Hyperlipoproteinemia, Primary

AUTHOR: Fred F. Ferri, MD

Definition

Primary hyperlipoproteinemia is a group of genetic disorders of the lipid transport proteins in the blood that manifests as abnormally elevated levels of cholesterol, triglycerides, or both in the serum of affected patients.
Usually defined as total cholesterol, low-density lipoprotein (LDL), triglycerides, or lipoprotein A levels above 90th percentile or high-density lipoprotein (HDL) or apo A-1 levels below the 10th percentile for the general population. Fig. E1 illustrates the structure of lipoproteins. Plasma lipoprotein composition is described in Table E1.

Figure E1 Structure of lipoproteins.

Phospholipids are oriented with their polar group toward the aqueous environment of plasma. Free cholesterol is inserted within the phospholipid layer. The core of the lipoprotein is made up of cholesteryl esters and triglycerides. Apolipoproteins are involved in the secretion of the lipoprotein, provide structural integrity, and act as cofactors for enzymes or as ligands for various receptors.

From Bonow RO et al: Heart disease, ed 9, Philadelphia, 2012, Saunders.

TABLE E1 Plasma Lipoprotein Composition

Component	Origin	Density (g/ml)	Size (nm)	Protein (%)	Cholesterol in Plasma (mmol/L)^†	Triglyceride in Fasting Plasma (mmol/L)^‡	Apoprotein
Component	Origin	Density (g/ml)	Size (nm)	Protein (%)	Cholesterol in Plasma (mmol/L)^†	Triglyceride in Fasting Plasma (mmol/L)^‡	Major	Other
Chylomicron ∗	Intestine	<0.95	100-1000	1-2	0.0	0.0	B48	A-I, Cs
Chylomicron remnants ∗	Chylomicron metabolism	0.95-1.006	30-80	3-5	0.0	0.0	B48, E	A-I, A-IV, Cs
VLDL	Liver	<1.006	40-50	10	0.1-0.4	0.2-1.2	B100	AI, Cs
IDL	VLDL	1.006-1.019	25-30	18	0.1-0.3	0.1-0.3	B100, E
LDL	IDL	1.019-1.063	20-25	25	1.5-3.5	0.2-0.4	B100
HDL	Liver, intestine	1.063-1.210	6-10	40-55	0.9-1.6	0.1-0.2	A-I, A-II	A-IV
Lipoprotein(a)	Liver	1.051-1.082	25	30-50			B100, (a)

HDL, High-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very low-density lipoprotein.

^∗In the fasted state, serum (or plasma) should not contain chylomicrons or their remnants.

^†In mmol/L. For mg/dl, multiply by 38.67.

^‡In mmol/L. For mg/dl, multiply by 88.5.

From Bonow RO et al: Heart disease, ed 9, Philadelphia, 2012, Saunders.

Synonym

Hyperlipidemia

ICD-10CM CODES
E78.0		Pure hypercholesterolemia
E78.2		Mixed hyperlipidemia
E78.1		Pure hyperglyceridemia
E78.4		Other hyperlipidemia
E78.3		Hyperchylomicronemia

Epidemiology & Demographics

Incidence

The most common types are lipoprotein A excess, hypertriglyceridemia, and combined hyperlipidemia.

Incidence of heterozygous familial hypercholesterolemia: 1:500
Incidence of homozygous familial hypercholesterolemia: 1:1 million
Familial hypercholesterolemia: Autosomal dominant disorder
Familial combined hyperlipidemia: Possibly an autosomal dominant disorder
Multifactorial predilection: Apparent in majority of affected individuals

