Diagnosis: Familial Hypercholesterolemia (Heterozygous)
This lipid pattern—isolated elevation of LDL-C with normal triglycerides and HDL-C—is the hallmark presentation of heterozygous familial hypercholesterolemia (FH), a genetic disorder requiring immediate aggressive treatment regardless of age or presence of atherosclerosis. 1
Clinical Diagnosis
The diagnosis of FH is primarily clinical and does not require genetic testing to initiate treatment, though genetic confirmation is valuable for cascade screening of family members 2, 1:
- Use the Dutch Lipid Clinic Network or Simon Broome criteria to establish clinical diagnosis in adults, which incorporate LDL-C levels, family history of premature coronary artery disease, and physical stigmata such as tendon xanthomas 2
- LDL-C ≥190 mg/dL (≥4.9 mmol/L) in adults without secondary causes strongly suggests FH and warrants phenotypic screening of first-degree relatives 2, 3
- In children, diagnosis relies on elevated LDL-C plus positive family history of premature coronary disease or high LDL-C in at least one parent 2, 1
Critical Diagnostic Steps
Before confirming FH, you must exclude secondary causes of hypercholesterolemia 4:
- Rule out hypothyroidism, poorly controlled diabetes, nephrotic syndrome, obstructive liver disease, and medications that raise LDL-C 4
- Adjust LDL-C values if the patient is already on lipid-lowering therapy when making the phenotypic diagnosis 2, 3
- Measure lipoprotein(a) [Lp(a)] as very high Lp(a) can falsely elevate calculated LDL-C and lead to overdiagnosis of FH 2
Why This Pattern Indicates FH
The isolated LDL-C elevation with normal triglycerides and HDL-C distinguishes monogenic FH from other dyslipidemias 5:
- FH results from mutations in LDLR, APOB, or PCSK9 genes that impair hepatic LDL clearance, causing isolated LDL-C elevation from birth 1
- Normal triglycerides exclude combined hyperlipidemia and other metabolic disorders that typically elevate both LDL-C and triglycerides 4
- Normal HDL-C is typical in pure FH, though low HDL-C when present increases cardiovascular risk further 1
Genetic Testing Recommendations
While not required to start treatment, genetic testing provides definitive diagnosis and enables family screening 1, 3:
- Test for pathogenic variants in LDLR, APOB, and PCSK9 genes in the index case 1, 3
- Offer cascade genetic testing to all first-degree relatives once a pathogenic variant is identified in the proband 1, 3
- Provide pre-test and post-test genetic counseling as an integral component of testing 1
Important Caveat
A negative genetic test does not exclude FH—approximately 20% of clinically diagnosed FH cases have no identifiable mutation due to polygenic hypercholesterolemia or unidentified variants 1, 6. Treat based on the clinical phenotype.
Immediate Management Implications
All patients with this diagnosis require aggressive lifelong cholesterol-lowering therapy starting immediately 1, 7:
- Initiate high-intensity statin therapy (rosuvastatin 20-40 mg or atorvastatin 40-80 mg) as first-line treatment 2, 1
- Target LDL-C <100 mg/dL (2.6 mmol/L), or <70 mg/dL (1.8 mmol/L) if atherosclerotic cardiovascular disease is present 2, 4, 6
- Add ezetimibe if <50% LDL-C reduction or target not achieved on maximally tolerated statin 2
- Consider PCSK9 inhibitors if LDL-C remains ≥70 mg/dL despite statin plus ezetimibe 2
Common Pitfall to Avoid
Never dismiss this as "mild" hypercholesterolemia based on the absence of extremely high LDL-C or lack of xanthomas 7. Even genetically confirmed FH can present with LDL-C levels below traditional thresholds, and all FH patients have cumulative atherosclerotic burden from lifelong LDL-C elevation starting at birth 1, 7. Every 10-15 mg/dL increase in non-HDL-C corresponds to an additional year of vascular aging 1.
Screening Family Members
FH is autosomal dominant—50% of first-degree relatives are affected 1: