View source for Familial hypercholesterolemia

{{DiseaseDisorder infobox |
  Name           = Familial hypercholesterolemia |
  Image          = Xanthelasma palpebrarum.jpg|
  Caption        = [[Xanthelasma|Xanthelasma palpebrarum]], yellowish patches consisting of cholesterol deposits above the eyelids. These are more common in people with FH.|
  ICD10          = {{ICD10|E|78|0|e|70}} |
  ICD9           = {{ICD9|272.0}} |
  ICDO           = |
  OMIM           = 143890 |
  DiseasesDB     = 4707 |
  MedlinePlus    = 000392 |
  eMedicineSubj  = med |
  eMedicineTopic = 1072 |
  MeshID         = D006938 |
}}
'''Familial hypercholesterolemia''' (abbreviated '''FH''', also spelled '''familial hypercholesterolaemia''') is a [[genetic disorder]] characterized by [[hypercholesterolemia|high cholesterol levels]], specifically very high levels of [[low-density lipoprotein]] (LDL, "bad cholesterol"), in the blood and early [[cardiovascular disease]]. Many patients have mutations in the ''LDLR'' gene that encodes the [[LDL receptor]] [[protein]], which normally removes LDL from the circulation, or [[apolipoprotein B]] (ApoB), which is the part of LDL that binds with the receptor; mutations in other genes are rare. Patients who have one abnormal copy (are [[Zygosity|heterozygous]]) of the ''LDLR'' gene may have premature cardiovascular disease at the age of 30 to 40. Having two abnormal copies (being ''homozygous'') may cause severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disorder, occurring in 1:500 people in most countries; homozygous FH is much rarer, occurring in 1 in a million births.<ref name="Rader2003"/>

Heterozygous FH is normally treated with [[statin]]s, [[bile acid sequestrant]]s or other [[hypolipidemic agent]]s that lower cholesterol levels. New cases are generally offered [[genetic counseling]]. Homozygous FH often does not respond to medical therapy and may require other treatments, including [[LDL apheresis]] (removal of LDL in a method similar to [[dialysis]]) and occasionally [[liver transplantation]].<ref name="Rader2003"/>

== Signs and symptoms ==
===Physical signs===
High cholesterol levels normally do not cause any symptoms. Cholesterol may be deposited in various places in the body that are visible from the outside, such as in yellowish patches around the eyelids ([[Xanthelasma|xanthelasma palpebrarum]]), the outer margin of the [[Iris (anatomy)|iris]] ([[Arcus senilis|arcus senilis corneae]]) and in the form of lumps in the [[tendon]]s of the hands, elbows, knees and feet, particularly the [[Achilles tendon]] ([[xanthoma|tendon xanthoma]]).<ref name="Rader2003">{{cite journal |author=Rader DJ, Cohen J, Hobbs HH |title=Monogenic hypercholesterolemia: new insights in pathogenesis and treatment |journal=J. Clin. Invest. |volume=111 |issue=12 |pages=1795–803 |year=2003 |pmid=12813012 |doi=10.1172/JCI18925 |pmc=161432}} {{PMC|161432}}</ref><ref name="pmid15816992">{{cite journal |author=Tsouli SG, Kiortsis DN, Argyropoulou MI, Mikhailidis DP, Elisaf MS |title=Pathogenesis, detection and treatment of Achilles tendon xanthomas |journal=Eur. J. Clin. Invest. |volume=35 |issue=4 |pages=236–44 |year=2005 |pmid=15816992 |doi=10.1111/j.1365-2362.2005.01484.x}}</ref>

===Cardiovascular disease===
Accelerated deposition of cholesterol in the walls of [[artery|arteries]] leads to [[atherosclerosis]], the underlying cause of cardiovascular disease. The most common problem in FH is the development of [[coronary artery disease]] (atherosclerosis of the [[coronary artery|coronary arteries]] that supply the [[heart]]) at a much younger age than would be expected in the general population. This may lead to [[angina pectoris]] (chest tightness on exertion) or [[heart attack]]s. Less commonly, arteries of the [[brain]] are affected; this may lead to [[transient ischemic attack]]s (brief episodes of weakness on one side of the body or inability to talk) or occasionally [[stroke]]. [[Peripheral artery occlusive disease]] (obstruction of the arteries of the legs) occurs mainly in people with FH who [[tobacco smoking|smoke]]; this can cause pain in the calf muscles during walking that resolves with rest ([[intermittent claudication]]) and problems due to a decreased blood supply to the feet (such as [[gangrene]]).<ref name=Durrington>{{cite journal |author=Durrington P |title=Dyslipidaemia |journal=Lancet |volume=362 |issue=9385 |pages=717–31 |year=2003 |pmid=12957096 |doi=10.1016/S0140-6736(03)14234-1}}</ref>

