Introduction
Steroid use is becoming increasingly widespread in the general population.1 Steroids can downregulate the hyperactivation of the immune system2,3 and are widely used to treat many immune-related diseases, including rheumatoid arthritis, dermatitis, and allergic disorders. They are also used to manage adverse events after monoclonal antibody therapies using immune checkpoint inhibitors or severe pneumonic inflammation after COVID-19.4 Furthermore, corticosteroids are administered to relieve acute nerve compression, especially metastatic spinal cord compression, and facial nerve compression.5,6
Natural therapeutic agents, including herbs and healthcare supplements, are considered relatively safe because their use overlaps daily food intake. However, although these natural remedies have been used safely for years, their safety has not been indicated in academic research, especially in intervention studies.7 Nevertheless, awareness of the safety of these natural products is gradually increasing. Interactions between herbs and conventional medicine are another clinically significant issue. For instance, warfarin has the potential to interact with herbs and dietary supplements.8 Herbs that could interact with conventional medicines include Chinese wolfberry, ginkgo biloba, American ginseng, ginger, and St. John’s wort.9 Considering how potentially harmful some drug interactions can be, it is necessary to re-examine the interactions between herbal medicines and commonly used conventional drugs. Specifically, it is necessary to confirm whether concomitant use of herbal medicines and corticosteroids, including glucocorticoids, is safe. Steroids are among the most common causes of iatrogenic illnesses. Steroid use is associated with several adverse events, including osteoporosis, infection, edema, weight changes, skin changes, sleep disturbances, gastrointestinal bleeding, ulcers, and cataracts.10,11 Glucocorticoids may cause hepatic adverse events such as drug-induced liver injury (DILI), hepatic steatosis, or cirrhosis.12,13 However, whether the combined use of steroids and herbal medicines is safe and whether it aggravates liver damage remains unclear.
Therefore, this study was conducted to confirm the safety of concurrent administration of herbal medicines to a homogenous group of patients using steroids and to determine whether concomitant use of herbal medicines and steroids is associated with a risk of liver or renal damage.
Materials and Methods
Study Design and Study Population
This was a retrospective study of the safety of the concomitant use of herbal medicines and corticosteroids in patients with facial nerve palsy. This study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Kyung Hee University Korean Medicine Hospital at Gangdong (approval number and date: KHNMCOH 2021-02-005, March 12, 2021). The flowchart of the study is shown in Figure 1.
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Figure 1 Flow diagram. Abbreviations: DILI, drug-induced liver injury; AKI, acute kidney injury; CIOMS, The Council for International Organization of Medical Sciences; RUCAM, Roussel Uclaf Causality Assessment Method.
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Any patient who visited the Facial Palsy Center at the Kyung Hee University Korean Medicine Hospital in Gangdong, Republic of Korea, was eligible for the study. The study period was from January 1, 2011, when the electronic medical record system was established and combined treatment of facial nerve palsy was initiated, to June 30, 2020. Patients who were diagnosed with facial nerve palsy within one month from the time of onset and received at least a single dose of corticosteroids, including methylprednisolone (MPD) and prednisolone, were considered eligible for inclusion. Patients with no laboratory liver or renal function test results were excluded. All medical data were recorded electronically and stored on a computer server. To maintain data consistency, we established a standard procedure for data collection and extracted and collated information according to the procedure. In this procedure, a trained independent researcher extracted data from complete medical records, and a professional coordinator coded the data. Another independent investigator conducted data cleaning by reviewing missing data and possible bias. An independent statistician performed the statistical analyses to ensure data consistency.
The following data were obtained from the medical records: demographic data, including age and sex; medical history of facial palsy; comorbidities, including diabetes mellitus, hypertension, cerebrovascular and cardiovascular disease, liver and renal disease, cancer history, and dyslipidemia. Results of liver and renal function tests performed at three time points (at admission and initiation of corticosteroid therapy, on the transfer date and initiation of herbal medicines, and at discharge) were obtained. If available, physical examination and imaging results and data on the duration of admission and administration of each medication were obtained.
