A suggestion for familial hypercholesterolemia (FH) heterozygosity clinical diagnosis based on epidemiological observations in a large Italian population

We selected 247 subjects from 29 large familial hypercholesterolemia (FH) kindreds from 550 probable FH subjects in Emilia Romagna (Italy) on the basis of LDL-cholesterol plasmatic levels and family trees, in order to define the best diagnostic criteria for heterozygous patients. Familial hypercholesterolemia is a monogenic disease of cholesterol metabolism inherited as an autosomal dominant trait and characterised by early cardiovascular disease. A low xanthomas and xanthelasmas prevalence was found (8.6%); coronary heart disease (CHD) death occurs very frequently in heterozygous males (72% of all deaths; mean age at death 52 years), while in females the primary cause of death was thrombotic stroke (55%; mean age 69 years). Total cholesterol (TC) mean values were 389.8 (m) and 373.3 mg/dl (f) for FH trait carriers, and 223.3 (m) and 228.8 (f) for healthy relatives. No age-related change in TC was found in heterozygotes, while unaffected relatives of FH families showed mean TC and LDL-C values, and a TC frequency distribution and a TC age-related increasing trend similar to the expected values for the Italian population. The TC frequency distribution curve appeared bimodal, with a mid-point between heterozygous and homozygous FH modal values of 280 mg/dl. To identify the FH patients, the final FH heterozygosity risk was evaluated in an unselected free-living population (from 0.07 to 0.8%, respectively, for TC between 265–274 and 295–304 mg/dl) and in hypercholesterolemic families (31 to 83%, and the same TC classes). Our conclusion is that the clinical picture is rarely pathognomonic, while the FH heterozygosity final risk evaluation and the 280 mg/dl cut-off point can be used to guide the practical clinical diagnosis and to select the patients destined for B-E receptor activity evaluation.