Familial hypercholesterolemia: Difference between revisions

Jump to navigation Jump to search
Line 95: Line 95:


===History and Symptoms===
===History and Symptoms===
*Elevated serum [[cholesterol]], most notably the [[LDL]] fraction ([[VLDL]]. [[Triglyceride]]s are typically normal)
** On lipoprotein [[electrophoresis]] (rarely done), a [[hyperlipoproteinemia type II]] pattern is recognised
History is usually suggestive of:
*Premature [[cardiovascular disease]], such as:
**[[Angina pectoris]], leading to [[PTCA]] or [[CABG]]
**[[Myocardial infarction]]
**[[Transient ischemic attack]]s (TIA's)
**[[Cerebrovascular accident]]s/[[Stroke]]s
**[[Peripheral artery disease]] (PAOD)
*A ''[[family history]]'' of premature [[atherosclerosis]]
===Physical examinations===
===Physical examinations===
Ptients with familial hypercholesterolemia may present with the following:
Ptients with familial hypercholesterolemia may present with the following:

Revision as of 21:29, 8 November 2016

WikiDoc Resources for Familial hypercholesterolemia

Articles

Most recent articles on Familial hypercholesterolemia

Most cited articles on Familial hypercholesterolemia

Review articles on Familial hypercholesterolemia

Articles on Familial hypercholesterolemia in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Familial hypercholesterolemia

Images of Familial hypercholesterolemia

Photos of Familial hypercholesterolemia

Podcasts & MP3s on Familial hypercholesterolemia

Videos on Familial hypercholesterolemia

Evidence Based Medicine

Cochrane Collaboration on Familial hypercholesterolemia

Bandolier on Familial hypercholesterolemia

TRIP on Familial hypercholesterolemia

Clinical Trials

Ongoing Trials on Familial hypercholesterolemia at Clinical Trials.gov

Trial results on Familial hypercholesterolemia

Clinical Trials on Familial hypercholesterolemia at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Familial hypercholesterolemia

NICE Guidance on Familial hypercholesterolemia

NHS PRODIGY Guidance

FDA on Familial hypercholesterolemia

CDC on Familial hypercholesterolemia

Books

Books on Familial hypercholesterolemia

News

Familial hypercholesterolemia in the news

Be alerted to news on Familial hypercholesterolemia

News trends on Familial hypercholesterolemia

Commentary

Blogs on Familial hypercholesterolemia

Definitions

Definitions of Familial hypercholesterolemia

Patient Resources / Community

Patient resources on Familial hypercholesterolemia

Discussion groups on Familial hypercholesterolemia

Patient Handouts on Familial hypercholesterolemia

Directions to Hospitals Treating Familial hypercholesterolemia

Risk calculators and risk factors for Familial hypercholesterolemia

Healthcare Provider Resources

Symptoms of Familial hypercholesterolemia

Causes & Risk Factors for Familial hypercholesterolemia

Diagnostic studies for Familial hypercholesterolemia

Treatment of Familial hypercholesterolemia

Continuing Medical Education (CME)

CME Programs on Familial hypercholesterolemia

International

Familial hypercholesterolemia en Espanol

Familial hypercholesterolemia en Francais

Business

Familial hypercholesterolemia in the Marketplace

Patents on Familial hypercholesterolemia

Experimental / Informatics

List of terms related to Familial hypercholesterolemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Synonyms and keywords: FHC; FH; type IIA hyperlipoproteinemia; hyper-low-density-lipoproteinemia; familial hypercholesterolemic xanthomatosis; LDL receptor disorder

Overview

Familial hypercholesterolemia (also spelled familial hypercholesterolaemia) is a rare genetic disorder characterized by very high LDL cholesterol and early heritable cardiovascular disease.

Historical perspective

  • The Norwegian physician Dr C Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938.
  • In the early 1970s and 1980s, the genetic cause for familial hypercholesterolemia was described by Dr Joseph L. Goldstein and Dr Michael S. Brown of Dallas, Texas [3].

