Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis

Maria, Vasco A. J.; Pinto, Lígia A.; Victorino, Rui M. M.

doi:10.1016/s0168-8278(05)80388-5

Cited by 45 publications

(25 citation statements)

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“…Serological assessments for toxic drug metabolites are limited to a few drugs, and they have uncertain clinical correlations [161,162]. Immunological tests, such as the lymphocyte transformation test, have high specificity but low sensitivity [163][164][165][166]. Clinical judgment is the timehonored basis for diagnosis, but decisions based on ''guilt by association'' can be flawed [167].…”

Section: Diagnosis and Assessments Of Causalitymentioning

confidence: 99%

Drug-Induced Autoimmune-Like Hepatitis

2011

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The clinical phenotype of classical autoimmune hepatitis can be mimicked by idiosyncratic drug-induced liver injury, and differentiation can be difficult. The goals of this review are to enumerate the major agents of drug-induced autoimmune-like hepatitis, describe the clinical findings and risk factors associated with it, detail the clinical tools by which to assess causality, discuss putative pathogenic mechanisms, and describe treatment and outcome. The frequency of drug-induced autoimmune-like hepatitis among patients with classical features of autoimmune hepatitis is 9%. Minocycline and nitrofurantoin are implicated in 90% of cases. Female predominance, acute onset, and absence of cirrhosis at presentation are important clinical manifestations. Genetic factors affecting phase I and phase II transformations of the drug, polymorphisms that protect against cellular oxidative stress, and human leukocyte antigens that modulate the immune response may be important pathogenic components. Clinical judgment is the mainstay of diagnosis as structured diagnostic methods for drug-induced liver injury are imperfect. The covalent binding of a reactive drug metabolite to a hepatocyte surface protein (commonly a phase I or phase II enzyme), formation of a neoantigen, activation of CD8 T lymphocytes with nonselective antigen receptors, and deficient immune regulatory mechanisms are the main bases for a transient loss of self-tolerance. Discontinuation of the offending drug is the essential treatment. Spontaneous improvement usually ensues within 1 month. Corticosteroid therapy is warranted for symptomatic severe disease, and it is almost invariably effective. Relapse after corticosteroid withdrawal probably does not occur, and its absence distinguishes drug-induced disease from classical autoimmune hepatitis.

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Section: Diagnosis and Assessments Of Causalitymentioning

confidence: 99%

Drug-Induced Autoimmune-Like Hepatitis

2011

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“…at the extremes of the spectrum of DILI probability, namely cases † Normalization Å decrease to values below 21 the upper limit of normal with a high degree of suspicion (based on a highly consistent tempo- [13][14][15][16] Three experts in DILI, including two specialists in hepatology and a specialist in internal medicine, classified independently the Statistical Analysis 50 cases of the sample in 1 of 5 degrees of probability: definite, Data were analyzed using contingency tables. To test agreement probable, possible, unlikely, and excluded.…”

Section: Preexisting Liver Diseasementioning

confidence: 99%

“…These data suggest tivity. [13][14][15][16] In spite of significant improvements in the underthat the scale is suitable for use in clinical practice and may standing of the metabolic and immunological basis of contribute to overcome the difficulties in the process of causal-DILI, 14,15,17,18 the diagnosis still is dependent predominantly ity assessment in DILI. (HEPATOLOGY 1997;26:664-669.)…”

