ABSTRACT

Hypertriglyceridemia (HTG) is often secondary to obesity-related insulin resistance (1,2), which is caused by excessive intake of fats and carbohydrates without compensatory utilization of these calories, but other common and rare causes should be considered (3,4,5). Genetic influences, gestational conditions, and nutrition in infancy and childhood contribute to HTG associated with formation of an atherogenic dyslipidemia profile consisting of high TG, low high-density lipoprotein-cholesterol (HDL-C), increased LDL particle number, smaller LDL size and density, and elevated apolipoprotein B. Very high TG levels generally result from defective disposal by lipoprotein lipase and can cause pancreatitis. Defining and treating the underlying cause are necessary to restore the lipids and lipoproteins to normal. Renal, hepatic, endocrine, immune, and pharmacological causes are in the differential diagnosis. Rare diseases such as lipodystrophy and glycogen storage disease are particularly challenging and require specific management strategies. Prevention of acute pancreatitis by lowering TG is a priority when TG is very high (> 1000 mg/dl), and lifestyle modification is the basis of management for all cases with high and moderately high levels. Since TG metabolism is associated with generation of an atherogenic dyslipidemia profile, predictors of coronary artery disease (CAD) such as LDL-C and non-HDL-C become targets when they exceed cut points. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

This chapter is an overview of causes of hypertriglyceridemia (HTG) that begin during gestation and present in childhood and adolescence, either interacting with genetic background or directly contributing to the TG levels. These disorders are common, such as obesity, or less common such as glycogen storage disease and lipodystrophy for which treatment can be more challenging. Also, both common and unique pharmaceutical agents need to be considered as causes since treatment modification can contribute to reversing the HTG. Dyslipidemia presenting in adolescence is often associated with one or more components of the metabolic syndrome, i.e., obesity, hypertension, and impaired glucose tolerance, and presents with high TG and low HDL-C (6,7,8, 9,10) however, a wide variety of other causes can contribute to the differential diagnosis of HTG. Genetic background, gestational factors, nutrition during infancy and childhood, demographic, and environmental factors are important considerations. Also, understanding how TG is distributed among lipoproteins and how it influences lipoprotein composition and subsequent lipolysis, uptake by receptors and the arterial wall provides important background for understanding associations with specific diagnoses and when treatment can be effective.

DIET

Although the Cardiovascular Health Integrated Lifestyle Diet (CHILD 1) (11) recommends a balanced diet of carbohydrates (50%), which includes fiber, fat (30%) of which no more than 10% of total calories come from saturated fats, and protein (20%), these guidelines are often not well adhered to. Nutritional intake by many individuals comprises additional consumption of nonessential calories consisting of fats, both saturated and trans fats, as well as carbohydrates such as High-Energy Fructose Corn Syrup (HFCS) and sucrose. This coupled with a decrease in physical activity and increased time spent in leisure activities (i.e., screen time) leads to excessive weight gain, often starting at a young age, metabolic syndrome, and insulin resistance. In an active pediatric preventive cardiology program, the number of children referred because of secondary hypertriglyceridemia and obesity is approximately twice that of children referred for Familial Hypercholesterolemia (12). As excessive consumption of fat and sugar will result in increased levels of triglycerides, it is important to understand both these metabolic pathways and nutritional management is the first step in any treatment algorithm (13).

Because of the 2011 NHLBI recommendations for universal screening between 9 and 11 years of age, pediatric medical providers are encouraged to evaluate patients at this time with a non-fasting non-HDL cholesterol (14). However, children with additional risk factors notably including a BMI >95^th %ile, should be screened with a fasting lipid profile as early as 2 years of age. Other children in this category include those whose parent or grandparent have a known history of a cardiac event such as myocardial infarction (mother or grandmother <65 years of age; father or grandfather <55 years of age), children with diabetes or hypertension.

Dietary consumption of HFCS has increased rapidly since its discovery in 1965 (15). It is a low-cost sweetener, similar in taste to granulated sugar (sucrose), made from cornstarch and is commonly used in two forms. The first form HFCS is widely used commercially in some beverages, processed foods, cereals, and baked goods; the second HFCS is used in manufacturing of soft drinks (the numerical values reflect the percent fructose) (16). Although there is some dispute whether HCFS has led to the increase in obesity (17), it is apparent that both forms are consumed in larger quantity in the American diet. In 2018, the average American consumed approximately 22.l pounds of HFCS and 40.3 pounds of refined cane and beet sugar (18).

Both sucrose and HFCS are rapidly absorbed during digestion and hydrolyzed by the enzyme sucrase to form glucose and fructose in the microvilli lining the duodenum (19). Unlike fat metabolism which is slow, both fructose and glucose are usually metabolized within two hours in individuals who are not diabetic (20). Whereas most dietary glucose will pass through the liver and be used by skeletal muscle to form ATP for cell energy or processed by fat cells to glycerol phosphate for triglyceride synthesis and stored energy, fructose is almost exclusively metabolized in the liver (Figure 1). The first step of fructose metabolism is the conversion to fructose 1-phosphate (F-1-P) by the enzyme fructokinase. F-1-P can then form either glycerol or dihydroxyacetone (DHAP). Whereas glycerol will form glycerol-3 Phosphate (G3P), DHAP can either form G3P or be isomerized to glyceraldehyde 3-phosphate (Ga-3-P). Ga-3-P will be oxidized to form pyruvate and reduced to lactate or be decarboxylated to form acetyl CoA. Acetyl CoA is a central intermediate in metabolism and can form a variety of byproducts including cholesterol, ATP, and fatty acids. G3P can then combine with fatty acids to form triglyceride which the liver packages as VLDL, the latter circulated in the blood stream. Hepatic glucose can either undergo glycogenesis which forms glycogen or glycolysis which can form DHAP. Like fructose metabolism, DHAP can form either G3P or Ga-3-P. From here the two pathways are similar to fructose metabolism with the ultimate formation of triglyceride which is then released from the liver within VLDL.

Figure 1.

Fructose and Glucose Metabolism.

TG-RICH LIPOPROTEIN COMPOSITION

Triglyceride (TG) is normally located in the core of spherical circulating plasma lipoproteins. In the fasting state, VLDL is typically composed of 55% TG and 22% cholesterol, LDL has 5% TG and 50% cholesterol, and HDL has 5% TG and 20% cholesterol (21). Increases in hepatic production of VLDL account for the majority of HTG cases resulting in a disproportionate increase in TG. However, VLDL is 22% cholesterol, which also is increased when VLDL production is excessive or when its disposal is defective leading to an elevation of the total cholesterol. In contrast, intestinally derived chylomicrons increase after meals and contain 90% triglyceride and only 3% cholesterol, but are efficiently catabolized by lipoprotein lipase, and their resulting remnant particles are taken up by hepatic receptors. Normally, TG reaches a peak 3 to 6 hours after a fat-containing meal and declines until there are no chylomicrons after ten hours of fasting. However, when disposal mechanisms are defective, chylomicrons account for very high TG levels and VLDL particles compete for lipolysis by lipoprotein lipase. Under these conditions the ratio of triglyceride to cholesterol approaches 10 to1, whereas the ratio is closer to 5 to1 when VLDL predominates. Excessive cholesterol enrichment of VLDL approaching a 1:1 ratio occurs when disposal of chylomicron and VLDL remnants are delayed – a defect usually presenting in adulthood and termed familial dysbetalipoproteinemia, a disorder attributed to variation in the amino acid sequence of Apo E (22).

NON-HDL CHOLESTEROL IN HTG

Since increased TG levels are often associated with atherogenic dyslipidemia, early plaque formation can occur. The Bogalusa Heart Study found that TG, total cholesterol and LDL-C in children and young adults aged 2 to 39 years of age were associated with post-mortem lesions in the coronary arteries and aorta (23), findings supported by the autopsy-based Pathological Determinants of Atherosclerosis in Youth (PDAY) study (24). While HTG has long been known as a biomarker associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD) (25), the role for TG in atherosclerosis has remained less clear than for LDL-C but recent data supports a compelling role for TG and TG-rich lipoproteins as a cause of ASCVD rather simply as a biomarker (26,27,28). Consistently stronger prediction by non-HDL-C than LDL-C indicates that the cholesterol content of TG-rich lipoproteins (VLDL, IDL) represented by non-HDL-C can be regarded as a better predictor of risk than TG. This is also supported by the PDAY study in which non-HDL-C was associated with fatty streaks and raised lesions (29), and risk factors, including non-HDL-C and low HDL-C, accelerated progression of flat fatty streaks to raised lesions in the second decade. Childhood non-HDL-C, TG, Apo B, and Apo B:Apo A-I ratio all predicted carotid IMT after more than 20 years of follow-up, with non-HDL-C being superior to TG. (30) Therefore, targeting non-HDL-C in cases with intermediate triglyceride levels is a useful and productive strategy endorsed by the 2011 NHLBI (National Heart Lung and Blood Institute) Expert Panel’s recommendations (14).

