eMedicine Specialties > Endocrinology > Metabolic Disorders

Hypercholesterolemia, Familial

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael

Updated: Aug 4, 2009

Introduction

Background

Familial hypercholesterolemia (FH) is an autosomal dominant disorder that causes severe elevations in total cholesterol and low-density lipoprotein cholesterol (LDLc). Although moderate hypercholesterolemia is a common finding in industrialized countries, heterozygous FH occurs in approximately 1 per 500 persons worldwide.

Because FH is associated with a high risk for premature coronary artery disease (CAD), health professionals should be alert to the signs found during a physical examination and to the laboratory values suggestive of FH. Early detection and aggressive management to lower the LDLc level helps prevent or slows the progression of coronary atherosclerosis. Moreover, if the first-degree relatives of a patient with FH are screened, other gene carriers can be identified and treated.

Pathophysiology

FH is a disorder of absent or grossly malfunctioning low-density lipoprotein (LDL) receptors. The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. It is the primary determinant of hepatic LDL uptake, which normally processes approximately 70% of circulating LDL. Two ligands on LDL bind to the receptor, apolipoprotein B-100 (apoB-100) and apoE. The LDL receptor also binds another ligand, apoE, and is, therefore, more accurately termed the B,E receptor. ApoE is found on most lipoproteins other than LDL, including very low-density lipoprotein (VLDL) and chylomicrons and their remnants, intermediate-density lipoprotein (IDL), and a subclass of high-density lipoprotein (HDL). The LDL receptor binds apoE with higher affinity than apoB-100, and some mutations in the receptor may spare uptake of LDL by allowing binding to apoE.

Goldstein and Brown discovered the LDL receptor and determined that FH was caused by an autosomal dominant mutation. Since then, more than 700 mutations have been identified that have a meaningful impact on receptor function. LDL receptor function ranges from completely absent to approximately 25% of normal receptor activity.

Five classes of mutations have been defined as follows:

• Class 1 includes null alleles that result in complete absence of the LDL receptor. 
• Class 2 includes defective transport alleles, which disrupt normal folding of the receptor and cause either failure in transport to the cell surface or successful transport of truncated, mutated receptors.
  • Class 2a mutations completely block the transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
  • Class 2b mutations result in a partial blockade of transport of the receptor from the endoplasmic reticulum to the Golgi apparatus.
• Class 3 includes defective binding alleles that affect binding of LDL and, in some cases, binding of VLDL as well.
• Class 4 includes defective internalization alleles that affect the concentration of normal receptors in clathrin-coated pits for internalization by the hepatocyte. 
• Class 5 includes defective recycling alleles that prevent dissociation of the receptor and the ligand and thereby interrupt recycling of the receptor.

Frequency

United States

The prevalence of heterozygous FH is approximately 1 case per 500 persons. The prevalence of homozygous FH is 1 case per 1 million persons.

International

The prevalence of heterozygous FH in Europe approximates that of the United States, but certain regions, such as Iceland and Finland, or populations have a higher incidence. The prevalence of heterozygous FH among French Canadians is 1 case per 270 persons and is 1 case per 170 persons in Christian Lebanese. Due to the founder effect and relatively isolated populations, 3 distinct populations within South Africa have an extremely high prevalence of FH: 1 case per 67 in Ashkenazi Jews and 1 case per 100 persons in both Afrikaners and South African Indians.

Mortality/Morbidity

• Homozygous FH
  • Severe and widespread atherosclerosis affects all major arterial beds, including the carotid, coronary, femoral, and iliac.
  • Children are at risk for early coronary events, and sudden death or acute myocardial infarction may occur in patients as young as 1-2 years. Without heroic interventions to lower blood cholesterol levels, survival beyond young adulthood is unlikely.
  • Valve abnormalities are common, particularly aortic stenosis.
  • Accumulation of cholesterol in nonvascular tissue is of less clinical significance. Corneal arcus and planar, tendon, and tuberous xanthomas are present early in childhood and sometimes at birth. Recognition of the cutaneous manifestations of FH permits early diagnosis and treatment to prevent the otherwise severe and inevitable cardiovascular complications.
• Heterozygous FH
  • Premature CAD is the most serious and preventable manifestation. Untreated men are likely to develop symptoms by the fourth decade of life. The onset of symptoms in women lags behind men by approximately 10-15 years. No accurate estimates of mortality rates are available.
  • Cholesterol deposition in nonvascular tissue is common, although heterozygous children do not usually have physical manifestations; adults do not invariably develop them. Corneal arcus is the most frequent finding, particularly in patients older than 30 years, but this finding is also common in older patients and African Americans without hypercholesterolemia. Similarly, xanthelasmas (palpebral xanthomas) can occur in older individuals with normal cholesterol levels. Neither xanthelasma nor corneal arcus is of clinical significance, except possibly cosmetically.
  • Xanthomas, most commonly of the Achilles tendon and extensor tendons of the hands, are rare in children and common in untreated adults. Tendon xanthomas may occur with other conditions such as familial defective apoB-100 and type III hyperlipoproteinemia. These deposits can cause Achilles tendonitis and articular symptoms, particularly of the hands, wrists, knees, and ankles.

Race

Certain populations with Finnish, Lebanese, Ashkenazi Jewish, Afrikaner, or French Canadian origins have a higher prevalence of FH.

Sex

• The gene for FH is on chromosome 19; therefore, the inheritance pattern is the same for males and females.
• In heterozygous FH, the consequences of severe hypercholesterolemia manifest earlier in men than in women because of the sex protection that benefits women until the postmenopausal years. Although a woman with no other major risk factors for CAD may not develop symptomatic CAD during her lifetime, men are rarely so fortunate.
• Homozygous girls and boys have the same risk for a very early cardiovascular event.

Age

• The consequences of a defective LDL receptor and subsequent elevations of LDLc are present at birth, but age is relevant because the longer patients live with extremely elevated LDLc levels, the higher their risk of CAD.
• Early diagnosis and treatment to lower LDL levels and treat other coronary risk factors slows the progression of coronary atherosclerosis.

Clinical

History

• Children with homozygous FH
  • These patients may have symptoms consistent with ischemic heart disease, peripheral vascular disease, cerebrovascular disease, or aortic stenosis. Such symptoms may be confused with conditions that are more benign unless the diagnosis of homozygous FH is considered.
  • Patients may have articular symptoms such as tendonitis or arthralgias.
  • Patients have a history of unusual skin lesions.
  • Because they are obligate heterozygous hypercholesterolemics, both parents must have severe elevations in LDLc; although they are often too young to have developed symptomatic CAD. Because each must have a parent with heterozygous FH, a history of significant hypercholesterolemia and premature CHD can be traced to the patient’s second degree relatives. 
• Children with heterozygous FH
  • Children with heterozygous FH do not have symptoms related to CHD.
  • One parent will have severe hypercholesterolemia and will probably have either a personal or family history for early CAD.
  • Statistically, because the gene for FH is dominant, 50% of the patient’s siblings will also have heterozygous FH.
• Adults with homozygous FH
  • Most patients do not survive beyond age 30 years unless treated with unusual methods, such as liver transplantation, LDL apheresis, or ileal bypass surgery to dramatically lower their LDLc levels.
  • Their family history should be positive for severe hypercholesterolemia and premature CAD in both parental family lines.
• Adults with heterozygous FH
  • These patients have a long-standing history of severe hypercholesterolemia dating back to childhood.
  • If an acute coronary event has not already occurred, symptoms consistent with ischemic heart disease are not uncommon, especially if other cardiovascular risk factors (especially smoking) are present.
  • Past or present symptoms of recurrent Achilles tendonitis or arthritic complaints may be present.
  • Premature CAD and severe hypercholesterolemia are present in one or more first-degree relatives.
• If carefully questioned, patients with either homozygous or heterozygous FH may describe first-degree relatives who had visible tendon xanthomas on their hands.

