Autoimmunity Reviews 1(2002)220–225
1568-9972/02/$-e front matter ᮊ2002Elvier Science B.V .All rights rerved.PII:S1568-9972(02)00050-2
Primary biliary cirrhosis and hepatocellular carcinoma
Jorge Findor ,Xiao-Song He ,Juan Sord ,Ruben Terg ,M.EricGershwin *
a b a a b ,University of Buenos Aires,Parguay 2068PB B,Buenos Aires,1425,Argentina
a
Division of Rheumatology,Allergy and Clinical Immunology,University of California at Davis,TB 192,One Shields Avenue,
b
Davis,CA 95616,USA
Received 20September 2001;accepted 10October 2001
fontshow
Abstract
The findings by epidemiological studies on the link between PBC and HCC are in general agreement with the notion that cirrhosis is a risk factor for HCC development.From the clinical perspective,this implies that in PBC patients with cirrhosis,the screening for HCC should be considered for evaluating prognosis as well as therapeutic options.At this time,it is not possible to determine whether any PBC-specific risk factors other than cirrhosis per exist for the development of HCC.Identification of such risk factors may point to new mechanisms involved in the carcinogenesis of HCC.In order to answer the question whether the underlying mechanisms for PBC are risk factors for HCC,more aggressive clinical studies with larger patient populations are needed.Such studies should include patients with PBC as well as patients with cirrhosis of other ethiologies,both have to be carefully matched for patient characteristics including race,gender,age,dia stage and period of follow-up.On the other hand,the resolution of this issue also relies on a better understanding of the molecular pathogenesis of PBC itlf.ᮊ2002Elvier Science B.V .All rights rerved.
cost的用法
Keywords:Primary biliary cirrhosis;Hepatic carcinoma;HCV;HBV
1.Introduction
Primary biliary cirrhosis (PBC )is an autoim-mune liver dia characterized by chronic inflammatory destruction of bile ducts,with an unknown etiology.This dia affects mostly females.It is progressive with a significant pro-portion of patients eventually developing cirrhosis
*Corresponding author.Tel.:q 1-530-752-2884;fax:q 1-530-752-4669.
E-mail address:megershwin@ucdavis.edu (M.E.Gershwin ).
w 1–3x .Hepatocellular carcinoma (HCC ),one of the most common malignant tumors worldwide w 4x ,has been reported in patients with PBC.The median survival time after diagnosis of HCC is less than 1year w 5x .Becau of the very high and rapid mortality rate of HCC,the risk of developing HCC is a concern for patients with PBC.2.Hepatocellular carcinoma
Unlike some other malignancies,such as colo-rectal carcinoma for which a model can be gener-ated bad on known molecular events occurred
221 J.Findor et al./Autoimmunity Reviews1(2002)220–225
during the process of carcinogenesis w6x,pathogen-esis of HCC is largely unknown.However,there are veral clearly identified risk factors associated with HCC,including hepatitis B virus(HBV), hepat
itis C virus(HCV),alcohol,cirrhosis,older age,male gender,etc.Chronic infection with HBV or HCV,especially in patients with liver lesion progresd to cirrhosis,is the most frequent under-lying cau of HCC w7,8x,although the exact molecular mechanisms of hepatocarcinogenesis associated with the virus are still not clear. The prence of cirrhosis is generally considered to be a major risk factor for the development of HCC,as indicated by the fact that the vast majority of virus-associated HCC are accompanied by cir-rhosis.However,veral studies have shown that the risk of developing HCC differs according to the underlying cau of cirrhosis.The cancer risk of hepatitis virus-associated cirrhosis appears to be greater than alcohol-associated cirrhosis,while HCV-associated cirrhosis ems to carry a greater risk of HCC than HBV-associated cirrhosis w9–11x.In addition,although90%of HCC in Amer-ica,Asia and Europe are associated with cirrhosis, up to40%of HCC in South Africa occurred in non-cirrhotic liver tissue w12x.The findings sug-gest that in addition to cirrhosis per ,other factors may also play important roles in the car-cinogenesis of HCC.
