Kota Matsuki
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine
| | | | - Mariko Harada-Shiba
- Department of Molecular Pathogenesis, National Cerebral and Cardiovascular Center Research Institute
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Karantas ID, Okur ME, Okur NÜ, Siafaka PI. Dyslipidemia Management in 2020: An Update on Diagnosis and Therapeutic Perspectives. Endocr Metab Immune Disord Drug Targets 2021; 21:815-834. [PMID: 32778041 DOI: 10.2174/1871530320666200810144004] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 06/10/2020] [Accepted: 06/19/2020] [Indexed: 11/22/2022]
Abstract
Cardiovascular diseases are the leading cause of death in the modern world and dyslipidemia is one of the major risk factors. The current therapeutic strategies for cardiovascular diseases involve the management of risk factors, especially dyslipidemia and hypertension. Recently, the updated guidelines of dyslipidemia management were presented, and the newest data were included in terms of diagnosis, imaging, and treatment. In this targeted literature review, the researchers presented the most recent evidence on dyslipidemia management by including the current therapeutic goals for it. In addition, the novel diagnostic tools based on theranostics are shown. Finally, the future perspectives on treatment based on novel drug delivery systems and their potential to be used in clinical trials were also analyzed. It should be noted that dyslipidemia management can be achieved by the strict lifestyle change, i.e., by adopting a healthy life, and choosing the most suitable medication. This review can help medical professionals as well as specialists of other sciences to update their knowledge on dyslipidemia management, which can lead to better therapeutic outcomes and newer drug developments.
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Affiliation(s)
| | - Mehmet E Okur
- University of Health Sciences, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey
| | - Neslihan Ü Okur
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Health Sciences, Istanbul, Turkey
| | - Panoraia I Siafaka
- Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Health Sciences, Istanbul, Turkey
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20
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Posener S, Weiss N, Le Guennec L. Milky effluent after therapeutic plasma exchange. Acta Neurol Belg 2021; 122:1595-1596. [PMID: 33914295 DOI: 10.1007/s13760-021-01679-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 04/10/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Sacha Posener
- Sorbonne Université, Faculté de Médecine, Paris, France.
- Médecine Intensive Réanimation Neurologique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
| | - Nicolas Weiss
- Sorbonne Université, Faculté de Médecine, Paris, France
- Médecine Intensive Réanimation Neurologique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Loïc Le Guennec
- Sorbonne Université, Faculté de Médecine, Paris, France
- Médecine Intensive Réanimation Neurologique, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
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21
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Secondary Causes of Hypertriglyceridemia are Prevalent Among Patients Presenting With Hypertriglyceridemia Induced Acute Pancreatitis. Am J Med Sci 2021; 361:616-623. [PMID: 33618838 DOI: 10.1016/j.amjms.2021.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 09/19/2020] [Accepted: 01/08/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Hypertriglyceridemia induced acute pancreatitis (HIAP) is the third common cause of acute pancreatitis. HIAP can result in recurrent attacks of severe AP with significant morbidity and mortality. Hypertriglyceridemia (HTG) could be primary or secondary. Although genetic causes of HTG are well studied, the prevalence of secondary causes of HTG in patients presenting with HIAP is not well characterized. This study aimed to identify the prevalence of risk factors for secondary hypertriglyceridemia among patients presenting with HIAP in a tertiary referral center in a large metropolitan area. METHODS This is a retrospective analysis of all patients admitted with AP from August 2012-2017. A subgroup of patients with triglycerides >880 mg/dl were included for analysis. Secondary causes of HTG were identified. Secondary analysis evaluating the severity of pancreatitis was performed. RESULTS There were 3,746 patients admitted for AP of which 57 patients had AP and HTG. Of these 57 patients, 70.2% had history of diabetes mellitus, 26.3% had history of heavy alcohol use, 22.8% had chronic kidney disease, 47.3% with obesity, and 21.1% with metabolic syndrome. Two patients were classified as unexplained HTG. Secondary analysis showed a total of 45.6% of patients requiring ICU admission. 26.3% of patients with severe inflammatory pancreatitis and 17.5% of patients with severe necrotizing pancreatitis. CONCLUSIONS In our cohort of HIAP, 55 out of 57 patients had secondary causes for HTG. Identifying secondary causes of HTG during acute hospitalization is important to tailor outpatient treatment in order to prevent future admissions with HIAP.
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Maltais M, Brisson D, Gaudet D. Non-Alcoholic Fatty Liver in Patients with Chylomicronemia. J Clin Med 2021; 10:669. [PMID: 33572376 PMCID: PMC7916177 DOI: 10.3390/jcm10040669] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/28/2021] [Accepted: 02/05/2021] [Indexed: 01/21/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is frequent in patients with features of the metabolic syndrome (MetS), obesity, or type 2 diabetes. Lipoprotein lipase (LPL) is the main driver of triglyceride (TG) hydrolysis in chylomicrons and very-low density lipoproteins (VLDL). In some patients with MetS, dysfunction of this pathway can lead to plasma TG values > 10 mmol/L (multifactorial chylomicronemia or MCS). Chylomicronemia also characterizes LPL deficiency (LPLD), a rare autosomal recessive disease called familial chylomicronemia syndrome (FCS), which is associated with an increased risk of recurrent pancreatitis. This study aims to investigate the expression of NAFLD, as assessed by transient elastography, in MCS and FCS subjects. Data were obtained from 38 subjects with chylomicronemia; 19 genetically confirmed FCS and 19 sex- and age-matched MCS. All participants underwent liver ultrasonography and stiffness measurement after a 4-h fast using transient elastography (FibroScan®, Echosens, Waltham, MA, USA). NAFLD (controlled attenuation parameter (CAP) > 280 dB/m) was observed in 42.1% of FCS and 73.7% of MCS subjects (p = 0.05). FCS subjects had lower body mass index (BMI) than MCS. Only 25% of FCS subjects with NAFLD had a BMI ≥ 30 compared to 64.3% in MCS (p = 0.004). In FCS, NAFLD occurred even in the presence of very low (≤18 kg/m2) BMI. In both FCS and MCS, CAP was negatively associated with acute pancreatitis risk. In this study, NAFLD was commonly observed in both FCS and MCS subjects and occurred independently of the BMI and fasting glucose values in FCS; NAFLD was associated with a lower occurrence of acute pancreatitis episodes.
