The diagnosis and treatment of familial dysbetalipoproteinaemia is challenging but very important

Phenotype and genotype of familial dysbetalipoproteinaemia (FD) [1-3]

Literature - Koopal C, J Clin Lipidol, 2016

Autosomal dominant Familial Dysbetalipoproteinemia: a pathophysiological framework and practical approach to diagnosis and therapy

Koopal C, Marais DA, Westerink J, et al.
J Clin Lipidol. 2016; published online ahead of print
 FD is a genetic lipid disorder associated with a 10-fold increased risk for premature atherogenic diseases compared to population-based controls and is characterised by:
  • a lipoprotein phenotype of mixed hyperlipidaemia
  • a genotype that consists of mutations in the apolipoprotein E gene (APOE).
The APOE gene locus has three main variants: ε2, ε3 and ε4. These result in three homozygous (ε2ε2, ε3ε3 and ε4ε4) and three heterozygous (ε2ε3, ε3ε4 and ε4ε2) genotypes. Approximately 15% of subjects with an ε2ε2 genotype develop FD. Moreover, the development of FD is associated with secondary risk factors, like for example obesity and insulin resistance. Carriers of only one ε2 allele do generally not develop a lipid disorder, making FD a recessive disease. However, about 10% of the patients with FD have a mutation in APOE with a dominant or co-dominant inheritance pattern.

Diagnostic challenges in autosomal dominant FD [4,5]

Diagnosing autosomal dominant FD (ADFD) is important because:
  • ADFD patients have the same atherogenic lipid profile as recessive FD patients. As a consequence they are exposed to the same increased risk of atherosclerosis.
  • There are specific lipid treatment targets and lipid-lowering treatments for FD.
  • Diagnosing ADFD will have consequences for family members due to the dominant inheritance of the disease.
The diagnostic challenges include:
  • The wide variety in clinical presentations ranging from palmar crease, eruptive, cutaneous, or tendon xanthomata, to pancreatitis and premature atherosclerosis.
  • FD is part of any differential diagnosis of mixed dyslipidaemia. The alternative explanations for an altered lipid phenotype can mask the presence of FD.
  • Dominant inheritance pattern in a disease that is usually recessive.
  • There are many ways to diagnose the lipid phenotype in FD, which vary in reliability and practicality.
  • Routine genotyping methods may not detect ADFD.
  • ADFD may be mistaken for familial hypercholesterolemia.

Treatment of autosomal dominant FD [6]

Treatment goals:
  • Primary treatment goal: non-HDL-C <3.3 mmol/L
  • Alternative treatment goal: TG <2.0 mmol/L
Treatment strategy:
  • Low-glycaemic diet and modification of secondary factors (obesity, insulin resistance, hypothyroidism)
  • Pharmacological therapeutic options: the treatment of choice for FD is a combination therapy of statins and fibrates
  • The final component of ADFD treatment is family counselling, because first degree relatives of ADFD patients have a 50% risk of developing ADFD. When diagnostic characteristics of ADFD are present in family members, an APOE gene sequence should be performed and, when ADFD is confirmed, adequate treatment should be initiated.

Find this article online at J Clin Lipidol


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2. Koopal C, van der Graaf Y, Asselbergs FW, et al. Influence of APOE-2 genotype on the relation between adiposity and plasma lipid levels in patients with vascular disease. Int J Obes (Lond). 2015;39(2):265-9.
3. Zannis VI. Genetic polymorphism in human apolipoprotein E. Methods Enzymol. 1986;128:823-51.
4. Blom DJ, Byrnes P, Jones S, et al. Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia. Journal of lipid research. 2003;44(1):212-7.
5. Sniderman A, Tremblay A, Bergeron J, et al. Diagnosis of type III hyperlipoproteinemia from plasma total cholesterol, triglyceride, and apolipoprotein B. J Clin Lipidol. 2007;1(4):256-63.
6. Reiner Z, Catapano AL, De Backer G, et al.  ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769-818.

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