Physical

The presence of tendon xanthomas is usually stated to be pathognomonic for FH, but that is not the case. As described in Causes, patients with familial ligand defective apoB-100 may have tendon xanthomas and elevated LDLc levels. 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. However, this rare disease causes other abnormalities (eg, dementia, ataxia, cataracts) with reference range cholesterol levels and, therefore, cannot be confused with FH. Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. Tendon xanthomas are present at an early stage although cholesterol levels are within the reference range or only mildly elevated. Uncommonly, patients with dysbetahyperlipoproteinemia have tendon xanthomas.

Homozygous FH

• These patients may have cutaneous xanthomas at birth or by early childhood.
• Several types of xanthomas are usually obvious in the first decade of life, and they include (1) planar xanthomas (on hands, elbows, buttocks, or knees), which are diagnostic for the homozygous state and are distinct from other cutaneous xanthomas because of their yellow-to-orange coloration; (2) tuberous xanthomas (on hands, elbows, or knees); and (3) tendon xanthomas (especially on extensor tendons of hands or Achilles tendon) will occur somewhat later.
• Children may have corneal arcus, which is sometimes circumferential. While occasionally present in older adults with normal cholesterol levels, corneal arcus is highly unusual in children, and this finding should prompt a workup for homozygous FH.
• The murmur of aortic stenosis may be heard.

Heterozygous FH

Most children with heterozygous FH do not develop tendon xanthomas or corneal arcus. By the third decade of life, more than 60% of patients with untreated FH develop tendon xanthomas as in the image below.

Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.

Xanthomas are noted commonly on the Achilles tendons and metacarpal phalangeal extensor tendons of the hands.

The figures in many textbooks suggest that tendon xanthomas in heterozygous patients are readily apparent upon gross inspection. Unfortunately, this often is not the case. Careful palpation rather than simple inspection may be necessary for detection of Achilles tendon xanthomas. A diffusely thickened tendon or one with discreet irregularities is suggestive of a xanthoma.

Tendon xanthomas of the metacarpophalangeal joints may be seen by careful inspection and palpation. Slowly flexing and extending the digits and watching for nodules that move with the motion of the tendon make these xanthomas more noticeable and distinguish them from cutaneous or subcutaneous nodules.

Xanthelasmas may occur in older patients with normal cholesterol levels and this finding is, therefore, not specific for FH.

The presence of tendon xanthomas is often stated to be pathognomonic for FH but that is not the case.

• As described below, patients with familial ligand defective apoB-100 may have tendon xanthomas and equivalent laboratory values.
• 27-hydroxylase deficiency (cerebrotendinous xanthomatosis) causes tendon xanthomas due to the accumulation of both cholesterol and cholestanol. But this rare disease causes other abnormalities (dementia, ataxia, cataracts) with normal cholesterol levels and, therefore, cannot be confused with FH.
• Sitosterolemia (phytosterolemia), a rare autosomal recessive disease, is characterized by hyperabsorption of plant sterols. Tendon xanthomas may be present though cholesterol levels are normal or only mildly elevated.
• Uncommonly, patients with dysbetalipoproteinemia have tendon xanthomas.

Causes

A major change in the number or functional status of LDL receptors directly affects serum cholesterol levels. If the liver does not take up LDL particles, serum LDLc levels increase. Also, when LDL is not internalized by hepatocytes, hepatic synthesis of cholesterol is not suppressed. This leads to further cholesterol production despite high levels of circulating cholesterol. Therefore, circulating cholesterol levels are increased dramatically. The total and LDLc levels of infants and children with homozygous FH are higher than 600 mg/dL. In patients with heterozygous FH, half the LDL receptors are normal and half are rendered ineffective by the mutation. These patients' total cholesterol and LDLc levels are twice as high as the population average. LDLc levels of 200-400 mg/dL are common.

High levels of LDLc increase cholesterol uptake in nonhepatic cells that is independent of LDL receptors. These scavenger pathways allow cholesterol uptake by monocytes and macrophages, leading to foam cell formation, plaque deposition in the endothelium of coronary arteries, and premature CAD. Cholesterol also accumulates in other areas, particularly the skin, causing xanthelasmas and a variety of xanthomas. Early corneal arcus is frequent, and, in patients with the homozygous condition, valvular abnormalities, most frequently aortic stenosis, are common secondary to the deposition of cholesterol.

Several conditions other than FH cause severely elevated LDL levels, and each is caused by a single gene abnormality.

Familial ligand defective apoB-100

Familial ligand defective apoB-100 (FLDB), also called familial defective apoB-100, is responsible for a syndrome almost indistinguishable from heterozygous FH.  Instead of an abnormal or absent LDL receptor, this syndrome is caused by an abnormality at the binding site of apoB-100, which impedes its role as a ligand for the receptor. ApoB-100 is a single polypeptide chain composed of 4536 amino acids. The gene resides on the short arm of chromosome 2 and the first described mutation was a substitution of glycine for arginine at the codon for amino acid 3500.  Different mutations at the same and different codons have since been described.

 Although the LDL receptors are normal in both number and function, LDL is taken up inefficiently, leading to elevated LDLc levels that can be indistinguishable from those associated with heterozygous FH. These patients can present with cutaneous manifestations and an increased risk of premature CAD similar to patients with heterozygous FH. Because LDL receptors function normally with respect to the apoE ligand, uptake of very low-density lipoprotein, very low-density lipoprotein remnants, and intermediate-density lipoprotein is normal. The consequence may be that patients with defective apoB-100 may have a clinically more benign course than patients with heterozygous FH. The finding that patients homozygous for familial defective apoB-100 are clinically similar to those with the heterozygous condition supports this supposition.

Autosomal recessive hypercholesterolemia

Another recently identified molecular defect that also causes severely elevated LDL levels is autosomal recessive hypercholesterolemia. These patients have LDLc levels that are higher 400 mg/dL; however, heterozygous individuals have normal levels.

Differential Diagnoses

Dysbetahyperlipoproteinemia (type III hyperlipidemia)
Familial ligand defective apoB-100, familial defective apoB-100
Homozygous autosomal recessive hypercholesterolemia
Sitosterolemia (Phytosterolemia)

Other Problems to Be Considered

Familial combined hyperlipidemia
Hypothyroidism
Lipoprotein X
Nephrotic syndrome
Severe hypertriglyceridemia  
Polygenic hypercholesterolemia

Workup

Laboratory Studies

• The diagnosis of both homozygous and heterozygous FH is based primarily on the finding of severe LDLc elevations in the absence of secondary causes of hypercholesterolemia with triglyceride levels that are within the reference range or mildly elevated and HDL cholesterol (HDLc) levels that are within the reference range or slightly low. A probable diagnosis of heterozygous FH can be made if the LDLc level is greater than 330 mg/dL or if tendon xanthomas are present in a patient with an LDLc level above the 95th percentile. Definitive diagnosis can be made only with gene or receptor analysis.
• A substantial increase in serum triglyceride levels should raise the possibility of another lipid disorder.
• Lipid analysis
  • Cholesterol levels are severely elevated in children and adults with homozygous FH, with total cholesterol and LDLc levels greater than 600 mg/dL and triglyceride levels within the reference range.
  • In patients with heterozygous FH, LDLc levels are commonly higher than 250 mg/dL and usually increase with age. An LDLc level higher than 200 mg/dL in a patient younger than 20 years is highly suggestive of heterozygous FH or, possibly, familial ligand defective apoB-100 (see Pathophysiology). In adults, LDLc levels higher than 290-300 mg/dL suggest heterozygous FH.
  • Lipoprotein (a) may be measured because patients with both heterozygous FH and high levels of lipoprotein (a) (>30 mg/dL) have a worse prognosis than those with normal levels of lipoprotein (a). However, all patients with FH are at very high risk for CAD and because no data are available to suggest that lipoprotein (a) should be specifically targeted for treatment. 
• Tests to rule out secondary hypercholesterolemia
  • Other laboratory testing may be suggestive by findings discerned thorough history and physical examination.
  • In the absence of symptoms or signs suggestive of a particular disorder, a limited workup should be performed to rule out secondary hypercholesterolemia.
  • Basic tests to rule out diabetes, hypothyroidism, hepatic disease, and renal disease are usually sufficient.