TG METABOLISM IN THE SETTING OF INSULIN RESISTANCE

Common secondary HTG occurs in insulin resistant states such as obesity and type 2 diabetes (T2D) and can often become modified or exacerbated by other secondary causes. Since the abnormal lipid metabolism in insulin resistance has been extensively studied it serves as a foundation for understanding secondary dyslipidemia and potential for exacerbation by other causes (Figure 2).

Figure 2.

Lipoprotein Metabolism in Insulin Resistance. A combination of excess production and disposal processes results in secondary HTG and atherogenic dyslipidemia in the insulin resistant state. Chylomicrons and VLDL production originating from the intestine and liver are increased. Mobilization of free fatty acids (FFA) from fat cells by hormone sensitive and TG lipases (HSL/TGL) provides the liver with substrate for VLDL formation. Dietary intake of fat provides the intestine with TG for chylomicron formation, which is upregulated in insulin resistance. Hepatic VLDL containing excess Apo C-III relative to Apo E is increased; Apo C-III delays receptor-mediated hepatic uptake of VLDL and chylomicron remnants resulting in formation of intermediate density lipoproteins (IDL, not shown) and smaller and denser low-density lipoproteins (LDL). Lipoprotein lipase (LPL) is inhibited by Apo C-III and decreased by insulin resistance and/or deficiency. Cholesterol ester transfer protein (CETP) is upregulated resulting in exchange of TG and cholesterol ester (CE), leading to TG enrichment of LDL and HDL. Both become substrates for hepatic triglyceride lipase (HTGL), which is upregulated and acts on TG-enriched HDL and LDL to make them smaller, atherogenic and dysfunctional. Apolipoproteins A-I, B-48, B-100, C-I, C-II, C-III (C), and E are labelled and play important roles in lipoprotein metabolism.

HTG PREVALENCE

In the U.S., the latest prevalence data for HTG comes from the 1999 - 2006 NHANES study, which found prevalence rates of 5.9% in normal weight children, 13.8% in overweight children and 24.1% in obese children (31). Given that Skinner et al found a positive linear trend for all definitions of overweight and obesity among children 2-19 years old, most prominently among adolescents and children aged 2 to 5 years (32), the current prevalence of HTG is almost certainly significantly higher. Abnormal TG levels for children are generally classified on the basis of cut points based on population norms recommended by the American Academy of Pediatrics and the American Heart Association (33). The 50^th to 95^th percentile values for TG in children are presented in Table 1. Acceptable levels in children defined by the Expert Panel on Integrated Guidelines for Cardiovascular Health (14) are summarized in Table 2.

The non-HDL-C which is equally accurate when measured on a fasting or non-fasting lipid panel reflects the sum of all apolipoprotein (Apo)-B-containing, triglyceride-rich lipoprotein subfractions (LDL, VLDL, Intermediate-Density Lipoprotein (IDL), lipoprotein (a), and chylomicron remnants. As triglycerides increase, there is a corresponding increase in the non–HDL-C level which correlates with Apo B much better than LDL-C. Hypertriglyceridemia can be diagnosed if TG level is ≥100 mg/dL in children (<10 year) or ≥130 mg/dL in adolescents (10–19 years) based on an average of two fasting measurements. Severe secondary hyper-TG, defined as levels above 1000 mg/dL, presents a risk for acute pancreatitis, especially when lipoprotein lipase-mediated clearance is saturated (> 800 mg/dL) causing the triglyceride to attain very high levels often exceeding 1000 mg/dL, with appearance of chylomicrons on standing plasma. Moderate HTG, defined as levels 150-499 mg/dL, is a risk factor for CVD. These children tend to be undertreated despite potential for reversal and primary prevention of cardiovascular disease (34).

MEASUREMENT ASPECTS

Although the non-HDL-cholesterol does not require fasting, the standard lipid profile which includes total cholesterol (TC), LDL-C, HDL-C, TG, and very low-density lipoprotein-cholesterol (VLDL-C) should be performed in pediatric patients in the fasting state (at least 8 hours) and guideline directed therapy is based on fasting values. Currently, some laboratories still use a calculated value for VLDL-C and LDL-C based on the Friedewald Formula (35) which estimates the VLDL-C by a fixed ratio of 5 (VLDL-C = TG/5). Because of the significant deviation from linearity at high TG levels (typically 400 mg/dL is used as a cut-point), VLDL-C and LDL-C values are not reported. This is especially important in dyslipidemias where both the TG and LDL-C can be elevated (i.e., familial combined hyperlipidemia) or where the TG level is severely elevated as a result of genetic and/or nutritional factors because it can lead to an under appreciation of the extent of the LDL-C elevation, the latter being especially important for guideline-directed therapy to lower cholesterol and in particular, LDL-C. Recently several equations have been developed that improved the accuracy of the calculated LDL-C. The Martin-Hopkins equation uses an adjustable factor based on lipid profiles from the Very Large Database of Lipids where TG levels were directly measured on samples separated using vertical spin density-gradient ultracentrifugation rather than a fixed ratio to calculate VLDL-C and subsequently the LDL-C (36). While this equation is more accurate than the Friedewald equation at high TG levels, there is still significant error for TG> 400 mg/dL addressed by the extended Martin/Hopkins calculation (37) and the Sampson equation (38). The Sampson equation was derived using beta quantification LDL-C values (the “gold standard” for LDL-C values) using multiple least squares regression analysis to derive a fixed equation to calculate the LDL-C value. All three equations have been proven to be superior to the Friedewald equation and many laboratories have already incorporated these equations when reporting lipid measures. Several pediatric studies have specifically addressed these improved methods to calculate VLDL-C and LDL-C (39,40,41).

GENETIC BACKGROUND

Commonly encountered HTG is usually multigenic and results from small-effect variants (single nucleotide polymorphisms) in many genes or heterozygotes in genes such as APOA5, GCKR, LPL, and APOB that have larger effects and together, more than 20% of susceptibility is accounted for by common and rare variants (42). The population frequency of the HTG phenotype was shown in the Copenhagen General Population Study in which a small percentage have a non-fasting TG level greater than 1000 mg/dL, whereas the majority have intermediate levels ranging from greater than the 95^th percentile to 500 mg/dL and higher, often secondary to an underlying disorder (43).

DEVELOPMENTAL FACTORS

A sequence of factors, beginning during gestation, influence the development of hypertriglyceridemia (HTG) later in life (Figure 3).

Figure 3.

Developmental Influences. Metabolic processes are programmed during gestation and early childhood and are influenced by disease states and environmental factors such as dietary excess and inactivity. The HTG is associated with atherogenic dyslipidemia consisting of increased non-HDL-C (non-high-density lipoprotein-cholesterol), LDL-P (LDL particle number), Apo B (apolipoprotein B), decreased HDL-C (high density lipoprotein cholesterol) and decreased Apo A-I.

Maternal nutrition and placental function affect nutrient supply for fetal growth and influence subsequent development of the metabolic syndrome (52). Overweight children who were small for gestational age (SGA) have increased risk for components of the metabolic syndrome compared to overweight children who were appropriate for gestation age (AGA). These effects on growth are attributed to restriction in intrauterine growth (53). After gestational programming, nutritional and endocrine factors play a role during childhood and affect development of risk factors including dyslipidemia (Figure 3). Preterm infants have higher meal frequency than older children and adults, but less efficient fat digestion and absorption, making it difficult to cope with a high fat intake relative to their body weight (54). Consequently, HTG is a frequent occurrence. Since pancreatic lipase and bile salt secretion is often inadequate for facilitating absorption of fat and its utilization as a source of energy, premature babies often fail to thrive and need exogenous fat as a component of total intravenous parenteral nutrition titrated according to the TG level (55). If lipoprotein lipase is genetically defective plasma clearance is even more compromised and severe HTG occurs during lipid infusions. If clinical circumstances necessitate that fats be restricted, essential omega-3 and omega-6 fatty acids are supplied for development of the brain and retina, and medium chain TG are an effective energy source without raising TG levels since they are directly transported to the liver via the portal system (56).

Increases in obesity, particularly as abdominal fat, during childhood predict the metabolic syndrome and compound the effect of an abnormal birth weight (57). Also, low adiponectin has been associated with insulin resistance, particularly in African American youth and compounds dyslipidemia (58). The adrenal axis may be involved; urinary free cortisol is associated with the metabolic syndrome in children (59), but the role of cortisol is controversial. Conversion of cortisone to cortisol by 11 beta -hydroxysteroid dehydrogenase type 1 (11 beta -HSD1) results in cortisol excess leading to insulin resistance, hypertension, and dyslipidemia. Inhibition of the enzyme results in reversal of metabolic syndrome criteria providing potential for pharmaceutical intervention (60). Normal puberty causes a transient increase in insulin resistance, attributed to maturational increases in sex and growth hormones, and may increase prevalence of both the metabolic syndrome and type 2 diabetes (61).

SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA

While primary HTG is associated with relatively rare monogenic and more common polygenic forms, there are many secondary non-genetic factors. The lipid abnormalities associated with these causes are summarized in Table 3.

