Discussion
FH is a genetic disorder in which LDL-C levels are significantly
elevated in the blood. It is an underdiagnosed autosomal dominant
condition presenting with arcus cornealis, xanthomas, and premature
coronary artery disease. All these findings directly result from the
abnormally elevated LDL-C levels in the plasma.
(6) The genes that
encode LDL receptors are apolipoprotein B (ApoB), proprotein convertase
subtilisin kexin-9 (PCSK9), and low-density lipoprotein receptor adaptor
protein 1 (LDLRAP1), and these are the main genes which are affected in
FH. (1) It is inherited in an autosomal dominant pattern, so there is a
50% chance of inheriting the mutated gene. Some forms of FH are
inherited in an autosomal recessive pattern, due to mutations in the LDL
receptor adaptor protein 1 ( LDLRAP1) gene, but it is very rare.
(7) The mutation in
the LDL receptor gene causes various clinical features like tendon
xanthoma, premature coronary artery disease, and aortic valve
involvement. They present early in childhood in cases of homozygous
disease variants. (8)
The high levels of LDL present in patients of FH lead to progressive
atherosclerosis from a young age, which results in a high risk of
coronary artery disease in the future (up to 20-fold). (9,10)
The US MedPed Programme, the Dutch Lipid Clinic Network, and the Simon
Broome Register Group in the United Kingdom are the three groups that
have produced clinical diagnostic methods for familial
hypercholesterolemia.
(Figure 6;
4,5,11) The Simon-Broome Criteria offers advantages in ease of
remembrance and economic viability for diagnosing familial
hypercholesterolemia (FH) in lipid clinics, being widely used by
physicians. Its reliance on conventional methods avoids expensive DNA
testing, making it suitable for healthcare centers. However, a major
disadvantage is its inability to differentiate between FH types and
non-FH conditions, potentially overlooking patients with mild phenotypes
or in the pediatric population. It lacks consideration for
genotype-phenotype correlations, hindering its ability to discern
responses to specific therapies. Overall, while advantageous in
simplicity and cost-effectiveness, its limitations in precision and
scope should be acknowledged. The Simon-Broome criteria have been
modified to become the Dutch criteria for the diagnosis of FH. The
primary motivation behind the creation of the Dutch criteria was the
fact that the Simon-Broome criteria uses the patient’s medical history,
physical examination, and test results to diagnose FH. However, the
Simon-Broome criteria ignores the fundamental molecular defect of FH.
The Dutch criteria took into account the molecular flaw of FH and
proposed a point system to solve this deficit. Age- and
relative-specific criteria for total cholesterol are used in the US
MEDPED criteria. Despite being easy to apply, the criteria ignores
FH-associated gene alterations and clinical features. It does not take
into account factors influencing cholesterol levels, as demonstrated by
a study on seasonal fluctuations in lipid levels, although it does urge
cascade screening after diagnosis. Increased temperature and physical
activity were associated with changes in plasma volume, particularly
relative hypervolemia during the summer, which was associated with
higher variations in women and hypercholesterolemic people.
(12,13)
Cessation of tobacco use and treating hypertension and diabetes are
important parts of managing cardiovascular complications in
FH.(14) But LDL
lowering remains the mainstay of FH management. Statin therapy remains
the cornerstone of lipid lowering in the scenario of FH. High dose
statins reduce LDL-C by almost 50% and moderate dose statins by 30%.
(15) Based on data from clinical trials over past 2 decades, the 2013
ACC/AHA cholesterol guidelines define Atorvastatin 40-80 mg or
Rosuvastatin 20-40 mg as high intensity statins. The guidelines define -
Atorvastatin 10-20 mg , Rosuvastatin 5-10 mg ,Pitavastatin 2-4 mg and
simvastatin 20-40 mg as moderate intensity statins. Long term studies
have demonstrated their role in retarding the progression of
atherosclerosis and ameliorating risk of cardiovascular events.(16,17)
However, because of high baseline LDL-C levels many FH patients will
need combination therapy to attain LDL-C levels. Ezetimibe and Bempedoic
acid are two additional oral lipid lowering drug who have shown to
reduce LDL-C by about 15-20% when added to statins and also improvement
in cardiovascular outcomes.(18,19) Bile acid sequestrants can reduce
LDL-C by 20% but gastrointestinal side effects limit their use in
clinical practice. Most FH patients will need dual or triple lipid
lowering therapy as in our case. But despite the use of combination of
oral lipid lowering therapy a substantial proportion of FH will need
parenteral lipid lowering therapies which are more potent and longer
acting.
Antibodies against proprotein convertase subtilisin-kexin type 9 (PCSK9)
have a notable effect on decreasing LDL-C, and it is anticipated that
they will be helpful in lipid-lowering therapy for FH, which is poorly
controlled by conventional oral lipid lowering
treatment.(20,21)
Evolocumab the PCSK-9 approved by US FDA can be given every 2 weeks or 4
weeks and produces up to 60% LDL-C reduction. More recently, small
interfering RNA against PCSK-9 (Inclisiran) and monoclonal antibody
against ANGPTL3 (Evinacumab) have been shown to reduce LDL-C effectively
in FH patients.(22) Inclisiran has the advantage of administration every
6 months. In a pooled analysis of phase 3 trials in FH patients, the
twice yearly dose of Inclisiran has been shown to reduce LDL -C by 50%
(over maximally tolerated statin) and is also safe barring minor
injection site issues.(23) Because LDL-C receptors (LDL-R) are severely
depleted in Homozygous FH, the efficacy of many lipid lowering therapies
(LDL-R dependent - statin, PCSK-9 I , Bempedoic acid and ezetimibe) is
attenuated. Evinacumab inhibits ANGPTL3 and reduces LDL-C independent of
LDL-R in patients with FH. In the ELIPSE-HoFH study, the drug given
every 4 weeks , achieved 50% LDL-C reduction at 6 months.(24) Gene
editing technology has been utilized to silence PCSK-9 gene in liver and
consequently decrease LDL-C levels. VERVE 101 is a CRISPER based gene
editing technique given as a single infusion and has been shown to
reduce LDL-C by 39%-55% levels in 10 FH patients in the phase1B
Heart-1 trial (NCT05398029 ).(25)The effect on LDL-C lowering
were durable up to 6 months. Figure 7 details the expected LDL
lowering with currently available agents.
The HeFH phenotype is identified using the Dutch Lipid Clinic Network
criterion, which is based on LDL-C level, family history of FH, the
existence of tendon xanthoma, and arcus cornealis. The early detection
of FH by a family member of the index case and the prevention of
CAD-related morbidity and mortality through dietary changes and prudent
use of hypolipidemic medications are both made possible by the early
diagnosis of FH
(6).Still, FH remains
widely underdiagnosed, undertreated, and understudied, especially in
pediatric patients.
(26)
The most effective way to perform cascade testing for FH is to do a
genotype analysis of the relatives of the index patients with a known
mutation, however, this practice is only in its infancy in middle-income
nations like India. This is a more precise way than doing plasma
cholesterol screening on the family members.
(27)