Dyslipidaemia is an abnormal elevation or reduction of lipids (cholesterol, triglycerides, or both) in the blood, increasing the risk of atherosclerotic cardiovascular disease.

Dyslipidaemia — Definition, Epidemiology, Risk Factors, Anatomy & Function, Etiology, Pathophysiology, Classification, and Clinical Features

2. Epidemiology

Category	Risk Factors
Non-modifiable	Age (↑ with age), male sex, family history of premature CHD (M < 55y, F < 65y), genetic predisposition (FH, FCHL, etc.) [3, 4]
Modifiable — Lifestyle	High saturated/trans-fat diet, physical inactivity, obesity (especially central/abdominal obesity), excessive alcohol intake, smoking [3, 4]
Modifiable — Medical	Type 2 DM (insulin resistance → ↑TG, ↓HDL-C, small dense LDL), hypothyroidism (↓LDL receptor activity), nephrotic syndrome (↑hepatic lipoprotein synthesis), CKD, cholestasis, drugs (thiazides, β-blockers, corticosteroids, OCP, protease inhibitors) [2, 4]

High Yield

Major risk factors for ASCVD (from ATP III and 2019 ESC/EAS, frequently tested) [3, 4]:

Age: M ≥45y, F ≥55y
Premature CHD in first-degree relative: M < 55y, F < 65y
Cigarette smoking
Hypertension ≥140/90 mmHg or on medication
Low HDL-C < 1.0 mmol/L
High HDL-C > 1.55 mmol/L is protective (negative risk factor — subtract one risk factor)
Diabetes mellitus

4. Anatomy and Physiology of Lipid Metabolism

Understanding dyslipidaemia from first principles requires knowing how lipids are transported, metabolised, and cleared. This section is critical — it underpins every drug mechanism and every clinical feature.

Lipoprotein	Size	Density	Main Lipid	Key Apolipoprotein	Origin	Atherogenic?
Chylomicron	Largest	Lowest	Dietary TG	apoB-48, apoC-II, apoE	Intestine	No (too large to cross endothelium)
VLDL	Large	Very low	Endogenous TG	apoB-100, apoC-II, apoE	Liver	Yes (via remnants and conversion to LDL)
IDL (VLDL remnant)	Medium	Intermediate	TG + cholesterol	apoB-100, apoE	Intravascular (from VLDL)	Yes
LDL	Small	Low	Cholesterol esters	apoB-100	Intravascular (from IDL)	Yes — most atherogenic
HDL	Smallest	Highest	Cholesterol esters + phospholipids	apoA-I, apoA-II	Liver, intestine, intravascular	No — anti-atherogenic
Lp(a)	Similar to LDL	Low	Cholesterol	apoB-100 + apo(a)	Liver	Yes — independent risk factor

Memory aid: Think "Bigger = more TG, Smaller = more cholesterol." Chylomicrons are TG-rich behemoths; LDL are small cholesterol-rich particles.

4.3 The Three Lipid Pathways

5. Etiology of Dyslipidaemia

Dyslipidaemia is classified as primary (genetic) or secondary (acquired). Always exclude secondary causes before diagnosing a primary dyslipidaemia [4, 7].

This is crucial clinically because treating the underlying cause may normalise lipids without needing lipid-lowering drugs [4, 7].

Biochemical Pattern	Secondary Causes	Mechanism
↑LDL-C	Hypothyroidism	↓thyroid hormone → ↓LDLr expression → ↓LDL clearance
	Nephrotic syndrome	↓albumin → compensatory ↑hepatic lipoprotein synthesis (liver "sees" low oncotic pressure and ramps up protein/lipoprotein production)
	Cholestasis (obstructive jaundice)	Bile acid excretion blocked → ↑intrahepatic cholesterol → ↓LDLr expression; also formation of lipoprotein X
	Anorexia nervosa	↓bile acid excretion + ↓LDLr activity
	Immunoglobulin disorders (myeloma)	Paraproteins bind lipoproteins → ↓clearance
	Drugs: cyclosporine, thiazides	Variable mechanisms
↑TG	Diabetes mellitus (T2DM)	Insulin resistance → ↑hepatic VLDL-TG secretion + ↓LPL activity
	Alcohol excess	↑hepatic FFA flux → ↑VLDL-TG synthesis
	Obesity	↑FFA delivery to liver → ↑VLDL production
	CKD/renal failure	↓LPL activity + ↑VLDL production
	Oestrogen/OCP	↑hepatic VLDL production
	Corticosteroid excess (Cushing's / exogenous)	↑lipolysis → ↑FFA → ↑hepatic VLDL
	Post-prandial (physiological)	Normal chylomicron-TG clearance takes 6–8 hours
	Glycogen storage diseases	↑hepatic TG synthesis
Mixed (↑LDL + ↑TG)	DM, nephrotic syndrome, hypothyroidism	Combination of mechanisms above
↓HDL-C	Smoking, physical inactivity, very high-carb diet, obesity, T2DM, anabolic steroids, β-blockers	Various: ↑CETP activity (DM), ↑HDL catabolism, ↓apoA-I synthesis

[Adapted from 2, 4]

Clinical Pearl

A common exam mistake: diagnosing "familial hypercholesterolaemia" before checking TFT. A patient with TC 9 mmol/L may simply have untreated hypothyroidism. Always check TFT, fasting glucose/HbA1c, LFT, RFT, urine protein as a secondary screen before attributing dyslipidaemia to a primary cause [4, 7].

5.2 Primary (Genetic) Causes

These are inherited disorders of lipoprotein metabolism. The Fredrickson classification is purely a biochemically descriptive classification — it provides no information about aetiology and does NOT affect treatment or management ^[2].

Type	Elevated Lipoprotein	Lipid Abnormality	Clinical Example	Atherogenic?
I	Chylomicrons	↑↑TG	Familial fasting chylomicronaemia (LPL/apoC-II deficiency)	No (pancreatitis risk)
IIa	LDL	↑TC, ↑LDL-C	Familial hypercholesterolaemia (FH)	Yes — very high
IIb	LDL + VLDL	↑TC + ↑TG	Familial combined hyperlipidaemia (FCHL)	Yes
III	IDL (β-VLDL)	↑TC + ↑TG (ratio ≈ 2:1)	Familial dysbetalipoproteinaemia (apoE mutation)	Yes
IV	VLDL	↑TG	Familial hypertriglyceridaemia	Moderate
V	Chylomicrons + VLDL	↑↑TG	Mixed	No (pancreatitis risk)

[2, 4, 7]

5.2.2 Major Primary Dyslipidaemias in Detail

Epidemiology: heterozygous ~1 in 500 (AD), homozygous ~1 in 300,000 (AR) [2, 6]
Cause: functional mutation of LDL receptor (LDLR, ~90%), apoB-100 (FDB, ~5%), or PCSK9 gain-of-function (~1%) [2, 6]
- All three mutations converge on the same pathology: defective LDL uptake by hepatocytes → extreme ↑LDL-C with propensity for early-onset ASCVD
Pathophysiology:
- LDLR mutation → fewer functional LDL receptors on hepatocyte surface → ↓LDL clearance → ↑circulating LDL → ↑subendothelial LDL retention → accelerated atherosclerosis
- PCSK9 gain-of-function → excessive LDLr degradation → same effect
- ApoB-100 mutation → LDL cannot bind LDLr properly → same effect
Clinical features:
- Heterozygous FH: early (< 23y) coronary artery calcification, premature (< 60y) severe ASCVD/fatal MI ^[6]
- Homozygous FH: most develop severe ASCVD or death before 20y ^[6]
- Signs of hypercholesterolaemia: xanthelasma (yellowish deposits around eyelids), corneal arcus (arcus senilis if < 45y), tendon xanthomas (pathognomonic — especially Achilles tendon and extensor tendons of hands) ^[6]
Investigations: grossly elevated LDL-C (generally ≥4.9 mmol/L without FHx, ≥6.2 mmol/L with FHx before treatment) ^[6]
Diagnosis ^[6]:
- Dutch Lipid Clinic Network (DLCN) criteria: scoring system incorporating FHx, personal Hx of premature CVD, physical signs, LDL-C level, and genetic testing
  - > 8 = definite FH, 6–8 = probable FH, 3–5 = possible FH
- Simon Broome diagnostic criteria (UK)
Note that phenotype depends on environmental factors — penetrance of LDLR can reach > 90% in heterozygous genotype living a Western lifestyle, but Mainland China individuals with heterozygous FH do not have a markedly elevated LDL ^[2]
Note that statins are relatively ineffective in homozygous FH as their efficacy depends on upregulation of functional LDLr in liver ^[2]
Treatment of homozygous FH: LDL apheresis every 1–4 weeks, pre-emptive liver transplant to replace dysfunctional hepatic LDLr before onset of significant coronary artery disease [2, 6]

6. Pathophysiology of Atherogenesis — How Dyslipidaemia Causes Disease

This is the central question: Why does elevated LDL-C cause heart attacks and strokes?

7. Classification of Dyslipidaemia

Pattern	TC	LDL-C	TG	HDL-C	Clinical Significance
Isolated hypercholesterolaemia	↑	↑	Normal	Normal	ASCVD risk (commonest pattern in FH)
Isolated hypertriglyceridaemia	Normal/↑	Normal/↓	↑	↓	Pancreatitis if severe; ASCVD if moderate
Mixed hyperlipidaemia	↑	↑	↑	↓	High ASCVD risk
Isolated low HDL-C	Normal	Normal	Normal	↓	ASCVD risk

Category	Examples
Primary (genetic)	FH, FCHL, FDBL, familial hypertriglyceridaemia, familial chylomicronaemia
Secondary (acquired)	Hypothyroidism, DM, nephrotic syndrome, CKD, drugs, alcohol, obesity

This is the clinically important classification — it determines treatment targets:

Risk Category	Definition	LDL-C Target
Low	SCORE < 1%	< 3.0 mmol/L (116 mg/dL)
Moderate	SCORE ≥1% and < 5%; young patients (T1DM < 35y, T2DM < 50y) with DM duration < 10y without other risk factors	< 2.6 mmol/L (100 mg/dL)
High	Markedly elevated single risk factors: TC > 8 mmol/L, LDL-C > 4.9 mmol/L, or BP ≥180/110 mmHg; FH without other major risk factors; moderate CKD (eGFR 30–59 mL/min); DM without target organ damage, with DM duration ≥10y or other additional risk factor; SCORE ≥5% and < 10%	< 1.8 mmol/L (70 mg/dL) AND ≥50% reduction from baseline
Very High	ASCVD (clinical or imaging); SCORE ≥10%; FH with ASCVD or with another major risk factor; severe CKD (eGFR < 30 mL/min); DM with target organ damage: ≥3 major risk factors; or early onset of T1DM of long duration (> 20y)	< 1.4 mmol/L (55 mg/dL) AND ≥50% reduction from baseline

^[3]

Updated 2019 ESC/EAS Targets

The 2019 ESC/EAS guidelines pushed LDL-C targets lower than ever before — for very high-risk patients, the target is now < 1.4 mmol/L. This reflects the "lower is better" paradigm supported by trials like IMPROVE-IT, FOURIER, and ODYSSEY OUTCOMES. There is no lower threshold below which LDL-C reduction ceases to be beneficial.

8. Clinical Features

Dyslipidaemia itself is almost always asymptomatic. It is a "silent" metabolic risk factor — patients have no symptoms until complications develop. This is why screening is so important.

However, certain clinical presentations may point to dyslipidaemia:

Symptom	Pathophysiological Basis
Asymptomatic (most common)	Lipid deposition in arteries is a slow, decades-long process. No nerve endings are stimulated until ischaemia or plaque rupture occurs.
Chest pain / angina	Advanced coronary atherosclerosis → fixed stenosis → myocardial O₂ supply-demand mismatch → ischaemic chest pain on exertion. If plaque ruptures → ACS.
Claudication / rest pain in legs	Peripheral arterial disease from atherosclerosis of iliac/femoral/popliteal arteries → ↓blood flow to exercising muscles → ischaemic pain
TIA / stroke symptoms	Carotid / cerebral atherosclerosis → thromboembolism or haemodynamic insufficiency → focal neurological deficit
Recurrent abdominal pain / epigastric pain	Severe hypertriglyceridaemia (TG > 10 mmol/L) → acute pancreatitis — epigastric pain radiating to back, worse after fatty meals
Visual disturbance	Lipemia retinalis (milky retinal vessels in severe hypertriglyceridaemia); also ASCVD-related amaurosis fugax from carotid disease
Recent memory loss	Associated with severe hypertriglyceridaemia (mechanism uncertain, possibly microvascular or hyperviscosity-related) ^[6]

8.2 Signs

Physical signs of dyslipidaemia represent tissue deposition of lipid (xanthomas, xanthelasma, arcus) or consequences of atherosclerosis.

