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
Extrahepatic
Organs

LDL

IDL
Cholesterol
Synthesis
900 mg/day

Cholesterol
Synthesis

Transport
via HDL & LDL

VLDL

Dietary
Cholesterol
300 mg/day
25%

Biliary
Cholesterol
75%

Chylomicron transport
50% intestinal
Cholesterol absorbed

Faecal sterols
50% cholesterol
excreted

Triglyceride-rich lipoproteins:
size, structure and composition

5/2/2013

HDL metabolism

Inhibits oxidation
of LDLs

HDL

Inhibits
tissue factor

Inhibits endothelial
adhesion molecules

Stimulates
endothelial NO
production

Enhances reverse
cholesterol transport

Opposes atherothrombosis
Potential mechanisms by which HDLs oppose atherothrombosis.
(Barter. EMCNA (2004):398)

LDL metabolism

Presentation Point of View

Definition
Obesity is caused by imbalance of high
Food intake and or low energy expenditure

Classification of Overweight
and Obesity (WHO,2004)

BMI
Waist Circumference

Eropa

Asia

> 30 kg/m2

> 25 kg/m2

> 90
> 102

> 80 cm
> 90 cm

BMI
Classification
<18.5
Underweight
18.5-24.9
Normal weight
25-29.9
Overweight
30-34.9
Obesity Class I
35-39.9
Obesity Class II
40-49.9
Obesity Class III
50 and above Super Obesity

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

Mengapa Orang Jadi Gemuk?

Makanan yang
diproses

Banyak gerak

25 tahun

Hidup santai

50 tahun

Kegemukan (Obesitas)

Android/ central
Gemuk tidak sehat

Ginekoid/ trunkal
Gemuk sehat
16

AKUPUNTUR

Overweight and Obesity widespread, serious

But treatable

Penurunan Berat Badan 5-10%

Hipertensi

Diabetes

Kolesterol HDL

Trigliserid

Jantung
koroner
19

LIFESTYLE

LIPO SUCTION

LIPOTRIPSY

BYPASS
SURGERYBYPASS
SURGERY

Overweight and Obesity widespread, serious

But treatable

Surgery

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

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

Stroke
Cataracts
CHD
Diabetes
Dyslipidemia
Hypertension

Severe pancreatitis

Gynecologic abnormalities

Cancer

abnormal menses
infertility
Osteoarthritis
PCOS

breast, uterus, cervix

colon, esophagus, pancreas
kidney, prostate

Phlebitis

Gout

venous stasis

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

MONOSIT
LDL

LUMEN

Glukose

fibrinolisis
agregasi tr.

DM
tissue factor
S
LDL
kecil

S S

i i

PAI-1
PLAQUE
PLAQUE

LDL
ox

Hiperinsulin

SEL BUSA

Radikal
Bebas.
AGEs

INTIMA

Migrasi

Makrofag

Sitokin+ f. pertumbuhan
MEDIA

SEL OTOT POLOS

Proliferasi

SS

PENATALAKSANAAN DISLIPIDEMIA
Target Lipid

Non-farmakologik :
- Life style obesitas
- Terapi nutrisi
- Batasi minuman
beralkohol
- Hindari merokok
Farmakologik :
- obat hipolipidemik

Kolesterol Total
< 200
200 239
240
Kolesterol LDL
< 100
100 129
130 159
160 189
190
Kolesterol HDL
< 40
> 60
Trigliserida
< 150
150 199
200 499
500

yg diinginkan
batas tinggi
tinggi
optimal
di atas optimal
batas tinggi
tinggi
sangat tinggi
rendah
tinggi
normal
batas tinggi
tinggi
sangat tinggi

Evolution of Lipid Management

Driving the Need for More Effective Statin Therapy

European
1994

European
2003

European
1998

Lower LDL-C goals; wider target population;

need for more effective therapies
ATP I
1988

ATP II
1993

ATP III
2001

ATP III
update
2004

Relative Risk of CHD also Decreases with

Increasing Serum Concentrations of HDL-C
The risk of CVD can be
reduced by:

Relationship between LDL-C, HDL-C and CHD risk

Lowering LDL-C levels1

Increasing HDL-C
levels2-5
1%
increase
in HDL-C
reduces
CHD risk
by 3%2-5

Relative Risk

1%
decrease
in LDL-C
reduces
CHD risk
by 1%1

30

20

25

10

45
85

100

160

85
220

LDL-C (mg/dL)

Figure adapted from Boden et al. 20006

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

Intensive LDL-C Goals for High-Risk Patients

Recommended LDL-C treatment goals
2004

Update

ATP III
Update 20041

2001

<100 mg/dL:
Patients with
CHD or CHD risk
equivalents
(10-year risk >20%)1
<70 mg/dL:
Therapeutic
option for very
high-risk patients1

<100 mg/dL

<70 mg/dL

AHA/ACC guidelines
for patients with
CHD*,2

2006

Update

<100 mg/dL:
Goal for all
patients with CHD,2
<70 mg/dL:
A reasonable
goal for all patients
with CHD,2

If it is not possible to attain LDL-C <70 mg/dL because of

a high baseline LDL-C, it generally is possible to achieve
LDL-C reductions of >50% with more intensive LDLClowering therapy, including drug combinations.
* And other forms of atherosclerotic disease.2
Factors that place a patient at very high risk: established cardiovascular disesase (CVD) plus:
multiple major risk factors (especially diabetes); severe and poorly controlled risk factors (eg, cigarette smoking); metabolic syndrome (triglycerides
[TG] 200 mg/dL + nonHDL-C 130 mg/dL with HDL-C <40 mg/dL); and acute coronary syndromes.1

1.
2.

Grundy SM et al. Circulation. 2004;110:227239;

Smith SC Jr et al. Circulation, 2006; 113:23632372.

OBAT HIPOLIPIDEMIK ORAL

1.
2.

3.
4.
5.

6.

Penghambat HMG-CoA reduktase (statin)

Sequestran asam empedu (resin)
Asam fibrat
Asam nikotinat (niacin)
Penghambat absorbsi kolesterol
(ezetimibe)
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)

TARGET HIPOLIPIDEMIK ORAL

Extrahepatic
Organs

LDL

IDL
Cholesterol
Synthesis
900 mg/day

Cholesterol
Synthesis

Transport
via HDL & LDL

VLDL

Biliary
Cholesterol
75%

Chylomicron transport
50% intestinal
Cholesterol absorbed

Cholesterol lowering drugs

5/2/2013

Statins

Ezetimibe

Dietary
Cholesterol
300 mg/day
25%

Plant stanols

Faecal sterols
50% cholesterol
excreted

Resins

FIBRATES
gemfibrozil, fenofibrates

Glitazones

Eicosanoids

PPAR

PPAR

Nucleus
PPAR

AGGTCA

- Activated PPAR
- Retinoid R

AGGTCA

PPRE

Target Genes Regulating 5

Lipoprotein Metabolism

(Peroxysome Proliferator Responsive Elements)

Mechanism of action of fibrates on lipoprotein metabolism.

