Cholesterol Screening in

Children and Young Adults.

Where are we going?

Don P. Wilson, M.D., FNLA

Fellow, American Board of Clinical Lipidology
Pediatric Endocrinology
Cook Children’s Medical Center
Fort Worth, Texas
 Disclosures
• Osler Institute - Speaker
• Insulet - Speaker
• Aegerion Pharmaceuticals - Advisory Board
• Alexion Pharmaceuticals - Advisory Board
• Merck Sharp & Dohme - Research Funding
• Novo Nordisk Inc.- Research Funding
 Rationale for
Cholesterol Screening
1. Abnormal lipid values are highly prevalent.
2. Well documented relationship between total
and LDL-C levels and CHD risk.
3. Treatment decreases the risk of CVD
events.
4. Early knowledge of a lipid disorder creates
the best opportunity for early intervention.
 Principles of Screening
Congenital Hypothyroidism
Affects 1:4000 newborns

Increased Risk
Shared Decision Willing Serious

• Physician to
Morbidity • Developmental
and
• Parent
Treat Mortality Delay
• Mental
Retardation

Treatment Effective Reliable Testing - TSH

• Thyroid Hormone Treatment Testing • Reliable
• 10-15 mcg/kg/d • Specific
• Reliable monitoring
 Newborn Screening
Mandatory “Op-Out Only”
State Screening

Regulation Centralized Testing Professional

and and and
Advocacy Case Management Public Education

Notification of Abnormal Test Results

Primary Regional
Care Consultant
Annual Follow-up
Statistics and Reporting
 Question
Which of the following is the key goal of cholesterol
screening?
a. Familial hypercholesterolemia.
b. All genetic disorders associated with increased
atherogenic cholesterol.
c. All acquired conditions associated with
increased atherogenic cholesterol.
d. a and b.
e. b and c.
 Cholesterol Screening
World Health Organization
9 Key Principles of Screening

Wilson JMG, Jungner G. PRINCIPLES AND PRACTICE

OF SCREENING FOR DISEASE. In: Organization WH,
editor. Geneva: World Health Organization; 1968.
 #
1
An important health problem.
1. CVD is the leading cause of morbidity and
mortality worldwide.
2. In the U.S. more than 600,000 ( ̴ 1 in 4) die of
heart disease each year.
3. Of those with heart disease, coronary heart
disease is the most common, killing > 370,000
people annually.
4. Abnormalities in lipoprotein metabolism
represent approximately 50% of the
population attributable risk of CVD.

CDC, 2015; Mozaffarian D, 2015

 #
1
An important health problem.

Cholesterol screening has the potential to

identify a wide variety of primary and secondary
conditions, including:
1. Genetic mutations in lipid and lipoprotein
metabolism.
2. Acquired dyslipidemia, especially related to
unhealthy lifestyles, obesity, medications,
etc.

It is, therefore, critical to identify the primary

goal of cholesterol screening.
 #
1
An important health problem.

Many believe familial hypercholesterolemia (FH)

should be the primary goal of cholesterol
screening. Why FH?
1. Mortality rates from CHD in FH:
a. 100x greater in those age 20-39
b. 4x greater in those age 40-59
2. Children with untreated HeFH have a
dramatic increase in risk of premature CHD
after 20 years of age.
Youssef AA, Srinivasan SR, Elkasabany A, Chen W, Berenson GS. Trends of lipoprotein variables from childhood to
adulthood in offspring of parents with coronary heart disease: the Bogalusa Heart Study. Metabolism. 2001; 50:1441–
6.
 Question
In the U.S. how frequently, on average, is a child
born with familial hypercholesterolemia (FH)?
a. Every 1 minute
b. Every 5 minutes
c. Every 10 minutes
d. Every 60 minutes

Familial hypercholesterolemia 1:250

 #
1
An important health problem.
2. Current diagnosis and treatment of FH is:
a. Very inadequate (<1% indentified)
b. Often delayed
c. Despite effective interventions, late
treatment often results in significant
residual risk and poor outcomes.
 #
1
An important health problem.

Cholesterol screening – What are the cons?

1. Some argue that screening young adults
w/out other risk factors for CVD should be
delayed until > 40 yrs of age, since absolute
risk reduction in CVD events will be small.
2. There are no studies showing a positive
effect of screening in young adults (e.g.,
ages 18-35)
 #
1
An important health problem.

Cholesterol screening – What are the cons?

1. Screening the entire population:
a. Can be costly
b. May result in the use of unnecessary
medication in lower-risk individuals.