Sign	Description	Associated Pattern	Pathophysiological Basis
Tendon xanthomas	Firm, non-tender nodules within tendons (Achilles, extensor tendons of hands, patellar tendon)	FH (type IIa) — virtually pathognomonic	Cholesterol deposition in tendons due to extremely high LDL-C. Macrophages engulf LDL → foam cells within tendon sheaths.
Xanthelasma	Yellowish, flat or slightly raised plaques on/around the eyelids	Hypercholesterolaemia (FH, FCHL), but also seen in normolipaemic individuals (~50%)	Lipid-laden macrophage deposits in the dermis. In normolipidaemic individuals, may reflect local tissue factors promoting cholesterol deposition.
Corneal arcus (arcus senilis)	White-grey opaque ring at the periphery of the cornea, separated from the limbus by a clear zone (lucid interval of Vogt)	Significant if < 45 years — suggests FH	Cholesterol and phospholipid deposition in the corneal stroma. In the elderly (> 60y), this is a normal age-related finding and not necessarily related to dyslipidaemia.
Eruptive xanthomas	Small (1–4 mm), yellow-red papules with an erythematous base, appearing in crops on buttocks, shoulders, extensor surfaces	Severe hypertriglyceridaemia (TG > 10 mmol/L) — types I, IV, V	TG-laden macrophages deposited in the skin. These appear rapidly when TG rises acutely and regress when TG is controlled.
Palmar xanthomas (xanthoma striata palmaris)	Yellowish deposits in palmar creases	Pathognomonic of type III (familial dysbetalipoproteinaemia) ^[6]	Cholesterol-laden IDL/β-VLDL deposits in palmar creases.
Tuberoeruptive xanthomas	Larger nodular lesions over pressure points (elbows, knees)	Type III (familial dysbetalipoproteinaemia)	Similar mechanism to other xanthomas; IDL/β-VLDL remnant deposition.
Tuberous xanthomas	Large, lobulated, yellowish nodules over joints (elbows, knees, knuckles)	FH, FCHL (types IIa, IIb, III)	Cholesterol deposition in subcutaneous tissues.

Sign	Description	Pathophysiological Basis
Lipemia retinalis	Retinal blood vessels appear milky/creamy white	TG > 10 mmol/L — plasma is so lipaemic that vessels appear white on fundoscopy
Corneal arcus	As above	As above
Xanthelasma	As above	As above

Sign	Description	Pathophysiological Basis
Absent peripheral pulses	PAD from atherosclerosis	Stenosis/occlusion of peripheral arteries
Carotid bruit	Turbulent flow through stenosed carotid artery	Atherosclerotic plaque in carotid → ↓lumen → turbulence
Signs of heart failure	If chronic IHD → LV dysfunction	Post-MI remodelling → ↓LVEF
Abdominal aortic aneurysm	Pulsatile abdominal mass	Atherosclerotic weakening of aortic wall
Hepatosplenomegaly	Seen in familial chylomicronaemia (type I/V)	Reticuloendothelial uptake of excess chylomicrons by liver and spleen ^[6]

9. Screening and Clinical Approach [4, 5, 7]

Component	Recommendation
CHO	60% — substrate for energy, will be used up, no accumulation
Protein	12% — maintain muscle mass
Saturated fat	10%
Mono-unsaturated fat	10%
Poly-unsaturated fat	10% — 30% total fat at 1/3 each → essential fatty acid

Modifiable	Non-modifiable
Smoking	Male sex
Hypertension	Familial tendency
Diabetes mellitus	Increasing age
↑LDL, ↓HDL, ↑IDL
? ↓VLDL
? Obesity
Alcohol
Diet
Exercise

10. Measurement of Lipid Profile

11. Metabolic Syndrome — The Broader Context

Dyslipidaemia rarely occurs in isolation. It is a key component of the metabolic syndrome [1, 5]:

Central obesity is the driver ^[1]:

Adipocytes release large amounts of FFA → insulin resistance ^[1]
Adipocytes release adipokines (e.g., TNF-α, IL-6, resistin) → insulin resistance ^[1]
Physical inactivity contributes: ↓AMPK activation → ↓glucose uptake + ↓FFA metabolism ^[1]
Insulin resistance → ↑hepatic VLDL-TG production → ↑TG
Insulin resistance → ↑CETP activity → ↓HDL-C, ↑small dense LDL
Insulin resistance → ↓LPL activity → ↓TG clearance

Dyslipidaemia of metabolic syndrome: ↑LDL-C, ↑TG, ↓HDL-C ^[1]

Manifestations of metabolic syndrome ^[1]:

Hypertension
Dyslipidaemia (↑LDL-C, TG, ↓HDL-C)
Type 2 DM
Polycystic ovarian syndrome (PCOS)
Non-alcoholic fatty liver disease (NAFLD)

High Yield Summary

Key Points for Exams:

Dyslipidaemia is usually asymptomatic — it is found on screening or when complications (MI, stroke, pancreatitis) develop.
Always exclude secondary causes before diagnosing primary: check TFT, fasting glucose, RFT, LFT, urine protein.
Fredrickson classification is purely biochemical/descriptive — does NOT guide management.
Familial hypercholesterolaemia (FH): AD, 1 in 500 heterozygous; mutations in LDLR (90%), apoB-100, or PCSK9; tendon xanthomas are virtually pathognomonic; diagnose with DLCN criteria (>8 = definite).
Palmar xanthomas are pathognomonic of type III (familial dysbetalipoproteinaemia).
Eruptive xanthomas + lipaemic serum + hepatosplenomegaly = severe hypertriglyceridaemia → risk of pancreatitis when TG > 10 mmol/L.
Statins work by inhibiting HMG-CoA reductase → ↓intracellular cholesterol → ↑LDLr expression → ↑LDL clearance.
2019 ESC/EAS targets: Very high risk → LDL-C < 1.4 mmol/L AND ≥50% reduction from baseline.
Clinical approach: Pattern → secondary causes → primary causes → CVD risk factors → manage accordingly.
Metabolic syndrome = central obesity + ↑TG + ↓HDL-C + ↑BP + ↑glucose — insulin resistance is the driver.
Statins are relatively ineffective in homozygous FH because their efficacy depends on upregulation of functional LDLr.
Corneal arcus in a patient < 45 years is significant and suggests FH; in the elderly it is a normal finding.

Active Recall - Dyslipidaemia: Definition, Epidemiology, Risk Factors, Etiology, Pathophysiology, Classification, and Clinical Features

Differential Diagnosis of Dyslipidaemia

1. Differential Diagnosis by Biochemical Pattern

The first step is always: look at the numbers and decide the pattern. This immediately narrows your differential.

Category	Condition	Key Distinguishing Features	Mechanism
Primary	Familial hypercholesterolaemia (FH, type IIa) ^[6]	Tendon xanthomas (pathognomonic), corneal arcus < 45y, xanthelasma; LDL-C ≥4.9 mmol/L (without FHx) or ≥6.2 (with FHx); premature ASCVD; FHx of early CVD/sudden cardiac death; AD inheritance	Mutations in LDLR (~90%), apoB-100 (~5%), or PCSK9 gain-of-function (~1%) → defective LDL uptake by hepatocytes → markedly ↑circulating LDL-C [2, 6]
	Familial defective apoB-100 (FDB)	Clinically indistinguishable from heterozygous FH but milder; moderate ↑LDL-C	Mutation in apoB-100 (Arg3500Gln most common) → LDL cannot bind LDLr properly → ↓LDL clearance
	Polygenic hypercholesterolaemia	Most common cause of moderate ↑LDL-C in the population; no dramatic physical signs; modest FHx; LDL-C usually 3.5–5.5 mmol/L	Multiple common genetic variants (SNPs), each with small effect, combined with environmental factors (diet, obesity) → cumulative ↑LDL-C
	Autosomal recessive hypercholesterolaemia (ARH) ^[2]	Clinical phenotype similar to homozygous FH but AR inheritance; important d/dx when diagnosing FH	↓LDLRAP1 expression, sitosterolaemia (ABCG5/G8 deficiency), CYP7A1 deficiency ^[2]
Secondary	Hypothyroidism	Fatigue, weight gain, cold intolerance, constipation, bradycardia, delayed relaxation of reflexes; ↑TSH, ↓fT4	↓Thyroid hormone → ↓LDLr gene expression → ↓hepatic LDL clearance → ↑LDL-C. Also ↓bile acid excretion and ↓cholesterol conversion to bile acids
	Nephrotic syndrome	Oedema (periorbital, pedal), proteinuria > 3.5 g/day, hypoalbuminaemia, lipiduria	Hypoalbuminaemia → liver senses ↓oncotic pressure → compensatory ↑hepatic lipoprotein synthesis (the liver upregulates protein production generally, and lipoproteins are swept up in this). Also ↓LPL activity and ↓LCAT activity → ↓HDL metabolism
	Cholestasis (obstructive jaundice)	Jaundice, pruritus, pale stools, dark urine; ↑conjugated bilirubin, ↑ALP, ↑GGT	Bile acid excretion blocked → bile acids accumulate → ↓bile acid-mediated cholesterol excretion → ↑intrahepatic cholesterol → ↓LDLr expression. Also formation of abnormal lipoprotein X (LP-X, rich in phospholipid and unesterified cholesterol)
	Anorexia nervosa	Severely underweight, amenorrhoea, lanugo hair, bradycardia	↓Bile acid excretion + ↓LDLr activity (mechanism not fully understood; may relate to ↓thyroid hormone conversion, ↓oestrogen)
	Drugs	Cyclosporine, thiazides, retinoids	Variable: cyclosporine inhibits bile acid synthesis; thiazides may alter hepatic lipid metabolism
	Immunoglobulin disorder (paraproteinaemia)	Myeloma features: bone pain, anaemia, renal impairment; serum protein electrophoresis shows M-band	Paraproteins bind to lipoproteins or LDLr → ↓LDL clearance

Exam Favourite

Hypothyroidism is the single most important secondary cause to exclude in isolated hypercholesterolaemia. A TSH should be checked in EVERY patient with a newly discovered elevated LDL-C. Why? Because simply starting levothyroxine may normalise the lipid profile without needing a statin.

Category	Condition	Key Distinguishing Features	Mechanism
Primary	Familial fasting chylomicronaemia (type I/V) ^[6]	AR inheritance; presents in childhood; hepatosplenomegaly, eruptive xanthomas; TG > 10 mmol/L → acute pancreatitis, lipemia retinalis, recent memory loss; lipaemic (milky) serum	LPL, apoC-II, or apoA-V deficiency → chylomicrons cannot be hydrolysed → massive chylomicronaemia ^[6]
	Familial hypertriglyceridaemia (type IV) ^[6]	AD inheritance; ~1% of population; moderate ↑TG (2.3–5.6); associated with metabolic syndrome (insulin resistance, obesity, ↑glucose), ↑urate	Genetically heterogeneous (LPL heterozygous, apoA-V, lipase I mutations); marked ↑TG generally only occurs with concomitant factors (acquired disease, HRT) ^[6]
Secondary	Type 2 DM / insulin resistance	Features of metabolic syndrome; ↑HbA1c, ↑fasting glucose; central obesity; acanthosis nigricans	Insulin resistance → ↑hepatic VLDL-TG secretion (insulin normally suppresses VLDL output) + ↓LPL activity (insulin normally stimulates LPL) → ↑TG ^[1]
	Alcohol excess	History of heavy drinking; ↑GGT, ↑MCV, AST:ALT > 2	Alcohol → ↑hepatic fatty acid synthesis via ↑NADH/NAD+ ratio → ↑FFA esterification to TG → ↑VLDL-TG output
	Obesity	↑BMI, central adiposity	↑FFA delivery to liver from visceral adipose tissue → ↑VLDL-TG synthesis
	CKD / renal failure	↑creatinine, ↑urea; symptoms of uraemia	↓LPL activity + ↓hepatic lipase → ↓TG clearance; also ↑VLDL production
	Oestrogen / OCP	History of oral contraceptive use or HRT	Oestrogen → ↑hepatic VLDL-TG production (hepatic lipogenic effect)
	Corticosteroid excess (Cushing's / exogenous) ^[8]	Moon face, buffalo hump, central obesity, striae, proximal myopathy, glucose intolerance ^[8]	Cortisol → ↑lipolysis → ↑FFA → ↑hepatic VLDL-TG synthesis; also insulin resistance → same pathway as DM
	Glycogen storage diseases (types I, III, V, VII)	Childhood onset; hepatomegaly, hypoglycaemia	↑hepatic glycolysis → ↑acetyl-CoA → ↑de novo lipogenesis → ↑VLDL-TG
	Post-prandial (physiological)	TG elevated if sample taken within 6–8 hours of eating	Normal chylomicron-TG clearance takes 6–8 hours; this is NOT pathological

Clinical Pearl

A common trap: attributing severe hypertriglyceridaemia (TG > 10 mmol/L) to a secondary cause alone. While secondary causes (DM, alcohol) are common contributors, TG this high almost always has an underlying primary genetic susceptibility (e.g., heterozygous LPL mutation) unmasked by a secondary trigger. The secondary cause pushes an already vulnerable patient over the edge. Always consider BOTH.

