OIKOΓΕΝΗΣ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ ΔΙΑΓΝΩΣΗ ΚΑΙ ΘΕΡΑΠΕΙΑ

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1 OIKOΓΕΝΗΣ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑ ΔΙΑΓΝΩΣΗ ΚΑΙ ΘΕΡΑΠΕΙΑ Νικόλαοs Ιωακειμίδηs Καρδιολόγοs, Επιστημονικόs Συνεργάτηs Α Καρδιολογική Κλινική, Ιπποκράτειο ΓΝΑ

2 FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions 2.0 Frequency per 1,000 Births of Common Genetic Disorders 1 FH 2 Neurofibromatosis 1 Familial combined hyperlipidemia has a frequency of 1:200 births; however, the genetic cause is unknown. 2 Sickle cell disease varies greatly by ethnicity. 1. Genetic Alliance UK. Available at 2. Streetly A, et al. J Clin Path. 2010;63:

3 FH: A Clinically Recognizable Genetic Disorder Inheritable, autosomal dominant disorder 1 Usually due to mutations in LDL receptor gene 2,3 that result in decreased clearance of LDL particles from plasma 1 Other mutations include those in the Apo B and PCSK9 genes Clinical manifestations include 1,2 Severe hypercholesterolemia due to accumulation of plasma LDL May be accompanied by cholesterol deposition in tendons and skin (xanthomas) and in the eyes Evidence of CVD early in life 1. Marais AD. Clin Biochem Rev. 2004;25: Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology Rader DJ, et al. J Clin Invest. 2003;111:

4 Visible Signs of FH A- Xanthelasma B Corneal arcus (Arcus senilis) C - Achilles tendon xanthomas D - Tendon xanthomas E - Tuberous xanthomas F - Palmar xanthomas

5 Despite the Importance of Early Detection, FH Is Under-diagnosed < < B.G. Nordestgaard et al. Eur Heart J 2013

6 Prevalence of FH pts Heterozyg FH Benn M et al J Clin Endocrinol Metab 2012

7 Prevalence Is Much Higher in Specific Sub-populations or Founder Groups North America and Europe: HeFH ~1:500 HoFH ~<1:10 6 Higher incidence of HoFH: Québec, Tunisia, South Africa, Lebanon Naoumova RP, et al. Curr Opin Lipidol. 2004;15:

8 Massive undertreatment of individuals with FH -the dose of statin therapy provided resulted in insufficient cholesterol-lowering medication -introduced too late in life, when severe atherosclerosis had already developed Benn M et al J Clin Endocrinol Metab 2012 Huijgen R et al. Expert Rev Cardiovasc Ther 2008

9 Pathophysiology and Genetics

The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations LDLR codes for the LDL Receptor, which clears LDL particles from the circulation by binding to surface Apo B PCSK9 induces degradation

10 The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations LDLR codes for the LDL Receptor, which clears LDL particles from the circulation by binding to surface Apo B PCSK9 induces degradation of LDLR FH may be caused by mutations in Apo B, LDL-R, or PCSK9 Extracellular Fluid LDL Particle: Apo B (site where receptor binds to LDL particle) Cell membrane PCSK9 Cytosol LDL receptor 1. Kumar: Robbins and Cotran. Pathologic Basis of Disease, Rader DJ et al. J Clin Invest. 2003;111: Image reproduced from:

12 Pathophysiology of heterozygous familial hypercholesterolaemia.

13 Clinical vs. mutation diagnosis Heterozygous FH Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia

14 Whom to screen: how do we recognize index cases? (i) plasma total cholesterol 8 mmol/l ( 310 mg/dl) in an adult or adult family member(s) (or >95th percentile by age and gender for country) (ii) premature CHD in the subject or family member(s) (iii) tendon xanthomas in the subject or family member(s) (iv) sudden premature cardiac death in a family member

15 FH Scoring Methods for Clinical Diagnosis Require LDL Levels and Family History

16 FH Scoring Methods for Clinical Diagnosis Require LDL Levels and Family History Comparison of FH Clinical Diagnostic Criteria by Method Simon Broome Register 1 MEDPED 2 Dutch Lipid Clinic Network 1 Definite FH TC or LDL levels Tendon xanthoma in patient or relative Probable FH TC or LDL levels Family history of early MI or high TC/LDL TC or LDL levels based on family history and age (eg, age <20 y, with an FH relative) Score based on : Family history of premature CHD, high LDL, or xanthoma Clinical history of premature CAD or vascular disease Presence of xanthoma or arcus cornealis LDL panel 1. As summarized in: Marks D, et al. Atherosclerosis. 2003;168: As summarized in: Civiera F, et al. Circulation. 2004;173:55-68.

