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Javed F, Hegele RA, Garg A, Patni N, Gaudet D, Williams L, Khan M, Li Q, Ahmad Z. Familial chylomicronemia syndrome: An expert clinical review from the National Lipid Association. J Clin Lipidol 2025:S1933-2874(25)00066-2. [PMID: 40234111 DOI: 10.1016/j.jacl.2025.03.013] [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: 03/18/2025] [Accepted: 03/20/2025] [Indexed: 04/17/2025]
Abstract
Familial chylomicronemia syndrome (FCS) is a rare Mendelian autosomal recessive disorder (MIM 238600) characterized by extreme and sustained hypertriglyceridemia due to profound reduction of lipoprotein lipase (LPL) activity. This expert opinion statement synthesizes current knowledge on the definition, pathophysiology, genetics, prevalence, diagnosis, and management of FCS. FCS typically manifests at a young age with persistent severe hypertriglyceridemia-defined as ≥10 mmol/L (≥885 mg/dL), or ≥1000 mg/dL (≥11.2 mmol/L) depending on region and whether Systeme International (SI) units are utilized-in the absence of secondary factors, resistance to conventional lipid-lowering therapies, and a high lifetime risk of acute pancreatitis. It is caused by biallelic pathogenic variants in the LPL gene encoding LPL, or 1 of 4 other related genes that encode proteins that interact with LPL. Affected individuals require a strict, lifelong very low-fat diet with <15% of energy from fat. Emerging therapies inhibiting apolipoprotein C-III show promise in reducing serum triglycerides and pancreatitis risk in patients with FCS. A multidisciplinary approach, encompassing dietary management, pharmacotherapy, and patient education, is pivotal in mitigating the significant morbidity associated with FCS.
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Affiliation(s)
- Fiza Javed
- Department of Medicine, Faculty of Health Sciences, McMaster University, Hamilton, ON, Canada (Dr Javed)
| | - Robert A Hegele
- Department of Medicine and Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada (Dr Hegele)
| | - Abhimanyu Garg
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine and the Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA (Dr Garg)
| | - Nivedita Patni
- Division of Pediatric Endocrinology, Department of Pediatrics, UT Southwestern Medical Center, Dallas, TX, USA (Dr Patni)
| | - Daniel Gaudet
- ECOGENE-21 Department of Medicine, Université de Montréal, Chicoutimi, QC, Canada (Dr Gaudet)
| | - Lauren Williams
- Department of Pediatric Cardiology, Baylor Scott & White McLane Children's Medical Center, Temple, TX, USA (Ms Williams)
| | - Mohamed Khan
- FCS Foundation, San Diego, CA, USA (Mrs Khan and Li)
| | - Qingyang Li
- FCS Foundation, San Diego, CA, USA (Mrs Khan and Li)
| | - Zahid Ahmad
- Section of Nutrition and Metabolic Diseases, Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, USA (Dr Ahmad).
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Gutiérrez J, Castaño P, Fariña G, Berg G, Gálvez JM, Nogueira JP. Familial chylomicronemia syndrome caused by two genetic variants in the APOA5 gene: Severe hypertriglyceridemia that complicates pregnancy. J Clin Lipidol 2025:S1933-2874(24)00304-0. [PMID: 40023744 DOI: 10.1016/j.jacl.2024.12.020] [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: 08/24/2024] [Revised: 12/21/2024] [Accepted: 12/26/2024] [Indexed: 03/04/2025]
Abstract
A case of a 29-year-old female patient with a history of a single episode of hypertriglyceridemia-induced pancreatitis 4 years prior is reported. She had been treated with fibrates until 2 months before conception and required hospitalization at 33 weeks of gestation due to severe hypertriglyceridemia (6690 mg/dL) and gestational diabetes. Upon hospital admission, there was no evidence of pancreatitis. A comprehensive treatment approach was initiated, combining a low-fat diet, fibrates, omega-3 fatty acids (2 g/d), and continuous insulin infusion. This regimen resulted in a significant reduction of triglyceride levels to 960 mg/dL. The pregnancy progressed to full term without any maternal-fetal complications. Genetic analysis revealed 2 compound heterozygous mutations in the APOA5 gene, which encodes apolipoprotein AV. Notably, these specific mutations have not been previously reported as causative factors for familial chylomicronemia syndrome (FCS). The diagnosis of FCS was confirmed by the patient's markedly reduced lipoprotein lipase activity of 3.2%.
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Affiliation(s)
- Johnayro Gutiérrez
- Universidad de Antioquia, Clínica Somer, Rionegro, Colombia (Gutiérrez).
| | | | - Gregorio Fariña
- Laboratorio de Lípidos y Aterosclerosis, Departamento de Bioquímica Clínica, Cátedra de Bioquímica Clínica I, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina (Fariña)
| | - Gabriela Berg
- Professor at Facultad de Farmacia y Bioquímica, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Buenos Aires, Argentina (Berg)
| | | | - Juan Patricio Nogueira
- Centro de Investigación en Nutrición, Endocrinología y Metabolismo, Facultad de Ciencias de la Salud, Universidad Nacional de Formosa, Formosa, Argentina (Nogueira)
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Wang D, Chen J, Luo H, Wang Z, Cheng G. Psychological experience and coping strategies of pregnant women with acute pancreatitis: a qualitative descriptive study. J Matern Fetal Neonatal Med 2024; 37:2374438. [PMID: 38973016 DOI: 10.1080/14767058.2024.2374438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 06/19/2024] [Indexed: 07/09/2024]
Abstract
BACKGROUND To clarify the psychological experience and coping strategies in patients with acute pancreatitis in pregnancy (APIP) and propose interventional measures to improve pregnancy outcomes in these women. With an increasing trend of pregnant women in advanced ages and multiparous women, the incidence of APIP has significantly increased. Pregnancy accompanied by concurrent pancreatitis may subject these women to notable psychological stress, which is a factor that has been infrequently reported in previous studies. METHODS APIP patients were interviewed from December 2020 to June 2021. Data were collected through semi-structured interviews based on an outline, including six questions. The interviews were recorded and analyzed using qualitative content analysis until data saturation was reached. RESULTS Ten APIP patients were interviewed and four themes were identified, including excessive psychological burden, uncomfortable experience, urgent requirement for adequate medical resources, and importance of social support. CONCLUSION Patients with APIP suffer from significant psychological stress due to their medical conditions and management. They desired adequate medical resources and social support. The local health department, hospital administrators, and medical staff should understand the psychological requirements and provide adequate healthcare and education that are easily accessible to these APIP patients. In addition, family support should also be encouraged to promote APIP patients' recovery.
