US (MEDPED) Criteria for Familial Hypercholesterolemia

Why use it

Familial hypercholesterolemia is a dominant inherited condition causing lifelong extremely high LDL-C from birth, resulting in up to 20-fold increased risk of premature coronary artery disease. Untreated, men with heterozygous FH have a ~50% chance of a coronary event by age 50, and women by age 60. Early diagnosis and treatment with high-intensity statins (and PCSK9 inhibitors when needed) markedly reduces this excess risk — potentially normalizing it with early treatment initiation. The MEDPED criteria provide the simplest validated diagnostic approach requiring only a total cholesterol and family history, making it suitable for primary care, cascade screening programs, and resource-limited settings where LDL-C measurement or genetic testing is unavailable.

About

The US MEDPED (Make Early Diagnosis to Prevent Early Deaths) criteria for familial hypercholesterolemia (FH) were developed by Williams and colleagues at the University of Utah and published in the Journal of the American Medical Association in 1993. MEDPED provides a simple, total-cholesterol-based diagnostic framework that adjusts the diagnostic threshold based on two independent factors: the patient's age and the degree of family relationship to a known FH-affected individual. The logic is straightforward — the closer the family relationship to a confirmed FH patient, the lower the total cholesterol threshold required for diagnosis, because the prior probability of FH is much higher. Six age categories and four family relationship categories create a matrix of 16 diagnostic thresholds (ranging from 220 mg/dL for a first-degree relative under age 20 to 360 mg/dL for the general population aged ≥40). A total cholesterol at or above the age- and relationship-specific threshold yields a presumptive diagnosis of FH. The MEDPED program uses a population-based cascade screening approach — systematically testing relatives of identified probands — which has been implemented in over 40 countries and has identified hundreds of thousands of FH patients who would otherwise be undiagnosed. FH is the most common serious inherited disorder in humans, affecting approximately 1 in 200–500 individuals in the heterozygous form worldwide (previously estimated at 1 in 500, revised upward in recent large population studies). Despite its frequency, an estimated 80–90% of patients with FH remain undiagnosed globally.

When to use

• Adults and children with unexplained markedly elevated total cholesterol or LDL-C (especially LDL-C >190 mg/dL in adults, >160 mg/dL in children)
• Cascade screening of first- and second-degree relatives of a confirmed FH proband
• Patients with premature cardiovascular disease (men <55 years, women <60 years) or family history of premature ASCVD
• Patients with physical stigmata of FH: tendon xanthomas (virtually pathognomonic), corneal arcus in patients under 45, xanthelasma
• Screening in populations with known FH founder effects (Afrikaner, French-Canadian, Lebanese-Christian, Finnish, South African Indian, Dutch)
• Resource-limited settings where Dutch Lipid Clinic Network (DLCN) or Simon Broome criteria requiring LDL-C are not available
• NOT a replacement for LDL-C-based criteria (DLCN or Simon Broome) when LDL-C is available — LDL-C is more specific than total cholesterol for FH diagnosis
• NOT applicable in secondary hypercholesterolemia (hypothyroidism, nephrotic syndrome, obstructive liver disease, medications) — exclude these causes first