The transformation from a normal cell into a malignant tumor cell is believed to be a multi-step process that involves multiple changes at the molecular level,while different risk factors may accelerate this process at different steps.Identifi-cation of the individual risk factors may provide in
sight to the pathogenesis of HCC.For example, in patients with chronic HBV infection,veral viral factors are thought to contribute directly to the malignant transformation of hepatocytes.HBV DNA fragments can be found integrated randomly into the chromosomal DNA of the host cells.This integration ems to occur during the hepatocyte regeneration that follows necroinflammatory activ-ity related to HBV infection.Integration of viral DNA can disrupt the function of regulatory genes and may promote chromosomal instability,a fea-ture of many malignancies w13x.The X protein encoded by HBV appears to have multiple effects on the host cell,including stimulation of cell growth,inactivation of tumor suppressor genes and interference of DNA repair.All the may promote the process of carcinogenesis w14x.Similar phe-nomena are found in HCV.The core protein of HCV is known to interact with veral host pro-teins involved in the regulation of apoptosis and hepatocyte proliferation including:the tumor sup-pressor p53;tumor necrosis factor(TNF)receptor 1;the Fas system;nuclear factor kappa B;and the cell cycle regulator p21WAF1w15–18x.The impact of the interactions on apoptosis and proliferation of the infected cell is not clear at this time but may result in the development of HCC w13x. Moriya et al.w19x examined two independent transgenicmou lines expressing the c oding quence for the core protein of HCV.HCCs developed in mice from both lines,but not in transgenicmic e expressing HCV envelope pro-teins.The HCCs occurred predominantly in male mice and occurred in the abnce of significant in
flammation or fibrosis,indicating the condi-tions are not esntial prerequisites for malignant transformation of HCV-infected hepatocytes.The findings suggest that some viral factors may induce HCC by mechanisms independent from the cirrho-sis condition.
lacros是什么意思The association of PBC and HCC is not known. Epidemiological studies on this issue are limited and sometimes with conflicting results.Some stud-ies suggested that PBC is a relatively rare precursor to HCC development w20–25x,with a prevalence similar to that of normal population,or lower than cirrhosis associated with viral infections,idiopathic hemochromatosis,or alcohol abu w11,26,27x; while in other studies no difference was found in the HCC incidence between cirrhosis caud by PBC and that of other etiologies w28–31x.One of the reasons for the controversy is that PBC is a relatively rare dia.Therefore,the sample size in the studies was usually small and the studies were not always well controlled.In particular,PBC is a female-dominant dia,while male gender is known to be associated with a higher risk of HCC.Therefore,it is difficult to asmble a gender-matched ca control study.It has also been reported that PBC patients in certain countries appeared to have a higher incidence of HCC than
222J.Findor et al./Autoimmunity Reviews1(2002)220–225
Table1
Characteristics of PBC patients developing HCC during follow-up
Ca1234
Sex F F F F
Age(at time of HCC69705868 diagnosis)
Clinical stage of PBC at Symptomatic Symptomatic Symptomatic Symptomatic diagnosis
Histological stage at IV IV IV II
diagnosis of PBC
Histological stage at IV IV IV IV diagnosis of HCC
uniform怎么读Months from PBC to56.275.1057.1
HCC diagnosis
Survival with HCC8 5.3Unknown 4.5 (months)
a-fetoprotein at16003601200800 diagnosis of HCC(ng y ml)
beneficialChild’s classification at B C A C
HCC diagnosis
Ultrasound UN y3.5cm UN y4.5cm UN y7c m UN y4c m characteristics y size
Histologic al c onfirmation Hepaticbiopsy Autopsy Hepaticbiopsy Hepaticbiopsy UN s unifocal.
patients of other countries w32x.In addition,differ-ent studies may have employed different method-ologies.In some of the studies,patients with other risk factors like HCV were not excluded.All the make the comparison of data from different studies very difficult.Therefore,more studies on this issue are required.
3.Incidence of HCC in PBC
We have studied HCC incidence in a ries of Argentina PBC patients en in our institution over the last2decades.Between1978and1998,all patients with the diagnosis of PBC were prospec-tively included in this study.The criteria ud to diagno PBC included:a positive test for antim-itochondrial antibodies at a titer higher than1y80;
a liver biopsy compatible with the diagnosis;and an elevation of alkaline phosphata and g-gluta-myltransfera.The histological stage was estab-lished according to Scheuer’s classification w2x. Patients were followed every3or6months by clinical and biochemical examination.Liver ultra-sound and a-fetoprotein testing were performed every12months in patients with precirrhotic stage (stage I,II and III)and every6months in tho with cirrhosis(stage IV).HBsAg was tested for all patients,while antibodies to hepatitis C virus (HCV)were tested for patients en after1990 when the tests became available.All patients who tested positive for HBsAg or anti-HCV were excluded.
