Lipoprotein metabolism disorders
Lipid & lipoprotein transport
1) lipoprotein structure
major lipid : cholesterol, TG(nonpolar, lipid-nonsoluble) and phospholipid(soluble)
* 5 major classes(Tab 344-2)
2) Apolipoprotein Tab 344-3
* ¿ªÇÒ i) structural stability to the lipoproteinÁ¦°ø
ii) metabolic fate°áÁ¤
¨ç apo B: B100, B48
i) B100 : major apolipoprotein of VLDL(30%), IDL(60%), LDL(95%)
liver¿¡¼ ÇÕ¼º
VLDL assembly & secretion¿¡ ÇʼöÀû
LDL receptor¿¡ ÀÇÇÑ LDL removal¿¡ ÇÊ¿äÇÑ ligand
ii) B48 : chylomicronÀÇ assembly & secretion¿¡ ÇʼöÀû
¨è C series : °¢°¢ ±â´ÉÀÌ ´Ù¸£´Ù.
C I : liver¿¡¼ chylomicron & VLDL remnant uptake¹æÇØ(Áã½ÇÇè)
C II: essential activator of LPL
C III: LPL inhibition(Áã½ÇÇè)
¨é apo E
ÁÖ·Î liver¿¡¼ ÇÕ¼ºµÇ³ª other cell¿¡¼µµ ÇÕ¼º°¡´É
3 major alleles : E2, E3, E4
apo E2: LDL receptor¿¡ °áÇÕ(E3, E4º¸´Ü lower affinity)
apo E2¿¡ ´ëÇÑ homozygosity = severe hyperlipidemiaÀ¯¹ß
(type III dysbetalipoproteinemia)
apo E°áÇ̽à chylomicron & VLDL remnant¡è
=> early atherosclerosisÀ¯¹ß
¨ê AI, AII(¼ÒÀå, °£¿¡¼ ÇÕ¼º), AIV(only intestine) : HDL
AI : LCAT activation, CHD¾ïÁ¦È¿°ú
¨ë Apoprotein(a) : plasminogen°ú »ó´çÇÑ Á¤µµÀÇ sequence homology
hepatocyte¿¡¼ ¸¸µé¾îÁ® plasma·Î ¹æÃâ
-> apo B100°ú °øÀ¯°áÇÕÀ» ÇÏ¿© lipoprotein(a) Çü¼º
: atherosclerosis risk¡è
3) exogenous(dietary) lipid transport Fig 344-1A
S.I ¢¢ liver
4) endogenous lipid transport
liver ¢¢ peripheral tissue
2°¡Áö systemÀ¸·Î ÀÌ·ç¾îÁø´Ù.
(1) Apo B100 lipoprotein system(Fig 344-1B)
: VLDL, IDL, and LDL
°£¿¡¼ÀÇ TG´Â VLDLÀÇ ÇüÅ·ΠsecretionµÇ¾î LPL¿¡ ÀÇÇØ FFA¿Í VLDL remnant(IDL)
·Î ³ª´µ¾îÁø´Ù. VLDL remnantÁß ÀϺδ HTGL¿¡ ÀÇÇØ °£À¸·Î ÀçÈí¼öµÇ°í ÀϺδÂ
LDLÀÌ µÈ´Ù. À̶§ LDL¿¡´Â apo B100¸¸ ³²À¸¸ç peripheral tissue¿¡ ÃàÀûµÈ´Ù.
very large TG-rich VLDL secretion: TG°ú´ÙÇÕ¼º»óÅ¿¡¼ ¹ß»ý
¿¹> caloric excess, DM, alcohol consumption
¡Å plasma LDL cholesterol & apo B100ÀÇ Áõ°¡´Â atherosclerosisÀÇ À§ÇèÀÎÀÚÀÌ´Ù.
