Acute Liver Failure in a Patient Treated With Metamizole

Diagnosis of drug hypersensitivity is difficult, as an enormous amount of different drugs can elicit various immune-mediated diseases with distinct pathomechanism. The lymphocyte transformation test (LTT) measures the proliferation of T cells to a drug in vitro--from which one concludes to a previous in vivo reaction due to a sensitization. This concept of the LTT has been confirmed by the generation of drug-specific T-cell clones and the finding that drugs can directly interact with the T-cell receptor, without previous metabolism or need to bind to proteins. In this review, technical aspects and usefulness of this test for the diagnosis of drug hypersensitivity are discussed. The main advantage of this test is its applicability with many different drugs in different immune reactions, as drug-specific T cell are almost always involved in drug hypersensitivity reactions. Its main disadvantages are that an in vitro proliferation of T cells to a drug is difficult to transfer to the clinical situation and that the test per se is rather cumbersome and technically demanding. In addition, its sensitivity is limited (for beta-lactam allergy it is in the range of 60-70%), - although at least in our hands - it is higher than of other tests for drug hypersensitivity diagnosis. Consequently, drug hypersensitivity diagnosis needs to rely on a combination of history and different tests, as none of the single tests available has per se a sufficiently good sensitivity. Within this setting, the LTT has proven to be a useful test for the diagnosis of drug hypersensitivity reactions and helped to better understand these reactions. Further work on the simplification of this test and systematic evaluation of its sensitivity and specificity in some main groups of drugs are necessary to make this test more widely available. Show more

Drug-induced mitochondrial dysfunction has been hypothesized to be an important determining factor in the onset of drug-induced liver injury. It is essential to develop robust screens with which to identify drug-induced mitochondrial toxicity and to dissect its role in hepatotoxicity. In this study we have characterised a mechanistically refined HepG2 model, using a panel of selected hepatotoxicants and non-hepatotoxicants. We have demonstrated that acute metabolic modification, via glucose-deprivation over a 4 h period immediately prior to compound addition, is sufficient to allow the identification of drugs which induce mitochondrial dysfunction, in the absence of cell death over a short exposure (2-8 h) using a plate-based screen to measure cellular ATP content and cytotoxicity. These effects were verified by measuring changes in cellular respiration, via oxygen consumption and extracellular acidification rates. Overall, these studies demonstrate the utility of HepG2 cells for the identification of mitochondrial toxins which act directly on the electron transport chain and that the dual assessment of ATP content alongside cytotoxicity provides an enhanced mechanistic understanding of the causes of toxicity. Show more

Agranulocytosis is a potentially lethal adverse drug reaction of dipyrone (metamizole). According to case-control studies, the frequency is low, approximately one per million users. The aim of the study was to describe the pattern of blood dyscrasias associated with dipyrone, identify possible risk factors and calculate the incidence of agranulocytosis associated with dipyrone. All spontaneous reports of serious blood dyscrasias associated with dipyrone in Sweden were reviewed. The reports were scrutinised for additional information, including bone marrow findings. The reported incidence of agranulocytosis was estimated from total prescription sales of dipyrone. The reported incidence of agranulocytosis with dipyrone in Sweden was estimated to be at least 1:1439 (95% confidence interval 1:850, 1:4684) prescriptions. Ninety-two percent of the cases of blood dyscrasias occurred during the first 2 months of treatment. Additional risk factors were identified in 36% of the patients. In a total of five cases of which four were fatal, all three haematopoieses were affected according to bone marrow sample findings. Among the fatal cases, a higher proportion had bi- or tricytopenia than among the non-fatal cases ( P<0.005). Based on sales data and spontaneous reporting of adverse drug reactions in Sweden, the risk of agranulocytosis with dipyrone seems to be considerably higher than the previously estimated risks. Dipyrone is also associated with other blood dyscrasias, and the prognosis for combined dyscrasias seems to be poorer than for isolated agranulocytosis. Show more