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Affiliation(s)
- Dingxi Wang
- Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, People's Republic of China
| | - Jie Chen
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Huilin Luo
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, People's Republic of China
| | - Zhengbo Wang
- Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, People's Republic of China
| | - Guilan Cheng
- Division of Internal Medicine, Institute of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University/West China School of Nursing, Sichuan University, Chengdu, People's Republic of China
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Kay HY, Jang HY, Kim IW, Oh JM. Fibrates and risk of congenital malformations: a nationwide cohort study in South Korea. Arch Gynecol Obstet 2024; 310:1967-1973. [PMID: 38553644 PMCID: PMC11393199 DOI: 10.1007/s00404-023-07357-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 12/19/2023] [Indexed: 09/13/2024]
Abstract
PURPOSE To examine the association between maternal prescriptions for fibrates and congenital malformations in live births. METHODS Nationwide retrospective cohort study was conducted using the data sourced from the Korean National Health Insurance database. A cohort of 756,877 completed pregnancies linked to live-born infants in 215,600 women with dyslipidemia between 2012 and 2021. The study compared data on congenital anomalies between pregnancies who were exposed to fibrates and those who were not exposed to fibrates in the first trimester. Odds ratios (OR) were calculated by a multivariable analyses using logistic regression models to adjust for potential confounders. RESULTS 260 pregnancies (0.12%) were exposed to fibrates during the first trimester. The prevalence of malformations in exposed offspirng was 10.77%, not significantly different compared with 9.68% in offspring of women who were not prescribed fibrates during pregnancy in patients with dyslipidemia (OR 1.13; 95% CI 0.75-1.70). CONCLUSION This study implies that the use of fibrates during pregnancy may be safe, as it did not show any association with congenital anomalies. However, caution is warranted due to an elevated risk associated with prolonged exposure.
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Affiliation(s)
- Hee Yeon Kay
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Ha Young Jang
- College of Pharmacy, Gachon University, Incheon, 21936, Republic of Korea
| | - In-Wha Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
| | - Jung Mi Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.
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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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Bashir B, Ho JH, Downie P, Hamilton P, Ferns G, Datta D, Cegla J, Wierzbicki AS, Dawson C, Jenkinson F, Delaney H, Mansfield M, Teoh Y, Miedzybrodzka Z, Haso H, Durrington PN, Soran H. Severe Hypertriglyceridaemia and Chylomicronaemia Syndrome-Causes, Clinical Presentation, and Therapeutic Options. Metabolites 2023; 13:metabo13050621. [PMID: 37233662 DOI: 10.3390/metabo13050621] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 03/27/2023] [Accepted: 04/11/2023] [Indexed: 05/27/2023] Open
Abstract
We have reviewed the genetic basis of chylomicronaemia, the difference between monogenic and polygenic hypertriglyceridaemia, its effects on pancreatic, cardiovascular, and microvascular complications, and current and potential future pharmacotherapies. Severe hypertriglyceridaemia (TG > 10 mmol/L or 1000 mg/dL) is rare with a prevalence of <1%. It has a complex genetic basis. In some individuals, the inheritance of a single rare variant with a large effect size leads to severe hypertriglyceridaemia and fasting chylomicronaemia of monogenic origin, termed as familial chylomicronaemia syndrome (FCS). Alternatively, the accumulation of multiple low-effect variants causes polygenic hypertriglyceridaemia, which increases the tendency to develop fasting chylomicronaemia in presence of acquired factors, termed as multifactorial chylomicronaemia syndrome (MCS). FCS is an autosomal recessive disease characterized by a pathogenic variant of the lipoprotein lipase (LPL) gene or one of its regulators. The risk of pancreatic complications and associated morbidity and mortality are higher in FCS than in MCS. FCS has a more favourable cardiometabolic profile and a low prevalence of atherosclerotic cardiovascular disease (ASCVD) compared to MCS. The cornerstone of the management of severe hypertriglyceridaemia is a very-low-fat diet. FCS does not respond to traditional lipid-lowering therapies. Several novel pharmacotherapeutic agents are in various phases of development. Data on the correlation between genotype and phenotype in FCS are scarce. Further research to investigate the impact of individual gene variants on the natural history of the disease, and its link with ASCVD, microvascular disease, and acute or recurrent pancreatitis, is warranted. Volanesorsen reduces triglyceride concentration and frequency of pancreatitis effectively in patients with FCS and MCS. Several other therapeutic agents are in development. Understanding the natural history of FCS and MCS is necessary to rationalise healthcare resources and decide when to deploy these high-cost low-volume therapeutic agents.
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Affiliation(s)
- Bilal Bashir
- Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
| | - Jan H Ho
- Department of Endocrinology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK
| | - Paul Downie
- Department of Laboratory Medicine, Salisbury NHS Foundation Trust, Salisbury SP2 8BJ, UK
| | - Paul Hamilton
- Centre for Medical Education, Queen's University Belfast, Belfast BT7 1NN, UK
- Department of Clinical Biochemistry, Belfast Health and Social Care Trust, Belfast BT13 1FD, UK
| | - Gordon Ferns
- Brighton and Sussex Medical School, Brighton BN1 9PH, UK
| | - Dev Datta
- Lipid Unit, University Hospital Llandough, Cardiff CF64 2XX, UK
| | - Jaimini Cegla
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, London SW7 2BX, UK
| | - Anthony S Wierzbicki
- Department of Metabolic Medicine and Chemical Pathology, Guy's and St. Thomas' Hospitals, London SE1 7EH, UK
| | - Charlotte Dawson
- Department of Metabolic Medicine, Queen Elizabeth Hospital NHS Foundation Trust, Birmingham PE30 4ET, UK
| | - Fiona Jenkinson
- Clinical Biochemistry and Metabolic Medicine, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK
| | - Hannah Delaney
- Department of Clinical Chemistry, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield S10 2JF, UK
| | - Michael Mansfield
- Leeds Centre for Diabetes & Endocrinology, Leeds Teaching Hospitals NHS Trust, Leeds LS9 7TF, UK
| | - Yee Teoh
