JOURNAL OF INTERFERON AND CYTOKINE RESEARCH 18:21-22 (1998)Mary Ann Liebert, Inc. SHORT COMMUNICATION

Histamine and the Response to IFN-a in Chronic Hepatitis C

KRISTOFFER HELLSTRAND, MATS BRUNE, ULF-HENRIK MELLQVIST, GUNNAR NORKRANS,PER-ARNE LUNDBERG, SVANTE HERMODSSON, and RUNE WEJSTÂL

ABSTRACT

Whole blood concentrations of histamine were examined in 20 patients with chronic hepatitis C after long-term treatment with interferon-a (IFN-a). In 13 of these patients, a transient (n = 5) or sustained (n = 8)normalization of liver enzymes and elimination of viral RNA were noted at the end of therapy. Seven patientsdid not respond to IFN-a. Nonresponding patients had significantly lower histamine levels in blood than tran-sient (p = 0.0005) or sustained (p = 0.04) responders. Histamine levels were not different in patients with asustained vs. a transient IFN response. Confounding factors, such as ongoing viral replication or liver cir-rhosis, did not account for the differences in histamine levels. Our data suggest that hypohistaminism in pe-ripheral blood may determine a poor response to IFN-a in chronic hepatitis C.

The efficacy of iNTERFERON-a (IFN-a) in chronic hepatitisC is well documented.'1' The benefit of IFN-a has been at-

tributed to antiviral and T cell-modulating effects, but recentstudies suggest a significant contribution also by IFN-a-acti-vated natural killer (NK) cells. Van Thiel et al. demonstratedthat IFN-a activates NK cells within the liver parenchyma onlyin patients with a transient or complete clinical response to IFN-a,'2) and Donahue et al. reported that a high degree of NK cellactivation during the first days of IFN-a therapy determines a

favorable outcome of treatment.'3'Histamine, a biogenic amine stored in mast cells and ba-

sophilic leukocytes, effectively augments NK cell-mediated de-struction of foreign cells in vitro and in vivo. Histamine acti-vates NK cells in synergy with other NK cell activators, suchas IFN-a.'4) Indeed, IFN-a therapy in humans is remarkably ef-fective in myeloproliferative disorders, such as polycythemiavera, essential thrombocythemia, and chronic myelogenousleukemia, all of which are characterized by pronounced hyper-histaminism in peripheral blood.'5,6'

With this background, we asked if there is any associationbetween the levels of histamine in blood and the therapeutic re-

sponse to IFN-a. Whole blood levels of histamine were mea-

sured in 20 patients with chronic hepatitis C (mean age 41 years,range 29-79) after therapy with IFN-a (3 MIU thrice weeklyfor up to 14 months, mean 7.2 months). Thirteen of the patientsresponded with normalized liver enzymes and clearance of vi-ral RNA from serum at the end of treatment. Seven patients didnot respond to IFN-a (nonresponders). Five of the respondingpatients relapsed within 6 months after cessation of therapy

(transient responders). The IFN-a response was sustained in 8patients (sustained responders).

Histamine levels were measured at a mean of 2 years afterIFN-a therapy. The duration of clinical hepatic disease, the du-ration of IFN-a therapy, or the time from completion of IFN-a therapy to histamine analysis did not differ significantlyamong the three patient groups. It was found that whole bloodhistamine levels in nonresponding patients were significantlylower than in responding patients (nonresponders vs. transientresponders: p = 0.0005; nonresponders vs. sustained respon-ders: p = 0.04; nonresponders vs. all responding patients: p =

0.006; Student's Mest, two sided) (Fig. 1). Histamine levelswere not significantly different in transient responders as com-

pared with sustained responders (p = 0.2).Several factors, including liver cirrhosis, viral load, and vi-

ral genotype, predict a poor response to IFN-a in hepatitis C,'1'and the low histamine levels in nonresponders may relate tothese confounding factors rather than responsiveness to IFN-a.Our data suggest that the extent of liver damage or ongoing vi-ral replication at the time of histamine determination did notaccount for the observed differences, as (1) incipient or mani-fest liver cirrhosis was noted in 2 of 7 nonresponding patientsand in 5 of 13 responders, and (2) histamine levels were con-

siderably lower in nonresponders than in patients with only a

transient response, although both these groups of patients hadongoing viral replication.

The lack of difference in histamine levels between transientresponders vs. sustained responders and the significantly lowerlevels in nonresponders vs. transient responders suggest that a pu-

Departments of Virology, Hematology, Clinical Chemistry, and Infectious Diseases, University of Göteborg, Sweden.

21

22 HELLSTRAND ET AL.

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responders non-respondersFIG. 1. Data points are whole blood histamine levels in pa-tients with chronic hepatitis C after treatment with IFN-a. His-tamine was assayed using a coated tube radioimmunoassay (Im-munotech, ref. No. 1659). The intraassay and interassayvariability was consistently less than 5%. Histamine levels inpatients with sustained response (filled squares, n = 8); withtransient response (filled triangles, n = 5). Histamine levels innonresponding patients (open circles, n = 7).

tative role of histamine is confined to the early response to TFN-a rather than to maintaining the response. The question whetherhistamine in blood determines the therapeutic efficacy of IFN-ain hepatitis C needs to be addressed in a prospective study.

ACKNOWLEDGMENTS

This study was supported by the Swedish Medical ResearchCouncil, the Swedish Society against Cancer, and Maxim Phar-maceuticals, Inc., San Diego, CA. We are indepted to Prof. Or-jan Strannegârd for advice.

REFERENCES

1. WEILAND, O. (1994). Interferon therapy in chronic hepatitis Cvirus infection. FEMS Microbiol. Rev. 14, 279-288.

2. VAN THIEL, D.H., ZHANG, X., and BADDOUR, N. (1994). In-trahepatic mononuclear cell populations and MHC antigen expres-sion in patients with chronic hepatitis C. Effect of interferon-a. Dig.Dis. Sei. 39, 970-976.

3. DONAHUE, S.M., WONKE, B., and HOFFBRAND, A.V. (1993).Alpha interferon in the treatment of chronic hepatitis C infection inthalassemia major. Br. J. Haematol. 83, 491^197.

4. HELLSTRAND, K., ASEA, A., DAHLGREN, C, and HER-MODSSON, S. (1994). Histaminergic regulation of natural killercell function: role ofmonocyte-derived reaction oxygen metabolites.J. Immunol. 153, 4940-4947.

5. GILBERT, H.S., WARNER, R.R.P., and WASSERMAN, L.R.(1996). A study of histamine in myeloproliferative disease. Blood28, 795-805.

6. HELLSTRAND, K., BRUNE, M., MELLQVIST, U.-H., andNAREDI, P. (1996). Histamine, cimetidine and colorectal cancer.Nature Med. 2, 364-365.

Address reprint requests to:Kristoffer Hellstrand

Department of VirologyUniversity of Göteborg

Guldhedsgatan ¡0BS-413 46 Göteborg

Sweden

Received 6 January 1997/Accepted 16 September 1997