Dr Sachin Sondhi IGMC Shimla

1. Familial hypercholesterolaemia
SEMINAR ON 24/7/2017

2. • Structure of phospholipid
• Brief on lipoprotein metabolism
• Definition of FH
• Diagnostic Criteria's
• Clinical Features
• Screening
• Treatment
• Natural History

4. Dietary intake mainly from TG and small
amount from cholestrol
• Life requires fats.
• Fat typically furnishes 20% to 40% of daily calories.
• Triglycerides account for the major portion of ingested
fats.
• For an individual consuming 2000 kcal/day, with 30% in
the form of fat, this represents approximately 66 g of
triglycerides and 250 mg (0.250 g) of cholesterol per
day

5. Why VLDL is necessary
• Food is not always available, and dietary fat content varies.
• The body must ensure that triglyceride is readily available
to meet energy demands.
• Hepatic secretion of VLDL particles serves this function .
• They contain apo B100 as their main lipoprotein. As
opposed to apo B48, apo B100 contains a domain
recognized by LDL-R (the apo B/E receptor). VLDL particles
follow the same catabolic pathway through LPL as
chylomicrons

6. Lipoprotein Metabolism
• Intestinal Pathway (Chylomicrons to Chylomicron Remnants)
• Hepatic Pathway (Very Low-Density Lipoprotein to
Intermediate-Density Lipoprotein)
• High-Density Lipoprotein and Reverse Cholesterol Transport

8. Cellular cholesterol homeostasis in various tissues. A, Cholesterol
homeostasis (hepatocytes). B, Selective uptake of cholesterol (adrenal cells,
hepatocytes, endothelial cells).C, Cellular cholesterol efflux (peripheral cells).
D, Macrophage foam cells.

11. Introduction
• Familial Hypercholesterolaemia (FH, OMIM #143890) is a common
genetic cause of premature Coronary Heart Disease (CHD). It is an
autosomal, dominant, inherited disorder of lipoprotein metabolism
that results in a raised Low Density Lipoprotein Cholesterol (LDL-C)
plasma concentration.
• Heterozygous FH (HeFH) is the most common monogenic disorder,
affecting 1 in 200–250, twice as high as previously thought with a
penetrance of greater than 90 %.
• It is believed that there are 34 million FH cases worldwide [1, 3]
and that less than 1 % of potential patients with FH have been
identified in most countries [3].

12. • If HeFH is left untreated, there is a significant likelihood
of CHD onset prior to age 55 (men) and 60 (women).
• Half of all untreated HeFH men and 15 % of women
will die of CHD-induced myocardial infarction (MI)
before these ages.
• Homozygous FH (HoFH) is rare with an estimated
global prevalence of 1/160,000–300,000 [5]. However,
when left untreated, patients with HoFH can succumb
to MI as teenagers.

13. • In certain populations, the frequency of
heterozygous FH may be markedly higher than
1 in 200. When a population is descended
from a small number of colonizing ancestors
amongst whom the prevalence of the
condition was high, a founder effect occurs.

15. • After the LDL Receptor discovery by Brown
and Goldstein that mutations in the low-
density lipoprotein receptor (LDLR) was the
cause of monogenetic FH, over 1,500
mutations of this gene have been detected
and these account for more than 80% of
cases.

17. • The majority of FH cases are caused by mutations in the LDLR gene,
resulting in defective synthesis, assembly, transport, recycling or vesicle
formation .Mutations in the LDLR gene cause FH in 79 % of cases.
• Apolipoprotein B (ApoB) helps the LDL-receptor bind LDL and mutations
in ApoB account for ~5 % of FH cases.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades the LDL-
receptor and gain of function mutations in PCSK9 account for <1 % of FH
cases.
• A very rare recessive form of FH is caused by mutations in low-density
lipoprotein receptor adaptor protein 1 (LDLRAP1).
• The remaining 15 % of FH cases are either polygenic or are driven by
monogenic mutations whose prevalence is not yet determined [18]. The
latter include mutations in APOE [1], APOB [20], SREBP2 [21] and STAP1
[22].

