Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics

Abstract

Heterozygous familial hyperchotesterolemia (FH) is a serious disorder causing twice normal lowdensity lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications and diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. Previously published blood cholesterol criteria greatly underdiagnosed new cases of FH among members of known families with FH in Utah and overdiagnosed FH among participants of general population screening, revealing 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 criteria: one for persons participating in general population screening studies and another for close relatives of confirmed FH cases, showing dramatic differences. At a cholesterol level of 310 mg/dl, only 4% of persons in the general population would have FH but 95% of persons who were first-degree relatives of known cases would have FH. Detailed tables were derived to provide practical total and tow-density lipoprotein blood cholesterol screening criteria for diagnosing FH in different screening settings and specific age groups. In population screening the new FH criteria require a total cholesterol >360 mg/dl for age 40+ (or 270 mg/dl in youth). Among first-degree relatives of confirmed cases in families with FH, the new total cholesterol criteria are much tower (>290 mg/dl for age 40+, >220 mg/dl for youth). These cholesterol criteria were validated among 207 persons in 5 large FH pedigrees in whom molecular genetic testing established (n = 75) or ruled out (n = 132) the diagnosis of FH, revealing 98% specificity and 87% sensitivity. Because familial combined hyperlipidemia is frequently confused with FH, practical differences between these 2 disorders are listed to illustrate the need for making an accurate diagnosis of FH. When compared with the usual guidelines in current medical textbooks, the criteria and practical concepts presented in this article provide substantial improvement in the sensitivity of diagnosing FH in relatives of known cases and better specificity for diagnosing FH in population screening.