Transcript NASH

Chapter 11
Non-alcoholic steatohepatitis
Wen-Ying, Chen
2006, 10
Definition of nonalcoholic fatty liver
disease
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Nonalcoholic Fatty Liver Disease (NAFLD) or
Non-alcoholic steatohepatitis (NASH) is fatty
inflammation of the liver when this is not due to
excessive alcohol use. It is a major cause of
cryptogenic cirrhosis of the liver.
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It differs from the simple accumulation of fat in
the liver (fatty liver, or hepatic steatosis) in that
the inflammation of NASH causes damage to the
liver cells while simple fatty liver probably does
not.
Chronic liver disease
prevalence in the U.S.
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Nonalcoholic fatty liver disease
20 %
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Nonalcoholic steatohepatitis
3%
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Chronic hepatitis C
2%
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Alcoholic liver disease
0.7 %
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Chronic hepatitis B
0.4 %
NASH is one of the commonest liver diseases in Western countries.
Introduction
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NASH is the most prevalent from of progressive
liver disease and it is suggested that it affects
between 10-39% of the global population, with
an average incidence of 20%.
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Diabetes, obesity and hypertriacylglycerolaemia
are all well-known risk factors for NASH.
Progression of NAFLD
Fibrosis (35 %)
Cirrhosis (15 %)
10 %
STEATOSIS
NASH
Liver Failure
Hepatocellular
Carcinoma
(Caldwell SH. Hepatol. 2003; 37: 1202)
Aetiology
Conditions associated with non-alcoholic fatty liver disease
Nutritional abnormalities
Obesity 90% and lean people 6%
Total parenteral nutrition; rapid weight loss
Metabolic disorders
DM; insulin resistance; lipodystrophy
Hypertriglyceridaemia; abetalipoproteinaemia
Hypolipoproteinaemia---Glucocorticoid
Aspirin
Synthetic oestrogen
Tetracycline-----Jejuno-ileal bypass
Gastopexy ---
Drugs
Surgery
Occupational exposure
Environmental toxins
Diagnosis
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Clinical features
Biochemistry tests
Imaging
Histopathological features
Clinical features
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often asymptomatic----delays early diagnosis
Discomfort in the upper right quadrant, fatigue----
NASH is another feature of the metabolic syndrome
In one study of 66 patients: 98% insulin resistance and
39% diabetic
Obesity and insulin resistance are linked with NASH
Biochemistry tests
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Liver dysfunction in NASH
serum alkaline phosphatase (ALP) and γglutamyltransferase (γ-GT) are increased
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Increased serum ferritin----- 50%
Imaging
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Ultrasound
87% sensitivity and 77% specificity
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Computed tomography scanning
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Magnetic resonance imaging
quantitative assessment of fatty infiltration is best
achieved
Histopathological features
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Steatosis
Inflammatory cell infiltration
Hepatocyte ballonning and necrosis
Glycogen nuclei
Mallory’s hyaline
Fibrosis
liver biopsy is recommended for : 1. increased liver
enzymes 2. metabolic syndrome: type 2 diabetes,
hyperlipidaemia and obesity.
Pathogenesis
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Insulin resistance
Obesity
Oxidative stress
Nuclear receptor regulation of gene
expression
Pathogenesis
insulin resistance
Insulin resistance enhances TG lipolysis and inhibits esterification of free fatty
acids (FFA) within adipose tissue.
Hepatic TG synthesis is driven by the increased influx of FFA and favoured by
insulin upregulated lipogenic transcription factors, such as PPARγ and SREBP-1c.
TG export via VLDL may be inhibited by decreased synthesis of apo B.
Pathogenesis
insulin resistance
Several molecular targets have now been identified linked to the actions of insulin that
contribute to the dyslipidaemia that may inform the pathogenesis of NASH.
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Rad (ras associated with DM),which interferes with essential cell
functions (growth, differentiation, vesicular transport, and signal
transduction).
PC-1 (a membrane glycoprotein that has a role in I.R.), which reduces
insulin-stimulated tyrosine kinase activity.
leptin, which induces dephosphorylation of insulin-receptor substrate-1
fatty acids, which inhibit insulin-stimulated peripheral glucose uptake.