(2) Apo AI-containing lipoprotein system = antiatherogenic
HDL : reverse cholesterol transport¿¡ °ü¿©
The hyperlipoproteinemia
1. Hypercholesterolemia(TG=normal)
LDL cholesterolÁõ°¡(type IIa)
: single-gene defects, polygenic disorders, other ds·Î ÀÎÇÑ secondary effect
1) Familial hypercholesterolemia(FH)
¨ç heterozygous form(1/500)
LDL receptor gene mutation
-> LDL receptor°¨¼Ò
LDL apoBÀÇ fractional clearance°¨¼Ò
LDL productionÁõ°¡
¡ñ liver¿¡¼ VLDL, IDLÀ» º¸´Ù ¸¹ÀÌ ¹æÃâÇÏ¿© LDL·Î ÀüȯÀÌ Áõ°¡Çϴ¹ݸé
hepatic DLD receptor¿¡¼ÀÇ Èí¼ö´Â ÀûÀ¸¹Ç·Î
Ãâ»ý½ÃºÎÅÍ Áõ°¡ÇÏ¿© Æò»ý ³ô´Ù(275-500 mg/dL)
TG´Â Á¤»óÀ̸ç HDLÀº Á¤»ó ȤÀº °¨¼ÒµÇ¾î ÀÖ´Ù.
early or middle age¿¡ severe atherosclerosis ¹ß»ý
tendon xanthoma(75%): intracellular or extracellular deposit
mc : Achilles tendon & extensor tendon of the Knuckles
tuberous xanthoma : elbow & buttock¿¡ softer, painless nodules
xanthelasma: eyelids
=> À̰͵éÀº heterozygous FH¿¡¼ ÈçÇÏ´Ù.
³²ÀÚ¿¡¼ 30´ë ȤÀº ±×ÀÌÀü¿¡ CHD¹ß»ý
¨è homozygous form(1/10,000,000) >500mg/dL
large xanthoma, prominent tendon & palnar xanthoma
childhood¶§ severe, premature CHD¹ß»ý
(1) familial defective ApoB100
(2) polygenic hypercholesterolemia
: most moderate hypercholesterolemia(240-350 mg/dL)
2. Hypertriglyceridemia
hypertriglyceridemia¸¦ Áø´ÜÇϱâ À§Çؼ´Â overnight fast(12½Ã°£)ÈÄ¿¡ plasma lipid¸¦
ÃøÁ¤ÇØ¾ß ÇÑ´Ù.
TG´Â CHD¿ÍÀÇ °ü·Ã¼ºÀÌ È®¸³µÇ¾î ÀÖÁö ¾ÊÀ¸¹Ç·Î age, sex¿¡ ´ëÇØ 90-95% percentile
ÀÌ»óÀ» hypertriglyceridemia·Î Á¤ÀÇÇϰí ÀÖ´Ù. ±×·¯³ª ÀϺבּ¸¿¡¼ plasma TG>130-150
mg/dLÀÏ ¶§ low HDL cholesterol & small, dense LDL particle°ú °ü·ÃÀÖ´Ù°í ÇÏ¿´´Ù.
TG´Üµ¶ÀÇ »ó½ÂÀº
VLDLÁõ°¡·Î ÀÎÇϰųª(type IV)
VLDL + chylomicronÇÔ²² Áõ°¡(type V)
µå¹°°Ô´Â chylomicron´Üµ¶ Áõ°¡(type I)¿¡ ÀÇÇÑ´Ù.
400 mg/dLÀÌÇÏÀÏ ¶§ plasma´Â ¸¼À¸¸ç ±× ÀÌ»óÀÌ µÇ¸é È¥Å¹ÇØÁø´Ù.
chylomicronÀÌ ÀÖÀ» ¶§ ¼ö½Ã°£ ¿ø½ÉºÐ¸®ÈÄ plasma »óÃþ¿¡ creamy layer¸¦ °üÂûÇÒ¼ö ÀÖ´Ù.
tendon xanthoma, xanthelasma´Â »ý±âÁö ¾ÊÀ¸³ª eruptive xanthoma(small orange-red
papule)Àº »ý±æ¼ö ÀÖ´Ù(trunk, extremity).
1000 mg/dLÀÌ»ó ¿Ã¶ó°¥¼ö Àִµ¥ À̶§´Â retinal vsÀÌ orange-yellow color·Î º¸ÀδÙ.
