DISLIPIDEMIA

Krishna W Sucipto Divisi Endokrinologi/Metabolik Bgn. Ilmu Penyakit Dalam FK Unsyiah/RSU Dr. Zainoel Abidin Banda Aceh

Roles of Lipids
Disadvantageous
Source of energy Atherosclerosis Body protector Xanthomatosis Component of cell formation Pankreatitis Synthesis of steroid hormon Precursor of prostaglandin

dvantageous

LIPID PLASMA
CH3 H CH3 HO H C O CH2 O CH CH2 C H2.O.CO.R R.COO.CH C H2O O C O (CH2)16 CH3 O CH3 C CH2 CH2 CH2

H
C CH3 O C (CH2)14 CH3 CH3 Kolesterol

H3 C

(CH2)7

(CH2)7

Trigliserid

O
P O OCH2.CH2 .N+

CH3 CH3 CH3

Fosfolipid

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

LIPID PLASMA Kolesterol

- Kolesterol - Trigliserida - Fosfolipid

- 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

Cholesterol Ester Trigliserida

Tak larut (Hidrofobik)

+ Apoprotein

Lipoprotein
Larut dalam air

(Hidrofilik)

Cholesterol Ester
Cholesterol Bebas

Trigliserida Fosfolipid

Apoprotein

= LIPOPROTEIN

Structure of Lipoprotein

Apoprotein + Lipid = Lipoprotein Berfungsi sebagai transportasi lipid

LIPOPROTEIN
Jenis Lipoprotein Kilomikron VLDL IDL LDL HDL Jenis apoprotein apo B48 apo B100 apo B100 apo B100 apo AI & apo AII Lipid, % Trigliserida 80-95 55-80 20-50 5-15 5-10 Kolesterol 2-7 5-15 20-40 40-50 15-25 Fosfolipid 3-9 10-20 15-25 20-25 20-30

Harrisons 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

METABOLISME LIPOPROTEIN
Endogen
Hati

Makrofag

RCTP

kolesterol

remnants

Eksogen
kilomikron

Kolseterol makanan

Usus halus

Tinja

RCTP = reverse cholesterol transport pathway

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

Lemak dlm Makanan

TG
U S U S
L
I P A

Cholesterol +

Asam Lemak

Chylomicron

S
E

Cholesterol Ester

A.L + Glis

Trigliserida
Apoprotein B 48
Fosfolipid

FL

sel Enterosit

JALUR METABOLISME ENDOGEN

Hati
Reseptor LDL Scavenger receptor-A / CD 36 Adenosine triphosphate-binding cassette transporter-1 (ABC-1)

VLDL IDL LDL

Timbunan kolesterol

Makrofag

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

Jalur metabolisme HDL Untuk 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 transporter Terdapat suatu transporter protein, yaitu adenosinetriphosphate-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)

HDL Metabolism

METABOLISME LIPOPROTEIN PADA RESISTENSI INSULIN Sel Lemak ALB*

TG ApoB VLDL

Hati
(CETP)
HDL

VLDL besar

RI**
(CETP)

TG

TG
LDL
LDL kecil padat

ApoA1 Ginjal

Insulin
*Asam lemak bebas ** Resistensi insulin

(lipoprotein atau lipase hati)

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

DISLIPIDEMI DIABETIK

Trigliserid tinggi HDL - kolesterol rendah LDL kecil padat tinggi LDL - kolesterol sering normal

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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.2 This 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 nonthrombotic, non-adherent surface, acting as a semipermeable 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 proinflammatory, 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 < 100 100 - 129 130 - 159 160 - 189 > 190 Total kolesterol < 200 200 - 239 > 240 HDL kolesterol < 40 > 60
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Optimal Mendekati optimal Sedikit tinggi (Borderline) Tinggi Sangat tinggi

Diinginkan Sedikit tinggi (Borderline) Tinggi Rendah Tinggi
JAMA 2001;285:24862-497

TRIGLISERID (NCEP-ATP III)

Optimal
Sedikit tinggi (borderline) Tinggi Sangat tinggi

< 150 mg/dl

150 - 199 mg/dl 200 - 499 mg/dl > 500 mg/dl

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

Merokok sigaret

Hipertensi

(tekanan darah > 140/90 mmHg, atau yang sedang mendapat obat antihipertensi)
(< 40 mg/dl)* ayah usia < 55 tahun, ibu < 65 tahun pria > 45 tahun, wanita > 55 tahun

HDL kolesterol rendah Riwayat keluarga PAK dini Umur

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

11
JAMA 2001;285:24862-497

TIGA KELOMPOK RISIKO YANG MENENTUKAN SASARAN LDL-KOLESTEROL YANG INGIN DICAPAI
Kelompok risiko Mereka dengan PAK atau yang disamakan Sasaran LDL (mg/dl) < 100

Faktor risiko multipel ( > 2)

0 - 1 faktor risiko
13

< 130 < 160

JAMA 2001;285:24862-497

PENATALAKSANAAN

Perubahan gaya hidup (therapeutic lifestyle changes )

Perencanaan makan (diet) Olahraga Berhenti merokok Batasi alkohol

Obat penurun lipid

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KETERANGAN
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.

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SUSUNAN MAKANAN HIPERKOLESTEROLEMI

Jenis makanan
Jumlah lemak Lemak jenuh Polyunsaturated fat

UNTUK

PENDERITA

Rekomendasi
25-30% jumlah kalori < 7% jumlah kalori 10% jumlah kalori

Monounsaturated fat
Karbohidrat

10% jumlah kalori

60% jumlah kalori (terutama karbohidrat kompleks) 10 gm/ 1000 kkal per hari Sekitar 15% jumlah kalori < 200 mg / hari

Serat
Protein Kolesterol
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KETERANGAN

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.

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OLAHRAGA TERATUR

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OBAT PENURUN LIPID

Persentasi penurunan LDL-kolesterol dan trigliserid, serta kenaikan HDL-kolesterol Drug LDL-K 18 - 55% 15 - 30% 5 - 25%* 5 - 25% HDL-K 5 - 15% 3 - 5% 10 - 20%* 15 - 35% TG 7 - 30% - / 20 - 50%* 20 - 50%

Statin
Resin Fibrat Asam nikotinik

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