Classification

Familial hypercholesterolemia may be classified according to the severity of the mutation involving the LDL-cholesterol (LDL-C) receptor or depending on the mode of inheritance as follows:

Pathophysiology

Genetics

Pathogenesis

  • Familial disorders of cholesterol metabolism may result from one of the following:
  • LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver.
  • In Familial hypercholesterolemia (FH), the half-life of an LDL particle is almost doubled to 4.5 days.
    • This leads to markedly elevated LDL levels, with the other forms of cholesterol remaining normal, most notably HDL.
  • The classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.[4]
  • Although atherosclerosis can occur in all people, many familial hypercholesterolemia patients develop accelerated atherosclerosis due to the presence of excess LDL. Some studies of familial hypercholesterolemia cohorts suggest that additional risk factors are generally present when a familial hypercholesterolemic patient develops atherosclerosis.[5][6]
    • The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body, as well as the functionality of these receptors. In heterozygous FH, there is at least 50% of the normal LDL receptor activity however, in homozygous FH, both alleles are damaged to some degree, which may lead to extremely high levels of LDL. Children with this form of FH may develop severe premature heart disease. A further complication is the ineffectiveness of statins.

Causes

Differentiating familial hypercholesterolemia from other diseases

Epidemiology and demographics

Risk factors

Screening

Universal screening for elevated serum cholesterol is recommended.[7]

General population screening

Familial hypercholesterolemia (FH) should be suspected when untreated fasting LDL cholesterol or non HDL cholesterol levels are at or above the following:

  • Adults (≥ 20 years):
    • LDL cholesterol ≥ 190 mg/dL or non-HDL cholesterol ≥ 220 mg/dL
  • Children, adolescents and young adults (< 20 years):
    • LDL cholesterol ≥160 mg/dL or non- HDL cholesterol ≥ 190 mg/dL

Cholesterol screening should be considered beginning at age 2 for children with a family history of premature cardiovascular disease or elevated cholesterol. All individuals should be screened by age 20.

Although not present in many individuals with familial hypercholesterolemia (FH), the following physical findings should prompt the clinician to strongly suspect FH and obtain necessary lipid measurements if not already available:

  • Tendon xanthomas at any age (most common in Achilles tendon and finger extensor tendons, but can also occur in patellar and triceps tendons). B Arcus corneae in a patient under age 45.
  • Tuberous xanthomas or xanthelasma in a patient under age 20 to 25

At the LDL cholesterol levels listed below the probability of FH is approximately 80% in the setting of general population screening.

  • These LDL cholesterol levels should prompt the clinician to strongly consider a diagnosis of FH and obtain further family information:
    • LDL cholesterol ≥ 250 mg/dL in a patient aged 30 or more
    • LDL cholesterol ≥ 220 mg/dL for patients aged 20 to 29
    • LDL cholesterol ≥ 190 mg/dL in patients under age 20

Screening in children

Lipid screening recommendations for familial hypercholesterolemia in children varies by age and risk factors.[8][9]

Child-parent familial hypercholesterolemia screening in primary care

  • Recent studies show the feasibility and efficacy of child-parent familial hypercholesterolemia screening in primary care setting.
  • The conclusion remains that child–parent familial hypercholesterolemia screening is a simple, practical, and effective way of screening the population to identify and prevent a common inherited cause of premature cardiovascular disease.[10]

Natural history, complication and prognosis

Natural history

If left untreated, the majority of affected individuals will have symptomatic coronary artery disease by 60 years and half of the men and 15% of the women will have died. On the other hand, patients who start attending a lipid clinic before they develop clinical CAD may enjoy a normal life expectancy if well managed.[11][12]

Complication

Prognosis

Diagnosis

History and Symptoms

History is usually suggestive of:

Physical examinations

Ptients with familial hypercholesterolemia may present with the following:

Eyes

Extremities

Laboratory findings

In FH, a genetic diagnosis is important for family screening, to establish the diagnosis in patients with borderline LDL-C and to improve patient adherence to therapy.[13]

Genetic testing is generally undertaken when:

  • A family member has been shown to have a mutation
  • High cholesterol is found in a young patient with atherosclerotic disease
  • Tendon xanthomas are found in a patient with high cholesterol

FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria[14] as shown below:

Dutch Lipid Clinic Network (DLCN) diagnostic criteria for familial hypercholesterolaemia
Variable Criteria Score
Family History First-degree relative with known premature (i.e men < 55 years, or women < 60 years) coronary heart disease (CHD) 1
First-degree relative with known LDL-C > 95th percentile by age and sex for country 1
First-degree relative with tendon xanthoma and/or corneal arcus 2
Child/children aged < 18 years with LDL-C > 95th percentile by age and sex for country 2
Clinical History Premature CHD (i.e men < 55 years, or women < 60 years) 2
Premature (i.e men < 55 years, or women < 60 years) cerebral or peripheral vascular disease 1
Physical Examination The presence of tendon xanthoma 6
Corneal arcus in a person aged < 45 years 4
LDL Cholesterol Level LDL-C concentrations: ≥ 8.5 mmol/L (≥ 330 mg/dL) 8
≥ 6.5 to < 8.5 mmol/L (≥ 250 to < 330 mg/dL) 5
≥ 5.0 to < 6.5 mmol/L (≥ 190 to < 250 mg/dL) 3
≥ 4.0 to < 5.0 mmol/L (≥ 155 to < 190 mg/dL) 1
DNA Analysis Deoxyribonucleic acid (DNA) analysis and the finding of a causative mutation inolving LDLR, apoB, or PCSK9 gene 8


The table below shows the interpretation of the DLCN diagnostic criteria.


Interpretation of DLCN score
Score Diagnosis
>8 Definite FH diagnosis
6-8 Probable FH diagnosis
3-5 Possible FH diagnosis
0-2 Unlikely FH diagnosis

Electrocardiogram

Chest X Ray

CT Scan / MRI

Echocardiography or Ultrasound

Other imaging findings

Treatment

Medical therapy

Heterozygous FH

The initial drug of choice are high-dose statin therapy especially atorvastatin, simvastatin or rosuvastatin. [15][16][17] Statins work by forcing the liver to produce more LDL receptor to maintain the amount of cholesterol in the cell. This requires at least one functioning copy of the gene. In cases where monotherapy with statins are ineffective, combination therapy with statin and other lipid lowering medication can be considered although their utility is not well established. The following can be added to statins:[18]

The combination of fibrates and statins is associated with a markedly increased risk of myopathy and rhabdomyolysis (breakdown of muscle tissue, leading to acute renal failure), so patients must be monitored closely.

Homozygous FH

According to the 2015 AHA scientific statement on FH, early diagnosis of homozygous FH and prompt initiation of diet and lipid-lowering therapy are critical.[21][22]

As previously mentioned, the LDL levels are much higher and the most effective treatments (statins) require at least one copy of the functional LDL receptor gene. In this case, high amounts of bile acid sequestrants are often given. Occasionally, high-dosed statins can help express a dysfunctional (but some times working) LDL receptor. Other treatments used are LDL apheresis (clearing LDL by blood filtration, similar to dialysis) with liver transplant as last result. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.