If lipids start infiltrating the [[aortic valve]] (the [[heart valve]] between the [[left ventricle]] and the [[aorta]]) or the [[aortic root]] (just above the valve), thickening of these structures may result in a narrow passage called [[aortic stenosis]].<ref name="pmid4698125">{{cite journal |author=Roberts WC, Ferrans VJ, Levy RI, Fredrickson DS |title=Cardiovascular pathology in hyperlipoproteinemia. Anatomic observations in 42 necropsy patients with normal or abnormal serum lipoprotein patterns |journal=Am. J. Cardiol. |volume=31 |issue=5 |pages=557–70 |year=1973 |month=May |pmid=4698125 |doi=10.1016/0002-9149(73)90323-8}}</ref> Supravalvular aortic stenosis (tightening of the aorta above the level of the aortic valve) can occur in up to half of homozygous patients, whereas heterozygotes are less frequently affected.<ref name="pmid9714107">{{cite journal |author=Summers RM, Andrasko-Bourgeois J, Feuerstein IM, ''et al.'' |title=Evaluation of the aortic root by MRI: insights from patients with homozygous familial hypercholesterolemia |journal=Circulation |volume=98 |issue=6 |pages=509–18 |date=11 August 1998|pmid=9714107 |url=http://circ.ahajournals.org/cgi/content/full/98/6/509 }}</ref><ref name="pmid10065027">{{cite journal |author=Rallidis L, Naoumova RP, Thompson GR, Nihoyannopoulos P |title=Extent and severity of atherosclerotic involvement of the aortic valve and root in familial hypercholesterolaemia |journal=Heart |volume=80 |issue=6 |pages=583–90 |year=1998 |month=December |pmid=10065027 |url=http://heart.bmj.com/cgi/content/full/80/6/583 |pmc=1728866}} {{PMC|1728866}}</ref><ref name="pmid16205026">{{cite journal |author=Ozumi K, Tasaki H, Yamashita K, ''et al.'' |title=Valvular and supravalvular aortic stenosis in heterozygous familial hypercholesterolemia, a case report |journal=J. Atheroscler. Thromb. |volume=12 |issue=5 |pages=289–93 |year=2005 |pmid=16205026  |url=http://www.jstage.jst.go.jp/article/jat/12/5/289/_pdf |format=PDF}}</ref><ref name="pmid2736820">{{cite journal |author=Brook GJ, Keidar S, Boulos M, ''et al.'' |title=Familial homozygous hypercholesterolemia: clinical and cardiovascular features in 18 patients |journal=Clin Cardiol |volume=12 |issue=6 |pages=333–8 |year=1989 |month=June |pmid=2736820 |doi=10.1002/clc.4960120608}}</ref> Aortic stenosis is characterized by [[shortness of breath]], [[chest pain]] and episodes of [[dizziness]] or [[collapse (medical)|collapse]].

Atherosclerosis risk is increased further with age and in those who smoke, have [[diabetes mellitus|diabetes]], [[hypertension|high blood pressure]] and a [[Family history (medicine)|family history]] of cardiovascular disease.<ref name="Rader2003"/><ref name="pmid15554949">{{cite journal |author=Jansen AC, van Aalst-Cohen ES, Tanck MW, ''et al.'' |title=The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients |journal=J. Intern. Med. |volume=256 |issue=6 |pages=482–90 |year=2004 |pmid=15554949 |doi=10.1111/j.1365-2796.2004.01405.x}}</ref>

==Diagnosis==
===Lipid measurements===
[[Cholesterol]] levels may be determined as part of health screening for [[health insurance]] or [[Occupational safety and health|occupational health]], when the external physical signs such as xanthelasma, xanthoma, arcus are noticed, symptoms of cardiovascular disease develop, or a family member has been found to have FH. A pattern compatible with [[hyperlipoproteinemia type II]]a on the [[Hyperlipidemia#Classification|Fredrickson classification]] is typically found: raised level of total cholesterol, markedly raised level of low-density lipoprotein (LDL), normal level of [[high-density lipoprotein]] (HDL), and normal level of [[triglyceride]]s. The LDL is typically above the 95th [[percentile]], that is, 95% of the healthy population would have a lower LDL level, although patients with ApoB mutations have LDLs below this level in 25% of cases.<ref name="Rader2003"/> Cholesterol levels can be drastically higher in FH patients who are also [[obesity|obese]].<ref name=Durrington/>

