Hyperlipoproteinemia
Hyperlipoproteinemia Microchapters |
ACC/AHA Guideline Recommendations |
Intensity of statin therapy in primary and secondary prevention |
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]
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[2][3] | ↑
|
↓
|
↑
|
↑
|
|
Alcohol Abuse[4][5][6] | ↓
|
↓
|
↑
|
↑
|
|
Estrogen Therapy[7] | ↓
|
↑
|
↑
|
↓
|
|
Glucocorticoid therapy[8][9][10] | ↑
|
↑
|
↑ or N
|
↑
|
|
Renal Disease [11][12] [12] [6] | ↑
|
↓ or N
|
↑
|
↑
|
|
Obesity[13] | ↑
|
↓
|
↑
|
-
|
|
Pregnancy[14] | ↑
|
↑
|
↑
|
↑
|
|
Paraproteinemic disorders[15][16] | -
|
↓
|
↑
|
-
|
|
Hypothyroidism[17][18] | ↑↑↑
|
↑ or N
|
↑
|
↑
|
|
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
-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) | ||
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.[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 children and adolescents
Lipid screening recommendations vary by age and risk factors as shown below:[20][21] [22]
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 |
References
- ↑ Brahm AJ, Hegele RA (2016). "Lomitapide for the treatment of hypertriglyceridemia". Expert Opin Investig Drugs. 25 (12): 1457–1463. doi:10.1080/13543784.2016.1254187. PMID 27785928.
- ↑ Ozder A (2014). "Lipid profile abnormalities seen in T2DM patients in primary healthcare in Turkey: a cross-sectional study". Lipids Health Dis. 13: 183. doi:10.1186/1476-511X-13-183. PMC 4271485. PMID 25481115.
- ↑ Lindegaard ML, Damm P, Mathiesen ER, Nielsen LB (2006). "Placental triglyceride accumulation in maternal type 1 diabetes is associated with increased lipase gene expression". J Lipid Res. 47 (11): 2581–8. doi:10.1194/jlr.M600236-JLR200. PMID 16940551.
- ↑ Phukan JP, Sinha A, Deka JP (2013). "Serum lipid profile in alcoholic cirrhosis: A study in a teaching hospital of north-eastern India". Niger Med J. 54 (1): 5–9. doi:10.4103/0300-1652.108886. PMC 3644745. PMID 23661892.
- ↑ HENEGAR GC, TURNER JL (1950). "Medical progress in cholesterol metabolism in relation to diseases of the liver and the biliary tract". Calif Med. 73 (6): 489–93. PMC 1520771. PMID 14792338.
- ↑ 6.0 6.1 Yuan G, Al-Shali KZ, Hegele RA (2007). "Hypertriglyceridemia: its etiology, effects and treatment". CMAJ. 176 (8): 1113–20. doi:10.1503/cmaj.060963. PMC 1839776. PMID 17420495.
- ↑ Nanda S, Gupta N, Mehta HC, Sangwan K (2003). "Effect of oestrogen replacement therapy on serum lipid profile". Aust N Z J Obstet Gynaecol. 43 (3): 213–6. PMID 14712987.
- ↑ Quinkler M, Ekman B, Marelli C, Uddin S, Zelissen P, Murray R (2016). "Prednisolone is associtaed with a worse lipid profile than hydrocortisone in patients with adrenal insufficiency". Endocr Connect. doi:10.1530/EC-16-0081. PMID 27864317 Check
|pmid=
value (help). zero width space character in|pmid=
at position 9 (help) - ↑ Yadav A, Jahan A, Yadav TP, Sachdev N, Chitkara A, Asare R (2013). "Effect of glucocorticoids on serum lipid profile and endothelial function and arterial wall mechanics". Indian J Pediatr. 80 (12): 1007–14. doi:10.1007/s12098-013-1035-6. PMID 23696151.
- ↑ Zimmerman J, Fainaru M, Eisenberg S (1984). "The effects of prednisone therapy on plasma lipoproteins and apolipoproteins: a prospective study". Metabolism. 33 (6): 521–6. PMID 6727652.
- ↑ Trevisan R, Dodesini AR, Lepore G (2006). "Lipids and renal disease". J Am Soc Nephrol. 17 (4 Suppl 2): S145–7. doi:10.1681/ASN.2005121320. PMID 16565240.
- ↑ 12.0 12.1 Vaziri ND (2003). "Molecular mechanisms of lipid disorders in nephrotic syndrome". Kidney Int. 63 (5): 1964–76. doi:10.1046/j.1523-1755.2003.00941.x. PMID 12675893.
- ↑ Nishide R, Ando M, Funabashi H, Yoda Y, Nakano M, Shima M (2015). "Association of serum hs-CRP and lipids with obesity in school children in a 12-month follow-up study in Japan". Environ Health Prev Med. 20 (2): 116–22. doi:10.1007/s12199-014-0433-3. PMC 4597345. PMID 25511645.
- ↑ Geraghty AA, Alberdi G, O'Sullivan EJ, O'Brien EC, Crosbie B, Twomey PJ; et al. (2016). "Maternal Blood Lipid Profile during Pregnancy and Associations with Child Adiposity: Findings from the ROLO Study". PLoS One. 11 (8): e0161206. doi:10.1371/journal.pone.0161206. PMC 4999287. PMID 27560495.
- ↑ van Gorselen EO, Diekman T, Hessels J, Verhorst PM, von Birgelen C (2010). "Artifactual measurement of low serum HDL-cholesterol due to paraproteinemia". Clin Res Cardiol. 99 (9): 599–602. doi:10.1007/s00392-010-0186-y. PMC 2928922. PMID 20593189.
- ↑ Brahm A, Hegele RA (2013). "Hypertriglyceridemia". Nutrients. 5 (3): 981–1001. doi:10.3390/nu5030981. PMC 3705331. PMID 23525082.
- ↑ Duntas LH (2002). "Thyroid disease and lipids". Thyroid. 12 (4): 287–93. doi:10.1089/10507250252949405. PMID 12034052.
- ↑ Nikkilä EA, Kekki M (1972). "Plasma triglyceride metabolism in thyroid disease". J Clin Invest. 51 (8): 2103–14. doi:10.1172/JCI107017. PMC 292367. PMID 4341014.
- ↑ Sniderman A, Tremblay A, Bergeron J, Gagné C, Couture P (2007). "Diagnosis of type III hyperlipoproteinemia from plasma total cholesterol, triglyceride, and apolipoprotein B". Journal of Clinical Lipidology. 1 (4): 256–63. doi:10.1016/j.jacl.2007.07.006. PMID 21291689. Retrieved 2012-10-24. Unknown parameter
|month=
ignored (help) - ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents. National Heart, Lung, and Blood Institute (2011). "Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report". Pediatrics. 128 Suppl 5: S213–56. doi:10.1542/peds.2009-2107C. PMC 4536582. PMID 22084329.
- ↑ Gooding HC, Rodday AM, Wong JB, Gillman MW, Lloyd-Jones DM, Leslie LK; et al. (2015). "Application of Pediatric and Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood". JAMA Pediatr. 169 (6): 569–74. doi:10.1001/jamapediatrics.2015.0168. PMID 25845026.
- ↑ Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents http://www.nhlbi.nih.gov/guidelines/cvd_ped/peds_guidelines_full.pdf.