Exploring the association between herbal medicine usage and drug-induced liver injury: insights from a nationwide population-based cohort study using SCCS in South Korea

Drug-induced liver damage (DILI) is a situation during which the liver is broken as a consequence of publicity to prescription prescribed drugs, over-the-counter medicines, and natural and dietary dietary supplements (HDS) (Real et al., 2019). It’s characterised by a spread of liver abnormalities, various from gentle elevations in liver enzyme ranges (transaminases) to extreme liver injury or failure, which will be life-threatening (Real et al., 2019; Nunes et al., 2022). The incidence of DILI is rising worldwide due to the prevalence and widespread use of wholesome purposeful meals and self-medication, accessible from a wide range of sources.

Latest research have highlighted the rising DILI danger posed by HDS, alongside conventional danger components akin to antibiotics and anti inflammatory medication (Real et al., 2019; Nunes et al., 2022). In South Korea, stories have introduced conflicting findings concerning the first causative brokers of DILI, significantly regarding natural medicines prescribed by conventional Korean drugs (TKM) medical doctors (Kim et al., 2003; Yoo et al., 2007; Suk et al., 2012). Preliminary stories in 2003 recommended a big affiliation between natural medicines and DILI, accounting for 57.9% of instances (Kim et al., 2003); subsequent research in 2007 and 2012 additionally discovered they accounted for roughly 30% of instances (Yoo et al., 2007; Suk et al., 2012). Nonetheless, stories from multi-pharmacovigilance facilities in South Korea have revealed that antibiotics, anti-epileptics, anti-inflammatory medication, and statins are the foremost brokers related to DILI (>80%), whereas natural medicines accounted for under 0.5% of instances (Shin et al., 2009; Kwon et al., 2012). Retrospective research amongst sufferers taking natural medicines prescribed by TKM medical doctors additionally indicated a low DILI prevalence (∼0.5%), with subclinical or gentle signs (Lee A. R. et al., 2012; Lee et al., 2015). Moreover, a nationwide potential examine carried out between April 2013 and January 2016 estimated the incidence of DILI from natural medicines to be 0.6% (Cho et al., 2017).

Taken collectively, the protection profiles of natural medicines in South Korea exhibit discrepancies (Lee et al., 2019). It’s crucial to conduct a nationwide population-based examine encompassing all DILI instances to handle the constraints inherent in relying solely on research carried out in Western or TKM establishments. Given the great healthcare protection supplied by South Korea’s common healthcare system, strong knowledge from nationwide medical insurance claims are readily accessible by way of the Well being Insurance coverage and Assessment Evaluation (HIRA) course of.

Right here, we adopted the self-controlled case sequence (SCCS) as a consequence of a number of compelling causes. In the beginning, SCCS successfully controls for all confounders that don’t range over time inside a person, akin to genetic components, way of life decisions, and long-term well being situations (Petersen et al., 2016). That is essential in our examine the place such confounders might considerably influence the outcomes. By utilizing SCCS, we reduce bias arising from these time-invariant confounders, guaranteeing extra correct and dependable findings. Furthermore, SCCS is very environment friendly because it solely contains people who’ve skilled the occasion of curiosity—on this case, DILI (Lee C. H. et al., 2012; Brauer et al., 2016). This permits for a targeted and environment friendly evaluation, which is especially invaluable given the potential rarity of DILI occasions. One other key purpose for the need of SCCS in our examine is its skill to attenuate choice bias (Mostofsky et al., 2018). In conventional cohort or case-control research, there’s a danger of choice bias as a consequence of variations between uncovered and non-exposed teams. SCCS mitigates this danger through the use of every particular person as their very own management, thereby enhancing the validity of our findings. By SCCS, we investigated the relative incidence of DILI related to publicity to TKM hospitals/clinics and natural medicines prescribed by TKM medical doctors 15, 30, 45, 60, 75, and 90 days earlier than the onset of DILI signs.

To categorize DILI severity, the examine inhabitants was divided into three teams: outpatients (people who obtained a DILI prognosis and weren’t admitted to hospital), inpatients (people admitted to hospital on the time of DILI prognosis), and sufferers with liver illness (a high-risk DILI group comprising people with pre-existing liver situations akin to hepatitis, malignant neoplasm of liver and intrahepatic bile ducts, alcoholic liver illness, hepatic failure, fibrosis and cirrhosis of liver, and different inflammatory liver illnesses; detailed in Supplementary Table S1). The investigation workflow is illustrated in Figure 1A.

