Traditional Chinese Medicine (TCM) Syndromes In Immunotolerant Phase (ITP) And Histological Features In Natural History Of Hepatitis B Virus (HBV) Infection

Part I HBV carrier：classifications，characters，and its relationwith natural history of hepatitis B virus infectionBackgroundAbout350-420million people in the world are infected chronically by HBV andmost of them are on the chronic HBV carrier state. Quite a few words or phrases havebeen applied for the denomination of HBV carrier in literatures because there are stillno standard criteria for classifying for HBV carrier. In fact many of them representdifferent states or phases of the natural history of HBV infection. However，patients inthe different phase or state in the natural history of HBV chronic infection areinterlinked or included in one kind of carrier’s name in available documents thatnaming or defining of HBV carrier. Hence it is necessary to classify and de fine thosedifferent states or phases of HBV carrier on the basis of natural history of HBVinfection. ObjectiveTo find a new way，which is in conformity with the principle of treatment basedon differentiation and the ever-moving point of TCM，for classifying and definingHBV carriers in different states or phases.MethodsWe have subdivided and defined chronic HBV carriers according to thepositivity or negativity of HBeAg and HBsAg by imitating the classification ofchronic hepatitis B.ResultsChronic HBV carrier into HBeAg positive carrier, HBeAg negative carrier,HBsAg positive carrier and HBsAg negative and HBeAg positive carrier，HBsAgnegative and HBeAg negative carrier，HBsAg negative and HBVDNA negativecarrier，on the basis of natural history of HBV infection and consideration of thefollowing factors，including the activity of ALT，statuses of HBV markers, HBVDNA levels, and HBV variants. The above six kinds of chronic HBV carriers are ininactive state. The former three are in immunotolerant phase(ITP)，the latter three inthe phase of immune clearance (ICP). What is more，the differential diagnosisbetween chronic HBV carrier and hepatitis B has also been mentioned in this paper.SignificanceMost of chronic HBV carriers，both in ITP and low or non-replication phase（LRP），can be included using this new way for those subversions and definitions. Itsadvantages lie in every kind of carrier only referring to ITP or LRP with or withoutHBV mutation in patients. Their connotations and denotations are different and clear.Obviously, this way for HBV carriers’ classification and definition will be of greathelp for making measures of the management of patients chronically suffered fromHBV，and for undertaking clinical researches and evaluating documents，as well ascorrespond to the core of traditional Chinese medicine. PartⅡ Traditional Chinese medicine (TCM) SyndromeDistribution of Chronic hepatitis B virus (HBV)Carriers in Immunotolerant Phase(ITP)BackgroundMost of patients infected chronically by HBV，thought to be responsible formother to-child transmission，especially residing in the Asia-Pacific region includingour country，are in ITP of natural history. These suffered cases are defined as chronicHBV carriers in the Chinese guidelines，issued in2010，of prevention and treatmentfor chronic hepatitis B. They are the major infectious reservoir due to high viremiaand their long-term outcome are not good. So if want to eradicate HBV infection, themanage of infected patients in ITP is especially important. However, studies on theirTCM syndromes distribution are few up to now.ObjectiveTo explore TCM syndrome distribution of chronic HBV carriers in ITP.MethodsOne hundred and eighty-five chronic HBV carriers in ITP, seen in the thirdaffiliated hospital of Sun Yat-sen university from May2009to December2010, wereadmitted in an observational study under the guidance of TCM. Patients’ TCMsymptoms and signs, demographics, liver biochemistries, and qualitative HBV DNAwere recorded in the questionnaires firstly. Then TCM syndromes were differentiatedto15detailed types and analyzed by generalization. Lastly, the location, pathogenicfactors and nature of the disease were also assessed.ResultsWhen TCM syndrome patterns were differentiated to15types, no syndromecases were27（15%）, single syndrome cases were94（50%）and compoundsyndromes presented in64cases（35%）. The main detailed syndromes included liver-qi depression （LQD）, kidney-qi deficiency(KQD), spleen-qi deficiency(SQD)and kidney-yang deficiency(KYAD). After TCM syndromes generalized tofive types, their frequency was spleen-kidney deficiency (SKD)＞LQD＞innerdamp-heat retention (IDHR)＞liver-kidney deficiency (LKD)＞blood stasis blockingcollateral (BSBC). SKD and LQD occupied64%. The disease location included liver,gallbladder, spleen, stomach and kidney. The pathogenic factors were mainly qistagnation, qi deficiency, yang deficiency, concurrently damp-heat blood stasis. Thedeficiency syndrome was more than excess syndrome in its nature.ConclusionMost of chronic HBV carriers in ITP have their TCM syndrome, and the mostcommon types are SKD, LQD, while IDHR is less than chronic hepatitis B(CHB).This study suggests that the natural history may be improved through breaking thestate of immune tolerance or shorten the time of ITP by strengthening spleen-kidneyand reliving