DISLIPIDEMIA

Krishna W SuciptoDivisi Endokrinologi/MetabolikBgn. Ilmu Penyakit Dalam FK

Unsyiah/RSU Dr. Zainoel Abidin Banda Aceh

Roles of LipidsRoles of LipidsRoles of LipidsRoles of Lipids

AdvantageousAdvantageous•Source of energySource of energy•Body protectorBody protector•Component of cell formationComponent of cell formation•Synthesis of steroid hormon Synthesis of steroid hormon •Precursor of prostaglandinPrecursor of prostaglandin

AdvantageousAdvantageous•Source of energySource of energy•Body protectorBody protector•Component of cell formationComponent of cell formation•Synthesis of steroid hormon Synthesis of steroid hormon •Precursor of prostaglandinPrecursor of prostaglandin

DisadvantageousDisadvantageous•AtherosclerosisAtherosclerosis•XanthomatosisXanthomatosis•Pankreatitis Pankreatitis

DisadvantageousDisadvantageous•AtherosclerosisAtherosclerosis•XanthomatosisXanthomatosis•Pankreatitis Pankreatitis

HOHO

HH

CHCH33 CHCH33

CC

CHCH33

CHCH22CHCH22 CHCH22 CC

CHCH33

CHCH33

HH

KolesterolKolesterol

OO

HH33CC (CH(CH22))77 CCHH

CC (CH(CH22))77 CC

OO

OO CHCH

CHCH22

CHCH22

OO CC (CH(CH22))1414 CHCH33

OO CC

OO

(CH(CH22))1616 CHCH33

TrigliseridTrigliserid

Pickup J, Williams G. Lipid Disorders in diabetes mellitus. Text Book of Diabetes. 1997:p. 55.1-31Pickup J, Williams G. Lipid Disorders in diabetes mellitus. Text Book of Diabetes. 1997:p. 55.1-31

FosfolipidFosfolipid

C HC H22.O.CO.R.O.CO.R

R.COO.CHR.COO.CH

C HC H22OO PP OCHOCH22.CH.CH22.N.N++

CHCH33

CHCH33

CHCH33

OO

OO

LIPID PLASMALIPID PLASMA

22

LIPID PLASMA - Trigliserida

- FosfolipidKolesterol

- Bgn Membran sel- Sintesa asam empedu- Steroidogenesis

- 75% sebagai C.E dgn As.Linoleat & Linolenat

Trigliserida- Ester As.Lemak & Gliserol

- Cadangan Energi di adiposa

Fosfolipid - Ikatan Gliserol dgn As Lemak dan Asam Fosfat

- Pembentuk membran sel

- Pembentukan Lipoprotein

- Kolesterol

Cholesterol Ester

Trigliserida

Tak larut (Hidrofobik)

+ ApoproteinLipoprotein

Larut dalam air

(Hidrofilik)

Cholesterol Ester

Trigliserida

Fosfolipid

Apoprotein Cholesterol Bebas

= LIPOPROTEIN

Apoprotein + Lipid = Lipoprotein Berfungsi sebagai transportasi lipid

Structure of Lipoprotein

LIPOPROTEIN

JenisLipoprotein

Jenis apoprotein

Lipid, %

Trigliserida Kolesterol Fosfolipid

Kilomikron apo B48 80-95 2-7 3-9

VLDL apo B100 55-80 5-15 10-20

IDL apo B100 20-50 20-40 15-25

LDL apo B100 5-15 40-50 20-25

HDL apo AI & apo AII 5-10 15-25 20-30

Harrison’s Principles of Internal Medicine 14th

Metabolisme Lipoprotein

Jalur Eksogen (Penyerapan lipid dari usus)

Jalur Endogen (Sintesa lipid di hati)

Reverse Cholesterol Transport

= Penarikan Cholesterol oleh HDL-Choles terol dari jaringan periferal (makrofag)

ke hati untuk di ekskresi

Shepherd J. Eur Heart J Supplements 2001;3(suppl E):E2-E5

Tinja

remnants

kilomikron

Usus halus

kolesterol

Kolseterolmakanan

HDL

Eksogen

Hati

VLDL

Makrofag

VLDL IDL LDL

Endogen

METABOLISME LIPOPROTEIN

RCTP

RCTP = reverse cholesterol transport pathway

10

Lemak dlm Makanan

TGL

I

P

A

S

E

A.L

Glis +

Trigliserida

sel Enterosit

Cholesterol

Asam Lemak

+

Cholesterol Ester

Apoprotein B 48Fosfolipid

ChylomicronUSUS

FL

Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L

IDL

LDL

Hati

VLDLVLDL

Makrofag

VLDL

Timbunan kolesterol

JALUR METABOLISME ENDOGEN

Reseptor LDL

Scavenger receptor-A / CD 36

Adenosine triphosphate-binding cassette transporter-1 (ABC-1)

