OBESITAS
DISLIPIDEMIA
SINDROMA METABOLIK
Dr. M a h a t m a SpPD Fak.Kedokteran UMS
SURAKARTA
Presentation Point of View
Presentation Point of View
OBESITY NOT A NEW FENOMENA
1.7 billion worldwide are overweight or obese
The US has the highest percentage of obese people.
Di Indonesia wanita sebesar 23,8% dan laki-laki sebesar 13,8%.
Digestion, metabolism of fat
Cholesterol balance
VLDL
Chylomicron transport
50% intestinal
Cholesterol absorbed
IDL
Faecal sterols
50% cholesterol
excreted
LDL Dietary
Cholesterol
300 mg/day
25%
Biliary
Cholesterol
75%
Extrahepatic
Organs
Cholesterol Synthesis
900 mg/day Cholesterol Synthesis
Transport
via HDL & LDL
Triglyceride-rich lipoproteins: size, structure and composition
5/2/2013
HDL metabolism
Potential mechanisms by which HDLs oppose atherothrombosis. (Barter. EMCNA (2004):398)
Inhibits oxidation
of LDLs
Inhibits
tissue factor
Inhibits endothelial
adhesion molecules
Stimulates endothelial NO
production
Enhances reverse cholesterol transport
Opposes atherothrombosis
HDL
LDL metabolism
Presentation Point of View
Obesity is caused by imbalance of high
Food intake and or low energy expenditure
Definition
Eropa Asia
B M I > 30 kg/m2 > 25 kg/m2
Waist Circumference > 90
> 102
> 80 cm
> 90 cm
BMI Classification
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
25 tahun 50 tahun
Banyak gerak
Makanan yang
diproses
Hidup santai
Mengapa Orang Jadi Gemuk?
16
Kegemukan (Obesitas)
Android/ central
Gemuk tidak sehat
Ginekoid/ trunkal
Gemuk sehat
Overweight and Obesity widespread, serious But treatable
AK
UP
UN
TU
R
19
Diabetes Hipertensi
Jantung
koroner
Trigliserid Kolesterol HDL
Penurunan Berat Badan 5-10%
Overweight and Obesity widespread, serious But treatable
LIP
OT
RIP
SY
LIP
O S
UC
TIO
N
SU
RG
ER
Y B
YP
AS
S
SU
RG
ER
Y B
YP
AS
S
LIF
ES
TY
LE
Roux-en-Y gastric bypass.
Lap band procedure .Criteria: a) BMI > 40 or >35 with 2 comorbidities.
b) Failure of non surgical methods
c) Presence of 2 or more medical conditions
Surgery
Berbagai macam obat
Penurun Berat Badan
1. Bekerja di saluran cerna ( penghambat ensim
lipase pankreas ) : orlistat, 120 mg/ hr.
2. Bekerja menekan pusat nafsu makan di otak :
Lewat jalur serotoninergik : fenfluramine & dexfenfluramine
Lewat jalur noradrenergik : phentermine
lewat jalur serotoninergik & jalur noradrenergik : sibutramine, 10 mg
per hari, max 20 mg / hr.
5/2/2013
Medical Complications of
Obesity
Pulmonary disease abnormal function
obstructive sleep apnea
hypoventilation syndrome
Non Alcoholic fatty liver disease steatosis steatohepatitis cirrhosis
Gall stone disease
Gynecologic abnormalities abnormal menses
infertility
PCOS Osteoarthritis
Gout Phlebitis venous stasis
Cancer breast, uterus, cervix colon, esophagus, pancreas kidney, prostate
Severe pancreatitis
CHD Diabetes Dyslipidemia Hypertension
Cataracts
Stroke
Presentation Point of View
Dyslipidemia
Kelainan metabolisme lipid, ditandai dengan peningkatan serta penurunan
fraksi lipid plasma
TRIAD LIPID
Kol-total/ kol-LDL
Trigliserid (TG)
Kol-HDL.