Therefore for some, the benefits of screening

individuals < 40 yrs of age is uncertain.
 #
2 Accepted treatment for
patients with recognized disease.
A variety of effective lipid lowering medications
are available for the treatment of FH:
1. Children 6 yrs of age and older:
rosuvastatin*
2. Children 8 yrs of age and older: pravastatin
3. Children 10 yrs of age and older:
a. All statins (except pitavastatin)
b. Ezetimibe
c. Colesevelam *Europe
 #
2 Accepted treatment for
patients with recognized disease.
2011 NHLBI’s Expert Panel
“What was said…” What was heard…”

All children should All children who are obese

undergo lipid screening should undergo lipid
and interventions for screening and treated with
genetic and acquired risk statins.
factors and conditions.
 #
3 Recognizable latent or early
symptomatic stage.
1. Children and young adults with FH are rarely
symptomatic.
2. While CVD typically manifests in adulthood, the
process begins in childhood.
3. Identifying children is critical to reducing the
burden of disease in adulthood.
4. Some, but not all, guidelines underscore the
value of noninvasive imaging of atherosclerosis
(e.g. cIMT) in assessing and managing
asymptomatic FH subjects.
 #
4
Suitable test or examination.
1. The majority of FH children and young adults have no
physical signs/symptoms of hypercholesterolemia.
2. Blood testing
a. Cholesterol - quick, easy, inexpensive and
generally reliable.
b. Genetic Testing - costs are high, but improving.
 #
4
Suitable test or examination.
Question: True or False?
The US Preventative Task Force recommended against
cholesterol screening in children and adolescents?

“The USPTF concludes that the current evidence is

insufficient to assess the balance of benefits and harms
of screening for lipid disorders in children and
adolescents 20 years or younger.”
Therefore, the USPTF statement is neither for or against.

Screening for Lipid Disorders in Children and Adolescents: US Preventive

Services Task Force Recommendation Statement. JAMA. 2016; 316(6):625-33.
 #
4
Suitable test or examination.
Summary of USPTF Screening Recommendations
Men Recommendation Criteria
20-35 Recommended If at increased risk for CHD

35 and Older Strongly recommended None

Women Recommendation Criteria

20-45 Recommended  If at increased risk for CHD

45 and Older Strongly recommended If at increased risk for CHD

Final Recommendation Statement: Lipid Disorders in Adults (Cholesterol,

Dyslipidemia): Screening. U.S. Preventive Services Task Force. December 2014.
 #
4
Suitable test or examination.
1. USPTF preferred screening tests: TC and HDL-C
on non-fasting or fasting samples.
2. Measuring TC alone is acceptable.
3. Optimal interval for screening is uncertain;
reasonable options include every 5 years, or
sooner if clinically indicated.
4. An age to stop screening has not been
established.

Screening for Lipid Disorders in Children and Adolescents: US Preventive

Services Task Force Recommendation Statement. JAMA. 2016; 316(6):625-33.
 What age to screen?
Cholesterol Screening
Age Type Criteria
> 2 yrs of age Selective  1 or both biologic parents known to
have hypercholesterolemia or are
receiving LLM; or
 Family history of premature CVD (i.e.
men < 55 yrs; women < 65 yrs); or
 Whose family history is unknown
(e.g. children who were adopted).

> 10 yrs of age* Universal  Regardless of general health or the

presence/absence of CVD risk
factors.
 If normal, repeat every 5 yrs.
*Selective screening if clinically indicated.
LLM = lipid-lowering medications; CVD = cardiovascular disease
National Lipid Association Annual Summary of Clinical Lipidology 2017. J of Clinical Lipidology (2016) , S1-S50
European Atherosclerosis Society

• Children suspected of FH should be screened

from the age of 5 years.
• Cascade screening of families is recommended
using a combined phenotypic and genotypic
strategy.
• Universal screening of children may be another
option, depending on practical and cost
considerations.
 What age to screen?
The literature suggests that the optimal
age range for screening is between 1 - 9
years, as determined by optimal
discrimination using cholesterol
measurement between children with and
without FH.

Wald David S, Bestwick Jonathan P, Wald Nicholas J. Child-parent screening for familial
hypercholesterolaemia: screening strategy based on a meta-analysis BMJ 2007; 335 :599
Detection Rate (%) Detection rate plotted against the
false positive rate for total and
LDL-C measured at different
ages.

This illustrates the maximum

discrimination at 1-9 yrs and
shows that there is little
additional increase in the
detection rate as the false
positive rate increases above 1%.
Detection Rate (%)

At a false positive rate of 0.1%, the

detection rate in the 1-9 yr age group
was:

• Total Cholesterol 88%

• LDL Cholesterol 85%

Wald David S, Bestwick Jonathan P, Wald Nicholas J. Child-parent screening for familial
hypercholesterolaemia: screening strategy based on a meta-analysis BMJ 2007; 335 :599
 #
5 Test should be acceptable
to the population.
Cholesterol Screening – Patient/Family Concerns
1. Testing methods
a. Finger prick vs. venipuncture
b. Fasting vs. non-fasting
c. POC vs. Lab
2. Psychological issues (e.g. “fatalism”)
3. Practical issues
a. Cost of testing/insurance coverage
b. Increased life insurance premiums
A systematic review and meta-analysis
on screening lipid disorders in the
pediatric age group.
Aim: Assess the effectiveness of lipid screening in
youth (2 to 20 yr) according to the existence of
positive family history of CVD risk factors.

