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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