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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 >95th %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.
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.
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 50th to 95th 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.
Table 1.
Percentile | Males | Females | ||||
---|---|---|---|---|---|---|
5-9 yrs | 10-14 yrs | 15-19 yrs | 5-9 yrs | 10-14 yrs | 15-19 yrs | |
50th | 48 | 58 | 68 | 57 | 68 | 64 |
75th | 58 | 74 | 88 | 74 | 85 | 85 |
90th | 70 | 94 | 125 | 103 | 104 | 112 |
95th | 85 | 111 | 143 | 120 | 120 | 126 |
Mean concentration of triglycerides (mg/dL). Adapted from: Tamir I, Heiss G, Glueck CJ,
Christensen B, Kwiterovich P, Rifkind B. Lipid and lipoprotein distributions in white children ages 6–19 yrs: the Lipid Research Clinics Program Prevalence Study. J Chronic Dis. 1981; 34(1):27– 39.
Table 2.
Acceptable | Borderline | High | |
---|---|---|---|
Total Cholesterol | <170 | 170-199 | ≥200 |
LDL-C | <110 | 110-129 | ≥130 |
Non-HDL-C | < 120 | ||
Triglycerides | |||
0-9 years | <75 | 75-99 | ≥100 |
10-19 years | <90 | 90-129 | ≥130 |
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 95th percentile to 500 mg/dL and higher, often secondary to an underlying disorder (43).
Gene-Environment Interaction
Heterozygous relatives of cases with autosomal recessive familial chylomicronemia carry loss-of-function mutations in genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP are generally asymptomatic. Although they have close to normal lipids they may develop severe HTG (44) when exposed to exogenous factors such as alcohol, oral estrogen treatment, obesity, and pregnancy posing a risk for acute pancreatitis (45,46). These observations suggest that adolescent carriers, such as siblings of severely affected homozygotes, should be identified by genotyping to detect carriage of a single allele. If identified as carriers, they should be advised on avoiding risk factors such as alcohol and pharmaceutical agents discussed further in this review.
Susceptibility to environmental factors is common; for example, a typical case scenario occurs in a child with a mild increase in LDL-C who develops an increase in triglyceride and non-HDL-C during adolescence. The HTG is worsened by the onset of obesity and participation in social activities involving alcohol consumption and taking oral estrogens as birth control pills. Since insulin resistance and T2D have become more common in adolescence, the gene-environment interaction results in mixed dyslipidemia (47) with variable elevations in TG and cholesterol (48). The interaction is common in cases with a pedigree suggestive of familial combined hyperlipidemia (FCHL) reported to have a prevalence of 1 per 100 and characterized by variable lipid profiles among family members with apparent dominant inheritance, but some have a high cholesterol and others have a high triglyceride or elevations in both. The phenotype has also been defined as having elevated Apo B and TG levels in at least two affected family members, and has been associated with several variants including USF1, supporting a multigenic rather than a monogenic origin as originally thought (49).
Mendelian Randomization
The important role of genetics in determining HTG associated risk is highlighted by recent Mendelian randomization studies in which individuals carrying a protective mutation were compared to unaffected carriers over a lifetime. Recent studies on loss of function APOC3 mutations are a classic example. As compared with non-carriers, carriers of APOC3 mutations had 39% lower TG levels, 16% lower LDL-C levels, and 22% higher HDL-C levels (50). The risk of coronary heart disease was reduced by 40% and was attributed to the lifetime effect of the normal or low levels. These remarkable findings were replicated in a Danish study with similar reductions in TG and cardiovascular disease in individuals with the protective APOC3 mutations (51). Randomization occurs in populations when sorted according to genotype and provides study design analogous to that used in pharmaceutical trials, but with the added benefit that exposure to lower levels of atherogenic lipoproteins in the genetically protected arm of the study begins at birth and continue over the lifespan. These landmark studies contribute evidence that a low TG and an associated improved lipid profile is beneficial, and supports interventions such as lifestyle, and pharmaceutical lowering when indicated, beginning at young ages.
DEVELOPMENTAL FACTORS
A sequence of factors, beginning during gestation, influence the development of hypertriglyceridemia (HTG) later in life (Figure 3).
Figure 3.
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.
Table 3.