Imaging Studies

• An echocardiogram is indicated for children with homozygous FH, especially those who have a murmur or symptoms suggestive of aortic stenosis or another valve abnormality.
• Children with homozygous FH should be referred to a pediatric cardiologist for consideration of vascular imaging studies (Pet scan, determination of carotid intima medial thickness, coronary catheterization) that can direct treatment for hypercholesterolemia.
• Radiographic imaging of the Achilles tendon helps accurately measure Achilles tendon xanthomas, but the findings do not change lipid management.

Other Tests

• Lipoprotein electrophoresis is expensive and is unnecessary for the diagnosis of FH. Moreover, in the absence of preparative ultracentrifugation, it has no place in the workup of any lipid disorder. If fasting lipid analysis reveals elevated triglyceride levels and the diagnosis of FH is in doubt, beta quantification (ultracentrifugation and electrophoresis) may be performed at a major lipid center or one of the few commercial sites in the United States and other countries that performs this procedure.
• LDL receptor analysis can be used to identify the specific LDL receptor defect. However, this analysis can only be performed at certain research laboratories and is expensive; and the results have no impact on management. LDL receptor or apoB-100 studies can help distinguish heterozygous FH from the similar syndrome of familial defective apoB-100, but this finding would not alter treatment.

Procedures

• The presence of an unusually high LDLc level should make identifying a cutaneous lesion straightforward. Possible entities include xanthelasmas or xanthomas.
• If identification of a cutaneous lesion is unclear and the diagnosis of heterozygous FH is uncertain, a biopsy can be performed. Both xanthelasmas and the xanthomas of FH contain accumulations of cholesterol. By contrast, eruptive xanthomas in patients with severe hypertriglyceridemia (levels >1000 mg/dL) contain triglycerides (fat).

Treatment

Medical Care

The National Cholesterol Education Program (NCEP) ATPIII defined LDLc goals and cutpoints for therapeutic intervention based on risk for CHD (see Table 2 and Table 3).

The guidelines were updated in 2004 to reflect the findings of several interventional trials demonstrating that coronary event rate was reduced after lowering the LDLc well below 100 mg/dL.

• Clinical CHD
• Symptomatic carotid artery disease or carotid stenosis greater than 70%
• Peripheral artery disease
• Abdominal aortic aneurysm
• Diabetes
• Global 10-year risk of major CHD event (ie, fatal or nonfatal myocardial infarction) greater than 20%

In patients without atherosclerotic disease, the risk for developing CHD is defined by the number of major risk factors for CHD and by the following:

• Hypertension (blood pressure >140/90 mm Hg or treatment for hypertension)
• Cigarette smoking (any within the past mo)
• HDLc level below 40 mg/dL
• Male sex and age 45 years or older
• Female sex and age 55 years or older
• Family history of premature CHD: Clinical CHD or sudden death in first-degree male relative younger than 55 years or first-degree female relative younger than 65 years

Percent risk for developing CHD or having a major CHD event (ie, fatal or nonfatal myocardial infarction) is determined by calculating the Framingham risk score, which is available through the US National Heart, Lung, and Blood Institute (see Risk Assessment Tool for Estimating 10-Year Risk of Developing Hard CHD).

• LDLc goal less than 100 mg/dL
• Therapeutic lifestyle changes (TLC) instituted at LDL 100 mg/dL or more
• Medical therapy initiated at LDL 100 mg/dL or more (new 2004 cut off point)
• Optional LDLc goal less than 70 mg/dL, especially for very high risk patients:
  • Patients with CHD and multiple other major risk factors for CHD, especially diabetes
  • Severe, poorly controlled risk factors, especially continued cigarette smoking
  • Multiple risk factors of the metabolic syndrome
  • Patients admitted with an acute coronary syndrome

• See Table 2
• Global risk 10-20%
  • LDLc goal less than 130 mg/dL
  • Optional LDLc goal less than 100 mg/dL
• Consider medical therapy for LDL 100-129

Moderate risk, 2 risk factors or more

• Global risk less than 10%
  • LDLc goal less than 130 mg/dL

• None to 1 major risk factor for CHD
• LDLc goal less than 160 mg/dL
• Low-risk patients have fewer than 2 risk factors and a 10-year risk for a major CHD event that is almost always less than 10%. The goal LDLc is less than 160 mg/dL.
• Moderate risk patients have 2 or more factors and a 10-year risk for CHD of less than 10%. The goal LDLc is less than 130 mg/dL.
• Moderately high risk patients have 2 or more risk factors and a 10-year risk of 10-20%. The goal LDLc is less than 130 mg/dL and the update suggested an optional goal LDLc of less than 100 mg/dL.
• The highest category of risk includes CHD and CHD risk equivalents
  • Clinical CHD
  • Symptomatic carotid artery disease (transient ischemic attack or stroke of carotid origin)
  • Peripheral artery disease
  • Abdominal aortic aneurysm
  • Diabetes
  • 10-year risk less than 20%
• The LDLc goal for high-risk patients is less than 100 mg/dL and the 10-year risk is greater than 20%. In addition to lifestyle changes, institution of medication is recommended if LDLc level is greater than 100 mg/dL. Patients at high or very high risk have an optional LDLc goal of less than 70 mg/dL.
• Patients with cardiovascular disease who are at very high risk have an optional LDLc goal of less than 70 mg/dL.
• Very high risk is defined as the presence of the following:
  • Multiple other major risk factors for CHD, especially diabetes
  • Severe, poorly controlled risk factors, especially continued cigarette smoking
  • Multiple risk factors for the metabolic syndrome (especially triglycerides >200 mg/dL, non-HDLc >130 mg/dL, and HDLc <40 mg/dL)
  • Patients with acute coronary syndromes

