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Mutations in the LPL gene lead to familial hypertriglyceridemia (FHTG) . We have previously generated an iPSC line (AHQUi001-A) from a FHTG patient with a heterozygous p.C310R (c.928 T > C) mutation in the LPL gene. Here we genetically corrected the C310R mutation in the LPL gene using CRISPR/Cas9 technology to generate AHQUi001-A-1, which demonstrates normal karyotype, morphology, pluripotency, and potential to differentiate towards three germ layers.

Background Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. Methods This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. Results Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901–0.970, 98.5% sensitivity, 92.2% specificity, P Conclusions The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.

Familial hypertriglyceridemia (FHTG) is an autosomal dominant disorder of lipoprotein metabolism, partly caused by mutations in the LPL gene, which encodes for the lipoprotein lipase. LPL deficiency can impair triglyceride hydrolysis which causes elevated plasma triglyceride levels. An induced pluripotent stem cell (iPSC) line was generated from peripheral blood mononuclear cells (PBMCs) of a 53 years-old male patient with FHTG who had a heterozygous p.C310R (c.928 T > C) mutation in the LPL gene based on the sendai virus delivery system. The cellular model will offer a powerful tool to investigate pathogenic mechanisms in FHTG and to develop a treatment for FHTG.

BACKGROUND The aim of this study was to determine the prognosis of severe disease and treatment approaches of both normal and pregnant, especially in patients with severe pancreatitis due to hypertriglyceridemia. MATERIAL AND METHODS We included 30 patients (20 females and 10 males) in this study whose follow-ups and treatments were performed after a diagnosis of hypertriglyceridemia-induced acute pancreatitis between January 2011 and May 2017. Patient personal information, such as age, sex, pre-treatment and post-treatment triglyceride levels, receipt of anti-hyperlipidemic treatments or plasmapheresis, and family history, were collected from hospital records and patient files. Patients with severe pancreatitis history, score, and prognosis were included to increase the value of our study. Mild and moderate cases were excluded. RESULTS The mean age of the patients was 35±6 years. Twenty-four patients (80%) received an anti-hyperlipidemic treatment before their pancreatitis attacks. Plasmapheresis was performed on 8 patients before their pancreatitis attacks. Eighteen patients (60%) had a family history suggesting familial hypertriglyceridemia. Twelve patients (40%) were pregnant. CONCLUSIONS The treatment of hypertriglyceridemia-induced acute pancreatitis was mostly confined to supportive, palliative treatments. However, plasmapheresis is a possible treatment option and should be used in the early stages of this disease. The response to medical treatment and support treatment was better in pregnant patients than in the other patient group, and pregnant patients did not require plasmapheresis.

// Yu Lun 1, * , Xiaofang Sun 1, * , Ping Wang 1 , Jingwei Chi 1 , Xu Hou 1 and Yangang Wang 1 1 Department of Endocrinology and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao, China * Yu Lun and Xiaofang Sun contributed equally to this work Correspondence to: Yangang Wang, email: wangyangang9111@126.com Xu Hou, email: lunyu9111@gmail.com Keywords: lipoprotein lipase, hypertriglyceridemia, mutation, acute pancreatitis, compound heterozygosity Received: November 16, 2016 Accepted: April 11, 2017 Published: May 10, 2017 ABSTRACT Lipoprotein lipase (LPL) is widely expressed in skeletal muscles, cardiac muscles as well as adipose tissue and involved in the catabolism of triglyceride. Herein we have systematically characterized two novel loss-of-function mutations in LPL from a Chinese family in which afflicted members were manifested by severe hypertriglyceridemia and recurrent pancreatitis. DNA sequencing revealed that the proband was a heterozygote carrying a novel c.T928C (p.C310R) mutation in exon 6 of the LPL gene. Another member of the family was detected to be a compound heterozygote who along with the c.T928C mutation also carried a novel missense mutation c.A1187T (p.E396V) in exon 8 of the LPL gene. Furthermore, COS-1 cells were transfected with lentiviruses containing the mutant LPL genes. While C310R markedly reduced the overall LPL protein level, COS-1 cells carrying E396V or double mutations contained similar overall LPL protein levels to the wild-type. The specific activity of the LPL mutants remained at comparable magnitude to the wild-type. However, few LPL were detected in the culture medium for the mutants, suggesting that both mutations caused aberrant triglyceride catabolism. More specifically, E396V and double mutations dampened the transport of LPL to the cell surface, while for the C310R mutation, reducing LPL protein level might be involved. By characterizing these two novel LPL mutations, this study has expanded our understanding on the pathogenesis of familial hypertriglyceridemia (FHTG).

Cholesterol reduction has markedly reduced major cardiovascular disease (CVD) events and shown regression of atherosclerosis in some studies. However, CVD has for decades also been associated with increased levels of circulating triglyceride (TG)-rich lipoproteins. Whether this is due to a direct toxic effect of these lipoproteins on arteries or whether this is merely an association is unresolved. More recent genetic analyses have linked genes that modulate TG metabolism with CVD. Moreover, analyses of subgroups of hypertriglyceridemic (HTG) subjects in clinical trials using fibric acid drugs have been interpreted as evidence that TG reduction reduces CVD events. This review will focus on how HTG might cause CVD, whether TG reduction makes a difference, what pathophysiological defects cause HTG, and what options are available for treatment.

Introduction: Hypertriglyceridemia (HTG) is one of the most common metabolic disorders leading to pancreatitis and cardiovascular disease. HTG develops mostly due to impaired metabolism of triglyceride-rich lipoproteins. Although monogenic types of HTG exist, most reported cases are polygenic in nature. Aim: This review article is focused on the classification of Primary HTG and the genetic factors behind its development with the aim of providing clinicians a useful tool for early detection of the disease in order to administer proper and effective treatment. Discussion: HTG is often characterized by a complex phenotype resulting from interactions between genetic and environmental factors. In many instances, the complexity, perplexing causes, and classification of HTG make it difficult for clinicians to properly diagnose and manage the disorder. Better availability of information on its pathophysiology, genetic factors involved, environmental causes, and their interactions could help in understanding such complex disorders and could support its effective diagnosis and treatment. Conclusion: The current review has summarized the case definition, epidemiology, pathophysiology, clinical presentation, classification, associated genetic factors, and scope of genetic screening in the diagnosis of primary HTG.

Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).

