barcelona . spain - European Association for the Study of the Liver

BARCELONA . SPAIN
28 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 29
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
Figure 1
Ethanol indirectly increases oxygen use by hepatocytes through lipopolysaccharide-induced activation of
Kupffer cells, resulting in the release of prostaglandin E2 and stimulation of hepatocyte metabolic activity,
further contributing to the onset of hypoxia. Binge drinkers have could have severe hypoxia and hepatic
reperfusion injury (French, 2004).
ALCOHOLIC LIVER DISEASE (ALD)
The disease profiles associated with chronic alcohol consumption show a great deal of individual variability
in severity and progression for comparable levels of alcohol consumption. It has traditionally been assumed
that this variability may reflect individual genetic factors, such as the expression and activity of individual
isoforms of the alcohol-metabolizing enzymes ADH and ALDH, but is also influenced by variations in
temporal intake patterns (binge vs chronic drinking), nutritional status, gender, exposure to other damaging
factors such as smoking, or use of other drugs of abuse. In addition, the onset and severity of alcoholic liver
disease is strongly influenced by other comorbid conditions such as obesity or HCV infection. The origin
of this increase in susceptibility to alcoholic liver disease is not due solely to intrahepatic factors, but may
also involve alcohol-induced changes in other tissues, ranging from adipose tissue to the CNS, the gut, and
the immune system. Thus, although the factors contributing to alcohol-induced liver disease remain poorly
understood, they are complex and systemic.
Figure 2
Figure 1. ADH = Alcohol d ehydrogenase; ALDH = Aldehyde dehydrogenase; NAD = Nicotinamide adenine
dinucleotide; NADH = reduced NAD; NADP = Nicotinamide adenine dinucleotide phosphate; H 2
O 2
=
Hydrogen peroxide.
CONSEQUENCES OF INCREASED NADH/NAD + RATIO:
Increased NADH/NAD + ratios in both the cytosol and mitochondria of hepatocytes influence the direction
of several reversible reactions leading to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric
acid metabolism. These changes happen after binge drinking, and seem to be attenuated with chronic
ethanol ingestion.
1. Alcoholic hypoglycemia. The increase in NADH due to alcohol metabolism prevents pyruvate
conversion to glucose by lowering the concentration of pyruvate, which in turn decreases the pyruvate
carboxylase reaction, one of the rate limiting steps of gluconeogenesis (Krebs et al., 1969). Collectively, this
could result in clinically significant hypoglycemia.
2. Alcoholic acidosis. Ketoacidosis is common in chronically malnourished alcoholics, and is due to the
formation of ketone bodies, primarily β-hydroxybutyrate (Gauthier et al., 2002). In addition, the increase in
NADH favors the conversion of pyruvate to lactate, resulting in lactic acidosis. Binge drinkers may present
with severe acidosis with relatively low ketone bodies and hypoglycemia. The increase in NADH/NAD + ratio
diminishes pyruvate dehydrogenase (PDH) activity in the mitochondria, resulting in diminished conversion
of pyruvate to acetyl CoA. PDH activity is further diminished in chronic alcoholics due to hypomagnesemia
and thiamine deficiency, resulting in the inhibition of pyruvate utilization in the TCA cycle.
3. Hyperuricemia. Patients who drink too much frequently may develop hyperuricemia because lactate and
ketone bodies formed after alcohol metabolism compete with urate for excretion in the distal tubules of the
kidney (Yamanaka, 1996). Alcohol metabolism also releases the ATP degradation products, hypoxanthine and
adenosine which enter the purine nucleotide degradation pathway, resulting in increased formation of urate.
4. Hypertriglyceridemia. Heavy alcohol consumption increases the synthesis of triglycerides, resulting
in fatty liver and hypertriglyceridemia, and may exacerbate diabetic hypertriglyceridemia. The increase
in NADH/NAD + ratio results in an increase in v-glycerophosphate, which favors hepatic triglyceride
accumulation, and also inhibits mitochondrial β-oxidation of fatty acids (Lieber, 1984).
5. Hypoxia. Metabolism of ethanol by hepatocytes tends to increase oxygen uptake, resulting in significant
hypoxia in the perivenous hepatocytes, the site of early liver damage due to chronic alcohol consumption.
As shown in Figure 2, ALD includes a broad range of defects that vary considerably in severity, including:
a) Fatty liver (hepatic steatosis) histologically characterized by the occurrence of lipid droplets in
hepatocytes. This condition is long thought to be a relatively innocuous side effect of heavy drinking,
because it is usually readily reversible upon cessation of alcohol consumption.
b) Alcoholic hepatitis, an inflammatory condition characterized by significantly increased serum levels of
liver enzymes (ALT and AST) and moderate to severe tissue damage, including necrotic foci with neutrophil
infiltration.
c) Liver fibrosis/cirrhosis, a modest (10-15%) fraction of chronic heavy drinkers proceeds to develop
fibrosis and cirrhosis.
d) Hepatocellular carcinomas occur in about 2% of cirrhotic patients.