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
5. Natural history
Homozygous
Depends on
1.
The degree of functional LDL receptor
activity
1.
LDL-C levels
2.
Varying prognosis
2.
Symptom onset is age-dependent
3.
Typically in the 2nd decade
4.
Atherosclerosis burden α LDL-C level
and duration = cholesterol year score
5.
Precocious onset :Severe
atherosclerosis affecting
CVS/CNS/PAD
6.
Heterozygous
CAD in about 50% of males by
the age of 50yrs and 30% of
females by 60yr
1.
Prognosis is better
2.
6. Natural History………
More morbidity and mortality
1.
CAD is most common CVS
2.
Survival :18-40 yrs
3.
stroke risk is more
controversial
4.
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. D I A G N O S I S
So also looks for
F/H,earlier age of
atheroma, elevated
cholesterols
10. Simon Broome criteria
POSSIBLE PROBABLE DEFINITE
mg/dl in first or second degree
patients >18 years
Tendon xanthomas in the
2
y ( )
patients >18 years
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
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
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