Determine 1. The flowchart for the examine inhabitants inclusion/exclusion and the ultimate three teams (A), evaluation move for self-controlled case sequence (B), and the detailed examine design (C). Threat of hospital go to or prescription and the management interval of sufferers have been outlined. DILI, drug-induced liver damage; HIRA, Well being Insurance coverage and Assessment Evaluation; ICD-10, Worldwide Statistical Classification of Ailments, tenth Revision; RI, relative incidence; TKM, conventional Korean drugs; SCCS, self-controlled case sequence.

A SCCS design was used to mitigate the influence of time-invariant confounding variables (Figures 1B, C). Age and publicity have been handled as time-variant variables. Exposures have been outlined as i) hospital/clinic visits or ii) prescriptions, respectively. Particularly, hospital/scientific go to refers to any go to, whether or not or not drugs have been prescribed. Though knowledge on most drugs prescribed in Western medical establishments have been accessible within the nationwide well being claims database, 56 natural extracts prescribed in TKM establishments have been collected. Subsequently, a go to to both a Western or TKM establishments could possibly be conservatively thought of as exposures to industrial medication or natural medicines.

For each publicity varieties, danger durations have been outlined inside 15, 30, 45, 60, 75, and 90 days following every publicity to watch the temporal sample of DILI incidence. This enabled an analysis of the consistency and time of DILI relative to preliminary publicity. The first end result was the primary incidence of DILI, coded as K71. To cut back the potential for the reverse causation between publicity and end result, K71 occasions occurring inside 0–2 days after publicity have been excluded. Circumstances the place sufferers had concurrent exposures to each natural and traditional medicines inside the similar danger interval have been excluded from the evaluation to keep away from potential confounding results.

Demographic and scientific traits are reported as imply ± commonplace deviation for steady variables and as frequencies and percentages for categorical variables. The important thing assumptions of the SCCS mannequin included the independence of recurrent end result occasions, the place the incidence of 1 occasion doesn’t affect the likelihood of subsequent occasions or the independence of end result occasions from subsequent publicity (Petersen et al., 2016). The primary incidence of DILI was targeted on, for which the estimated relative incidence (RIs) could also be conservative. RIs with 95% CIs as compared with the management interval have been individually estimated in response to outlined danger durations (Figure 1C). Statistical analyses have been carried out utilizing R (model 4.3.1) with the SCCS bundle of the R Basis for Statistical Computing and SAS Enterprise Information (model 7.13; SAS Institute, Cary, NC, United States) (Farrington et al., 2018).

A complete of 586,608 outpatients (Group A), 85,803 inpatients (Group B), and 62,877 sufferers with liver illness (Group C) have been included; demographic and scientific traits can be found in Table 1. Throughout all teams, the common age was roughly 50 years, with the next proportion of males than females; Group C had the very best variety of male sufferers (61.38%). Nearly all of Group A obtained their prognosis at major care establishments (58.96%), whereas most inpatients have been recognized at secondary or tertiary care hospitals (73.32% and 23.24%, respectively). Mortality charges have been highest in Group B, indicating extra extreme DILI. Group C had the next prevalence of comorbidities, with dyslipidemia being the commonest. The predominant subtype of DILI in Group C was poisonous liver illness with cholestasis (45.27%), whereas unspecified DILI was extra prevalent in Teams A and B (>55%).

Desk 1. Affected person demographics and scientific options at prognosis of drug-induced liver damage (DILI) for outpatients, inpatients, and sufferers with liver illnesses.

The dangers of DILI related to every medical establishment are proven in Figures 2A–C. The dangers inside 3–15 days following visits to Western hospitals/clinics have been persistently greater than these for visits to different medical establishments throughout Group A, B, and C (RI = 1.55 [95% CI: 1.55–1.56]; RI = 1.67 [95% CI: 1.65–1.70]; RI = 1.76 [95% CI: 1.71–1.81], respectively). The elevated RIs converged to 1.0 after 3–15 days, indicating a lower within the danger of DILI over time.

Determine 2. Relative incidence of drug-induced liver damage after publicity to hospital/scientific visits left panel: (A, C, E) or prescriptions proper panel: (B, D, F). The examine inhabitants was divided into three teams: outpatients higher panel: (A, B), inpatients center panel: (C, D), and sufferers with liver illness decrease panel: (E, F). Publicity to hospital/scientific go to refers to any go to, with or with out prescriptions for industrial medication or natural medicines. CI, confidence interval; RI, relative incidence.

