Update on screening, etiology, and treatment of dyslipidemia in children.

S P E C I A L

F E A T U R E U p d a t e

Update on Screening, Etiology, and Treatment of Dyslipidemia in Children Vaneeta Bamba, MD1 1The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA USA

Context: Cardiovascular disease is a leading cause of morbidity and mortality. Early identification and treatment of risk factors that accelerate this condition are paramount to preventing disease. To this effect, the National Heart Lung and Blood Institute (NHLBI), endorsed by the American Academy of Pediatrics, issued updated pediatric guidelines for cardiovascular (CV) risk reduction in 2011. Integration of these guidelines into pediatric practice may lessen cardiovascular morbidity. Evidence Acquisition: In addition to reviewing the NHLBI guidelines, a detailed literature search was performed on Pub Med for clinical studies published between 2010 –2013. Key search terms included pediatric dyslipidemia/hyperlipidemia, cardiovascular disease, atherosclerosis, familial hypercholesterolemia, hypertriglyceridemia, and diabetes. Additional citations from these publications were also reviewed. Final publications were selected for their relevance to the topic. Evidence Synthesis: These guidelines contain several important recommendations relative to lipid management, including screening all children with nonfasting non-HDL- C at ages 9 –11 years, incorporation of aggressive lifestyle changes to meet cholesterol targets, and initiation of statin therapy for those with LDL-C elevation. In addition, both type 1 and type 2 diabetes are now considered high risk conditions and have stringent cholesterol targets. The primary aim is early identification of children with familial hypercholesterolemia; however, these recommendations have met with some controversy. The purpose of this update is to summarize these recent lipid guidelines, present the relevant controversies, highlight common cholesterol disorders, and discuss dyslipidemia specific to the pediatric diabetes population. Conclusion: Identification and treatment of youth with dyslipidemia is of paramount importance to the reduction of future cardiovascular disease. Increasing the comprehension and application of the newest NHLBI guidelines is critical to improving CV outcomes.

C

ardiovascular disease (CVD) is a primary cause of adult morbidity and mortality; pathologic studies have demonstrated this process begins with aortic fatty streaks in the second decade of life (1, 2). Longitudinal epidemiologic studies have demonstrated that dyslipidemia, obesity, and other risk factors in childhood predict adult CVD. Importantly, normalization of childhood risk factors can decrease or even eliminate adult risks (3–5). Non-HDL-C, calculated by subtracting the HDL-C from the total cholesterol measurement, is a reflection of highly atherogenic apolipoprotein B (ApoB) particles. Evidence

demonstrates that non-HDL-C and LDL-C track into adulthood and predict severity of atherosclerosis and adult CVD (6, 7). These principles form the basis of pediatric cholesterol screening guidelines. In 2011, the National Heart, Lung, and Blood Institute (NHLBI), backed by the American Academy of Pediatrics, issued integrated recommendations for cardiovascular risk reduction, including guidelines for management of hypertension, obesity, and hyperlipidemia (7). Specific rationale and grading of evidence may be reviewed here (8). Universal lipid screen-

ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received October 22, 2013. Accepted May 15, 2014.

Abbreviations: Cardiovascular: CV; Cardiovascular disease: CVD; LDL-C: Low Density Lipoprotein – Cholesterol; HDL-C: High Density Lipoprotein-Cholesterol; VLDL: Very Low Density Lipoprotein; T1DM: Type 1 Diabetes Mellitus; T2DM: Type 2 Diabetes Mellitus

doi: 10.1210/jc.2013-3860

J Clin Endocrinol Metab

jcem.endojournals.org

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 08 June 2014. at 11:32 For personal use only. No other uses without permission. . All rights reserved.

1

2

Update: Dyslipidemia in Children


ing should be performed with measurement of nonfasting non-HDL-C in all children between ages 9 –11 and 17–21 years. Those with abnormal levels (Table 1) should have two additional fasting lipid profiles measured 2 weeks to 3 months apart and averaged. Abnormal levels are then stratified by LDL-C, TG levels and risk factors (Table 2). The guidelines offer comprehensive recommendations for evaluation and treatment of dyslipidemia, which start with lifestyle modification for 6 months. If LDL-C remains ⱖ 130 mg/dl after lifestyle modifications in an individual with additional risk factors, medication may be considered (Table 3). Persistent elevation of LDL-C level ⱖ 190 mg/dl suggests a genetic etiology and statin therapy is advised. Guidelines for triglyceride (TG) lowering are primarily geared towards diet and lifestyle changes. Pediatric treatment guidelines are focused on prevention of pancreatitis and medication is currently indicated only for those with severe hypertriglyceridemia. The aim of this update is to review the relevant discussions on evaluation and treatment of dyslipidemia in children, highlight cholesterol disorders that may be uncovered by the new screening guidelines, and review dyslipidemia in the pediatric diabetes population. Controversial Aspects of Screening Recommendations Cholesterol screening recommendations in youth have been debated for decades, but these are the most aggressive recommendations to date. The screening guidelines are thorough by suggesting targeted screening for those at risk as well as universal screening at two different ages. The primary goal of universal screening is to identify those with familial hypercholesterolemia (FH), a condition without identifiable risk factors except family history. It has been shown that family history is incomplete in young individuals, since parents and even grandparents may be too young to have demonstrated early CVD. One study

showed that 1.2% of children with family history vs 1.7% of children without qualified for pharmacotherapy for dyslipidemia (9). The second goal of universal screening is to use non-HDL-C to identify children with components of metabolic syndrome in an effort to highlight and prevent progression of additional components. These are two key pediatric populations that benefit from early recognition and management of cholesterol abnormalities. There are several practical critiques. First, the guidelines do not adequately define the risk to benefit ratio, particularly regarding moderate dyslipidemia (10). Mild to moderate dyslipidemia may not persist into adulthood and unnecessary therapy may have adverse effects. Although proven safe and effective in adults, there is a paucity of long-term pediatric data on statin therapy. Statin trials have primarily included children with known highrisk disease such as familial hypercholesterolemia and studies have been limited in duration. Second, screening may potentially lead to anxiety in patients and families because of multiple blood draws, the label of a chronic medical condition, the stress of undergoing lifestyle and behavior modification, and possible contribution to eating disorders (11, 12). Lastly, there is consideration of financial costs, which include repeated lipid measurements, additional medical visits, and intervention with counseling, nutrition referrals, and medications (10 –15). Information on costs of screening for FH and metabolic syndrome in youth in the United States is incomplete. A cascade screening program for FH in the Netherlands demonstrates that newly identified individuals gain 3.3 years of life. For every 100 people treated, 26 myocardial infarcts were prevented, and there was an average lifetime cost of $8700 per year gained (15, 16). The modifiable outcome of metabolic syndrome is diabetes. One group estimates lifetime direct costs of type 2 diabetes in those diagnosed at ages 25– 44 years is between $124K and 130K (17). Therefore, economic considerations are rele-

