| ObjectiveThe objective of this study is to verify the traditional Chinese medicine (TCM) thoughts for the treatment of liver cirrhosis based on the TCM theory of’liver storing blood and governing free flow of qi’ and also try to explore the modern scientific connotation of the theory by analyzing the efficacy mechanism of the two Chinese herbal compounds on liver cirrhosis in western medicine. For this purpose, we did a systematic review on Chinese herbal medicine combined with nucleotide analogues for compensated HBV-related cirrhosis, and then explored a new research idea and project, and finally observed, analyzed the formulas’ effective trend difference.Methods1. PubMed, Cochrane library, China Network Knowledge Infrastructure Database (CNKI), Wan Fang Database, Chinese Scientific Journals Database (VIP) and Sino-Med Database were searched. Randomized controlled trials (RCTs) and quasi-RCTs comparing NAs and NAs plus CHM therapy on patients with compensated HBV-related cirrhosis were included. Two reviewers independently extracted information and assessed the methodological quality of the trials. RevMan5.3 was used to do data analysis. Different CHM herbal fonnulas used in the trials were considered. Primary meta-analysis was conducted when there were at least two trials comparing the same CHM formula. 2. This is a blinded, multicenter, three armed, randomized clinical control study.144 subjects with compensated hepatitis B cirrhosis were enrolled in this study, and randomized with a ratio of 1:1:1 into Group A, Group B, and Group C, each containing 48 subjects. Patients in Group A, Group B, and Group C were treated for six months with Formula A (to boost and regulate qi, fortify spleen, soothe liver, soften hard masses and unblock collaterals), Formula B (Formula A plus medicinals to nourish yin and blood), and Formula C (placebo) respectively. The macro indicators are the symptoms lists questionnaire of TCM, chronic liver disease questionnaire (CLDQ) and fatigue self-assessment scale. The micro indicators include liver function, full parameters of blood coagulation, abdominal ultrasound scan, portal vein ultrasonic blood flow and fibroscan. There are two time points, i.e. the baseline (TO) and six months after treatment (T6). We analyzed these indicators from the perspective of overall and stratified comparison (with gender, active stage and quiescent stage as stratified factors). The difference has statistical significance (P<0.05).Results1 Chinese herbal medicine combined with nucleotide analogues for compensated HBV-related cirrhosis:a systematic review of randomized controlled trials Forty-five trials comprising 3497 participants were included. Twenty-six herbal formulations and three NAs were identified. The results of meta-analysis showed a beneficial effect of FFBJ plus entecavir (ETV), and DHZC plus adefovir dipivoxil (ADV) on hyaluronic acid (HA); FFBJ plus ADV on laminin (LN); and FZHY plus ADV on HA, LN, and precollagen type Ⅲ (PC-Ⅲ). The results from other studies suggested significant benefits of CHM plus NAs compared with NAs alone, except those on albumin (ALB). None of the trials evaluated the quality of life or reported severe adverse events.2 Effect of Chinese medicine on compensated HBV-related cirrhosis:A randomized, blinded and controlled clinical trial 144 subjects that met the inclusion and exclusion criteria were randomly enrolled in this study. Finally,132 cases were included since 12 cases were expulsed. All patients’gender, age, quiescent stage and active stage, macro and micro indicators did not have statistically significant difference at baseline (P>0.05).(1) The effects of Chinese herbal medicine in treating patients with compensated HBV-related cirrhosis on health-related quality of life. The CLDQ total score and factor scores of the three groups showed a rising trend after treatment. ①Intra-group comparison before and after treatment:Compared with T0, the CLDQ total score and factor score increased in all three groups. There was statistical significance in the scores of Group A (including CLDQ total score, WO; male total score, EF, WO; female WO; active stage total score, WO; quiescent stage total score, WO), Group B (including SS, EF, WO; female SS, EF; quiescent stage SS, EF) and Group C (including CLDQ total score, FA, EF, WO; male total score, FA, EF, WO; female FA; active stage total score, FA; quiescent stage total score, FA, EF, WO). ②Inter-group comparison:There was statistical significance only in FA (Group C> Group B> Group A). ③The comparison between male and female, active stage and quiescent stage in each group:In terms of gender, there was only statistical significance in Group B, with female scored higher than male in total score, AS, FA, AC, and WO. In terms of active and quiescent stage, there was only statistical significance in Group C, with FA higher in the active stage than the quiescent stage.