Rare Variants in Triglycerides-Related Genes Increase Pancreatitis Risk in Multifactorial Chylomicronemia Syndrome.

CONTEXT: Severe hypertriglyceridemia (fasting triglycerides [TG] concentration ≥10 mmol/L) can be caused by multifactorial chylomicronemia syndrome (MCS) or familial chylomicronemia syndrome (FCS). Both conditions are associated with an increased risk of acute pancreatitis. The clinical differences between MCS patients with or without a rare variant in TG-related genes have never been studied. OBJECTIVE: To compare the clinical and biochemical characteristics of FCS, positive-MCS patients, and negative-MCS patients, as well as to investigate the predictors of acute pancreatitis in MCS patients. METHODS: All patients referred at the clinic for severe hypertriglyceridemia underwent genetic testing for the 5 canonical genes involved in TG metabolism (LPL, APOC2, GPIHBP1, APOA5, and LMF1) using next-generation sequencing. RESULTS: A total of 53 variant negative-MCS, 22 variant positive-MCS and 28 FCS subjects were included in this retrospective cross-sectional study. A significant difference was observed in the prevalence of pancreatitis (9%, 41%, and 61%) and multiple pancreatitis (6%, 23%, and 46%) in the negative-MCS, the positive-MCS, and the FCS groups, respectively (P < 0.0001). Predictors of pancreatitis among MCS subjects included the presence of a rare variant, lower apolipoprotein B, as well as higher gamma-glutamyl transferase, maximal TG value, and fructose consumption. CONCLUSION: We observed that the MCS individuals who carried a rare variant have an intermediate phenotype between FCS and negative-MCS subjects. Since novel molecules such as the antisense oligonucleotide against APOC3 mRNA showed high efficacy in reducing TG levels in patients with multifactorial chylomicronemia, identification of higher-risk MCS patients who would benefit from additional treatment is essential.

Primary Hypertriglyceridemia: A Look Back on the Clinical Classification and Genetics of the Disease.

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.

Practical definitions of severe versus familial hypercholesterolaemia and hypertriglyceridaemia for adult clinical practice.

Diagnostic scoring systems for familial hypercholesterolaemia and familial chylomicronaemia syndrome often cannot differentiate between adults who have extreme dyslipidaemia based on a simple monogenic cause versus people with a more complex cause involving polygenic factors and an environmental component. This more complex group of patients carries a substantial risk of atherosclerotic cardiovascular disease in the case of marked hypercholesterolaemia and pancreatitis in the case of marked hypertriglyceridaemia. Complications are mainly a function of the degree of disturbance in lipid metabolism resulting in elevated lipid levels, so the added value of knowing the precise genetic cause in clinical decision making is unclear and does not lead to clinically meaningful benefit. We propose that for severe elevations of plasma low density lipoprotein cholesterol or triglyceride, the primary factor driving intervention should be the biochemical perturbation rather than the clinical risk score. This underscores the importance of expanding the definition of severe dyslipidaemias and to not rely solely on clinical scoring systems to identify individuals who would benefit from appropriate treatment approaches. We advocate for the use of simple, practical, clinical, and largely biochemically based definitions for severe hypercholesterolaemia (eg, LDL cholesterol >5 mmol/L) and severe hypertriglyceridaemia (triglyceride >10 mmol/L), which complement current definitions of familial hypercholesterolaemia and familial chylomicronaemia syndrome. Irrespective of the precise genetic cause, individuals diagnosed with severe hypercholesterolaemia and severe hypertriglyceridaemia require intensive therapy, including special consideration for new effective but more expensive therapies.

Treatment options for hypertriglyceridemia: from risk reduction to pancreatitis.

While there has been considerable focus on the role and treatment of LDL cholesterol levels, a definitive role of triglycerides in the management of cardiovascular disease has been uncertain. Notably, with increasing triglyceride levels, there is a parallel increase in cholesterol levels carried by triglyceride-rich lipoproteins, which has prompted interest in the use of non-HDL cholesterol levels as a tool guiding interventions. Recent studies have provided evidence for an independent role of triglyceride levels as a cardiovascular risk factor, and recently, an Endocrine Society guideline was published for treatment of hypertriglyceridemia. In contrast to the relative uncertainty regarding triglycerides and cardiovascular disease, a role of very high triglyceride levels as a risk factor for pancreatitis has been well known. The present paper summarizes the underlying evidence for a risk role for triglyceride levels in cardiovascular disease and pancreatitis, current treatment recommendations and areas of future research.

