Hyperlipoproteinemia

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Hyperlipoproteinemia Microchapters

Hypercholesterolemia Patient Information

Hypertriglyceridemia Patient Information

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.[1]

Causes

To view a full list of causes of hypercholesterolemia click here

To view a full list of causes of hypertriglyceridemia click here

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[2][3]
  • Fasting glucose
  • Hemoglobin A1C
  • Oral glucose tolerance test
Alcohol Abuse[4][5][6]
  • Patient history
  • CAGE questionnaire
Estrogen Therapy[7]
  • Patient history
  • History of menopause
Glucocorticoid therapy[8][9][10]
or N
  • Patient history
  • History of long-standing autoimmune disease
Renal Disease[11][12] [12] [6]
or N
  • BUN/Cr
  • eGFR
  • Urinalysis for proteinuria
  • BMP for electrolyte disturbances
Obesity[13]
-
  • General appearance
  • Body Mass Index
Pregnancy[14]
  • Urinary or Serum B-hCG
  • Pelvic ultrasound
Paraproteinemic disorders[15][16]
-
-
  • Serum protein electrophoresis
  • ESR
Hypothyroidism[17][18]
↑↑↑
or N
  • Thyroid panel (TSH↑, T3/T4↓)
  • History of weight gain, somnolence, fatigue

Classification

Hyperlipoproteinemias are classified into primary and secondary based on the etiology. The following is the classification for primary hyperlipopoproteinemias by Friedrickson:

 
 
 
 
 
 
 
 
 
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
 
 
 
 
 
 
 
 
 
 
 

The following table is a brief description of the different types of hyperlipoproteinemias:

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.

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

The following algorithm describes the approach to a patient with hyperlipoproteinemia: [19]

 
 
 
 
 
 
 
 
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 adults

In 2008, the United States Preventive Services Task Force recommended screening with total cholesterol and HDL-C[20].

In 2016, the [United States Preventive Services Task Force]] recommended treating based on the pooled cohort calculation of cardiac risk (example online calculator) which requires total cholesterol, LDL-C and HDL-C[21].

In 2017, the American Association of Clinical Endocrinologists and American College Of Endocrinology made joint recommendations for screening[22][23].

Screening in children and adolescents

Lipid screening recommendations vary by age and risk factors as shown below:[24][25] [26]

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

2018 AHA/ACC/ Guideline on the Management of Blood Cholesterol (Do not edit please) [27]

Measurements of LDL-C  and Non–HDL-C:

Class I
"1. In adults who are 20 years of age or older and not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting baseline LDL-C (Level of Evidence: B-NR) "
"2.    In adults who are 20 years of age or older and in whom an initial nonfasting lipid profile reveals a triglycerides level of 400 mg/dL or higher (≥4.5 mmol/L), a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL-C(Level of Evidence: B-NR) "

[27]

Class IIa
"3. For adults with an LDL-C level less than 70 mg/dL (<1.8 mmol/L), measurement of direct LDL-C or modified LDL-C estimate is reasonable to improve accuracy over the Friedewald formula (Level of Evidence: C-LD) "
"4. In adults who are 20 years of age or older and without a personal history of ASCVD, but with a family history of premature ASCVD or genetic hyperlipidemia, measurement of a fasting plasma lipid profile is reasonable as part of an initial evaluation to aid in the understanding and identification of familial lipid disorders(Level of Evidence:C-LD) "

[27]

Treatment and Management

Mendelian randomization studies suggest a linear relationship between LDL and cardiac event reduction[28].


Clinical practice guidelines direct treatment.

Secondary ASCVD Prevention. 2018 AHA/ACC/ Guideline on the Management of Blood Cholesterol (Please, do not edit ) [27]

Class I
"1. In patients who are 75 years of age or younger with clinical ASCVD,*high-intensity statin therapy should be initiated or continued with the aim of achieving a 50% or greater reduction in LDL-C levels (Level of Evidence: A) "
"2. In patients with clinical ASCVD in whom high-intensity statin therapy is contraindicated or who experience  statin-associated side effects, moderate-intensity statin therapy should be initiated  or continued with the aim of achieving  a 30% to 49% reduction in LDL-C (Level of Evidence: A) "
"3. In patients with clinical ASCVD who are judged to be very high risk and considered for PCSK9 inhibitor therapy, maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimib (Level of evidence B-NR)''