PHARMACOLOGICAL CAUSES

Pharmacological agents have significant effects on plasma lipids. In some cases the mechanism is known but is frequently uncertain or unknown. The potential for causing dyslipidemia is particularly important in a patient that has an underlying genetic predisposition. Changing the offending medication or treating the dyslipidemia are both options, especially when the disease requires long term management and alternative medications are limited or not available. Each medication class has characteristic effects on the lipid profile but some, such as glucocorticoids, oral estrogens, and alcohol, may increase HDL-C and others may increase both cholesterol and triglyceride (Table 4).

MANAGEMENT

Drug Therapy

Treatment of the primary disorder is the first priority, i.e., treating HTG associated with T2D diabetes requires specific therapies based on the severity of the TG elevation and response to lifestyle. Rare disorders require specific therapies such as complex carbohydrates for maintaining euglycemia in GSD, and leptin therapy for lipodystrophy (discussed above). If pharmaceutical agents are the cause, modification of the treatment plan can be considered in consultation with the primary specialist. Sunil et al recently summarized medications targeted for HTG (157) as well as hypercholesterolemia and the former are summarized in figure 4 and several are discussed in detail herein, Unfortunately, none of these medications are approved below age 18 years-of-age, therefore treatment of HTG in children and adolescents is largely restricted to lifestyle changes. The most important aspect of dietary counseling is also discerning if the HTG is associated with insulin resistance where lowering simple sugars and carbohydrates is key or hyperchylomicronemia where fat restriction is paramount or where these disorders overlap.

Figure 4.

Triglyceride lowering medications. From Ref. 157.

STATINS

Statins which are not described in figure 4 lower cholesterol, specifically LDL-C and have minimal effect on HTG. However, for commonly encountered dyslipidemia there is good reason to follow established guidelines to reduce the future CVD risk through the use of statin therapy (14). If a six-month trial of intensive lifestyle is not effective in reaching the recommended goal, the LDL-C and non-HDL-C become targets using appropriate agents such as statins. As discussed previously, non-HDL-C is a preferred target for individuals with mild to moderate TG elevations (150-499 mg/dl) as recommended by the 2011 expert NHLBI panel (14). For LDL-C and non-HDL-C above 95^th percentiles in the presence of HTG and at least one other risk factor, statin therapy is indicated selecting from approved statins for children over age 10 years (15). The reported statin association with type 2 diabetes (158,159) should be considered when obesity and associated genetic risk for diabetes is present.

It should be emphasized that when statin treatment is indicated for drug-induced hypercholesterolemia, care should be taken to avoid interactions with drugs that are metabolized by pathways utilizing cytochrome P450 enzymes, such as CYP3A4 for atorvastatin, lovastatin and simvastatin and CYP2C9 for fluvastatin and rosuvastatin (159). Drugs such as clarithromycin, cyclosporine A, diltiazem, erythromycin, ketoconazole, itraconazole, mibefradil, midazolam, nefazodone, nifedipine, protease inhibitors, quinidine, sildenafil, terbinafine, verapamil and warfarin are CYP3A4 utilizers and will raise the statin levels when used together, thus increasing risk of toxicity. Likewise, alprenolol, diclofenac, fluconazole, hexobarbitoal, n-desmethyldiazepan, tolbutamide and warfarin are CYP2C9 utilizers and will be incompatible with fluvastatin and rosuvastatin. Several of these drugs have common pediatric usage including certain antibiotics and antifungal agents.

FIBRATES

Based on adult evidence of harmful effects of TG-rich lipoproteins, small dense LDL, and remnant lipoproteins derived from VLDL and chylomicrons (160) and the metabolic effects of TG and associated increase in fatty acids (161), pharmacological TG lowering in childhood is indicated for selected cases resistant to lifestyle (14). Individuals with severe isolated HTG at risk for acute pancreatitis should have a trial of a TG-lowering agent such as a fibrate (i.e., gemfibrozil or fenofibrate), beginning with the lowest available dose while monitoring for adverse effects. Fibrates, approved for use over age 18 years, have limited trial evidence in children but a fibrate (bezafibrate, not available in the United States) was shown to be safe when used for children with familial hypercholesterolemia before statins were available for use (162). It is however notable that few adult trials have shown benefit of fibrates on cardiovascular event reduction. Niacin while historically used (163), no longer has a place in the management of dyslipidemia.

OMEGA-3 FATTY ACIDS

Omega-3-fatty acids have appeal as a potential TG-lowering agent for children because of their relatively low adverse effect profile and recent availability as a prescription grade preparation following purification to remove heavy metals and fatty acids (164). Although adults have had up to 30% TG lowering with 4-gram doses, 2 gram doses are less effective and increased LDL-C is a recognized adverse effect (165,166). but the LDL-C to HDL-C ratio is unchanged (167). A retrospective survey of children treated for TG lowering with omega-3 fatty acids at a dose of 0.5 to 1 gram per day, did not show significant TG lowering suggesting that prescription of relatively low doses may not be helpful. The study supports use of higher doses in combination with lifestyle measures. A high purity prescription form of icosapent ethyl (eicosapentaenoic acid ethyl ester), lowers TG while lowering LDL particle concentration and LDL-C in cases with TG over 500mg/L (168, 169), but it is not yet available for use under 18 years of age, however it appears to be a reasonable consideration for testing in pediatric settings. The free fatty acid form as shown in the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial is effective for TG-lowering (170), but not yet available for use in children. Non-prescription marine omega-3s can be safely used if patients are instructed on what to look for on the label (e.g., distilled, USP approved) and specific marine sources with high concentrations are recommended (171).

SEVERE SECONDARY HTG

Treatment for HTG with levels above 1000 mg/dl in patients with partial defects in chylomicron clearance by LPL or its co-factors requires total dietary fat restriction for 72 hours followed by dietary management in the longer term. The approach is similar to the management of homozygous familial chylomicronemia for which there is more information (172) (reviewed in another chapter). It should be recognized that small increments in fat can cause striking increases in plasma TG because when TG levels saturate LPL activity, any additional TG entering the plasma will face zero order kinetics and increase the TG in a non-linear fashion. TG can be substantially lowered by restricting dietary fat to less than 15% of the total daily caloric intake and cases vary in their response to fibrates depending on their effect on residual lipoprotein lipase and on suppression of hepatic TG production. Adherence to a very low-fat diet requires supplementation with linoleic acid and fat-soluble vitamins (A, D, E and K), but frequent monitoring is advised. Supplemental medium chain triglycerides (MCT) may be beneficial in providing additional calories and improving compliance. Fenofibrate can be helpful in cases with residual lipoprotein lipase activity and also may reduce hepatic TG production. New agents are being developed to increase clearance and/or reduce the production of triglyceride-rich lipoproteins, but their clinical efficacy, cost effectiveness, and indications, especially in children, are yet to be established (173).

CONCLUSION

In addition to obesity accompanied by metabolic syndrome, other common and rare causes of secondary dyslipidemia require diagnosis-specific management strategies. Identification and prioritization of reversible causes and risk factors, use of comprehensive lifestyle approaches, and optimal choice of medications based on guidelines can lead to improved outcomes. Lifestyle modification with selective prescription of medications designed to reduce risk of cardiovascular disease is indicated for individuals with intermediate TG levels ranging from 150499 mg/dL, but severely elevated levels imposing risk for acute pancreatitis, require more intense dietary restriction combined with TG-lowering medications. The results of AAP’s recent recommendation of a more aggressive approach to treatment of childhood obesity await outcome data. Since non-HDL-C is a known predictor of cardiovascular disease and represents an estimate of all atherogenic lipoprotein particles TG-rich lipoproteins, it is recommended as a preferred target especially in most cases with intermediate elevations of TG.

REFERENCES

1.

Blackett PR, Wilson DP, McNeal CJ. Secondary hypertriglyceridemia in children and adolescents. Journal of clinical lipidology. 2015 Sep 1;9(5):S29-40. [PubMed: 26343210]

2.

Jung MK, Yoo EG. Hypertriglyceridemia in obese children and adolescents. Journal of obesity & metabolic syndrome. 2018 Sep;27(3):143. [PMC free article: PMC6504196] [PubMed: 31089556]

3.

Shah AS, Wilson DP. Primary hypertriglyceridemia in children and adolescents. Journal of Clinical Lipidology. 2015 Sep 1;9(5):S20-8. [PubMed: 26343209]

4.

Shah AS, Wilson DP. Genetic disorders causing hypertriglyceridemia in children and adolescents. Endotext [Internet]. 2020 Jan 22.

5.

Sunil B, Ashraf AP. Childhood Hypertriglyceridemia: Is It Time for a New Approach?. Current Atherosclerosis Reports. 2022 Apr;24(4):265-75. [PubMed: 35107763]

6.

Magge SN, Goodman E, Armstrong SC, Daniels S, Corkins M, de Ferranti S, Golden NH, Kim JH, Schwarzenberg SJ, Sills IN, Casella SJ. The metabolic syndrome in children and adolescents: shifting the focus to cardiometabolic risk factor clustering. Pediatrics. 2017 Aug 1;140(2). [PubMed: 28739653]

7.

Reisinger C, Nkeh-Chungag BN, Fredriksen PM, Goswami N. The prevalence of pediatric metabolic syndrome—A critical look on the discrepancies between definitions and its clinical importance. International Journal of Obesity. 2021 Jan;45(1):12-24. [PMC free article: PMC7752760] [PubMed: 33208861]

8.