Jalur metabolisme HDLUntuk memahami metabolisme HDL, perlu diketahui dulu beberapa hal yang berhubungan dengan reverse cholesterol transport yaitu sumber HDL, reseptor HDL dan protein transporter. Sumber HDL: HDL dibentuk di usus halus dan hati, dikenal sebagai nascent HDL, terutama mengandung fosfolipid dan apo-A1 dengan sedikit sekali kolesterol.Reseptor HDL: Di hati dan jaringan steroidogenik lainnya (ovarium, testis, adrenal) terdapat suatu reseptor HDL yang disebut scavenger receptor class B type 1 (SR-B1). Reseptor ini berfungsi untuk menangkap kolesterol ester yang berada di kolesterol-HDL. Kolesterol ester yang ditangkap akan dihidrolisis dan kolesterol yang terlepas akan digunakan untuk membentuk hormon steroid, dan sebagian akan dimetabolisme sebagai asam empedu ke usus halus.

Protein transporterTerdapat suatu transporter protein, yaitu adenosine-triphosphate-binding cassette transporter-1 (ABC-1), yang bertugas membawa kolesterol yang berada di makrofag ke tepi sel untuk keudian ditangkap oleh HDL.

HDL nascent (Pre-beta HDL) berasal dari usus halus dan hati, berbentuk gepeng dan mengandung apo A1. HDL nascent akan mendekati makrofag untuk mengambil kolesterol yang tersimpan di makrofag. Agar dapat diambil oleh HDL nascent, kol. bebas di bagian dalam makrofag harus dibawa ke permukaan membran sel makrofag oleh suatu transporter yang disebut ABC-1 (ATP -binding cassette transporter-1) Setelah mengambil kol. dari makrofag, HDL nascent berubah menjadi HDL dewasa yang berbentuk bulat.

Kol. bebas yang diambil dari makrofag tsb akan diesterifikasi menjadi kol. ester oleh enzim LCAT (lecithin cholesterol acyl transferase). Selanjutnya kol. ester yang dibawa oleh HDL akan mengambil 2 jalur: Jalur I. ke hati dan ditangkap oleh reseptor SR-B1 (scavenger receptor class B type 1). Jalur II. kol. dalam HDL akan dipertukarkan dengan TG dari VLDL dan IDL dengan bantuan CETP (cholesterol ester transfer protein). Dengan demikian fungsi HDL sebagai “penyerap” kolesterol dari makrofag mempunyai dua jalur yaitu 1. Jalur langsung ke hati yang di tangkap oleh reseptor SRB-1 2. Jalur tidak langsung melalui VLDL dan IDL untuk membawa kolesterol kembali ke hati (titip kolesterol)

Liver LDLR/LRP

SR-BI

HDLR?

Adrenal

LDL

VLDL

HDL

HDL

HDL

HDL

HDL

Cholesterol

SR-BI

HDL- Bile- Cholesterol- Bile Salts

Cholesterol

CholesterolKidneyPeripheral Tissues

SR-BIABC1

LCAT

CETP

ApoA-IR

ApoA-I

OvaryTestis

1

2

3

64 7

8

9 HL

HS-PG

5

HDL Metabolism

Insulin

METABOLISME LIPOPROTEIN PADA RESISTENSI INSULIN

RI**

Sel Lemak

ALB*

Hati

TG ApoB VLDL

VLDLbesar

(CETP)

(CETP)

LDLkecil padat

(lipoprotein atau lipase hati)

ApoA1

Ginjal

TG

HDL

LDL

TG

Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L

*Asam lemak bebas

** Resistensi insulin

DISLIPIDEMI DIABETIKDISLIPIDEMI DIABETIK

Trigliserid tinggiTrigliserid tinggi

HDL - kolesterol rendahHDL - kolesterol rendah

LDL kecil padat tinggiLDL kecil padat tinggi

LDL - kolesterol sering normalLDL - kolesterol sering normal

4242

The primary event in atherosclerosis is thought to be damage caused to the endothelium of arterial walls, resulting in endothelial dysfunction. This damage may be caused by a variety of factors; haemodynamic forces (shear stress caused by eg. hypertension), a number of vasoactive substances, mediators (cytokines) from blood cells, cigarette smoke, atherogenic diet, elevated glucose levels and oxidised LDL-C.1

Initially, damage causes the endothelial cells to express cellular adhesion molecules such as cytokines (interleukin-1, (IL-1); tumour necrosis factor alpha, (TNF-alpha)), chemokines (monocyte chemoattractant factor 1, (MCP-1; IL-8)) and growth factors (platelet-derived growth factor, (PDGF); basic fibroblast growth factor, (bFGF)).1 This ‘sticky’ surface encourages inflammatory cells such as monocytes and T-lymphocytes to attach to the endothelial surface. Once attached they migrate through the intact endothelium into the subendothelial space. Many of the monocytes differentiate into macrophages and take up oxidised LDL, which is more atherogenic than native LDL; these macrophages then become foam cells.1

Oxidised LDL promotes death of endothelial cells and an inflammatory response resulting in impairmen impairment of normal function of the endothelium. In addition, it modifies the response to angiotensin II, resulting in vasodilatory impairment, and induces a prothrombic state by affecting platelets and coagulation factors.Thus, the endothelium responds to damage by inducing a protective response which will eventually lead to the formation of fibrofatty and fibrous lesions, the atherosclerotic plaque, preceded and accompanied by inflammation.2This schematic linear diagram represents part of a network of complex processes that include various disease (and protecting) mechanisms that occur simultaneously.

The normal artery consists of three distinctive layers: the tunica intima, the innermost layer comprising a single layer of endothelial cells on the luminal surface; the tunica media, a tube of vascular smooth muscle cells (VSMCs) and their extracellular matrix shown in this slide; and the tunica adventitia, (not shown in this slide), the outer protective layer comprising loose connective tissue containing blood vessels and nerves which supply the artery itself.1,2

The endothelial cells of the tunica intima have a number of important functions; forming a non-thrombotic, non-adherent surface, acting as a semi-permeable membrane, synthesising and releasing chemical mediators, maintaining the basement membrane, and modifying lipoproteins as they cross into the artery wall.The VSMCs of the tunica media contract and relax to alter the lumen diameter of the vessel in response to a variety of circulating and local stimuli, regulating vascular tone, blood flow and blood pressure. This is effected through the production of a number of vasoactive substances including prostaglandins, endothelin and nitric oxide (NO).1,2

Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation. The changes include greater permeability of the endothelium, up-regulation of leucocyte and endothelial adhesion molecules and migration of leucocytes into the artery wall.

The development of an atherosclerotic plaque indicates an advanced stage in the atherosclerotic process and results from death and rupture of the lipid-laden foam cells in the fatty streak. Migration of vascular smooth muscle cells (VSMCs) to the tunica intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core. The fibrous cap is a crucial component of the mature atherosclerotic plaque as it separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors. Stable atherosclerotic plaques are characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap. Lesions expand at the shoulders by continued leucocyte adhesion. 1

Pathological studies have shown that rupture of atherosclerotic plaques and subsequent luminal thrombosis underlies the aetiology of acute ischaemic coronary syndromes, including myocardial infarction and unstable angina. A lipid-rich core (particularly in the shoulder regions of lesions), abundance of inflammatory cells, a thin fibrous cap and dysfunctional overlying endothelium characterise morphological features of lesions prone to rupture. Dysfunctional endothelium may contribute to the propensity of plaque rupture owing to its pro-inflammatory, prothrombotic and vasoconstrictive properties that modulate lesion composition, growth responses, vascular tone and local shear stress.

Coronary heart disease Restriction of blood flow to the myocardium may be caused by an atherosclerotic plaque narrowing the lumen of the coronary arteries. If the diameter of the coronary artery is reduced by more than 50%, ischaemia will develop and the patient will experience tightness or crushing pain in the chest (angina pectoris). However, pain does not always accompany myocardial ischaemia: this is called silent ischaemia.

Coronary plaque rupture and erosion have been shown to result in thrombus formation within coronary arteries. If blood flow is completely obstructed, either due to a thrombus or by a large atherosclerotic plaque, death to part of the myocardium may ensue, resulting in an MI. Depending on the magnitude or site of the damage to the myocardium the pumping action of the heart may be impaired and/or the heart rate and rhythm may become disturbed. These can result in congestive heart failure or, if very severe, sudden cardiac death.1

Cerebrovascular disease Narrowing of the carotid, vertebral and cerebral arteries supplying blood to the brain can cause a brief interruption in the blood supply to the brain resulting in a transient ischaemic attack. This may cause temporary impairment of vision, speech, sensation or movement and may be followed by a stroke. A stroke may also be caused by formation of a thrombus or embolus, arterial rupture or haemorrhage of the cerebral arteries stopping the oxygen supply to parts of the brain. Sudden loss of consciousness often occurs with subsequent paralysis of parts of the body. It can lead to permanent damage and disability and sudden death.

