Teaching case construct. An adult without pain has LDL-C of 6.8 mmol/L, tendon xanthomas over the Achilles tendons, and a brother who had a myocardial infarction before 50. Calculating SCORE2 is pointless: this is not "lifestyle high cholesterol" until familial hypercholesterolaemia (FH) has been excluded.
FH is an autosomal dominant disease caused by mutations in the genes for the LDL receptor (LDLR), apolipoprotein B-100 (APOB) or PCSK9. The Kazakhstan Ministry of Health protocol No. 196/2023 gives a prevalence of the heterozygous form of 1/200–250 and of the homozygous form of 1/160 000–320 000. The clinical meaning of these figures: heterozygous FH is not a rarity; it is bound to turn up in the flow of an outpatient clinic.
The Kazakhstan Ministry of Health protocol bases the diagnosis of heterozygous FH in adults on the Dutch Lipid Clinic Network (DLCN) criteria. The points sum family history, personal history of premature ASCVD, tendon xanthomas (6 points) or arcus cornealis before 45 years (4 points; together a maximum of 6), LDL-C level (≥8.5 mmol/L — 8 points; 6.5–8.4 — 5; 5.0–6.4 — 3; 4.0–4.9 — 1) and a functional LDLR/APOB/PCSK9 mutation (8 points). "Definite" FH is more than 8 points, "probable" 6–8, "possible" 3–5. The clinical diagnosis of HeFH is "definite" or "probable". Molecular genetic testing is indicated at a total of ≥6, but the diagnosis is possible without it.
According to the Kazakhstan Ministry of Health protocol (class I, level C), FH should be suspected in patients with coronary heart disease at age ≤55 years in men and ≤60 years in women; in those with relatives with tendon xanthomas; with LDL-C ≥5 mmol/L in adults (≥190 mg/dL) and ≥4 mmol/L in children; in first-degree relatives of the index patient. Next comes cascade screening of first- and second-degree relatives.
Homozygous FH: two mutant alleles in LDLR, APOB, PCSK9 or LDLRAP1 or untreated LDL-C >10 mmol/L (~400 mg/dL) plus tendon/skin xanthomas before age 10 or LDL-C levels consistent with HeFH in both parents. This is a condition in which even PCSK9 inhibitors are often insufficient. ESC/EAS 2025: evinacumab (a monoclonal antibody to ANGPTL3) should be considered (IIa B) in homozygous FH from 5 years of age and older if the target is not reached on maximal lipid-lowering therapy; LDL-C reduction of about 50% in the ELIPSE HoFH programme studies.
Primary dyslipidaemias are broader than FH. The Kazakhstan Ministry of Health protocol gives a genetic table: familial combined hyperlipidaemia (frequency 1/100–200, USF1 gene, ↑LDL-C, ↑VLDL, ↑ApoB); familial dysbetalipoproteinaemia (1/5000, APOE, ↑IDL); familial chylomicronaemia syndrome (2/1 000 000). The Fredrickson phenotypes, as adapted by the WHO, in the same protocol: IIa and IIb are the most atherogenic and frequent (about 10% and 40% of dyslipidaemias in the protocol's table); IV is VLDL hypertriglyceridaemia (about 45%); types I, III and V are rare. The protocol rates atherogenicity as "+++" for IIa, IIb and III.
Secondary dyslipidaemias, according to the Kazakhstan Ministry of Health protocol, account for about 30–40% of all dyslipidaemias. They are sought before starting statins: hypothyroidism, nephrotic syndrome, CKD, Cushing's syndrome, cholestasis and primary biliary cholangitis, diabetes mellitus, obesity, alcohol, drugs (Appendix No. 5 of the protocol). Correcting the cause can change the lipid profile without a "lifelong" high-intensity regimen.
The boundary of the lesson. The DLCN criteria are a clinical tool, not a genetic verdict. A score of 5 is "possible" FH, which is not enough to declare a monogenic disease. Conversely, the absence of xanthomas does not exclude FH. The course does not cover paediatric statin dosing or management of pregnancy in FH — these are separate protocols.
Practical conclusion. LDL-C ≥5 mmol/L in an adult is not "prescribe statins and forget", but a checklist: DLCN, cascade screening, exclusion of secondary causes. The target in very-high-risk FH with ASCVD in the Kazakhstan Ministry of Health protocol No. 196: LDL-C <1.4 mmol/L and a reduction of at least 50% from baseline (I, A); if not achieved, combination therapy.