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Correspondence

LINA JANSEN Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg, Germany CHRISTIAN STOCK Division of Clinical Epidemiology and Aging Research German Cancer Research Center and Institute of Medical Biometry and Informatics University of Heidelberg Heidelberg, Germany MICHAEL HOFFMEISTER Division of Clinical Epidemiology and Aging Research German Cancer Research Center Heidelberg, Germany

Gastroenterology Vol. 147, No. 3 GIN-HO LO Department of Medical Research E-DA Hospital, Kaohsiung I-Shou University Kaohsiung, Taiwan

References 1. 2. 3. 4. 5.

El-Serag HB, et al. Gastroenterology 2014;146: 1249–1255. European Association for the Study of the Liver. J Hepatol 2014;60:392–420. Di Bisceglie AM, et al. J Hepatol 2005;43:434–441. Asahina Y, et al. Hepatology 2013;58:1253–1262. Bruix J, et al. Hepatology 2011;53:1020–1022.

References 1. 2. 3. 4. 5.

Pan J, et al. Gastroenterology 2014;147:717. Brenner H, et al. Gastroenterology 2014;146:709–717. Brenner H, et al. J Clin Epidemiol 2013;66:1144–1450. Brenner H, et al. J Clin Epidemiol 2014;67:184–189. Brenner H, et al. BMJ 2014;348:g2467.

Conflicts of interest The authors disclose no conflicts.

http://dx.doi.org/10.1053/j.gastro.2014.07.032

The Use of AFP-Based Algorithm to Predict Hepatocellular Carcinoma Dear Editor: I read with interest the article by El-Serag et al1 showing that an a-fetoprotein (AFP)-based algorithm is useful in the prediction of hepatocellular carcinoma (HCC). The authors made a great effort to improve the predictive value of serum AFP levels in diagnosis of HCC. Although interesting, the clinical applicability of this model deserves further consideration. The subjects included in the analysis were patients with hepatitis C virus (HCV)-related cirrhosis. Whether these patients had ever received antiviral therapy was not mentioned in detail. Based on clinical practice guidelines,2 subjects with compensated cirrhosis should receive antiviral therapy in the absence of contraindications. If these patients received antiviral therapy, both serum AFP levels and aminotransferase (ALT) could be reduced in those without development of HCC.3,4 Thus, the time point of AFP and ALT levels opted for analysis is a matter of concern. The predictive value of AFP-based algorithm indeed enhanced significantly in the diagnosis of HCC. However, the necessity of using ultrasonography as a surveillance tool for HCC is not altered5 and utilization of this model is greatly limited by being restricted to HCV-related cirrhotic patients only rather than all subjects with chronic liver disease.

Conflicts of interest The author discloses no conflicts.

http://dx.doi.org/10.1053/j.gastro.2014.05.047

The Use of Tenofovir Disoproxil Fumarate in Hepatitis B e Antigen–Positive Patients With Normal Levels of Alanine Aminotransferase Dear Editor: I read with interest the article by Chan et al1 regarding the use of tenofovir disoproxil fumarate (TDF) in hepatitis B e antigen (HBeAg)–positive patients with normal levels of alanine aminotransferase (ALT). The authors demonstrated that both TDF alone and the combination of TDF and emtricitabine are effective in the suppression of hepatitis B virus (HBV) DNA in patients with high viral loads and normal levels of ALT. As shown in the article, only 5% of patients achieved HBeAg seroconversion after 192 weeks of therapy with combination of TDF and emtricitabine. We applaud the authors for carrying out the trial. Unfortunately, among 52 patients entering 24-week offtherapy follow-up period, 51 (98%) were noted to have a rapid increase in HBV DNA at week 4 of treatment-free follow-up. This once again suggests that antiviral therapy should not be initiated in chronic HBV patients with high HBV DNA and persistently normal ALT levels.2,3 Although no resistant strain developed during therapy, the occurrence of hepatitis flare after withdrawal of nucleos(t)ide analog therapy could result in hepatic decompensation and close follow-up is mandatory.4,5 GIN-HO LO Department of Medical Research E-DA Hospital, Kaohsiung I-Shou University Kaohsiung, Taiwan

September 2014

References 1. 2. 3. 4. 5.

Chan HLY, et al. Gastroenterology 2014;146:1240–1248. Lok AS, et al. Hepatology 2009;50:661–662. Liaw YF, et al. Hepatology Int 2012;6:531–561. Jeng WJ, et al. Hepatology 2013;58:1888–1896. Han KH, et al. Hepatol Int 2008;2:185–189.

