What diagnostic tests are recommended for individuals with hypercholesterolemia (high cholesterol) to assess cardiovascular disease risk?

Diagnostic Testing for High Cholesterol

For individuals with high cholesterol, obtain a comprehensive fasting lipid panel including total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, and measure lipoprotein(a) at least once in every adult's lifetime. 1, 2

Essential Lipid Panel Components

Primary Measurements

• LDL-cholesterol (LDL-C) is the primary lipid measurement for screening, risk assessment, diagnosis, and treatment monitoring—this serves as the main therapeutic target 1, 2
• HDL-cholesterol (HDL-C) must be measured as it is an independent risk factor and improves identification of persons at increased cardiovascular risk 1, 2
• Total cholesterol provides baseline assessment and is used to calculate non-HDL cholesterol 2
• Triglycerides identify hypertriglyceridemia and assess need for additional therapies 1
• Non-HDL cholesterol (calculated as total cholesterol minus HDL-cholesterol) is particularly valuable in patients with elevated triglycerides, diabetes, obesity, or very low LDL-C 1, 2

Critical One-Time Measurement

• Lipoprotein(a) [Lp(a)] should be measured at least once in every adult's lifetime to identify those at very high lifetime cardiovascular risk, as levels are genetically determined and remain stable throughout life 1, 2
• This is especially important for patients with family history of premature cardiovascular disease or personal history of cardiovascular disease not explained by major risk factors 2

Fasting Requirements

• Non-fasting samples are acceptable for initial screening in most patients, as total cholesterol and HDL levels can be measured accurately without fasting 2
• A 12-hour fasting sample is required when triglycerides exceed 4.5 mmol/L (>400 mg/dL), and LDL-cholesterol should be measured using a direct assay in these cases 3, 2

Additional Testing for Suspected Familial Hypercholesterolemia

When LDL-cholesterol is severely elevated (≥190 mg/dL or ≥4.9 mmol/L), additional diagnostic steps are essential:

Confirmation Testing

• Repeat the lipid panel on a separate occasion to confirm the elevation before proceeding with further evaluation 3, 2
• Use the average of both results for risk assessment 2

Secondary Causes Evaluation

Screen for conditions that can cause secondary hypercholesterolemia 3, 2:

• Thyroid function tests (TSH, free T4) to exclude hypothyroidism
• Renal function tests (creatinine, eGFR) to exclude chronic kidney disease
• Liver function tests to exclude obstructive liver disease
• Fasting glucose or HbA1c to assess for diabetes mellitus

Genetic Testing

• Consider genetic testing using targeted next-generation sequencing of LDLR, APOB, PCSK9, and LDLRAP1 genes to confirm familial hypercholesterolemia 4, 2
• Genetic testing is the most accurate way to diagnose FH and enables cascade testing of family members 4
• Pre-test and post-test genetic counseling should be offered to all patients and at-risk relatives 4

Risk Stratification Testing

Beyond lipid measurements, comprehensive cardiovascular risk assessment requires:

• Calculate total cardiovascular risk using validated systems (SCORE in Europe, pooled cohort equations in US) for asymptomatic adults >40 years without established cardiovascular disease, diabetes, chronic kidney disease, or familial hypercholesterolemia 1
• Additional biomarkers with strongest evidence include high-sensitivity C-reactive protein (hs-CRP), coronary artery calcium (CAC) scoring, and ankle-brachial index 1
• Incorporate age, gender, diabetes status, blood pressure, family history, and smoking status into overall risk calculation 2

Monitoring After Treatment Initiation

• Follow-up lipid testing at 8 weeks to assess treatment adherence, response to therapy, and achievement of risk-based LDL-C goals 1
• Target LDL-C <70 mg/dL (<1.8 mmol/L) for very high-risk patients or <100 mg/dL (<2.6 mmol/L) for high-risk patients 1
• Adjust LDL-cholesterol values for concurrent use of statins, ezetimibe, PCSK9 inhibitors when interpreting results 2

Common Pitfalls and Caveats

• Do not use the Friedewald equation when triglycerides are elevated (>4.5 mmol/L or >400 mg/dL), as it becomes inaccurate; instead obtain a fasting sample and use direct LDL-C measurement 3
• Repeat testing after recovery from acute illness if diagnosis is uncertain, as acute illness can temporarily alter lipid levels 2
• Confirm abnormal results by repeated sampling on a separate occasion before making definitive treatment decisions 2
• A pathogenic variant may not be found in all clinically diagnosed FH cases due to polygenic hypercholesterolemia or unidentified pathogenic variants 4