Christian Flemming GM, Bussler S, Körner A, Kiess W. Definition and early diagnosis of metabolic syndrome in children. Journal of Pediatric Endocrinology and Metabolism. 2020 Jul 28;33(7):821-33. [PubMed: 32568734]

9.

Weihe P, Weihrauch-Blüher S. Metabolic syndrome in children and adolescents: diagnostic criteria, therapeutic options and perspectives. Current obesity reports. 2019 Dec;8:472-9. [PubMed: 31691175]

10.

Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH 2008 Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes Federation. Diabetes care 31:587-589 [PubMed: 18071007]

11.

Regis A. The CHILD 1 diet: from strategy to practicality. Pediatric Annals. 2013 Sep 1;42(9):e188-90. [PubMed: 23992208]

12.

Selvarj K, Olave-Pichon A, Benuck I, et al. Characteristics of children referred to a lipid clinic before and after the universal screening guidelines. Clinical Pediatrics. (2019) 58(6):656-664. [PubMed: 30854883]

13.

Capra ME, Biasucci G, Banderali G, Pederiva C. Nutritional Treatment of Hypertriglyceridemia in Childhood: From Healthy-Heart Counselling to Life-Saving Diet. Nutrients. 2023 Feb 22;15(5):1088. [PMC free article: PMC10005617] [PubMed: 36904088]

14.

Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: summary report. Pediatrics. (2011) 128:S213-56; Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents: full report. U.S. Department of Health and Human Services. (2011)] [PMC free article: PMC4536582] [PubMed: 22084329]

15.

White JS. Sucrose, HFCS, and Fructose: History, Composition, Applications, and Production. Chapter 2 in J.M. Rippe (ed.), Fructose, High Fructose Corn Syrup, Sucrose and Health, Nutrition and Health. Springer Science+Business Media New York. (2014) ISBN 978-1-4899-8077-9

16.

High Fructose Corn Syrup Questions and Answers. U.S. Food and Drug Administration. (2018)

17.

White JS. Misconceptions about high-fructose corn syrup: Is it uniquely responsible for obesity, reactive dicarbonyl compounds, and advanced glycation endproducts? Journal of Nutrition. (2009) 139(6):1219S-1227S [PubMed: 19386820]

18.

Lee JH, Duster M, Roberts T, Devinsky O. United States Dietary Trends Since 1800: Lack of Association Between Saturated Fatty Acid Consumption and Non-communicable Diseases. Front Nutr. 2022 Jan 13;8:748847. doi: . PMID: ; PMCID: PMC8805510.10.3389/fnut.2021.748847 [PMC free article: PMC8805510] [PubMed: 35118102] [CrossRef]

19.

Drozdowski LA, Thomson AB. Intestinal sugar transport. World J Gastroenterol. (2006) 12(11):1657-70. [PMC free article: PMC4124338] [PubMed: 16586532]

20.

Chernecky CC, Berger BJ. Glucose tolerance test (GTT,OGTT) – blood. In: Chernecky CC, Berger BJ, eds. Laboratory Tests and Diagnostic Procedures. 6th ed. Philadelphia, PA: Elsevier Saunders. (2013) 591-593

21.

Kwiterovich PO 2010 Lipid, apolipoprotein, and lipoprotein metabolism: implications for the diagnosis and treatment of dyslipidemia: Wolters Kluwer/Lippincott Williams & Wilkins

22.

Smelt AH, de Beer F 2004 Apolipoprotein E and familial dysbetalipoproteinemia: clinical, biochemical, and genetic aspects. Seminars in vascular medicine 4:249-257 [PubMed: 15630634]

23.

Berenson GS, Srinivasan SR, Bao W, Newman WP, 3rd, Tracy RE, Wattigney WA 1998 Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. The New England journal of medicine 338:1650-1656 [PubMed: 9614255]

24.

McGill HC, Jr., McMahan CA, Zieske AW, Sloop GD, Walcott JV, Troxclair DA, Malcom GT, Tracy RE, Oalmann MC, Strong JP 2000 Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arteriosclerosis, thrombosis, and vascular biology 20:1998-2004 [PubMed: 10938023]

25.

Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-Etherton PM, Lennie TA. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011 May 24;123(20):2292-333. [PubMed: 21502576]

26.

Hussain A, Ballantyne CM, Saeed A, Virani SS. Triglycerides and ASCVD risk reduction: recent insights and future directions. Current Atherosclerosis Reports. 2020 Jul;22:1-0. [PubMed: 32494924]

27.

Budoff M. Triglycerides and triglyceride-rich lipoproteins in the causal pathway of cardiovascular disease. The American journal of cardiology. 2016 Jul 1;118(1):138-45. [PubMed: 27184174]

28.

Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circulation research. 2016 Feb 19;118(4):547-63. [PubMed: 26892957]

29.

McGill HC, Jr., McMahan CA, Herderick EE, Tracy RE, Malcom GT, Zieske AW, Strong JP 2000 Effects of coronary heart disease risk factors on atherosclerosis of selected regions of the aorta and right coronary artery. PDAY Research Group. Pathobiological Determinants of Atherosclerosis in Youth. Arteriosclerosis, thrombosis, and vascular biology 20:836-845 [PubMed: 10712411]

30.

Frontini MG, Srinivasan SR, Xu J, Tang R, Bond MG, Berenson GS 2008 Usefulness of childhood non-high density lipoprotein cholesterol levels versus other lipoprotein measures in predicting adult subclinical atherosclerosis: the Bogalusa Heart Study. Pediatrics 121:924-929 [PubMed: 18450895]

31.

Centers for Disease Control and Prevention (CDC) Prevalence of abnormal lipid levels among youths: United States, 1999–2006. MMWR Morb Mortal Wkly Rep. 2010;59:29–33 [PubMed: 20094024]

32.

Skinner AC, Ravanbakht SN, Skelton JA, Perrin EM, Armstrong SC. Prevalence of Obesity and Severe Obesity in US Children, 1999-2016. Pediatrics. 2018 Mar;141(3):e20173459. doi: . Erratum in: Pediatrics. 2018 Sep;142(3): PMID: 29483202; PMCID: PMC6109602.10.1542/peds.2017-3459 [PMC free article: PMC6109602] [PubMed: 29483202] [CrossRef]

33.

Kavey RE, Daniels SR, Lauer RM, Atkins DL, Hayman LL, Taubert K, American Heart A 2003 American Heart Association guidelines for primary prevention of atherosclerotic cardiovascular disease beginning in childhood. Circulation 107:1562-1566 [PubMed: 12654618]

34.

Wilson DP, McNeal C, Blackett P 2015 Pediatric dyslipidemia: recommendations for clinical management. Southern medical journal 108:7-14 [PubMed: 25580750]

35.

Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. (1972) 18:499-502.] [PubMed: 4337382]

36.

Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. Jama. 2013 Nov 20;310(19):2061-8. [PMC free article: PMC4226221] [PubMed: 24240933]

37.

Sajja A, Park J, Sathiyakumar V, Varghese B, Pallazola VA, Marvel FA, et al. Comparison of Methods to Estimate LowDensity Lipoprotein Cholesterol in Patients With High Triglyceride Levels. JAMA Netw Open. 2021;4(10):e2128817 [PMC free article: PMC8554644] [PubMed: 34709388]

38.

Sampson M, Ling C, Sun Q, Harb R, Ashmaig M, Warnick R, Sethi A, Fleming JK, Otvos JD, Meeusen JW, Delaney SR. A new equation for calculation of low-density lipoprotein cholesterol in patients with normolipidemia and/or hypertriglyceridemia. JAMA cardiology. 2020 May 1;5(5):540-8. [PMC free article: PMC7240357] [PubMed: 32101259]

39.

Steyn N, Rossouw HM, Pillay TS, Martins J. Comparability of calculated LDL-C with directly measured LDL-C in selected paediatric and adult cohorts. Clinica Chimica Acta. 2022 Dec 1;537:158-66. [PubMed: 36265577]

40.

Chan KK, Dickerson JA. Assessment of LDL-C Calculation Using the Newly Adopted NIH LDL-C Equation in a Pediatric Population. Clinical Chemistry. 2022 Oct 6;68(10):1338-9. [PubMed: 35897134]

41.

Garoufi A, Drakatos A, Tsentidis C, Klinaki E, Paraskakis I, Marmarinos A, Gourgiotis D. Comparing calculated LDL-C with directly measured LDL-C in healthy and in dyslipidemic children. Clinical biochemistry. 2017 Jan 1;50(1-2):16-22. [PubMed: 27836622]

42.

Johansen CT, Hegele RA 2011 Genetic bases of hypertriglyceridemic phenotypes. Current opinion in lipidology 22:247-253 [PubMed: 21519249]

43.

Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, Kuivenhoven JA, Averna M, Boren J, Bruckert E, Catapano AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray KK, Santos RD, Stalenhoef AF, Stroes E, Taskinen MR, Tybjaerg-Hansen A, Watts GF, Wiklund O, European Atherosclerosis Society Consensus P 2014 The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. The lancet. Diabetes & endocrinology 2:655-666 [PMC free article: PMC4201123] [PubMed: 24731657]

44.

