Familial Hyperlipidemias

Introduction

Blood levels of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides are determined by interactions among a person’s genes, lifestyle, physiologic and medical conditions and various drug exposures.

Lifetime exposure to high LDL-C levels causes early and rapidly progressive atherosclerosis. If untreated, familial hypercholesterolemia (FH) results in premature coronary events and death, tragedies that could have been prevented with early and effective LDL-C lowering therapy.

Severe hypercholesterolemia (LDL-C ≥190 mg/dL) and severe hypertriglyceridemia (triglycerides ≥500 mg/dL) almost always occur in the setting of an adverse genetic background, although they may be exacerbated by secondary causes. Severe hypertriglyceridemia is most often due to secondary causes such as poorly controlled diabetes or excessive weight gain. Therefore, before making the diagnosis of genetic hyperlipidemia, secondary causes should be ruled out.

The Fredrickson classification was developed in the 1960s to describe various phenotypes of hyperlipidemia based on electrophoretic patterns and is provided at the end of this module for reference.

A simpler clinical approach is to group the genetic etiologies of hyperlipidemia by whether they increase LDL-C or total cholesterol, without or with triglyceride elevations, since LDL-C and triglyceride levels will guide the treatment strategy (Table 6-1).

Clinical Highlights I

• Children—Universal cholesterol screening for familial hypercholesterolemia (FH) at age 9-11 y and again at age 17-21 y (and by age 2 if family history of early ASCVD or hypercholesterolemia).
• Adults—Screening cholesterol in healthy adults by age 21 and every 5 y thereafter.
• Rule out secondary causes of hypercholesterolemia.
• Treat all adults with LDL-C ≥190 mg/dL with maximally tolerated stain (statins may be reasonable in children and adolescents age 10 y and older with LDL-C ≥190 mg/dL or with LDL-C ≥160 mg/dL and a clinical presentation consistent with FH).
• If LDL-C not reduced by at least 50% or still ≥100 mg/dL on maximally-tolerated statin, ezetimibe may be added; if goal not reached on statin+ezetimibe, addition of PCSK9 inhibitors may be considered.
• For triglycerides ≥500 mg/dL, rule out secondary causes (especially poorly controlled diabetes) and address lifestyle.
• Consider adding fenofibrate if triglycerides remain ≥500 mg/dL after maximizing statin and lifestyle therapy, provided the potential for benefit outweighs the potential for adverse effects.

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Familial Hypercholesterolemia: LDL-C ≥190 mg/dL

Familial hypercholesterolemia (FH) is recognized clinically as hereditary severe elevations in LDL-C characterized by an autosomal dominant or codominant pattern transmission with ≥90% penetrance.

Due to lifetime exposure to very high LDL-C levels, these individuals are at a 20- to 100-fold higher risk of premature atherosclerotic cardiovascular disease (ASCVD) and death without treatment. About one half of men and one third of women will suffer a nonfatal or fatal coronary artery disease (CAD) event before age 50 years for men and age 60 years for women.

Clinical Highlights II

• Familial hypercholesterolemia (FH) is a common (1 in 200) treatable genetic disease.
• Early treatment with statin and nonstatin LDL-C lowering therapy will prevent the high burden of coronary events and premature death in FH patients.
• Screen children aged 6 through 11 and again at age 17 through 21 for FH.
• Screen children by age 2 if early CVD or hypercholesterolemia is present in the family history.
• Screen adults by age 21.
• Cascade screen relatives.

The 2018 multi-society cholesterol guideline strongly recommends using an LDL-C ≥190 mg/dL as the threshold for initiating statin therapy to reduce the increased ASCVD risk of lifetime genetic hypercholesterolemia. The average LDL-C is 300 mg/dL in patients with autosomal dominant LDL receptor mutations and 240 mg/dL for patients with inherited polygenic hypercholesterolemia.

Homozygous FH (HoFH) patients may have LDL-C levels of 500-1,000 mg/dL. HoFH patients typically develop CAD by the second decade of life, although many cases are fatal in childhood. Many HoFH patients also develop severe aortic stenosis.

FH is the most common monogenic disorder in populations around the world. The large majority of cases of FH are autosomal dominant, with loss-of-function mutations of the LDL receptor gene the most common at 85% to 90%. ApoB and PCSK9 autosomal dominant mutations occur uncommonly, and autosomal recessive mutations very rarely. However, up to 40% of inherited hyperlipidemias may not have a known monogenic disorder.

