Skip to main content
PMC home page
Gut logoLink to Gut
. 1997 Oct;41(4):534–540. doi: 10.1136/gut.41.4.534

Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury

V Maria 1, R Victorino 1
PMCID: PMC1891538  PMID: 9391255

Abstract

Background—Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC). 
Aim—To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor. 
Patients—Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs. 
Methods—Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by 3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI). 
Results—When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI>2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC. 
Conclusions—This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis. 



Keywords: drug induced hepatitis; drug hypersensitivity; specific T cells; prostaglandin E2; suppressor cells; diagnostic tests

Full Text

The Full Text of this article is available as a PDF (153.0 KB).

Figure 1 .

Figure 1

Open in a new tab

: Lymphocyte stimulation indexes in patients and controls (A) in the presence of the suspected drug and (B) in the presence of the suspected drug and a prostaglandin inhibitor. The numbers in brackets represent the stimulation indexes of cases that fall outside the scale. The horizontal line represents the level of stimulation index above which results are considered positive. 


Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ballardini G., Mirakian R., Bianchi F. B., Pisi E., Doniach D., Bottazzo G. F. Aberrant expression of HLA-DR antigens on bileduct epithelium in primary biliary cirrhosis: relevance to pathogenesis. Lancet. 1984 Nov 3;2(8410):1009–1013. doi: 10.1016/s0140-6736(84)91108-5. [DOI] [PubMed] [Google Scholar]
  2. Berg P. A., Becker E. W. The lymphocyte transformation test--a debated method for the evaluation of drug allergic hepatic injury. J Hepatol. 1995 Jan;22(1):115–118. doi: 10.1016/0168-8278(95)80270-3. [DOI] [PubMed] [Google Scholar]
  3. Betz M., Fox B. S. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991 Jan 1;146(1):108–113. [PubMed] [Google Scholar]
  4. Brod S. A., Benjamin D., Hafler D. A. Restricted T cell expression of IL-2/IFN-gamma mRNA in human inflammatory disease. J Immunol. 1991 Aug 1;147(3):810–815. [PubMed] [Google Scholar]
  5. Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990 Sep;11(2):272–276. doi: 10.1016/0168-8278(90)90124-a. [DOI] [PubMed] [Google Scholar]
  6. Cattral M. S., Altraif I., Greig P. D., Blendis L., Levy G. A. Toxic effects of intravenous and oral prostaglandin E therapy in patients with liver disease. Am J Med. 1994 Oct;97(4):369–373. doi: 10.1016/0002-9343(94)90305-0. [DOI] [PubMed] [Google Scholar]
  7. Danan G. Causality assessment of drug-induced liver injury. Hepatology Working Group. J Hepatol. 1988 Aug;7(1):132–136. doi: 10.1016/s0168-8278(88)80517-8. [DOI] [PubMed] [Google Scholar]
  8. Davies M. H., Harrison R. F., Elias E., Hübscher S. G. Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis. J Hepatol. 1994 Jan;20(1):112–116. doi: 10.1016/s0168-8278(05)80476-3. [DOI] [PubMed] [Google Scholar]
  9. DeLeve L. D., Kaplowitz N. Mechanisms of drug-induced liver disease. Gastroenterol Clin North Am. 1995 Dec;24(4):787–810. [PubMed] [Google Scholar]
  10. Fink A., Eliraz A., Bruderman I., Wishnitzer R., Shindler D., Shani A., Offer S., Harpaz N., Bentwich Z. A computerized tube leukocyte adherence inhibition assay in the diagnosis of human lung cancer. Diagn Immunol. 1985;3(4):171–176. [PubMed] [Google Scholar]
