Herbal medicines have been used for thousands of years in East Asia and are now actively consumed worldwide for the treatment and prevention of diseases. A survey in Korea revealed that 61.1% of the total Korean population took herbal medicines in 20161). In a systematic review conducted in the United Kingdom, the average 1-year prevalence of the use of complementary and alternative medicine was 41.1%2).
A survey conducted by the Ministry of Health and Welfare in Korea showed that, among Korean medicine consumers, the first to seventh most common diseases treated in Korean medicine clinics were all musculoskeletal disorders, and more than half of the patients with these conditions also had previously or concurrently visited Western medicine clinics3). It can be inferred that it is common for patients to concurrently use both types of medications, as reported in a retrospective chart review on musculoskeletal disorders in Korea (prevalence rate 35.9%, 2,475 of 6,894 inpatients)4).
Recently, the hepatic safety of herbal medications was investigated in terms of the occurrence of drug-induced liver injury (DILI), and it was concluded that herbs are relatively safe5), as the incidence rate of DILI was similar to that with conventional medications (~ 1%)6,7). Meanwhile, with respect to drug-induced kidney injury (DIKI) due to herbal medications, large-scale studies conducted in Korean medicine hospitals reported that taking herbal medicines does not have significant adverse effects on renal function8-10).
However, there are relatively fewer reports on the safety of the concurrent use of conventional and herbal medications, despite the increasing popularity of this practice. In a retrospective Korean study that screened for DILI among inpatients who were administered both herbal and conventional medications for at least 14 days between 2006 and 2010, 5 of the 892 patients (0.56%) were identified to have DILI11). In another study, the prevalence rate of DILI was 2.3% of the 256 total patients with a broad range of diseases12). Considering that the main diseases requiring the concurrent use of conventional and herbal medicines are musculoskeletal disorders, there is a need to investigate the safety of the practice in this patient population, with attention to the fact that non-steroidal anti-inflammatory drugs (NSAIDs) are the main drugs causing DILI and DIKI7,13).
In this study, we retrospectively reviewed changes in liver and renal function based on blood test results, and investigated the incidence of DILI and DIKI in inpatients with musculoskeletal disorders and injuries to examine the safety of the concurrent use of conventional and herbal medications.
Patients who were admitted to Kyung Hee University Korean Medicine Hospital between January 1, 2013, and December 31, 2017, were included in this study. The total number of included patients was 590.
The inclusion criteria were as follows: (1) hospitalization for at least 7 days, (2) a musculoskeletal disorder or injury as the main diagnosis (International Statistical Classification of Diseases and Related Health Problems 10th revision codes: M01-M99, S01-S99, or T01-T10), (3) administration of both conventional and herbal medications for >7 days during the hospitalization period, (4) available blood test results for assessing hepatic and renal function at admission and at discharge (i.e., before and after taking both conventional and herbal medications), and (5) age >19 years.
The exclusion criteria were as follows: (1) a history of liver or kidney disease before the hospitalization period, such as viral hepatitis or chronic kidney failure, and (2) chief complaints other than musculoskeletal diseases.
The need for informed consent from patients was waived owing to the retrospective nature of this study. After obtaining approval for the study from the Kyung Hee University Korean Medicine Center Institutional Review Board (KHMCIRB 2018-08-002-001), we retrospectively collected and analyzed related laboratory data by examining the electronic medical records (EMRs) of patients who satisfied the inclusion and exclusion criteria. Two authors (SY Kim and H Kim) collected and analyzed the data, and the procedure was monitored and approved by another author (WS Chung). The clinical chemistry data collected before and after taking herbal medications included aspartate transaminase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), total bilirubin (TB), direct bilirubin (DB), blood urea nitrogen (BUN), and creatinine.
On the basis of the examination and analysis of the blood test data, cases of DILI and DIKI were identified. The identified cases were reviewed by analyzing the diagnosis, sex, age, length of hospital stay, type of administered conventional and herbal medications, and major changes in clinical symptoms. When relevant liver or kidney injury was detected, the following items were investigated using EMRs to identify the definite cause: (1) recent patient history, including exposure to contrast medium or immunosuppressants, and (2) results of other evaluations including urine analysis, urine microscopy, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), radiography (abdominal or pelvic), and biopsy.
The DILI cases were identified using the updated Roussel Uclaf Causality Assessment Method (RUCAM) criteria for liver injury, as follows: (a) an increase of > 5 × upper limit of normal (ULN) in ALT or (b) an increase of > 2 × ULN in ALP14).