- Department of Chemical Pathology & Metabolic Medicine, Wrexham Maelor Hospital, Wrexham LL13 7TD, UK
| | - Zosia Miedzybrodzka
- Department of Medical Genetics, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB24 3FX, UK
| | - Haya Haso
- School of Medicine, University of Kurdistan Hewler, Erbil 44001, Iraq
| | - Paul N Durrington
- Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK
| | - Handrean Soran
- Faculty of Biology Medicine and Health, University of Manchester, Manchester M13 9PL, UK
- Department of Endocrinology, Diabetes & Metabolism, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK
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Rodriguez FH, Estrada JM, Quintero HMA, Nogueira JP, Porras-Hurtado GL. Analyses of familial chylomicronemia syndrome in Pereira, Colombia 2010-2020: a cross-sectional study. Lipids Health Dis 2023; 22:43. [PMID: 36978188 PMCID: PMC10045250 DOI: 10.1186/s12944-022-01768-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 12/28/2022] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND AND AIM Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive metabolic disorder caused by mutations in genes involved in chylomicron metabolism. On the other hand, multifactorial chylomicronemia syndrome (MCS) is a polygenic disorder and the most frequent cause of chylomicronemia, which results from the presence of multiple genetic variants related to chylomicron metabolism, in addition to secondary factors. Indeed, the genetic determinants that predispose to MCS are the presence of a heterozygous rare variant or an accumulation of several SNPs (oligo/polygenic). However, their clinical, paraclinical, and molecular features are not well established in our country. The objective of this study was to describe the development and results of a screening program for severe hypertriglyceridemia in Colombia. METHODS A cross-sectional study was performed. All patients aged >18 years with triglyceride levels ≥500 mg/dL from 2010 to 2020 were included. The program was developed in three stages: 1. Review of electronic records and identification of suspected cases based on laboratory findings (triglyceride levels ≥500 mg/dL); 2. Identification of suspected cases based on laboratory findings that also allowed us to exclude secondary factors; 3. Patients with FCS scores <8 were excluded. The remaining patients underwent molecular analysis. RESULTS In total, we categorized 2415 patients as suspected clinical cases with a mean age of 53 years, of which 68% corresponded to male patients. The mean triglyceride levels were 705.37 mg/dL (standard deviation [SD] 335.9 mg/dL). After applying the FCS score, 2.4% (n = 18) of patients met the probable case definition and underwent a molecular test. Additionally, 7 patients had unique variants in the APOA5 gene (c.694 T > C; p. Ser232Pro) or in the GPIHBP1 gene (c.523G > C; p. Gly175Arg), for an apparent prevalence of familial chylomicronemia in the consulting population of 0.41 per 1.000 patients with severe HTG measurement. No previously reported pathogenic variants were detected. CONCLUSION This study describes a screening program for the detection of severe hypertriglyceridemia. Although we identified seven patients as carriers of a variant in the APOA5 gene, we diagnosed only one patient with FCS. We believe that more programs of these characteristics should be developed in our region, given the importance of early detection of this metabolic disorder.
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Affiliation(s)
- Franklin Hanna Rodriguez
- International Center Research In Health Comfamiliar, Comfamiliar Risaralda, Pereira, Risaralda, Colombia.
| | - Jorge Mario Estrada
- International Center Research In Health Comfamiliar, Comfamiliar Risaralda, Pereira, Risaralda, Colombia
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Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia. J Clin Med 2023; 12:jcm12041382. [PMID: 36835917 PMCID: PMC9962307 DOI: 10.3390/jcm12041382] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 02/05/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend clinical evaluation and lifestyle-based interventions to address potential secondary causes of elevated triglyceride (TG) levels. For individuals with mild to moderate HTG at risk of ASCVD, statin therapy alone or in combination with other lipid-lowering medications known to decrease ASCVD risk are guideline-endorsed. In addition to lifestyle modifications, patients with severe HTG at risk of acute pancreatitis may benefit from fibrates, mixed formulation omega-3 fatty acids, and niacin; however, evidence does not support their use for ASCVD risk reduction in the contemporary statin era. Novel therapeutics including those that target apoC-III and ANGPTL3 have shown to be safe, well-tolerated, and effective for lowering TG levels. Given the growing burden of cardiometabolic disease and risk factors, public health and health policy strategies are urgently needed to enhance access to effective pharmacotherapies, affordable and nutritious food options, and timely health care services.
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Wang J, Zhao Y, Chang P, Liu B, Yao R. Double filtration plasmapheresis for pregnancy with hyperlipidemia in glycogen storage disease type Ia: A case report. World J Clin Cases 2022; 10:10273-10278. [PMID: 36246825 PMCID: PMC9561557 DOI: 10.12998/wjcc.v10.i28.10273] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Revised: 07/04/2022] [Accepted: 08/23/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Glycogen storage disease type Ia (GSDIa) is an autosomal recessive inborn error of carbohydrate metabolism that is caused by deficiency of the enzyme glucose-6-phosphatase (G6Pase), leading to disturbed glycogenolysis and gluconeogenesis. Patients with GSDIa show severe fasting hypoglycemia, hyperlipidemia, hyperlactacidemia, and hyperuricemia, which are associated with fatal outcomes in pregnant women and fetuses.
CASE SUMMARY Herein, we report the case of a 24-year-old female who on her first visit to the hospital, presented with pregnancy combined with extremely high hyperlipidemia and hyperlactic acidosis with anemia, and frequent hypoglycemia occurred during the treatment. Genetic tests revealed a mutation in the G6Pase gene (G6PC) at 17q21, the patient was finally diagnosed with glycogen storage disease type Ia for the first time after 22 years of inaccurate treatment. She has been treated with a continuous double filtration plasmapheresis (DFPP) strategy to remove blood lipids, and a cornstarch diet therapy. The patient did not develop pancreatitis during the course of the disease and a healthy baby girl weighing 3 kg was delivered.
CONCLUSION Patients with GSDIa may be misdiagnosed as epilepsy. DFPP can be used to control hyperlipidemia in GSDIa patients during pregnancy.
