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 cardiovascular disease running in families.
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 FH 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.
- 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
Both forms of FH are caused by the same problem: a mutation in either the LDL receptor or the ApoB protein. There is one known ApoB defect (R3500Q) and a multitude of LDL receptor defects, the frequency of which is different for each population. 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.
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).
LDL cholesterol normally circulates in the body for 2.5 days, after which it is cleared by the liver. In 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. Goldstein and Brown (1974) showed that the classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.
The excess circulating LDL is taken up by cells all over the body but most notably by macrophages and especially 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 FH patients develop accelerated atherosclerosis due to the excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.[3][4]
The degree of atherosclerosis roughly depends of the amount of LDL receptors still expressed by the cells in the body and the functionality of these receptors. In the hetrozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious forms, the homozygouse form, the "broken" receptor is not expressed at all.
In heterozygous FH, only one of the two DNA copies (alleles) is damaged, and there will be at least 50% of the normal LDL receptor activity (the "healthy" copy and whatever the "broken" copy can still contribute).
In homozygous FH, however, both alleles are damaged in some degree, which can lead to extremely high levels of LDL, and to children with extremely premature heart disease. A further complication is the lack of effect of statins (see below).
Causes
Differentiating familial hypercholesterolemia from other diseases
Epidemiology and demographics
Risk factors
Screening
Universal screening for elevated serum cholesterol is recommended.[5]
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 recommnedations for familial hypercholesterolemia in children are varies by age and their risk factors.[6][7]
Child-parent familial hypercholesterolemia screening in primary care
- Recent study shows 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.[8]
Natural history, complication and prognosis
Diagnosis
History and Symptoms
Physical examinations
Laboratory findings
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.
- ↑ 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.
- ↑ 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.
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)