===Mutation analysis===
On the basis of the isolated high LDL and clinical criteria (which differ by country), genetic testing for LDL receptor mutations and [[ApoB]] mutations can be performed. Mutations are detected in between 50 and 80% of cases; those without a mutation often have higher triglyceride levels and may in fact have other causes for their high cholesterol, such as [[combined hyperlipidemia]] due to [[metabolic syndrome]].<ref name="pmid16825289">{{cite journal |author=van Aalst-Cohen ES, Jansen AC, Tanck MW, ''et al.'' |title=Diagnosing familial hypercholesterolaemia: the relevance of genetic testing |journal=Eur. Heart J. |volume=27 |issue=18 |pages=2240–6 |year=2006 |pmid=16825289 |doi= 10.1093/eurheartj/ehl113| url=http://eurheartj.oxfordjournals.org/cgi/content/full/27/18/2240}}</ref>

===Differential diagnosis===
FH needs to be distinguished from [[familial combined hyperlipidemia]] and [[polygenic hypercholesterolemia]]. Lipid levels and the presence of xanthomata can confirm the diagnosis. [[Sitosterolemia]] and [[cerebrotendineous xanthomatosis]] are two rare conditions that can also present with premature atherosclerosis and xanthomas. The latter condition can also involve neurological or psychiatric manifestations, [[cataracts]], [[diarrhea]] and skeletal abnormalities.<ref name="pmid11939886">{{cite journal |author=Moghadasian MH, Salen G, Frohlich JJ, Scudamore CH |title=Cerebrotendinous xanthomatosis: a rare disease with diverse manifestations |journal=Arch. Neurol. |volume=59 |issue=4 |pages=527–9 |year=2002 |month=April |pmid=11939886 |doi= 10.1001/archneur.59.4.527|url=http://archneur.ama-assn.org/cgi/content/full/59/4/527}}</ref>

==Genetics==
The most common genetic defects in FH are ''LDLR'' mutations ([[prevalence]] 1 in 500, depending on the population), ApoB mutations (prevalence 1 in 1000), ''[[PCSK9]]'' mutations (less than 1 in 2500) and ''[[LDLRAP1]]''. The related disease [[sitosterolemia]], which has many similarities with FH and also features cholesterol accumulation in tissues, is due to ''[[ABCG5]]'' and ''[[ABCG8]]'' mutations.<ref name="Rader2003"/>

===LDL receptor===
[[Image:PBB Protein LDLR image.jpg|right|thumb|Schematic representation of the LDL receptor protein.]]
The [[LDL receptor]] [[gene]] is located on the short arm of [[Chromosome 19 (human)|chromosome 19]] (19p13.1-13.3). It comprises 18 [[exon]]s and spans 45 [[base pair#Length measurements|kb]], and the protein gene product contains 839 [[amino acid]]s in mature form. A single abnormal copy (heterozygote) of FH causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR activity of less than 2%, while heterozygotes have a defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known.<ref name="Rader2003"/>

There are five major classes of FH due to ''LDLR'' mutations:<ref name=Hobbs1992>{{cite journal |author=Hobbs HH, Brown MS, Goldstein JL |title=Molecular genetics of the LDLR gene in familial hypercholesterolemia |journal=Hum. Mutat. |volume=1 |issue=6 |pages=445–66 |year=1992 |pmid=1301956 |doi=10.1002/humu.1380010602}}</ref>
*Class I: LDLR is not synthesized at all.
*Class II: LDLR is not properly transported from the [[endoplasmic reticulum]] to the [[Golgi apparatus]] for expression on the cell surface.
*Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R).
*Class IV: LDLR bound to LDL does not properly cluster in [[clathrin]]-coated pits for [[receptor-mediated endocytosis]].
*Class V: LDLR is not recycled back to the cell surface.

