Non-Alcoholic steatohepatitis

( NASH)

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

NASH

Second hit

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
Excess carbohydrate delivered to the liver

The first hit

Fat metabolism

Dietary fat

hepatocyte

Triglyceride

Chylomicrons

Apoprotein
chylomicron
remnants

Lipolysis

AT

VLDL

non-esterified
fatty acids
fatty acids
triglycerides

Fatty acids

Synthesis and oxidation

In mitochondria
carbohydrate

Factors that make NAFLD to be NASH

Oxydative stress
Free radical
Ischemia
Endotoxin from GI track

Second hit

Hepatic fibrogenesis
Early phase
Fas receptors
Accumulation of ROS
Release of proinflamatory
cytokine
Release of anti inflamatory
cytokine

Hepatocellular
damage

immunocytes

Hepatic fibrogenesis
Later phase
Inflamatory cells
inflitration

Growth factor
TGF beta,leptin,angiotensin II

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

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
Obesitas, DM, drugs

NAFLD ( 80%)

NASH ( 20%)

Liver Cirrhosis (10%)

Alcoholic
Daily alcohol
consumption > 30 g.

AFLD ( 45% )

ASH ( 85% )

Liver Cirrhosis ( 3-5%)

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 threating of risk factors