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Affiliation(s)
| | | | - Daniel Gaudet
- Lipidology Unit, Community Genomic Medicine Center, Department of Medicine, Université de Montréal, ECOGENE-21 Clinical and Translational Research Center, Chicoutimi, QC G7H 7K9, Canada; (M.M.); (D.B.)
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Esan O, Wierzbicki AS. Volanesorsen in the Treatment of Familial Chylomicronemia Syndrome or Hypertriglyceridaemia: Design, Development and Place in Therapy. DRUG DESIGN DEVELOPMENT AND THERAPY 2020; 14:2623-2636. [PMID: 32753844 PMCID: PMC7351689 DOI: 10.2147/dddt.s224771] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 06/18/2020] [Indexed: 02/04/2023]
Abstract
Severe hypertriglyceridaemia is associated with pancreatitis and chronic pancreatitis-induced diabetes. Familial chylomicronaemia syndrome (FCS) is a rare autosomal recessive disorder of lipid metabolism characterised by high levels of triglycerides (TGs) due to failure of chylomicron clearance. It causes repeated episodes of severe abdominal pain, fatigue and attacks of acute pancreatitis. There are few current options for its long-term management. The only universal long-term therapy is restriction of total dietary fat intake to <10-15% of daily calories (15 to 20g per day). Many patients have been treated with fibrates and statins with a variable response, but many remain susceptible to pancreatitis. Other genetic syndromes associated with hypertriglyceridaemia include familial partial lipodystrophy (FPLD). Targeting apolipoprotein C3 (apoC3) offers the ability to increase clearance of chylomicrons and other triglyceride-rich lipoproteins. Volanesorsen is an antisense oligonucleotide (ASO) inhibitor of apoC3, which reduces TG levels by 70–80% which has been shown also to reduce rates of pancreatitis and improve well-being in FCS and reduce TGs and improve insulin resistance in FPLD. It is now undergoing licensing and payer reviews. Further developments of antisense technology including small interfering RNA therapy to apoC3 as well as other approaches to modulating triglycerides are in development for this rare disorder.
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Affiliation(s)
- Oluwayemisi Esan
- Department of Metabolic Medicine/Chemical Pathology, Guy's & St Thomas' Hospitals, London SE1 7EH, UK
| | - Anthony S Wierzbicki
- Department of Metabolic Medicine/Chemical Pathology, Guy's & St Thomas' Hospitals, London SE1 7EH, UK
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Gaudet D, Stevenson M, Komari N, Trentin G, Crowson C, Hadker N, Bernard S. The burden of familial chylomicronemia syndrome in Canadian patients. Lipids Health Dis 2020; 19:120. [PMID: 32487261 PMCID: PMC7268343 DOI: 10.1186/s12944-020-01302-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Accepted: 05/28/2020] [Indexed: 12/27/2022] Open
Abstract
Background Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. Objective To understand the burden of illness of FCS on Canadian patients’ lives. Methods IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. Results A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FCS-related comorbidities. Notably, 35% of those who answered the survey have experienced acute pancreatitis, averaging 14 lifetime episodes per patient. In the preceding 12 months, 46% of patients had an FCS-related hospitalization, averaging 3 nights’ stay. All respondents restricted fat intake, with 27% following an extremely low-fat diet. Despite this, 100% of patients reported fasting TG levels above the normal range. FCS impacted career choice in nearly all patients (97%) and employment status in all patients who were employed part time, disabled, or homemakers, causing many (> 75%) to choose careers below their level of abilities. Furthermore, 2/3 of patients reported FCS had a significant impact on their decision regarding whether to have children. Most report significant interference with their emotional/mental well-being, social relationships, and the majority were concerned about the long-term impact of FCS on their health (89%). Conclusions This study provides the first and largest study to investigate the multi-faceted psychosocial and cognitive impacts of FCS on patients. Canadian patients with FCS experience significant multi-faceted burdens that diminish their quality of life, employment opportunities, social relationships, and mental/emotional well-being. These results highlight the need for greater disease awareness, improved clinical diagnosis, broader clinical management for heterogenous symptoms, and more effective treatment options for FCS.
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Affiliation(s)
- Daniel Gaudet
- Clinical Lipidology Unit, Department of Medicine, Université de Montréal, Chicoutimi, QC, Canada. .,ECOGENE-21 Clinical and Translational Research Center, Department of Medicine, Université de Montréal, 350 Jacques-Cartier B210, Chicoutimi, Québec, G7H 7P2, Canada.
| | | | - Nelly Komari
- Akcea Therapeutics, 1220-55 Metcalfe Street, Ottawa, ON, K1P 6L5, Canada
| | - Grace Trentin
- Akcea Therapeutics, 1220-55 Metcalfe Street, Ottawa, ON, K1P 6L5, Canada
| | | | | | - Sophie Bernard
- Lipids, Nutrition and Cardiovascular Prevention Clinic, Montreal Clinical Research Institute, 110 Avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.,Department of Medicine, Division of Endocrinology, Université de Montreal, Montréal, QC, Canada
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25
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Baass A, Paquette M, Bernard S, Hegele RA. Familial chylomicronemia syndrome: an under-recognized cause of severe hypertriglyceridaemia. J Intern Med 2020; 287:340-348. [PMID: 31840878 DOI: 10.1111/joim.13016] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
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.
