Familial hypercholesterolemia

A patient (often a child or young adult) identified through extremely elevated LDL-C, premature coronary disease, characteristic physical findings (tendon xanthomas, corneal arcus before age 45), or a family history of early MI. Familial hypercholesterolemia is the most common autosomal-dominant monogenic disorder in humans (heterozygous prevalence ~1:250 globally) and the most underdiagnosed: an estimated 90% of cases are unrecognized at the time of first cardiac event. The clinical job is to identify the proband, confirm the diagnosis, start a statin (yes, in children), and cascade-test every first-degree relative.

Three questions structure the work-up:

1. Heterozygous (HeFH) or homozygous (HoFH)? HeFH is common (~1:250) and has a treatable LDL of 190-400 mg/dL. HoFH is rare (~1:160,000 to 1:300,000), severe (LDL > 500 mg/dL), and presents with cutaneous and tendon xanthomas in infancy plus coronary disease in childhood; needs LDL apheresis plus advanced therapies (lomitapide, evinacumab).
2. Which gene? LDLR accounts for 85-90% of FH; APOB for 5-10% (defective ligand for the LDL receptor); PCSK9 gain-of-function variants are rare. The phenotype is nearly identical across the three; the gene matters for cascade testing of relatives.
3. Monogenic or polygenic hypercholesterolemia? Polygenic hypercholesterolemia (many small-effect variants summing to a high LDL) is much more common but lacks the same urgency and cardiovascular risk gradient. Genetic testing distinguishes them.

Monogenic dyslipidemia (the high-yield differential)

• Heterozygous FH (LDLR, APOB, PCSK9; AD): the dominant phenotype. LDL-C > 190 mg/dL in an adult or > 160 mg/dL in a child + family history of premature CAD + tendon xanthomas or arcus before age 45. Lifetime risk of CAD without treatment is dramatically elevated (first MI in men in 30s-40s, women in 40s-50s); on statins the risk approaches baseline.
• Homozygous FH (biallelic LDLR, APOB, PCSK9; AR pattern from two HeFH parents): LDL-C > 500 mg/dL untreated. Cutaneous xanthomas on hands, knees, buttocks in infancy. Aortic stenosis from cholesterol deposition. CAD in childhood. Needs LDL apheresis + statin + ezetimibe + PCSK9 inhibitor + lomitapide + evinacumab (ANGPTL3 inhibitor, approved for HoFH). Liver transplant is curative.
• Sitosterolemia (ABCG5, ABCG8; AR): looks like FH (xanthomas, premature CAD) but is plant-sterol accumulation rather than cholesterol. Elevated plasma sitosterol and campesterol confirm. Treatable with ezetimibe (blocks the sterol absorber NPC1L1) and a low-sterol diet. Don't miss it because statins alone don't fix it.
• Lysosomal acid lipase deficiency / cholesteryl ester storage disease (CESD) (LIPA, AR): hepatomegaly + elevated transaminases + hyperlipidemia + premature atherosclerosis. Treatable with sebelipase alfa (ERT). Severe infantile form is Wolman disease.
• Tangier disease (ABCA1, AR): low HDL (often near zero) + orange tonsils + peripheral neuropathy + corneal opacities + premature CAD.

Polygenic and acquired

• Polygenic hypercholesterolemia: many small-effect variants; usually milder LDL elevation (180-250 mg/dL); no monogenic test result; family pattern not strictly AD. Common, less urgent, statins still indicated for risk reduction.
• Secondary causes: hypothyroidism, nephrotic syndrome, cholestatic liver disease, anorexia, certain drugs (steroids, retinoids, antiretrovirals). Rule out before settling on a genetic diagnosis.

1. Fasting lipid panel with LDL-C (directly measured if triglycerides > 400). Apolipoprotein B refines the diagnosis.
2. Lipoprotein(a) at least once in every FH patient (genetically determined cardiovascular risk modifier independent of LDL).
3. Rule out secondary causes: TSH, urinalysis (proteinuria), creatinine, LFTs.
4. Three-generation pedigree focused on early MI (men < 55, women < 65), early stroke, sudden cardiac death, premature CAD.
5. FH gene panel (LDLR, APOB, PCSK9; many panels also include LDLRAP1 for AR FH). A negative panel in a clinically diagnosed patient is still actionable; treat to LDL goal.
6. Cascade screening of first-degree relatives: lipid panel + targeted variant testing once the proband's variant is known. This is the single highest-impact intervention in FH care.
7. Statin in children with FH starting age 8-10 (rosuvastatin, atorvastatin, pravastatin have pediatric data); ezetimibe added if not at goal; PCSK9 inhibitor for refractory cases.
8. For suspected HoFH: LDL apheresis evaluation, evinacumab + lomitapide referral, cardiac surveillance starting in childhood, hepatology consult.