Category	Condition	Key Distinguishing Features	Mechanism
Primary	Familial combined hyperlipidaemia (FCHL, type IIb) [4, 6]	Prevalence 0.5%; AD inheritance; ↑synthesis of apoB-100 → elevated VLDL & LDL; no distinctive clinical features; diagnosis by demonstration of multiple phenotypes in family (some members ↑LDL, some ↑TG, some both); premature CHD, xanthelasma (10%), obesity ± DM; accounts for 1/3 to 1/2 of familial CHD	↑hepatic apoB-100 + VLDL secretion → ↑VLDL (→ ↑TG) and ↑LDL (→ ↑cholesterol) [4, 6]
	Familial dysbetalipoproteinaemia (FDBL, type III) ^[6]	Rare (1 in 5,000–10,000); TC:TG ratio ≈ 2:1 during fasting; palmar xanthomas (pathognomonic); tuberoeruptive xanthomas; premature CHD and PVD	ApoE2/E2 homozygosity → apoE2 binds poorly to hepatic remnant receptors → ↓clearance of IDL and chylomicron remnants → accumulation of β-VLDL ^[6]
Secondary	DM, nephrotic syndrome, hypothyroidism ^[2]	Each has its own clinical features as above	Combination of mechanisms — e.g., DM causes both ↑VLDL (↑TG) and ↑small dense LDL (↑LDL-C); hypothyroidism ↓LDLr (↑LDL-C) and ↓LPL (↑TG); nephrotic syndrome ↑hepatic lipoprotein production generally
	Immunoglobulin disorders ^[2]	Paraproteinaemia features	Paraprotein-lipoprotein complexes → ↓clearance

Category	Condition	Key Features	Mechanism
Lifestyle/Acquired	Smoking	Pack-year history	↑CETP activity → ↑cholesterol ester transfer from HDL to VLDL/LDL → ↓HDL-C
	Physical inactivity	Sedentary lifestyle	↓LPL activity → ↓VLDL lipolysis → ↓surface material transfer to nascent HDL
	Obesity / insulin resistance	Central adiposity, metabolic syndrome	↑hepatic lipase activity → ↑HDL catabolism; ↑CETP activity
	Very high-carb diet	Dietary history	↑VLDL production → ↑CETP-mediated exchange → ↓HDL-C
	Drugs	β-blockers, anabolic steroids, progestins, protease inhibitors	Variable: β-blockers ↑hepatic lipase; anabolic steroids ↓hepatic apoA-I production
Primary (rare)	Tangier disease	Orange tonsils (!), hepatosplenomegaly, peripheral neuropathy; near-absent HDL	Homozygous ABCA1 mutation → cannot efflux cholesterol from macrophages to nascent HDL → cholesterol accumulates in reticuloendothelial system
	ApoA-I deficiency	Very low HDL, premature ASCVD	No functional apoA-I → cannot form HDL particles
	LCAT deficiency (Fish-eye disease)	Corneal opacities, renal impairment, haemolytic anaemia	Cannot esterify cholesterol on HDL → HDL remains immature → rapidly catabolised

2. Differential Diagnosis by Clinical Presentation

Sometimes the patient does not come with a lipid panel in hand. Instead, they present with a clinical scenario that should prompt you to think about dyslipidaemia.

Xanthoma Type	Differential Diagnosis	How to Differentiate
Tendon xanthomas	FH (type IIa) — most common and characteristic ^[6]; also cerebrotendinous xanthomatosis (CTX — very rare, AR, a/w neurological features and cataracts due to CYP27A1 deficiency)	FH: grossly ↑LDL-C, AD FHx, premature ASCVD. CTX: normal cholesterol but ↑cholestanol, neurological features
Eruptive xanthomas	Severe hypertriglyceridaemia from any cause (type I, IV, V; or secondary: uncontrolled DM, alcohol) ^[6]	Appear acutely in crops; TG > 10 mmol/L; may have lipaemic serum; resolve when TG controlled
Palmar xanthomas	Type III (FDBL) — pathognomonic ^[6]	TC:TG ≈ 2:1; lipoprotein electrophoresis shows broad beta band; apoE genotyping shows E2/E2
Xanthelasma	FH, FCHL, polygenic hypercholesterolaemia, BUT ~50% of patients with xanthelasma have normal lipids	Always check lipid profile; if normal, this is a cosmetic issue, not a metabolic one
Tuberous / tuberoeruptive xanthomas	FH (type IIa), FCHL (type IIb), FDBL (type III) ^[6]	Pressure points (elbows, knees); check lipid pattern + lipoprotein electrophoresis

"Premature" = MI/angina/stroke/PAD before age 55 in men or 65 in women ^[5].

Differential	Key Features
FH (type IIa)	Markedly ↑LDL-C, tendon xanthomas, strong FHx ^[6]
FCHL (type IIb)	No distinctive clinical features; demonstration of multiple lipid phenotypes in family; accounts for 1/3–1/2 of familial CHD [4, 6]
FDBL (type III)	Palmar xanthomas, mixed lipids, TC:TG ≈ 2:1 ^[6]
Elevated Lp(a)	Often no other lipid abnormality; Lp(a) > 50 mg/dL is an independent risk factor; genetically determined, not responsive to statins
Other conventional risk factors	DM, smoking, HTN, family history — may coexist with or mimic familial dyslipidaemia

Differential	Key Features
LPL / apoC-II deficiency (type I) ^[6]	Childhood onset, AR, hepatosplenomegaly, eruptive xanthomas, TG > 10
Type V	Combination of ↑chylomicrons + ↑VLDL; may present later in life
Secondary severe hypertriglyceridaemia	Uncontrolled DM (especially new-onset T1DM or severe T2DM with DKA/HHS), heavy alcohol binge, pregnancy, drugs (oestrogen, retinoids, atypical antipsychotics) unmasking underlying genetic susceptibility

The following investigations form the secondary cause screen — they should be done in every patient with newly diagnosed dyslipidaemia before attributing it to a primary cause ^[5]:

Investigation	What It Excludes	Rationale
TSH (± fT4)	Hypothyroidism	↓T4 → ↓LDLr → ↑LDL-C
Fasting glucose / HbA1c	Diabetes mellitus	Insulin resistance → ↑TG, ↓HDL-C, ↑small dense LDL
RFT (creatinine, eGFR)	CKD	↓LPL → ↑TG; also ↑CVD risk
LFT	Cholestasis, hepatic disease	↑ALP/GGT with jaundice → cholestasis; also baseline before starting statin ^[9]
Urine protein (dipstick ± ACR)	Nephrotic syndrome	Proteinuria > 3.5 g/day → compensatory ↑hepatic lipoprotein synthesis
Drug history	Drug-induced	Thiazides, β-blockers, corticosteroids, OCP, cyclosporine, retinoids, protease inhibitors, atypical antipsychotics
Alcohol history	Alcohol-related	↑VLDL-TG production

Only after secondary causes have been excluded (or treated and lipids remain abnormal) should primary causes be investigated ^[5]:

Lipoprotein electrophoresis (to identify broad beta band in type III, or chylomicron band in type I) ^[5]
Family/genetic studies (cascade screening of first-degree relatives; genetic testing for LDLR, apoB, PCSK9 mutations in suspected FH) ^[5]

Feature	FH (IIa)	FCHL (IIb)	FDBL (III)	Familial Chylomicronaemia (I/V)	Familial HTG (IV)	Secondary
Inheritance	AD	AD	Variable (apoE2/E2 + trigger)	AR	AD	N/A
Main lipid abnormality	↑↑LDL-C	↑LDL + ↑TG	↑TC + ↑TG (≈2:1)	↑↑↑TG	↑TG (moderate)	Variable
Distinctive signs	Tendon xanthomas	None ^[4]	Palmar xanthomas	Eruptive xanthomas, HSM	None specific	Depends on cause
Pancreatitis risk	Low	Low	Low	Very high	Moderate (if severe ↑TG)	Depends on TG level
ASCVD risk	Very high	High	High	Low (particles too large)	Moderate	Depends on pattern
Prevalence	~1/500	~1/200 (0.5%)	~1/5–10k	~1/1M	~1/100	Very common
Diagnosis	DLCN criteria / genetic testing	Multiple phenotypes in family ^[4]	ApoE genotyping + broad beta band	LPL activity assay, genetic testing	Exclusion	Treat underlying cause

5. Special Differentials Worth Remembering

AR; LAL enzyme breaks down cholesterol esters and TG in lysosomes
Infantile form (Wolman disease): severe, fatal in infancy
Late-onset form (cholesteryl ester storage disease, CESD): hepatomegaly, ↑LDL-C, ↓HDL-C, accelerated atherosclerosis — mimics FH
Diagnosis: LAL enzyme activity assay
Treatment: enzyme replacement therapy (sebelipase alfa)

High Yield Summary — Differential Diagnosis

Pattern first: Identify whether it is ↑LDL-C, ↑TG, mixed, or ↓HDL-C. This narrows the differential immediately.
Always exclude secondary causes before diagnosing primary: Check TFT, glucose, RFT, LFT, urine protein, drug history, alcohol history ^[5].
FH (type IIa): Tendon xanthomas + markedly ↑LDL-C + AD FHx + premature ASCVD → DLCN criteria ^[6].
FCHL (type IIb): No distinctive clinical features; diagnosed by demonstrating multiple lipid phenotypes in family; accounts for 1/3–1/2 of familial CHD [4, 6].
Type III (FDBL): Palmar xanthomas are pathognomonic; TC:TG ≈ 2:1; apoE2/E2 ^[6].
Type I (familial chylomicronaemia): TG > 10 → pancreatitis risk; eruptive xanthomas + hepatosplenomegaly; LPL/apoC-II deficiency ^[6].
Hypothyroidism is the #1 secondary cause of ↑LDL-C to exclude.
Severe hypertriglyceridaemia (TG > 10) almost always has a genetic predisposition unmasked by a secondary trigger (DM, alcohol, drugs).
Rare mimics of FH: sitosterolaemia, CTX, LAL deficiency — differentiated by specific biochemical tests.

Active Recall - Differential Diagnosis of Dyslipidaemia

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (Section: Type 2 DM, Metabolic Syndrome, p77) ^[2] Senior notes: Ryan Ho Chemical Path.pdf (Section: Lipid Profile and Fredrickson Classification, p46–48) ^[4] Lecture slides: Teaching Clinic - Endocrinology - Three cases of lipid disorders - by Prof KCB Tan.pdf.pdf (p4, p7) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Section: Clinical approach to dyslipidaemia, screening, ASCVD risk assessment, p125) ^[6] Senior notes: Ryan Ho Endocrine.pdf (Section: FH, primary dyslipidaemias, p131) ^[8] Senior notes: Maksim MEDICINE notes.pdf (Section: Cushing's syndrome, p99) ^[9] Senior notes: Ryan Ho Cardiology.pdf (Section: Baseline evaluation of stable IHD, p116)

Diagnostic Criteria, Algorithm, and Investigation Modalities for Dyslipidaemia

There is no single universal threshold that defines "dyslipidaemia" — what is considered abnormal depends on the patient's overall ASCVD risk. However, the following reference values provide a practical framework:

Parameter	Desirable	Borderline High	High
Total cholesterol	< 5.2 mmol/L ( < 200 mg/dL)	5.2–6.2 mmol/L (200–239 mg/dL)	≥6.2 mmol/L ( ≥240 mg/dL)
LDL-C	< 2.6 mmol/L ( < 100 mg/dL)	2.6–4.1 mmol/L (100–159 mg/dL)	≥4.1 mmol/L ( ≥160 mg/dL)
HDL-C	≥1.55 mmol/L ( ≥60 mg/dL) — protective	1.0–1.55 mmol/L (40–59 mg/dL)	< 1.0 mmol/L ( < 40 mg/dL) — risk factor
Triglycerides	< 1.7 mmol/L ( < 150 mg/dL)	1.7–2.3 mmol/L (150–199 mg/dL)	2.3–5.6 = high; > 5.6 = very high; > 10 = pancreatitis risk ^[6]
Non-HDL-C	< 3.4 mmol/L	—	≥4.9 mmol/L

Why non-HDL-C? Non-HDL-C = TC − HDL-C. It captures ALL atherogenic particles (LDL + VLDL + IDL + Lp(a)). It is especially useful when TG is elevated and the Friedewald equation becomes unreliable ( > 4.5 mmol/L). The 2019 ESC/EAS guidelines use non-HDL-C as a secondary target ^[3].