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Affiliation(s)
- A Baass
- From the, Lipids, Nutrition and Cardiovascular Prevention Clinic, Montreal Clinical Research Institute, Québec, Canada.,Divisions of Experimental Medicine and Medical Biochemistry, Department of Medicine, McGill University, Québec, Canada
| | - M Paquette
- From the, Lipids, Nutrition and Cardiovascular Prevention Clinic, Montreal Clinical Research Institute, Québec, Canada
| | - S Bernard
- From the, Lipids, Nutrition and Cardiovascular Prevention Clinic, Montreal Clinical Research Institute, Québec, Canada.,Division of Endocrinology, Department of Medicine, Université de Montreal, Montreal, Canada
| | - R A Hegele
- Department of Medicine, University of Western Ontario and Robarts Research Institute, Ontario, Canada
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Goldberg RB, Chait A. A Comprehensive Update on the Chylomicronemia Syndrome. Front Endocrinol (Lausanne) 2020; 11:593931. [PMID: 33193106 PMCID: PMC7644836 DOI: 10.3389/fendo.2020.593931] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/02/2020] [Indexed: 12/13/2022] Open
Abstract
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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Affiliation(s)
- Ronald B. Goldberg
- Departments of Medicine, Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, United States
- *Correspondence: Ronald B. Goldberg,
| | - Alan Chait
- Department of Medicine, University of Washington, Seattle, WA, United States
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27
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O'Dea LSL, MacDougall J, Alexander VJ, Digenio A, Hubbard B, Arca M, Moriarty PM, Kastelein JJP, Bruckert E, Soran H, Witztum JL, Hegele RA, Gaudet D. Differentiating Familial Chylomicronemia Syndrome From Multifactorial Severe Hypertriglyceridemia by Clinical Profiles. J Endocr Soc 2019; 3:2397-2410. [PMID: 31777768 PMCID: PMC6864364 DOI: 10.1210/js.2019-00214] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Accepted: 10/07/2019] [Indexed: 12/21/2022] Open
Abstract
Context Differentiation between familial chylomicronemia syndrome (FCS, type 1 hyperlipoproteinemia), a rare metabolic disorder, and the more common multifactorial severe hypertriglyceridemia (sHTG, type 5 hyperlipoproteinemia) is challenging because of their overlapping symptoms but important in patient management. Objective To assess whether readily obtainable clinical information beyond triglycerides can effectively diagnose and differentiate patients with FCS from those with sHTG, based on well-curated data from two intervention studies of these conditions. Methods The analysis included 154 patients from two phase 3 clinical trials of patients with sHTG, one cohort with genetically confirmed FCS (n = 49) and one with multifactorial sHTG (n = 105). Logistic regression analyses were performed to determine the ability of variables (patient demographics, medical history, and baseline lipids, individually or in sets) to differentiate the patient populations. Receiver operating characteristics were used to determine the variable sets with the highest accuracy (percentage of times actual values matched predicted) and optimal sensitivity and specificity. Results The primary model diagnosed 45 of 49 patients with FCS and 99 of 105 patients with sHTG correctly. Optimal sensitivity for all available parameters (n = 17) was 91.8%, optimal specificity was 94.3%, and accuracy was 93.5%. Fasting low-density lipoprotein cholesterol (LDL-C) provided the highest individual predictability. However, a three-variable set of ultracentrifugally measured LDL-C, body mass index, and pancreatitis history differentiated the diseases with a near similar accuracy of 91.0%, and adding high-density lipoprotein cholesterol and very low-density lipoprotein cholesterol for a five-variable set provided a small incremental increase in accuracy (92.2%). Conclusions In the absence of genetic testing, hypertriglyceridemic patients with FCS and sHTG can be differentiated with a high degree of accuracy by analyzing readily obtainable clinical information.
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Affiliation(s)
| | | | | | | | | | - Marcello Arca
- Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy
| | - Patrick M Moriarty
- Department of Medicine, Division of Clinical Pharmacology, University of Kansas Medical Center, Kansas City, Kansas
| | - John J P Kastelein
- Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, AZ Amsterdam, Netherlands
| | - Eric Bruckert
- Institut E3M et IHU Cardiométabolique, Hôpital Pitié-Salpêtrière, Paris, France
| | - Handrean Soran
- Manchester University Hospital NHS Trust, Manchester, England
| | | | - Robert A Hegele
- Robarts Research Institute, Western University, London, Ontario, Canada
| | - Daniel Gaudet
- Department of Medicine, Université de Montréal and ECOGENE 21, Chicoutimi, Quebec, Canada
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28
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Paquette M, Bernard S, Hegele RA, Baass A. Chylomicronemia: Differences between familial chylomicronemia syndrome and multifactorial chylomicronemia. Atherosclerosis 2019; 283:137-142. [DOI: 10.1016/j.atherosclerosis.2018.12.019] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/29/2018] [Accepted: 12/05/2018] [Indexed: 12/20/2022]
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Adiamah A, Psaltis E, Crook M, Lobo DN. A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis. Clin Nutr 2018; 37:1810-1822. [PMID: 29056284 DOI: 10.1016/j.clnu.2017.09.028] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Accepted: 09/28/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The aims of this systematic review were to define the epidemiology and pathophysiology of hyperlipidaemic pancreatitis, establish its association with clinical outcome and define management strategies. METHODS The Cochrane, Embase and Medline databases were searched, limited to the last decade, for articles on hyperlipidaemic pancreatitis. All randomised controlled trials, observational studies and case series (with a minimum of 10 patients) on hyperlipidaemic pancreatitis were included. RESULTS Thirty-eight studies with 1979 patients were included. The median admission triglyceride concentration was 42.8 mmol/L (range 13.6-108.6 mmol/L) [3785 mg/dL (range 1205-9612 mg/dL)]. Severe hypertriglyceridaemia (>1000 mg/dL, 11.0 mmol/L) was present in 1.7% of the adult population, and about 15-20% of these developed hyperlipidaemic acute pancreatitis. Medical management of severe hyperlipidaemia at onset of acute pancreatitis has not been investigated fully. However, tight regulation of triglyceride concentration after presentation with acute pancreatitis was found to reduce the risk of recurrence. Plasmapheresis reduced concentrations of triglycerides by up to 85%, but this did not impact morbidity or mortality. All studies included defined hyperlipidaemia as a more severe form of pancreatitis. CONCLUSION The available evidence suggests an increasing risk of acute pancreatitis in patients with hyperlipidaemia and a more severe form of pancreatitis. There is some evidence to suggest biochemical benefit of using novel techniques like plasmapheresis without the desired physiological benefit. However, there is a need for an international consensus on the management of hyperlipidaemic pancreatitis. More rigorous and methodologically robust studies are required to inform such consensus guidelines.
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Affiliation(s)
- Alfred Adiamah
- Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Emmanouil Psaltis
- Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK
| | - Martin Crook
- Department of Clinical Biochemistry, Guy's and St. Thomas' Hospital NHS Trust, London SE1 9RT, UK
| | - Dileep N Lobo
- Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.
