• Certain populations have higher prevalence: French Canadians, Dutch Afrikaners, Lebanese Christians, and Ashkenazi Jews can have rates as high as 1 in 100 due to founder effects ^[5].
• In Hong Kong/Chinese populations: The prevalence is similar globally (~1 in 250–500), but the phenotypic expression may differ (see below) ^[2][6].
• Underdiagnosis is a major problem: It is estimated that < 10% of FH patients worldwide are diagnosed, and < 25% receive adequate treatment ^[3].

• Chinese heterozygous FH patients usually do not have a markedly elevated LDL compared to Western FH patients, because environmental factors (traditional Chinese diet, lower saturated fat intake) modulate the phenotype ^[2][5].
• However, Chinese homozygous FH patients are severely affected regardless of diet ^[2].
• With Westernisation of diet in Hong Kong, the phenotypic gap is narrowing.

Cholesterol is a hydrophobic lipid — it cannot dissolve in blood. Therefore, it must be transported in lipoproteins: spherical particles with a hydrophilic outer shell (phospholipids + apolipoproteins) surrounding a hydrophobic core (cholesterol esters + triglycerides).

This is the pathway disrupted in FH:

1. LDL particles circulate in blood, each carrying one ApoB-100 molecule on their surface.
2. ApoB-100 on LDL binds to the LDL receptor (LDLR) on hepatocyte surfaces.
3. The LDL-LDLR complex is internalised via clathrin-coated pits (receptor-mediated endocytosis).
   • The adaptor protein LDLRAP1 (also called ARH) facilitates the coupling of LDLR to the clathrin machinery.
4. Inside the cell, the endosome acidifies → LDL dissociates from the receptor.
5. LDL is delivered to lysosomes → cholesterol esters are hydrolysed → free cholesterol is released for cellular use.
6. LDLR is recycled back to the cell surface to bind more LDL.

• PCSK9 (Proprotein Convertase Subtilisin/Kexin type 9) is a protein secreted by hepatocytes that binds to the LDLR on the cell surface.
• When PCSK9 binds LDLR, it targets the receptor for lysosomal degradation instead of recycling.
• Net effect: PCSK9 reduces the number of LDLRs on the hepatocyte surface → fewer LDL particles are cleared → higher plasma LDL-C.

Think of PCSK9 as a "receptor destroyer" — it prevents LDLRs from being recycled.

• When intracellular cholesterol is adequate, the cell downregulates LDLR expression (via SREBP-2 pathway) and upregulates cholesterol ester storage.
• When intracellular cholesterol is low (e.g., statin therapy inhibits HMG-CoA reductase → ↓ de novo cholesterol synthesis), the cell upregulates LDLR expression → more LDL clearance from blood.

This is exactly why statins work — but also why they are less effective in homozygous FH (where there are no functional LDLRs to upregulate).

FH is caused by mutations that impair the LDL receptor pathway. The four main genes are ^[1][2][5]:

Over 2,000 different LDLR mutations have been described. They are classified into 5 classes based on which step of the receptor lifecycle is disrupted:

Class 1 (null) mutations cause the most severe phenotype — essentially no functional receptor at all.

Several autosomal recessive conditions mimic homozygous FH ^[5]:

The key concept is cumulative LDL exposure over time. Imagine LDL-C as a toxic substance constantly bathing your arteries:

• A normal individual might have LDL-C of ~3 mmol/L
• A HeFH patient has LDL-C of ~5–10 mmol/L from birth
• A HoFH patient has LDL-C of ~13–25+ mmol/L from birth

By age 20, a HoFH patient has had the same cumulative LDL exposure as a 60-year-old normal individual. This explains why most HoFH individuals experience severe coronary heart disease by their mid-20s ^[2][5].

When LDL-C is chronically elevated:

1. LDL particles infiltrate tendons, skin, and cornea
2. Macrophages phagocytose oxidised LDL via scavenger receptors → become foam cells
3. Foam cell accumulation in tendons → tendon xanthomas
4. Foam cell accumulation in periorbital skin → xanthelasma
5. Lipid deposition at the corneal periphery → arcus corneae

FH corresponds primarily to:

• Type IIa (major): Isolated ↑ LDL-C, normal triglycerides ^[2][5]
• Sometimes Type IIb: ↑ LDL-C + ↑ VLDL (i.e., elevated cholesterol AND triglycerides) ^[2]

FH itself is often asymptomatic until ASCVD manifests. This is one of the reasons it is so dangerous — the first "symptom" may be a myocardial infarction.

