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Hyperlipoproteinemia type 3

Orpha number ORPHA412
Synonym(s) Broad-betalipoproteinemia
Dyslipidemia type 3
Familial dysbetalipoproteinemia
Familial hyperlipoproteinemia type 3
HLP type 3
Hyperlipidemia type 3
Remnant disease
Prevalence 1-5 / 10 000
Inheritance
  • Multigenic/multifactorial
Age of onset Variable
ICD-10
  • E78.2
OMIM -
UMLS
  • C0020479
MeSH
  • D006952
MedDRA
  • 10060751
SNOMED CT
  • 398796005

Summary

Hyperlipoproteinemia (HLP) type 3 is a rare combined hyperlipidemia characterized by high levels of cholesterol and triglycerides transported by intermediate density lipoproteins (IDLs), and a high risk of premature atherosclerosis and cardiovascular disease.

The prevalence is estimated at 1/10,000 in the general population. Men are predominantly affected (male-female ratio about 2:1). The disease is very rare before adulthood and in premenopausal women.

Most patients are asymptomatic. Clinical signs that may appear during adulthood are xanthomas of the eyelids (i.e. xanthelasma), transient xanthomas on palms (i.e. planar palmar xanthomas) or tuberous xanthomas over elbows or knees. Sensitive hepatomegaly can also be observed. Patients progressively develop atherosclerosis that can lead to cardiovascular disease (stroke, coronary artery disease with myocardial infarction, lower limb arteriopathy) before the age of 50.

The disease results from mutations in the APOE gene (19q13.2) encoding apolipoprotein E, a protein involved in cellular uptake of triglyceride-rich lipoprotein remnants (i.e., IDLs with roughly equal amounts of cholesterol and triglycerides). Mutations result in plasma accumulation of remnant lipoproteins and their retention in the arterial wall. Many patients carry two copies of the APOE ''E2'' allele which acts as a susceptibility genotype for the development of the disease. Dietary (saturated fat, refined sugars or alcohol), metabolic (e.g. diabetes, metabolic syndrome, non-alcoholic steato-hepatitis, nephropathy), and hormonal factors (e.g. hypothyroidism, polycystic ovary syndrome, pregnancy) may aggravate the disease, as well as chronic inflammation, xenobiotics (e.g. immune suppressants, retinoids, antidepressants) or other genetic cofactors (e.g. APOA5, APOC3, LIPC, LPL variants).

Diagnosis is based on the evidence of an abnormal lipoprotein profile with increased fasting serum concentrations of total cholesterol and triglycerides, and lowered plasma high-density lipoprotein (HDL) cholesterol (<40 mg/dL). A Very-Low-Density Lipoprotein (VLDL)-cholesterol/triglyceride ratio higher than 0.3, and a broad-beta band (i.e., -VLDL) on agarose gel electrophoresis reflect the presence of IDLs, all unexpected features in fasting plasma. Genetic testing confirms the diagnosis. In young adults, signs of silent atherosclerosis may be observed with arterial imaging (e.g., increased carotid intima-media thickness, carotid or femoral atherosclerotic plaques, coronary calcifications), or signs of silent ischemia with a cardiac stress test.

Differential diagnosis includes all other forms of atherogenic hyperlipidemias such as familial hypercholesterolemia, and familial hypertriglyceridemia (see these terms).

In most cases associated with the APOE ''E2'' genotype, inheritance is pseudo-dominant or conditionally recessive. Carriers of this genotype exhibit the phenotype of HLP type 3 only when other metabolic or genetic factors are present. Some patients however, are heterozygous for rare APOE variants that are sufficient for the development of the disease; in this case transmission is autosomal dominant.

Treatment includes a diet low in saturated fat, exercise, and lipid-lowering drugs (e.g. fibrates, statins) that is usually sufficient for complete regression of the disease within a few months. In severe cases, intensive therapies (e.g. proprotein convertase subtilisin kexin type 9 (PCSK9) or microsomal triglyceride transfer protein (MTP) inhibitors, LDL apheresis) may be proposed.

Without treatment, patients present a 5-10 time higher risk of premature and recurrent atherothrombotic events than in the general population.

Expert reviewer(s)

  • Dr Pascale BENLIAN

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