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Familial hypercholesterolaemia: history, diagnosis, screening, management and challenges
  1. Erik Berg Schmidt1,2,
  2. Berit Storgaard Hedegaard2,3,
  3. Kjetil Retterstøl4,5
  1. 1 Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
  2. 2 Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
  3. 3 Department of Cardiology, Viborg Regional Hospital, Viborg, Midtjylland, Denmark
  4. 4 Department of Nutrition, Institute of Basic Medical Science, University of Oslo, Oslo, Norway
  5. 5 The Lipid Clinic, Oslo University Hospital, Oslo, Norway
  1. Correspondence to Professor Erik Berg Schmidt, Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark; ebs{at}

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Learning objectives

  • Acknowledge the history of familial hypercholesterolaemia (FH).

  • Understand the pathophysiology of FH.

  • Acknowledge the importance and significance of FH.

  • Make a diagnosis of FH.

  • Acknowledge the importance of (genetic) screening for FH.

  • Acquire basic knowledge about treatment of FH.


Clinical familial hypercholesterolaemia (FH) was systematically described for the first time in 1937. In 17 families and in four generations, xanthomatosis, hypercholesterolaemia and cardiovascular disease (CVD) followed a pattern of an inborn error of metabolism and monogenetic autosomal dominant inheritance.1–3

However, single-patient cases of xanthomatosis and CVD had been reported as early as in 1873 by Fagge, by Lebzen and Knauss in 1889, by Török in 1893 and by Raeder in 1936.4


In 1964, the clinical heterozygous and homozygous forms of the disease were described3 and in 1973 Brown and Goldstein showed that FH was caused by defects in the gene coding for the low-density lipoprotein (LDL) receptor (LDLr) resulting in decreased removal of LDL-cholesterol (LDL-C) from the circulation.4 Brown and Goldstein were in 1985 awarded the Nobel Prize for their work. Several genes are known to cause FH, although mutations in the LDLr gene coding for defective LDLr are by far (>90%) the most common. More than 1700 mutations in the LDLr gene have now been described, and of those more than 12005 are believed to be expressed as a severe hypercholesterolaemic phenotype.6 7 Mutation in the apolipoprotein B (apoB) gene may inhibit the receptor-mediated uptake of atherogenic apoB containing particles and thereby cause FH. Gain of function mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) cause FH by degrading the LDLr, while LDL adaptor protein 1 (LDLRAP1) may cause FH by inhibiting the LDLr function.8 All, except the recessive LDLRAP1 mutation, cause FH in an autosomal dominant pattern.7 9

In this …

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  • Contributors Design of paper, first draft, final draft (shared by all coauthors).

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

  • Data availability statement There are no data in this work

  • Author note References which include a * are considered to be key references