Familial combined hyperlipidemia (FCH) describes polygenic hyperlipidemia which may be variably expressed as severe elevations in LDL-C, triglycerides, or both.

Population studies report rates of heterozygous FH (HeFH) of 1 in 200 to 1 in 300 individuals. Therefore, it is likely that every clinical practice has many patients with FH who would benefit from identification and treatment. Some populations have rates of HeFH as high as 1 in 100, such as French Canadians, Dutch Afrikaners, Christian Lebanese, South African populations of Ashkenazi Jews and Asian Indians. HoFH and compound HeFH (different hypercholesterolemia mutations from both parents) occurs at rate of one in 1 million to 160,000.

In the Netherlands, substantial efforts have been devoted to identifying and treating individuals with FH. Early treatment largely ameliorates the excess risk of genetic hypercholesterolemia, such that the ASCVD rate in the early-treatment FH population is similar to the general population.

Screening

Early treatment of FH can prevent the development of atherosclerosis and subsequent premature onset of ASCVD events. Therefore, screening is recommended for children between the ages of 6 and 11, and again after puberty or age 17 to 21. Adults should be screened by age 21 (Table 6-2).

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Cascade Screening

Cascade screening of relatives should be undertaken once a case is identified. Cascade screening is the most cost-effective method of finding previously undiagnosed cases and treatment is cost effective in terms of years of life saved.

Diagnosis

Several FH diagnostic criteria have been developed (Table 6-3). However, making a strict diagnosis of FH is less important from the standpoint of initiating cholesterol-lowering drug therapy to reduce ASCVD risk. From a practical standpoint, all that should be needed for a clinical diagnosis for the treatment of FH is an LDL-C level ≥190 mg/dL and a family history of hypercholesterolemia or premature ASCVD (Table 6-4). If the family history is unknown, the patient should be assumed to have FH.

A family history of premature ASCVD is informative and further increases the urgency for treatment and cascade screening.

Physical stigmata of hypercholesterolemia, such as tendon xanthoma, xanthelasma and premature corneal arcus, are less common, especially in statin-treated FH patients and not required for FH diagnosis (Figure 6-1). If physical stigmata of hyperlipidemia are found, they are highly specific and further evaluation of lipids is required. The examiner can assess tendon size by comparing to one’s own in relation to body size.

An adult is likely to have FH if the LDL-C is ≥250 mg/dL age ≥30 years, LDL-C is ≥220 age 20-29 years, or LDL-C ≥190 mg/dL <20 years.

It may be possible that insurers will require a formal FH diagnosis either by FH criteria or genotyping to gain approval to use expensive cholesterol-lowering drugs. Criteria may include those of the US MedPed, UK Simon Broome, or Netherlands Dutch Lipid Clinics (Table 6-3). However, these definitions are unnecessarily restrictive and FH can be defined as LDL-C ≥190 mg/dL plus a family history of high cholesterol or premature ASCVD.

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Treatment

The treatment strategy for patients with FH and other genetic hypercholesterolemias is summarized in Table 6-1. See also Primary Prevention: LDL-C ≥190 mg/dL for treatment recommendations for adults and children with ≥190 mg/dL.

A hierarchy of treatment goals is outlined in Table 6-5. After establishing maximal adherence to drug statin therapy and lifestyle, nonstatin therapy will need to be considered for additional LDL-C lowering in many patients with genetic hypercholesterolemia. The 2018 multi-society cholesterol guidelines recommended achieving at least a 50% reduction in LDL-C for patients with untreated LDL-C levels ≥190 mg/dL. It was also noted that patients receiving high-intensity statins in the randomized trials also achieved an LDL-C <100 mg/dL.

It should be noted that patients with severe hypercholesterolemia were usually excluded from the randomized trials for ethical reasons. Therefore, in the high-intensity statin trials TNT and IDEAL, patients with high cholesterol levels were excluded. In TNT, patients in the high-intensity statin therapy group achieved LDL-C levels <100 mg/dL (mean 77 mg/dL) and experienced a reduction in cardiovascular events compared to the moderate-intensity statin therapy group. IDEAL reported similar results. Therefore, it does seem reasonable to try to achieve an LDL-C as close as possible to 100 mg/dL for patients with genetic hypercholesterolemia by maximizing statin therapy and adding nonstatin therapy for additional LDL-C lowering. Moreover, epidemiologic data have shown that atherosclerosis does not develop if the non–HDL-C remains <125 mg/dL (corresponds to an LDL-C <95 mg/dL) in early to middle adulthood.

