Pemeriksaan LaboratoriumGangguan Metabolisme Lemak /

Dislipidemia

JUSAK NUGRAHA2010

Prasyarat Kuliah

• Telah menguasai dasar2 Biokimia & FaalLemak dalam tubuh manusia

GANGGUAN METABOLISME LEMAK

• HIPERLIPOPROTEINEMIA = Lipoprotein• HIPERLIPIDEMIA = Fraksi lipid • HIPERLIPEMIA à kekeruhan serum (lipemik)• HIPOLIPOPROTEINEMIA / ALIPOPROTEINEMIA• SEKARANG à DISLIPIDEMIA:

ABNORMALITAS FRAKSI LIPID DALAM SERUM

LEMAK DARAH• MENGAPA Mempelajari lemak darah?à PATOGENESIS ATEROSKLEROSIS (penyebabmortalitas & morbiditas terpenting)

1. PJK 2. Stroke • FAKTOR RESIKO:

- GENETIK - OBESITAS - DISLIPIDEMIA - INAKTIVITAS FISIK- DM - STRES MENTAL- HIPERTENSI - KEPRIBADIAN TIPE A - MEROKOK (RESPONSIF BERLEBIHAN)

KULIAH PRASYARAT

Familial Combined Hyperlipidemia

The most common familial cause of elevated LDL The most common familial cause of elevated LDL cholesterol is known as familial combined cholesterol is known as familial combined hyperlipidemiahyperlipidemia, found in about 15% of patients , found in about 15% of patients with premature CHD . These patients have been with premature CHD . These patients have been shown to have increased production of veryshown to have increased production of very--lowlow--density lipoprotein (VLDL) density lipoprotein (VLDL) apolipoproteinapolipoprotein ((apoapo) ) BB--100. Affected family members have elevated 100. Affected family members have elevated triglyceride levels, elevated LDL cholesterol triglyceride levels, elevated LDL cholesterol levels, or both. Moreover, affected family levels, or both. Moreover, affected family members often have low HDL cholesterol. The members often have low HDL cholesterol. The final steps in the cholesterol synthesis pathway final steps in the cholesterol synthesis pathway are shown in Fig. 2. Here are shown in Fig. 2. Here squalenesqualene is converted is converted into into lanosterollanosterol

Tahap akhir sintesis kolesterol

PATOKIMIAWI LEMAK1. MEMAHAMI BATASAN LEMAK 2. MEMAHAMI MACAM LEMAK & SISTIM

TRANSPORTASINYA DALAM DARAH3. MEMAHAMI BEBERAPA GANGGUAN

METABOLISME LEMAK4. MENGETAHUI PRINSIP PEMERIKSAAN

LABORATORIUM DARI LEMAK DARAH & CARA INTERPRETASINYA.

LEMAK (LIPID): SENYAWA YG SECARA LANGSUNG/TIDAK LANGSUNG BERHUBUNGAN DENGAN ASAM LEMAK

LEMAK DARAH (LIPID)• LIPID dalam darah berupa:

- KOLESTEROL (20%)- TRIGLISERIDA (30%)- FOSFOLIPID (45%)- ASAM LEMAK- LEMAK LAIN DALAM JUMLAH KECIL

DAN TAK PUNYA ARTI PENTING• LIPID ini berasal dari:

1. MAKANAN: absorbsi usus2. SINTESIS ENDOGEN: biosintesis dari kabohidrat danprotein

LIPID: sumber energi yang besar & water-insoluble à perlusistim transportasi khusus

LIPOPROTEIN• Lipid + Apoproteinà kompleks makromolekul

yang water-soluble• 4 lipoprotein utama: kilomikron, VLDL, LDL, HDL• 2 lipoprotein khusus: Lp (a) , LpX• Bentuk antara: IDL• Lipoprotein dapat dipisahkan dengan:

Ultrasentrifus: berdasarkan densitasElektroforesis: berdasarkan muatan apo-prot

- +β

ki β Pre-β a

APOPROTEIN (APO-LIPOPROTEIN)• ADALAH FRAKSI PROTEIN PADA LIPOPROTEIN• APOPROTEIN – AI / AII / AIV• APOPROTEIN – B48 / B100• APOPROTEIN – CI / C II / CIII• APOPROTEIN – E • APOPROTEIN – a (Apo-a)

• • ApoA-I: principal structural protein of HDL but also found in chylomicrons and activates lecithin:cholesterol acyltransferase (LCAT).

• • ApoA-II: another structural protein of HDL also found in chylomicrons and activates hepatic lipase (HL).

• • ApoA-IV: predominantly found in HDL and activates LCAT and lipoprotein lipase (LPL).• • ApoB-48: exclusively found in chylomicrons, derived from the apoB-100 gene, and reduced

to 48% of the N-terminal component of B-100 by RNA editing, with no LDL receptor (LDLr) binding domain.

• • ApoD: exclusively found in HDL and possibly activates CE transfer protein (CETP) (2).• • ApoE: also found broadly in HDL, IDL, LDL, VLDL, and chylomicrons and binds to• LDLr with varying affinity dependent on the inherited apoE allele. Three different apoE• isoforms exist in humans: apoE2 with lower affinity to LDLr, apoE3 with intermediate• binding affinity, and apoE4 with higher affinity (3).• • Apo(a): distinguishing structural protein of Lp(a) that is covalently bound to apoB-100and inhibits plasminogen activation (4,5).

• ApoB-100: principal structural protein of LDL, alsofound in VLDL, IDL, and Lp(a); ligand for LDLr.

• ApoC-I: primarily found in HDL and chylomicronsand also in IDL and VLDL and

activates LCAT.• ApoC-II: protein primarily of VLDL and chylomicrons

and also found in HDL and IDLand activates LPL.• ApoC-III: found broadly in HDL, IDL, LDL, VLDL, and

chylomicrons but more consistentlyin VLDL and chylomicrons and inhibits LPL .

• ApoD: exclusively found in HDL and possibly activates CE transfer protein (CETP) .

• ApoE: also found broadly in HDL, IDL, LDL, VLDL, and chylomicrons and binds to LDLr with varying affinity dependent on the inherited apoE allele. Three different apoE isoforms exist in humans: apoE2 with lower affinity to LDLr, apoE3 with intermediate binding affinity, and apoE4 with higher affinity .

• Apo(a): distinguishing structural protein of Lp(a) that is covalently bound to apoB-100 and inhibits plasminogen activation

apoprotein

Fosfolipid

Kolesterolbebas

Kolesterolester

Trigliserida

KILOMIKRON

• d < 0,94• Mobilitas elektroforesis: origin• Kaya akan TG exogen, à absorbsi lemak oleh

usus• Hanya ada di darah post prandial• Fungsi: transpost lipid exogen

VLDL (Pre ß Lipoprotein)• d = 0,96-1,006. • Mobilitas elektroforesis: pre-Beta• Mengangkut TG & lemak lain yang disintesis di

hati• Fungsi: mengangkut lipid ke jaringan perifer

LDL (ß-Lipoprotein)• d = 1,006 – 1.063• Kaya akan kolesterol &

Dibentuk di plasma, berasal dari degradasi VLDL.

• Fungsi: mengangkut kolesterol ke jaringan perifer.

• Apoprotein: B100, B48

HDL (α-Lipoprotein)

• d = 1,063 – 1,21• Kandungan protein tinggi (Apo A,C,E, tu A1)• Fungsi: mengambil kolesterol dari jaringan perifer ke

hati, lalu didegradasi atau diekskresi empedu (removal / reverse transport dari kolesterol)

• Dari degradasi VLDL & kilomikron. Inti HDL = kolesterol ester yang diambil di jaringan perifer dengan bantuan enzim LCAT.

• Faktor protektif

Beberapa reaksi yang penting• LIPOLISIS : penguraian Trigliserida menjadi

asam lemak bebas dan gliserol oleh enzim LPL – Lipoprotein Lipase

• Esterifikasi kolesterol : oleh enzim LCAT = Lecithin Cholesterol- acyltransferase

• Sintesis Kolesterol intraseluler: oleh enzim HMG-CoA reduktase

Metabolic Map of Lipoproteins

Chylomicron CMremnant

Liver

Intestine

Capillary endothelial cellsUnesterified cholesterol

Receptor

Peripheral cell

Bloodstream

LPL: lipoprotein lipase

HTGL: Hepatic triglyceride lipoprotein

LCAT: Lethitin cholesterol acyltransferase

VLDL I DL LDL

I, V IIb, IV, V III IIa, IIb

TEORI TERJADINYA ATEROSKLEROSIS

1. HIPOTESIS INFILTRASI LIPID: infiltrasi lipoprotein ke intima

2. Hipotesis Kerusakan Endotel: trombogenesis & PDGF

3. TEORI RESEPTOR & RADIKAL BEBAS

Small dense (sd)-LDL

• Sd-LDL: mudah teroksidasià : peran pentingaterogenesis.