18. LDLR gene. a. Location of the LDLR gene, the short (p) arm of chromosome 19 at position 13.2. b. Numbered
vertical bars represent exons,
lone exons or sets of exons that encode the various domains of the LDLR protein. c. Currently 1,741 mutations
have been identified in the exons
of the LDLR gene. T

21. • ApoB variants are principally located on one exon, number
26. Patients with Familial Ligand-Defective Apolipoprotein
B may have a milder form of presentation of FH than that
caused by LDLR mutations
• Missense mutations in PCSK9 that cause a gain-of-function
lead to a rare form of FH. Loss-of-function in certain ethnic
populations has been shown to result in lower LDL-C levels
and protect against CHD.
• LDLRAP1 mutations show a recessive model of inheritance.
As such, this rarely-occurring disease is termed autosomal
recessive hypercholesterolaemia (ARH, OMIM #603813)

22. Different criteria's to diagnose FHC
• Simpson Broome diagnostic criteria - UK
• Dutch Criteria -
• MEDPED criteria – USA
• No international criteria

23. ADVANTAGES- Ease of Remembrance, Economic viability:
Disadvantages- fails to differentiate between classical FH due to LDLR
mutations and the other genetic origins of FH such as ApoB-100 and PCSK9

25. • Dutch criteria for the diagnosis of FH are the
modification of the Simon-Broome criteria. The
principal reason for developing the Dutch criteria
is that the Simon-Broome criteria diagnoses FH
based on personal and family history, physical
examination, and laboratory findings. However,
the underlying molecular defect of FH is
overlooked in the Simon-Broome criteria. To
address this shortcoming, the Dutch criteria
introduce a point system and take into
consideration the molecular defect of FH

26. One of the key advantages of the Dutch criteria is that it addresses the
molecular defect that leads to FH and this in turn will help to provide the
diagnosed FH patient with a better therapeutic strategy/treatment

27. Although easy to use, the criteria does not take into consideration the clinical
characteristics such as tendinous xanthomata and/or an identified mutation
in the FH-associated gene although it advocates cascade screening

28. Clinical features and diagnosis

29. • Exclude secondary causes of hypercholesterolaemia
• Phenotypic and/or genetic testing
• Genetic testing increases diagnostic accuracy
• Assess additional CVD risk factors
• Hypertension, diabetes, obesity, smoking
• Lipoprotein(a)
• Level and duration of untreated LDL cholesterol
• Prematurity of the family & personal history of CVD
• Framingham and other CVD risk equations should not be used

30. • Homozygous or compound HeFH, on the other hand, presents in
the 1st decade of life with a distinctive and severe clinical
phenotype. The age a t presentation depends on the degree of LDL
receptor activity,those with the null phenotype (<2% LDL receptor
activity) tend to present earlier, resulting even in intrauterine
death.
• These patients have primarily dermatological and ocular
manifestations — tendon xanthomas and interdigital xanthomas are
pathognomic of HoFH .
• Tendon xanthomas are frequently missed on visual inspection alone
and necessitate careful palpation in the Achilles, biceps and triceps
tendons for early detection.

32. SCREENING FOR FH
• Former lipid guidelines advocated ‘targeted screening’, which
comprised a fasting lipid profile test in children with risk factors for
FH such as a family history of premature cardiovascular diseases
(CVDs), dyslipidemia, or obesity. However, despite its cost
effectiveness, this approach entailed the risk of missing 30-60% of
affected patients
• An alternative approach to screening is termed ‘cascade
screening’,wherein health workers actively screen for disease
among the first and second degree relatives of patients diagnosed
by targeted screening. Although this method is associated with
improved detection rates, there remains a considerable risk of
missing affected individual
• Universal screening is not cost effective

33. • Recent National Institute for Health and Care Excellence (NICE)
guidelines recommend a DNA testing on all patients diagnosed with
FH and a subsequent genetic screening among their close relatives
in order to augment case detection rates.
• Although intuitively attractive, a significant number of patients
clinically diagnosed with FH are negative for mutations
conventionally tested for by genetic screening, probably due to
polygenic inheritance.
• In such patients, genetic cascade testing is expected to have a very
low yield and is unlikely to be cost effective. Hence, genetic cascade
screening is likely to benefit only probands where a definite
mutation is identified; in others, a strategy of lipid profile-based
cascade screening is preferable.

