Familial Hypercholesterolemia: Symptoms, Diagnosis and Treatment

Older estimates assumed 1 in 500, and direct screening in a Northern European general population found about 1 in 200 (according to the 2013 EAS consensus). More recent summaries fall in between: about 1 in 300, which is also repeated in the 2026 EAS consensus on children, according to which heterozygous FH affects about 1 in 300 people worldwide and the much more severe homozygous form about 1 in 300,000. In practice this means that in a country of 38 million inhabitants there are more than a hundred thousand people with the disease, most of whom do not know it.

The meta-analysis also shows how strongly FH is concentrated in risk groups: in people with premature heart attack or coronary disease and with an LDL-C above 190 mg/dL it occurs 20-23 times more often than in the general population. These are exactly the situations that should trigger thinking about FH.

The liver removes LDL from the blood thanks to LDL receptors, which capture particles carrying apolipoprotein B. In FH this system does not work efficiently. Most often the cause is a mutation of the LDLR gene, which codes for the receptor itself; less often a mutation of the APOB gene, altering the site where LDL binds the receptor, or a variant of the PCSK9 gene, which increases the breakdown of receptors. In every case the effect is similar: LDL circulates in the blood for much longer, and the LDL-C concentration is high from birth.

FH is inherited in an autosomal dominant manner: one mutated allele is enough, so every child of a person with FH has a 50% chance of inheriting the disease. The heterozygous form (one faulty copy) is common and usually gives an LDL-C in the range of several hundred mg/dL. The homozygous form (two faulty copies) is very rare but much more severe: very high LDL, xanthomas already in childhood and atherosclerosis at a young age, requiring treatment in specialized centers, sometimes with lipoprotein apheresis.

Because this is about long-term exposure, the concept of cumulative LDL is key: a person with FH has had a raised LDL since childhood, so by age 40 has accumulated a 'dose' of LDL that another person would not reach for several decades. That is why coronary disease appears early, and by the time the first lipid panel is done it may already be advanced.

Most often FH causes no symptoms, and the high cholesterol is found by chance. When physical signs do appear, they are very characteristic, though by no means obligatory. The most specific are tendon xanthomas, that is thickenings in the tendons, especially the Achilles tendon and the extensor tendons of the fingers, which are deposits of cholesterol. Xanthelasmas (yellow patches around the eyes) and corneal arcus, a white or grey ring around the cornea, which at a young age (before 45) is worrying, may also occur.

The absence of xanthomas or arcus does not exclude FH: in many patients, especially those treated early, they are not there. The diagnosis therefore rests on a combined assessment of the lipid panel, family history, physical examination and, if possible, a genetic test.

The most commonly used clinical tool is the Dutch Lipid Clinic Network (DLCN) score, which adds up points for family history, personal history, physical examination, LDL-C level and genetic test result. According to the version quoted in the EAS consensus (2013), a 'definite' diagnosis is made with a score above 8 points, 'probable' with 6-8, 'possible' with 3-5, and FH is 'unlikely' with 0-2 points.

The 2013 EAS consensus recommends testing for FH in people in whom an adult LDL-C of at least 8 mmol/L (310 mg/dL) or a child LDL-C of at least 6 mmol/L (230 mg/dL), premature coronary disease, tendon xanthomas, sudden premature cardiac death or FH in a family member appears. The earlier European recommendations for children (EAS 2015) set a phenotypic diagnosis at an LDL-C of at least 190 mg/dL, or at least 160 mg/dL with additional familial features, and with a known mutation in a parent the threshold for the child falls to 130 mg/dL.

An important practical caveat: before diagnosing FH, secondary causes of a high LDL must be excluded, such as hypothyroidism, nephrotic syndrome, cholestasis, some drugs and a diet very rich in saturated fat or ketogenic. A case series described in the literature showed that severe diet-induced hypercholesterolemia can mimic FH (we write about this in our article on the ketogenic diet).

What follows in practice? First, a negative genetic test does not cancel treatment: in most people with an LDL-C above 190 mg/dL no mutation is found in LDLR, APOB or PCSK9, and the risk is nevertheless about six times higher than in the reference group. Second, a positive result means even greater risk and, most importantly, opens the way to precise testing of relatives, because a known mutation makes it possible to say unambiguously who has inherited it. Third, a genetic test does not replace clinical assessment, and its availability in Poland depends on the center and indications, so it is worth asking at a lipid clinic.

