The underdiagnosed, undertreated condition needs more evaluation, screening and early management - early initiation rather than the lower target

1. Dr. Nagula Praveen, MD,DM
Assistant Professor of Cardiology,
Osmania General Hospital,
Hyderabad
Email: drpraveennagula@gmail.com
Twitter: @kizashipraveen

2. Introduction
 Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism
characterized by premature cardiovascular disease.
 It is one of the most common metabolic disorders affecting humans.
 There are two clinical manifestations: the milder heterozygous form and more severe
homozygous form.
 Despite posing a significant health risk, FH is inadequately diagnosed and managed.
 As the clinical outcome is related to the degree and duration of exposure to elevated
low-density lipoprotein cholesterol (LDL-C) levels, early treatment is vital.
 Diagnosis can usually be made using a combination of clinical characteristics such as
family history, lipid levels, and genetic testing.

3. First reported by Carl Muller (1939)

4. Why it needs to be given importance
 Untreated HeFH begins to manifest its clinical consequences in the fourth decade in
men and fifth decade in women.
 Patients with HoFH, however, may suffer significant CV events as early as in the first
decade of life.
 By early adulthood, these patients without treatment have 100 times greater mortality
risk from CV disease resulting from coronary atherosclerosis or supra-vascular aortic
valve calcification as compared to those without FH.

5. Epidemiology of the problem
 Ever since the work of Goldstein and Brown in 1983, it had been generally accepted
that FH has a population prevalence of 1:500 in HeFH and 1:1,000,000 in HoFH.
 Recent work by the European Atherosclerosis Society (EAS) noted widening
inconsistency of diagnosis, with 71 % of patients with FH diagnosed in Netherlands,
43 % in Norway, and only 6 % in Spain.

7. What is needed?
 Optimal care for familial hypercholesterolemia (FH) requires patient centered
management, multidisciplinary teamwork, involvement of primary care
practitioners,patient networks, support groups and high quality clinical
registries, implemented through models of care adapted to FH.
 Models of care – evidence based and context specific frameworks that aim to
deliver the highest quality of care for patients and their families.
 They can serve as paradigms for the prevention of premature atherosclerotic
cardiovascular disease in all- risk patients and families worldwide.

8. What we are upto..
 Exponential growth in the number of publications on diverse aspects of FH has
provided new knowledge for developing essential elements of existing models
of care
 Clinical diagnostic criteria and genetic testing
 Risk restratification strategies
 LDL Cholesterol treatment targets
 Management protocols for children
 Care of women in pregnancy
 Use of pharmacotherapies – including ezetimibe, PCSK9 inhibitors
 Use of lipoprotein apheresis
 Addressing barriers to care

9. Familial dyslipidemias -classification
Familial dyslipidemias
Familial combined
hyperlipidemia
Familial
hypercholesterolemia
Heterozygous familial
hypercholesterolaemia
Homozygous familial
hypercholesterolaemia
Familial
hypercholesterolaemia
in children
Familial
dysbetalipoproteinaemia
Genetic causes of
hypertriglyceridaemia
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk European Heart Journal (2020) 41, 111-188.

10. Genetic defects in familial dyslipidemia
Apo = apolipoprotein; FCH = familial combined hyperlipidaemia; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolaemia; HoFH =homozygous familial
hypercholesterolaemia; IDL = intermediate-density lipoprotein; LCAT = lecithin cholesterol acyltransferase; LDL-C = low-density lipoprotein cholesterol; VLDL = very low-density lipoprotein cholesterol
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 111-188.

11. The genetics of heterozygous familial hypercholesterolaemia
Monogenic disease
caused by loss-of-function
mutations in LDLR or apoB
genes or a gain-of-
function mutation in the
PCSK9 gene
95% of FH cases are
caused by mutations in
LDLR
More than 1000 different
mutations that cause FH
have been identified in
LDLR.
Mutations cause reduced
function or complete loss-
of-function
Loss of function is
associated with more
severe
hypercholesterolaemia and
CVD.
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk European Heart Journal (2020) 41, 111-188;2019.