Genetics

Familial lipoprotein lipase deficiency: Autosomal recessive, resulting in an elevation in the plasma chylomicrons and triglycerides
Familial apoprotein CII deficiency: Autosomal recessive, resulting in increased serum chylomicrons, very low-density lipoprotein (VLDL), and hypertriglyceridemia
Familial type 3 hyperlipoproteinemia: Single-gene defect requiring contributory factors to manifest
Familial hypercholesterolemia: Autosomal dominant defect of the LDL receptor, resulting in an elevated serum cholesterol level and normal triglycerides. HoFH is the most severe form of the disease. LDL levels can reach over 500 mg/dl and can cause death in childhood
Familial hypertriglyceridemia: Common, autosomal dominant defect resulting in elevated VLDL and triglycerides
Multiple lipoprotein-type hyperlipidemia: Autosomal dominant, manifesting as isolated hypercholesterolemia, isolated hypertriglyceridemia, or hyperlipidemia
Polygenic hypercholesterolemia: Multifactorial
Polygenic hyperalphalipoproteinemia: Autosomal dominant or polygenic, causing an elevated HDL
A classification of lipoprotein disorders and their clinical findings and management are summarized in Table 2

TABLE 2 Disorders of Lipids: Clinical Findings and Management

Disorder	Xanthomas	Cardiovascular	Gastrointestinal	Neurologic	Ophthalmologic	Other Findings	Management
Type I	Eruptive, tendinous, xanthelasmas	None	Acute abdomen, hepatosplenomegaly, pancreatitis	None	Lipemia retinalis, retinal vein occlusion	Diabetes, lipemic plasma	Diet, plasmapheresis
Type II	Planar, especially intertriginous, tendinous, tuberous	Generalized atherosclerosis	None	None	Arcus cornea	None	Type IIa: Bile acid sequestrants, statins, niacin, fish oil Type IIb: Statins, niacin, fibrate
Type III	Planar, especially palmar, tuberous	Atherosclerosis	None	None	None	Abnormal glucose tolerance, hyperuricemia	Statins, fibrate
Type IV	Eruptive, tuberous	Atherosclerosis	Acute abdomen, hepatosplenomegaly, pancreatitis	None	Lipemia retinalis	Obesity	Statins, fibrate, niacin
Type V	Eruptive, tuberous	Atherosclerosis	Acute abdomen, hepatosplenomegaly, pancreatitis	None	Lipemia retinalis	Obesity, hyperinsulinemia	Niacin, fibrate
Tangier	Macular rash, foam cells in biopsies	Atherosclerosis	Acute abdomen, hepatosplenomegaly	Peripheral neuropathy	Corneal infiltration	Enlarged orange tonsils, lymphadenopathy
Apolipoprotein A-I and C-III deficiency	Planar and tendon xanthomas, foam cells in biopsies	Atherosclerosis	Normal	Normal	Corneal clouding	None
HDL deficiency with planar xanthomas	Planar xanthomas, foam cells in biopsies	Atherosclerosis	Hepatomegaly	Normal	Corneal opacity	None

HDL, High-density lipoprotein.

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

Physical Findings & Clinical Presentation

Familial lipoprotein lipase deficiency: Recurrent bouts of abdominal pain in infancy, eruptive xanthomas, hepatomegaly, splenomegaly, lipemia retinalis
Familial apoprotein CII deficiency: Occasional eruptive xanthomas
Familial type 3 hyperlipoproteinemia: Xanthoma striata palmaris or tuberoeruptive xanthomas, xanthelasmas, arterial bruits at a young age, gangrene of the lower extremities at a young age
Familial hypercholesterolemia: Tendon xanthomas, arcus corneae, xanthelasma
Familial hypertriglyceridemia: Associated obesity; eruptive xanthomas (Fig. E2) can develop with exacerbations

Figure E2 Xanthomas in homozygous familial hypercholesterolemia (plaques of yellow color).

From Micheletti RG et al: Andrews’ diseases of the skin: clinical atlas, ed 2, Philadelphia, 2023, Elsevier.