• Inheritance: Autosomal dominant (LDLR, APOB, PCSK9) ^[1][5][8]
• Lipid pattern: Type IIa (isolated ↑ LDL-C) or sometimes IIb ^[2][5]
• Key features: Tendon xanthomas (pathognomonic), arcus corneae in young patients, premature ASCVD, strong family history
• LDL-C: HeFH ~5–10 mmol/L; HoFH ~13–25+ mmol/L

ARH is an important differential diagnosis when evaluating FH ^[5].

• Inheritance: Autosomal recessive
• Genes: LDLRAP1 (most classic), ABCG5/ABCG8 (sitosterolaemia), CYP7A1 ^[5]
• Clinical phenotype: Similar to classical homozygous FH — very high LDL-C, tendon xanthomas, premature ASCVD ^[5]
• Key distinguishing feature: AR inheritance pattern → both parents are carriers (often normal lipids), consanguinity common, no vertical transmission pattern
• Why it matters: ARH patients may respond better to statins than true HoFH patients, because they have functional LDLRs — the problem is in receptor internalisation, not receptor function per se. Also, sitosterolaemia requires treatment with ezetimibe (blocks sterol absorption) rather than statins.

• Prevalence: Common (~1–2% of population); the most common primary hyperlipidaemia overall
• Inheritance: Complex/oligogenic (not a single gene); sometimes considered AD with variable penetrance
• Lipid pattern: Type IIb — ↑ LDL-C AND ↑ triglycerides (↑ VLDL). The lipid phenotype may fluctuate between visits (sometimes mainly ↑ cholesterol, sometimes mainly ↑ TG, sometimes both)
• Key distinguishing features from FH:
  • No tendon xanthomas (this is a critical differentiator — tendon xanthomas are specific to FH, not FCHL)
  • Metabolic syndrome features are common (obesity, insulin resistance, hypertension)
  • Variable lipid phenotype between family members and over time
  • Family history of mixed lipid abnormalities rather than isolated ↑ LDL-C
• Mechanism: Hepatic overproduction of ApoB-100-containing lipoproteins (VLDL and LDL)

Another inherited cause of hypercholesterolaemia that is an important differential ^[5].

• Inheritance: Autosomal recessive (homozygous ApoE2/E2 genotype — but E2/E2 is necessary but not sufficient; a "second hit" like obesity, DM, or hypothyroidism is usually required to manifest)
• Lipid pattern: Type III — ↑ total cholesterol AND ↑ triglycerides roughly equally (characteristic "combined" elevation with TC:TG ratio ~1:1)
• Pathophysiology: ApoE2 has poor binding affinity for hepatic receptors → impaired clearance of chylomicron remnants and IDL → accumulation of β-VLDL (remnant particles)
• Key distinguishing features from FH:
  • Palmar crease xanthomas (xanthoma striata palmaris) — pathognomonic for Type III (yellow-orange deposits in palmar creases)
  • Tuberous xanthomas (elbows, knees) — also seen, but these can overlap with severe FH
  • Equal elevation of TC and TG (FH typically has isolated ↑ LDL-C with normal TG)
  • Responds well to fibrates (unlike FH which needs statins)
• Diagnosis: ApoE genotyping (E2/E2); lipoprotein electrophoresis showing broad-β band

• Prevalence: The most common cause of moderately elevated LDL-C in the general population
• Inheritance: No single gene; cumulative effect of many common genetic variants (SNPs), each contributing a small amount to LDL-C elevation, combined with environmental factors (diet, obesity)
• Lipid pattern: Moderately ↑ LDL-C (usually 4–6 mmol/L), much lower than typical FH levels
• Key distinguishing features from FH:
  • No tendon xanthomas
  • No clear Mendelian inheritance pattern in the family (sporadic or variable)
  • LDL-C less markedly elevated than in FH
  • No causal monogenic mutation on genetic testing
  • Good response to lifestyle modification + moderate-dose statin

Xanthoma present but no hypercholesterolaemia ^[5] — this is the key distinguishing feature.

