Hyperlipoproteinemia

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Hypercholesterolemia Patient Information
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Overview
Classification Familial hyperchylomicronemia Familial hypercholesterolemia Familial combined hyperlipidemia Dysbetalipoproteinemia Primary hypertriglyceridemia Mixed hyperlipoproteinemia
Differential Diagnosis
Screening
ACC/AHA Guideline Recommendations
Summary
Treatment
Major recommendations for statin therapy
Therapeutic response to statin therapy
Blood cholesterol LDL and non-HDL treatment goals
Treatment in heart failure and hemodialysis
Primary prevention
Secondary prevention
Intensity of statin therapy in primary and secondary prevention
Safety Recommendations
Guideline on Lifestyle Management

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

Overview

Hyperlipoproteinemia (also known as hyperlipidemia or high lipoproteins) is defined as presence of high levels of one or more type of lipoproteins. Hyperlipoproteinemia may be caused by primary genetic disorders or as a secondary complications of underlying medical conditions. After ruling out common secondary causes of hyperlipoproteinemia, the clinician must begin the work-up for primary causes.

Patients with hyperlipoproteinemia may present with elevated LDL, HDL, or triglycerides. Hyperlipoproteinemias have a high clinical significance due to the increased risk of cardiovascular, cerebrovascular, and peripheral arterial disease which they confer. Other complications of long-standing hyperlipidemia (specifically hypertriglyceridemia) may include pancreatitis, and steatohepatitis.

Primary causes of hyperlipoproteinemia have been classified into 5 subtypes by Friedrickson. The exact genetic cause of these conditions is not clearly understood. Secondary causes of hyperlipoproteinemia are more common and workup must be targeted at excluding them prior to evaluating primary causes. Regardless of the underlying pathogenesis of the disease, management is targeted at normalizing the affected lipid or lipoproteins either pharmacologically or by lifestyle modifications. However, gene therapy has been a subject of several investigational therapies aiming to treat familial hyperlipoproteinemias at the genomic level.

Classification

Hyperlipoproteinemia

Type I: Familial hyperchylomicronemia

Type II

Type III: Dysbetalipoproteinemia

Type IV: Primary hypertriglyceridemia

Type V: Mixed hyperlipoproteinemia

Type A: Familial hypercholesterolemia

Type B: Familial combined hyperlipidemia

Synopsis

Hyperlipoproteinemia	Disease Name	Pathophysiology	Notable Laboratory Findings	Mainstay of treatment
Type I	Familial hyperchylomicronemia	Decreased lipoprotein lipase (LPL) or altered ApoC2	Elevated chylomicrons	Diet control
Type IIa	Familial hypercholesterolemia	LDL receptor deficiency	Elevated LDL only	Bile acid sequestrants, statins, niacin
Type IIb	Combined hyperlipidemia	Decreased LDL receptor and increased ApoB	Elevated LDL, VLDL and triglycerides	Statins, niacin, gemfibrozil
Type III	Familial Dysbetalipoproteinemia	Defect in ApoE synthesis	Increased IDL	Drug of choice: Gemfibrozil
Type IV	Familial Hypertriglyceridemia	Increased VLDL production and decreased elimination	Increased VLDL	Drug of choice: Niacin
Type V	Mixed hyperlipoproteinemia	Increased VLDL production and decreased LPL	Increased VLDL and chylomicrons	Niacin, gemfibrozil

Differential Diagnosis

Hyperlipoproteinemia may be caused by primary genetic disorders or as secondary complications of underlying medical conditions. After ruling out common secondary causes of hyperlipoproteinemia, the clinician must begin the work-up for primary causes.

For a full list of causes of hypercholesterolemia click here.

For a full list of causes of hypertriglyceridemia click here.