Hypertriglyceridemia.

Hypertriglyceridemia (HTG) is commonly encountered in lipid and cardiology clinics. Severe HTG warrants treatment because of the associated increased risk of acute pancreatitis. However, the need to treat, and the correct treatment approach for patients with mild to moderate HTG are issues for ongoing evaluation. In the past, it was felt that triglyceride does not directly contribute to development of atherosclerotic plaques. However, this view is evolving, especially for triglyceride-related fractions and variables measured in the non-fasting state. Our understanding of the etiology, genetics and classification of HTG states is also evolving. Previously, HTG was considered to be a dominant disorder associated with variation within a single gene. The old nomenclature includes the term "familial" in the names of several hyperlipoproteinemia (HLP) phenotypes that included HTG as part of their profile, including combined hyperlipidemia (HLP type 2B), dysbetalipoproteinemia (HLP type 3), simple HTG (HLP type 4) and mixed hyperlipidemia (HLP type 5). This old thinking has given way to the idea that genetic susceptibility to HTG results from cumulative effects of multiple genetic variants acting in concert. HTG most is often a "polygenic" or "multigenic" trait. However, a few rare autosomal recessive forms of severe HTG have been defined. Treatment depends on the overall clinical context, including severity of HTG, concomitant presence of other lipid disturbances, and the patient's global risk of cardiovascular disease. Therapeutic strategies include dietary counselling, lifestyle management, control of secondary factors, use of omega-3 preparations and selective use of pharmaceutical agents.

Hipertrigliceridemias de origen genético / Hypertriglyceridemias of genetic origen

Hypertriglyceridemia (HTG) is defined as plasma triglycerides (TG) > 150 mg/dL, and it is a frequent disease in the general population. When plasma TG reach concentrations > 500 mg/dL (severe HTG), there is usually a genetic defect involved. This defect can involve a single gene or be of polygenic inheritance. In polygenic HTG, the phenotypic expression of the disease is usually associated to the presence of certain diseases such as diabetes, obesity or insulin resistance. The most common known genes associated with monogenic hypertriglyceridemia are LPL and APOC2, but in recent years a few cases caused by mutant APOA5, GPIHBP1 and LMF1, have been identified. Furthermore, genome wide association studies (GWA) have brought up new genes that are related to discrete changes in triglyceride plasma levels of the general population. Among them, it is worth mentioning GCKR, TRIB1, MLXIPL, GALNT2, APOB, APOC2, APOA5, APOE, LPL, ANGPTL3 and NCAN. It is remarkable that most severe hypertriglyceridemias are of polygenic origin, and they could involve a major susceptibility gene. Only in a few cases of severe or very severe HTG (TG > 2.000 mg/dL) the genetic cause is known.

Hypertriglyceridemia: phenomics and genomics.

Hypertriglyceridemia is a common complex metabolic trait that is associated with increased atherosclerosis risk, presence of the metabolic syndrome and, with extreme elevation, increased risk of pancreatitis. Hierarchical cluster analysis using clinical and biochemical features of the Frederickson hyperlipoproteinemia types can generate hypotheses for molecular genetic studies. High throughput resequencing of individuals at the extremes of plasma triglyceride concentration has shown that both rare genetic variants with large effects and common genetic variants with moderate effects explain a relatively large proportion of variation. Very recent progress using high-density sets of genome-wide markers have identified additional genetic determinants of plasma triglyceride concentrations, albeit within largely normolipidemic subjects and with small effect sizes. Phenomic evaluation of patients with hypertriglyceridemia might help to clarify genotype-phenotype correlations and responses to interventions.

Management of hypertriglyceridemia.