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Rodriguez Camargo DC, Garg D, Buday K, Franko A, Rodriguez Camargo A, Schmidt F, Cox SJ, Suladze S, Haslbeck M, Mideksa YG, Gemmecker G, Aichler M, Mettenleiter G, Schulz M, Walch AK, Hrabě de Angelis M, Feige MJ, Sierra CA, Conrad M, Tripsianes K, Ramamoorthy A, Reif B. hIAPP forms toxic oligomers in plasma. Chem Commun (Camb) 2018; 54:5426-5429. [PMID: 29745410 PMCID: PMC5970100 DOI: 10.1039/c8cc03097a] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
In diabetes, hyperamylinemia contributes to cardiac dysfunction. The interplay between hIAPP, blood glucose and other plasma components is, however, not understood. We show that glucose and LDL interact with hIAPP, resulting in β-sheet rich oligomers with increased β-cell toxicity and hemolytic activity, providing mechanistic insights for a direct link between diabetes and cardiovascular diseases.
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31
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Guichelaar T, van Erp EA, Hoeboer J, Smits NAM, van Els CACM, Pieren DKJ, Luytjes W. Diversity of aging of the immune system classified in the cotton rat (Sigmodon hispidus) model of human infectious diseases. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2018; 82:39-48. [PMID: 29305168 DOI: 10.1016/j.dci.2017.12.026] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/01/2017] [Revised: 12/28/2017] [Accepted: 12/29/2017] [Indexed: 06/07/2023]
Abstract
Susceptibility and declined resistance to human pathogens like respiratory syncytial virus (RSV) at old age is well represented in the cotton rat (Sigmodon hispidus). Despite providing a preferred model of human infectious diseases, little is known about aging of its adaptive immune system. We aimed to define aging-related changes of the immune system of this species. Concomitantly, we asked whether the rate of immunological alterations may be stratified by physiological aberrations encountered during aging. With increasing age, cotton rats showed reduced frequencies of T cells, impaired induction of antibodies to RSV, higher incidence of aberrations of organs and signs of lipemia. Moreover, old animals expressed high biological heterogeneity, but the age-related reduction of T cell frequency was only observed in those specimens that displayed aberrant organs. Thus, cotton rats show age-related alterations of lymphocytes that can be classified by links with health status.
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Affiliation(s)
- Teun Guichelaar
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
| | - Elisabeth A van Erp
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands; Laboratory of Pediatric Infectious Diseases, Department of Pediatrics, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen Hoeboer
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Noortje A M Smits
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Cécile A C M van Els
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Daan K J Pieren
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Willem Luytjes
- Centre for Infectious Disease Control (CIb), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
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Brown WV, Goldberg I, Duell B, Gaudet D. Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management. J Clin Lipidol 2018. [PMID: 29534878 DOI: 10.1016/j.jacl.2018.02.018] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Université de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana.
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Affiliation(s)
| | - Ira Goldberg
- Department of Medicine, Langone - NYU Medical Center, New York, NY, USA
| | - Barton Duell
- Division of Cardiovascular Medicine, School of Medicine, Oregon Health Sciences University, Portland, OR, USA
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The role of antisense oligonucleotide therapy against apolipoprotein-CIII in hypertriglyceridemia. ATHEROSCLEROSIS SUPP 2017; 30:19-27. [PMID: 29096837 DOI: 10.1016/j.atherosclerosissup.2017.05.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Increased triglyceride levels (higher than ∼1000 mg/dL) are associated with an increased risk for pancreatitis. Apolipoprotein-CIII (apo-CIII) plays a key role in the metabolism of triglycerides and triglyceride-rich lipoproteins. While loss of function mutations in the gene encoding apo-CIII (APOC3) are associated with low triglyceride levels and a decreased risk for cardiovascular disease (CVD), overexpression of APOC3 is associated with hypertriglyceridemia. Although many drugs such as fibrates, statins and omega-3 fatty acids modestly decrease triglyceride levels (and apo-CIII concentrations), there are many patients who still have severe hypertriglyceridemia and are at risk for pancreatitis and potentially CVD. The antisense oligonucleotide (ASO) against APOC3 mRNA volanesorsen (previously called ISIS 304801, ISIS-ApoCIIIRx and IONIS-ApoCIIIRx) robustly decreases both, apo-CIII production and triglyceride concentrations and is being currently evaluated in phase 3 trials. In this narrative review we present the currently available clinical evidence on the efficacy and safety of volanesorsen for the treatment of hypertriglyceridemia.
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Gaudet D, Stroes ES, Méthot J, Brisson D, Tremblay K, Bernelot Moens SJ, Iotti G, Rastelletti I, Ardigo D, Corzo D, Meyer C, Andersen M, Ruszniewski P, Deakin M, Bruno MJ. Long-Term Retrospective Analysis of Gene Therapy with Alipogene Tiparvovec and Its Effect on Lipoprotein Lipase Deficiency-Induced Pancreatitis. Hum Gene Ther 2016; 27:916-925. [PMID: 27412455 DOI: 10.1089/hum.2015.158] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Alipogene tiparvovec (Glybera) is a gene therapy product approved in Europe under the "exceptional circumstances" pathway as a treatment for lipoprotein lipase deficiency (LPLD), a rare genetic disease resulting in chylomicronemia and a concomitantly increased risk of acute and recurrent pancreatitis, with potentially lethal outcome. This retrospective study analyzed the frequency and severity of pancreatitis in 19 patients with LPLD up to 6 years after a single treatment with alipogene tiparvovec. An independent adjudication board of three pancreas experts, blinded to patient identification and to pre- or post-gene therapy period, performed a retrospective review of data extracted from the patients' medical records and categorized LPLD-related acute abdominal pain events requiring hospital visits and/or hospitalizations based on the adapted 2012 Atlanta diagnostic criteria for pancreatitis. Both entire disease time period data and data from an equal time period before and after gene therapy were analyzed. Events with available medical record information meeting the Atlanta diagnostic criteria were categorized as definite pancreatitis; events treated as pancreatitis but with variable levels of laboratory and imaging data were categorized as probable pancreatitis or acute abdominal pain events. A reduction of approximately 50% was observed in all three categories of the adjudicated post-gene therapy events. Notably, no severe pancreatitis and only one intensive care unit admission was observed in the post-alipogene tiparvovec period. However, important inter- and intraindividual variations in the pre- and post-gene therapy incidence of events were observed. There was no relationship between the posttreatment incidence of events and the number of LPL gene copies injected, the administration of immunosuppressive regimen or the percent triglyceride decrease achieved at 12 weeks (primary end point in the prospective clinical studies). Although a causal relationship cannot be established and despite the limited number of individuals evaluated, results from this long-term analysis suggest that alipogene tiparvovec was associated with a lower frequency and severity of pancreatitis events, and a consequent overall reduction in health care resource use up to 6 years posttreatment.