17 Lifetime risk assessment and risk factors LDL cholesterol burden in individuals with or without FH as a function of the age of initiation of statin therapy

18 Lipoprotein(a) levels in Familial Hypercholesterolaemia Cardiovascular risk is higher in those patients with lipoprotein(a) > 50 mg/dl carrying a receptor-negative mutation in LDLR gene compared with other less severe mutations. Alonso R et al J Am Coll Cardiol 2014

20 Biomarkers in assessment of CV risk in pts with familiar hypercholesterolemia In asymptomatic individuals, CAC score may be superior to CT coronary angiography in risk prediction, and more clinically useful than CIMT. Cho I et al. Circulation 2012 Anderson T et al Can J Cardiol 2013

21 National Collaborating Centre for Primary Care (UK). (2008). NICE clinical guideline 71: Identification and management of familial hypercholesterolaemia, London European Heart Journal 2013

22 Family Screening Has Dramatically Increased Treatment Rates in the Netherlands Effects of Family-Based Screening on Treatment Rates in People with FH N = 5,442 37% identified as HeFH (based on LDL-R mutations) Umans-Eckenhausen MAW, et al. Lancet. 2001;357:

23 Role of Genetic Typing in FH Highlights from this discussion include the role of genetic typing for diagnosis Understanding disease mechanism Potential guidance in treatment algorithms Journal of Clinical Lipidology, Vol 6, No 3, June 2012

24 LDL cholesterol targets (i) children,3.5 mmol/l (135 mg/dl), (ii) adults,2.5 mmol/l (100 mg/dl),6 (iii) adults with CHD or diabetes,1.8 mmol/l (70 mg/dl) These targets are for both heterozygous and homozygous FH regardless of age. However, in children and adults with homozygous FH, these values are extremely difficult to achieve with current treatments. Reiner Z, Catapano AL, De BG, Eur Heart J 2011

25 C. Baigent, Lancet 2010

28 Treatment Children: (i) Statin, (ii) Ezetimibe, (iii) Bile acid-binding resin, (iv) Lipoprotein apheresis in homozygotes. Statins for children should only be those that have been shown to be safe in this group. Adults: (i) Maximal potent statin dose, (ii) Ezetimibe, (iii) Bile acid-binding resins, (iv) Lipoprotein apheresis in homozygotes and in treatment resistant heterozygotes with CHD.

29 Maximal potent statin dose is essential. (i),1/20 achieve the recommended LDL cholesterol targets; (ii) most need to decrease LDL cholesterol by at least 50%; (iii) many receive statin doses insufficient to attain LDL cholesterol targets; (iv) many physicians do not uptitrate statin doses despite suboptimal treatment.

30 MI Rates in FH patients vs. Non-Statin Rx and Normals Age >55 y/o Versmissen J, et al. BMJ. 2008;337:a2423.

31 Reduction in Mortality in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in Lipid- Lowering Therapy 149 pts with homozygous FH mean reduction in lowdensity lipoprotein cholesterol = only 26.4% Raal FJ et al. Circulation. 2011

33 Novel therapies LDL- and Lp(a)-lowering agents Currently at advanced stages of development, therapies targeting PCSK9 anti-sense oligonucleotides targeting APOB (mipomersen) microsomal triglyceride transfer protein inhibitors cholesteryl ester transfer protein inhibitors

35 Diagnostic and treatment: summary

36 Συμπεράσματα Η οικογενής υπερχοληστερολαιμία οφείλεται κυρίως σε μεταλλάξεις του γονιδίου του υποδοχέα της LDL. Η σημαντικότερη επιπλοκή είναι η αυξημένη επίπτωση πρώϊμης και επιταχυνόμενης αθηρωματικής νόσου, ιδιαίτερα στους ομοζυγώτες όπου η στεφανιαία νόσος εμφανίζεται ήδη από την ηλικία των 10 ετών. Η θεραπεία της οικογενούς υπερχοληστερολαιμίας σήμερα περιλαμβάνει μία σειρά φαρμακευτικών υπολιπιδαιμικών παραγόντων με σημαντικότερο εκπρόσωπο τις στατίνες, που στοχεύουν στην αναστολή της ενδογενούς σύνθεσης της χοληστερόλης, και τις ρητίνες δέσμευσης των χολικών αλάτων και την εζετιμίμπη που παρεμποδίζουν την απορρόφησή της από το έντερο. Παράλληλα πραγματοποιείται σειρά ερευνών και κλινικών μελετών με ικανοποιητικά αποτελέσματα για την ανακάλυψη νέων υπολιπιδαιμικών παραγόντων που θα συμβάλλουν μελλοντικά στην επίτευξη του στόχου της περαιτέρω μείωσης των επιπέδων της LDL χοληστερόλης στους ασθενείς με οικογενή υπερχοληστερολαιμία. Η μη φαρμακευτική θεραπεία περιλαμβάνει την LDL- αφαίρεση, η οποία αποτελεί μία μέθοδο ικανή να απορροφήσει την LDL χοληστερόλη κατευθείαν από το πλήρες αίμα, με σημαντικότατα οφέλη κυρίως για τους ομοζυγώτες αλλά και τους βαρειάς μορφής ετεροζυγώτες ασθενείς.

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