An LDL-C <100 mg/dL is often achievable with a high-intensity statin plus ezetimibe in HeFH patients. More aggressive LDL-C lowering with multiple drugs could be of particular benefit for those with high LDL-C or non–HDL-C levels despite maximal statin and ezetimibe therapy or who have additional risk factors.

An LDL-C <70 mg/dL could be desirable for extremely high-risk FH patients who have clinically evident ASCVD, diabetes, or additional high-risk characteristics (Table 6-5). Additional high-risk characteristics include age ≥35 years with risk factors (smoking or hypertension, HDL-C <40 mg/dL, very premature family history of ASCVD, metabolic syndrome, untreated LDL-C >250 mg/dL, lipoprotein(a) [Lp(a)] ≥50 mg/dL for European ancestry or ≥30 mg/dL for African ancestry) or a high burden of subclinical atherosclerosis.

More effective LDL-C lowering drugs, such as PCSK9 inhibitors, are now becoming available. These drugs will allow many patients with FH to achieve LDL-C levels <70 mg/dL. The 2018 multi-society cholesterol guidelines state that PCSK9 inhibitors may be considered in patients with HeFH who are 30-75 years of age and whose LDL-C levels remain ≥100 mg/dL on a maximally-tolerated statin and ezetimibe regimen.

No Need for Risk Assessment: Treat All FH Patients

There is no role for ASCVD risk assessment or noninvasive testing for initiating therapy in these patients. There are several important reasons to not perform risk stratification on patients with untreated LDL-C ≥190 mg/dL:

• All should receive high-intensity statin therapy unless contraindicated.
• Risk assessment equations do not accurately assess risk when LDL-C levels are ≥190 mg/dL.
• Noninvasive testing does not accurately predict ASCVD risk for several reasons, among which are the rapidly accelerated atherosclerotic process in those with genetic hypercholesterolemia and often uncalcified plaque with early cholesterol-rich unstable lesions.

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Statins

Statins are the first-line therapy in patients with FH. The 2018 multi-society cholesterol guideline identified individuals with LDL-C ≥190 mg/dL as one of four patient groups with a clear net ASCVD risk reduction benefit from statin therapy Adults 20-75 years with primary elevations in LDL-C ≥190 mg/dL should receive high-intensity statin therapy to reduce their very high risk of premature ASCVD and death from their genetic disorder. High-intensity statins are atorvastatin 80 mg or rosuvastatin 20 mg (which can be increased to 40 mg if further LDL-C lowering is needed).

Women With FH

Women with FH are not protected from the premature risk of ASCVD. However, statins are contraindicated during pregnancy and lactation due to the potential for fetal malformations from the statin mechanism of action (see Statins). Niacin and ezetimibe should be avoided in pregnancy (see Ezetimibe and Niacin). PCSK9 monoclonal antibodies cross the placenta and should also be avoided during pregnancy.

A reasonable approach to women with FH is to initiate statin therapy by age 21, with counseling for both the patient and partner to remain on effective birth control such as oral contraceptives or an intrauterine device until conception is contemplated. Of course, it would be ideal for all FH patients to be identified by age 9-11 years to begin statin therapy even earlier in the atherosclerotic disease process. Earlier treatment in girls during adolescence would also allow for several years of treatment prior to childbearing.

Statin and other lipid-lowering therapy should be discontinued at least 8 weeks before beginning efforts to conceive. Lipid-lowering therapy should not be restarted until pregnancy and lactation is complete. Depending on untreated LDL-C levels and severity of the family history or premature ASCVD, it may be reasonable to entirely discontinue statin therapy during the anticipated child-bearing period, then resume once child-bearing is complete.

Diabetes in FH

Statin-associated diabetes is not a concern in patients with FH due to the high potential for a net ASCVD risk reduction benefit from statin therapy. Individuals with FH appear have some protection against the development of diabetes, despite being treated with statin therapy. For a number of reasons, all patients with FH should be counseled to maintain healthy lifestyle habits and control their weight.

Nonstatins for LDL-C Lowering

Additional information on each drug class is provided in the respective sections. See Nonstatins for discussion of issues surrounding nonstatins for ASCVD prevention.