Familial hypertriglyceridemia is a rare autosomal recessive inborn error of metabolism. Mutation within the LPL gene constitutes the first cause of monogenic etiology. Lipoprotein lipase (LPL) is the key enzyme in triglyceride-rich lipoproteins catabolism. Familial LPL deficiency is expressed by eruptive xanthomatosis and acute pancreatitis. We report a Moroccan case with a monstrous hypertriglyceridemia caused by LPL gene mutation. We discuss pathophysiology aspects according to available investigations data and the relevance of familial screening. The proband is a 19-year-old woman originating from the village of Taourirt (South of Morocco). She was admitted in emergency for diabetic ketoacidosis. Clinical investigations and routine laboratory tests were performed upon admission. Then lipoprotein electrophoresis and sequencing of the LPL gene were practiced. A monstrous hypertriglyceridemia up to 199 mmol/L was found. Lipoprotein electrophoresis has objectified profound disturbances on chylomicrons, VLDL and IDL. The sequencing detected a missense mutation p.S286R at homozygous state in a consanguinity context. Discovery of this LPL gene mutation is the first indigenous and documented case, never related in any other ethnic group. It constitutes a novel proof of a founder effect in the south Moroccan population. Prevalence studies with familial screening should be done for preventative action which is the only acceptable way to limit the cardiovascular and pancreatitis risks in this population where inbreeding is a general rule.

Serum levels of maternal lipids rise physiologically in normal pregnancy, and women with underlying hypertriglyceridemia may experience dramatic elevations which place them at risk for pancreatitis. We describe the case of a woman with severe familial hypertriglyceridemia and prior pancreatitis who discontinued her lipid-lowering therapy early in pregnancy. She promptly developed severe abdominal pain and was hospitalized with acute pancreatitis during the late first trimester. Despite aggressive medical treatment and critical care monitoring, she developed abdominal compartment syndrome (ACS) with associated acute renal failure, which progressed to cardiorespiratory failure and was ultimately fatal. ACS is an alarming complication of acute pancreatitis that has been poorly studied in pregnancy.

We present a patient with familial hyperchylomicronemia. Family history was burdened with hypertriglyceridemia: patient's father, his mother, sisters and nieces were diagnosed with hypertriglyceridemia. During childhood and adolescence, her triglyceride levels were well controlled with a low carbohydrate and fat diet. At the age of 25, the patient developed acute pancreatitis for the first time. Over the subsequent two years, the patient experienced two episodes of acute pancreatitis and immediately gemfibrozil therapy was introduced.

Familial severe hypertriglyceridemia (levels greater than 1000 mg/dL) is a known cause of acute pancreatitis. Pregnancy can dysregulate controlled lipid levels in women with familial hypertriglyceridemia and lead to acute pancreatitis and significant morbidity in both mother and fetus. We report a case of hypertriglyceridemia-induced pancreatitis during pregnancy that was successfully treated using therapeutic plasma exchange, resulting in delivery of a healthy preterm infant. Therapeutic plasma exchange is an effective approach to treat gestational hypertriglyceridemia-induced pancreatitis. Other treatment options include combined heparin and insulin infusion. Moreover, particular caution should be applied when interpreting the results of prothrombin time in the setting of severe hypertriglyceridemia as false elevation with testing methods could happen.

Iron deposits are associated with lipid phenotype in familial hypertriglyceridemias, mainly familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG). In turn, diet plays an important role in hypertriglyceridemias although it is not known if dietary patterns are associated with iron concentration in these disorders. The objective was to determine the relationship between diet and iron deposits, measured through serum ferritin concentration, in patients with FCH and FHTG. The study was composed of 140 patients, 107 with FCH and 33 with FHTG. Subjects completed a validated 137-item food frequency questionnaire. Dividing subjects by ferritin tertiles adjusted by sex, there were no significant differences in dietary patterns except in dairy products consumption which was lower in the highest ferritin tertile. Subjects were also divided by triglycerides tertiles adjusted by sex. Those subjects in the highest tertile had lower HDL cholesterol and higher ferritin concentrations. Regarding to dietary parameters, there were significant differences in marine omega three fatty acids and vegetables presenting higher and lower consumption, respectively, those patients in the highest tertile of triglycerides. Moreover, there was not a significant correlation between dietary iron intake and any parameter, both biochemical and dietary, including ferritin concentrations. In conclusion, in patients with primary hypertriglyceridemia, triglycerides are associated with ferritin concentrations but dietary patterns are not related to iron deposits. Our results highly support the concept that the genetic mechanisms driven to hypertriglyceridemia also favor iron overload.

Familial combined hyperlipidemia (FCH) and familial hypertriglyceridemia (FHTG) share pathogenic mechanisms and a high interaction with components of the metabolic syndrome. The metabolic syndrome associates increased serum ferritin concentration and high cardiovascular risk. The objective was to describe the frequency of iron overload and the relationship between serum ferritin and the phenotype in patients with FCH and FHTG. The study was composed of 211 consecutive unrelated patients aged at least 18 years with primary hypertriglyceridemia, 149 with FCH, and 62 with FHTG. The prevalence of the metabolic syndrome and hyperferritinemia was very high in both hypertriglyceridemic groups (51.7% and 20.1% in FCH and 62.9% and 16.1% in FHTG, respectively), without significant statistical differences between them. Serum ferritin concentration did not show any significant association with the number of metabolic syndrome criteria. Subjects in the highest tertile of ferritin concentration (ferritin >200 mug/L) presented higher concentrations of triglycerides and liver enzymes than subjects in the first tertile of ferritin concentration (ferritin

Severe hypertriglyceridemia is a rare condition in pregnancy. All the cases of severe gestational hypertriglyceridemia that have been reported previously in the literature were caused by genetic mutations or familial hypertriglyceridemia secondary to lipoprotein lipase deficiency or apolipoprotein C-II deficiency. We report the first case of severe, non-genetic, non-familial, pregnancy-induced hypertriglyceridemia. The genetic underlying causes were excluded by molecular genetic investigation. The reported case was managed solely by strict dietary control. Hypertriglyceridemia was diagnosed incidentally during pregnancy, in this case, while taking a blood sample to check her hemoglobin level. Acute pancreatitis, which is a relatively common life threatening complication of this condition, was avoided. This report reviews the subtypes of hyperlipidemia, clinical picture, antenatal management and its effect on pregnancy and vice versa. It is important that the clinician has a clear understanding of the normal lipid profile during pregnancy, the clinical picture, the potential complications, available treatment options of hypertriglyceridemia particularly during pregnancy. The timing and route of delivery should be individualized.

Objectives: Chronic diarrhea caused by primary bile acid diarrhea (PBAD) is a common condition. We have previously shown PBAD is associated with low fasting serum levels of the ileal hormone, fibroblast growth factor 19 (FGF19). FGF19 is a negative regulator of hepatic bile acid synthesis and is stimulated by farnesoid X receptor agonists, which produce symptomatic improvement in PBAD. We aimed to assess possible causes for low serum FGF19 in patients with PBAD.Methods: Patients with PBAD, defined by reduced (75)Se-labelled homocholic acid taurine (SeHCAT) retention, and idiopathic diarrhea controls had measurements of fasting lipids and fasting/post-prandial FGF19 serum profiles. Specific functional variants in candidate genes were investigated in exploratory studies. In further groups, basal and bile acid-stimulated transcript expression was determined in ileal biopsies and explant cultures by quantitative PCR.Results: FGF19 profiles in PBAD patients included low fasting and meal-stimulated responses, which were both strongly correlated with SeHCAT. A subgroup of 30% of PBAD patients had fasting hypertriglyceridemia and higher FGF19. No clear significant differences were found for any genetic variant but there were borderline associations with FGFR4 and KLB. SeHCAT retention significantly correlated with the basal ileal transcript expression of FGF19 (rs=0.59, P=0.03) and apical sodium-dependent bile acid transporter (ASBT) (rs=0.49, P=0.04), and also with the degree of stimulation by chenodeoxycholic acid at 6 h for transcripts of FGF19 (median 184-fold, rs=0.50, P=0.02) and ileal bile acid binding protein (IBABP) (median 2.2-fold, rs=0.47, P=0.04). Median stimulation of FGF19 was lower in patients with SeHCAT retention Conclusions: These studies demonstrate a complex, multifactorial etiology of PBAD, including impairments in ileal FGF19 expression and responsiveness.