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Affiliation(s)
- Daniel Gaudet
- 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada
| | - Erik S Stroes
- 2 Academic Medical Center , Amsterdam, The Netherlands
| | - Julie Méthot
- 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada
| | - Diane Brisson
- 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada
| | - Karine Tremblay
- 1 Ecogene-21 Clinical and Translational Research Center and Lipidology Unit, Community Genetic Medicine Centre, Department of Medicine, Université de Montreal , Montreal, Canada
| | | | | | | | | | | | | | | | | | - Mark Deakin
- 6 University Hospital of North Midlands , Stoke-on-Trent, United Kingdom
| | - Marco J Bruno
- 7 Erasmus Medical Centre , Rotterdam, The Netherlands
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Carr RA, Rejowski BJ, Cote GA, Pitt HA, Zyromski NJ. Systematic review of hypertriglyceridemia-induced acute pancreatitis: A more virulent etiology? Pancreatology 2016; 16:469-76. [PMID: 27012480 DOI: 10.1016/j.pan.2016.02.011] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 02/02/2016] [Accepted: 02/19/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVE We sought to define the severity and natural history of hypertriglyceridemia induced acute pancreatitis (HTG-AP), specifically whether HTG-AP causes more severe AP than that caused by other etiologies. METHODS Systematic review of the English literature. RESULTS Thirty-four studies (15 countries; 1972-2015) included 1340 HTG-AP patients (weighted mean prevalence of 9%). The median admission triglyceride concentration was 2622 mg/dl (range 1160-9769). Patients with HTG have a 14% weighted mean prevalence of AP. Plasmapheresis decreased circulating triglycerides, but did not conclusively affect AP mortality. Only 7 reports (n = 392 patients) compared severity of HTG-AP to that of AP from other etiologies. Of these, 2 studies found no difference in severity, while 5 suggested that HTG-AP patients may have increased severity compared to AP of other etiology. CONCLUSIONS 1) hypertriglyceridemia is a relatively uncommon (9%) cause of acute pancreatitis; however, patients with hypertriglyceridemia have a high (14%) incidence of acute pancreatitis; 2) plasmapheresis may offer specific therapy unique to this patient population; and 3) data specifically comparing the severity of HTG-AP with AP caused by other etiologies are heterogeneous and scarce.
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Affiliation(s)
- Rosalie A Carr
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Benjamin J Rejowski
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Gregory A Cote
- Gastroenterology, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Henry A Pitt
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nicholas J Zyromski
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.
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Koopal C, Geerlings MI, Muller M, de Borst GJ, Algra A, van der Graaf Y, Visseren FLJ. The relation between apolipoprotein E (APOE) genotype and peripheral artery disease in patients at high risk for cardiovascular disease. Atherosclerosis 2016; 246:187-92. [PMID: 26800308 DOI: 10.1016/j.atherosclerosis.2016.01.009] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Revised: 12/23/2015] [Accepted: 01/08/2016] [Indexed: 12/20/2022]
Abstract
INTRODUCTION The apolipoprotein E gene (APOE) is associated with coronary heart disease and stroke, but the relation with peripheral artery disease (PAD) is unknown. We investigated the relation of APOE genotype with PAD and other types of vascular disease. METHODS The cross-sectional association between APOE genotype and ankle-brachial index (ABI) and vascular disease prevalence; and the prospective relation with incident PAD and other types of vascular disease (coronary artery disease, stroke and vascular mortality) were evaluated in 7418 patients from the Secondary Manifestations of ARTerial disease (SMART) study. This is a prospective cohort study in patients with cardiovascular disease or a cardiovascular risk factor. Analyses were adjusted for age and sex. RESULTS Mean age was 56.7 ± 12.4 years and 68% of the patients was male. APOE genotype frequencies were ε2ε2 1.3%; ε2ε3 9.9%; ε2ε4 2.4%; ε3ε3 56.9%; ε3ε4 26.7% and ε4ε4 2.8%. Median follow-up time was 8.1 years (IQR 5.4-11.4) in which 452 new PAD events occurred. The ε2ε2 genotype was significantly associated with a lower ABI (regression coefficient -0.04, 95%CI -0.07 to -0.01), increased PAD prevalence (prevalence ratio 1.54, 95%CI 1.01-2.17) and a higher risk of incident PAD (HR 2.31, 95%CI 1.29-4.12) compared with ε3ε3. No relations between APOE genotypes and other vascular disease were observed. CONCLUSION Of the six APOE genotypes, the ε2ε2 variant is associated with an increased risk for PAD in patients at high risk for cardiovascular disease. No association was observed between APOE genotype and coronary artery disease, stroke or vascular mortality in this population.
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Affiliation(s)
- Charlotte Koopal
- Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Mirjam I Geerlings
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Majon Muller
- Department of Geriatrics, University Medical Center, Leiden, The Netherlands
| | - G J de Borst
- Department of Vascular Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Ale Algra
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Yolanda van der Graaf
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Frank L J Visseren
- Department of Vascular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
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Nosso G, Capaldo B, Cocozza S, Vaccaro O. A 19 year follow-up of a woman with lipoprotein lipase deficiency treated with biliopancreatic diversion. Clin Case Rep 2016; 3:1030-3. [PMID: 26734140 PMCID: PMC4693709 DOI: 10.1002/ccr3.433] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 09/14/2015] [Accepted: 10/02/2015] [Indexed: 11/12/2022] Open
Abstract
We show the long‐term efficacy and safety of modified biliopancreatic diversion for the treatment of LPL‐deficiency. How this option compares with gene therapy is difficult to evaluate due to limited experience. Surgery may be the first option in patients in whom medical therapy is ineffective and gene therapy not applicable.
