Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence

doi:10.1016/j.jacl.2018.09.007

Journal of Clinical Lipidology

Volume 13, Issue 1, January–February 2019, Pages 89-99

https://doi.org/10.1016/j.jacl.2018.09.007 Get rights and content

Highlights

•
Extreme hypertriglyceridemia (>2000 mg/dL) is associated with pancreatitis.
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The prevalence of this condition in a reference laboratory population is 0.01%.
•
Pregnancy exacerbates hypertriglyceridemia and may require plasmapheresis.
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Effective therapies include a low-fat diet, medium-chain triglyceride(s) oil, fibrates, and fish oil.
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The underlying molecular defects should be characterized by DNA analysis.

Background

Triglyceride (TG) concentrations >2000 mg/dL are extremely elevated and increase the risk of pancreatitis.

Objectives

We characterized five cases and two kindreds and ascertained prevalence in a reference laboratory population.

Methods

Plasma lipids and DNA sequences of LPL, GPIHBP1, APOA5, APOC2, and LMF1 were determined in cases and two kindreds. Hypertriglyceridemia prevalence was assessed in 440,240 subjects.

Results

Case 1 (female, age 28 years) had TG concentrations >2000 mg/dL and pancreatitis since infancy. She responded to diet and medium-chain triglycerides, but not medications. During two pregnancies, she required plasma exchange for TG control. She was a compound heterozygote for a p.G236Gfs*15 deletion and a p.G215E missense mutation at LPL, as was one sister with hypertriglyceridemia and pancreatitis during pregnancy. Her father was heterozygous for the deletion and had hypertriglyceridemia and recurrent pancreatitis. Other family members had either the missense mutation or the deletion, and had hypertriglyceridemia but no pancreatitis. In kindred 2, three preschool children had severe hypertriglyceridemia and were homozygous for a GPIHBP1 p.T108R missense mutation. Case 5 (male, age 43 years) presented with pancreatitis and TG levels >5000 mg/dL and had heterozygous GPIHBP1 p.G175R and APOC2 intron 2-4G>C mutations. On diet, fenofibrate, fish oil, and atorvastatin, his TG concentration was 2526 mg/dL, but normalized to <100 mg/dL with added pioglitazone. In our population study, 60 subjects (0.014%) of 440,240 had TG concentrations >2000 mg/dL, and 66.7% were diabetic and had elevated insulin levels.

Conclusions

Extreme hypertriglyceridemia is rare (0.014%); and during pregnancy, it may require plasma exchange.

Introduction

Severe hypertriglyceridemia is an uncommon disorder characterized by fasting plasma that is usually lipemic, with triglyceride (TG) concentrations > 885 mg/dL and an excess of TG-containing lipoprotein particles known as chylomicrons and very low-density lipoproteins (VLDL).¹ Chylomicrons are produced in the intestine in response to dietary fat, while VLDL is produced in the liver to export lipids, especially TG, into the bloodstream.¹ The classification of hyperlipoproteinemias published by Fredrickson, Levy, and Lees at the National Institutes of Health in 1967 associated severe hypertriglyceridemia with two types of hyperlipoproteinemias accordingly: type I, or chylomicronemia, and type V, or hyperprebetalipoproteinemia.² Patients with type I hyperlipoproteinemia had isolated chylomicron elevation on lipoprotein electrophoresis, whereas patients with type V hypertriglyceridemia had increases in both chylomicrons and VLDL.²

Milky or lipemic plasma was first noted to be associated with eruptive xanthomas and with uncontrolled diabetes in 1921, and later cases without diabetes were described.¹ Subsequently, it was documented that such patients develop recurrent abdominal pain, which could be treated with a fat-free diet.¹ Havel and Gordon documented the deficiency of lipoprotein lipase (LPL) activity in these patients.¹ Thereafter, Brown et al at the National Institutes of Health showed that (1) the C apolipoproteins (apo) were important constituents of chylomicrons and VLDL, (2) apoC-II was the major activator of LPL, (3) apoC-III was the major inhibitor, modulating the catabolism of TG-rich lipoproteins, and (4) both LPL and hepatic lipase promoted postheparin lipolytic activity in plasma.3, 4, 5, 6, 7 A study of 32 kindreds with primary type V hyperlipoproteinemia by Greenberg and Levy in 1977 documented linkage with diabetes, obesity, excess alcohol intake, and gout, but not premature coronary heart disease or abnormalities in postheparin lipolytic activity.⁸ Breckenridge et al described a 59-year-old man with a long history of abdominal pain, marked hypertriglyceridemia, absent postheparin lipase activity, and a deficiency of apoC-II.⁹ The patient's hypertriglyceridemia improved dramatically when he received a transfusion for anemia.