• Tak dikenali oleh reseptor LDL• Di”makan” melalui scavenger receptor macrophage. • Merangsang endotel mengeluarkan MCP-1

(Monocyte-chemotactic protein) & M-CSF (Macrophage-colony stimulating factor)

• Migrasi monosit ke endotel• Ferritin: besi bebasà peran penting oksidasi LDL

DISLIPIDEMIA

• DISLIPIDEMIA PRIMER : FAKTOR GENETIK• DISLIPIDEMIA SEKUNDER :

‘’GAYA HIDUP” & DASAR PENYAKIT LAIN

Batas normal Lipid (NCEP-ATP III)

• Kolesterol total : < 200 mg/dl• Kolesterol-HDL : > 45 mg/dl• Kolesterol-LDL : < 100 mg/dl• Trigliserida : < 150 mg/dl• Rasio Kolesterol total/HDL : < 5

• Kolesterol LDL:– Asai laboratorik, pengendapan polianion– Perhitungan Formula Friedewald

Pemeriksaan Laboratorium dasar• Pengamatan plasma/ serum segar: apakah

keruh seperti susu = lipemik.• Tes kilomikron (Plasma standing test)• Kadar Kolesterol (total)• Kadar Trigliserida• Pengendapan dengan poli-anion bervalensi

dua : heparin-Mn.HDL ètdpt pd supernatanLDL à tdpt pd bagian endapan

TES KILOMIKRON (PLASMA STANDING TEST)TES KILOMIKRON (PLASMA STANDING TEST)

•• SERUM/PLASMA DALAM TABUNG DIDIAMKAN SERUM/PLASMA DALAM TABUNG DIDIAMKAN SEMALAM PADA SUHU 4SEMALAM PADA SUHU 400CC

NN I IIA IIB III IV V

Formula Friedewald

• Kol-LDL = Kol Total – (Kol-HDL) – TG/5• Berlaku untuk serum/plasma puasa

(kilomikron = 0 )• Syarat: TG < 400 mg/dl (Kol-VLDL≠TG/5)

KLASIFIKASI HIPERLIPOPROTEINEMIA MENURUT FREDRICKSON

TIPETIPE KELAINAN LIPOPROTEINKELAINAN LIPOPROTEIN

II Lapisan kilomikron di atas plasma puasaLapisan kilomikron di atas plasma puasa

IIaIIa KenaikanKenaikan LDLLDL

IIbIIb Kenaikan LDL , disertai VLDLKenaikan LDL , disertai VLDL

IIIIII Terdapat bentuk Intermediate (Terdapat bentuk Intermediate (floating ß floating ß ))

kilomikron mungkin meningkatkilomikron mungkin meningkat

IVIV Kenaikan VLDL sajaKenaikan VLDL saja

VV KenaikanKenaikan kilomikronkilomikron & VLDL & VLDL padapada plasma plasma puasapuasa

TIPE 1 (Hiperkilomikronemia)

• Etiologi: Primer – GENETIK.Def LipoProteinLipaseSekunder: SLE

Dis-γ-Globulinemia

Insulinopenic DM

• Resiko aterosklerosis: rendah

DISLIPIDEMIA SEKUNDER

HIPERKOLESTEROLEMIA HIPOTIROIDSINDROMA NEFROTIKDIS-GAMMAGLOBINEMIAPORPHYRIAPENYAKIT HATI

HIPERTRIGLISERIDEMIADIABETES MELLITUSOBESITASALKOHOLISMEPANKREATITISGAGAL GINJAL KRONISDIS-GAMMAGLOBULINEMIAGLIKOGEN STORAGE DISEASE

Pengukuran Apoprotein• Pengukuran Apo A1 àmewakili HDL• Pengukuran Apo B (apo B100) àmewakili LDL +

(VLDL)• Pengukuran Apo A1 & Apo B à Lebih baik

daripada Kolesterol-HDL &-LDL untuk menentukanresiko hiperlipidemia.

