Focus on FH (Familial Hypercholesterolemia) Joshua W. Knowles, MD PhD for PCNA May, 2013
Conflicts CMO for The FH Foundation
Pre-talk quiz
What is cascade screening? 1. screening all family members 2. screening potentially affected family members 3. screening kids 69% 28% 4%
What is the goal LDL cholesterol for an FH patient? < 50% of pre-treatment LDL 100mg/dl 130mg/dl 60% 19% 22%
Mutations in 3 genes cause FH, what gene is not an FH gene? APOB LDLR PCSK9 LPA 12% 10% 57% 21%
DIAGNOSIS Familial Hypercholesterolemia
Can t find FH if you don t look! For adults > 20 yo: Suspect FH if LDL 190 mg/dl Average LDL in adult FH patients ~ 220 mg/dl FH more likely if FHx of premature coronary disease Look for physical exam findings of FH Xanthomas, xanthelasma, corneal arcus (< 45 yo) For children suspect FH if LDL 160 mg/dl
Formal Diagnostic criteria Three validated criteria MEDPED Dutch Lipid Clinic Network Simon Broome Register Once FH proband identified lower cut-offs for LDL should be used
Slide from MEDPED, courtesy of Dr. Hopkins
Dutch Lipid Clinic Network criteria Haase and Goldberg, 2012 Curr Op Lipidology WHO report on FH 1999
There s an app for that!
GENETICS and CASCADE SCREENING Familial Hypercholesterolemia
Genetics of FH Autosomal dominant, > 90% penetrance Prevalence heterozygous FH ~ 1 in 500 Homozygous FH ~ 1 in 1 Million Mutations in 3 genes known to cause FH: LDLR (>1000 variants identified, 80-95% of cases) PCSK9 (< 5% of cases): increased activity leads to degradation of LDLR APOB (5-10% of FH in Northern Europe) Decreased binding of ApoB containing particles to LDLR
Genetic mutations that cause FH impair LDL clearance FH is typically caused by mutations in LDLR, Apo B, PCSK9 Apo B: acts as ligand-binding LDL particle to receptor 1:1000 or 10% of FH cases Circulation Liver cell LDL receptor (LDLR): on hepatocyte, binds to Apo B on LDL particle, inducing endocytosis of LDL 1:500 or >85% of mutations PCSK9 enzyme: degrades LDL receptors 1:2500 or <5% of FH cases LDLRAP1 = low-density lipoprotein receptor adaptor protein 1. Image reproduced from: Department of Life Sciences and Institute and Institute of Genome Sciences Web site. http://www.dls.ym.edu.tw/ol_biology2/ultranet/endocytosis.html. Published June 11, 2001. Accessed January 19, 2012. 1. De Castro-Oros I, et al. Appl Clin Genet. 2010;3:53-64. 2. Rader DJ, et al. J Clin Invest. 2003;111:1795-1803. Slide courtesy of NSGC 3. Hopkins PN, et al. J Clin Lipol. 2011;5(3 suppl):s9-s17.
Genetic testing is not: Or
Genetic testing for FH In the US, the FH usually diagnosed on clinical grounds. Genetic testing can be used in cases where the diagnosis is unclear. Genetic testing is widely used in many countries. Testing generally involves sequencing 3 genes (LDLR, APOB and PCSK9). The yield on genetic testing is ~85% in definite FH cases and ~50% in possible FH. It is probable that this method will be used more widely. May be particularly useful for cascade screening.
Whether or not genetic testing is used cascade screening is a MUST! UK screening algorithm NICE guidelines (UK), FH 2008 (Natl Inst. Health and Clin. Ex.)
Every family tree is a Family Pre-treatment lipids: TC 327 LDL 265 HDL 51 TG 55
If no genetic test results you must use less stringent LDL levels in screening relatives!
