Highlights
- •About 10% of FD cases are caused by autosomal dominant mutations.
- •The LDLR and HSPG-R are responsible for hepatic remnant clearance.
- •HSPG-R inhibition by insulin resistance might be the second hit causing FD.
- •The diagnosis of dominant FD is complicated by various diagnostic challenges.
- •Statin and fibrate combination is the preferred lipid-lowering therapy in FD.
Abstract
Familial dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism
associated with an increased risk for premature cardiovascular disease. In about 10%
of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E
gene (APOE). This review article provides a pathophysiological framework for autosomal dominant
FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical
presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with
premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to
increased remnants. Remnants are hepatically cleared by the low-density lipoprotein
receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD
is associated with secondary factors like insulin resistance that lead to HSPG-R degradation
through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical
presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible
misdiagnosis as familial hypercholesterolemia. FD patients respond well to lifestyle
changes and to combination therapy with statins and fibrates. To conclude, diagnosing
ADFD is important to adequately treat patients and their family members. In patients
presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered
as part of the diagnostic work up.
Keywords
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Article info
Publication history
Published online: October 13, 2016
Accepted:
October 2,
2016
Received:
May 3,
2016
Identification
Copyright
© 2016 National Lipid Association. All rights reserved.