AIM Whole exome sequencing (WES) is a recently developed method for discovering rare mutations associated with hereditary disorders. However, the feasibility and utilization of this method in identifying familial hypertriglyceridemia is not well known. The purpose of the study was to identify the genetic locus that causes hypertriglyceridemia and assess its prevalence in Taiwanese subjects with hypertriglyceridemia. METHODS We performed WES among two individuals with hypertriglyceridemia and one control subject in an index family (22 members). Based on the WES findings, we extended the study to genotype 65 unrelated adult index patients with a fasting serum triglyceride level of ＞ 500 mg/dL and 125 normal controls using polymerase chain reaction. RESULTS Using WES alignment, variant calling and annotation, 15 presumptive causal variants were initially identified, including 13 cases by the autosomal dominant model and two cases by the autosomal recessive model. Only APOA5 c.553 G ＞ T (rs2075291), resulting in the amino acid mutation Gly185Cys, co-segregated well with hypertriglyceridemia in terms of autosomal recessive inheritance (homozygote TT: mean triglyceride level: 1,071 mg/dL vs non TT (GT and GG): mean triglyceride level: 118 mg/dL; p ＜ 0.001) in the index family. In the unrelated cohorts, the frequency of the TT genotype of rs2075291 was 12.3% in the hypertriglyceridemic group; however, no TT genotype was found in the control group. CONCLUSIONS Our results demonstrate that WES is feasible for identifying the genetic locus that causes hypertriglyceridemia. The TT genotype of APOA5 c.553G ＞ T acts as an important indicator of hypertriglyceridemia in patients in Taiwan.

Cardiovascular disease is a leading cause of mortality in the United States, and is a significant cause of death worldwide. In 2002, it accounted for 38.0% of all deaths in the US, and approximately one-third of all global deaths. It has a significant economic impact, with an estimated cost in the US of 393.5 billion US dollars for 2005. The most common form of heart disease is coronary heart disease (CHD)(1)/coronary artery disease (CAD) resulting from atherosclerosis. Thirteen million Americans are affected by CHD annually, with 7.1 million of these experiencing a myocardial infarction (MI). Five to ten percent of new MI's occur in individuals younger than age 50, and the lifetime risk of developing CAD after age 40 ranges from 32% in women to 49% in men. Because of its major impact on morbidity and mortality, as well as its contribution to annual health care costs, it is of the utmost importance that improved strategies for preventing and treating CAD be developed. A promising, but inherently difficult, area of study is the identification of genes that predispose to or directly cause CAD. The identification of these genes may lead to screening tests that will allow persons at risk for developing CAD to be identified early enough that prevention/intervention strategies can be implemented to prevent or ameliorate the disease process, and may also lead to the development of gene therapy mechanisms useful in the treatment of ischemic heart disease (IHD). Because an exhaustive review of all the genes being studied in relation to CAD and MI is difficult within the confines of a review article, this review will focus on describing representative studies investigating the genes considered most likely to potentially contribute toward an increased risk for CAD and MI. Genes resulting in inherited disorders with which an increased risk of CAD and MI is associated will be discussed, as well as a number of candidate genes that may play a role in the multifactorial inheritance of CHD risk.

Small, dense LDLs and hypertriglyceridemia, two highly correlated and genetically influenced risk factors, are known to predict for risk of coronary heart disease. The objective of this study was to perform a whole-genome scan for linkage to LDL size and triglyceride (TG) levels in 26 kindreds with familial hypertriglyceridemia (FHTG). LDL size was estimated using gradient gel electrophoresis, and genotyping was performed for 355 autosomal markers with an average heterozygosity of 76% and an average spacing of 10.2 centimorgans (cMs). Using variance components linkage analysis, one possible linkage was found for LDL size [logarithm of odds (LOD) = 2.1] on chromosome 6, peak at 140 cM distal to marker F13A1 (closest marker D6S2436). With adjustment for TG and/or HDL cholesterol, the LOD scores were reduced, but remained in exactly the same location. For TG, LOD scores of 2.56 and 2.44 were observed at two locations on chromosome 15, with peaks at 29 and 61 cM distal to marker D15S822 (closest markers D15S643 and D15S211, respectively). These peaks were retained with adjustment for LDL size and/or HDL cholesterol. These findings, if confirmed, suggest that LDL particle size and plasma TG levels could be caused by two different genetic loci in FHTG.

Background— Conventional wisdom suggests that a diagnosis of familial combined hyperlipidemia (FCHL) carries a substantially greater risk of premature coronary artery disease (CAD) than a diagnosis of familial hypertriglyceridemia (FHTG). However, no population-based studies have critically addressed this issue. Methods and Results— FCHL and FHTG were diagnosed in 10.2% and 12.3% of 334 random control families and in 16.7% and 20.5% of 293 families with at least one case of premature CAD. The diagnosis of either FCHL or FHTG in an individual was associated with an odds ratio for CAD of 2.0 ( P =0.003 and 0.002, respectively). However, odds ratios for premature CAD associated with both lipid disorders decreased substantially and identically with further adjustment for hypertension, diabetes, and especially HDL cholesterol, triglycerides, or apolipoprotein B. Similar results were found for differences in carotid intima-medial thickness and ankle-brachial index. Metabolic syndrome was identified in 65% of FCHL and 71% of FHTG patients compared with 19% in controls without FCHL or FHTG and was associated with an odds ratio of 3.3 ( P Conclusions— FCHL and FHTG appear more alike than dissimilar. Further, the risk of CAD in FCHL and FHTG was strongly related to features of the metabolic syndrome. These findings suggest that the hypertriglyceridemia in FHTG is not benign and may warrant a change in epidemiological, genetic, and clinical approaches to these lipid disorders.

Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explains the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia.

Background —Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death. Methods and Results —The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7, P =0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant ( P =0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7, P =0.02) but not in FCHL families (relative risk 1.5, P =0.16) after adjustment for baseline covariates. Conclusions —This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.

