Diagnosis and Natural History of HoFH
Dirk Blom
UCT Cape Heart Centre
Lipid Clinic - Groote Schuur Hospital
Diagnosis
Classical Clinical Definition
• Untreated LDL-C> 13.0 mmol/L or treated LDL-C > 8.0 mm/L
AND
• Cutaneous or tendinous xanthomata before the age of 10 years
• LDL-C in both parents compatible with a diagnosis of heterozygous FH
Genetic Definition
• Genetic confirmation of two alleles with pathogenic mutations in the following genes
• LDL receptor
• ApoB
• PCSK9
• LDL receptor adaptor protein 1 (recessive phenotype)
Genetic Complexity
• True homozygotes• Same gene, same mutation• Predominantly seen in founder populations
• Compound heterozygote• Same gene, different mutations
• Double heterozygotes• Heterozygous mutations in different genes
• Complex genetic situations• Complex combinations of mutations in different genes
Gene Dose Effect
• Heterozygous FH• Tendon xanthomata in adults• LDLC 5-13 mmol/L• IHD in adults
• Homozygous FH• Skin and tendon xanthomata before age of 10• LDLC > 13.0 mmol/L• Markedly premature CHD: childhood,
adolescence• Supravalvular aortic stenosis
Phenotypic Variability
Eur Heart J. 2014 Aug 21; 35(32): 2146–2157.
Phenotypic Variability
+ Null, Null
◊ Null, Defective
■ Defective/ Defective
All patients lower than mean are defective/defective
Eur Heart J. 2014;36(9):560-565. doi:10.1093/eurheartj/ehu058
Groote Schuur Hospital Experience
‘Hidden Homozygotes’
Making the Diagnosis
Consider the Diagnosis
Clinical
• Family history• Hypercholesterolaemia in both parents
• Exceptions• Autosomal recessive hypercholesterolaemia
• Paternity in doubt
• LDL-C hypercholesterolaemia• The likelihood of a diagnosis of HoFH increases with LDL-C
• Physical stigmata• Interdigital xanthoma
Physical Stigmata
Genetic Diagnosis
• Often easier in countries with founder mutations
• Should be undertaken in close collaboration with the clinician caring for the patient• Define phenotype precisely before undertaking genetic
investigations
• It can remain challenging to assess the pathogenicity of novel mutations
Functional Diagnosis
• LDL uptake studies• Fibroblasts
• Lymphocytes
• Turnover studies
• Currently functional tests are rarely performed and residual LDLR functionality is usually inferred based on genotype
Differential Diagnosis
• Genetic disorders• Sitosterolaemia
• Dysbetalipoproteinaemia
• Other conditions with severe hypercholesterolaemia• Lipoprotein X
• Nephrotic syndrome
• Hypothyroidism• Severe hypertriglyceridaemia
Natural History
Circulation. 2011;124:2202–2207
Lipid Outcomes
UntreatedTaking Modern Lipid-
Lowering TherapyChange, %
Total cholesterol, mmol/L
17.3±3.8 13.1±3.3* −24.3
Triglycerides, mmol/L 1.28±0.81 1.18±0.63 −7.8
HDL-C, mmol/L 0.89±0.33 0.91±0.25 2.2
LDL-C, mmol/L 15.9±3.9 11.7±3.4* −26.4
LDL/HDL ratio 21.4±10.9 13.5±5.9* −36.9
149 patients with HoFHJohannesburg and Cape Town clinicsCirculation 2011;124:2202-2207
Statins + EzetimibeLittle apheresis
Other Cohorts
Atherosclerosis 2016 248, 238-244DOI: (10.1016/j.atherosclerosis.2016.03.009)
Recent Clinical Trials
• Mean (SD) LDLC on treatment/ Primary Endpoint
• Mipomersen 8.4 (3.1) mmol/L
• Lomitapide 4.3 (2.5) mmol/L
• Evolocumab 7.1 (0.8) mmol/L
• Evinacumab 5.6 (4.9) mmol/L (pilot study)
• Note: Baseline LDLC and treatments (e.g. apheresis) differed between studies
Vascular Complications
• Premature atherosclerosis• Predominantly coronary artery disease
• Ostial stenosis occurs frequently
• Aortic root and valve disease• Aortic valve stenosis
• Supravalvular aortic stenosis
• Frequently requires AVR as well as an aortic graft
Cholesterol Year Score
Atherosclerosis. 2012 Aug;223(2):262-8
Dutch /ZA/Mipomersen Cohort
• 167 patients• Mean age at first CV event 26.2 (range 6-63)
• 19 patients had AVR at mean age of 25.9 years
• 34 patients had undergone CABG at mean age of 28.6 years
• Marked phenotypic variability noted
• HICC Registry to document homozygous phenotypes worldwide
Atherosclerosis 2016 248, 238-244DOI: (10.1016/j.atherosclerosis.2016.03.009)
Outcome and LDL-C
European Heart Journal, Volume 39, Issue 14, 07 April 2018, Pages 1162–1168,
TC on treatment• Quartile 1 < 8.1 mmol/L• Quartile 2+3 8.1-15.1 mmol/L• Quartile 4 >15.1 mmol/L
All death
Cardiovascular death
‘Outcome Study’
Circulation, Volume: 124, Issue: 20, Pages: 2202-2207, DOI: (10.1161/CIRCULATIONAHA.111.042523)
Annualized MACE Rates
HoFH background Mipomersen-treated HoFH Lomitapide-treated Evolocumab treated
Number of patients 23 23 19 106
Mean age at baseline 31 years 30.7 years 34 years
Mean baseline LDL-C 455mg/dL 336mg/dL 324mg/dL
Mean LDL-C between 6 and 12 months on treatment*
NA 331mg/dL 166mg/dL 286mg/dL
Apheresis NR None 62% 32%CVD at baseline NR NR 93% 51%
Number of major CV events§ 12 4 2 4
Number of patient years 46 35 98 185
Annualized event rate 26.1% 11.4% 2.0% 2.1%
Events/1000 months 21.7 9.5 1.7 1.8
Orphanet J Rare Dis. 2018; 13: 96
Conclusions - Diagnosis
• Suspect diagnosis based on clinical features and family history• Severe phenotypes are clinically obvious
• Milder phenotypes can usually only be identified following genetic testing
• Identification of milder phenotypes is relevant for genetic counselling
• Therapeutically severe phenotypes are of most concern
Conclusions – Natural History
• Survival is determined by on-treatment LDL-C
• Lower LDL-C is associated with better survival
• Novel therapies are allowing us to reduce LDL-C to previously unimaginable levels in patients with HoFH
• Early and aggressive therapy is likely to alter the natural history of HoFH substantially
• Do not shy away from combination therapy!