In distinction, no elevated danger of DILI was noticed in Group A and Group B inside 3–15 days following visits to TKM hospitals/clinics (RI = 1.01 [95% CI: 1.00–1.01] and RI = 0.98 [95% CI: 0.93–1.05], respectively) (Figures 2A, B). This development persevered throughout the opposite danger durations for as much as 90 days. Equally, the RIs of DILI for all danger durations related to visits to dental hospitals/clinics have been near 1.0, indicating minimal danger. In Group C, the danger of DILI was mildly elevated 61–75 days after visits to TKM hospitals/clinics (RI = 1.15 [95% CI: 1.05–1.25]) (Figure 2C).

The chance of DILI from prescription is proven in Figures 2D–F. The dangers inside 3–15 days following prescription of business medication have been persistently greater in comparison with natural drugs prescribed by TKM medical doctors throughout Teams A, B, and C (RI = 2.44 [95% CI: 2.43–2.44]; RI = 1.85 [95% CI: 1.83–1.87]; RI = 2.11 [95% CI: 2.07–2.15], respectively). The elevated RIs progressively converged to 1.0 after 16 days, indicating a lower within the danger of DILI over time.

Conversely, there was no elevated danger of DILI inside 3-15 days following natural drugs prescription in Group A or B (RI = 0.99 [95% CI: 0.99–1.00] and RI = 0.98 [95% CI: 0.92–1.06], respectively) (Figures 2D, E). In Group C, the danger of DILI was mildly elevated at 16–30 and 61–75 days following natural drugs prescription (RI = 1.16 [95% CI: 1.05–1.28] and RI = 1.16 [95% CI: 1.05–1.27], respectively) (Figure 2F).

The chance components for DILI stay poorly understood as a result of most idiosyncratic instances are unpredictable and happen inside the therapeutic doses of prescribed remedy, indicating the absence of a dose-response relationship (Hoofnagle and Bjornsson, 2019). The pathophysiology of DILI is profoundly influenced by a number of variables together with particular person traits and environmental components (Hussaini and Farrington, 2007; Chalasani and Bjornsson, 2010). Conventional epidemiological examine designs, akin to cohort and case-control research, usually battle to adequately account for the myriad confounding variables inherent in DILI instances, significantly as a result of figuring out appropriate management teams is difficult (Lee C. H. et al., 2012; Petersen et al., 2016). Figuring out the publicity timing to a candidate substance in DILI instances poses a pivotal problem (Mostofsky et al., 2018). The SCCS design is especially effectively fitted to analyzing the influence of natural medicines on DILI, addressing these complexities (Petersen et al., 2016; Nunes et al., 2022) Nonetheless, the SCCS methodology additionally has some weaknesses (Mostofsky et al., 2018; Takeuchi et al., 2018) It requires correct timing of each the publicity (akin to natural drugs utilization) and the occasion (DILI), as misclassification can result in biased outcomes. Moreover, whereas SCCS controls for time-invariant confounders, it doesn’t mechanically management for time-varying confounders, which may introduce bias if not correctly accounted for. There can be points with reverse causality, the place the end result would possibly affect the publicity timing, which must be fastidiously thought of and addressed within the examine design. Lastly, if there are underlying temporal tendencies within the incidence of the occasion or publicity, these must be accounted for to keep away from biased estimates.

On this examine, each visitation and prescription of medication in Western establishments resulted in a considerably greater danger of DILI throughout all teams. The sequentially reducing danger from 3 to fifteen days following publicity means that each these components affect DILI improvement. In distinction, inpatients and outpatients visiting and/or prescribed drugs at TKM establishments confirmed a minimal danger of DILI, although elevated danger was noticed inside 75 days of publicity in sufferers with liver illnesses. This means that getting affected person histories is important earlier than prescription by TKM physicians.

