Autotaxin Linked to Itch Intensity in Cholestatis Liver Disease
By Thomas R. Collins
Medscape Medical News
April 27, 2010 (Vienna, Austria) — New research from the Netherlands implicates autotaxin in the intensity of pruritis experienced by patients with cholestatic disorders. The findings suggest that autotaxin should be the target of therapy, announced Andreas Kremer, MD, a PhD candidate at the University of Amsterdam Tytgat Institute for Liver and Intestinal Research, here at the European Association for the Study of the Liver (EASL) 45th Annual Meeting.
Patients with intrahepatic cholestatis of pregnancy showed marked increases in autotaxin activity, compared with control sunjects, Dr. Kremer reported. So did patients with chronic cholestatis disorders, mainly primary biliary cirrhosis and pruritis (P?< .0001 in both cases).
The severity of the pruritis also tended to be greater in patients with higher levels of autotaxin. "Inhibition of autotaxin may represent a potential antipruritic treatment strategy in patients with cholestasis," Dr. Kremer said.
About 0.5% of pregnant women develops intrahepatic cholestasis of pregnancy and, by definition, have pruritis. Pruritis and cholestatis quickly resolve after childbirth.
Patients with primary biliary cirrhosis commonly have pruritis, which paradoxically diminishes as patients develop end-stage liver disease.
Dr. Kremer showed a graph with itch intensity on one axis and autotaxin activity on the other. As itch intensity increased, so, generally, did autotaxin activity.
"We found a moderate correlation between these 2 parameters," Dr. Kremer said.
Similar analyses for histamine, tryptase, and bile salts did not show any correlation with itch intensity, he noted.
The researchers also showed that as itch intensity quickly drops with the start of nasal biliary drainage treatment, autotaxin levels decrease.
Researchers also tested the effects of the 3,7-dihydroxy-bile salts on autotaxin activity, since these bile salts are more abundant in end-stage liver disease, when pruritis tends to go away.
In in?vitro studies conducted by the Dutch team, autotaxin activity was suppressed by the 3,7-dihydroxy-bile salts chenodeoxycholate and ursodeoxycholate, and their glyco- and tauroconjugates. Lisophosphatidic acid, but not bile salts, injected intradermally into mice induced scratch responses, Dr. Kremer reported.
"Autotaxin, but not bile salts, correlate with the severity of pruritis in patients with various cholestatic disorders," Dr. Kremer said. "Inhibition of autotaxin by 3,7-dihydroxy-bile salts may contribute to the enigmatic improvement of pruritis in end-stage liver disease."
Dr. Kremer was asked about the "moderate" relationship between autotaxin activity and itch intensity. He said that didn't diminish the significance of his team's findings.
"It's even more surprising that there was any correlation at all," he said.
Heiner Wedemeyer, MD, senior physician and assistant professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hanover Medical School in Germany, and secretary general of EASL, told Medscape Gastroenterology that a focus on autotaxin could benefit a lot of patients.
"It's an important new molecule that may explain the pruritis, which is actually a completely underestimated symptom in cholestatic liver diseases," he said. "Patients are really suffering. It's really so severe."
"We all talk about survival, cancer, viruses. But this really matters. Thus, any study investigating potential mechanisms of pruritis is so important.?.?.?. I think this is a major step forward," Dr. Wedemeyer asserted.
The study received no relevant commercial financial support. Dr. Kremer and Dr. Wedemeyer have disclosed no relevant financial relationships.
European Association for the Study of the Liver (EASL) 45th Annual Meeting. Presented April?15, 2010.