Disease | TG | Chol | HDL-C | Mechanism |
---|---|---|---|---|
a) HTG (variable hypercholesterolemia) | ||||
Obesity | ++ | sdLDL + Apo B | - | Hepatic production |
Type 2 diabetes | ++ | sdLDL + Apo B | - | Hepatic production and deficient disposal |
Type 1 diabetes | + or ++ | + | - | Hepatic production and deficient disposal |
NAFLD | ++ | sdLDL | _ | Hepatic production of large VLDL |
GSD 1 | ++ | ++ | Hepatic production | |
Bile duct obstruction | +++ | LpX formation from albumin, globulin & lipids. | ||
Cushing’s disease | + | + | - | Insulin resistance effects |
Lipodystrophy | ++ | - | Secondary LPL deficiency and diabetes | |
Stress and trauma | + | + | Increased stress hormones | |
Pregnancy | + | + | Progesterone effects | |
CRI | ++ | + | - | Similar to metabolic syndrome |
HIV | + | + | Inflammation, treatments, lipodystrophy | |
Rheumatoid arthritis | + | + | Inflammation, cytokines | |
Lupus | + | + | Inflammation, cytokines | |
Gammopathies | + | + | Antibodies to LDL-R and LPL | |
b) Hypercholesterolemia (variable HTG) | ||||
Lysosomal acid lipase def. | ++ | - | Excess cholesterol synthesis (high liver enzymes and excess cholesterol storage), | |
Bile duct obstruction | +++ | LpX formation from albumin, globulin & lipids. | ||
Hypothyroidism | + | ++ | LDL receptor deficiency | |
Growth hormone deficiency | + | LDL receptor deficiency | ||
Nephrotic syndrome | + | ++ | Increased synthesis (low fatty acids) | |
Saturated and trans fats | + | Dietary excess and LDL-R down-regulation | ||
Anorexia nervosa | + | Nutrient deficiencies |
Endocrine
OBESITY
In early 2023, the AAP published a clinical pathway guideline aimed at treatment interventions for the 14.4 million children and adolescents who are now obese, noting that it is the most common chronic pediatric disease in the United States (62). It focuses on the child’s health status, family system, community context, and the resources for treatment to create the best evidence-based treatment plan. These include 13 Key Action Statements some of which pediatricians and other children healthcare providers are already engaged in including assessing for overweight/obesity, various screening including social determinants of health, and diagnostic studies. As with all children and adolescents, universal lipid screening is recommended but screening should also include screening for pre-diabetes and a hepatic profile to evaluate for the presence of fatty liver disease. Intervention can take place in the medical home or using the chronic care model, engaging in a family-centered non-stigmatizing approach. Referrals for overweight and obese children as young as 2 years-of-age may be referred for intensive health behavior and lifestyle treatment. Pharmacotherapy can be initiated by the pediatric healthcare provider at age 12 as an adjunct to health behavior and lifestyle treatment. At age 13, adolescents with BMI ≥ 120% of the 95th percentile for age and sex may be referred to metabolic and bariatric surgery programs.
Obesity has prevailed as the most prominent cardiovascular risk factor beginning in childhood and associated with dietary factors such as excessive consumption of refined carbohydrates, saturated fat and trans fatty acids which not only contribute to weight gain but also cause dyslipidemia (32). Children and adolescents are increasingly referred for obesity associated with dyslipidemia constituting HTG coupled with small dense LDL and low HDL-C (63,64), and with resistance to insulin in muscle and adipose tissue leading to increased plasma insulin and free fatty acids (65). Consumption of high amounts of carbohydrate and fat, being physically unfit, and having close relatives with similar presentations and progression to T2D or manifestations of the metabolic syndrome is often evident (66). Physical characteristics include being overweight or obese; the distribution of fat is generalized but consistently associated with an increased waist circumference, the latter strongly predicting adolescent-onset risk factors (67,68). The skin is hyper-pigmented and thickened at characteristic locations around the neck, knees, elbows, and sites of friction. This condition, called acanthosis nigricans, is associated with insulin resistance (69) and thought by many to be a central component of the metabolic syndrome for which American Indian and Hispanic ethnic groups are particularly predisposed, but Caucasians and African Americans also have high rates (69).