Exam Pearl

The treatment target for LDL-C depends on ASCVD risk category, not just whether LDL-C is "high" in absolute terms ^[3]:

Very high risk: < 1.4 mmol/L AND ≥50% reduction from baseline
High risk: < 1.8 mmol/L AND ≥50% reduction from baseline
Moderate risk: < 2.6 mmol/L
Low risk: < 3.0 mmol/L

This is the most important diagnostic step in clinical practice. Always exclude secondary causes before diagnosing a primary dyslipidaemia ^[5].

Investigation	What It Screens For	Key Findings	Interpretation / Mechanism
TSH (± fT4)	Hypothyroidism	↑TSH, ↓fT4	Thyroid hormone upregulates LDL receptor gene transcription. ↓T4 → ↓LDLr on hepatocyte surface → ↓LDL clearance → ↑LDL-C. Treat with levothyroxine → lipids may normalise.
Fasting glucose, HbA1c	Diabetes mellitus / insulin resistance	↑FBG ≥7.0, HbA1c ≥6.5%	Insulin resistance → ↑hepatic VLDL-TG output (insulin normally suppresses VLDL secretion) + ↓LPL activity → ↑TG, ↓HDL-C, ↑small dense LDL ^[1]
RFT (creatinine, eGFR)	CKD	↑creatinine, ↓eGFR	CKD → ↓LPL activity, ↓hepatic lipase → ↓TG clearance; also ↑VLDL production; uraemia-associated ↓HDL
LFT (ALT, AST, ALP, GGT, bilirubin)	Cholestasis; hepatic disease; also baseline before starting statin ^[9]	↑ALP, ↑GGT, ↑conjugated bilirubin (cholestasis); ↑ALT (hepatic steatosis/NAFLD)	Cholestasis → ↓bile acid excretion → ↑intrahepatic cholesterol → ↓LDLr → ↑LDL-C. Also check LFT as baseline because statins can rarely cause hepatotoxicity.
CK	Baseline before starting statin ^[9]	Normal at baseline	Statins can rarely cause myopathy/rhabdomyolysis. Baseline CK allows comparison if patient develops muscle symptoms later.
Urine protein (dipstick, ACR, or 24h urine protein)	Nephrotic syndrome	Proteinuria > 3.5 g/day, ACR > 300 mg/mmol	Hypoalbuminaemia → compensatory ↑hepatic lipoprotein synthesis → ↑TC, ↑LDL-C, ↑TG ^[10]
Serum albumin	Nephrotic syndrome	↓albumin ( < 25 g/L in nephrotic range)	Confirms nephrotic syndrome when combined with heavy proteinuria ^[10]
Drug history	Drug-induced dyslipidaemia	Identify culprit medications	Thiazides (↑LDL 5–10%), β-blockers (↑TG, ↓HDL), corticosteroids (↑TG), OCP/oestrogen (↑TG), cyclosporine (↑LDL), retinoids (↑TG), atypical antipsychotics (↑TG, ↑TC), protease inhibitors (↑TG)
Alcohol history	Alcohol-related hypertriglyceridaemia	Quantify intake (units/week)	Alcohol → ↑NADH:NAD⁺ → ↑hepatic fatty acid synthesis → ↑VLDL-TG production

Practical Point

Students commonly forget to check LFT and CK as baselines before initiating statin therapy ^[9]. This is not for diagnosing dyslipidaemia per se, but it is an integral part of the diagnostic workup because you need these values before starting treatment. If a patient later develops elevated ALT or CK on a statin, you need to know what the baseline was.

5. Step 3: Diagnosing Specific Primary Dyslipidaemias

Other than lipid profile, lipoprotein diseases can be investigated by ^[2]:

Ultracentrifugation: different lipoproteins have different densities — gold standard for separating lipoproteins but not routine (research/specialist labs)
Lipoprotein electrophoresis: different lipoproteins have different charge-to-mass ratios ^[2] — clinically useful for:
- Detecting broad beta band (fusion of pre-β and β bands) → pathognomonic of type III (familial dysbetalipoproteinaemia)
- Detecting chylomicron band (remains at the origin because chylomicrons are too large to migrate) → type I or V

Additional Test	Indication	What It Tells You
ApoB	When LDL-C may underestimate atherogenic particle burden (e.g., metabolic syndrome with ↑TG, normal/borderline LDL-C)	Each atherogenic particle (LDL, VLDL, IDL) has exactly one apoB-100. ApoB reflects total atherogenic particle number. ApoB ≥130 mg/dL is an ASCVD risk enhancer ^[3].
Lp(a)	Once-in-a-lifetime measurement recommended for all; essential in unexplained premature ASCVD or FH phenotype with borderline LDL-C	Genetically determined, independent ASCVD risk factor. Lp(a) > 50 mg/dL or > 125 nmol/L is an ASCVD risk enhancer ^[3]. Not significantly lowered by statins.
Non-HDL-C	Calculated (TC − HDL-C); used when TG elevated and Friedewald unreliable	Captures all atherogenic lipoproteins. Secondary target in 2019 ESC/EAS guidelines.
ApoE genotyping	Suspected type III dyslipidaemia	ApoE2/E2 homozygosity confirms diagnosis of FDBL
LPL activity assay / apoC-II level	Suspected familial chylomicronaemia syndrome	Confirms LPL or apoC-II deficiency as cause of severe hypertriglyceridaemia
Serum plant sterols (sitosterol, campesterol)	Suspected sitosterolaemia	Markedly elevated → confirms ABCG5/G8 deficiency
Genetic testing	Suspected FH; cascade screening of family	Identifies causative mutations in LDLR, APOB, PCSK9 genes; gold standard for FH diagnosis

5C. Diagnostic Criteria for Familial Hypercholesterolaemia (FH)

FH is the most important primary dyslipidaemia to diagnose because:

It is common (~1 in 250–500)
It is treatable — early statin therapy dramatically reduces ASCVD events
It is transmissible — cascade screening of first-degree relatives can identify affected family members before they develop ASCVD

Diagnosis is based on genetic testing, or if not available, clinical criteria ^[6].

This is the most widely used scoring system internationally. It integrates family history, clinical history, physical examination, LDL-C level, and (optionally) genetic testing.

Category	Criterion	Score
Family history	1st-degree relative with known premature CVD (M < 55y, F < 60y) OR 1st-degree relative with known LDL-C > 95th percentile	1
	1st-degree relative with tendon xanthomas and/or corneal arcus OR child < 18y with LDL-C > 95th percentile	2
Clinical history	Patient with premature CAD (M < 55y, F < 60y)	2
	Patient with premature cerebral or peripheral vascular disease (M < 55y, F < 60y)	1
Physical examination	Tendon xanthomas	6
	Corneal arcus before age 45	4
LDL-C level (untreated)	≥8.5 mmol/L (≥330 mg/dL)	8
	6.5–8.4 mmol/L (250–329 mg/dL)	5
	5.0–6.4 mmol/L (190–249 mg/dL)	3
	4.0–4.9 mmol/L (155–189 mg/dL)	1
Genetic testing	Functional mutation in LDLR, APOB, or PCSK9 identified	8

Interpretation ^[6]:

Total Score	Diagnosis
> 8	Definite FH
6–8	Probable FH
3–5	Possible FH
< 3	Unlikely FH

Use only the highest-scoring item in each category (do not sum within a category). Then sum across all categories.

Criterion	Description
Criterion 1 (lipid level)	TC > 7.5 mmol/L (adults) or > 6.7 mmol/L (children < 16y); OR LDL-C > 4.9 mmol/L (adults) or > 4.0 mmol/L (children)
Criterion 2 (physical signs)	Tendon xanthomas in patient OR first/second-degree relative
Criterion 3 (genetic)	DNA-based evidence of LDLr, apoB-100, or PCSK9 mutation
Criterion 4 (family history)	FHx of MI < 50y in 2nd-degree relative OR < 60y in 1st-degree relative
Criterion 5 (family lipid)	FHx of ↑TC > 7.5 mmol/L in 1st/2nd-degree relative; OR > 6.7 mmol/L in child < 16y

Interpretation ^[6]:

Definite FH: Criterion 1 + 2, OR Criterion 1 + 3
Probable FH: Criterion 1 + 4, OR Criterion 1 + 5

Key Difference Between DLCN and Simon Broome

The DLCN criteria are quantitative (scoring system) and more nuanced — they can grade the probability of FH. The Simon Broome criteria are more categorical (definite vs. probable). Both are clinically acceptable. In Hong Kong, the DLCN criteria are generally preferred for clinical and research purposes. Genetic testing is the gold standard but not always available or affordable, particularly in Hong Kong public hospitals where it may not be routinely offered ^[6].

6. Step 4: ASCVD Risk Assessment

After diagnosing dyslipidaemia and characterising it (primary vs. secondary, specific subtype), you must determine the patient's overall cardiovascular risk, because treatment targets depend on risk category, not just LDL-C level [3, 5].

Generally consider: age, gender, smoking, systolic BP, TC/HDL-C, FHx, ± BMI ^[5]:

Tool	Notes
Chinese Multiprovincial Cohort Study (CMCS, 2005)	Chinese-specific; limited validation
Framingham risk assessment (2008)	Well-established; may overestimate in Asian populations
ACC/AHA ASCVD risk calculator (2013)	Pooled Cohort Equation; 10-year ASCVD risk; includes stroke
SCORE risk charts (2016)	Used in ESC guidelines; 10-year risk of fatal CVD events
JBS3 risk calculator (2014)	Estimates lifetime risk; useful for younger patients

Risk Category	Who Qualifies	LDL-C Target
Very High	Documented ASCVD (clinical or imaging: ACS, angina, revascularisation, stroke/TIA, PAD, significant plaque on coronary angiography or CT scan or carotid ultrasound); SCORE ≥10%; FH with ASCVD or with another major risk factor; severe CKD (eGFR < 30); DM with target organ damage or ≥3 major risk factors or early-onset T1DM of long duration (> 20y) ^[3]	< 1.4 mmol/L AND ≥50% reduction from baseline
High	Markedly elevated single risk factors: TC > 8 mmol/L, LDL-C > 4.9 mmol/L, or BP ≥180/110 mmHg; FH without other major risk factors; moderate CKD (eGFR 30–59); DM without target organ damage, with DM duration ≥10y or other additional risk factor; SCORE ≥5% and < 10% ^[3]	< 1.8 mmol/L AND ≥50% reduction
Moderate	Young patients (T1DM < 35y, T2DM < 50y) with DM duration < 10y without other risk factors; SCORE ≥1% and < 5% ^[3]	< 2.6 mmol/L
Low	SCORE < 1% ^[3]	< 3.0 mmol/L

The table below consolidates all investigations relevant to the diagnosis and workup of dyslipidaemia, categorised by purpose.