(=lipemia retinalis)
¶ÇÇÑ 1000ÀÌ»óÀ϶§´Â pancreatitisÀÇ major risk°¡ µÈ´Ù.
TGÀÇ Áõ°¡´Â liver¿¡¼ VLDLÇÕ¼ºÀÇ Áõ°¡ ¹× secretionÀÇ Áõ°¡´ë¹®ÀÌ´Ù.
*ÇÕ¼ºÁ¶Àý = free fatty acid availability, glycogen storage level,
hormonal status(insulin°ú glucagon balance)
*obesity, sugar, saturated fat, inactivity, alcohol => TG¡è
1) familial hypertriglyceridemia : AD
200-750 mg/dL : only VLDL TG¡è
markedly elevated level : chylomicron TG(+)
20 yr follow up½Ã CHD riskÁõ°¡´Â moderate
2) familial lipoprotein lipase deficiency: AR
massive accumulation of chylomicron
benign in infancy: pancreatitis, eruptive xanthoma, hepatomegaly,
splenomegaly, foam cell infiltration of the BM
lipemia retinalis(TG>1000mg/dLÀÏ ¶§)
atherosclerosis: not accelerated
Áø´Ü: creamy layer(chylomicron) 4¡É overnight incubationÈÄ
È®Áø: heparinÅõ¿©ÈÄ LPL levelÁõ¸í
´ëºÎºÐ¿¡¼ LPL levelÀº normal range
=> moderate hypertriglyceridemia(250-500 mg/dL)
heterozygous mutation in the LPL gene(5-10%)
: LPL activity°¡ 20-50%°¨¼Ò
severe hypertriglyceridemia
: poorly controlled DM, pregnancy, excessive alcohol,
exogenous estrogen, obesity
3) familial apoprotein CII deficiency: rare AR disorder
functional deficiency of LPL
children or adult¿¡¼ recurrent pancreatitis¹ß»ý
Æò»ý dietary fat restriction
4) hepatic lipase deficiency
total deficiency of HTGL : rare AR disorder
3. Hypercholesterolemia with hypertriglyceridemia
1) familial combined hyperlipidemia : AD
isolated hypertriglyceridemia or isolated LDL¡è combine
clear plasma
xanthoma & xanthelasma´Â ¾ø´Ù.
Ä¡·á: wt reduction, dietray restriction
bile acid-binding resinÀº ±Ý±â(¡ñTG¸¦ »ó½Â½ÃŰ¹Ç·Î)
2) dysbetalipoproteinemia(1/10000)
apo E2ÀÇ homozygosity¶§¹®
apo E2: chylomicron & VLDL remnantÀÇ catabolism¿¡ Áß¿äÇÑ ¿ªÇÒ
µû¶ó¼ apo E2ÀÇ ÀÌ»ó½Ã VLDL Tg & VLDL cholesterol, and chylomicron
remnant¸ðµÎ Áõ°¡ÇÑ´Ù.
Àü Àα¸ÀÇ 1%°¡ apo E2¿¡ ´ëÇØ homozygousÇÏÁö¸¸, ´ëºÎºÐÀº TG, cholesterol levelÀÌ
Á¤»óÀÌ´Ù. dysbetalipoproteinemiaÀÇ 0.01%¿¡¼ lipid metabolismÀÇ second defect°¡
Á¸ÀçÇÑ´Ù.
ÀÌ·± ȯÀÚµéÀº tuberous xanthoma
palmar crease¿¡ cholesterolÀÌ Ä§Âø(striae palmaris)
(= dysbetalipoproteinemia¿¡ specific)
atherosclerosis risk°¡ Áõ°¡Çϰí peripheral vascular diseaseºóµµ°¡ FHº¸´Ù ´õ ³ô´Ù.
