OIKOΓΕΝΗΣ ΥΠΕΡΧΟΛΗΣΤΕΡΟΛΑΙΜΙΑΔΙΑΓΝΩΣΗ ΚΑΙ ΘΕΡΑΠΕΙΑ

Νικόλαοs Ιωακειμίδηs

Καρδιολόγοs, Επιστημονικόs ΣυνεργάτηsΑ’ Καρδιολογική Κλινική, Ιπποκράτειο ΓΝΑ

FH Is Not a Rare Genetic Disease: Prevalence is 2x Other Inherited Conditions

1. Genetic Alliance UK. Available at http://www.geneticalliance.org.uk/education3.htm.2. Streetly A, et al. J Clin Path. 2010;63:626-629.

Neuro-fibromatosis

1Familial combined hyperlipidemia has a frequency of 1:200 births; however, the genetic cause is unknown.2Sickle cell disease varies greatly by ethnicity.

Frequency per 1,000 Births ofCommon Genetic Disorders1

2

FH

2.0

FH: A Clinically Recognizable Genetic Disorder

• Inheritable, autosomal dominant disorder1

• Usually due to mutations in LDL receptor gene2,3 that result in decreased clearance of LDL particles from plasma1

– Other mutations include those in the Apo B and PCSK9 genes

• Clinical manifestations include1,2

– 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;25:49-68.2. Mahley RW, et al. In: Kronenberg: Williams Textbook of Endocrinology. 2008.3. Rader DJ, et al. J Clin Invest. 2003;111:1795-1803.

Visible Signs of FH

A- Xanthelasma

B – Corneal arcus (Arcus senilis)

C - Achilles tendon xanthomas

D - Tendon xanthomas

E - Tuberous xanthomas

F - Palmar xanthomas

Despite the Importance of Early Detection, FH Is Under-diagnosed

<<

B.G. Nordestgaard et al. Eur Heart J 2013

Benn M et al J Clin Endocrinol Metab 2012

69 016 ptsHeterozyg FH

Prevalence of FH

Prevalence Is Much Higher in Specific Sub-populations or “Founder Groups”

North America and Europe:HeFH ~1:500 HoFH ~<1:106

Higher incidence of HoFH:Québec, Tunisia, South Africa, Lebanon

Naoumova RP, et al. Curr Opin Lipidol. 2004;15:413-422.

-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

Massive undertreatment of individuals with FH

Pathophysiology and Genetics

The Phenotype of FH May Reflect LDL-R, Apo B, or PCSK9 Mutations

Apo B (site where receptor binds to LDL particle)

LDL receptor

Image reproduced from: http://www.dls.ym.edu.tw/ol_biology2/ultranet/Endocytosis.html.

Cytosol

Cell membrane

Extracellular Fluid

• 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

PCSK9

1. Kumar: Robbins and Cotran. Pathologic Basis of Disease, 2009.2. Rader DJ et al. J Clin Invest. 2003;111:1795-1803

LDL Particle:

Pathophysiology of heterozygous familial hypercholesterolaemia.

Clinical vs. mutation diagnosis

Overlap of clinical and mutation diagnosis of heterozygous familial hypercholesterolaemia

Heterozygous FH

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 andgender 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

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

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

Simon Broome Register1 MEDPED2 Dutch Lipid Clinic

Network1

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;168:1-14.2. As summarized in: Civiera F, et al. Circulation. 2004;173:55-68.

Comparison of FH Clinical Diagnostic Criteria by Method

LDL cholesterol burden in individuals with or without FH as a function of the age of initiation of statin therapy

Lifetime risk assessment and risk factors

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

Biomarkers in assessment of CV risk in pts with familiar hypercholesterolemia

In asymptomatic individuals, CAC score may be superior to CT coronary angiography inrisk prediction, and more clinically useful than CIMT. Cho I et al. Circulation 2012 Anderson T et al Can J Cardiol 2013

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

European Heart Journal 2013

Family Screening Has Dramatically Increased Treatment Rates in the Netherlands

Umans-Eckenhausen MAW, et al. Lancet. 2001;357:165–168.

Effects of Family-Based Screening on Treatment Rates in People with FH

N = 5,442

• 37% identified as HeFH (based on LDL-R mutations)

Role of Genetic Typing in FH

Journal of Clinical Lipidology, Vol 6, No 3, June 2012

Highlights from this discussion include the role of genetic typing for diagnosis

Understanding disease mechanism

Potential guidance in treatment algorithms

• (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.

LDL cholesterol targets

Reiner Z, Catapano AL, De BG, Eur Heart J 2011

C. Baigent, Lancet 2010

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.

Treatment

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.

MI Rates in FH patients vs. Non-Statin Rx and Normals

Versmissen J, et al. BMJ. 2008;337:a2423.

Age >55 y/o

Reduction in Mortality in Subjects With HomozygousFamilial Hypercholesterolemia Associated With Advances in Lipid-

Lowering Therapy

Raal FJ et al. Circulation. 2011

mean reduction in low-density lipoprotein cholesterol = only 26.4%

149 pts with homozygous FH

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

Novel therapies

Diagnostic and treatment: summary

Η οικογενής υπερχοληστερολαιμία οφείλεται κυρίως σε μεταλλάξεις του γονιδίου τουυποδοχέα της LDL.

Η σημαντικότερη επιπλοκή είναι η αυξημένη επίπτωση πρώϊμης και επιταχυνόμενηςαθηρωματικής 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 τιςρητίνες δέσμευσης των χολικών αλάτων και την εζετιμίμπη που παρεμποδίζουν τηναπορρόφησή 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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