Sandbox:Prince
Pathophysiology
Familial hypercholesterolemia is a common autosomal dominant[1][2] disorder caused by mutations involving three genes.
These mutations include the following:[2][1]
- The LDL receptor
- The apolipoprotein B gene, which impairs binding of LDL particles to the LDL receptor
- Proprotein convertase subtilisin/kexin type 9 gene, which leads to decreased LDL metabolism
Familial hypercholesterolemia has 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. The classic form of familial hypercholesterolemia results from defects in the cell surface receptor that normally removes LDL particles from the blood plasma.[3]
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 FH patients develop accelerated atherosclerosis due to the presence of excess LDL. Some studies of FH cohorts suggest that additional risk factors are generally present when an FH patient develops atherosclerosis.[4][5]
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 the heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In more serious form (i.e., the homozygous 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 (i.e., the "healthy" copy and whatever the "broken" copy can still contribute).
In homozygous FH, however, both alleles are damaged to some degree, which can lead to extremely high levels of LDL. Children with this form of FH may develop extremely premature heart disease. A further complication is the ineffectiveness of statins.
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Familial hypercholesterolemia from other Diseases
Epidemiology and Demographics Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population [6]
Risk Factors smoking cesation [7] weight/lack of exercise [8][9][10] t2dm [11] high fat diet [12][13] Screening
Natural History, Complications and Prognosis
Diagnosis
History and Symptoms
Physical Examination
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.[14]
FH are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L. [6] Electrocardiogram
Chest X Ray
CT
MRI
Echocardiography or Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Lomitapide is a microsomal triglyceride transfer protein inhibitor currently approved for treatment of homozygous familial hypercholesterolemia that may be useful in the management of severe hypertriglyceridemia.[15]
Surgery
Prevention
References
- ↑ 1.0 1.1 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.
- ↑ 2.0 2.1 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.
- ↑ 6.0 6.1 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.
- ↑ Maeda K, Noguchi Y, Fukui T (2003). "The effects of cessation from cigarette smoking on the lipid and lipoprotein profiles: a meta-analysis". Prev Med. 37 (4): 283–90. PMID 14507483.
- ↑ Huffman KM, Hawk VH, Henes ST, Ocampo CI, Orenduff MC, Slentz CA; et al. (2012). "Exercise effects on lipids in persons with varying dietary patterns-does diet matter if they exercise? Responses in Studies of a Targeted Risk Reduction Intervention through Defined Exercise I." Am Heart J. 164 (1): 117–24. doi:10.1016/j.ahj.2012.04.014. PMC 3399760. PMID 22795291.
- ↑ Slentz CA, Houmard JA, Johnson JL, Bateman LA, Tanner CJ, McCartney JS; et al. (2007). "Inactivity, exercise training and detraining, and plasma lipoproteins. STRRIDE: a randomized, controlled study of exercise intensity and amount". J Appl Physiol (1985). 103 (2): 432–42. doi:10.1152/japplphysiol.01314.2006. PMID 17395756.
- ↑ Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB, McCartney JS; et al. (2002). "Effects of the amount and intensity of exercise on plasma lipoproteins". N Engl J Med. 347 (19): 1483–92. doi:10.1056/NEJMoa020194. PMID 12421890.
- ↑ Liu S, Manson JE, Stampfer MJ, Holmes MD, Hu FB, Hankinson SE; et al. (2001). "Dietary glycemic load assessed by food-frequency questionnaire in relation to plasma high-density-lipoprotein cholesterol and fasting plasma triacylglycerols in postmenopausal women". Am J Clin Nutr. 73 (3): 560–6. PMID 11237932.
- ↑ Mensink RP, Zock PL, Kester AD, Katan MB (2003). "Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials". Am J Clin Nutr. 77 (5): 1146–55. PMID 12716665.
- ↑ Nordmann AJ, Nordmann A, Briel M, Keller U, Yancy WS, Brehm BJ; et al. (2006). "Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials". Arch Intern Med. 166 (3): 285–93. doi:10.1001/archinte.166.3.285. PMID 16476868.
- ↑ 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.
- ↑ Brahm AJ, Hegele RA (2016). "Lomitapide for the treatment of hypertriglyceridemia". Expert Opin Investig Drugs. doi:10.1080/13543784.2016.1254187. PMID 27785928.
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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.
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).
Epidemiology
Prevalence
- The prevalence of FH is 1 in 300 to 500 in many populations, making FH among the most common of serious genetic disorders
Ethnicity
- In a few populations (such as French Canadians and Dutch Afrikaners), the prevalence of FH may be as high as 1 in 100
United States
- There are approximately 620,000 FH patients currently living in the United States
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]
Prognosis
- Approximately 1 in one million persons is homozygous (or compound heterozygous) for LDLR mutations and has extreme hypercholesterolemia with rapidly accelerated atherosclerosis when left untreated.
Diagnosis
Signs and symptoms
- Elevated serum cholesterol, most notably the LDL fraction (VLDL and triglycerides are typically normal)
- on lipoprotein electrophoresis (rarely done), a hyperlipoproteinemia type II pattern is recognised
- Premature cardiovascular disease, such as:
- Angina pectoris, leading to PTCA or CABG
- Myocardial infarction
- Transient ischemic attacks (TIA's)
- Cerebrovascular accidents/Strokes
- Peripheral artery disease (PAOD)
- A family history of premature atherosclerosis
Physical Examination
The following signs are not always present:
Eyes
- Xanthelasma palpabrum (yellowish patches above the eyelids)
- Arcus senilis corneae, whitish discoloration of the iris
Extremities
- Tendon xanthomas (thickening of tendons due to accumulation of macrophages filled with cholesterol).
Laboratory Studies
LDL-receptor gene defects can be identified with genetic testing. 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.
Treatment
Heterozygous FH
Heterozygous FH can be treated effectively with statins. These are drugs that inhibit the body's ability to produce cholesterol by blocking the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-reductase). Maximum doses are often necessary. 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 (see below).
In case statins are not effective, either a drug from the fibrate or bile acid sequestrant class can be added, as well as niacin/acipimox. As 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), these patients are monitored closely.
Homozygous FH
Homozygous FH is a different story. 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) and - as a last resort - a liver transplant. The last option will introduce liver cells with working LDL receptors, effectively curing the condition.
History
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].
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)