A combination of diet therapy, nutritional support with medium-chain triglycerides (MCT), and well-planned preterm Cesarean delivery on demand is an effective measure to prevent gestational hyperlipidemic pancreatitis and leads to successful childbirth. Prevention and therapy of gestational hyperlipidemic pancreatitis are important, although difficult, because the condition carries a high maternal and fetal morbidity and mortality. We describe a 32-yr-old female with lipoprotein lipase-deficient familial hypertriglyceridemia who had recurrent episodes of acute pancreatitis. The third episode occurred with worsened hyperlipidemia 7 yr earlier at 32 wk of her first pregnancy and resulted in fetal death. The fourth and fifth episodes were also accompanied by marked hyperlipidemia probably caused by drug discontinuance and dietary noncompliance. She became pregnant. Serum triglyceride levels were controlled below 2000 mg/dL by strict monitoring with low-fat, low-calorie diet and MCT nutritional support. A premature but healthy infant was born by Cesarean delivery at 36 wk of gestation when the mother presented with mild abdominal pain and was found to have uterine contractions. The ensuing clinical course has been uneventful.

Impaired postprandial lipoprotein metabolism has been found to be related to the extent of coronary artery disease. Moreover, since dyslipoproteinemias are associated with impaired hemorrheology, we investigated the effect of postprandial hypertriglyceridemia on hemorrheological parameters before and after triglyceride-lowering therapy. Triglyceride-rich lipoproteins (TRLs) separated by ultracentrifugation (d1.006 g/dL) and chylomicrons and chylomicron remnants (quantified by apolipoprotein [apo] B-48 determination) were determined after a fat load in 10 patients with familial hypertriglyceridemia before and after therapy with gemfibrozil (900 mg daily). Lipid and hemorrheological parameters (plasma and whole-blood viscosity [PV and BV], red cell aggregation [RCA], hematocrit, and fibrinogen) were determined at baseline and every hour up to 6 hours postprandially. Fasting total triglycerides and TRL triglycerides significantly decreased with gemfibrozil therapy (P.01). Total triglycerides postprandially increased from 9.53 +/- 1.72 to 14.47 +/- 2.07 mmol/L (TRL triglycerides by 61%) before therapy (P.05) and from 4.61 +/- 1.28 to 7.17 +/- 0.99 mmol/L (TRL triglycerides by 57%) after therapy (P.05). The postprandial TRL apo B increase was reduced with gemfibrozil (from 11.6 +/- 2.8 to 20.7 +/- 5.0 mg/dL with therapy v 19.0 +/- 7.6 to 33.0 +/- 12.5 mg/dL before therapy, P.05, respectively) with a proportionally greater increase in apo B-48 (119% and 169%, respectively) compared with apo B-100 (64% and 64%, respectively). Fasting RCA was improved with lipid-lowering therapy (P.05), but PV, BV, RCA, and fibrinogen did not show any statistically significant postprandial changes either before or after lipid-lowering therapy. In summary, we did not find any statistically significant changes in hemorrheological parameters, despite a strong postprandial increase of triglycerides. In particular, these findings were independent of fasting triglyceride levels. We conclude that triglyceride-lowering therapy by gemfibrozil had no substantial beneficial effects with respect to hemorrheology in patients with familial hypertriglyceridemia.

One hundred forty-seven relatives of 43 patients with "classical" type III hyperlipoproteinemia (HLP) having the apolipoprotein (apo) E2/2 phenotype were studied to determine the occurrence of hyperlipidemia and the presence of further possible genes for lipoprotein disorders in these families. In 12 pedigrees primary dyslipidemia was prevalent among patients and respective blood-relatives. In these kindreds the coexistent presence of genes for familial combined hyperlipidemia (n = 6), familial hypertriglyceridemia (n = 5), and familial hypercholesterolemia (n = 1), respectively, was supposed. Our results, therefore, confirm and extend previous data on the multifactorial genesis of the diseases. Besides homozygosity for a receptor binding-defective isoform of apo E (apo E2), additional genes for familial lipoprotein disorders might operate in the pathogenesis of type III HLP. This is the largest family study performed so far in this primary lipoprotein disorder.

There is increasing evidence that hemorrheological abnormalities are associated with an enhanced risk of atherosclerosis. The n-3 fatty acids (n-3-FA) have been shown to have beneficial effects on atherosclerosis in patients with dyslipoproteinemias. We studied 23 patients with elevated plasma triglycerides to evaluate the influence of fish oil and fenofibrate therapy on hemorrheological parameters (15 patients with familial hypertriglyceridemia [FHTG] and eight with familial dysbetalipoproteinemia [FDL]). The patients (one woman and 22 men aged 45.7 +/- 2.0 years) were treated with increasing doses of n-3-FA (1.8 to 3.6 g/d: 0.9 to 1.8 g eicosapentaenoic acid and 0.6 to 1.2 g docosahexaenoic acid) for 8 weeks. Lipid parameters, whole-blood viscosity at different shear rates, plasma viscosity, fibrinogen concentration, and red blood cell aggregation (RCA) were measured at baseline and at weeks 2, 4, 8 (end of n-3-FA therapy), and 12. Compliance was ensured by measuring plasma concentrations of eicosapentaenoic acid and docosahexaenoic acid. After 12 weeks, patients began treatment with fenofibrate (250 mg daily); investigations were performed again at week 20. Total triglycerides (from 6.90 +/- 1.70 to 3.61 +/- 0.78 mmol/L in FDL and 7.44 +/- 1.50 to 4.15 +/- 0.55 in FHTG), very-low-density lipoprotein (VLDL) triglycerides, and VLDL cholesterol were significantly decreased with n-3-FA therapy in both groups (P < .05). In FHTG, low-density lipoprotein (LDL) cholesterol increased significantly (from 2.75 +/- 0.28 to 3.97 +/- 0.35 mmol/L, P < .01); in FDL, total cholesterol decreased (from 9.76 +/- 1.32 to 7.34 +/- 1.07 mmol/L, P < .05). No significant changes were observed in hemorrheological parameters, except for reduced RCA with 3.6 g n-3-FA in FHTG. However, with fenofibrate therapy, in addition to comparable lipoprotein changes seen with fish oil, fibrinogen levels and plasma and blood viscosity decreased in patients with FDL. We conclude that n-3-FA and fenofibrate have comparable effects on lipid parameters in patients with FDL and FHTG. Because of additional beneficial effects on hemorrheological parameters, fenofibrate may be preferred for the treatment of FDL.

