The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice

doi:10.1016/j.jhep.2008.10.021

Journal of Hepatology

Volume 50, Issue 3, March 2009, Pages 511-517

https://doi.org/10.1016/j.jhep.2008.10.021 Get rights and content

Background/Aims

Chronic evolution after drug-induced liver injury (DILI) has been reported. How often this leads to liver-related morbidity and mortality is unexplored.

Methods

Patients who survived DILI and concomitant jaundice reported to the Swedish Adverse Drug Reaction Advisory Committee (1970–2004) were linked to the Swedish Hospital Discharge and Cause of Death Registries.

Results

Among the 712 survivors, 27 could not be retrieved but 685 patients could be linked to the registries, 392 females (57.2%) and 293 males (42.8%) median age 58 (41–74), a mean follow-up of 10 years. A total of 23/685 (3.4%) patients had been hospitalized for liver disease and 5 had liver-related mortality. Eight patients developed cirrhosis (7 decompensated, 5 died), 5 had “cryptogenic” cirrhosis in which DILI might have played a role in this development. Duration of therapy before DILI was longer in patients with liver-related morbidity/mortality (135 ± 31 days vs. 53 ± 3; p < 0.0001). Autoimmune hepatitis developed in 5/23 (22%), all of female gender after a mean of 5.8 years.

Conclusions

Development of clinically important liver disease after severe DILI associated with jaundice is rare after acute DILI. However decompensated “cryptogenic” cirrhosis developed in some patients with fatal outcome in which DILI might have played a role in this development.

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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Drug induced liver injury (DILI) is sometimes similar to autoimmune hepatitis (AIH) in serology and histology. Clinicians empirically screened DILI with significant autoimmune characteristics to implement clinical intervention. We tried to characterize DILI with autoantibodies by metabolomics.
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In terms of metabolic signature, DILI^Ab+ may not be a community of same pathogenesis, including AIH-inclined parts. Which deserves further study.
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Citation 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
Drug-induced liver injury (DILI) has a very variable clinical and biochemical phenotype and differs widely in severity, from mild injury to life-threatening liver failure. Chronic injury has also been reported to occur at a variable frequency, ranging from 3.4% to 39%, 6-12 months after discontinuing the implicated agent. This wide range is probably related to various definitions of chronic liver injury and variable selection of patients. The long-term sequalae of this chronic injury in terms of morbidity and mortality are unclear, although rare vanishing bile duct syndrome is associated with an unfavourable prognosis, with increased risk of chronic liver failure and need for liver transplantation. Other forms of long-term sequalae associated with DILI are progressive fibrosis, autoimmune-like hepatitis, secondary sclerosing cholangitis, sinusoidal obstruction syndrome and, as a common final stage, the development of cirrhosis, portal hypertension and its complications. Immune checkpoint inhibitors, which can cause an autoimmune-like phenotype have also recently been shown to cause sclerosing cholangitis with cytotoxic T CD8+ cell infiltration in biliary tracts. DILI has been shown to have a significant impact on health-related quality of life but very little is known about its psychological consequences in the long-term. Further investigations with structured long-term follow-up and periodic quality of life surveys are needed to assess the impact of DILI on psychological outcomes, particularly in those with chronic sequelae.
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We applied an accelerated failure time model to 294 cases collected by the International Drug-Induced Liver Network Consortium (iDILIC). Factors included in the multivariate recovery score model were selected through univariate analysis. The model was externally validated using 257 cases from the Spanish DILI Registry and 191 cases from the LiverTox database.
Higher serum bilirubin and alkaline phosphatase (ALP) at DILI onset, a longer time to onset, and non-significant drug metabolism were associated with a longer recovery and were included in the recovery score model. We defined high- and low-risk groups based on the scores assigned by the model. The estimated probability of recovery by 6 months was 0.46 (95% CI 0.26–0.61) for the high-risk group and 0.93 (95% CI 0.58–0.99) for the low-risk group in the iDILIC. Model performance was validated in both validation sets. The high- and low-risk cases identified by the model showed a significantly different time course for recovery, with a majority of low-risk cases recovering sooner.
The trajectory of biochemical recovery from DILI is predicted by the extent of drug metabolism, serum bilirubin and ALP at DILI onset. The model can be used to compute an estimated DILI recovery and, when a significant delay is predicted, clinicians may consider additional investigations such as histologic evaluation or extended follow-up.
In this study, we investigated whether drug properties and clinical factors are associated with the time it takes to recover from drug-induced liver injury (DILI). We found that total bilirubin, alkaline phosphatase level at DILI onset, time to onset, and extent of drug metabolism were consistently associated with recovery time. Using these factors, we built a model to predict the trajectory of recovery from DILI and validated this model in 2 independent cohorts. Our findings offer important insights into the factors influencing the trajectory of recovery from DILI. Additional investigations and longer follow-ups can be planned in those for whom a delayed recovery is predicted.

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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.

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The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice☆

Background/Aims

Methods

Results

Conclusions

Introduction

Section snippets

Patients and methods

Results

Discussion

J Hepatol

J Hepatol

Gastroenterology

Gastroenterology

J Hepatol

J Clin Epidemiol

J Hepatol

J Hepatol

Ramipril-associated hepatotoxicity

Arch Pathol Lab Med

Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: a case report

World J Gastroenterol

Chronic active hepatitis associated with diclofenac sodium therapy

Br J Clin Pract

Chronic hepatitis after successive halothane anesthetics

Digestion