Hypertriglyceridemia is associated with an increased risk of cardiovascular events and acute pancreatitis. Along with lowering low-density lipoprotein cholesterol levels and raising high-density lipoprotein cholesterol levels, lowering triglyceride levels in high-risk patients (e.g., those with cardiovascular disease or diabetes) has been associated with decreased cardiovascular morbidity and mortality. Although the management of mixed dyslipidemia is controversial, treatment should focus primarily on lowering low-density lipoprotein cholesterol levels. Secondary goals should include lowering non-high-density lipoprotein cholesterol levels (calculated by subtracting high-density lipoprotein cholesterol from total cholesterol). If serum triglyceride levels are high, lowering these levels can be effective at reaching non-high-density lipoprotein cholesterol goals. Initially, patients with hypertriglyceridemia should be counseled about therapeutic lifestyle changes (e.g., healthy diet, regular exercise, tobacco-use cessation). Patients also should be screened for metabolic syndrome and other acquired or secondary causes. Patients with borderline-high serum triglyceride levels (i.e., 150 to 199 mg per dL [1.70 to 2.25 mmol per L]) and high serum triglyceride levels (i.e., 200 to 499 mg per dL [2.26 to 5.64 mmol per L]) require an overall cardiac risk assessment. Treatment of very high triglyceride levels (i.e., 500 mg per dL [5.65 mmol per L] or higher) is aimed at reducing the risk of acute pancreatitis. Statins, fibrates, niacin, and fish oil (alone or in various combinations) are effective when pharmacotherapy is indicated.

Hypertriglyceridemia: its etiology, effects and treatment.

Elevated plasma triglyceride concentration is a common biochemical finding, but the evidence for the benefit of treating this lipid disturbance remains less robust than that for treating elevated low-density lipoprotein-cholesterol. Part of the difficulty in the provision of specific recommendations has been the frequent coexistence of elevated triglycerides with other conditions that affect cardiovascular disease risk, such as depressed high-density lipoprotein-cholesterol, obesity, metabolic syndrome, proinflammatory and prothrombotic biomarkers, and type 2 diabetes. Recent investigations of outcomes of cardiovascular disease when medications are used to reduce triglyceride levels suggest that, although a net benefit probably exists, both relative and absolute risk reductions seem underwhelming when compared with the benefit of reducing low-density lipoprotein-cholesterol levels with treatment. However, the totality of evidence suggests that elevated triglyceride levels likely contribute independently to increased risk of cardiovascular disease, although there is no consensus about appropriate target levels. Furthermore, severe hypertriglyceridemia is associated with an increased risk of acute pancreatitis, irrespective of its effect on risk of cardiovascular disease. We review the causes and classification of elevated triglyceride levels, the clinical manifestations of primary hypertriglyceridemia and the management of patients with elevated triglyceride levels.

Treatment of hypertriglyceridemia.

Hypertriglyceridemia is a disorder commonly encountered in clinical practice. Treatment of this condition aims to prevent the major complications of hypertriglyceridemia, which differ depending on whether triglyceride elevations are moderate or severe. This review discusses the pathophysiology and clinical consequences of hypertriglyceridemia and outlines treatment approaches based on the degree of triglyceride elevation. Special consideration is given to clinical trials using medications that primarily target triglycerides.

Glucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein metabolic abnormality.

To examine the serum triglyceride (TG)-lowering effect of a soluble hesperidin derivative, glucosyl hesperidin (G-hesperidin), and its mechanisms, we carried out a G-hesperidin administration test in hypertriglyceridemic subjects. G-Hesperidin was administered to the subjects at 500 mg/d for 24 wk. In this study, the subjects were classified into high-TG type (TG > 150 mg/dL), borderline-TG type (TG 110-150 mg/dL) and normal-TG type (TG < 110 mg/dL) on the basis of their initial serum TG values. Among these phenotypes, serum TG level significantly decreased in the high-TG type during the G-hesperidin administration period. It was also observed that elevated values of serum remnant-like particle cholesterol (RLP-C), apolipoprotein (apo) B, apo C-II, apo C-III and apo E occurred in the high-TG type and that these serum levels were significantly reduced by G-hesperidin administration. Moreover, polyacrylamide gel electrophoresis analysis of serum lipoproteins revealed that the very low-density lipoprotein (VLDL)/low-density lipoprotein (LDL) ratio and LDL migration index of the high-TG type were remarkably higher than those of the other phenotypes but that their high values were significantly reduced by the administration. These results indicate that G-hesperidin preferentially lowers serum TG in hypertriglyceridemic subjects and that this effect is possibly caused by the improvement of VLDL metabolic abnormality, leading to the reduction of small dense LDL.