Table 1. NHLBI Cholesterol Screening Guidelines and Cut Points Adapted from(7) 1. All children should have a nonfasting lipid profile measured between ages 9 –11 yr and again 17–21 yr of age. 2. If abnormal, then repeat fasting lipid profile 2 weeks to 3 months apart

Total Cholesterol LDL-Cholesterol Non-HDL-Cholesterol Triglycerides Age 0 –9 yr Age 10 –19 yr HDL-Cholesterol

Acceptable

Borderline1

Abnormal2

⬍170 mg/dl ⬍110 mg/dl ⬍120 mg/dl

170 –199 mg/dl 110 –129 mg/dl 120 –144 mg/dl

ⱖ200 mg/dl ⱖ130 mg/dl ⱖ145 mg/dl

⬍75 mg/dl ⬍90 mg/dl ⬎45 mg/dl

75–99 mg/dl 90 –129 mg/dl 40 – 45 mg/dl

ⱖ100 mg/dl ⱖ130 mg/dl ⬍40 mg/dl

1

Borderline values represent the 75th percentile, except for HDL-C, which represents the 10th percentile.

2

Abnormal values represent the 95th percentile, except for the HDL-C, which represents the 10th percentile.

To convert to SI units, divide Total Cholesterol, LDL-C, HDL-C, and non-HDL-C by 38.6; For triglycerides (TG), divide by 88.6.


doi: 10.1210/jc.2013-3860

Table 2.

Risk Factors for CVD Adapted from(7) Family History ● Parent, Grandparent, Aunt, Uncle, sibling with any of the following before age 55 yr in a male or before age 65 yr in a female: myocardial infarction, stroke, angina, coronary artery bypass, stent, angioplasty, sudden cardiac death ● Parent with TC ⬎240 mg/dl or known dyslipidemia High Risk Conditions ● Diabetes Mellitus-Type 1 and Type 2 ● Chronic Renal Disease/end stage renal disease/post renal transplant ● Postorthotopic Heart Transplant ● Kawasaki Disease with current aneurysms Moderate Risk Conditions ● Chronic Inflammatory Disease ● Systemic lupus erythematosus ● Juvenile inflammatory arthritis ● Kawasaki Disease regressed coronary aneurysms ● Nephrotic Syndrome ● HIV Infection High-Level Risk Factors ● Hypertension (BP ⱖ 99th%tile ⫹ 5 mm Hg) requiring medication ● Cigarette smoker ● BMI ⬎ 97th percentile ● Presence of high-risk condition(s) Moderate-Level Risk Factors ● Hypertension not requiring medication ● BMI ⱖ95- ⬍97th percentile ● HDL ⬍40 mg/dl ● Presence of moderate risk condition(s)

vant and we need additional studies to properly project


3

estimates of pediatric universal screening, evaluation, and treatment. Placebo-controlled studies to assess statin efficacy are unlikely to be done at this stage given known benefits but long term, prospective studies of guideline implementation will be informative. The impact of diet and lifestyle modification is unclear. Importantly, this should be identified as a teaching moment - an opportunity to educate families as well as redirect anxiety that may come from universal screening. Longitudinal studies demonstrate that interventions in youth are effective in prevention of adult disease (3, 4, 18).. For some, this provides tangible evidence that even minimal lifestyle modifications may delay or prevent devastating adult conditions. Other Considerations Many youth are anticipated to have abnormal lipid levels uncovered by this screening. Data from the National Health and Nutrition Examination Survey suggests that 20- 25% of children would qualify for retesting of their cholesterol levels; an estimated 0.85% would be considered for statin medication (19). Obese children are more likely than nonobese (3.1 vs. 0.6%) to need statins, although this includes children who may respond to lifestyle changes alone (20). Some question the validity of placing this otherwise healthy population under such scrutiny. Conversely, there is lack of consensus on how aggressive to be even with high risk populations, such as those with diabetes (see “Diabetes Mellitus – A High Risk Condition”). The concept of prescribing statins is daunting for most pediatricians. Until now, training in its management has been limited, as dyslipidemia has been considered an adult disorder. The recommendations are written to provide guidance, but children should be assessed practically and age appropriately. It may be reasonable to monitor children with mild to moderate dyslipidemia who have no other risk factors, with close attention to family history and subsequent risk for developing additional associated conditions. The lipid guidelines are only one aspect of overall cardiovascular risk factor reduction; weight, blood pressure (BP), physical activity, and other factors are also critical to CVD risk, and the NHLBI guidelines address these issues as well. Etiology of Hyperlipidemia This section briefly reviews common and important primary disorders of cholesterol metabolism. A full review of dyslipidemia may be found separately (21). Correction of secondary causes (Table 4) should normalize lipid levels if not compounded by underlying genetic factors.


4


Table 3.


Criteria for Pharmacotherapy of Dyslipidemia - Adapted from(7) Elevation in LDL-C LDL-C ⱖ 190 mg/dl Lifestyle changes ⫻ 6 months (may be abbreviated) Consider statin therapy after age ⬎ 10 yr or after Tanner 2 in boys, post menarche in girls LDL-C ⱖ 130 –189 mg/dl with no Family History or Risk Factors/Conditions Lifestyle changes Reassess every 6 –12 months LDL-C ⱖ 160 –189 mg/dl with ⴙ Family History or 1 High-Level Risk Factor/Condition or ⱖ2 Moderate-Level Risk Factors/Conditions Lifestyle changes ⫻ 6 –12 months Consider statin therapy after age ⬎ 10 yr or after Tanner 2 in boys, post menarche in girls LDL-C ⱖ 130 –159 mg/dl with Clinical CVD OR 2 High-Level Risk Factors/Conditions OR (1 High-Level Risk Factor/Condition and 2 Moderate Level Risk Factors/Conditions) Lifestyle changes ⫻ 6 –12 months Consider statin therapy after age ⬎ 10 yr or after Tanner 2 in boys, post menarche in girls Elevation in Triglycerides TGs ⱖ 500 mg/dl Lifestyle Changes* Counsel on risk of pancreatitis Referral to lipid specialist Fish oil, fibrate/other medication TG ⬎ 200 – 499 mg/dl Lifestyle changes* 6 –12 months Consider Omega ⫺3 fish oil therapy Consider referral to lipid specialist, especially if LDL-C target achieved TG ⱖ 100 –200 mg/dl (⬍10 yr) or ⱖ 130 –200 mg/dl (⬎10 yr) Lifestyle changes* ⫻ 6 –12 months Increase dietary fish content Fasting Lipid panel every 6 months TG ⬍ 100 mg/dl (⬍10 yr) or ⬍130 (⬎10 yr) Continue Lifestyle changes* Fasting lipid panel annually

*Lifestyle changes: Diet and Physical Activity Diet: CHILD-1 diet for 3– 6 months. If no improvement in lipids, then CHILD-2 Diet Physical Activity: Vigorous activity 60 min a day ⫹ screen time (television, texting, computer, etc.) limited to less than 2 h per day.