Since that time, significant increases in our understanding of the genetic causes of severe hypertriglyceridemia have occurred. The condition often results from homozygous or compound heterozygous mutations in the genes which encode LPL (LPL), its cofactors apoC-II (APOC2) and apoA-V (APOA5), the LPL chaperone lipase maturation factor 1 (LMF1), or glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1).¹⁰

Patients with type I hyperlipoproteinemia generally present in childhood or adolescence with marked hypertriglyceridemia, very high levels of plasma chylomicrons, and often pancreatitis. Treatment of hypertriglyceridemia in a type I patient focuses on the restriction of dietary fat and control of secondary factors, as available pharmacological therapies, namely, fibrates and omega-3 fatty acids, are generally only minimally effective.¹⁰ These patients generally have fasting TG levels > 2000 mg/dL and, in our view, should be characterized as having extreme hypertriglyceridemia.

Patients with type V hyperlipoproteinemia, also known as polygenic late-onset hypertriglyceridemia, generally have elevated plasma concentrations of both chylomicrons and VLDL.² This form of severe hypertriglyceridemia is approximately ten times more common than early-onset chylomicronemia. It is usually caused by an accumulation of several genetic variants, along with secondary factors such as uncontrolled diabetes, obesity, a poor diet, alcohol intake, and/or oral estrogens.¹⁰ It also is associated with an increased risk of pancreatitis and may be associated as well with an increased risk of cardiovascular disease (CVD).¹ Polygenic late-onset hypertriglyceridemia is generally quite responsive to lifestyle modifications with diet (restriction of fat and sugar), exercise, weight loss, control of hyperglycemia, and therapy with fibrates and/or omega-3 fatty acids.¹⁰

Our objective in this investigation was to report five cases of severe hypertriglyceridemia, which have been characterized at the molecular level, along with their clinical course and treatment response. Two of the patients had recurrent pancreatitis, one exacerbated by pregnancy. We also describe the efficacy of plasma exchange in controlling marked hypertriglyceridemia in one case that was successfully carried through two pregnancies with no subsequent episodes of pancreatitis and the delivery of three healthy offspring. The kindreds of two index cases were characterized. We aimed, in addition, to assess the prevalence of hypertriglyceridemia in a large reference population, using the European guideline cutpoints for fasting plasma TG levels, and to review the literature with regard to such cases. A European Atherosclerosis Society Consensus Panel has categorized hypertriglyceridemia as “mild-to-moderate” when fasting plasma TG concentrations are 177 to 885 mg/dL (2.0–10.0 mmol/L) and as “severe” when TG concentrations are > 885 mg/dL (>10 mmol/L).¹¹ However, many patients with these types of values do not develop pancreatitis and are often quite treatable with lifestyle modification, fibrates, and omega-3 fatty acid therapy. Patients with fasting plasma TG concentrations > 2000 mg/dL, who have been classified as having extreme hypertriglyceridemia, are much more likely to develop pancreatitis and are often much more difficult to treat. Therefore, we have added this category in our analyses.

Section snippets

Case reports

In all patients, plasma lipids were analyzed, after an overnight fast, for the measurement of total cholesterol, TG, and high-density lipoprotein cholesterol (HDL-C) using automated standardized assays as previously described.¹² Isolated DNA was sequenced at the APOA5, APOC2, LPL, GPIHBP1, and LMF1 gene loci by next-generation sequencing, at the London Regional Genomics Centre (London, ON, Canada) under the supervision of Dr Robert Hegele, as previously described.¹³ Informatics analysis was

Case 1

A 28-year-old female presented with a history of multiple episodes of severe pancreatitis beginning when she was 3 months of age. Her disease had been reasonably stable and well controlled on a strict low-fat diet, until her early twenties, when she again had recurrent attacks of pancreatitis resulting in at least 15 hospitalizations over a 4-year period. She had had limited follow-up by a lipidologist, likely due to issues with health insurance. She had been treated with fenofibrate 160 mg/d,

