Familial hypercholesterolemia

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Familial hypercholesterolemia

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Familial hypercholesterolemia

  1. 1. Familial hypercholesterolemia Heterozygous does better than Homozygous
  2. 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. 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. 4. Brief
  5. 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. 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. 7. Modified Natural History • Homozygous • With statins :Mortality and cardiovascular events decrease [HR: 0.49] with modest 26% reduction in LDL levels.
  8. 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. 9. Diagnosis • So also looks for F/H,earlier age of atheroma, elevated cholesterols
  10. 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. 11. MEDPED criteria 87%- sensitivity 98%- specificity
  12. 12. Dutch Lipid Clinic criteria
  13. 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. 14. Prescription TO WHOM CONVENTIONAL NOVEL GENETIC NON RESPONDERS LIPID TARGET
  15. 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. 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. 17. Conventional • Bile acid Sequestrants • Statins • Ezetamibe
  18. 18. Genetic therapy • Trial failed
  19. 19. Non Responder • Mipomirsen • monoclonal antibodies that bind to PCSK9 • Lomitapide • LDL apheresis • Surgical
  20. 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. 21. CONCLUSION • Starts before birth and progress • Life style modification useful • Medications and investigational therapy do not achieve target • Heterozygous responds better
  22. 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. 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. 24. That's Not What I Heard • Heterozygous responds better than homozygous

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