Family hypercholesterolemia revealed by myocardial infarction: Case report and literature data

Familial hypercholesterolemia (FH) is a monogenetic, autosomal dominant disease, most often heterozygous and rarely homozygous, characterized by a very high virulence [1],[2],[3]. One in 200 to one in 300 people are affected in its heterozygous form, i.e., 1/500 births in France. Fifty percent of the children of affected parents have a risk of developing the disease. The homozygous form, most often composite, is much rarer (1 in 1,000,000 cases) [1],[4]. Familial hypercholesterolemia is due to the mutation of a single allele in the heterozygous form, resulting in a 50% reduction in hepatic clearance of low-density lipoproteins (LDL), producing LDL cholesterol (LDL-C) levels that are twice as high as usual from birth and ten times higher if the mutation involves both alleles in the homozygous form [2]. The diagnosis is based on three basic characteristics: a family history, clinical manifestations related to hypercholesterolemia and its complications, and the presence of hypercholesterolemia in biology with genetic confirmation of the mutation after the MedPed score. Complications occur early, before the age of 55 in men and 60 in women [1]. It is theore one of the most common genetic diseases but is under-diagnosed with only 20% of confirmed cases.

We present a case of myocardial infarction in a young patient, revealing familial hypercholesterolemia.

We report the case of a 31-year-old non-obese patient, with no particular personal history, presenting with a notion of a stroke in the mother at the age of 52 and an acute coronary syndrome on two occasions at the age of 44 (Figure 1 and Figure 2). He was hospitalized for a myocardial infarction in inferior left ventricular ejection fraction (LVEF) 62%, revascularized on the right coronary by primary angioplasty, at 96 minutes (Figure 3). Clinical examination was normal, including a blood pressure (BP) of 135/82 mmHg and a heart rate of 92 beats/min. The lipid profile showed hypercholesterolemia (HCT) with LDL-CT of 3.64 g/L, HDL-CT of 0.32 g/L, and TG of 2.1 g/L. The patient had a MedPed score of 12 points associated with genetic sampling, showing a copy of the LDL receptor gene.

The patient received high dose statin (Atorvastatin 80 mg/day and Ezetimibe 10 mg/day) combined with adherence to dietary hygiene measures, followed by further treatment of coronary syndrome: Ticagrelor 90 mg × 2/day, Karegic 75 mg/day; Bisoprol 2.5 mg/day, and Ramipril 2.5 mg/day. Family genetic screening was performed including those of the mother and brother. Progression on treatment after three months showed a reduction in LDL-CT to 1.80 g/L.

Familial hypercholesterolemia (FH) is by definition one of the most common autosomal dominant monogenic diseases, highly fatal but often unrecognised, accounting for only 20% of diagnosed patients [1],[2],[3]. There are two forms of familial hypercholesterolemia [5]:

• The homozygous form is much rarer (1 in 1,000,000 cases) with a very severe phenotypic expression that can lead to vascular accidents from adolescence. Its very specific management is only done in a specialised environment.
• The heterozygous form, which is much more frequent, affects 50% of children whose parents are affected.

Familial hypercholesterolemia leads to an increase in LDL-CT levels from birth. The atherosclerosis it causes begins in childhood and predisposes to premature coronary events in adulthood. For this reason, any late development of it in adult life is not suggestive of a familial form [1],[4].

The pathophysiology of FH is due to the mutation of a single allele (heterozygous state) of the LDLR genes, coding for the LDL receptor, APOB, responsible for the binding of LDL particles to their receptor, or PCSK9 coding for the “Protein convertase subtilisin/kexin type 9” which facilitates the lysosomal degradation of the LDL receptor [6]. A 50% reduction in hepatic clearance of LDL lipoproteins due to mutation of a single allele results in LDL cholesterol (LDL-C) levels twice as high as normal levels since birth.

The diagnosis of FH is based on a triad of MedPed scores combining [1],[7]:

• History:
  • Family history:
    • Of premature coronary or vascular disease present in first-degree relatives (male < 55 years, female < 60 years) [1].
    • First-degree relative with LDL-C > 95th percentile [1].
    • First-degree relative with tendon xanthomas and/or corneal arc [2].
    • Child < 18 years with LDL-C > 95th percentile [2].
  • Personal
    • Premature coronary artery disease (male < 55 years, female < 60 years) [2].
    • Premature cerebral or arterial occlusive disease of the lower limbs [1].
• Clinical signs
  • Tendon Xanthomas [6]
  • Corneal arc before 45 years [4]
• Biological data
  • Biochemical:
    • LDL-C > 3.30 g/L (> 8.5 mmol/L) [8]
    • LDL-C: 2.50–3.29 g/L (6.5–8.4 mmol/L) [5]
    • LDL-C: 1.90–2.49 g/L (5.0–6.4 mmol/L) [3]
    • LDL–C:1.55–1.89 g/L (4.0–4.9 mmol/L) [1]
  • DNA analysis
    • Genetic mutations identified [8]

The MedPed score is classified into three:

• Possible (3–5 points)
• Probable (6–8 points)
• Certain (greater than 8 points)

In our case, our patient had a high MedPed score of 12, based on family history, clinic, and biochemistry, topped by the presence of an LDL receptor gene copy. Family screening should be done very early once the diagnosis is evoked because complications are early. In our case the notion of hypercholesterolemia was objectified in the brother and the mother with complications such as myocardial infarction and a stroke.

When the LDL-C level remains above 1.9 g/L in children and adolescents aged 8 to 10 years, management begins with dietary hygiene measures for a period of at least six months [1]. If hypercholesterolemia persists, a statin is recommended as first-line treatment in children, adolescents, and even adults at the lowest effective dose [3],[8]. This makes them the most important class of drugs for reducing LDL-C. Several molecules are marketed, allowing a reduction in LDL-C of 30–50% to be achieved. The latter depends on both the molecule chosen and the dose used [1]. In practice, the most potent statins, in particular atorvastatin or rosuvastatin, are used because of the significant increase in LDL-C. Ezetimibe, on the other hand, allows an average reduction of LDL-C of about 20%, as do anti-PCSK9 antibodies.

In our case, the patient received a high dose of statin and ezetimibe from the start.

Familial hypercholesterolemia is a common but very poorly understood genetic condition, usually objectified at the complication stage in developed countries where genetic testing can be performed. Management should be early once the diagnosis has been made and this should be done even in adolescence using statins at a lower effective dose.