KLASIFIKASI DISLIPIDEMIA
DISLIPIDEMIA PRIMER - kelainan pada ensim atau apoprotein
- bersifat genetik
DISLIPIDEMIA SEKUNDER
Secondary Dislipidemi
Pathological states Diabetes
Hypothyroidism
Cushings syndrome
Nephrotic syndrome
Chronic renal failure
Monoclonal gammapathy
Obstructive liver disease
Lifestyle habits Obesity
Alcohol
Stress
Merokok
Drugs Oral estrogens
Progestins
Anabolic steroids
Corticosteroids
Retinoids, such as isotretinoin
Sertraline hydrochloride
ARV protease inhibitors
Non-selective -adrenergic
inhibitor
Cyclosporine
Thiazide diuretics
Dyslipidemia Major of
Atherogenicity
Non modifiable risk factors : Age, gender, family
5/2/2013
LUMEN
SEL OTOT POLOS
Sitokin+ f. pertumbuhan
MEDIA
fibrinolisis
agregasi tr.
PLAQUE
Migrasi
Hiperinsulin
Proliferasi SS
Radikal
Bebas.
AGEs
LDL
kecil
Glukose
LDL
DM
Makrofag
SEL BUSA LDL
ox
PLAQUE
INTIMA
MONOSIT
tissue factor PAI-1 S S S i i i i i
PENATALAKSANAAN DISLIPIDEMIA
Non-farmakologik :
- Life style obesitas
- Terapi nutrisi
- Batasi minuman
beralkohol
- Hindari merokok
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
Evolution of Lipid Management Driving the Need for More Effective Statin Therapy
Lower LDL-C goals; wider target population;
need for more effective therapies
ATP III
2001
ATP II
1993
ATP I
1988
European
2003 European
1998
European
1994
ATP III
update
2004
Figure adapted from Boden et al. 20006
The risk of CVD can be reduced by:
Lowering LDL-C levels1
Increasing HDL-C levels2-5
1%
decrease in LDL-C reduces CHD risk by 1%1
1%
increase
in HDL-C
reduces
CHD risk
by 3%2-5
1. Grundy SM et al. Circulation. 2004; 110: 22739; 2. Gordon DJ, et al. Circulation 1989; 79: 8-15; 3. Boden W. American Journal of Cardiology 2000; 86 (suppl): 19L-22L; 4. Manninen V, et al. JAMA 1988; 260:641-651; 5. Rubins HB, et al. N Engl J Med 1999; 341:410-418; 6. Boden et al, Am J Card, 2000; 85: 645-650
Relative Risk of CHD also Decreases with Increasing Serum Concentrations of HDL-C
30
100
20
10
0 160 220
85
85
25
45
LDL-C (mg/dL)
Rel
ati
ve
Ris
k
Relationship between LDL-C, HDL-C and CHD risk
AHA/ACC guidelines
for patients with
CHD*,2
OBAT HIPOLIPIDEMIK ORAL
1. Penghambat HMG-CoA reduktase (statin)
2. Sequestran asam empedu (resin)
3. Asam fibrat
4. Asam nikotinat (niacin)
5. Penghambat absorbsi kolesterol
(ezetimibe)
6. Probucol
Obat baru : - NIACIN extended release (NIASPAN)
- Fix kombinasi NIACIN ER + LOVASTATIN (advicor)
Obat masa depan:
- Penghambat cholesteryl ester transfer protein (CETP)--> HDL
- Penghambat microsomal transfer protein (MTP)
- Penghambat intestinal bile-acid transporter. (IBAT)
5/2/2013
VLDL
Chylomicron transport
50% intestinal
Cholesterol absorbed
IDL
Faecal sterols
50% cholesterol
excreted
LDL Dietary
Cholesterol
300 mg/day
25%
Biliary
Cholesterol
75%
Extrahepatic
Organs
Cholesterol Synthesis
900 mg/day Cholesterol Synthesis
Transport
via HDL & LDL
Plant stanols Ezetimibe Resins Statins
Cholesterol lowering drugs
TARGET HIPOLIPIDEMIK ORAL
5/2/2013
PPAR
PPAR PPAR
Mechanism of action of fibrates on lipoprotein metabolism.
