Table 1
Selected conditions associated with marked low-density lipoprotein cholesterol elevation. TSH: thyroid-stimulating hormone
| CONDITION | SCREENING |
|---|---|
| Hypothyroidism | TSH, T4, T3 |
| Nephrotic syndrome | Urinary protein |
| Biliary cirrhosis | Liver function tests |
| Ketogenic diet | History |
Rare genetic disorders
| Specialized genetic testing (referral) ABCG5/8 gene complex CYP27A1 LIPA ALB |
Figure 1
Simplified algorithm for the diagnosis of familial hypercholesterolemia (FH). Modified from Ruel 2018 and Ahmad 2026.7
Figure 2
LDL receptor-mediated uptake of low-density lipoprotein (LDL) particles and PCSK9-mediated LDL receptor degradation. Pathogenic variants in LDLR, APOB, PCSK9, and LDLRAP1 cause familial hypercholesterolemia. Modified with permission from Awan et al.
Table 2
Genetic basis for FH (modified from Ahmad 20267). LDLR: low-density lipoprotein receptor; FH: familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol
| GENE | MODE OF INHERITANCE | PERCENT OF FH CASES | |
|---|---|---|---|
| LDLR | Autosomal semi-dominant | ~85%–90% | Over 2,000 variants identified. Reduce LDLR function (null or defective alleles). Clinical severity varies by mutation type |
| APOB | Autosomal semi-dominant | ~5%–10% | Impair binding of LDL particles to LDLR. Milder phenotype than LDLR mutations |
| PCSK9 | Autosomal semi-dominant | 1%–3% | Gain-of-function mutations increase LDLR degradation |
| LDLRAP1 | Autosomal recessive | Rare | LDLR endocytosis is defective |
| Polygenic hypercholesterolemia | Cumulative effect of multiple genes causing small elevations in LDL-C | ~30–40% of clinically diagnosed FH | Non-Mendelian inheritance |
Figure 3
Continuum of cardiovascular risk across LDL-C levels. A population distribution curve for LDL-C in adults is shown in blue, with the 95th percentile at 190 mg/dL. Increasing severity of the FH phenotype increases ASCVD risk. LDL-C: low-density lipoprotein cholesterol; ASCVD: atherosclerotic cardiovascular disease; FH: familial hypercholesterolemia; HeFH: heterozygous FH; HoFH: homozygous FH; HyperChol: hypercholesterolemia; LDL PGS: low-density lipoprotein polygenic score