Ezetimibe

Ezetimibe has been shown to further reduce ASCVD risk in statin-treated patients in the IMPROVE-IT trial. Because of its favorable cost-benefit profile , ezetimibe is the preferred nonstatin choice for additional LDL-C lowering.

PCSK9 Inhibitors

The PCSK9 monoclonal antibodies alirocumab and evolocumab reduce LDL-C by an additional 50% to 60% when added to background statin ± ezetimibe therapy in patients with FH. The majority will reach LDL-C levels <70 mg/dL. The LDL-C lowering efficacy of the PCSK9 siRNA inclisiran in patients with HeFH was demonstrated to be approximately 40%.

Other Nonstatins

Cardiovascular outcomes trials for nonstatins used as monotherapies are available from the pre-statin era. Crystalline niacin (average dose 2 g/d) and cholestyramine monotherapy have been shown to reduce CAD events in men with severe hypercholesterolemia, with or without coronary disease at baseline (CDP and LRC-CPPT). Adverse effects of niacin and bile acid sequestrants may limit adherence. These drugs should be continued only if a reasonable reduction in LDL-C or non–HDL-C occurs (at least 15%).

Shared Decision-Making

Shared decision-making is especially important when adding nonstatin therapies beyond ezetimibe. Adherence to evidence-based therapies needs to be reinforced.

Homozygous FH

Patients with HoFH or compound HeFH often have some response to statins and ezetimibe since they may have some LDL receptor function.

PCSK9 monoclonal antibodies have also been shown to lower LDL-C in these patients. Lomitapide is approved by the FDA for LDL-C lowering only in patients with HoFH due to its potential for hepatotoxicity. Evinacumab is another novel pharmacologic option for patients with HoFH. These drugs are very expensive due to its orphan drug status.  LDL apheresis is another alternative. Patients with HoFH should be referred to a lipid specialist for management.

LDL Apheresis

LDL apheresis selectively removes apoB-containing particles from the blood through extracorporeal precipitation with either dextran sulfate cellulose or heparin. The procedure is repeated every 2 weeks for most patients due to the rate of LDL-C synthesis. Apheresis may be needed more frequently for HoFH patients.

LDL apheresis is generally efficacious at reducing LDL-C levels. One systematic review which examined 14 trials with data on apheresis efficacy, 9 (64%) reported a relative LDL-C reduction of 60-79%, 4 (29%) a reduction of 50-59% and 1 (7%) a reduction of 82%. In the 7 studies which reported LDL-C reduction efficacy separately for patients with HoFH and HeFH, the percent reduction was similar regardless of the genotype.

LDL apheresis is approved by the FDA for LDL-C lowering in FH patients with an inadequate response to maximally tolerated drug therapy after 6 months. Insurers have generally followed the FDA approval criteria when reimbursing LDL apheresis. Some insurers may also cover apheresis to remove Lp(a) in patients with progressive ASCVD despite maximal diet and drug therapy.

LDL apheresis is approved for:

• Clinically diagnosed HoFH patients with LDL-C >500 mg/dL
• Clinically diagnosed HeFH patients with LDL-C ≥300 mg/dL
• Clinically diagnosed HeFH patients with LDL-C ≥100 mg/dL and either documented CAD or documented peripheral artery disease (PAD)
• Clinically diagnosed HeFH patients with LDL-C ≥100 mg/dL, Lp(a) ≥60 mg/dL and either documented CAD or documented PAD.

Genetic Testing

Genetic characterization of hypercholesterolemia is now available, although not widely reimbursed in the United States. Genetic testing is less useful for initial diagnosis, since the treatment strategy is the same regardless of the genetic polymorphism. However, genetic testing may motivate some patients to adhere to treatment.

Genetic testing maybe more useful for cascade screening in FH, although treatment still is guided by the LDL-C level. About 40% of patients with severe hypercholesterolemia do not have an identifiable genetic mutation. Moreover, genetic mutations may vary by race/ethnicity. Treatment and reimbursement for FH treatment should not be based on the identification of a genetic mutation.

Familial Combined Hyperlipidemia: Total Cholesterol ≥240 mg/dL or LDL-C ≥190 mg/dL or Non–HDL-C >220 mg/dL

Familial combined hyperlipidemia (FCH) is a diagnostic term that can be used to describe individuals with a family history of premature ASCVD, which may or may not have an autosomal dominant pattern and some manifestation of severe hyperlipidemia: LDL-C ≥190 mg/dL, non–HDL-C >220 mg/dL, triglycerides >500 mg/dL, or both cholesterol and triglyceride elevations.

