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 ).