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0JTCM
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JTradit Chin Med 2012 December 15; 32(4): 538-544
ISSN 0255-2922 © 2012 JTCM. All rights reserved.
CLINICAL OBSERVATION
Distribution of Traditional Chinese Medicine patterns in 324 cases with hepatitis B-related acute-on-chronic liver failure: a prospective, cross-sectional survey
Xiaoyu Hu, Yang Zhang, Guo Chen, Yibei Li, SenZhong
Xiaoyu Hu, Yang Zhang, Guo Chen, Sen Zhong, Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Chinese Medicine, Chengdu 610072, China Yibei Li, Department of Endocrinology, Affiliated Hospital of Chengdu University of Chinese Medicine, Chengdu 610072, China
Supported by the National Science and Technology Major Project of the Ministry of Science and Technology of China (No. 2008ZX1005)
Correspondence to: Prof. Xiaoyu Hu, Department of Infectious Diseases, Affiliated Hospital of Chengdu University of Chinese Medicine, Chengdu 610072, China. meddmail@ya-hoo.com.cn
Telephone: +86-28-88020249 Accepted: March 13,2012
Abstract
OBJECTIVE: To determine the distribution of Traditional Chinese Medicine (TCM) patterns in hepatitis B-related acute-on-chronic liver failure (HB-ACLF) in different stages for guiding clinical prescriptions and treatments.
METHODS: A prospective, cross-sectional survey method was used in this study. A total of 324 cases with HB-ACLF in China were involved.
RESULTS: The general frequency of TCM patterns in HB-ACLF were as follows: Heat Toxin Stagnation Pattern (134/324, 41.36%), Damp-heat Obstruction Pattern (66/324, 20.37% ), Yang Qi Deficiency Pattern (52/324,16.05%), and Liver and Kidney Yin Deficiency Pattern (26/324, 8.02%). In the early stage of HB-ACLF, there was a remarkably higher percentage of excessive patterns than those in the middle
and late stage. The incidence of Heat Toxin Stagnation reached 58.57% (82/140) in the early stage, while it was 33.96% (36/106) in the middle stage and 20.51% (16/78) in the late stage. In the early stage of HB-ACLF, excessive patterns, such as the Heat Toxin Stagnation Pattern, were more prevalent than those in the middle and late stages (P<a'= 0.003). However, in the late stage of HB-ACLF, deficient patterns, such as the Yang Qi Deficiency Pattern, were more prevalent than those in the early and middle stages. The Yang Qi Deficiency Pattern had a higher rate of 41.03% (32/78) in the late stage compared with that of 20.75% (22/106) in the middle stage and 8.57% (12/140, P<a' =0.003) in the early stage. The distribution of the other patterns was not significant between the three stages (P>0.003).
CONCLUSIONS: There are four major patterns of HB-ACLF, including the Heat Toxin Stagnation Pattern, the Damp-heat Obstruction Pattern, the Yang Qi Deficiency Pattern, and the Liver and Kidney Yin Deficiency Pattern. The Heat Toxin Stagnation and Yang Qi Deficiency Patterns are the representative patterns in the early and late stages of HB-ACLF. In the middle stage of HB-ACLF, the TCM patterns vary in a complicated manner, with no significant difference among the patterns. Treatment for HB-ACLF should vary with the different representative patterns in the early and late stages.
© 2012 JTCM. All rights reserved.
Keywords: Hepatitis B; Liver failure, Acute; Statistical distributions;Traditional Chinese Medicine patterns
INTRODUCTION
Acute-on-chronic liver failure (ACLF) is a severe liver disease. ACLF develops from chronic liver diseases under acute occasions, manifesting as jaundice and disturbance of blood coagulation, with complications of ascites and (or) hepatic encephalopathy within 4 weeks. Hitendra Garg1 showed that 30% to 50% of ACLF patients have liver-related complications and most of them die of multiple organ dysfunction. Approximately 75% of untreated ACLF patients die,2 and therefore it is an acute and severe disease. The three main causes of ACLF are hepatitis B virus (HBV) infection (90.29%), alcoholic liver disease (2.65%), and superinfection of HBV and hepatitis E virus (HEV) (2.26%).3 An epidemiological study on TCM patterns of hepatitis B-related (HB)-ACLF in different stages would be useful for classification and treatment, as well as basic data for establishment of national medicare policies. In recent years, there has been little research on TCM patterns of chronic severe hepatitis, of which diagnostic criteria were determined at the 10th National Viral Hepatitis Conference in 2000, Xi'an. None of these diagnostic criteria are on the basis of the diagnostic standard given in the Guideline of Diagnosis and Treatment of Liver Failure in 2006.