Interventions
Steroids and antiviral agents were administered to patients by an otolaryngologist. The dosage and tapering schedule were planned according to the Korean clinical practice guidelines for acute facial nerve palsy. The dosage and schedule protocol was as follows: Systemic corticosteroid therapy was initiated within 72 hours of symptom onset. Prednisolone or MPD was prescribed, and doses were calculated using the steroid conversion table The starting dose was 1 mg/kg/day, which was maintained for 5 days, after which tapering was recommended. A total treatment duration of 10 to 14 days was recommended. The specific schedule was determined according to the guidelines and based on the clinical feasibility of each case. Some patients were not allowed to take the drug for up to 10–14 days for the following reasons: late visit after the onset of facial nerve palsy, medical fragility, or contraindicated by physicians.
Assessment of Acute Liver Injury
According to the American College of Gastroenterology guidelines, the normal alanine transaminase (ALT) levels for males range from 29 IU/L to 33 IU/L, whereas those for females range from 19 IU/L to 25 IU/L; levels above these values require further evaluation.14 Elevated ALT levels refer to an increase of more than five times the upper limit of normal (ULN) ALT levels.15 In the present study, 33 IU/L and 25 IU/L were considered the ULN ALT levels for males and females, respectively. The ULN alkaline phosphatase (ALP) level was set at 147 IU/L.
Liver injury was defined according to Hy’s law. Hepatocellular liver injury was defined as abnormal liver function with suspected symptoms of liver injury, more than three times the ULN serum ALT or aspartate transaminase (AST) levels, with or without an increase in serum total bilirubin to more than twice the ULN. Cholestatic liver injury was defined as ALP levels more than twice the ULN. The reaction type was defined using the R ratio (ratio of serum ALT to ALP levels), calculated as R = (ALT value/ALT ULN) / (ALP value/ALP ULN).
Acute liver injuries were categorized as hepatocellular, cholestatic, and mixed injuries. The hepatocellular injury was defined as having ALT levels more than twice the ULN or R ≥ 5. Cholestatic injury was defined as having ALP levels more than twice the ULN or R ≤ 2. Mixed injury was defined as 2 < R < 5 and having ALP levels more than twice the ULN, with increased ALT levels.
If acute liver injury was present, causality was assessed using the Roussel Uclaf Causality Assessment Method (RUCAM) score and classified as highly probable (>8), probable (6–8), possible (3–5), unlikely (1–2), or excluded (0).16
Assessment of Acute Kidney Injury
Kidney injury was defined in accordance with the Kidney Disease Improving Global Outcomes criteria. Acute kidney injury (AKI) was defined as an increase in the serum creatinine concentration or an abnormal urinalysis result that developed within hours to days. Consensus criteria for AKI include an increase in serum creatinine level by ≥0.3 mg/dL (27 µmol/L) relative to a known baseline value within 48 hours, an increase to ≥1.5 times the known or presumed baseline value within seven days, or a decrease in urine volume to <0.5 mL/kg over six hours.17
Statistical Analysis
Statistical analyses were performed using Statistical Package for the Social Sciences for Windows (version 18.0; IBM, Armonk, NY, USA). General patient characteristics and blood test results are expressed as numbers (percentages), whereas continuous data are expressed as means ± standard deviations. The average age and duration of hospitalization in the liver injury and normal groups were analyzed using the Mann–Whitney U-test. Unless stated otherwise, continuous variables were analyzed using Student’s t-test. Statistical significance was set at p < 0.05.
Results
Patient Characteristics
Based on the inclusion and exclusion criteria, 3011 patients were identified. All the patients were Korean. A total of 1100 patients for whom glucocorticoids were not recommended because they were past the acute stage of facial nerve palsy, and 597 patients with unavailable blood test results were excluded. Additionally, 238 patients with acute disease who had contraindications for glucocorticoids were excluded. The remaining 1076 patients were assessed for DILI and AKI. DILI and AKI were evaluated separately.