• Inheritance: Autosomal recessive (CYP27A1 mutation)
• Pathophysiology: Deficiency of sterol 27-hydroxylase → impaired bile acid synthesis → accumulation of cholestanol (not cholesterol) in tissues, especially tendons and brain
• Key distinguishing features from FH:
  • Tendon xanthomas present (especially Achilles — mimics FH!)
  • But plasma cholesterol is NORMAL or even low
  • Neurological features: progressive cerebellar ataxia, dementia, spasticity, cataracts (bilateral juvenile cataracts are a classic clue)
  • ↑ Plasma cholestanol on sterol analysis (diagnostic)
  • Chronic diarrhoea in childhood (bile acid deficiency)
• Treatment: Chenodeoxycholic acid (CDCA) replacement — replaces deficient bile acids, suppresses cholestanol production

This enters the differential only when severe hyperlipidaemia is present, but the lipid pattern is completely different from FH:

• Inheritance: Autosomal recessive (~1–2 per million)
• Genes: LPL, ApoC-II, ApoA-V deficiency ^[7]
• Lipid pattern: ↑↑ Triglycerides ( > 10 mmol/L), milky/lipaemic serum
• Key features: Hepatosplenomegaly, eruptive xanthomas (small yellow papules on trunk/buttocks), acute pancreatitis, lipaemia retinalis, recent memory loss ^[7]
• Distinction from FH: Completely different lipid profile (TG >> cholesterol); eruptive xanthomas rather than tendon xanthomas

• Inheritance: AD, genetically heterogeneous (~1% of population) ^[7]
• Lipid pattern: Moderate ↑ TG (2.3–5.6 mmol/L), associated with metabolic syndrome features
• Distinction from FH: TG elevation dominates; LDL-C usually normal or low; no tendon xanthomas

The DLCN uses a point-based system across five domains. Only the highest scoring item from each category is counted (you do not sum within categories — pick the single highest-scoring criterion per domain).

Score Interpretation ^[7]:

Key points about the DLCN scoring:

• Tendinous xanthomata score 6 points — they are so specific for FH that finding them alone nearly makes the diagnosis (add even LDL-C 4.0–4.9 = 1 point → total 7 = probable FH).
• A confirmed pathogenic mutation scores 8 points — this alone makes it "definite FH" regardless of cholesterol level. This reflects the fact that genetic testing is the gold standard.
• LDL-C ≥ 8.5 mmol/L also scores 8 points — because such extreme elevations are virtually diagnostic of a monogenic cause.
• The system is designed to estimate pre-test probability before genetic testing — elevated cholesterol, family history, etc. determine pre-test probability ^[4].

This system classifies FH as "definite" or "probable" ^[7]:

Criterion 1 — Cholesterol levels (must be present):

• Total cholesterol > 7.5 mmol/L in adults (or > 6.7 mmol/L in children < 16 years)
• OR LDL-C > 4.9 mmol/L in adults (or > 4.0 mmol/L in children < 16 years)

Criterion 2 — Tendon xanthomas:

• Tendon xanthomas in the patient OR in a first- or second-degree relative

Criterion 3 — DNA-based evidence:

• DNA-based evidence of an LDLR, ApoB, or PCSK9 mutation

Criterion 4 — Family history of MI:

• Family history of MI: < 50 years in second-degree relative, or < 60 years in first-degree relative

Criterion 5 — Family history of elevated cholesterol:

• Family history of raised total cholesterol: > 7.5 mmol/L in adult first- or second-degree relative, or > 6.7 mmol/L in child/sibling < 16 years

The Simon Broome system is particularly useful in the UK. For HKUMed exams, the DLCN criteria are more commonly tested, but know both ^[7].

This is the simplest system — it uses age- and family-specific LDL-C cut-offs alone:

All values in mmol/L of total cholesterol.

The logic: the closer you are genetically to a known FH case, the lower the threshold needed to diagnose FH in you (because your prior probability is already higher).

