Overview of Familial Hypercholesterolemia (FH)
Familial hypercholesterolemia (FH) is an autosomal dominant trait with complete penetrance (all affected individuals exhibit symptoms), causing congenitally elevated levels of low-density lipoprotein (LDL). There is a gene dosage effect: homozygotes have significantly greater elevations of LDL and earlier onset of cardiovascular disease compared to patients who are heterozygous. With a frequency of between 1 in 300 and 1 in 500 in the general population, or more than 600,000 people affected in the US, heterozygous FH is one of the most widely prevalent genetic diseases encountered in clinical practice.
The clinical effects of familial hypercholesterolemia (FH) are the result of cumulative exposure to abnormally high levels of low-density lipoprotein (LDL) over an extended period of time. This exposure predisposes individuals to early atherosclerotic events, and potentially, if untreated, to premature death. Compared to unaffected relatives, patients diagnosed either genetically or clinically with FH have an almost twelve-fold increase in the risk of coronary artery disease (CAD). The difference in risk is greatest at 35 years of age, underscoring how early in life untreated FH manifests its effects.
The risk of myocardial infarction (MI) without treatment is 24 times higher than normal before age 40 years. However, FH is highly responsive to therapy, and early detection, followed by long-term statin treatment, has been found to largely ameliorate the excess cardiovascular disease (CVD) risk due to FH. In fact, the long-term CHD risk of statin-treated FH patients closely resembles that of the general population.
FH in the Pediatric Population
Recent Expert Panel Recommendations from the National Lipid Association advocate universal screening for children aged 9 to 11 years, with a fasting lipid profile or nonfasting non-HDL-C (total cholesterol minus HDL cholesterol). This age identifies individuals at the potential onset of advanced atherosclerosis and provides the best discrimination between those with and without inherited dyslipidemias by avoiding confounding due to changes in lipid levels associated with puberty.
Levels of LDL-C >160 mg/dL or non HDL-C >190 mg/dL is suggestive of FH, although levels are commonly higher than 190 mg/dL in affected children. If a nonfasting non-HDL-C concentration of >145 mg/dL is detected, then a fasting lipid profile should be performed. Specific diagnostic algorithms (Simon Broome, Dutch Lipid Clinic Registry, or US MEDPED) that integrate physical findings, family history, lipid values, and presence of cardiovascular disease, are used to help confirm the diagnosis.
Screening should occur earlier (2 or more years of age) if there is a family history of hypercholesterolemia or premature CHD, or if other major CHD risk factors are present. Identifying FH in those with other major CHD risk factors is critical for risk stratification. An evaluation (history, physical examination, selected laboratory tests) of possible secondary causes of dyslipidemia (hypothyroidism, nephrotic syndrome, liver disease) should be performed. Cascade screening, discussed previously, should be employed as new FH patients are identified.
Pharmacologic Treatment of Pediatric FH Patients
As with adults, statins are the initial pharmacologic treatment of choice for children, following initiation of diet and physical activity management. Rosuvastatin, atorvastatin, simvastatin, lovastatin, and fluvastatin are FDA-approved as an adjunct to diet for the treatment of markedly elevated LDL-C in children over the age of 10 years. Pravastatin is indicated for children over 8 years of age. It is appropriate to consider treating an FH patient who merits drug therapy beginning at age 8, or even younger in special cases, such as a child with homozygous FH.
Statins usually reduce LDL-C in children with FH from 23% to 40%. Adverse effects for statin therapy in children are similar to those reported for adults, and may include muscle aches, pains, or weakness in a small number of individuals, as well as liver enzyme elevations. No adverse effects on growth, hormone levels, or sexual maturation have been found. Evidence from noninvasive vascular endothelial function testing and carotid intima media thickness measurements show that lipid lowering with statins in FH patients delays the atherosclerotic disease process.
The goal of lipid-lowering therapy in pediatric FH patients is a >50% reduction in LDL-C or LDL-C <130 mg/dL. In pediatric FH, it is essential to strike a balance between increased dosing and the potential for side effects versus achieving lipid targets. However, the natural history of the disease is clearly one which requires early treatment and therapy should not be deferred merely because of age. More aggressive LDL-C targets should be considered for those with additional CHD risk factors.
Agents other than statins are available for use in the pediatric population. Bile acid sequestrants lower LDL-C by approximately 10% to 20%, but are often poorly tolerated due to gastrointestinal adverse effects, although this is less often the case with colesevelam than with the older agents cholestyramine and colestipol. Although bile acid sequestrants are generally considered safe in childhood, cholestyramine and colestipol do not have a pediatric indication, whereas colesevelam is indicated for boys and post-menarchal girls aged from 10 to 17 years, either as a monotherapy or in combination with a statin.
The cholesterol absorption inhibitor ezetimibe has been shown to reduce LDL-C by an additional 20% when added to a statin. Recent studies support its use as a monotherapy or in combination with a statin in FH populations, including children and adolescents. However, ezetimibe has not received an indication by the FDA for use in children with hypercholesterolemia.
There is limited published experience in children with the use of niacin or fibrates, neither of which is used routinely in the treatment of pediatric FH. Potential adverse effects (flushing, hepatic dysfunction, myopathy, glucose intolerance, hyperuricemia) may limit the use of niacin. Fibrates (particularly gemfibrozil) may increase the risk of statin-induced myositis. They are not recommended for use in pediatric patients with FH unless triglyceride levels are elevated (which often suggests a different disease process), in which case they may be used with caution.
Lipidology Services for Pediatric Lipid Disorders
The Lipoprotein and Metabolic Disorders Institute (LMDI) is a center of excellence for comprehensive evaluation and management of genetic and acquired lipoprotein disorders affecting patient of all ages. We schedule appointments by referral from area providers, as well as by patient request, to provide a range of evaluation and management services. Diagnostically, we perform detailed evaluation of primary (genetic), secondary (co-morbid), and mixed etiologies responsible for a patient's laboratory abnormality. Additionally, as a center of excellence in non-invasive vascular imaging we frequently use carotid intima-media thickness testing to establish the presence of the earliest stages of vascular disease (arterial wall thickening and plaque formation), as well as to follow vascular response to therapy. Therapeutically, we provide family centered therapeutic lifestyle counseling and mono- or combination pharmacologic management as indicated for children with severe lipid disorders.
Details regarding our practice and scheduling office visits can be found in our Winter 2011 News Letter (http://bit.ly/xjedwi) or at our website (www.cromwellmd.com).
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