(2)The effects of Chinese herbal medicine in treating patients with compensated HBV-related cirrhosis on syndrome elements and symptoms. The syndrome elements and symptoms score of the three groups showed a descending trend after treatment. ①Intra-group comparison before and after treatment:There was statistical significance in the scores of Group A (including qi deficiency, qi stagnation, xue stasis, yin deficiency, yang deficiency, xue deficiency, total score of symptom, irritability-degree, pruritus, surface-dull degree, dry eye-frequency, flank pain-frequency, flank pain-degree, flank discomfort-frequency, flank discomfort-degree, nausea, abdominal pain-frequency, tendons spasm-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting water, abnormal stools-loose stools and diarrhea; Male:qi deficiency, qi stagnation, yang deficiency, xue deficiency, total score of symptom, fatigue and weakness-degree, spontaneous-frequency, pruritus, dry eye-frequency, hypochondriac-frequency, hypochondriac-degree, flank fullness-frequency, flank fullness-degree, flank pain-frequency, flank pain-degree, flank discomfort-frequency, flank discomfort-degree, nausea, tendons spasm-frequency, anorexia greasy and thirsty without wanting water; Female:yang deficiency, chilliness-frequency, chilliness-degree, surface-dull degree, flank pain-degree, anorexia greasy and thirsty without wanting water, abnormal stools-loose stools and diarrhea; Active stage:xue deficiency, total score of symptom, pruritus, surface-dull degree, dizziness-degree, flank pain-frequency, flank pain-degree, nausea, epigastric pain-degree, epigastric pain-frequency, waist and leg chills-frequency, tendons spasm-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting water; Quiescent stage:qi deficiency, yin deficiency, yang deficiency, total score of symptom, fatigue and weakness-degree, irritability-degree, surface-dull degree, dry eye-frequency, dry eye-degree, flank pain-frequency, nausea, anorexia greasy, thirsty with wanting water-frequency and thirsty without wanting water.), Group B (including qi stagnation, yin deficiency, yang deficiency, total score of symptom, fatigue and weakness-frequency, irritability-degree, teeth bleed-frequency, teeth bleed-degree, dry skin, dry eye-degree, chest tightness-frequency, sigh, nausea, epigastric distension or fullness-frequency, tendons spasm-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting water, abnormal stools-loose stools and diarrhea; Male:qi deficiency, yin deficiency, yang deficiency, xue deficiency, total score of symptom, fatigue and weakness-degree, fatigue and weakness-frequency, irritability-frequency, teeth bleed-frequency, chest tightness-degree, sigh, nausea, waist and knee soreness-frequency, waist and knee soreness-degree, anorexia greasy, abnormal stools-loose stools and diarrhea; Female:dry skin, nausea, anorexia greasy and thirsty without wanting water, dreaminess, foot and shank edema-degree; Active stage:yin deficiency, xue deficiency, total score of symptom, night sweat-frequency, night sweat-degree, irritability-frequency, hemorrhinia-frequency, hemorrhinia-degree, squamous and dry skin, dry skin, dry eye-degree, nausea, hiccup, tendons Lsm-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting water; iescent stage:yang deficiency, total score of symptom, fatigue and akness-frequency, irritability-degree, teeth bleed-frequency, surface-dull degree, sigh, isea, anorexia greasy, night sweat-frequency, abnormal stools-loose stools and diarrhea), Group C (including qi deficiency, qi stagnation, yin deficiency, yang deficiency, xue iciency, total score of symptom, fatigue and weakness-frequency, fatigue and akness-degree, short of breath and reluctant to speak-frequency, short of breath and actant to speak-degree, feverish palms and soles, chilliness-frequency, spontaneous spiration-frequency, night sweet-frequency, night sweet-degree, surface-dull degree, sigh, isea, hiccup, abdominal distension-degree, waist and knee soreness-frequency, waist and ee soreness-degree, waist and