The 1076 patients (males, 42.0%) were patients diagnosed with facial nerve palsy who either took herbal medicine concomitantly with steroids or took herbal medicine following steroid therapy as prescribed by an otolaryngologist. All the patients took herbal medicines at least once (100.0%). All patients with possible or probable DILI were prescribed MPD. The mean number of prescription days was insignificant; however, the prescribed doses tended to be high. Yupung-dan was the most commonly prescribed herbal medicine (94.9%); however, several other types of herbal medicines were prescribed as well. Table 1 shows the herbal medicines prescribed to more than 5% of the patients. Yupung-dan, Boigyangwi-tang, Gamiigigeopung-san, Hwangnyeonhaedok-tang, Daehwang agents (Rhei Rhizoma or Rhei Rhizoma-Erigeron canadensis combination) were prescribed to the patients.
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Table 1 Demographic Details of the Patients with Facial Nerve Palsy
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Rhei Rhizoma agents were prescribed to 24.1% of the patients in the possible DILI group and 66.7% in the probable DILI group (5.7% overall prescription rate). The duration of treatment with herbal medicines was generally 1–3 days. However, ten patients took herbal medicines for ten days or more (0.9% of the entire patient population), and 3 of 32 (9.4%) patients in the possible DILI group took the medicine for ten days or longer.
A total of 29 patients were determined to have possible DILI based on the significance of the timing of medication use (began taking steroids and herbal medicine simultaneously), reduced symptoms or lack of information after completion of the prescribed drug therapy, alcohol exposure, age, alternative causes of liver injury, and concomitant use of drugs. Three patients developed liver dysfunction, which was considered probable DILI. The characteristics of the entire study population and the possible and probable DILI groups are presented in Table 2.
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Table 2 Characteristics of the Patients with Liver Injury
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Herbal Medicines
All herbal medicines were provided in the form of capsules, powders, and water decoctions. Daehwang agents were provided as Rhei Rhizoma capsules or combined Rhei Rhizoma or Rhei Rhizoma-Erigeron canadensis capsules. Most herbal prescriptions, including Boigyangwi-tang, Gamiigigeopung-san, Hwangnyeonhaedok-tang, Sihogayonggolmoryeo-tang, were provided in powder form. All patients took herbal medicines at least once. Details of the number of patients who took each herbal medicine and the compositions of the most frequently prescribed herbal medicines are provided in Supplementary Table 1.
Assessment of DILI
Forty-eight patients had normal blood test results between the time of facial nerve palsy diagnosis and initiation of steroid therapy. However, they showed elevated liver enzyme levels after taking steroids alone or in combination with herbal medicine. Of these, six patients who showed elevated liver enzyme levels did not meet the criteria for DILI, and ten patients who had normal liver function test results at the time of concomitant use of herbal medicine and steroids but showed elevated enzyme levels subsequently due to another suspected cause were excluded from the analysis.
Of the remaining 32 patients, 29 were considered to have possible DILI based on their RUCAM scores, which were determined in consideration of significant timing of medication use (began taking steroids and herbal medicine simultaneously), recovery of liver function during medication use, alcohol exposure, age, other causes of liver injury, and concomitant use of other drugs. Three patients began taking herbal medicines sequentially after starting steroid therapy and developed liver dysfunction while taking the herbal medicines. These patients had significant timing of medication use (2 points) and had no information or showed a reduction in symptoms 30 days after completing the prescription (0 points). One patient was younger than 55 years, and two were 55 years or older (1 point), and the patients had no alcohol exposure. Potential causes of liver injury other than the drugs were ruled out (2 points). Steroids or herbal medicines were associated with a risk of hepatotoxicity (2 points). However, the drugs were not restarted for the patients; thus, 0 points were assigned for rechallenge. Therefore, one patient scored 6 points, and two scored 7 points, indicating probable causality. Two patients had the hepatocellular type of injury, whereas one patient had the mixed type of injury.
Assessment of AKI
None of the patients developed drug-induced AKI. Of the 1076 patients, six had a class III estimated glomerular filtration rate or more severe kidney function impairment, whereas 1070 had normal kidney test results throughout the test period.
