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Eur J Gastroenterol Hepatol. 2012 Apr;24(4):427-30. doi: 10.1097/MEG.0b013e3283509197.

Hepatic Methionine-enkephalin may interfere with response to antiviral therapy in chronic hepatitis C.

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Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy.



The immunoreactivity of methionine-enkephalin (Met-enkephalin), one of the endogenous opioid peptides, is expressed in the liver in different types of chronic diseases. This finding suggests that the liver may be a source of endogenous opioids in disease state. In-vitro studies have shown that morphine, which exerts its effect by binding to opioid receptors, enhances hepatitis C virus replication and that it interferes with the antiviral effects of interferon. Thus, it was hypothesized that liver-derived endogenous opioids, which also bind to opioid receptors, may interfere with the response to antiviral therapy with interferon.


To correlate the expression of Met-enkephalin immunoreactivity (MEIR) in the liver of patients with chronic hepatitis C with their response to treatment with pegylated interferon and ribavirin.


We sought to investigate the expression of the immunoreactivities of Met-enkephalin and of the δ-opioid receptor 1 (DOR1), to which Met-enkephalin binds, preferentially, in liver samples from 23 patients with chronic hepatitis C who had undergone antiviral therapy. Twelve patients obtained a sustained virological response, and 11 patients were relapsers after or nonresponders to treatment. Among the 12 patients with sustained virological response, one patient (8.3%) expressed MEIR and another one expressed DOR1 immunoreactivity (8.3%), whereas none of the patients expressed both immunoreactivities. Among the group of nonresponders/relapsers, one patient expressed MEIR (9%), two patients expressed DOR1 immunoreactivity (18.2%), and seven patients expressed both (63.6%). The difference between responders and nonresponders in the expression of both immunoreactivities was significantly different (P<0.001).


Our data are in favor of the hypothesis that enhanced expression of MEIR and DOR1 immunoreactivity correlates with poor response to antiviral therapy that includes interferon. Thus, this study provides a rationale to study the effect of opiate antagonists in combination with antiviral therapy with interferon and ribavirin in patients who express MEIR in the liver and who have not responded to or who have relapsed after treatment with those antiviral medications.

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