We collected data on 324 HB-ACLF inpatients of the Sichuan Region and determined the distribution of the TCM patterns for HB-ACLF in different stages to guide clinical prescriptions and treatments.
METHODS
Patients
This prospective, cross-sectional survey was conducted using data of 324 inpatients who were admitted to the Affiliated Hospital of Chengdu University of Chinese Medicine from September 2007 to October 2009. This study was approved by the appropriate ethics committees and was performed in accordance with the ethical standards laid down in the Declaration of Helsinki. All persons signed their informed consent prior to their inclusion in the study.
Diagnostic standard
According to the Guideline for the Diagnosis and Treatment of Liver Failure4 formulated in 2006 by the Chinese Academic Association of Infectious Diseases and the Chinese Academic Association of Liver Diseases, ACLF is a rapid and acute liver disease based on chronic liver disease, and is divided into three stages. In the early stage, symptoms are as follows: 1) extreme fatigue with severe digestive symptoms, such as obvious anorexia, vomiting, and abdominal distention; 2) aggressive jaundice (serum bilirubin >171 |xmol/L or a daily increase by >17.1 |xmol/L); 3) a trend of hemorrhage, with 30% <prothrombin activity (PTA) <40%; and 4)
no symptoms of hepatic encephalopathy or obvious as-cites. In the middle stage, patients either have liver en-cephalopathy below the second degree and (or) obvious ascites, or an obvious trend of hemorrhage (bleeding point or suggillation), with 20% <PTA <30%. In the late stage, patients become worse with any one of the following conditions: 1) intractable complications, such as hepatorenal syndrome, massive hemorrhage of the upper gastrointestinal tract, serious infection, and intractable electrolyte disturbance; 2) hepatic encepha-lopathy beyond the third degree; and 3) a severe trend of hemorrhage (petechiae in the injection position), with PTA <20%.
Exclusion criteria
Exclusion criteria were as follows: 1) acute liver failure, sub-acute liver failure, and chronic liver failure; 2) non-HBV-infection related ACLF; 3) pregnant or lac-tating women; 4) patients with primary liver cancer; 5) patients with other serious systemic or psychiatric diseases; 6) patients younger than 18 years or older than 65 years.
Inclusion criteria
Inclusion criteria were 1) inpatients in accordance with the above-mentioned diagnostic criteria; 2) patients without any one item of exclusion criteria; 3) patients who coordinated with doctors; 4) patients who had the necessary clinical examinations.
Collection of patient's data
Every patient was examined by two trained researchers and their information was analyzed with a prospective, cross-sectional survey method. The valid information collection period was within 24 h from patients' confirmation of HB-ACLF. If the two researchers disagreed about the TCM syndrome differentiation, the case was excluded from the study.
Criteria of TCM differentiation and diagnosis
The criteria of TCM differentiation and diagnosis ref-fered to the TCM Differentiation Criteria on Viral Hepatitis Draft5 formulated by the Chinese TCM Academic Association of Hepatic Diseases, the Guidelines for Clinical Research on Chinese New Herbal Treatment on viral hepatitis formulated by the Sino-Food and Drug Administration6, and other sources.7 Heat Toxin Stagnation Pattern: Major symptoms of the Heat Toxin Stagnation Pattern were as follows: 1) yellow and normal urine; 2) skin itching, bleeding point after scratching, or a burning sensation; 3) purple and dark tongue with suggillation, and an enlarged and prolonged sublingual vein.
Minor symptoms were as follows: 1) feeling thirsty but drinking little; 2) dry stool; 3) bleeding nose and gums, or suggillation in the skin; 4) undesirable hypo-chondrial mass; 5) less tongue coating, a thin and white coating or a thin and yellow coating, or a wiry, or wiry and choppy pulse.