• Healthy diet, regular exercise, and maintenance of desirable weight
• Because of improved diet normally results in upregulation of LDL receptors, the impact of diet changes on LDLc levels in homozygous patients is negligible (there are no receptors to upregulate), but lifestyle changes have other cardiovascular benefits and should be strongly encouraged.
• Because of the severity of CHD and lack of response, homozygous FH patients require heroic intervention.
• Occasionally, the LDL receptors retain some degree of function and diet control and high doses of HMG-CoA reductase inhibitors combined with bile acid sequestrants, ezetimibe, and niacin can be effective. Estrogen replacement therapy in postmenopausal women is also effective, but this therapy is not recommended because of its adverse effects in older women. However, in some women the benefits may outweigh risks.
• When the LDL receptors are absent or nonfunctional, one of the following is necessary:
  • LDL apheresis for homozygous FH involves selective removal of lipoproteins that contain apo-B by heparin precipitation, dextran sulfate cellulose columns, or immunoadsorption columns.
    • All methods reduce LDLc levels more than 50% and also lower lipoprotein (a), VLDL, and triglyceride levels. HDL is spared.
    • The procedure takes 3 or more hours and is performed at 1- to 2-week intervals. Few adverse events are experienced, most of which are noncritical episodes of hypotension.
    • LDL apheresis is an extremely expensive procedure and is not readily available.
  • Portacaval anastomosis
    • Compared to liver transplantation (see Surgical Care), this procedure is less hazardous and requires no immunosuppression.
    • Although cholesterol levels are not reduced as dramatically when compared with transplantation or apheresis, the clinical benefits appear comparable.
    • LDLc reductions 50% have been reported; regression of coronary lesions, aortic lesions, and xanthomas have been documented.
    • The exact mechanism by which LDLc is lowered is unclear.
• Other treatments for homozygous FH
  • Probucol, a medication with only mild LDL-lowering effects and an undesirable HDL-lowering impact, has been shown to cause regression of cutaneous and tendon xanthomas in patients with both homozygous and heterozygous FH. An animal model has demonstrated reduced coronary atherosclerosis. No long-term benefits have been documented for patients with FH.
  • Gene therapy is still at the investigational stage. Initially, expectations were high that genetic manipulation would be a less hazardous method for providing functional LDL receptors compared with liver transplantation; however, advances have been slow.

In patients with heterozygous FH, lifestyle modification should always be instituted but is unlikely to result in acceptable LDLc levels; therefore, cholesterol-lowering medication (usually more than one) is necessary.

• A diet that severely limits saturated fats, trans fats, and cholesterol (see Table 2)
• Desirable weight should be attained. Significant weight loss should improve all lipid parameters (LDLc, HDLc, triglycerides).
• Aerobic and toning exercises improve blood lipid levels if performed for longer than 30 minutes, 4 or more days per week.
• While these efforts often have only a modest impact on LDLc levels, rigorous dietary intervention works synergistically with lipid-lowering medications, especially diet.
• With 50% functional LDL receptors, heterozygous FH patients have an excellent response to the usual cholesterol-lowering drugs, but treatment still remains difficult.
• To approach the recommended LDLc goals, a high dose of one of the 3 strongest HMG-CoA reductase inhibitors (statins), simvastatin, atorvastatin, or rosuvastatin, and one or more other LDL lowering medications, bile acid sequestrants, ezetimibe, or niacin, is recommended. To decrease the risk of myopathy, one step below the maximum dose of the statin should be considered. For additional resources, please visit Landmark Statin Trials.
• Because doubling the dose of any statin lowers the LDLc only 6-7%, adding a second, third, or even fourth agent is more effective.
• Fibrates have no place in treatment of patients with FH unless triglyceride levels are elevated.
• Estrogen replacement therapy in postmenopausal women also helps lower LDLc levels, but this therapy is not recommended because of its adverse effects in older women, although the benefits may sometimes outweigh risks.
• Patients with documented CHD whose LDLc level cannot be lowered below 200 mg/dL by conventional therapy are candidates for LDL apheresis. Patients without CHD but with an LDLc level of higher than 300 mg/dL also qualify for this intervention. However, health insurance coverage is not automatic, and decisions are made on a case-by-case basis because of the costs, which approach $3000 for each treatment, every 2 weeks, for the patient's lifetime.

Surgical Care

• Liver transplantation for homozygous FH
  • Liver transplantation is rarely performed because of the considerable risks associated with the surgery itself and long-term immunosuppression. But a new liver provides functional LDL receptors and causes dramatic decreases in LDLc levels.
  • If not normalized, LDLc levels then can be treated with the usual LDL-lowering medications. 
• Portacaval anastomosis for homozygous FH

Consultations

• Homozygous FH
  • Because the risk of sudden death or nonfatal myocardial infarction is so high, early or highly specialized treatment is necessary.
  • As soon as a child is diagnosed with homozygous FH, a referral should be made to a medical center specializing in severe lipid disorders.
  • Referral to center providing LDL apheresis
• Heterozygous FH
  • Refer to qualified nutritionist to provide guidance in reducing intake of saturated and trans fats and cholesterol and assist in weight reduction if indicated.
  • If patients do not reach recommended treatment goals under the care of their primary care physicians, they should be referred to an endocrinologist or lipid specialist and to a qualified nutritionist.
  • If patients are considered candidates for LDL apheresis and are willing to undertake this arduous procedure, referral should be made to a medical facility offering this procedure.

Diet

Predicting the degree of improvement in an individual's lipids levels with dietary change is difficult because many variables affect the response, including the makeup of the baseline diet, the degree of patient compliance, and the individual's LDL responsiveness to the diet, which is genetically determined. A decrease of at least 15% can be expected in heterozygous patients who are willing to make significant dietary changes.

The 2001 NCEP ATPIII guidelines emphasize a multifaceted approach to the prevention of CHD. Designated therapeutic lifestyle changes (TLC), its features include increased physical activity, weight reduction, and diet modification. The same diet is recommended for all patients with lipid abnormalities.

The NCEP recommendations for the dietary management of hypercholesterolemia are not highly restrictive, but a more stringent regimen may have a greater impact on lipid levels (see Table 2).

Restricting total fat is less important than reducing the intake of saturated fat, trans fat, and cholesterol. Moreover, diets very low in total fat are high in carbohydrates, which may increase triglyceride levels and lower HDLc levels. Substituting monounsaturated fats (eg, olive and canola oils, avocados, nuts) for carbohydrates does not increase LDLc levels and, in the absence of weight gain, may increase HDLc levels and lower triglyceride levels in patients who have maintained a diet very low in fat.

Diets should be rich in whole grains, whole fruit, and legumes and other vegetables. These foods are high in soluble fiber, which has a small (approximately 5%) cholesterol-lowering effect; they are also high in antioxidants and flavonoids, which may be cardioprotective.

Other features of the NCEP diet are as follows:

• Fiber (soluble fiber): Intake should be 20-30 g/d.
• Carbohydrates: Intake should be 50-60% of total energy (caloric) intake. Carbohydrates should be derived predominantly from foods rich in complex carbohydrates, including grains, especially whole grains, fruits, and vegetables.
• Plant sterols and stanols: Intake should be 2 g/d. These are present in commercial margarines (eg, Benacol, Take Control).
• Total energy (caloric) intake: Balance energy intake and expenditure to maintain desirable body weight and prevent weight gain. Daily energy expenditure should include at least moderate physical activity, contributing approximately 200 Kcal/d (eg, a brisk walk of 2 miles or more).
• Trans- fatty acids (trans fats): Intake should be avoided. Products made with hydrogenated fats contain variable amounts of trans fats. Similar to saturated fats, trans fats increase LDLc levels. However, unlike saturated fats, trans fats decrease HDLc levels. Hydrogenated fats and trans fats are found in many margarines, cakes, cookies, crackers, and frosting.

Activity

• Exercise has many cardiovascular benefits and can improve blood lipid levels. Although a greater proportion of time should be spent doing aerobic exercise because of its greater impact on lowering blood pressure and decreasing insulin resistance, resistance training also has benefits.
• Patients with CAD or symptoms suggestive of ischemic heart disease should undergo a symptom-limited exercise stress test before undertaking a new program of vigorous exercise.

