DOE003

作者：Thomas R. Collins  
出處：WebMD醫學新聞

　　April 27, 2010 (奧地利維也納) — 荷蘭的新研究指出，自家趨化素(autotoxin)與膽管堵塞患者的搔癢強度有關。阿姆斯特丹大學博士候選人、Tytgat肝臟與腸道研究中心的Andreas Kremer醫師在歐洲肝臟研究協會第45屆年會(EASL)中宣稱，研究發現認為自家趨化素可以作為治療目標。
　　
　　Kremer醫師報告指出，肝內膽管阻塞的孕婦其自家趨化素活性顯著比對照組增加，原發性膽汁鬱積性肝硬化和搔癢症等慢性膽管阻塞病患也是(兩者之P均<.0001 )。
　　
　　Kremer醫師表示，自家趨化素較高者其搔癢症嚴重度也較大，抑制自家趨化素可能是膽管阻塞型患者的抗搔癢治療策略。
　　
　　在懷孕時發生肝內膽管阻塞的孕婦中，根據定義，約有0.5%發生搔癢症，搔癢症和膽管阻塞在產後都可迅速緩解。
　　
　　原發性膽汁鬱積性肝硬化病患一般都有搔癢症，當病患發展成末期肝病之後，會反常地減少。
　　
　　Kremer醫師用一張圖介紹，其中一軸為搔癢強度，另一軸為自家趨化素活性，當搔癢強度增加時，一般而言，自家趨化素活性也增加。
　　
　　Kremer醫師表示，我們發現這兩個參數之間有適度關聯。
　　
　　他指出，對組織胺、胰蛋白酶和膽鹽進行類似的分析後，並未顯示和搔癢強度之間有任何關聯。
　　
　　研究者也顯示，當開始使用經鼻膽道引流治療之後，搔癢強度降低，自家趨化素值也降低。
　　
　　研究者也檢測了3、7-二羥基膽鹽(3,7-dihydroxy-bile salts)對自家趨化素活性的影響，因為這些膽鹽量在末期肝病、搔癢情況消失時更顯著。
　　
　　荷蘭團隊進行的體外研究中，自家趨化素活性被3、7-二羥基膽鹽chenodeoxycholate和ursodeoxycholate、和它們的glyco-conjugates與tauroconjugates抑制，Kremer醫師報告指出，將具有生物功能之水解磷酸酯、Lisophosphatidic acid經皮注射到老鼠體內可誘發搔癢反應。
　　
　　Kremer醫師表示，自家趨化素與各種膽道阻塞異常病患的搔癢嚴重度有關，膽鹽則無，3、7-二羥基膽鹽對自家趨化素之抑制可能是因為肝病末期時，搔癢症難以理解的改善。
　　
　　Kremer醫師被問到關於自家趨化素活性和搔癢強度之間的適度關聯，他表示，這無損於其團隊發現的強度。
　　
　　更令人驚訝的是，究竟有任何關聯。
　　
　　EASL 秘書長、德國漢諾瓦醫學院胃腸肝臟與內分泌科助理教授、資深醫師、Heiner Wedemeyer醫師向Medscape Gastroenterology表示，聚焦在自家趨化素對許多病患有所幫助。
　　
　　他表示，這是一個可以解釋搔癢症的重要的新分子，搔癢症是膽管阻塞型肝病中被低估的症狀，病患實際上飽受此症之苦，它一般相當嚴重。
　　
　　Wedemeyer醫師主張，我們總是討論存活率、癌症與病毒，但是，這也很重要，因此，任何探討搔癢症之可能機轉的研究也相當重要。我認為這是一大進步。
　　
　　該研究並未接受相關商業財經補助，Kremer醫師和Wedemeyer醫師都宣告沒有相關財務關係。
　　
　　歐洲肝臟研究協會(EASL)第45屆年會，發表於2010年4月15日。  


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.