EASILY MISSED? Familial hypercholesterolaemia Peter J Gill MD/PhD student 12 , Anthony Harnden university lecturer in general practice 1 , Fredrik Karpe professor of metabolic medicine 3 1 Department of Primary Care Health Sciences, University of Oxford, Oxford OX1 2ET, UK; 2 Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada; 3 Oxford Centre for Diabetes, Endocrinology & Metabolism, Churchill Hospital, Oxford OX3 7LJ This is one of a series of occasional articles highlighting conditions that may be more common than many doctors realise or may be missed at first presentation. The series advisers are Anthony Harnden, university lecturer in general practice, Department of Primary Care Health Sciences, University of Oxford, and Richard Lehman, general practitioner, Banbury. To suggest a topic for this series, please email us at easilymissed@bmj.com. A 25 year old man visits his general practitioner concerned after his 52 year old father suddenly died of a heart attack. His paternal uncle and grandfather died of heart attacks in their 40s. On examination he has xanthomas on the extensor tendons of his hands. Laboratory investigations reveal total cholesterol 9.3 mmol/L and low density lipoprotein (LDL) cholesterol 6.6 mmol/L. He is diagnosed with familial hypercholesterolaemia, given lifestyle advice, started on simvastatin 80 mg, and referred to a specialist for genetic testing and cascade screening of his relatives. What is familial hypercholesterolaemia? Familial hypercholesterolaemia is an inherited autosomal dominant genetic disorder characterised by high serum cholesterol concentrations detectable at a young age. 12 It is associated with early cardiovascular disease, and an underlying genetic cause can be identified in about 80% of cases. 23 Why is familial hypercholesterolaemia missed? Underdiagnosis is a global challenge, with correct identification ranging from less than 1% in Russia to 20% in the Netherlands and 44% in Iceland. 2 In the UK only 15% of patients with familial hypercholesterolaemia are expected to have been recognised in general practice. 5-7 It is not known why patients with familial hypercholesterolaemia are often missed in primary care, but many seem to be diagnosed in middle age when family members present with coronary heart disease. 5 Although patients diagnosed with familial hypercholesterolaemia are instructed to contact their relatives, several studies have shown that this is not effective in practice. 6 The low referral rate to specialists for cascade DNA testing, the lack of national screening programmes, and the limited usefulness of clinical evaluation in relatives all probably contribute. 489 Underdiagnosis is an even greater challenge among children and young adults, in whom clinical signs are rarely present. 1 10 Why does this matter? Patients with familial hypercholesterolaemia have a high risk of mortality as they are exposed to high concentrations of plasma LDL cholesterol from birth. 13 By early adulthood, without treatment they will have a 100-fold greater mortality risk from coronary disease than other young adults aged 20–39 years. 11 12 Half of untreated heterozygous men and 30% of untreated women will have a myocardial infarction by the age of 50 and 60 years respectively. 3 13 However, the development of effective cholesterol lowering drugs has reduced cardiovascular mortality, prolonging life by approximately nine years. 12 14 15 A long term follow-up study showed that statins can delay atherosclerotic progression in children and young adults with familial hypercholesterolaemia. 16 The risk of coronary heart disease is considerably higher in patients with homozygous familial hypercholesterolaemia. 1 17 How is familial hypercholesterolaemia diagnosed? There is no individual diagnostic test with sufficient specificity and sensitivity to reliably detect familial hypercholesterolaemia. 10 18 Therefore, three international groups have developed diagnostic tools for familial hypercholesterolaemia based on clinical signs, family history, and cholesterol measurements. 10 The National Institute for Health and Clinical Excellence (NICE) guideline on identification and management of familial hypercholesterolaemia Correspondence to: P J Gill peter.gill@phc.ox.ac.uk For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ 2012;344:e3228 doi: 10.1136/bmj.e3228 (Published 11 May 2012) Page 1 of 3 Practice PRACTICE