Dyslipidaemia

Dyslipidaemia is an abnormality of one or more plasma lipoproteins — raised LDL cholesterol, raised triglycerides, low HDL, or a combination — that drives atherosclerotic cardiovascular disease (ASCVD). For NEET PG it is a high-yield intersection of biochemistry (lipoprotein metabolism), pharmacology (statins, fibrates, PCSK9 inhibitors) and clinical medicine (familial hypercholesterolaemia, risk-based LDL targets).

Lipoprotein primer (the metabolic backbone)

Lipids are insoluble in plasma and travel packaged in lipoproteins, graded by density (inversely proportional to size and lipid content):

Lipoprotein	Major lipid	Key apoprotein	Atherogenicity
Chylomicron	Dietary (exogenous) triglyceride	ApoB-48, C-II, E	Remnants atherogenic
VLDL	Endogenous triglyceride	ApoB-100, C-II, E	Atherogenic
IDL (remnant)	TG + cholesterol	ApoB-100, E	Highly atherogenic
LDL	Cholesterol ester	ApoB-100	Most atherogenic
HDL	Cholesterol (reverse transport)	ApoA-I, A-II	Anti-atherogenic

Two pathways:

• Exogenous: dietary fat → chylomicrons (via intestine, ApoB-48) → lipoprotein lipase (LPL, activated by ApoC-II) hydrolyses TG → chylomicron remnants cleared by hepatic LDL-receptor-related protein (LRP) via ApoE.
• Endogenous: liver secretes VLDL (ApoB-100) → LPL action → IDL → hepatic lipase → LDL → taken up by LDL receptor (recognises ApoB-100/ApoE).

High-yield: Lipoprotein lipase is activated by ApoC-II and inhibited by ApoC-III. Hepatic LDL-receptor uptake recognises ApoB-100 and ApoE. ApoB-48 (chylomicron) lacks the LDL-receptor binding domain because of intestinal RNA editing (CAA→stop codon).

Reverse cholesterol transport: HDL collects peripheral cholesterol (via ABCA1/ABCG1 transporters), esterified by LCAT (lecithin-cholesterol acyltransferase, activated by ApoA-I), and CETP exchanges HDL cholesteryl esters for VLDL/LDL triglycerides.

Classification

Fredrickson (WHO) classification

Based on which lipoprotein fraction accumulates on electrophoresis/ultracentrifugation. Classic and repeatedly examined.

Type	Elevated lipoprotein	Lipid pattern	Defect	Clinical clue
I	Chylomicrons	↑↑ TG	LPL or ApoC-II deficiency	Eruptive xanthomas, lipaemia retinalis, pancreatitis; no ↑ ASCVD
IIa	LDL	↑ Cholesterol	LDL-receptor defect (familial hypercholesterolaemia)	Tendon xanthoma, arcus, premature CAD
IIb	LDL + VLDL	↑ Chol + ↑ TG	Familial combined hyperlipidaemia (overproduction ApoB)	Premature CAD
III	IDL (β-VLDL remnants)	↑ Chol + ↑ TG (equal)	ApoE2/E2 (dysbetalipoproteinaemia)	Palmar (tuberoeruptive) xanthomas, premature CAD
IV	VLDL	↑↑ TG	Familial hypertriglyceridaemia	Most common; assoc. with metabolic syndrome
V	Chylomicrons + VLDL	↑↑↑ TG	LPL/ApoC-II + VLDL overproduction	Pancreatitis risk

High-yield mnemonic — Fredrickson xanthomas: Type I/V → eruptive (high TG), Type IIa → tendon (Achilles, knuckles), Type III → palmar crease (xanthoma striata palmaris) and tuberoeruptive — the palmar crease xanthoma is pathognomonic of Type III.

High-yield: Type I dyslipidaemia (pure chylomicronaemia) does NOT cause premature atherosclerosis because chylomicrons are too large to enter the arterial intima — its danger is acute pancreatitis when TG > 1000 mg/dL. Atherogenic risk tracks with ApoB-containing remnants and LDL.

Practical classification

• Primary (genetic): familial hypercholesterolaemia, familial combined hyperlipidaemia, dysbetalipoproteinaemia, familial hypertriglyceridaemia.
• Secondary (acquired): far more common — see below.

