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Management of familial hypercholesterolemia in children and adolescents. Position paper of the Polish Lipid Expert Forum Ma1gorzata Mysliwiec, MD, PhD, Mieczys1aw Walczak, MD, PhD, ska, MD, PhD, Ewa Ma1ecka-Tendera, MD, PhD, Anna Dobrzan Barbara Cybulska, MD, PhD, Krzysztof Filipiak, MD, PhD, Artur Mazur, MD, PhD, Przemys1awa Jarosz-Chobot, MD, PhD, Agnieszka Szadkowska, MD, PhD, Andrzej Rynkiewicz, MD, PhD, Alicja Chybicka, MD, PhD, Piotr Socha, MD, PhD, Agnieszka Brandt, MD, PhD, Joanna Bautembach-Minkowska, MD, PhD, Tomasz Zdrojewski, MD, PhD, Janusz Limon, MD, PhD, Samuel S. Gidding, MD, Maciej Banach, MD, PhD* Faculty and Clinic of Pediatrics, Diabetes and Endocrinology, Medical University of Gdansk, Gdansk, Poland (Dr. Mysliwiec, Dr. Brandt, Dr. Bautembach-Minkowska); Clinic of Pediatrics, Endocrinology, Diabetes, Metabolic Diseases and Cardiology of the Developmental Period, Pomerian Medical University in Szczecin, Szczecin, Poland (Dr. Walczak); Clinic of Pediatrics, Endocrinology and Diabetes, Medical University of Silesia, Silesia, Poland (Dr. Małecka-Tendera, Dr. Jarosz-Chobot); Neonatal Pathology Clinic of Pediatrics at Children’s Memorial Health Institute, Warsaw, Poland (Dr. Dobrza nska); National Food and Nutrition Institute, Warsaw, Poland (Dr. Cybulska); First Faculty and Clinic of Cardiology, Medical University of Warsaw, Warsaw, Poland (Dr. Filipiak); Medical Faculty at the University in Rzesz ow, Rzesz ow, Poland (Dr. Mazur); Clinic of Pediatrics, Hematology, Oncology and Diabetes, Medical University of Łodz, Ł odz, Poland (Dr. Szadkowska); Clinic of Cardiology and Cardiosurgery, University of Warmia and Mazury, Olsztyn, Poland (Dr. Rynkiewicz); Faculty and Clinic of Pediatric Bone Marrow Transplantation, Oncology and Hematology, Medical University of Wrocław, Wrocław, Poland (Dr. Chybicka); Clinic of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Memorial Health Institute, Warsaw, Poland (Dr. Socha); Clinic for Prevention and Education, Faculty of Hypertension and Diabetes, Medical University of Gdansk, Gdansk, Poland (Dr. Zdrojewski); Faculty and Clinic of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland (Dr. Limon); Nemours Cardiac Center, A. I. DuPont Hospital for Children, Wilmington, DE (Dr. Gidding); and Faculty of Nephrology and Hypertension, Medical University of Ł odz, Ł odz, Poland (Dr. Banach) KEYWORDS: Adolescents; Children; Cardiovascular disease;
Abstract: Familial hypercholesterolemia (FH) affects on average 1 in 500 individuals in European countries, and it is estimated that FH in Poland may affect more than 80,000 people. However, in Poland, only about 20% of the population is estimated to have been diagnosed with FH, of which only a small number receive adequate treatment. FH results in more rapid development of
* Corresponding author. E-mail address: [email protected] Submitted August 26, 2013. Accepted for publication January 4, 2014. 1933-2874/$ - see front matter Ó 2014 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.01.001
174 Familial hypercholesterolemia; Statins; Therapy
Journal of Clinical Lipidology, Vol 8, No 2, April 2014 atherosclerosis and is associated with a high risk of cardiovascular events. Atherosclerosis develops beginning in childhood in patients with FH and reaches advanced stages before clinical manifestations develop. Inadequate diagnostics and treatment of FH in Polish children suggests a need for raising the level of awareness and understanding of the condition in both society and among health professionals. These recommendations present the current epidemiological status, guidelines for diagnosing FH in Polish children and adolescents, and effective treatment options. Ó 2014 National Lipid Association. All rights reserved.
Familial hypercholesterolemia (FH) is one of the betterknown genetic disorders; FH results in more rapid development of atherosclerosis and is associated with a high risk of cardiovascular (CV) events.1–3 Atherosclerosis develops beginning in childhood in patients with FH and reaches advanced stages before clinical manifestations develop.4,5 FH creates a significant economic burden on society because it impairs the ability to work early in life, whereas its treatment requires enormous expense. CV mortality in FH patients between ages 20 and 39 is 100-fold greater than that of the general population.6 Because of the ability to identify patients with FH at an early stage, even from childhood, the prompt introduction of effective lifestyle modifications and medical treatments may sufficiently delay the incidence of CV events in adults to improve life expectancy closer to that of the general population.7,8 Inadequate diagnostics and treatment of FH in Polish children suggests a need for raising the level of awareness and understanding of the condition in both society and among health professionals. A key issue in educating people relates to the importance of screening in the developmental age population and using cascade screening tests in the families of patients diagnosed with FH. These recommendations will present the current epidemiological status, guidelines for diagnosing FH in Polish children and adolescents, and effective treatment options. This document is an addition to the Position of the Polish Lipid Expert Forum on FH in adults.9
Epidemiology and pathogenesis of FH FH is the most common monogenetic condition.1 Its autosomal dominant mode of inheritance allows for distinguishing 2 forms of the disease: heterozygous (HeFH) and homozygous (HoFH). The prevalence of HoFH in the Caucasian population is 1 per million live births, whereas the heterozygous form can be found in 1 per 500 European citizens.6 An estimated amount of more than 80,000 people are affected with HeFH in Poland. However, this number may be underestimated. The FH phenotype is associated with a mutation in 1 of 3 genes: the low-density lipoprotein (LDL) receptor gene (approximately 1600 various mutations have been described), the apolipoprotein B (Apo B) gene, or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene.10–12 A
mutation in the LDL receptor (LDLR) gene can be found in approximately 85–90% of FH patients. Abnormal structure of either LDL receptors or their ligand Apo B disturbs the binding of Apo B–containing lipoproteins with their receptors.10–12 This results in impaired hepatic metabolism of LDLs.13,14 In HeFH, half of LDLRs or half of Apo B molecules are affected.13,14 The third and recently discovered cause of FH is a mutation in the PCSK9 gene, which is associated with an increased degradation activity of the corresponding protein (gain-of-function mutation) toward LDLRs.12,15 PCSK9 protein binds to the epidermal growth factor–like repeat A domain of the LDLR, inducing its degradation. Reduced LDLR levels result in decreased metabolism of LDL-cholesterol (LDL-C), which leads to hypercholesterolemia.15 This mutation is relatively rare, with fewer than 5% of patients affected.12,15
Clinical manifestations of FH in children and adolescents The heterozygous form of familial hypercholesterolemia is often asymptomatic in the young population. Mean total cholesterol (TC) levels in this form of the disease ranges from 250 mg/dL (6.5 mmol/L) to 500 mg/dL (12.9 mmol/ L).6 Affected parents and close relatives are at risk of early coronary artery disease (CAD) or diagnosis of hypercholesterolemia. A clinical examination in 20-to-39-year-old patients with this form of FH may reveal xanthomas in the Achilles tendons and tendons of hand extensor muscles as well as senile corneal arcus; although xanthomas are pathognomonic for FH, they are not always present.6,9 Clinical manifestations of CAD often develop when the patients reach their 40s. The homozygous form of familial hypercholesterolemia shows virtually no activity of the LDL receptor, with TC levels typically rising up to 700 to 1200 mg/dL (18.1– 31 mmol/L).6 Largely elevated cholesterol levels can already be observed in newborns. Xanthomas in the skin may form as early as the first months of life, and those in tendons take a nodular form. Young patients with HoFH develop signs and symptoms of CAD, diffuse peripheral artery atherosclerosis, aortic stenosis, and cerebrovascular disease. Skin and tendon lesions as well as positive family history of early cardiovascular disease (CVD) may suggest the correct diagnosis.6,9
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Principles of lipid metabolism testing Prenatal and early postnatal serum TC levels are lower. Total and LDL-C levels rise rapidly in the first week of postnatal life and then gradually increase until the age of 2.16 In subsequent years, lipid and lipoprotein levels stay relatively constant until adolescence.16–18 During puberty, LDL-C drops on average by a mean of 15%, and during that time, false-negative results in FH diagnostic tests are possible19,20; therefore, the optimal period to assess lipid metabolism is between the ages of 9 and 11.16–18 If lipid levels are normal at the ages of 9 to 11, tests should be repeated at around the age of 18 because lipid panel results obtained at that age allow for the best prediction of lipid levels during the next 20 years of life.16–18 General practitioners should be responsible for conducting universal screening for lipid disturbances and, if needed, refer patients to specialist clinics that deal with lipid metabolism disturbances for additional diagnostic assessments and treatment. The children of parents diagnosed with FH should undergo their first lipid panel tests as early as between ages 2 and 11 (possibly closer to the lower age range).16 A child’s lipid panel should be conducted in plasma or serum from venous blood samples collected after fasting (ie, at least 9–12 hours after the last meal). The test involves an evaluation of TC, triglycerides, and highdensity lipoprotein (HDL)-C levels, as well as calculation of LDL-C and non–HDL-C levels.19 A lipid panel should be repeated after a 2- to 3-week interval to calculate the average value.19 This is necessary also because of significant differences in test results both resulting from biological and laboratory factors. Lipid profiles should be tested no earlier than 3 months after any acute infectious disease.