Secondary Hyperlipoprotinemia

Secondary causes of hyperlipoproteinemia must be initially ruled out and differentiated from one another. The table below gives a synopsis of the lipid profile of the most common causes of secondary hyperlipidemias:

Diseases	LDL	HDL	Triglycerides	Total Cholesterol	Diagnostic test(s)
Diabetes Mellitus	↑	↓	↑	↑	Fasting glucose Hemoglobin A1C
Alcohol Abuse	↓	↓	↑	↑	Patient history CAGE questionnaire
Estrogen Therapy	↓	↑	↑	↓	Patient history History of menopause
Glucocorticoid therapy	↑	↑	↑ or N	↑	Patient history History of long-standing autoimmune disease ACTH stimulation test CBC
Renal Disease	↑	↓ or N	↑	↑	BUN/Cr eGFR Urinalysis for proteinuria BMP for electrolyte disturbances
Obesity	↑	↓	↑	-	General appearance Body Mass Index
Pregnancy	↑	↑	↑	↑	Urinary or Serum B-hCG Pelvic ultrasound
Paraproteinemic disorders	-	↓	↑	-	Serum protein electrophoresis ESR
Hypothyroidism	↑↑↑	↑ or N	↑	↑	Thyroid panel (TSH↑, T3/T4↓) History of weight gain, somnolence, fatigue

Primary Hyperlipoproteinemias

Primary causes of hyperlipoproteinemia have been classified into 5 subtypes by Friedrickson. The exact genetic cause of these conditions is not fully understood. The table below may help distinguish the subtypes from one another:

Diseases	Mode of Inheritance	Laboratory Findings								Other Findings	Management	Complications
		Lipid Profile					Other Laboratory Findings
		Total Cholesterol	LDL	HDL	Triglycerides	Plasma Appearance	Chylomicrons	VLDL	Genetic mutations
Type I	Autosomal Recessive & Autosomal Dominant(Rare)	Normal or ↑	↓	↓↓↓	↑↑↑	Milky	↑↑↑	↓	-LPL gene mutation	-Fat tolerance markedly abnormal -Carbohydrate inducibility may be abnormal	Treatment for hyperlipoproteinemia type 1 is intended to control blood triglyceride levels with a very low-fat diet	-Recurrent Pancreatitis -Rarely life threatening
Type IIA	Autosomal Dominant & Autosomal Recessive(Rare)	↑↑	↑↑↑	Normal/↓	Normal	Clear			- LDL recptor mutation - Apolipoportein B gene mutation -Proprotein convertase subtilisin/kexin type 9 mutation.		Lipid management with lifestyle modifications and pharmacotherapy	-Symptomatic coronary artery disease by 50-60 years and half of the men and 15%-30% of the women will have died
Type IIB	Mostly Dominant mode	↑↑	↑↑	↓	↑↑	Clear or turbid		↑	-Locus 1q21-q23 -APOAI/CIII/AIV cluster -Gene encoding upstream transcription factor 1 (USF1)		Lipid management with lifestyle modifications and pharmacotherapy	-Coronary heart disease -Coronary artery disease -Peripheral artery disease -Gangrene of the extremities
Type III	Autosomal Recessive	↑↑	↓	Normal	↑↑↑	Clear, cloudy,or turbid			-Apo E mutations	-IDL is elevated	Lipid management with lifestyle modifications and pharmacotherapy	-Atherosclerotic complications (e.g., coronary artery disease) -Pancreatitis -Stroke -Peripheral vascular disease -Intermittent claudication
Type IV	Autosomal Recessive & Autosomal Dominant	Normal or ↑	↓	Prebeta-HDL ↑ & HDL-C ↓	↑↑	Clear or Cloudy	Normal	↑	-LPL genes (Gly188Glu,Asp9Asn, Asn291Ser,Ser447Ter) -APOA5 -LMF1 -GPIHBP1	Hyperglycemia, Pancytopneia and pseudo-Niemann pick cells	-Weight reduction -Niacin or Fibrates -Gene therapy	-Ischemic Heart Disease -Recurrent Pancreatitis -NIDDM -NAFLD
Type V	Variable	↑ to ↑↑	↓	↓↓↓	↑↑↑	Creamy supernatant and turbid infranatant	↑	↑↑↑	❑ Apo E, Apo A5 mutations ❑ LPL gene mutation in 10% of western population patients	❑ Restriction of dietary fat eliminates Chylomicrons and reverts to type IV HLP ❑ When triglyceride levels are >1000mg/dl given the rarity of type I it is almost always type V HLP	- Weight reduction - Niacin or Fibrates or Strong statins - Low fat diet	❑ Recurrent Pancreatitis