Medication

HMG-CoA reductase inhibitors (statins) are the medications of choice for the treatment of LDLc elevations in patients with heterozygous FH because they have the greatest efficacy and are easily tolerated and because multiple randomized, placebo-controlled trials have shown that lowering LDLc levels with statins reduces coronary morbidity and mortality and, in some cases, total mortality. The strongest statins, rosuvastatin and atorvastatin, at their maximum approved doses, can be expected to reduce LDLc levels 50-60%.

The ATPIII update advises that the starting dose of a statin be sufficient to lower the LDLc 30-40% (see Table 3).

Even the maximum doses of the strongest statins are usually inadequate for patients with FH, and the addition of one or more nonstatin cholesterol-lowering medications is necessary.

Bile acid sequestrants (eg, cholestyramine, colestipol, colesevelam) can be added with no risk of drug interaction, with the exception of absorption of the statin (and many other medications) if taken at the same time. Bile acid sequestrants modestly decrease LDLc levels with a small increase in HDLc and triglyceride levels. Other medications should be taken 1 hour before or 4 hours after a bile acid sequestrant. Colesevelam, which is a polymer, has less gastrointestinal side effects than the older resins and is effective at a lower dose (maximum 7 tabs/d).

Nicotinic acid (niacin) not only lowers LDLc levels but also has significant HDL-raising and triglyceride-lowering effects. There are few data to support the belief that niacin increases the risk of myopathy if combined with a statin.

Fibric acid derivatives include gemfibrozil (Lopid) and fenofibrate (Tricor). Outside of the United States, bezafibrate is also available. The fibrates lower triglyceride levels and raise HDLc levels, but they do not reliably lower LDLc levels. They increase the risk of statin-induced myositis more so than niacin. Therefore, this class of drugs is not usually useful in patients with FH.

Ezetimibe reduces LDLc levels approximately 18%, with small HDLc-raising and triglyceride-lowering effects. Because the mechanism by which it inhibits cholesterol absorption is quite specific, it does not interfere with the absorption of other drugs and does not cause the constipation associated with bile acid sequestrants. This medication has a major role in LDL-lowering when a statin alone is not sufficient and can be administered as a single tablet when combined with simvastatin (Vytorin).

Another useful statin combination is lovastatin combined with extended-release niacin (Advicor).

These statin combinations are particularly appropriate for patients with FH, most of whom will require 2 or more drugs to reach their LDLc goals. In addition, significantly greater than expected decreases in the LDLc level are frequently observed.

HMG-CoA reductase inhibitors (statins)

Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis. Reduction in hepatocyte cholesterol causes up-regulation of LDL (B,E) receptors, which, in turn, reduces plasma LDL levels. Statins are used adjunctively with diet and exercise to treat hypercholesterolemia and are the most potent LDL-lowering medications. All statins have modest triglyceride-lowering and HDL-raising effects. Randomized, double-blind, placebo-controlled trials demonstrate regression of coronary atherosclerosis but, even more importantly, reduction in rates of total mortality, coronary events, and stroke.

• Because hepatic cholesterol synthesis is greatest at night, most of the statins should be taken at bedtime. Lovastatin is better absorbed with food and is most effective taken with supper. Rosuvastatin and atorvastatin are the strongest statins because they have long half-lives.
• Atorvastatin, simvastatin, and lovastatin are metabolized by the P450 cytochrome 3A4, which is inhibited by many other drugs and may thereby increase the risk of myopathy. Rosuvastatin, fluvastatin, and pravastatin are metabolized by other pathways.
• The weaker statins (pravastatin, fluvastatin, lovastatin) do not lower LDLc levels as much and, therefore, are not the statins of choice for patients with FH. However, myopathy is dose and strength-related and thus these statins may not be as likely to cause severe myopathy.
• The Report of the National Lipid Association's Statin Safety Task Force published in the American Journal of Cardiology (Volume 97, Issue 8, Supplement 1, pages S1-S98, 17 April 2006) provides the results of a rigorous, unbiased assessment of statin safety. It includes specific reports on the muscle, liver, renal, and neurologic effects of statins; as well as addressing drug interactions and other safety issues.

Atorvastatin and rosuvastatin are long-acting statins and do not require evening dosing.  Simvastatin is the third strongest statin and should be administered at bedtime.  The three weaker statins (pravastatin, fluvastatin, lovastatin) are not the statins of choice for patients with FH.  Rosuvastatin, unlike atorvastatin and simvastatin is not metabolized by the cytochrome 3A4; and, therefore, may have fewer drug interactions.

Atorvastatin (Lipitor)

Second strongest LDL-lowering drug approved to date. Long half-life. Clinical trial has shown reduction in CHD events.
As an adjunct to diet, approved indications are to reduce total cholesterol, LDLc, triglycerides, and apoB; increase HDLc in patients with Fredrickson types IIa and IIB; decrease triglycerides in patients with type IV; and treat patients with type III dysbetalipoproteinemia.
Only statin approved for treatment of patients with homozygous FH as an adjunct to other LDL-lowering measures (eg, LDL apheresis) or if other treatments are not available.

Dosing

Adult

Starting dose: 10 mg PO qd
Maximum dose: 80 mg PO qd
Can be taken at any time of day, with or without food
Dosage adjustment in renal insufficiency is unnecessary
Because patients with FH have extreme elevations in LDLc, highest dose may be indicated

Pediatric

Not established, although no adverse events were observed in studies of patients <10 y treated with high-dose statins

Interactions

Risk of myositis increased when used in combination with cyclosporine, fibric acid derivatives, niacin, erythromycin, azole antifungals, nefazodone, and many HIV protease inhibitors; bile acid sequestrants reduce serum concentrations; statins and other medications should be taken at least 1 h before or 4 h after a bile acid sequestrant

Contraindications

Documented hypersensitivity; active liver disease or unexplained persistent elevations of AST and ALT; pregnancy or breastfeeding; women of child-bearing age who are likely to conceive

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

AST and ALT should be measured prior to and at approximately 12 wk after starting atorvastatin or after increasing dose and periodically thereafter (eg, semiannually); if persistent increases occur in ALT or AST levels >3 times the upper limit of reference range, reduce dose or withdraw
Advise patients to refrain from consuming excessive quantities of alcohol
Rare occurrence of rhabdomyolysis with acute renal failure secondary to myoglobinuria has been reported with statins
Multiple, large, randomized, double-blind, placebo-controlled trials have shown no statistical difference in myalgias, myositis, or dropout rate in subjects treated with statins compared with controls; counsel patients to report unexplained diffuse myalgias or weakness; such symptoms should prompt CK measurements; discontinue if CK levels are markedly elevated (>10 times upper limit of reference range); risk of myositis is increased with concurrent use of certain medications
Grapefruit juice can inhibit cytochrome 3A4 in the intestinal cell and, in large quantities (>32 oz/d), raise levels of many statins if taken at same time; drinking the juice and taking the statin at different times probably reduces this interaction
Because patients with FH have extreme LDLc elevations, the highest dose is usually indicated

Simvastatin (Zocor)

Third strongest LDL-lowering drug approved to date. Several randomized clinical trials in patients with and without CHD have shown clinically significant reductions in CHD morbidity and mortality rates and, in some cases, total mortality rates.
In addition to its multiple effects in improving lipid profiles (decrease in total cholesterol, LDLc, triglycerides, and apoB and increase in HDLc), has been approved for reducing risk of total mortality by reducing CHD death, reducing risk of nonfatal MI and stroke, reducing need for coronary and noncoronary revascularization procedures, and for adolescents with heterozygous FH.