Purpose	Investigation	Key Findings / Interpretation
Confirm dyslipidaemia	Fasting lipid profile (TC, LDL-C, HDL-C, TG) — at least 2 readings ^[4]	Pattern identification: ↑LDL, ↑TG, mixed, ↓HDL
	Non-HDL-C (calculated: TC − HDL-C)	Secondary target; useful when TG > 4.5 and Friedewald unreliable
Secondary cause screen	TSH	↑TSH → hypothyroidism → ↑LDL-C
	Fasting glucose / HbA1c	↑ → DM → ↑TG, ↓HDL-C
	RFT (creatinine, eGFR)	↑creatinine / ↓eGFR → CKD → ↑TG
	LFT	Cholestasis pattern (↑ALP, ↑GGT, ↑bilirubin) → ↑LDL-C; also baseline before statin ^[9]
	CK	Baseline before statin ^[9]
	Urine protein (dipstick / ACR)	Proteinuria → nephrotic syndrome → ↑LDL-C, ↑TC ^[10]
	Serum albumin	↓albumin → nephrotic syndrome ^[10]
	Drug + alcohol history	Identify iatrogenic/lifestyle causes
Primary dyslipidaemia workup	Lipoprotein electrophoresis ^[2]	Broad beta band → type III; chylomicron band at origin → type I/V
	ApoE genotyping	E2/E2 → type III (FDBL)
	Genetic testing (LDLR, APOB, PCSK9)	Identifies FH-causing mutations; gold standard for FH
	LPL activity assay / apoC-II level	Confirms familial chylomicronaemia syndrome
	Serum plant sterols	↑↑sitosterol → sitosterolaemia
Atherogenic particle burden	ApoB	≥130 mg/dL → risk enhancer ^[3]
	Lp(a)	> 50 mg/dL or > 125 nmol/L → independent risk factor ^[3]
	hs-CRP	≥2.0 mg/L → risk enhancer ^[3]
Subclinical atherosclerosis	CAC score (CT)	0 = very low risk; 1–99 = favours statin if age > 55; ≥100 = favours statin ^[3]
	Carotid intima-media thickness (CIMT) / carotid ultrasound	Significant plaque = very high risk per 2019 ESC/EAS ^[3]
	ABI (ankle-brachial index)	< 0.9 → PAD → risk enhancer / very high risk ^[3]
ASCVD risk assessment	Risk calculators (Framingham, SCORE, ACC/AHA PCE)	10-year risk → guides risk category → determines LDL-C target
Organ damage assessment (in high-risk patients)	ECG	Evidence of prior MI (pathological Q waves), LVH
	Echocardiography	LVEF, regional wall motion abnormalities ^[9]
	Fundoscopy	Retinal atherosclerotic changes; also relevant in DM patients for diabetic retinopathy screening

8. Special Diagnostic Scenarios

Worth mentioning because it is occasionally tested:

If serum appears lipaemic (milky), you can perform the refrigerator test:

Leave serum sample in the refrigerator overnight
Chylomicrons (density < water) will float to the top as a creamy layer
VLDL remains diffusely turbid throughout

Appearance	Interpretation
Creamy supernatant, clear infranatant	Predominant chylomicronaemia (type I)
No supernatant, diffusely turbid	Predominant ↑VLDL (type IV)
Creamy supernatant AND turbid infranatant	Both ↑chylomicrons + ↑VLDL (type V)
Clear serum	Normal TG (or ↑LDL-C only — LDL does not cause turbidity because it carries cholesterol, not TG)

Once an index case of FH is identified, family screening is essential ^[4]:

Screen all first-degree relatives (parents, siblings, children) with a fasting lipid profile ± genetic testing
If genetic mutation is known in the index case, genotype-based cascade screening is most efficient (test for the specific mutation)
If genetic testing unavailable, phenotypic screening (lipid profile + clinical criteria) is acceptable
Children of an FH parent should be screened from age 2 years (by some guidelines) or by age 10 years at the latest
Statins are contraindicated for children younger than 8 years ^[2]
Primary prevention (未雨綢繆) — with mainly statins, can reduce CHD, stroke; secondary prevention (亡羊補牢); (family screening) ^[4]

High Yield Summary — Diagnosis

Never rely on a single lipid reading — repeat checking, best with 2 baseline measurements ^[4].
The secondary cause screen is mandatory: TSH, glucose/HbA1c, RFT, LFT (+ baseline before statin), CK (baseline before statin), urine protein, drug and alcohol history [5, 9].
LDL-C is usually estimated by the Friedewald equation; unreliable when TG > 4.5 mmol/L ^[2].
Lipoprotein electrophoresis: broad beta band = type III; chylomicron band at origin = type I/V ^[2].
FH diagnostic criteria ^[6]:
- DLCN: > 8 = definite, 6–8 = probable, 3–5 = possible
- Simon Broome: Criterion 1 + 2 or 3 = definite; Criterion 1 + 4 or 5 = probable
- Tendon xanthomas score 6 points in DLCN — this single finding almost clinches the diagnosis
ASCVD risk assessment determines LDL-C target: Very high risk → < 1.4; High → < 1.8; Moderate → < 2.6; Low → < 3.0 (all mmol/L) ^[3].
CAC score = 0 means very low risk and can reclassify a patient out of statin therapy (unless DM, FHx premature CHD, or smoking) ^[3].
Cascade screening of first-degree relatives is essential after diagnosing an FH index case ^[4].
In ACS: take lipid profile within 24 hours (before acute-phase response lowers values) ^[11].

Active Recall - Diagnostic Criteria, Algorithm, and Investigations for Dyslipidaemia

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (Section: Type 2 DM, Metabolic Syndrome, p77) ^[2] Senior notes: Ryan Ho Chemical Path.pdf (Section: Lipid Profile and Fredrickson Classification, p46–48) ^[3] Lecture slides: three cases of lipid disorder.pdf (p33, p38, p90 — 2019 ESC/EAS Guidelines, ACC/AHA risk categories and risk enhancers) ^[4] Lecture slides: Teaching Clinic - Endocrinology - Three cases of lipid disorders - by Prof KCB Tan.pdf.pdf (p4, p7 — systematic approach, dietary recommendations, prevention, family screening) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Section: Clinical approach to dyslipidaemia, screening, ASCVD risk assessment, p125) ^[6] Senior notes: Ryan Ho Endocrine.pdf (Section: FH, primary dyslipidaemias, diagnostic criteria, p131) ^[8] Senior notes: Maksim MEDICINE notes.pdf (Section: NAFLD, p148) ^[9] Senior notes: Ryan Ho Cardiology.pdf (Section: Baseline evaluation of stable IHD, p116) ^[10] Senior notes: Ryan Ho Urogenital.pdf (Section: Nephrotic syndrome investigations, p55) ^[11] Senior notes: Ryan Ho Fundamentals.pdf (Section: Approach to acute chest pain — lipid profile within 24h, p203) ^[12] Senior notes: Ryan Ho GI.pdf (Section: NAFLD, p309–310)

Management of Dyslipidaemia — Algorithm, Treatment Modalities, Indications, and Contraindications

2. Lifestyle Modification — The Foundation

Lifestyle measures are indicated for ALL patients with dyslipidaemia, regardless of risk category. They form the non-pharmacological backbone of management.

Component	Recommendation	Rationale
CHO	60%	Substrate for energy — will be used up, no accumulation ^[4]
Protein	12%	Maintain muscle mass ^[4]
Saturated fat	10%	Replace saturated with unsaturated fats → ↓LDL-C by 10–15%
Mono-unsaturated fat	10%	Olive oil, avocado — ↓LDL-C without ↓HDL-C
Poly-unsaturated fat	10%	30% total fat at 1/3 each → essential fatty acid ^[4]; omega-3 (EPA/DHA) may ↓TG

Additional dietary advice:

Reduce trans fats (partially hydrogenated vegetable oils, fried food, baked goods) — trans fats ↑LDL-C AND ↓HDL-C (worst of both worlds)
Increase dietary fibre (soluble fibre: oats, barley, legumes) — binds bile acids in gut → ↑faecal bile acid excretion → ↓intrahepatic cholesterol → ↑LDLr expression
Plant stanols/sterols (2 g/day in fortified foods) — compete with cholesterol for NPC1L1-mediated absorption → ↓cholesterol absorption by ~30–50% → ↓LDL-C by ~10%
Limit alcohol — small amounts may ↑HDL-C but excess ↑TG via ↑VLDL production

Measure	Lipid Effect	Mechanism
Regular exercise (≥150 min/week moderate-intensity aerobic)	↓TG 10–20%, ↑HDL-C 5–10%, modest ↓LDL-C	↑LPL activity → ↑TG clearance; ↑AMPK → ↑fatty acid oxidation ^[1]
Weight loss (5–10% of body weight if overweight/obese)	↓TG 20%, ↑HDL-C 5–10%, ↓LDL-C 5–10%	↓visceral adiposity → ↓FFA flux to liver → ↓VLDL production; ↓insulin resistance
Smoking cessation	↑HDL-C 5–10% (within weeks)	Smoking ↑CETP activity → ↑cholesterol ester transfer from HDL to VLDL → ↓HDL-C; cessation reverses this
Limit alcohol	↓TG if excessive; modest ↑HDL if moderate	Alcohol → ↑hepatic NADH:NAD⁺ → ↑FFA esterification → ↑VLDL-TG

Key Concept

Drug therapy is warranted if dietary and lifestyle measures fail [4, 13]. In very high-risk and high-risk patients, pharmacotherapy should be started simultaneously with lifestyle measures (do not wait 3–6 months). In low/moderate-risk patients, lifestyle should be trialled first for 3–6 months before adding drugs ^[5].

Indications for drug therapy [4, 5, 13]:

Setting	When to Start Drug Therapy	Notes
Secondary prevention (existing ASCVD)	Always indicated — start simultaneously with lifestyle [5, 13]	Aim for LDL-C < 1.4 mmol/L (very high risk); statins started within 24h of ACS regardless of lipid level
Primary prevention — very high or high risk	Immediately alongside lifestyle ^[3]	DM with target organ damage, FH with additional risk factors, SCORE ≥5%, etc.
Primary prevention — moderate risk	If not meeting target after lifestyle for 3–6 months ^[5]
Primary prevention — low risk	If LDL-C persistently ≥4.9 mmol/L despite lifestyle	Per 2019 ESC/EAS — "markedly elevated single risk factors" automatically become high risk ^[3]
↑TG > 5.7 mmol/L	Consider fibrates to prevent acute pancreatitis ^[5]	Regardless of overall ASCVD risk category — this is about preventing pancreatitis, not ASCVD

Priorities for CHD prevention ^[13]:

Patients with established disease
Asymptomatic high-risk patients
First-degree relatives of the above
Others

If with secondary prevention, aim for LDL < 2.6 mmol/L (older guideline threshold). If with primary prevention, start drug with LDL > 4.5 mmol/L (older guideline). NB: only cost-effective with secondary prevention ^[13]. (Note: 2019 ESC/EAS targets are more aggressive than these older thresholds — use the more recent targets in practice.)

4. Pharmacological Therapy — Drug-by-Drug

4A. HMG-CoA Reductase Inhibitors (Statins) — First-Line for Hypercholesterolaemia

Statins (from "stat-" = HMG-CoA reductase inhibitor) are the cornerstone of lipid management.

Generally more conservative in Asians (higher plasma concentration with same dose) ^[5].

Intensity	LDL-C Reduction	Simvastatin (Zocor)	Atorvastatin (Lipitor)	Rosuvastatin (Crestor)
High intensity (≥50% ↓LDL-C)	≥50%	(80mg) ^[5]	40mg	40mg
Moderate intensity (30–49% ↓LDL-C)	30–49%	20–80mg	10–40mg	10–40mg
Low intensity ( < 30% ↓LDL-C)	< 30%	10mg	—	—

"Rule of 6": Doubling the statin dose results in only an additional 6% reduction in LDL-C, but increased risk of LFT derangement ^[14]. This is why adding a second agent (ezetimibe) is preferred over pushing the statin to maximum dose — you get more LDL-C lowering with fewer side effects.

Individual statin characteristics ^[14]:

Simvastatin (Zocor): CYP3A4 metabolite; SLCO1B1 variant associated with ↑risk of myopathy ^[14]; numerous drug interactions
Atorvastatin (Lipitor): CYP3A4 metabolite; long half-life; no renal adjustment ^[14]; most commonly used worldwide
Rosuvastatin (Crestor): CYP2C9 metabolite; long half-life; renal adjustment if GFR < 60 ^[14]; most potent at equivalent dose

Administered at night time (for short half-life statins like simvastatin, because hepatic cholesterol synthesis peaks overnight; atorvastatin and rosuvastatin have long half-lives so timing is less critical), and avoid grapefruit juice within 4 hours (grapefruit inhibits CYP3A4 → ↑statin levels → ↑risk of myopathy) ^[14].

Generally very well-tolerated (serious side effects < 2%) ^[5].

