STEPTRACKERBIOCHEMISTRY + CARDIOLOGY + GENETICS | LIPID METABOLISM | HIGH-YIELD REVIEW

Familial Dyslipidemias

Classify by which particle piles up and why — each type has a signature xanthoma, risk (pancreatitis vs MI) and inheritance.

FOCUS ON
Type I (LPL or ApoC-II ↓, AR): ↑ chylomicrons → pancreatitis, eruptive xanthomas, hepatosplenomegaly, lipemia retinalis; no ↑ atherosclerosis. Type IIa (LDL receptor/ApoB-100/PCSK9, AD): ↑ LDL → tendon xanthomas, corneal arcus, early MI. Type III (ApoE2 homozygote): ↑ chylomicron remnants + IDL → palmar and tuberoeruptive xanthomas. Type IV (hepatic VLDL overproduction, AD): ↑ TG → pancreatitis risk at TG > 1000.
TYPE
DEFECT · INHERITANCE
LIPIDS RAISED
CLINICAL CLUES
I — hyperchylomicronemia
LPL deficiency or ApoC-II deficiency · AR
Chylomicrons, TG (very high), cholesterol
Childhood pancreatitis, eruptive xanthomas, lipemia retinalis, creamy plasma layer · no early atherosclerosis
IIa — familial hypercholesterolemia
LDL receptor (or ApoB-100, ↑ PCSK9) · AD
LDL, cholesterol (heterozygote ~300; homozygote > 700)
Achilles tendon xanthomas, xanthelasma, corneal arcus < 45 y, MI by 20s (homozygote)
IIb — combined hyperlipidemia
Polygenic / VLDL overproduction
LDL and VLDL
Most common familial dyslipidemia; premature CAD
III — dysbetalipoproteinemia
ApoE2 homozygosity (plus a second hit) · AR
Chylomicron remnants, IDL (cholesterol and TG)
Palmar crease xanthomas, tuberoeruptive xanthomas, premature CAD and PAD
IV — hypertriglyceridemia
Hepatic VLDL overproduction · AD
VLDL, TG
Pancreatitis when TG > 1000; worsened by alcohol, diabetes, estrogen
Abetalipoproteinemia
MTP (microsomal transfer protein) · AR
Absent ApoB-48 and B-100 → no chylomicrons, VLDL, LDL
Steatorrhea in infancy, acanthocytes, ataxia, retinitis pigmentosa (vitamin E, A deficiency); lipid-laden enterocytes
Lp(a) elevation
Inherited (LPA gene)
Lipoprotein(a)
Independent risk for MI, stroke, aortic stenosis
Secondary causes
Hypothyroidism, nephrotic syndrome, cholestasis, diabetes, obesity, alcohol, drugs (thiazides, β-blockers, steroids, protease inhibitors, isotretinoin)
Variable
Check TSH, glucose, urine protein first

Mechanism — where each type breaks the loop

Type ILPL/C-II → chylomicrons can't unload TG
→
Type IIIApoE2 → remnants not cleared
→
Type IVLiver overmakes VLDL
→
Type IIaLDL receptor absent → LDL can't be cleared

High TG (I, IV) → pancreatitis. High LDL/remnant cholesterol (IIa, IIb, III) → atherosclerosis.

Xanthomas tell the type

XANTHOMA
WHERE
TYPE
Eruptive
Buttocks, trunk (yellow papules)
I, IV (high TG)
Tendinous
Achilles, knuckles
IIa
Palmar crease
Palms
III
Xanthelasma
Eyelids
IIa (or normal lipids)

How it's tested

COMMON CONFUSIONType I raises triglycerides enormously but does not accelerate atherosclerosis — chylomicrons are too large to enter the arterial wall.
THE TRAPStatins don't help homozygous FH much (no receptors to upregulate) — PCSK9 inhibitors, LDL apheresis or lomitapide are used.
YOUR APPROACHLook at the lab pattern (TG vs LDL), the xanthoma site and the complication (pancreatitis vs MI) → type → defective protein.

If you see… think…

Child with recurrent pancreatitis and creamy plasma → type I (LPL / ApoC-II)
Achilles tendon xanthomas, MI at 35 → type IIa (LDL receptor)
Yellow streaks in palm creases → type III (ApoE2)
TG 1500 in a drinker with diabetes → type IV, pancreatitis risk
Infant with steatorrhea, acanthocytes, ataxia → abetalipoproteinemia (MTP)
Corneal arcus in a 30-year-old → familial hypercholesterolemia
Eruptive xanthomas on the buttocks → severe hypertriglyceridemia
Hyperlipidemia + weight gain, cold intolerance → hypothyroidism (secondary)
Most common inherited dyslipidemia → familial combined hyperlipidemia (IIb)
Lipoprotein linked to aortic stenosis and MI → Lp(a)