What labs should be considered when a patient has hypercholesterolemia?

Laboratory Evaluation for Hypercholesterolemia

When a patient presents with high cholesterol, obtain a fasting lipid profile that includes total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides, and measure lipoprotein(a) at least once. 1, 2

Primary Lipid Panel

The essential laboratory tests for evaluating hypercholesterolemia include:

• Total cholesterol and HDL-cholesterol are recommended as the minimum screening tests, with good evidence that measuring HDL along with total cholesterol improves identification of persons at increased cardiovascular risk 1
• LDL-cholesterol is the primary lipid analysis for screening, risk estimation, diagnosis, and management, and serves as the primary target of lipid-lowering therapies 1, 3
• Triglycerides should be measured as part of the complete lipid panel, though evidence for routine triglyceride screening remains insufficient according to older guidelines 1
• Non-HDL cholesterol (calculated as total cholesterol minus HDL-cholesterol) should be calculated and used as a secondary therapeutic target, particularly in patients with mild-to-moderate hypertriglyceridemia (2-10 mmol/L or 175-880 mg/dL) 1, 3

Fasting vs Non-Fasting Samples

Non-fasting samples are acceptable for initial screening in most patients, as total cholesterol and HDL levels can be measured on either fasting or non-fasting samples 1. However, specific situations require fasting samples:

• Obtain a 12-hour fasting sample when triglycerides exceed 4.5 mmol/L (>400 mg/dL) and measure LDL-cholesterol using a direct assay 1, 2
• Fasting samples are necessary when calculating LDL-cholesterol using the Friedewald equation, as hypertriglyceridemia interferes with accurate calculation 1, 2

Lipoprotein(a) Testing

Measure lipoprotein(a) at least once in all patients at cardiovascular risk, including those with a family history of premature atherosclerotic cardiovascular disease or personal history of cardiovascular disease not explained by major risk factors 2, 3. This single measurement is important because:

• Lipoprotein(a) is included in LDL-cholesterol measurements and can explain poor response to statin treatment 3
• Elevated lipoprotein(a) cannot be lowered with currently available oral medications 4

Additional Testing for Suspected Familial Hypercholesterolemia

When LDL-cholesterol is severely elevated (≥190 mg/dL or ≥4.9 mmol/L), additional workup is necessary:

• Repeat the lipid panel to confirm the elevation 1
• Test for secondary causes including thyroid function tests (TSH, free T4) for hypothyroidism, renal function tests (creatinine, eGFR) for chronic kidney disease, and liver function tests for obstructive liver disease 1
• Consider genetic testing using targeted next-generation sequencing of LDLR, APOB, PCSK9, and LDLRAP1 genes to confirm familial hypercholesterolemia 1, 5
• Measure apolipoprotein B as it may be useful in certain circumstances, particularly in patients with hypertriglyceridemia, providing an estimate of atherogenic lipoprotein particles 2, 3

Confirmation and Follow-up Testing

Abnormal results should be confirmed by a repeated sample on a separate occasion, and the average of both results should be used for risk assessment 1. This is critical because:

• Biological variation and measurement errors can affect single measurements 6
• Treatment decisions are based on confirmed lipid values rather than isolated measurements 1

Important Caveats

Several factors can affect lipid measurements and must be accounted for:

• Adjust LDL-cholesterol values for concurrent use of statins, ezetimibe, PCSK9 inhibitors, and other lipid-lowering therapies when interpreting results 1, 2
• Repeat testing after recovery from acute illness if the diagnosis is uncertain, as acute illness can temporarily alter lipid levels 1, 2
• The Friedewald equation should be used with caution due to the confounding effect of hypertriglyceridemia on LDL-cholesterol estimation 1, 2
• Direct LDL-cholesterol assays are preferred when triglycerides are very elevated (>4.5 mmol/L or >400 mg/dL) 1, 2

Risk Assessment Integration

The lipid panel results should be integrated with overall cardiovascular risk assessment:

• Include age, gender, diabetes status, blood pressure, family history, and smoking status in the overall risk calculation 1
• Tools that incorporate specific information on multiple risk factors provide more accurate cardiovascular risk estimation than simply counting risk factors 1
• Treatment decisions should consider overall cardiovascular risk rather than lipid levels alone 1