Transcript NASH

Non alcoholic steatohepatitis
Raika Jamali M.D.
Gastroenterologist and hepatologist
Tehran University of Medical Sciences
Is an intermediate stage in the spectrum of
non alcoholic fatty liver disease (NAFLD),
Simple fatty liver --> Steatohepatitis --> Cirrhosis
Shows the same histopathology but
occurs in the absence of excess alcohol
consumption (<20 gr/day)
Associated with the metabolic syndrome
(insulin-resistant state):
Truncal obesity,
Type 2 DM,
Dyslipidemia (high TG and low HDL levels).
Though strongly associated with obesity, NASH
has also been demonstrated in 3% of lean
individuals (generalized lipodystrophy)
The prevalence varies based on the
diagnostic test used
 Population-based surveys of adults >18 y
with US have demonstrated fatty liver
disease in 20% of the populations of
Japan, Western Europe, and the US
 MRI: ≈34% in the general population >18 y
Hispanic Americans (50%), Whites (33%),
African Americans (25%) have fatty livers
80% of individuals with steatosis by MRI
have normal ALT levels,
 Indicating that blood tests are the least
sensitive tool for diagnosis
Prevalence of fatty liver disease falls to
8% if elevations in ALT are used for
NASH is the main cause of elevated liver
enzymes in the Western world
The true prevalence of NASH is unknown:
because neither imaging tests nor blood tests
reliably differentiate steatosis from more
advanced stages of fatty liver disease (NASH
and cirrhosis)
and because liver biopsy studies show that
NASH or cirrhosis sometimes occurs in
individuals with normal ALT levels,
Liver biopsy studies suggest:
 Steatosis is twice as common as NASH
 at least 10% of patients with NASH
progress to cirrhosis over time
in the adult U.S. population:
 Fatty liver (34%)
 Steatohepatitis (17%)
 Cirrhosis (2%)
The prevalence of NAFLD in Iran was:
2.04% in a population based study in
Golestan province. (2006)
 2.1% in autopsies from forensic medicine of
Tehran. (2006)
 2.35% in healthy blood donors in Tehran.
In the early stages of non alcoholic fatty liver
disease (NAFLD), fat accumulates within
hepatocytes when mechanisms that promote
lipid removal (by oxidation or export) cannot
keep pace with mechanisms that promote lipid
import or biosynthesis.
Although alcohol consumption has long been
known to promote lipid biosynthesis while
inhibiting lipid export, it has been appreciated
only recently that the molecular mechanisms
involved are very similar to those that promote
steatosis in nonalcoholic fatty liver disease.
Factors that modulate the evolution of NAFLD:
Fatty acids
Tumor necrosis factor-α (TNF-α)
Fatty acids routinely traffic between the liver and
adipose tissue.
Fat and the liver are also important sources of
TNF-α and adiponectin.
Adiponectin reduces lipid accumulation within
by inhibiting fatty acid import and increasing fatty acid
oxidation and export.
It is also a potent insulin-sensitizing agent.
TNF-α antagonizes the actions of diponectin
 promotes
hepatocyte steatosis
 increases mitochondrial generation of reactive
oxygen species, which induce insulin
 promotes hepatocyte apoptosis and recruits
inflammatory cells to the liver.
 generates oxidative and apoptotic stress that
sometimes overwhelms antioxidant and
antiapoptotic defenses and leads to
Thus the relative risk for the development of
NASH correlates with increases in TNF-α or
decreases in adiponectin levels
Fatty acids within hepatocytes
Inhibitor κ kinase-β
Nuclear transcription factor NFκB
TNF-α and IL-6
insulin resistance
Therefore, like adipose tissue, fatty livers also
make soluble factors that circulate to distant
tissues and contribute to systemic insulin
resistance (the metabolic syndrome).
NASH can develop in nonobese individuals.
The mechanism of liver damage in nonobese
and obese individuals may be similar:
excessive exposure of hepatocytes to fatty acids
fatty acid–inducible inflamma-tory mediators (TNF-α)
reactive oxygen species.
Intestinal microflora help regulate intestinal
uptake of diet-derived lipids, in addition to
hepatic fatty acid synthesis,
the gut bacteria of some nonobese individuals
might promote excessive hepatic accumulation
of fatty acids, as well as exposure to other
bacterial factors (e.g., lipopolysaccharide) that
trigger hepatic TNF production
The role of intestinal flora in the
pathogenesis of alcohol-induced fatty liver
disease has been well demonstrated:
 Experimental
animals housed under germfree conditions or treated with poorly
absorbed oral antibiotics are protected from
alcohol-induced hepatotoxicity.
 Products from intestinal bacteria are thought
to injure the liver by increasing hepatic
production of TNF-α and reactive oxygen
 because mice that are genetically deficient in
either TNF-α or certain enzyme that generate
reactive oxygen species are also protected
from the alcoholic liver damage
Progression from fatty liver disease to cirrhosis
is predominately dictated by the severity of
oxidant stress and the consequent necroinflammation.
However, findings in animal models of steatohepatitis
cast some doubt on this assumption because mice in
which severe steatohepatitis develops do not
uniformly progress to cirrhosis
In fact, progression to cirrhosis is also poorly
predicted by the gravity of the injurious insult in
human fatty liver disease
For example, although there is no doubt that alcohol
is hepatotoxic, most lifelong heavy drinkers do not
become cirrhotic
Similarly, although obesity clearly increases exposure
to fat-derived inflammatory mediators and is an
independent risk factor for progression of alcoholic
fatty liver disease to cirrhosis, some morbidly obese
individuals have normal livers at the time of gastric
bypass surgery
Individuals in whom just steatosis develops despite
constant bombardment with inflammatory factors might
be better at repairing their liver damage without the
development of fibrosis than those in whom NASH or
cirrhosis develops.
In this regard, leptin, angiotensin, and norepinephrine:
promote the proliferation of hepatic stellate cells
upregulate their expression of profibrogenic cytokines (TGF β)
induce collagen gene expression.
Conversely, adiponectin appears to inhibit the activation
of hepatic stellate cells and decrease liver fibrosis.
Angiotensin is an independent risk factor for advanced
liver fibrosis in NASH and the suggestion,that
angiotensin receptor blockade might decrease liver
fibrosis and slow disease progression in patients with
NASH and arterial hypertension.