Study cohort: 37,304 assessed for dyslipidemia.

Results:
Sensitivity = 42.65% / Specificity = 59%
Predictive value = 20.7%

Kelishadi R, Haghdoost AA, Moosazadeh M, Keikha M, Aliramezany M. A systematic review and meta-
analysis on screening lipid disorders in the pediatric age group. J Res Med Sci 2015;20:1191-9.
 Family History
Reliance on family history alone as a basis for
lipid screening fails to identify as many as 30-
60% of children and adolescents with elevated
levels of cholesterol.

Dennison 1989, Griffin 1989, Freedman 1992

 Natural history of the condition
#
6
should be adequately understood.
Ischemic Heart
Disease

Cerebrovascular
Disease

Peripheral Vascular
Lesion: Initiation  Progression  + Stable Disease

No Symptoms + Symptoms Symptoms

Reversible + Reversible Non - Reversible

Years
 #
7 Agreed policy on
whom to treat.
Guidelines and Recommendations are available from a
variety of professional organizations and societies:
1. National lipid Association
2. ACC/AHA
3. NHLBI/NIH
4. USPSTF
5. American Academy Pediatrics
6. American Academy of Clinical Endocrinologist
7. American Diabetes Association
8. … and others, including European guidelines
 #
7 Agreed policy on
whom to treat.
Application of pediatric vs adult
guidelines for lipid levels, which
consider additional CVD risk factors
beyond age and LDL-C, might result in
statin treatment for more than 400,000
additional adolescents and young adults

JAMA Pediatr. 2015 Jun;169(6):569-74. doi: 10.1001/jamapediatrics.2015.0168. Application of Pediatric and

Adult Guidelines for Treatment of Lipid Levels Among US Adolescents Transitioning to Young Adulthood.
Gooding HC1, et. al.
 #
8 Cost of case-finding should
be economically balanced.
Cost effectiveness of screening for FH is
dependent upon 3 factors:
1. Cost effectiveness of treatment, once FH
is identified.
2. The underlying prevalence of FH among
the screened population.
3. The accuracy (validity) of the screening
test.
A systematic review of economic evaluations of the detection and
treatment of familial hypercholesterolemia. Ademi, et al. International
Journal of Cardiology 167 (2013) 2391–2396.
 #
8 Cost of case-finding should
be economically balanced.
• For the vast majority of children with
FH, there is 1 affected parent.
• Child-parent screening strategies
have the potential to prevent medical
consequences of FH in 2 generation
simultaneously.

Wald David S, Bestwick Jonathan P, Wald Nicholas J. Child-parent screening for

familial hypercholesterolaemia: screening strategy based on a meta-analysis BMJ
2007; 335 :599
 #
8 Cost of case-finding should
be economically balanced.
Conclusion:
1. Cascade screening is more cost effective than
any other screening strategy currently available.
2. However, cost of genetic testing has
dramatically decreased in recent years, and may
become more acceptable and feasible in the
future.
Ademi, et al. International Journal of Cardiology 167 (2013) 2391–2396.
Marks D, Wonderling D, et al. BMJ. 2002;324(7349):1303. National Institute for
Health and Clinical Excellence (NICE). Familial Hypercholesterolaemia –
Costing Report: Implementing NICE guidance. 2009. pp.1–42.
https://www.nice.org.uk/guidance/cg71/resources/familialhypercholesterolaemi
a-costing-report2.
 Question
On average, how long does it take for
evidence from RCTs to be incorporated
into clinical practice?
a. 3 years
b. 9 years
c. 17 years
d. >20 years
 Why Don’t Physicians Follow
Clinical Practice Guidelines?
• Physician adherence is critical in
improving outcomes.
• Historically, guidelines have had
limited effect on changing physician
behavior.

M. Cabana, et al. JAMA. 1999;282:1458-1465

 Clinical Practice Guidelines -
Barriers that undermine the process.
1. Physician knowledge: Lack of
awareness and familiarity.
2. Physician attitudes: Lack of
agreement, outcome expectancy,
and the inertia of previous
practices.

M. Cabana, et al. JAMA. 1999;282:1458-1465

 Clinical Practice Guidelines -
Barriers that undermine the process.
3. External barriers:
a. Guideline related - not easy to use,
not convenient, confusing.
b. Patient related - lack of acceptance,
not covered by insurance.
c. Environmental - lack of time,
insufficient staff, lack of consultative
support.
M. Cabana, et al. JAMA. 1999;282:1458-1465
 #
9 Case-finding should be a
continuing process.