leg chills-frequency, waist and leg chills-degree, tendons sin-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting water, omnia-degree; Male:qi deficiency, qi stagnation, yin deficiency, yang deficiency, xue iciency, total score of symptom, fatigue and weakness-frequency, fatigue and akness-degree, short of breath and reluctant to speak-frequency, short of breath and ictant to speak-degree, afternoon fever, chilliness-frequency, chilliness-degree, night set-frequency, night sweet-degree, pruritus, surface-dull degree, flank discomfort-degree, isea, abdominal distension-degree, waist and knee soreness-degree, waist and leg lls-frequency, anorexia greasy and thirsty without wanting water, insomnia-frequency, omnia-degree, dreaminess; Female:yin deficiency, surface-dull degree, nausea, waist and ;e soreness-frequency, tendons spasm-frequency, tendons spasm-degree, anorexia greasy; tive stage:qi deficiency, yang deficiency, damp and heat, xue deficiency, total score of nptom, pruritus, dry skin, surface-dull degree, flank discomfort-degree, nausea, hiccup, gastric pain-frequency, waist and knee soreness-degree, waist and leg chills-frequency, >rexia greasy and thirsty without wanting water; Quiescent stage:qi deficiency, yin iciency, yang deficiency, xue deficiency, total score of symptom, fatigue and akness-frequency, fatigue and weakness-degree, short of breath and reluctant to ;ak-frequency, short of breath and reluctant to speak-degree, depression-degree, face-dull degree, nausea, waist and leg chills-frequency, waist and leg chills-degree, dons spasm-frequency, tendons spasm-degree, anorexia greasy and thirsty without wanting ter.②Inter-group comparison:There was statistical significance in qi deficiency (C>B>A), ;gue and weakness-frequency (C>B>A), blurred vision (C>B>A), waist and knee eness-frequency(C>B>A), waist and leg chills-frequency(C>B>A), waist and leg lls-degree(C>B>A); Male:afternoon fever(C>B>A); Female:waist and knee soreness-frequency(C>B>A), waist and knee soreness-degree(C>B>A); Active stage:night sweet-frequency (B>C>A), night sweet-degree (C>A>B); Quiescent stage:qi deficiency(C>A>B), fatigue and weakness-frequency(C>B>A), fatigue and weakness-degree(C>A>B), anorexia-frequency(C>A>B), anorexia-degree(C>A>B). ③The comparison between male and female, active stage and quiescent stage in each group:In terms of gender, there was statistical significance in Group A (including yin deficiency, total score of symptom, dry eye-frequency, dry eye-degree, sigh, waist and knee soreness-frequency, waist and knee soreness-degree, waist and leg chills-frequency, waist and leg chills-degree, anorexia greasy, insomnia-frequency, insomnia-degree), Group B (including qi deficiency, yin deficiency, total score of symptom, fatigue and weakness-frequency, fatigue and weakness-degree, short of breath and reluctant to speak-frequency, short of breath and reluctant to speak-degree, foot shank edema-frequency, foot shank edema-degree, dizziness-frequency, dizziness-degree, chest tightness-frequency, chest tightness-degree, sigh, flank pain-frequency, flank pain-degree, belching, hiccup, waist and knee soreness-frequency, waist and knee soreness-degree, waist and leg chills-frequency, waist and leg chills-degree, drowsiness-frequency), and Group C (including total score of symptom, afternoon fever, suggillation, foot shank edema-frequency, foot shank edema-degree, surface-dull degree, dizziness-frequency, dizziness-degree, nausea, vomit, sweet taste in mouth-frequency, sweet taste in mouth-degree, insomnia-frequency, insomnia-degree). In terms of active and quiescent stage, there was statistical significance in Group A (including fatigue and weakness-degree, bitter taste in mouth-frequency, bitter taste in mouth-degree, night urination), Group B (including night sweet-frequency, night sweet-degree), and Group C(including qi stagnation, fatigue and weakness-frequency, fatigue and weakness-degree, depression-frequency, depression-degree, irritability-frequency, irritability-degree, anorexia-frequency, anorexia-degree).