Dosing

Adult

Starting dose: 10 mg PO qhs
Maximum dose: 80 mg PO qhs
More efficacious if given hs
Dosage adjustment with mild-to-moderate renal insufficiency is unnecessary but caution is advised in patients with a CrCl <30 mg/dL: 5 mg hs starting dose with close monitoring thereafter

Pediatric

Not established, although no adverse events have been reported in studies of patients <10 y treated with high-dose statins
FDA approved for adolescents with heterozygous FH who are at least 1 y postmenarche to treat LDLc >190 mg/dL or LDLc >160 mg/dL with 2 or more risk factors for CHD or with a positive family history for premature CHD

Interactions

Rifampin and nicotinic acid may decrease effects; risk of myositis increased when used in combination with cyclosporine, fibric acid derivatives, niacin, erythromycin, azole antifungals, nefazodone, and many HIV protease inhibitors; patients taking cyclosporine or gemfibrozil should not exceed 10 mg/d of simvastatin; patients taking amiodarone or verapamil should not exceed 20 mg/d of simvastatin; bile acid sequestrants reduce serum concentrations; take at least 1 h before or 4 h after a bile acid sequestrant

Contraindications

Documented hypersensitivity; active liver disease or unexplained persistent elevations of AST and ALT; pregnancy or breastfeeding; women of child-bearing age who are likely to conceive

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Patients should try to control hypercholesterolemia with diet, exercise, and appropriate weight reduction
AST and ALT should be measured prior to therapy and semiannually thereafter up to 1 y after initiating treatment or increasing dose; if ALT or AST levels remain persistently >3 times the upper limit of reference range, reduce dose or withdraw
Refrain from consuming excessive quantities of alcohol
Rare occurrence of rhabdomyolysis with acute renal failure secondary to myoglobinuria reported with statins
Counsel patients to report unexplained diffuse myalgias or weakness; such symptoms should prompt CK measurement; discontinue if CK levels are markedly elevated (>10 times the upper limit of reference range); risk of myositis is increased with concurrent use of certain medications
Multiple, large, randomized, double-blind, placebo-controlled trials have shown no statistical difference in myalgias, myositis, or dropout rate in subjects treated with statins compared with controls
Grapefruit juice can inhibit cytochrome 3A4 in the intestinal cell and, in large quantities (>32 oz/d), raises levels of many statins if taken at the same time. Drinking the juice and taking the statin at different times probably reduces this interaction

Rosuvastatin (CRESTOR)

Strongest cholesterol-lowering medication released to date.

Dosing

Adult

10 mg PO qd initially; may increase dose if needed; not to exceed 40 mg/d
For severe renal insufficiency (CrCl <30 mg /dL), start at 5 mg qd; not to exceed 10 mg qd

Pediatric

Not established

Interactions

Cyclosporine and gemfibrozil significantly increase C_max and AUC, thereby increasing myopathy and rhabdomyolysis risk; limit dose to 5 mg/d when coadministered with cyclosporine and to 10 mg/d when coadministered with gemfibrozil; coadministration with aluminum and magnesium hydroxide antacids decreases plasma concentrations (administer antacids 2 h after rosuvastatin); may increase oral contraceptive plasma concentrations; alcohol may increase hepatotoxic risk

Contraindications

Documented hypersensitivity; active liver disease; unexplained serum transaminase elevation

Precautions

Pregnancy

X - Contraindicated in pregnancy

Precautions

Patients should try to control hypercholesterolemia with diet, exercise, and appropriate weight reduction
AST and ALT should be measured prior to therapy and periodically thereafter; if ALT or AST levels persistently remain >3 times the upper limit of reference range, reduce dose or withdraw
Refrain from consuming excessive quantities of alcohol
Rare occurrence of rhabdomyolysis with acute renal failure secondary to myoglobinuria reported with statins
Multiple, large, randomized, double-blind, placebo-controlled trials have shown no statistical difference in myalgias, myositis, or dropout rate in subjects treated with statins compared to controls; counsel patients to report unexplained diffuse myalgias or weakness; such symptoms should prompt a CK measurement; discontinue if CK levels are markedly elevated (>10 times the upper limit of reference range); risk of myositis is increased with concurrent use of certain medications
Grapefruit juice can inhibit cytochrome 3A4 in the intestinal cell and, in large quantities (>16 oz/d), raises levels of most statins if taken at the same time; drinking the juice and taking the statin at different times probably reduces this interaction
Due to higher concentrations of rosuvastatin in Asian subjects, a lower starting dose and maximum dose should be used.

Pitavastatin (Livalo)

HMG-CoA reductase inhibitor (statin) indicated for primary or mixed hyperlipidemia. In clinical trials, 2 mg/d reduced total cholesterol and LDL cholesterol similar to atorvastatin 10 mg/d and simvastatin 20 mg/d.

Dosing

Adult

2 mg PO qd; not to exceed 4 mg/d

Pediatric

Not established

Interactions

Data limited; CYP2C9 substrate; OATP1B1 transporter substrate; 4-fold increase in AUC when coadministered with cyclosporine (an OATP1B1 inhibitor); coadministration with other drugs that cause myopathy (eg, gemfibrozil) may increase risk; CYP2C9 inhibitors (eg, fluconazole, gemfibrozil, nevirapine, sulfisoxazole) may decrease metabolism and thereby increase serum concentration

Contraindications

Documented hypersensitivity; active liver disease; pregnancy

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Common adverse effects include myalgias and myopathy, joint pain, back pain, and constipation; caution with history of liver/renal impairment

Vitamins

Niacin at doses of at least 1-1.5 g/d lowers LDLc levels 10-25%. HDLc levels can increase substantially, 30% or more, particularly at higher doses. Triglyceride levels decrease approximately 50%. Niacin, whether OTC or by prescription, costs less than any other lipid-lowering medication. For reasons not clearly understood, changing brands during treatment is more likely to cause hepatotoxicity, more so with time-release niacin than with regular niacin, particularly at does of 3 g/d or more. Nicotinamide, while acceptable treatment for vitamin B-3 deficiency, does not affect lipid levels, nor do most of the "no flush" niacin preparations, including inositol hexaniacinate.

Immediate-release niacin/vitamin B-3 (nicotinic acid, Niacor, Nicolar)

Less hepatotoxic than SR niacin but not as well tolerated by patients because of prostaglandin-mediated flushing, itching, or rash. IR niacin started at low doses and gradually increased over several wk allows some patients to accommodate to these adverse effects.
Higher doses (4-6 g/d) can be used more safely than those of SR niacin.
Niacor and Nicolar are prescription formulations of IR niacin that, while more expensive than OTC brands, may decrease likelihood of patient switching brands. Changing formulation of niacin while on high doses may increase risk of hepatotoxicity.