Resistance to insulin action results in mobilization of adipocyte TG and increased fatty acid availability for uptake by muscle and an inverse association with insulin resistance (70). The increased hepatic supply of fatty acids coupled with insulin-stimulated hepatic TG synthesis results in increased VLDL formation and HTG (71) constituting a component of Apo B-containing VLDL particles (72, 73); and increased chylomicron production contributes to the TG level (Figure 2) (74). The effect on lipoproteins is significant since it alters function in favor of atherogenesis. An entropic mechanism involves TG-rich particles exchanging their TG for cholesterol ester via cholesterol-ester transfer protein (CETP) thereby enriching LDL and HDL with TG; a process that is increased by insulin resistance (75). Both LDL and HDL become substrates for hepatic TG lipase, which is up-regulated (76) leading to formation of small dense LDL and small HDL prone to degradation (77, 78).
TYPE 2 DIABETES
Atherogenic dyslipidemia with increased triglyceride and low HDL-C precedes the onset of prediabetes and T2D in association with persisting insulin resistance (79). LDL glycation and oxidation is increased (80, 81) accounting for increased atherogenesis (82). In the Treatment Options for T2D in Adolescents and Youth (TODAY) trial, 699 adolescents were studied in three treatment groups receiving metformin alone, metformin with rosiglitazone, and metformin with intensive lifestyle. Twenty one percent (21%) had a high triglyceride or were on a lipid-lowering medication at baseline and 23% had a high level after three years. During this same period Apo B increased from a mean value of 76.6 mg/dl to 80.1 mg/dl associated with deterioration in glycemic control attributed to a decline in β-cell function. However, the intensive lifestyle arm had significantly lower TG levels after three years (83). The data indicate that T2D in youth is associated with significant cardiovascular risk and difficult to control requiring a multidisciplinary approach (84).
TYPE 1 DIABETES
Children with type 1 diabetes (T1D) tend to have elevations in TG and cholesterol when insulin is insufficient, reflecting the dependence of lipoprotein lipase on insulin for synthesis and secretion. Increased triglyceride and cholesterol correct after two weeks of intensified insulin delivery (85), and the low HDL-C increases after two months (86). When cases present with severe insulin deficiency and ketoacidosis, TG and cholesterol attain very high levels but normalize on standard treatment with insulin and intravenous fluids (87, 88). These changes reflect the role of insulin in lipoprotein lipase transcription, synthesis, and secretion. Intensified insulin delivery increases Apo A-I and HDL-C even when control of the diabetes reflected by glycosylated hemoglobin remains unchanged (89). However, the relatively normal lipid profiles seen in treated patients with T1D is a paradox since the risk for CVD persists and remains a frequent cause of death (90), but development of renal complications plays a compounding role (91). Subcutaneous insulin bypasses physiological insulin delivery to the liver, and also results in a delayed plasma insulin peak compared to physiological insulin secretion from the pancreas (92), but the resulting delay in chylomicron clearance was not found to be associated with glucose control or elevated fasting TG in adolescents. However, potentially atherogenic apoB-48 containing remnants are increased after a meal challenge (93) and increases in free fatty acids, a correlate of post-prandial TG (94), are harmful to the endothelium by inducing pro-inflammatory effects (95).
Apo C-III, a correlate of triglyceride, has been implicated in the pathogenesis of atherosclerosis (96) in hyperglycemic and insulin resistant states and may have an atherosclerotic role in T1D. The Apo C-III promoter contains both a carbohydrate response element that is responsive to glucose fluctuations (97) and an insulin response element (98) making it susceptible to both glucose fluctuations and insulin deficiency since it is normally down-regulated by insulin. Observations in patients with T1D provide supportive evidence that increased Apo C-III is associated with poor glucose control (99, 100) and being overweight (101). In the DCCT/EDIC T1D cohort with a significant adolescent aged population at onset, Apo C-III was associated with retinopathy (102) and albuminuria (103), implicating Apo C-III and associated TG-rich lipoproteins in microvascular disease (104).