5/2/2013 Proliferator-Activated Receptor- a transcription factor
Peroxisome

Terapi Farmakologik untuk Koreksi Profil Lipid

KELOMPOK
PREPARAT
Statin

NAMA OBAT

EFEK THD LIPOPROTEIN

KONTRA INDIKASI

Lovastatin
Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Rosuvastatin

LDL 18-55%
HDL 5-30%
Trigliserid 7-30%

Gangguan fungsi hepar akut

atau kronik

LDL 15-20%
HDL 1-4%
Trigliserid 5-10%

Bila dikombinasi dgn statin,

kontra indikasi utk ggn fungsi
hepar akut atau kronik

LDL 15-30%
HDL 3-5%
Trigliserid sqa

Disbetaliproteinemia
Trigliserid > 400 mg/dl

LDL 5-25%
HDL 15-35%
Trigliserid 20-50%

Gangguan hepar kronik gout

LDL 5-20% (mgk pd

kasus2 dgn trigliserid tinggi)
HDL 10-20%
Trigliserid 20-50%

Gangguan fungsi hepar berat

Gangguan fungsi ginjal berat

Ezetimibe

Bile acid squestrants

Cholestyramin
Colestipol
Colesevalam

Nicotinic acid

Fibric acid derivatives

Gemfibrozil
Fenofibrate

The NECP ATP III & Physicians Desk Ref, 59th ed. 2005

Dosis Obat Hipolipidemik

Obat

Dosis

Gol. Statin
- Fluvastatin
- Lovastatin
- Pravastatin
- Simvastatin

40 80 mg malam hari
5 40 mg malam hari
5 40 mg malam hari
5 40 mg malam hari

- Atorvastatin

10 80 mg malam hari

-Rosuvastatin

10 40 mg malam hari

Gol. Asam fibrat

Bezafibrat

200 mg 3 x sehari atau

400 mg sekali sehari (retard)
100 mg 3 x sehari atau

Fenofibrat

300 mg sekali sehari

600 mg 2 x sehari atau

Gemfibrozil

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

Insulin resistance

IV

III

glycemic disorders
( Prediabetes )
<< HDL , >> LDL
Hypertriglyceridemia
Hypertension
Endothel Disfunction
Hiperuricemia
Microalbuminuria
inflammation (hsCRP)
Impaired thrombolysis
PAI-1

DIABETES MELLITUS
HIPERTENSI
P C O S dan NAFLD
HIPERURICEMIA
DISLIPIDEMIA
ATHEROSCLEROSIS
ACANTHOSIS NIGRICANS

II

VI

Central Obesity
JARANG OLAHRAGA
PENUAAN
OBAT OBATAN
SEBAB LAIN

VII
STROKE

CHD

Obese adipose tissue and inflammation

ADIPOCYTE

WEIGHT GAIN

WEIGHT GAIN
IR
JNK
NFB
TNF-
Endothelial
Cell

PREADIPOCYTE

MCP-1

Leptin
VEGF

IL-6
IL-1
TNF-

Angiogenesis

Physical stress/oxidative
damage to endothelium?

FFA

MCP-1

MACROPHAGE
RECRUITMENT
MACROPHAGE PREADIPOCYTE

NORMAL ADIPOCYTE

ADIPOCYTE DYSFUNCTION
ASK-DNC

MACROPHAGE
RECRUITMENT

INFLAMED ADIPOSE TISSUE

Autocrine
Paracrine

Endocrine

Leptin

PAI-1
TGF-

?TNF
?IL-6

TF

Sex steroids
Glucocorticoids

Adipsin/ASP
?TNF- /IL-6/Leptin

?Angiotensin

Renin-Angiotensin
system
Steroid hormones

?PAI-1

Adipose tissue

?Adiponectin
?AdipoQ

Factors FFA, TNF and PAI-1 can affect peripheral tissues

5/2/2013

PROTEIN YANG DISEKRESI ADIPOSIT

1.

ESTROGEN

16.

2.

17.

13.

LEPTIN
AGOUTI RELATED PROTEIN
TNF
IL1B
IL-6
ANGITENSINOGEN
ASP
ADIPSIN
FACTORS B,C3
ADHESIVE PROTEIN
PAI-1
TF

14.

RESISTIN

29.

3.
4.
5.
6.
7.
8.
9.
10.
11.
12.

15.

18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.

30.

VISFATIN
HSL
LIPOTRANSIN
PERILIPINS
FFAs
TGF-
VEGF
IGF-1
PGE2
PGI1
GLUCOCORTICOID
11HSD
AROMATASE
METALLOTHIONIEN
MIF

31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.

RBP
APO-E
ICAL
LPL
CETP
PLTP
NO
PC-1
AQUAPORINS
FIAF
LACTATE
MONOBUTYRIN
GALACTIN-12
ESM-1
APELIN

ADIPONECTIN

AUGUST 3-7TH 2006

INTERNATIONAL SYMPOSIUM SHOCK AND CRITICAL CARE

patofisiologi
ANTI INSULIN RESISTANCE

ANTI ATHEROSCLEROSIS

1 TISSUE TG CONTENT

1 ENDOTHELIUM
THE Expression of Adhesion Mol. :

2 UPREGULATE INSULIN
SIGNALING

ACTIVATE PPAR

ACTIVATE AMPK

ICAM-1, VCAM-1, E-selectin, also

TNF-induced NFkB Activation

Endothelial Cell Apoptosis via

5 ROLES OF
ADIPONECTIN

AMPK Activation by HMW multiform

Of Adiponectin

2 MACROPHAGE

SRA- 1
Uptake of Ox-LDL, Foam Cell

SMC :

