Dyslipidemia & Atherosclerosis
A board-focused walk through dyslipidemia and atherosclerosis: LDL-driven plaque pathophysiology, the classic xanthoma/vignette buzzwords, inherited (Fredrickson) dyslipidemias, ACC/AHA statin benefit groups with LDL thresholds, risk-enhancing factors and CAC scoring, drug mechanisms/toxicities, and next-best-step management including hypertriglyceridemic pancreatitis.
Pathophysiology: LDL drives the plaque
Atherosclerosis is a chronic inflammatory response of the arterial wall to endothelial injury, and LDL is the causal driver ("lower is better"). The Step 1 sequence:
- Endothelial dysfunction from shear stress (arterial branch points), hypertension, smoking, hyperglycemia, and high LDL → increased permeability and leukocyte adhesion.
- LDL enters the intima and is oxidized (oxLDL).
- Monocytes enter, become macrophages, and engulf oxLDL via scavenger receptors → foam cells → fatty streak (earliest lesion; reversible; present even in children).
- Smooth muscle cells migrate media → intima and lay down collagen, forming a fibrous cap over a necrotic lipid core = atheroma.
- Stable plaque (thick cap) → fixed stenosis/stable angina. Vulnerable plaque (thin cap, large lipid core, macrophage-rich) → rupture → thrombosis → ACS/MI.
Favored sites: abdominal aorta > proximal LAD (coronary) > popliteal > internal carotid.
- LDL is causal and the primary drug target; HDL is protective but not a validated therapeutic target (HDL-raising drugs have not reduced events).
- Friedewald: LDL = TC − HDL − (TG/5) mg/dL; invalid if TG > 400 → measure LDL directly.
- Foam cell = lipid-laden macrophage; fatty streak = earliest, reversible lesion.
- Rupture-prone plaques are often non-obstructive (<50% stenosis) — why MIs strike without prior severe angina.
- Tendon (Achilles) xanthomas + corneal arcus before age 45 + premature CAD = familial hypercholesterolemia until proven otherwise.
- Eruptive xanthomas + milky/lipemic serum = severe hypertriglyceridemia (pancreatitis risk).
- Statins are contraindicated in pregnancy (and avoided in breastfeeding).
- First-line for lowering LDL/ASCVD events = statin; add-on = ezetimibe → PCSK9 inhibitor.
Inherited dyslipidemias — classic clues
| Disorder (Fredrickson) | Defect | Elevated | Buzzwords |
|---|---|---|---|
| Familial hypercholesterolemia (IIa) | LDL receptor (autosomal dominant) | LDL | Tendon/Achilles xanthomas, arcus <45, premature CAD |
| Familial combined (IIb) | Hepatic ↑ApoB overproduction (polygenic) | LDL + VLDL | Most common inherited dyslipidemia; mixed pattern; CAD |
| Dysbetalipoproteinemia (III) | ApoE2/E2 | IDL + chylomicron remnants | Palmar (xanthoma striatum palmare) + tuberoeruptive xanthomas |
| Hyperchylomicronemia (I) | LPL or ApoC-II deficiency | Chylomicrons (TG) | Childhood pancreatitis, eruptive xanthomas, lipemia retinalis; no ↑CAD |
| Hypertriglyceridemia (IV) | Hepatic ↑VLDL | VLDL (TG) | Pancreatitis when TG very high |
A 35-year-old man has firm nodules on both Achilles tendons and the extensor tendons of the hands, a corneal arcus, and an untreated LDL of 290 mg/dL. His father had an MI at age 44.
- Diagnosis: heterozygous familial hypercholesterolemia (LDL-receptor mutation; autosomal dominant; ~1 in 250).
- Next best steps:
- Start a high-intensity statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) targeting a ≥50% LDL reduction.
- Add ezetimibe, then a PCSK9 inhibitor if LDL stays above goal.
- Cascade screening of first-degree relatives.