4. Reduced HDL cholesterol
Á¤ÀÇ: ³²ÀÚ<35 mg/dL ¿©ÀÚ<40-45 mg/dL
i)coexistent hypertriglyceridemia¿Í ÈçÈ÷ °ü·Ã
ii)primary hyperalphalipoproteinemia: HDL cholesterolÀÌ ½ÉÇÏ°Ô °¨¼ÒµÇ¾î ÀÖÀ¸³ª
plasma TG´Â Á¤»óÀÎ »óÅÂ
apo AI ÇÕ¼º°¨¼Ò
Tab 344-5 Rare genetic disorders of lipid metabolism
5. Secondary causes of hyperlipoproteinemia
1) DM
¨ç type I DM: DM controlÀÌ Àߵǰí insulin levelÀÌ ÀûÀýÇÒ¶§´Â plasma lipid levelµµ
Á¤»óÀÌ´Ù. ±×·¯³ª DKA‹š´Â VLDL, chylomicronÀÇ Áõ°¡·Î hypertriglyceridemia°¡
½ÉÇØÁø´Ù.
ÀÌÀ¯ i) VLDL overproduction
ii) LPL deficiency secondary to insulinopenia
DMÀ» tightÇÏ°Ô controlÇϸé È£ÀüµÈ´Ù.
¨è type 2 DM: insulin resistance & obesity
-> mild to moderate hypertriglyceridemia & low HDL cholesterol
LDL cholesterolÀº ÈçÈ÷ Á¤»ó
Ä¡·á> wt reduction
hyperlipidemia°¡ ÀÖÀ»¶§´Â Áï½Ã Ä¡·áÇϵµ·Ï ÇÑ´Ù(¡ñCHD risk¡è)
¸ñÇ¥ LDL < 100 mg/dL
2) hypothyroidism
LDL¡è, HDL¡è(¡ñHTGL activity¡é)
obesity°¡ ÀÖ´Ù¸é TGÁõ°¡
TSH¸¸ ³ôÀº subclinical hypothyroidism¶§µµ LDLÁõ°¡
Ä¡·á> hypothyroidismÄ¡·á
3) renal disease
¨ç nephrotic syndrome: LDL, VLDLÁõ°¡
hypoproteinemia½ÉÇÑ Á¤µµ¿Í ºñ·Ê
¨è renal failure : TG¡è, HDL¡é
4) ethanol
VLDL¡è(TG¡è)
severe hypertriglyceridemia´Â genetic hyperlipidemia & heavy alcohol intake¶§ ¹ß»ý
apo AIÇÕ¼ºÀ» ÀÚ±Ø, CETP¾ïÁ¦
=>ethanol-associated hypertriglyceridemia´Â ÈçÈ÷ HDLÁõ°¡¿Í µ¿¹Ý
5) AIDS
TG¡è, fat distributionº¯È, °¡²û type 2 DM
6. Áø´Ü
1) LDL cholesterolÀÇ °è»ê(TG<400 mg/dLÀÏ ¶§ °£Á¢ÀûÀ¸·Î °è»ê)
= TC-HDL-TG/5
2) TG>400 mg/dL À϶§´Â TG/cholesterol>5À̹ǷΠ°ø½ÄÀ» »ç¿ëÇÒ¼ö ¾ø°í
Á÷Á¢ ÃøÁ¤ÇØ¾ß ÇÑ´Ù.
: ultracentrifuged plasma¿¡¼ Á÷Á¢ ÃøÁ¤, »ó¾÷ÈµÈ ¹æ¹ýÀ» ÀÌ¿ëÇÑ´Ù.
estimated LDLº¸´Ù 5-15 mg/dLÁ¤µµ ³·Àºµ¥
estimated LDL = LDL + IDLÀ̱⠶§¹®ÀÌ´Ù.
NCEP guidelines¿¡¼ÀÇ LDLÀº estimated LDLÀ» ÀǹÌÇÑ´Ù.
