Effects of yinzhihuang granule on liver enzyme indicators in jaundice patients
TCM has a long history in treating jaundice. Yinzhihuang granule was derived from Yinchenhao decoction, a classic prescription in Zhongjing Zhang’s “Treatise on Febrile Diseases.” The prescription, consisting of four Chinese medicines (Artemisiae Scopariae Herba, Scutellariae Radix, Gardeniae Fructus, Lonicerae Japonicae) , is used to treat jaundice caused by liver-gallbladder dampness-heat. According to TCM, the monarch drug Artemisiae Scopariae Herba is bitter, acrid, slightly cold and has the effects of clearing damp-heat, increasing choleresis, and relieving jaundice ; the minister drug Gardeniae Fructus is bitter, cold and has the effects of purging fire, relieving restlessness, and clearing damp-heat ; Scutellariae Radix is bitter, cold and has the effects of clearing away heat and dry dampness, purging fire to eliminate toxin ; Lonicerae Japonicae Flos is cold, tastes sweet, and has the effects of clearing heat and detoxifying, anti-inflammation . The four Chinese medicines work together compatibly to play the role of clearing heat and detoxifying, clearing dampness and removing jaundice. The clinical application of yinzhihuang granules is mostly to treat neonatal jaundice , whose effectiveness has been verified in clearing jaundice and reducing enzyme activity. For example, some scholars demonstrated that yinzhihuang granules, when combined with intermittent blue light irradiation, can reduce the bilirubin levels in jaundice neonates , the GGT levels, and the ALP levels; the differences were statistically significant (P＜0.05); the effectiveness and safety were both better than the sole blue light irradiation treatment .
The present study demonstrated that the jaundice patients’ average serum TBil, IBil, AST, GGT, and ALP levels decreased after the yinzhihuang granule treatment (P＜0.05), but their ALT levels were not significantly affected. Although the ALT levels decreased by 17.11U/L, the difference was not statistically significant because P = 0.0656. After the yinzhihuang granule treatment, the average DBil level increased by 3.77μmol/L (P＞0.05). This elevation might be associated with the change of the conditions of the patients, who had not yet recovered. These results, which were obtained by analyzing the existing real-world HIS data, demonstrate that yinzhihuang granules help to reduce the jaundice patients’ TBil (P < 0.0001), IBil (P = 0.0017 < 0.05), AST (P = 0.0278 < 0.05), GGT (P = 0.0002 < 0.05), ALP (P = 0.0009 < 0.05) levels, but do not imply that yinzhihuang granules help to reduce the jaundice patients’ DBil (P = 0.3801 > 0.05) and ALT (P = 0.0656 > 0.05) levels.
The pharmacological mechanisms of yinzhihuang granule have not yet been completely understood due to its complex active ingredients and versatile action pathways. Modern pharmacological studies have found that the volatile oil component contained in the monarch drug Artemisiae Scopariae Herba can obviously antagonize the serum ALT and AST activities induced by carbon tetrachloride (CCl4) in mice with liver injury and can thus protect the liver from CCl4 injury . By inducing the liver enzyme system, Artemisiae Scopariae Herba enhances the liver’s absorption, binding, excretion of bilirubin, and promotes the removal of bilirubin . The minister drug Gardeniae Fructus may play an anti-cholestasis role by participating in biological processes such as acute inflammatory response, positive regulation of reactive oxygen metabolism, and nitric oxide anabolism , thereby promoting bilirubin excretion . In one study, yinzhihuang granules were used to intervene estrogen-induced cholestasis in rats. After 14 days, it was found that the bile flow rate and the total bile flux increased and that the levels of ALT, AST, ALP, TBil, DBil, IBil and total bile acid (TBA) were significantly reduced . The mechanism of removing jaundice and increasing choleresis may be the up-regulation of the expression of multidrug resistance transporters Mrp2 and Mrp3 in hepatocyte membrane and the enhancing of the excretion capability of hepatocytes with cholestasis , thereby reducing the accumulation of bilirubin and cholate in the hepatocytes . Through network pharmacology studies, some scholars found that the target of yinzhihuang granule aided liver disease treatment may be the epidermal growth factor receptor (EGFR). Studies have confirmed that EGFR plays an indispensable role in hepatocytes repair and regeneration and is a key regulator of the hepatocytes proliferation in the early stage of liver regeneration . By promoting the proliferation of hepatocytes, EGFR plays a role in resisting liver damage .