TNF-  ,which down-regulates insulin-induced phosphorylation of
insulin-receptor substrate-1 and reduces the expression of the insulindependent glucose-transport molecule Glut4.
Adiponectin, which suppress TNF-  .
Pathogenesis
Obesity
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70-100 % of NASH patients are obese.
Steatosis is a common observation in obesity and may be
associated with inflammatory signs of non-specific
hepatitis.
The TNF-α gene is overexpressed in adipose tissue in the
obese and in overweight or obese patients with type 2
diabetes, resulting in higher plasma TNF-α concentations
that may contribute NASH.
Pathogenesis
Oxidative stress
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Mitochondria are the main cellular source of reactive
oxygen species, which may trigger the inflammatory
component of NASH.
Numberous studies
have emphasized the critical
importance of oxidative stress as a crucial
pathophysiological mechanism of NASH.
Pathogenesis
Oxidative stress
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Nitric oxide: iNOS may facilitate regeneration by inhibiting cell
death in NASH.
In iNOS knockout mice: unscavenged superoxide production may
cause toxic lipid peroxidation and ultimately microvesicular steatosis
and NASH.
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Adiponectin: have hepatoprotective effects.
1). Increased lipid clearance through β-oxidation possibly mediated
via activation of CPT-1.
2). Direct anti-inflammatory effects through inhibition of TNF-α
3). Reduce hepatomegaly, steatosis and serum ALT
Adiponectin may play a role in directly or indirectly regulating factors
involved in the development of NASH.
Pathogenesis
Oxidative stress
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Cytochrome P450 enzymes: CYP2E1 & CYP4A
are capable of generating free radicals to increase
oxidative stress.
CYP2E1:
1). to be up-regulated persistently in type 2 diabetes,
insulin resistance, central obesity and NASH;
2). also is up-regulated by a high-fat/low-carbohydrate
diet.
3). may play a role in initiating hepatic fibrosis.
Insulin resistance
Obesity/lipodystrophy
Increased lipolysis/decreased
Re-esterification
PPARγ activity
adiponectin
Leptin
FFA
Rad
TNF-α
PC-1
NEFAs
Hepatocytes/stellate/
Kupffer cells
NO
TNF-α
ATP
Inadequate oxidation of FFA & di/triacylglycerols
Cyto P450 A
P450E1
Glutathione
Free radicals
antioxidants
Oxidative
stress
Decreased:
PPARα activity
PPARδ activity
Increased:
SREBP 1a/1c
SREBP2 activity
NASH
Kupffer cell
NF-κB
Oxidative stress & inflammation
Pathogenesis
Nuclear receptor regulation of gene
expression
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Peroxisome proliferator-activated receptors (PPAR)
members a nuclaer receptor superfamily and key regulators
of adipogenesis----involved in the pathogenesis of NASH.
Insulin resistance
Obesity/lipodystrophy
Increased lipolysis/decreased
Re-esterification
PPARγ activity
adiponectin
Leptin
FFA
Rad
TNF-α
PC-1
NEFAs
Hepatocytes/stellate/
Kupffer cells
NO
TNF-α
ATP
Inadequate oxidation of FFA & di/triacylglycerols
Cyto P450 A
P450E1
Glutathione
Free radicals
antioxidants
Oxidative
stress
Decreased:
PPARα activity
PPARδ activity
Increased:
SREBP 1a/1c
SREBP2 activity
NASH
Kupffer cell
NF-κB
Oxidative stress & inflammation
Pathogenesis
Nuclear receptor regulation of gene
expression
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Sterol regulatory element-binding proteins
(SREBPs): important members of transcription factors that
regulate hepatocyte cholesterol homeostasis.
In the liver, three SREBP isoforms, SREBP-1a, SREBP-1c
and SREBP-2, regulate the production of lipid for export into
the plasma as lipoproteins and into the bile as micelles.
Expression of SREBP-1c in the liver is regulated by LXR,
which increases fatty acid synthesis.
Pathogenesis
Nuclear receptor regulation of gene
expression
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Sterol regulatory element-binding proteins
(SREBPs)
1). SREBP-1c levels are increased in the fatty livers of obese (ob/ob) mice
with insulin resistance and hyperinsulinaemia caused by leptin deficiency,
and SREBP-1c increases lipogenic gene expression, enhances fatty acid
synthesis and accelerates triacyglycerol accumulation.
