Mortality from familial hypercholesterolemia (FH)

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Mortality from familial hypercholesterolemia (FH)
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Eric Sijbrands
resume

• Eric Sijbrands is consultant in internal medicine
  and head of the lipid clinic of the Erasmus
  University Medical Center Rotterdam. After he
  obtained his qualification as medical doctor in
  1990, he was given the opportunity to receive his
  training in internal medicine and to work in
  scientific research at the Universities of Leiden
  and Amsterdam. He made a Ph.D. thesis on
  gene-gene and gene-environment interaction in
  patients with genetic hyperlipidemia. His present
  research is focussed on genetic epidemiology of
  cardiovascular disease (hyperlipidemia, diabetes
  mellitus, and pharmacogenetics of hypertension).

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Learning objectives

• selection on outcome
• standardization
• burden of monogenetic disorder
• genetic heterogeneity
• gene-environment interaction

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Performance objectives

• understand the clinical consequences of
  monogenetic disorders

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FH - characteristics
introduction

• autosomal dominant
• heterozygosity 1500
• mutations in the LDL receptor gene on chromosome
  19
• total cholesterol gt 8 mmol/L
• tendon xanthomas

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FH - what is already known
introduction

• cardiovascular disease
• at young age
• excess mortality
• population data are lacking

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Burden of untreated FH
introduction

• analyses of mortality in
• a large pedigree
• free from selection on CVD
• 113 small pedigrees
• referred to a lipid clinic

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Monogenetic disorder
introduction
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Monogenetic disorder
introduction
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Natural history
introduction
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Large pedigree FH-V408M
introduction
Sijbrands EJG, et al. BMJ 20013221019-23.
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Standardization
introduction
SMR observed / expected deaths strata per
gender strata per age category strata per
calendar period
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SMR
large pedigree

• V408M death p.y. SMR (95CI)
• 50 70 6950 1.32 (1.03-1.67)
• 100 30 3186 1.59 (1.07-2.26)

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SMR
large pedigree
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Kaplan-Meier
large pedigree
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Conclusion 1
large pedigree

• gene-environment
• interaction

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113 small pedigrees
outpatient lipid clinic
number cardiologist 39 GP 51 insurance
4 other 19 total 113
Sijbrands EJG, et al. Atherosclerosis
1998136247-54.
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113 FH patients
outpatient lipid clinic
characteristic n113 male / female 55/58 age 48
(20 to 69) xanthomas 66 cholesterol 11.04 mmol/L
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SMR
outpatient lipid clinic
age deaths p.y. SMR (95CI) 1-
19 6 11091 0.45 (0.17-0.98) 20-
39 12 10796 1.01 (0.52-1.76) 40-
54 43 6317 1.88 (1.36-2.53) 55-
69 69 2973 1.76 (1.36-2.22) 70-
79 38 688 1.22 (0.87-1.68) 80-103 22 184 0.96 (0.6
0-1.46) 1-103 190 32048 1.34 (1.16-1.55)
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SMR
outpatient lipid clinic
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Other risk factors
outpatient lipid clinic

• premature CVD SMR 95 CI
• (51 families) 1.10 0.86-1.34
• (62 families) 1.62 1.32-1.93
• RR versus 1.46 1.09-1.94

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Type of LDLR mutation
outpatient lipid clinic
characteristic mRNA mRNA - p (n24) (n14) ma
le, 58 43 0.4 age 50 47 0.4 BMI 25.1 25.1 1.0 xa
nthomas, 42 93 0.001 LDL-C 8.86 10.21 0.04 HDL-C
1.20 1.04 0.05
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Type of LDLR mutation
outpatient lipid clinic
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Conclusion 2
outpatient lipid clinic

• other risk factors for CVD
• type of mutation is not relevant

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FH - what these studies add

• many untreated patients (40) reach a normal life
  span
• burden of FH depends on time
• variation in mortality suggests an interaction
  between genetic and environmental CVD risk factors

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Future ...

• individual risk
• molecular diagnosis
• additional genes
• environmental factors
• exact indication for
• tailored intervention