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!