Diagnostic criteria: 1) all major symptoms were present; and 2) two of the three major symptoms and two of the five minor symptoms were present. Damp-heat Obstruction Pattern: major symptoms of the Damp-heat Obstruction Pattern were as follows: 1) jaundice of the body, and the eyes are a bright yellow color; 2) a yellow and greasy tongue coating. Minor symptoms of the Damp-heat Obstruction Pattern were as follows: 1) nausea, aversion to oil, and poor appetite; 2) hypochondrial distention and abdominal fullness; and 3) yellow urine.
Diagnostic criteria: 1) two major symptoms were present; 2) major symptom 2) and any two of the three minor symptoms were present; and 3) major symptom 1) and minor symptoms 1) and 2) were present. Yang Qi Deficiency Pattern: major symptoms of the Yang Qi deficiency pattern were as follows: 1) chilly and cold limbs; and 2) fatigue and a weak pulse. Minor symptoms of the Yang Qi Deficiency Pattern were as follows: 1) cold sensation and pain in the hypogastrium, waist and knees; 2) bad appetite and diarrhea even in the morning; 3) lower limb edema; and 4) a clammy scrotum.
Diagnostic criteria: 1) two major symptoms were present; 2) major symptom 1) or 2) and any two of the four minor symptoms were present; 3) the first three minor symptoms were present, or for males, any two of the first three minor symptoms and minor symptom 4). Spleen Failing to Control Blood Pattern: Major symptoms of the Spleen Failing to Control Blood Pattern were as follows: 1) bleeding nose and gums, suggilla-tion, hamatemesis, and hematochezia; 2) jaundice, with a dark yellow color in the whole body. Minor symptoms of the Spleen Failing to Control Blood Pattern were as follows: 1) energy sag; 2) fatigue and bad appetite; and 3) a pale tongue, and deep and thin pulse.
Diagnostic criteria: 1) two major symptoms and any two of the three major symptoms were present; 2) one major symptom and all three minor symptoms were present. Turbid Dampness Overflowing Pattern: major symptoms of the Turbid Dampness Overflowing Pattern were as follows: 1) wandering mind; 2) jaundice, with a dark yellow color in the whole body; and 3) loose stool. Minor symptoms of the Turbid Dampness Overflowing Pattern were as follows: 1) oliguria; 2) bad appetite or vomiting; and 3) a soggy and choppy pulse. Diagnostic criteria: 1) all major symptoms were present; 2) major symptoms both 1) and 2), or 3), and any two of the three minor symptoms were present; and 3) major symptom 1) and all three minor symptoms were present.
Yin and Yang Separation and Collapse Pattern: major symptoms of the Yin and Yang Separation and Collapse Pattern were as follows: 1) coma; 2) polypnea; and 3) dark facial color with red cheeks. Minor symptoms of the Yin and Yang Separation and Collapse Pattern were as follows: 1) urinary and fecal
incontinence; 2) sweating severely; and 3) an enlarged and hollow pulse or a slippery, faint and thin pulse. Diagnostic criteria: 1) all major symptoms were present; 2) major symptoms both 1) and 2), or 3), and any two of the three minor symptoms were present; 3) major symptom 1) and all three minor symptoms were present.
Liver and Kidney Yin Deficiency Pattern: major symptoms of the Liver and Kidney Yin Deficiency Pattern were as follows: 1) dizziness and blurred vision; 2) aching and weakness of the waist and knees; and 3) a red tongue with little fluid.
Minor symptoms of the Liver and Kidney Yin Deficiency Pattern were as follows: 1) heat in the chest, palms and soles; 2) insomnia with dreams; 3) pain in the hypochondrial region, which is aggravated when fatigued; and 4) a thin and rapid pulse. Diagnostic criteria: 1) all major symptoms were present; 2) any two major symptoms and any two of the four minor symptoms were present; 3) any one major symptom and any three minor symptoms were present; and 4) all minor symptoms were present. Liver Depression and Spleen Deficiency Pattern: major symptoms of the Liver Depression and Spleen Deficiency Pattern were as follows: 1) hypochondrial distending pain; and 2) abdominal distention with loose stool. Minor symptoms ofthe Liver Depression and Spleen Deficiency Pattern were as follows: 1) depression and vexation; 2) fatigue; and 3) a pale tongue with teeth prints. Diagnostic criteria: 1) two major symptoms were present; 2) major symptom 1) and minor symptoms 2) and 3) were present; 3) major symptom 2) and minor symptom 1) were present.