Dosing

Adult

Starting dose: 100 mg PO tid pc
Increase by 100 mg tid at weekly intervals
After fourth week (500 mg tid), 500-mg tab may be substituted for smaller tabs
Usual dose: 1.5-3 g PO qd; not to exceed 6 g/d

Pediatric

Not established

Interactions

Increase risk of myopathy and rhabdomyolysis in patients receiving statins is small if not absent and combination statin-niacin therapy not contraindicated; cutaneous vasodilation may be a problem if high dose used with peripheral dilators such as nitroglycerine; taking aspirin 30-60 min before first dose of day may help alleviate adverse prostaglandin-mediated effects (eg, flushing, itching); clonidine may inhibit niacin-induced flushing

Contraindications

Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; large doses, especially when administered in SR form (associated with severe hepatotoxicity); patients with definite and recent history of peptic ulcer disease (can reactivate ulcers); patients with a history of gout if not treated with allopurinol

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Most serious and life-threatening complication of high-dose therapy is chemical hepatitis
Frequent monitoring (quarterly) of AST and ALT is mandatory for therapy at doses >1 g/d; if AST and ALT rise to >3 times upper limit of normal, stop and monitor transaminases until return to normal
Most common adverse effects are flushing and mild dyspepsia; these are more common with IR than SR formulations; if initially started at small doses and gradually increased, symptoms can often be tolerated and eventually resolve (tachyphylaxis); ethanol or hot drinks can exacerbate flushing; flushing can be minimized if taken after meals or if 325 mg of aspirin taken 30-60 min before each dose
Most serious GI complication is exacerbation of peptic ulcer disease; niacin may cause a variety of adverse GI effects, most frequently benign dyspepsia
High doses may increase insulin resistance and can cause a small increase in fasting glucose levels in patients with or without diabetes; caution in known diabetes mellitus
High doses can cause hyperuricemia and should be used with caution in patients with elevated uric acid levels or history of gout; patients with history of gout whose uric acid levels have been normalized with allopurinol may be treated if uric acid levels are closely monitored
Patients should refrain from consuming excessive quantities of alcohol

SR niacin (Slo-Niacin, Niaspan)

More hepatotoxic than IR niacin; therefore, strongly advise against switching formulations or brands during treatment. Both OTC and prescription SR niacin is available. OTC brands cost less, but if using this option, only recommend reliable manufacturers.
Slo-Niacin is an OTC formulation available in 250-, 500-, and 750-mg tabs. Sundown also manufactures OTC SR niacin. Prescription SR niacin, Niaspan, is available in 375-, 500-, and 1000-mg tabs.

Dosing

Adult

Niaspan recommended dosage schedule:
500 mg PO qhs with small snack for 1 mo
1000 mg PO qhs with small snack for 1 mo
1500 mg PO qhs with small snack for 1 mo
2000 mg PO qhs with small snack for 1 mo
Other SR formulations usually require bid dosing beginning with smallest dose available and gradually increasing to a total dose not to exceed 3 g/d

Pediatric

Not established

Interactions

Cutaneous vasodilation may occur if high dose used with peripheral dilators such as nitroglycerin; taking aspirin 30-60 min before first dose of day may help alleviate adverse prostaglandin-mediated effects (eg, flushing, itching); clonidine may inhibit niacin-induced flushing

Contraindications

Documented hypersensitivity; active liver disease or unexplained significant increases in AST and ALT; large doses, especially when administered in SR form (associated with severe hepatotoxicity); definite and recent history of peptic ulcer disease (can reactivate ulcers)

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

See IR niacin
More importantly than with IR niacin, strongly counsel patients to not change formulations or brands; if change is necessary, dose should be dropped back to initial recommended dose, with gradual titration over several weeks or months to former final dose; changing brands at high dose (>1.5 g/d) has been reported to cause severe chemical hepatitis and even fulminant hepatic failure
Periodic monitoring of AST and ALT is mandatory for patients on doses of SR niacin >2 g/d

Bile acid sequestrants (resins)

Anion-exchange compounds that work by preventing reabsorption of bile in the intestine. Modestly lower LDLc and increase HDLc levels but can raise triglyceride levels. When used with a statin, the LDLc-lowering effects are additive. Not absorbed systemically and, therefore, are safer than most medications. Powder should never be taken in dry form. Combine with water, other noncarbonated fluid, or soft food (eg, applesauce, soup). Probably more effective at mealtime. Colestipol is formulated both as a powder and a tablet; however, 1 tablet contains only 1 g of colestipol. Given that the maximum dose of colestipol powder is 30 g, taking an even 10 tablets (which most patients will object to) will have only minimal LDL-lowering impact.

Because resins can decrease absorption of many other medications, those medications should be taken 1 h before or 4 h after the resin. Major adverse effect is constipation, and patient compliance is often an issue.

WelChol is a polymer (not a resin) and is the newest bile acid sequestrant to enter the market. It is formulated as a tablet, and the maximum number is 7 tab/d, which may improve compliance. Reportedly causes fewer adverse GI effects and fewer drug interactions. Added to a statin, further LDLc reductions of as much as 20% can be expected.

Cholestyramine (Questran)

Orange-flavored and sweetened with either sucrose (Questran) or aspartame (Questran Light). Must be mixed with fluids or soft, high-moisture foods.
Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.
Safer than most medications.

Dosing

Adult

Starting dose: 4 g (1 packet or scoop) PO qd
Maximum dose: 24 g (6 packets or scoops) PO qd in divided doses
Except in tab form, resins should always be mixed with water, other fluids, or soft food and should never be consumed in dry form (to avoid inhalation or esophageal irritation)

Pediatric

Not established; adult dosing suggested

Interactions

Can delay or reduce absorption of many other medications, including warfarin, thyroid medications, digoxin, propranolol, thiazides, penicillin G, tetracycline, estrogen, and progestins; fat-soluble vitamin absorption also may be impaired; all medications should be taken at least 1-2 h before or at least 4-6 h after resin
If a high dose is used, supplement with a multivitamin
Discontinuing a resin could be hazardous if a drug that may be toxic at high levels is significantly bound to the resin and has been titrated to a maintenance level while patient was taking the resin

Contraindications

Documented hypersensitivity; complete biliary obstruction

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Increased bleeding tendency due to decreased absorption of vitamin K has been reported
Multivitamin supplementation is recommended for patients on higher doses; constipation may be produced or worsened (gradually increasing dose and increasing water and fiber intake can minimize this risk); instruct patients to mix each dose with at least 4-6 oz of fluid

Colestipol (Colestid)

Formulated as dry, flavorless powder and as a tab. Otherwise, similar to cholestyramine. Because contains no flavoring or sweeteners, can be mixed with a wider variety of liquid foods (eg, soup, tomato juice).

Dosing

Adult

5-30 g PO qd or divided bid/qid; increase dose by 5 g at 1- to 2-mo intervals
Single dose is 1 scoop or packet of powder or 5, 1-g tab

Pediatric

Not established; adult dose recommended

Interactions

Bile acid sequestrants can delay or reduce absorption of many other medications, including warfarin, thyroid medications, digoxin, propranolol, thiazides, penicillin G, tetracycline, estrogen, and progestins; fat-soluble vitamin absorption may be impaired; all medications should be taken at least 1-2 h before or at least 4-6 h after resin (if a high dose is used, supplement with a multivitamin)
Discontinuing a resin could be hazardous if a drug toxic at high levels and significantly bound to resin has been titrated to maintenance level while patient was taking resin

Contraindications

Documented hypersensitivity; complete biliary obstruction

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Increased bleeding tendency due to decreased absorption of vitamin K reported (multivitamin supplementation recommended for patients on higher doses)
Constipation may be induced or worsened (gradually increasing dose and increasing water and fiber intake can minimize this risk)
Instruct patients to mix each dose with at least 4-6 oz of fluid

Colesevelam (WelChol)

Better tolerated than older agents (eg, cholestyramine, colestipol), and drug interactions are less of a problem. Can lower LDLc 15-18% as monotherapy. Useful in patients who cannot tolerate statins, who have contraindications for statin therapy, or who request nonsystemic therapy. Can also be used in combination with a statin for additive LDLc lowering. Has no effect on serum triglycerides or beneficial effects on HDLc. Available in a 643-mg tab.