[27]

Class IIa
" 4. In patients with clinical ASCVD who are judged to be very high risk and who are on maximally tolerated LDL-C lowering therapy with LDL-C 70 mg/dL or higher (≥1.8 mmol/L) or a non–HDL-C level of 100 mg/dL or higher (≥2.6 mmol/L), it is reasonable to add a PCSK9 inhibitor following a clinician-patient discussion about the net benefit, safety, and cost. (Level of Evidence A)".
'' 5. In patients with clinical ASCVD who are on maximally tolerated statin therapy and are judged to be at very high risk and have an LDL-C level of 70 mg/dL or higher (≥1.8 mmol/L), it is reasonable to add ezetimibe therapy (Level of Evidence B-R)''.
6. Value Statement: Low Value (LOE: B-NR). At mid-2018 list prices, PCSK9 inhibitors have a low cost value (>$150 000 per QALY) compared to good cost value (<$50 000 per QALY) (Section 7 provides a full discussion of the dynamic interaction of different prices and clinical benefit)
'' 7.  In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug–drug interactions, as well as patient frailty and patient preferences (Level of Evidence B- R)''
''8.   In patients older than 75 years of age who are tolerating high-intensity statin therapy, it is reasonable to continue it after evaluating the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences. (Level of Evidence C-LD)''

[27]

Class IIb
" 4. In patients with clinical ASCVD who are receiving maximally tolerated statin therapy and whose LDL-C level remains 70 mg/dL or higher (≥1.8 mmol/L), it may be reasonable to add ezetimibe (Level of Evidence B-R)".
'' 5. In patients with heart failure (HF) with reduced ejection fraction attributable to ischemic heart disease who have a reasonable life expectancy (3 to 5 years) and are not already on a statin because of ASCVD, clinicians may consider initiation of moderate-intensity statin therapy to reduce the occurrence of ASCVD events (Level of Evidence B-R)''.

[27]

Severe Hypercholesterolemia  (LDL-C ≥190 mg/dL [≥4.9 mmol/L]). Secondary ASCVD Prevention. 2018 AHA/ACC/ Guideline on the Management of Blood Cholesterol (Please, do not edit )

Class I
"1.   In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), maximally tolerated statin therapy is recommended(Level of Evidence: B-R) "

[27]

Class IIa
" 2.   In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L), ezetimibe therapy is reasonable (Level of Evidence B-R)".

[27]

Class IIb
" 3. In patients 20 to 75 years of age with a baseline LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower (≤3.4 mmol/L), while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be considered(Level of Evidence B-R)".
'' 4. In patients, 30 to 75 years of age with heterozygous FH and with an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered. (Level of Evidence B-R)''
''5. In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) and who achieve an on-treatment LDL-C level of 130 mg/dL or higher (≥3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered (Level of Evidence C-LD)''
6. Value Statement: Uncertain Value  (B-NR). Among patients with FH without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at mid-2018 US list prices.

[27]

Diabetes Mellitus in Adults. 2018 AHA/ACC/ Guideline on the Management of Blood Cholesterol (Please, do not edit )

Class I
"1. In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated (Level of Evidence: A) "

[27]

Class IIa
" 2. In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific PCE to help stratify ASCVD risk(Level of Evidence B-NR)".
'' 3. In adults with diabetes mellitus who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more (Level of Evidence B-R)''
''4. In adults older than 75 years of age with diabetes mellitus and who are already on statin therapy, it is reasonable to continue statin therapy(Level of Evidence B-NR)''

[27]

Class IIb
" 5. In adults with diabetes mellitus and a 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more(Level of Evidence C-LD)".
'' 6. In adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician–patient discussion of potential benefits and  risks (Level of Evidence C-LD)''
''7. In adults, 20 to 39 years of age with diabetes mellitus that is either of long duration (≥10 years of type 2 diabetes mellitus, ≥20 years of type 1 diabetes mellitus), albuminuria (≥30 mcg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m2, retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin therapy(Level of Evidence B-NR)''

[27]


Barriers to treatment

Patient preference, especially among minority populations, is a barrier to treatment[32].

References

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