Dampness Obstructing the Spleen and Stomach Pattern: major symptoms of the Dampness Obstructing the Spleen and Stomach Pattern were as follows: 1) stomach fullness with a poor appetite; and 2) a greasy tongue coating.
Minor symptoms of the Dampness Obstructing the Spleen and Stomach Pattern were as follows: 1) heavy sensation of limbs; 2) sticky sensation in the mouth; and 3) loose stool and diarrhea.
Diagnostic criteria: 1) two major symptoms were present; 2) one major symptom and two minor symptoms were present.
Stasis-heat and Phlegm Obstruction Pattern: Major symptoms of the Stasis-heat and Phlegm Obstruction Pattern were as follows: 1) a long period of jaundice with a dark color; and 2) itchy skin. Minor symptoms of the Stasis-heat and Phlegm Obstruction Pattern were as follows: 1) a dark red tongue; 2) distending pain at the right hypochondrial region; and 3) stool with a light color or gray color. Diagnostic criteria: 1) major symptom 2) was present; 2) major symptom 1) and two minor symptoms were present.
Liver Depression and Qi Stagnation Pattern: major symptoms of the Liver Depression and Qi Stagnation Pattern were as follows: 1) hypochondrial distending pain; and 2) a wiry pulse.
Minor symptoms of the Liver Depression and Qi Stagnation Pattern were as follows: 1) poor appetite; 2) dizziness; 3) depressive mood; and 4) for females: irregular menstruation and distending sensation of the breasts during menses.
Diagnostic criteria: 1) two major symptoms were present; 2) major symptom 1) and two minor symptoms were present; 3) major symptom 2) and three minor symptoms were present.
Typing ofHBVGenotypes/subgenotypes
Genotyping was based on S-gene sequences encompassing the reverse-transcriptase domain of HBV, which was amplified by an in-house nested PCR assay as previously described.8 The entire 1225 bp fragments (nt 54-1278) amplified were directly sequenced. HBV genotypes and subgenotypes were determined by molecular evolutionary analysis of the viral sequences using MEGA 4 software (www.megasoftware.net). Phyloge-netic trees were constructed using neighbor-joining analysis with bootstrap test confirmation performed on 1000 resamplings. Standard reference sequences were acquired from the online Hepatitis Virus Database (http://www.ncbi.nlm.nih.gov/projects/genotyping/ formpage.cgi) as previously reported.9
Research flow chart
A flow chart of the research is shown in Figure 1.
Figure 1 Flow chart of the research Statistics analysis
We analyzed the data with SPSS 17.0 (Cabit Information Technology Co, Ltd). The trial used RxC test statistical methods, and P<0.01 indicated the distribution of the TCM patterns in the different stages showed a significant difference. The Bonferroni method was used to adjust for multiple comparisons, which was P< a'=2a/k(k-1) =0.003, for comparison among the groups,
and this showed whether there was a significant difference of the constituent ratio of the TCM patterns in the different stages.
RESULTS
Clinical data
Among the 324 HB-ACLF inpatients studied from September 2007 to October 2009, 236 were male patients (72.84%) and 88 were female patients (27.16%), aged 19-65 years [(44±9) years old]. There were 140, 106, and 78 cases in the early, middle and late stages, respectively.
Baseline information
The patients' basic information, laboratory information, and complications are shown in Table 1.
