The diagnosis of familial dyslipidemia is based on diagnostic algorithms that include biochemical, clinical, and anamnestic criteria.
First, since familial forms are characterized by elevated lipid levels, in adults, the finding, at least once, of a total cholesterol value >250 mg/dL and/or triglycerides >250 mg/ dL may lead to the diagnostic suspicion of familial dyslipidemia (Table 1). It is, therefore, necessary to evaluate the complete lipid profile following a period of adequate diet, reduction of any excess weight, and regular physical activity. In addition, it is necessary to evaluate family history (early cardiovascular events and dyslipidemia), complete physical examination aimed at searching for xanthomas, xanthelasmas, corneal arch and retinalis lipemia, and the exclusion of secondary forms by appropriate laboratory investigations, which include the evaluation of TSH, renal and hepatic function, and fasting blood glucose. Then, it will be possible to evaluate the diagnosis of a familial form of dyslipidemia.
Table1. Main primary dyslipidemias classified according to the lipid alteration
Familial Hypercholesterolemia
Heterozygous Familial Hypercholesterolemia
The diagnostic pathway is quite complex, and it is generally based on the criteria of the Dutch Lipid Clinic Network (Table 14.11).
Table2. Criteria of Dutch Lipid Clinic Network for heterozygous familial hypercholesterolemia diagnosis
Homozygous Familial Hypercholesterolemia It is a much rare and severe condition. The diagnosis is made based on the finding of:
–TC ≥ 13 mmol/L (≥500 mg/dL) –Early clinical manifestations (around 10 years of age), which include xanthomas in the tendons of the hands and Achilles tendons
–Premature cardiovascular disease, as early as the first 10 years of age. The diagnosis is usually made in child hood. Early identification of affected children and immediate referral to a specialized center are crucial. Patients should be treated with cholesterol-lowering drugs and, when possible, lipoprotein apheresis.
Combined Familial Hyperlipidemia
It represents an important cause of premature coronary artery disease. It is a complex disease whose phenotype is determined by the interaction among several susceptibility genes and environmental factors. It is characterized by a high phenotypic variability, both inter- and intraindividual based on lipid values (TG, C-LDL, C-HDL, and ApoB). Consequently, it is often misrecognized in clinical practice.
The diagnosis is made following the finding of:
– C-LDL ≥4.15 mmol/L (≥160 mg/dL) and/or triglyceridemia ≥2.25 mmol/L (≥200 mg/dL)
– Documentation of hypercholesterolemia and/or hypertriglyceridemia (multiple phenotypes) in the proband’s first- and second-degree relatives, often with phenotypic variability over time (transition from hypercholesterolemia to hypertriglyceridemia, or to mixed forms).
In the absence of documentation on family members, dyslipidemia is strongly suspected in the presence of an anamnestic or clinical or instrumental diagnosis of early atherosclerosis.
It is essential to exclude families in which only hypercholesterolemia or hypertriglyceridemia is present.
Familial Dysbetalipoproteinemia
It is a very rare disease occurring in homozygous for the E2 isoform of ApoE. However, not all subjects with E2/E2 genotype manifest the disease.
The diagnosis is based on the following criteria:
• Cholesterol and triglyceridemia around 400–500 mg/dL
• Presence on electrophoresis of the broad beta band due to the fusion of VLDL and LDL
• The presence of any of the following factors increases the validity of the diagnosis:
– Tuberous xanthomas
– Palmar striated xanthomas (yellowish striae in the interdigital folds or on the palmar surface of the hands, to be considered very specific)
Familial Hypertriglyceridemia
The diagnosis is based on the detection of elevated plasma triglyceride levels (TG > 400 mg/dL) in the patient and in at least one first-degree relative, and the exclusion of secondary forms.