Familial Hypercholesterolemia (FH) A child with significant and isolated elevation of LDLC ⱖ 160 mg/dl should be considered to have FH, particularly if there is family history of early CVD. This is an important diagnosis as risk of premature coronary artery disease (CAD) is substantially elevated compared to the general population. The National Lipid Association has published recommendations for diagnosis and management of this condition (22).. FH is a monogenic, autosomal dominant disorder due to mutations of the LDL receptor (LDLR) or a component affecting LDLR activity (22–24). Patients with heterozygous FH often have CV events such as myocardial infarction (MI), stroke, and renal artery stenosis prior to age 50. Homozygous FH (HoFH), evidenced by extremely elevated LDL-C levels, is associated with rapidly progressive atherosclerosis, CV events and mortality in the first two

decades of life. Heterozygous FH affects approximately 1 in 500 individuals in the United States while HoFH occurs in 1 in 106. Early detection is critical to early intervention; diagnosis of FH is possible in early childhood, but will be unrecognized if LDL-C is not measured, especially in patients whose parents are unaware of their own diagnosis due to young age or lack of assessment. It is worrisome that some may escape diagnosis until the time of a CV event (25). A clinical diagnosis of FH can be made when there are more than two first degree relatives with characteristic LDL-C levels (with or without premature CVD) or by the presence of tendon xanthomas. Notably, xanthomas are rarely seen in children and adolescents. After diagnosis, cascade screening should occur in all first degree relatives after age 2 years and appropriate treatment pursued. As a condition of early atherosclerosis, lipid goals in-


doi: 10.1210/jc.2013-3860

Table 4. Common Causes of Secondary Dyslipidemia Adapted from(7) Endocrine/Metabolic Diabetes -- Type 1, Type 2 Hypothyroidism Polycystic ovarian syndrome Lipodystrophy Klinefelter Syndrome Glycogen Storage Disease Gaucher Disease Niemann Pick Disease Cardiac Kawasaki Disease Orthotopic heart transplant Rheumatologic Juvenile Inflammatory arthritis Systemic lupus erythematous Gastrointestinal Obstructive liver disease/other cholestatic conditions Alagille syndrome Biliary cirrhosis Hepatitis Renal Nephrotic syndrome Chronic renal disease Renal transplant Medications/Exogenous Glucocorticoids Isotretinoin Oral contraceptive therapy ␤ blockers Antipsychotics Alcohol

clude LDL-C ⱕ 130 mg/dl, lower if there are additional CVD risk factors (22). Treatment of heterozygous FH prior to puberty is focused on lifestyle changes. After puberty, treatment with statins may be indicated. Crucially, individuals with HoFH should be evaluated by a lipid specialist and statins started earlier due to substantially earlier


5

risk of CAD. LDL apheresis and/or liver transplant have been the historical treatment in this subset, although efficacy and success is variable. Novel medical therapies for adults with HoFH have recently been approved in the US (26, 27). Hypertriglyceridemia Mild to Moderate Hypertriglyceridemia (TG 150 –500 mg/dl) Identification of hypertriglyceridemia is common, particularly in youth with diabetes, overweight, and obesity. Secondary causes of TG elevation such as hypothyroidism, polycystic ovarian syndrome, and medication effects (eg, oral contraceptives and isotretinoin), should be assessed. Treatment or amelioration of secondary causes is generally effective in normalizing TG levels when not compounded by inherited disorders. In the setting of obesity, TG management is primarily aimed at weight control. Reduced caloric intake and increased exercise are associated with a significant reduction and stabilization of TG as well as elevation of HDL-C (28). Severe Hypertriglyceridemia (TG > 500 mg/dl) Severe hypertriglyceridemia is less common. Of 300 hypertriglyceridemia patients followed at one pediatric preventive cardiology clinic, 7% had TG above 400 mg/dl, and 2% above 1000 mg/dl (29). Patients with severe hypertriglyceridemia are more likely to have a defect in lipoprotein lipase (LPL). Inherited defects in the LPL gene, its associated apolipoproteins (ApoC2, Apo E, ApoC5) or in GH1HBP1, an endothelial binding site for LPL, have all been shown to cause defective LPL activity (30, 31). In these conditions, TG may rise up to 10,000 mg/dl. Complete defects are extremely rare and typically present early in life. Partial defects of LPL are also uncommon but may be unmasked by a secondary cause. Therapy is aimed at prevention of pancreatitis, which is associated with severe hypertriglyceridemia and postprandial TG excursions. Patients with TG ⱖ 500 mg/dl should be prudently counseled on the symptoms of pancreatitis (nausea, vomiting, and abdominal pain, especially after a high fat meal). Treatment is generally focused on limiting fat intake. Unfortunately, even extreme fat-restricted diets may not be effective prevention. Familial Combined Hyperlipidemia (FCHL) FCHL is characterized by a mixed dyslipidemia, (high risk of) premature CVD and a vertical transmission profile (32). The LDL-C and TG may be high or normal, HDL-C can be normal or reduced, and there is significant production of small, dense LDL particles. Contrary to FH, FCHL


6


is less likely to be diagnosed in children because LDL-C elevations may not occur until after adolescence. At a prevalence of 1%–2%, particularly among those with early CVD, this is one of the most common inherited dyslipidemia syndromes (32). Uniquely, there may be significant heterogeneity even within a single family. The pathophysiologic hallmark of FCHL is overproduction of VLDL-C. Circulating ApoB levels may rise before cholesterol levels, so in those with family history of early CV events, measurement of ApoB levels may be a better marker for this condition. In adults, FCHL is often associated with features of metabolic syndrome. Given the common association of insulin resistance and VLDL overproduction in both disorders, some suggest that FCHL is a continuum that progresses into metabolic syndrome and then type 2 diabetes (T2DM) (33). Several genetic loci have been associated with ApoB regulation and T2DM, including Upstream Stimulating factor 1 (USF1), Transcription factor 7-Like 2 (TCF7L2), and Hepatocyte Nuclear factor 4 –alpha (HNF4␣) (34, 35). Most groups agree that the FCHL phenotype is likely polygenic, or at least pleiotropic. Treatment is related to lifestyle changes and obesity management to reduce comorbidities. If FCHL, metabolic syndrome and T2DM are on the same spectrum, then early diagnosis and treatment are critical. Treatment of Dyslipidemia Lifestyle Changes Lifestyle changes are the core of dyslipidemia treatment. This includes physical activity 60 minutes a day, screen time ⱕ 2 hours/ day, attainment of ideal body weight (BMI ⱕ 85th%tile for age and gender) and optimization of BP. Dietary therapy is initiated with the Cardiovascular Health Integrated Lifestyle Diet-1 (CHILD-1) for 3– 6 months, which includes total fat less than 30% of daily caloric intake, saturated fat 8%–10%, avoidance of trans fats, and cholesterol intake less than 300 mg/d. This may be advanced to a CHILD-2 diet specific to LDL or TG elevation (below), which includes further restriction of saturated fat less than 7% and cholesterol intake less than 200 mg/d. This safe and effective diet is associated with normal growth and development in children as early as 6 –7 months of age (7). For LDL-C reduction, water-soluble fiber and plant sterols may complement the CHILD-2 diet. Intake of psyllium 6 g/d for children 2–12 years and 12 g/d for those above 12 years can modestly lower LDL-C levels by approximately 7% (36). Plant sterols and plant stanol esters compete with cholesterol for intestinal absorption via Niemann-Pick C1-Like Protein (NPC1L1). Plant sterols can be taken as supplements or found in specially formulated