FH diagnostic criteria in children and adolescents American Academy of Pediatrics guidelines17 recommend targeted screening tests of fasting lipids of: children .2 years of age of parents diagnosed with FH; Table 1
175 children .2 years of age with a family history that is difficult to determine as well as risk factors such as: overweight–body mass index (BMI) .85th centile (.90th centile in Poland), obesity–BMI .95th centile (.97th centile in Poland), high normal blood pressure (systolic and/or diastolic blood pressure in 3 measurements $90th centile, but ,95th centile for the particular age, height, and sex), hypertension (systolic and/or diastolic blood pressure in 3 measurements $95th centile for the particular age, height and sex), diabetes, little physical activity (,60 minutes per day). The latest guidelines of the National Lipid Association (NLA) and the NLA Expert Panel on Familial Hypercholesterolemia recommend a lipid panel to be obtained in all children aged from 9 to 11.16 Diagnostic criteria for dyslipidemia in children remain controversial. The National Education Cholesterol Program (NCEP)–Expert Panel on Blood Cholesterol Levels In Children and Adolescents Report considers the threshold of TC levels to be at $170 mg/dL (4.4 mmol/L), and abnormally high levels to be at $200 mg/dL (5.2 mmol/L). For LDL-C, these values are $110 mg/dL (2.8 mmol/L) and $130 mg/dL (3.4 mmol/L), respectively.19 The pediatric population with cholesterol levels of $240 mg/dL (6.2 mmol/L) and LDL-C of $160 mg/dL (4.1 mmol/L) is highly likely to be diagnosed with the heterozygous form of HF.16,17 Table 1 presents target, threshold, and lipoprotein levels currently recommended for children and adolescents. The National Institute for Health and Clinical Excellence and the NLA Expert Panel recommend cascade screening in families of patients diagnosed with FH.1,16,21 In the family members of patients diagnosed with FH, this involves a measurement of LDL-C levels and/or molecular tests (if the proband’s mutation has been identified). This includes first-degree relatives as well as seconddegree relatives, if possible. This method helps detect
Target, threshold, and lipoprotein levels currently recommended for children and adolescents
Category
Acceptable levels
Threshold levels
High levels
TC (mg/dL, mmol/L) LDL-C (mg/dL, mmol/L) Non-HDL-C (mg/dL, mmol/L) Apo-B (mg/dL) TG (mg/dL, mmol/L) 0–9 years of age 10–19 years of age HDL-C (mg/dL, mmol/L)
,170/4.4 ,110/2.8 ,123/3.2 ,90
170–199 (4.4–5.2) 110–129 (2.8–3.3) 123–143 (3.2–3.7) 90–109
$200/5.2 $130/3.36 $144/3.7 $110
,75/0.9 ,90/1.0 .45/1.2
75–99/0.9–1.1 90–129/1.0–1.5 35–45/0.9–1.2
$100/1.1 $130/1.5
Apo-B, apolipoprotein B; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglycerides. Lipid and lipoprotein levels modified according to the National Education Cholesterol Program Expert Panel.19 Cutoff points for high and low values correspond to the 95th and 75th centiles, respectively.
176 Table 2 for FH
Journal of Clinical Lipidology, Vol 8, No 2, April 2014 Simon Broome Register Group’s diagnostic criteria
Criterion
Description
A
Total cholesterol .260 mg/dL (6.7 mmol/L) (,16 years of age) .290 mg/dL (7.5 mmol/L) (.16 years of age) Or LDL-cholesterol .155 mg/dL (4.0 mmol/L) (,16 years of age) .190 mg/dL (4.9 mmol/L) (.16 years of age) Xanthomas in the proband or a first-degree relative Evidence of LDL-receptor or APOB gene mutation History of myocardial infarction in first-degree relatives before 60 years of age or in seconddegree relatives before 50 years of age TC concentration .290 mg/dL (7.5 mmol/L) in a first- or second-degree relative
B C D
E
FH diagnosis Definitive Criteria A and B or C Possible Criteria A and D or A and E Apo-B, apolipoprotein B; FH, familial hypocholesterolemia; LDL, low-density lipoprotein; TC, total cholesterol.
new cases of FH in the highest risk population. A serum lipid panel in children from families with a history of FH is recommended immediately after 2 years of age, but always before age 11. This method of cascade screening is more efficient than LDL-C screening in the entire population (universal screening). One drawback of cascade screening in comparison to universal screening is the risk of overlooking children with autosomally dominant hypercholesterolemia whose parents are young and have no symptoms of CVD or are unaware of their high cholesterol levels.16 The tool most useful in detecting FH in the Polish pediatric population is the classification suggested by British specialists (The Simon Broome Register Group) (Table 2), because it is the only available tool in which FH diagnostic criteria do not include the proband’s clinical manifestations; these may not occur in children with the heterozygous form of the disease.4,22
In uncertain cases, it is always recommended to confirm FH diagnosis via genetic methods, if funds allow.
FH differential diagnosis A number of factors affect high TC and LDL-C levels. The lipid profile in patients with FH may be similar to that in secondary hypercholesterolemia in the course of a number of diseases: hypothyroidism, nephrotic syndrome, Cushing syndrome, porphyria, and during chronic treatment with certain drugs, such as thiazide and loop diuretics, corticosteroids, cyclosporine, estrogens, progesterones, and protease inhibitors.23,24 Detecting reasons for secondary hypercholesterolemia allows for a significant reduction in the number of children with suspected FH. Familial combined hyperlipidemia (FCH) should be considered while differentiating elevated TC and LDL-C levels, especially in overweight and obese patients. FCH is the most common genetic disorder of increased blood lipids (occurs approximately in 1/200 persons) that causes premature CVD; however, the genetic and metabolic basis of FCH has yet to be fully unveiled (it is probably caused by decreased LDLR and increased ApoB). Children with FCH have elevated TC and/or triglyceride levels and low HDL-C levels with normal, threshold, or elevated LDL-C.19,25,26 These lipid disorders are present in at least 2 members of the same family, with intraindividual and intrafamilial variability of the lipid phenotype. FCH may be enhanced by concomitant overweight or obesity and is usually associated with insulin resistance.19,25,26 The marked variability of lipid profile, not explained by diet or body weight, can represent the best diagnostic criterion to reduce the overlapping between metabolic syndrome and FCH.19,25,26 This is why diagnostic assessments for FH should be considered in the case of persistent dyslipidemia with LDL-C of $130 mg/ dL (3.4 mmol/L) after weight reduction in overweight or obese patients with a positive family history of early CVD.19,25 Unfortunately, no mutation responsible for the abnormalities found in FCH patients has been identified, which would significantly facilitate differentiating uncertain cases due to the growing accessibility of molecular tests.19,25
Treatment of FH in children and adolescents Molecular diagnostics The only worldwide accepted method of establishing a definitive diagnosis of FH is to find a mutation in the LDLR, Apo-B, or PCSK9 gene in a molecular test. Despite increasing accessibility of molecular diagnostics of the FH rate of mutated genes, detection varies from 30% to 80%.1,9 A negative result on the genetic test does not exclude an FH diagnosis. The genetic test will be conducted with genetic material isolated from the patient’s blood collected into an EDTA test tube. If an LDLR or APOB gene mutation is confirmed in the family, the genetic test can be also performed from a cheek swab.