Homozygous FH (LDL often >500, CAD in childhood) requires LDL apheresis and agents such as evinacumab (anti-ANGPTL3) or lomitapide (MTP inhibitor).
Risk stratification: who gets a statin
After a lipid panel (fasting or nonfasting is acceptable for initial screening), assign statin therapy by the four ACC/AHA benefit groups:
- Clinical ASCVD (prior MI, ischemic stroke/TIA, PAD) → high-intensity statin (secondary prevention).
- LDL ≥ 190 mg/dL → high-intensity statin.
- Diabetes, age 40–75, LDL 70–189 → at least moderate-intensity (high-intensity if added risk).
- Age 40–75, LDL 70–189, no diabetes → estimate 10-yr ASCVD risk (pooled cohort equations); ≥7.5% favors a statin.
Risk-enhancing factors — family history of premature ASCVD, elevated Lp(a), metabolic syndrome, CKD, chronic inflammatory disease — tip borderline/intermediate-risk patients toward treatment. When intermediate risk (7.5–<20%) remains uncertain, a coronary artery calcium (CAC) score refines the decision: CAC 0 may allow deferral (barring diabetes, smoking, or strong family history); CAC ≥100 or ≥75th percentile favors starting a statin. In very-high-risk ASCVD, if LDL ≥ 70 mg/dL on maximally tolerated statin → add ezetimibe → PCSK9 inhibitor.
Lipid-lowering drugs: mechanism & key toxicity
| Drug | Mechanism | Best for | Key adverse effects |
|---|---|---|---|
| Statins | ↓ HMG-CoA reductase (rate-limiting step of cholesterol synthesis) | ↓LDL, ↓events (1st line) | Myalgia/myopathy, ↑LFTs; avoid in pregnancy |
| Ezetimibe | Blocks NPC1L1 (gut brush border) | Add-on ↓LDL | Mild ↑LFTs |
| PCSK9 inhibitors | mAb → less LDL-receptor degradation → more recycled receptors | Big ↓LDL (FH, high risk) | Injection-site reaction; costly |
| Bempedoic acid | ↓ ATP citrate lyase (prodrug activated in liver, not muscle) | Statin-intolerant | ↑Uric acid/gout, tendon rupture |
| Fibrates | PPAR-α → ↑LPL, ↓ApoC-III | ↓TG | Myopathy (esp. gemfibrozil + statin), gallstones |
| Bile acid resins | Bind bile acids | ↓LDL | GI upset, ↑TG, fat-soluble vitamin malabsorption |
| Niacin | ↓VLDL synthesis (↓adipose lipolysis) | ↑HDL, ↓TG | Flushing (↓ by aspirin), hyperglycemia, gout |
A 40-year-old with poorly controlled diabetes has severe epigastric pain radiating to the back, eruptive xanthomas over the buttocks, and blood that appears milky/lipemic in the tube. Triglycerides = 2,400 mg/dL; lipase is elevated.
- Diagnosis: hypertriglyceridemia-induced acute pancreatitis (risk climbs when TG > 1,000 mg/dL).
- Acute management: NPO, IV fluids, analgesia; IV insulin infusion ± plasma apheresis in severe cases to rapidly lower TG (insulin activates LPL).
- Long-term: a fibrate (fenofibrate) is first-line for very high TG, plus a very-low-fat diet and glycemic control.
Key point: statins primarily lower LDL/ASCVD risk and are not the acute driver here — the pancreatitis is TG-driven.
Match the xanthoma to the lipoprotein — a heavily tested association:
- Tendon (Achilles/extensor) xanthoma → cholesterol / LDL → familial hypercholesterolemia
- Eruptive xanthoma (+ lipemic serum) → triglycerides / chylomicrons → severe hypertriglyceridemia
- Palmar xanthoma (xanthoma striatum palmare) → remnants / IDL → type III dysbetalipoproteinemia (ApoE2/E2)
Caveat: xanthelasma (eyelid) and corneal arcus suggest hyperlipidemia but can also occur in normolipidemic people.
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