Discussion

Pedersen et al recently examined the relationship between nonfasting plasma TG concentrations and the risk of pancreatitis in 116,550 Danish subjects followed over a median of 6.7 years. Compared with individuals with plasma TG levels < 89 mg/dL, the multivariable adjusted hazard ratio (HR) and event rate per 10,000 person years for acute pancreatitis were: 1.6 and 4.3 events with TG concentrations of 89 to 176 mg/dL; 2.3 and 5.5 events with TG of 177 to 265 mg/dL; 2.9 and 6.3 events with TG of

Acknowledgments

Authors' contributions: V.C., A.S.B., A.D.D., L.C.H., and E.J.S. contributed to conception and design; V.C., S.K., A.S.B., L.C.H., T.J.S., A.D.D., T.C.B., A.S.G., R.A.H., and E.J.S. contributed to data acquisition on case reports; M.R.D., L.H., A.S.G., and E.J.S. contributed to data acquisition and analysis on the population cohort; V.C., A.S.B., M.R.D., R.A.H., and E.J.S. contributed to overall data analysis and interpretation; V.C., A.S.B., A.D.D., L.C.H., M.R.D., and E.J.S. contributed to

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Cited by (28)

Efficacy and safety of volanesorsen in patients with multifactorial chylomicronaemia (COMPASS): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
2021, The Lancet Diabetes and Endocrinology
Citation Excerpt :
For instance, in other cohorts with severe hypertriglyceridaemia and chylomicronaemia, the prevalence of familial chylomicronaemia syndrome was 1–2%,11 but in COMPASS it was 6% because we recruited a small cohort. Furthermore, the 19% prevalence of patients with heterozygous mutations in genes related to lipoprotein lipase activity is increased by almost five times compared with a 4% prevalence in the normolipidaemic population.6,7,11 In addition, 49% of patients in our study had a polygenic score for triglycerides in the top 5th percentile, which is almost a ten-times increase compared with the score in the general population.
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.
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).
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.
Volanesorsen significantly reduced triglyceride concentrations in patients with multifactorial chlyomicronaemia and might reduce acute pancreatitis events in these patients.
Ionis Pharmaceuticals and Akcea Therapeutics.
Chylomicronemia from GPIHBP1 autoantibodies
2020, Journal of Lipid Research
Citation Excerpt :
For example, a p.M404R substitution in LPL abolishes LPL's ability to bind GPIHBP1 by introducing a charged amino acid (arginine) into the hydrophobic GPIHBP1–LPL binding interface (11). Similarly, mutations in GPIHBP1 Thr-108 (22, 33) or Trp-109 (31) disrupt the GPIHBP1–LPL binding interface (11). Allan et al. (34) recently generated a Gpihbp1 knock-in mouse harboring a LU domain amino acid substitution (p.C65Y) that had been shown to cause chylomicronemia in humans (23).
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.
Prevalence of hypertriglyceridemia in adults and related cardiometabolic factors. SIMETAP-HTG study
2020, Clinica e Investigacion en Arteriosclerosis
Determinar en la población adulta las tasas de prevalencia brutas y ajustadas por edad y sexo de hipertrigliceridemia (HTG) y valorar su asociación con factores de riesgo cardiovascular, enfermedad renal crónica y enfermedades cardiovasculares y cardiometabólicas.
Estudio observacional transversal realizado en Atención Primaria, con 6.588 sujetos de estudio adultos, seleccionados aleatoriamente con base poblacional. Los pacientes tenían HTG si la concentración de triglicéridos era ≥ 150 mg/dL (≥ 1,7 mmol/L) o estaban en tratamiento hipolipidemiante para reducir los triglicéridos. Se valoraron las asociaciones mediante análisis univariado y multivariante, y se determinaron las prevalencias brutas y ajustadas por edad y sexo.
Las medias aritméticas y geométricas de las concentraciones de triglicéridos fueron respectivamente 120,5 y 104,2 mg/dL en la población global, 135,7 y 116,0 mg/dL en hombres, y 108,6 y 95,7 mg/dL en mujeres. Las prevalencias brutas de HTG fueron 29,6% en población global, 36,9% en hombres y 23,8% en mujeres. Las prevalencias ajustadas por edad y sexo de HTG fueron 27,0% en población global, 34,6% en hombres y 21,4% en mujeres. Las variables independientes que más se asociaban con la HTG fueron hipercolesterolemia (OR: 4,6), c-HDL bajo (OR: 4,1), esteatosis hepática (OR: 2,8), diabetes (OR: 2,0) y obesidad (OR: 1,9).
Las medias de triglicéridos y las prevalencias de HTG se encuentran intermedias entre las de otros estudios nacionales e internacionales. La quinta parte de la población adulta femenina y más de un tercio de la masculina presentaba HTG. Los factores independientes asociados con HTG fueron hipercolesterolemia y c-HDL bajo, y las variables cardiometabólicas diabetes, esteatosis hepática y obesidad.
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.
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 ≥ 150 mg/dL (≥ 1.7 mmol/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.
The arithmetic and geometric means of triglyceride levels were respectively 120.5 and 104.2 mg/dL in global population, 135.7 and 116.0 mg/dL in men, and 108.6 and 95.7 mg/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).
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.
GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism
2019, Cell Metabolism
Citation Excerpt :
Chylomicronemia was also observed in the setting of a T80K mutation, which interferes with N-linked glycosylation and trafficking of GPIHBP1 to the plasma membrane (Ariza et al., 2016). A G175R substitution has been observed in several patients with hypertriglyceridemia (Beigneux et al., 2017; Charrière et al., 2011; Chyzhyk et al., 2019) but is unlikely to be causative. G175 is located in the signal peptide that is normally replaced by the GPI anchor (i.e., it is not present in mature GPIHBP1).
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.
Gene–environment interaction between APOA5 c.553G>T and pregnancy in hypertriglyceridemia-induced acute pancreatitis
2020, Journal of Clinical Lipidology
Citation Excerpt :
This increase is well tolerated by most women with normal baseline TG levels but may render those with genetic defects in TG metabolism prone to severe HTG and, consequently, HTG-induced AP (HTG-AP). In this regard, numerous studies have reported the identification of rare pathogenic variants in the lipoprotein lipase (LPL; OMIM# 609708),17–26 glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1; OMIM# 612757), and apolipoprotein C2 (APOC2; OMIM# 608083) genes24,26 in patients experiencing HTG-AP during pregnancy (HTG-APIP). LPL, GPIHBP1, and APOC2, together with apolipoprotein A5 (APOA5; OMIM# 606368) and lipase maturation factor 1 (LMF1; OMIM# 611761), constitute the 5 primary TG-related genes.12,27–29
The etiology of hypertriglyceridemia (HTG) and, consequently, HTG-induced acute pancreatitis (HTG-AP), is complex.
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.
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.
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.
Our findings provide evidence for an interaction between APOA5 rs2075291 and pregnancy in HTG-AP.
Fibrates and risk of congenital malformations: a nationwide cohort study in South Korea
2024, Archives of Gynecology and Obstetrics