Dosing

Adult

3 tab PO bid with meals; alternatively, 6 tab PO qd with meal
May be increased to 7 tab PO qd with meal

Pediatric

Not established, adult dose recommended

Interactions

Bile acid sequestrants can delay or reduce absorption of many other medications, including warfarin, thyroid medications, digoxin, propranolol, thiazides, penicillin G, tetracycline, estrogen, and progestins; fat-soluble vitamin absorption may be impaired; all medications should be taken at least 1-2 h before or at least 4-6 h after resin (if high dose is used, supplement with a multivitamin)
Discontinuing a resin could be hazardous if a drug toxic at high levels and significantly bound to resin has been titrated to maintenance level while patient was taking the resin

Contraindications

Documented hypersensitivity; complete biliary or GI obstruction; cholelithiasis

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Increased bleeding tendency reported due to decreased absorption of vitamin K (multivitamin supplementation recommended for patients on higher doses of resins); constipation may be induced or worsened (gradually increasing dose and increasing water and fiber intake can minimize this risk); instruct patients to mix each dose of resin with at least 4-6 oz of fluid

Cholesterol inhibitors

Inhibits intestinal absorption of cholesterol.

Ezetimibe (Zetia)

First in a new class of cholesterol-lowering agents. Inhibits cholesterol intestinal absorption. Approved as monotherapy or in combination with HMG-CoA reductase inhibitors.

Dosing

Adult

10 mg PO qd

Pediatric

<10 years: Not established
>10 years: Data limited; administer as in adults

Interactions

Cholestyramine decreases bioavailability; fenofibrate and gemfibrozil increase bioavailability; cyclosporine may increase bioavailability

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Caution in moderate-to-severe hepatic impairment

Follow-up

Deterrence/Prevention

• Identifying relatives who are carriers of the FH gene allows medical intervention to prevent patients from developing CAD.
• In addition to treating hypercholesterolemia, cardiovascular risk factors should be identified and treated aggressively. Advise patients to begin aerobic exercise and, if indicated, a weight-loss program.

Complications

• The adverse effects of medications used to treat hypercholesterolemia can pose major, though uncommon, complications.
• Statin therapy carries a negligible risk of liver toxicity.
• Myositis progressing to rhabdomyolysis is a rare but life-threatening complication of statin therapy.
• Statins in combination with a variety of medications (particularly cyclosporine, as well as gemfibrozil, verapamil, amiodarone, etc) increase the risk of myositis (see Medication).
• Niacin may cause gout, peptic ulcer disease, increased insulin resistance, and severe hepatotoxicity. Fulminant hepatic failure has been reported with time-release niacin therapy.

Prognosis

• Prognosis depends heavily on the extent to which LDLc levels can be reduced.
• Patients with homozygous FH have and extremely limited life expectancy without major medical intervention.
• Treatment of other modifiable risk factors such as smoking, hypertension, and diabetes further decreases the risk of CAD.
• Because long-term prospective studies on subjects with FH are not available, precise predictions regarding improved outcomes are difficult.

Patient Education

• Adult patients with FH must understand their high risk for premature CAD. Emphasizing the importance of complying with dietary and drug management of their hypercholesterolemia must be emphasized.
• Other modifiable risk factors should be identified, and their additive impact on the risk of a cardiovascular event should be explained.
  • Offer assistance with stopping smoking.
  • Explain the importance of exercise and appropriate weight reduction in terms of the lipid and cardiovascular effects and the prevention or improvement in diabetes and hypertension.
• For excellent patient education resources, visit eMedicine's Cholesterol Center and Statins Center. Also, see eMedicine's patient education articles High Cholesterol, Understanding Your Cholesterol Level, Lifestyle Cholesterol Management, Understanding Cholesterol-Lowering Medications, and StatinsandCholesterol.

Miscellaneous

Medicolegal Pitfalls

• Failure to lower the LDLc level to goal
• Failure to recognize symptoms consistent with coronary ischemia in adult patients with other CAD risk factors
• Failure to identify affected relatives
  • Although the physician caring for a patient with FH is not directly responsible for the patient's relatives, good medical care dictates that other affected individuals should be identified whenever possible.
  • See Deterrence/Prevention for information on the MED-PED FH project, an organization that assists in identifying relatives of patients with FH.
• Failure to recognize drug interactions
  • Patients treated with high-dose statins have a small risk of developing myositis, which can progress to life-threatening rhabdomyolysis.
  • If a medication that may increase the risk of myositis (eg, fibric acid derivative) is used, the symptoms of myositis should be described (ie, unexplained persistent and generalized muscle soreness or weakness). The risks and benefits of the drug combination should be discussed with the patient and should be well documented in the medical record.
  • If a patient develops muscle symptoms, the patient’s creatine kinase level should be checked immediately. If it is within the reference range, stopping the statin is not mandatory. Given the severity of hypercholesterolemia and risk of CAD, statin therapy is life saving, and a search should be made for some other cause of the symptoms before withdrawing the statin. In many large double-blind statin trials lasting 5 years, the incidence of muscle symptoms and increases in creatine kinase levels were no different in the treatment groups than in the placebo groups.
  • Although the administration of statins requires monitoring hepatic transaminase levels for at least 1 year, the risk of significant injury is insignificant, if it exists at all. Multiple large double-blind statin trials lasting 5 years have shown no difference in liver function test results or liver toxicity in the treatment groups compared to the placebo groups. Moreover, until transaminase levels increase to greater than 3 times the upper limit of normal, statins should be continued.

Special Concerns

• Women with FH who want to or may become pregnant should stop statin therapy. Pregnant or breastfeeding women should not take statins.
• Although LDLc levels are much higher baseline, the cholesterol levels of pregnant women with FH increase approximately the same amount as those without FH (approximately 30% over baseline). Triglyceride levels also increase to a similar extent, approximately doubling during the course of the pregnancy.

Multimedia

Media file 1: Metacarpophalangeal joint tendon xanthomas in a 45-year-old man with heterozygous familial hypercholesterolemia.

References

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Keywords

familial hypercholesterolemia, FH, heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, monozygous hypercholesterolemia, low-density lipoprotein cholesterol, LDL cholesterol, LDLc, hypercholesterolemia, coronary artery disease, CAD, premature CAD, coronary atherosclerosis, xanthelasma, xanthoma, valvular abnormalities, heart valve anomaly, aortic stenosis, heart disease, corneal arcus, planar xanthoma, tendon xanthoma, tuberous xanthoma, ischemic heart disease, peripheral vascular disease, cerebrovascular disease, lipid abnormalities, lipid abnormality, lipid disorder

lipid disease, coronary heart disease, CHD, high cholesterol, bad cholesterol, acute myocardial infarction, acute MI, palpebral xanthomas, Achilles tendonitis, cutaneous xanthomas, Achilles tendon xanthomas

Contributor Information and Disclosures

Author

Elena Citkowitz, MD, PhD, FACP, Clinical Professor of Medicine, Yale University School of Medicine; Director, Cholesterol Management Center, Director, Cardiac Rehabilitation, Department of Medicine, Hospital of St Raphael
Elena Citkowitz, MD, PhD, FACP is a member of the following medical societies: American College of Physicians, American Heart Association, National Lipid Association, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Gregory William Rutecki, MD, Associate Professor, Program Director, Department of Internal Medicine, Feinberg School of Medicine, Northwestern University
Gregory William Rutecki, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Society of Nephrology, National Kidney Foundation, and Society of General Internal Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Yoram Shenker, MD, Chief of Endocrinology Section, Veterans Affairs Medical Center of Madison; Interim Chief, Associate Professor, Department of Internal Medicine, Section of Endocrinology, Diabetes and Metabolism, University of Wisconsin at Madison
Yoram Shenker, MD is a member of the following medical societies: American Heart Association, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

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