Established diagnosis of FH is an indication to provide medical care for the entire family, educate the patient, introduce dietary recommendations, and undertake medical treatment. Medical care should be provided by a team of specialists (pediatricians specializing in diabetes and/or endocrinology, lipid specialists, and geneticists), a nurse, dietician, and psychologist. There are still no separate clinics designated to deal with lipid issues in the Polish health care system; dyslipidemias are treated in clinics dealing with diabetes or metabolic or cardiovascular disturbances. The aim of FH therapy in children is to reduce LDL-C by .50% or to maintain LDL-C levels ,130 mg/dL
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(3.4 mmol/L); in children with concomitant diabetes, a level ,100 mg/dL (2.6 mmol/L) is recommended.16,21
demonstrating their efficacy.23,30 However, it needs to be emphasized that data on the use of lipid-lowering agents in children are limited to short-term interventions (up to 2 years), not including long-term drug tolerance and safety.31–33 In terms of statin safety in children and adolescents, the possible association of statins and other lipidlowering medications on puberty should be discussed. Given the effects of statins on endogenous cholesterol biosynthesis, growth and sexual development might be negatively influenced by long-term exposure to these drugs in children.1 However, the available randomized controlled trials with statins in children, which investigated the influence of these drugs on pubertal development and hormonal status, showed no significant effect of statin treatment on hormonal regulation and sexual maturation.1,33 The statins seem to also be safe in adolescents, without any significant adverse effect on growth and development or on adrenal and gonadal hormones.33–35 A meta-analysis of clinical trials of statins in children and adolescents with FH with a follow-up of 2 years showed no adverse effects on growth, development, cognition, or sexual maturation and other endocrine function parameters.33,36,37 The age currently recommended by the NLA Expert Panel on Familial Hypercholesterolemia, when adding statins to the treatment of FH in children, is 8 years of age with an approved drug.16,21 The Polish Lipid Expert Forum, taking into account available data, has also accepted this age limit. Before a child with FH is qualified for medical treatment, not only his or her age, but also his or her sex, detailed family history, risk factors (ie, muscle damage; liver, kidney, or nervous system disease; severe infections; metabolic, hormonal, and electrolyte disturbances) must be considered. Medical treatment is recommended when:
Patient education Education of patients is an increasingly more appreciated and better known factor that may play a significant role in achieving positive treatment effects. Patients should receive detailed information on the causes of FH and its association with early CAD, additional risk factors for CAD, the methods and necessity of their modification, treatment options, and FH possible complications.
Dietary treatment The NCEP Expert Panel recommendations questioned the necessity of a 6- to 12-month period of low-cholesterol diet before initiating medical treatment in children diagnosed with FH.18,19 However, experts emphasized the significant role of diet as supportive treatment in every child with dyslipidemia.18,19 The pediatric panel of NCEP recommends initiating treatment with diet in children after the age of 2; nonetheless, data from the Special Turku Coronary Risk Factor Intervention Project and the Dietary Intervention Study in Children show that a low-fat diet may be safely introduced in children as early as 7 months old, if it is conducted under medical supervision.27 The Polish Lipid Expert Forum agrees with the NCEP recommendations on introducing dietary treatment from the age of 2, and even earlier in urgent cases, if it is being conducted under strict medical supervision. The American Academy of Pediatrics nutritional recommendations should be followed in older children and dietary treatment should be used.17,28 This involves mainly limiting consumption of saturated fatty acids to ,7% of total energy and dietary cholesterol ,200 mg/day.4,17,19 The important role of such substances as dietary fiber and plant sterols and stanols has been emphasized as well as oily sea fish consumption. Dietary advice should be provided by a dietician. A low-fat diet in the treatment of FH is useful but not primary treatment. Replacing saturated fats with polyunsaturated fats may lead to lowering LDL-C levels by only 15%, insufficient to reach treatment goals.17–19 Therefore, FH requires medical treatment initiation.
Medical treatment Introduction of early lipid-lowering therapy in patients diagnosed with FH significantly reduces the incidence of CAD, myocardial infarction, the necessity of revascularization procedures, and early CV deaths.29 Statins are the first-choice agents in the treatment of FH.4,9,17,23,24,30 The use of formulations previously used in the treatment of children with FH (ie fibrates or cholestyramine) has been significantly reduced because of a lack of robust studies
- LDL-C levels $130 mg/dL (2.6 mmol/L) in children with diabetes, - LDL-C levels $160 mg/dL (4.1 mmol/L) in children with at least 2 risk factors for CVD (ie, obesity, hypertension, and smoking) or with family history positive for early CVD, - LDL-C levels $190 mg/dL (4.9 mmol/L), in children without risk factors. Introducing medication in children younger than 8 years of age is warranted at LDL-C levels .500 mg/dL (12.9 mmol/L) (eg, in the course of the HoFH).16,21 Unfortunately, these LDL-C levels are arbitrary. No robust studies in the pediatric population have been conducted that would help accurately determine the LDL-C concentration above which there is a significantly higher risk of developing early atherosclerosis.30,31 Moreover, there is no known so-called ‘‘safe’’ concentration of LDL-C that would protect against developing CV complications. Current recommendations are based on data extrapolated from studies conducted in adults.30,31 Lipid-lowering treatment in children must always be balanced between a specific dose of the drug and potential side effects of treatment.
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General principles of statin use
Ezetimibe
Individual statins vary in terms of potency at a given dose. They are typically administered once a day in the evening, because physiological synthesis of cholesterol increases at night. In children with FH, treatment begins from small doses of statins (2.5–5–10 mg/day, depending on the formulation) and the dosage is titrated up to when the desired therapeutic effect is achieved. The full effect of statins on lipid metabolism is observed after 4 to 6 weeks. The lowering of LDL-C concentration achieved after 2 weeks of treatment with a given dose of statin typically corresponds to 90% of this dose’s potency.16,21,31,32 Before the statin therapy is initiated, transaminase levels, especially alanine aminotransferase as well as creatinine kinase activity, should be determined. Transaminase levels should be retested 6 weeks after introduction of a statin, and monitored every 6 months in subsequent years. If transaminase levels increase above the upper limit of normal by 3fold or more, the statin must be discontinued.2 An increase in transaminase levels is usually transient and resolves after 2 to 3 months of treatment discontinuation.31–33 Currently, routine creatinine kinase tests are not recommended during treatment and should be conducted only if muscle-related symptoms, such as myopathy (muscle pain and/or weakness) develop. If creatinine kinase levels exceed the upper limit of normal by 5-fold, the statin must be discontinued.33 Other, though rare, side effects of statins include: gastrointestinal disturbances, fatigue, insomnia, headaches, skin rash, peripheral neuropathy, and lupus-like syndrome. After treatment initiation in children, cholesterol levels should be regularly assessed and any drug side effects that may affect the child’s development, nutritional status, and sexual maturity should be monitored.30 Contraindications to the use of statins in children include: hypersensitivity to the drug; muscle damage; statin-related myopathy; active liver disease or persistently elevated transaminase levels; transaminase level increased by 3-fold above the upper limit of normal during statin administration; renal impairment; severe infections; major surgery; major trauma; severe metabolic, hormonal, or electrolyte disturbances; or uncontrolled epileptic seizures. Currently, statins are the most potent lipid-lowering treatments available for treating FH; however, when used in monotherapy, they do not always achieve the target levels of LDL-C.