Peripheral vascular disease When the lumen of arteries such as the femoral and iliac arteries supplying blood to the legs has been significantly narrowed, by 60% or more, the symptoms of intermittent claudication become evident. These include an aching or cramping pain, most often in the legs when walking, which occurs when insufficient oxygen is reaching the muscles in the legs. In advanced cases of peripheral vascular disease, blood supply to the legs may become completely blocked, possibly by thrombus formation, and painful leg and foot ulcers may develop. If left untreated gangrene may eventually ensue, requiring amputation of the affected limb.

KLASIFIKASI TOTAL, LDL, HDL-KOLESTEROL, DAN TRIGLISERID MENURUT NCEP ATP III

(mg/dl)

LDL kolesterol< 100100 - 129130 - 159160 - 189> 190

Total kolesterol< 200200 - 239> 240

HDL kolesterol< 40> 60

OptimalMendekati optimalSedikit tinggi (Borderline) TinggiSangat tinggi

DiinginkanSedikit tinggi (Borderline) Tinggi

RendahTinggi

JAMA 2001;285:24862-49719

TRIGLISERID (NCEP-ATP III)

Optimal < 150 mg/dl

Sedikit tinggi (borderline) 150 - 199 mg/dl

Tinggi 200 - 499 mg/dl

Sangat tinggi > 500 mg/dl

20

FAKTOR RISIKO PENTING (SELAIN LDL-KOLESTEROL) YANG MENENTUKAN SASARAN LDL-KOLESTEROL

• Merokok sigaret

• Hipertensi (tekanan darah > 140/90 mmHg, atau yang sedang mendapat obat antihipertensi)

•HDL kolesterol rendah (< 40 mg/dl)*

• Riwayat keluarga PAK dini ayah usia < 55 tahun, ibu < 65 tahun

• Umur pria > 45 tahun, wanita > 55 tahun

JAMA 2001;285:24862-497

* HDL kolesterol > 60 mg/dl mengurangi satu faktor risiko

11

TIGA KELOMPOK RISIKO YANG MENENTUKAN SASARAN LDL-KOLESTEROL

YANG INGIN DICAPAI

Kelompok risiko Sasaran LDL (mg/dl)

Mereka dengan PAK atau yang disamakan

Faktor risiko multipel ( > 2)

0 - 1 faktor risiko

< 100

< 130

< 160

JAMA 2001;285:24862-49713

PENATALAKSANAAN

Perubahan gaya hidup (therapeutic lifestyle changes ) Perencanaan makan (diet) Olahraga Berhenti merokok Batasi alkohol

Obat penurun lipid

22

Perubahan gaya hidup terutama diet dan olahraga harus merupakan urutan pertama penatalaksanaan dislipidemi. Pada penderita dislipidemi gemuk, diet dan olahraga tidak hanya menurunkan berat badan saja tetapi juga memperbaiki kadar trigliserid dan kolesterol penderita. Obat penurun berat badan seperti orlistat (Xenical) dan sibutramin (Reductyl) yang banyak dipakai pada saat ini akan membantu menurunkan berat badan dan memperbaiki profil lipid penderita. Sibutramin sebagai contoh selain menurunkan dan mempertahankan berat badan yang sudah turun juga meningkatkan kadar HDL-kolesterol cukup baik.

KETERANGAN

23

2626

SUSUNAN MAKANAN UNTUK PENDERITA HIPERKOLESTEROLEMI

Jenis makanan Rekomendasi

Jumlah lemak

Lemak jenuh

Polyunsaturated fat

Monounsaturated fat

Karbohidrat

Serat

Protein

Kolesterol

25-30% jumlah kalori

< 7% jumlah kalori

10% jumlah kalori

10% jumlah kalori

60% jumlah kalori (terutama

karbohidrat kompleks)10 gm/ 1000 kkal per hari

Sekitar 15% jumlah kalori

< 200 mg / hari

27

Beberapa hal penting mengenai jenis makanan yaitu banyak buah, sayur, kacang-kacangan. Perlu menghindari kulit ayam atau ikan, dan untuk mereka yang kadar trilgiserid tinggi sebaiknya menghindari alkohol berlebihan, makanan yang kaya karbohidrat seperti kue manis.

KETERANGAN

28

OLAHRAGA TERATUROLAHRAGA TERATUR

2424

OBAT PENURUN LIPID

Drug LDL-K HDL-K TG

Statin

Resin

Fibrat

Asam nikotinik

18 - 55%

15 - 30%

5 - 25%*

5 - 25%

5 - 15%

3 - 5%

10 - 20%*

15 - 35%

7 - 30%

- /

20 - 50%*

20 - 50%

* bezafibrat, cipofibrat dan fenofibrat menurunkan LDL-kolesterol lebih banyak daripada gemfibrozil

Persentasi penurunan LDL-kolesterol dan trigliserid, serta kenaikan HDL-kolesterol