B.G. Nordestgaard et al. European Heart Journal. doi:10.1093/eurheartj/eht273

 Principles of Screening
Familial hypercholesterolemia

FH Affects 1:250

Shared Decision
Willing Serious
• Physician to
Morbidity Premature CVD
and
• Parent Treat Mortality • MI
• CVA
LLMs • Death
• Statins Tests - Cholesterol
• Ezetimibe + Genetic Testing
Effective Reliable
• BAS Treatment Testing • Reliable
• New agents* • Accurate
• Accessible
* Not FDA approved <18 yr • Inexpensive
Cholesterol Screening Guidelines
  1
NHLBI NLA ACC/AHA
Who to Screen?
Selective Screening Yes Yes Yes
Universal Screening Yes Yes Yes
Age at First Screening?   
Selective Screening >2 yrs >20 yrs >20 yrs
Universally Screening 9-11 yrs >20 yrs >20 yrs
2
Repeat Screening 17-20 yrs 3Every 5 yrs ---
What to Order?   
Fasting or non-fasting lipid panel Yes Yes Yes
Calculate non HDL-C Yes Yes Yes
Risk Factors Assessment? Yes Yes Yes
ASCVD Risk 10 Year Estimate? 4
N/A 4
Yes 4
Yes
1
These recommendations have been endorsed by the American Academy Pediatrics, National lipid Association and American Heart Association. If 2

initial levels of artherogenic cholesterol (non-HDL-C and LDL-C) are in the desirable range. 3 Or sooner based upon clinical judgement. 4 Risk
calculators are not applicable to children and adolescents, and may either over- or under estimate risk in those < 40 years of age. 5Every 4-6 yrs
 
NLA = National Lipid Association. J Clin Lipidol. 2014 Sep-Oct; 8 (5):473-88. Part 2. J Clin Lipidol. 2015 Nov-Dec; 9 (6 Suppl):S1-122. ACC/AHA =
American College of Cardiology/American Heart Association. Circulation. 2014;129 [suppl 2]:S1-S45). NHLBI = National Heart, Lung, and Blood
Institute: Summary Report. Pediatrics 2011; 128(Suppl 5):S1-S44.
 Final thoughts…
• There is no generally accepted
screening program for children,
adolescents, and young adults.
• Universal screening, started at age
10 and continued every 5 years
thereafter, may help simplify the
process for busy clinicians.

Wiegman A, Gidding SS, et al. Familial hypercholesterolaemia in children and adolescents:

gaining decades of life by optimizing detection and treatment. Eur Heart J. 2015;36(36):2425–37.
 Final thoughts…
• Many feel FH should be the primary
goal of cholesterol screening.
• Early recognition of a child or young
adult with FH, coupled with therapy
from a young age, will impede, if not
arrest, the onset of atherosclerosis.

Wiegman A, Gidding SS, et al. Familial hypercholesterolaemia in children and adolescents:

gaining decades of life by optimizing detection and treatment. Eur Heart J.
2015;36(36):2425–37.
 Final thoughts…
• Statin therapy alone could potentially
avert 96-98% of FH-related CHD
deaths in individuals < 40 years of
age.

Austin MA, Zimmern RL, Humphries SE. High “population attributable

fraction” for coronary heart disease mortality among relatives in monogenic
familial hypercholesterolemia. Genet Med. 2002;4(4):275–8.
 Final thoughts…
• Identification of a child with FH combined
with effective screening of 1st and 2nd
degree relatives (i.e. reverse cascade
screening):
– Combines the benefits of universal +
cascade screening.
– Has the potential, within 1 generation, of
detecting all cases of FH.
Morris JK, Wald DS, Wald NJ. The evaluation of cascade testing for familial
hypercholesterolemia. Am J Med Genet A. 2012;158(1):78–84.
 Time Course of Human Atherogenesis
Years Events

Ischemic Heart
Disease

Cerebrovascular
Disease

Peripheral Vascular
Lesion: Initiation  Progression  + Stable Disease

No Symptoms + Symptoms Symptoms

Reversible + Reversible Non - Reversible

Intervention
 Time Course of Human Atherogenesis
Years No Events

Early Detection/ Early Intervention

Lifelong Heart
Healthy Living

Lesion: prevention

No Symptoms

Reversible

Intervention
Cholesterol Screening in
Children and Young Adults.
Where are we going?

Don P. Wilson, M.D., FNLA

Fellow, American Board of Clinical Lipidology
Pediatric Endocrinology
Cook Children’s Medical Center
Fort Worth, Texas