Brunzell JD, Schrott HG 2012 The interaction of familial and secondary causes of hypertriglyceridemia: role in pancreatitis. Journal of clinical lipidology 6:409-412 [PubMed: 23009776]

45.

Julien P, Vohl MC, Gaudet D, Gagne C, Levesque G, Despres JP, Cadelis F, Brun LD, Nadeau A, Ven Murthy MR 1997 Hyperinsulinemia and abdominal obesity affect the expression of hypertriglyceridemia in heterozygous familial lipoprotein lipase deficiency. Diabetes 46:2063-2068 [PubMed: 9392497]

46.

Gupta M, Liti B, Barrett C, Thompson PD, Fernandez AB. Prevention and management of hypertriglyceridemia-induced acute pancreatitis during pregnancy: a systematic review. The American Journal of Medicine. 2022 Jun 1;135(6):709-14. [PubMed: 35081380]

47.

Kelishadi R, Poursafa P. A review on the genetic, environmental, and lifestyle aspects of the early-life origins of cardiovascular disease. Current problems in pediatric and adolescent health care. 2014 Mar 1;44(3):54-72. [PubMed: 24607261]

48.

Zhang Z, Gillespie C, Welsh JA, Hu FB, Yang Q. Usual intake of added sugars and lipid profiles among the US adolescents: National Health and Nutrition Examination Survey, 2005–2010. Journal of Adolescent Health. 2015 Mar 1;56(3):352-9. [PMC free article: PMC4494648] [PubMed: 25703323]

49.

Bello-Chavolla OY, Kuri-García A, Ríos-Ríos M, Vargas-Vázquez A, Cortés-Arroyo JE, Tapia-González G, Cruz-Bautista I, Aguilar-Salinas CA. Familial combined hyperlipidemia: current knowledge, perspectives, and controversies. Revista de investigacion clinica. 2018 Nov 15;70(5):224-36. [PubMed: 30307446]

50.

Tg, Hdl Working Group of the Exome Sequencing Project NHL, Blood I, Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, Lu Y, Tang ZZ, Zhang H, Hindy G, Masca N, Stirrups K, Kanoni S, Do R, Jun G, Hu Y, Kang HM, Xue C, Goel A, Farrall M, Duga S, Merlini PA, Asselta R, Girelli D, Olivieri O, Martinelli N, Yin W, Reilly D, Speliotes E, Fox CS, Hveem K, Holmen OL, Nikpay M, Farlow DN, Assimes TL, Franceschini N, Robinson J, North KE, Martin LW, DePristo M, Gupta N, Escher SA, Jansson JH, Van Zuydam N, Palmer CN, Wareham N, Koch W, Meitinger T, Peters A, Lieb W, Erbel R, Konig IR, Kruppa J, Degenhardt F, Gottesman O, Bottinger EP, O'Donnell CJ, Psaty BM, Ballantyne CM, Abecasis G, Ordovas JM, Melander O, Watkins H, Orho-Melander M, Ardissino D, Loos RJ, McPherson R, Willer CJ, Erdmann J, Hall AS, Samani NJ, Deloukas P, Schunkert H, Wilson JG, Kooperberg C, Rich SS, Tracy RP, Lin DY, Altshuler D, Gabriel S, Nickerson DA, Jarvik GP, Cupples LA, Reiner AP, Boerwinkle E, Kathiresan S 2014 Loss-of-function mutations in APOC3, triglycerides, and coronary disease. The New England journal of medicine 371:22-31 [PMC free article: PMC4180269] [PubMed: 24941081]

51.

Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A 2014 Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. The New England journal of medicine 371:32-41 [PubMed: 24941082]

52.

Barker DJ, Thornburg KL 2013 Placental programming of chronic diseases, cancer and lifespan: a review. Placenta 34:841-845 [PubMed: 23916422]

53.

Reinehr T, Kleber M, Toschke AM 2009 Small for gestational age status is associated with metabolic syndrome in overweight children. European journal of endocrinology / European Federation of Endocrine Societies 160:579-584 [PubMed: 19155319]

54.

Lindquist S, Hernell O 2010 Lipid digestion and absorption in early life: an update. Current opinion in clinical nutrition and metabolic care 13:314-320 [PubMed: 20179589]

55.

Adamkin DH, Radmacher PG 2014 Current trends and future challenges in neonatal parenteral nutrition. Journal of neonatal-perinatal medicine [PubMed: 25318631]

56.

Johnson PJ 2014 Review of macronutrients in parenteral nutrition for neonatal intensive care population. Neonatal network : NN 33:29-34 [PubMed: 24413034]

57.

Brufani C, Fintini D, Giordano U, Tozzi AE, Barbetti F, Cappa M 2011 Metabolic syndrome in italian obese children and adolescents: stronger association with central fat depot than with insulin sensitivity and birth weight. International journal of hypertension 2011:257168 [PMC free article: PMC3057027] [PubMed: 21423680]

58.

Lee S, Bacha F, Gungor N, Arslanian SA 2006 Racial differences in adiponectin in youth: relationship to visceral fat and insulin sensitivity. Diabetes care 29:51-56 [PubMed: 16373895]

59.

Reinehr T, Kulle A, Wolters B, Knop C, Lass N, Welzel M, Holterhus PM 2014 Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children. The Journal of clinical endocrinology and metabolism 99:2391-2399 [PubMed: 24670085]

60.

Schnackenberg CG, Costell MH, Krosky DJ, Cui J, Wu CW, Hong VS, Harpel MR, Willette RN, Yue TL 2013 Chronic inhibition of 11 beta -hydroxysteroid dehydrogenase type 1 activity decreases hypertension, insulin resistance, and hypertriglyceridemia in metabolic syndrome. BioMed research international 2013:427640 [PMC free article: PMC3613092] [PubMed: 23586038]

61.

Goran MI, Gower BA 2001 Longitudinal study on pubertal insulin resistance. Diabetes 50:2444-2450 [PubMed: 11679420]

62.

Clinical Practice Guideline for the Evaluation and Treatment of Children and Adolescents With Obesity. Pediatrics (2023) 151 (2): e2022060640. https://doi.org/10.1542/peds.2022-060640 [PubMed: 36622115] [CrossRef]

63.

Copeland KC, Zeitler P, Geffner M, Guandalini C, Higgins J, Hirst K, Kaufman FR, Linder B, Marcovina S, McGuigan P, Pyle L, Tamborlane W, Willi S, Group TS 2011 Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. The Journal of clinical endocrinology and metabolism 96:159-167 [PMC free article: PMC3038479] [PubMed: 20962021]

64.

Giannini C, Santoro N, Caprio S, Kim G, Lartaud D, Shaw M, Pierpont B, Weiss R 2011 The triglyceride-to-HDL cholesterol ratio: association with insulin resistance in obese youths of different ethnic backgrounds. Diabetes care 34:1869-1874 [PMC free article: PMC3142016] [PubMed: 21730284]

65.

Olefsky JM, Farquhar JW, Reaven GM 1974 Reappraisal of the role of insulin in hypertriglyceridemia. The American journal of medicine 57:551-560 [PubMed: 4372881]

66.

Vassy JL, Shrader P, Yang Q, Liu T, Yesupriya A, Chang MH, Dowling NF, Ned RM, Dupuis J, Florez JC, Khoury MJ, Meigs JB 2011 Genetic associations with metabolic syndrome and its quantitative traits by race/ethnicity in the United States. Metabolic syndrome and related disorders 9:475-482 [PMC free article: PMC3225057] [PubMed: 21848424]

67.

Burns SF, Arslanian SA 2009 Waist circumference, atherogenic lipoproteins, and vascular smooth muscle biomarkers in children. The Journal of clinical endocrinology and metabolism 94:4914-4922 [PMC free article: PMC2795649] [PubMed: 19846736]

68.

Lee S, Bacha F, Arslanian SA 2006 Waist circumference, blood pressure, and lipid components of the metabolic syndrome. The Journal of pediatrics 149:809-816 [PubMed: 17137898]

69.

Stoddart ML, Blevins KS, Lee ET, Wang W, Blackett PR, Cherokee Diabetes S 2002 Association of acanthosis nigricans with hyperinsulinemia compared with other selected risk factors for type 2 diabetes in Cherokee Indians: the Cherokee Diabetes Study. Diabetes care 25:1009-1014 [PubMed: 12032107]

70.

Pan DA, Lillioja S, Kriketos AD, Milner MR, Baur LA, Bogardus C, Jenkins AB, Storlien LH 1997 Skeletal muscle triglyceride levels are inversely related to insulin action. Diabetes 46:983-988 [PubMed: 9166669]

71.

Tobey TA, Greenfield M, Kraemer F, Reaven GM 1981 Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man. Metabolism: clinical and experimental 30:165-171 [PubMed: 7007804]

72.

Basu A, Basu R, Shah P, Vella A, Rizza RA, Jensen MD 2001 Systemic and regional free fatty acid metabolism in type 2 diabetes. American journal of physiology. Endocrinology and metabolism 280:E1000-1006 [PubMed: 11350782]

73.