foods. Doses of up to 2 g/d have been demonstrated to reduce LDL-C by 10%–15%. Intake of 2–3 g/d may slightly reduce alpha and beta carotene absorption, but a daily multivitamin or increased fruit and vegetable intake will prevent this. Absorption of vitamin D and A have not been affected. Individuals with elevation in TG should follow the CHILD-2 TG diet with a focus on sugar reduction; plant sterols are not indicated. Simple sugars should be replaced with complex carbohydrates, sugar sweetened beverages eliminated, and consumption of fish encouraged to increase omega-3 fatty acid intake. For obese children, nutrition therapy should include calorie restriction and ageappropriate increased physical activity. For those with severe hypertriglyceridemia, intake is restricted to an ultralow fat diet containing less than 10% total fat. This should be implemented and followed under the guidance of a pediatric nutrition expert to assure adequate essential fatty acid and caloric intake. Unfortunately, even extreme fat-restriction may not be effective prevention. Pharmacologic Treatment of Hypercholesterolemia If lifestyle changes over 6 –12 months are inadequate to achieve target LDL-C levels, medication may be indicated in children above the age of 10 years (Table 3). Guidelines for pharmacotherapy of pediatric dyslipidemia were published in 2007 (7, 37). Consultation with a lipid specialist may be considered. Statin therapy in children with FH has been shown to reduce LDL-C by 20%– 40% (38, 39). Though limited in number, enrollment, and duration, statins have been demonstrated to be safe, well-tolerated and efficacious in children. Statins that are FDA-approved in children include pravastatin, simvastatin, lovastatin, atorvastatin, and fluvastatin. While adult guidelines do not recommend routine screening of liver and muscle enzymes while on statin therapy, pediatric guidelines have not followed suit. Adult guidelines are based on study populations that rarely include children, so conservative approaches in pediatrics may be appropriate. In youth, statins should be started at the lowest dose with baseline measurements of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine kinase (CK) performed. These levels plus a fasting lipid profile should be repeated four and eight weeks after initiation of therapy and then every 3– 6 months (37). If liver enzymes are above 3 times the upper limit of normal (ULN), if CK is above 10 times ULN, or the patient reports any adverse effects, medication should be stopped to determine if there is improvement. Importantly, statins may be teratogenic, so females should be


doi: 10.1210/jc.2013-3860

counseled and prescribed contraceptive therapy when indicated. Target LDL-C is typically below 130 mg/dl, but ideally under 100 mg/dl in high risk populations such as FH. If target levels are not achieved within 3 months, the dose can be incrementally increased to maximum dose. Occasionally, a second agent such as a bile acid sequestrant (BAS) may be useful (40). Multiple drug therapy should be guided by a lipid specialist. Pharmacologic Treatment of Hypertriglyceridemia Treatment of hypertriglyceridemia is primarily driven towards lifestyle changes delineated above. Historically, the influence of hypertriglyceridemia on atherosclerotic lesions has been less clear. Only recently has there been evidence that triglyceride elevations may predispose to atherosclerosis and CVD independent of metabolic risks (41– 43). For severe hypertriglyceridemia, pharmacologic therapy is limited and treatment should be guided by a lipid specialist. While omega-3 fatty acids in the form of DHA and EPA at 2– 4 g daily have been shown in adults to lower TG by 20%–30% (44), prescription forms of omega-3 fatty acids are not currently FDA approved for children. Fibrates and niacin lower TG levels via modulations of LPL and thus may be largely ineffective in those with defective LPL activity. Orlistat, a pancreatic lipase inhibitor, was combined with a very low fat diet in 2 siblings with compound heterozygous mutations in LPL. Three years of treatment led to reduction of fasting TG below 600 mg/dl and recurrent pancreatitis had all but resolved (45). Novel treatment for inherited defects of LPL via gene therapy has been approved in Europe. Alipogene tivarovec contains a gain of-function LPL variant and short term trials show improved postprandial chylomicron metabolism and metabolic parameters (46). Diabetes Mellitus – A High Risk Condition Previously, type 1 diabetes (T1DM) was labeled a high risk condition for CVD whereas T2DM was conferred a moderate risk. Now, T1DM and T2DM are both accorded the highest possible risk classification and considered a CVD equivalent (7, 47). Diabetes is associated with more severe and earlier onset of CVD compared to the general population. Despite clinical and etiologic distinction, both forms are associated with vascular damage and accelerated atherosclerosis. Long term studies of complications in early onset diabetes remain limited in scope, but outcome is particularly worrisome since incidence of diabetes is increasing and macrovascular complications correlate with duration of diabetes as well as glycemic control.


7

type 1 Diabetes Mellitus (T1DM) The leading cause of death in adults with T1DM is CAD, despite similar or less atherogenic profiles when compared to age-, sex-, and BMI-matched controls (48, 49). This is one of the rare important instances, like HoFH, when CVD presents in childhood. While the etiology remains enigmatic, glycemic control, hypertension, nephropathy, and dyslipidemia at least contribute to this process. Relative insulin deficiency increases hepatic release of VLDL and subsequent elevation in TG and LDL. Therefore, prevention of dyslipidemia is partly related to glycemic control; long term studies have shown that improved glucose control is beneficial (50, 51). However, intensive glucose management has its drawbacks, including weight gain and hypoglycemia, as evident in adult studies (52). Individuals with T1DM are more likely to be overweight (53). Metabolic risk factors may be lower in the T1DM group than in matched overweight nondiabetics (54, 55); however, as insulin sensitivity decreases, adolescents with T1D develop more atherogenic risk factors while those with the highest markers of insulin sensitivity have a risk profile comparable to the nondiabetic adolescent (56). Endothelial dysfunction in DM appears to be present as early as preadolescence, and pulse wave velocity as a measure of arterial stiffness has been shown to worsen with increase in LDL-C, adiposity, and glycemic control (57). Optimization of these parameters may improve outcomes; therefore, reduction of LDL-C is another focus of therapy. Total cholesterol and non-HDL-C are higher in children with type 1 diabetes than the general population (58). One group identified that 31% of their T1DM population had LDL-C levels ⱖ 100 mg/dl (53). Interestingly, a recent study showed that cholesterol synthesis in T1DM is not elevated compared to nondiabetic subjects (59), suggesting that enhanced cholesterol absorption may be a significant but modifiable contributor to dyslipidemia in T1DM. If substantiated, the role of cholesterol absorption inhibitors (CAI) may become more prominent. One small study showed additional 15%–16% reduction in both LDL-C and non-HDL-C levels in T1DM patients who had CAI added to statin therapy (60). Levels of HDL-C have been shown paradoxically elevated in T1DM compared to the general population. There is much speculation about the mechanism and relevance of this, but prospective studies have not consistently identified this as a significant cause for CVD events (61). type 2 Diabetes (T2DM) The increased prevalence of obesity in youth has led to an increase in T2DM in adolescents. Duration of disease