The Relationship between TCM patterns and clinical stages in HB-ACLF cases
The distribution of TCM patterns in the 324 HB-ACLF cases were as follows. In the early stage of HB-ACLF, the main patterns were the Heat Toxin Stagnation Pattern (82/140, 58.57%), the Damp-heat Obstruction Pattern (22/140, 15.71%), the Yang Qi Deficiency Pattern (12/140, 8.57%), and the Liver and Kidney Yin Deficiency Pattern (8/140, 5.71%). In the middle stage, the main patterns were the Heat Toxin Stagnation Pattern (36/106, 33.96%), the Damp-heat Obstruction Pattern (20/106, 18.87% ), the Yang Qi Deficiency Pattern (22/106, 20.75% ), and the Liver and Kidney Yin Deficiency Pattern (12/106, 11.32%). In the late stage, the main patterns were the Yang Qi Deficiency Pattern (32/78, 41.03% ), the Heat Toxin Stagnation Pattern (16/78, 20.51%), the Damp-heat Obstruction Pattern (10/78, 12.82%), and the Liver and Kidney Yin Deficiency Pattern (6/78, 7.69%). The TCM patterns were processed into binomial information (positive and negative) with the Rx C test. The Heat Toxin Stagnation Pattern and Yang Qi Deficiency Pattern had a significant difference in the distribution of different stages, that is, the Heat Toxin Stagnation and Yang Qi Deficiency Patterns were the representative patterns in the early and late stages of HB-ACLF. However, the other patterns, including Damp-heat Obstruction, Liver and Kidney Yin Deficiency, Liver Depression and Spleen Deficiency, Dampness Obstructing the Spleen and Stomach, Stasis-heat and Phlegm Obstruction, and Liver Depression with Qi Stagnation, did not show any significant differences in the distribution of different stages (P>0.05, Table 2). The incidence of the Heat Toxin Stagnation Pattern in the early stage was much higher than that in the middle and later stages (P<a' =0.003, Table 3). The incidence of the Yang Qi Deficiency Pattern was higher in the late stage than that in the early and middle stages. (P<a'=0.003, Table 4).
able 3 Distribution of the Heat-toxin Stagnation Pattern |the three stages of HB-ACLF_
Stage Positive Negative Total „ .„,.
6 6 Rate (%)
Early 82 58 140 58.57ab
Middle 36 70 106 33.96
Late 16 62 78 20.51
Total 134 190 324 44.95
Notes: HB-ACLF: hepatitis B-related acute-on-chronic liver failure; aP<0.003, x2=14.638, compared with middle stage; bP<0.003, x2=14.638, compared with late stage.
DISCUSSION
The diagnostic criteria of liver failure have been rapidly updated in recent years. Liver failure is a syndrome with characteristics of hepatic encephalopathy and coagulation disturbance caused by acute hepatocyte necrosis or progressive liver function impairment. In
Table 4 Distribution of the Yang Qi Deficiency Pattern in the .three stages of HB-ACLF_
Stage Positive Negative Total Positive Rate (%)
Late 32 46 78 41.03ab
Middle 22 84 106 20.75
Early 12 128 140 8.57
Total 44 174 218 20.18
Notes: HB-ACLF: hepatitis B-related acute-on-chronic liver failure; aP<0.003, x2=13.429, compared with middle stage; bP<0.003, X2=32.751, compared with early stage. 2000, the 10th National Viral Hepatitis Conference in Xi'an, China changed the diagnostic criteria of severe hepatitis10 and confirmed the diagnostic criteria of hepatic failure. In 2005, the American Association for the Study of Liver Failure issued the Management of Acute Liver Failure.11 In 2006, the Liver Failure and Artificial Liver Group of the Chinese Society of Infectious Diseases and the Severe Liver Diseases and Artificial Liver
Table 1 Baseline analysis of the 324 HB-ACLF cases
Demographic Data Laboratory Data Complication
Sex (male/female) 236/88 TBIL (pmol/L) 468±122 Ascites [n (%)] 268 (82.7)
