Familial hypercholesterolemia (FH) is the most common monogenicdisorder in humans. While numerous genes have been implicatedin FH, all known underlying genetic defects lead to impairedclearance of low-density lipoprotein (LDL) particles from the circulationwith subsequent severe hypercholesterolemia. Without diagnosis andappropriate treatment, patients are at dramatically increased risk ofpremature atherosclerotic cardiovascular disease (ASCVD).1
This first clinical description of FH was provided by the Norwegianphysician, Carl Müller, in 1938 as elevated levels of serum cholesteroltogether with tendon xanthomas and coronary artery lesions.2 In 1964,Khachadurian demonstrated the autosomal dominant inheritance patternof FH.3 A decade later, Brown and Goldstein made their seminal discoveryof LDLR and its feedback regulation. Their work was largely inspiredby a young patient with homozygous FH, the more severe form of thecondition in which casual mutations are inherited from both parents, whohad a heart attack during childhood.4,5 Building on that work, theyidentified LDLR as the causative gene for FH.6 As it turned out, thecausal mutations in families with pathognomonic clinical presentationssuch as xanthomas, corneal arcus, and early onset ASCVD mostcommonly were found to be highly penetrant (co-dominant) mutations thatcompletely abolished or greatly diminished LDLR function.1
FH is caused by mutations in genes encoding key proteinsinvolved in the LDLR endocytic and recycling pathways andleading to both reduced LDLR-mediated endocytosis andsevere hypercholesterolemia.1 Plasma cholesterol is mostlymanufactured, exported, and eventually recaptured byhepatocytes. Cholesterol synthesis is a complex, multistepand highly regulated pathway with 3-hydroxy-3-methylglutarylcoenzyme A (HMG CoA) reductase being the key, rate-limitingenzyme. Statins antagonize the activity of HMG CoA reductasethereby reducing hepatic cholesterol synthesis and upregulatingthe transcription of LDLR via a sensing mechanism linked tothe sterol regulatory element binding protein pathway. The mainobjective of each cell, and a hepatocyte in particular, is to keepmembrane cholesterol close to 5% of total cell mass, a criticalconcentration that assures proper membrane function. It is thusevident that the cell uses a series of quick adjustments torespond to increases and decreases in membrane cholesterolstraying from the critical value range. These includesynthetic, assembly, secretory, and re-uptake activities. Thelipid cargo, mostly triglycerides and cholesterol, is packagedwithin apolipoprotein B (APOB)-containing very low-densitylipoproteins (VLDL), the intravascular precursors of LDL,which primarily transport triglycerides from the liver to peripheraltissues, with cholesterol joining for the ride, so to speak. Over15,000 molecules of triglycerides are packed into one VLDL,which contains over 1,000 cholesterol molecules as well.Receptor mediated endocytosis is facilitated by the binding ofAPOB on the LDL particle to the LDLR and coordinated byan adaptor protein (LDLRAP) that positions LDLR on thesinusoidal side of the polarized hepatocyte, clustered incoated pits.7 After LDLR -mediated endocytosis, the LDL/LDLR complex is transported to the endosomal pathway to mergewith the lysosome. The pH gradient in the descent toward thelysosome induces dissociation between receptor and cargo. Inthe lysosome, the LDL particle is digested and the cholesteroland triglycerides are de-esterified for transport into the cytosol,where they can take on myriad fates. On the other hand, theLDLR is recycled back to the hepatocyte surface to participatein many more rounds of LDL binding and endocytosis.However, when the LDLR eventually meets a different ligand,the low abundance proprotein convertase subtilisin/kexin type9 (PCSK9), the normal recycling loop is short-circuited asPCSK9 disables the LDLR from escaping lysosomal digestion,thereby reducing cell surface receptor density. It must be notedthat up to half of plasma PCSK9 is associated with the LDLparticle, for a frequency of one PCSK9 molecule for every500–1000 LDL particles.8,9 This introduces the intriguingpossibility that the carefully orchestrated cellular regulationof cholesterol concentration is ultimately under the whims ofa stochastic extracellular system, where every few hundredencounters with canonical LDL the LDLR meets its fate byinteracting with a PCSK9-carrying LDL that terminates thereceptor’s life cycle.
