Mapping the incidence of drug-induced liver injury worldwide: a systematic review and meta-analysis

Abstract

Background: Drug-induced liver injury (DILI), an increasing etiology of liver dysfunction in hepatology, its incidence has been variably reported worldwide. To better understand the disease burden hence make appropriate preventive and treatment strategies, we conducted this meta-analysis from global perspective.

Methods: PubMed, EMBASE, Web of Science and Cochrane Library were searched for studies on the incidence of DILI published from inception to Aug 1, 2021. According to the predefined criteria, only population-based studies were included. Incidence was calculated as cases per 100,000 person-years with its confidence interval (CI) using random effects model.

Results: A total of 31 studies were included. The overall incidence of DILI was 4.94 (95%CI: 4.05-5.83) per 100,000 person-years. Time-based cumulative meta-analysis suggested that the incidence of DILI had increased over time since 2010. It varied by regions: Asia had the highest incidence, at 17.82 (95%CI: 6.26-29.38) per 100,000 person-years, while America had the lowest, at 1.72 (95%CI: 0.48-2.95) per 100,000 person-years. All studies had a consistent result of higher incidence of DILI in elders; but comparable incidence between male and female (3.42 vs 4.64 per 100,000 person-years). As for the specific implicated drug(s), the incidence of statins induced liver injury was 11.30 (95%CI: 6.48-19.69) per 100,000 person-years, while the incidence among patients using antifungal drugs, antidepressants, paracetamol, antidiabetic, anti-tuberculosis, nonsteroidal anti-inflammatory drugs, anti-thyroid drugs and iron chelator ranged from 0.16 to 180.97 per 100,000 person-years.

Conclusions: The incidence of DILI has been increasing since 2010 worldwide, with the highest incidence in Asia. Understanding the epidemiological characteristics of DILI aids in making specific strategies to deal with the emerging health problems. 

Introduction

Drug-induced liver injury (DILI) is emerging as one of the most challenging liver diseases during daily practice. It is associated with high disease burden worldwide.¹ Actually, DILI is the main reason for the withdrawal of many drugs after their marketing.² Until now, there are only scattered reports regarding the epidemiology of DILI, but with noticeable variations. In the West, the incidence of DILI has been estimated to be 1.0 in 100,000 to 20.0 in 100,000 person-years in general population.³ In the East, the incidence of DILI has been estimated to be 12.0 in 100,000 to 23.8 in 100,000 person-years.⁴ This variation may be partly due to differences in genetic background, culprit drugs and lack of specific diagnostic biomarkers.

The most common insulting drugs for DILI were antibiotics, including anti-tuberculosis (anti-TB) drugs, Herbal and Dietary Supplement (HDS) and immune checkpoint inhibitors, etc.^5,6 DILI occurred in 5%-33% of patients with TB and affected 9%-30% of patients with human immunodeficiency virus (HIV) infection, who received either anti-TB or antiretroviral therapy.^7,8 Additionally, statins being the most widely prescribed medication could result in rare but severe idiosyncratic liver injury. A European study reported that the incidence rate of DILI is 16 per 100,000 person-years after initiation of statins,⁹ and the data from Taiwan described an incidence rate of 768 per 100,000 person-years for patients with chronic liver disease who took statins.¹⁰

Moreover, DILI accounts for up to 60% acute liver failure and 5–10% mortality, which highlighting the importance to better understand this disease, given that DILI are preventable.^11–13 Thus, to better understand the disease burden hence make appropriate preventive and treatment strategies, we conducted this systematic review and meta-analysis. Our aims were to pool the worldwide incidence of DILI together, characterize the global and regional differences, and highlight the common insulting drugs.

Method

This meta-analysis was reported according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) statement, and was registered with PROSPERO (CRD42021272634).

Data sources and search strategy

PubMed, EMBASE, Web of Science and Cochrane Library were searched from inception to Aug 1, 2021 for studies reporting the incidence of DILI, using the following keywords: drug-induced liver injury, drug toxicity, incidence, prevalence, epidemiology and frequency (Supplementary file 1 for full details about the searching strategy and result). In addition, we checked the websites of the American Association for the Study of Liver Diseases (AASLD), European Association for the Study of the Liver (EASL), Asian-Pacific Association for the study of the Liver (APASL) and International Association for the study of the Liver (IASL) for annual conference abstracts published up to Aug 1, 2021, as well as the reference lists of all relevant articles to identify additional studies. No language restriction was applied. 