(3) The effects of Chinese herbal medicine in treating patients with compensated HBV-related cirrhosis on liver function. After treatment, the generating function of the liver protein had more significant improvement. ①Intra-group comparison before and after treatment:There was statistical significance in the scores of Group A (including albumin(ALB), prealbumin(PA), aspartate amino transferase(AST), direct bilirubin(DBIL), total bilirubin (TBIL), indirect bilirubin(IBIL), alkaline phosphatase(ALP); Male:ALB, PA, cholinesterase(CHE),TBIL,IBIL,ALP; Quiescent stage:DBIL,TBIL,IBIL,ALP), Group B (including ALB,A/G,PA,DBIL,TBIL,IBIL; Male:ALB, PA, DBIL, TBIL,IBIL; Female: albumin/globulin(A/G), y-glutamyl endopeptidase(y-GGT); Active stage: ALB,PA,DBIL,TBIL,IBIL; Quiescent stage:GLB,TBIL,IBIL,ALP), and Group C (including PA,CHE; Male:CHE; Quiescent stage:A/G,PA,DBIL,ALP).②Inter-group comparison: There was statistical significance in Male:ALP(B>A>C); Female:A/G(A>B>C), CHE(A>C>B); Active stage:DBIL(C>A>B),TBIL(C>A>B),IBIL(C>A>B);③The comparison between male and female, active stage and quiescent stage in each group:In terms of gender, there was statistical significance in Group A (including PA), Group B (including PA, GGT, TBA, CHE, ALT), and Group C (including GLB, A/G, ALB, PA, ALP). In terms of active and quiescent stage, there was statistical significance in Group A (including DBIL, TBIL, IBIL, ALT, AST, GGT, TBA), Group B (DBIL, TBIL, IBIL), and Group C(including TP, DBIL, TBIL, IBIL).(4) The effects of Chinese herbal medicine in treating patients with compensated HBV-related cirrhosis on liver coagulation. After treatment, the coagulation parameters had some improvement. ①Intra-group comparison before and after treatment:There was statistical significance in the scores of Group A (including prothrombin activity(PA); Female:PTA; Quiescent stage:PTA, activated partial thromboplastin time(APTT), Group B (including PTA, Male:PTA, plasma fibrinogen(FIB), prothrombin time ratio(INR); Quiescent stage:PTA), and Group C (including PTA, APTT, FIB, prothrombin time(PT), INR; Male:PTA, APTT, FIB, PT, INR; Female:APTT; Active stage:PTA,APTT,FIB; Quiescent stage:PTA, INR, PT). ②Inter-group comparison:There was statistical significance in Male:FIB(A>B>C); Female: APTT(C>A>B);③The comparison between male and female, active stage and quiescent stage in each group:In terms of gender, there was statistical significance on FIB in Group C. In terms of active and quiescent stage, there was statistical significance in Group A (including PT, INR, APTT), Group B [PT, PTA, INR, APTT, Thrombin time(TT), FIB], and Group C(including FIB).(5) The effects of Chinese herbal medicine in treating patients with compensated HBV-related cirrhosis on hemodynamics of portal vein and splenic. After treatment, the hemodynamics of portal vein and splenic had some improvement. ①Intra-group comparison before and after treatment:There was statistical significance in the scores of Group A (including portal vein diameter(Dpv)), Group B (including portal vein mean velocity(Vpv) and Portal vein blood flow(Qpv). ②Inter-group comparison:There was no statistical significance among the three groups. ③The comparison between male and female, active stage and quiescent stage in each group:In terms of gender, there was statistical significance on Vpv in Group B. In terms of active and quiescent stage, there was statistical significance in Group A (including Dpv), Group B [splenic vein diameter(Dsv), splenic venous blood flow (Qsv).Conclusions(1) Based on literature research, CHM combined with NAs have some advantages in treating patients with compensated HBV-related cirrhosis than NAs.(2) After the intervention of Formula A, Formula B and Formula C, there has a certain extent improvement on macro indicators (health-related quality of life, syndrome elements and symptoms) and micro indicators (liver function, liver coagulation, portal vein and splenic hemodynamics), and some of them have statistical difference. However, there is no statistical difference among the three groups.(3) Formula A had a greater magnitude of improvement on male and active stage patients. Formula B had a greater magnitude of improvement on female patients, while it had a negative effect on active stage patients.(4) According to the intervention effect trend differences of Formula A and Formula B between male and female, active stage and quiescent stage, we can draw some inspiration and provide some basis evidence on illustrating traditional Chinese medicine "Liver Storing Blood and Governing Free Flow of Qi" theory and clinical practice. In clinic, when we treat complicated disease by Chinese herbal medicine such as HBV-related cirrhosis, we should consider comprehensively of the diseases’stages (such as resting stage and active stage, etc.) and the patient’s individual differences (such as male, female, etc.) to adjust medication. |
