Familial hypercholesterolemia

1. Familial
hypercholesterolemia
Heterozygous does better than Homozygous

2. Brief
Define Diagnosis Treatment Prognosis
 A genetic
disorder of
lipoprotein
metabolism
 Rise of LDL
increased risk
for
premature CVD

 Clinical features
 Family history
 Elevated LDL-C
 genetic testing.
 Earlier better
 Statin is key
 Plasma pharesis
 Heterozygous is
better than
homozygous

3. GENETICS
Chromosome 15
One gene :LDL-receptor
Brown and Goldstein :Discovered
One gene but >1,500 mutation
> 80% of cases of monogenetic
Heterozygous : 1 in 500
 Homozygous:<1/1000000
Autosomal dominant or rececive

4. Brief

5. Natural history
Homozygous
1. Depends on
1. The degree of functional LDL receptor
activity
2. LDL-C levels
2. Varying prognosis
3. Symptom onset is age-dependent
4. Typically in the 2nd decade
5. Atherosclerosis burden α LDL-C level
and duration = cholesterol year score
6. Precocious onset :Severe
atherosclerosis affecting CVS/CNS/PAD
Heterozygous
1. CAD in about 50% of males by
the age of 50yrs and 30% of
females by 60yr
2. Prognosis is better

6. Natural History………
7. More morbidity and
mortality
8. CAD is most common CVS
9. Survival :18-40 yrs
10. stroke risk is more
controversial

7. Modified Natural History
• Homozygous
• With statins :Mortality and
cardiovascular events decrease
[HR: 0.49] with modest 26%
reduction in LDL levels.

8. Clinical features
Heterozygous
• Asymptomatic in childhood and
adolescence
• Caught in screening
• Total/ LDL-C >95th centile
• Tendon xanthoma or arcus
lipoides
Homozygous
• Rare
• 1st decade
• α to LDL-R mutation degree
• Null phenotype (<2% LDL receptor
activity):intrauterine death
• Skin/ocular lipid deposits
• CVS/CNS/PAD+
• Aortic stenois/CAD frequent
• Hypothyroid and DM

9. Diagnosis
• So also looks for F/H,earlier age
of atheroma, elevated
cholesterols

10. Simon Broome criteria
POSSIBLE PROBABLE DEFINITE
1. Total-cholesterol (LDL-C) in
mg/dl >260 in patients with
age <18 years and >290 (190) in
patients >18 years
2. F/H of elevated total-C >290
mg/dl in first or second degree
relative or
3. F/H of CAD at age <60 years in
1st degree relative or <50 years
in 2nd degree relative
1. Total-cholesterol (LDL-C) in
mg/dl >260 in patients with
age <18 years and >290 (190) in
patients >18 years
2. Tendon xanthomas in the
patient or in first/2nd degree
relative
1. Total-cholesterol (LDL-C) in
mg/dl >260 in patients with
age <18 years and >290 (190) in
patients >18 years
2. DNA mutation consistent with
FH

11. MEDPED criteria
87%- sensitivity
98%- specificity

12. Dutch Lipid Clinic criteria

13. Screening of FH
• Elevated LDL-C or non-HDL-C
• Suspected if children, adolescents, or young adults <20 years of age has LDL-C ≥160 mg/dl or non-
HDL-C ≥190 mg/dl
• LDL-C >190 : 80% is Dx in general population screening
• F/H of elevated cholesterol/premature CAD among 1st degree relatives
• Positive family history increases the likelihood of diagnosis of FH
• All individuals should be screened before the age of 20 years.
• Screening should be considered beginning at the age of 2 years for children with family history of
elevated cholesterol or premature coronary artery disease
• Tendon xanthoma at any age, arcus corneae at the age <45 years and xanthelasma at the age <25
years strongly suggest FH

14. Prescription
TO WHOM
CONVENTIONAL
NOVEL
GENETIC
NON RESPONDERS
LIPID TARGET

15. To whom
• American Heart Association/AAP
Statins were proposed as first-line drugs and the age of initiation of therapy was
lowered to 8 years
 NHLBI
Bile acid sequestrants can be used up to age 10 yrs

16. Life style changes
• physical activity
• limitation of alcohol intake
• total avoidance of tobacco products
• Low calorie diet with a total fat intake of ≤3% of the total dietary
intake
• <8% of saturated fat
• <75 mg/1,000 kcal cholesterol for these patients

17. Conventional
• Bile acid Sequestrants
• Statins
• Ezetamibe

18. Genetic therapy
• Trial failed

19. Non Responder
• Mipomirsen
• monoclonal antibodies that bind to PCSK9
• Lomitapide
• LDL apheresis
• Surgical

20. 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
• 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

21. CONCLUSION
• Starts before birth and progress
• Life style modification useful
• Medications and investigational therapy do not achieve target
• Heterozygous responds better

22. RUTHERFORD-2
• Of 415 screened patients, 331 were eligible and were randomly assigned to
the four treatment groups: evolocumab 140 mg every 2 weeks (n=111),
evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or
placebo monthly (n=55). 329 patients received at least one dose of study
drug. Compared with placebo, evolocumab at both dosing schedules led to
a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks
dose: 59·2% reduction [95% CI 53·4–65·1], monthly dose: 61·3% reduction
[53·6–69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2%
reduction [95% CI 54·5–65·8] and 65·6% reduction [59·8–71·3]; both
p<0·0001). Evolocumab was well tolerated, with rates of adverse events
similar to placebo. The most common adverse events occurring more
frequently in the evolocumab-treated patients than in the placebo groups
were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group)
and muscle-related adverse events (ten patients [5%] vs 1 [1%]).

23. Inhibition of PCSK9 with evolocumab in homozygous
familial hypercholesterolaemia (TESLA Part B): a
randomised, double-blind, placebo-controlled trial
• Findings
• Of the 50 eligible patients randomly assigned to the two treatment
groups, 49 actually received the study drug and completed the study
(16 in the placebo group and 33 in the evolocumab group). Compared
with placebo, evolocumab significantly reduced ultracentrifugation
LDL cholesterol at 12 weeks by 30·9% (95% CI −43·9% to −18·0%;
p<0·0001). Treatment-emergent adverse events occurred in ten (63%)
of 16 patients in the placebo group and 12 (36%) of 33 in the
evolocumab group. No serious clinical or laboratory adverse events
occurred, and no anti-evolocumab antibody development was
detected during the study.

24. That's Not What I Heard
• Heterozygous responds better
than homozygous