Etiology

Genetic defects causing lipid abnormalities
Environmental influences, including diet, drugs, and alcohol intake

Diagnosis ⬆ ⬇

Differential Diagnosis

Secondary causes of hyperlipoproteinemias:

Hypothyroidism
Diabetes mellitus
Pancreatitis
Autoimmune hyperlipoproteinemia
Nephrotic syndrome
Biliary obstruction; Table E3 describes the differential diagnosis of hyperlipidemia and dyslipidemia

TABLE E3 Differential Diagnosis of Hyperlipidemia and Dyslipidemia

Hypertriglyceridemia	Hypercholesterolemia	Increased Cholesterol and Triglycerides	Low HDL
Primary Disorders
LPL deficiency	Familial hypercholesterolemia	Familial combined hyperlipidemia	Familial hypoalphalipoproteinemia
ApoC-II deficiency	Familial defective apoB-100	Dysbetalipoproteinemia	ApoA-I mutations
Familial hypertriglyceridemia	Polygenic hypercholesterolemia	Diabetes mellitus	LCAT deficiency
Dysbetalipoproteinemia	Sitosterolemia	Hypothyroidism	ABCA1 deficiency
Secondary disorders	Hypothyroidism	Glucocorticoids	Anabolic steroids
Diabetes mellitus	Obstructive liver disease	Immunosuppressives	Retinoids
Hypothyroidism	Nephrotic syndrome	Protease inhibitors
High-carbohydrate diets	Thiazides	Nephrotic syndrome
Renal failure		Lipodystrophies
Obesity/insulin resistance
Estrogens
Ethanol
β-Blockers
Protease inhibitors
Glucocorticoids
Retinoids
Bile acid-binding resins
Antipsychotics
Lipodystrophies
Thiazides

ABCA1,Adenosine triphosphate-binding cassette transporter 1; apo, apolipoprotein; HDL, high-density lipoprotein; LCAT, lecithin:cholesterol acyltransferase; LPL, lipoprotein lipase.

From Melmed S et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2011, Saunders.

Workup

Family history for premature cardiac disease
Personal history of recurrent pancreatitis
Detailed physical examination

Laboratory Tests

Standard lipid profile; Table 4 summarizes laboratory findings in lipid disorders
If normal, further testing with measurement of lipoprotein A, apo B, and apo A-1
Lipoprotein electrophoresis and ultracentrifugation (for phenotypic classification)
Workup for secondary causes: Thyroid-stimulating hormone, fasting glucose, liver function, renal function, urinary protein

TABLE 4 Laboratory Findings in Lipid Disorders

Disorder	Inheri-tance	OMIM No.	Prevalence	Choles-terol	Trigly-cerides	VLDL	Chylomi-crons	LDL	HDL	Serum	Cause
Type I	AR		1/million	↑	↑↑↑	↑	↑	↓	↓↓↓	Creamy top
a: Familial hyperchylo-micronemia		239600, 246650, 615947									a. Deficiency from mutations in lipoprotein lipase; LMF1; GPIHBP1
b: Familial apoprotein C2 or A-V deficiency		207750, 133650									b. Deficient ApoC-2 or ApoA-5 (see Type V)
c: -		118830									c. LP lipase inhibitor in blood
Type II			1 in 500 for het-erozygotes	↑	NI or ↑	↑	NI	↓	↓	Clear
a: Familial hyper-cholesterolemia	AD	143890, 144010, 603776									LDL receptor defect in 60%-80%; APOB, PCSK9, each <5%
a: Familial hyper-cholesterolemia	AR	603813									LDLRAP1
b: Familial combined hyperlipidemia	AD, AR	144250	1 in 100							Clear	Polygenic
b: Familial combined hyperlipidemia	AD, AR	144250	1 in 100							Clear	Decreased LDL receptor and ApoB-100 dysfunction
Type III	AR	107741	1 in 10,000	↑	↑	↑	↑	↓	NI	Turbid	ApoE-2 synthesis
Familial dysbetalipoproteinemia	AR	107741	1 in 10,000	↑	↑	↑	↑	↓	NI	Turbid	ApoE-2 synthesis
Type IV	AD	144600	1 in 100	↑	NI ↑	↑	NI	↓	↓↓	Turbid	Renal disease, diabetes
Familial hyper-triglyceridemia	AD	144600	1 in 100	↑	NI ↑	↑	NI	↓	↓↓	Turbid	Renal disease, diabetes
Type V	AR	144650	Very rare	↑	↑↑↑	↑	↑	↓	↓↓↓	Creamy top, turbid bottom	Apo A-V (ApoA-5) deficiency

AD, Autosomal dominant; Apo, apolipoprotein; AR, autosomal recessive; HDL, high-density lipoprotein; LDL, low-density lipoprotein; LP, lipoprotein; NI, normal; OMIM, Online Mendelian Inheritance in Man; VLDL, very low-density lipoprotein; ↑, increased; ↓, decreased.