Âü°í C1097 Tab 206-3
Chol¡è: NS, hypothyroidism, dysgammaglobulinemia, AIP, obstructive liver ds
TG¡è: DM, uremia, sepsis, obesity, SLE, dysgammaglobulinemia
glycogen storage ds(type I), lipodystrophy
drug: alcohol, estrogen, ¥â-blocker, isotretinoin
combined: NS, hypothyroidism, glucocorticoid excess/cushing, diuretics, uncontrolled
DM
7. Approach to the patient
1) Elevated LDL cholesterol
primary prevention: complication»ý±â±â Àü¿¡ ¿¹¹æ
secondary prevention: complicationÈÄ Ä¡·á
2) Diet
¨ç NCEP step1 diet
fat: total calÀÇ 30%, saturated fat<10%, cholesterol <300mg/d
¨è NCEP step2 diet
fat: 30%, saturated fat<7%, cholesterol<200mg/d
average diet --> step1 diet --> step2 diet
(LDL 8-10%°¨¼Ò) (LDL 5-7%°¨¼Ò)
3) primary prevention
¸ñÇ¥: LDL<130 mg/dL, TG<150 mg/dL
HDL>40mg/dL(³²), >50mg/dL(¿©)
* risk factors
age(³²>45¼¼, ¿©>55¼¼ or premature menopause without ERT)
CHD family history(³²<55¼¼, ¿©<65¼¼)
DM, hypertension, smoking, HDL<35mg/dL
HDL>60mg/dL=negative risk factor
1st-line drug: HMG-CoA reductase inhibitor
2nd-line drug: niacin, resin
4) secondary prevention
¸ñÇ¥ < 100mg/dL DMȯÀÚ¿¡¼µµ ¸ñÇ¥<100mg/dL
LDL<130mg/dL: 4-6ÁÖÀÇ step1 dietÈÄ ¾ÈµÇ¸é step2 diet
>130mg/dL: drug tx + diet tx½ÃÇà
5) TG¡è, HDL¡é
lowering TG: fibric acid
lowering LDL: HMG-CoA reductase inhibitor
TG¡Â500À϶§´Â risk factor¸¦ °í·ÁÇÏ¿© Ä¡·á. Áï, 200-500»çÀÌ¿¡¼ risk¾ø´Ù¸é Ä¡·á°¡
ÇÊ¿ä¾ø´Ù.
TG>500À϶§´Â pancreatitis À§ÇèÀÌ Áõ°¡ÇϹǷΠ¹Ù·Î ¾à¹°Ä¡·áÇϵµ·Ï ÇÑ´Ù.
8. Ä¡·á
* 3 classes of lipid-lowering agent(1st-line tx)
i) HMG-CoA reductase inhibitor
ii) Niacin
iii) bile acid-binding resins(Tab 344-8)
* Fibric acid : 2nd-line agent, TG¸¦ ³·Ãߴµ¥ °¡Àå È¿°úÀûÀÌ´Ù.
1) HMG CoA reductase inhibitor
¨ç ±âÀü i) LDL¡é: LDL receptor¼ö¸¦ Áõ°¡½Ã۰í receptor-mediated LDL clearance¸¦ Áõ°¡
½ÃŲ´Ù.
Åë»ó¿ë·®¿¡¼ total cholesterol 20-30%, LDL 25-40%°¨¼ÒÇϰí
°í¿ë·®¿¡¼´Â ´õ °¨¼ÒÇÑ´Ù(45-60%).
ii) TG¡é: liver¿¡¼ VLDL secretion¡é
Åë»ó¿ë·®¿¡¼ 10-20%, °í¿ë·®¿¡¼ 30-45%±îÁö °¨¼Ò
¨è ºÎÀÛ¿ë: °ÅÀÇ ¾øÀ¸³ª
i) liver enzymeÁõ°¡: 3¹èÀÌ»ó Áõ°¡(<2%)µÇ¸é ¾à Áß´Ü
ii) myopathy(1%): muscle pain, CPK¡è
2) Niacin
ÀÛ¿ë±âÀüÀÌ ¿ÏÀüÈ÷ ¹àÇôÁöÁø ¾Ê¾ÒÀ¸³ª liver¿¡¼ apoB100À» Æ÷ÇÔÇÏ´Â lipoprotein secretion
À» ¾ïÁ¦ÇÏ´Â °ÍÀ¸·Î º¸ÀδÙ.