Age [year (range)] 44 (19-65) ALT (IU/L) 325±96 Infection [n (%)] 141 (43.5)
Genotype B [n (%)] 104 (32.10) HBV DNA Gastrointestinal hemorrhage 2 2 /Ifl 1\
Genotype C [n (%)] 217 (66.98) (logcps/mL) 6±2 Encephalopathy [n (%)] 33 (10.2)
I-II [n (%)] 107 (33.0)
Genotype D [n (%)] 3 (0.93) HBeAg+ [n (%)] 122 (37.7) 54 (16.7)
III-IV [n (%)]
- - PTA 28±10 Hepatorenal syndrome
- - CPT score 9±4 I [n (%)] 6(1.9)
- - MELD score 25±12 II [n (%)] 5(1.5)
Notes: HB-ACLF: hepatitis B-related acute-on -chronic liver failure;TBIL: total bilirubin; ALT: alanine aminotransferase;HBV: hepatitis B
virus; PTA: prothrombin activity;
|Table 2TCM patterns of 324 HB-ACLF cases
Stage (n, %) Total Percentage
Pattern (%)
Early Middle Later
Heat Toxin Stagnation 82 58.57 36 33.96 16 20.51 41.36
Damp-heat Obstruction 22 15.71 20 18.87 10 12.82 16.05
Yang Qi Deficiency 12 8.57 22 20.75 32 41.03 20.37
Spleen failing to Control 2 1.43 4 3.77 5 6.41 3.40
Turbid Dampness 6 4.29 7 6.60 11 14.10 7.41
Overflowing
Yin and Yang Separation 4 2.86 11 10.38 16 20.51 9.57
and Collapse
Liver and Kidney Yin 8 5.71 12 11.32 6 7.69 8.02
Deficiency
Liver Depression and 10 7.14 4 3.77 4 5.13 5.56
Spleen Deficiency 4.32
Dampness Obsructing 2 1.43 6 5.66 6 7.69
the Spleen and Stomach
Stasis-heat and Phlegm 4 2.86 2 1.89 0 0.00 1.85
Obstruction
Liver Depression and Qi 0 0.00 4 3.77 4 5.13 2.47
Stgnation
Total 140 100.00 ) 106 100.00 78 100.00 100.00
Notes: overall distribution of different stages: Heat Toxin Stag. P<0.01, x2=33.469; Yang Qi Def. P<0.01, x2=32.54l
Group of the Chinese Medical Association issued the first Diagnostic and Treatment Guidelines for Liver Failure.4 In 2009, the APASAL conference issued the Acute-on-chronic Liver Failure Consensus and Discussion Draft, which differentiated ACLF from chronic liver failure (CLF). The Acute-on-chronic Liver Failure Consensus and Discussion Draft defined ACLF' s diagnostic criteria from a functional aspect and discussed details regarding ACLF (for example, definition, cause, pathophysiology, clinical manifestations, diagnosis, differential diagnosis, prognosis, and treatment). The issued guidelines and consensus mentioned above remarkably improved the understanding, diagnosis, and treatment of ACLF.
Most scholars believe that chronic severe hepatitis discussed in the 10th National Viral Hepatitis Conference in 2000, Xi'an includes ACLF and CLF which were discussed in the Guideline of Diagnosis and Treatment of Liver Failure in 2006. However, CLF is chronic liver decompensation on the basis of cirrhosis accompanied by ascites or portal hypertension, dysfunction of coagulation, and hepatic encephalopathy.12 ACLF and CLF have remarkable differences in results of laboratory examinations, complications and prognosis, such as alanine ami-notransferase, aspartate aminotransferase, albumin, globulin, coagulation parameters, cholinesterase, complications of hepatic encephalopathy, upper digestive tract hemorrhage, ascites, spontaneous bacterial peritonitis, infection, and mortality.13-14 In summary, the clinical manifestations, treatment, and prognosis of ACLF and CLF have significant differences and should be differentiated, which also applies in the study of TCM patterns. The differentiation for ACLF and CLF applies not only for conception, but also for treatment and prognosis according to differentiation.
Recent studies on the TCM patterns in China have mainly focused on chronic severe hepatitis which were discussed in the 2000 Xi'an Conference. It is important to determine the distribution of TCM patterns for HB-ACLF because the Guideline of the Diagnosis and Treatment of Liver Failure confirmed new diagnostic criteria of ACLF and CLF.