Surgery

Prevention

References

  1. Grossman M, Rader DJ, Muller DW, Kolansky DM, Kozarsky K, Clark BJ; et al. (1995). "A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia". Nat Med. 1 (11): 1148–54. PMID 7584986.
  2. 2.0 2.1 2.2 Austin MA, Hutter CM, Zimmern RL, Humphries SE (2004). "Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review". Am J Epidemiol. 160 (5): 407–20. doi:10.1093/aje/kwh236. PMID 15321837.
  3. 3.0 3.1 van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC; et al. (2011). "Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children". Circulation. 123 (11): 1167–73. doi:10.1161/CIRCULATIONAHA.110.979450. PMID 21382890.
  4. Goldstein JL, Brown MS (1974). "Binding and degradation of [[low density lipoproteins]] by cultured human [[fibroblasts]]. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia". J Biol Chem. 249 (16): 5153–62. PMID 4368448. URL–wikilink conflict (help)
  5. Scientific Steering Committee on behalf of the Simon Broome Register Group (Ratcliffe Infirmary, Oxford, England), "Risk of fatal coronary heart disease in familial hypercholesterolaemia", British Medical Journal 303 (1991), pp. 893-896.
  6. E.J.G. Sijbrands, et al., "Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study", British Medical Journal 322 (2001), pp. 1019-1023.
  7. Journal of Clinical Lipidology. Clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. Familial Hypercholesterolemia: Screening, diagnosis and management of pediatric and adult patients. (2011) https://www.lipid.org/sites/default/files/articles/familial_hypercholesterolemia_1.pdf Accessed on October 27 2016
  8. 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.
  9. 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.
  10. Wald DS, Bestwick JP, Morris JK, Whyte K, Jenkins L, Wald NJ (2016). "Child-Parent Familial Hypercholesterolemia Screening in Primary Care". N Engl J Med. 375 (17): 1628–1637. doi:10.1056/NEJMoa1602777. PMID 27783906.
  11. Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P; et al. (2008). "Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study". Eur Heart J. 29 (21): 2625–33. doi:10.1093/eurheartj/ehn422. PMC 2577142. PMID 18840879.
  12. Authors/Task Force Members:. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ; et al. (2016). "2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR)". Atherosclerosis. 253: 281–344. doi:10.1016/j.atherosclerosis.2016.08.018. PMID 27594540.
  13. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS; et al. (2013). "Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society". Eur Heart J. 34 (45): 3478–90a. doi:10.1093/eurheartj/eht273. PMC 3844152. PMID 23956253.
  14. Benn M, Watts GF, Tybjærg-Hansen A, Nordestgaard BG (2016). "Mutations causative of familial hypercholesterolaemia: screening of 98 098 individuals from the Copenhagen General Population Study estimated a prevalence of 1 in 217". Eur Heart J. 37 (17): 1384–94. doi:10.1093/eurheartj/ehw028. PMID 26908947.
  15. Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF (2001). "Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial". Lancet. 357 (9256): 577–81. PMID 11558482.
  16. Davidson MH, Stein EA, Dujovne CA, Hunninghake DB, Weiss SR, Knopp RH; et al. (1997). "The efficacy and six-week tolerability of simvastatin 80 and 160 mg/day". Am J Cardiol. 79 (1): 38–42. PMID 9024733.
  17. Jones P, Kafonek S, Laurora I, Hunninghake D (1998). "Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES study)". Am J Cardiol. 81 (5): 582–7. PMID 9514454.
  18. Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A; et al. (2007). "Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia". N Engl J Med. 356 (2): 148–56. doi:10.1056/NEJMoa061189. PMID 17215532.
  19. Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF; et al. (2008). "Simvastatin with or without ezetimibe in familial hypercholesterolemia". N Engl J Med. 358 (14): 1431–43. doi:10.1056/NEJMoa0800742. PMID 18376000.
  20. Illingworth DR, Stein EA, Mitchel YB, Dujovne CA, Frost PH, Knopp RH; et al. (1994). "Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial". Arch Intern Med. 154 (14): 1586–95. PMID 8031206.
  21. Gidding SS, Champagne MA, de Ferranti SD, Defesche J, Ito MK, Knowles JW; et al. (2015). "The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Association". Circulation. 132 (22): 2167–92. doi:10.1161/CIR.0000000000000297. PMID 26510694.
  22. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA; et al. (2014). "Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society". Eur Heart J. 35 (32): 2146–57. doi:10.1093/eurheartj/ehu274. PMC 4139706. PMID 25053660.

External links

  • MEDPED (Make Early Diagnosis to Prevent Early Deaths)
  • NCBI (Familial Hypercholesterolemia Page at National Center for Biotechnology Information)
  • H·E·A·R·T UK (H·E·A·R·T UK, Familial Hypercholesterolemia charity based in the United Kingdom)

Template:Endocrine, nutritional and metabolic pathology


Template:WikiDoc Sources