NAFLD

- 1970 has been known in different names

- 1980 Ludwig et al found NASH ( Non Alcoholic Steatohepatitis )

- Nowadays approved as a whole spectrum of metabolic fatty liver abnormality, because more metabolic fatty liver abnormality, because more complete than NASH

- Consists of :

simple steatosis (simple fatty liver)

steatohepatitis (NASH) : advanced fibrosis

cirrhosis hepatis

Non-alcoholic criteria

- Female : < 70 gram/week alcohol consumption

- Male : < 140gram/week alcohol consumption

Non-Alcoholic Fatty Liver Disease

- Accumulation of fatty acid >5% of liver weight

- Non-alcoholic consumption

- Much etiology

Non alcoholic fatty liver disease / NAFLD

◊. Accumulation of fat in liver cells.

◊. Doesn’t damage the liver.

◊. Common in patients who are obese orhave DM type 2.

◊ . Treatment depents on the cause.

� Inflammation of the liver associated with

accumulation of fat in the liver

� Inflammation causes damage to the liver

� Typically occurs in middle-aged, overweight, and

6

� Typically occurs in middle-aged, overweight, and

often diabetic patients who do not drink alcohol

� NASH can result in the development of fibrosis in

up to 40% of patients or cirrhosis in 5-10% of

patients

� No specific treatment

Nonalcoholic fatty liver ( NAFL ) atauNonalcoholic fatty liver disease ( NAFLD )

PERJALANAN PENYAKIT ?( Disease Progression )

Simple steatosis

Nonalcoholic fatty liver disease ( NAFLD )

Nonalcoholic steatohepatitis ( NASH ).

BUKU AJAR Ed.IV.2007.Hal.462.dr.Irsan Hasan SpPDKGEH

Fibrosis

Sirosis hepatis

NAFLDNAFLD

NASH NASH NASH NASH

FibrosisFibrosis

CirrhosisCirrhosis

HepatocellularHepatocellular CarcinomaCarcinoma

OBESITASSENTRAL

ADIPONECTIN TNF-αADIPOCYTOKIN

ADIPONECTIN TNF-α

RESISTENSIINSULIN

ADIPOCYTOKINESlain

Adiponectin berfungsi :◊.Memacu oksidasi asam lemak.◊.Menurunkan TG.◊.Meningkatkan sensitifitas insulin.◊.Menekan respon inflamasi endotel.◊.Menghambat proliferasi otot polos

ADIPOCYTOKINES

◊.Leptin.◊.PAI -1.*◊.Adipsin.◊.Resistin

PAI-1 *= Plasminogen Activator Inhibitor tiDiabetes update,Prof.Dr.dr.Darmono. SpPD-KEMD,10-11 Sept 2005

KERJA INSULIN

FFA

GLUKOSA

Glukoneogenesis

Re-esterifikasi

TGJar adiposa

Khilomikron.

VLDL LDLFFA

darah

INSULINSEL

LIVER

Re-esterifikasi

Diabetes update,Prof.Dr.dr,Sri Hartini KS Kariadi SpPD-KEMD,10-11 Sept 2005

PATOGENESIS TERJADINYAFATTY LIVER ?

>>>FFA

GLUKOSA

Glukoneogenesis

Re-esterifikasi>>

>>TGJar adiposa

Khilomikron.

VLDL LDL>>>FFA

darah

RESISTENSI INSULINSEL

LIVER

TNF-α

OBESITAS

DM.tipe-2

DISLIPIDEMIA

•Fat

content

increases•UCP2

increases

•Macropha

ge function

reduced

•First “Hit”

•Influx of free fatty

acids

•Oxidative stress

•Ischemia

•Second “Hit”

•Fatty liver•High-calorie

diet Obesity

•Activation

•of lipid

peroxidation

•ATP in liver

tissue decreases

•Increased

sensitivity to

endotoxins

•Steatohepati

tis Fibrosis

•Cirrhosis

• The “two-hit” hypothesis is the pathogenesis

of NASH

• UCP2 = uncoupling protein 2

• First “Hit”: Development of fatty liver

• Second “Hit”: Increased sensitivity to stress,

endotoxins amd ischemia

PerlemakanPerlemakan HatiHati((steatosissteatosis makrovesikularmakrovesikular) )

11stst HitHit

Stres oksidatifKepekaan

Makanan berlemak(FFA)*

Akumulasi lemak (trigliserida) di

hepatosit

PATOGENESIS

NASHNASH

SirosisSirosis

2nd Hit

Stres oksidatif

Toksin

Mediator inflamasi(sitokin: IL, TNF)

Donnelly et al. J. Clin. Invest. 113: 1343, 2005

Day and James. Gastroenterol. 114: 842, 1998

Toksin:• Toksin bakterial• Zat besi• Leptin*FFA = Free Fatty Acids

LIPID PEROXIDATION

ROS

Cell death Mallory bodies Neutrophilic

infiltratesFibrosis

Influence of free radicals and cytokines on the development of NASH

infiltrates

Introduction of

cytokines

ROS

TNF ἀ

TGF

�

TGF �TGF � IL 8

PENATALAKSANAAN 1. Atasi faktor risiko.

◊. Turunkan berat badan.���� Untuk mengoreksi resistensi insul◊. Metformin ���� Menambah sensitifitas insulin,menekan glukon

genesis.( Konsensus pengelolaan DM tipe 2,2002,PERKENI ).

◊. Tiazolidindion����.Menambah sensitifitas insulin.( Konsensus pengelolaan DM tipe 2,2002,PERKENI ).

◊. Gemfibrozil ���� Menurunkan kadar TG dalam darah.◊. Gemfibrozil ���� Menurunkan kadar TG dalam darah.( Penatalaksanaan dislipidemia 2004 PB.PERKENI ).

◊. Antioksidan ���� Mencegah progresi NAFLD ���� NASH & FibroN-asetilsistein ( Fluimucil ),vit.E,vit.C,betain.( Buku ajar Ed.IV.2007,hal.467.dr.Irsan Hasan.SpPD-KGEH ).

2. Hepatoprotektor :Ursochol ( Ursodeoxycholic acid / UDCA ).

TERIMA KASIHTERIMA KASIHTERIMA KASIHTERIMA KASIH