Glitazones
Nucleus
AGGTCA N AGGTCA
PPRE Target Genes Regulating 5
Lipoprotein Metabolism
FIBRATES
Eicosanoids
gemfibrozil, fenofibrates
Peroxisome Proliferator-Activated Receptor- a transcription factor
(Peroxysome Proliferator Responsive Elements)
- Activated PPAR
- Retinoid R
KELOMPOK
PREPARAT NAMA OBAT EFEK THD LIPOPROTEIN KONTRA INDIKASI
Statin Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Rosuvastatin
LDL 18-55%
HDL 5-30%
Trigliserid 7-30%
Gangguan fungsi hepar akut
atau kronik
Ezetimibe LDL 15-20%
HDL 1-4%
Trigliserid 5-10%
Bila dikombinasi dgn statin,
kontra indikasi utk ggn fungsi
hepar akut atau kronik
Bile acid squestrants Cholestyramin
Colestipol
Colesevalam
LDL 15-30%
HDL 3-5%
Trigliserid sqa
Disbetaliproteinemia
Trigliserid > 400 mg/dl
Nicotinic acid LDL 5-25%
HDL 15-35%
Trigliserid 20-50%
Gangguan hepar kronik gout
Fibric acid derivatives Gemfibrozil
Fenofibrate
LDL 5-20% (mgk pd
kasus2 dgn trigliserid tinggi)
HDL 10-20%
Trigliserid 20-50%
Gangguan fungsi hepar berat
Gangguan fungsi ginjal berat
Terapi Farmakologik untuk Koreksi Profil Lipid
The NECP ATP III & Physicians Desk Ref, 59th ed. 2005
Dosis Obat Hipolipidemik
Obat Dosis
Gol. Statin - Fluvastatin
- Lovastatin
- Pravastatin
- Simvastatin
- Atorvastatin -Rosuvastatin
Gol. Asam fibrat
Bezafibrat
Fenofibrat
Gemfibrozil
40 80 mg malam hari
5 40 mg malam hari
5 40 mg malam hari
5 40 mg malam hari
10 80 mg malam hari 10 40 mg malam hari
200 mg 3 x sehari atau
400 mg sekali sehari (retard)
100 mg 3 x sehari atau
300 mg sekali sehari
600 mg 2 x sehari atau
900 mg sekali sehari
Presentation Point of View
Metabolic Syndrome is not a disease, but rather a cluster of disorders of your bodys metabolism, including:
o High blood pressure
o High insulin levels
o Excess body weight
o Abnormal cholesterol levels
Each of these disorders is by itself a risk factor for other diseases.
In combination, however, these disorders dramatically boost the chances of developing potentially life-threatening illnesses, such as diabetes,heart disease or stroke.
The syndrome is closely related to a generalized metabolic disorder called insulin resistance, in which the body cant use insulin efficiently.
Metabolic syndrome has been called many names, including:
o Syndrome X
o The deadly quartet
o Insulin Resistance Syndrome
Central Obesity
CHD
glycemic disorders
( Prediabetes ) > LDL
Hypertriglyceridemia Hypertension
Endothel Disfunction Hiperuricemia
Microalbuminuria inflammation (hsCRP) Impaired thrombolysis
PAI-1
Insulin resistance
JARANG OLAHRAGA PENUAAN OBAT OBATAN SEBAB LAIN
DIABETES MELLITUS HIPERTENSI P C O S dan NAFLD HIPERURICEMIA DISLIPIDEMIA ATHEROSCLEROSIS ACANTHOSIS NIGRICANS
STROKE I
II
III IV V
VI
VII
ASK-DNC
IL-6 IL-1
TNF-
MCP-1
JNK NFB
MACROPHAGE RECRUITMENT
MCP-1
FFA
Angiogenesis
Leptin VEGF
Endothelial
Cell
TNF-
Physical stress/oxidative
damage to endothelium?