Taken the present information together, yinzhihuang granules have the following four mechanisms to remove jaundice, protect liver, and reduce enzyme activities: (1) preventing liver injury by antagonizing the serum ALT and AST activities induced by CCl4; (2) anticholestasis, promoting bilirubin excretion and clearance; (3) up-regulating the expression of Mrp2 and Mrp3, reducing the accumulation of bilirubin; (4) promoting the proliferation, repair, regeneration of hepatocytes, thereby protecting the liver.
Although the above studies have beneficially explored from different angles the mechanisms of yinzhihuang granules in removing jaundice and reducing enzyme activities, more bioinformatics studies and experimental verifications are further needed to learn the mechanisms of multi-ingredient, multi-target, and multi-pathway drug action to remove jaundice and reduce enzyme activities, in consideration that the active ingredients of yinzhihuang granules are complex and unclear, as well as the ingredient targets.
Real-world research based on HIS database
As a new research field, real-world studies have received ever-increasing attentions from the broad masses of doctors, researchers, policy makers and have thus exerted profound influences upon the formulation of health policies. In 2010, Yanming Xie’s research group published an article entitled “real-world research: a new idea for evaluating the effect of traditional Chinese medicine intervention measures,” which introduced the concept of real-world research to China for the first time . After nearly a decade of development, China’s real-world research has made progress in the fields of post-marketing evaluation of drugs, medical insurance decision-making, and medical equipment supervision. In the field of TCM, some scholars found that the primary applications of real-world research are the effectiveness and safety evaluation of the proprietary Chinese medicines after their entering the market. Because 49.60% of the data were from HIS , HIS based data analysis is the main mode of real-world research in the present field of TCM. The real-world evidences obtained by the HIS based analysis makes up to certain degree the extrapolation limits of randomized controlled trial conclusions and can better evaluate the actual therapeutic effect and safety of a proprietary Chinese medicine in the practical medical environment . Although the efficacy of yinzhihuang granules in treating jaundice has been confirmed by a number of randomized controlled trials, the questions have not been answered by relevant researches such as the actual effects of clinical application and the influence upon the liver enzyme indicators. By extracting a huge amount of data from many 3A hospitals in China, a large-scale electronic medical record integration data warehouse was established by Institute of Basic Research in Clinical Medicine,China Academy of Chinese Medical Science. Through processes such as data cleaning and standardization, the analyzable real-world data were finally formed, which laid the groundwork for the evaluation of the safety and real-world effectiveness of yinzhihuang granules after their entering into the market. Through the analysis of HIS data by descriptive statistical method and non-parametric test (Wilcoxon sign-ranked), we obtained the actual intervention effect of yinzhihuang granules on the serum liver enzymes of jaundice patients in the real medical environment, and the results were consistent with the relevant literature. The real-world evidence obtained in this study can supplement to some degree the evidence chain of the effectiveness evaluation of yinzhihuang granules after their entering into the market, and provide reference and basis for further clinical trials and researches on pharmacological mechanisms.
However, HIS-data based real-world studies are limited by data missing and confounding factors, which reduce to some degree the accuracy of causal inference. This study only described the changes of serum liver enzyme indicators in jaundice patients, without considering the other factors that could affect the curative effect (e.g., the use of other drugs to treat jaundice may decrease the levels of serum liver enzymes); thus, the causal inference of therapeutic outcomes was not very convincing. Randomized controlled trials remained the primary means of efficacy evaluation. For the next step, the results should be verified by carrying out multicenter, randomized, double-blind, controlled trials that are of high-quality and prospective; the pharmacological mechanisms also need to be further studied. Moreover, this study was not able to evaluate the safety of treating jaundice patients with yinzhihuang granules, due to the lack of records of adverse reactions and the fact that the patients were not followed up for a certain period. Prospective, multi-center, safe hospital monitoring should also be the focus of the next step research.