34. • The ideal age of lipid screening among children is also a keenly
debated issue.
• The Lipid Research Clinics prevalence studies demonstrated that by
the age of 2 years, the serum lipid level reached that of young
adults
• While the National Health and Nutrition Examination Surveys
(NHANESs), reported that the peak lipid levels are reached by the
age of 9-11 years.
• Therefore, universal screening is best performed between 9 and
11 years of age, whereas a screening at any time after the age of 2
years is preferred in those who are candidates of targeted
screening.

37. If genetic testing does not detect a variant, FH cannot be
excluded, particularly if clinical phenotype is strongly
suggestive of FH
• Clinical criteria may not identify all patients with FH, and
genetic testing is part of the screening strategies in many
countries, with the costs covered by national health
services.
• In the United States, it is done infrequently, partly because
of cost and lack of insurance coverage. Genetic testing in
certain populations has changed the understanding of the
frequency of both heterozygous and homozygous FH.
• However, a mutation is not always found in patients with
clinical FH, and lack of a mutation should not change
treatment

38. Management -
• Lipid Targets - National Lipid Association guidelines recommend a
target LDL level of <130 mg/dl or >50% reduction from baseline
values
• More rigorous targets are proposed in patients with additional risk
factors such as diabetes, obesity, and a family history of CVD
• In children aged 10-14 years, an LDL level of <160 mg/dl or >30%
reduction from baseline levels is targeted. A rigorous target lipid
level of <130 mg/dl is recommended in children between the ages
of 14 and 18 years. In patients older than 18 years, a lipid target of
<100 mg/dl is deemed appropriate

40. • Lifestyle modification
• In a recent statement by the American Heart Association,
later endorsed by the American Academy of Pediatrics,
statins were proposed as first-line drugs and the age of
initiation of therapy was lowered to 8 years

41. • Statins - they inhibit the rate-limiting step in
cholesterol synthesis, thus, increasing the expression of
LDL receptors, resulting in the rapid clearance of LDL
from the blood. However, they have a restricted role
in patients of HoFH with null phenotype in view of
the need for receptor production for their action
• The US Food and Drug Administration (FDA) has
approved lovastatin, atorvastatin, simvastatin, and
rosuvastatin in children over the age of 10 years and
pravastatin in those over 8 years of age

42. • No major side effects with regard to growth, sexual development, muscle,
and liver toxicity.
• Concurrently, they showed excellent efficacy in lipid lowering with a 26.5%
mean relative reduction in LDL-cholesterol levels.
• Give moderate to high intensity statin.
• Patients with FH who have a higher risk of CHD require more intensive
drug therapy
• Children and adolescents being treated with statins should have regular
follow-up with close monitoring of creatinine kinase, aspartate
aminotransferase (AST), and alanine aminotransferase levels (ALT).
Baseline levels, then repeat testing, should be done at 1

45. • When targets are not met, doubling the dose of statins additionally lowers
only 6-8% of LDL
• Drugs that can be added to statins for LDL-C reduction include ezetimibe,
bile-acid sequestrants, and niacin
• Women with FH who are of child-bearing age should be advised to use
contraception while on therapy and to stop any statin (category X),
niacin category C), or ezetimibe (category C) therapy at least 4 weeks
before stopping contraception.24
• Those who become pregnant on therapy or are breastfeeding should be
advised to discontinue therapy immediately.
• Colesevelam is a category B drug and can used when clinically indicated
• For pregnant women with homozygous FH, or heterozygous FH and
atherosclerotic disease, LDL apheresis should be considered.