MACROPHAGE RECRUITMENT
MACROPHAGE PREADIPOCYTE
NORMAL ADIPOCYTE ADIPOCYTE DYSFUNCTION INFLAMED ADIPOSE TISSUE
IR
WEIGHT GAIN ADIPOCYTE
WEIGHT GAIN
PREADIPOCYTE
Obese adipose tissue and inflammation
5/2/2013
Factors FFA, TNF and PAI-1 can affect peripheral tissues
Autocrine
ParacrineEndocrine
Leptin
?TNF
?IL-6
Sex steroids
Glucocorticoids
?Angiotensin
?PAI-1
?Adiponectin
?AdipoQ
PAI-1
TGF-
TF
Adipsin/ASP
?TNF- /IL-6/Leptin
Renin-Angiotensin
system
Steroid hormonesAdipose tissue
AUGUST 3-7TH 2006 INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE
PROTEIN YANG DISEKRESI ADIPOSIT
1. ESTROGEN 2. LEPTIN
3. AGOUTI RELATED PROTEIN
4. TNF
5. IL1B
6. IL-6
7. ANGITENSINOGEN
8. ASP
9. ADIPSIN
10. FACTORS B,C3
11. ADHESIVE PROTEIN
12. PAI-1
13. TF
14. RESISTIN
15. ADIPONECTIN
16. VISFATIN
17. HSL
18. LIPOTRANSIN
19. PERILIPINS
20. FFAs
21. TGF-
22. VEGF
23. IGF-1
24. PGE2
25. PGI1
26. GLUCOCORTICOID
27. 11HSD
28. AROMATASE
29. METALLOTHIONIEN
30. MIF
31. RBP
32. APO-E
33. ICAL
34. LPL
35. CETP
36. PLTP
37. NO
38. PC-1
39. AQUAPORINS
40. FIAF
41. LACTATE
42. MONOBUTYRIN
43. GALACTIN-12
44. ESM-1
45. APELIN
ANTI INSULIN RESISTANCE ANTI ATHEROSCLEROSIS
TISSUE TG CONTENT
UPREGULATE INSULIN
SIGNALING
ACTIVATE PPAR
ACTIVATE AMPK
1
2
3
4
THE Expression of Adhesion Mol. : ICAM-1, VCAM-1, E-selectin, also TNF-induced NFkB Activation
Endothelial Cell Apoptosis via AMPK Activation by HMW multiform
Of Adiponectin
1 ENDOTHELIUM
Cell Proliferation Migration
SRA- 1 Uptake of Ox-LDL, Foam Cell
2 MACROPHAGE
3 SMC :
5 ROLES OF ADIPONECTIN
V IV III
ANTI OXIDANT
OXIDATIVE STRESS
ANTI INFLAMMATION
INFLAMMATORY MARKERS
APOPTOSIS
BRAIN, HEART, - CELL
Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002
Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011
FIGURE 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES
patofisiologi
The Metabolic Syndrome
5/2/2013
Definitions of the metabolic syndromeDefinitions of the metabolic syndrome((BloomgardenBloomgarden 2004, 1st 2004, 1st ConggressConggress on Insulin Resistance Syndrome)on Insulin Resistance Syndrome)
FPG 6,1 mmol/l
(exc.DM)
FBG 110-125 or
2hpc 140-200
110 mg/dlBlood glucose
140/90 mmHg or treated for Hyp.
