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DISLIPIDEMI
SINDROMA METABOLIK
Dr. M a h a t m a SpPD
SMF Penyakit Dalam F.K. UMS
10/15/2017 SURAKARTA
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Digestion and metabolism of dietary fat
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Lipemia is normal , however dyslipidemia is abnormal. We need lipid for
normal body metabolism . There are several kinds of lipids. Lipids are
hydrophobic therefore its must be tranferred in a hydrophilic form as
lipoprotein 11
Bile Acids
Dietary + LIVER
Cholesterol 7 LDL
Fat
2 Apo, B-100
1
Endogenous
Cholesterol
INTESTINES EXTRAHEPATIC
10 TISSUES
3 5
NASCENT HDL
LPL LPL
4 6
HDL3
LDL
REMNANTS VLDL 8 9
CHYLOMICRONS Apo E, B-100
Apo E, B-48 Apo E, C-II, LCAT HTGL
Apo E, C-II, B-48 B-100
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Triglyceride-rich lipoproteins:
size, structure and composition
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High-Density Lipoprotein
Apo A-
I
HDL, apo A-I 1 mg/dl (0.026 mmol/l)
and HDL cholesterol
Apo A-II rich
lipoprotein
Cardiovascular
risk
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LDL metabolism and reverse cholesterol transport
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INTRODUCTION
OBESITY NOT A NEW FENOMENA
THE VENOUS OF WILLENDORF (25OOO YEARS AGO)
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Obesitas
Eropa Asia
> 90 > 80 cm
Waist Circumference
> 102 > 90 cm
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PATOGENESIS OBESITAS
Faktor genetik
Parental fatness
7 gen penyebab : - Leptin receptor
- Melanocortin receptor 4
- Alpha-melanocyte stimulating hormone
- Prohormone convertase 1
- Leptin
- Bardert-Biedl
- Dunnigan partial lypodystrophy
Faktor lingkungan : - Nutrisional - Medikasi
- Aktifitas fisik - Sosial ekonomi
- Trauma
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Overweight and Obesity can be treated
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Low Calorie Balance Diets
( LCD )
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Very Low Calorie Diets
( LCD )
Formula pabrik
Sering sebabkan gangguan metabolisme
Perlu pengawasan di RS
Utk persiapan operasi
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Berbagai macam obat
Penurun Berat Badan
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Complication
Cancer
Cardiovascular
Diabetes Mellitus
Gallstones
Hiperlipidemia
Obstructive Sleep Apneu
Obesity Hypoventilation Syndrome
Osteoarthritis
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Polycystic Ovarian Syndrome
DISLIPIDEMIA
Kelainan metabolisme lipid, ditandai
dengan peningkatan serta penurunan
fraksi lipid plasma.
TRIAD LIPID
Kol-total/ kol-LDL
Trigliserid (TG)
Kol-HDL.
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Dyslipidemia
Abnormal levels of lipoproteins
(cholesterol, TG. HDL, Lp) or apo-B-
E- A
The metabolic pathways may become
abnormal due to several reasons, whether
primary or secondary :
(HCT, tegretol, niacin, estrogen, glucocorticoids, retinoic
acid, -blockers, diabetes, liver disease, renal failure,
malnutrition etc)
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KLASIFIKASI DISLIPIDEMIA
DISLIPIDEMIA PRIMER
- kelainan pada ensim atau apoprotein
- bersifat genetik
DISLIPIDEMIA SEKUNDER
- akibat penyakit: DM, Peny.ginjal, Tiroid
- akibat obat: diuretika, penyekat beta,
kontrasepsi oral, kortikosteroid.
