By Liz Highleyman

The number of patients with acute liver failure (ALF) is growing in one way that can be prevented: toxicity due to acetaminophen (marketed as Tylenol and many other brands and generics). Therapeutic advances are improving the outlook for people with acetaminophen hepatotoxicity, though some of these are not yet ready for widespread use.

During an American Association for the Study of Liver Disease (AASLD) clinical symposium held at the annual Digestive Disease Week meeting (DDW 2009) taking place this week in Chicago, 4 experts in the field offered a look at future strategies for preventing and treating acetaminophen-related liver disease, according to DDW Daily News, the official conference newspaper.

"This is not only something that we need to be aware of, but so do others all around us," said Robert Fontana, MD, director of the Liver Transplant Program at the University of Michigan Health System at Ann Arbor. Between 1998 and 2004, he noted, the proportion of ALF cases caused by acetaminophen toxicity increased from 28% to 51%.

This past year the ALF Study Group looked at the link between the acetaminophen and liver disease, and found that accidental and intentional ingestion of high doses of the drug -- sometimes as a suicide attempt -- was the most common cause for ALF; for women, acetaminophen-related liver failure constituted a large majority of the cases. The second most common cause of ALF among both men and women was idiosyncratic pharmacological reactions (unpredictable and unusual individuals responses).

One factor that contributes to accidental overdose is that acetaminophen is an ingredient in many compound medications, including those sold over the counters. People may combine such products and end up taking more than the total recommended dose. Dr. Fontana said that heightened vigilance for acetaminophen misuse is warranted, but so is early recognition of overdose as cause of ALF.

In order to diagnose acetaminophen hepatotoxicity quickly, Dr. Fontana recommended that it should be assumed until proven otherwise if a patient's records indicate a history of previous toxic ingestion. Another good screen is ALT greater than 1000 IU/mi with normal bilirubin. In addition, symptoms of ALF are well established and dramatic, including altered mental status -- including coma -- and extreme vasodilatation as well as kidney and lung failure.

Managing Acetaminophen Toxicity

Acetaminophen overdose is associated with the highest rate of transplant-free survival -- about two-thirds -- in short-term studies. It is treatable with gastric lavage ("stomach pumping"), charcoal, and N-acetylcysteine (NAC).

Early studies of NAC suggested that it might also be effective for people with ALF due to causes other than acetaminophen poisoning. A multicenter trial in which patients were randomized by coma grade and other factors showed no improvement in overall 3-week survival in those treated with intravenous NAC compared with placebo; however, the researchers did observed a trend toward differences in length of hospital stay, and the study is continuing.

In another presentation, Rajiv Jalan, MBBS, from the London Clinic in the U.K. noted that NAC also helps control inflammation in the brain, one of the most lethal manifestations of ALF. Although ammonia remains central to the pathogenesis of encephalopathy in people with ALF, management of elevated ammonia constitutes "an unmet clinical need," he said.

Using a bioartificial liver in conjunction with an extracorporeal liver-assist device is one method that warrants more study, said Norman Sussman, MD, of the University of Utah at Salt Lake City. Non-metabolic liver support methods developed thus far are simple, but relatively ineffective, and in many cases a new liver is needed.

Using prophylactic hypothermia (chilling) to treat ALF due to acetaminophen toxicity has also known promise, according to Todd Stravitz, MD, of Virginia Commonwealth University in Richmond. Hypothermia also shows benefits when used therapeutically for uncontrolled intracranial hypertension.

6/05/09

Source
Liver experts take therapeutic, preventive aim at acetaminophen overdose. DDW Daily News. Digestive Disease Week (DDW 2009). Chicago. June 2, 2009.