===ApoB===
ApoB, in its ApoB100 form, is the main [[apoprotein]], or protein part of the lipoprotein particle. Its gene is located on the [[chromosome 2 (human)|second chromosome]] (2p24-p23) and is between 21.08 and 21.12&nbsp;[[megabase|Mb]] long. FH is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like ''LDLR'', the number of abnormal copies determines the severity of the hypercholesterolemia.<ref name="Rader2003"/><ref name=Grundy1986>{{cite journal |author=Vega GL, Grundy SM |title=In vivo evidence for reduced binding of low density lipoproteins to receptors as a cause of primary moderate hypercholesterolemia |journal=J. Clin. Invest. |volume=78 |issue=5 |pages=1410–4 |year=1986 |pmid=3771801 |doi=10.1172/JCI112729 |pmc=423848}} {{PMC|423848}}</ref>

===PCSK9===
Mutations in the [[PCSK9|proprotein convertase subtilisin/kexin type 9]] (''PCSK9'') gene were linked to autosomal dominant (i.e. requiring only one abnormal copy) FH in a 2003 report.<ref name="Rader2003"/><ref>{{cite journal |author=Abifadel M, Varret M, Rabès JP, ''et al.'' |title=Mutations in PCSK9 cause autosomal dominant hypercholesterolemia |journal=Nat. Genet. |volume=34 |issue=2 |pages=154–6 |year=2003 |pmid=12730697 |doi=10.1038/ng1161}}</ref> The gene is located on the [[chromosome 1 (human)|first chromosome]] (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes FH mainly by reducing the number of LDL receptors on liver cells.<ref>{{cite journal |author=Seidah NG, Khatib AM, Prat A |title=The proprotein convertases and their implication in sterol and/or lipid metabolism |journal=Biol. Chem. |volume=387 |issue=7 |pages=871–7 |year=2006 |pmid=16913836 |doi=10.1515/BC.2006.110| url=http://www.atypon-link.com/WDG/doi/pdf/10.1515/BC.2006.110|format=PDF}}</ref>

===LDLRAP1===
Abnormalities in the ''ARH'' gene, also known as ''[[LDLRAP1]]'', were first reported in a family in 1973.<ref>{{cite journal |author=Khachadurian AK, Uthman SM |title=Experiences with the homozygous cases of familial hypercholesterolemia. A report of 52 patients |journal=Nutr Metab |volume=15 |issue=1 |pages=132–40 |year=1973 |pmid=4351242 |doi=10.1159/000175431}}</ref> In contrast to the other causes, two abnormal copies of the gene are required for FH to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. Patients with autosomal recessive hypercholesterolemia tend to have more severe disease than ''LDLR''-heterozygotes but less severe than ''LDLR''-homozygotes.<ref name="Rader2003"/>

==Pathophysiology==
[[Image:HMG-CoA reductase pathway.png|right|thumb|Cholesterol is synthetised in the [[HMG-CoA reductase pathway]].]]
{{main|LDL receptor|atherosclerosis}}

LDL cholesterol normally circulates in the body for 2.5 days, and subsequently binds to the LDL receptor on the [[hepatocyte|liver cells]], undergoes [[endocytosis]], and is digested. LDL is removed, and synthesis of [[cholesterol]] by the liver is suppressed in the [[Mevalonate pathway|HMG-CoA reductase pathway]].<ref>{{cite journal |author=Brown MS, Goldstein JL |title=Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=71 |issue=3 |pages=788–92 |year=1974 |pmid=4362634 |doi=10.1073/pnas.71.3.788 |pmc=388099}} {{PMC|388099}}</ref> In FH, LDL receptor function is reduced or absent, and LDL circulates for an average duration of 4.5 days, resulting in significantly increased level of LDL cholesterol in the blood with normal levels of other lipoproteins.<ref name=Durrington/> In mutations of ''ApoB'', reduced binding of LDL particles to the receptor causes the increased level of LDL cholesterol. It is not known how the mutation causes LDL receptor dysfunction in mutations of ''PCSK9'' and ''ARH''.<ref name="Rader2003"/>

Although atherosclerosis occurs to a certain degree in all people, FH patients may develop accelerated atherosclerosis due to the excess level of LDL. The degree of atherosclerosis approximately depends of the ''number'' of LDL receptors still expressed and the ''functionality'' of these receptors. In many heterozygous forms of FH, the receptor function is only mildly impaired, and LDL levels will remain relatively low. In the more serious homozygous forms, the receptor is not expressed at all.<ref name="Rader2003"/>