A total of292patients(281female,11male) with diagnosis of PBC were included in this ries. Mean follow-up was36.5months(range1–200 months).Eighty-ven(29.7%)patients,81 females and6males,had cirrhosis(stage IV)at the time of diagnosis of PBC and mean follow-up in this group was26months(range0.3–133 months).During the follow-up,82patients died, 39(44.8%)of them with an initial diagnosis of cirrhosis.
During follow-up,four cas of HCC were identified(Table1).The diagnosis was confirmed histologically,in three cas by ultrasound guided liver biopsy and in one ca during autopsy.All four cas of HCC were found in patients with histological stage IV of PBC.In one ca(ca 3),diagnosis of PBC stage IV and HCC was established simultaneously.In another ca(ca
美式英语对英式英语的影响
223
J.Findor et al./Autoimmunity Reviews 1(2002)
catti三级笔译
220–225Fig.1.The interrelationships of hepatocellular carcinoma and primary biliary cirrhosis.
4)the initial biopsy showed stage II PBC,which progresd into stage IV cirrhosis later and ulti-mately to HCC.Elevated a -fetoprotein levels were obrved in the HCC patients 3–5months prior to diagnosis of PBC in ca 1,2and 4.None of the four HCC patients showed tumor-associated clini-cal symptoms at the time of HCC diagnosis.In all four cas,ultrasound showed unifocal appearance of the tumor.Three of the four patients died between 1and 8months after the diagnosis of HCC.In the fourth ca,the time of death is unknown.Although autopsy was performed infre-quently in our ries,none of the other patients who died prented ultrasound images compatible with HCC or elevated level of rum a -fetoprotein,suggesting that the majority of HCC cas are likely to have been detected.
In this ries,the overall prevalence of HCC in all patients was 1.3%.The frequency of HCC in patients with initial diagnosis of PBC stage IV was 3.4%.If only female patients were included,the frequencies became 1.4and 4.9%,respectively.HCC incidence in PBC patient populations has been reported in veral studies.In a recent Amer-ican study that included 614PBC patients,the estimated prevalence of HCC was only 0.65%
w 25x .Since rum a -fetoprotein test and liver ultrasound were not systematically performed in this ries,some of the clinically inapparent HCCs might not have been detected,resulting in the low incidence rate.Other studies have shown higher prevalence.In an autopsy study with a ries of 98patients dying with PBC,it was found to be 4.1%w 30x .In a ries of 130patients from the UK that have been monitored for rum a -fetopro-tein level,five cas (3.8%)of HCC were identi-fied w 31x .In a study that included stage III and IV PBC patients only,the incidence of HCC was reported to be 5.9%w 33x .Recently Caballeria et al.published a prospective study of 140patients from Spain w 29x .In this study,the incidence of HCC in all PBC patients was 3.6%after a mean follow-up of 5.6years (67.2months ),while that in stages III and IV patients was 11.1%after a mean follow-up of 6.2years (74.4months ).Com-pared to our data,the higher incidence of HCC in this Spanish study may be due to its significantly longer follow-up period (67.2vs.36.5months for all patients and 74.4vs.26months for cirrhotic patients ).All four cas of HCC identified in our study were monofocal,while four out of five cas in the Spanish study w 29x were multifocal.The reason for this difference is unknown.However,all the HCC cas identified in our study,as well as tho reported by Caballeria et al.,were asso-ciated with stage IV cirrhosis while none of them occurred in the earlier stages of PBC,which is in agreement with previous reports w 29,32–34x and supports the notion that cirrhosis per is a risk factor for HCC.
Caballeria et al.also showed that the incidence of HCC in stage III and IV PBC patients is similar to that of a group of patients with HCV-associated cirrhosis matched for age,x and follow-up peri-od w 29x .This result is intriguing and needs to be verified with a larger sample size.HCV-associated cirrhosis has been found to carry a greater risk of HCC than other types of alcohol-associated cirrhosis and even HBV-associated cir-rhosis w 9–11x ,suggesting the involvement of HCV-specific factors in the carcinogenesis of HCC.If the overall incidence of HCC in PBC-associated cirrhosis is indeed similar to that of HCV-associated cirrhosis,does this suggest that
224J.Findor et al./Autoimmunity Reviews1(2002)220–225
some underlying mechanism for PBC also contrib-utes to the development of HCC directly,similar to the hypothetical roles played by the core protein of HCV w19x or the X antigen of HBV(HBxAg) (Fig.1)w14x?
PBC is considered to be an autoimmune liver dia characterized by antibodies and T cells reactive to host proteins w35x.However,the caus-ative factor for the autoimmunity is unknown.One of the hypothes is molecular mimicry,which suggests that an acute or chronic infection of a virus or bacterium carrying antigen homologous to a host protein may elicit B cell and T cell respons that c
ross-react with the autoantigen.Should future studies identify an infection involved in the path-ogenesis of PBC,the role of the infecting pathogen in the development of HCC will certainly need to be explored.
