Bottom-line: In the UK, a child-parent FH screening strategy done at the time of routine immunizations by a GP identified FH in 1 child and 1 parent for every 360 children screened.
Lipid or FH mutation testing alone are each inadequate to diagnose FH in this population due to high false-positive rates.
- Familial hypercholesterolemia (FH) is a genetic dyslipidemia that affects ~1 in 500 Canadians
- Untreated FH leads to accelerated atherosclerosis;
- By age 50, almost half of men and 20% of women with untreated FH have experienced a coronary event.
- Only 5% of individuals with FH are properly diagnosed, often only after experiencing a cardiovascular event
- Multiple countries have implemented various screening strategies, including screening of all adults +/- children ("universal screening"), to more selective screening of first-degree relatives of individuals identified to have FH ("cascade screening")
- The goal of screening programs is to identify and treat FH before patients manifest clinical atherosclerosis
Who was involved in this study?
- Timeframe: 2012-2015
- Country: UK
- Setting: 92 GP offices
- Participants: 11,010 children (10,095 with valid screening test) presenting for their routine immunizations at ~1 year of age
- Baseline characteristics
- Median age 12.7 months
- Family hx of premature MI 11%
- Lipid panel, median
- Total cholesterol 3.93 mmol/L
- LDL 2.20 mmol/L
- HDL 0.93 mmol/L
- Triglycerides 0.67 mmol/L
- Median age of parents: Mother 31 y, father 34 y
What was the screening intervention?
- Heel-stick capillary blood sample from the child to measure:
- Lipid panel (total cholesterol, HDL, triglycerides)
- Possible FH mutations (48 tested, including mutations of the LDL receptor, ApoB, & PCSK9)
- Both parents of a child with a positive screening test for either of the above: Venipuncture for same screening test
What counted as a "positive" screening test?
- Total cholesterol >5.95 mmol/L (>99th percentile) + at least 1 FH mutation, or
- Total cholesterol >5.95 mmol/L x2 (test repeated 3 months later)
- Parents of children with a positive screening test
- If child had a FH mutation: Same FH mutation, or
- Higher cholesterol level of the 2 parents
How many children & parents had a positive screen for FH?
- Children: Positive screening test = ~0.28% (prevalence & number needed to screen = ~360)
- False positives:
- 0.6% (64/10,095) had a single elevated cholesterol level (negative on repeat + no known FH mutation)
- 0.17% (17/10,095) had a FH mutation without hyperlipidemia
- False positives:
- Parents: Prevalence 0.28% (based on definition above)
What was the impact of screening?
- Identified 1 in 360 children with FH. Notably, this likely captured every case of FH in this population based on a previous estimated prevalence of ~1 in 500;
- Identified parents with FH at an age (31-34 y/o) where they may have already had years of atherosclerotic buildup, but were not likely to have developed a coronary event. These parents could therefore receive therapy early enough to modify their cardiovascular risk and at least delay their first coronary event.
What gaps in our knowledge remain?
- How do we treat these children with FH once we've identified them? At what age do we start lipid-lowering therapies?
- How do we treat and/or monitor individuals with a FH mutation but normal cholesterol levels?
- What is the financial impact of child-parent screening? Considerations include costs to society (cost of lipid + FH mutation screening, lipid-lowering therapies including PCSK9 inhibitors) and to individuals (lipid-lowering therapy and insurance premiums).
- Which is most effective and cost-effective between the 3 available screening methods: Cascade, child-parent, or universal screening? Would a hybrid cascade+child-parent screening strategy be best?