12. Pathophysiology of familial
hypercholesterolemia
e
Cardiol Clin. 2015 May ; 33(2): 169–179. Eur Heart J. 2013 Dec 1; 34(45): 3478–3490
Decreased LDL receptor function due to a genetic defect, typically one
of the following classes:
• LDL receptor is not synthesized
• LDL receptor is not properly transported from the endoplasmic reticulum to the Golgi
apparatus for expression on the cell surface
• LDL receptor does not properly bind LDL on the cell surface
• LDL receptor does not properly cluster in clathrin-coated pits for receptor endocytosis
• LDL receptor is not recycled back to the cell surface
Therefore, LDL receptor-mediated endocytosis is decreased
Leading to markedly elevated LDL levels
Premature development of atherosclerotic plaque

13. Heterozygous familial hypercholesterolaemia
The prevalence -
1/200-250, translating
to a total number of
cases between 14 –
34 million worldwide.
Only a minor fraction
of these cases is
identified and properly
treated.
Risk of CHD
increases at least 10-
fold
Leads to premature
CVD before the ages
of 55 - 60
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk European Heart Journal (2020) 41, 111 -188; 2019

14. Homozygous familial hypercholesterolaemia
A rare and life-
threatening
disease.
Clinical picture :
Extensive
xanthomas,
marked
premature and
progressive
CVD, and TC
>500 mg/dL
Develop CAD
and aortic
stenosis before
the age of 20
years and die
before 30 years
of age.
The frequency of
HoFH is
estimated to be
1/160 000-1/320
000.
Treatment
should be with
intensive LDL-
lowering drug
therapy and,
when available,
with lipoprotein
apheresis.
This treatment
(every 1-2
weeks) can
decrease
plasma LDL-C
levels by 55-
70%.
Maximally
tolerated
pharmacological
therapy must be
maintained
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 111-188; 2019

15. Familial hypercholesterolemia in children
Diagnosis based on
phenotypic criteria
including elevated
LDL-C plus a family
history of elevated
LDL-C, premature
CAD, and/or positive
genetic testing.
In children with a
family history of high
cholesterol or
premature CHD, an
accepted cut-off is
>_160 mg/dL
If a parent has a
known genetic
defect, the diagnostic
level for the child is
>_130 mg/dL
In children, testing for
FH is recommended
from the age of 5
years, or earlier if
HoFH is suspected.
Children with FH
should be educated
to adopt a proper
diet and treated with
a statin from 8-10
years of age.
Goals for treatment
should be LDL-C
<135 mg/dL at >10
years of age.
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 111-188; 2019

16. FH is a poorly recognised clinical entity
FH is often diagnosed late and after the occurrence of a major coronary
event.
Many individuals and family members with FH who have CAD have
other common CAD risk factors; thus genetic hypercholesterolemia
is not suspected and ultimately not diagnosed.
Risk assessment tools do not adequately predict 10-year CHD risk in
FH patients
Risk calculators underestimate risk in patients with FH because of
the significant effect of exposure to high cholesterol levels from birth.
Bouhairie, VE et al Cardiol Clin. 2015 May ; 33(2): 169–179.

17. “Substantial deficit” in awareness and knowledge regarding
FH among the GPs in Mumbai, India
Asia has the largest numbers of FH
patients compared to Africans,
Americans or Europeans, however
there is a major shortfall in the
detection and treatmen
https://japi.org/r2d47454/familial-
hypercholesterolemia-fh-awareness-amongst-
physicians-in-mumbai-india

18. Recommendations
ESC-EAS 2019
Detection/diagnosis Screening
Risk stratification
and treatment goals
Treatment
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 1111882019

19. Recommendations for the detection and screening of
patients with heterozygous familial
hypercholesterolaemia
FH should be
diagnosed using
clinical criteria *
01
Confirmed, when
possible, via DNA
analysis.
02
Once the index
case is diagnosed,
family cascade
screening is
recommended.
03
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 1111882019

21. Genetic testing
 In some patients with severe FH, genetic testing might be the only way in
which to distinguish between hoFH and HeFH
 It could increase the accuracy and usefulness of conception genetic
counselling when both parents are uncertain whether they have heFH.
 In patients with hoFH, the type of LDLR mutations can be used to predict
response to therapies
 null mutations – impaired response to statins and PCSK9 inhibitors
 they might require novel therapies – lipoprotein apheresis and liver
transplantation.