8


and glycemic control are important factors in development of long term complications. Despite increasing incidence of T2DM in youth, many targeted medications are not approved in adolescents and there is little data to guide treatment strategies. The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study group was created with this goal in mind. Recently, three year data became available and show disheartening results. Loss of glycemic control (defined as hemoglobin A1c ⱖ 8%) occurred in 52%, 39%, and 47% of participants assigned metformin, metformin ⫹ rosiglitazone, and metformin ⫹ lifestyle intervention, respectively (62). Data regarding lipid outcome was also disappointing. Dyslipidemia was present at baseline and worsened over 36 months. Prevalence of elevated LDL-C (ⱖ130 mg/dl) and treatment for hyperlipidemia increased from 4.5% to 10.7%, with fewer individuals maintaining LDL-C below 100 mg/ dl. Only 10 of the 46 statin-treated patients achieved target LDL-C level. Prevalence of triglyceride abnormalities rose from 21% to 23% (63). Of note, highly atherogenic, small, dense LDL particles did decline somewhat. Studies in adults with diabetes demonstrate that optimal statin therapy lowers LDL-C and improves cardiovascular risk. In fact, the American Heart Association revised adult guidelines in 2013 and controversially eliminated specific LDL-C targets, instead recommending high dose statin therapy in all diabetes patients over age 40 years, earlier for those with evidence of CV disease (64). Pediatric recommendations do not reflect this very recent change yet. However, the inability to improve dyslipidemia in youth over the short term in a randomized, controlled study bodes poorly for the future. Management of Dyslipidemia in Diabetes Despite the association with CVD, many adults and children with diabetes have been shown to have suboptimal lipid management (53, 65). The target LDL-C is below 130 mg/dl, ideally below 100 mg/dl. Aggressive management strategies are advocated in pursuit of this goal. Like the NHLBI, the American Diabetes Association (ADA) guidelines for pediatrics do not distinguish between T1DM and T2DM. A fasting lipid panel should be obtained at age ⱖ 10 years (at puberty) in those without family history of hypercholesterolemia or early CVD; in those with family history or known CV risk factors, lipid screening should be performed once glycemic control has been achieved in all children after the age of 2 years (68). From here, the ADA guidelines diverge slightly from the NHLBI in this high risk population. The ADA guidelines state that if LDL-C is greater than 130 mg/dl with one or more CVD risk factors or LDL-C is above 160 mg/dl with no risk factors, efforts should focus on optimal glycemic


control and overall lifestyle changes; lipid panel should be repeated annually (66). Adjunctively, other comorbidities of diabetes should be addressed. If target LDL-C levels are not met, then statin therapy may be indicated after the age of 10 years. This divergence leaves LDL-C levels between 130 –160 mg/dl open to interpretation. Many are following the more aggressive NHLBI guidelines in this youthful, high risk population. It may be reasonable to monitor these patients closely if glycemic control is optimal and there are no other risk factors. It may also be sensible to delay statin therapy if there is an opportunity to optimize glycemic control and comorbidities. However, relatives may be too young to have a known history of early CVD, so detailed family history should be revisited at every opportunity. Updated guidelines for cardiovascular risk reduction specific to children with type 1 diabetes are in press at the time of this publication, so it is hopeful that this divergence will be addressed. Only one completed pediatric statin trial in T1DM was identified. In a population with low risk LDL-C, atorvastatin led to modest reductions in LDL-C and possible benefits of reduced arterial stiffness (67). Another group initiated a trial of statin plus cholesterol absorption inhibitor in children and adolescents, but of 109 eligible candidates, only 9 were actually enrolled (68). Large, prospective study data may be forthcoming, including information from an international multicenter study of statin and antihypertensive therapies, as well as from a T1DM registry in the United States (69, 70). It is anticipated that these large studies may provide additional evidence for recommendations in this field of tremendous uncertainty. Clearly, there is a distinct need for additional studies in youth with diabetes to assess efficacy of therapy as well as impact on coronary end points. Conclusions Early recognition and treatment of dyslipidemia in children may lead to modification of risk factors that contribute to adult CVD. Aggressive management should continue to focus on youth with high risk conditions associated with accelerated atherosclerosis, but prevention of additional risk factors is also key. As we address lipid abnormalities in youth, outcome data must be tracked meticulously so that guidelines may be revised accordingly to optimize the risk to benefit ratio. Prevention of disease states such as T2DM is just as critical as early identification of genetic disorders in improving quality of life (QOL) as well as reducing cardiovascular morbidity.

Acknowledgments The author expresses sincere gratitude to Daniel Rader, MD for critical review of the manuscript, as well as to Sara Pinney, MD


doi: 10.1210/jc.2013-3860

and Shana McCormack, MD for helpful suggestions and review of earlier versions of the manuscript. Address all correspondence and requests for reprints to: Vaneeta Bamba, MD, Division of Endocrinology, Children’s Hospital of Philadelphia, 34th and Civic Center Blvd, Philadelphia, PA 19104, (T) 215–590-3174, (F) 215–590-3053, [email protected]. Disclosures: None Clinical Trial Registration Number: N/A Update on Screening, Etiology, and Treatment of Dyslipidemia in Children This work was supported by Grant Support: N/A.