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Affiliation(s)
- Jie Wang
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yi Zhao
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Pan Chang
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Bin Liu
- Department of Anesthesiology, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Rong Yao
- Department of Emergency, West China Hospital of Sichuan University, Chengdu 610041, Sichuan Province, China
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Dash S, Tiwari M, Dash P, Kar K, Mohakud NK. Complications of Hypertriglyceridemia in Pregnancy and Its Impact on Neonates: a Hospital-Based Study From Odisha. Cureus 2022; 14:e28399. [PMID: 36171850 PMCID: PMC9508935 DOI: 10.7759/cureus.28399] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/25/2022] [Indexed: 11/17/2022] Open
Abstract
Objective Hypertriglyceridemia (HTG) in pregnancy causes an increased risk for maternal and fetal complications. But, reports on the impact of HTG in pregnancy on maternal and fetal outcomes are scarce in developing countries. We aim to determine the maternal and neonatal complications of HTG in pregnancy. Materials and methods This prospective observational study was conducted on 150 pregnant women with HTG in the department of obstetrics and gynecology, KIMS, Bhubaneswar, from December 2019 to November 2020. Measurement of triglycerides during the first trimester, second trimester, and delivery was done. Maternal complications and neonatal outcomes in HTG mothers and mothers with normal triglyceride levels were compared. Results Out of 150 HTG cases, hypothyroidism, preeclampsia, acute pancreatitis, and sickle cell crisis occurred in 41 (27.3%), 22 (14.7%), six (4%), and three (2%) cases, respectively. The triglyceridemia (TG) levels raised from 133.7±48.2 mg/dl in the first trimester to 232.8±151.0 mg/dl in the third trimester. There is a significant increase in TG levels at the time of delivery compared to the first and second trimesters (p< .001). Out of 140 neonates, 30 (21.4%) were preterm, eight (5.7%) had intrauterine growth restriction (IUGR), and four (6.06%) were macrosomic. Intrauterine death, preterm, and macrosomia are significantly associated with maternal HTG compared to normal mothers (p < .032). All mortalities were due to acute pancreatitis (6; 4%) among mothers and four intrauterine fetal death. Conclusion There is a steady increase in TG levels in the successive trimesters of pregnancy. Gestational severe hypertriglyceridemia causes life-threatening complications. HTG-induced acute pancreatitis needs to be managed aggressively to prevent maternal death. Neonates of HTG mothers suffer from complications like prematurity, IUGR, and macrosomia.
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11
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Sustar U, Groselj U, Khan SA, Shafi S, Khan I, Kovac J, Bizjan BJ, Battelino T, Sadiq F. A homozygous variant in the GPIHBP1 gene in a child with severe hypertriglyceridemia and a systematic literature review. Front Genet 2022; 13:983283. [PMID: 36051701 PMCID: PMC9424485 DOI: 10.3389/fgene.2022.983283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Due to nonspecific symptoms, rare dyslipidaemias are frequently misdiagnosed, overlooked, and undertreated, leading to increased risk for severe cardiovascular disease, pancreatitis and/or multiple organ failures before diagnosis. Better guidelines for the recognition and early diagnosis of rare dyslipidaemias are urgently required. Methods: Genomic DNA was isolated from blood samples of a Pakistani paediatric patient with hypertriglyceridemia, and from his parents and siblings. Next-generation sequencing (NGS) was performed, and an expanded dyslipidaemia panel was employed for genetic analysis. Results: The NGS revealed the presence of a homozygous missense pathogenic variant c.230G>A (NM_178172.6) in exon 3 of the GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1) gene resulting in amino acid change p.Cys77Tyr (NP_835466.2). The patient was 5.5 years old at the time of genetic diagnosis. The maximal total cholesterol and triglyceride levels were measured at the age of 10 months (850.7 mg/dl, 22.0 mmol/L and 5,137 mg/dl, 58.0 mmol/L, respectively). The patient had cholesterol deposits at the hard palate, eruptive xanthomas, lethargy, poor appetite, and mild splenomegaly. Both parents and sister were heterozygous for the familial variant in the GPIHBP1 gene. Moreover, in the systematic review, we present 62 patients with pathogenic variants in the GPIHBP1 gene and clinical findings, associated with hyperlipoproteinemia. Conclusion: In a child with severe hypertriglyceridemia, we identified a pathogenic variant in the GPIHBP1 gene causing hyperlipoproteinemia (type 1D). In cases of severe elevations of plasma cholesterol and/or triglycerides genetic testing for rare dyslipidaemias should be performed as soon as possible for optimal therapy and patient management.
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Affiliation(s)
- Ursa Sustar
- Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Urh Groselj
- Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University, Stanford, CA, United States
- *Correspondence: Urh Groselj, ; Fouzia Sadiq,
| | - Sabeen Abid Khan
- Department of Paediatrics, Shifa College of Medicine, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Saeed Shafi
- Department of Anatomy, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Iqbal Khan
- Department of Vascular Surgery, Shifa International Hospital, Islamabad, Pakistan
- Department of Vascular Surgery, Shifa Tameer-e-Millat University, Islamabad, Pakistan
| | - Jernej Kovac
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Clinical Institute for Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Barbara Jenko Bizjan
- Clinical Institute for Special Laboratory Diagnostics, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Tadej Battelino
- Department of Endocrinology, Diabetes and Metabolism, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Fouzia Sadiq
- Directorate of Research, Shifa Tameer-e-Millat University, Islamabad, Pakistan
- *Correspondence: Urh Groselj, ; Fouzia Sadiq,
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12
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Abstract
Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents-especially antisense RNA and monoclonal antibodies-targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.
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Affiliation(s)
- Amanda J Berberich
- Department of Medicine; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.,Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5B7
| | - Robert A Hegele
- Department of Medicine; Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5C1.,Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada, N6A 5B7
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13
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Yang DJ, Lu HM, Liu Y, Li M, Hu WM, Zhou ZG. Development and validation of a prediction model for moderately severe and severe acute pancreatitis in pregnancy. World J Gastroenterol 2022; 28:1588-1600. [PMID: 35582133 PMCID: PMC9048464 DOI: 10.3748/wjg.v28.i15.1588] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Revised: 02/02/2022] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The severity of acute pancreatitis in pregnancy (APIP) is correlated with higher risks of maternal and fetal death.
AIM To develop a nomogram that could predict moderately severe and severe acute pancreatitis in pregnancy (MSIP).
METHODS Patients with APIP admitted to West China Hospital between January 2012 and December 2018 were included in this study. They were divided into mild acute pancreatitis in pregnancy (MAIP) and MSIP. Characteristic parameters and laboratory results were collected. The training set and test set were randomly divided at a ratio of 7:3. Least absolute shrinkage and selection operator regression was used to select potential prognostic factors. A nomogram was developed by logistic regression. A random forest model was used to validate the stability of the prediction factors. Receiver operating characteristic curves and calibration curves were used to evaluate the model’s predictive performance.
RESULTS A total of 190 patients were included in this study. A total of 134 patients (70.5%) and 56 patients (29.5%) were classified as having MAIP and MSIP, respectively. Four independent predictors (lactate dehydrogenase, triglyceride, cholesterol, and albumin levels) were identified for MSIP. A nomogram prediction model based on these factors was established. The model had areas under the curve of 0.865 and 0.853 in the training and validation sets, respectively. The calibration curves showed that the nomogram has a good consistency.
CONCLUSION A nomogram including lactate dehydrogenase, triglyceride, cholesterol, and albumin levels as independent predictors was built with good performance for MSIP prediction.