The vast majority of FH can be explained by mutations inthree key genes; LDLR (receptor not synthesized or notfunctional), APOB (ligand not properly recognizing LDLR), and PCSK9 (gain of function mutations causing excessiveelimination of LDLR LR). In those with detectable mutations,heterozygous LDLR, APOB, and PCSK9 mutations are foundin >90, ~5, and ~1%, respectively.10 Clinically homozygousFH results from true homozygous, or more often fromcompound heterozygous, mutations in either these same genesor in ARH, which codes for LDLRAP1, the adaptor thatplaces LDLR on the sinusoidal side of the hepatocyte, and isinherited in an autosomal recessive fashion.11 The prevalenceof individual mutations varies geographically, though moststudies point to a frequency ranging from 1:200 to 1:500 births,depending on whether a founder effect is in place (i.e., FrenchCanadians, South Africans, and Ashkenazi Jews).1 Althoughthere have been reports of LDLR mutations in Thai patients,the spectrum and prevalence of various mutations associatedwith FH in Thailand and the whole of South East Asia is notknown and should be prioritized as a target of investigation.12
The two most widely used clinical diagnostic criteria foridentifying FH are the UK Simon Broome and Dutch LipidClinic Network (DLCN) criteria (see Table). Both the SimonBroome and DLCN include clinical, laboratory, and geneticvariables. Both algorithms heavily weight the results ofgenetic testing and the presence or absence of tendon xanthomata,and prioritize specificity (true negative rate) over sensitivity(true positive rate), which means they are more useful in thecontext of cascade screening rather than index case identification(more on this below). Fortunately, the medical community isadvancing a more sophisticated view on the diagnosis of FH.First, both secular trends and improvements in therapy havealtered the ‘classic’ presentation of FH. For example, theprevalence of xanthomas today is lower than observed decadesago, perhaps due to improved control of cholesterol from anearlier age. The SAFEHEART registry demonstrated thepresence of tendon xanthomas in only 14% of 2,752 individualswith genetically confirmed FH.13,14 These findings have beenrecapitulated in FH registries based in both United States andCanada.15
Furthermore, both the Simon Broome and the DutchLipid Clinic Network Criteria (DLNC) rely greatly on afamily history of premature ASCVD. This slavish reliance onfamily history is now problematic given the statinization oflarge swaths of the developed world. Entire generations havereceived statin therapy, thus dramatically attenuating theutility of the family history data. Moreover, family historyinformation is also often difficult to obtain or is unreliable, atleast in the western world, due to high divorce rates, whichnow occurs in approximately 50% of U.S. marriages, and tohigh rates of adoption. Finally, secular trends in the U.S.,including decreased saturated fat intake and the ubiquitousprescription of statins have led to decreases in average LDL-Clevels across the population in general, making LDL-C lessuseful as a diagnostic criterion.16 Recognizing the significantlimitations of the clinical diagnostic algorithms, the AmericanHeart Association sponsored a scientific statement thatdiscusses these issues and endorses a new and more practical clinical tool for making a diagnosis of FH.17 These diagnosticcriteria are not likely to demonstrate favorable diagnosticcharacteristics in Asian populations, where the phenotype fromthe genetic component is less amplified by lifestyle andco-morbid factors compared to patients in the western world.Thus, there is a large unmet need to develop diagnosticcriteria for the diagnosis of FH in specific populations,particularly those of South East Asia, due to relative ethnichomogeneity and uniqueness.
Table 1: Diagnostic criteria for Familial Hypercholesterolemia according to the Dutch Lipid Clinic Network
New causal gene identification
The role of genetic testing in the diagnosis and screeningof FH remains controversial. There are some parts of the world(primarily Western Europe), where this is considered standardof care and is covered by payers without patients having toendure part or all of the financial burden. In the U.S., as wellas most parts of the world, genetic testing is employedsporadically and inconsistently, and rarely covered by healthinsurance. Mutations in LDLR represent, by far and away, the mostcommon causal defects in FH. However, pathognomonicphenotypic expression in patients and families withoutmutations in LDLR enabled discovery of other less commoncausal abnormalities in genes of the LDLR clearance pathway,including APOB, PCSK9, APOE, and LDLRAP.