References 1. Berenson, G.S., Srinivasan, S.R., Bao, W., Newman, W.P., 3rd, Tracy, R.E., and Wattigney, W.A. Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. The Bogalusa Heart Study. N Engl J Med. 1998;338:1650 – 1656. 2. McGill, H.C., Jr., McMahan, C.A., Zieske, A.W., Sloop, G.D., Walcott, J.V., Troxclair, D.A., Malcom, G.T., Tracy, R.E., Oalmann, M.C., and Strong, J.P. 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. Arterioscler Thromb Vasc Biol. 2000;20:1998 – 2004. 3. Juonala, M., Magnussen, C.G., Berenson, G.S., Venn, A., Burns, T.L., Sabin, M.A., Srinivasan, S.R., Daniels, S.R., Davis, P.H., Chen, W., et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med. 2011;365:1876 –1885. 4. Juonala, M., Viikari, J.S., and Raitakari, O.T. Main findings from the prospective Cardiovascular Risk in Young Finns Study. Curr Opin Lipidol. 2013;24:57– 64. 5. McGill, H.C., Jr., McMahan, C.A., Zieske, A.W., Malcom, G.T., Tracy, R.E., and Strong, J.P. Effects of nonlipid risk factors on atherosclerosis in youth with a favorable lipoprotein profile. Circulation. 2001;103:1546 –1550. 6. Frontini, M.G., Srinivasan, S.R., Xu, J., Tang, R., Bond, M.G., and Berenson, G.S. Usefulness of childhood non-high density lipoprotein cholesterol levels versus other lipoprotein measures in predicting adult subclinical atherosclerosis: the Bogalusa Heart Study. Pediatrics. 2008;121:924 –929. 7. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics 128 Suppl 2011;5:S213–256. 8. Gidding, S.S., Daniels, S.R., and Kavey, R.E. Developing the 2011 Integrated Pediatric Guidelines for Cardiovascular Risk Reduction. Pediatrics. 2012;129:e1311–1319. 9. Ritchie, S.K., Murphy, E.C., Ice, C., Cottrell, L.A., Minor, V., Elliott, E., and Neal, W. Universal versus targeted blood cholesterol screening among youth: The CARDIAC project. Pediatrics. 2010; 126:260 –265. 10. de Ferranti, SD, Daniels, S.R., Gillman, M., Vernacchio, L., Plutzky, J., and Baker, A.L. NHLBI Integrated Guidelines on Cardiovascular Disease Risk Reduction: can we clarify the controversy about cholesterol screening and treatment in childhood? Clin Chem. 2012; 58:1626 –1630. 11. Newman, T.B., Pletcher, M.J., and Hulley, S.B. Re: Childhood lipid screening: evidence and conflicts. Pediatrics. 2013;131:e1385– 1386. 12. Newman, T.B., Pletcher, M.J., and Hulley, S.B. Overly aggressive


13.

14.

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

25.

26.

27.

28.

9

new guidelines for lipid screening in children: evidence of a broken process. Pediatrics. 2012;130:349 –352. Brown, WV, McNeal, C.J., and Gidding, S.S. Screening and management of cardiovascular risk factors in children. J Clin Lipidol. 2013;7:390 –398. McCrindle, B.W., Kwiterovich, P.O., McBride, P.E., Daniels, S.R., and Kavey, R.E. Author’s response. Universal lipid screening: in response to ongoing debate. Pediatrics. 2013;131:e1387–1388. McCrindle, B.W., Kwiterovich, P.O., McBride, P.E., Daniels, S.R., and Kavey, R.E. Guidelines for lipid screening in children and adolescents: bringing evidence to the debate. Pediatrics. 2012;130: 353–356. Wonderling, D., Umans-Eckenhausen, M.A., Marks, D., Defesche, J.C., Kastelein, J.J., and Thorogood, M. Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands. Semin Vasc Med. 2004;4:97–104. Zhuo, X., Zhang, P., and Hoerger, T.J. Lifetime Direct Medical Costs of Treating Type 2 Diabetes and Diabetic Complications. American journal of preventive medicine. 2013;45:253–261. Kaikkonen, J.E., Mikkila, V., Magnussen, C.G., Juonala, M., Viikari, J.S., and Raitakari, O.T. Does childhood nutrition influence adult cardiovascular disease risk?–insights from the Young Finns Study. Ann Med. 2013;45:120 –128. Centers for Disease Control and Prevention (CDC). 2010. Prevalence of abnormal lipid levels among youths — United States, 1999 – 2006. MMWR Morb Mortal Wkly Rep 59:29 –33. McCrindle, B.W., Tyrrell, P.N., and Kavey, R.E. Will obesity increase the proportion of children and adolescents recommended for a statin? Circulation. 2013;128:2162–2165. Kwiterovich, P.O., Jr. Diagnosis and management of familial dyslipoproteinemias. Curr Cardiol Rep. 2013;15:371. Goldberg, A.C., Hopkins, P.N., Toth, P.P., Ballantyne, C.M., Rader, D.J., Robinson, J.G., Daniels, S.R., Gidding, S.S., de Ferranti, SD, Ito, M.K., et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S1– 8. Usifo, E., Leigh, S.E., Whittall, R.A., Lench, N., Taylor, A., Yeats, C., Orengo, C.A., Martin, A.C., Celli, J., and Humphries, S.E. Lowdensity lipoprotein receptor gene familial hypercholesterolemia variant database: update and pathological assessment. Ann Hum Genet. 2012;76:387– 401. van der Graaf, A., Avis, H.J., Kusters, D.M., Vissers, M.N., Hutten, B.A., Defesche, J.C., Huijgen, R., Fouchier, S.W., Wijburg, F.A., Kastelein, J.J., et al. Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. Circulation. 2011;123:1167–1173. Avis, H.J., Kusters, D.M., Vissers, M.N., Huijgen, R., Janssen, T.H., Wiegman, A., Kindt, I., Kastelein, J.J., Wijburg, F.A., and Hutten, B.A. Follow-up of children diagnosed with familial hypercholesterolemia in a national genetic screening program. J Pediatr. 2012; 161:99 –103. Cuchel, M., Meagher, E.A., du Toit Theron, H., Blom, D.J., Marais, A.D., Hegele, R.A., Averna, M.R., Sirtori, C.R., Shah, P.K., Gaudet, D., et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013; 381:40 – 46. Thomas, G.S., Cromwell, W.C., Ali, S., Chin, W., Flaim, J.D., and Davidson, M. Mipomersen, an Apolipoprotein B Synthesis Inhibitor, Reduces Atherogenic Lipoproteins in Patients with Severe Hypercholesterolemia at High Cardiovascular Risk: A Randomized, Double-Blind, Placebo-Controlled Trial. J Am Coll Cardiol. 2013. Ho, M., Garnett, S.P., Baur, L.A., Burrows, T., Stewart, L., Neve, M., and Collins, C. Impact of dietary and exercise interventions on weight change and metabolic outcomes in obese children and adolescents: a systematic review and meta-analysis of randomized trials. JAMA Pediatr. 2013;167:759 –768.


