Elevated ALT Levels Predict Risk of Death From Liver Cancer

Martha Kerr

November 02, 2006

November 2, 2006 (Boston) — The currently accepted upper limit of normal for serum alanine aminotransferase (ALT) levels is "artificially high," officials from the American Association for the Study of Liver Diseases (AASLD) believe. The current normal range excludes a number of individuals who feel well but who are at increased risk for liver disease.

AASLD officials are working to "recalibrate" the normal range, based in part on a number of studies presented here this week at the AASLD 57th annual meeting, which show that elevated liver enzymes are a risk factor for mortality in general and liver disease, specifically.

Elevated serum aminotransferases, such as ALT and aspartate aminotransferase (AST), predict mortality in the general population, according to W. Ray Kim, MD, associate professor of medicine at the Mayo Clinic College of Medicine in Rochester, Minnesota.

Dr. Kim presented data on 18,330 community residents who had AST levels measured at least once in 1995. Of these, 15,991 had normal results and 2339 had elevated AST levels.

Also in 1995, 6792 residents had ALT levels measured, and of these, 907 had elevated values.

Dr. Kim reported "a significant increase in the standardized mortality ratio with increasing AST and ALT levels, whereas a normal AST or ALT level was associated with a risk of death lower than expected."

AST levels 2 times the upper limit of normal had a mortality ratio of 1.79 and ALT levels 2 times the upper limit of normal had a mortality ratio of 1.63. There was "a near-linear relationship between AST and ALT values and subsequent risk of death in both genders," Dr. Kim showed.

He suggested that AST and ALT screening be a part of the general medical evaluation of patients. "[Elevated] ALT may identify patients at risk of death from liver disease early in their disease," he told AASLD meeting attendees.

Dr. Kim's study was independently funded. Dr. Kim reported no relevant financial relationships.

In a separate study, John McHutchison, MD, director of gastroenterology and hepatology research at Duke University Medical Center in Durham, North Carolina, and colleagues presented data on an investigational agent, PF-03491390 (Pfizer Ltd, Sandwich, UK), used in chronic active hepatitis C virus (HCV) infection.

The agent, a pancaspase inhibitor, lowers elevated ALT and AST levels by blocking apoptosis of hepatocytes.

The dose-ranging study involved 204 patients with chronic active HCV infection and liver fibrosis, who were randomized to placebo, 5 mg, 25 mg, or 50 mg of PF-03491390 twice a day orally for 12 weeks.

If ALT and AST levels were still elevated at week 10, the dose was doubled for the remaining 2 weeks.

Reductions in both liver enzymes were seen within the first week of treatment and were sustained throughout. Reductions were dose-related in a linear fashion.

Adverse events were primarily mild or moderate, with headache and fatigue reported in 24 and 22 patients, respectively, the most common.

The pancaspase inhibitor did not affect HCV RNA levels.

Dr. McHutchison's study was funded in part by Pfizer, Ltd, Sandwich, UK. He has also received funding grants from Vertex Pharmaceuticals, Inc, GlaxoSmithKline, and Coley Pharmaceutical Group, Inc, for other research.

AASLD Chairman of Public Policy Adrian DiBisceglie, MD, chief of hepatology at St. Louis University School of Medicine in Missouri, told Medscape that the association is in the process of "recalibrating" the ALT normal range.

"We are setting [upper] limits lower than they have been to include people with abnormal ALT levels who feel well but who still have an increased risk of liver disease," he said. Setting the upper limit of normal lower will decrease the specificity some, but it will increase the sensitivity."

Upper limits of normal range from 30 IU/L to 60 IU/L, depending on the laboratory. "We want to reset it southward of 30 IU/L," Dr. DiBisceglie said.

"ALT levels are a reflection of the general vascular condition," he said. "If the level is above 30, then that person probably has a problem — fatty liver or some vascular disease, including occlusive coronary artery disease."

AASLD 57th Annual Meeting: Abstract 95, presented October 30, 2006; abstract 1251, presented October 31, 2006.

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