LIPODYSTROPHY
Congenital and autoimmune lipodystrophies (105) are a group of genetic and acquired disorders characterized by loss of body fat, either partial or generalized (106). The degree of fat loss determines the severity of metabolic complications such as HTG, ectopic fat accumulation, insulin resistance, and progression to diabetes. Loss of adipocytes results in progressive LPL deficiency and chylomicronemia. Reduction in fat intake is effective in reducing risk for pancreatitis; however, insulin resistance and high carbohydrate intake may result in excess VLDL production requiring the use of prescription omega-3 fatty acids and fibrates. Metformin is the drug of choice for diabetes but trial evidence is lacking for the specific use of glucose-lowering agents in lipodystrophy (106). Loss of adipocytes also leads to acquired leptin deficiency and severe hyperphagia making dietary management of HTG, glucose intolerance, and overt diabetes difficult. Recent approval of recombinant leptin (metreleptin, Amylin Pharmaceuticals) has greatly improved outcomes and quality of life; treatment trials for children are in process. Although formation of leptin antibodies has attenuated the effects (107), follow-up studies suggest that low titers may not result in significant decline in the clinical response.
HYPOTHYROIDISM
Overt hypothyroidism, either autoimmune or congenital, commonly presents in childhood and at onset may be characterized by an increase in LDL-C and Apo B because of a reduced number of LDL receptors (85). In subclinical hypothyroidism the lipid profile is characterized by normal or slightly elevated total cholesterol levels and LDL-C in adults (108) but this observation has been less evident in children (109).
GROWTH HORMONE
Growth hormone deficiency and excess are both causes of hyperlipidemia. GH deficiency down-regulates the LDL receptor (110) and can result in elevations in total cholesterol and LDL-C that are reduced by treatment (111); whereas excess GH tends to mobilize fatty acids and increase VLDL triglyceride (112, 113), as seen in cases with acromegaly or gigantism in childhood.
Hepatic
NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
NAFLD, manifesting as ectopic fat deposition in the liver, is observed in obese children and adolescents in association with increased visceral fat and features of metabolic syndrome (114). The condition is associated with insulin resistance and high TG independent of intra-myocellular fat.
HEPATITIS C
Hepatitis C is associated with steatosis and a unique dysmetabolic syndrome characterized by insulin resistance, inflammation-induced atherosclerosis but a low cholesterol level.(115) The virus interferes with distal steps in cholesterol synthesis and with Apo B secretion. Risk for atherosclerosis is attributed to vascular inflammation (116, 117).
GLYCOGEN STORAGE DISEASE (GSD)
GSDs are associated with HTG (118, 119) and present as significant diagnostic and therapeutic challenges since the onset is at an early age. Type I GSD is caused by a recessively inherited defect in glucose-6-phosphatase, and accounts for more than 60% of the GSD types involving the liver and results in the highest TG levels due to excessive VLDL production. It presents during the first year of life with severe hypoglycemia and hepatomegaly caused by the accumulation of hepatic glycogen. Increased VLDL production is associated with TG-rich particles containing excess Apo C-III and Apo E (120). In addition, the metabolic consequences of impeded glucose formation and excessive anaerobic glycolysis manifest as hypoglycemia with lactic acidemia, hyperuricemia and dyslipidemia. Impaired growth factor production and acidosis result in poor growth and delayed puberty. Many of these effects, including impaired growth, can be reversed by sustained correction of hypoglycemia with dietary sources of complex carbohydrate. Restoration of euglycemia results in less stress-hormone induced stimulation of metabolic excesses derived from activated anaerobic glycolysis. Continuous complex carbohydrate feeding regimens are prescribed as frequent meals and supplementation with corn-starch. However, to effectively normalize the TG, frequent corn-starch dosing is needed to achieve blood glucose levels continuously above 75 mg/dL, especially at night. This approach involves high carbohydrate intakes, which in the long term may increase VLDL production often resulting in requirement for lipid lowering medications.
Renal
Nephrosis is associated with increased cholesterol synthesis and increased TG attributed to lipoprotein lipase inhibition (121). A two-phase dyslipidemia occurs in which TG hydrolysis by lipoprotein lipase is impaired when albumin levels are too low to remove fatty acids at an adequate rate after hydrolysis (122). Association with atherosclerosis is in part attributed to increases in Lp(a) and Apo C-III (123,124). Findings in chronic kidney disease in children resemble those in adults and simulate atherogenic dyslipidemia seen in the metabolic syndrome.