Dutch experience National lipid and genetic cascade screening program for FH (prevalence 1:400) Set up 1994 So far identified over 25000 FH patients First 5 years screened 5442 relatives of 237 FH patients and identified 2039 carriers. Initially only 39% were on meds 2 years after molecular diagnosis 85% on meds Cascade genetic testing is cost effective $8700 per life year gained Work from JJP Kastelein s group Leren, T et al. Comm Genetics 2008
CDC has classified FH as a Tier 1 condition FH is a Winnable battle
FH Foundation and Registry
MANAGEMENT Familial Hypercholesterolemia
Management Diet/lifestyle changes important Reduce saturated fat High soluble fiber: 10-20g/day Consider dietician referral Statins are the mainstay of therapy Many will require 2 or more drugs Treat other risk factors (HTN, smoking) DO NOT USE standard risk assessment tools (like Framingham) to estimate risk
Goals of therapy FH patients are considered high risk based on NCEP, AHA/ACC, NLA guidelines Rule of thumb to try to cut LDL by 50% Ultimate goal LDL < 100 or even < 70 mg/dl Unlike garden variety HLD non-statin agents like ezetimibe are standard of care Proper therapy can reduce risk of CHD by 80% NCEP ATP Guidelines, Circ 2002.
In properly treated FH patients, mortality is similar to the general population Data starting Jan 1, 1990 Just after first statin introduced in the Netherlands Versmissen, J et al. BMJ. 2008
Many FH patients cannot get to goal LDL levels with current therapies HeFH Only ~ 20% of patients achieve LDL < 100 mg/dl Only ~ 40% of patients achieve LDL < 130 mg/dl Statin intolerance is a big problem. In clinical practice ~ 10-15% of FH patients are statin intolerant or have significant side effects Majority of HoFH do not have a healthy LDL. Most have disease progression even with apheresis Pijlman et al. Atherosclerosis. 2009
LDL apheresis is indicated for HoFH and sometimes for HeFH Apheresis lowers LDL ~80% acutely and ~40% chronically (weekly or biweekly) Indicated if LDL not at goal after 6 mo of diet/meds: HoFH with LDL 300mg/dl HeFH with LDL 300mg/dl plus 0-1 risk factors HeFH with LDL 200mg/dl and 2+ high risk factors HeFH with LDL 160mg/dl very high risk (known CAD) Limited by availability, cost and duration of therapy Usually require weekly sessions, offered ~ 40 centers in US Raal and Santos. Atherosclerosis. 2012 Horton. J. Lipid. Res. 2009
Drug therapies PCSK9 inhibitors Slide adapted from Dan Rader
Class Statins Bile Acid Sequestrants Cholesterol Absorption Inhibitor Stanol esters Nicotinic acid LDL apheresis Primary Mechanism of Action (Effects on Lipoprotein Metabolism 1 ) Inhibition of HMG-CoA Reductase ( LDLC clearance via LDL receptors) Bile acid re-absorption ( LDLC clearance via LDL receptors) Intestinal Cholesterol absorption via NPC1L1 ( LDLC clearance via LDL receptors) Intestinal Cholesterol absorption ( LDLC clearance via LDL receptors) Inhibits lipolysis in adipocytes ( VLDL/LDL synthesis; HDLC clearance) Removal of ApoB containing particles ( VLDL, IDL, LDL, RLP) % Reduction in LDL-C HeFH HoFH >35% 2 Up to 28% 3 Usually 10-20% 15% <10% 15% <10% 10% <10% 20% <10% ~40% 4 (up to 75% acutely 5 ) Lomitapide Inhibition of MTP Not indicated ~ 40% Mipomersen ApoB antisense Not indicated ~ 25% Table adapted from Rader DJ, et al. J Clin Invest. 2003;111(12):1796-1803. 1. Stone, NJ and Blum, CB. (2005) Management of Lipids in Clinical Practice. 5 th Ed. 2. Kastelein JJ, et al. N Engl J Med. 2008;358(14);1431-1443. 3. Raal FJ, et al. Atherosclerosis. 2000;150(2):421-428. 4. Ito MK, et al. J Clin Lipidol. 2011;5(3 Suppl):S38-S45. 5. Gordon BR, et al. Am J of Card. 1998;81(4):407-411.
29 HoFH patients Avg LDL 340mg/dl
Mipomersen Antisense to ApoB. Weekly injection Lowers LDL and Lp(a) Raal et al. Lancet 2010
Summary FH is a serious cause of morbidity and mortality Prevalence HeFH 1:500 Vastly under diagnosed and treated Suspect FH if untreated LDL > 190 in an adult Take additional family history, look for xanthomas With proper therapy, morbidity is similar to general population Most will require 2 or more drugs Imperative to initiate cascade screening in family members
Post-test quiz What is cascade screening? Screening relatives of affected individuals What is the goal LDL for an FH patient? Half or < 100 mg/dl Mutations in 3 genes cause FH, what are they? LRLR, APOB, PCSK9