Earlier research in East Asian international locations have additionally had controversial outcomes concerning the consequences of natural medicines on DILI. In Taiwan, a population-based cohort examine highlighted acetaminophen (35.0%) and anti-tuberculous medication (34.7%) are main causes of DILI, whereas natural medicines weren’t (Sobhonslidsuk et al., 2016). One other potential examine in Taiwan from 2011 to 2019 recommended 78.0% of DILI instances have been attributable to standard medication, with 22.0% attributable to HDS, however included numerous dietary dietary supplements with out prescriptions (Huang et al., 2021). In mainland China, a retrospective examine recognized Conventional Chinese language Medication (TCM) or HDS because the main reason for DILI, accounting for 26.81% of instances (Shen et al., 2019). Nonetheless, a big methodological concern has been raised concerning the examine by Shen et al. (Shen et al., 2019), significantly the choice to categorise TCM and HDS as a single class (Cong et al., 2019; Yang et al., 2019). TCM, like TKM, is a extremely regulated observe, prescribed by licensed practitioners, which is in stark distinction to HDS, a class encompassing a wide selection of merchandise with various levels of regulation and high quality. By combining these distinct entities into one class, the examine oversimplifies the information, probably exaggerating the danger related to TCM whereas obscuring the particular risks posed by much less regulated HDS merchandise. This flawed classification leads to an unequal comparability with standard medication, probably resulting in deceptive conclusions about the primary contributors to DILI. For a extra correct evaluation, TCM and HDS must be categorized individually, with additional subcategories to account for his or her variety and regulatory variations. Total, the clear hepatotoxicity dangers related to unregulated natural medicines emphasizes the necessity for these merchandise to prescribed inside medical establishments, as advocated by our examine.

This examine had a number of limitations. First, the K71 code used to establish instances of DILI encompasses each idiosyncratic and intrinsic types of liver damage, and we have been unable to carry out additional distinctions or stratified analyses because of the absence of related info, akin to laboratory knowledge, within the HIRA database (Kim et al., 2017). The reliance on ICD-10 codes, which lack detailed scientific info, might have led to the potential misclassification of DILI instances in comparison with diagnoses established by way of scientific analysis. Because of this, we have been unable to use the Roussel Uclaf Causality Evaluation Technique (RUCAM) causality grading (Roussel Uclaf Causality Assessment Method (RUCAM) in Drug Induced Liver Injury (2012)) to substantiate the affiliation between publicity and DILI occasions. Second, the HIRA database doesn’t embrace particulars on particular drugs indicating the exact causes of liver damage. Info on natural medicines within the HIRA database was restricted to insurance-covered extracts, excluding decoctions and non-insured natural formulations, that are generally utilized in observe. The restricted scope of knowledge on non-insured natural medicines introduces potential bias and restricts the generalizability of our findings. Consequently, we couldn’t clearly distinguish herb-induced liver damage from different types of DILI inside the K71-coded occasions. Third, the noticed IRs inside 3–15 days of publicity in Western establishments might have been overestimated because of the case-only design, which targeted on the primary episode of DILI. Nonetheless, the elevated danger noticed in the course of the subsequent 16–30 days, adopted by a decline, helps the temporal affiliation. As a reference level, visits to dental clinics confirmed no related danger for any group all through the examine interval, reinforcing the reliability of the findings. Lastly, pre-existing liver illness has been reported to lead to extra extreme outcomes upon the incidence of DILI slightly than influencing its incidence (Chalasani and Bjornsson, 2010). Nonetheless, the danger related to particular natural elements in sufferers with liver illness couldn’t be evaluated.

Future analysis on natural drugs security ought to undertake a multifaceted strategy by integrating digital medical information with medical insurance claims knowledge to establish particular herbs or formulations that will pose greater dangers for DILI. This integration would supply a extra complete understanding by combining scientific observations with prescription knowledge. Moreover, community pharmacology approaches must be employed to foretell hepatotoxicity dangers of particular person herbs or compounds (Hong et al., 2017), uncovering potential interactions and aiding in proactive danger administration methods. Regulatory and legislative assist is important to ascertain strong pharmacovigilance methods for natural prescriptions, together with real-time monitoring, reporting, and danger mitigation mechanisms. Moreover, future research ought to deal with the protection profiles of particular herbs, significantly their results on weak populations, akin to people with pre-existing liver situations or these utilizing concurrent drugs, to handle current data gaps and improve the protected use of natural medicines in scientific observe.

In conclusion, this examine highlights a big affiliation between industrial medication and DILI incidence, whereas confirming that natural medicines prescribed by TKM medical doctors have minimal influence on DILI danger. These findings contribute to our understanding of the DILI dangers related to natural drugs, significantly by emphasizing the heightened vulnerability of sufferers with liver illnesses. Furthermore, they underscore the need for additional analysis into the danger components underlying DILI improvement. Moreover, there’s an pressing demand to evaluate the hepatotoxicity danger posed by unregulated natural merchandise compared to natural medicines prescribed inside medical establishments.

The Supplementary Materials for this text will be discovered on-line at: https://www.frontiersin.org/articles/10.3389/fphar.2025.1498124/full#supplementary-material