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Affiliation(s)
- Gabriella Nosso
- Department of Clinical Medicine and Surgery Federico II University of Naples Via S. Pansini 5 Naples 80131 Italy
| | - Brunella Capaldo
- Department of Clinical Medicine and Surgery Federico II University of Naples Via S. Pansini 5 Naples 80131 Italy
| | - Sara Cocozza
- Department of Clinical Medicine and Surgery Federico II University of Naples Via S. Pansini 5 Naples 80131 Italy
| | - Olga Vaccaro
- Department of Clinical Medicine and Surgery Federico II University of Naples Via S. Pansini 5 Naples 80131 Italy
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Norata GD, Caligiuri G, Chavakis T, Matarese G, Netea MG, Nicoletti A, O'Neill LAJ, Marelli-Berg FM. The Cellular and Molecular Basis of Translational Immunometabolism. Immunity 2016; 43:421-34. [PMID: 26377896 DOI: 10.1016/j.immuni.2015.08.023] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2015] [Indexed: 12/11/2022]
Abstract
The immune response requires major changes to metabolic processes, and indeed, energy metabolism and functional activation are fully integrated in immune cells to determine their ability to divide, differentiate, and carry out effector functions. Immune cell metabolism has therefore become an attractive target area for therapeutic purposes. A neglected aspect in the translation of immunometabolism is the critical connection between systemic and cellular metabolism. Here, we discuss the importance of understanding and manipulating the integration of systemic and immune cell metabolism through in-depth analysis of immune cell phenotype and function in human metabolic diseases and, in parallel, of the effects of conventional metabolic drugs on immune cell differentiation and function. We examine how the recent identification of selective metabolic programs operating in distinct immune cell subsets and functions has the potential to deliver tools for cell- and function-specific immunometabolic targeting.
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Affiliation(s)
- Giuseppe Danilo Norata
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy; Center for the Study of Atherosclerosis, Bassini Hospital, Cinisello Balsamo, 20092 Milan, Italy.
| | - Giuseppina Caligiuri
- Unité 1148, INSERM, Hôpital X Bichat, 75018 Paris, France; Université Paris Diderot, Sorbonne Paris Cité, 75013 Paris, France; Département Hospitalo-Universitaire "FIRE," 75018 Paris, France
| | - Triantafyllos Chavakis
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Giuseppe Matarese
- Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Baronissi, 84081 Salerno, Italy; IRCCS MultiMedica, 20138 Milan, Italy
| | - Mihai Gheorge Netea
- Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
| | - Antonino Nicoletti
- Department of Clinical Pathobiochemistry and Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, 01307 Dresden, Germany
| | - Luke A J O'Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Federica M Marelli-Berg
- William Harvey Research Institute, Bart's and the London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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Effect of the DGAT1 inhibitor pradigastat on triglyceride and apoB48 levels in patients with familial chylomicronemia syndrome. Lipids Health Dis 2015; 14:8. [PMID: 25889044 PMCID: PMC4337059 DOI: 10.1186/s12944-015-0006-5] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 01/28/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS. METHODS Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored. RESULTS Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events. CONCLUSION The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT01146522 .
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Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol 2015; 64:2525-40. [PMID: 25500239 DOI: 10.1016/j.jacc.2014.09.042] [Citation(s) in RCA: 180] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 09/18/2014] [Accepted: 09/21/2014] [Indexed: 12/31/2022]
Abstract
Triglycerides represent 1 component of a heterogeneous pool of triglyceride-rich lipoproteins (TGRLs). The reliance on triglycerides or TGRLs as cardiovascular disease (CVD) risk biomarkers prompted investigations into therapies that lower plasma triglycerides as a means to reduce CVD events. Genetic studies identified TGRL components and pathways involved in their synthesis and metabolism. We advocate that only a subset of genetic mechanisms regulating TGRLs contribute to the risk of CVD events. This "omic" approach recently resulted in new targets for reducing CVD events.
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Affiliation(s)
- Robert S Rosenson
- Mount Sinai Heart, Cardiometabolic Disorders, Icahn School of Medicine at Mount Sinai, New York, New York.
| | - Michael H Davidson
- Division of Cardiology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois
| | | | - Sekar Kathiresan
- Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Daniel Gaudet
- ECOGENE-21 and Lipid Clinic, Department of Medicine, Université de Montreal, Chicoutimi, Quebec, Canada
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Gaudet D, Brisson D, Tremblay K, Alexander VJ, Singleton W, Hughes SG, Geary RS, Baker BF, Graham MJ, Crooke RM, Witztum JL. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med 2014; 371:2200-6. [PMID: 25470695 DOI: 10.1056/nejmoa1400284] [Citation(s) in RCA: 373] [Impact Index Per Article: 33.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The familial chylomicronemia syndrome is a genetic disorder characterized by severe hypertriglyceridemia and recurrent pancreatitis due to a deficiency in lipoprotein lipase (LPL). Currently, there are no effective therapies except for extreme restriction in the consumption of dietary fat. Apolipoprotein C-III (APOC3) is known to inhibit LPL, although there is also evidence that APOC3 increases the level of plasma triglycerides through an LPL-independent mechanism. We administered an inhibitor of APOC3 messenger RNA (mRNA), called ISIS 304801, to treat three patients with the familial chylomicronemia syndrome and triglyceride levels ranging from 1406 to 2083 mg per deciliter (15.9 to 23.5 mmol per liter). After 13 weeks of study-drug administration, plasma APOC3 levels were reduced by 71 to 90% and triglyceride levels by 56 to 86%. During the study, all patients had a triglyceride level of less than 500 mg per deciliter (5.7 mmol per liter) with treatment. These data support the role of APOC3 as a key regulator of LPL-independent pathways of triglyceride metabolism.