Some studies of FH cohorts suggest that additional risk factors are generally at play when an FH patient develops atherosclerosis.<ref name="Broome1993">{{cite journal |author=Scientific Steering Committee on behalf of the Simon Broome Register Group  |title=Risk of fatal coronary heart disease in familial hypercholesterolaemia |journal=BMJ |volume=303 |issue=6807 |pages=893–6 |year=1991 |pmid=1933004 |doi=10.1136/bmj.303.6807.893 |pmc=1671226}} {{PMC|1671226}}</ref><ref name=Sijbrands2001>{{cite journal |author=Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, Kastelein JJ |title=Mortality over two centuries in large pedigree with familial hypercholesterolaemia: family tree mortality study |journal=BMJ |volume=322 |issue=7293 |pages=1019–23 |year=2001 |pmid=11325764 |url=http://www.bmj.com/cgi/content/full/322/7293/1019 |doi=10.1136/bmj.322.7293.1019 |pmc=31037}} {{PMC|31037}}</ref> In addition to the classic risk factors such as smoking, high blood pressure, and diabetes, genetic studies have shown that a common abnormality in the [[prothrombin]] gene (G20210A) increases the risk of cardiovascular events in patients with FH.<ref name="pmid15879303">{{cite journal |author=Jansen AC, van Aalst-Cohen ES, Tanck MW, ''et al.'' |title=Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia |journal=Arterioscler. Thromb. Vasc. Biol. |volume=25 |issue=7 |pages=1475–81 |year=2005 |pmid=15879303 |doi=10.1161/01.ATV.0000168909.44877.a7| url=http://atvb.ahajournals.org/cgi/content/full/25/7/1475}}</ref> Several studies found that a high level of [[apolipoprotein A]] was an additional risk factor for ischemic heart disease.<ref name="pmid1971660">{{cite pmid|1971660}}</ref><ref name="pmid2139920">{{cite pmid|2139920}}</ref> The risk was also found to be higher in patients with a specific [[genotype]] of the [[angiotensin-converting enzyme]] (ACE).<ref name="pmid9603531">{{cite journal |author=O'Malley JP, Maslen CL, Illingworth DR |title=Angiotensin-converting enzyme DD genotype and cardiovascular disease in heterozygous familial hypercholesterolemia |journal=Circulation |volume=97 |issue=18 |pages=1780–3 |date=19 May 1998|pmid=9603531 |url=http://circ.ahajournals.org/cgi/content/full/97/18/1780 }}</ref>

==Screening==
Although [[case finding]] among family members of patients with known FH is a [[cost-effective]] approach, other strategies such as [[universal screening]] at the age of 16 have also been suggested.<ref name="BMJ-screening">{{cite journal |author=Marks D, Wonderling D, Thorogood M, Lambert H, Humphries SE, Neil HA |title=Cost effectiveness analysis of different approaches of screening for familial hypercholesterolaemia |journal=BMJ |volume=324 |issue=7349 |pages=1303 |year=2002 |month=June |pmid=12039822 |doi=10.1136/bmj.324.7349.1303 |url=http://www.bmj.com/cgi/content/full/324/7349/1303 |pmc=113765}} {{PMC|113765}}</ref><ref name="pmid11213091">{{cite journal |author=Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ |title=Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands |journal=Lancet |volume=357 |issue=9251 |pages=165–8 |year=2001 |month=January |pmid=11213091 |doi=10.1016/S0140-6736(00)03587-X}}</ref> The latter approach may however be less cost-effective in the short term.<ref name="pmid12669918">{{cite journal |author=Marks D, Thorogood M, Neil HA, Wonderling D, Humphries SE |title=Comparing costs and benefits over a 10 year period of strategies for familial hypercholesterolaemia screening |journal=J Public Health Med |volume=25 |issue=1 |pages=47–52 |year=2003 |month=March |pmid=12669918 |doi=10.1093/pubmed/fdg010 |url=http://jpubhealth.oxfordjournals.org/cgi/reprint/25/1/47 | format=PDF}}</ref> Screening at an age lower than 16 would lead to an unacceptably high rate of [[Type I and type II errors|false positives]].<ref name=Durrington/>

==Treatment==
=== Heterozygous FH ===
FH is usually treated with [[statin]]s. Statins act by inhibiting the enzyme [[HMG-CoA reductase|hydroxymethylglutaryl CoA reductase]] (HMG-CoA-reductase) in the liver. In response, the liver produces more LDL receptors, which remove circulating LDL from the blood. Statins effectively lower cholesterol and LDL levels, although sometimes add-on therapy with other drugs is required, such as [[bile acid sequestrant]]s ([[cholestyramine]] or [[colestipol]]), [[nicotinic acid]] preparations or fibrates.<ref name="Rader2003"/> Control of other risk factors for cardiovascular disease is required, as risk remains somewhat elevated even when cholesterol levels are controlled. Professional guidelines recommend that the decision to treat an FH patient with statins should not be based on the usual risk prediction tools (such as those derived from the [[Framingham Heart Study]]), as they are likely to underestimate the risk of cardiovascular disease; unlike the rest of the population, FH have had high levels of cholesterol since birth, probably increasing their relative risk.<ref name=NICE>{{NICE|71|Familial hypercholesterolaemia|2008}}</ref> Prior to the introduction of the statins, [[clofibrate]] (an older fibrate that often caused [[gallstone]]s), [[probucol]] (especially in large xanthomas) and [[thyroxine]] were used to reduce LDL cholesterol levels.