Side Effect	Detail	Mechanism / Management
Myopathy [5, 14]	Ranges from myalgia, myopathy, myositis to rhabdomyolysis	Spectrum: Myalgia (muscle pain, CK normal) → Myopathy (muscle weakness ± ↑CK) → Myositis (muscle inflammation, CK ↑ > 10× ULN) → Rhabdomyolysis (CK ↑ > 40× ULN, myoglobinuria, AKI) — rhabdo is rare (~1/10,000 patient-years)
	Risk factors: lipophilic statins (e.g., simvastatin), hypothyroidism, CYP3A4 inhibitors ^[5]	Lipophilic statins penetrate skeletal muscle more readily; hypothyroidism ↓drug clearance; CYP3A4 inhibitors (macrolides, azole antifungals, HIV PIs, grapefruit) ↑statin plasma levels
	S/S: proximal symmetric muscle weakness and/or soreness ± tenderness ^[5]
	Dx: clinical + biochemical (↑CK) evidence of muscle injury with compatible temporal pattern ^[5]
	Mx: stop statin if severe; switch to pravastatin, fluvastatin, or pitavastatin if mild ^[5]	These are hydrophilic statins with lower myopathy risk. Stop if CK > 10× ULN or CK > 3× ULN + symptomatic ^[14]
Deranged LFT (dose-related)	↑transaminases (ALT, AST)	Stop if ALT > 3× ULN ^[14]. Usually reversible. Check LFT before initiating statin [9, 14].
Headache, dyspepsia	Non-specific	Symptomatic management
New-onset DM	Small ↑risk (OR ~1.1)	Statins may impair insulin secretion and insulin sensitivity. Risk is dose-dependent. Benefit of ASCVD reduction far outweighs small DM risk in most patients.

4B. Ezetimibe — Second-Line Add-on

Ezetimibe (ez-ET-ih-mibe): "eze-" relates to its selective mechanism on the intestinal epithelium.

4C. PCSK9 Inhibitors — Third-Line for High/Very High Risk

PCSK9 inhibitors — "PCSK9" = proprotein convertase subtilisin/kexin type 9.

4D. Fibrates (Fibric Acids) — First-Line for Severe Hypertriglyceridaemia

Fibrates — examples: gemfibrozil (Lopid), fenofibrate, bezafibrate.

4E. Bile Acid Sequestrants (Anion Exchange Resins)

Examples: cholestyramine, colestipol, colesevelam.

4F. Nicotinic Acid (Niacin, Vitamin B3)

Agent	Mechanism	Lipid Effect	Indications	Key Points
Bempedoic acid (Nexletol)	Inhibits ATP citrate lyase (ACL) — upstream of HMG-CoA reductase in the cholesterol synthesis pathway; only active in hepatocytes (requires activation by hepatic ACSVL1 enzyme, which is absent in muscle)	↓LDL-C ~18% (monotherapy), ~15% added to statin	Statin-intolerant patients; add-on when statin + ezetimibe not sufficient	No myopathy (because inactive in muscle cells); may ↑uric acid → gout risk
Inclisiran (Leqvio)	siRNA (small interfering RNA) targeting PCSK9 mRNA in hepatocytes → ↓PCSK9 protein synthesis → ↑LDLr	↓LDL-C ~50%	Same as PCSK9 inhibitors; advantage: given only twice yearly (SC injection)	ORION trials; long dosing interval improves adherence
Icosapent ethyl (Vascepa)	Purified EPA (omega-3 fatty acid); mechanism beyond TG lowering — ↓inflammation, ↓oxidative stress, membrane stabilisation	↓TG ~20%; ↓ASCVD events	Statin-treated patients with TG 1.5–5.6 AND established ASCVD or DM + ≥1 RF	REDUCE-IT trial: 25% relative risk reduction in MACE
Volanesorsen	Antisense oligonucleotide targeting apoC-III mRNA → ↓apoC-III → ↑LPL activity	↓TG ~70%	Familial chylomicronaemia syndrome (severe TG > 10)	Approved in EU; risk of thrombocytopenia
LDL apheresis ^[6]	Extracorporeal removal of LDL from blood using immunoadsorption or precipitation	↓LDL-C ~60% per session	Homozygous FH; severe heterozygous FH not responding to maximal therapy ^[6]	Every 1–4 weeks ^[6]; expensive, time-consuming
Liver transplantation ^[6]	Replaces dysfunctional hepatic LDLr with normal LDLr	Normalises LDL-C	Pre-emptive liver transplant in homozygous FH to replace dysfunctional hepatic LDLr before onset of significant coronary artery disease ^[6]	Significant operative risk + long-term immunosuppression

5. Management by Clinical Scenario

Approach depends on severity:

TG Level	Action	Rationale
1.7–5.6 mmol/L	Lifestyle (especially diet, exercise, weight loss, limit alcohol); optimise glycaemic control if DM	Moderate ↑TG contributes to ASCVD risk but pancreatitis risk is low
> 5.7 mmol/L	Consider fibrates to prevent acute pancreatitis ^[5] + aggressive lifestyle; may need to hold/reduce oestrogen, retinoids, or other TG-raising drugs	Pancreatitis risk becomes significant
> 10 mmol/L	Urgent fibrate ± dietary fat restriction; consider hospitalisation if symptomatic	Imminent pancreatitis risk; dietary restriction, fibrates, ± fish oil ^[6]
After TG controlled	Reassess ASCVD risk and LDL-C — may need statin for residual ASCVD risk	↓TG alone may not adequately address LDL-C-driven atherosclerosis

Drug Class	LDL-C	TG	HDL-C	Major Side Effects	Contraindications	Primary Role
Statins	↓18–55%	↓7–30%	↑5–15%	Myopathy, ↑liver enzymes	Severe liver disease; pregnancy; untreated hypothyroidism	1st line for ↑LDL-C
Ezetimibe	↓up to 20%	No change	↑2–3%	Headache, abdominal pain, diarrhoea	Moderate/severe hepatic insufficiency	2nd line add-on to statin
PCSK9 inhibitors	↓60–70%	Modest ↓	Modest ↑	Injection site reactions	Hypersensitivity	3rd line for very high/high risk
Fibrates	↓5–20%	↓20–50%	↑10–20%	Dyspepsia, gallstones, myopathy	Severe renal or hepatic disease	1st line for severe ↑TG
Bile acid sequestrants	↓15–30%	May ↑TG	↑3–5%	GI distress, constipation, ↓drug absorption	Type III dyslipoproteinaemia; ↑TG (> 400 mg/dL)	Adjunct for ↑LDL-C
Nicotinic acid	↓5–25%	↓20–50%	↑15–35%	Flushing, hyperglycaemia, hyperuricaemia, hepatotoxicity	Liver disease, severe gout, peptic ulcer	Largely abandoned
Bempedoic acid	↓15–18%	Minimal	Minimal	↑Uric acid, tendon rupture	Hypersensitivity	Statin-intolerant patients
Icosapent ethyl	Minimal	↓~20%	Minimal	AF, bleeding	Hypersensitivity to fish/shellfish	ASCVD risk reduction with ↑TG on statin

Monitor levels, side effects, and clinical manifestations ^[4].

Parameter	Frequency	Action
Fasting lipid profile	4–6 weeks after starting/changing therapy; then every 6–12 months once stable	Assess if LDL-C target achieved
LFT (ALT)	Before starting statin; 8–12 weeks after starting; annually thereafter	Stop statin if ALT > 3× ULN ^[14]
CK	At baseline; only recheck if symptoms of myalgia/weakness develop	Stop if CK > 10× ULN, or CK > 3× ULN + symptomatic ^[14]
Fasting glucose / HbA1c	Annually (patients on high-dose statin)	Screen for new-onset DM
Symptoms	Every visit	Ask about muscle pain, weakness, GI symptoms
Clinical ASCVD events	Ongoing	Adjust risk category if new events occur

Primary prevention (未雨綢繆): With mainly statins, can reduce CHD, stroke ^[4].

Secondary prevention (亡羊補牢): Treatment after established ASCVD ^[4].

(Family screening): Cascade screening of first-degree relatives — especially for FH ^[4].

High Yield Summary — Management

Lifestyle modification is the foundation for ALL patients: diet (60% CHO, 12% protein, 30% fat as 1/3 each of saturated/mono-/polyunsaturated), exercise ≥150 min/week, weight loss, smoking cessation ^[4].
Statins are first-line for hypercholesterolaemia — mechanism: ↓HMG-CoA reductase → ↓intracellular cholesterol → ↑LDLr → ↑LDL clearance. Also have pleiotropic benefits (plaque stabilisation, ↓inflammation) ^[5].
Check LFT, CK, TSH before starting a statin [9, 14].
Rule of 6: doubling the statin dose only gives an additional 6% LDL-C reduction → add ezetimibe rather than push dose ^[14].
Stepwise escalation: Statin → + ezetimibe → + PCSK9 inhibitor (for very high/high risk not at target) [5, 6].
Fibrates are first-line when TG > 5.7 mmol/L to prevent pancreatitis ^[5].
Bile acid sequestrants are contraindicated in type III dyslipidaemia and ↑TG ^[3].
Nicotinic acid raises HDL-C the most (15–35%) but has largely fallen out of favour due to lack of ASCVD benefit in trials and significant side effects ^[3].
In homozygous FH, statins are relatively ineffective → LDL apheresis ± liver transplantation ^[6].
Secondary prevention: statin always indicated in established ASCVD, stroke, PAD — regardless of LDL level [13, 15, 16].
2019 ESC/EAS targets: Very high risk < 1.4 mmol/L AND ≥50% reduction; high risk < 1.8 AND ≥50%; moderate < 2.6; low < 3.0 ^[3].

Active Recall - Management of Dyslipidaemia

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (Section: Type 2 DM, Metabolic Syndrome, p77) ^[3] Lecture slides: three cases of lipid disorder.pdf (p33, p38, p52, p58, p62, p65, p72 — 2019 ESC/EAS Guidelines, drug classes) ^[4] Lecture slides: Teaching Clinic - Endocrinology - Three cases of lipid disorders - by Prof KCB Tan.pdf.pdf (p4, p7, p8 — systematic approach, dietary recommendations, drug treatment, prevention priorities) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Section: Management of dyslipidaemia, statins, p125, p128) ^[6] Senior notes: Ryan Ho Endocrine.pdf (Section: FH management, familial chylomicronaemia management, p131) ^[9] Senior notes: Ryan Ho Cardiology.pdf (Section: Baseline evaluation of stable IHD — LFT, CK before statin, p116) ^[13] Lecture slides: Teaching Clinic - Endocrinology - Three cases of lipid disorders - by Prof KCB Tan.pdf.pdf (p8 — indications for drug therapy, priorities for CHD prevention) ^[14] Senior notes: Maksim MEDICINE notes.pdf (Section: Drugs for hyperlipidaemia, p63) ^[15] Senior notes: Ryan Ho Neurology.pdf (Section: Secondary prevention of stroke — statins, p83) ^[16] Senior notes: Maksim SURGERY notes.pdf (Section: PAD management — statin regardless of lipid level, p167) ^[17] Senior notes: Ryan Ho Urogenital.pdf (Section: CKD cardiovascular risk factor management, p109; Nephrotic syndrome management, p76) ^[18] Senior notes: Ryan Ho Fundamentals.pdf (Section: Glomerulonephropathy management — statins, p368)

Complications of Dyslipidaemia

1. ASCVD Complications — The Central Consequence

The unifying pathology is atherosclerosis: subendothelial retention of apoB-containing lipoproteins → oxidation → foam cell formation → chronic inflammation → fibrous plaque → plaque rupture/erosion → thrombosis → end-organ ischaemia/infarction. The higher the lifetime exposure to ↑LDL-C (the "cholesterol-years" concept), the greater the plaque burden and the earlier the events.

This is the most important and most common complication of dyslipidaemia.

Aspect	Detail	Pathophysiological Explanation
Stable angina	Exertional chest pain relieved by rest or nitrate	Fixed atherosclerotic plaque causes ≥70% stenosis of a coronary artery → myocardial O₂ supply cannot meet demand during exertion → reversible ischaemia
Acute coronary syndrome (ACS)	Unstable angina, NSTEMI, STEMI	Vulnerable plaque (thin fibrous cap, large lipid-rich necrotic core, heavy macrophage infiltration) → rupture or erosion → exposure of thrombogenic subendothelial material → platelet adhesion + coagulation cascade activation → thrombus formation → partial (UA/NSTEMI) or complete (STEMI) coronary occlusion
Sudden cardiac death	Cardiac arrest, often VF/VT	Acute MI → electrical instability → lethal arrhythmia; or chronic IHD → scar-mediated re-entrant VT
Heart failure (ischaemic cardiomyopathy)	Progressive dyspnoea, orthopnoea, peripheral oedema	Recurrent or large MI → myocardial necrosis → scar tissue → ↓LVEF → cardiac remodelling → systolic HF

Risk of MI is 3–5× higher in DM patients; CHD is the leading cause of death in T2DM ^[14].