FCH occurs at a rate of 1 in 50 adults, thus is more common than autosomal dominant FH described above. FCH is more common in South Asian populations. FCH is often expressed later in life than autosomal dominant FH, often in the presence of increasing adiposity or diabetes. LDL-C levels are not as high and severe hypertriglyceridemia is more common than in autosomal dominant FH. Early treatment is as important and long-term treatment has been shown to normalize carotid intimal thickness.

FCH appears largely due to increased production of very low-density lipoprotein (VLDL), leading to higher levels of apoB-containing lipoproteins. This oversaturates the ability of lipoprotein lipase to remove triglycerides. Triglyceride-enriched LDL is further metabolized to dense LDL particles by hepatic lipase and decreased clearance of LDL.

Diagnosis

When LDL-C level is ≥190 mg/dL or non–HDL-C >220 mg/dL, once secondary causes of hyperlipidemia are ruled out,  there is no need for additional laboratory testing and treatment can commence.

In patients with triglycerides ≥500 mg/dL and LDL-C and non–HDL-C below these levels, elevated apolipoprotein B levels can differentiate FCH from other hypertriglyceridemic disorders that do not appear to confer increased cardiovascular risk.

Treatment

Prevention of ASCVD is the highest priority in these high-risk patients. The treatment strategy for patients with FCH is as summarized for LDL-C ≥190 mg/dL in Table 6-1.

Patients with FCH and clinical ASCVD or diabetes should be treated with a high-intensity statin unless contraindicated.

Ezetimibe can be considered for additional LDL-C or non–HDL-C lowering. PCSK9 inhibitors and niacin (in nondiabetic patients) are options for additional LDL-C lowering. Bile acid sequestrants should generally be avoided in FCH patients due to their hypertriglyceridemic effects.

FCH patients without ASCVD or diabetes should be considered for initiation of statin therapy primary prevention when LDL-C levels are ≥160 mg/dL, 10-year ASCVD risk is ≥5%, or there is a family history of premature ASCVD or other characteristics indicating increased ASCVD risk.

Triglycerides ≥500 mg/dL

Patients with FCH often experience secondary hypertriglyceridemia, especially in those with poorly controlled diabetes. Lifestyle and diabetes control are crucial for achieving triglyceride levels <500 mg/dL. A diet low in refined carbohydrates and fat should be recommended, along with regular physical activity and weight loss if excess adiposity is present. Referral to a dietician is often helpful.

When triglycerides remain ≥500 mg/dL despite lifestyle efforts, triglyceride-lowering therapy may be considered in addition to the statin, although there is no evidence that this will further reduce ASCVD risk.

As a rule of thumb, triglycerides <750 mg/dL can often be managed with a high-intensity statin and improved lifestyle.

When triglycerides are closer to or greater than 1,000 mg/dL, fenofibrate is a good choice for initial management of hypertriglyceridemia (with dose adjustment for renal function). For safety, the dose of statin should be reduced from the highest intensity, and patients instructed on the increased potential for myopathy with statin-fenofibrate therapy. The risk of serious myopathy with fenofibrate added to statin therapy is five times higher than with statin therapy alone. The safety of fenofibrate has not been established in the setting of high-intensity statin therapy.

Gemfibrozil is contraindicated when using statins due to the increased risk of serious myopathy. Fenofibrate may reduce ASCVD events in statin-treated individuals with high triglycerides and low HDL-C, and is a safer choice than gemfibrozil.

Omega-3 fatty acids are the safest option and can be used with high-intensity statins. However, adherence is an issue since 3-3.5 g of DHA+EPA are necessary to reduce triglycerides by a meaningful amount (four tablets of 850 mg DHA+EPA per 1,000 mg fish oil).

Shared decision-making is important when adding a nonstatin to statin therapy. The anticipated benefit of the additional ASCVD risk reduction and possibly the reduction in risk of pancreatitis should outweigh the potential adverse effects.

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Monitoring Therapy

Since the atherogenic contribution of excess VLDL and small dense LDL may not be completely captured by LDL-C levels, non–HDL-C may be a better indicator of response to therapy in patients with FCH. Non–HDL-C = total cholesterol minus HDL-C, and is particularly useful when triglycerides approach 400-500 mg/dL. A 50% reduction in non–HDL-C and a non–HDL-C <130 mg/dL may be indicators of therapeutic efficacy.

