DIAGNOSING HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA USING NEW PRACTICAL CRITERIA VALIDATED BY MOLECULAR-GENETICS

Heterozygous familial hypercholestrolemia (FH) is a serious disorder c ausing twice normal low-density lipoprotein cholesterol levels early i n childhood and very early coronary disease in both men and women. Tre atment with multiple medications and diet can normalize cholesterol le vels in many persons with FH and prevent or delay the development of c oronary atherosclerosis. Thus, there is a need for accurate and geneti cally validated criteria for the early diagnosis of heterozygous FH. P reviously published blood cholesterol criteria greatly underdiagnosed new cases of FH among members of known families with FH in Utah and ov erdiagnosed FH among participants of general population screening reve aling the need for different cholesterol screening criteria in persons from these 2 different settings. The statistical concept of a priori probabilities was applied to derive 2 sets of practical screening crit eria: one for persons participating in general population screening st udies and another for close relatives of confirmed FH cases, showing d ramatic differences. At a cholesterol level of 310 mg/dl, only 4% of p ersons in the general population would have FH but 95% of persons who were first-degree relatives of known cases would have FH. Detailed tab les were derived to provide practical total and low-density lipoprotei n blood cholesterol screening criteria for diagnosing FH in different screening settings and specific age groups. In population screening th e new FH require a total cholesterol > 360 mg/dl for age 40+ (or 270 m g/dl in youth). Among first-degree relatives of confirmed cases in fam ilies with FH, the new total cholesterol criteria are much lower (> 29 0 mg/dl for age 40+, > 220 mg/dl for youth). These cholesterol criteri a were validated among 207 persons in 5 large FH pedigrees in whom mol ecular genetic testing established (n = 75) or ruled out (n = 132) the diagnosis of FH, revealing 98% specificity and 87% sensitivity. Becau se familial combined hyperlipidemia is frequently confused with FH, pr actical differences between these 2 disorders are listed to illustrate the need for making an accurate diagnosis of FH. When compared with t he usual guidelines in current medical textbooks, the criteria and pra ctical concepts presented in this article provide substantial improvem ent in the sensitivity of diagnosing FH in relatives of known cases an d better specificity for diagnosing FH in population screening.