Study selection

Observational studies were eligible for inclusion if they met the following criteria: 1) Longitudinal or registry studies were conducted in a general population or selected population (eg, patients treated with statins, oral antifungal drugs or paracetamol, etc.). 2) Incidence rate of DILI was reported or calculable. 3) Patients with DILI was identified by the RUCAM score, ICD code, or clinical, laboratory, and pathological profiles with exclusion of other liver diseases. For studies reporting on similar populations or overlapped enrollment period, we used the most recent study or the study with the greater amount of person-year. Reviews, editorials, letters, guidelines and protocols as well as articles only focused on basic science research were excluded. 

Data extraction and quality assessment

Two investigators (M.L. and Y.W.) independently assessed the eligibility of studies and extracted data in duplicate. Any disagreements on study inclusion or interpretation of data were resolved by consulting senior investigator (XY.Z.). The extracted data included study information (first author, region of study, study design, study period), patients’ characteristics (age and gender), details of incidence rate (number of DILI cases, number of total population, annual incidence with 95% confidence interval (CI), diagnostic criteria and source of cases. Study period was defined as the year of patients’ enrollment.

Two investigators assessed study quality according to seven previously published criteria, including defined catchment, accurate denominator, population-based case finding, standardized disease diagnosis, blinding to demographic factors, inclusion criteria, and leakage study.¹⁴ This quality rating system scored from 0 (highest degree of bias) to 7 (lowest degree of bias). 

Statistical analysis

Characteristics of enrolled studies were described. Heterogeneity among studies was quantified by I² test. An I² statistic above 50% was considered substantial heterogeneity. Random-effect models were used to calculate the pooled incidence rates as well as their 95% CIs. 

Firstly, we estimated the overall incidence rate of DILI in the general population. Studies reporting on selected population were analyzed separately (eg, patients treated with statins). Then, a subgroup analysis was conducted on the basis of clinical considerations: regions (Asia vs. Europe vs. America), median time of patients’ enrollment (before 2000 vs. 2000-2010 vs. after 2010), source of patients’ data (Insurance/administrative databases vs. hospital-based case series vs. physicians’ report), study quality (≥5 score vs. <5 score), and study design (prospective vs. retrospective). Additionally, a meta-regression was performed to explore the heterogeneity caused by regions, median time of patients’ enrollment, source of patients’ data, study quality and study design. Cumulative meta-analyses were performed to decide how estimates changed as subsequent studies were added to the pool. 

In sensitivity analyses, we restricted our analysis to studies with causality assessment, studies published after the detection of hepatitis C at year of 1990,¹⁵ as well as excluding the study of Goldberg et al which reported the incidence of drug-induced acute liver failure. Begg’s and Egger's test were performed to evaluate publication bias. STATA software version 15.0 (Stata Corp, College Station, TX, USA) and R software version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria) was used for meta-analysis. P value <0.05 was considered statistically significant.

Result

Study Characteristics

The initial search yielded 3,901 non-duplicated studies. A total of 110 studies were identified as potentially meeting our inclusion criteria and full-text of the studies were reviewed. After reviewing, another 79 studies were further excluded mainly due to lack of extractable or calculable incidence data, or different study population (ie. none general population-based study). Finally, a total of 31 studies were included in this meta-analysis (Figure 1). List of included studies were showed in supplementary file 2.

The characteristics of individual study were summarized in table 1 and supplementary table 1. The quality assessment of each paper included in the study was shown in supplementary table 2. The average score in the quality assessment was 4.8. The major risks of bias existed in “blinding to demographic variables” domain due to blind the person/panel who diagnosed cases to certain demographic characteristics, and “leakage study” domain due to lack of attempting to identify the original cases. 

The pooled annual incidence of DILI

The overall incidence of DILI among the general population was 4.94 (95% CI: 4.05-5.83) per 100,000 person-years (14 studies,supplementary file 2 for reference list). There was high heterogeneity among the studies (I²=99%, P<0.01, Supplementary Figure 1). Figure 2 showed the incidence of DILI of each country with at least one study. 

Pooled result of five studies showed the incidence of DILI in terms of hepatocellular, cholestatic and mixed patterns was 1.51 (95%CI: 0.72-2.29), 0.78 (95%CI: 0.37-1.18) and 0.58 (95%CI: 0.21-0.96) per 100,000 person-years, respectively (Supplementary Figure 2). 

The DILI incidence varied by regions, as noted in table 2. The incidence was 17.82 (95%CI: 6.26-29.38) per 100,000 person-years (2 studies) in Asia, 3.89 (95%CI: 2.81-4.97) per 100,000 person-years in Europe (7 studies), and 1.72 (95%CI: 0.48-2.95) per 100,000 person-years in America (5 study). 

Time-based cumulative meta-analysis showed an overall increase of the incidence of DILI over time (Figure 3). Subgroup analysis showed that the highest incidence among studies whose patients’ enrollment were after 2010 (15.14 per 100,000 person-years, 95%CI: 0.00-30.39) compared to those enrolling patients at 2000-2010 (4.44 per 100,000 person-years, 95%CI: 0.84-8.05), and before 2000 (2.55 per 100,000 person-years, 95%CI: 1.63-3.47). 