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confidence: 99%

Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis

1997

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to more severe or chronic forms of the disease 5,6 and avoid The objective of this study is to present and validate a the occurrence of new episodes, including some cases of clinical scale for the diagnosis of drug-induced liver injury fulminant hepatic failure. 7 (DILI). Five components were selected to be included in the Because there are no specific markers or tests for DILI, the scale: temporal relationship between drug intake and the ondiagnosis is usually based on circumstantial evidence. 8 It set of clinical picture, exclusion of alternative causes, extraherelies on a great deal of speculation by the clinician, the patic manifestations, rechallenge or accidental re-exposure, collection of a detailed pharmacological history, the estaband previous report in medical literature. The relative imporlishment of a consistent relationship between drug intake tance of each component was weighed, and arbitrary scores and the onset of the clinical picture, and the exclusion of were attributed. The probability of the diagnosis of DILI was alternative causes. Clinical improvement following drug expressed as a final score, which could vary from 06 to 20.withdrawal is another element that may indicate a drugContent validity, criterion validity, construct validity, and inrelated cause, although there is an increased recognition of ter-rater reliability were studied. To analyze validity and reliaprolonged cholestatic hepatitis, sometimes lasting for more bility, a random sample of 50 cases of suspected DILI was than 6 months, after drug withdrawal. 9 Rechallenge is fredrawn from a series of 120 cases reported to our unit. The quently considered to be the most reliable test in the diagnoclassification of the 50 cases by three experts in DILI was sis of suspected cases of DILI, 10 but it is clearly dangerous used as the external standard in the study of criterion validity.and is best avoidable. 7 Agreement between the scale and the standard, and agreement This complex process of diagnosis usually requires an exbetween two independent raters (inter-rater reliability) was perienced clinician who is deeply aware of the critical compoanalyzed by weighted k coefficient. There was agreement benents to be weighed for an accurate diagnosis, including a tween the scale and the standard in 42 cases (84%) with a good knowledge of the published literature. The translation weighted k coefficient of 0.90. A good discriminatory capacity of such experience and subjective clinical judgment into a of the scale was found when construct validity was studied.quantitative measurement to define, by more objective criteAgreement between raters was observed in 86% of the cases, ria, the probability of an adverse event being related to a corresponding to the weighted k of 0.93. In conclusion, the drug, is of major importance. The complexity of the clinical clinical scale was shown to have a high-level of validity and diagnosis has led to attempts to improve in vitro diagnostic inter-rater reliability as well as a good discriminatory capacity tests to...

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“…Lymphocytes are sensitized not to the parent compound, but toward haptens or metabolites, which are not available for the in vitro test [25,[28][29][30]. 2.…”

mentioning

confidence: 99%

Diagnostic relevance of the lymphocyte transformation test for sensitization to beryllium and other metals (IUPAC Technical Report)

Klein¹,

Schwenk²,

Heinrich‐Ramm³

et al. 2004

Pure and Applied Chemistry

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The lymphocyte transformation test (LTT) has been proven useful especially in the diagnosis of drug-induced allergic disorders. It is an in vitro test which is based on the fact that lymphocytes, which have been sensitized by a certain antigen, transform into blasts and proliferate when they are again exposed to this antigen. This proliferation is determined by measurement of the incorporation of [3H ]-thymidine or bromodeoxyuridine into replicating DNA. The test has the advantage over skin tests of avoiding re-exposure of individuals, and it was, therefore, hoped that it may also help to diagnose metal allergies and especially sensitization toward beryllium. However, the LTT measures only the sensitization of lymphocytes, but not the effector reaction, i.e., there may be positive results in exposed individuals even in the absence of clinical symptoms. There are several reports evaluating the LTT toward gold salts (Au), amalgam (Hg), nickel (Ni), beryllium (Be), and several other metals. With metals other than Be, the LTT appears to be of little use. In contrast, the LTT with Be may, indeed, define patients at risk of developing chronic beryllium disease (CBD), which affects mainly the respiratory tract and may even cause death. Beryllium sensitization progresses to CBD at a rate of 7-11 % per year. Since the Be-LTT can detect sensitization in workers who have not yet developed a disease it is an important diagnostic tool to detect individuals at risk. In conclusion, the LTT can detect a cell-mediated immunological response of an individual to metals. However, for most metals its usefulness is questionable, with the exception of Be; a positive Be-LTT can identify not only patients with CBD, but also persons at risk of developing CBD in later years.

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Lymphocyte reactivity to ex-vivo drug antigens in drug-induced hepatitis

Cited by 45 publications

References 18 publications

Drug-Induced Autoimmune-Like Hepatitis

Drug-Induced Autoimmune-Like Hepatitis

Development and validation of a clinical scale for the diagnosis of drug-induced hepatitis

Diagnostic relevance of the lymphocyte transformation test for sensitization to beryllium and other metals (IUPAC Technical Report)

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