Zhang YL, Hernandez-Ono A, Ko C, Yasunaga K, Huang LS, Ginsberg HN 2004 Regulation of hepatic apolipoprotein B-lipoprotein assembly and secretion by the availability of fatty acids. I. Differential response to the delivery of fatty acids via albumin or remnant-like emulsion particles. The Journal of biological chemistry 279:19362-19374 [PubMed: 14970200]

74.

Nogueira JP, Maraninchi M, Beliard S, Padilla N, Duvillard L, Mancini J, Nicolay A, Xiao C, Vialettes B, Lewis GF, Valero R 2012 Absence of acute inhibitory effect of insulin on chylomicron production in type 2 diabetes. Arteriosclerosis, thrombosis, and vascular biology 32:1039-1044 [PubMed: 22308041]

75.

Coniglio RI, Merono T, Montiel H, Malaspina MM, Salgueiro AM, Otero JC, Ferraris R, Schreier L, Brites F, Gomez Rosso L 2012 HOMA-IR and non-HDL-C as predictors of high cholesteryl ester transfer protein activity in patients at risk for type 2 diabetes. Clinical biochemistry 45:566-570 [PubMed: 22366373]

76.

Deeb SS, Zambon A, Carr MC, Ayyobi AF, Brunzell JD 2003 Hepatic lipase and dyslipidemia: interactions among genetic variants, obesity, gender, and diet. Journal of lipid research 44:1279-1286 [PubMed: 12639974]

77.

Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK, Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A, Watts GF, European Atherosclerosis Society Consensus P 2011 Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. European heart journal 32:1345-1361 [PMC free article: PMC3105250] [PubMed: 21531743]

78.

Ginsberg HN 2002 New perspectives on atherogenesis: role of abnormal triglyceride-rich lipoprotein metabolism. Circulation 106:2137-2142 [PubMed: 12379586]

79.

Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK 1990 Cardiovascular risk factors in confirmed prediabetic individuals. Does the clock for coronary heart disease start ticking before the onset of clinical diabetes? Jama 263:2893-2898 [PubMed: 2338751]

80.

Cohen MP, Lautenslager G, Shea E 1993 Glycated LDL concentrations in non-diabetic and diabetic subjects measured with monoclonal antibodies reactive with glycated apolipoprotein B epitopes. European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies 31:707-713 [PubMed: 7508270]

81.

Bowie A, Owens D, Collins P, Johnson A, Tomkin GH 1993 Glycosylated low density lipoprotein is more sensitive to oxidation: implications for the diabetic patient? Atherosclerosis 102:63-67 [PubMed: 8257453]

82.

Wang W, Khan S, Blackett P, Alaupovic P, Lee E 2013 Apolipoproteins A-I, B, and C-III in young adult Cherokee with metabolic syndrome with or without type 2 diabetes. Journal of clinical lipidology 7:38-42 [PMC free article: PMC3558999] [PubMed: 23351581]

83.

Today Study Group 2013 Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes care 36:1758-1764 [PMC free article: PMC3661790] [PubMed: 23704675]

84.

George MM, Copeland KC 2013 Current treatment options for type 2 diabetes mellitus in youth: today's realities and lessons from the TODAY study. Current diabetes reports 13:72-80 [PMC free article: PMC3545061] [PubMed: 23065368]

85.

Sherwin RS, Tamborlane WV, Genel M, Felig P 1980 Treatment of juvenile-onset diabetes by subcutaneous infusion of insulin with a portable pump. Diabetes care 3:301¬308 [PubMed: 6993144]

86.

Dunn FL, Pietri A, Raskin P 1981 Plasma lipid and lipoprotein levels with continuous subcutaneous insulin infusion in type I diabetes mellitus. Annals of internal medicine 95:426-431 [PubMed: 7025720]

87.

Blackett PR, Holcombe JH, Alaupovic P, Fesmire JD 1986 Plasma lipids and apolipoproteins in a 13-year-old boy with diabetic ketoacidosis and extreme hyperlipidemia. The American journal of the medical sciences 291:342-346 [PubMed: 3085497]

88.

Weidman SW, Ragland JB, Fisher JN, Jr., Kitabchi AE, Sabesin SM 1982 Effects of insulin on plasma lipoproteins in diabetic ketoacidosis: evidence for a change in high density lipoprotein composition during treatment. Journal of lipid research 23:171-182 [PubMed: 6799600]

89.

Wilson DP, Fesmire JD, Endres RK, Blackett PR 1985 Increased levels of HDL-cholesterol and apolipoprotein A-I after intensified insulin therapy for diabetes. Southern medical journal 78:636-638 [PubMed: 3923627]

90.

Katz M, Laffel L 2015 Mortality in type 1 diabetes in the current era: two steps forward, one step backward. Jama 313:35-36 [PubMed: 25562263]

91.

Orchard TJ, Secrest AM, Miller RG, Costacou T 2010 In the absence of renal disease, 20 year mortality risk in type 1 diabetes is comparable to that of the general population: a report from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetologia 53:2312-2319 [PMC free article: PMC3057031] [PubMed: 20665208]

92.

Van Waarde WM, Odink RJ, Rouwe C, Stellaard F, Westers M, Vonk RJ, Sauer PJ, Verkade HJ 2001 Postprandial chylomicron clearance rate in late teenagers with diabetes mellitus type 1. Pediatric research 50:611-617 [PubMed: 11641456]

93.

Mangat R, Su JW, Lambert JE, Clandinin MT, Wang Y, Uwiera RR, Forbes JM, Vine DF, Cooper ME, Mamo JC, Proctor SD 2011 Increased risk of cardiovascular disease in Type 1 diabetes: arterial exposure to remnant lipoproteins leads to enhanced deposition of cholesterol and binding to glycated extracellular matrix proteoglycans. Diabetic medicine : a journal of the British Diabetic Association 28:61-72 [PubMed: 21166847]

94.

Lewis GF, O'Meara NM, Cabana VG, Blackman JD, Pugh WL, Druetzler AF, Lukens JR, Getz GS, Polonsky KS 1991 Postprandial triglyceride response in type 1 (insulin-dependent) diabetes mellitus is not altered by short-term deterioration in glycaemic control or level of postprandial insulin replacement. Diabetologia 34:253-259 [PubMed: 2065859]

95.

Goldberg IJ, Bornfeldt KE 2013 Lipids and the endothelium: bidirectional interactions. Current atherosclerosis reports 15:365 [PMC free article: PMC3825167] [PubMed: 24037142]

96.

Ooi EM, Barrett PH, Chan DC, Watts GF 2008 Apolipoprotein C-III: understanding an emerging cardiovascular risk factor. Clinical science 114:611-624 [PubMed: 18399797]

97.

Caron S, Verrijken A, Mertens I, Samanez CH, Mautino G, Haas JT, Duran-Sandoval D, Prawitt J, Francque S, Vallez E, Muhr-Tailleux A, Berard I, Kuipers F, Kuivenhoven JA, Biddinger SB, Taskinen MR, Van Gaal L, Staels B 2011 Transcriptional activation of apolipoprotein CIII expression by glucose may contribute to diabetic dyslipidemia. Arteriosclerosis, thrombosis, and vascular biology 31:513-519 [PubMed: 21183731]

98.

Altomonte J, Cong L, Harbaran S, Richter A, Xu J, Meseck M, Dong HH 2004 Foxo1 mediates insulin action on apoC-III and triglyceride metabolism. The Journal of clinical investigation 114:1493-1503 [PMC free article: PMC525736] [PubMed: 15546000]

99.

Blackett P, Sarale DC, Fesmire J, Harmon J, Weech P, Alaupovic P 1988 Plasma apolipoprotein C-III levels in children with type I diabetes. Southern medical journal 81:469-473 [PubMed: 3128878]

100.

al Muhtaseb N, al Yousuf A, Bajaj JS 1992 Apolipoprotein A-I, A-II, B, C-II, and C-III in children with insulin-dependent diabetes mellitus. Pediatrics 89:936-941 [PubMed: 1579407]

101.

Krishnan S, Copeland KC, Bright BC, Gardner AW, Blackett PR, Fields DA 2011 Impact of type 1 diabetes and body weight status on cardiovascular risk factors in adolescent children. Journal of clinical hypertension 13:351-356 [PMC free article: PMC3089739] [PubMed: 21545396]

102.

Klein RL, McHenry MB, Lok KH, Hunter SJ, Le NA, Jenkins AJ, Zheng D, Semler A, Page G, Brown WV, Lyons TJ, Garvey WT, Group DER 2005 Apolipoprotein C-III protein concentrations and gene polymorphisms in Type 1 diabetes: associations with microvascular disease complications in the DCCT/EDIC cohort. Journal of diabetes and its complications 19:18-25 [PubMed: 15642486]

103.

Jenkins AJ, Yu J, Alaupovic P, Basu A, Klein RL, Lopes-Virella M, Baker NL, Hunt KJ, Lackland DT, Garvey WT, Lyons TJ, Group DER 2013 Apolipoprotein-defined lipoproteins and apolipoproteins: associations with abnormal albuminuria in type 1 diabetes in the diabetes control and complications trial/epidemiology of diabetes interventions and complications cohort. Journal of diabetes and its complications 27:447-453 [PMC free article: PMC4064461] [PubMed: 23850262]

104.