We found that the DILI incidence varied among the reporting sources. The incidence was 11.78 per 100,000 person-years (95%CI: 1.32-22.24) among studies whose DILI cases were reported by physicians and 9.57 per 100,000 person-years (95%CI: 5.06-14.09) among those whose cases were identified based on hospital case series, compared to 1.61 per 100,000 person-years (95%CI: 0.82-2.41) for studies using insurance/administrative databases. Moreover, the pooled estimates of DILI incidence were higher in studies with prospective design and studies with quality score<5. 

Incidence of DILI: Subgroup analysis by age and gender 

The DILI incidence by age group was not pooled in this meta-analysis because of the high variability of age groups used. Nonetheless, consistent higher incidence in old age group was observed (Supplementary Figure 3). For example, in the study conducted in Iceland, the incidence of DILI ranged from 8.5 per 100,000 person-years (95% CI: 3.7-16.8) in people aged 15-24 years to 41 per 100,000 person-years (95% CI: 18.7-77.8) in people aged 80-106 years.¹⁶ 

                Five studies reported the incidence of DILI in male and female separately, but with inconsistent results (Supplementary Figure 3). The pooled results of these studies showed similar incidence of DILI between male (3.42 per 100,000 person-years, 95%CI: 1.83-5.00) and female (4.64 per 100,000 person-years, 95%CI: 2.74-6.55). Heterogeneity was substantial in both female and male sets (I²=96%, I²=98%).

Incidence of DILI: By given drug(s)

As to the incidence of drug-specific DILI among the users, we found that the incidence of statins-induced DILI was 11.30 per 100,000 person-years (95% CI: 6.48-19.69, five studies). Notably, rosuvastatin users had a slighter lower incidence of DILI (8.31 per 100,000 person-years, 95% CI: 2.21-31.18) compared with other statins users (12.60 per 100,000 person-years, 95% CI: 7.44-21.34) (Table 3) (supplementary file 2 for reference list).

                The incidence of antifungal, antidepressants, paracetamol and antidiabetic drugs induced DILI was 63.46 (95%CI: 33.39-120.57, three studies), 3.83 (95%CI: 0.97-15.03, three studies), 0.16 (95%CI: 0.02-1.08, two studies), and 18.20 (95%CI: 1.51-219.20, two studies) per 100,000 person-years, respectively. Only one study reported the incidence of anti-TB, non-steroidal anti-inflammatory drugs (NSAIDs), anti-thyroid drugs (ATD), and oral iron chelator induced liver injury, respectively. 

Meta-regression

Univariate and multivariate meta-regression analysis was conducted to explore the reasons accounting for the high heterogeneity observed in our meta-analysis (Supplementary Table 3). The results showed that region distribution could partly explain this high heterogeneity among the studies (P<0.05).

Sensitivity analysis and publication bias

The pooled estimate was 7.42 per 100,000 person-years (95%CI: 5.52-9.32) for studies with case ascertainment by causality assessment, 5.90 per 100,000 person-years (95%CI: 4.85-6.95) for studies published after the detection of hepatitis C of 1990 year, and 6.02 per 100,000 person-years (95%CI: 4.85-7.18) after removing the study of Goldberg DS et al. The sensitivity analysis showed a slightly increase in the pooled estimates, mainly because most of the studies included in the sensitivity analysis were relatively recent published studies. This was consistent with the temporal trend of DILI incidence over time. 

There was no evidence of publication bias as assessed neither by Begg’s nor Egger’s test for meta-analyses (p=0.32 and p=0.08).

Discussion

We found that the global incidence of DILI among the general population was 4.94 per 100,000 person year, with the highest incidence reported in Asia compared with that in Europe and America. Additionally, the DILI incidence has increased since 2010.

There is marked geographic variation of DILI incidence. In fact, the incidence of DILI was 17.82 per 100,000 person-years in Asia, 3.89 per 100,000 person-years in Europe, and 1.72 per 100,000 person-years in America. Not surprisingly, meta-regression analysis also showed that the high heterogeneity could be partly explained by regions’ variability. The reason for the observed difference in DILI incidence between Asia and other regions is unclear but one potential explanation might be related to the usage of HDS. In Asian countries, HDS are the most common causes of DILI (26.81%), while HDS induced DILI currently represent less than 10% of all cause DILI in Western countries.^6,17 In addition, about 20% of DILI cases were attributed to anti-TB drugs.⁶ Asian countries have the highest TB burden, which may further contribute to higher risk of DILI development.¹⁸ The cornerstone of TB therapy is at least a 6-month course of isoniazid, rifampicin, pyrazinamide, and ethambutol. All these anti-TB drugs have potential hepatotoxicity and could lead to a higher incidence of DILI (180.97 per 100,000 person-years).^19,20 The potential geographic variation of the incidence of DILI would be informative in more appropriately allocation of the medical resources in order to design sustainable health recommendation and reduce associated costs. However, the incidences of DILI in Asian were only reported from China and Korea, which has limitation of extrapolation to the whole Asian countries. We advocated future studies to be conducted in order to deeply understand the potential high DILI incidence in Asia. 