  11. Foley P., Kazazi F., Biti R., Sorrell T. C., Cunningham A. L. HIV infection of monocytes inhibits the T-lymphocyte proliferative response to recall antigens, via production of eicosanoids. Immunology. 1992 Mar;75(3):391–397. [PMC free article] [PubMed] [Google Scholar]
  12. Goodwin J. S., Messner R. P., Bankhurst A. D., Peake G. T., Saiki J. H., Williams R. C., Jr Prostaglandin-producing suppressor cells in Hodgkin's disease. N Engl J Med. 1977 Nov 3;297(18):963–968. doi: 10.1056/NEJM197711032971802. [DOI] [PubMed] [Google Scholar]
  13. Goodwin J. S., Webb D. R. Regulation of the immune response by prostaglandins. Clin Immunol Immunopathol. 1980 Jan;15(1):106–122. doi: 10.1016/0090-1229(80)90024-0. [DOI] [PubMed] [Google Scholar]
  14. Gómez-Lechón M. J., Carrasquer J., Berenguer J., Castell J. V. Evidence of antibodies to erythromycin in serum of a patient following an episode of acute drug-induced hepatitis. Clin Exp Allergy. 1996 May;26(5):590–596. [PubMed] [Google Scholar]
  15. Hagley M. T., Benak R. L., Hulisz D. T. Suspected cross-reactivity of enalapril- and captopril-induced hepatotoxicity. Ann Pharmacother. 1992 Jun;26(6):780–781. doi: 10.1177/106002809202600607. [DOI] [PubMed] [Google Scholar]
  16. Hasler F., Bluestein H. G., Zvaifler N. J., Epstein L. B. Analysis of the defects responsible for the impaired regulation of EBV-induced B cell proliferation by rheumatoid arthritis lymphocytes. II. Role of monocytes and the increased sensitivity of rheumatoid arthritis lymphocytes to prostaglandin E. J Immunol. 1983 Aug;131(2):768–772. [PubMed] [Google Scholar]
  17. Hofer T., Becker E. W., Weigand K., Berg P. A. Demonstration of sensitized lymphocytes to trimethoprim/sulfamethoxazole and ofloxacin in a patient with cholestatic hepatitis. J Hepatol. 1992 May;15(1-2):262–263. doi: 10.1016/0168-8278(92)90045-q. [DOI] [PubMed] [Google Scholar]
  18. Ishii M., Miyazaki Y., Yamamoto T., Miura M., Ueno Y., Takahashi T., Toyota T. A case of drug-induced ductopenia resulting in fatal biliary cirrhosis. Liver. 1993 Aug;13(4):227–231. doi: 10.1111/j.1600-0676.1993.tb00635.x. [DOI] [PubMed] [Google Scholar]
  19. Liblau R. S., Singer S. M., McDevitt H. O. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today. 1995 Jan;16(1):34–38. doi: 10.1016/0167-5699(95)80068-9. [DOI] [PubMed] [Google Scholar]
  20. Maria V. A., Pinto L. A., Victorino R. M. Inhibition of lymphocyte proliferation induced in vitro by microbial antigens in HIV-infected subjects. J Med Virol. 1991 Dec;35(4):241–245. doi: 10.1002/jmv.1890350406. [DOI] [PubMed] [Google Scholar]
  21. Maria V. A., Pinto L., Victorino R. M. Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis. J Hepatol. 1994 Aug;21(2):151–158. doi: 10.1016/s0168-8278(05)80388-5. [DOI] [PubMed] [Google Scholar]
  22. Maria V. A., Victorino R. M. Hypersensitivity immune reaction as a mechanism for dilevalol-associated hepatitis. Ann Pharmacother. 1992 Jul-Aug;26(7-8):924–926. doi: 10.1177/106002809202600713. [DOI] [PubMed] [Google Scholar]
  23. Maria V. A., da Silva J. A., Victorino R. M. Agranulocytosis and liver damage associated with pyrazinobutazone with evidence for an immunological mechanism. J Rheumatol. 1989 Nov;16(11):1484–1485. [PubMed] [Google Scholar]
  24. Miyamoto T., Maeda T., Onishi S., Yamamoto Y. T cell autoreactivity against a 28 kD biliary protein (B1-p28) in primary biliary cirrhosis. J Hepatol. 1995 Apr;22(4):423–430. doi: 10.1016/0168-8278(95)80105-7. [DOI] [PubMed] [Google Scholar]