10


29. de Ferranti, SD, Crean, S., Cotter, J., Boyd, D., and Osganian, S.K. Hypertriglyceridemia in a pediatric referral practice: experience with 300 patients. Clin Pediatr (Phila). 2011;50:297–307. 30. Rios, J.J., Shastry, S., Jasso, J., Hauser, N., Garg, A., Bensadoun, A., Cohen, J.C., and Hobbs, H.H. Deletion of GPIHBP1 causing severe chylomicronemia. J Inherit Metab Dis. 2012;35:531–540. 31. Surendran, R.P., Visser, M.E., Heemelaar, S., Wang, J., Peter, J., Defesche, J.C., Kuivenhoven, J.A., Hosseini, M., Peterfy, M., Kastelein, J.J., et al. Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. J Intern Med. 2012;272:185–196. 32. Goldstein, J.L., Schrott, H.G., Hazzard, W.R., Bierman, E.L., and Motulsky, A.G. Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia. J Clin Invest. 1973; 52:1544 –1568. 33. Brouwers, M.C., de Graaf, J., van Greevenbroek, M.M., Schaper, N., Stehouwer, C.D., and Stalenhoef, A.F. Novel drugs in familial combined hyperlipidemia: lessons from type 2 diabetes mellitus. Curr Opin Lipidol. 2010;21:530 –538. 34. Huertas-Vazquez, A., Plaisier, C., Weissglas-Volkov, D., Sinsheimer, J., Canizales-Quinteros, S., Cruz-Bautista, I., Nikkola, E., Herrera-Hernandez, M., Davila-Cervantes, A., Tusie-Luna, T., et al. TCF7L2 is associated with high serum triacylglycerol and differentially expressed in adipose tissue in families with familial combined hyperlipidaemia. Diabetologia. 2008;51:62– 69. 35. Pajukanta, P., Lilja, H.E., Sinsheimer, J.S., Cantor, R.M., Lusis, A.J., Gentile, M., Duan, X.J., Soro-Paavonen, A., Naukkarinen, J., Saarela, J., et al. Familial combined hyperlipidemia is associated with upstream transcription factor 1 (USF1). Nat Genet. 2004;36: 371–376. 36. Guardamagna, O., Abello, F., Baracco, V., Federici, G., Bertucci, P., Mozzi, A., Mannucci, L., Gnasso, A., and Cortese, C. Primary hyperlipidemias in children: effect of plant sterol supplementation on plasma lipids and markers of cholesterol synthesis and absorption. Acta Diabetol. 2011;48:127–133. 37. McCrindle, B.W., Urbina, E.M., Dennison, B.A., Jacobson, M.S., Steinberger, J., Rocchini, A.P., Hayman, L.L., and Daniels, S.R. Summary of the American Heart Association’s scientific statement on drug therapy of high-risk lipid abnormalities in children and adolescents. Arterioscler Thromb Vasc Biol. 2007;27:982–985. 38. Daniels, S.R., Gidding, S.S., and de Ferranti, SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:S30 –37. 39. Vuorio, A., Kuoppala, J., Kovanen, P.T., Humphries, S.E., Strandberg, T., Tonstad, S., and Gylling, H. Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev. 2010; CD006401. 40. Stein, E.A., Marais, A.D., Szamosi, T., Raal, F.J., Schurr, D., Urbina, E.M., Hopkins, P.N., Karki, S., Xu, J., Misir, S., et al. Colesevelam hydrochloride: efficacy and safety in pediatric subjects with heterozygous familial hypercholesterolemia. J Pediatr 2010; 156:231–236 e231–233. 41. Murad, M.H., Hazem, A., Coto-Yglesias, F., Dzyubak, S., Gupta, S., Bancos, I., Lane, M.A., Erwin, P.J., Berglund, L., Elraiyah, T., et al. The association of hypertriglyceridemia with cardiovascular events and pancreatitis: a systematic review and meta-analysis. BMC Endocr Disord. 2012;12:2. 42. Berglund, L., Brunzell, J.D., Goldberg, A.C., Goldberg, I.J., Sacks, F., Murad, M.H., and Stalenhoef, A.F. Evaluation and treatment of hypertriglyceridemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2969 –2989. 43. Do, R., Willer, C.J., Schmidt, E.M., Sengupta, S., Gao, C., Peloso, G.M., Gustafsson, S., Kanoni, S., Ganna, A., Chen, J., et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–1352. 44. Skulas-Ray, A.C., Kris-Etherton, P.M., Harris, W.S., Vanden Heu-


45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

vel, J.P., Wagner, P.R., and West, S.G. Dose-response effects of omega-3 fatty acids on triglycerides, inflammation, and endothelial function in healthy persons with moderate hypertriglyceridemia. Am J Clin Nutr. 2011;93:243–252. Blackett, P., Tryggestad, J., Krishnan, S., Li, S., Xu, W., Alaupovic, P., Quiroga, C., and Copeland, K. Lipoprotein abnormalities in compound heterozygous lipoprotein lipase deficiency after treatment with a low-fat diet and orlistat. J Clin Lipidol. 2013;7:132– 139. Carpentier, A.C., Frisch, F., Labbe, S.M., Gagnon, R., de Wal, J., Greentree, S., Petry, H., Twisk, J., Brisson, D., and Gaudet, D. Effect of alipogene tiparvovec (AAV1-LPL(S447X)) on postprandial chylomicron metabolism in lipoprotein lipase-deficient patients. J Clin Endocrinol Metab. 2012;97:1635–1644. Kavey, R.E., Allada, V., Daniels, S.R., Hayman, L.L., McCrindle, B.W., Newburger, J.W., Parekh, R.S., and Steinberger, J. Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2006;114:2710 –2738. Guy, J., Ogden, L., Wadwa, R.P., Hamman, R.F., Mayer-Davis, E.J., Liese, A.D., D’Agostino, R., Jr., Marcovina, S., and Dabelea, D. Lipid and lipoprotein profiles in youth with and without type 1 diabetes: the SEARCH for Diabetes in Youth case-control study. Diabetes Care. 2009;32:416 – 420. Margeirsdottir, H.D., Larsen, J.R., Brunborg, C., Overby, NC, and Dahl-Jorgensen, K. High prevalence of cardiovascular risk factors in children and adolescents with type 1 diabetes: a population-based study. Diabetologia. 2008;51:554 –561. Lachin, J.M., Orchard, T.J., and Nathan, D.M. Update on cardiovascular outcomes at 30 years of the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care. 2014;37:39 – 43. Gerstein, H.C., Miller, M.E., Genuth, S., Ismail-Beigi, F., Buse, J.B., Goff, DC, Jr., Probstfield, J.L., Cushman, W.C., Ginsberg, H.N., Bigger, J.T., et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364:818 – 828. Miller, M.E., Williamson, J.D., Gerstein, H.C., Byington, R.P., Cushman, W.C., Ginsberg, H.N., Ambrosius, W.T., Lovato, L., and Applegate, W.B. Effects of Randomization to Intensive Glucose Control on Adverse Events, Cardiovascular Disease and Mortality in Older Versus Younger Adults in the ACCORD Trial. Diabetes Care. 2013. Wood, J.R., Miller, K.M., Maahs, D.M., Beck, R.W., DiMeglio, L.A., Libman, I.M., Quinn, M., Tamborlane, WV, and Woerner, S.E. Most youth with type 1 diabetes in the T1D Exchange Clinic Registry do not meet American Diabetes Association or International Society for Pediatric and Adolescent Diabetes clinical guidelines. Diabetes Care. 2013;36:2035–2037. van Vliet, M., van der Heyden, J.C., Diamant, M., von Rosenstiel, I.A., Schindhelm, R.K., Heymans, M.W., Brandjes, D.P., Beijnen, J.H., Aanstoot, H.J., and Veeze, H.J. Overweight children with type 1 diabetes have a more favourable lipid profile than overweight non-diabetic children. European Journal of Pediatrics. 2012;171: 493– 498. Krishnan, S., Copeland, K.C., Bright, B.C., Gardner, A.W., Blackett, P.R., and Fields, D.A. Impact of type 1 diabetes and body weight status on cardiovascular risk factors in adolescent children. J Clin Hypertens (Greenwich). 2011;13:351–356. Specht, B.J., Wadwa, R.P., Snell-Bergeon, J.K., Nadeau, K.J., Bishop, F.K., and Maahs, D.M. Estimated Insulin Sensitivity and Cardiovascular Disease Risk Factors in Adolescents with and without Type 1 Diabetes. The Journal of Pediatrics. 2013;162:297–301.