Yu JY, Lyons TJ 2013 Modified Lipoproteins in Diabetic Retinopathy: A Local Action in the Retina. Journal of clinical & experimental ophthalmology 4 [PMC free article: PMC4109058] [PubMed: 25068073]

105.

Agarwal AK, Garg A 2003 Congenital generalized lipodystrophy: significance of triglyceride biosynthetic pathways. Trends in endocrinology and metabolism: TEM 14:214-221 [PubMed: 12826327]

106.

Garg A 2011 Clinical review#: Lipodystrophies: genetic and acquired body fat disorders. The Journal of clinical endocrinology and metabolism 96:3313-3325 [PMC free article: PMC7673254] [PubMed: 21865368]

107.

Beltrand J, Lahlou N, Le Charpentier T, Sebag G, Leka S, Polak M, Tubiana-Rufi N, Lacombe D, de Kerdanet M, Huet F, Robert JJ, Chevenne D, Gressens P, Levy-Marchal C 2010 Resistance to leptin-replacement therapy in Berardinelli-Seip congenital lipodystrophy: an immunological origin. European journal of endocrinology / European Federation of Endocrine Societies 162:1083-1091 [PubMed: 20236991]

108.

Duntas LH 2002 Thyroid disease and lipids. Thyroid : official journal of the American Thyroid Association 12:287-293 [PubMed: 12034052]

109.

Catli G, Abaci A, Buyukgebiz A, Bober E 2014 Subclinical hypothyroidism in childhood and adolescense. Journal of pediatric endocrinology & metabolism : JPEM 27:1049-1057 [PubMed: 25153584]

110.

Rudling M, Norstedt G, Olivecrona H, Reihner E, Gustafsson JA, Angelin B 1992 Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proceedings of the National Academy of Sciences of the United States of America 89:6983-6987 [PMC free article: PMC49629] [PubMed: 1495990]

111.

Bengtsson BA, Abs R, Bennmarker H, Monson JP, Feldt-Rasmussen U, Hernberg-Stahl E, Westberg B, Wilton P, Wuster C 1999 The effects of treatment and the individual responsiveness to growth hormone (GH) replacement therapy in 665 GH-deficient adults. KIMS Study Group and the KIMS International Board. The Journal of clinical endocrinology and metabolism 84:3929-3935 [PubMed: 10566630]

112.

Angelin B, Rudling M 1994 Growth hormone and hepatic lipoprotein metabolism. Current opinion in lipidology 5:160-165 [PubMed: 7952909]

113.

Elam MB, Wilcox HG, Solomon SS, Heimberg M 1992 In vivo growth hormone treatment stimulates secretion of very low density lipoprotein by the isolated perfused rat liver. Endocrinology 131:2717-2722 [PubMed: 1446613]

114.

Cali AM, Caprio S 2009 Ectopic fat deposition and the metabolic syndrome in obese children and adolescents. Hormone research 71 Suppl 1:2-7 [PubMed: 19153496]

115.

Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP 2004 Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 126:586-597 [PubMed: 14762795]

116.

Clark PJ, Thompson AJ, Vock DM, Kratz LE, Tolun AA, Muir AJ, McHutchison JG, Subramanian M, Millington DM, Kelley RI, Patel K 2012 Hepatitis C virus selectively perturbs the distal cholesterol synthesis pathway in a genotype-specific manner. Hepatology 56:49-56 [PubMed: 22318926]

117.

Domitrovich AM, Felmlee DJ, Siddiqui A 2005 Hepatitis C virus nonstructural proteins inhibit apolipoprotein B100 secretion. The Journal of biological chemistry 280:39802¬39808 [PubMed: 16203724]

118.

Sever S, Weinstein DA, Wolfsdorf JI, Gedik R, Schaefer EJ 2012 Glycogen storage disease type Ia: linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism. Journal of clinical lipidology 6:596-600 [PMC free article: PMC3812663] [PubMed: 23312056]

119.

Fernandes J, Alaupovic P, Wit JM 1989 Gastric drip feeding in patients with glycogen storage disease type I: its effects on growth and plasma lipids and apolipoproteins. Pediatric research 25:327-331 [PubMed: 2542871]

120.

Shah KK, O'Dell SD 2013 Effect of dietary interventions in the maintenance of normoglycaemia in glycogen storage disease type 1a: a systematic review and meta-analysis. Journal of human nutrition and dietetics : the official journal of the British Dietetic Association 26:329-339 [PubMed: 23294025]

121.

Kronenberg F 2005 Dyslipidemia and nephrotic syndrome: recent advances. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation 15:195-203 [PubMed: 15827892]

122.

de Sain-van der Velden MG, Kaysen GA, Barrett HA, Stellaard F, Gadellaa MM, Voorbij HA, Reijngoud DJ, Rabelink TJ 1998 Increased VLDL in nephrotic patients results from a decreased catabolism while increased LDL results from increased synthesis. Kidney international 53:994-1001 [PubMed: 9551409]

123.

Attman PO, Alaupovic P 1990 Pathogenesis of hyperlipidemia in the nephrotic syndrome. American journal of nephrology 10 Suppl 1:69-75 [PubMed: 2256478]

124.

Saland JM, Ginsberg HN 2007 Lipoprotein metabolism in chronic renal insufficiency. Pediatric nephrology 22:1095-1112 [PubMed: 17390152]

125.

Feingold KR, Krauss RM, Pang M, Doerrler W, Jensen P, Grunfeld C 1993 The hypertriglyceridemia of acquired immunodeficiency syndrome is associated with an increased prevalence of low density lipoprotein subclass pattern B. The Journal of clinical endocrinology and metabolism 76:1423-1427 [PubMed: 8501146]

126.

Riddler SA, Li X, Chu H, Kingsley LA, Dobs A, Evans R, Palella F, Visscher B, Chmiel JS, Sharrett A 2007 Longitudinal changes in serum lipids among HIV-infected men on highly active antiretroviral therapy. HIV medicine 8:280-287 [PubMed: 17561873]

127.

Beaumont JL, Berard M, Antonucci M, Delplanque B, Vranckx R 1977 Inhibition of lipoprotein lipase activity by a monoclonal immunoglobulin in autoimmune hyperlipidemia. Atherosclerosis 26:67-77 [PubMed: 836349]

128.

Nozaki S, Ito Y, Nakagawa T, Yamashita S, Sasaki J, Matsuzawa Y 1997 Autoimmune hyperlipidemia with inhibitory monoclonal antibodies against low density lipoprotein binding to fibroblasts in a case with multiple myeloma. Internal medicine 36:920-925 [PubMed: 9475252]

129.

Karafin MS, Humphrey RL, Detrick B 2014 Evaluation of monoclonal and oligoclonal gammopathies in a pediatric population in a major urban center. American journal of clinical pathology 141:482-487 [PubMed: 24619747]

130.

Sholter DE, Armstrong PW 2000 Adverse effects of corticosteroids on the cardiovascular system. The Canadian journal of cardiology 16:505-511 [PubMed: 10787466]

131.

Schroeder LL, Tang X, Wasko MC, Bili A 2014 Glucocorticoid use is associated with increase in HDL and no change in other lipids in rheumatoid arthritis patients. Rheumatology international [PubMed: 25540049]

132.

Bhojwani D, Darbandi R, Pei D, Ramsey LB, Chemaitilly W, Sandlund JT, Cheng C, Pui CH, Relling MV, Jeha S, Metzger ML 2014 Severe hypertriglyceridaemia during therapy for childhood acute lymphoblastic leukaemia. European journal of cancer 50:2685-2694 [PMC free article: PMC4180109] [PubMed: 25087182]

133.

Duvillard L, Dautin G, Florentin E, Petit JM, Gambert P, Verges B 2010 Changes in apolipoprotein B100-containing lipoprotein metabolism due to an estrogen plus progestin oral contraceptive: a stable isotope kinetic study. The Journal of clinical endocrinology and metabolism 95:2140-2146 [PubMed: 20200333]

134.

Guazzelli CA, Lindsey PC, de Araujo FF, Barbieri M, Petta CA, Aldrighi JM 2005 Evaluation of lipid profile in adolescents during long-term use of combined oral hormonal contraceptives. Contraception 71:118-121 [PubMed: 15707561]

135.

Beasley A, Estes C, Guerrero J, Westhoff C 2012 The effect of obesity and low-dose oral contraceptives on carbohydrate and lipid metabolism. Contraception 85:446-452 [PubMed: 22078632]

136.

Chasan-Taber L, Stampfer MJ 1998 Epidemiology of oral contraceptives and cardiovascular disease. Annals of internal medicine 128:467-477 [PubMed: 9499331]

137.

Zane LT, Leyden WA, Marqueling AL, Manos MM 2006 A population-based analysis of laboratory abnormalities during isotretinoin therapy for acne vulgaris. Archives of dermatology 142:1016-1022 [PubMed: 16924051]

138.

McCarter TL, Chen YK 1992 Marked hyperlipidemia and pancreatitis associated with isotretinoin therapy. The American journal of gastroenterology 87:1855-1858 [PubMed: 1449157]

139.