22. Criterion for diagnosis
Dutch Lipid
Clinic Network
Simon
Broome
register
WHOcriteria
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskEuropean Heart Journal (2020) 41, 111-188; 2019

23. https://www.mdcalc.com/simon-broome-diagnostic-criteria-familial-hypercholesterolemia-fh
Simon Broome
Diagnostic Criteria
for Familial
Hypercholesterolem
ia (FH)

24. Dutch Lipid Clinic Network diagnostic criteria for
familial hypercholesterolaemia
ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk European Heart Journal (2020) 41, 111-188;2019

27. Risk stratification and treatment goals in FH
Very-high-risk
• FH patients with ASCVD or
who have another major risk
factor
High-risk
• Those with no prior
ASCVD or other risk
factors
Treatment to achieve a >_50% reduction
from baseline and an LDL-C < 55 mg/dL is
recommended.
If goals are not achieved, a drug combination
is recommended –with high intensity statin
and ezetemibe
Treatment with a PCSK9 inhibitor is
recommended if the treatment goal is not
achieved on maximal tolerated statin plus
ezetimibe ESC/EAS Guidelines for the management of dyslipidaemias: lipid
modification to reduce cardiovascular riskEuropean Heart Journal (2020)

28. Treatment algorithm for pharmacological low-density
lipoprotein cholesterol lowering
Treatment goals for low-density lipoprotein cholesterol
across categories of total cardiovascular disease risk.
ESC/EAS Guidelines for the management of dyslipidaemias: lipid
modification to reduce cardiovascular riskEuropean Heart Journal
(2020) 41, 1111882019

29. CVD risk assessment
Interestingly though, a recent cross-sectional cohort
study demonstrated that the inclusion of age, HDL, gender,
hypertension, and smoking in the context of a cumulative clinical
score, named as the Montreal-FH-SCORE, can predict the CVD
risk in FH patients, regardless of their LDL levels (Paquette et al.,
2017a).
It is also noteworthy that, Apo A-I and ApoB apolipoproteins are
considered as better CVD risk predictors than LDL, even in
patients who are on lipid-lowering treatment
(Walldius and Jungner, 2004).

31. Diet modifications in FH
Cardiol Clin. 2015 May ; 33(2): 169–179
Dietary modification contributes to improvement in lipid profiles
A heart healthy diet including vegetables, fruit, non-fat dairy, beans, tree nuts, fish and lean meats should be encouraged
Restrict intake of saturated fat to less than 7% of calories
Avoid trans fats
If alcohol is used, amount should be moderate
Addition of plant stanols (2 g/day) and insoluble fiber (10–20 g/day) can provide some LDL-C lowering
Dietitian counseling is beneficial
Physical activity
Avoidance of weight gain
Avoidance and cessation of smoking is mandatory
Discourage exposure to passive smoking
Treat diabetes and hypertension
Consider low-dose aspirin

33. Familial hypercholesterolemia remains
undertreated- Need for statin use
 The risk of CHD was increased 13-fold (95% CI: 10- to 17-fold) among individuals with definite/probable FH not receiving
statins
 The corresponding increase in risk for CHD among individuals with FH on statin was ten-fold (8- to 14-fold)
 This suggests that the dose of statin therapy provided resulted in insufficient cholesterol-lowering medication, and was
introduced too late in life, when severe atherosclerosis had already developed
Risk of coronary heart disease as a
function of the Dutch Lipid Clinic
Network Criteria for a diagnosis of
familial hypercholesterolaemia in
individuals on or off statin from the
general population
Data are based on 69 016
individuals from the Copenhagen
General Population Study
Eur Heart J. 2013 Dec 1; 34(45): 3478–3490

34. Cumulative LDL cholesterol burden illustrates the importance
of early treatment.
LDL cholesterol burden in individuals with or without
familial hypercholesterolaemia as a function of the age of
initiation of statin therapy
• Risk calculators such as the
European SCORE or the US
Framingham Risk Score are
not appropriate for FH
subjects, as such individuals
are at considerably higher risk
due to lifelong elevated LDL
cholesterol levels
• Not all individuals with FH
develop atherosclerosis and
CHD to the same extent
• Risk factor counting is critical
to assess CHD risk
• Elevated LDL cholesterol is the
major problem in FH
Eur Heart J. 2013 Dec 1; 34(45): 3478–3490.

