What is the diagnostic approach for hyperlipidemia?

Diagnosing Hyperlipidemia: A Systematic Approach

The diagnosis of hyperlipidemia should be based on fasting serum lipid levels, including total cholesterol, LDL-C, HDL-C, and triglycerides, with specific cutoff values defining different types and severities of lipid disorders. 1

Initial Laboratory Assessment

• Baseline lipid panel should include:

  • Total cholesterol (TC)
  • Triglycerides (TG)
  • High-density lipoprotein cholesterol (HDL-C)
  • Low-density lipoprotein cholesterol (LDL-C)
  • Non-HDL-C
  • TC/HDL-C ratio 1

• Fasting vs. non-fasting:

  • Fasting samples (12 hours) are preferred for initial diagnosis
  • Non-fasting samples may be considered for screening but have limitations
  • Fasting is particularly important for accurate triglyceride assessment 1

• LDL-C calculation:

  • Calculate using the Friedewald formula: LDL-C = TC - HDL-C - TG/2.2 (mmol/L) or LDL-C = TC - HDL-C - TG/5 (mg/dL)
  • Valid only when TG < 4.5 mmol/L (< 400 mg/dL)
  • For patients with TG > 4.5 mmol/L, direct LDL-C measurement is required 1

Diagnostic Criteria and Classification

Hypercholesterolemia

• LDL-C levels:
  • Borderline high: 130-159 mg/dL (3.4-4.1 mmol/L)
  • High: 160-189 mg/dL (4.1-4.9 mmol/L)
  • Very high: ≥190 mg/dL (≥4.9 mmol/L) 1

Hypertriglyceridemia

• Triglyceride levels (per Endocrine Society):
  • Mild: 150-199 mg/dL (1.7-2.3 mmol/L)
  • Moderate: 200-999 mg/dL (2.3-11.3 mmol/L)
  • Severe: 1,000-1,999 mg/dL (11.3-22.6 mmol/L)
  • Very severe: ≥2,000 mg/dL (≥22.6 mmol/L) 1

Low HDL-C

• Men: <40 mg/dL (<1.0 mmol/L)
• Women: <50 mg/dL (<1.3 mmol/L) 2

Evaluation for Secondary Causes

Always evaluate for secondary causes of hyperlipidemia before confirming primary hyperlipidemia. Common secondary causes include:

• Metabolic conditions:

  • Diabetes mellitus (uncontrolled)
  • Hypothyroidism
  • Obesity
  • Metabolic syndrome

• Lifestyle factors:

  • Excessive alcohol intake
  • Physical inactivity
  • Diet high in saturated fats or simple carbohydrates

• Medical conditions:

  • Renal disease (nephrotic syndrome, chronic kidney disease)
  • Liver disease (cholestasis, primary biliary cirrhosis)
  • Pregnancy
  • Autoimmune disorders

• Medications:

  • Thiazide diuretics
  • Beta-blockers
  • Estrogens
  • Corticosteroids
  • Isotretinoin
  • Antiretroviral protease inhibitors
  • Immunosuppressants
  • Antipsychotics 1

Screening for Familial Hypercholesterolemia (FH)

Consider FH in patients with:

• Very high LDL-C levels (≥190 mg/dL or ≥4.9 mmol/L)
• Family history of premature cardiovascular disease
• Physical findings such as:
  • Tendon xanthomas (especially Achilles tendons and extensor tendons of hands)
  • Xanthelasmas
  • Premature arcus cornealis 3

Diagnostic criteria for FH include:

• Dutch Lipid Clinic Network criteria
• Simon Broome criteria
• US MED-PED criteria 3

Genetic testing for pathogenic variants in LDLR, APOB, or PCSK9 genes is the gold standard for FH diagnosis 3

Special Considerations

1. In patients with hypertriglyceridemia >4.5 mmol/L (>400 mg/dL):

   • Use direct LDL-C measurement methods instead of the Friedewald formula
   • Re-screen with a 12-hour fasting sample 1

2. In patients on lipid-lowering therapy:

   • Adjust LDL-C values to account for treatment effects
   • For statins: multiply LDL-C by 1.43 (for moderate intensity) or 1.67 (for high intensity)
   • For ezetimibe: multiply LDL-C by 1.18
   • For PCSK9 inhibitors: multiply LDL-C by 2.0 3

3. In children and adolescents:

   • Screen children with family history of FH or premature CVD as early as age 2
   • For children without risk factors, consider screening once between ages 9-11 and again between 17-21 1

Common Pitfalls to Avoid

1. Failure to obtain fasting samples for triglyceride assessment

   • Non-fasting samples can lead to overestimation of triglycerides and underestimation of LDL-C

2. Relying solely on total cholesterol

   • Total cholesterol alone can be misleading, especially in women with high HDL-C or in patients with metabolic syndrome who often have low HDL-C 1

3. Not accounting for medication effects

   • Failure to adjust LDL-C values for patients already on lipid-lowering therapy can lead to missed diagnoses of FH 3

4. Overlooking secondary causes

   • Always evaluate and treat secondary causes before confirming primary hyperlipidemia diagnosis 1

5. Missing familial disorders

   • Consider cascade screening of family members when diagnosing severe hyperlipidemia or FH 3

By following this systematic approach to diagnosing hyperlipidemia, clinicians can accurately identify the type and severity of lipid disorders, determine whether they are primary or secondary, and guide appropriate treatment decisions to reduce cardiovascular risk.