Because FH is inherited dominantly, every child, parent and sibling of a person with FH has a 50% chance of having inherited it. According to the EAS consensus, the most cost-effective way of finding new cases is cascade screening of families, that is systematic testing of first-degree relatives (parents, siblings, children) and then second-degree ones (grandparents, grandchildren, uncles, aunts, nephews, nieces, half-siblings). It is best done at a specialized center, combining a lipid panel with genetic testing; if the causative mutation was not known, a lipid panel is enough.

This is particularly important for children and adolescents: according to the 2015 EAS consensus, testing is recommended from about age 5, and earlier if the homozygous form is suspected. Early detection and treatment give a chance for normal life expectancy.

The basis of treatment is a statin at the highest tolerated dose, usually with ezetimibe added when the statin alone is not enough to reach the target. Treatment goals depend on risk. According to the 2019 ESC/EAS guidelines, people with FH without atherosclerotic disease and without other major risk factors are placed in the high-risk group with a goal of lowering LDL-C by at least 50% and to below 70 mg/dL (1.8 mmol/L), and people with atherosclerotic disease or another major risk factor in the very-high-risk group with a goal of lowering it by at least 50% and to below 55 mg/dL (1.4 mmol/L). The older 2013 EAS consensus proposed less stringent goals (below 100 mg/dL in adults and below 70 mg/dL with coronary disease or diabetes), so when reading older sources pay attention to the year of publication.

PCSK9 inhibitors (monoclonal antibodies, and also inclisiran) are reserved for people who do not reach the goal despite maximal statin and ezetimibe, and for those who do not tolerate statins. Lipoprotein apheresis may be offered to people with the homozygous form and to treatment-resistant heterozygous FH with coronary disease. Indications for drug treatment and its intensity are set by the doctor, best at a lipid clinic, because FH requires lifelong treatment and decisions should take into account Lp(a) (about which we write in a separate article), blood pressure, diabetes and smoking.

For children with FH the key is early diagnosis and starting treatment before puberty. The 2015 EAS consensus indicates that a healthy lifestyle and statin treatment are recommended from age 8-10, with a goal of LDL-C below 130 mg/dL in children over 10 and, in younger ones, ideally a reduction of about 50% from baseline. The 2019 ESC/EAS guidelines speak of considering a statin at age 6-10, starting at low doses, with a goal below 135 mg/dL over age 10. The latest 2026 EAS consensus stresses the importance of starting treatment before puberty in children with heterozygous FH, if needed from age 6, and proposes revised diagnostic criteria, because current ones often fail to identify children with an FH-causing genetic variant.

Parents often ask about the safety of statins in children. According to the EAS consensus, the benefits of early treatment of FH are judged to outweigh the long-term risk of side effects, but every decision should be made at a specialist clinic, with monitoring of growth, puberty and liver and muscle parameters. Children should also benefit from a healthy diet, physical activity and avoiding smoking.

For women with FH planning a pregnancy, it is key to discuss treatment with the doctor beforehand. The 2019 ESC/EAS guidelines state that lipid-lowering drugs should not be given when pregnancy is planned, during pregnancy or while breastfeeding, and that in severe FH bile acid sequestrants or LDL apheresis can be considered. A 2024 review indicates that the only drugs officially approved in pregnancy are bile acid sequestrants, and that ezetimibe and fenofibrate can be considered when the benefits outweigh the risks.

The same review notes that statins are still regarded as contraindicated mainly because of animal studies and case reports, but newer systematic reviews and data on FH in pregnant women suggest that their use may not be harmful and in selected cases (very high risk, for example after a heart attack or with severe FH) may even be beneficial. The authors stress that decisions should be individualized and made with a doctor, and that before pregnancy it is worth planning a change of treatment. Do not stop or restart a statin on your own.

The second common mistake is to assume that a 'normal cholesterol in a child' means no FH: in children the level can be lower than in adults, and age-specific thresholds are used for diagnosis (for example an LDL-C of at least 160 mg/dL with a family history). The third is to assume that FH is present only in someone who has xanthomas. Most patients do not have them.

Familial hypercholesterolemia is one of those diseases in which early diagnosis and treatment can largely reverse the natural course. For many families the turning point is a single lipid panel in a child or sibling. If your LDL exceeds 190 mg/dL, if someone in the family had a heart attack before age 55-60, or if someone close has diagnosed FH, see a doctor or a lipid clinic and suggest testing to your relatives. This is a rare case in which information about risk translates into decades of health.