Alcoholics with cirrhosis of the liver have more brain damage than noncirrhotic alcoholics

August 27, 2007

Sustained exposure to alcohol can cause scarring and dysfunction of the liver, referred to as cirrhosis. Heavy alcohol use can also cause brain damage. An examination of gene expression in the frontal cortex has found that brain function is even more impaired in cirrhotic than non-cirrhotic alcoholics.

Results are published in the September issue of Alcoholism: Clinical & Experimental Research.

"The liver's main function is to remove poisons from the blood," explained R. Dayne Mayfield, research scientist at the Waggoner Center for Alcohol and Addiction Research at The University of Texas at Austin. "It also helps the body absorb certain nutrients like fats and fat-soluble vitamins. You cannot live without a functioning liver." Mayfield is also the corresponding author for the study.

He added that about 10 to 20 percent of heavy drinkers develop cirrhosis. It is the seventh leading cause of death among young and middle-aged adults in the United States; approximately 10,000 to 24,000 deaths from cirrhosis each year may be due to alcohol consumption. "Cirrhotic patients [have] dysfunctional livers that cannot remove poisons from the blood stream," he said. These poisons are able to move into the brain and disrupt normal function.

"When a gene or deoxyribonucleic acid (DNA) is 'turned on,'" said Mayfield, "it serves as a template for synthesis of ribonucleic acid (RNA), which in turn produces protein, the key element in cell function. These 'genes' hold the key or code for the ultimate production of proteins that control all functions of the brain. We know that heavy alcohol drinking changes the regulation of genes in the brain. We predicted that alcohol-related changes in brain genes would be magnified in alcoholics with cirrhosis."

Researchers obtained brain samples from the Brisbane Node of the National Health & Medical Research Council Brain Bank and the Tissue Resource Centre at the University of Sydney, Australia. They compared roughly 47,000 element cDNA microarrays taken from two groups (n=21): seven cirrhotic and 14 non-cirrhotic alcoholic cases.

"We found that the levels of many important brain genes changed in the cirrhotic patients," said Mayfield. "These genes are important in regulating cell death and how individual cells in the brain talk to each other in a meaningful way."

"The level of gene expression differed significantly between tissue from cirrhotic and non-cirrhotic alcoholics," added John H. Krystal, Robert L. McNeil, Jr. professor of clinical pharmacology and deputy chairman for research in the department of Psychiatry at Yale University School of Medicine and the VA Connecticut Healthcare System. "Out of 1,125 genes, 482 genes showed increased expression and 643 genes showed reduced expression in the cirrhotic individuals. With the levels of so many genes changing, this study suggests widespread effects in many cellular pathways related to cirrhosis in the alcoholic group." Krystal is also a principal investigator at the NIAAA Center for the Translational Neuroscience of Alcoholism and the VA Alcohol Research Center.

More specifically, those genes involved in neurite growth, neuronal cell adhesion, and synaptic transmission showed greater inhibition at the mRNA level among the alcoholic cases.

"Cells in the brain have to maintain connections in order to operate," explained Mayfield. "This is similar to the way the internet works to transmit information across the globe. The internet would slow down or stop if enough connections are interrupted or changed. Similarly, the genes outlined above are responsible for proper connections and communication between cells in the brain. Without them, normal function would not be possible."

Krystal suggested several possible interpretations of the findings. "One, alcoholics who develop cirrhosis likely drink more heavily than those alcoholics who do not develop cirrhosis," he said. "Therefore, some of the findings may be related to the effects of heavy drinking upon the brain. A second contribution could be the effects of impaired liver function upon the brain. The liver plays a major role in the production and metabolism of a large number of substances that influence brain function, and impaired liver function would be expected to affect the brain. A third possibility is that cellular processes that are stimulated by alcohol consumption might influence both liver and brain. That is, the cirrhotic and non-cirrhotic groups differ in their cellular resilience to the toxic effects of alcohol rather than differences in their level of alcohol consumption. A fourth possible contributing factor could be changes in diet. If patients with cirrhosis have a more profound disruption of their nutrition than patients who do not develop cirrhosis, differences in brain damage may be related to nutritional deficiencies."

Both Mayfield and Krystal said that the central message of the study is that alcoholism, especially when accompanied by a serious medical complication such as cirrhosis of the liver, can produce widespread changes in the body and brain.

"One hopes that a better understanding of the cellular processes related to the destructive impact of alcoholism upon the brain may help to guide the development of treatments that might protect people from neural damage related to alcoholism, and help them to recover from alcoholism," said Krystal. "Important questions are: 'How reversible are the changes in gene expression in the brain when alcoholics stop drinking"' and 'How dependent is the recovery of the brain upon the recovery of the liver"'"
Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, "Altered Gene Expression Profiles in the Frontal Cortex of Cirrhotic Alcoholics," were: Jianwen Liu and R. Adron Harris of the Waggoner Center for Alcohol and Addiction Research at The University of Texas at Austin; and Joanne M. Lewohl and Peter R. Dodd of the Department of Biochemistry at the University of Queensland in Australia. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, and the Brisbane Node of the National Health and Medical Research Council Brain Bank.

Alcoholism: Clinical & Experimental Research

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