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Both genetics and dopaminergic neurotransmission have a role in delirium tremens

Alcohol-dependent individuals have a five to 10 percent lifetime risk of developing delirium tremens (DT) following alcohol withdrawal. DT is characterized by a clouding of consciousness, mental confusion or disorientation, and is often accompanied by hallucinations and agitation.

Although the symptoms of DT are relatively well known, the pathophysiology of DT is less clear. A review of formerly published research has found that both genetics and the regulation of dopaminergic neurotransmission appear to play a role in the pathophysiological process of the development of DT.

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

"DT can develop one to four days after the onset of acute alcohol withdrawal in persons who have been drinking excessively for years," said Barbara C. van Munster, a researcher at the University of Amsterdam and corresponding author for the study. DT is at the extreme end of the alcohol withdrawal spectrum; most people experience minor symptoms such as insomnia and tremulousness, or possibly more severe complications such as seizures.

"The symptoms of alcohol withdrawal relate proportionally to the amount of alcohol intake and the duration of a patient's recent drinking habit," van Munster added. "However, other risk factors for developing DT include concurrent acute medical illness, older age and abnormal liver function." Although death may occur in up to five percent of patients with DT, risk of death can be reduced in patients who receive adequate medication and medical support.

As noted previously, the exact pathophysiologic mechanism for developing DT is unclear, however, the gamma-aminobutyric acid and glutamate neurosystems are believed to be involved. "My review was designed to augment knowledge about the pathophysiology of DT from genetic research and to establish commonality," said van Munster. "Finding one association between a genetic polymorphism and DT could happen easily on coincidence. Finding it twice could really mean something"

Van Munster and her colleagues collected all studies listed on the MEDLINE and EMBASE databases until February 2006 that met the following criteria: written in English; entailed an analysis of any association between a genetic polymorphism and DT; and excluded all other alcohol-withdrawal syndromes.

"We found that of the 25 studies reviewed that dealt with 30 polymorphisms, located in 19 different genes, eight positive associations seemed to support a genetic basis for DT," said van Munster.

"Specifically, we found positive associations in three different candidate genes involved in dopamine transmission, one gene involved in the glutamate pathway, one neuropeptide gene and one cannabinoid gene," van Munster said. "Only the candidate genes involved in dopamine transmission were each associated with DT in different study populations. The replication of this association makes coincidence less plausible. Moreover, both these polymorphisms are functional, which means the mutation gives a change in the final protein product. This makes it even more probable that dopaminergic neurotransmission plays an important role in the pathophysiological process of the development of DT."

Van Munster said that her review helps to shed light on the genetics of DT, an area not fully explored previously. "In the medical literature," she said, "I could not find anything about the genetic basis for DT. It appears that a genetic base was never studied by epidemiological family studies or by linkage analysis, probably because of the rare occurrence of DT in the same family. Moreover, the diagnosis is not always clear. Having hallucinations does not mean that someone has experienced DT; they have to meet DT criteria as diagnosed by an experienced physician. Probably, the cause of DT is multifactorial, with a relatively minor contribution of each genetic polymorphism."

Van Munster plans to continue with her research on delirium among elderly people. "Roughly 30 percent of elderly patients acutely admitted to the medical ward experience delirium," she said. "This delirium is not provoked by alcohol withdrawal, but by their medical condition, especially in those patients with older age and diminished cognition. Until now, this type of delirium was supposed to have another pathophysiological pathway than DT, with a larger role for the dopaminergic neurotransmission. However, based on the findings in this review, it is possible that the pathophysiological mechanisms for both types of delirium are more equal than previously supposed."

Barbara C. van Munster, M.D. | EurekAlert!
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