Ezetimibe inhibits cholesterol absorption from the small intestine at the level of enterocyte cell membrane and sterol-binding proteins. Because of different points of action of ezetimibe and statins, adding 10 mg/day ezetimibe to statin therapy reduces LDL-C levels by additional 15% to 25%.17 Full lipid-lowering activity of ezetimibe can be achieved as early as 2 weeks of its use.17 The drug should be used carefully in patients with liver dysfunction and malabsorption syndromes. In children, the American Academy of Pediatrics allows the use of ezetimibe conditionally if treatment with statins is not tolerated.17 This medication is often a valuable supplement in FH treatment in Poland, especially because it is subsidized (payable at 30%) in this group of patients.
Bile acid–binding resins Bile acid–binding resins decrease LDL-C levels by 10% to 30%.31–33 However, because of the large dosage volume and bothersome gastrointestinal side effects, including constipation, they are rarely used in children.31–33 A welltolerated resin is colesevelam (Welchol). It has been approved in the United States for the treatment of the HeFH in children. In Poland, its use is marginal.
Conclusion Familial hypercholesterolemia is a relatively common dyslipidemia, although it is still quite rarely diagnosed and undertreated. In Poland, only about 20% of the population is estimated to have been diagnosed with FH, of whom only a small number receive adequate treatment. FH is characterized by significantly elevated LDL-C levels present since birth. Functional and structural changes in vascular walls in the course of FH can be found in children. This condition contributes to a rapid development of atherosclerosis and early CAD and mortality. Early diagnosis and adequate treatment of FH initiated in the developmental age population may considerably reduce the risk of CVD and sudden death in adults. General practitioners should be aware of their key role in early diagnosis and treatment of FH complementary to the necessary specialist care in dyslipidemias. Universal lipid metabolism screening tests in children aged 9 to 11 as well as cascade screening in families affected with FH may translate into a significant reduction in treatment costs for complications resulting from untreated hypercholesterolemia.38,39 The funding of FH diagnostics, treatment, education, and research should come from multiple sources, including the Polish National Health Fund, governmental (Polish Ministry of Health) and research agencies, and the pharmaceutical industry. This position statement on FH in children and adolescents has been developed by a team of Polish experts. After puberty, recommendations for FH treatment in adults should be followed, including recent guidelines of Polish Lipid Expert Forum.40
Summary of recommendations In Poland, only about 20% of the population is estimated to have been diagnosed with FH The pediatric population with cholesterol levels of $240 mg/dL (6.2 mmol/L) and LDL-C of $160 mg/
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dL (4.1 mmol/L) is highly likely to be diagnosed with the heterozygous form of FH The optimal period to assess lipid metabolism is between the ages of 9 and 11; however, the children of parents diagnosed with FH should undergo their first lipid panel tests as early as between ages 2 and 11, possibly closer the lower age range The tool most useful in detecting FH in the Polish pediatric population is the Simon Broome Register Group classification; however, in uncertain cases, it is always recommended to confirm FH diagnosis via genetic methods The aim of FH therapy in children is to reduce LDL-C by .50% or to maintain LDL-C levels ,130 mg/dL (3.4 mmol/L), and in children with concomitant diabetes ,100 mg/dL (2.6 mmol/L) Statins are the first-choice agents in the treatment of FH. We recommend using statins in the therapy of FH in children $8 years of age with an approved drug; however, introducing medication in children younger than 8 years of age is warranted at LDL-C levels .500 mg/dL (12.9 mmol/L) We suggest the introduction of dietary treatment from the age of 2, and even earlier in urgent cases, if it is being conducted under strict medical supervision.
hypercholesterolemia: a prospective registry study. Eur Heart J. 2008;29:2625–2633. Pijlman AH, Huijgen R, Verhagen SN, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2010;209:189–194. Rynkiewicz A, Cybulska B, Banach M, et al. Management of familial heterozygous hypercholesterolemia: Position Paper of the Polish Lipid Expert Forum. J Clin Lipidol. 2013;7:217–221. Innerarity TL, Weisgraber KH, Arnold KS, et al. Familial defective apolipoprotein B-100: low density lipoproteins with abnormal receptor binding. Proc Natl Acad Sci U S A. 1987;84:6919–6923. Abifadel M, Varret M, Rab JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34: 154–156. Abifadel M, Rabes JP, Devillers M, et al. Mutations and polymorphisms in the proprotein convertase subtilin kexin 9 (PCSK9) gene in cholesterol metabolism and disease. Hum Mut. 2009;30:520–529. Varret M, Abifadel M, Rabes JP, et al. Genetic heterogeneity of autosomal dominant hypercholesterolemia. Clin Genet. 2008;78:1–13. _ J, et al. Molecular characterization of Polish Chmara M, Wasa˛g B, Zuk patients with familial hypercholesterolemia: novel and recurrent LDLR mutations. Appl Genet. 2010;51:95–106. Huang CC, Fornage M, Lloyd-Jones DM, et al. Longitudinal association of PCSK9 sequence variations with low-density lipoprotein cholesterol levels: the Coronary Artery Risk Development in Young Adults Study. Circ Cardiovasc Genet. 2009;2:354–361. Goldberg AC, Hopkins PN, Toth PP, 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: 133–140. Daniels SR, Greer FR, and the Committee on Nutrition. Lipid screening and cardiovascular health in childhood. Pediatrics. 2008; 122:198–208. National Cholesterol Education Program. Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents. Pediatrics. 1992;89:525–584. Kwiterovich POJ. Recognition and management of dyslipidemia in children and adolescents. J Clin Endocrinol Metab. 2008;93: 4200–4209. Jolliffe CJ, Janssen I. Distribution of lipoproteins by age and gender in adolescents. Circulation. 2006;114:1056–1062. Daniels SR, Gidding SS, de Ferranti SD. Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:30–37. Marks D, Thorogood M, Neil HA, et al. A review on the diagnosis, natural history, and treatment of familial hypercholesterolemia. Atherosclerosis. 2003;168:1–14. Catapano AL, De Backer G, et al. ESC/EAS guidelines for Reiner Z, management of dyslipidemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–1818. Ito MK, McGowan MP, Moriaty PM. Management of familial hyperlipidemias in adult patients. Recommendations from National Lipid Association Expert Panel of Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:38–45. Lifshitz F. Obesity in children. J Clin Res Pediatr Endocrinol. 2008;1: 53–60. Freedman DS, Mei Z, Srinivasan SR, et al. Cardiovascular risk factor and excess adiposity among overweight children and adolescents: the Bogalusa Heart Study. J Pediatr. 2007;150:12–17. Simell O, Niinikoski H, R€onnemaa T, et al. Special Turku Coronary Risk Factor Intervention Project for Babies (STRIP). Am J Clin Nutr. 2000;72:1316–1331. American Academy of Pediatrics, Committee on Nutrition. Cholesterol in childhood. Pediatrics. 1998;101:141–147.
Acknowledgments The position paper has been officially endorsed by Polish Lipid Association (PoLA). The current position paper has been also published in parallel in Polish in Kardiologia Polska (Polish Journal of Cardiology), Endokrynologia Pediatryczna, and Pediatria Polska, the official journal of the Polish Pediatric Society.
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11.
12.
13. 14.
15.
16.
17.
18.
19.
20. 21.
