f a t f k u ms 013

OBESITAS

DISLIPIDEMIA

SINDROMA METABOLIK

Dr. M a h a t m a SpPD Fak.Kedokteran UMS

SURAKARTA

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

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

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


160 189 tinggi

190 sangat tinggi

Kolesterol HDL

< 40 rendah

> 60 tinggi

Trigliserida

< 150 normal


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)


300 mg sekali sehari


900 mg sekali sehari

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%

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

f a t f k u ms 013

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