Secondary causes of dyslipidaemia

Always exclude before labelling "primary." Mnemonic: think of conditions that change insulin, thyroid, kidney, liver and drugs.

Cause	Predominant lipid effect
Diabetes mellitus / metabolic syndrome	↑ TG, ↓ HDL, small dense LDL ("atherogenic dyslipidaemia")
Hypothyroidism	↑ LDL (reduced LDL-receptor expression) — commonest secondary cause of ↑ LDL; always check TSH
Nephrotic syndrome	↑ LDL + ↑ TG (hepatic overproduction, urinary loss of regulators)
Chronic kidney disease	↑ TG (↓ LPL activity)
Cholestasis / obstructive jaundice	↑ Lipoprotein-X, ↑ cholesterol
Alcohol	↑ TG (↑ VLDL)
Pregnancy	↑ TG, ↑ cholesterol (physiological)
Drugs	Thiazides, beta-blockers (↑TG, ↓HDL), oestrogens/OCP (↑TG), retinoids/isotretinoin, protease inhibitors, second-generation antipsychotics (olanzapine, clozapine), glucocorticoids, ciclosporin

High-yield: A patient with refractory/new dyslipidaemia → screen for hypothyroidism (TSH), diabetes (HbA1c/glucose), renal (urine protein, creatinine) and liver disease, plus a drug history before starting/escalating therapy.

Familial hypercholesterolaemia (FH)

The single most exam-relevant primary disorder.

• Genetics: autosomal dominant; most commonly loss-of-function mutation of the LDL receptor (LDLR) gene. Other causes: ApoB-100 defect (defective ligand) and gain-of-function PCSK9 mutations.
• Heterozygous FH (HeFH): ~1 in 250; LDL typically 190–400 mg/dL; CAD in 4th–5th decade.
• Homozygous FH (HoFH): rare (~1 in a million); LDL often > 500 mg/dL; xanthomas in childhood; CAD and aortic stenosis in childhood/adolescence.

Clinical signs (Type IIa pattern):

• Tendon xanthomas — Achilles tendon, extensor tendons of knuckles (most specific).
• Corneal arcus (arcus lipoides) before age 45 — premature arcus is significant.
• Xanthelasma — periorbital lipid deposits (less specific; can occur with normal lipids).
• Premature CAD, family history of early MI.

Diagnosis — Dutch Lipid Clinic Network criteria (also Simon Broome criteria) combine LDL level, tendon xanthomas, family history and genetic testing to grade "definite/probable/possible" FH.

High-yield: Tendon xanthoma (Achilles) + premature arcus + LDL > 190 mg/dL + dominant family history = familial hypercholesterolaemia. First-line drug is a high-intensity statin; HoFH may need PCSK9 inhibitors, lomitapide, or LDL apheresis.

Screening and investigation

• Lipid profile: total cholesterol, LDL-C, HDL-C, triglycerides. Traditionally fasting (9–12 h), but non-fasting samples are now acceptable for screening; fasting preferred if TG very high or for monitoring hypertriglyceridaemia.
• Friedewald formula: LDL = Total cholesterol − HDL − (TG/5) (mg/dL). Invalid when TG > 400 mg/dL or in Type III — then use directly measured LDL or non-HDL cholesterol.
• Non-HDL cholesterol = Total cholesterol − HDL; captures all ApoB-containing atherogenic particles; useful when TG is high. Target = LDL target + 30 mg/dL.
• ApoB and Lipoprotein(a) [Lp(a)] are residual-risk markers; Lp(a) is genetically determined and an independent ASCVD/aortic stenosis risk factor.
• Cardiovascular risk calculators: the ASCVD Pooled Cohort Equations (ACC/AHA) estimate 10-year risk; SCORE2/SCORE2-OP (ESC) used in Europe; WHO/ISH charts used in resource-limited settings. These drive the decision to treat in primary prevention.

LDL targets and statin-benefit groups

Management is risk-stratified. The lower the LDL, the lower the event rate ("lower is better"). ESC 2019/2021 targets are the most quoted cut-offs:

Risk category	Example	LDL-C goal
Very high risk	Established ASCVD, diabetes with target-organ damage, severe CKD, FH + 1 major risk factor	< 55 mg/dL (and ≥50% reduction)
High risk	Markedly raised single risk factor, FH without other factors, moderate CKD	< 70 mg/dL (and ≥50% reduction)
Moderate risk	Younger diabetics, intermediate 10-yr risk	< 100 mg/dL
Low risk	Low calculated 10-yr risk	< 116 mg/dL

For recurrent events within 2 years (ESC), an even lower goal of < 40 mg/dL may be considered.