liver qi. Part Ⅲ Relationship between TCM syndromes andHBVDNA in HBeAg positive HBV carriersBackgroundHBV DNA level is significant in predicting the exacerbation of hepatitis B, inevaluating anti-viral effectiveness, and is the risk factor of cirrhosis and HCC.ObjectiveTo explore the relationship between Chinese medicine syndromes and HBVDNAin HBeAg positive HBV carriers.MethodsChinese medicine syndromes of185cases of HBeAg positive HBV carriers weredivided into single syndrome (liver-qi depression, kidney-qi deficiency, spleen-qideficiency, kidney-yang deficiency), compound syndrome and no syndrome, and intoexcess, deficiency and coexistence of deficiency and excess in nature of disease.And serum HBVDNA levels were examined in all cases. Then the relationshipbetween Chinese medicine syndromes and HBVDNA was analyzed. ResultsHBVDNA levels were not significantly different among single syndrome, compoundsyndrome and no syndrome（F=0.910, P=0.404）. HBVDNA levels of singlesyndrome were not significantly different in five different Chinese syndromes（χ~2=4.672，P=0.323）. There was also no significant difference in HBVDNA levelsamong three kinds of nature（F=0.631, P=0.596）.ConclusionHBVDNA levels can not be considered as micro evidence of syndromedifferentiation in HBeAg positive HBV carriers. Part Ⅳ Liver histopathological manifestation in thecontinuous phases of the natural history of hepatitis B virus(HBV)-infectionBackgroundNowadays hepatic histopathologic researches mainly tend to be limited to one ortwo phases of natural history of chronic HBV infection. Great differences lie inpathological changes of ITP. Studies that pathological characteristics in fourcontinuous phases are explored at the same time are seldom undertaken. It is still notknown whether no biopsy-proven inactive states, including immune tolerance and lowor non-replication, are true or not.Objective（ⅰ）To analyze pathological profiles in four continuous phases in the course ofchronic HBV infection and correlation with clinical features.（ⅱ）To judge thesignificance of BU evaluating the inactive state of chronic HBV infection.Methods307chronic HBV-monoinfected patients were categorized according to the phaseof HBV-infection: immune tolerance phase (ITP, n=87), immune clearance phase(ICP, n=96), low or non-replicative phase (LRP, n=34), reactive phase (RAP, n=43),and compensated hepatic cirrhosis (HC，n=27). Liver biopsies were performed andHAI were correlated with their clinical parameters. In addition, the non-discordancebetween “evaluated”state（or phase） and “true” state（or phase） was analyzed.Results①R ates of the grade of inflammation equalto or more than2were52.9%，83.3%，50%，88.4%respectively，and of the stage of fibrosis equal to or more than2were32.2%，64.5%，38.9%，69.8%，in the sequential orders of natural history advance.The degree of liver tissue in the patients belonging to evaluated inactive state destructed significantly less severe than evaluated active state（P=0.000）.②Therewas significantly positive correlation (P <0.01) between ALT, AST and HAI in87cases in ITP. The degree of liver tissue in the patients whose AST more than or equalto30U/L（1.75ULN）destructed significantly more severe than AST less than or equalto30U/L（P＜0.05）.③Patients in evaluated inactive state were also found obviouspathological changes. Rates of the grade of inflammation and the stage of fibrosisequal to or more than2were52.9%，32.2%in patients categorized into ITP. Rates ofthe grade of inflammation and the stage of fibrosis equal to or more than2were50%，38.9%in patients categorized into LRP.④There was significantly positive correlationbetween age, ALT, AST and the degree of liver pathological injury withoutconsideration of patients’different phases. The difference of pathlogical characteristicsamong gender，HBeAg status and HBVDNA levels were not statistically significant.⑤P athlogical changes were more severe in patients with splenomegaly than without.⑥Pathlogical changes were more severe in patients with the TCM syndromes ofBSBC，IDHR，LQD than of LKD, SKD.⑦The rates of non-discordance between BUevaluated ITP and the grade of inflammation and the stage of fibrosis were47%and68%，and50%and61%in LRP.⑧The sensitivity，specificity，positive predictivevalue，and negative predictive value of ultrasonic diagnosis in compensated cirrhosiswere16.7%，92.5%，87.5%，and29.9%respectively.⑨T he sensitivity，specificity，positive predictive value，and negative predictive value of BU evaluation in the gradeof inflammation of true inactive state were72.3%，65.7%,84.3%and48.2%respectively. And in the stage of fibrosis they were63.4%，69.8%,68.1%and64.5%respectively.Conclusion①Elder age，elevated ALT AST，splenomegaly in ultrasonic diagnosis indicatemore severe in hepatic pathological changes. HBVDNA level can not be predictivefactor of pathological changes’degree.②AST may be superior to ALT in reflectingdegree of hepatic injury in ITP.③BU evaluation can be as basic method of thejudgement of true inactive state. But liver biopsy must be performed in order to obtaining more accurate histological activity，especially in those cases， having clinicfeatures of elder age，elevated ALT AST，splenomegaly and TCM syndromes ofBSBC，in whom compensated cirrhosis may has already taken shape.