Suboptimal lipolysis of very low density lipoproteins (VLDL) due to reduced substrate affinity for lipoprotein lipase (LPL) may contribute to the accumulation of apolipoprotein (apo) B in familial combined hyperlipidemia (FCH) or the characteristic increase in triglyceride-rich lipoproteins in familial hypertriglyceridemia (FHTG). To investigate this hypothesis in detail, the VLDL composition and substrate affinity for lipoprotein lipase was determined in 22 normolipidemic controls, 16 FCH probands, and 12 FHTG subjects. VLDL from FCH subjects were enriched in cholesterol and phospholipid. VLDL from FHTG subjects were enriched in triglycerides, cholesterol and phospholipid. Potential apolipoprotein regulators of LPL activity including apo C-II, apo C-III and apo E were not significantly different between FCH and controls when expressed per VLDL apo B. High apo C-III concentrations were present in FHTG-VLDL, and the apo C-III/E-ratio was significantly higher than in FCH- and control-VLDL. An increase of C-III-0, the desialylated isoform, was observed in FHTG-VLDL. The kinetic indicators for in vitro triglyceride hydrolysis by LPL, KM and VMAX, were not significantly different between the groups. KM values measured in vitro were remarkably and consistently high (1.54 mmol VLDL-TG/I), predicting saturation of LPL when VLDL-TG levels exceed 5.5 mmol/l (2 times KM + 2S.D.). In conclusion, VLDL from individuals with FCH or FHTG are normal substrate for lipoprotein lipase in spite of significant differences in lipid and apolipoprotein composition. The high apo C-III content of FHTG-VLDL supports a role in the expression of hypertriglyceridemia.

[Figure][1] An asymptomatic 51-year-old man with familial hypertriglyceridemia presented with pancytopenia (white blood cells, 2.8 × 109/L; hemoglobin, 11.9 g/L; and platelets, 77 × 109/L). His only medications were 3 antihyperlipidemic drugs. Lymphadenopathies, hepatosplenomegaly, and/or

OBJECTIVE To determine the 10 -yr incidence of impaired glucose tolerance and NIDDM in families with a clustering of endogenous hypertriglyceridemia. RESEARCH DESIGN AND METHODS The prospective population study, where the oral glucose tolerance test and the measurement of serum lipids and lipoproteins were performed at the baseline examination and after the 10-yr followup, was conducted on 56 subjects (17–60 yr of age at the baseline). The subjects were from six pedigrees with a clustering of endogenous hypertriglyceridemia, and 47 of these subjects attended the follow-up 10 yr later. RESULTS In the study families, the prevalence of glucose intolerance and NIDDM increased from 15 to 49% (P < 0.001) and from 2 to 21% (P < 0.001), respectively, over the 10-yr period. When grouped according to the baseline serum triglyceride tertiles, 76% (P < 0.01) of the family members with highest serum triglycerides were glucose intolerant (29% impaired glucose tolerance, 47% NIDDM) at follow-up compared with 20% of those with lowest serum triglycerides. In discriminant analysis, including age, body mass index, treatment with thiazides and β-blocking agents, and 2-h serum insulin concentration, the baseline serum triglycerides still remained as an independent predictor of development of impaired glucose tolerance and NIDDM. CONCLUSIONS Families with a clustering of hypertriglyceridemia are at increased risk of NIDDM, and in these families elevation of serum triglycerides serves as a risk marker of glucose intolerance and NIDDM.

Patients with familial dysbetalipoproteinemia (FD) associated with the apo E2/2 phenotype exhibit a marked interindividual variability in serum cholesterol and triglyceride concentrations. It has been proposed that this variability is due to a combination of the apo E2/2 phenotype and additional genetic factors implicated in diseases like familial hypercholesterolemia, familial combined hyperlipoproteinemia, and familial hypertriglyceridemia. To further explore the nature of this variability, the lipoprotein profiles of 17 patients with FD associated with the apo E2/2 phenotype were analyzed by a density-gradient ultracentrifugation technique and by 2-16% polyacrylamide gel electrophoresis. It was found that all patients with FD were characterized by 1) markedly increased cholesterol concentrations of large very low density lipoprotein (VLDL) (VLDL1) (2.98 +/- 3.08 versus 0.08 +/- 0.03 mmol/L), small VLDL (VLDL2) (4.68 +/- 1.93 versus 0.27 +/- 0.13 mmol/L), and intermediate density lipoprotein (IDL) (2.25 +/- 0.72 versus 0.39 +/- 0.16 mmol/L); 2) decreased low density lipoprotein (LDL) cholesterol level (1.84 +/- 0.54 versus 3.36 +/- 0.53 mmol/L); and 3) altered composition (enrichment by cholesteryl ester) of VLDL1 and VLDL2 compared with normolipidemic control subjects. The cholesterol levels of IDL and LDL showed minor interindividual variabilities and were not correlated with serum cholesterol and triglyceride levels. The compositions of VLDL1 and VLDL2 were independent of the concentrations of lipids in serum. However, the cholesterol concentrations of VLDL1 and VLDL2 showed considerable interindividual variabilities and were positively correlated with the serum cholesterol concentration (r = 0.84 and r = 0.95, respectively, both p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Hypertriglyceridemia-induced pancreatitis is a serious complication of familial dyslipidemias. Hormonal influences during pregnancy can compromise otherwise controlled lipid levels in women with familial hypertriglyceridemia and predispose to pancreatitis leading to increased morbidity in both mother and fetus. We report the successful use of therapeutic plasma exchange (TPE) in the management of hypertriglyceridemia during pregnancy resulting in avoidance of pancreatitis and delivery of a healthy term infant. Thirteen TPEs were performed from 19 to 36 weeks gestation to maintain tight control of triglyceride levels.

In order to learn whether patients with diabetic ketosis who had very severe hypertriglyceridemia had underlying genetic hyperlipidemia, the authors measured plasma lipids in 211 episodes. They report the findings in the 15 patients who had initial plasma triglyceride concentrations above 11.3 mmol/L (1,000 mg/dL). These patients were detected during a prospective study of 155 episodes of ketoacidosis and 56 episodes of ketosis. Eleven of the 15 patients had definite or probable insulin-dependent diabetes mellitus (IDDM), but eight of the 15 were not acidemic despite their ketosis. Twelve of the 15 patients (80%) were men, a far higher percentage of men than the 53.6% in the base population of 211 episodes. Plasma triglyceride concentrations returned to normal levels either during the acute episode (seven cases) or well within a year (two more cases) in most of the patients. From that and other considerations, the authors infer that at least ten, and perhaps 12 of the 15 patients did not have an underlying genetic hyperlipidemia contributing to their original severe hypertriglyceridemia. That contrasts with the findings of others who reported that most patients with severe hypertriglyceridemia associated with noninsulin-dependent diabetes mellitus (NIDDM) (usually without ketosis) did have coexisting familial hypertriglyceridemia.

Familial lipoprotein lipase (LPL) deficiency is a rare genetic disorder accompanied by well-characterized manifestations. The phenotypic expression of heterozygous LPL deficiency has not been so clearly defined. We studied the pedigree of a proband known to be homozygous for a mutation resulting in nonfunctional LPL. Hybridization of DNA from 126 members with allele-specific probes detected 29 carriers of the mutant allele. Adipose tissue LPL activity, measured previously, was reduced by 50% in carriers, but did not reliably distinguish them from noncarriers. Carriers were prone to the expression of a form of familial hypertriglyceridemia characterized by increased plasma triglyceride, VLDL cholesterol and apolipoprotein B, and decreased LDL and HDL cholesterol concentrations. These manifestations were age modulated, with conspicuous differences between carriers and noncarriers observed only after age 40. Several noncarriers exhibited similar lipid abnormalities, but without the inverse relationship between VLDL cholesterol and LDL cholesterol noted among carriers. In addition to age and carrier status, the potentially reversible conditions, obesity, hyperinsulinemia and lipid-raising drug use were contributory. Thus heterozygous lipoprotein lipase deficiency, together with age-related influences, may account for a form of familial hypertriglyceridemia.