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Affiliation(s)
- Du-Jiang Yang
- Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Hui-Min Lu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yong Liu
- Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Mao Li
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Wei-Ming Hu
- Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Zong-Guang Zhou
- Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
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14
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Zhang X, Chen Y, Tong N, Shao Q, Zhou Y, Mu T, Yang X, Zhang Y. Maternally inherited diabetes and deafness coexists with lipoprotein lipase gene mutation-associated severe hyperlipidemia that was resistant to fenofibrate and atorvastatin, but sensitive to bezafibrate: A case report. J Diabetes Investig 2022; 13:397-401. [PMID: 34460997 PMCID: PMC8847153 DOI: 10.1111/jdi.13651] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 08/20/2021] [Accepted: 08/25/2021] [Indexed: 02/05/2023] Open
Abstract
Maternally inherited diabetes and deafness is a rare genetic disease mainly caused by a point mutation in mitochondrial deoxyribonucleic acid. Lipoprotein lipase gene mutations are associated with familial dyslipidemias, which are difficult to manage. We reported for the first time a case that had both maternally inherited diabetes and severe hyperlipidemia caused by lipoprotein lipase gene mutation (C.347(exon3)G>C) that was resistant to fenofibrate and atorvastatin. We were able to manage the patient's hyperlipidemia with bezafibrate, and her diabetes was well controlled with insulin. In conclusion, genetic testing is helpful in identifying rare and interesting cases when clinicians suspect inheritable diseases. Additionally, when one fibrate drug is ineffective in treating hyperlipidemia, it might be worthwhile trying another fibrate.
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Affiliation(s)
- Xiaojuan Zhang
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Yongyong Chen
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
- Department of Endocrinology and MetabolismThe Fifth People's Hospital of ChongqingChongqingChina
| | - Nanwei Tong
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Qing Shao
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Yueyang Zhou
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Tong Mu
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Xiaoling Yang
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
| | - Yuwei Zhang
- Department of Endocrinology and MetabolismWest China Hospital of Sichuan UniversityChengduChina
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15
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Abstract
PURPOSE OF REVIEW Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. RECENT FINDINGS More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.
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Affiliation(s)
- Germán D. Carrasquilla
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Mærsk Building, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Malene Revsbech Christiansen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Mærsk Building, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Tuomas O. Kilpeläinen
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Mærsk Building, Blegdamsvej 3B, 2200 Copenhagen, Denmark
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16
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Laufs U, Parhofer KG, Ginsberg HN, Hegele RA. Clinical review on triglycerides. Eur Heart J 2021; 41:99-109c. [PMID: 31764986 PMCID: PMC6938588 DOI: 10.1093/eurheartj/ehz785] [Citation(s) in RCA: 318] [Impact Index Per Article: 79.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 08/20/2019] [Accepted: 10/23/2019] [Indexed: 12/23/2022] Open
Abstract
Hypertriglyceridaemia is a common clinical problem. Epidemiologic and genetic studies have established that triglyceride-rich lipoproteins (TRL) and their remnants as important contributors to ASCVD while severe hypertriglyceridaemia raises risk of pancreatitis. While low-density lipoprotein is the primary treatment target for lipid lowering therapy, secondary targets that reflect the contribution of TRL such as apoB and non-HDL-C are recommended in the current guidelines. Reduction of severely elevated triglycerides is important to avert or reduce the risk of pancreatitis. Here we discuss interventions for hypertriglyceridaemia, including diet and lifestyle, established treatments such as fibrates and omega-3 fatty acid preparations and emerging therapies, including various biological agents. ![]()
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Affiliation(s)
- Ulrich Laufs
- Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig, Liebigstr. 20, Leipzig, Germany
| | - Klaus G Parhofer
- University Munich, Medical Department 4 - Grosshadern, Marchioninistr. 15, Munich, Germany
| | - Henry N Ginsberg
- Irving Institute for Clinical and Translational Medicine, Vagelos College of Physicians and Surgeons, Columbia University, 630 West 168th Street, New York, NY, USA
| | - Robert A Hegele
- Department of Medicine, Robarts Research Institute, Western University, London, Ontario, Canada
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17
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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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18
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Gouni-Berthold I, Alexander VJ, Yang Q, Hurh E, Steinhagen-Thiessen E, Moriarty PM, Hughes SG, Gaudet D, Hegele RA, O'Dea LSL, Stroes ESG, Tsimikas S, Witztum JL. Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2021; 9:264-275. [PMID: 33798466 DOI: 10.1016/s2213-8587(21)00046-2] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 02/05/2021] [Accepted: 02/10/2021] [Indexed: 12/17/2022]
Abstract
BACKGROUND Volanesorsen is an antisense oligonucleotide that targets hepatic apolipoprotein C-III synthesis and reduces plasma triglyceride concentration. The aim of this study was to explore the safety and efficacy of volanesorsen in patients with multifactorial chylomicronaemia syndrome. METHODS The COMPASS trial was a randomised, placebo-controlled, double-blind, phase 3 study done at 38 international clinical sites in Canada, France, Germany, the Netherlands, UK, and USA. Eligible patients were aged 18 years or older with multifactorial severe hypertriglyceridaemia or familial chylomicronaemia syndrome, who had a BMI of 45 kg/m2 or less and fasting plasma triglyceride of 500 mg/dL or higher. Patients were randomly assigned (2:1) with an interactive response system using an allocation sequence and permuted block randomisation to receive subcutaneous volanesorsen (300 mg) or a matched volume of placebo (1·5 mL) once a week for 26 weeks. After 13 weeks of treatment, dosing was changed to 300 mg of volanesorsen or placebo every 2 weeks for all patients, except those who had completed 5 months or more of treatment as of May 27, 2016. Participants, investigators, sponsor personnel, and clinical research staff were all masked to the treatment assignments. The primary outcome was percentage change from baseline to 3 months in fasting triglyceride in the full analysis set (all patients who were randomly assigned and received at least one dose of study drug and had a baseline fasting triglyceride assessment). This trial is registered with ClinicalTrials.gov, NCT02300233 (completed). FINDINGS Between Feb 5, 2015, and Jan 24, 2017, 408 patients were screened for eligibility. 294 were excluded and 114 randomly assigned to receive either volanesorsen (n=76) or placebo (n=38). One patient in the volanesorsen group discontinued before receiving the study drug. The total number of dropouts was 28 (four in the placebo group and 24 in the treatment group). Volanesorsen reduced mean plasma triglyceride concentration by 71·2% (95% CI -79·3 to -63·2) from baseline to 3 months compared with 0·9% (-13·9 to 12·2) in the placebo group (p<0·0001), representing a mean absolute reduction of fasting plasma triglycerides of 869 mg/dL (95% CI -1018 to -720; 9·82 mmol/L [-11·51 to -8·14]) in volanesorsen compared with an increase in placebo of 74 mg/dL (-138 to 285; 0·83 mmol/L [-1·56 to 3·22]; p<0·0001). In the key safety analysis, five adjudicated events of acute pancreatitis occurred during the study treatment period, all in three of 38 patients in the placebo group. The most common adverse events were related to tolerability and included injection-site reactions (average of 24% of all volanesorsen injections vs 0·2% of placebo injections), which were all mild or moderate. One participant in the volanesorsen group had a platelet count reduction to less than 50 000 per μL and one patient had serum sickness, both of which were regarded as serious adverse events. INTERPRETATION Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients. FUNDING Ionis Pharmaceuticals and Akcea Therapeutics.