View all citing articles on Scopus

: Presented in part at the 2018 Scientific Sessions and the 1st Donald Fredrickson Conference of the National Lipid Association, Las Vegas, NV on April 27 and 29, 2018 and at the XVIIIth International Symposium on Atherosclerosis, Toronto, ON, Canada on June 11, 2018.

¹: Present affiliation: Prairie Heart Institute, St. John's Hospital, Springfield, IL USA.

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Original ArticleExtreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence

Highlights

Background

Objectives

Methods

Results

Conclusions

Introduction

Section snippets

Case reports

Case 1

Discussion

Acknowledgments

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

J Lipid Res

Lancet Diabetes Endocrinol

J Lipid Res

Atherosclerosis

J Clin Lipidol

J Biol Chem

Pharmacol Ther

J Clin Lipidol

Familial lipoprotein lipase deficiency and other causes of chylomicronemia syndrome

Fat transport in lipoproteins – an integrated approach to mechanisms and disorders

N Engl J Med

Further observations on the activation and inhibition of lipoprotein lipase by apolipoproteins

Circ Res

Primary type V hyperlipoproteinemia. A descriptive study in 32 families

Ann Intern Med

Hypertriglyceridemia associated with deficiency of apolipoprotein C-II

N Engl J Med

Original Article
Extreme hypertriglyceridemia: Genetic diversity, pancreatitis, pregnancy, and prevalence