Discussion
Bell’s palsy is a peripheral neuropathy affecting the seventh cranial nerve, with an annual incidence estimated at 20–40 cases per 100,000 individuals.18 The incidence increases with advancing age and is most commonly observed in individuals in their 40s; it is also notably higher among patients with diabetes mellitus.19 In recent years, machine learning techniques have been increasingly employed to enhance prognostic prediction and inform clinical decision-making in the diagnosis and management of Bell’s palsy. Notably, predictive models based on early clinical data have demonstrated the potential to guide individualized treatment strategies. Early administration of high-dose corticosteroids remains a cornerstone of treatment, with evidence supporting its significant impact on improving clinical outcomes.20
Assessing the risk of herb-induced liver or renal injury in patients receiving corticosteroids is essential to ensure treatment safety and optimize therapeutic benefit. We used the RUCAM scores to investigate whether the concomitant use of herbal medicines and steroids is associated with a risk of liver injury in patients with facial nerve palsy. The RUCAM score is a globally recognized, structured, and validated tool designed to quantitatively assess the likelihood that liver injury is attributable to a specific drug. It is widely used in cases of suspected DILI or HILI.21 We selected patients with facial nerve palsy because, compared with other internal medical diseases, their characteristics do not differ significantly from those of the general population. Additionally, patients with facial nerve palsy exhibit characteristics that make them a homogeneous group suitable for evaluating causality. Moreover, drug interactions in facial nerve palsy require further research.
The patients included in this study were treated using a comprehensive clinical pathway. They started using herbal medicine after using steroids for 5 to 7 days. As a result, it was possible to exclude the increase in liver enzyme levels caused by steroids and clearly understand only the safety of the concomitant use of herbal medicine and steroids. In particular, treating the patients according to a uniform clinical pathway enhanced the data quality by ensuring the homogeneity of the study population regarding the duration of steroid and herbal medicine use.
Causality in herb-induced liver injury (HILI) is generally more difficult to evaluate than that in other types of DILI. Herbal medicines are prescribed much less frequently than other drugs, and patients take herbal extracts without medical supervision.22 In addition, it is often difficult to evaluate the exact times patients take herbal medicines and the amount of the medicine they take. Furthermore, some herbal ingredients are also used as food ingredients and are taken for prolonged periods, such as food. Thus, determining causality in these scenarios is challenging owing to the lack of monitoring by healthcare professionals.
Safety data for herbal medicines, including data on the risk of HILI, are inconsistent across studies. Compared to the assessment of DILI, where the injury is assessed as an outcome of the inherent hepatotoxicity of the drug ingredient or an idiopathic liver injury specific to the organism, the assessment of HILI features several distinctive characteristics. First, the reporting rate varies markedly according to study design. In an 11-year prospective study conducted in China, 26 of the 21,470 (0.12%) analyzed patients developed DILI.23 Similarly, the incidence of HILI in a nationwide study conducted in Korea was 0.6%.24 Multiple cohort studies in Taiwan indicated that 49% of patients with chronic hepatitis concomitantly took herbal medicine for two years or more and that this group had a significantly lower rate of acute exacerbation of hepatitis, risk for liver cirrhosis, and hepatocellular carcinoma, and mortality rate than the group of patients who did not use herbal medicine. The results of this abovementioned study indicate that herbal medicines have hepatoprotective effects.25 In a study of patients with liver cancer conducted in China, the use of herbal medicines significantly increased survival rate, specifically the 3-year survival rate, in patients with huge hepatocellular carcinoma, a finding that supports the reports of the hepatoprotective effects of herbal medicine.26 In contrast, a Korean study reported that herbal medicine is responsible for 27.5% of all DILI cases. These inconsistent results demonstrate that the risks associated with the use of herbal medicines remain controversial.27
These disparities in the results of previous studies could be attributed to the fact that herbal medicines have a combination of ingredients that vary widely in terms of their effects, toxicity, and therapeutic ranges but are all categorized under the umbrella term “herbal medicine.” Additionally, even in herbal medicines with the same common name, the concentrations of the ingredients may vary widely depending on factors such as the scientific name of the drug, quality, timing of harvest, processing method, and dose. For example, Mahuang is an herbal prescription with varying ephedrine concentrations. Although the clinical standards for the appropriate dose of ephedrine have been established, the ephedrine content per gram of Mahuang ranges from 0.7–1.0% depending on the measurement method, heating time, and region of harvest.28,29
In the present study, none of the patients (men and women who were not of childbearing age or pregnant) had liver-related symptoms such as chronic liver disease or hepatic encephalopathy. However, six patients already had elevated liver enzyme levels at the time the first blood test was performed upon diagnosis of facial nerve palsy before the initiation of steroid therapy. These patients and patients who continued to show normal liver function were excluded. Twenty-nine patients were determined to have possible DILI caused by steroids or herbal medicines, and three patients were determined to have probable DILI caused by concomitant use of herbal medicines and steroids. This translates to an incidence rate of 2.97%, which is relatively high compared to the rates reported in previous studies on the safety of herbal medicine as well as in prospective randomized clinical trials on steroids that did not include data in specific parameters for liver dysfunction. None of the patients in the present study had elevated serum creatinine levels, indicating kidney injury, while taking steroids and herbal medicines.