Recently, considerable progress has been made in understanding the genetic basis of dyslipidemias and in studying the safety and efficacy of lipid-lowering drugs for coronary heart disease (CHD) prevention. Novel loci have been identified for monogenic hypercholesterolemia, such as low-density lipoprotein (LDL) receptor (LDLR)-associated protein, proprotein convertase subtilisin-like kexin type 9, and ATP-binding cassette transporters ABCG5 and ABCG8. LDLR-associated protein promotes clustering of LDLRs into clathrin-coated pits for LDL uptake; proprotein convertase subtilisin-like kexin type 9 is involved in LDLR degradation; and ABCG5 and 8 pump sterols out of the hepatic and intestinal cells into bile and intestinal lumen, respectively. A novel gene encoding apolipoprotein AV, an activator of lipoprotein lipase, has also been linked to familial hypertriglyceridemia. Linkage of familial combined hyperlipidemia to upstream stimulatory factor 1 remains controversial. Recent guidelines of the Adult Treatment Panel III emphasize intensive reduction of LDL or non-high-density lipoprotein cholesterol in patients at high risk of CHD. However, of the four recently concluded trials comparing high- vs. low-dose statin therapy, only two showed an unequivocal reduction in cardiovascular endpoints. Because intensive statin therapy can increase the risk of myopathy and hepatotoxicity, it is important to consider its risk-benefit ratio in individual patients. Restriction of dietary saturated and trans-fat and cholesterol, along with increased intake of soluble fiber, can also achieve substantial LDL cholesterol lowering. Fibrates may reduce the risk of acute pancreatitis in severely hypertriglyceridemic patients and may be beneficial for CHD prevention. However, the safety and efficacy of combined therapy of fibrates and statins needs to be established.

There is a paucity of data concerning the metabolic syndrome (MetS) in families with familial combined hyperlipidemia (FCHL), familial hypertriglyceridemia (FHTG), familial hypercholesterolemia (FH) and normolipidemic families in China. This study investigated the prevalence of MetS in these families and explored potential factors relevant to MetS. We recruited 70 families with 560 individualsor = 20 years of age, including 43 FCHL families with 379 individuals, 3 FHTG families with 30 individuals, 16 FH families with 102 individuals and 8 normolipidemic families with 49 individuals. The definition of MetS is determined using modified criteria of National Cholesterol Education Program substituting body mass index for waist circumference. MetS is identified in 60.7% of FCHL patients and 71.4% of FHTG patients. The prevalence of MetS in family members is 36.7% for FCHL, 33.3% for FHTG, 17.6% for FH and 16.3% for normolipidemic families, with an odds ratio (OR) of 2.97 (95% CI 1.29-7.07, P=0.007) in FCHL families compared with normolipidemic families. Apolipoprotein B (apoB) is associated with MetS by multiple logistic analysis with an OR of 1.05 (1.03-1.07, P0.001) in FCHL families, OR of 1.26 (1.03-1.55, P=0.026) in FHTG and OR of 1.07 (1.01-1.12, P=0.014) in FH families, independent of variables including age, gender, apolipoprotein A1, and low density lipoprotein cholesterol. Apolipoprotein A1 provided an OR of 0.95 (0.94-0.97, P0.001) in FCHL families and OR of 0.94 (0.90-0.97, P=0.011) in FH families, but neither in FHTG nor in normolipidemic families (both P0.05). Thus, apoB may be regarded as a relevant factor in the assessment of MetS in FCHL, FHTG and FH families. However, this finding needs to be verified by prospective studies in diverse ethnicities and warrants additional studies to elucidate possible mechanisms linking apoB to MetS.

Stroke in pediatric patients is distinctive as compare to adults. The authors report a rare case of familial hypertriglyceridemia type IV who had left hemiparesis with cerebellar signs. There was no history of oral trauma, head injury, convulsions, acute gastroenteritis, meningitis or otitis media.

We assessed severe hypertriglyceridemia, hypertriglyceridemic acute pancreatitis, and failure of triglyceride-lowering therapy when estrogens were given to 56 women with and without familial hypertriglyceridemia. The 56 women had been consecutively referred to our center over a 3-year period because of triglycerides400 mg/dl despite diet-drug treatment and/or a history of hypertriglyceridemic acute pancreatitis (AP). Of the 56 women, 17 had received estrogen replacement therapy (ERT), hormone replacement (HRT, n=6), or selective estrogen receptor modulators (SERM, n=1).After study at entry, in 56 women (median age, 52 years), 36 with familial hypertriglyceridemia, to lower triglycerides, estrogens and SERMs (hormone treatment, HT) were stopped; a very low fat diet (15% of calories), gemfibrozil (1.2-1.5 mg/day), and omega-3-fatty acid (4-12 g/day) were started, with restudy 2-4 weeks later.Of the 56 women, 24 (43%) were taking HT at entry, with median fasting triglycerides 1270 mg/dl in the HT group and 1087 mg/dl in the no-HT group. Seventeen women (30%) had a history of AP, nine of whom (53%) were/had been on HT at the development of AP. Significant positive correlates of triglycerides at entry in a stepwise regression model were hemoglobin A(1C) (partial r(2)=10.7%, p0.05) and an interaction between estrogen use and familial hypertriglyceridemia (partial r(2)=15%, p=0.017). After 2-4 weeks on therapy, median triglycerides in the previous-HT group fell from 1270 to 284 mg/dl (p0.0001) and in the no-HT group from 1087 to 326 mg/dl (p0.0001).Before starting HT, to avoid HT induced hypertriglyceridemic AP and exacerbation of overt or covert familial hypertriglyceridemia, triglycerides must be measured. HT is contraindicated in women with preexisting hypertriglyceridemia (triglyceridesor =500 mg/dl). Triglyceride-lowering diets and drugs often fail in the presence of HT and/or poorly controlled diabetes mellitus, but commonly succeed when HT is stopped and diabetes mellitus is tightly controlled.

Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na + /bile acid cotransporter gene ( SLC10A2 ) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5′ flanking sequence of SLC10A2 . The SLC10A2 missense mutations and 5′ flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2 . The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2 .

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P.05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P.05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P.05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.

