What additional tests should be ordered for a patient with elevated Low-Density Lipoprotein (LDL) cholesterol?

Additional Testing for Elevated LDL Cholesterol

For patients with elevated LDL cholesterol, you should first confirm the elevation with a repeat lipid panel, then test for secondary causes including thyroid-stimulating hormone (TSH), comprehensive metabolic panel for kidney and liver function, and consider genetic testing for familial hypercholesterolemia in specific scenarios. 1

Initial Confirmation Testing

• Repeat fasting lipid panel to confirm the elevation, as LDL-C values can vary due to biological and analytical variability 1
• The repeat panel should include total cholesterol, LDL-C, HDL-C, triglycerides, and calculated non-HDL-C 1, 2
• Two or more measurements should be obtained and averaged before making treatment decisions 1

Screening for Secondary Causes

Before diagnosing primary hypercholesterolemia, you must exclude secondary metabolic causes 1:

• Thyroid function testing (TSH) to rule out hypothyroidism 1
• Comprehensive metabolic panel including:
  • Liver function tests (ALT, AST) to exclude obstructive liver disease 1
  • Creatinine and estimated GFR to assess for chronic kidney disease 1
  • Fasting glucose or hemoglobin A1c to screen for diabetes mellitus 1

Genetic Testing Considerations

Genetic testing for familial hypercholesterolemia (FH) should be offered in the following scenarios 1:

• Children with persistent LDL-C ≥190 mg/dL or adults with persistent LDL-C ≥250 mg/dL without secondary causes, even without family history 1
• Adults with personal history of premature coronary artery disease (CAD) (men ≤55 years, women ≤65 years) and family history of hypercholesterolemia and premature CAD 1
• Children with persistent LDL-C ≥160 mg/dL when at least one parent has LDL-C ≥190 mg/dL or family history of hypercholesterolemia and premature CAD 1

Genetic testing should include analysis of LDLR, APOB, and PCSK9 genes 1. If a pathogenic variant is identified, cascade genetic testing should be offered to all at-risk family members 1.

Additional Cardiovascular Risk Assessment

Beyond lipid testing, assess for other cardiovascular risk factors 1:

• Blood pressure measurement at every visit to screen for hypertension 1
• Lipoprotein(a) testing on a single occasion for additional risk stratification, as elevated levels cannot be lowered with current oral medications but inform overall risk 1, 2
• Screening for metabolic syndrome components including waist circumference, fasting glucose, and blood pressure 1

Special Population Considerations

Children and Adolescents

• Lipid screening should be performed after optimizing glycemia in those with diabetes 1
• Screen for thyroid autoantibodies (IgA tissue transglutaminase) if type 1 diabetes is present, as thyroid dysfunction can affect lipid metabolism 1
• Consider screening for polycystic ovary syndrome in female adolescents with elevated lipids 1

Patients with Diabetes

• Perform annual lipid screening after initial diagnosis 1
• Screen for diabetic kidney disease with urine albumin-to-creatinine ratio and estimated GFR, as nephropathy affects lipid management 1

Common Pitfalls to Avoid

• Do not rely on a single lipid measurement before initiating treatment, as biological variability can lead to misclassification of cardiovascular risk 1, 3
• Do not overlook secondary causes, particularly hypothyroidism and kidney disease, which are common and treatable contributors to elevated LDL-C 1
• Do not skip lipoprotein(a) testing in patients with very high LDL-C or strong family history, as this provides important prognostic information even though it cannot be pharmacologically lowered 1, 2
• Do not assume normal total cholesterol excludes high LDL-C, as up to 14.5% of patients with total cholesterol <200 mg/dL may have elevated LDL-C or other lipid abnormalities requiring intervention 3