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Affiliation(s)
- Daniel Gaudet
- From the ECOGENE-21 Clinical Research Center, Chicoutimi Hospital, Chicoutimi, and the Department of Medicine, Université de Montréal, Montreal - both in Canada (D.G., D.B., K.T.); and Isis Pharmaceuticals, Carlsbad (V.J.A., W.S., S.G.H., R.S.G., B.F.B., M.J.G., R.M.C.), and the Department of Medicine, Division of Endocrinology-Metabolism, University California, San Diego, School of Medicine, La Jolla (J.L.W.) - both in California
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Buonuomo PS, Bartuli A, Rabacchi C, Bertolini S, Calandra S. A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene. J Clin Lipidol 2014; 9:265-70. [PMID: 25911085 DOI: 10.1016/j.jacl.2014.10.003] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/01/2014] [Accepted: 10/06/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Familial chylomicronemia is a genetic defect of the intravascular lipolysis of triglyceride (TG)-rich lipoproteins. Intravascular lipolysis involves the TG-hydrolase lipoprotein lipase (LPL) as well as other factors such as apolipoprotein CII and apolipoprotein AV (activators of LPL), GPIHBP1 (the molecular platform required for LPL activity on endothelial surface), and LMF1 (a factor required for intracellular formation of active LPL). METHODS We sequenced the familial chylomicronemia candidate genes in a neonate with chylomicronemia. RESULTS A 3-day-old newborn was found to have chylomicronemia (plasma TG 18.8 mmol/L, 1.667 mg/dL). The discontinuation of breastfeeding for 24 hours reduced plasma TG to 2.3 mmol/L (201 mg/dL), whereas its resumption induced a sharp TG increase (7.9 mmol/L, 690 mg/dL). The child was switched to a low-fat diet, which was effective in maintaining TG level below 3.5 mmol/L (294 mg/dL) during the first months of life. The child was found to be a compound heterozygous for 2 novel mutations in GPIHBP1 gene. The first mutation was a 9-bp deletion and 4-bp insertion in exon 2, causing a frameshift that abolished the canonical termination codon TGA. The predicted translation product of the mutant messenger RNA is a peptide that contains 51 amino acids of the N-terminal end of the wild-type protein followed by 252 novel amino acids. The second mutation was a nucleotide change (c.319T>C), causing an amino acid substitution p.(Ser107Pro) predicted in silico to be damaging. CONCLUSIONS GPIHBP1 mutations should be considered in neonates with chylomicronemia negative for mutations in LPL gene.
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Affiliation(s)
| | - Andrea Bartuli
- Rare Diseases and Medical Genetics, Bambino Gesù Children Hospital, Rome, Italy
| | - Claudio Rabacchi
- Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Stefano Bertolini
- Department of Internal Medicine, University of Genova, Genova, Italy
| | - Sebastiano Calandra
- Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy.
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Tremblay K, Dubois-Bouchard C, Brisson D, Gaudet D. Association of CTRC and SPINK1 gene variants with recurrent hospitalizations for pancreatitis or acute abdominal pain in lipoprotein lipase deficiency. Front Genet 2014; 5:90. [PMID: 24795752 PMCID: PMC4000989 DOI: 10.3389/fgene.2014.00090] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2014] [Accepted: 04/02/2014] [Indexed: 12/29/2022] Open
Abstract
Background: There are important inter-individual variations in the incidence and severity of acute pancreatitis in patients with severe hypertriglyceridemia. Several genes involved in triglyceride-rich lipoprotein metabolism or serine proteases pathways are known to influence the risk of pancreatitis. Aim: To evaluate the association between genes regulating serine proteases, chymotrypsin C (CTRC) and serine peptidase inhibitor kazal type1 (SPINK1), and recurrence of hospitalizations for acute pancreatitis or severe abdominal pain in patients with Lipoprotein Lipase Deficiency (LPLD), a rare and extreme monogenic model of severe hypertriglyceridemia and pancreatitis. Method: The CTRC and SPINK1 genes promoter and coding regions sequencing has been performed in a sample of 38 LPLD adults (22 men and 16 women) and 100 controls (53 men and 47 women). Estimation of the association of CTRC and SPINK1 gene variants or combinations of variants with history of hospitalizations for pancreatitis or acute abdominal pain in LPLD was investigated using non-parametric analyses with correction for multiple testing and logistic regression models controlling for age, gender, family history, and life habits. Results: Gene sequencing followed by genotype-stratified analyses of the CTRC and SPINK1 genes in LPLD and controls revealed a positive association between recurrence of hospitalizations and the rs545634 (CTRC)—rs11319 (SPINK1) combination [OR = 41.4 (CI: 2.0–848.0); p = 0.016]. In all models, a positive family history of pancreatitis was a significant predictor of recurrent hospitalizations independently of the contribution of SPINK1 or CTRC (p < 0.001). Conclusion: These results suggest that a positive family history of pancreatitis and genetic markers in the serine protease pathways could be associated with a risk of recurrent hospitalization for acute pancreatitis in severe hypertriglyceridemia due to LPLD.
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Affiliation(s)
- Karine Tremblay
- Department of Medicine, Université de Montréal Montreal, Canada ; ECOGENE-21 Clinical Research Center Saguenay, QC, Canada
| | - Camélia Dubois-Bouchard
- Department of Medicine, Université de Montréal Montreal, Canada ; ECOGENE-21 Clinical Research Center Saguenay, QC, Canada
| | - Diane Brisson
- Department of Medicine, Université de Montréal Montreal, Canada ; ECOGENE-21 Clinical Research Center Saguenay, QC, Canada
| | - Daniel Gaudet
- Department of Medicine, Université de Montréal Montreal, Canada ; ECOGENE-21 Clinical Research Center Saguenay, QC, Canada
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Marais AD, Solomon GAE, Blom DJ. Dysbetalipoproteinaemia: a mixed hyperlipidaemia of remnant lipoproteins due to mutations in apolipoprotein E. Crit Rev Clin Lab Sci 2014; 51:46-62. [PMID: 24405372 DOI: 10.3109/10408363.2013.870526] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Atherosclerosis is strongly associated with dyslipoproteinaemia, and especially with increasing concentrations of low-density lipoprotein and decreasing concentrations of high-density lipoproteins. Its association with increasing concentrations of plasma triglyceride is less clear but, within the mixed hyperlipidaemias, dysbetalipoproteinaemia (Fredrickson type III hyperlipidaemia) has been identified as a very atherogenic entity associated with both premature ischaemic heart disease and peripheral arterial disease. Dysbetalipoproteinaemia is characterized by the accumulation of remnants of chylomicrons and of very low-density lipoproteins. The onset occurs after childhood and usually requires an additional metabolic stressor. In women, onset is typically delayed until menopause. Clinical manifestations may vary from no physical signs to severe cutaneous and tendinous xanthomata, atherosclerosis of coronary and peripheral arteries, and pancreatitis when severe hypertriglyceridaemia is present. Rarely, mutations in apolipoprotein E are associated with lipoprotein glomerulopathy, a condition characterized by progressive proteinuria and renal failure with varying degrees of plasma remnant accumulation. Interestingly, predisposing genetic causes paradoxically result in lower than average cholesterol concentration for most affected persons, but severe dyslipidaemia develops in a minority of patients. The disorder stems from dysfunctional apolipoprotein E in which mutations result in impaired binding to low-density lipoprotein (LDL) receptors and/or heparin sulphate proteoglycans. Apolipoprotein E deficiency may cause a similar phenotype. Making a diagnosis of dysbetalipoproteinaemia aids in assessing cardiovascular risk correctly and allows for genetic counseling. However, the diagnostic work-up may present some challenges. Diagnosis of dysbetalipoproteinaemia should be considered in mixed hyperlipidaemias for which the apolipoprotein B concentration is relatively low in relation to the total cholesterol concentration or when there is significant disparity between the calculated LDL and directly measured LDL cholesterol concentrations. Genetic tests are informative in predicting the risk of developing the disease phenotype and are diagnostic only in the context of hyperlipidaemia. Specialised lipoprotein studies in reference laboratory centres can also assist in diagnosis. Fibrates and statins, or even combination treatment, may be required to control the dyslipidaemia.
