What lab tests are used to diagnose familial hyperlipidemia?

Laboratory Tests for Diagnosing Familial Hyperlipidemia

The primary laboratory test for diagnosing familial hyperlipidemia is LDL-cholesterol measurement, with levels >4.9 mmol/L (≥190 mg/dL) warranting further evaluation for familial hypercholesterolemia (FH). 1

Core Diagnostic Tests

• LDL-cholesterol measurement is the cornerstone test for FH diagnosis, with age-specific, sex-specific and country-specific LDL-cholesterol concentrations above the 95th percentile used to screen for index cases 1
• Fasting lipid profile including total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides is recommended for initial evaluation in adults with a family history of premature ASCVD or suspected genetic hyperlipidemia 1
• Non-fasting samples may be considered when screening for FH, though the Friedewald equation should be used with caution due to the confounding effect of hypertriglyceridemia 1
• Direct LDL-cholesterol assay should be used in patients with hypertriglyceridemia >4.5 mmol/L (>400 mg/dL) in whom FH is strongly suspected 1

Genetic Testing

• Genetic testing is the most accurate way to diagnose FH, identifying pathogenic variants in genes that impair LDL receptor function 1
• Cascade genetic testing should be offered to all first-degree relatives of an index case with definite FH, followed by second-degree and third-degree relatives 1
• Known familial variant testing should be initially offered to all first-degree relatives of a proband with an identified mutation 1
• Genes commonly tested include LDL receptor (most common), apolipoprotein B, proprotein convertase subtilisin/kexin 9 (PCSK9), and low-density lipoprotein receptor adaptor protein (LDLRAP) 2

Additional Tests

• Apolipoprotein B (apoB) measurement may be useful in certain circumstances, particularly in patients with hypertriglyceridemia, as it provides an estimate of the number of atherogenic lipoprotein particles 1, 3
• Lipoprotein(a) [Lp(a)] testing should be considered in those with a family history of premature ASCVD or personal history of ASCVD not explained by major risk factors 1
• Small dense LDL assessment may be helpful in distinguishing familial combined hyperlipidemia (FCH), as these patients show persistently lower values of parameter K, reflecting small dense LDL 4

Special Considerations

• Adjustment for medications is necessary when phenotypically screening for FH; LDL-cholesterol concentrations should be adjusted for the use of statins, ezetimibe, PCSK9 inhibitors and other therapies 1
• Repeat testing after recovery from acute illness is recommended if the diagnosis of FH is in doubt 1
• For children with suspected homozygous FH (HoFH), testing should be done as early as possible (at newborn stage or by 2 years of age) 1
• For children at risk of heterozygous FH (HeFH), screening should be considered using LDL-cholesterol at or after age 5, or as early as age 2 in those with strong family history of premature ASCVD 1

Diagnostic Algorithms

• Multiple screening strategies (selective, opportunistic, and/or universal) should be used to detect index cases with FH 1
• Selective screening should target adults with premature ASCVD and a family history of premature ASCVD and/or hypercholesterolemia 1
• Opportunistic screening using LDL-cholesterol >4.9 mmol/L (≥190 mg/dL) should be used to detect cases in the community 1
• Universal screening using age-specific and sex-specific criteria for LDL-cholesterol should be considered for children and adolescents 1

Common Pitfalls and Caveats

• Hypertriglyceridemia can interfere with LDL-cholesterol calculation using the Friedewald formula; direct LDL-cholesterol measurement is recommended when triglycerides exceed 4.5 mmol/L (400 mg/dL) 1, 5
• Mixed hyperlipidemia can mask underlying FH; patients with very high total and LDL-cholesterol with moderately elevated triglycerides may have FH with a secondary cause of hypertriglyceridemia 5
• Clinical criteria alone are insufficient to distinguish between genetic and environmental dyslipidemia; molecular diagnosis is necessary for definitive identification 6
• Apolipoprotein measurements remain accurate in non-fasting states but carry extra expense and may not be reliable in all laboratories 1, 3