Our study showed that the excessive patterns comprised the major part of the early stage of HB-ACLF, (e. g., Heat Toxin Stagnation Pattern, Damp-heat Obstruction Pattern, Yang Qi Deficiency Pattern, and Liver and Kidney Yin Deficiency Pattern). In the late stage of HB-ACLF, the deficient patterns comprised the greatest proportion (e.g., Yang Qi Deficiency Pattern, Heat Toxin Stagnation Pattern, Damp-heat Obstruction Pattern, and Liver and Kidney Yin Deficiency Pattern). In the middle stage, distribution of TCM patterns for HB-ACLF were prone to an intermediate state of excessive and deficient patterns with the Heat Toxin Stagnation Pattern, the Damp-heat Obstruction Pattern, the Yang Qi Deficiency Pattern, and the Liver and Kidney Yin Deficiency Pattern. The general frequency of TCM patterns in HB-ACLF can be present-
ed as follows: Heat Toxin Stagnation Pattern (134/324, 41.36% ), Damp-heat Obstruction Pattern (66/324, 20.37% ), Yang Qi Deficiency Pattern (52/324, 16.05%) and Liver and Kidney Yin Deficiency Pattern (26/324, 8.02%). Our results indicated that the TCM patterns in HB-ACLF transformed in each stage. The Heat Toxin Stagnation Pattern was the representative pattern in the early stage, and it was significantly more prevalent than that in the middle and late stages. The Yang Qi Deficiency Pattern was the representative pattern in the late stage, and it was significantly more prevalent than that in the early and middle stages. Other patterns, including Damp-heat Obstruction, Liver and Kidney Yin Deficiency, Liver Depression and Spleen Deficiency, Dampness Obstructing the Spleen and Stomach, Stasis-heat and Phlegm Obstruction, and Liver Depression with Qi Stagnation were not significantly different among the early, middle and late stages of
HB-ACLF.
HB-ACLF has different immunological backgrounds in different stages according to modern medicine. In the early stage of HB-ACLF, the immune system induces massive and submassive necrosis of liver cells as a result of immune hyperfunction.15 Studies indicate that clearing therapy of TCM can decrease the mortality of HB-ACLF in the early stage by eliminating immune complexes and endotoxin, inhibiting inflammation, promoting regeneration, and ameliorating symptoms as a result of suppression of immune hyperfunction.16 In the late stage of HB-ACLF, immune hypofunction develops, with significantly less total lymphocytes, CD4+, CD8+T cells, and NK cells compared with those in the early stage. Therefore, the lymphocyte subset is an effective marker to predict the prognosis of HB-ACLF patients. HB-ACLF death cases were more concentrated in the late stage with much less total lymphocytes, CD4 +, CD8 + T cells, and NK cells than those in cases that survive (P<0.05), which demonstrates that a reduction in immunocompetent cells in peripheral blood may be the driving factor for deterioration of HB-ACLF.17 TCM-supplementing therapy lessens the mortality of HB-ACLF in the late stage by blocking inflammation reactions, improving hepato-cyte regeneration, and reducing secondary infection.18,19 Treatment for HB-ACLF should vary with different representative patterns in the early and late stages, by clearing and reducing internal heat in the early stage, and warming and supplementing organs in the late stage. In the middle stage of HB-ACLF, a combination of clearing and warming should be applied according to our results of not finding any representative patterns. Our results showed that in different stages of HB-ACLF, the distribution of the TCM patterns remarkably varied. HB-ACLF stages can proclaim ups and downs of not only pathogens but also anti-pathogenic Qi. In the early stage of HB-ACLF, the pathogen and anti-pathogenic Qi are both strong and excessive. In the middle stage, deficiency and excess are mixed. In
the late stage, anti-pathogenic Qi and the pathogen are both weak, altering the disease from excessive to deficient with various complications. This transformation corresponds with general TCM understanding of a change in disease, for which different measures should be taken in each stage as follows: reducing the excess and strengthening the deficiency are important in the early stage and the late stage, respectively, while in the middle stage, the combination of relieving and strengthening should be applied according to pattern differentiation.
Our study provides new ideas for clinical strategies. For example, regular treatment for HB-ACLF patients in the early and late stage could be administered by adding and subtracting components of a root prescription according to TCM patterns. However, in the middle stage, there is no representative pattern, and therefore confirming a root prescription would be difficult, as well as adding and subtracting components of a root. Attention should be paid to designing a flexible therapy according to pattern differentiation to decrease mortality and increase curative effects.
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