46. Therapeutic options in patients who failed to attain
lipid targets despite maximal medical therapy
• LDL APHRESIS- Patients with homozygous and compound HeFH
frequently have elevated lipid levels in spite of optimal medical
therapy. These are fitting candidates for LDL apheresis, which has
proved to be a very beneficial treatment option to reducing LDL
levels.
• lower LDL-cholesterol levels by 55-75%
• Commonly used techniques of LDL apheresis include heparin-
induced extracorporeal LDL-cholesterol precipitation (HELP),
dextran sulfate cellulose adsorption (DSA), double filtration
plasmapheresis (DFPP), polyacrylate full blood adsorption (PFBA
also known as DALI), and immune adsorption

47. • The decline in LDL-cholesterol levels by apheresis is a
transitory event and is associated with a rebound
escalation of lipid levels after the procedure
• Weekly to fortnightly sessions are advocated for patients
with HoFH, as such episodic sittings have been shown to
reduce the degree of rebound and retard the progression
of atherosclerosis
• Regular apheresis therapy along with medications in
patients of HoFH has improved the average life expectancy
to over 50 years of age compared to the formerly bleak
prognosis of death in the2nd or 3rd decade

48. • LDL apheresis is the selective removal of all apoB-
containing lipoproteins: LDL, very low-density lipoprotein,
and lipoprotein (a). They are lowered acutely by 60% to
75%.
• There is little effect on other plasma components. HDL is
lowered minimally, and albumin and immunoglobulin are
not affected.
• The time averaged lowering with LDL apheresis is approxi-
mately 50%, and there have been a number of small
noncontrolled clinical trials in which the authors found
improvement in cardiovascular disease

50. • Gene therapy
HoFH was among the first disorders wherein gene
therapy was experimented. Contrary to other
treatment alternatives, the possibility of a definitive
cure by a one-time procedure for a disease that lasts a
lifetime renders this an appealing choice. However,
due to the problems related to appropriate gene
vector, lack of persistent gene expression as well as
due to safety concerns,[80] this modality failed to
demonstrate substantial clinical efficacy in preliminary
trials

51. • SURGICAL THERAPY
• For patients who do not achieve sufficient lipid reduction
by the above-mentioned modalities, other potential
treatment options include partial ileal bypass and liver
transplantation. Liver transplantation produces a
significant lowering of LDLC by providing normal LDLRs.
Liver transplantation is now used primarily in children
with homozygous FH when apheresis is not an option or
with concurrent heart transplantation.13,45 Its use,
however, is limited due to the risk of transplant surgery and
the limited number of donor livers. Partial ileal bypass is
rarely used and works by interrupting enterohepatic bile
acid circulation.

52. The FDA has approved 2
novel treatments for
homozygous FH individuals
older than 18 years of age:
lomitapide and
mipomersen . Lomitapide also
has European approval.
Lomitapide is a microsomal
triglyceride transfer (MTP)
protein inhibitor available
as a capsule and used as an
adjunct to other cholesterol-
lowering medications
The function of MTP, which resides in the lumen of endoplasmic reticulum of enterocytes
and hepatocytes, is to assist in the transfer of triglycerides to apolipoprotein B to form
very-low-density lipoprotein particles.

