Cirrhosis may worsen alcohol-induced brain dysfunction by altering neural gene expression,
according to investigators here.

　Comparison of gene expression patterns in cirrhotic and noncirrhotic alcoholics revealed widespread
differences in the frontal cortex, R. Dayne Mayfield, Ph.D., of the University of Texas, and colleagues,
reported in the September issue of Alcoholism: Clinical and Experimental Research.

　Both astrocytes and neuronal cells were affected at the transcriptional level in cirrhotic alcoholics.

　"Genes involved in neurite growth, neuronal cell adhesion, and synaptic transmission were inhibited
at the mRNA level in cirrhotic alcoholics," the authors stated.

　Collectively, the alterations in gene expression are consistent with more severe brain dysfunction in
cirrhotic versus noncirrhotic alcoholics, they concluded.

　In cirrhotic patients, neurotoxins that cannot be removed from circulation cross the blood-brain
barrier and cause brain dysfunction that include hepatic encephalopathy. Imaging and pathology studies
have suggested that chronic alcohol abuse causes brain damage that is more severe in alcoholics with
cirrhosis. The reasons for the worse brain dysfunction in cirrhotic alcoholics have not been completely
explained.

　Dr. Mayfield and colleagues had previously reported extensive transcriptional reprogramming in the
cortex of noncirrhotic alcoholics. In the current study, they used 47,000-element cDNA microarray
technology to examine gene expression profiles in the frontal cortex of cirrhotic alcoholics and to
compare the profiles with those of noncirrhotic alcoholics.

The study involved seven cirrhotic and 14 noncirrhotic alcoholics. RNA from the frontal cortex of all 21
participants was analyzed by means of cDNA microarray, and investigators compared the
transcriptome (entire set of RNA molecules) of the cirrhotic and noncirrhotic alcoholics.

　The total number of spots detected on each array was similar between the two groups. Of 15,833
genes detected in both groups, 1,125 met criteria for differential expression (increased or decreased in
cirrhotic patients). These genes were compared with 531 genes expressed in a control group versus
noncirrhotic alcoholics (reported in a previous study).

　In general, the magnitude of different expression between cirrhotic and noncirrhotic alcoholics
exceeded that of the comparison between controls and noncirrhotic alcoholics.

　By computerized analysis, the investigators grouped differentially expressed genes into
biologically relevant themes. Genes involved in cell adhesion, mitochondrial function, and synaptic
transmission were overrepresented among down-regulated genes. Upregulated genes had
overrepresentation of genes involved in apoptosis and mitosis.

　"Interestingly, all of the stress-response genes that were upregulated in uncomplicated alcoholics
compared with nonalcoholic controls were further upregulated in the current cirrhotic alcoholic cases,"
the authors observed.


　The investigators summarized the state of knowledge about alcohol-induced brain damage, including
findings from the current study:

　• Long-term alcohol exposure causes persistent liver inflammation and elevated serum cytokine
levels.
　• As liver damage progression, some neurotoxins cannot be removed from circulation, and the supply
of some necessary elements is reduced.
　• Progressive cirrhosis adversely affects neuronal and glial-cell functions, including cell
communication, signal transduction, ion transport, and mitochondrial function.
　• In glial cells (astrocytes), apoptosis is induced, leading to increased brain atrophy and
proliferation of progenitor cells.
　• In neuronal cells synaptic transmission is inhibited, potentially causing more severe cognitive
dysfunction.

　　The authors had no disclosures. The study was supported by the National Institute of Alcoholism
and Alcohol Abuse.