LDL°¨¼ÒÈ¿°ú: 15-25%
VLDL°¨¼ÒÈ¿°ú: 25-35%
HDLÁõ°¡È¿°ú: 15-25%
hypertriglyceridemia°¡ ÀÖÀ» ¶§ lst-line drug
*ºÎÀÛ¿ë: cutaneous flushing with/without pruritus
-¼öÁÖÈÄ ¼Ò½ÇµÇ¸ç À̶§ ¼Ò·®ºÎÅÍ ´Ù½Ã ½ÃÀÛÇÏ¸ç ¸Ô±â 30ºÐÀü¿¡ aspirinÀ» º¹¿ëÇÑ´Ù.
less common S/E: liver enzyme¡è, GI distress, impaired glucose intolerance, serum
uric acid¡è with/without gouty arthritis
3) Bile acid-binding resins: cholestyrame, colestipol
Àå¿¡¼ bile acidÈí¼ö¹æÇØÇÏ¿© hepatocyte¿¡¼ compensatory bile acid synthesisÁõ°¡
LDL receptor upregulation
TC: 15-25%°¨¼Ò, LDL:25-35%°¨¼Ò HDL:Áߵ Áõ°¡
´ÜÁ¡:TG»ó½Â(¡ñVLDL compensatory synthesis¡è)
µû¶ó¼, hypertriglyceridemia¿¡¼± Åõ¿©±ÝÁö
GI side effect(+) - constipation, bloating, and gas
4) combination tx
severe, isolated LDL¡è¿¡¼ È¿°úÀû
¨ç LDL¡è, HDL¡é
i) reductase inhibitor + niacin: myositis risk(2-3%)
ii) resin + niacin
¨è TG¡è, LDL¡è
i) resin + niacinÀÌ excellent combination
ii) resin + gemfibrozil: alternative
¨é reductase inhibitor + gemfibrozil : LDLÀÌ ¾ÆÁÖ ³ô°í TG°¡ Áõ°¡µÇ¾î ÀÖÀ» ¶§ »ç¿ëÇÒ ¼ö
ÀÖÀ¸¸ç myositis risk(2-3%)¸¦ °í·ÁÇÏ¿© »ç¿ëÇÑ´Ù.
5) LDL apheresis
homozygous FH: 7-14ÀÏ °£°ÝÀ¸·Î
6) Fibric acid: gemfibrozil & fenofibrate
LPL activity¡è, apo AI»ý»ê¡è, VLDL¡é,
apo CIIIÇÕ¼º¡é(=> LPL-induced lipolysisÃËÁø, VLDL secretion¡é)
=> TG-lowering action(25-40%)
dysbetalipoproteinemia¿¡¼ fibric acid + low-fat diet°¡ 1st-line tx
(postmenopausal womenÀ» Á¦¿ÜÇϰí=ERT°¡ choice)
*ºÎÀÛ¿ë: liver enzyme¡è(2-3%) ²÷À»Çʿ䡿, µå¹°°Ô hepatitis
gallstone(2¹è), myopathy(rare)
7) Fish oils: omega-3 fatty acid: TG¡é
Hypocholesterolemia
1) Inherited <100mg/dL
apo B100 gene mutation -> apo B100ÇÕ¼º¡¿ -> hypobetalipoproteinemia
¨ç heterozygote :50-100 mg/dL, asymptomatic
¨è homozygote: 50mg/dL¡é, fat & fat-soluble vitamin(A,E) malabsorption
abetalipoproteinemia : rare AR disorder
vit E deficiency in infancy & early childhood -> neurologic problem
vitamin replacement°¡ ÀûÀýÇÏ´Ù¸é Á¤»óÀûÀÎ »îÀ» »ì¼ö ÀÖ´Ù.
2) secondary
¨ç malnutrition: alcoholism, GI disease
¨è hyperthyroidism
¨é uncontrolled AIDS(<80mg/dL) ¡ñsevere wasting, diarrhea = poor prognosis
¨ê several neoplasm: leukemia, myeloid metaplasia with splenomegaly
¨ë lipid storage ds: Gaucher's ds, Niemann-Pick ds