This review provides an overview of the recent data evaluating triglyceride and low-density lipoprotein (LDL) size, two highly interrelated, genetically influenced, risk factors for cardiovascular disease (CVD). An examination of new epidemiologic studies continues to demonstrate that plasma triglyceride levels predict CVD. The first prospective study of the familial forms of hypertriglyceridemia has shown that relatives in familial-combined hyperlipidemia families are at increased risk for CVD mortality and that triglyceride levels predicted 20-year, CVD mortality among relatives in familial hypertriglyceridemia families. A meta-analysis of three, large-scale, prospective studies in men, and the first study to examine the correlation of LDL particle size distribution and vascular changes measured by B-mode ultrasound, add to growing evidence that small, dense LDL is atherogenic. Quantitative genetic analysis has recently shown substantial pleiotropic (common) genetic effects on triglyceride and LDL size. At least part of this may be explained by variation at the cholesterol ester transfer protein locus on chromosome 16, possibly through its role in reverse cholesterol transport. Taken together, these data provide new insights into the importance of triglyceride and LDL particle size for understanding genetic susceptibility to cardiovascular disease and its prevention.

We evaluated platelet function in patients with familial hypertriglyceridemia (FHTG). Compared with healthy gender-matched controls, platelets from patients showed lower aggregation (P < .01) and thromboxane formation (P < .01) in response to collagen. Very-low-density lipoprotein (VLDL) particles obtained from the patients inhibited collagen-induced aggregation, whereas VLDL particles from controls had opposite effects. The VLDL-induced effect was regulated by its apolipoprotein E (apoE) content. Indeed, apoE-VLDL-rich fractions caused antiaggregative effects, whereas apoE-VLDL-poor fractions produced a strong proaggregative response. Since we have recently demonstrated that VLDL particles may regulate the activity of platelet low-density lipoprotein (LDL) receptor by a phenomenon of downregulation and desensitization, in this study, we have investigated the effect of prolonged exposure to circulating VLDL levels on the activity of platelet LDL receptor by a double-blind controlled study with gemfibrozil (600 mg twice daily) in 18 subjects with FHTG. Platelets from patients exhibited fewer platelet LDL receptors and 125I-LDL binding was saturable at a lower protein concentration. After 6 months, gemfibrozil therapy versus placebo had a marked lipid-lowering effect, significantly decreased triglycerides (61%), VLDL cholesterol (72%), apoB (28%), and apoE (55%), and increased high-density lipoprotein (44%) and apoA-I (18%). Furthermore, gemfibrozil affected the apoprotein composition of VLDL: total protein increased by 28%, the molar ratio of apoE to apoB decreased 64%, and apoE content decreased 55%. However, no differences in phospholipid, triglyceride, or total cholesterol were detected. Moreover, platelet function was markedly altered by gemfibrozil therapy. Collagen-induced aggregation and thromboxane formation were significantly enhanced (P < .01). The initial antiaggregative pattern of VLDL particles was changed to a significant proaggregative effect (P < .01), and the number of LDL binding sites was markedly upregulated (P < .001). Both receptor upregulation and the change in the aggregative effect of VLDL particles were associated with the reduction of apoE content in VLDL particles (P < .05). The overall results indicate that in the regulation of platelet reactivity in hypertriglyceridemic patients, apoE content of VLDL particles and their interaction with the platelet LDL receptor are involved.

Chylomicronemia syndrome (CMS) is a rare disorder characterized by the presence of chylomicrons in the fasting state causing a milky appearance of plasma, eruptive xanthomas, and hepatosplenomegaly; an acute and potentially life threatening complication is severe acute pancreatitis. The underlying defects are inborn errors of metabolism such as deficiencies of lipoprotein lipase (LPL) or apoprotein C-II (apo C-II) as well as familial hypertriglyceridemia. Moreover, CMS can be precipitated when mild hypertriglyceridemia is exacerbated by additional factors such diabetes mellitus, ethanol abuse, or pregnancy. The purpose of the present study was to retrospectively analyze the results of therapeutic plasma exchange (TPE) in 5 patients transferred to our hospital for severe acute pancreatitis due to chylomicronemia syndrome. In a total of 7 TPE sessions, on average 3,286 +/- 247 ml of plasma (i.e., about 1 patient plasma volume) were treated per session. Triglyceride (TG) levels were decreased from 4,972 +/- 2,469 mg/dl on admission to 1,614 +/- 1,276 mg/dl (-70%) after the TPE sessions, and a further decrease was achieved by conservative treatment. Part of the TG reducing effect of the treatment was probably due to heparin induced lipolysis. Acute pancreatitis was resolved in all cases, and 1 pregnant patient delivered without problems at term. In summary, 1 or 2 TPE sessions sufficed to substantially decrease the bulk of triglycerides in acutely exacerbated chylomicronemia syndrome causing a rapid resolution of acute severe pancreatitis.

Familial hypertriglyceridemia (FHTG) is an uncommon primary (genetic) dyslipidemia. FHTG is characterized by moderately elevated serum triglycerides, usually in the absence of significant hypercholesterolemia and rarely manifests in childhood. We report an eight-month-old boy incidentally diagnosed as a case of FHTG due to lipemic serum (patient was admitted for malaria with anemia). He had elevated serum triglycerides with normal serum cholesterol, but had no symptoms related to the primary disorder (FHTG).

Excessive production of cholesterol has been associated with type IV hyperlipidemia, but the influence of the confounding variable of obesity has been difficult to ascertain. Moreover, cholesterol metabolism has not been systematically evaluated in patients with familial hypertriglyceridemia (FHT), one of the two major subsets of type IV patients. We used isotope dilution to measure cholesterol production, pools, and kinetic constants in 8 hypertriglyceridemic subjects, 6 of whom could be confidently classified as FHT. These were compared with measurements in 9 control subjects matched for sex, age, serum cholesterol, and body mass index (BMI). By t test, hypertriglyceridemic subjects did not differ from controls with respect to cholesterol production, size of readily or slowly miscible pools, or kinetic transfer coefficients. Results were the same whether controls were compared with all hypertriglyceridemic patients or only the 6 with definite FHT. By analysis of covariance (ANCOVA), serum triglyceride level was not a significant determinant of any parameter of cholesterol metabolism. However, BMI was a highly significant determinant of cholesterol production (p = 0.0001) and size of both readily and slowly miscible pools (p = 0.001 to 0.008). These data suggest that FHT per se is not associated with abnormalities of cholesterol metabolism but that an apparent association could result from the confounding variable of obesity.

Hypertriglyceridemia is common among individuals with noninsulin-dependent diabetes mellitus (NIDDM), and heterozygous lipoprotein lipase (LPL) mutations may result in the syndrome of familial hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. To test the hypothesis that heterozygous LPL mutations predispose to the hypertriglyceridemia and low HDL cholesterol levels observed among members of familial NIDDM families, we examined 36 members and 3 unrelated spouses selected from members of 20 pedigrees for triglyceride levels exceeding the age- and sex-specific 95th percentile. Eighteen pedigree members and 2 spouses were diabetic. LPL exons 1-9 were screened by single strand conformation polymorphism analysis. Six different variants were detected in exons 2, 3, 4, 8, and 9, including 4 (exons 3, 4, and 8) silent nucleotide substitutions. A common nonsense mutation (exon 9; Ser--Ter) was present in 2 pedigrees, and a missense mutation (exon 2; Asp--Asn) was also present in members of 2 pedigrees. Analysis of members of these families suggested an association of the exon 2 variant with hypertriglyceridemia, although this trend was no longer significant when individuals with diabetes were excluded from the analysis. The variant enzyme was not present among 83 random control individuals, and when expressed in COS-1 cells, it was similar to the wild type with respect to specific activity, heparin binding, and heat stability. Our data suggest that coding region mutations of the LPL gene cannot account for the elevated triglyceride and low HDL levels noted in diabetic individuals and their relatives in most NIDDM pedigrees, but the exon 2 Asn variant may contribute to the hypertriglyceridemia in some families.

