Primary Hyperlipoproteinemia

Primary Hyperlipoproteinemia

1. 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.
2. •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. 

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.

Plasma Lipoprotein Composition

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

Component	Origin	Density (g/ml)	Size (nm)	Protein (%)	Cholesterol in Plasma (mmol/L)	Triglyceride in Fasting Plasma (mmol/L)	Apoprotein
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.

Synonym

• Hyperlipidemia

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
• •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 the below table.

Disorders of Lipids: Clinical Findings and Management

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

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.

What are the symptoms of Primary Hyperlipoproteinemia – 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 can develop with exacerbations

What causes Primary Hyperlipoproteinemia?

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

Differential Diagnosis

Secondary causes of hyperlipoproteinemias:

• •Hypothyroidism
• •Diabetes mellitus
• •Pancreatitis
• •Autoimmune hyperlipoproteinemia
• •Nephrotic syndrome
• •Biliary obstruction;

The below table describes the differential diagnosis of hyperlipidemia and dyslipidemia.

Differential Diagnosis of Hyperlipidemia and Dyslipidemia

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

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.

Workup

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

Laboratory Tests

• •Standard lipid profile; The below table summarizes laboratory findings in lipid disorders

Laboratory Findings in Lipid Disorders

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

Disorder	Inheritance	OMIM No.	Prevalence	Cholesterol	Triglycerides	VLDL	Chylomicrons	LDL	HDL	Serum	Cause
Type I	AR		1/million	↑︎	↑︎↑︎↑︎	↑︎	↑︎	↓︎	↓︎↓︎↓︎	Creamy top
a: Familial hyperchylomicronemia		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 heterozygotes	↑︎	NI or ↑︎	↑︎	NI	↓︎	↓︎	Clear
a: Familial hypercholesterolemia	AD	143890, 144010, 603776	LDL receptor defect in 60%-80%; APOB, PCSK9, each <5%
AR	603813	LDLRAP1
b: Familial combined hyperlipidemia	AD, AR	144250	1 in 100	Clear	Polygenic
Decreased LDL receptor and ApoB-100 dysfunction
Type III	AR	107741	1 in 10,000	↑︎	↑︎	↑︎	↑︎	↓︎	NI	Turbid	ApoE-2 synthesis
Familial dysbetalipoproteinemia
Type IV	AD	144600	1 in 100	↑︎	NI ↑︎	↑︎	NI	↓︎	↓︎↓︎	Turbid	Renal disease, diabetes
Familial hypertriglyceridemia
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.

• 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

How is this condition treated?

Nonpharmacologic Therapy

• •Cornerstone of treatment: Dietary therapy
  • 1.TLC diet (therapeutic lifestyle changes):
• •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

Acute General Treatment

No acute treatment is needed.

Chronic Treatment

• •Medications commonly used to treat hyperlipidemias are summarized in the below table

Drugs Used to Treat Hyperlipidemia

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

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

bid, Twice a day; EPA, highly concentrated ethyl esters of eicosapentaenoic acid; DHA, docosahexaenoic 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; qd, every day; sc, subcutaneously; VLDL, very low-density lipoprotein.

a There are several different preparations of fenofibrate with different doses.

• 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 can be added to statins to achieve LDL goals. Alirocumab and evolocumab are subcutaneously injected PCSK9 (protein convertase subtilisin kexin type 9) inhibitors available as an adjunct diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia (HeFH). They can be added to statins and ezetimibe. Evinacumab, a monoclonal antibody against the gene encoding angiopoietin-like protein 3 (ANGPTL3) has shown potential benefits in patients with homozygous familial hypercholesterolemia. In a recent phase 3 trial in patients with a homozygous familial hypercholestrolemia receiving maximum doses of lipid-lowering therapy, the reduction from baseline in the LDL cholesterol level in the Evinacumab group, as compared with the subtle increase in the placebo group, resulted in a between-group difference of 49.0 percentage points at 24 weeks. 1Raol FJ et al: Evinacumab for homozygous familial hypercholesterolemia, N Engl J Med 383;711–20, 2020
• •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 ATP 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.

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

Pearls & Considerations

• •Patient information is available through the American Heart Association.
• •Lipid-lowering drug therapy is recommended for children ≥10 yr whose LDL-C levels remain extremely elevated after 6 mo to 1 yr of dietary modification. Drug therapy also can be considered for children with LDL-C levels of ≥190 mg/dl.

Suggested Readings

• Bhatt D.L., et al.: Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019; 380 (1): pp. 11-22.
• Last A.R., et al.: Hyperlipidemia: drugs for cardiovascular risk reduction in adults. Am Fam Physician 2017; 95 (2): pp. 78-87.
• Lozano P., et al.: Lipid screening in childhood and adolescence for detection of familial hypercholesterolemia: evidence report and systematic review for the US Preventive Services Task Force. J Am Med Assoc 2016; 316 (6): pp. 645-655.
• Ray K.K., et al.: Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019; 380 (11): pp. 1022-1032.