Discussion
iDILI is best defined as a rare, dose-independent adverse hepatic reaction that is unexpected on the basis of the pharmacological action of the administered drug.7 Similarly, the hepatic metabolism of OC is deemed negligible.3 4 The pathogenesis of iDILI is poorly understood, but could likely arise from complex interactions between genetic, non-genetic and environmental factors including drug–drug interactions.8 Recently, it has been suggested that a common human leucocyte antigen phenotype promotes both MS and iDILI and may help to explain the increased incidence of iDILI found in patients with MS.9
In the present case, OC in combination with high-dose steroids during the first treatment cycle, but not without steroids during the second treatment cycle, led to moderate, hepatocellular iDILI, which was diagnosed based on clinical chemistry, liver biopsy findings and after ruling out other differential diagnoses including autoimmune hepatitis.7
Regarding causality assessment, we used the updated RUCAM score which is a point-based, standardised and validated tool to estimate the likelihood that iDILI is due to OC or prednisolone treatment.7 Liver injury was classified as hepatocellular according to an ALT/ALP R-ratio of >5.7 Considering the negative re-exposure test for OC (−2 points) and the higher points of OC than for oral prednisolone (+2 vs +1 points) for officially labelled drug hepatotoxicity, a RUCAM score of +4 was calculated for OC and +5 for prednisolone, indicating a possible relationship between each drug and iDILI.7 Hepatotoxicity of OC, but not of oral prednisolone, has been officially labelled in the product characteristics in Germany. The higher RUCAM score of prednisolone compared with OC suggests a higher likelihood that prednisolone, rather than OC, was the precipitating factor in the development of iDILI. In fact, pulsed high-dose treatment with the steroid MP, which is structurally closely related to prednisolone, has prospectively been shown to cause liver injury in up to 8.6% of patients treated for MS10 which is a much higher rate than the estimated incidence of OC-associated liver injury of 1:1000 based on UK pharmacovigilance register data.5 Yet, no public information about concomitant steroid treatment is available in the register.
The RUCAM score of +4 we calculated for OC is significantly lower than that of +6 reported by the only published case report on suspected OC-induced iDILI.3 However, no re-exposure test was available in that case report resulting in a higher RUCAM score. Interestingly, the authors excluded previous high-dose MP treatment in their patient as a possible cause of iDILI and did not report the respective RUCAM score. In their opinion, a steroid-induced liver injury was unlikely due to the time lag of 6 weeks after MP administration. It should be noted, however, that a delayed onset of hepatotoxicity of up to 84 days after high-dose MP exposure has already been described in MS and other neurological patients.9–12
We cannot rule out the possibility that interactions between prednisolone and OC may have fostered development of iDILI rather than OC or prednisolone treatment itself. Indeed, several drug–drug interactions have been shown to influence the incidence and/or the severity of iDILI in an in vitro study using monocyte-derived hepatocyte-like cells from 48 patients with iDILI.13 Most iDILI events are thought to be mediated by the adaptive immune system which is activated by the respective drug, its metabolites or sublethal cell stress.13 Even though the exact mechanism remains speculative, it has been hypothesised that drug–drug interactions may lead to a delayed and prolonged immune activation causing iDILI.13 A relationship between the contraceptive oestrogen pill and iDILI seems unlikely because the former was also taken during the negative re-exposure test. The role of the interferon appears to be negligible, as it was discontinued approximately 2 months before OC intake.
In conclusion, OC is a highly efficient treatment option in MS with a favourable overall safety profile. However, concerns have been raised about the hepatotoxic potential of OC in some patients. In our case of iDILI associated with OC and steroid cotreatment, prednisolone received a higher causality score for the development of iDILI than OC. Our case study underlines the need for more information about concomitant steroid exposure in cases of liver injury attributed to OC treatment as well as potential drug–drug interactions with prednisolone and OC.