From Paller AS, Mancini AJ: Hurwitz clinical pediatric dermatology: a textbook of skin disorders of childhood and adolescence, ed 5, 2016, Elsevier.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

Cornerstone of treatment: Dietary therapy
1. TLC diet (therapeutic lifestyle changes): See “Hypercholesterolemia” topic
Risk factor reduction includes smoking cessation, treatment of hypertension, exercise
Familial lipoprotein lipase deficiency and familial apoprotein CII deficiency: Fat-free diet
Remainder of cases, except those with polygenic hyperalphalipoproteinemia: Fat- and cholesterol-restricted diets
Nonpharmacologic interventions can include LDL apheresis and liver transplantation

Acute General Rx

No acute treatment is needed.

Chronic Rx

Medications commonly used to treat hyperlipidemias are summarized in Table 5. Table 6 differentiates statins based on potency.
Familial lipoprotein lipase deficiency, polygenic hyperalphalipoproteinemia, or familial apoprotein CII deficiency: No chronic drug therapy.
Familial type 3 hyperlipoproteinemia: Usually responds well to secondary causes being treated and diet therapy; if not, fibric acids may be tried.
Familial hypercholesterolemia: Statins, bile acid sequestrants, or niacin. Ezetimibe and proprotein convertase subtilisin/Kexin type 9 (PCSK9 inhibitors) can be added to statins to achieve LDL goals.¹ PCSK9 binds to LDL receptors on hepatocytes, promote receptor degradation, and prevent LDL-C clearance from the circulation thereby increasing serum concentrations of LDL-C. PCSK9 monoclonal antibody inhibitors alirocumab (Praluent), evolocumab (Repatha), and inclisiran (Leqvio), a PCSK9-directed small interfering RNA, are currently indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL cholesterol. PCSK9 inhibitors lower risk for ischemic cardiovascular events in persons with stable CAD and elevated atherogenic lipoproteins despite statin therapy. These medications are administered by subcutaneous injection and are expensive.
Familial hypertriglyceridemia: Fibric acids (fenofibrate), niacin, omega-3 PUFA-containing fish oil capsules. Icosapent ethyl, a highly purified eicosapentaenoic acid ester, has been shown to lower triglyceride levels and cardiovascular risk in patients with hypertriglyceridemia. Icosapent ethyl (Vascepa) is indicated as an adjunct to diet to relieve triglyceride levels in adult patients with severe (≥500 mg/dl) hypertriglyceridemia. It is also indicated as an adjunct to maximally tolerated statin therapy to reduce the risk of myocardial infarction, stroke, coronary revascularization and unstable angina requiring hospitalization in adult patients with elevated triglyceride levels (≥150 mg/dl) and established cardiovascular disease or diabetes mellitus and two or more additional risk factors for cardiovascular disease.
Multiple lipoprotein-type hyperlipidemia: Drug therapy aimed at the predominant lipid abnormality noted.
Recent data suggest in patients with lipoprotein abnormalities that treatment goals should be based on non-HDL cholesterol rather than LDL cholesterol.
The FDA has approved mipomersen and lomitapide in patients with homozygous familial hypercholesterolemia already taking maximum doses of other lipid-lowering drugs. Both medicines are hepatotoxic and very expensive.
Recent trials with bempedoic acid, an inhibitor of adenosine triphosphate citrate lyase that lowers LDL cholesterol, have shown to significantly lower LDL when bempedoic acid was added to maximally tolerated statin therapy. The FDA has recently approved bempedoic acid for use alone (Nexletol) and in a fixed-dose combination with ezetimibe (Nexlizet) as an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or established ASCVD who require additional LDL-C lowering.

