Introduction on Current Treatment of Familial Hypercholesterolaemia
Familial hypercholesterolaemia (FH) is an autosomal-dominant disorder associated with mutations in the LDL receptor (LDLR) gene resulting in markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous FH (HeFH) (mutation in one allele) is associated with plasma LDL-C levels >190 mg/dl, whereas homozygous FH (HoFH) (mutation in both alleles) is associated with plasma LDL-C levels >500 mg/dl.1,2 As a result, there is a 20-fold increase in risk of premature coronary heart disease (CHD) in untreated patients compared to control.3 HeFH patients usually develop CHD before age 55 and 60 respectively for men and women without treatment.4 HoFH patients, however, develop CHD very early in life and can die before age 20 without treatment.4
In general, an estimated 20 million people worldwide have FH.4 Approximately 1 in 300–500 people have HeFH and 1 in 1 million have HoFH.3 In certain populations, such as French Canadians and Dutch Afrikaners, the prevalence is as high as 1 in 100.3 Despite the high prevalence and increased risk of premature ASCVD in untreated patients, less than 1 % are diagnosed with FH worldwide.4
Family history, physical examination and a lipid profile are essential to establishing a diagnosis of FH. FH should be suspected with fasting LDL-C ≥190 mg/dl in adults and ≥160 mg/dl in children if secondary causes of hypercholesterolaemia such as hypothyroidism, nephrotic syndrome and liver disease are ruled out.2,5 The clinical diagnosis of FH can be established by five criteria: 1) the presence of early coronary artery disease (CAD) in the index case; 2) family history of premature CAD; 3) elevated LDL-C; 4) tendon xanthomas; 5) corneal arcus.2 In addition, validated clinical tools such as US Make Early Diagnosis Prevent Early Death (MEDPED), Dutch Lipid Clinic Network and Simon- Broome Registry can assist in the diagnosis of FH.5
Although genetic screening is not necessary for the diagnosis and clinical management of FH (studies report 5–20 % of FH patients are without identifiable mutation), it can augment screening strategies and help predict cardiovascular risk if a specific genetic anomaly can be identified.5,6,7 In a large Dutch cohort of nearly 30,000 individuals, finding a pathogenic LDL receptor mutation nearly tripled the cardiovascular risk for that patient (HR 3.64, CI 3.24–4.08, P<0.001).6 Data also show improved sensitivity of a genetic diagnosis compared to one based on epidemiologic LDL distributions. In a study of over 26,000 individuals in the Netherlands, an LDL above the 90th percentile provided a 68.5 % sensitivity while an LDL receptor mutation genetic screen demonstrated a sensitivity of 91.3 %.8 Once an accurate diagnosis is made of FH, cascade screening of all firstdegree relatives is paramount.