Research Society on Alcohol Postgraduate Course

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Research Society on Alcohol Post-graduate
Course

• Anna Mae Diehl
• June, 2001

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France
USSR
Germany
Mexico
Liver-related Deaths
Great Britain
USA
Australia
Canada
Japan
Alcohol Consumption (per 106 people)
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Serious Liver Disease
Unusual !!
Habitual
Drinkers
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Liver Damage
Age Sex Viruses Drugs Nutrition
Alcohol Metabolites
Co-morbidity Factors
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Alcoholic Liver Disease
Steatosis
Normal
Steatohepatitis
Cirrhosis
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Alcoholic Liver Disease
EtOH
Steatosis
Normal
2nd hit (TNFa?)
3rd hit
Steatohepatitis
Cirrhosis
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Steatosis (Fatty Liver)

• Common
• Reversible
• Few symptoms
• Hepatomegaly
• Slightly liver enzymes

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Steatohepatitis (Fat inflammation injury)

• Less common
• Precursor of cirrhosis
• Generally few symptoms
• Can multi-organ failure,
• death

Can also occur in patients with cirrhosis
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Cirrhosis Scar, nodules

• Eventually develops in 20
• Morbidity common
• (jaundice, ascites, bleeding, cachexia,
• infections, encephalopathy)
• Liver cancer, death in most
• within 10 years

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EtOH
hepatocyte
hepatocyte
Products
Death!
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Direct Hepatotoxicity
ADH
EtOH
Acetaldehyde
MEOS (Cyp2E1)
ALDH
Acetate
ROS
CO2 H2O
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Direct Hepatotoxicity
Pros

• ADH/ALDH polymorphisms
• Cyp2E1 induction a liver injury
• (chronicity, zonality, other drugs,
• over-expressing cell lines)

Cons

• Dietary effects (CHO, PUFA)
• Kupffer cell depletion

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EtOH
hepatocyte
hepatocyte
Products
Death!
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EtOH
Injury!
bacteria
TNFa
Acetald.
Endotoxin
Liver
Intestine
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Indirect Hepatotoxicity
Pros

• Risk factors for bacterial
• translocation in liver disease
• endotoxin, TNFa, cytokines in
• patients with steatohepatitis
• Experimental animal data

Cons

• Co-location of EtOH/bacteria
• Usual TNF effects on hepatocytes

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Sensitization to Endotoxin Liver Injury
P. acnes
IL-12
CD4NKT
KC
IL-4
IL-18
hepatocyte
TH-2 cytokines
TH-1 cytokines
LPS
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TNFa
mitochondria
NF kB
caspases
cytochrome c
ROS
Survival factors
Death!
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TNFa
EtOH
c
c
c
NF kB
ROS
caspases
survival
factors
Die
Survive
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EtOH
TNFa

• Inhibits mitochondrial
• e-transport _at_ complex I
• mitochondrial GSH

Induces UCP-2 MMP
ATP
mROS
Overwhelming Death Signals!
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Mitochondrial Uncoupling
Outer membrane

UCP
e- e- e- e-
ATP
Heat
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EtOH
TNFa

• Activates
• caspases
• mROS

• Inhibits TNF-activation
• of NF-kB stress-related
• protein kinases

Un-opposed Death Signals !
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EtOH
TNFa

• Inhibits
• insulin
• signaling

• Inhibits signaling by
• insulin other growth
• factors

hepatocyte proliferation
Impaired recovery from injury!
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Multiple hit hypothesis
EtOH TNFa
EtOH
TNFa
O.K.
O.K.
Liver Disease
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Therapy
Rx Efficacy Patients Animals
Abstinence Y(incomplete) Y
Nutrition Y/N ?? Antibiotics
?? Y Anti-TNF ??(steroids)
Y Anti-oxidants Maybe Y Insulin sensitizers
?? ??
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Multiple hit hypothesis
EtOH
TNFa
EtOH TNFa
Acetald. ROS Anti-insulin
Caspases ROS, UCP Anti-insulin
O.K.
O.K.
Liver Disease