More controversial is the addition of [[ezetimibe]], which inhibits cholesterol absorption in the gut. While it reduces LDL cholesterol, it does not appear to improve a marker of atherosclerosis called the [[intima-media thickness]]. Whether this means that ezetimibe is of no overall benefit in FH is unknown.<ref>{{cite journal |author=Kastelein JJ, Akdim F, Stroes ES, ''et al.'' |title=Simvastatin with or without ezetimibe in familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=358 |issue=14 |pages=1431–43 |year=2008 |month=April |pmid=18376000 |doi=10.1056/NEJMoa0800742}}</ref>

There are no interventional studies that directly show mortality benefit of cholesterol lowering in FH patients. Rather, evidence of benefit is derived from a number of trials conducted in people who have polygenic hypercholesterolemia (in which heredity plays a smaller role). Still, an observational study of a large British registry showed that mortality in FH patients had started to improve in the early 1990s, when statins were introduced.<ref>{{cite journal | author=Scientific Steering Committee on behalf of the Simon Broome Register Group | title=Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management | journal=Atherosclerosis | year=1999 | volume=142 | issue=1 | pages=105–12 | doi=10.1016/S0021-9150(98)00200-7 | pmid=9920511}}</ref>

=== Homozygous FH ===
Homozygous FH is harder to treat. The LDL receptors are minimally functional, if at all. Only high doses of statins, often in combination with other medications, are modestly effective in improving lipid levels.<ref>{{cite journal |author=Marais AD, Blom DJ, Firth JC |title=Statins in homozygous familial hypercholesterolemia |journal=Curr Atheroscler Rep |volume=4 |issue=1 |pages=19–25 |year=2002 |month=January |pmid=11772418 |doi=10.1007/s11883-002-0058-7}}</ref> If medical therapy is not successful at reducing cholesterol levels, [[LDL apheresis]] may be used; this filters LDL from the bloodstream in a process reminiscent of [[dialysis]].<ref name="Rader2003"/> Very severe cases may be considered for a [[liver transplant]]; this provides a liver with normally functional LDL receptors, and leads to rapid improvement of the cholesterol levels, but at the risk of complications from any solid [[organ transplant]] (such as [[Transplant rejection|rejection]], [[infection]]s, or [[Adverse effect (medicine)|side-effects]] of the medication required to suppress rejection).<ref>{{cite journal |doi=10.1056/NEJM198412273112603 |author=Bilheimer DW, Goldstein JL, Grundy SM, Starzl TE, Brown MS |title=Liver transplantation to provide low-density-lipoprotein receptors and lower plasma cholesterol in a child with homozygous familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=311 |issue=26 |pages=1658–64 |year=1984 |month=December |pmid=6390206}}</ref><ref>{{cite journal |author=Revell SP, Noble-Jamieson G, Johnston P, Rasmussen A, Jamieson N, Barnes ND |title=Liver transplantation for homozygous familial hypercholesterolaemia |journal=Arch. Dis. Child. |volume=73 |issue=5 |pages=456–8 |year=1995 |month=November |pmid=8554367 |doi=10.1136/adc.73.5.456 |pmc=1511367}} {{PMC|1511367}}</ref> Other surgical techniques include [[partial ileal bypass surgery]], in which part of the [[small bowel]] is bypassed to decrease the absorption of nutrients and hence cholesterol, and [[portacaval shunt|portacaval shunt surgery]], in which the [[portal vein]] is connected to the [[vena cava]] to allowing blood with nutrients from the intestine to bypass the liver.<ref name="pmid10770402">{{cite journal |author=López-Santamaria M, Migliazza L, Gamez M, ''et al.'' |title=Liver transplantation in patients with homozygotic familial hypercholesterolemia previously treated by end-to-side portocaval shunt and ileal bypass |journal=J. Pediatr. Surg. |volume=35 |issue=4 |pages=630–3 |year=2000 |month=April |pmid=10770402 |doi=10.1053/jpsu.2000.0350630 |url=http://linkinghub.elsevier.com/retrieve/pii/S0022-3468(00)56892-4}}</ref><ref name="pmid9625405">{{cite journal |author=Buchwald H, Varco RL, Boen JR, ''et al.'' |title=Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias |journal=Arch. Intern. Med. |volume=158 |issue=11 |pages=1253–61 |year=1998 |month=June |pmid=9625405 |doi= 10.1001/archinte.158.11.1253|url=http://archinte.ama-assn.org/cgi/content/full/158/11/1253}}</ref><ref name="pmid172531">{{cite journal |author=Bilheimer DW, Goldstein JL, Grundy SM, Brown MS |title=Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia |journal=J. Clin. Invest. |volume=56 |issue=6 |pages=1420–30 |year=1975 |month=December |pmid=172531 |doi=10.1172/JCI108223 |url=http://www.jci.org/articles/view/108223 |pmc=333120}} {{PMC|333120}}</ref> 

