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hyperlipoproteinemia type 2 (familial hypercholesterolemia)

Etiology: 1) primary: defect in LDL receptor 2) secondary increases in LDL Epidemiology: - gene frequency 0.2-0.5% in USA, but as high as 1.3% in white South Africans & in Lebanon Pathology: - receptor defect impairs the catabolism of LDL, & the resultantelevation in plasma LDL-cholesterol promotes deposition of cholesterol in the skin (xanthelasma), tendons (xanthomas), & coronary arteries (atherosclerosis) Genetics: - autosomal dominant form - genetic variation in GHR may act as phenotype modifier in familial hypercholesterolemia patients carrying a mutation in the LDLR gene - APOB, PCSK9, & LDLRAP1 may also play a role [5] Clinical manifestations: 1) cutaneous xanthomas before 10 years of age for homozygous familial hypercholesterolemia 2) corneal arcus 3) premature atherosclerosis Laboratory: - increased serum cholesterol & LDL cholesterol - untreated LDL cholesterol > 500 mg/dL (before 10 years of age for homozygous familial hypercholesterolemia [5] - genetic testing - LDLR gene mutations - APOB gene+LDLR gene mutations - APOB+LDLR+PCSK9 gene mutations Radiology: - echocardiogram & evaluation of aorta annually - CT coronary angiography every 5 years or more frequently accounting for severity of disease & radiation exposure [5] Complications: - 10% with myocardial infarction at a young age [7] Management: 1) diet is the foundation of treatment a) weight loss b) AHA diet step 1 or step 2 c) maximum diet affect is observed in 4-5 weeks d) more frequent eating may reduce serum cholesterol & LDL cholesterol [3] {6-10 mg/dL decrease for cholesterol} 2) pharmaceutical agents a) HMG CoA reductase inhibitors (statins) - statins for children improve LDL cholesterol & reduce risk of cardiovascular events in adulthood [8] - mean LDL cholesterol achieved 161 mg/dL (untreated 237 mg/dL) [8] b) lomitapide (Juxtapid) [5] c) mipomersen (Kynamro) [5] d) bile acid sequestrants, niacin & fibrates not recommended [5] 3) apheresis with selective LDL cholesterol removal [4] - begin 5-8 years of age 4) target LDL cholesterol - < 100 mg/dL (adults) - < 70 mg/dL (adults with cardiovascular disease) - < 135 mg/dL (children) [5] 5) no benefit in screening for dyslipidemia children or adolescents [6]

Interactions

disease interactions

Related

bile acid sequestrant fibrate HMG CoA reductase inhibitor (statin) low-density lipoprotein receptor; LDL receptor; apoB/E receptor (LDLR) National Cholesterol Education Program (NCEP) step 1 diet nicotinic acid (niacin, vitamin B3, Niaspan)

Specific

autosomal recessive hypercholesterolemia hyperlipoproteinemia type 2A hyperlipoproteinemia type 2B

General

hyperlipoproteinemia (HLP) lipid metabolism, inborn error; lipid storage disease; lipidosis

References

  1. Clinical Diagnosis & Management by Laboratory Methods, J.B. Henry (ed), W.B. Saunders Co., Philadelphia, PA. 1991, pg 208
  2. Tietz Textbook of Clinical Chemistry, 2nd ed. Burtis CA & Ashwood ER (eds), WB Saunders Co, Philadelphia PA, 1993, pg 1038
  3. Journal Watch 22(3):21, 2002 Titan SM et al Frequency of eating and concentrations of serum cholesterol in the Norfolk population of the European prospective investigation into cancer (EPIC-Norfolk): cross sectional study. BMJ. 2001 Dec 1;323(7324):1286-8 PMID: 11731392
  4. Medical Knowledge Self Assessment Program (MKSAP) 16, 18. American College of Physicians, Philadelphia 2012, 2018.
  5. Anello J, Feinberg B, Heinegg J, Lindsey R, Wojdylo C, Wong O. Medcsape Oncology. August 2014 Guidelines on homozygous familial hypercholesterolemia (HoFH) from the European Atherosclerosis Society http://reference.medscape.com/features/slideshow/guidelines-review/august2014
  6. Lozano P, Henrikson NB, Dunn J 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. JAMA. 2016;316(6):645-655 PMID: 27532919 http://jama.jamanetwork.com/article.aspx?articleid=2542641
  7. Singh A, Gupta A, Collins BL et al. Familial hypercholesterolemia among young adults with myocardial infarction. J Am Coll Cardiol 2019 May 21; 73:2439. PMID: 31097165 https://www.sciencedirect.com/science/article/pii/S0735109719345528
  8. Luirink IK, Wiegman A, Kusters DM et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med 2019 Oct 17; 381:1547-1556 PMID: 31618540 https://www.nejm.org/doi/10.1056/NEJMoa1816454

Databases & Figures

OMIM 143890 Figures/diagrams/slides/tables related to hyperlipoproteinemia type 2