Familial hypercholesterolaemia 

Familial Hypercholesterolaemia (FH) is a relatively common inherited cause of premature coronary artery disease, transmitted in an autosomal dominant pattern. It is an inherited lipid disorder, where, if left untreated, men have a 50% risk of developing coronary heart disease (CHD) by age 50, while women have a 30% risk by age 60.

This condition is prevalent in certain populations, including Ashkenazi Jews from South Africa, Christian Lebanese, and Dutch Afrikaaners, due to a genetic founder effect. In Australia, it is estimated that around 45,000 people have FH, yet fewer than 10% have been formally diagnosed.

Before confirming a phenotypic diagnosis of FH, it is essential to exclude secondary causes of hypercholesterolaemia, such as:

• Hypothyroidism
• Nephrosis
• Cholestasis
• Steroid use

When to consider familial hypercholesterolaemia:

FH should be suspected in adults with:

• A total cholesterol level of ≥7.5 mmol/L, or
• LDL-C ≥5.0 mmol/L, or
• A personal or family history of premature coronary heart disease.

Types of Familial Hypercholesterolaemia:

1. Heterozygous Familial Hypercholesterolaemia (HeFH):
   • Autosomal dominant disorder with high phenotypic penetrance, affecting approximately 1 in 250 people worldwide.
   • It is recognized as a major public health concern, with 50% of first-degree relatives also likely to have the condition.
   • Around 30% of individuals with HeFH have elevated lipoprotein(a) levels.
   • Mutations in genes such as APOB and PCSK9 can also cause dominant forms of FH, leading to markedly elevated LDL-C due to defective LDL receptor function in liver cells, resulting in premature cardiovascular disease (CVD) and, if untreated, death.
2. Homozygous Familial Hypercholesterolaemia (HoFH):
   • A more severe condition, affecting 1 in 300,000 people.
   • It occurs when two HeFH carriers have offspring, with a 25% chance of the child inheriting the homozygous form.
   • Children with HoFH present with extremely elevated LDL-C from birth and rarely survive beyond their teenage years without aggressive treatment starting in infancy.
3. Elevated Lipoprotein(a):
   • Lipoprotein(a) is a dominantly inherited disorder affecting about 20% of the population, characterized by the accumulation of lipoprotein(a) particles in plasma.
   • A high level (>50 mg/dL) increases the risk of coronary artery disease, peripheral artery disease, calcific aortic stenosis, and strokes.
   • Testing for lipoprotein(a) is not covered by the Medical Benefits Schedule in Australia and is typically performed by lipid specialists, particularly when there is a family history of heart disease.
   • Currently, there is no specific treatment available, though lipoprotein(a) apheresis is sometimes used. RNA-based therapies targeting the overproduction of apolipoprotein(a) are under investigation.

Summary of inherited lipid disorders
Type	Heterozygous (Homozygous familial hypercholesterolaemia)	Lipoprotein(a)	Familial combined hyperlipidaemia	Familial hypertri-glyceridaemia	Type III familial dysbetalipo-proteinaemia	Familial chylomicronaemia syndrome
Inheritance	Monogenic co-dominant		Polygenic with variable penetrance and secondary causes, environmental factors			Monogenic, recessive
Prevalence	1 in 250 (1 in 300,000)	1 in 5	1 in 100	1 in 500	1 in 5000	13 per million
Effect on lipids	Elevated LDL	Elevated lipoprotein(a)	Elevated LDL-C, triglyceride, ApoB	Elevated VLDL	Elevated intermediate density lipoprotein	Elevated chylomicrons
Clinical features	Premature CAD	CAD	Premature CAD	CAD, acute pancreatitis	CAD	Recurrent acute pancreatitis
Gene variants	LDLR, APOB, PCSK9	APOA	Several gene variants	APOE2/E2		Deficiency lipoprotein lipase or APOC-11
APO, apolipoprotein; CAD, coronary artery disease; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL, very low-density lipoprotein

Criteria: 

Dutch Lipid Clinic Network criteria for making a phenotypic diagnosis of familial hypercholesterolaemia in adults
Criteria		Score
Family history
First degree relative with known premature coronary and/or vascular disease (men aged <55 years, women aged <60 years)  OR First degree relative with known LDL-cholesterol above the 95th percentile for age and gender		1
First degree relative with tendinous xanthomata and/or arcus cornealis OR Children aged <18 years with LDL-cholesterol above the 95th percentile for age and gender		2
Clinical history
Patients with premature coronary artery disease (men aged <55 years, women aged <60 years)		2
Patients with premature cerebral or peripheral vascular disease (men aged <55 years, women aged <60 years)		1
Physical examination
Tendinous xanthomata		6
Arcus cornealis before 45 years of age		4
Investigation
LDL-cholesterol (mmol/L)	LDL-C ≥8.5	8
	LDL-C 6.5–8.4	5
	LDL-C 5.0–6.4	3
	LDL-C 4.0–4.9	1
Diagnosis		Total score
Definite FH		>8
Probable FH		6–8
Possible FH		3–5
Unlikely FH		<3

Screening approach

• opportunistic screening for family history
• opportunistic screening of lipids, systematic searching of general practice electronic records, and universal screening of children. 
• The use of Absolute Cardiovascular Disease Risk Assessment tools are best avoided in patients with suspected FH. These patients are already at increased risk of CHD, and the relative risk from their lifelong cholesterol burden is so great that it overrides all other risk factors
• The role of specialist lipid clinics is important in the GP management of patients with FH

The most cost effective method of screening for FH is cascade screening family members of known ‘index cases’ of FH but at a population level this requires that an efficient method be adopted to detect index cases. 

Treatment

• children with HeFH commence lifelong treatment from the age of 8–10 years
• statins should be avoided in pregnancy
• High-risk adults with HeFH should commence maximally tolerated doses of high potency statins on diagnosis and continue for life
• recommended that relevant specialist advice is sought for the care of children and pregnant women