References 1. Wierzbicki AS, Humphries SE, Minhas R, , on behalf of the Guideline Development Group. Familial hypercholesterolaemia: summary of NICE guidance. BMJ. 2008;337:a1095. 2. Cicero AF, Derosa G, Maffioli P, et al. Influence of metabolic syndrome superposition on familial combined hyperlipoproteinemia cardiovascular complication rate. Arch Med Sci.. 2013;9:238–242. 3. Austin MA, Hutter CM, Zimmern RL, et al. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004;160:421–429. 4. Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Management: Summary Report. Pediatrics. 2011;128: 212–258. 5. Juonala M, Vikari JS, R€onnemaa T, et al. Associations of dyslipidemias from childhood to adulthood with carotid intima-media thickness, elasticity, and brachial flow mediated dilatation in adulthood: the Cardiovascular Risk in Young Finns Study. Arterioscler Thromb Vasc Biol. 2008;28:1012–1017. 6. Familial hypercholesterolemia. A report of a WHO consultation. Geneva, Switzerland: WHO; 1998. 7. Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer and coronary mortality in statin-treated patients with heterozygous
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180 29. Ballantyne CM, O’Keefe JJH, Gotto AM. Dyslipidemia essentials. Royal Oak, MI: Physicians Press; 2005. p. 98–123. 30. O’Gorman CSM, O’Neill MBO, Conwell LS. Considering statins for cholesterol-reduction in children if lifestyle and diet changes do not improve their health: a review of the risks and benefits. Vasc Health Risk Manage. 2011;7:1–14. 31. Avis HJ, Vissers MN, Stein EA, et al. A systematic review and meta-analysis of statin therapy in children with familial hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2007;27: 1803–1810. 32. Arambepola C, Farmer AJ, Perera R, et al. Statin treatment for children and adolescents with heterozygous familial hypercholesterolaemia: a systematic review and meta-analysis. Atherosclerosis. 2007; 195:339–347. 33. Wiegman A, Hutten BA, De Groot E, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia. A randomized controlled trial. JAMA. 2004;292:331–337. 34. Rodenburg J, Vissers MN, Wiegman A, et al. Statin treatment in children with familial hypercholesterolemia: the younger, the better. Circulation. 2007;116:664–668.
Journal of Clinical Lipidology, Vol 8, No 2, April 2014 35. Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill, 2001. p. 2863–2913. 36. Mysliwiec M, Walczak M, Ma1ecka-Tendera E, et al. Postepowanie w rodzinnej hipercholesterolemii u dzieci i mlodziezy. Stanowisko Forum Ekspertow Lipidowyc. [Management in familial hypercholesterolaemia in children and adolescents. Position of the Lipid Expert Forum]. Kardiol Pol. 2013;71:1099–1105 [in Polish]. 37. Ayyobi AF, Brunzell JD. Lipoprotein distribution in the metabolic syndrome, type 2 diabetes mellitus, and familial combined hyperlipidemia. Am J Cardiol. 2003;92:27J–33J. 38. Hamilton-Craig IR, Watts GF. Familial hypercholesterolaemia in Australia: new insights and developments. Med J Aust. 2013;198:72–73. 39. Harada-Shiba M, Arai H, Oikawa S, et al. Guidelines for the management of familial hypercholesterolemia. J Atheroscler Thromb. 2012; 19:1043–1060. 40. Rynkiewicz A, Cybulska B, Banach M, et al. Management of familial heterozygous hypercholesterolaemia. Position paper of the Polish Lipid Expert Forum. Kardiol Pol. 2013;71:107–111.
Management of familial hypercholesterolemia in children and adolescents. Position paper of the Polish Lipid Expert Forum Ma1gorzata Mysliwiec, MD, PhD, Mieczys1aw Walczak, MD, PhD, ska, MD, PhD, Ewa Ma1ecka-Tendera, MD, PhD, Anna Dobrzan Barbara Cybulska, MD, PhD, Krzysztof Filipiak, MD, PhD, Artur Mazur, MD, PhD, Przemys1awa Jarosz-Chobot, MD, PhD, Agnieszka Szadkowska, MD, PhD, Andrzej Rynkiewicz, MD, PhD, Alicja Chybicka, MD, PhD, Piotr Socha, MD, PhD, Agnieszka Brandt, MD, PhD, Joanna Bautembach-Minkowska, MD, PhD, Tomasz Zdrojewski, MD, PhD, Janusz Limon, MD, PhD, Samuel S. Gidding, MD, Maciej Banach, MD, PhD* Faculty and Clinic of Pediatrics, Diabetes and Endocrinology, Medical University of Gdansk, Gdansk, Poland (Dr. Mysliwiec, Dr. Brandt, Dr. Bautembach-Minkowska); Clinic of Pediatrics, Endocrinology, Diabetes, Metabolic Diseases and Cardiology of the Developmental Period, Pomerian Medical University in Szczecin, Szczecin, Poland (Dr. Walczak); Clinic of Pediatrics, Endocrinology and Diabetes, Medical University of Silesia, Silesia, Poland (Dr. Małecka-Tendera, Dr. Jarosz-Chobot); Neonatal Pathology Clinic of Pediatrics at Children’s Memorial Health Institute, Warsaw, Poland (Dr. Dobrza nska); National Food and Nutrition Institute, Warsaw, Poland (Dr. Cybulska); First Faculty and Clinic of Cardiology, Medical University of Warsaw, Warsaw, Poland (Dr. Filipiak); Medical Faculty at the University in Rzesz ow, Rzesz ow, Poland (Dr. Mazur); Clinic of Pediatrics, Hematology, Oncology and Diabetes, Medical University of Łodz, Ł odz, Poland (Dr. Szadkowska); Clinic of Cardiology and Cardiosurgery, University of Warmia and Mazury, Olsztyn, Poland (Dr. Rynkiewicz); Faculty and Clinic of Pediatric Bone Marrow Transplantation, Oncology and Hematology, Medical University of Wrocław, Wrocław, Poland (Dr. Chybicka); Clinic of Pediatric Gastroenterology, Hepatology and Nutrition, Children’s Memorial Health Institute, Warsaw, Poland (Dr. Socha); Clinic for Prevention and Education, Faculty of Hypertension and Diabetes, Medical University of Gdansk, Gdansk, Poland (Dr. Zdrojewski); Faculty and Clinic of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland (Dr. Limon); Nemours Cardiac Center, A. I. DuPont Hospital for Children, Wilmington, DE (Dr. Gidding); and Faculty of Nephrology and Hypertension, Medical University of Ł odz, Ł odz, Poland (Dr. Banach) KEYWORDS: Adolescents; Children; Cardiovascular disease;
Abstract: Familial hypercholesterolemia (FH) affects on average 1 in 500 individuals in European countries, and it is estimated that FH in Poland may affect more than 80,000 people. However, in Poland, only about 20% of the population is estimated to have been diagnosed with FH, of which only a small number receive adequate treatment. FH results in more rapid development of
* Corresponding author. E-mail address: [email protected] Submitted August 26, 2013. Accepted for publication January 4, 2014. 1933-2874/$ - see front matter Ó 2014 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.01.001
174 Familial hypercholesterolemia; Statins; Therapy
Journal of Clinical Lipidology, Vol 8, No 2, April 2014 atherosclerosis and is associated with a high risk of cardiovascular events. Atherosclerosis develops beginning in childhood in patients with FH and reaches advanced stages before clinical manifestations develop. Inadequate diagnostics and treatment of FH in Polish children suggests a need for raising the level of awareness and understanding of the condition in both society and among health professionals. These recommendations present the current epidemiological status, guidelines for diagnosing FH in Polish children and adolescents, and effective treatment options. Ó 2014 National Lipid Association. All rights reserved.