[[Enzyme inhibition|Inhibition]] of the [[microsomal triglyceride transfer protein]], for example with the investigational drug [[lomitapide]], and infusion of [[Recombinant DNA|recombinant]] human [[apolipoprotein A1]] are being explored as medical treatment options.<ref name="pmid17215532">{{cite journal |author=Cuchel M, Bloedon LT, Szapary PO, ''et al.'' |title=Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia |journal=N. Engl. J. Med. |volume=356 |issue=2 |pages=148–56 |year=2007 |month=January |pmid=17215532 |doi=10.1056/NEJMoa061189 |url=http://content.nejm.org/cgi/content/full/356/2/148}}</ref><ref name="pmid10441095">{{cite journal |author=Eriksson M, Carlson LA, Miettinen TA, Angelin B |title=Stimulation of fecal steroid excretion after infusion of recombinant proapolipoprotein A-I. Potential reverse cholesterol transport in humans |journal=Circulation |volume=100 |issue=6 |pages=594–8 |year=1999 |month=August |pmid=10441095 |doi= |url=http://circ.ahajournals.org/cgi/content/full/100/6/594}}</ref> [[Gene therapy]] is a possible future alternative.<ref name="pmid7584986">{{cite journal |author=Grossman M, Rader DJ, Muller DW, ''et al.'' |title=A pilot study of ex vivo gene therapy for homozygous familial hypercholesterolaemia |journal=Nat. Med. |volume=1 |issue=11 |pages=1148–54 |year=1995 |month=November |pmid=7584986 |doi=10.1038/nm1195-1148}}</ref> [[Mipomersen]] is in phase 3 trials.

===Pediatric patients===
Given that FH is present from birth and atherosclerotic changes may begin early in life,<ref name="pmid2914343">{{cite journal |author=Mabuchi H, Koizumi J, Shimizu M, Takeda R |title=Development of coronary heart disease in familial hypercholesterolemia |journal=Circulation |volume=79 |issue=2 |pages=225–32 |year=1989 |month=February |pmid=2914343}}</ref> it is sometimes necessary to treat adolescents or even teenagers with agents that were originally developed for adults. Due to safety concerns, many doctors prefer to use [[bile acid sequestrants]] and [[fenofibrate]] as these are licensed in children.<ref name=Greene>{{cite journal |author=Greene O, Durrington P |title=Clinical management of children and young adults with heterozygous familial hypercholesterolaemia in the UK |journal=J R Soc Med |volume=97 |issue=5 |pages=226–9 |year=2004 |month=May |pmid=15121812 |doi=10.1258/jrsm.97.5.226 |url=http://jrsm.rsmjournals.com/cgi/content/full/97/5/226 |pmc=1079462}} {{PMC|1079462}}</ref> Nevertheless, statins seem safe and effective,<ref>{{cite journal |author=Rodenburg J, Vissers MN, Wiegman A, Trip MD, Bakker HD, Kastelein JJ |title=Familial hypercholesterolemia in children |journal=Curr. Opin. Lipidol. |volume=15 |issue=4 |pages=405–11 |year=2004 |month=August |pmid=15243213 |doi=10.1097/01.mol.0000137228.92396.f3}}</ref><ref name="pmid15265847">{{cite journal |author=Wiegman A, Hutten BA, de Groot E, ''et al.'' |title=Efficacy and safety of statin therapy in children with familial hypercholesterolemia: a randomized controlled trial |journal=JAMA |volume=292 |issue=3 |pages=331–7 |year=2004 |month=July |pmid=15265847 |doi=10.1001/jama.292.3.331 |url=http://jama.ama-assn.org/cgi/content/full/292/3/331}}</ref> and in older children may be used as in adults.<ref name=Durrington/><ref name=Greene/>