Cell Proliferation
Migration

IV

III

APOPTOSIS

ANTI INFLAMMATION

ANTI OXIDANT

BRAIN, HEART, - CELL

INFLAMMATORY MARKERS

OXIDATIVE STRESS

FIGURE 2 ADIPONECTIN WITH ITS CARDIOPROTECTIVE PROPERTIES

Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002
Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011

The Metabolic Syndrome

5/2/2013

Definitions of the metabolic syndrome

(Bloomgarden 2004, 1st Conggress on Insulin Resistance Syndrome)
ATP III

WHO

AACE (IRS)

EGIR (IRS)

IGT/HOMA-IR,
IFG/DM and
2 of 4 below

One of **

Fasting hyperinsulinemia( highest

quartile) and

And 2 of 4

2 of 4

At least 3 of 5
Uirinary alb exc

> 20 g / m

WHR

90 in men
85 in women

male
female

94 cm
80 cm

Waist CF male
female

>102 cm
> 88 cm

Triglycerides

150 mg/dl

150 mg/dl or

150 mg/dl or

2.0 mmol/l or

HDL chol male

female

40 mg/dl
50 mg/dl

35 mg/dl
39 mg/dl

40 mg/dl
50 mg/dl

1.0 mmol/l

Blood pressure

130/8 5mmHg

140/90 mmHg

130/85 mmHg

140/90 mmHg or
treated for Hyp.

Blood glucose

110 mg/dl

FBG 110-125 or
2hpc 140-200

FPG 6,1 mmol/l

(exc.DM)

** 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)
1. Abdominal obesity
( Waist circumference :
90 Cm / 80 Cm )
102 Cm / 88 Cm )
2. Atherogenic dyslipidemia
HDL-Chol.( < 40 / < 50 mg/dl )
TRIGLYCERIDE ( > 150 mg/dl)
3. Raised blood pressure
130 / 85 mmHg
4. Insulin Resistence
glucose intolerance
Fasting blood sugar 110 mg/dl
5. Proinflammatory state
(elevated of CRP)
6. Prothrombotic state
(elevated of PAI-1)

WC male 90 cm
and female 80 cm

1. Fasting Glucose

3. Triglyceride

> 100 mg/dl

> 150 mg/dl

4. HDL-Chol
2. Blood Pressure
> 130/85 mmHg

male < 40 mg/dl

female< 50 mg/dl

Indonesian classification for Metabolic Syndrome

WC ( male 90cm / female 80 cm), plus 2 of the 4 factors

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
Insulin
sensitizers

Sibutramine (Meridia) and Orlistat (Xenical).

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

Definisi

O B E S ITAS

DISLIPIDEMI

SINDROMA
METABOLIK
( pre sakit )

Dx

Terapi

Komplikasi
Cancer, CHD
Hipertensi
Dislipidemia
OsteoArthritis
D M, PCOS
Sleep Apneu
Obesity H S
Gout, Gallstone

Akumulasi FAT di
Jaringan Lemak
berlebihan, baik
Besar dan jumlahnya

BMI
WC

Exercise, Diet
Orlistat
Sibutramine
Akupunktur
Lipotripsy
Liposuction
Surgery

Kelainan
Metabolisme
LIPID

TG
CH
LDL
HDL

Exercise, Diet
STATIN
Ezetimibe
Fibrat, Niacin
Nicotinic

ATHERO
SCLEROSIS
Yang dipercepat
CHD
SNH

KUMPULAN GEJALA
YANG DISEBABKAN
OLEH KARENA
RESISTENSI INSULIN.
DAN...........
RESISTENSI INSULIN
KARENA
OBESITAS SENTRAL

TG
CH
LDL
HDL
WC
AU
GDP
Alb
Tensi

Exercise, Diet
STATIN
Metformin
Glitazone
CCB,BB
ACE Inhibitor
Sibutramine
Orlistat
Allopurinol
Aspilet

CHD
Hipertensi
Dislipidemia
DM
SNH
PCOS, Gout
Gallstone
NAFL
Acanthosis
nigricans

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

The NEJM, Vol. 342 : 145-153, Jan

2000

60