53. • Lomitapide enabled some homozygous FH patients to
discontinue or decrease the frequency of apheresis in small
in a clinical trials.
• Because of concerns about hepatotoxicity, prescription of
lomitapide requires an FDA-approved Risk Evaluation and
Mitigation Strategy (REMS) program
• Mipomersen is delivered by subcutaneous injection with
weekly dosing. It is an antisense oligonucleotide that
causes a reduction in LDL by binding to messenger RNA and
inhibiting apolipoprotein B-100 synthesis. LDL, apo B, and
lipoprotein (a) concentrations are reduced

54. • Serum PCSK9 are proteins which bind to LDL receptors and
promote their degradation, thus, raising LDL levels in the
blood. PCS9 Inhibitor - Evolucumab, alirocumab,
bococizumab
• The drug is not without side effects. Muscle aches as seen
with statins have been observed in patients injected PCSK9
blockers. Memory loss was noticed in 0.9% treated patients
in the OSLER trials, and alirocumab in the ODDESEY trial
produced cognition problems in 1.2% vs. 0.5% (placebo).
The third adverse effect observed with PCSK9 blockers is
development of cataract when LDL is reduced <20mg %.

55. • proprotein convertase subtilisin/kexin type 9 (PCSK9)
antibodies have obtained approval by the United States
Food and Drug Administration: evolocumab (Amgen)
and alirocumab (Sanofi/Regeneron). Per their package
inserts, both are "indicated as an adjunct to diet and
maximally tolerated statin therapy for the treatment of
adults with heterozygous familial hypercholesterolemia
(FH) or clinical atherosclerotic cardiovascular disease,
who require additional lowering of low-density
lipoprotein-cholesterol (LDL-C)." Evolocumab has an
additional indication for homozygous FH patients.

59. ANGPTL3 Inhibition in Homozygous Familial
Hypercholesterolemia
• Angiopoietin-like 3 (ANGPTL3) is a secreted protein
expressed in the liver. It acts to increase plasma levels
of triglycerides, LDL cholesterol, and high-density
lipoprotein (HDL) cholesterol.
• Preclinical studies and human genetic analyses suggest
that inhibition of ANGPTL3 lowers levels of LDL
cholesterol independently of LDL receptor function and
could reduce the risk of cardiovascular events.
Evinacumab, a fully human ANGPTL3-blocking
antibody, was found to lower cholesterol and
triglyceride levels in healthy human volunteers.

60. • Loss-of-function variants in ANGPTL4 a
negative regulator of lipoprotein lipase (LPL)
activity, are associated with decreased
triglyceride levels, elevated high-density
lipoprotein (HDL) cholesterol levels, and a
reduced risk of coronary heart disease in
humans.

63. Natural history of FH
• The natural history of FH depends primarily on the
degree of functional LDL receptor activity present, and
in turn, on LDL-cholesterol levels, resulting in widely
varying prognosis even among homozygous individuals.
Symptom onset is age-dependent and typically occurs
in the 2nd decade in homozygous patients.
• some studies in this interval purported a mean survival
of 18 years among patients with HoFH,[87] others
observed an average survival of 40 years

64. • Raal et al., involving 149 patients, wherein
patients treated with statins had hazard ratios
for mortality and cardiovascular events of 0.34
and 0.49, respectively when compared with
patients in the pre-statin era, despite achieving
only a modest 26% reduction in LDL levels.
• Among patients with untreated HeFH, coronary
artery disease (CAD) develops in about 50% of
males by the age of 50 years and 30% of females
by 60 years. Although CAD appears 10years later
in females compared to males, an accelerated
development of CAD is observed after
menopause

65. • Simon Broome registry data from England in the pre-statin era showed
that mortality associated with CAD was increased a 100-fold in the age
group of 20-40 years and four-fold in the 40-59 year age group.[38] Among
those surviving to the age of 60 years, however, the risk seems akin to that
in the general population.[38] The benefits of present day therapeutic
advances in this population is confirmed by a large prospective study
from the UK, which reveals a 37% relative reduction in standardized
mortality rate from 3.4 in the pre-statin era to 2.1 after widespread use
of statins.
• Despite strong association of FH with coronary and peripheral vascular
disease, its relation with stroke risk is more controversial. A large
prospective registry data from United Kingdom showed that ischemic
stroke mortality among treated HeFH patients not to be different from
general population.[91] The reason for this difference is presently
unknown

66. • Thanks