A multidisciplinary expert panel in 2006 advised on early combination therapy with LDL apheresis, statins and cholesterol absorption inhibitors in children with homozygous FH at the highest risk.<ref name="pmid17130340">{{cite journal |author=Kavey RE, Allada V, Daniels SR, ''et al.'' |title=Cardiovascular risk reduction in high-risk pediatric patients: a scientific statement from the American Heart Association Expert Panel on Population and Prevention Science; the Councils on Cardiovascular Disease in the Young, Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism, High Blood Pressure Research, Cardiovascular Nursing, and the Kidney in Heart Disease; and the Interdisciplinary Working Group on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics |journal=Circulation |volume=114 |issue=24 |pages=2710–38 |year=2006 |month=December |pmid=17130340 |doi=10.1161/CIRCULATIONAHA.106.179568 |url=http://circ.ahajournals.org/cgi/content/full/114/24/2710}}</ref>

==Epidemiology==
In most populations studied, heterozygous FH occurs in about 1:500 people, but not all develop symptoms.<ref name="Rader2003"/> Homozygous FH occurs in about 1:1,000,000.<ref name="Rader2003"/><ref name=Durrington/>

''LDLR'' mutations are more common in certain populations, presumably because of a genetic phenomenon known as the ''[[founder effect]]''—they were founded by a small group of individuals, one or several of whom was a carrier of the mutation. The [[Afrikaner]], [[French Canadian]]s, [[Lebanon|Lebanese]] [[Christian]]s, and [[Finns]] have high rates of specific mutations that make FH particularly common in these groups. ''APOB'' mutations are more common in Central Europe.<ref name="Rader2003"/>

==History==
The Norwegian physician Dr C. Müller first associated the physical signs, high cholesterol levels and autosomal dominant inheritance in 1938.<ref>{{cite journal|author=Müller C|title=Xanthoma, hypercholesterolemia, angina pectoris|journal=Acta Med Scandinav|year=1938|volume=89|pages=75}}</ref> 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. Initially, they found increased activity of HMG-CoA reductase, but studies showed that this did not explain the very abnormal cholesterol levels in FH patients.<ref>{{cite journal |author=Goldstein JL, Brown MS |title=Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=70 |issue=10 |pages=2804–8 |year=1973 |month=October |pmid=4355366 |doi=10.1073/pnas.70.10.2804 |pmc=427113}}</ref> The focus shifted to the binding of LDL to its receptor, and effects of impaired binding on metabolism; this proved to be the underlying mechanism for FH.<ref>{{cite journal |author=Brown MS, Goldstein JL |title=Receptor-mediated control of cholesterol metabolism |journal=Science (journal) |volume=191 |issue=4223 |pages=150–4 |year=1976 |month=January |pmid=174194 |doi=10.1126/science.174194 | url=http://www.sciencemag.org/cgi/reprint/191/4223/150 |format=PDF}}</ref> Subsequently numerous mutations in the protein were directly identified by sequencing.<ref name=Hobbs1992/> They later won the 1985 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]] for their discovery of cholesterol and lipoprotein metabolism.<ref>{{cite web | author=Nobelprize.org| url=http://nobelprize.org/nobel_prizes/medicine/laureates/1985 |title=Medicine 1985 |accessdate=2008-02-28}}</ref>

== See also ==
* [[Primary hyperlipoproteinemia]]
* [[Familial hypertriglyceridemia]]
* [[Lipoprotein lipase deficiency]]
* [[Familial apoprotein CII deficiency]]

==References==
{{Reflist|2}}

==External links==
* [http://www.medped.org MEDPED] (Make Early Diagnosis to Prevent Early Deaths) - US screening program based at the University of Utah, Salt Lake City
* [http://www.heartuk.org.uk/ H·E·A·R·T UK] - Hypercholesterolemia charity based in the United Kingdom
* [http://www.ucl.ac.uk/fh Database of all known ''LDLR'' mutations] (maintained by [[Leiden University Medical Centre]], hosted by [[University College London]])
* [http://www.medped.org/who/index.html Familial hypercholesterolaemia - report of a WHO consultation] - reproduction of [[World Health Organization|WHO]] report WHO/HGN/FH/CONS/98.7 (1998) on the diagnosis and treatment of FH

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[[Category:Cardiology]]
[[Category:Lipid disorders]]

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