Familial Dysbetalipoproteinemia (Type 3): Total Cholesterol >240 mg/dL and Triglycerides >500 mg/dL

Familial dysbetalipoproteinemia (Type 3) is an uncommon but extremely high-risk genetic condition for premature CAD. The patients have two copies of apolipoprotein E2. Hypercholesterolemia is caused by decreased clearance of VLDL remnant and IDL through the VLDL receptor. Hypertriglyceridemia is caused primarily by impaired lipolytic processing of remnants and increased production of VLDL associated with increased level of apoE.

Familial dysbetalipoproteinemia (Type 3) occurs in 1 in 10,000 adults. ApoE2/E2 alone is not sufficient to cause severe hyperlipidemia. Hyperlipidemia is more common in men and postmenopausal women, and is usually exacerbated in the setting of other conditions that slow VLDL clearance, including obesity, diabetes, or hypothyroidism.

Total cholesterol levels are often >300 mg/dL, along with triglycerides >500 mg/dL. Physical findings include xanthoma striatum palmare (orange or yellow discoloration of the palms) and tubero-eruptive xanthomas over the elbows and knees.

Diagnosis

Phenotyping or genotyping for apoE2/E2 is diagnostic. ApoB levels will be markedly elevated.

Treatment

Diagnosis and treatment of secondary causes of hyperlipidemia are required. High-intensity statin therapy should be initiated to decrease ASCVD risk. Depending on the triglyceride response to high-intensity statin therapy, addition of a fibrate or omega-3 fatty acids may be further reduce triglyceride and non–HDL-C levels.

Polygenic Hypercholesterolemia

Polygenic hypercholesterolemia is often used to describe sporadic severe hypercholesterolemia without a clear genetic mutation. A familial pattern of autosomal dominant inheritance is not usually evident. This may represent a summation of adverse genetic mutations inherited from both parents or, as genetic sequencing studies are emerging, represent very rare or even private genetic mutations with a strong lipid effect.

Familial Hypertriglyceridemia

A consensus panel from the European Atherosclerosis Society has redefined hypertriglyceridemia into two states on the basis of genetic data:

• Triglycerides >900 mg/dL (>~10 mmol/L) more likely to result from monogenic causes.
• Triglycerides 175-899 (~2 to 10 mmol/L) usually results from the cumulative burden of more than 30 common and rare genetic variants.

Since hypertriglyceridemia susceptibility alleles and environmental contributors cluster in families, screening and counseling for families is essential. However, routine genetic testing is not recommended.

Monogenic Hypertriglyceridemia

Monogenic hypertriglyceridemia in patients with very severe hypertriglyceridemia (>900 mg/dL) displays classic autosomal recessive inheritance, with a population prevalence of about one in 1 million. The disorder is typically expressed in childhood and adolescence. Affected individuals are usually homozygous or compound heterozygous for large-effect loss-of-function mutations in one or more of six genes regulating the metabolism of triglyceride-rich lipoproteins (LPL, APOC2, APOA5, LMF1, GP1HBP1, GPD1). Severe hypertriglyceridemia results from high fasting concentrations of chylomicrons. The primary treatment objective in these patients is to prevent pancreatitis. These patients typically do not have premature ASCVD.

Multigenic Hypertriglyceridemia

Individuals with fasting triglycerides >300 mg/dL (>3.3 mmol/L; >95th percentile in the United States) are 2.5 times more likely to have rare, heterozygous loss-of-function mutations in one of over 30 genes affecting triglyceride metabolism. However, gene expression is highly variable and transmission does not follow an autosomal dominant pattern in most families.

Hypertriglyceridemia susceptibility is a result of multiple common small-effects and rare large-effect gene variants that influence production and/or catabolism of triglyceride-risk lipoproteins. However, genetic variants taken together account for only 25% of variation in triglyceride levels, with the remainder determined by lifestyle habits and other secondary contributors. 

Rare Genetic Lipid Disorders

Rare genetic hyperlipidemias and hypolipidemias are briefly described in Table 6-6. Interested readers are referred to comprehensive textbooks for information on pathophysiology, diagnosis and treatment.

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Fredrickson Classification

Table 6-7 shows the Fredrickson classification of hyperlipidemias by phenotype.

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Classification Schemes for FH

The classification criteria for hypercholesterolemia in the US, UK and Netherlands are shown in Table 6-3.

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