Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia

Life expectancy of patients with familial hypercholesterolaemia is decrease d. Some untreated patients reach a normal life span and, therefore, additio nal risk factors and the type of mutation in the low-density lipoprotein (L DL) receptor gene are likely to influence the clinical outcome. We determin ed all cause mortality in kindreds with the disorder, who were untreated, i n order to study (a) additional risk factors for coronary artery disease (C AD) 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 u nrelated patients was compared to the Dutch population after standardisatio n for age, gender, and calendar period. Analyses restricted to affected rel atives could have underestimated the mortality risk due to lack of informat ion about severe cases, who died prematurely. Therefore, all first-degree r elatives were analysed and as a result the standardised mortality ratios (S MRs) exhibit only 50% of the excess mortality from familial hypercholestero laemia. 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 exces s 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. T his change of mortality over calendar time shows that additional risk facto rs modulate the mortality from the disorder. The SMR of 62 families referre d 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 m ortality 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 significant ly and are highlighted by the presence of premature CAD among first-degree relatives. This underscores the need for active identification of all hyper cholesterolaemic relatives of such patients. (C) 2000 Elsevier Science Irel and Ltd. All rights reserved.