Familial hypercholesterolemia (FH) is one of the betterknown genetic disorders; FH results in more rapid development of atherosclerosis and is associated with a high risk of cardiovascular (CV) events.1–3 Atherosclerosis develops beginning in childhood in patients with FH and reaches advanced stages before clinical manifestations develop.4,5 FH creates a significant economic burden on society because it impairs the ability to work early in life, whereas its treatment requires enormous expense. CV mortality in FH patients between ages 20 and 39 is 100-fold greater than that of the general population.6 Because of the ability to identify patients with FH at an early stage, even from childhood, the prompt introduction of effective lifestyle modifications and medical treatments may sufficiently delay the incidence of CV events in adults to improve life expectancy closer to that of the general population.7,8 Inadequate diagnostics and treatment of FH in Polish children suggests a need for raising the level of awareness and understanding of the condition in both society and among health professionals. A key issue in educating people relates to the importance of screening in the developmental age population and using cascade screening tests in the families of patients diagnosed with FH. These recommendations will present the current epidemiological status, guidelines for diagnosing FH in Polish children and adolescents, and effective treatment options. This document is an addition to the Position of the Polish Lipid Expert Forum on FH in adults.9
Epidemiology and pathogenesis of FH FH is the most common monogenetic condition.1 Its autosomal dominant mode of inheritance allows for distinguishing 2 forms of the disease: heterozygous (HeFH) and homozygous (HoFH). The prevalence of HoFH in the Caucasian population is 1 per million live births, whereas the heterozygous form can be found in 1 per 500 European citizens.6 An estimated amount of more than 80,000 people are affected with HeFH in Poland. However, this number may be underestimated. The FH phenotype is associated with a mutation in 1 of 3 genes: the low-density lipoprotein (LDL) receptor gene (approximately 1600 various mutations have been described), the apolipoprotein B (Apo B) gene, or the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene.10–12 A
mutation in the LDL receptor (LDLR) gene can be found in approximately 85–90% of FH patients. Abnormal structure of either LDL receptors or their ligand Apo B disturbs the binding of Apo B–containing lipoproteins with their receptors.10–12 This results in impaired hepatic metabolism of LDLs.13,14 In HeFH, half of LDLRs or half of Apo B molecules are affected.13,14 The third and recently discovered cause of FH is a mutation in the PCSK9 gene, which is associated with an increased degradation activity of the corresponding protein (gain-of-function mutation) toward LDLRs.12,15 PCSK9 protein binds to the epidermal growth factor–like repeat A domain of the LDLR, inducing its degradation. Reduced LDLR levels result in decreased metabolism of LDL-cholesterol (LDL-C), which leads to hypercholesterolemia.15 This mutation is relatively rare, with fewer than 5% of patients affected.12,15
Clinical manifestations of FH in children and adolescents The heterozygous form of familial hypercholesterolemia is often asymptomatic in the young population. Mean total cholesterol (TC) levels in this form of the disease ranges from 250 mg/dL (6.5 mmol/L) to 500 mg/dL (12.9 mmol/ L).6 Affected parents and close relatives are at risk of early coronary artery disease (CAD) or diagnosis of hypercholesterolemia. A clinical examination in 20-to-39-year-old patients with this form of FH may reveal xanthomas in the Achilles tendons and tendons of hand extensor muscles as well as senile corneal arcus; although xanthomas are pathognomonic for FH, they are not always present.6,9 Clinical manifestations of CAD often develop when the patients reach their 40s. The homozygous form of familial hypercholesterolemia shows virtually no activity of the LDL receptor, with TC levels typically rising up to 700 to 1200 mg/dL (18.1– 31 mmol/L).6 Largely elevated cholesterol levels can already be observed in newborns. Xanthomas in the skin may form as early as the first months of life, and those in tendons take a nodular form. Young patients with HoFH develop signs and symptoms of CAD, diffuse peripheral artery atherosclerosis, aortic stenosis, and cerebrovascular disease. Skin and tendon lesions as well as positive family history of early cardiovascular disease (CVD) may suggest the correct diagnosis.6,9
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Principles of lipid metabolism testing Prenatal and early postnatal serum TC levels are lower. Total and LDL-C levels rise rapidly in the first week of postnatal life and then gradually increase until the age of 2.16 In subsequent years, lipid and lipoprotein levels stay relatively constant until adolescence.16–18 During puberty, LDL-C drops on average by a mean of 15%, and during that time, false-negative results in FH diagnostic tests are possible19,20; therefore, the optimal period to assess lipid metabolism is between the ages of 9 and 11.16–18 If lipid levels are normal at the ages of 9 to 11, tests should be repeated at around the age of 18 because lipid panel results obtained at that age allow for the best prediction of lipid levels during the next 20 years of life.16–18 General practitioners should be responsible for conducting universal screening for lipid disturbances and, if needed, refer patients to specialist clinics that deal with lipid metabolism disturbances for additional diagnostic assessments and treatment. The children of parents diagnosed with FH should undergo their first lipid panel tests as early as between ages 2 and 11 (possibly closer to the lower age range).16 A child’s lipid panel should be conducted in plasma or serum from venous blood samples collected after fasting (ie, at least 9–12 hours after the last meal). The test involves an evaluation of TC, triglycerides, and highdensity lipoprotein (HDL)-C levels, as well as calculation of LDL-C and non–HDL-C levels.19 A lipid panel should be repeated after a 2- to 3-week interval to calculate the average value.19 This is necessary also because of significant differences in test results both resulting from biological and laboratory factors. Lipid profiles should be tested no earlier than 3 months after any acute infectious disease.
FH diagnostic criteria in children and adolescents American Academy of Pediatrics guidelines17 recommend targeted screening tests of fasting lipids of: children .2 years of age of parents diagnosed with FH; Table 1
175 children .2 years of age with a family history that is difficult to determine as well as risk factors such as: overweight–body mass index (BMI) .85th centile (.90th centile in Poland), obesity–BMI .95th centile (.97th centile in Poland), high normal blood pressure (systolic and/or diastolic blood pressure in 3 measurements $90th centile, but ,95th centile for the particular age, height, and sex), hypertension (systolic and/or diastolic blood pressure in 3 measurements $95th centile for the particular age, height and sex), diabetes, little physical activity (,60 minutes per day). The latest guidelines of the National Lipid Association (NLA) and the NLA Expert Panel on Familial Hypercholesterolemia recommend a lipid panel to be obtained in all children aged from 9 to 11.16 Diagnostic criteria for dyslipidemia in children remain controversial. The National Education Cholesterol Program (NCEP)–Expert Panel on Blood Cholesterol Levels In Children and Adolescents Report considers the threshold of TC levels to be at $170 mg/dL (4.4 mmol/L), and abnormally high levels to be at $200 mg/dL (5.2 mmol/L). For LDL-C, these values are $110 mg/dL (2.8 mmol/L) and $130 mg/dL (3.4 mmol/L), respectively.19 The pediatric population with cholesterol levels of $240 mg/dL (6.2 mmol/L) and LDL-C of $160 mg/dL (4.1 mmol/L) is highly likely to be diagnosed with the heterozygous form of HF.16,17 Table 1 presents target, threshold, and lipoprotein levels currently recommended for children and adolescents. The National Institute for Health and Clinical Excellence and the NLA Expert Panel recommend cascade screening in families of patients diagnosed with FH.1,16,21 In the family members of patients diagnosed with FH, this involves a measurement of LDL-C levels and/or molecular tests (if the proband’s mutation has been identified). This includes first-degree relatives as well as seconddegree relatives, if possible. This method helps detect
Target, threshold, and lipoprotein levels currently recommended for children and adolescents
Category
Acceptable levels
Threshold levels
High levels
TC (mg/dL, mmol/L) LDL-C (mg/dL, mmol/L) Non-HDL-C (mg/dL, mmol/L) Apo-B (mg/dL) TG (mg/dL, mmol/L) 0–9 years of age 10–19 years of age HDL-C (mg/dL, mmol/L)
,170/4.4 ,110/2.8 ,123/3.2 ,90
170–199 (4.4–5.2) 110–129 (2.8–3.3) 123–143 (3.2–3.7) 90–109
$200/5.2 $130/3.36 $144/3.7 $110
,75/0.9 ,90/1.0 .45/1.2
75–99/0.9–1.1 90–129/1.0–1.5 35–45/0.9–1.2
$100/1.1 $130/1.5
Apo-B, apolipoprotein B; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TC, total cholesterol; TG, triglycerides. Lipid and lipoprotein levels modified according to the National Education Cholesterol Program Expert Panel.19 Cutoff points for high and low values correspond to the 95th and 75th centiles, respectively.