Incidence of macrovascular complications is partly explained by HTN, ↓HDL-C, ↑TG ^[1].

Why Is LDL-C the Primary Target?

Because LDL is the lipoprotein most responsible for initiating and propagating atherosclerosis. LDL is small enough to cross the endothelium, gets retained in the subendothelial space by binding proteoglycans, undergoes oxidation, and triggers the entire inflammatory cascade. Lowering LDL-C reduces plaque formation, stabilises existing plaques (↑fibrous cap thickness, ↓lipid core, ↓macrophage content), and reduces ASCVD events — this has been proven in > 30 major randomised trials involving > 200,000 patients.

Aspect	Detail	Pathophysiology
Ischaemic stroke (75–80% of all strokes)	Focal neurological deficit lasting > 24h	Atherosclerosis of carotid arteries or intracranial vessels → either in situ thrombosis (large vessel occlusion) or artery-to-artery embolism (plaque fragment dislodges and embolises distally) → cerebral ischaemia → infarction
TIA	Focal deficit resolving within 24h, no infarct on imaging	Same mechanism but transient — either clot lyses spontaneously or collateral circulation compensates before irreversible injury
Carotid artery stenosis	Often asymptomatic; carotid bruit on examination	Progressive atherosclerotic plaque in the carotid bifurcation (the site of greatest haemodynamic shear stress, which promotes atherogenesis)

Risk of stroke is 2.5× higher in DM ^[14]. Statins for all ischaemic stroke due to thrombosis, regardless of LDL level — because of their plaque stabilisation and endothelial dysfunction correction effects beyond LDL lowering ^[15].

Stroke is the 2nd and 3rd leading cause of death in China and HK ^[15].

Aspect	Detail	Pathophysiology
Intermittent claudication	Calf/thigh pain on walking, relieved by rest	Atherosclerotic stenosis of iliac/femoral/popliteal arteries → ↓blood flow to exercising muscles → anaerobic metabolism → lactic acid accumulation → cramping pain
Critical limb ischaemia	Rest pain (especially at night), non-healing ulcers, gangrene	Severe stenosis/occlusion → chronic ischaemia at rest → tissue hypoxia → necrosis
Acute limb ischaemia	Sudden onset pain, pallor, pulselessness, paraesthesia, paralysis, perishing cold (6 Ps)	Acute thrombotic occlusion of a previously stenosed artery, or embolism from proximal plaque

Risk of lower limb amputation is 15× higher in DM ^[14].

Management of PAD involves CV risk factor modification: statin regardless of lipid level for overall CVS protection, smoking cessation, low-dose aspirin ^[16].

If conservative management fails after 6 months or critical limb ischaemia develops → endovascular treatment (PTA ± stenting) or bypass surgery ^[16].

Complication	Pathophysiology
Aortic atherosclerosis	Same atherogenesis process affecting the aortic wall → aortic plaque can embolise to distal vessels ("cholesterol crystal embolism" / "trash foot")
Abdominal aortic aneurysm (AAA)	Atherosclerotic weakening + chronic inflammation of aortic media → loss of elastic lamellae and smooth muscle → progressive dilatation → risk of rupture
Aortic stenosis (calcific)	Shares risk factors with atherosclerosis (age, ↑LDL-C, DM, HTN, smoking); lipid deposition and inflammation at aortic valve leaflets → calcification → stenosis. However, statin therapy has NOT been shown to slow progression of aortic stenosis in RCTs.

Complication	Pathophysiology
Renal artery stenosis (atherosclerotic)	Atherosclerosis at renal artery ostium → ↓renal perfusion → activation of RAAS → secondary hypertension; chronic ischaemia → ischaemic nephropathy → progressive CKD

2. Complications of Severe Hypertriglyceridaemia

These complications arise not from atherosclerosis but from the physical and biochemical effects of massive TG-rich lipoprotein excess.

Complication	TG Threshold	Pathophysiology
Lipemia retinalis [5, 6]	TG > 10 mmol/L	Retinal blood vessels appear milky/creamy white on fundoscopy because the plasma itself is so lipaemic that light is scattered
Hepatosplenomegaly ^[6]	TG > 10 mmol/L	Reticuloendothelial cells in the liver and spleen engulf excess chylomicrons → lipid-laden Kupffer cells → organ enlargement
Eruptive xanthomas [5, 6]	TG > 10 mmol/L	TG-laden macrophages deposit in dermis → small yellow-red papules appearing in crops on buttocks, shoulders, extensor surfaces; resolve when TG is controlled
Recent memory loss ^[6]	Severe ↑TG	Mechanism uncertain — possibly microvascular obstruction or hyperviscosity affecting cerebral circulation
Lipaemic serum	TG > ~4.5 mmol/L visible, markedly lipaemic at > 10	Excess TG-rich lipoproteins scatter light → serum appears turbid to milky-white; can interfere with laboratory assays

3. Complications Shared with Metabolic Syndrome Context

Dyslipidaemia is frequently one component of the metabolic syndrome. In this context, the complications are not from dyslipidaemia alone but from the synergistic interplay of multiple risk factors (insulin resistance, obesity, hypertension, hyperglycaemia, dyslipidaemia).

4. Complications of Lipid-Lowering Treatment (Iatrogenic)

These are not complications of dyslipidaemia itself, but they are frequently tested and clinically important.

Complication	Incidence	Pathophysiology	Management
Myopathy spectrum ^[5]	Myalgia ~5–10%; myositis < 0.1%; rhabdomyolysis ~1/100,000	Statins inhibit HMG-CoA reductase not only in liver but also in skeletal muscle → ↓coenzyme Q10 (ubiquinone, a component of the mitochondrial electron transport chain) + ↓isoprenoid intermediates → mitochondrial dysfunction in myocytes → muscle injury	Myalgia: continue if tolerable, consider CoQ10 supplementation, switch to hydrophilic statin (pravastatin, fluvastatin, pitavastatin). Myositis/rhabdo: stop statin immediately; IV fluids for rhabdomyolysis to prevent AKI from myoglobinuria ^[5]
		Risk factors: lipophilic statins (simvastatin), high doses, hypothyroidism, CYP3A4 inhibitors, older age, female sex, renal impairment, polypharmacy ^[5]	Stop if CK > 10× ULN or CK > 3× ULN + symptomatic ^[14]
Hepatotoxicity ^[14]	↑ALT in ~1–3% (dose-dependent)	Direct hepatocyte effect; mechanism not fully understood; usually transient and asymptomatic	Stop if ALT > 3× ULN ^[14]; usually reversible on discontinuation
New-onset diabetes	OR ~1.09–1.12 (small absolute ↑)	Statins may impair insulin secretion (↓glucose-stimulated insulin release) and ↓insulin sensitivity; mechanism involves ↓isoprenoid-mediated GLUT4 translocation and ↓CoQ10	Do NOT stop statin — the cardiovascular benefit far outweighs the small DM risk. Monitoring fasting glucose/HbA1c annually is sufficient.
Cognitive symptoms	Very rare; anecdotal reports	Uncertain; possibly related to ↓brain cholesterol (though statins poorly cross BBB)	Reassurance; rechallenge with different statin; no definitive causal link established

Statin Safety — The Big Picture

A common exam and clinical error is overemphasising statin side effects and inappropriately stopping them. The absolute risk of serious statin complications (rhabdomyolysis, severe hepatotoxicity) is vanishingly small compared to the massive ASCVD risk reduction they provide. Statins are generally very well-tolerated (serious side effects < 2%) ^[5]. The NNT for statins in secondary prevention is ~40 over 5 years to prevent one MACE — this is one of the most favourable NNTs in all of medicine.

Complication	Pathophysiology	Notes
Gallstones ^[5]	Fibrates (especially clofibrate) ↑biliary cholesterol secretion → ↑cholesterol saturation of bile → lithogenic bile → cholesterol gallstone formation	This is why clofibrate is no longer widely used
Myopathy ^[5]	Especially when co-treatment with statins or in CKD; usually within ≤2 months of initiation	Fenofibrate preferred over gemfibrozil when combining with statin (gemfibrozil inhibits statin glucuronidation → ↑statin levels)
Deranged LFT ^[5]	Characteristically ↑transaminases with smaller ↑bilirubin/ALP	Monitor LFT
Warfarin interaction ^[5]	Fibrates displace warfarin from albumin binding sites → ↑free warfarin → ↑anticoagulant effect	↓1/3 warfarin dosage with INR monitoring ^[5]

Complication	Mechanism
GI distress, constipation ^[3]	Bulky non-absorbable resin → osmotic/mechanical effects in bowel
↓Absorption of other drugs ^[3]	Resins bind warfarin, thyroxine, digoxin, thiazides, statins → ↓their bioavailability
↑Triglycerides ^[3]	Compensatory ↑VLDL-TG synthesis by liver

Complication	Mechanism
Flushing ^[3]	Prostaglandin D2-mediated cutaneous vasodilation — the most common reason for discontinuation
Hyperglycaemia ^[3]	↑Insulin resistance — problematic in diabetic patients
Hyperuricaemia ^[3]	Competes with uric acid for renal tubular excretion → may precipitate gout
Hepatotoxicity ^[3]	Direct hepatocyte toxicity (especially sustained-release formulations)

Lipid Abnormality	Primary Complications	Mechanism
↑LDL-C	Coronary heart disease, ischaemic stroke, PAD, aortic disease, renovascular disease ^[5]	Atherosclerosis — subendothelial LDL retention → oxidation → foam cells → plaque → rupture → thrombosis
↑TG ( > 10 mmol/L)	Acute pancreatitis, lipemia retinalis, hepatosplenomegaly, eruptive xanthomas [5, 6]	Pancreatic capillary obstruction + in situ FFA release → acinar cell toxicity; reticuloendothelial TG overload
↓HDL-C	Accelerated atherosclerosis	Impaired reverse cholesterol transport → ↓cholesterol removal from arterial wall → plaque progression
Mixed	All of the above	Synergistic — ↑atherogenic particles + ↓protective mechanisms
Dyslipidaemia in metabolic syndrome ^[1]	ASCVD, NAFLD, T2DM progression, CKD	Insulin resistance driving all components; each component amplifies the others

High Yield Summary — Complications

ASCVD is the dominant complication of dyslipidaemia — CHD (most common cause of death in T2DM), ischaemic stroke, PAD, aortic disease [14, 15].
Acute pancreatitis occurs when TG > 10 mmol/L — mechanism: chylomicrons obstruct pancreatic capillaries, pancreatic lipase hydrolyses TG in situ, releasing cytotoxic FFAs ^[5].
NAFLD is the hepatic manifestation of metabolic syndrome — CVD (not liver disease) is the most common cause of death in NAFLD ^[12].
Statin complications: myopathy spectrum (stop if CK > 10× ULN or > 3× ULN + symptomatic), hepatotoxicity (stop if ALT > 3× ULN), new-onset DM (do NOT stop — benefit >> risk) [5, 14].
Fibrate complications: gallstones (especially clofibrate), myopathy (especially with statin co-therapy), warfarin interaction (reduce dose by 1/3) ^[5].
Risk of MI is 3–5× higher and LL amputation 15× higher in DM ^[14] — dyslipidaemia is a key accelerating factor.
Statins are indicated for all ischaemic stroke due to thrombosis, regardless of LDL level — for plaque stabilisation and endothelial function correction ^[15].
Amylase may be falsely normal in hypertriglyceridaemia-induced pancreatitis due to assay interference — always check lipase.