• Apo A1 & B àDiperiksa bila Kolesterol HDL / LDL = abN atau ada faktor resiko + dislipidemia

Penanggulangan gangguan metabolismelemak

• Pengaturan “gaya hidup” : diet, BB, olahraga• Pengobatan farmakologis:

1. Sequestran asam empedu2. Asam nikotinat3. Golongan Fibrat4. Golongan Statin (HMG-CoA reductase inhibitor)

• Pembedahan

Lp (a)• Autosomal dominant• > 30 mg/dl à resiko PJK 2X• Faktor resiko sendiri, tak berhub. Dg fraksi lemak

lain• Struktur mirip LDL, tapi punya “ekor” apo(a) &

apoB100• Struktur Apo(a) mirip plasminogen à

menghambat kerja plasminogen à Plasmin tak terbentuk à tak terjadi Fibrinolisis .

• Jadi punya efek TROMBOGENIK

Sifat2 Lp(a)

• Bergerak pada pre-ß elektroforesis• Struktur mirip LDL• Ukuran LDL < Lp(a) < VLDL• Mempunyai bagian protease serine yang mirip

plasminogen

Peran Lp(a) pada aterosklerosis1. Lp(a) berikatan dgn reseptor plasminogen

(kompetitif) yg tdpt pd trombosit, endotel, fibroblast. Sehingga konsentrasi Lp(a) yg >> à aktivitas antifibrinolisis

2. Penimbunan Lp(a) pada endotel arteri, ikatan lp(a) dengan makrofag arteri

Hubungan TG & atherosklerosis

• Dahulu: TG bukan faktor resiko PJK, melainkan resiko pankreatitis akuta

• Sekarang: terbukti TG mempunyai peran penting pada Atherosklerosis. Peran TG:

1. TG mengganggu transpor oksigen ke jaringan2. TG memacu agregasi trombosit3. TG merangsang terbentuknya mikrotrombus4. TG menurunkan kadar HDL

•Metabolic syndrome (MetS) is a dyslipidemic state that is associated with a cluster of risk factors.

Metabolism of Triglyceride

> 3 Kriteria (IDF 2005)

• Obesitas sentral ( lingkar perut > 90 cm (L), > 80 cm (P)

• Trigliserida ( > 150 mg/dl)• HDL-C ( < 40 mg/dl (L); < 50 (P)• Blood Pressure (> 130/85 mmHg)• Glukosa puasa ( > 100 mg/dl)

Parameter Evaluasi

1. Atherogenic Dyslipidemian Elevated fasting TGn Elevated Apo Bn Elevated remnant Lipoproteinemian Increased sd-LDL : LDL/ApoB < 1,2

2. Insulin Resistancen Hyperinsulinemia, Hyperglycaemia

3. Prothrombotic State / Proinflammatory Staten Fibrinogenn Adiponectinn hs-CRP

Penyebab Hipertrigliseridemia Primer

• Familial combined hyperlipidemia• Familial Hypertriglyceridemia• Type III Hyperlipoproteinemia• Chylomicronemia:

– Lipoprotein lipase deficiency– Apolipoprotein C-II deficiency

Penyebab Hipertrigliseridemia Sekunder

• Resistensi Insulin– Diabetes Mellitus (DM)– Metabolic Syndrome

• Alkohol• Excess Carbohydrate intake• Nephrotic syndrome• Hypothyroidism• Medications: Beta-blockers, immunosupressive

drugs, protease inhibitor, estrogen replacement, isotretinoin.

Uji Laboratorium untuk Pengelolaan Penyakit Kardiovaskular

Faktor risiko Petanda baru Penyakit Arteri Koroner

Petanda Infeksi /

Inflamasi –– Total Cholesterol– HDL-Chol– LDL-Chol– Apolipoprotein A-I– Apolipoprotein B– Lp (a)– Triglyceride– CRP– SAA– Fibrin D-Dimer– Factor VII– von Willebrand Factor– Plasminogen Activator I– Fibrinogen

– Homocystein– etc.

Øsd-LDLØMyeloperoxidase(MPO)

Ø ox-LDLØF2Isoprostane

ØSphingomyelinase

Ø Phospholipase A2

family (Lp-PLA2; sPLA2)

Ø hsCRP

–Helicobacter pylori

– Chlamydia

– Cytomegalovirus

– CRP

– SAA

MS

PARAMETER LAIN RESIKO ATEROSKLEROSIS

• Fibrinogen & faktor VII• ACA (anti Cardiolipin antibodies)• Ferritin• Homocysteine• Hs-CRP