Formula

Pearls & pitfalls

• The MEDPED threshold for a FIRST-DEGREE RELATIVE under age 20 is only 220 mg/dL total cholesterol — this is a relatively low threshold designed to maximize sensitivity, as a child of an FH parent has a 50% prior probability of having inherited the mutation.
• The MEDPED criteria use TOTAL cholesterol, not LDL-C — this is both a strength (no fasting required, widely available) and a limitation (less specific than LDL-C-based criteria). In patients with high triglycerides or low HDL, total cholesterol overestimates LDL contribution.
• A total cholesterol >300 mg/dL in an adult is virtually always clinically significant and warrants full FH evaluation regardless of family history — homozygous FH (total cholesterol 400–1000 mg/dL) must not be missed.
• MEDPED criteria alone do NOT confer the FH diagnosis in isolation — they should be used together with LDL-C-based criteria (Dutch Lipid Clinic Network, Simon Broome) and genetic testing when available. DLCN score ≥6 (probable FH) or ≥8 (definite FH) is considered the gold standard clinical diagnostic approach.
• Tendon xanthomas (most commonly of the Achilles tendon) are PATHOGNOMONIC for FH — their presence virtually confirms the diagnosis regardless of cholesterol level. Examine the Achilles tendons in all patients with suspected FH.
• Heterozygous FH (HeFH) is caused by pathogenic variants in LDLR (>1700 known variants), APOB (p.Arg3527Gln most common), or PCSK9 (gain-of-function variants). Genetic testing identifies a causative mutation in approximately 60–80% of clinically diagnosed HeFH patients.
• Children of an FH parent should be screened by age 9–11 years (earlier if family history of very early ASCVD) — LDL-C >160 mg/dL in a child with an FH parent is presumptive FH. Statin therapy is recommended from age 8–10 if LDL-C remains high after dietary modification.
• FH should be considered in any patient requiring multiple cardiovascular interventions (CABG, PCI, carotid endarterectomy) under age 60 — these patients have very high rates of undiagnosed FH.
• PCSK9 inhibitors (evolocumab, alirocumab) reduce LDL-C by 50–60% ON TOP OF maximally tolerated statin therapy and have demonstrated cardiovascular outcome benefit in the FOURIER and ODYSSEY OUTCOMES trials — they are particularly important in FH patients who cannot reach LDL-C targets on statins alone.

Next steps

MEDPED Criteria MET (FH Diagnosis): Confirm with fasting LDL-C measurement. Complete family history of premature ASCVD. Physical examination for xanthomas, xanthelasma, corneal arcus. Exclude secondary causes (TSH, renal function, LFTs). Initiate HIGH-INTENSITY statin therapy: atorvastatin 40–80 mg/day or rosuvastatin 20–40 mg/day (AHA/ACC Class I, A). Target LDL-C reduction ≥50% from baseline; for very high-risk patients, target LDL-C <70 mg/dL (AACE) or <55 mg/dL (ESC 2019). If LDL-C target not achieved on maximal statin therapy: add ezetimibe 10 mg/day first; then PCSK9 inhibitor (evolocumab 140 mg SC q2w or alirocumab 75–150 mg SC q2w). Genetic testing (LDLR, APOB, PCSK9 mutations) is recommended when available to confirm diagnosis and enable cascade family testing. Cascade screening of all first-degree relatives. MEDPED Criteria NOT Met: FH less likely by this criterion. Consider Dutch Lipid Clinic Network (DLCN) criteria with LDL-C for more comprehensive assessment. Evaluate for polygenic hypercholesterolemia or secondary causes.

Evidence

Williams RR et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171-176. PMID:8328383. Original MEDPED criteria derivation. Validation: Hunt SC et al. Use of the MEDPED criteria to diagnose familial hypercholesterolemia in the US population. Am J Cardiol. 1999;84:1020-1023. Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease — consensus statement of the EAS. Eur Heart J. 2013;34(45):3478-3490. PMID:23956253. Grundy SM et al. 2018 AHA/ACC Cholesterol Guideline. J Am Coll Cardiol. 2019;73(24):3168-3209.

References

1. Williams RR et al. Diagnosing heterozygous familial hypercholesterolemia using new practical criteria validated by molecular genetics. Am J Cardiol. 1993;72(2):171-176. — link
2. Nordestgaard BG et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population. Eur Heart J. 2013;34(45):3478-3490. — link
3. Grundy SM et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol. J Am Coll Cardiol. 2019;73(24):3168-3209. — link
4. Mach F et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias. Eur Heart J. 2020;41(1):111-188. — link
5. Raal FJ, Santos RD. Homozygous familial hypercholesterolaemia: current perspectives on diagnosis and treatment. Atherosclerosis. 2012;223(2):262-268. — link