Information in drug databases and foundational literature indicate that steroids are potentially hepatotoxic; however, the specific types or rates of hepatic injuries caused by steroids have not been reported. The use of herbs often induces hepatocellular liver injury. It is associated with relatively unchanged ALP levels compared to AST/ ALT levels, a finding consistent with the results of the present study.
Rhei Rhizoma is a herb traditionally used as a laxative. It has hepatoprotective activities and therapeutic mechanisms and is reported to have the potential to treat liver failure in animals.30–32 However, its active ingredients—sennoside A, aloe-emodin, rhein, emodin, chrysophanol, and physcion—are known for their low bioavailability and potential hepatotoxicity.33 In the present study, the proportion of patients in the potential DILI group who took Rhei Rhizoma was markedly higher than that in the entire study population. This result highlights the need to be cautious when prescribing this herb to patients taking steroids.
This study has a few limitations. First, this was a retrospective analysis; therefore, the findings should be verified in large cohorts or other prospective studies. Second, the study population was not ethnically diverse and consisted of only patients from a single healthcare facility in one country. Third, considering the high prevalence of chronic viral hepatitis in Korea, whether the findings of Korean studies on liver function are generalizable to other regions or populations remains unclear. Lastly, there are different combinations of herbal medicines that have not been explored yet.
Despite these limitations, this study is significant in providing valuable information on the safety of herbal medicines, especially the safety of concomitant use of herbal medicines and steroids without the influence of other drugs, in a relatively homogeneous population.
Conclusion
This study, which used data from more than 1000 cases, indicated that Yupung-dan seems to be a relatively safe drug that could be taken concomitantly with steroids. Further prospective studies on the efficacy and safety of Yupung-dan will validate this finding. The results of this study also indicate that concomitant use of Rhei Rhizoma agents and high-dose steroids should be done with caution. The results of this study suggest that concomitant use of steroids and herbal medicine was safe for renal function but may be associated with hepatotoxicity in rare cases. Thus, proper monitoring is required when prescribing steroids and herbal medicines concurrently.
Ethics Approval
The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board of Kyung Hee University Korean Medicine Hospital at Gangdong (approval number and date: KHNMCOH 2021-02-005, March 12, 2021). This study was a retrospective analysis of medical records from patients who have completed treatment. No additional intervention or interaction with patients was conducted, and researchers collected only the data necessary for the study through a review of medical records. All information in the case report form was recorded in a manner that did not disclose the patients’ personal information. Additionally, it was practically impossible to obtain consent from the participants, and even if consent were waived, the risk to the participants would still be extremely low. For the reasons stated above, the Institutional Review Board approved a waiver of informed consent.
Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.
Funding
This study was supported by the Traditional Korean Medicine R&D program funded by the Ministry of Health and Welfare through the Korea Health Industry Development Institute (KHIDI) (RS-2020-KH087887).
Disclosure
The authors report no conflicts of interest in this work.
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