Immune
Immune causes are rare in adults and children but should be considered in specific clinical situations. HIV (human immunodeficiency virus) is associated with partial lipodystrophy and insulin resistance. The lipid profile before treatment shows a high triglyceride, low HDL-C, and small dense LDL (125), and subsequent treatment with protease inhibitors can make the situation worse (126). In gammopathies such as in Hodgkin’s disease, antibodies can sequester factors required for LPL activity (127) or they can impede lipoprotein uptake by receptors (128). Although less frequent than in adults, monoclonal or oligoclonal gammopathies, predominantly IgG mediated, occur in children with various autoimmune diseases, hematologic diseases, malignancies, transplantations, and immunodeficiencies (129).
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).
Table 4.
Medication Class | TG | TC | HDL-C | Examples |
---|---|---|---|---|
Glucocorticoids | ++ | + | + | prednisone, hydrocortisone |
Oral estrogens | + | + | + | ethinyl estradiol |
Anabolic steroids | + | + | - | depo-testosterone, oxandrolone |
Estrogen receptor blockade | + | tamoxifen | ||
Retinoids | + | - | isotretinoin | |
Immune suppressants | + | + | cyclosporine, sirolimus, tacrolimus | |
Protease inhibitors | + | - | ritonavir, nelfinovir and indinivir | |
Diuretics | ++ | - | chlorthiazide, diuril | |
Antipsychotics | + | - | clozapine, olanzapine, cimetidine | |
Beta blockers | + | - | propranolol, labetelol | |
Bile acid sequestrants | + | cholestyramine, colestipol, cholesevelam | ||
Alcohol | + | + | spirits, wines, beers |
Glucocorticoids
Glucocorticoids, especially in high doses, cause significant combined dyslipidemia and the effects on lipids may be compounded by other medications, the disease itself, or the patient’s genetic background. Lipid changes during treatment of chronic illnesses show elevations in triglyceride and LDL-C due to increased production, with variable changes in HDL-C but often increases (130). The effects may depend on the preparation used, dose and disease being treated (131). Combination drug therapy with L-asparaginase, an inhibitor of lipoprotein lipase, used for the induction phase in leukemia therapy can cause marked elevations in TG and is also diabetogenic (132). Lipid-lowering to prevent acute pancreatitis and thrombotic events is possible without stopping the chemotherapy.
Estrogens
Oral estrogens such as ethinyl estradiol usually prescribed with progestogen as oral contraceptives increase the production rate of Apo B-containing lipoproteins but the increase is counterbalanced by an increased catabolic rate (133). This finding accounts for only a slight increase in cholesterol and triglyceride within the normal range in adolescent girls (134), however interaction with obesity is possible with respect to LDL-C and fasting glucose (135). Reducing the dose of estrogen from the previously prescribed high dose preparations was effective in offsetting cardiovascular risk, however interactions with other risk factors such as smoking may occur (136).
Estrogen receptor blockade with tamoxifen has been associated with mild hyper-TG in women treated for breast cancer or its prevention, but it has rare use in childhood except for treatment of pubertal gynecomastia.
Retinoids
Retinoids such as isotretinoin (Accutane, 13-cis-retinoic acid) is indicated for treatment of severe nodular acne and can be prescribed for as long as 20 weeks, but careful monitoring is required. Severe HTG resulting from lipoprotein lipase inhibition frequently occurs, and can cause acute pancreatitis (137, 138). It acts via retinoic acid and retinoid x receptors (116) and there is also ongoing interest in use for cancer therapy and chemoprevention (139, 140).
Immune Suppressants
Cyclosporine (141), sirolimus (142), and tacrolimus are used in transplant patients and immune-mediated diseases in children requiring long term treatment and monitoring when indicated (143, 144). The mechanism is via down-regulation of hepatic 7alpha-hydroxylase and myocyte and adipocyte lipoprotein lipase down-regulation (145).
Protease Inhibitors
Protease inhibitors are associated with HTG and low HDL-C and add to the effects of the lipodystrophy syndrome occurring before anti-retroviral treatment of human immunodeficiency virus infections in pediatric cases, particularly during adolescence (146). Drugs such as ritonavir, nelfinovir and indinivir cause more severe dyslipidemia than others (147).
Nucleoside reverse transcriptase inhibitors can also cause TG and cholesterol elevations (148).
Bile Acid Sequestrants
Bile acid sequestrants should be avoided in cases with mixed dyslipidemia since they elevate TG (149). Fibrates or omega-3s, although effective in lowering TG, may transiently raise LDL-C during lipolysis of VLDL and conversion to LDL.