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Affiliation(s)
- Ioanna Gouni-Berthold
- Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany
| | | | | | | | | | | | | | - Daniel Gaudet
- Department of Medicine, Université de Montréal, Saguenay, QC, Canada
| | - Robert A Hegele
- Robarts Research Institute, Western University, London, ON, Canada
| | | | - Erik S G Stroes
- Department Vascular Medicine, Academic Medical Center, Amsterdam, Netherlands
| | - Sotirios Tsimikas
- Ionis Pharmaceuticals, Carlsbad, CA, USA; Department of Medicine, University California San Diego, La Jolla, CA, USA
| | - Joseph L Witztum
- Department of Medicine, University California San Diego, La Jolla, CA, USA.
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19
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Wu G, Bockman B, Perez J. Acute Myocardial Infarction Complicated by Very Severe Hypertriglyceridemia. CASE REPORTS IN ACUTE MEDICINE 2020. [DOI: 10.1159/000511065] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Hypertriglyceridemia (HTG) is the elevation of serum triglyceride levels above 150 mg/dL and is linked to complications such as pancreatitis and increased mortality risk. An uncommonly known co-presentation of HTG is acute ST-elevation myocardial infarction (STEMI), with the literature citing only one other case of acute STEMI complicated by very severe HTG. We report on a 36-year-old male with multiple comorbidities presenting with acute STEMI and elevated pancreatic enzymes suggestive of pancreatitis. A subsequent lipid profile revealed very severe HTG with a triglyceride level of 2,700 mg/dL. We discuss the pathogenesis, management, and screening guidelines of very severe HTG. Clinicians should be aware that acute STEMI complicated by HTG is rare and that earlier detection and intervention may allow for the prevention of life-threatening complications.
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20
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Miyashita K, Lutz J, Hudgins LC, Toib D, Ashraf AP, Song W, Murakami M, Nakajima K, Ploug M, Fong LG, Young SG, Beigneux AP. Chylomicronemia from GPIHBP1 autoantibodies. J Lipid Res 2020; 61:1365-1376. [PMID: 32948662 PMCID: PMC7604722 DOI: 10.1194/jlr.r120001116] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Some cases of chylomicronemia are caused by autoantibodies against glycosylphosphatidylinositol-anchored HDL binding protein 1 (GPIHBP1), an endothelial cell protein that shuttles LPL to the capillary lumen. GPIHBP1 autoantibodies prevent binding and transport of LPL by GPIHBP1, thereby disrupting the lipolytic processing of triglyceride-rich lipoproteins. Here, we review the "GPIHBP1 autoantibody syndrome" and summarize clinical and laboratory findings in 22 patients. All patients had GPIHBP1 autoantibodies and chylomicronemia, but we did not find a correlation between triglyceride levels and autoantibody levels. Many of the patients had a history of pancreatitis, and most had clinical and/or serological evidence of autoimmune disease. IgA autoantibodies were present in all patients, and IgG4 autoantibodies were present in 19 of 22 patients. Patients with GPIHBP1 autoantibodies had low plasma LPL levels, consistent with impaired delivery of LPL into capillaries. Plasma levels of GPIHBP1, measured with a monoclonal antibody-based ELISA, were very low in 17 patients, reflecting the inability of the ELISA to detect GPIHBP1 in the presence of autoantibodies (immunoassay interference). However, GPIHBP1 levels were very high in five patients, indicating little capacity of their autoantibodies to interfere with the ELISA. Recently, several GPIHBP1 autoantibody syndrome patients were treated successfully with rituximab, resulting in the disappearance of GPIHBP1 autoantibodies and normalization of both plasma triglyceride and LPL levels. The GPIHBP1 autoantibody syndrome should be considered in any patient with newly acquired and unexplained chylomicronemia.
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Affiliation(s)
- Kazuya Miyashita
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
- Immuno-Biological Laboratories (IBL), Fujioka, Gunma, Japan
| | - Jens Lutz
- Medical Clinic, Nephrology-Infectious Diseases, Central Rhine Hospital Group, Koblenz, Germany
| | - Lisa C Hudgins
- Rogosin Institute, Weill Cornell Medical College, New York, NY, USA
| | - Dana Toib
- Department of Pediatrics, Drexel University, Philadelphia, PA, USA
- Section of Pediatric Rheumatology, St. Christopher's Hospital for Children, Philadelphia, PA, USA
| | - Ambika P Ashraf
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Wenxin Song
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Masami Murakami
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Katsuyuki Nakajima
- Department of Clinical Laboratory Medicine, Gunma University, Graduate School of Medicine, Maebashi, Japan
| | - Michael Ploug
- Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark
- Biotechnology Research Innovation Center, Copenhagen University, Copenhagen, Denmark
| | - Loren G Fong
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Stephen G Young
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Anne P Beigneux
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
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21
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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: 56] [Impact Index Per Article: 11.2] [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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22
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Acar YA, Gunay G, Bilge S, Tezel O. Concomitant hypertriglyceridemia-induced pancreatitis in pregnant monozygotic twin siblings. Gynecol Endocrinol 2020; 36:654-656. [PMID: 32157928 DOI: 10.1080/09513590.2020.1737669] [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: 10/24/2022] Open
Abstract
Hypertriglyceridemia-induced pancreatitis (HTIP) is the third most common cause of pancreatitis. Hypertriglyceridemia shows familial transition and pregnancy increases the risk of HTIP. The treatment of HTIP is initiated with supportive treatment and continues with specific treatments including plasmapheresis, insulin, heparin infusion, and hemofiltration. The current study reports monozygotic twins who are pregnant at the same time having concurrent HTIP attack.
