In the context of primary CAD prevention, HeFH should be suspected by an incidental discovery of elevated plasma concentrations of TC or LDL-C; a family history of premature onset of symptomatic CAD (i.e., in a first-degree male relative under the age of 55 or a first-degree female relative under the age of 60 years) or even very high test results for TC or LDL-C; and suggestive physical findings (). For secondary CAD prevention, patients in whom atherosclerotic disease developed at a young age should be carefully evaluated for HeFH.
The clinical diagnosis of HeFH typically requires a combination of evidence from family history, clinical history, physical signs and biochemical markers (, ). Diagnostic guidelines for HeFH diagnosis in patients who either are18
or are not19
part of a family with known HeFH members are shown in , and . Because of Mendel's laws, a plasma LDL-C level above a critical threshold becomes a highly specific diagnostic marker when one family member has been diagnosed with HeFH (). The diagnostic value of newer biochemical analytes, such as apo B, is promising but not yet established.
HeFH is most effectively diagnosed when a family member is already known to have HeFH. With use of molecular diagnosis as the “gold standard,” the Utah Medical Pedigrees project to Make Early Diagnoses and Prevent Early Deaths (MEDPED) for people with familial hypercholesterolemia showed that a screening test that uses plasma LDL-C limits to attain 98% specificity would detect HeFH in the general population with only 54% sensitivity.18
In contrast, the greater likelihood of a positive diagnosis with use of the same screening method (but with relatively low plasma LDL-C thresholds, compared with the diagnostic levels used for screening of the general population) in relatives of patients already known to have HeFH was highly effective:18
while specificity remained high at 98%, sensitivity improved to 88% for first-degree relatives, 85% for second-and 81% for third-degree relatives because of the greater likelihood of a positive diagnosis. The authors18
strongly recommended biochemical screening of relatives of patients found to have HeFH (an approach that has been called cascade testing)20
over other detection strategies such as population-wide LDL-C testing.
Most often, a diagnosis of HeFH in a family member has not already been made, so standard diagnostic criteria are required. The Dutch Lipid Network (DLN)2,19
() and the United Kingdom Simon Broome Register (SBR)17
() have suggested diagnostic criteria for HeFH that use various clinical, biochemical and molecular genetic attributes. More than 80% of people with a DLN score above 8 had genetic mutations; this threshold was therefore used to specify individuals with “definite” HeFH.19
The SBR guidelines required documentation of tendon xanthomas, which are very specific for HeFH but relatively insensitive, since they are not clinically apparent in about 30% of people with HeFH and often not until the fourth decade of life.17,21
Efficacy of the DLN and SBR criteria was evaluated recently in a study involving 408 Danes with HeFH.21
Molecular diagnosis revealed little difference in sensitivity and specificity between the DLN and SBR criteria (), which suggests that either approach would be helpful in clinical diagnosis (although each left much to be desired).
Routine molecular genetic testing to diagnose HeFH is unclear at this time. Civeira and associates22
recommended limiting genetic analysis to populations in which only a few LDLR
mutations account for most HeFH cases; populations in which most causative mutations are known and rapid inexpensive genetic tools have been developed; and subjects with an uncertain clinical diagnosis who are members of HeFH-affected families in which the mutation is already known. Leren and colleagues23
further suggested that with cascade testing a clinical and biochemical diagnosis might be insufficient, and that DNA testing would increase diagnostic certainty. However, this position remains controversial for many care providers, including ourselves. The potential value of genetic diagnosis of HeFH in Canada is context-dependent.
In Quebec, about 90% of patients with HeFH will have 1 of about 11 mutations (Appendix 1, www.cmaj.ca/cgi/content/full/174/8/1124/DC1
), and in some areas over 80% of patients will have 1 of 5 or fewer possible mutations.6,24–30
Furthermore, the incidence of HeFH in Quebec is about 2.5-fold higher than in the rest of Canada because of founder effects.6,27
Quebec's high incidence and prevalence of HeFH and high rate of recurrence of mutation in affected people make diagnostic DNA testing a reasonable consideration. In contrast, there are very few recurrent HeFH mutations among Ontario patients (Appendix 1, www.cmaj.ca/cgi/content/full/174/8/1124/DC1
). Screening of a person's entire LDLR
gene to detect one of many possible known or unknown mutations is more costly than a dedicated screening method designed to provide a simple positive-or-negative result for a few well-characterized LDLR
mutations. Population-based genetic findings indicate that, with current technologies, DNA-based diagnosis of HeFH cannot yet be routinely considered in Ontario patients.
Thus, in nonfounder populations, there appear to be general obstacles to the imminent use of routine diagnostic genetic testing. Perhaps fortuitously, these impediments permit us to defer the potential psychological and ethical issues that might arise from DNA analysis. Pilot studies seem to indicate that the attitudes of members of HeFH families toward genetic methods of diagnosis are generally favourable.31
However, even without DNA testing, potential issues arise from approaching relatives to detect HeFH by screening plasma LDL-C. For instance, clinical geneticists in Canada have traditionally relied on probands to contact at-risk relatives (i.e., family contact) and advise them of the need for screening. But since HeFH is potentially fatal and easily treatable, some European investigators have argued that it is acceptable, and more efficient, for a health care worker to contact relatives on behalf of the consenting proband (direct contact). HeFH family-contact programs in Norway31
and direct-contact programs in Holland32
show no apparent differences in the reactions of contacted relatives. In general, relatives believed strongly that the contact had been beneficial.