familial hypercholesterolemia ( fh ) is a common autosomal dominant genetic disorder and is an important health issue .
patients with fh are exposed to a lifetime burden of high low density lipoprotein cholesterol ( ldl - c ) and have significantly increased cardiovascular risk . therefore ,
early and appropriate diagnosis in affected persons and prevention of vascular complications are critical . in this review ,
recent studies on the prevalence , diagnosis , vascular risk , and treatment of patient with fh are discussed .
the frequency of heterozygous fh has long been reported to be 1/500 ( 0.2% ) , while that of homozygous fh has been reported to be 1/1,000,000 in many studies conducted in various countries around the world . however , although heterozygous fh is influenced by diagnostic criteria including mutation positivity , the prevalence has been reported to be 1/217 in a very recent danish study   and 1/250 in an american study using dutch criteria .
clinical criteria most commonly used for diagnosis of fh include the simon broome register group criteria , dutch lipid clinic network criteria , and make early diagnosis to prevent early deaths ( medped ) criteria .
major items for these clinical diagnostic criteria are ( 1 ) severe hypercholesterolemia ; ( 2 ) physical findings such as xanthoma in the index case ; and ( 3 ) family history of premature coronary artery disease ( cad ) or severe hypercholesterolemia . while the above - mentioned criteria designed in different countries show similarity , they also show difference with respect to specific values ( table 1 ) . for cost - effective and efficient diagnosis ,
however , in real practice , diagnosis using only clinical findings from history taking , physical examination , and lipid profile is very common , especially when genetic screening is not available .
most monogenic causes of fh are mutations of low density lipoprotein receptor ( ldlr ) , apolipoprotein b ( apob ) , or proprotein convertase subtilisin / kexin type 9 ( pcsk9 ) genes .
all of these genes are involved in the pathway that clears circulating low - density lipoprotein . among monogenic
fhs , about 90% are caused by mutations of ldlr , for which 1,200 different mutations have been identified .
however , even family members who have the same mutation often have quite different ldl - c levels , responsiveness to lipid lowering therapy , and survival .
therefore , decision of whether to treat or the intensity of treatment depends mostly on the phenotype rather than genotype . in other words , the clinical importance of genetic diagnosis
pathogenic mutations are not identified in about 60% of clinically diagnosed fh patients , although the proportion differs according to the ethnicity or diagnostic criteria .
most fh patients without a monogenic cause are suspected to have polygenic fh that is caused by a multiple lipid - related common variants .
although ldl - c > 500 mg / dl or a xanthoma in a child is suspicious for homozygous fh , some patients with homozygous fh have lower ldl - c levels .
the most critical complication in fh is life - time cardiovascular disease due to longstanding ldl - c burden ( fig .
it has been reported that 25% of affected women and 50% of affected men experience cardiovascular complications .
the risk of cad is known to be 3.5- to 16-fold higher in heterozygous fh patients compared to non - fh individuals .
the results of studies on the risk of cerebrovascular disease have been inconsistent and the risk is not yet clear .
the guidelines recommend that risk assessment in patients with fh should not be made according to european systematic coronary risk estimation or american framingham risk score , because these scoring systems underestimate cardiovascular risk in fh . even with the same ldl - c levels , carriers of mutations for fh show higher risk for cad .
in addition , cardiovascular risk in fh is also influenced by other traditional risk factors , and these often also need to be considered when determining treatment .
thus , it is essential to implement pharmaco- and non - pharmacotherapy targeting hypercholesterolemia and other combined risk factors as well . as mentioned above , because vascular risk is very high and associated with cholesterol burden , lowering ldl - c is the mainstay of cardiovascular prevention in fh .
most recent guidelines indicate that it is desirable to reduce ldl - c to 50% of baseline levels or < 100 mg / dl in adults with fh .
statins are the first - line agent and ezetimibe or cholesterol - binding resins are recommended when needed .
data from the united kingdom have demonstrated that the mortality of patients with fh decreased by 25% to 48% after introduction of statins .
however , because the evidence is limited , there is no sufficient consensus on when to start treatment in children with fh .
lipoprotein apheresis can be considered in patients with persistently high ldl - c after treatment , extremely high cardiovascular risk , statin intolerance , or especially in patients who have homozygous fh .
meanwhile , the achievement rate of ldl - c goal ( < 100 mg / dl ) is reported to be 11%   and a large part of patients do not reach the target .
therefore , pcsk9 inhibitors , recently approved lipid - lowering agents , are spotlighted and expected to meet the unmet medical need ( table 2 ) .
although two pcsk9 inhibitors , evolocumab and alirocumab , have shown consistent and strong lipid - lowering efficacy , limitation is their high cost .
lomitapide inhibits microsomal triglyceride transfer protein and reduces very low density lipoprotein ( vldl ) assembly , whereas mipomersen blocks the translation of apob and decreases vldl synthesis .
. however , drug - related adverse events are relatively frequent and risk / benefit ratio needs to be taken into account for these drugs ( table 2 ) .
although asian data on fh are not sufficient , its reported prevalence is similar to that of western countries .
a recent korean study suggested that the best cutoff values for predicting mutation - positive fh are total cholesterol 310 mg / dl and ldl - c 225 mg / dl . in asian patients ,
80% to 100% of causing mutations were identified in ldlr , whereas the others were found in apob or pcsk9 .
however , the achievement rate of ldl - c by conventional lipid - lowering therapy was not satisfactory .
diagnosis of fh by clinical rather than genetic criteria is more common in real world practice .
although , the majority of patients can not reach a ldl - c goal by conventional pharmacotherapy , novel therapeutics such as pcsk9 inhibitors are expected to improve treatment results .
 in recent studies , the reported prevalence of heterozygous familial hypercholesterolemia ( fh ) has been higher than in previous reports . although cascade genetic screening is a good option for efficient identification of affected patients , diagnosis using only clinical criteria is more common in real clinical practice . 
 cardiovascular risk is much higher in fh patients due to longstanding low density lipoprotein cholesterol ( ldl - c ) burden and is also influenced by other risk factors . 
 although guidelines emphasize aggressive ldl - c reduction , the majority of patients can not reach the ldl - c goal by conventional pharmacotherapy . 
 novel therapeutics such as proprotein convertase subtilisin / kexin type 9 inhibitors have shown strong lipid lowering efficacy and are expected to improve treatment results in fh patients . 