doi: 10.1210/jc.2013-3860

57. Dabelea, D., Talton, J.W., D’Agostino, R., Jr., Wadwa, R.P., Urbina, E.M., Dolan, L.M., Daniels, S.R., Marcovina, S.M., and Hamman, R.F. Cardiovascular risk factors are associated with increased arterial stiffness in youth with type 1 diabetes: the SEARCH CVD study. Diabetes Care. 2013;36:3938 –3943. 58. Maahs, D.M., Maniatis, A.K., Nadeau, K., Wadwa, R.P., McFann, K., and Klingensmith, G.J. Total cholesterol and high-density lipoprotein levels in pediatric subjects with type 1 diabetes mellitus. J Pediatr. 2005;147:544 –546. 59. Lambert, J.E., Ryan, E.A., Thomson, A.B., and Clandinin, M.T. De novo lipogenesis and cholesterol synthesis in humans with longstanding type 1 diabetes are comparable to non-diabetic individuals. PLoS One. 2013;8:e82530. 60. Hallikainen, M., Kurl, S., Laakso, M., Miettinen, T.A., and Gylling, H. Plant stanol esters lower LDL cholesterol level in statin-treated subjects with type 1 diabetes by interfering the absorption and synthesis of cholesterol. Atherosclerosis. 2011;217:473– 478. 61. Cleland, S.J. Cardiovascular risk in double diabetes mellitus–when two worlds collide. Nat Rev Endocrinol. 2012;8:476 – 485. 62. Zeitler, P., Hirst, K., Pyle, L., Linder, B., Copeland, K., Arslanian, S., Cuttler, L., Nathan, D.M., Tollefsen, S., Wilfley, D., et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–2256. 63. TodayStudyGroup. Lipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial. Diabetes Care 2013;36:1758 –1764. 64. Stone, NJ, Robinson, J., Lichtenstein, A.H., Bairey Merz, C.N., Lloyd-Jones, D.M., Blum, C.B., McBride, P., Eckel, R.H., Schwartz,


65.

66. 67.

68.

69.

70.

11

J.S., Goldberg, A.C., et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013. Leiter, L.A., Lundman, P., da Silva, P.M., Drexel, H., Junger, C., and Gitt, A.K. Persistent lipid abnormalities in statin-treated patients with diabetes mellitus in Europe and Canada: results of the Dyslipidaemia International Study. Diabet Med. 2011;28:1343–1351. American Diabetes Association. Standards of medical care in diabetes–2014. Diabetes Care 2014;37 Suppl 1:S14 – 80. Haller, M.J., Stein, J.M., Shuster, J.J., Theriaque, D., Samyn, M.M., Pepine, C., and Silverstein, J.H. Pediatric Atorvastatin in Diabetes Trial (PADIT): a pilot study to determine the effect of atorvastatin on arterial stiffness and endothelial function in children with type 1 diabetes mellitus. J Pediatr Endocrinol Metab. 2009;22:65– 68. Bishop, F.K., Wadwa, R.P., Ellis, S., Rewers, M., and Maahs, D.M. Lessons learned from a lipid lowering trial in adolescents with type 1 diabetes. Int J Pediatr Endocrinol. 2012;2012:24. Marcovecchio ML, D.D., Dalton RN, Daneman D, Deanfield JE, Gray A, Jones TW, Neil A, Prevost AT, Acerini CL, Amin R, Anand B, Barrett TG, Bradley TJ, Cameron FJ, Celermajer DS, Cheetham TD, Cooper C, Couper J, Cotterill AM, Davis EA, Donaghue KC, Dutta A, Edge JA, Mann NP, Moudiotis C, Rayman G, Shield J, Thalange N, Wong TY. Adolescent type 1 Diabetes Cardio-renal Intervention Trial (AdDIT). BMC Pediatr. 2009;9:79. Beck, R.W., Tamborlane, WV, Bergenstal, R.M., Miller, K.M., DuBose, S.N., and Hall, C.A. The T1D Exchange clinic registry. J Clin Endocrinol Metab. 2012;97:4383– 4389.


Arthrogryposis: an update on clinical aspects, etiology, and treatment strategies.

Dyslipidemia in women: etiology and management.

Heart failure in children: etiology and treatment.

Update on Newborn Screening.

Hypodontia: An Update on Its Etiology, Classification, and Clinical Management.

Genetics: update on prenatal screening and diagnosis.

Tuberculosis screening and treatment in children.

Treatment of dyslipidemia in HIV.

Evidence update on the treatment of overweight and obesity in children and adolescents.

Update on melanocytic nevi in children.

Update on theophylline for asthma in children.

Retinopathy of prematurity: An update on screening and management.

Update on evaluation and treatment of scoliosis.

Dyslipidemia, Diet and Physical Exercise in Children on Treatment With Antiretroviral Medication in El Salvador: A Cross-sectional Study.

Metformin treatment improves weight and dyslipidemia in children with metabolic syndrome.

Etiology and treatment of urolithiasis.

Update on colon cancer screening: recent advances and observations in colorectal cancer screening.

Update on the etiology of revision TKA -- Evident trends in a retrospective survey of 1449 cases.

Update on hypertrophic scar treatment.

Hepatorenal syndrome: Update on diagnosis and treatment.

Update on PPHN: mechanisms and treatment.

Lung sarcoidosis in children: update on disease expression and management.

Update on otitis media - prevention and treatment.

Further observations on the diagnosis, etiology, and treatment of endophthalmitis.