Causal mutations are now identified in approximately70–80% of individuals with a definite phenotypic diagnosisof FH and 20–40% in those with a possible/probable diagnosisof FH.18,19 However, a negative genetic test does not excludea diagnosis of FH, especially in those with a strong clinicalphenotype.20 Nevertheless, a sizable proportion of individualswith the severe hypercholesterolemia phenotype who are foundto be negative by genetic testing have polygenic hypercholesterolemia.21 Polygenic hypercholesterolemia is an FHphenocopy that is due to the accumulation of a number of morecommon LDL-C raising single nucleotide variants at differentloci, though its inheritance does not follow a clear Mendelianpattern.18,21,22
FH is more common than previously recognized
The original estimates of the prevalence of FH suggestedthat it occurred in approximately one in 500 individuals amongthe free-living population in areas where FH-causing mutationsare not derived from a recent founder effect. This approximationwas based on the original estimate of the prevalence ofhomozygous FH, which was originally thought to occur in onein a million individuals.17 Recent unbiased genetic screeningof large populations has clearly demonstrated that the prevalenceof FH is twice as common as previously thought, with estimatesin western populations of 1:200-1:250.20,23-25 The higher prevalence noted in these studies is, at least in part, due to thefact that genetic screening detects individuals with milderdisease.24 We do not know the prevalence of FH in Asiancountries, and Thailand is well poised to lead the way andproduce a formal prevalence study for both genotypic andphenotypic FH, either as unbiased epidemiologic investigationor as a registry.
Despite its high risk status, FH remains underdiagnosedand undertreated. Fortunately, several large scale patientregistries have proliferated around the world. These registrieshave and continue to provide real-world data on prevalence andcurrent treatment patterns. In this way, they have highlightedmajor gaps in the identification, treatment, and follow-up ofpatients with FH. Importantly, longitudinal registry-level dataprovide insight into how trends in FH diagnosis and managementare changing over time. Additionally, country specific registriesallow comparison of these findings amongst different social,cultural, and ethnic groups. As in many other conditions, FHis quite heterogeneous and optimal methods for screening,diagnosis, evaluation, and treatment are likely to be differentacross the globe. Currently, there are well-developed FHregistries in the Netherland, United Kingdom, Spain, France,Norway, Brazil, Canada, and the United States. Notably absentfrom this list is the entirety of the Asian continent. Theopportunity for Thailand is enormous.
Despite differences in scale and approach amongstinternational registries, several common themes emerge. Notsurprisingly, there is a strikingly higher risk of ASCVD inindividuals with FH patients than in the general population.15Consistent with that observation, it was shown that the prevalenceof FH among patients with coronary artery disease is 8.3%and, not surprisingly, inversely related to age.26 Furthermore,the majority of patients with FH fail to attain optimal LDL-Clevels despite the use of combination lipid-lowering therapyin the pre-PCSK9 inhibitor era. Given the current low rate ofinsurance approvals for PCSK9 agents in the U.S., the situationoverall has not drastically changed for FH patients in thenearly three years since the approval of this new class ofagents.27
Other noteworthy, country-specific observations from these registries include the following:
In summary, patients with FH either remain undiagnosedor receive delayed diagnosis, there are low rates of LDL-Cgoal attainment even with combination lipid-lowering therapy,rates of ASCVD are remarkably higher than the generalpopulation and unaffected relatives, and genetic testing (ingeneral exquisitely underutilized worldwide) may play a rolein early detection, treatment, and cascade screening.
Some, but not all, FH registries collect genetic data.Analysis of these datasets has revealed intriguing relationshipsbetween genotype and phenotype. That is, specific mutationsconvey more precise prognostic information, though therelationship is not wholly deterministic. Complete loss offunction mutations in LDLR completely abolish LDLR activityand are therefore associated with more severe elevations inplasma LDL-C and higher rates of ASCVD. In this regard,recent data has demonstrated that there is a graded responsein phenotype between complete loss of function mutations,missense mutations that were predicted to be deleterious bymultiple algorithms, and those that were predicted to be lesspathogenic or nonpathogenic.24 A more recent analysisdemonstrated that, when compared to a reference group withLDL-C less than 130 mg/dl and no causative FH mutations,individuals with LDL-C at least 190 mg/dl and no causativeFH mutations had six-fold higher risk for whereas those withLDL-C at least 190 mg/dl as well as causative FH mutationshad a 22-fold increased risk.23 Thus, the presence of a definedmutation conveys increased risk, likely because it impliescertain lifelong exposure to elevated LDL-C. Additionally,they demonstrated that differences in mutation severity impactsthe severity of hypercholesterolemia and prognosis. In general,mutations in APOB and PCSK9 mutations are associated witha more modest phenotype and more variable presentation, sincethe LDLR itself is genetically intact and functional.32
Large genetic biorepositories linked to FH registryinformation will be vital to more completely clarify genotypephenotypecorrelations. This approach allows evaluation ofthose who are genotype(-)/phenotype(+), eg, those with the severe hypercholesterolemia phenotype but who have nomutation identifiable upon genetic testing. Evaluation of theseindividuals is critical for identification of additional causalgenes and mechanisms for hypercholesterolemia.
