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Atherosclerosis. 2000 Apr;149(2):421-5.

Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia.

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Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.


Life expectancy of patients with familial hypercholesterolaemia is decreased. Some untreated patients reach a normal life span and, therefore, additional risk factors and the type of mutation in the low-density lipoprotein (LDL) receptor gene are likely to influence the clinical outcome. We determined all cause mortality in kindreds with the disorder, who were untreated, in order to study (a) additional risk factors for coronary artery disease (CAD) and (b) the types of LDL receptor gene mutations that may contribute to a poor prognosis. The mortality in all 855 first-degree relatives of 113 unrelated patients was compared to the Dutch population after standardisation for age, gender, and calendar period. Analyses restricted to affected relatives could have underestimated the mortality risk due to lack of information about severe cases, who died prematurely. Therefore, all first-degree relatives were analysed and as a result the standardised mortality ratios (SMRs) exhibit only 50% of the excess mortality from familial hypercholesterolaemia. We observed 190 deaths in 32048 person-years leading to an overall SMR of 1.34 (95% confidence interval (CI) 1. 16-1.55, P=0.001). High excess mortality occurred in males between age 40 and 54 (SMR 2.34, 95% CI 1.60-3.31, P<0.001). The excess mortality decreased during the last decades. This change of mortality over calendar time shows that additional risk factors modulate the mortality from the disorder. The SMR of 62 families referred with premature CAD was 1.62 (95% CI 1.32-1.93, P<0.001) and the SMR was 1.10 (95% CI 0.86-1.34, P=0.4) in 51 families without premature CAD. The mortality risk of kindreds with null alleles was similar to that of kindreds with other mutations. In conclusion, the burden of the untreated disorder occurred mainly among middle-aged males and was not influenced by the type of mutation. Additional risk factors increased excess mortality significantly and are highlighted by the presence of premature CAD among first-degree relatives. This underscores the need for active identification of all hypercholesterolaemic relatives of such patients.

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