Take-home messages
●Epidemiological studies in literature,although
limited,in general suggest that late stage PBC is a risk factor for HCC.
●PBC patients with cirrhosis should be systemat-
ically screened for HCC.
●There may be a PBC-specific risk factor(s)for
英语演讲与辩论HCC that is independent from cirrhosis per , similar to the core protein of HCV or HBxAg of HBV.
●To explore for PBC-specific risk factors for
HCC,more extensive clinical studies are required.Such studies have to u carefully controlled patie
nt populations.
References
w1x Kaplan MM.Primary biliary cirrhosis.N Engl J Med 1996;335:1570–80.
w2x Scheuer P.Liver Biopsy Interpretation.London:Saun-ders,1994.
w3x Nakanuma Y,Tsuneyama K,Gershwin ME,Yasoshima M.Pathology and immunopathology of primary biliary
cirrhosis with emphasis on bile duct lesions:recent
progress.Semin Liver Dis1995;15:313–28.
w4x Basndine MF.Aetiological factors in hepatocellular cancer.Baillieres Clin Gastroenterol1987;1:1–16.
w5x el-Serag HB.Epidemiology of hepatocellular carcinoma.
Clin Liver Dis2001;5:87–107.vi.
w6x Kinzler KW,Vogelstein B.Lessons from hereditary colorectal cancer.Cell1996;87:159–70.
w7x Beasley RP,Hwang L Y,Lin CC,Chien CS.Hepatocel-lular carcinoma and hepatitis B virus.A prospective study of22707men in Taiwan.Lancet1981;2:1129–
33.
w8x Colombo M.Hepatitis C virus and hepatocellular car-cinoma.Semin Liver Dis1999;19:263–9.
宁波化妆学校w9x Colombo M,de Franchis R,Del Ninno E,et al.
Hepatocellular carcinoma in Italian patients with cirrho-sis.N Engl J Med1991;325:675–80.
w10x Taylor-Robinson SD,Foster GR,Arora S,Hargreaves S,Thomas HC.Increa in primary liver cancer in the UK,1979–94.Lancet1979;350:1142–3.
w11x Ikeda K,Saitoh S,Koida I,et al.A multivariate analysis of risk factors for hepatocellular carcinogenesis:a pro-spective obrvation of795patients with viral and alcoholic cirrhosis.Hepatology1993;18:47–53.
w12x Kew MC.Clinical,pathologic and etiologic heteroge-neity in hepatocellular carcinoma:evidence from south-ern Africa.Hepatology1981;1:366–9.
w13x Macdonald GA.Pathogenesis of hepatocellular carci-noma.Clin Liver Dis2001;5:69–85.
w14x Feitelson MA,Duan LX.Hepatitis B virus X antigen in the pathogenesis of chronic infections and the devel-opment of hepatocellular carcinoma.Am J Pathol 1997;150:1141–57.
w15x Lu W,Lo SY,Chen M,Wu K,Fung YK,Ou JH.
Activation of p53tumor suppressor by hepatitis C virus core protein.Virology1999;264:134–41.
w16x Ray RB,Meyer K,Steele R,Shrivastava A,Aggarwal BB,Ray R.Inhibition of tumor necrosis factor(TNF-alpha)-mediated apoptosis by hepatitis C virus core protein.J Biol Chem1998;273:2256–9.
w17x Ruggieri A,Harada T,Matsuura Y,Miyamura T.Sen-sitization to Fas-mediated apoptosis by hepatitis C virus core protein.Virology1997;229:68–76.
w18x Tai DI,Tsai SL,Chen YM,et al.Activation of nuclear factor kappaB in hepatitis C virus infection:implications for pathogenesis and hepatocarcinogenesis.Hepatology 2000;31:656–64.
w19x Moriya K,Fujie H,Shintani Y,et al.The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenicmic e.Nat Med1998;4:1065–7.
w20x Johnson PJ,Krasner N,Portmann B,Eddleston AL, Williams R.Hepatocellular carcinoma in Great Britain: influence of age,x,HBsAg status and aetiology of underlying cirrhosis.Gut1978;19:1022–6.
w21x Davidson AR,Tomlinson S,Calne RY,Williams R.
The variable cour of primary hepatocellular carcino-ma.Br J Surg1974;61:349–52.
w22x De BacC,Stroffolini T,Gaeta GB,Taliani G,Giusti G.