2). Overexpression of SREBP-1a in rats resulted in a 26-fold increase in
fatty acid synthesis and a 5-fold increase in cholesterol synthesis.
3). SREBP-2 overexpression in transgenic mice resulted in a 28-fold
increase in cholesterol synthesis and a 4-fold increase in fatty acid
synthesis.
Insulin resistance
Obesity/lipodystrophy
Increased lipolysis/decreased
Re-esterification
PPARγ activity
adiponectin
Leptin
FFA
Rad
TNF-α
PC-1
NEFAs
Hepatocytes/stellate/
Kupffer cells
NO
TNF-α
ATP
Inadequate oxidation of FFA & di/triacylglycerols
Cyto P450 A
P450E1
Glutathione
Free radicals
antioxidants
Decreased:
PPARα activity
PPARδ activity
Increased:
SREBP 1a/1c
SREBP2 activity
NASH
Kupffer cell
NF-κB
Oxidative stress & inflammation
Treatment
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Peroxisome proliferator-activated
receptor gamma agonists
Biguanides
Peroxisome proliferator-activated
receptor alpha agonists
Antioxidants
Weight loss
Treatment
PPARγ agonists
Rosiglitazone (24 weeks) in 30 NASH: improved insulin
sensitivity, reduced liver fat content and improved ALT
level. (may be due in part to the anti-inflammatory
effects of PPARγ ligants.
 Troglitazone (400 mg for 6 months) in 10 NASH women:
normal ALT level and mild histological improvement.
for 48 weeks: improved insulin sensitivity, reduced liver
fat content and improved the biochemical and
histological features of NASH.
The main side-effects reported in these studies were weight
gain and in total body fat.
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Treatment
Biguanides
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Metformin is the only biguanide FDA-approved for use
in the United Stated. It regulates AMP-activated protein
kinase in hepatocytes, which is a major cellular regulator
of lipid and glucose metabolism.
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Improvement in liver biochemical test, insulin sensitivity
and decreasing hepatic volume and body weight.
Thus, metformin may be beneficial in the treatment of
NASH but some of the benefit may be a direct benefit of
weight loss.
Treatment
PPARα agonists
a). Clofibrate (2g/day): no significant benefit in liver tests
or hepatic histology
b). Gemfibrozil (600 mg/day) in 46 NAFLD patients: a
significant improvement in aminotransferase levles
More evidence is needed from long-term studies with the
newer PPARα agonists.
Treatment
Antioxidants
It is uncertain at present whether antioxidant therapy is
beneficial in the treatment of NASH.
1. Ursodeoxycholic acid (UDCA) (a epimer of
chenodeoxycholic acid and non-hepatotoxic)
a). 4 open-label pilot studies: have evaluated the
therapeutic benefit of UDCA in patients with NAFLD.
b). 2 years randomized trials concluded that no
significant differences in the degree of stestosis,
inflammation or fibrosis occurred between the UDCA
and placebo groups.
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Treatment
Antioxidants
2. Betaine is a normal component of the metabolism of
methionine and increases the S-adenosylmethionine (SAM)
level, which has been shown to protect against
triacyglycerol deposition and liver injury in ethanol-fed
rats.
a). In a recent study: betaine (20g/day for 12 months)---7
NAFLD patients ------decrease hepatic steatosis
Treatment
Antioxidants
3. N-Acetylcysteine is an antioxidant that increases glutathione levels in
hepatocytes.
a). 11 NAFLD patients: N-acetylcysteine (1g/day for 3 m)----well
tolerated and with a significant improvement in aminotransferase
levles.
4. Vit E
5. α-tocopherol
Thus, it is still uncertain whether there is benefit from
treatment with antioxidants.
Treatment
Weight loss
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Obesity is the condition most commonly associated with
NASH and therefore weight loss is frequently advocated.
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However, the benefit of weight loss is difficult to evaluate
because obese patients with NASH rarely achieve or
maintain sustained reductions in body weight.
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Moreover, the effect of weight loss on NASH is not
consistent.
Treatment
Weight loss
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For the future, weight loss combined with PPARα or
perhaps PPARγ agonists will most likely be the
treatments of choice but before this recommendation can
be advocated more evidence of efficacy and safety is
required.