37. Rosuvastatin produced significantly greater reductions than
atorvastatin in LDL cholesterol
 All assessed doses of rosuvastatin (20,
40, and 80 mg) resulted in significantly
greater (p <0.001) reductions in LDL
cholesterol than did atorvastatin 20, 40,
or 80 mg
 Rosuvastatin appears to provide more
than a 1-dose greater decrease in LDL
cholesterol than is achievable by
atorvastatin
 Rosuvastatin enabled more patients to
achieve LDL cholesterol goals.
Change in HDL cholesterol and LDL cholesterol during 18 weeks of
treatment. Rosuvastatin and atorvastatin treatment began at 20 mg with
forced titration to 40 mg and 80 mg at weeks 6 and 12, respectively (*p
<0.001). LS least-squares.Am J Cardiol 2003;92:1287–1293

38. Rosuvastatin produced significant beneficial changes in all
lipid parameters in patients with heterozygous familial
hypercholesterolemia
Atheroscler Thromb, 2004; 11: 152–158
Mean %
change
from
baseline in
lipid
parameters
and ratios

39. Safe and effective LDL-C
reduction with rosuvastatin 20 mg
alone or added to ezetimibe and/or
apheresis : HYDRA study
 The HYDRA study, the first randomized,
placebo-controlled trial of any statin in pediatric
HoFH patients as young as 7 years of age,
demonstrated significant and sustained
reductions in LDL-C with rosuvastatin 20 mg
daily of 85.4 mg/dl (22.3%) compared with
placebo.
 The LDL-C response in children and adults
was related to underlying genetic mutations.
J Am Coll Cardiol . 2017 Aug 29;70(9):1162-1170

40. Comparison of Rosuvastatin Versus Atorvastatin in
Patients With Heterozygous Familial
Hypercholesterolemia
Am J Cardiol 2003;92:1287–1293
• At week 18, rosuvastatin
therapy produced a significantly
greater reduction in LDL
cholesterol than atorvastatin
(57.9% vs 50.4%; p <0.001) and a
significantly greater increase in
high-density lipoprotein (HDL)
cholesterol (12.4% vs 2.9%; p
<0.001).
• Rosuvastatin also produced
significantly greater reductions
in apolipoprotein-B andall 4
major lipid ratios, as well as a
significantly greater increases
in apolipoprotein A-I (all p
<0.001).

41. Comparison of Rosuvastatin Versus Atorvastatin in
Patients With Heterozygous Familial
Hypercholesterolemia
Am J Cardiol 2003;92:1287–1293
• More patients with HFH with coronary
artery disease achieved the National
Cholesterol Education Program Adult
Treatment Panel III goal of LDL
cholesterol <100 mg/dl (<2.6 mmol/L) on
rosuvastatin 40 and 80 mg than
atorvastatin 80 mg (17%, 24%, and 4.5%,
respectively).
• In HFH, rosuvastatin force titrated from 20
to 80 mg/day produced significantly
greater reductions than atorvastatin 20 to
80 mg/day in LDL cholesterol and
improvements in HDL cholesterol and
other lipid parameters, and enabled more
patients to achieve LDL cholesterol goals.

