The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice☆
Introduction
Chronic liver disease, including the development of cirrhosis, has been reported with a suspect causality to a number of different drugs [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]. Information concerning development of chronic evolution originates mostly from case reports or small case series, and chronic liver disease due to drug-induced liver injury (DILI) is considered rare. In general, the outcome of severe DILI has been considered an all-or-nothing phenomenon. Thus, the liver injury may lead to either death/liver transplantation or total recovery. Only a very few studies have analyzed the long-term outcome of patients with DILI. A retrospective study on patients identified by a histological database was the first study to assess the natural history of patients who had histologically proven DILI [12]. A total of 13 out of 33 (39%) patients with a median of five-years follow-up had persistent abnormalities in their liver tests or on imaging [12]. Recently, a prospective study from the Spanish DILI Registry revealed chronic evolution in 5.7% of cases after liver injury associated with idiosyncratic drug reactions [13]. Some of these patients appeared to have clinically relevant liver injury at follow-up as three patients developed cirrhosis and some developed chronic hepatitis [13]. In a single center study undertaken to analyze the long-term outcome in terms of chronicity of DILI patients, a chronic evolution not explained by other identifiable liver diseases was found to be uncommon [14]. Although two studies have reported that chronicity following DILI is common [12] and can be serious [13], it has not been convincingly demonstrated that the perceived chronic liver injury does indeed lead to any liver-related morbidity or mortality in the long run. We have in a previous study of 784 patients with suspected DILI reported to the Swedish Adverse Drug Reactions Committee (SADRAC) investigated the prognosis of the acute phase of the reaction. All these patients had serious liver injury with concomitant jaundice [15]. In this unique cohort of well-characterized DILI patients, we were able to demonstrate approximately 10% mortality or liver transplantation immediately following the reaction [15]. In the current study we aimed to better characterize the risk for the development of chronic liver injury in the surviving patients and further analyze whether the patients have experienced clinically important end-points due to the chronic liver injury. The aim of our study was to investigate whether patients with a previously well-documented DILI at long-term follow-up had been subsequently hospitalized for liver-related diagnoses and/or died from liver disease and whether this could be attributed to the previous drug-induced liver injury.
Section snippets
Patients and methods
The results presented in the current study originate from a cohort of patients with a diagnosis of DILI reported to the SADRAC 1970-2004 [15]. Out of more than 4000 reports to SADRAC with suspected DILI, the original analysis in the previous paper was limited to patients with jaundice (bilirubin ⩾2 times upper limit of normal) [15]. Although this criteria for jaundice (or hyperbilirubinaemia) was used, the vast majority of patients had quite obvious jaundice and >80% of patients had ⩾3 times
Results
Among the 784 cases in the original cohort with either possible, probable or highly probable relationship with the suspected drug, 72 patients died from the DILI and were described in the original study. Of the 712 patients who survived the drug reaction 27 (3.8%) reports could for different reasons not be retrieved by SADRAC. Thus, we were able to link 685 patients with the Swedish Hospital Discharge and the Cause of Death Registries. Fig. 1 shows a diagram of the patients included in the
Discussion
The current study of a large number of patients with a previous diagnosis of DILI with concomitant jaundice and a long follow-up demonstrates the following: (1) development of clinically important liver disease is rare when a patient has survived a severe DILI; (2) decompensated “cryptogenic” cirrhosis developed in some patients in which DILI might have played a role in this development, although the role of DILI is not proven in this context; (3) duration of drug therapy before diagnosis of
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2022, Journal of HepatologyCitation Excerpt :Most previous studies have not reported whether the patients with “chronic DILI” developed cirrhosis or liver-related mortality.5–8,10,11 In a retrospective follow-up study from Sweden, survivors with drug-induced jaundice were analysed in terms of hospitalisation over a mean follow-up of 10 years.9 This is by far the longest follow-up study on the long-term sequelae of prolonged DILI, wherein 23/685 (3.4%) patients were hospitalised for liver disease and 5 died of liver-related causes.9
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The authors declare that they do not have anything to disclose regarding funding from industries or conflict of interest with respect to this manuscript.