From the Guidelines
Familial hyperlipidemia should be diagnosed through a combination of clinical evaluation, family history assessment, and laboratory testing, with a focus on early identification and aggressive lipid-lowering therapy to reduce cardiovascular risk, as recommended by the most recent guidance from the International Atherosclerosis Society 1.
Diagnosis and Assessment
The initial diagnosis should include a complete lipid panel measuring total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides after a 12-hour fast. For suspected familial hypercholesterolemia (FH), LDL cholesterol levels typically exceed 190 mg/dL in adults or 160 mg/dL in children with a family history. Physical examination may reveal characteristic findings such as:
- Tendon xanthomas (particularly in the Achilles tendons and extensor tendons of the hands)
- Xanthelasmas (yellowish cholesterol deposits around the eyelids)
- Arcus cornealis (white ring around the cornea) in younger patients
A detailed family history is crucial, as FH follows an autosomal dominant inheritance pattern, meaning approximately 50% of first-degree relatives will be affected.
Genetic Testing and Scoring Systems
Genetic testing can confirm the diagnosis by identifying mutations in genes such as LDLR, APOB, PCSK9, or LDLRAP1, though it's not always necessary for clinical management. The Dutch Lipid Clinic Network criteria or Simon Broome criteria are commonly used scoring systems that incorporate lipid levels, physical findings, family history, and genetic testing to establish the diagnosis.
Importance of Early Diagnosis
Early diagnosis is essential as these patients have significantly elevated cardiovascular risk and require aggressive lipid-lowering therapy, typically starting with high-intensity statins, often in combination with ezetimibe or PCSK9 inhibitors, as supported by guidelines such as the 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease 1.
Clinical Recommendations
The most recent and highest quality study recommends a systematic approach to the detection and management of patients with FH, including implementation strategies to optimize care 1. This approach emphasizes the importance of translating clinical recommendations into routine practice to achieve maximal benefit for the population at risk.
From the Research
Diagnosing Familial Hyperlipidemia
- Familial hypercholesterolemia (FH) is a common, inherited disorder of cholesterol metabolism characterized by very high plasma concentrations of low-density lipoprotein cholesterol 2.
- The diagnosis of FH is made by combining cholesterol levels and clinical characteristics of the patient, with genetic testing usually reserved for equivocal cases 2.
- Physical signs such as cutaneous lesions (tendon xanthomas or xanthelasmata) and ocular signs (corneal arcus in individuals under 45 years) can raise suspicion or lead to the diagnosis of FH 2.
- The presence of these signs should prompt the physician to request lipid tests and use clinical scores to diagnose FH 2.
Characteristics of Familial Hypercholesterolemia
- FH is characterized by a significant elevation in levels of low-density lipoprotein cholesterol (LDL-C) and patients are at very high risk for premature coronary heart disease (CHD) 3.
- The etiology of FH includes known mutations in the gene of the LDL receptor, LDLR; the gene of apolipoprotein B, apo B; and the proprotein convertase subtilisin/kexin type 9 gene, PCSK9 3.
- Small, dense LDL and elevated apolipoprotein B are common characteristics of familial combined hyperlipidemia (FCHL) 4.
Screening and Treatment of Familial Hypercholesterolemia
- Early identification and aggressive treatment of FH in individual patients, as well as screening of all first-degree relatives, are recommended to minimize the risk for premature CHD 3, 5.
- Patients with FH should receive statins as initial treatment, but may require higher doses of statins, more potent statins, statin-based combination therapy, or adjunctive therapies 3.
- Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more, with even greater target LDL cholesterol reductions necessary for FH patients with other CHD risk factors 5, 6.