Pathogenic factors in cirrhosis with and without hepa-tocellular carcinoma:a multicenter Italian study.Hepa-tology1994;20:1225–30.
w23x Kaczynski J,Hansson G,Wallerstedt S.Incidence of primary liver cancer and aetiological aspects:a study
225 J.Findor et al./Autoimmunity Reviews1(2002)220–225
of a defined population from a low-endemicity area.Br J Cancer1996;73:128–32.
w24x Villa E,Baldini GM,Pasquinelli C,Melegari M,Cariani E,Di Chirico G,et al.Risk factors for hepatocellular carcinoma in Italy.Male x,hepatitis B virus,non-A non-B infection,and alcohol.Cancer1988;62:611–5. w25x Turissini SB,Kaplan MM.Hepatocellular carcinoma in primary biliary cirrhosis.Am J Gastroenterol 1997;92:676–8.
w26x Brechot C,Jaffredo F,Lagorce D,et al.Impact of HBV, HCV and GBV-C y HGV on hepatocellular carcinomas in Europe:results of a European concerted action.J Hepatol1998;29:173–83.
w27x Bradbear RA,Bain C,Siskind V,et al.Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver dias.J Natl Cancer Inst1985;75:81–4.
w28x Farinati F,Floreani A,De Maria N,Fagiuoli S,Naccar-ato R,Chiaramonte M.Hepatocellular carcinoma in primary biliary cirrhosis.J Hepatol1994;21:315–6.
w29x Caballeria L,Pares A,Castells A,Gines A,Bru C, Rodes J.Hepatocellular carcinoma in primary biliary cirrhosis:similar incidence to that in hepatitis C virus-related cirrhosis.Am J Gastroenterol2001;96:1160–3.w30x Krasner N,Johnson PJ,Portmann B,Watkinson G, Macsween R
N,Williams R.Hepatocellular carcinoma in primary biliary cirrhosis:report of four cas.Gut 1979;20:255–8.
w31x Melia WM,Johnson PJ,Neuberger J,Zaman S,Port-mann BC,Williams R.Hepatocellular carcinoma in primary biliary cirrhosis:detection by alpha-fetoprotein estimation.Gastroenterology1984;87:660–3.
w32x Floreani A,Baragiotta A,Baldo V,Menegon T,Farinati F,Naccarato R.Hepatic and extrahepatic malignancies in primary biliary cirrhosis.Hepatology1999;29:1425–8.
w33x Jones DE,Metcalf JV,Collier JD,Basndine MF,James OF.Hepatocellular carcinoma in primary biliary cirrho-sis and its impact on outcomes.Hepatology 1997;26:1138–42.
会计实操班w34x Nakanuma Y,Terada T,Doishita K,Miwa A.Hepato-cellular carcinoma in primary biliary cirrhosis:an autop-sy study.Hepatology1990;11:1010–116.
w35x Gershwin ME,Ansari AA,Mackay IR,et al.Primary biliary cirrhosis:an orchestrated immune respon against epithelial cells.Immunol Rev2000;174:210–
25.
The World of Autoimmunity:Literature Synopsis
Protein S Autoantibodies in The Antiphospholipid Syndrome
The antiphospholipid syndrome is characterized by many clinical manifestations,among them thrombosis is one of the most prominent.The association between the prence of antiphospholipid antibodies and the manifestations of the syndrome is relatively complex,as in general it is hard to correlate specific autoantibody or isotype with a given clinical manifestation.The ra of134patients from lupus clinic has been tested for autoantibodies towards protein S,beta-2-glycoprotein-I and prothrombin(Erkan et al.Lupus2002;11:215). Both autoantibodies to protein S and beta-2-glycoprotein-I have been associated with each other,but dual reactivity to both correlated with incread history of thrombosis when compared to either type of autoantibody alone,or neither activity(69%vs.37–38%,respectively).Among the patients,29had measurements of their functional protein S levels.All4patients in this group who had thrombosis had below-normal free protein S levels.In addition,the lowest levels of protein S were found in patients with antibodies to protein S and y or beta-glycoprotein-I.The findings provide an additional evidence for the importance and fine specificity of autoantibodies in the antiphospholipid syndrome.More specifically,in this ca,it ems that dual autoantibody activity might be more pathogenic than the prence of either alone.It
ems that anti-protein S antibodies could induce neutralization of the anticoagulant protein S,and thus have an additive effect to the pro-coagulant activity of anti-beta-2-glycoprotein-I antibodies.However,this assumption should be further evaluated.