From the senior notes and lecture slides, a simpler framework is also taught ^[2][5]:

Criteria for clinical diagnosis of FH:

• Positive family history + high LDL level ^[2][5]
• Presence of tendon xanthoma + high LDL level ^[2][5]
• Very high LDL level alone — patient aged < 20 years with LDL-C > 6.2 mmol/L is definite for FH ^[2][5]
• DNA testing — presence of causal mutation of FH (mutation identification rate can be as high as 86%) ^[2][5]

When to perform genetic testing:

• DLCN score ≥ 6 (probable or definite clinical FH)
• When diagnosis is uncertain ^[5]
• For cascade screening of family members once an index case is confirmed ^[5]

What is tested:

• Panel sequencing of LDLR, APOB, PCSK9 genes (± LDLRAP1, ABCG5/8 if AR pattern suspected) ^[1][5][12]
• Includes sequencing for point mutations, small insertions/deletions
• May include MLPA (Multiplex Ligation-dependent Probe Amplification) to detect large deletions/duplications in LDLR

Key findings and interpretation:

Why genetic testing matters beyond diagnosis:

1. Cascade screening: Once you identify the mutation in the proband, you can offer targeted mutation testing to all first-degree relatives (cheaper, faster, and more definitive than lipid testing alone)
2. Prognostic value: Certain LDLR mutation classes (e.g., Class 1 null mutations) predict more severe phenotype and poorer statin response
3. Treatment implications: PCSK9 gain-of-function mutations → consider PCSK9 inhibitors early
4. Depth of genetic sequencing also affects the prevalence of disease in a population — the more comprehensively you screen, the more cases you identify ^[4]

Lifestyle measures are the foundation but diet alone is ineffective in familial conditions ^[8][9] — the genetic defect means the body cannot clear LDL regardless of dietary cholesterol intake. Nevertheless, lifestyle modification remains important as an adjunct:

"Too high — will not be able to get it down based on diet alone → statins first line" ^[6]. This was the explicit teaching in the Three Cases lecture.

"Ezetimibe" = "eze" (ease) + "tim" + "-ibe" (cholesterol absorption inhibitor class).

Mechanism of Action

1. Ezetimibe selectively inhibits NPC1L1 (Niemann-Pick C1-Like 1) transporter on the brush border of enterocytes in the jejunum
2. This blocks intestinal absorption of dietary and biliary cholesterol
3. ↓ Cholesterol delivery to the liver → compensatory ↑ LDLR expression → ↑ LDL clearance
4. When combined with a statin: dual mechanism — statin ↓ synthesis + ezetimibe ↓ absorption → complementary and additive effect

The majority of HeFH patients will not achieve LDL-C target on statin alone — add ezetimibe or PCSK9 inhibitor ^[7].

FH patients must have all modifiable CV risk factors addressed simultaneously:

The relationship is dose-time dependent. Think of it as a "cholesterol-years" exposure model ^[10]:

• Normal individual (LDL-C ~3 mmol/L) accumulates arterial cholesterol burden gradually, reaching the atherosclerotic "threshold" for ischaemic events around age 50–60 in males and 60–70 in females.
• HeFH patient (LDL-C ~5–10 mmol/L) reaches this threshold decades earlier — typically age 30–50.
• HoFH patient (LDL-C ~13–25+ mmol/L) reaches this threshold by age 20 or earlier — some develop critical coronary disease in childhood ^[10].

"The fact that these patients have such early onset CAD helps emphasise the point that LDL-C is an important independent predictor for CAD events → the implication is that you aggressively treat this cholesterol to protect" ^[10].

Hypercholesterolaemia is a risk factor that only increases the risk of arterial thrombosis, but NOT venous thrombosis ^[17] — this is an important distinction. The thrombotic mechanism in FH is atherosclerotic plaque rupture → arterial thrombus, not the coagulation cascade abnormalities that drive venous thromboembolism.

This is the leading cause of death in FH.

Pathophysiology of coronary events in FH:

1. ↑↑ LDL-C → LDL particles penetrate coronary artery endothelium
2. Subendothelial oxidation of LDL → recruitment of monocytes → foam cell formation → fatty streak
3. Progressive plaque growth with smooth muscle cell migration, fibrous cap formation, necrotic lipid core
4. Plaque rupture or erosion → exposure of thrombogenic material to blood → acute coronary thrombosis
5. Acute myocardial infarction or, if thrombus is non-occlusive, unstable angina

Early ( < 23 years) coronary artery calcification is a useful marker for heterozygous FH ^[7] — this represents calcification of atherosclerotic plaques that have already formed by the second decade of life.

Stroke is less common than MI in FH but still significantly elevated compared to the general population, particularly in patients with additional risk factors.