176 Table 2 for FH
Journal of Clinical Lipidology, Vol 8, No 2, April 2014 Simon Broome Register Group’s diagnostic criteria
Criterion
Description
A
Total cholesterol .260 mg/dL (6.7 mmol/L) (,16 years of age) .290 mg/dL (7.5 mmol/L) (.16 years of age) Or LDL-cholesterol .155 mg/dL (4.0 mmol/L) (,16 years of age) .190 mg/dL (4.9 mmol/L) (.16 years of age) Xanthomas in the proband or a first-degree relative Evidence of LDL-receptor or APOB gene mutation History of myocardial infarction in first-degree relatives before 60 years of age or in seconddegree relatives before 50 years of age TC concentration .290 mg/dL (7.5 mmol/L) in a first- or second-degree relative
B C D
E
FH diagnosis Definitive Criteria A and B or C Possible Criteria A and D or A and E Apo-B, apolipoprotein B; FH, familial hypocholesterolemia; LDL, low-density lipoprotein; TC, total cholesterol.
new cases of FH in the highest risk population. A serum lipid panel in children from families with a history of FH is recommended immediately after 2 years of age, but always before age 11. This method of cascade screening is more efficient than LDL-C screening in the entire population (universal screening). One drawback of cascade screening in comparison to universal screening is the risk of overlooking children with autosomally dominant hypercholesterolemia whose parents are young and have no symptoms of CVD or are unaware of their high cholesterol levels.16 The tool most useful in detecting FH in the Polish pediatric population is the classification suggested by British specialists (The Simon Broome Register Group) (Table 2), because it is the only available tool in which FH diagnostic criteria do not include the proband’s clinical manifestations; these may not occur in children with the heterozygous form of the disease.4,22
In uncertain cases, it is always recommended to confirm FH diagnosis via genetic methods, if funds allow.
FH differential diagnosis A number of factors affect high TC and LDL-C levels. The lipid profile in patients with FH may be similar to that in secondary hypercholesterolemia in the course of a number of diseases: hypothyroidism, nephrotic syndrome, Cushing syndrome, porphyria, and during chronic treatment with certain drugs, such as thiazide and loop diuretics, corticosteroids, cyclosporine, estrogens, progesterones, and protease inhibitors.23,24 Detecting reasons for secondary hypercholesterolemia allows for a significant reduction in the number of children with suspected FH. Familial combined hyperlipidemia (FCH) should be considered while differentiating elevated TC and LDL-C levels, especially in overweight and obese patients. FCH is the most common genetic disorder of increased blood lipids (occurs approximately in 1/200 persons) that causes premature CVD; however, the genetic and metabolic basis of FCH has yet to be fully unveiled (it is probably caused by decreased LDLR and increased ApoB). Children with FCH have elevated TC and/or triglyceride levels and low HDL-C levels with normal, threshold, or elevated LDL-C.19,25,26 These lipid disorders are present in at least 2 members of the same family, with intraindividual and intrafamilial variability of the lipid phenotype. FCH may be enhanced by concomitant overweight or obesity and is usually associated with insulin resistance.19,25,26 The marked variability of lipid profile, not explained by diet or body weight, can represent the best diagnostic criterion to reduce the overlapping between metabolic syndrome and FCH.19,25,26 This is why diagnostic assessments for FH should be considered in the case of persistent dyslipidemia with LDL-C of $130 mg/ dL (3.4 mmol/L) after weight reduction in overweight or obese patients with a positive family history of early CVD.19,25 Unfortunately, no mutation responsible for the abnormalities found in FCH patients has been identified, which would significantly facilitate differentiating uncertain cases due to the growing accessibility of molecular tests.19,25
Treatment of FH in children and adolescents Molecular diagnostics The only worldwide accepted method of establishing a definitive diagnosis of FH is to find a mutation in the LDLR, Apo-B, or PCSK9 gene in a molecular test. Despite increasing accessibility of molecular diagnostics of the FH rate of mutated genes, detection varies from 30% to 80%.1,9 A negative result on the genetic test does not exclude an FH diagnosis. The genetic test will be conducted with genetic material isolated from the patient’s blood collected into an EDTA test tube. If an LDLR or APOB gene mutation is confirmed in the family, the genetic test can be also performed from a cheek swab.
Established diagnosis of FH is an indication to provide medical care for the entire family, educate the patient, introduce dietary recommendations, and undertake medical treatment. Medical care should be provided by a team of specialists (pediatricians specializing in diabetes and/or endocrinology, lipid specialists, and geneticists), a nurse, dietician, and psychologist. There are still no separate clinics designated to deal with lipid issues in the Polish health care system; dyslipidemias are treated in clinics dealing with diabetes or metabolic or cardiovascular disturbances. The aim of FH therapy in children is to reduce LDL-C by .50% or to maintain LDL-C levels ,130 mg/dL
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(3.4 mmol/L); in children with concomitant diabetes, a level ,100 mg/dL (2.6 mmol/L) is recommended.16,21
demonstrating their efficacy.23,30 However, it needs to be emphasized that data on the use of lipid-lowering agents in children are limited to short-term interventions (up to 2 years), not including long-term drug tolerance and safety.31–33 In terms of statin safety in children and adolescents, the possible association of statins and other lipidlowering medications on puberty should be discussed. Given the effects of statins on endogenous cholesterol biosynthesis, growth and sexual development might be negatively influenced by long-term exposure to these drugs in children.1 However, the available randomized controlled trials with statins in children, which investigated the influence of these drugs on pubertal development and hormonal status, showed no significant effect of statin treatment on hormonal regulation and sexual maturation.1,33 The statins seem to also be safe in adolescents, without any significant adverse effect on growth and development or on adrenal and gonadal hormones.33–35 A meta-analysis of clinical trials of statins in children and adolescents with FH with a follow-up of 2 years showed no adverse effects on growth, development, cognition, or sexual maturation and other endocrine function parameters.33,36,37 The age currently recommended by the NLA Expert Panel on Familial Hypercholesterolemia, when adding statins to the treatment of FH in children, is 8 years of age with an approved drug.16,21 The Polish Lipid Expert Forum, taking into account available data, has also accepted this age limit. Before a child with FH is qualified for medical treatment, not only his or her age, but also his or her sex, detailed family history, risk factors (ie, muscle damage; liver, kidney, or nervous system disease; severe infections; metabolic, hormonal, and electrolyte disturbances) must be considered. Medical treatment is recommended when:
Patient education Education of patients is an increasingly more appreciated and better known factor that may play a significant role in achieving positive treatment effects. Patients should receive detailed information on the causes of FH and its association with early CAD, additional risk factors for CAD, the methods and necessity of their modification, treatment options, and FH possible complications.
Dietary treatment The NCEP Expert Panel recommendations questioned the necessity of a 6- to 12-month period of low-cholesterol diet before initiating medical treatment in children diagnosed with FH.18,19 However, experts emphasized the significant role of diet as supportive treatment in every child with dyslipidemia.18,19 The pediatric panel of NCEP recommends initiating treatment with diet in children after the age of 2; nonetheless, data from the Special Turku Coronary Risk Factor Intervention Project and the Dietary Intervention Study in Children show that a low-fat diet may be safely introduced in children as early as 7 months old, if it is conducted under medical supervision.27 The Polish Lipid Expert Forum agrees with the NCEP recommendations on introducing dietary treatment from the age of 2, and even earlier in urgent cases, if it is being conducted under strict medical supervision. The American Academy of Pediatrics nutritional recommendations should be followed in older children and dietary treatment should be used.17,28 This involves mainly limiting consumption of saturated fatty acids to ,7% of total energy and dietary cholesterol ,200 mg/day.4,17,19 The important role of such substances as dietary fiber and plant sterols and stanols has been emphasized as well as oily sea fish consumption. Dietary advice should be provided by a dietician. A low-fat diet in the treatment of FH is useful but not primary treatment. Replacing saturated fats with polyunsaturated fats may lead to lowering LDL-C levels by only 15%, insufficient to reach treatment goals.17–19 Therefore, FH requires medical treatment initiation.