It is important to appreciate that for any specific mutation,there is large heterogeneity in the phenotype amongst affectedfamily members. To that end, there are some with known FHmutations who do not manifest severe hypercholesterolemiaor ASCVD. On the other hand, there are others with mutationspredicted to be less deleterious but sustain severe hypercholesterolemiaand early ASCVD. Some of this phenotypicheterogeneity is due to environmental influences. However,there are likely a large number of modifier genes, such as LPA,which codes for lipoprotein(a).33 Lipoprotein(a) is a highlyatherogenic LDL-like particle covalently bound to a truncatedform of plasminogen and its levels are, for the most part,genetically determined. Lipoprotein(a) is an independentpredictor of ASCVD in those with FH and thus, whenelevated, portends a worse prognosis.33 Currently, there areconcerted efforts to identify other modifier genes throughlarge-scale genome wide or exome wide sequencing initiatives.These modifier genes may be ethnically and geographicallyspecific, which again underscores the importance of developingan FH registry and biobank in Thailand.
Cascade screening (eg, lipid and/or genetic testing all firstdegreerelatives of an FH proband) has proved to be a costeffectivemethod for identifying new cases of FH.26,34-37 Thisapproach allows for family wide diagnosis and initiation ofappropriate treatment.34,38 Cascade genetic testing increasesdiagnostic accuracy versus strategies that use LDL-C alonesince there can be an overlap in LDL-C levels on those withand without FH.35,39 Detecting an FH mutation providesunequivocal confirmation that the vasculature has beenexposed to high LDL-C levels since birth. Cascade testingstrategies incorporating genetic testing have been shown to behighly cost-effective when pathogenicity is certain. Countriesthat have been using genetic cascade screening such as theNetherlands, Norway, and Spain have been successful in identifying large numbers of FH patients.1 In the Netherlands,those who received a positive test result had lower LDL-Clevels compared to those without positive genetic testing dueto timely initiation of lipid lowering therapy.40
On the basis of these data, cascade screening of closerelatives for FH has been recommended in the U.K. by theNational Institute for Health and Clinical Excellence. In theU.S., the Center for Disease Control Office of Public HealthGenomics classifies FH as a tier 1 condition for cascadegenetic screening. In most of the world, large-scale genetictesting and screening has not been performed giveneconomic constraints. However, given dramatic improvementsin sequencing technology, the cost of genetic testing hasplummeted and continues to decline, even beyond what Moore’slaw predicts. It is likely that genetic testing/screening for FHwill become standard care within the next decade in most partsof the world.
FH is the most common monogenic disorder in humans.New unbiased genetic data suggest that FH is far morecommon than previously thought with a prevalence as high as1:200 births. Left undiagnosed and treated it leads to acceleratedASCVD. Regrettably, most individuals with FH are not awareof their condition and do not receive optimal evaluation and/or treatment, leading to unacceptably high morbidity andmortality. With greater awareness, this readily identifiablecondition can be functionally eliminated by early screeningand aggressive lipid lowering therapy. International registrieshave allowed us to greatly enhance our knowledge of FH, andin fact, have been the seed for numerous genetic insights,improved diagnostics, and refined therapeutic approaches.Sadly, most countries do not have a national registry and relyon data derived from populations that are geneticallyheterogeneous and very distinct. As collaborating investigatorsin the largest U.S. based FH registry, we encourage the leadershipof clinical research in Thailand to take the first steps in bringinga national registry to life. At the practice level, we encouragethe clinician to keep in mind the signs of FH and make theappropriate diagnosis based on physical and biochemical data,family history, and consider genetic testing when feasible.