Long-term follow-up of patients with acute hypertriglyceridemia-induced pancreatitis.

BACKGROUND: An acute and potentially life-threatening complication of hypertriglyceridemia (HTG) is acute pancreatitis (AP). Hypertriglyceridemia, usually severe, may be primary in origin or secondary to alcohol abuse, diabetes mellitus, pregnancy, and use of drugs. STUDY: The efficacy of treatment to prevent relapses in 17 patients with AP attributed to HTG was investigated in the current prospective study. The mean follow-up period of patients was 42 months. Hypertriglyceridemia-induced AP comprised 6.9% of all patients with AP (n = 246) hospitalized in our clinic during the study (6 years). RESULTS: Causative conditions of HTG-induced AP were familial HTG in eight patients, HTG caused by uncontrolled diabetes mellitus in five, HTG aggravated by drugs in two (one by tamoxifen and one by fluvastatin), familial hyperchylomicronemia (HCM) in one, and lipemia of pregnancy in one. During the acute phase of pancreatitis, patients underwent standard treatment. Thereafter, HTG was efficiently controlled with high dosages of fibrates or a fibrate plus acipimox, except for the patient with HCM, who was on a specific diet (the only source of fat was a special oil consisting of medium chain triglyceride) and taking a high dosage of acipimox. One of the patients died during the acute phase of pancreatitis with acute respiratory distress syndrome. During follow-up, maintenance treatment was successful and only one patient relapsed, because he discontinued diet and drug treatment. CONCLUSION: Appropriate diet and drug treatment, including dose titration, of severe HTG is very effective in preventing relapses of HTG-induced AP.

Does hypertriglyceridemia increase risk for CAD? Growing evidence suggests it plays a role.

High triglyceride levels are associated with several risk factors that substantially increase the risk of CAD. The metabolic syndrome is a constellation of signs and symptoms (e.g., postprandial hypertriglyceridemia, low LDL cholesterol levels, insulin resistance) that has been linked to a high incidence of heart disease. Treatment of hypertriglyceridemia begins with an aggressive lifestyle modification program. Dietary restriction of alcohol and carbohydrates can significantly lower triglyceride levels in many patients. Pharmacotherapy should be considered for patients at high risk of cardiac disease.

Acarbose is an effective adjunct to dietary therapy in the treatment of hypertriglyceridaemias.

AIMS: In diabetics, acarbose causes a reduction of blood glucose and triglyceride levels. The aim of this study was to assess the effect of this drug in non diabetic subjects with hypertriglyceridaemia. METHODS: Thirty non diabetic patients with hypertriglyceridaemia type IIb or IV (24 males, six females; mean age 51.1+/-10.2 years) were studied. They were stratified into two groups depending on their basal triglyceride concentration (group A: triglyceride values 4.5 mmol l-1 ). Treatment consisted of 4 week courses of diet plus acarbose (50 mg twice daily) alternating with 4 weeks of diet alone for a total period of 16 weeks. RESULTS: Mean triglyceride values decreased significantly during the first and third cycles of therapy, i.e. diet plus acarbose treatment cycles in both patient groups. Group A also had significant reductions in total cholesterol and HDL cholesterol concentrations after completion of the acarbose treatment. Reduction of triglyceride levels was observed after both acarbose courses in patients affected by hypertriglyceridaemia type IIb. A marked reduction of triglyceride concentrations was achieved by patients affected by hypertriglyceridaemia type IV after the second acarbose course only. CONCLUSIONS: Diet alone did not reduce triglyceride concentrations to normal values in our patients. The data suggest that acarbose is a useful adjunct to dietary control in non-diabetic patients affected by severe hypertriglyceridaemia.