The injuries of the patients were classified into three types based on the R ratio ([ALT/ULN]/[ALP/ULN]): R ratio >5 and ALT > 2 × ULN, hepatocellular liver injury; 2 < R ratio < 5 and both ALT and ALP > 2 × ULN, mixed liver injury; and R ratio < 2 and ALP > 2 × ULN, cholestatic liver injury.
Each case was evaluated for the likelihood of DILI and judged as ‘excluded (0),’ ‘unlikely (1-2),’ ‘possible (3-5),’ ‘probable (6-8),’ or ‘highly probable (>8)’ according to the RUCAM score. On the basis of the evaluation, the characteristics of cases with DILI were further analyzed for those that were judged ‘possible,’ ‘probable,’ and ‘highly probable.’ The characteristics of cases were extracted, including diagnosis, sex, age, length of hospital stay, and type and dosage of the prescribed conventional and herbal medications.
Kidney injury was classified according to the Kidney Disease Improving Global Outcomes (KDIGO) definition. Acute kidney injury (AKI) was defined as any of the following: an increase in serum creatinine (SCr) by ≥0.3 mg/dL (≥26.5 mmol/L) within 48 h; or an increase in SCr to ≥1.5 times the baseline value, which is known or presumed to have occurred within the prior 7 days; or urine volume <0.5 mL/kg/h for 6 h. The patients were classified as having stage I, II, or III kidney injury15). Kidney disease was evaluated according to SCr and urine output. When SCr above the ULN was detected, the urine output of those cases was referred from the EMRs.
For patients with kidney injury, other evaluations including urine analysis, urine microscopy, ultrasound, CT, MRI, radiography (abdominal or pelvic), and tissue biopsy were performed to determine whether the injury was acute or chronic, and whether it was prerenal, renal, or postrenal.
The characteristics of the patients with DIKI were abstracted, including diagnosis, sex, age, length of hospital stay, body mass index (BMI), type and dosage of the prescribed conventional and herbal medications, and risk factors for AKI, as suggested by KDIGO.
SPSS 25.0 (IBM Corporation, Armonk, NY, USA) was used for statistical calculations. The Shapiro-Wilk test was used to ascertain the normality of the distribution of continuous data. Continuous data are presented as median and interquartile range, whereas categorical data are expressed as frequencies. The Wilcoxon signed-rank test or paired t-test was performed to compare changes in clinical chemistry values between admission and discharge. The non-inferiority test and Cohen’s kappa test were conducted to assess the similarity of the data between admission and discharge.
Linear regression analysis was performed to identify predictors of changes in blood test results between before and after taking the two types of medications. Statistical significance was set at p<0.05.
The patients’ characteristics are summarized in Table I. The data from 590 patients (161 men and 429 women) who satisfied the inclusion and exclusion criteria were analyzed after the review of EMRs.
Among the initial 590 patients, 3 patients with liver injury based on the updated RUCAM criteria were identified at admission. The characteristics of these cases are summarized in Table II. One case was excluded because the liver injury detected at admission was found to be caused by liver metastases during hospitalization. The DILI of the other two cases was assumed to be associated with the use of conventional drugs, especially NSAIDs, and the subsequent discontinuation of the suspected drug led to the normalization of liver enzyme levels.
Only one case of newly developed DILI (0.17%) during hospitalization was identified (Table III). The type of DILI in this case was categorized as mixed (R value=3.62) based on the RUCAM score. It was suspected to have been caused by a herbal medication composed of various herbs (Table IV), and was judged to be a ‘probable’ DILI with a RUCAM score of 7. The types of conventional medicines used by the patient were antihyperlipidemic agents and antidiabetics. The classification of patients according to the results of liver function tests at admission and discharge is presented in Table V.
Of the 590 patients, 1 (0.17%) had AKI according to KDIGO. This case corresponded to the 7-day diagnostic window for AKI and was classified as stage I (Table VI). The composition of the herbal medication administered in this DIKI case is shown in Table VII.
In the comparison of the blood test results of patients between before and after taking herbal medicines, the AST, ALT, GGT, ALP, BUN, and creatinine levels were significantly lower after taking medications (p<0.05). The mean levels of TB and DB were lower after the administration of medications, but the difference was not significant (p>0.05) (data not shown).
In the simple linear regression analysis, the changes in GGT, TB, DB, and ALP levels were higher in women. The changes in ALP levels were higher in patients with a higher BMI (Table VIII).
Women had a higher tendency than men to show changes in GGT, TB, DB, and ALP levels. Patients with a higher BMI had a greater change in ALP level.
