What is the diagnosis for isolated elevation of low‑density lipoprotein cholesterol (LDL‑C) with normal high‑density lipoprotein cholesterol (HDL‑C) and normal triglycerides?

Diagnosis: Isolated Hypercholesterolemia (Elevated LDL-C)

The diagnosis for isolated elevation of LDL cholesterol with normal HDL cholesterol and normal triglycerides is isolated hypercholesterolemia, also termed isolated elevated LDL cholesterol. 1 This lipid pattern represents a distinct dyslipidemia phenotype that differs from the atherogenic dyslipidemia triad (elevated triglycerides, low HDL-C, elevated remnant cholesterol) commonly seen in metabolic syndrome and diabetes. 2

Diagnostic Classification

This lipid profile indicates a primary LDL-driven dyslipidemia rather than a triglyceride-rich lipoprotein disorder. 3 The key distinguishing features are:

• Elevated LDL-C as the sole lipid abnormality 1
• Normal HDL-C (≥40 mg/dL in men, ≥46 mg/dL in women) 2
• Normal triglycerides (<150 mg/dL) 3, 2
• Normal calculated remnant cholesterol (total cholesterol minus LDL-C minus HDL-C) 3

Differential Diagnosis Considerations

When evaluating isolated LDL elevation, consider these specific etiologies:

Primary (Genetic) Causes

• Familial hypercholesterolemia (FH) - particularly if LDL-C ≥190 mg/dL, family history of premature cardiovascular disease, or physical findings like tendon xanthomas 3
• Polygenic hypercholesterolemia - more common, typically LDL-C 130-189 mg/dL 1

Secondary Causes to Exclude

• Hypothyroidism - check TSH 1, 4
• Nephrotic syndrome - check urinalysis, plasma creatinine, protein electrophoresis 3, 1
• Cholestatic liver disease - check alkaline phosphatase and transaminases 1
• Medications - retinoic acid, oral contraceptives, anticonvulsants 3

Clinical Significance and Risk Stratification

This lipid pattern indicates LDL-mediated atherosclerotic risk without the additional metabolic syndrome features. 3, 2 The absence of elevated triglycerides and low HDL-C means:

• No evidence of insulin resistance-related dyslipidemia 3, 2
• Lower likelihood of metabolic syndrome (which requires triglycerides ≥150 mg/dL or HDL-C <40 mg/dL in men) 5
• Primary focus should be LDL-C reduction as the sole lipid-driven cardiovascular risk factor 3, 5

Diagnostic Workup

Initial Laboratory Assessment

• Fasting lipid panel (total cholesterol, triglycerides, HDL-C, calculated LDL-C) - confirm with repeat measurement in 4-12 weeks 3
• Secondary cause screening: TSH, fasting glucose, creatinine, urinalysis, liver enzymes 1, 4
• Consider lipoprotein(a) measurement if premature cardiovascular disease, family history of premature CVD, or recurrent events despite optimal LDL lowering 3

When to Consider Advanced Testing

• Apolipoprotein B-100 may be useful in young patients with coronary artery disease and borderline LDL-C 1
• Genetic testing for FH if LDL-C ≥190 mg/dL or strong family history 3

Treatment Implications

The treatment target is absolute LDL-C reduction based on cardiovascular risk category, not lipid ratios. 3, 5 Specific LDL-C goals:

• Very high-risk patients (documented CVD, diabetes with target organ damage): LDL-C <70 mg/dL (1.8 mmol/L) 5
• High-risk patients: LDL-C <100 mg/dL (2.6 mmol/L) 5
• Moderate-risk patients: individualized based on 10-year cardiovascular risk assessment 3

Statin therapy is first-line pharmacologic treatment for isolated hypercholesterolemia, with intensity based on required LDL-C reduction. 3, 6, 4 High-intensity statins achieve approximately 50% LDL-C reduction, while moderate-intensity statins achieve 30-50% reduction. 3

Common Pitfalls to Avoid

• Do not use LDL/HDL ratios as treatment targets - focus on absolute LDL-C goals based on cardiovascular risk category 5
• Do not overlook secondary causes - always screen for hypothyroidism, kidney disease, and medication effects before diagnosing primary hypercholesterolemia 1
• Do not assume low cardiovascular risk - isolated LDL elevation still confers significant atherosclerotic risk requiring treatment 7
• Ensure fasting status - while total cholesterol can be measured non-fasting, a complete fasting lipid profile provides more accurate LDL-C calculation when triglycerides are in normal range 3, 2