High-yield (most-tested numbers): Very high risk LDL goal < 55 mg/dL; high risk < 70 mg/dL. TG > 500 mg/dL → priority is fibrate to prevent pancreatitis, not LDL lowering.

ACC/AHA "intensity" approach (an alternative framework): rather than absolute targets, treat 4 statin-benefit groups — (1) clinical ASCVD, (2) LDL ≥ 190 mg/dL, (3) diabetics aged 40–75, (4) 10-yr ASCVD risk ≥ 7.5% — with moderate- or high-intensity statins.

Pharmacology — drugs of choice

Statins (HMG-CoA reductase inhibitors) — first line for LDL

• Mechanism: competitively inhibit HMG-CoA reductase, the rate-limiting enzyme of cholesterol synthesis (mevalonate pathway). ↓ Intracellular cholesterol → upregulation of hepatic LDL receptors → increased clearance of plasma LDL. This receptor upregulation is the key downstream effect.
• Pleiotropic effects: plaque stabilisation, anti-inflammatory (↓ CRP), improved endothelial function.
• High-intensity: atorvastatin 40–80 mg, rosuvastatin 20–40 mg (≥50% LDL reduction). Moderate-intensity: atorvastatin 10–20, rosuvastatin 5–10, simvastatin 20–40.
• Adverse effects: myalgia/myopathy → rhabdomyolysis (check CK if symptomatic), transaminitis (hepatotoxicity), new-onset diabetes (small risk), and rarely immune-mediated necrotising myopathy. Best taken at night (except long-acting atorvastatin/rosuvastatin) as synthesis peaks nocturnally.
• Interactions: simvastatin/lovastatin metabolised by CYP3A4 — avoid with macrolides, azoles, grapefruit juice, gemfibrozil (myopathy risk). Pregnancy: contraindicated (Category X).

High-yield: Statin myopathy risk is highest with gemfibrozil (a fibrate); if a fibrate is essential with a statin, use fenofibrate instead. Stop statin and check creatine kinase if muscle pain with weakness.

Ezetimibe

• Mechanism: inhibits the intestinal sterol transporter NPC1L1, blocking cholesterol absorption. Add-on to statin (IMPROVE-IT trial showed event reduction). LDL ↓ ~18–25%.

PCSK9 inhibitors (evolocumab, alirocumab; inclisiran = siRNA)

• Mechanism: PCSK9 normally binds and promotes degradation of the LDL receptor. Monoclonal antibodies (or inclisiran's siRNA silencing) inhibit PCSK9 → more LDL receptors recycled to the surface → dramatic LDL ↓ (50–60%). Subcutaneous injection. Used in FH and very-high-risk patients not at goal on statin + ezetimibe.

Fibrates (gemfibrozil, fenofibrate) — drug of choice for high TG

• Mechanism: agonists of PPAR-alpha → ↑ LPL activity, ↓ ApoC-III, ↑ ApoA-I → potent triglyceride lowering and modest HDL ↑.
• Use: TG > 500 mg/dL to prevent pancreatitis (first-line). Adverse: myopathy (esp. with statins), gallstones (cholesterol), raised creatinine.

Bempedoic acid

• Inhibits ATP-citrate lyase (upstream of HMG-CoA reductase); prodrug activated mainly in liver, sparing muscle — useful in statin intolerance.

Other agents

Drug	Mechanism	Best for	Note
Bile-acid sequestrants (cholestyramine, colesevelam)	Bind bile acids → ↑ LDL-receptor	LDL; pregnancy-safe	Can raise TG; GI upset
Niacin (nicotinic acid)	↓ VLDL secretion; raises HDL most	Low HDL (historic)	Flushing (PGD2; ↓ by aspirin), hyperglycaemia, hyperuricaemia; little outcome benefit
Omega-3 (icosapent ethyl)	↓ hepatic TG synthesis	High TG residual risk	REDUCE-IT benefit

Treatment flow for high LDL: Lifestyle (diet, exercise, weight, stop smoking) → high-intensity statin → if not at goal add ezetimibe → still not at goal add PCSK9 inhibitor (or bempedoic acid in statin intolerance).