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Affiliation(s)
- Yahya Ayhan Acar
- Department of Emergency Medicine, University of Health Sciences, Ankara, Turkey
| | - Gizem Gunay
- Department of Emergency Medicine, University of Health Sciences, Ankara, Turkey
| | - Sedat Bilge
- Department of Emergency Medicine, University of Health Sciences, Ankara, Turkey
| | - Onur Tezel
- Department of Emergency Medicine, University of Health Sciences, Ankara, Turkey
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23
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Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study. CLINICA E INVESTIGACION EN ARTERIOSCLEROSIS 2020; 32:242-255. [PMID: 32534728 DOI: 10.1016/j.arteri.2020.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 04/11/2020] [Accepted: 04/22/2020] [Indexed: 12/11/2022]
Abstract
AIM To determine in the adult population the crude and the sex- and age-adjusted prevalence rates of hypertriglyceridaemia (HTG) and to assess its association with cardiovascular risk factors, chronic kidney disease, cardiovascular and cardiometabolic diseases. METHODS Cross-sectional observational study conducted in Primary Care, with 6,588 adult study subjects, randomly selected on base-population. Patients had HTG if the triglyceride level was≥150mg/dL (≥1.7mmol/L), or were on lipid-lowering therapy to lower triglyceride. Associations were assessed by univariate and multivariate analysis, and crude and sex- and age-adjusted prevalence rates were determined. RESULTS The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2mg/dL in global population, 135.7 and 116.0mg/dL in men, and 108.6 and 95.7mg/dL in women. The crude HTG prevalence rates were 29.6% in global population, 36.9% in men and 23.8% in women. The sex- and age-adjusted HTG prevalence rates were 27.0% in global population, 34.6% in men and 21.4% in women. The independent variables that were most associated with HTG were hypercholesterolemia (OR: 4.6), low HDL-C (OR: 4.1), hepatic steatosis (OR: 2.8), diabetes (OR: 2.0), and obesity (OR: 1.9). CONCLUSIONS The means of triglyceride levels and HTG prevalence rates are intermediate between those of other national and international studies. A fifth of the female adult population and more than a third of the male population had HTG. The independent factors associated with HTG were hypercholesterolemia and low HDL-C, and the cardiometabolic variables diabetes, hepatic steatosis and obesity.
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24
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Pu N, Yang Q, Shi XL, Chen WW, Li XY, Zhang GF, Li G, Li BQ, Ke L, Tong ZH, Cooper DN, Chen JM, Li WQ, Li JS. Gene-environment interaction between APOA5 c.553G>T and pregnancy in hypertriglyceridemia-induced acute pancreatitis. J Clin Lipidol 2020; 14:498-506. [PMID: 32561169 DOI: 10.1016/j.jacl.2020.05.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2019] [Revised: 03/15/2020] [Accepted: 05/13/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex. OBJECTIVE Herein, we explore a possible gene-environment interaction between APOA5 c.553G>T (p.185Gly>Cys, rs2075291), a common variant associated with altered triglyceride levels, and pregnancy in HTG-AP. METHODS We enrolled 318 Chinese HTG-AP patients and divided them into 3 distinct groups: Group 1, male patients (n = 183); Group 2, female patients whose disease was unrelated to pregnancy (n = 105); and Group 3, female patients whose disease was related to pregnancy (n = 30). APOA5 rs2075291 genotype status was determined by Sanger sequencing. A total of 362 healthy Han Chinese subjects were used as controls. Data on body mass index, peak triglyceride level, age of disease onset, episode number, and clinical severity of HTG-AP were collected from each patient. Multiple comparisons, between patient groups, between patient groups and controls, or within each patient group, were performed. RESULTS A robust association of APOA5 rs2075291 with HTG-AP in general, and HTG-AP during pregnancy in particular, was demonstrated. The minor T allele showed a stronger association with Group 3 patients than with either Group 1 or Group 2 patients. This stronger association was due mainly to the much higher frequency of TT genotype in Group 3 patients (20%) than that (<6%) in Group 1 and Group 2 patients. Moreover, the TT genotype was associated with a significantly higher peak triglyceride level in Group 3 patients compared with the GG genotype. CONCLUSION Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP.
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Affiliation(s)
- Na Pu
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Qi Yang
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Xiao-Lei Shi
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wei-Wei Chen
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Department of Gastroenterology, Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Xiao-Yao Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China; Department of Intensive Care Unit, The Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China
| | - Guo-Fu Zhang
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Gang Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Bai-Qiang Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lu Ke
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Zhi-Hui Tong
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - David N Cooper
- Institute of Medical Genetics, School of Medicine, Cardiff University, Cardiff, United Kingdom
| | - Jian-Min Chen
- EFS, Univ Brest, Inserm, UMR 1078, GGB, Brest, France
| | - Wei-Qin Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.
| | - Jie-Shou Li
- Surgical Intensive Care Unit (SICU), Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
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25
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Kim AS, Hakeem R, Abdullah A, Hooper AJ, Tchan MC, Alahakoon TI, Girgis CM. Therapeutic plasma exchange for the management of severe gestational hypertriglyceridaemic pancreatitis due to lipoprotein lipase mutation. Endocrinol Diabetes Metab Case Rep 2020; 2020:EDM190165. [PMID: 32168469 PMCID: PMC7077517 DOI: 10.1530/edm-19-0165] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Accepted: 02/21/2020] [Indexed: 12/15/2022] Open
Abstract
SUMMARY A 19-year-old female presented at 25-weeks gestation with pancreatitis. She was found to have significant hypertriglyceridaemia in context of an unconfirmed history of familial hypertriglyceridaemia. This was initially managed with fasting and insulin infusion and she was commenced on conventional interventions to lower triglycerides, including a fat-restricted diet, heparin, marine oil and gemfibrozil. Despite these measures, the triglyceride levels continued to increase as she progressed through the pregnancy, and it was postulated that she had an underlying lipoprotein lipase defect. Therefore, a multidisciplinary decision was made to commence therapeutic plasma exchange to prevent further episodes of pancreatitis. She underwent a total of 13 sessions of plasma exchange, and labour was induced at 37-weeks gestation in which a healthy female infant was delivered. There was a rapid and significant reduction in triglycerides in the 48 h post-delivery. Subsequent genetic testing of hypertriglyceridaemia genes revealed a missense mutation of the LPL gene. Fenofibrate and rosuvastatin was commenced to manage her hypertriglyceridaemia postpartum and the importance of preconception counselling for future pregnancies was discussed. Hormonal changes in pregnancy lead to an overall increase in plasma lipids to ensure adequate nutrient delivery to the fetus. These physiological changes become problematic, where a genetic abnormality in lipid metabolism exists and severe complications such as pancreatitis can arise. Available therapies for gestational hypertriglyceridaemia rely on augmentation of LPL activity. Where there is an underlying LPL defect, these therapies are ineffective and removal of triglyceride-rich lipoproteins via plasma exchange should be considered. LEARNING POINTS Hormonal changes in pregnancy, mediated by progesterone,oestrogen and human placental lactogen, lead to a two- to three-fold increase in serum triglyceride levels. Pharmacological intervention for management of gestational hypertriglyceridaemia rely on the augmentation of lipoprotein lipase (LPL) activity to enhance catabolism of triglyceride-rich lipoproteins. Genetic mutations affecting the LPL gene can lead to severe hypertriglyceridaemia. Therapeutic plasma exchange (TPE) is an effective intervention for the management of severe gestational hypertriglyceridaemia and should be considered in cases where there is an underlying LPL defect. Preconception counselling and discussion regarding contraception is of paramount importance in women with familial hypertriglyceridaemia.