This was a retrospective observational study that investigated the safety of the concurrent use of conventional and herbal medications with respect to liver and renal function, mainly in patients with musculoskeletal diseases and injuries. The main finding of this study was that the concurrent use of both types of medications is relatively safe, as shown by the low incidence rate of DILI according to RUCAM (0.17%, 1 case) and that of DIKI according to KDIGO (0.17%, 1 case) among a total of 590 patients. Furthermore, a statistically significant decrease was observed in the levels of blood test items related to hepatic and renal function (AST, ALT, GGT, ALP, BUN, and creatinine), although the non-inferiority test using categorized data suggested that this decrease was not clinically significant. The kappa coefficients of the serum laboratory data ranged from 0.26 to 0.72, indicating that the values before and after the concurrent use of conventional and herbal medications had a fair similarity. Therefore, it can be inferred that the concurrent use of conventional and herbal medications did not result in clinically significant changes in liver and renal function in patients with musculoskeletal disorders and injuries.
The DILI incidence rate of 0.17% corresponds to the results of previous studies. A safety study on the concurrent use of conventional and herbal medications reported an incidence of 0.56% (5 of 892 patients)11). Studies on herbal medication―induced DILI showed similar results. One retrospective study conducted in Japan reported that the incidence of DILI caused by herbal medicine was 0.24% (6 of 2,496 cases)16) and another study from Germany reported an incidence of 0.93% (14 of 1,507 cases)17). Moreover, systematic reviews conducted in Korea concluded that the incidence of DILI after treatment with herbal medications was <1%18,19). Furthermore, a large-scale study on herb-induced liver injury in 4,578 patients with musculoskeletal diseases, first published in 2015 and updated in 2019 with the updated RUCAM criteria4,20), detected DILI in only 3 patients (0.07%).
In the DILI case in the current study, the patient was identified to have taken conventional medications, including antihypertensive drugs and antidiabetics, which could have increased the levels of liver function parameters as an adverse effect21). In the DIKI case, the patient used conventional medications, including antibiotics, antihypertensive drugs (especially angiotensin II receptor antagonists), and NSAIDs, which are all known to potentially cause kidney injury22).
From the results of previous studies and the current study, it can be inferred that the use of herbs, regardless of the concurrent use of conventional medicines, does not increase the risks of DILI and DIKI.
To identify factors that influenced the levels of the blood test items during the administration of both types of medications, a multiple linear regression analysis was performed. Women had a higher tendency than men to show changes in GGT, TB, DB, and ALP levels. This seems to be related to the finding of a previous study that female patients experience greater difficulty in recovering from liver damage and are thus more susceptible to DILI23). Moreover, the change in ALP level was higher in patients with a higher BMI. Although the increase in the levels of these serum components did not lead to the occurrence of DILI or DIKI, clinicians need to be cautious when prescribing herbal medications in addition to conventional medicines in female patients or patients with a high BMI, and should monitor patients as closely and as frequently as possible.
The hypothesis of this study, based on empirical data, was that the concurrent use of conventional and herbal medications does not cause a deterioration in the liver and renal function of patients with musculoskeletal diseases and injuries. This study is relevant for the following reasons: (1) it surveyed patients with musculoskeletal diseases and injuries as the primary diagnoses, which are the most common diagnoses seen in Korean medicine clinics that easily lead to the concurrent use of herbal medicines with conventional medications, and (2) it used various appropriate statistical methods, including non-inferiority, Cohen’s kappa, and multiple regression tests, to analyze the data before and after taking both types of medications from various perspectives.
This study had the following limitations: (1) no control group was used, which could have consisted of patients taking either conventional medications alone or herbal medications alone, and (2) the exact herb that possibly caused hepatic or renal injury could not be identified because herbal medicines are usually prescribed in the form of a mixture of several different herbs.
To confirm the safety of the concurrent use of conventional and herbal medications in patients with musculoskeletal diseases and injuries, we retrospectively reviewed the EMRs of inpatients in a Korean medicine hospital. From the data of 590 cases, the incidence of both DILI and DIKI was found to be 0.17%. Further studies are warranted on the possibility of liver and kidney injuries with each herbal medication. In addition, toxicity from the interaction between conventional and herbal medicines should be identified to firmly prove the safety of taking herbal medications.
The authors thank Jae-Hyun Park, Hokyung Chang, and Hansol Lee from Kyung Hee University Korean Medicine Hospital for providing assistance in the analysis process.