TABLE 5 Drugs Used to Treat Hyperlipidemia

Class and Drugs Available	Dosage	Major Lipoprotein Decreased	Mechanism
HMG-CoA Reductase Inhibitors
Rosuvastatin	5-40 mg/day	LDL	Decrease cholesterol synthesis; increase LDL receptor-mediated removal of LL
Atorvastatin	10-80 mg/day
Simvastatin	5-40 mg/day
Lovastatin	10-80 mg/day
Pravastatin	10-40 mg/day
Fluvastatin	20-80 mg/day
Pitavastatin	1-4 mg//day
PCSK9 Inhibitors
Evolocumab	140 mg SC q2 wk or 420 mg SC monthly	LDL	Prevent degradation of the LDL receptor
Alirocumab	75-150 mg SC q2 wk	LDL	Prevent degradation of the LDL receptor
Intestinal Cholesterol Absorption Inhibitor
Ezetimibe	10 mg/day	LDL	Inhibits cholesterol absorption
Bile Acid Sequestrants
Cholestyramine	4-12 g bid	LDL	Increase sterol excretion and LDL clearance
Colestipol	5-15 g bid
Colesevelam	3.75-4.375 g/day
Fibric Acid Derivatives
Gemfibrozil	600 mg bid	VLDL (LDL)	Decrease VLDL production; enhance LPL action
Fenofibrate ^a	30-200 mg/day	VLDL (LDL)	Decrease VLDL production; enhance LPL action
Omega-3 Fatty Acids
Lovaza (1-g capsule contains EPA and DHA)	4 g/day	VLDL	Inhibit VLDL production
Vascepa (1-g capsule contains EPA)	4 g/day
Epanova (1-g capsule contains EPA and DHA free fatty acids)	2-4 g/day
Nicotinic Acid
Niacin (crystalline)	1-3 g/day	VLDL (LDL)	Decrease VLDL production; enhance LPL action
Niaspan (extended-release niacin)	500-2000 mg/day	VLDL (LDL)	Decrease VLDL production; enhance LPL action
ApoB Antisense Oligonucleotide
Mipomersen	200 mg weekly SC injection	VLDL, LDL, Lp(a)	Inhibits synthesis of apolipoprotein B
Microsomal Triglyceride Transfer Protein Inhibitor
Lomitapide	5-60 mg/day	VLDL, LDL, Lp(a)	Inhibits microsomal triglyceride transfer protein

bid, Twice a day; DHA, docosahexaenoic acid; EPA, highly concentrated ethyl esters of eicosapentaenoic acid; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoproteins; Lp(a), lipoprotein(a); LPL, lipoprotein lipase; PCSK9, proprotein convertase subtilisin/kexin type 9; q, every; SC, subcutaneously; VLDL, very low-density lipoprotein.

^aThere are several different preparations of fenofibrate with different doses.

From Melmed S et al: Williams textbook of endocrinology, ed 14, St Louis, 2019, Elsevier.

TABLE 6 High-, Moderate-, and Low-Intensity Statin Therapy

High Intensity	Moderate Intensity	Low Intensity
Daily dose lowers LDL on average by approximately ≥50%^a: Rosuvastatin 20-40 mg Atorvastatin 40-80 mg	Daily dose lowers LDL on average, by approximately 30% to <50%^a: Rosuvastatin 5-10 mg Atorvastatin 10-20 mg Simvastatin 20-40 mg Lovastatin 40 mg Pravastatin 40-80 mg Fluvastatin 40 mg bid Pitavastatin 2-4 mg	Daily dose lowers LDL, on average, by <30%^a: Simvastatin 10 mg Lovastatin 20 mg Pravastatin 10-20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg

bid, Twice a day; LDL, low-density lipoprotein cholesterol.

^aNote that individual responses vary.

Data from Robinson JG et al: ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol 63:2889-2934, 2014.

Disposition

Those with polygenic hyperalphalipoproteinemia: Excellent prognosis for longevity
Those with familial hypercholesterolemia, familial type 3 hypercholesterolemia, or multiple lipoprotein-type hyperlipidemia: Even with aggressive treatment, at high risk for accelerated atherosclerosis and coronary artery disease

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Basic Information ⬇

Diagnosis ⬆ ⬇

Treatment ⬆ ⬇

Pearls & Considerations ⬆ ⬇

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