Diagnostic Algorithm

Shown below is a diagnostic algorithm to diagnose hyperlipidemia.

Hyperlipidemia

Triglycerides > 75th Percentile

NO

Type IIa

YES

Types I, IIb, IV, V

Total Cholesterol/Apo B ratio ≥ 6.2

NO

Types IIb, IV

YES

Types I, III, V

Triglycerides/Apo B ratio < 10.0

NO

Types I, V

YES

Type III

Screening

Screening in children and adolescents

Lipid screening recommendations vary by age and risk factors as shown below:

Pediatric dyslipidemia screening guidelines from the 2011 Expert Panel Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents
Age	Screening recommendation	Reommendation level
birth- <2years	No lipid screening	C
2-8years ( No routine lipid screening, however screen if one of the following is present using FLP two times)	Parent, grandparent, aunt/uncle, or sibling with myocardial infarction (MI), angina, stroke, coronary artery bypass graft Strongly recommend (CABG)/stent/angioplasty at <55 years in males, <65 years in females	B
	Parent with TC ≥ 240 mg/dL or known dyslipidemia	B
	Child has diabetes, hypertension, BMI ≥ 95th percentile or smokes cigarettes	B
	Child has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms)	B
9-11years (Universal Screening)	Universal screening with a non-FLP screening using non-HDL-C levels ( Non-HDL–C = TC – HDL–C) when Non-HDL ≥ 145 mg/dL, HDL < 40 mg/dL check FLP × 2	B
	Do further FLP if LDL–C ≥ 130 mg/dL, non-HDL–C ≥ 145 mg/dL HDL–C < 40 mg/dL, TG ≥ 100 mg/dL if < 10 years; ≥ 130 mg/dL if ≥ 10 years. Repeat FLP after 2 weeks but within 3 months	B
12-16years (Selective screening using FLP x 2)	Lipid screening is not recommended for those ages 12–16 years because of significantly decreased sensitivity and specificity for predicting adult LDL–C levels and significantly increased false-negative results in this age group. Selective screening ( Interval between FLP measurements: after 2 weeks but within 3 months) is recommended for those with the clinical indications outlined below:	B
	Parent, grandparent, aunt/uncle or sibling with MI, angina, stroke, CABG/stent/ Strongly recommend angioplasty, sudden death at < 55 years in males, < 65 years in females	B
	• Parent with TC ≥ 240 mg/dL or known dyslipidemia	B
	Patient has diabetes, hypertension, BMI ≥ 85th pr\ercentile or smokes cigarettes	B
	Patient has a moderate- or high-risk medical condition (eg. Diabetes mellitus type 1 and type 2, chronic renal disease/end-stage renal disease/ postrenal transplant, Postorthotopic heart transplant, Kawasaki disease with current aneurysms)	B
17-19years	Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 145 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP if LDL-C ≥ 130 mg/dL, non-HDL-C ≥ 145 mg/dL HDL-C < 40 mg/dL, TG ≥ 130 mg/dL repeat FLP after 2 weeks but within 3 months	B
17-21years	Universal screening once during this time period with a nonfasting lipid screening using non-HDL-C levels. If Non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL do FLP × 2, Further screening with FLP when LDL-C ≥ 160 mg/dL, non-HDL-C ≥ 190 mg/dL, HDL-C < 40 mg/dL, TG ≥ 150 mg/dL repeat FLP after 2 weeks but within 3 months	B