Active Recall - Complications of Dyslipidaemia

References

^[1] Senior notes: Ryan Ho Endocrine.pdf (Section: Type 2 DM, Metabolic Syndrome, p77) ^[3] Lecture slides: three cases of lipid disorder.pdf (p52, p58, p62, p65, p72 — drug side effects and contraindications) ^[4] Lecture slides: Teaching Clinic - Endocrinology - Three cases of lipid disorders - by Prof KCB Tan.pdf.pdf (p4, p8 — FCHL risks, Case 2 pancreatitis) ^[5] Senior notes: Ryan Ho Endocrine.pdf (Section: Lipid disorders, risks, management, p124, p128, p130) ^[6] Senior notes: Ryan Ho Endocrine.pdf (Section: FH, familial chylomicronaemia complications, p131) ^[8] Senior notes: Maksim MEDICINE notes.pdf (Section: NAFLD, p148) ^[12] Senior notes: Ryan Ho GI.pdf (Section: NAFLD pathophysiology, clinical features, prognosis, p309–310) ^[14] Senior notes: Maksim MEDICINE notes.pdf (Section: DM complications macrovascular, drugs for hyperlipidaemia, p63, p88) ^[15] Senior notes: Ryan Ho Neurology.pdf (Section: Stroke risk factors, secondary prevention — statins, p74, p83) ^[16] Senior notes: Maksim SURGERY notes.pdf (Section: PAD management, p167) ^[19] Lecture slides: GC 042. Deterioration of eyesight in a diabetic patient diabetic complications [Update 2025] (1).pdf (p7, p12, p13, p15, p36 — chronic diabetic complications, pathogenesis, treatment principles, comprehensive management) ^[20] Lecture slides: GC 078. Polyuria and polydipsia glucose metabolism, diabetes mellitus, diabetic ketoacidosis [Update 2025] (1).pdf (p33 — screening for chronic complications, annual lipid levels)

High Yield Summary

Key Points for Exams:

Dyslipidaemia is usually asymptomatic — it is found on screening or when complications (MI, stroke, pancreatitis) develop.
Always exclude secondary causes before diagnosing primary: check TFT, fasting glucose, RFT, LFT, urine protein.
Fredrickson classification is purely biochemical/descriptive — does NOT guide management.
Familial hypercholesterolaemia (FH): AD, 1 in 500 heterozygous; mutations in LDLR (90%), apoB-100, or PCSK9; tendon xanthomas are virtually pathognomonic; diagnose with DLCN criteria (>8 = definite).
Palmar xanthomas are pathognomonic of type III (familial dysbetalipoproteinaemia).
Eruptive xanthomas + lipaemic serum + hepatosplenomegaly = severe hypertriglyceridaemia → risk of pancreatitis when TG > 10 mmol/L.
Statins work by inhibiting HMG-CoA reductase → ↓intracellular cholesterol → ↑LDLr expression → ↑LDL clearance.
2019 ESC/EAS targets: Very high risk → LDL-C < 1.4 mmol/L AND ≥50% reduction from baseline.
Clinical approach: Pattern → secondary causes → primary causes → CVD risk factors → manage accordingly.
Metabolic syndrome = central obesity + ↑TG + ↓HDL-C + ↑BP + ↑glucose — insulin resistance is the driver.
Statins are relatively ineffective in homozygous FH because their efficacy depends on upregulation of functional LDLr.
Corneal arcus in a patient < 45 years is significant and suggests FH; in the elderly it is a normal finding.

High Yield Summary

Pattern first: Identify whether it is ↑LDL-C, ↑TG, mixed, or ↓HDL-C. This narrows the differential immediately.
Always exclude secondary causes before diagnosing primary: Check TFT, glucose, RFT, LFT, urine protein, drug history, alcohol history ^[5].
FH (type IIa): Tendon xanthomas + markedly ↑LDL-C + AD FHx + premature ASCVD → DLCN criteria ^[6].
FCHL (type IIb): No distinctive clinical features; diagnosed by demonstrating multiple lipid phenotypes in family; accounts for 1/3–1/2 of familial CHD [4, 6].
Type III (FDBL): Palmar xanthomas are pathognomonic; TC:TG ≈ 2:1; apoE2/E2 ^[6].
Type I (familial chylomicronaemia): TG > 10 → pancreatitis risk; eruptive xanthomas + hepatosplenomegaly; LPL/apoC-II deficiency ^[6].
Hypothyroidism is the #1 secondary cause of ↑LDL-C to exclude.
Severe hypertriglyceridaemia (TG > 10) almost always has a genetic predisposition unmasked by a secondary trigger (DM, alcohol, drugs).
Rare mimics of FH: sitosterolaemia, CTX, LAL deficiency — differentiated by specific biochemical tests.

High Yield Summary

Never rely on a single lipid reading — repeat checking, best with 2 baseline measurements ^[4].
The secondary cause screen is mandatory: TSH, glucose/HbA1c, RFT, LFT (+ baseline before statin), CK (baseline before statin), urine protein, drug and alcohol history [5, 9].
LDL-C is usually estimated by the Friedewald equation; unreliable when TG > 4.5 mmol/L ^[2].
Lipoprotein electrophoresis: broad beta band = type III; chylomicron band at origin = type I/V ^[2].
FH diagnostic criteria ^[6]:
- DLCN: > 8 = definite, 6–8 = probable, 3–5 = possible
- Simon Broome: Criterion 1 + 2 or 3 = definite; Criterion 1 + 4 or 5 = probable
- Tendon xanthomas score 6 points in DLCN — this single finding almost clinches the diagnosis
ASCVD risk assessment determines LDL-C target: Very high risk → < 1.4; High → < 1.8; Moderate → < 2.6; Low → < 3.0 (all mmol/L) ^[3].
CAC score = 0 means very low risk and can reclassify a patient out of statin therapy (unless DM, FHx premature CHD, or smoking) ^[3].
Cascade screening of first-degree relatives is essential after diagnosing an FH index case ^[4].
In ACS: take lipid profile within 24 hours (before acute-phase response lowers values) ^[11].

High Yield Summary

Lifestyle modification is the foundation for ALL patients: diet (60% CHO, 12% protein, 30% fat as 1/3 each of saturated/mono-/polyunsaturated), exercise ≥150 min/week, weight loss, smoking cessation ^[4].
Statins are first-line for hypercholesterolaemia — mechanism: ↓HMG-CoA reductase → ↓intracellular cholesterol → ↑LDLr → ↑LDL clearance. Also have pleiotropic benefits (plaque stabilisation, ↓inflammation) ^[5].
Check LFT, CK, TSH before starting a statin [9, 14].
Rule of 6: doubling the statin dose only gives an additional 6% LDL-C reduction → add ezetimibe rather than push dose ^[14].
Stepwise escalation: Statin → + ezetimibe → + PCSK9 inhibitor (for very high/high risk not at target) [5, 6].
Fibrates are first-line when TG > 5.7 mmol/L to prevent pancreatitis ^[5].
Bile acid sequestrants are contraindicated in type III dyslipidaemia and ↑TG ^[3].
Nicotinic acid raises HDL-C the most (15–35%) but has largely fallen out of favour due to lack of ASCVD benefit in trials and significant side effects ^[3].
In homozygous FH, statins are relatively ineffective → LDL apheresis ± liver transplantation ^[6].
Secondary prevention: statin always indicated in established ASCVD, stroke, PAD — regardless of LDL level [13, 15, 16].
2019 ESC/EAS targets: Very high risk < 1.4 mmol/L AND ≥50% reduction; high risk < 1.8 AND ≥50%; moderate < 2.6; low < 3.0 ^[3].

High Yield Summary

ASCVD is the dominant complication of dyslipidaemia — CHD (most common cause of death in T2DM), ischaemic stroke, PAD, aortic disease [14, 15].
Acute pancreatitis occurs when TG > 10 mmol/L — mechanism: chylomicrons obstruct pancreatic capillaries, pancreatic lipase hydrolyses TG in situ, releasing cytotoxic FFAs ^[5].
NAFLD is the hepatic manifestation of metabolic syndrome — CVD (not liver disease) is the most common cause of death in NAFLD ^[12].
Statin complications: myopathy spectrum (stop if CK > 10× ULN or > 3× ULN + symptomatic), hepatotoxicity (stop if ALT > 3× ULN), new-onset DM (do NOT stop — benefit >> risk) [5, 14].
Fibrate complications: gallstones (especially clofibrate), myopathy (especially with statin co-therapy), warfarin interaction (reduce dose by 1/3) ^[5].
Risk of MI is 3–5× higher and LL amputation 15× higher in DM ^[14] — dyslipidaemia is a key accelerating factor.
Statins are indicated for all ischaemic stroke due to thrombosis, regardless of LDL level — for plaque stabilisation and endothelial function correction ^[15].
Amylase may be falsely normal in hypertriglyceridaemia-induced pancreatitis due to assay interference — always check lipase.

Dyslipidaemia

Dyslipidaemia — Definition, Epidemiology, Risk Factors, Anatomy & Function, Etiology, Pathophysiology, Classification, and Clinical Features

1. Definition

2. Epidemiology

2.1 Global Burden

2.2 Hong Kong Context

2.3 Demographics

3. Risk Factors for Dyslipidaemia

4. Anatomy and Physiology of Lipid Metabolism

4.1 Why Do We Need Lipoproteins?

4.2 Major Lipoprotein Classes

4.3 The Three Lipid Pathways

4.3.1 Exogenous Pathway (Dietary Fat → Peripheral Tissues)

4.3.2 Endogenous Pathway (Hepatic Lipid → Peripheral Tissues)

4.3.3 Reverse Cholesterol Transport (Peripheral Tissues → Liver)

4.4 Intracellular Cholesterol Homeostasis

5. Etiology of Dyslipidaemia

5.1 Secondary Causes (Must Exclude First)

5.2 Primary (Genetic) Causes

5.2.1 Fredrickson Classification

5.2.2 Major Primary Dyslipidaemias in Detail

A. Familial Hypercholesterolaemia (FH) — Fredrickson Type IIa

B. Autosomal Recessive Hypercholesterolaemia (ARH)

C. Familial Combined Hyperlipidaemia (FCHL) — Fredrickson Type IIb

D. Familial Dysbetalipoproteinaemia (FDBL) — Fredrickson Type III

E. Familial Fasting Chylomicronaemia — Fredrickson Type I/V

F. Familial Hypertriglyceridaemia — Fredrickson Type IV

6. Pathophysiology of Atherogenesis — How Dyslipidaemia Causes Disease

6.1 The "Response-to-Retention" Hypothesis

6.2 Role of TG and HDL-C

6.3 Severe Hypertriglyceridaemia and Pancreatitis

7. Classification of Dyslipidaemia

7.1 By Biochemical Pattern

7.2 By Etiology

7.3 Fredrickson Classification (Phenotypic)

7.4 2019 ESC/EAS Cardiovascular Risk Categories [3]

8. Clinical Features

8.1 Symptoms

8.2 Signs

8.2.1 Cutaneous / Soft Tissue Signs of Lipid Deposition

8.2.2 Ocular Signs

8.2.3 Signs of ASCVD Complications

8.2.4 Associated Metabolic Features

9. Screening and Clinical Approach [4, 5, 7]

9.1 Who to Screen

9.2 Clinical Approach to Dyslipidaemia [5]

9.3 Systematic Approach to Treatment of Primary Dyslipidaemia [7]

9.4 Lipid-Lowering Dietary Recommendations [7]

9.5 ASCVD Risk Assessment [5]

9.6 ASCVD Risk Enhancers (2018 ACC/AHA) [3]

9.7 CHD Death Rate Relationship to Cholesterol Level [7]

9.8 Major Risk Factors for CHD [7]

9.9 Prevention [7]

10. Measurement of Lipid Profile

10.1 Lipid Profile Components [2]

10.2 Other Investigations [2]

10.3 Fasting vs Non-fasting

11. Metabolic Syndrome — The Broader Context

11.1 Definition (IDF 2005 / Harmonised 2009)

11.2 Pathophysiology [1, 5]

Active Recall - Dyslipidaemia: Definition, Epidemiology, Risk Factors, Etiology, Pathophysiology, Classification, and Clinical Features

References

Differential Diagnosis of Dyslipidaemia

Framing the Problem

The Diagnostic Thinking Framework

1. Differential Diagnosis by Biochemical Pattern

1A. Isolated Elevated LDL-C (Hypercholesterolaemia)

1B. Isolated Elevated Triglycerides (Hypertriglyceridaemia)

1C. Mixed Hyperlipidaemia (↑LDL-C + ↑TG)

1D. Isolated Low HDL-C

2. Differential Diagnosis by Clinical Presentation

2A. Patient with Xanthomas

2B. Patient with Premature ASCVD

2C. Patient with Acute Pancreatitis and Very High TG

2D. Patient with Incidental ↑TC on Routine Blood Tests

3. Distinguishing Primary from Secondary — A Practical Approach

4. Key Differentiating Features — Summary Table

5. Special Differentials Worth Remembering

5A. Sitosterolaemia [2]

5B. Cerebrotendinous Xanthomatosis (CTX)