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Affiliation(s)
- Albert S Kim
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
- The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
| | - Rashida Hakeem
- Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Azaliya Abdullah
- Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Amanda J Hooper
- School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
- Department of Clinical Biochemistry, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital Network, Perth, Western Australia, Australia
| | - Michel C Tchan
- The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
- Department of Genetic Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Thushari I Alahakoon
- The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
- Department of Maternal-Fetal Medicine, Westmead Institute for Maternal-Fetal Medicine, Westmead Hospital, Westmead, New South Wales, Australia
| | - Christian M Girgis
- Department of Diabetes and Endocrinology, Westmead Hospital, Westmead, New South Wales, Australia
- The University of Sydney, Faculty of Medicine and Health, Sydney, New South Wales, Australia
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
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Dron JS, Wang J, McIntyre AD, Iacocca MA, Robinson JF, Ban MR, Cao H, Hegele RA. Six years' experience with LipidSeq: clinical and research learnings from a hybrid, targeted sequencing panel for dyslipidemias. BMC Med Genomics 2020; 13:23. [PMID: 32041611 PMCID: PMC7011550 DOI: 10.1186/s12920-020-0669-2] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2019] [Accepted: 01/23/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND In 2013, our laboratory designed a targeted sequencing panel, "LipidSeq", to study the genetic determinants of dyslipidemia and metabolic disorders. Over the last 6 years, we have analyzed 3262 patient samples obtained from our own Lipid Genetics Clinic and international colleagues. Here, we highlight our findings and discuss research benefits and clinical implications of our panel. METHODS LipidSeq targets 69 genes and 185 single-nucleotide polymorphisms (SNPs) either causally related or associated with dyslipidemia and metabolic disorders. This design allows us to simultaneously evaluate monogenic-caused by rare single-nucleotide variants (SNVs) or copy-number variants (CNVs)-and polygenic forms of dyslipidemia. Polygenic determinants were assessed using three polygenic scores, one each for low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol. RESULTS Among 3262 patient samples evaluated, the majority had hypertriglyceridemia (40.1%) and familial hypercholesterolemia (28.3%). Across all samples, we identified 24,931 unique SNVs, including 2205 rare variants predicted disruptive to protein function, and 77 unique CNVs. Considering our own 1466 clinic patients, LipidSeq results have helped in diagnosis and improving treatment options. CONCLUSIONS Our LipidSeq design based on ontology of lipid disorders has enabled robust detection of variants underlying monogenic and polygenic dyslipidemias. In more than 50 publications related to LipidSeq, we have described novel variants, the polygenic nature of many dyslipidemias-some previously thought to be primarily monogenic-and have uncovered novel mechanisms of disease. We further demonstrate several tangible clinical benefits of its use.
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Affiliation(s)
- Jacqueline S. Dron
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5B7 Canada
| | - Jian Wang
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
| | - Adam D. McIntyre
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
| | - Michael A. Iacocca
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5B7 Canada
- Department of Biomedical Data Science, Stanford School of Medicine, Stanford University, 450 Serra Mall, Stanford, CA 94305 USA
| | - John F. Robinson
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
| | - Matthew R. Ban
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
| | - Henian Cao
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
| | - Robert A. Hegele
- Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
- Department of Biochemistry, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, London, ON N6A 5B7 Canada
- Department of Medicine, Schulich School of Medicine and Dentistry, Western University, 1151 Richmond St, London, ON N6A 5B7 Canada
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27
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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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28
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Young SG, Fong LG, Beigneux AP, Allan CM, He C, Jiang H, Nakajima K, Meiyappan M, Birrane G, Ploug M. GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism. Cell Metab 2019; 30:51-65. [PMID: 31269429 PMCID: PMC6662658 DOI: 10.1016/j.cmet.2019.05.023] [Citation(s) in RCA: 98] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Lipoprotein lipase (LPL), identified in the 1950s, has been studied intensively by biochemists, physiologists, and clinical investigators. These efforts uncovered a central role for LPL in plasma triglyceride metabolism and identified LPL mutations as a cause of hypertriglyceridemia. By the 1990s, with an outline for plasma triglyceride metabolism established, interest in triglyceride metabolism waned. In recent years, however, interest in plasma triglyceride metabolism has awakened, in part because of the discovery of new molecules governing triglyceride metabolism. One such protein-and the focus of this review-is GPIHBP1, a protein of capillary endothelial cells. GPIHBP1 is LPL's essential partner: it binds LPL and transports it to the capillary lumen; it is essential for lipoprotein margination along capillaries, allowing lipolysis to proceed; and it preserves LPL's structure and activity. Recently, GPIHBP1 was the key to solving the structure of LPL. These developments have transformed the models for intravascular triglyceride metabolism.
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Affiliation(s)
- Stephen G Young
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| | - Loren G Fong
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| | - Anne P Beigneux
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Christopher M Allan
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Cuiwen He
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Haibo Jiang
- Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; School of Molecular Sciences, University of Western Australia, Crawley 6009, Australia
| | - Katsuyuki Nakajima
- Department of Clinical Laboratory Medicine, Gunma University Graduate School of Department of Medicine, Maebashi, Gunma 371-0805, Japan
| | - Muthuraman Meiyappan
- Discovery Therapeutics, Takeda Pharmaceutical Company Ltd., Cambridge, MA 02142, USA
| | - Gabriel Birrane
- Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA
| | - Michael Ploug
- Finsen Laboratory, Rigshospitalet, Copenhagen DK-2200, Denmark; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen DK-2200, Denmark.
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