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Secondary Dyslipidemia
Pathological states Drugs that raise LDL-C and/or
Diabetes lower HDL-C
Hypothyroidism Oral estrogens
Cushings syndrome Progestins
Nephrotic syndrome Anabolic steroids
Chronic renal failure Corticosteroids
Monoclonal gammapathy Retinoids, such as isotretinoin
Obstructive liver disease Sertraline hydrochloride
Human immunodeficiency virus (HIV)
Lifestyle habits protease inhibitors
Obesity Non-selective -adrenergic
Alcohol antagonists
Stress Cyclosporine
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CHD and CV risk factors
Non modifiable risk factors
Age, gender, family history
Modifiable risk factors
Overweight, dyslipidemia
high blood pressure, smoking
physical inactivity, diabetes
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Modifiable risk factors
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Dyslipidemia and Atherosclerosis
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Liver
SR-B1
9
Lipid + MTP
+ ApoB
Artery
2 Wall
LDLR
8 7 CETP 6
LRP
HDL ABC1
3
LPL Cholesterol
VLDL
Fatty Acids
IDL
HL LPL
1 4 LDL Oxidation
Matrix
HSL Triglycerides Ca++ 5
Inflammation
Smooth
Small muscle
Adipocyte dense cells
LDL
Cytokines
Mo
MCP-1
M-CSF
Proteo- Mo M + HSP-60
glycans
CD40
+ CD40L
MM-LDL LysoPC Oxygen CD36
radicals + T
+
+ SR-A1 CD14
Cell mediated oxidation TLR4 LPS
Oxidized LDL
SMC
Foam cell formation in the intima. LDL can pass into / out intima. If excess it is trapped in the matrix by proteoglycans
binding. At antioxidants lack, lipids and LDL proteins are oxydized by oxidating products from cells in the vessel wall. LDL
proteins are also glycated. Extensive uptake of m-LDL via scavenger receptors (CD36 and SR-A) macrophages are turned into
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foam cells. This process is accelerated by (1) MCSF, (2) LPS via receptor CD14 with toll-like receptor 4 (TLR4), (3) by heat shock
protein (HSP-60) via CD14, (4) by PAF and cytokines released from macrophages in an autocrine loop.(Mehrabian 2003)
Progression to advanced atherosclerotic lesions (3rd step)
Lumen MC
Native Monocytes
LDL
5LO MCP-1 Platelets
LTA4 LTB4
Chemotaxis BLTR
EC
Matrix
MM-LDL
ROS TC Advanced
M-CSF GM-CSF plaque
5LO
Lipid DC IL-1/TNF
Cell ROS
oxidation proliferation
SMC cell proliferation
Cytokine 5LO
oxLDL uptake induction
by SRA GM-CSF NC
5LO
Intima TNF-
Macrophage
IL-1 Procoagulants SMC
adhesion
NF-B, cytokines
Media
5LO (5 Lipoxyoxygenase) and (LTB4) (leukotriene B4) plays very important role in
1st, 2ndand
the10/15/2017 3rdstep of atherogenesis besides LDL oxidation and oxidized LDL
(Mehrabian, 2003)
Biological effect of C-reactive
protein on vascular cells
Adhesion molecules (VCAM-1 and E-selection)
Chemokines (MCP-1)
Expression of eNOS
Release of prostacyclin
Expression of plasminogen activator inhibitor-1
Expression of angiotensin type 1 receptor
LDL uptake by macrophages
Endothelium-independent relaxation of smooth
muscle cells
Generation of ROS
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CRP, inflammation, and endothelial activation
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Inhibits oxidation Inhibits endothelial
of LDLs HDL adhesion molecules
Inhibits Stimulates
tissue factor endothelial NO
production
Enhances reverse
cholesterol transport
Opposes atherothrombosis
Non-farmakologik :
- Life style obesitas
- Terapi nutrisi
- Batasi minuman beralkohol
- Hindari merokok
Farmakologik :
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- Non farmakologik + obat hipolipidemik
Target Lipid
Kolesterol Total
< 200 yg diinginkan
200 239 batas tinggi
240 tinggi
Kolesterol LDL
< 100 optimal
100 129 di atas optimal
130 159 batas tinggi
160 189 tinggi
190 sangat tinggi
Kolesterol HDL
< 40 rendah
> 60 tinggi
Trigliserida
< 150 normal
150 199 batas tinggi
200 499 tinggi
500 sangat tinggi
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Pengaturan makanan utk hiperkolesterolemia
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Primary Lipid Goal Drugs of Choice
The role of nicotinic acid in the treatment of the metabolic syndrome. Nicotinic acid is an effective agent
in the attainment of both primary and secondary goals set by the NCEP. (Meyers. EMCNA 33 (2004):570)
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Where to attack and site of action of some drugs
Cholesterol Absorption in the Intestine
1000 mg
Inhibitors
Resins
Ursodeoxycholate,
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Altmann et al. Science 2004; 303: 1201-1204
Cholesterol balance in man
Extrahepatic Dietary
Organs LDL IDL VLDL Cholesterol
300 mg/day
25%
Cholesterol
Synthesis
900 mg/day Biliary
Cholesterol Cholesterol
Synthesis 75%
Transport
via HDL & LDL Chylomicron transport
50% intestinal Faecal sterols
Cholesterol absorbed 50% cholesterol
excreted
Cholesterol lowering drugs
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Statins Ezetimibe Plant stanols Resins
Summary of the major drugs used for the treatment of hyperlipidemias
(Rader 2004)
Larosa 1995
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Tabel 7. Obat Hipolipidemik
Obat Dosis
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Lanjutan
Obat Dosis
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Sequestran asam empedu (resin)
Efektif kol-LDL
Mengikat as.empedu di usus ---- ekskresi garam
empedu feces .