Standeven AM, Thacher SM, Yuan YD, Escobar M, Vuligonda V, Beard RL, Chandraratna RA 2001 Retinoid X receptor agonist elevation of serum triglycerides in rats by potentiation of retinoic acid receptor agonist induction or by action as single agents. Biochemical pharmacology 62:1501-1509 [PubMed: 11728386]

140.

Freemantle SJ, Spinella MJ, Dmitrovsky E 2003 Retinoids in cancer therapy and chemoprevention: promise meets resistance. Oncogene 22:7305-7315 [PubMed: 14576840]

141.

Kuster GM, Drexel H, Bleisch JA, Rentsch K, Pei P, Binswanger U, Amann FW 1994 Relation of cyclosporine blood levels to adverse effects on lipoproteins. Transplantation 57:1479-1483 [PubMed: 8197611]

142.

Jankowska I, Czubkowski P, Socha P, Wierzbicka A, Teisseyre M, Teisseyre J, Pawlowska J 2012 Lipid metabolism and oxidative stress in children after liver transplantation treated with sirolimus. Pediatric transplantation 16:901-906 [PubMed: 23131059]

143.

Ballantyne CM, Podet EJ, Patsch WP, Harati Y, Appel V, Gotto AM, Jr., Young JB 1989 Effects of cyclosporine therapy on plasma lipoprotein levels. Jama 262:53-56 [PubMed: 2733125]

144.

Wissing KM, Unger P, Ghisdal L, Broeders N, Berkenboom G, Carpentier Y, Abramowicz D 2006 Effect of atorvastatin therapy and conversion to tacrolimus on hypercholesterolemia and endothelial dysfunction after renal transplantation. Transplantation 82:771-778 [PubMed: 17006324]

145.

Vaziri ND, Liang K, Azad H 2000 Effect of cyclosporine on HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, HDL receptor, VLDL receptor, and lipoprotein lipase expressions. The Journal of pharmacology and experimental therapeutics 294:778-783 [PubMed: 10900260]

146.

Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR 2012 Lipodystrophy among HIV-infected children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional study. Journal of the International AIDS Society 15:17427 [PMC free article: PMC3494170] [PubMed: 22814353]

147.

Tsiodras S, Mantzoros C, Hammer S, Samore M 2000 Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Archives of internal medicine 160:2050-2056 [PubMed: 10888979]

148.

Jones R, Sawleshwarkar S, Michailidis C, Jackson A, Mandalia S, Stebbing J, Bower M, Nelson M, Gazzard BG, Moyle GJ 2005 Impact of antiretroviral choice on hypercholesterolaemia events: the role of the nucleoside reverse transcriptase inhibitor backbone. HIV medicine 6:396-402 [PubMed: 16268821]

149.

Crouse JR, 3rd 1987 Hypertriglyceridemia: a contraindication to the use of bile acid binding resins. The American journal of medicine 83:243-248 [PubMed: 3618626]

150.

Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr., Jones DW, Materson BJ, Oparil S, Wright JT, Jr., Roccella EJ, National Heart L, Blood Institute Joint National Committee on Prevention DE, Treatment of High Blood P, National High Blood Pressure Education Program Coordinating C 2003 The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. Jama 289:2560-2572 [PubMed: 12748199]

151.

National High Blood Pressure Education Program Working Group on High Blood Pressure in C, Adolescents 2004 The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents. Pediatrics 114:555-576 [PubMed: 15286277]

152.

Libowitz MR, Nurmi EL. The burden of antipsychotic-induced weight gain and metabolic syndrome in children. Frontiers in Psychiatry. 2021 Mar 12;12:623681. [PMC free article: PMC7994286] [PubMed: 33776816]

153.

Takahashi H, Ono M, Hyogo H, Tsuji C, Kitajima Y, Ono N, Eguchi T, Fujimoto K, Chayama K, Saibara T, Anzai K, Eguchi Y 2015 Biphasic effect of alcohol intake on the development of fatty liver disease. Journal of gastroenterology [PubMed: 25733100]

154.

Pacifico L, Chiesa C, Anania C, De Merulis A, Osborn JF, Romaggioli S, Gaudio E 2014 Nonalcoholic fatty liver disease and the heart in children and adolescents. World journal of gastroenterology : WJG 20:9055-9071 [PMC free article: PMC4112863] [PubMed: 25083079]

155.

Richardson L, Paulis WD, van Middelkoop M, Koes BW 2013 An overview of national clinical guidelines for the management of childhood obesity in primary care. Preventive medicine 57:448-455 [PubMed: 23988494]

156.

Savoye M, Shaw M, Dziura J, Tamborlane WV, Rose P, Guandalini C, Goldberg-Gell R, Burgert TS, Cali AM, Weiss R, Caprio S 2007 Effects of a weight management program on body composition and metabolic parameters in overweight children: a randomized controlled trial. Jama 297:2697-2704 [PubMed: 17595270]

157.

Sunil B, Foster C, Wilson DP, Ashraf AP. Novel therapeutic targets and agents for pediatric dyslipidemia. Therapeutic Advances in Endocrinology and Metabolism. 2021 Nov;12:20420188211058323. [PMC free article: PMC8637781] [PubMed: 34868544]

158.

Park ZH, Juska A, Dyakov D, Patel RV 2014 Statin-associated incident diabetes: a literature review. The Consultant pharmacist : the journal of the American Society of Consultant Pharmacists 29:317-334 [PubMed: 24849689]

159.

De Ferranti SD, Steinberger J, Ameduri R, Baker A, Gooding H, Kelly AS, Mietus-Snyder M, Mitsnefes MM, Peterson AL, St-Pierre J, Urbina EM. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association. Circulation. 2019 Mar 26;139(13):e603-34. [PubMed: 30798614]

160.

Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, Pfeffer MA, Braunwald E 2000 VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation 102:1886-1892 [PubMed: 11034934]

161.

Triglyceride Coronary Disease Genetics C, Emerging Risk Factors C, Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ, Saleheen D, Lawlor D, Reilly MP, Hingorani AD, Talmud PJ, Danesh J 2010 Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375:1634-1639 [PMC free article: PMC2867029] [PubMed: 20452521]

162.

Wheeler KA, West RJ, Lloyd JK, Barley J 1985 Double blind trial of bezafibrate in familial hypercholesterolaemia. Archives of disease in childhood 60:34-37 [PMC free article: PMC1777065] [PubMed: 3882058]

163.

Colletti RB, Neufeld EJ, Roff NK, McAuliffe TL, Baker AL, Newburger JW 1993 Niacin treatment of hypercholesterolemia in children. Pediatrics 92:78-82 [PubMed: 8516088]

164.

Bays H 2006 Clinical overview of Omacor: a concentrated formulation of omega-3 polyunsaturated fatty acids. The American journal of cardiology 98:71i-76i [PubMed: 16919519]

165.

Harris WS 1997 n-3 fatty acids and serum lipoproteins: human studies. The American journal of clinical nutrition 65:1645S-1654S [PubMed: 9129504]

166.

Park Y, Harris WS 2009 Dose-response of n-3 polyunsaturated fatty acids on lipid profile and tolerability in mildly hypertriglyceridemic subjects. Journal of medicinal food 12:803-808 [PubMed: 19735180]

167.

Harris WS, Windsor SL, Dujovne CA 1991 Effects of four doses of n-3 fatty acids given to hyperlipidemic patients for six months. Journal of the American College of Nutrition 10:220-227 [PubMed: 1832701]

168.

Chahal N, Manlhiot C, Wong H, McCrindle BW 2014 Effectiveness of Omega-3 Polysaturated Fatty Acids (Fish Oil) Supplementation for Treating Hypertriglyceridemia in Children and Adolescents. Clinical pediatrics 53:645-651 [PubMed: 24647701]

169.

Bays HE, Braeckman RA, Ballantyne CM, Kastelein JJ, Otvos JD, Stirtan WG, Soni PN 2012 Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). Journal of clinical lipidology 6:565-572 [PubMed: 23312052]

170.

Kastelein JJ, Maki KC, Susekov A, Ezhov M, Nordestgaard BG, Machielse BN, Kling D, Davidson MH 2014 Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the EpanoVa fOr Lowering Very high triglyceridEs (EVOLVE) trial. Journal of clinical lipidology 8:94-106 [PubMed: 24528690]

171.

Harris WS 1996 n-3 fatty acids and lipoproteins: comparison of results from human and animal studies. Lipids 31:243-252 [PubMed: 8900453]

172.

Hypertriglyceridemia in Children and Adolescents. 2023 Feb 22. In: Feingold KR, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K, Hofland J, Kalra S, Kaltsas G, Kapoor N, Koch C, Kopp P, Korbonits M, Kovacs CS, Kuohung W, Laferrère B, Levy M, McGee EA, McLachlan R, New M, Purnell J, Sahay R, Singer F, Sperling MA, Stratakis CA, Trence DL, Wilson DP, editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000–. PMID: 27809432.

173.

Goldberg IJ. Hypertriglyceridemia: impact and treatment. Endocrinology and metabolism clinics of North America. 2009 Mar 1;38(1):137-49. [PubMed: 19217516]