What is the low-density lipoprotein (LDL) cholesterol level that defines severe primary hypercholesterolemia?

Severe Primary Hypercholesterolemia Definition

Severe primary hypercholesterolemia is defined as an LDL cholesterol level of ≥190 mg/dL (≥4.9 mmol/L). 1

Clinical Significance and Risk

• Patients with LDL-C ≥190 mg/dL face a 30-year hazard ratio of up to 5.0 for coronary heart disease and up to 4.1 for total atherosclerotic cardiovascular disease compared to those with LDL-C <130 mg/dL. 1

• This population is at high or very high risk of clinical ASCVD due to lifetime exposure of the endothelium to markedly elevated LDL-C levels. 1

• The severe hypercholesterolemia phenotype includes all causes of marked LDL-C elevation, whether from familial hypercholesterolemia (FH), polygenic causes, or other primary etiologies. 2

Initial Diagnostic Approach

Before confirming the diagnosis of primary severe hypercholesterolemia, you must:

• Obtain a repeat lipid panel to confirm the LDL-C ≥190 mg/dL finding. 1

• Exclude secondary causes including:

  • Hypothyroidism 1
  • Chronic kidney disease 1
  • Obstructive liver disease 1
  • Nephrotic syndrome 3

• Address any identified secondary disorders before proceeding with treatment for primary hypercholesterolemia. 1

Treatment Thresholds Within Severe Hypercholesterolemia

While ≥190 mg/dL defines severe hypercholesterolemia, the guidelines establish additional treatment thresholds:

• LDL-C ≥220 mg/dL (≥5.7 mmol/L) represents an even higher risk subset where PCSK9 inhibitors may be considered if on-treatment LDL-C remains ≥130 mg/dL despite maximally tolerated statin and ezetimibe therapy. 1

• Target LDL-C <100 mg/dL is the threshold below which increased odds of clinical ASCVD is reduced in patients with familial hypercholesterolemia. 1

Age Considerations

• The definition of severe primary hypercholesterolemia (LDL-C ≥190 mg/dL) applies to patients aged 20 to 75 years for treatment recommendations. 1

• In children and adolescents ≥10 years old, severe hypercholesterolemia is defined as LDL-C persistently ≥190 mg/dL, or ≥160 mg/dL with clinical presentation consistent with FH. 1

Risk Stratification Context

• Calculating 10-year ASCVD risk is not necessary in patients with LDL-C ≥190 mg/dL, as they are automatically considered high risk requiring treatment. 1, 4

• These patients should undergo cascade screening of first-, second-, and when possible, third-degree biological relatives to detect familial forms of hypercholesterolemia. 1