Non-Alcoholic steatohepatitis
( NASH)
Azzaki Abubakar
Department of Internal Medicine
Gastroenterohepatology Division
Syiah Kuala University-Zaionoel Abidin Hospital Banda Aceh
Nomenclature
Alcoholic fatty liver disease
• Alcoholic fatty liver
• Alcoholic steatohepatitis (ASH)
Non-alcoholic fatty liver disease (NAFLD)
• Non-alcoholic fatty liver
• Non-alcoholic steatohepatitis
Pathogenesis: two hits hypothesis
First hit Norm Liver
NAFLD Second hit
NASH
Mechanisme of fat accumulation in
hepatocyte
• Increased delivery of dietary fat
• Increased mitochondrial synthesis of fatty
acids
• Reduced mitochondrial oxidation of fatty
acids
• Impaired export of trigltceride out of the
liver
The first hit
• Excess carbohydrate delivered to the liver
Fat metabolism
Dietary fat
hepatocyte
VLDL
Chylomicrons Triglyceride
Apoprotein
chylomicron Fatty acids
remnants
Lipolysis non-esterified Synthesis and oxidation
fatty acids In mitochondria
fatty acids
triglycerides
AT carbohydrate
Factors that make NAFLD to be NASH
• Oxydative stress
• Free radical
• Ischemia
• Endotoxin from GI track
Second hit
Hepatic fibrogenesis
Early phase
Hepatocellular Fas receptors
damage Accumulation of ROS
Release of proinflamatory
f cytokine
Release of anti inflamatory
cytokine
immunocyt
es
Hepatic
fibrogenesis
Later phase Growth factor
TGF beta,leptin,angiotensin II
Inflamatory cells
inflitration
Activated HCs
Profibrogenic cytokine
Collagenase
Increase collagen synthesis
Decrease collagen removal
Risk factors
Metabolic condition
Obesity
DM
Hyperlipidemia
Rapid weigth loss
TPN
Surgical procedure
Small bowel resection, bypass, gastropexy
Other conditions
Bacterial overgrowth
Drugs
Obesity
Obesity most often associated with NAFLD
1151 obese patients :
- Only 12% histopathologically normal
- 80% fatty degeneration (simple FL)
- 33% portal inflamation
- 29% with fibrosis
- Abdominal fat positively correlated stronger with
NASH than BMI
( Scheen AJ, 2002)
Diabetes mellitus
At the time of diagnosis of NASH up to 33% of patients
have type 2 DM
Prevalence of NASH was higher among ODM than ONDM
DM and impaired glucose tolerance are strong independent
predictor of severe hepatic fibrosis in NASH
DM and impaired glucose tolerance have sevenfold
increase risk of fibrosis.
( Marcau et al 1999 )
Insulin resistence
Severity of steatosis positively correlated with
- BMI
- plasma triglyceride
- Fasting plasma glucose
- plasma insulin
Metabolic syndrome was an independent predictor of
NASH
Among 90 NASH patients, 85% have metabolic
syndrome at time of diagnosis.
( Scheen AJ 2002)
Natural history
Non-alcoholic Alcoholic
Obesitas, DM, drugs Daily alcohol
consumption > 30 g.
AFLD ( 45% )
NAFLD ( 80%)
ASH ( 85% )
NASH ( 20%)
Liver Cirrhosis ( 3-5%)
Liver Cirrhosis (10%)
Diagnosis
Laboratory parameter
• Serum transaminase increase
Ratio AST/ALT usualy < 1
Ratio AST/ALT > 1 : severe or late condition
• GGT and AP normal or slightly increase
• Transferin saturation and feritin increase in
60% cases
• If CH present, laboratory parameter is similar
with CH of other causes
Diagnosis
Clinical picture of NASH is similar with all other
chronic liver disease, uncharacteristic
Bright liver on USG, only in early stage
By exclusion :
- Alcohol consumption
- Serologic marker for viral hepatitis
- Serologic marker for autoimmune hepatitis
- Marker for hemochromatosis
Diagnosis
Histopatologic findings in NASH
- Vesicular fatty degeneration
- Lobular hepatitis
- Balloning, focal and individual cell necrosis
- Mallory bodies, apoptosis
- Mixed cell periportal infiltration
- Pericelular net work fibrosis
- central to central and periportal to periportal
fibrotic strand
- Complete cirrhosis
Therapy
• Limited to treating the risk factor
• Goal of the treatment :
To stop the progression
To prevent the development of
cirrhosis
Therapy
Body weight reduction
Slowly but sure
Reduction of BW about 10% is
beneficial in improving lab parameter
The best treatment is a low calorie diet
for rest of life
Therapy
Diabetes mellitus (with obesity)
Drugs improving insulin sensitivity
- Metformin
- Troglitazone
Lipid lowering drugs
- Gemfibrozil
- Clofibrate
Gemfibrozil better than clofibrate
Therapy
Ursodeoxycholic acid
Displaces the more hydrophobic bile acids
Cytoprotective
Immunomodulator
Antiapoptotic
Reduced the incidence of bacterial overgrowth
Beware,
NASH is an important etiologic
factor of cirrhosis of the liver
The most important risks factors of
NASH are metabolic syndrome, Type
2 DM and central obesity
Therapy is limited to the treating of
risk factors