Familial hypercholesterolemia

Heterozygous does better than Homozygous

Brief

Define Diagnosis Treatment Prognosis A genetic

disorder of lipoprotein metabolism

Rise of LDL increased risk for premature CVD

Clinical featuresFamily historyElevated LDL-C genetic testing.

Earlier betterStatin is keyPlasma pharesis

Heterozygous is better than homozygous

GENETICS

Chromosome 15One gene :LDL-receptorBrown and Goldstein :DiscoveredOne gene but >1,500 mutation> 80% of cases of monogenetic Heterozygous : 1 in 500 Homozygous:<1/1000000Autosomal dominant or rececive

Brief

Natural history

Homozygous

1. Depends on1. The degree of functional LDL receptor

activity 2. LDL-C levels

2. Varying prognosis3. Symptom onset is age-dependent4. Typically in the 2nd decade 5. Atherosclerosis burden α LDL-C level

and duration = cholesterol year score6. 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

Natural History………

7. More morbidity and mortality

8. CAD is most common CVS9. Survival :18-40 yrs10. stroke risk is more

controversial

Modified Natural History

• Homozygous• With statins :Mortality and

cardiovascular events decrease [HR: 0.49] with modest 26% reduction in LDL levels.

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

Diagnosis

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

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

MEDPED criteria 87%- sensitivity98%- specificity

Dutch Lipid Clinic criteria

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

Prescription

TO WHOMCONVENTIONALNOVELGENETICNON RESPONDERSLIPID TARGET

To whom

• American Heart Association/AAPStatins were proposed as first-line drugs and the age of initiation of therapy was lowered to 8 years

NHLBIBile acid sequestrants can be used up to age 10 yrs

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

Conventional

• Bile acid Sequestrants• Statins• Ezetamibe

Genetic therapy

• Trial failed

Non Responder

• Mipomirsen• monoclonal antibodies that bind to PCSK9• Lomitapide• LDL apheresis• Surgical

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

CONCLUSION

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

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%]).

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.

That's Not What I Heard

• Heterozygous responds better than homozygous