42. Media Thickness in Children With
Heterozygous Familial
Hypercholesterolemia: The CHARON Study
 In HeFH children 6 years or older, carotid IMT
was significantly greater at baseline
compared with unaffected siblings.
 Rosuvastatin treatment for 2 years resulted in
significantly less progression of increased
carotid IMT in HeFH children than untreated
unaffected siblings.
 As a result, no difference in carotid IMT could
be detected between the two groups after 2
years of rosuvastatin.
 These findings support the value of early
initiation of statin treatment for LDL-C
reduction in children with HeFH.
Carotid intima-media thickness for children with HeFH and
unaffected siblings Circulation. 2017;136:359–366

43. Moving on from the lower the better' but to
also 'the younger the better

44. Clinical management of FH in children and adolescents
•Early identification of children with FH ensures that adherence with lifestyle intervention is already established before
puberty.
•Children with HeFH should be treated with a fat-modified, heart-healthy diet at diagnosis, and begin statins at age 8–10
years.
•In HoFH, pharmacologic treatment should start at diagnosis.
•Early initiation of lifestyle is essential for ensuring long-term adherence.
•Children diagnosed with FH should have lipoprotein(a) [Lp(a)] measured for risk stratification.
•Boys and girls should start treatment at similar ages.
•For children aged 8–10 years, the Panel recommends that LDL-C is ideally reduced by 50% from pre-treatment
levels.
•For children aged ≥10 years, especially if there are additional cardiovascular risk factors, including elevated Lp(a),
the target LDL-C should be <3.5 mmol/L (130 mg/dL).
•The benefits of LDL-C reduction should be balanced against the long-term risk of treatment side effects.
European Heart Journal (2015) 36, 2425–24

45. Metanalysis Findings
 Ten trials : 1543 patients
High Intermediate Low
Reductions in
cholesterol levels
-104.61 mg/dl -67.60 mg/dl -56.96 mg/dl
Reduction in the
low-density
lipoprotein
cholesterol level
-105.03 mg/dl -67.85 mg/dl [-58.97 mg/dl
Statin treatment is efficient in lowering lipids in children
with FH. There is need of large, long-term and randomized
controlled trials to establish the long-term safety of
Arq Bras Cardiol. 2018 Dec; 111(6): 810–821.

46. Early treatment of FH can reduce LDL-C burden improve
endothelial function, substantially attenuate the progression of
atherosclerosis and improve coronary outcomes
IMPACT of EARLY Treatment of FH with statins
Kaplan–Meier curves of
event-free survival in a
cohort of 214 familial
hypercholesterolaemia
subjects treated from
childhood (n = 214)
compared with their parents
with familial
hypercholesterolaemia,
treated from adulthood (n =
156)
At the age of 30 years, the
CHD free survival was
100% in the group of young
adults who initiated statin
therapy in childhood and
93% in the affected parents
(p=0.023).
Circulation. 2013;128:A17837

47. Statins for children with familial hypercholesterolemia
 Statin treatment is an effective lipid‐lowering therapy in children with familial
hypercholesterolemia.
 Few or no safety issues were identified.
 Statin treatment seems to be safe in the short term, but long‐term safety
remains unknown.
 Children treated with statins should be carefully monitored and followed up by
their pediatricians and their care transferred to an adult lipidologist once they
reach 18 years of age.
 Large long‐term randomized controlled trials are needed to establish the
long‐term safety issues of statins.
Cochrane Systematic Review -
2019 :https://doi.org/10.1002/14651858.CD006401.pub5

49. The other modalities of treatment
 Microsomal triglyceride transfer protein inhibitors (lomitapide)
 Apo B synthesis inhibitors (mipomersen)
 PCSK9 inhibitors (PCSK9i) (alirocumab, evolocumab).
 Lipoprotein apheresis
 Liver transplantation
Indian J Endocrinol Metab. 2016 May-Jun; 20(3): 285–287.

54. What Gaps to be addressed
 Broad research agenda
 Implementation strategies
 Global collaboration and advocacy

57. Key takeaways
 Familial hypercholesterolemia is a common genetic disorder leading to high
cholesterol levels from birth and increased risk of atherosclerotic
cardiovascular disease
 Heterozygous FH occurs in approximately 1 in 250 people in many populations
 Homozygous FH can lead to CAD in childhood and adolescence
 Early treatment can decrease the risk of premature ASCVD in FH patients
 High intensity statins in combination can lower long term risk