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Affiliation(s)
- A D Marais
- Department of Chemical Pathology, Health Science Faculty, University of Cape Town , Cape Town , South Africa
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Gaudet D, Signorovitch J, Swallow E, Fan L, Tremblay K, Brisson D, Meyers C, Gruenberger JB. Medical resource use and costs associated with chylomicronemia. J Med Econ 2013; 16:657-66. [PMID: 23428107 DOI: 10.3111/13696998.2013.779277] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND The prevalence of severe hypertriglyceridemia (TG > 1000 mg/dl) is estimated at 150-400 per 100,000 individuals in North America. Severe hypertriglyceridemia in the fasting state is associated with increased acute pancreatitis risk and is a sign of chylomicronemia which reflects the accumulation in the bloodstream of chylomicrons, the large lipoprotein particles produced in the gut after a meal. OBJECTIVE To assess medical resource use and costs associated with chylomicronemia. METHODS Patients with chylomicronemia of different causes (≥2 diagnoses with ICD-9 code 272.3) were identified from a large US claims database (years 2000 to 2009) and matched 1:1 to controls free of chylomicronemia based on age, gender, demographics, comorbidities, and use of lipid lowering drugs. During a 1-year study period, medical resource use and costs associated with chylomicronemia or acute pancreatitis were compared between matched cases and controls. RESULTS Among 6472 matched pairs, annual per-patient medical costs, calculated independently of the occurrence of acute pancreatitis, were significantly greater by $808 for chylomicronemia cases vs controls ($8029 vs $7220, p < 0.01), half of which was attributable to chylomicronemia-related services (p < 0.01). Chylomicronemia cases with a history of acute pancreatitis (n = 46) had greater rates of inpatient visits (p < 0.05) and greater average costs for subsequent acute pancreatitis or abdominal pain (p < 0.01) as well as greater total medical costs ($33,587 vs $4402, p < 0.01) vs matched controls. The average episode of acute pancreatitis (n = 104 episodes) generated medical costs of $31,820, almost entirely due to inpatient stays. LIMITATIONS Triglyceride levels were not available to characterize disease severity. CONCLUSIONS Patients with chylomicronemia, and especially those with a history of acute pancreatitis, incurred significantly greater total medical costs compared with individuals without chylomicronemia but with an otherwise comparable health profile.
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Affiliation(s)
- Daniel Gaudet
- Ecogene-21 Clinical Research Center and Department of Medicine, Université de Montréal, Montreal, Canada.
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Abstract
PURPOSE OF REVIEW The present review summarizes the clinical development of adeno-associated viral vector (AAV)1-lipoprotein lipase (LPL)S447X gene therapy (alipogene tiparvovec) for lipoprotein lipase deficiency. Lipoprotein lipase deficiency is a rare inherited disease characterized by severe hypertriglyceridaemia, chylomicronaemia and risk of recurrent pancreatitis or other complications. AAV1-LPLS447X gene therapy is based on the rationale that by adding episomal copies of functional LPL genes into muscle cells lacking active LPL, metabolic function could be improved or restored. RECENT FINDINGS AAV1-LPLS447X is a nonreplicating and nonintegrating AAV of serotype 1 designed to deliver and express the human LPL gene variant S447X. The clinical development programme for AAV1-LPLS447X consisted of two observational studies, three open-label interventional studies and one case note review analysis. Intramuscular administration of AAV1-LPLS447X was generally well tolerated and was associated with reduction in overall pancreatitis incidence and signs of clinical improvement up to 2 years after administration. Results of interventional studies suggest that markers of postprandial metabolism could be more accurate than fasting plasma triglyceride concentration to monitor the effect of AAV1-LPLS447X . SUMMARY The overall benefit-risk ratio of AAV1-LPLS447X gene therapy appears positive to date, particularly for the patients presenting the highest risk of complications.
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Affiliation(s)
- Daniel Gaudet
- Lipid Clinic, Chicoutimi Hospital, ECOGENE-21 Clinical Research Center, Department of Medicine, Université de Montreal, Quebec, Canada.
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Gaudet D, Méthot J, Déry S, Brisson D, Essiembre C, Tremblay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-Ferreira V, van Deventer S. Efficacy and long-term safety of alipogene tiparvovec (AAV1-LPLS447X) gene therapy for lipoprotein lipase deficiency: an open-label trial. Gene Ther 2012; 20:361-9. [PMID: 22717743 PMCID: PMC4956470 DOI: 10.1038/gt.2012.43] [Citation(s) in RCA: 300] [Impact Index Per Article: 23.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL(S447X) gene therapy for lipoprotein lipase (LPL) deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially life-threatening pancreatitis. The LPL(S447X) gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10(11) gc kg(-1), and cohort 3 (n=8) received 1 × 10(12) gc kg(-1). Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3 and 12 weeks. TG subsequently returned to baseline, although sustained LPL(S447X) expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG.
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Affiliation(s)
- D Gaudet
- ECOGENE-21 Clinical Research Center, Chicoutimi Hospital, Chicoutimi, QC, Canada.
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