130/85 mmHg 140/90 mmHg130/8 5mmHgBlood pressure
1.0 mmol/l40 mg/dl
50 mg/dl
35 mg/dl
39 mg/dl
40 mg/dl
50 mg/dl
HDL chol male
female
2.0 mmol/l or150 mg/dl or150 mg/dl or 150 mg/dlTriglycerides
94 cm
80 cm
>102 cm
> 88 cm
Waist CF male
female
90 in men
85 in women
WHR male
female
> 20 g / m Uirinary alb exc
2 of 4And 2 of 4At least 3 of 5
Fasting hyperin-
sulinemia( highest
quartile) and
One of **IGT/HOMA-IR,
IFG/DM and
2 of 4 below
EGIR (IRS)AACE (IRS)WHOATP III
** CVD, hypertension, PCOS, NAFLD, family history of T2DM / hypertension / CVD, history of
gestational diabetes, non Caucasian, sedentary lifestyle, BMI>125 or WC>40 male, >35 female,
age>40yrs
Components of Metabolic Syndrome
ATP III that related to CVD (2004)
5. Proinflammatory state
(elevated of CRP)
6. Prothrombotic state
(elevated of PAI-1)
2. Atherogenic dyslipidemia
HDL-Chol.( < 40 / < 50 mg/dl )
TRIGLYCERIDE ( > 150 mg/dl)
1. Abdominal obesity
( Waist circumference :
90 Cm / 80 Cm )
102 Cm / 88 Cm )
4. Insulin Resistence
glucose intolerance
Fasting blood sugar 110 mg/dl
3. Raised blood pressure
130 / 85 mmHg
WC male 90 cm and female 80 cm
Indonesian classification for Metabolic Syndrome
WC ( male 90cm / female 80 cm), plus 2 of the 4 factors
1. Fasting Glucose
> 100 mg/dl
2. Blood Pressure
> 130/85 mmHg
3. Triglyceride
> 150 mg/dl
4. HDL-Chol
male < 40 mg/dl female< 50 mg/dl
Lose weight Losing as little as 5 to 10% of your body weight can reduce insulin levels thus reducing M S
Exercise Walking just 30 minutes a day can help prevent the serious diseases associated with MS.
Stop smoking Cigarettes increases insulin resistance and worsens health consequences with MS.
Eat fiber Whole grains, beans, fruits and vegetables, important to lower insulin levels.
Weight loss drugs
Sibutramine (Meridia) and Orlistat (Xenical).
Insulin sensitizers
Tthiazolidinediones and Metformin
Aspirin Aspirin is often prescribed to help reduce the risk for a heart attack.
Medications to lower blood
pressure
Major types of medications angiotensin-converting enzymes (ACE) inhibitors, calcium channel blockers and beta blockers.
Medications to regulate
cholesterol
statins
Pleitropic effect
Penurunan Berat Badan 5-10%
Presentation Point of View
O B E S I T A S
D I S L I P I D E M I
SINDROMA
METABOLIK
( pre sakit )
Definisi Dx Terapi Komplikasi
Akumulasi FAT di
Jaringan Lemak
berlebihan, baik
Besar dan jumlahnya
BMI
W C
Exercise, Diet
Orlistat
Sibutramine
Akupunktur
Lipotripsy
Liposuction
Surgery
Cancer, CHD
Hipertensi
Dislipidemia
OsteoArthritis
D M, PCOS
Sleep Apneu
Obesity H S
Gout, Gallstone
Kelainan
Metabolisme
L I P I D
T G
C H
LDL
HDL
Exercise, Diet
STATIN
Ezetimibe
Fibrat, Niacin
Nicotinic
ATHERO
SCLEROSIS
Yang dipercepat
C H D
S N H
KUMPULAN GEJALA
YANG DISEBABKAN
OLEH KARENA
RESISTENSI INSULIN.
DAN...........
RESISTENSI INSULIN
KARENA
OBESITAS SENTRAL
T G
C H
LDL
HDL
W C
A U
GDP
Alb
Tensi
Exercise, Diet
STATIN
Metformin
Glitazone
CCB,BB
ACE Inhibitor
Sibutramine
Orlistat
Allopurinol
Aspilet
CHD
Hipertensi
Dislipidemia
D M
SNH
PCOS, Gout
Gallstone
NAFL
Acanthosis
nigricans
The NEJM, Vol. 342 : 145-153, Jan
2000 60
Closing Remark
The relation between dyslipidemia, cardiovascular, stroke is confirmed.
Dyslipidemia fit also to the current concept of atherosclerosis
Statin should be the backbone of cardiovascular treatment due to its cholesterol lowering and its pleiotropic potencies
Prevalence of obese in the world is high.Intensive exercise, diet, Lifestyle may be more effective than farmacotheraphy
Metabolic syndrome is New phenomen in the Degenerative diseases
Obesity, Dyslipidemia, Diabetes Mellitus, Cigarrete, Hipertention, Sedentary
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