Medical treatment Introduction of early lipid-lowering therapy in patients diagnosed with FH significantly reduces the incidence of CAD, myocardial infarction, the necessity of revascularization procedures, and early CV deaths.29 Statins are the first-choice agents in the treatment of FH.4,9,17,23,24,30 The use of formulations previously used in the treatment of children with FH (ie fibrates or cholestyramine) has been significantly reduced because of a lack of robust studies
- LDL-C levels $130 mg/dL (2.6 mmol/L) in children with diabetes, - LDL-C levels $160 mg/dL (4.1 mmol/L) in children with at least 2 risk factors for CVD (ie, obesity, hypertension, and smoking) or with family history positive for early CVD, - LDL-C levels $190 mg/dL (4.9 mmol/L), in children without risk factors. Introducing medication in children younger than 8 years of age is warranted at LDL-C levels .500 mg/dL (12.9 mmol/L) (eg, in the course of the HoFH).16,21 Unfortunately, these LDL-C levels are arbitrary. No robust studies in the pediatric population have been conducted that would help accurately determine the LDL-C concentration above which there is a significantly higher risk of developing early atherosclerosis.30,31 Moreover, there is no known so-called ‘‘safe’’ concentration of LDL-C that would protect against developing CV complications. Current recommendations are based on data extrapolated from studies conducted in adults.30,31 Lipid-lowering treatment in children must always be balanced between a specific dose of the drug and potential side effects of treatment.
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General principles of statin use
Ezetimibe
Individual statins vary in terms of potency at a given dose. They are typically administered once a day in the evening, because physiological synthesis of cholesterol increases at night. In children with FH, treatment begins from small doses of statins (2.5–5–10 mg/day, depending on the formulation) and the dosage is titrated up to when the desired therapeutic effect is achieved. The full effect of statins on lipid metabolism is observed after 4 to 6 weeks. The lowering of LDL-C concentration achieved after 2 weeks of treatment with a given dose of statin typically corresponds to 90% of this dose’s potency.16,21,31,32 Before the statin therapy is initiated, transaminase levels, especially alanine aminotransferase as well as creatinine kinase activity, should be determined. Transaminase levels should be retested 6 weeks after introduction of a statin, and monitored every 6 months in subsequent years. If transaminase levels increase above the upper limit of normal by 3fold or more, the statin must be discontinued.2 An increase in transaminase levels is usually transient and resolves after 2 to 3 months of treatment discontinuation.31–33 Currently, routine creatinine kinase tests are not recommended during treatment and should be conducted only if muscle-related symptoms, such as myopathy (muscle pain and/or weakness) develop. If creatinine kinase levels exceed the upper limit of normal by 5-fold, the statin must be discontinued.33 Other, though rare, side effects of statins include: gastrointestinal disturbances, fatigue, insomnia, headaches, skin rash, peripheral neuropathy, and lupus-like syndrome. After treatment initiation in children, cholesterol levels should be regularly assessed and any drug side effects that may affect the child’s development, nutritional status, and sexual maturity should be monitored.30 Contraindications to the use of statins in children include: hypersensitivity to the drug; muscle damage; statin-related myopathy; active liver disease or persistently elevated transaminase levels; transaminase level increased by 3-fold above the upper limit of normal during statin administration; renal impairment; severe infections; major surgery; major trauma; severe metabolic, hormonal, or electrolyte disturbances; or uncontrolled epileptic seizures. Currently, statins are the most potent lipid-lowering treatments available for treating FH; however, when used in monotherapy, they do not always achieve the target levels of LDL-C.
Ezetimibe inhibits cholesterol absorption from the small intestine at the level of enterocyte cell membrane and sterol-binding proteins. Because of different points of action of ezetimibe and statins, adding 10 mg/day ezetimibe to statin therapy reduces LDL-C levels by additional 15% to 25%.17 Full lipid-lowering activity of ezetimibe can be achieved as early as 2 weeks of its use.17 The drug should be used carefully in patients with liver dysfunction and malabsorption syndromes. In children, the American Academy of Pediatrics allows the use of ezetimibe conditionally if treatment with statins is not tolerated.17 This medication is often a valuable supplement in FH treatment in Poland, especially because it is subsidized (payable at 30%) in this group of patients.
Bile acid–binding resins Bile acid–binding resins decrease LDL-C levels by 10% to 30%.31–33 However, because of the large dosage volume and bothersome gastrointestinal side effects, including constipation, they are rarely used in children.31–33 A welltolerated resin is colesevelam (Welchol). It has been approved in the United States for the treatment of the HeFH in children. In Poland, its use is marginal.
Conclusion Familial hypercholesterolemia is a relatively common dyslipidemia, although it is still quite rarely diagnosed and undertreated. In Poland, only about 20% of the population is estimated to have been diagnosed with FH, of whom only a small number receive adequate treatment. FH is characterized by significantly elevated LDL-C levels present since birth. Functional and structural changes in vascular walls in the course of FH can be found in children. This condition contributes to a rapid development of atherosclerosis and early CAD and mortality. Early diagnosis and adequate treatment of FH initiated in the developmental age population may considerably reduce the risk of CVD and sudden death in adults. General practitioners should be aware of their key role in early diagnosis and treatment of FH complementary to the necessary specialist care in dyslipidemias. Universal lipid metabolism screening tests in children aged 9 to 11 as well as cascade screening in families affected with FH may translate into a significant reduction in treatment costs for complications resulting from untreated hypercholesterolemia.38,39 The funding of FH diagnostics, treatment, education, and research should come from multiple sources, including the Polish National Health Fund, governmental (Polish Ministry of Health) and research agencies, and the pharmaceutical industry. This position statement on FH in children and adolescents has been developed by a team of Polish experts. After puberty, recommendations for FH treatment in adults should be followed, including recent guidelines of Polish Lipid Expert Forum.40
Summary of recommendations In Poland, only about 20% of the population is estimated to have been diagnosed with FH The pediatric population with cholesterol levels of $240 mg/dL (6.2 mmol/L) and LDL-C of $160 mg/
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dL (4.1 mmol/L) is highly likely to be diagnosed with the heterozygous form of FH The optimal period to assess lipid metabolism is between the ages of 9 and 11; however, the children of parents diagnosed with FH should undergo their first lipid panel tests as early as between ages 2 and 11, possibly closer the lower age range The tool most useful in detecting FH in the Polish pediatric population is the Simon Broome Register Group classification; however, in uncertain cases, it is always recommended to confirm FH diagnosis via genetic methods The aim of FH therapy in children is to reduce LDL-C by .50% or to maintain LDL-C levels ,130 mg/dL (3.4 mmol/L), and in children with concomitant diabetes ,100 mg/dL (2.6 mmol/L) Statins are the first-choice agents in the treatment of FH. We recommend using statins in the therapy of FH in children $8 years of age with an approved drug; however, introducing medication in children younger than 8 years of age is warranted at LDL-C levels .500 mg/dL (12.9 mmol/L) We suggest the introduction of dietary treatment from the age of 2, and even earlier in urgent cases, if it is being conducted under strict medical supervision.
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Acknowledgments The position paper has been officially endorsed by Polish Lipid Association (PoLA). The current position paper has been also published in parallel in Polish in Kardiologia Polska (Polish Journal of Cardiology), Endokrynologia Pediatryczna, and Pediatria Polska, the official journal of the Polish Pediatric Society.
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