Cumulative meta-analysis showed that the incidence of DILI had been significantly increased since 2010, with the highest incidence from 2010 to 2020 (15.14 per 100,000 person-years). Progress in the consensus-based diagnostic criteria and standardized DILI nomenclature and instruments were made by the global collaborative efforts in 2010.²¹ This resulted in better understanding and recognition of DILI worldwide, which might also contribute to the increase in DILI incidence. 

We also observed that DILI incidence increased with age. Youths appeared to be less susceptible to DILI than older population. Less frequently use of implicated drugs, lower doses, or inherent differences in DILI susceptibility may contribute to the observed lower incidence of DILI in young population. Whether gender is a risk factor for susceptibility to DILI remains controversial. Among five studies containing gender-specific DILI incidence, female individuals have been reported to have higher,^16,22 comparable,^23-24 or even lower ²⁵ incidence of DILI. It is worth to note among these gender-containing studies that female patients accounted for more than or nearly half of the cases. 

In addition to the incidence of all cause DILI, we also estimated the incidence of specific drug(s) induced DILI. The statins are among the most common implicated drugs, which is a preventive therapy for cardiovascular disease. Results showed that rosuvastatin may have a slightly lower incidence of DILI compared with non-rosuvastatin statins users. Our data also demonstrated that the incidence of DILI in patients using antifungal, antidepressants, paracetamol, antidiabetic, anti-TB, NSAIDs, antithyroid ATD and iron chelator ranged from 0.16 to 180.97 per 100,000 person-years. But no study incidence of HDS induced liver injury at population level is lacking and further study is indicated. The risk of developing DILI varied greatly among drug users due to pharmacokinetic and immunological actors. 

An important strength of our study is that it comprises, to our knowledge, the most comprehensive data geographically and chronologically on DILI incidence, which is derived from population-based studies to date. Also, we chose studies based on the incidence of DILI in general population which could better represent actual incidence of DILI in general population. Meanwhile, our study had several limitations. Firstly, patients exposure to other certain drugs (eg. antiretroviral agents, HDS) are believed to be at increased risk of drug hepatotoxicity. However, these studies were not included in our study due to the inclusion criteria of selecting studies conducted not base on the general population. Secondly, only ten countries in Europe (UK, Iceland, Spain, Sweden, Denmark and France), America (USA and Canada) and Asia (China and South Korea) were included in our study, no data on the incidence of DILI from Africa, and Oceania. Therefore, the incidence of DILI in our study might not truly reflect the DILI incidence in these continents. Thirdly, the high heterogeneity in the pooled results was not fully explained. Finally, some studies only included hospitalized DILI cases, this may result in an underestimation of the incidence of DILI.

Conclusion

This meta-analysis has pooled the incidence of all-cause DILI and demonstrated the increasing trend of DILI incidence in population-based studies. This global overview might serve as a reference for clinicians during their clinical practice. Certain factors, including age, region, source of patients, and study design et al, may be associated with different incidence of DILI. Understanding these differences may help prevent hence reduce the incidence of DILI.

Declarations

Data Availability: The original contributions presented in the study are included in the article/Supplementary Material. Additional data are available on request from the corresponding author.

Animal Research (Ethics): Not applicable.

Consent to Participate (Ethics): This study does not contain any studies with human participants or animals performed by any of the authors.

Consent to Publish (Ethics): Not applicable.

Clinical Trials Registration: Not applicable.

Author Contribution:

Study concept and design: Zhao XY.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Li M, Wang Y.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Li M.

Study supervision: Zhao XY.

Conflict of Interest: There are no conflicts of interest.

Funding: This work was supported by grants from the National Natural Science Foundation of China-Youth Science Fund (No. 82103902).

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Tables

Table 1. Characteristics of included studies reporting incidence of DILI

DILI: drug-induced liver injury.

*Dominated age range; ** Data was presented as median with ranges.

Table 2. Subgroup analysis of the incidence of DILI

DILI: drug-induced liver injury. 

Table 3. Incidence of specific drug(s) induced DILI

Anti-TB: anti-tuberculosis; NSAID: Non-steroidal anti-inflammatory drugs; ATD: anti-thyroid drugs.