  25. Park B. K., Pirmohamed M., Kitteringham N. R. Idiosyncratic drug reactions: a mechanistic evaluation of risk factors. Br J Clin Pharmacol. 1992 Nov;34(5):377–395. doi: 10.1111/j.1365-2125.1992.tb05647.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pessayre D. Role of reactive metabolites in drug-induced hepatitis. J Hepatol. 1995;23 (Suppl 1):16–24. [PubMed] [Google Scholar]
  27. Phipps R. P., Stein S. H., Roper R. L. A new view of prostaglandin E regulation of the immune response. Immunol Today. 1991 Oct;12(10):349–352. doi: 10.1016/0167-5699(91)90064-Z. [DOI] [PubMed] [Google Scholar]
  28. Pohl L. R. Drug-induced allergic hepatitis. Semin Liver Dis. 1990 Nov;10(4):305–315. doi: 10.1055/s-2008-1040486. [DOI] [PubMed] [Google Scholar]
  29. Rotmensch H. H., Leiser A., Dan M., Klejman A., Livni E., Ilie B., Messer G., Kadish U., Liron M. Evaluation of prajmalium-induced cholestasis by immunologic tests. Arch Intern Med. 1981 Dec;141(13):1797–1801. doi: 10.1001/archinte.141.13.1797. [DOI] [PubMed] [Google Scholar]
  30. Simon A. K., Seipelt E., Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci U S A. 1994 Aug 30;91(18):8562–8566. doi: 10.1073/pnas.91.18.8562. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tsujii H., Okamoto Y., Kikuchi E., Matsumoto M., Nakano H. Prostaglandin E2 and rat liver regeneration. Gastroenterology. 1993 Aug;105(2):495–499. doi: 10.1016/0016-5085(93)90725-r. [DOI] [PubMed] [Google Scholar]
  32. Tsutsui H., Terano Y., Sakagami C., Hasegawa I., Mizoguchi Y., Morisawa S. Drug-specific T cells derived from patients with drug-induced allergic hepatitis. J Immunol. 1992 Jul 15;149(2):706–716. [PubMed] [Google Scholar]
  33. Victorino R. M. Indomethacin sensitive suppressor cells in Crohn's disease: a possible role in decreased lymphocyte responsiveness. J Clin Lab Immunol. 1983 Aug;11(4):197–201. [PubMed] [Google Scholar]
  34. Victorino R. M., Maria V. A., Correia A. P., de Moura C. Floxacillin-induced cholestatic hepatitis with evidence of lymphocyte sensitization. Arch Intern Med. 1987 May;147(5):987–989. [PubMed] [Google Scholar]
  35. Victorino R. M., Maria V. A. Drug-induced hepatitis and lymphocyte transformation test in presence of prostaglandin inhibitor. Lancet. 1986 May 24;1(8491):1209–1210. doi: 10.1016/s0140-6736(86)91187-6. [DOI] [PubMed] [Google Scholar]
  36. Victorino R. M., Maria V. A., Pinto L. A. Evidence for prostaglandin-producing suppressor cells in drug-induced liver injury and implications in the diagnosis of drug sensitization. Clin Exp Immunol. 1992 Jan;87(1):132–137. doi: 10.1111/j.1365-2249.1992.tb06426.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Walton B., Dumonde D. C., Williams C., Jones D., Strunin J. M., Layton J. M., Strunin L., Simpson R. Lymphocyte transformation. Absence of increased responses in alleged halothane jaundice. JAMA. 1973 Jul 30;225(5):494–498. doi: 10.1001/jama.225.5.494. [DOI] [PubMed] [Google Scholar]
  38. de Gruijl T. D., Moore J. J., de Vries E., von Blomberg-van der Flier B. M., Fonk J. C., Scheper R. J. Augmentation of antigen-specific lymphoproliferative responses in vitro by biological response modifiers. Clin Exp Immunol. 1994 Jun;96(3):535–540. doi: 10.1111/j.1365-2249.1994.tb06062.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Gut are provided here courtesy of BMJ Publishing Group

RESOURCES