Diuretics
Diuretics including thiazides and loop diuretics such as furosemide alone or as combination therapy for hypertension raise cholesterol and TG and lower HDL-C in a dose dependent manner and more so in African Americans (150).
Beta-Blockers
Beta-blockers increase TG and lower HDL-C especially preparations without alpha-blocking activity but have rare indication in childhood since combination therapy for hypertension does not have trial evidence, (151) but they are used for management of arrhythmias.
Antipsychotics
Antipsychotics have pediatric psychiatric indications and agents such as clozapine and olanzapine induce HTG. However, it is not clear if the effect is independent of HTG induced by increased appetite and resulting weight gain typical of this class of medications and may require prescription changes or behavioral modification when possible (152).
Anabolic Steroids
Covert use of anabolic steroids in adolescent athletes and should be suspected with HTG and unusually low HDL-C levels. Medical use of oxandrolone for growth or androgens for aplastic anemia is rare and seldom has an indication.
Alcohol
Alcohol consumption has dyslipidemic effects, particularly with chronic use (153), and promotes development of fatty liver disease and associated HTG (154), particularly in susceptible Hispanic adolescents or in those with underlying genetic predisposition. As with steroids and estrogens, a typical presentation is with a markedly increased TG level with a higher-than-expected HDL-C (Table 4).
MANAGEMENT
General
Obesity and insulin resistance associated with dietary excess and inactivity should be assessed as potential targets in the therapeutic plan. If the identifiable cause(s) of secondary HTG cannot be corrected or optimally managed, as in patients with severe disorders or on essential drug therapy for their underlying diseases, lifestyle management is a priority. A six month trial of weight management by restricting excessive calories, saturated fat, and refined carbohydrate in the diet is recommended by the NHLBI Expert Panel (14). There is also consensus that diet, exercise and behavioral modalities should be used in combination for successful outcomes in children (155), which are dependent on self-motivation, family support, and access to skilled instruction, preferably provided by a dietitian with pediatric experience. A comprehensive team approach for use of exercise and behavioral modalities is considered optimal. Successful programs serve as role models for providers, particularly from centers with resources for team approaches similar to those designed for obesity management (156).
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.
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 95th 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.
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- ABSTRACT
- INTRODUCTION
- DIET
- TG-RICH LIPOPROTEIN COMPOSITION
- NON-HDL CHOLESTEROL IN HTG
- TG METABOLISM IN THE SETTING OF INSULIN RESISTANCE
- HTG PREVALENCE
- MEASUREMENT ASPECTS
- GENETIC BACKGROUND
- DEVELOPMENTAL FACTORS
- SECONDARY CAUSES OF HYPERTRIGLYCERIDEMIA
- PHARMACOLOGICAL CAUSES
- MANAGEMENT
- SEVERE SECONDARY HTG
- CONCLUSION
- REFERENCES
- Review Secondary hypertriglyceridemia in children and adolescents.[J Clin Lipidol. 2015]Review Secondary hypertriglyceridemia in children and adolescents.Blackett PR, Wilson DP, McNeal CJ. J Clin Lipidol. 2015 Sep-Oct; 9(5 Suppl):S29-40. Epub 2015 May 1.
- Review Triglyceride Lowering Drugs.[Endotext. 2000]Review Triglyceride Lowering Drugs.Feingold KR. Endotext. 2000
- Review Risk of Fasting and Non-Fasting Hypertriglyceridemia in Coronary Vascular Disease and Pancreatitis.[Endotext. 2000]Review Risk of Fasting and Non-Fasting Hypertriglyceridemia in Coronary Vascular Disease and Pancreatitis.Geier RR, Tannock LR. Endotext. 2000
- Review Hypertriglyceridemia: Pathophysiology, Role of Genetics, Consequences, and Treatment.[Endotext. 2000]Review Hypertriglyceridemia: Pathophysiology, Role of Genetics, Consequences, and Treatment.Subramanian S. Endotext. 2000
- Review Approach to the Patient with Dyslipidemia.[Endotext. 2000]Review Approach to the Patient with Dyslipidemia.Feingold KR. Endotext. 2000
- Secondary Hypertriglyceridemia - EndotextSecondary Hypertriglyceridemia - Endotext
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