Memotong siklus enterohepatik
Asam nikotinat (niacin)
Hambat mobilisasi as.lemak bebas jar. perifer ke
hepar.
Sintesis TG & VLDL di hepar
Hambat konversi VLDL menjadi IDL
Meningkatkan GLUKOSA & asam urat plasma
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NICOTINIC PERIPHERAL
ADIPOCYTE TISSUES
ACID
* Cholesterol
TG
HDL
HSL
Mechanisms of action of NA Nicotinic acid inhibits hepatic TG synthesis at the level of FA synthesis and
esterification of DG. NA also blocks apoAI-containing HDL holoparticle uptake at the liver without altering
transport of cholesterol from HDL to the liver by SRB1. Finally, NA acutely inhibits adipocyte lipolysis, but the
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Meyers EMCNA 33 (2004):561)
Liver
Mobilization
(-) (-) TG synthesis
Peripheral
Tissue FFA
(-)
Niacin
assembly of (-)
ApoB containing TG-rich VLDL
lipoproteins (-)
(-)
ApoB degradation Small dense LDL
Niacin (nicotinic acid) inhibits the mobilization of free fatty acids (FFA) from peripheral tissues, which
reduces the (TG) and decreases (VLDL), which lowers (LDL). Niacin decreases the activity (HDL)-
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catabolism receptor, reducing uptake and degradation of HDL, stimulates RCT. Niacin lowers (apoB)
Penghambat HMG-CoA reduktase
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Penghambat absorbsi kolesterol
(ezetimibe)
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Ezetimibe
glucuronide
Ezetimibe
Bile duct
Portal
Ezetimibe
vein
Ezetimibe
glucuronide Inhibition
of
cholesterol
absorption
Ezetimibe Ezetimibe
glucuronide
Enterohepatic recirculation of ezetimibe and its glucuronide. On first pass, ezetimibe inhibits cholesterol absorption in the
brush border of the small intestinal enterocytes. The drug is then partially transformed by the enterocytes into its main
metabolite, ezetimibe glucuronide. Further metabolism takes place in the liver and the active glucuronide metabolite is
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excreted back in the intestine through the bile duct. Inhibition of cholesterol absorption is prolonged and the glucuronide
is reabsorbed and recirculated through the bile duct. (Simord, Can J Clin Pharmacol 2003, etc)
Fibrat (derivat asam fibrat)
- Sangat tepat untuk hipertrigliseridemia.
- Dapat untuk hiperlipidemia kombinasi
- Dapat dikombinasi dengan RESIN & NIACIN, kom
binasi dengan statin dapat timbul miopati, Gemfi-
brosil jangan dikombinasi dengan statin.
- Bekerja pada peroxisome proliferator-activated re
ceptor- (ppar-)
- Jarang: transaminase hepar naik, batu empedu,
kreatin kinase otot naik, libido turun.
- Efek potensiasi dg Obat Hipoglikemik Oral dan an-
ti-koagulan oral.
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FIBRATES
gemfibrozil, fenofibrates
Glitazones
Eicosanoids
PPAR
PPAR
- Activated PPAR
Nucleus - Retinoid R
PPAR
AGGTCA N AGGTCA
Mechanism
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of action of fibrates on lipoprotein metabolism.