Hypoalphalipoproteinemia (HA) is a common finding in patients with premature coronary artery disease. To characterize the common familial forms of HA, we studied 102 families of probands with premature coronary artery disease; 40 probands (39.2%) had HA. Of these, 25 had at least one first-degree relative affected with HA; 11 had familial hypertriglyceridemia with HA (FTgHA); 10 had familial combined hyperlipidemia (FCH); and 4 had familial HA (FHA) with no other lipoprotein abnormalities. In the remaining 15 families, no lipoprotein abnormalities were observed in first-degree relatives. We measured apolipoprotein (apo) A-I, B, C-III, and E levels as well as lipoprotein particle (Lp) levels of LpA-I (containing apoA-I only), LpA-I:A-II (containing both apoA-I and A-II), LpB:E, and LpB:C-III. Compared with a reference group of healthy men (n = 103) and women (n = 106), probands with familial forms of HA had lower high-density lipoprotein cholesterol levels by selection criteria. Triglyceride levels were higher in FTgHA and FCH probands than in the reference group or FHA subjects. Despite selection of FTgHA and FCH by low-density lipoprotein (LDL) cholesterol, the latter was not significantly different between the three groups and the reference group. ApoA-I levels were decreased in FCH, FHA, and FTgHA probands, and LpA-I and LpA-I:A-II were lower in FHA and FTgHA probands. ApoB levels were significantly higher in all familial HA groups compared with the reference group, being highest in FCH individuals, but not significantly higher between FCH, FTgHA, or FHA probands. LpB:E levels were higher in the FCH and FTgHA groups than in the reference group. There were no significant differences between groups for apoE, apoC-III, and LpB:C-III. LDL particle size was smaller in all three forms of FHA, which, in combination with higher apoB levels, reflects an increased number of smaller, denser LDL particles. Affected children had, on average, higher apoB and LpB:E levels than nonaffected siblings. Our data suggest that common forms of FHA in subjects with coronary artery disease represent a spectrum of overlapping disorders characterized by an increase in apoB-containing lipoproteins, especially LpB:E particles, and smaller, denser LDL particles. When using appropriate age- and gender-adjusted cutpoints, approximately half the offspring (in young adulthood) appeared to be affected.

To establish whether insulin resistance and/or postprandial fatty acid metabolism might contribute to familial combined hyperlipidemia (FCH) we have examined parameters of insulin resistance and lipid metabolism in six FCH kindreds. Probands and relatives (n = 56) were divided into three tertiles on the basis of fasting plasma triglycerides (TG). Individuals in the highest tertile (TG > 2.5 mM; n = 14) were older and had increased body mass index, systolic blood pressure, and fasting plasma insulin concentrations compared with individuals in the lowest tertile (n = 24). The former also presented with decreased HDL cholesterol and increased total plasma cholesterol, HDL-TG, and apoprotein B, E, and CIII concentrations. Insulin concentrations were positively correlated with plasma apo B, apo CIII, apo E, and TG, and inversely with HDL cholesterol. Fasting nonesterified fatty acids (NEFA) were elevated in FCH subjects compared to six unrelated controls and five subjects with familial hypertriglyceridemia. Prolonged and exaggerated postprandial plasma NEFA concentrations were found in five hypertriglyceridemic FCH probands. In FCH the X2 minor allele of the AI-CIII-AIV gene cluster was associated with increased fasting plasma TG, apo CIII, apo AI, and NEFA concentrations and decreased postheparin lipolytic activities. The clustering of risk factors associated with insulin resistance in FCH indicates a common metabolic basis for the FCH phenotype and the syndrome of insulin resistance probably mediated by an impaired fatty acid metabolism.

Hypertriglyceridemia is common in the general population, but its mechanism is largely unknown. In previous work human apo CIII transgenic (HuCIIITg) mice were found to have elevated triglyceride levels. In this report, the mechanism for the hypertriglyceridemia was studied. Two different HuCIIITg mouse lines were used: a low expressor line with serum triglycerides of approximately 280 mg/dl, and a high expressor line with serum triglycerides of approximately 1,000 mg/dl. Elevated triglycerides were mainly in VLDL. VLDL particles were 1.5 times more triglyceride-rich in high expressor mice than in controls. The total amount of apo CIII (human and mouse) per VLDL particle was 2 and 2.5 times the normal amount in low and high expressors, respectively. Mouse apo E was decreased by 35 and 77% in low and high expressor mice, respectively. Under electron microscopy, VLDL particles from low and high expressor mice were found to have a larger mean diameter, 55.2 +/- 16.6 and 58.2 +/- 17.8 nm, respectively, compared with 51.0 +/- 13.4 nm from control mice. In in vivo studies, radiolabeled VLDL fractional catabolic rate (FCR) was reduced in low and high expressor mice to 2.58 and 0.77 pools/h, respectively, compared with 7.67 pools/h in controls, with no significant differences in the VLDL production rates. In an attempt to explain the reduced VLDL FCR in transgenic mice, tissue lipoprotein lipase (LPL) activity was determined in control and high expressor mice and no differences were observed. Also, VLDLs obtained from control and high expressor mice were found to be equally good substrates for purified LPL. Thus excess apo CIII in HuCIIITg mice does not cause reduced VLDL FCR by suppressing the amount of extractable LPL in tissues or making HuCIIITg VLDL a bad substrate for LPL. Tissue uptake of VLDL was studied in hepatoma cell cultures, and VLDL from transgenic mice was found to be taken up much more slowly than control VLDL (P < 0.0001), indicating that HuCIIITg VLDL is not well recognized by lipoprotein receptors. Additional in vivo studies with Triton-treated mice showed increased VLDL triglyceride, but not apo B, production in the HuCIIITg mice compared with controls. Tissue culture studies with primary hepatocytes showed a modest increase in triglyceride, but not apo B or total protein, secretion in high expressor mice compared with controls. In summary, hypertriglyceridemia in HuCIIITg mice appears to result primarily from decreased tissue uptake of triglyceride-rich particles from the circulation, which is most likely due to increased apo CIII and decreased apo E on VLDL particles. the HuCIIITg mouse appears to be a suitable animal model of primary familial hypertriglyceridemia, and these studies suggest a possible mechanism for this common lipoprotein disorder.