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:
- Heterozygous vs homozygous[1][2]
- This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low-density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease.
- These are more pronounced in homozygous than heterozygous individuals.
- This is particularly important because, phenotypically, familial hypercholesterolemia (FH) is characterized by increased plasma levels of total cholesterol and low-density lipoprotein cholesterol, tendinous xanthomata, and premature symptoms of coronary heart disease.
- Polygenic vs monogenic
- Polygenic hypercholesterolemia is a major source of atherosclerotic cardiovascular disease.
- Xanthelasma, premature CHD, tendon xanthomata, and childhood obesity are common in monogenic hypercholesterolemia.
- Tendon xanthomata and childhood obesity are not observed in polygenic hypercholesterolemia.
Pathophysiology
Genetics
- Familial hypercholesterolemia is a common autosomal dominant[2][3] disorder caused by mutations involving three genes:[3][2]
- The LDL receptor
- The apolipoprotein B gene (ApoB)
- ApoB is necessary for binding of LDL particles to the LDL receptor. Mutation in this gene leads to impaired binding to the LDL receptor.
- Proprotein convertase subtilisin/kexin type 9 gene
- Mutation in this gene leads to decreased LDL metabolism
- There are over 1600 known mutations of the LDL receptor gene documented to cause familial hypercholesterolemia, accounting for about 85 to 90% of familial hypercholesterolemia cases.
- The apolipoprotein B gene mutation (Arg3500Gln mutation in APOB) is mostly observed in Northern European population but rare in other populations. It accounts for 5 to 10% of familial hypercholesterolemia cases.
- Mutations involving Proprotein convertase subtilisin/kexin type 9 gene is a gain-of-function mutation causing fewer than 5% of familial hypercholesterolemia cases.
- The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45kb, and the gene product contains 839 amino acids in mature form.
Pathogenesis
- Familial disorders of cholesterol metabolism may result from one of the following:
- Overproduction of lipoproteins
- Impaired removal of lipoproteins (this may result from primary defect with the lipoprotein or its receptor) as described above.
- 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]
- The excess circulating LDL is taken up by cells all over the body—most notably, by macrophages, and particularly the ones in a primary streak (the earliest stage of atherosclerosis).
- Oxidation of LDL increases its uptake by foam cells.
- 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]
Diagnosis
History and Symptoms
Physical examinations
Laboratory findings
| Variable | Criteria | Score |
|---|---|---|
| Family History | Criteria here | 1 |
| Criteria here | 1 | |
| Criteria here | 2 | |
| Criteria here | 2 | |
| Clinical History | Criteria here | -1 |
| Criteria here | -1 | |
| Physical Examination | Criteria here | -1 |
| Criteria here | -1 | |
| LDL Cholesterol Level | Criteria here | -1 |
| Criteria here | -1 | |
| Criteria here | -1 | |
| Criteria here | -1 | |
| DNA Analysis | Criteria here | -1 |
Electrocardiogram
Chest X Ray
CT Scan / MRI
Echocardiography or Ultrasound
Other imaging findings
Treatment
Medical therapy
Surgery
Prevention
References
- ↑ 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.
- ↑ 2.0 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.
- ↑ 3.0 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.
- ↑ 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)
- ↑ 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.
- ↑ 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.
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
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)