Treatment flow for very high TG (>500): stop alcohol/control diabetes → fibrate (fenofibrate) ± omega-3 → address pancreatitis risk first, LDL later.

Complications

• Atherosclerotic cardiovascular disease: coronary artery disease/MI, ischaemic stroke, peripheral arterial disease — the dominant complication of high LDL/non-HDL.
• Acute pancreatitis: with TG > 1000 mg/dL (chylomicronaemia, Types I/V) — note serum amylase may be falsely normal due to interference.
• Xanthomas, xanthelasma, corneal arcus, lipaemia retinalis.
• Aortic stenosis: accelerated in HoFH and high Lp(a).
• Hepatic steatosis (NAFLD) with the metabolic-syndrome phenotype.

Key differentials / look-alikes

• Type IIa FH vs Familial combined hyperlipidaemia (IIb): FH has isolated high LDL with tendon xanthomas; FCHL has variable phenotype (high LDL and/or TG) within a family and usually no tendon xanthomas.
• Type III (dysbetalipoproteinaemia) vs others: roughly equal elevation of cholesterol and TG, broad-β band on electrophoresis, palmar crease xanthomas, ApoE2/E2.
• Secondary causes (hypothyroidism, nephrotic syndrome, cholestasis) mimicking primary hypercholesterolaemia — exclude with TSH, urine protein, LFTs.
• Xanthelasma with normal lipids — common, not diagnostic of dyslipidaemia.

Recently asked / exam angle

• Mechanism MCQs: "Rate-limiting enzyme inhibited by statins" → HMG-CoA reductase; "Statins lower LDL primarily by" → upregulating hepatic LDL receptors; "Fibrates act on" → PPAR-alpha; "PCSK9 inhibitors increase" → LDL-receptor recycling.
• Classification: match the Fredrickson type to the defect (Type I → LPL deficiency; Type III → ApoE2/E2) and the xanthoma (palmar crease → Type III).
• Target values: very high-risk LDL < 55 mg/dL, high-risk < 70 mg/dL — frequently tested as a single-best-answer.
• Friedewald formula and its invalidity when TG > 400 mg/dL.
• Clinical vignette: young adult, Achilles tendon swelling + premature corneal arcus + strong family history of early MI → familial hypercholesterolaemia, autosomal dominant, LDL-receptor mutation.
• Pharmacology safety: statin + gemfibrozil → rhabdomyolysis; statins contraindicated in pregnancy; bile-acid resins raise triglycerides.
• Pancreatitis from hypertriglyceridaemia with falsely normal amylase.

Rapid revision

1. HMG-CoA reductase is the rate-limiting step of cholesterol synthesis and the statin target; net effect = ↑ hepatic LDL receptors.
2. LPL is activated by ApoC-II; its deficiency = Fredrickson Type I (eruptive xanthomas, pancreatitis, no atherosclerosis).
3. Type III dysbetalipoproteinaemia = ApoE2/E2, palmar crease xanthomas, equal ↑ chol and TG.
4. Commonest secondary cause of raised LDL = hypothyroidism — always check TSH.
5. Friedewald: LDL = TC − HDL − TG/5; invalid if TG > 400 mg/dL.
6. Very high-risk LDL goal < 55 mg/dL; high-risk < 70 mg/dL (ESC), each with ≥50% reduction.
7. Fibrates = PPAR-alpha agonists, best for triglycerides; first-line when TG > 500 to prevent pancreatitis.
8. PCSK9 inhibitors (evolocumab, alirocumab) block PCSK9-mediated LDL-receptor degradation → ~60% LDL drop.
9. FH is autosomal dominant, LDL-receptor defect; tendon xanthoma + premature arcus are the classic signs.
10. Statin + gemfibrozil = highest rhabdomyolysis risk; prefer fenofibrate; statins are contraindicated in pregnancy.
11. Ezetimibe inhibits NPC1L1; bempedoic acid inhibits ATP-citrate lyase (muscle-sparing).
12. Non-HDL cholesterol (TC − HDL) is the better target when triglycerides are high; Lp(a) is an independent, genetically fixed risk marker.