Peroxisome Proliferator-Activated Receptor- a transcription factor
Obat baru :
- NIACIN extended release (NIASPAN)
- Fix kombinasi NIACIN ER + LOVASTATIN
(advicor)
Bile acid
sequestrants 32 g daily Bloating,
Cholestyramine Elevated LDL 4 g daily 40 g daily bile excretion constipation,
Colestipol 5 g daily 4375 mg LDL receptors elevated TG
Colesevelam 3750 mg daily daily
Cholesterol
absorbtion Elevated LDL 10 mg daily 10 mg daily Intestinal Elevated
inhibitors cholesterol transaminase
Ezetimibe absorbtion
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New antilipid drugs
Treatment Site of Dosage Change from base line (%)
action
LDLc HDLc TG
Monotherapy
Avasimibe ACAT-I 50-500 mg NS NS -23
JTT-705 CETP-I 300-900 mg -77 +34.5 NS
Colesevelan Bile acid sequestrant 3.75 gram -19.1 +11,2 NS
Ezetimibe Specific Cholesterol 10 mg -17.7 +1 -17
Absorption Inhibitor
Rosuvastatin HMG-CoA reductase 10-40 mg -63 +14 -23
inhibitor
Pitavastatin HMG-CoA reductase 2 mg -38 +4.2 -23
inhibitor
Combination therapy
ER niacin 500mg/10mg- -47 +30 -42
Lovastatin 2000mg / 40mg
Colesevelan - 2.5mg/40mg -34 NS NS
Lovastatin
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(Law et al. BMJ 2003 ; 326 : 1423-29)
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Pathogenesis ? Even suggested pathogenesis is useful for prevention program.
a. Genetic abnormality b. Fetal malnutrition c.Visceral obesity
Insulin Resistance
Pancreatic Hyperinsulinemia
-cell stress &
damage
*
Inadequate Compensatory
Insulin Response Hyperinsulinemia
CVD
Retinopathy Hypertension
Nephropathy Stroke
Neuropathy PCOS
NAFLD
*ACE position statement (2003)
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Differentiation between the Insulin Resistance Syndrome and type 2 diabetes.
Modified from ACE (2003) & Tenenbaum (2003) (Djokomoeljanto, 2004) DM-BR- 2004
Visceral Obesity Risk Factors CHD
Hyper- Dyslipidemia
tension
Type 2
Diabetes
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Presented by Prof. John MF Adam
FFA Lipid
FFA
Leptin
Adiponectin
Adipose Visfatin
Tissue Resistin
Adipsin (ASP)
Angiotensinogen/AT-II
Cytokines
(TNF-, IL-6)
Prostaglandin NO PAI-1
(TJOKROPRAWIRO 2003)
AUGUST 3-7TH 2006 INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE
Macrophage
ABCA1 Chol
FFA Liver ABCA1
FFA
pre HDL (nascent HDL)
Adipocytes CE
Kidney
Insulin VLDL CETP HDL
Resistance
(T2DM) TG
VLDL TG Apo AI
CE CETP
Insulin TG
small
LDL dense
(lipoprotein or
LDL
or hepatic lipase)
A simplified model that relates insulin resistance ( includes type 2 diabetes mellitus)
to high TG, low HDL-C, small-dense LDL (Assmann. EMCNA (2004):389)
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Insulin resistance Glucose
Insulin
Translocation
Insulin
receptor
X
X Synthesis GLUT 4
PPAR +RXR mRNA
PPRE transcription
promoter Coding reg
Muscle
Cells
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Modified from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.
S U M M A R Y
Definisi Dx Drug Komplikasi
Cancer
Akumulasi Cardiovascular
jaringan lemak Diabetes Mellitus
berlebihan, baik Orlistat Gallstones
IMT
Obesity besar maupun Sibutramine Hiperlipidemia
WC Obstructive Sleep Apneu
jumlahnya
Obesity Hypoventilation Syndrome
Osteoarthritis
Polycystic Ovarian Syndrome
Kelainan TG Statin
Dislipidemi metabolisme CH Niacin
Ezetimibe
Aterosklerosis
lipid LDL
HDL Nicoitinic C H D
WC
Dislipidemia
Kumpulan Aterosklerosis
Ht
gejala yang
Metabolic DM Metformin C H D
disebabkan oleh
Syndrome TG Glitazone
karena obesitas
CH
Hipertensi
sentral Diabetes Mellitus
LDL
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HDL
SUMMARY
The relation between dyslipidemia cardiovascular
disease is confirmed. Primary dyslipidemia should be
treated concomitantly
Dyslipidemia fit also to the current concept of athero-
sclerosis : lipid and inflammatory process
Any lipid abnormality (HDL, TG, etc) should also be
corrected.
Statin should be the backbone of cardiovascular
treatment due to its cholesterol lowering and its
pleiotropic potencies
Aggressive cholesterol lowering is beneficial
In combined dyslipidemia, treatment combination is
sometimes needed
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