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

BARCELONA . SPAIN
146 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE 147
APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012
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NOVEL TARGETS FOR ALCOHOLIC LIVER DISEASE (ALD) THERAPY
IDENTIFIED IN TRANSLATIONAL STUDIES
Bin Gao
Bethesda, Maryland, USA
E-mail: bgao@mail.nih.gov
KEY POINTS
• The mechanisms underlying the pathogenesis of ALD are not fully understood.
• Ethanol-mediated hepatotoxicity and activation of innate immunity contribute to the
pathogenesis of ALD; however activation of many innate immunity components also promotes
liver repair.
• Steroid treatment may be beneficial in some ALD patients by inhibiting inflammation; however,
such treatment may also block liver regeneration and increase bacterial infection.
• Several novel targets that can be used to block liver inflammation in ALD: CXC chemokines,
complement, gut microbiota and LPS pathways, osteopontin.
• Several novel targets that can be used to promote hepatocyte survival and proliferation in ALD:
apoptosis inhibitors and interleukin-22 (IL-22).
Alcoholic liver disease (ALD) is a major cause of chronic liver disease, leading to fibrosis and cirrhosis
worldwide. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism,
National Institutes of Health showed that liver cirrhosis was the 12th leading cause of death in the United
States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related (http://pubs.niaaa.nih.gov/
publications/surveillance88/Cirr07.htm). The mechanisms underlying the pathogenesis of ALD are not fully
understood. Several major factors contributing the progression of ALD have been proposed 1, 2 and are
summarized in Figure 1.
Figure 1. Mechanisms underlying the pathogenesis of ALD. Chronic alcohol consumption directly
induces hepatocyte death via multiple mechanisms, and indirectly causes hepatocellular damage via the
activation of innate immunity and adaptive immunity. All of these events can lead to liver inflammation
with accumulation of neutrophils. Inflammation then further promotes hepatocyte death; however, it also
plays an important role in promoting liver regeneration. In addition, activation of several innate immunity
components (such as TNF-α and complements) contributes significantly to the liver repair.
Despite the significant progress on the understanding of ALD pathogenesis, no targeted therapies are
available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence,
nutritional support, and corticosteroids. The clinical results from the steroid treatment of alcoholic hepatitis
have been controversial. Accumulated data indicate that steroid treatment can improve the short-term survival
rate in some patients with severe alcoholic hepatitis. The disappointing results from the anti-inflammatory
therapy of steroids may be due to several reasons. First, the broad inhibition of inflammation by steroids
may not only abolish the inflammation-mediated liver injury but also diminish the inflammation-mediated
liver repair. Second, inflammation may not be the major or the only factor contributing to hepatocellular
damage in ALD patients. Third, steroid treatment also increases the risk of bacterial infection.