Premature morbidity and mortality associated with potentially undiagnosed familial hypercholesterolemia in the general population

Background: Familial hypercholesterolemia (FH) is common, but underdiagnosed, and few systematic early screening programs exist. Objective: To assess health outcomes among those with a recorded diagnosis of FH and potential cases of FH with no recorded diagnosis. Methods: Retrospective cohort study using the UK Clinical Practice Research Datalink. Records of adults were classified as diagnosed FH (FH_Coded), or via accepted algorithms using LDL-C and clinical characteristics as potential FH (FH_Potential) or unlikely FH (FH_Unlikely) using the DLCN or EUROASPIRE criteria (but no record of FH). Outcomes assessed were premature cardiovascular (CV) events, premature deaths and life expectancy. Results: Among 1,729,046 individuals free from CV events, a record of FH_Coded before the age of 40 was 0.3/1000 (IQR 0.3–0.4) and increased with age. Where LDL-C levels were available, 1.8/1000 (IQR 1.6–2.0) could be classified as FH_Potential. LDL-C was higher for both FH_Coded and FH_Potential vs FH_Unlikely (185.6 and 216.6 vs 116 mg/dL, respectively, p<0.001). Compared to FH_Unlikely both FH_Coded and FH_Potential cohorts had a higher risk of premature cardiovascular events (both p<0.001) with highest rates among FH_Coded. Risk of premature deaths did not differ between FH_Coded and FH_Unlikely, but was 1.88 (95% CI 1.27–2.78, p = 0.002) for FH_Potential vs FH_Coded and 2.40 (95% CI 1.57–3.67, p<0.001) for FH_Potential vs FH_Unlikely. At age 18, the FH_Potential cohort had a life expectancy 16 years lower than the FH_Coded cohort (p<0.001). Conclusions: Potential cases of FH had a doubling in risk of premature death and a large reduction in life expectancy compared to individuals with a recorded diagnosis of FH. These findings strengthen the critical importance of identifying potential cases of FH early and early treatment.