Dysbetalipoproteinemia (ORPHA:412)
A rare combined hyperlipidemia (HLP type 3) characterized by high levels of cholesterol and triglycerides, transported by intermediate density lipoproteins (IDLs), and a high risk of progressive atherosclerosis and premature cardiovascular disease.
Epidemiology
Dysbetalipoproteinemia prevalence is estimated at 1/10,000 in the general population. Men are predominantly affected (male-female ratio about 2:1). The disease very rarely occurs before adulthood or in premenopausal women.
Clinical description
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 may be observed. Patients develop highly progressive atherosclerosis that can lead to premature cardiovascular disease (stroke, coronary and peripheral artery disease. Patients expressing major hypertriglyceridemia may also develop acute pancreatitis.
Etiology
The disease results from mutations in the APOE gene (19q13.31) encoding apolipoprotein E, a protein mediating the cellular uptake of triglyceride-rich lipoprotein remnants (i.e., IDLs with roughly equal amounts of cholesterol and triglycerides) with anti-oxidant and anti-inflammatory properties. Dietary, metabolic, hormonal factors 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).
Diagnostic methods
Diagnosis is based on the evidence of an abnormal lipoprotein profile with increased fasting serum concentrations of total cholesterol, triglycerides and Apolipoprotein B, and lowered plasma high-density lipoprotein (HDL) cholesterol (<40 mg/dL). Genetic testing confirms the diagnosis. In young adults, signs of silent atherosclerosis may be observed with arterial imaging.
Differential diagnosis
Differential diagnosis includes all other forms of atherogenic hyperlipidemias such as familial hypercholesterolemia, and familial hypertriglyceridemia.
Genetic counseling
In most cases associated with the APOE ''E2'' genotype, inheritance is semi-dominant or conditionally recessive. Carriers of this genotype exhibit the phenotype of HLP type 3 only when other metabolic, exogenous or genetic factors are present. Some patients however, carry heterozygous or compound heterozygous rare APOE variants that are sufficient for the development of the disease; in these cases, transmission is autosomal dominant or semi-dominant.
Management and treatment
Treatment includes a diet poor in carbohydrates and saturated fat, exercise, and lipid-lowering drugs (e.g. fibrates, statins) and is usually sufficient for complete regression of the disease within a few months. In severe cases with overt cardiovascular and/or pancreatic manifestations, intensive therapies (e.g. proprotein convertase subtilisin kexin type 9 (PCSK9), ApoC3 or microsomal triglyceride transfer protein (MTP) inhibitors, LDL apheresis) may be proposed.
Prognosis
Without treatment, patients have a 5-10 times higher risk of premature and recurrent atherothrombotic events than the general population.

                            Last update: 
                            August 2019


                            - Expert reviewer(s): 
                            Dr Pascale BENLIAN