Conflicts of interest The author discloses no conflicts.

http://dx.doi.org/10.1053/j.gastro.2014.06.042

PTPN3 Mutations and HBV May Exert Synergistic Effects in the Origin of the Intrahepatic Cholangiocarcinoma Dear Editor: We read with interest the paper by Gao et al,1 which showed how human intrahepatic cholangiocarcinoma (IHCCA) is associated with an extremely high (>40%) frequency of somatic mutations in PTPN3 gene. Most important, Gao et al substantiated the concept that PTPN3 is an oncogene. However, in our opinion, the study by Gao et al needs some clarification—first, with respect to the classification of CCA as adopted by the authors. Indeed, apart from the topographic classification, a new updated classification has been recently proposed where the IHCCA is comprised of (1) a pure mucin-producing form (similar to the extrahepatic [EH]CCA) and (2) a mixed type containing areas of hepatocytic differentiation and ductular neoplastic proliferation.2 On the basis of molecular and biologic analyses, the mixed IHCCA subtype probably originates from cuboidal cholangiocytes lining small intrahepatic bile ducts and is frequently associated with chronic viral hepatitis, whereas the mucin IHCCA originates from the mucinproducing cholangiocytes lining large bile ducts and is more frequently associated with inflammatory diseases of the bile ducts.2 These advances further indicate 2 forms of IHCCA with different epidemiologic, pathologic, and molecular profiles. In addition, we have recently proposed how in the origin of mucin IHCCA (and mucin EHCCA), the stem cell niche located in the peribiliary glands may play a role, because it is activated during the course of biliary diseases, whereas the stem cell niche located in canals of Hering and activated during chronic parenchymal diseases, may play a role in the development of mixed IHCCA.3 By analyzing the molecular spectrum and the etiologies, Gao et al selected a population of hepatitis B virus (HBV)-associated chronic liver diseases where, most likely, the mixed IHCCA subtype largely predominated. Consistently, KRAS mutation, the key molecular marker characterizing most mucin IHCCA but rarely found in the mixed IHCCA,4 was found only in 1 of 50 HBV-associated IHCCAs analyzed by the authors. This

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indicates that the etiology may influence the molecular pattern of IHCCA and, to this regard, HBV infection may favor PTPN3 mutation as an etiologic-specific carcinogen, being observed in 50% of HBV-infected patients. The alternative explanation to this finding is a possible favorable environment for HBV replication given by PTPN3 mutation, as observed for mutations of the gene encoding the phosphoinositide 5-phosphatase SKIP.5 Also, the coparticipation of an HBV induced PTPN3 mutation carcinogenesis and via the HBV replication increasing could be contemplated. In fact, a strict relationship has been described between HBV and PTPN3 product.6 Indeed, coexpression of PTPN3 protein and HBV in human hepatoma Huh7 cells significantly reduces the level of HBV gene expression and of the associated replication,5 whereas the opposite occurs when endogenous PTPN3 protein is inhibited by specific small interfering RNA.6 PTPN3 can interact with HBV core protein via the PDZ domain of PTPN3 and the carboxyl-terminal last 4 amino acids of the core.6 Several PTPN3 mutations reduce the interaction with HBV core but do not influence the PTPN3 effect on HBV. In contrast, mutations inactivating the phosphatase activity completely abolish PTPN3-mediated suppression of viral gene expression. More important, deletion of the FERM domain that abolishes binding to the core impairs the PTPN3 effect on HBV gene expression and viral replication suppression.5,6 Interestingly, in the study by Gao et al, all 4 PTPN3 mutations described in IHCCAs are located in or near the FERM domain. This further supports the hypothesis of a specific HBV carcinogenetic effect associated with the malfunctioning of the FERM domain of PTPN3 that in turn promotes viral replication. A number of observations indicate that HBV-associated chronic liver disease represent an ideal environment favoring the emerging of PTPN3mutated IHCCA, including (1) the direct mutagenesis exerted by HBV, (2) the correlation between HBV replication and cancer development, (3) activation and proliferation of the hepatic stem cell compartment, and (4) detection of HBV in proliferating hepatic progenitors.5–7 A possible synergistic effect could be postulated in IHCCA between the HBV-mediated carcinogenesis and PTPN3 mutation-induced oncogenesis: The appearance of the PTPN3 mutations in the HBV patients determines an increased viral replication and in turn a worsening of the hepatitis evolution and an increase of the HBV-direct oncogenesis, associated with the oncogenic effects of the mutated PTPN3. The paper by Gao et al confirmed the heterogeneity of the IHCCA at molecular level and this could depend either on different cells of origin and/or on different etiological factors.7 A better understanding of these concepts may provide significant advances in targeted therapy specifically addressing the different CCA subtypes.

VINCENZO CARDINALE Department of Medico-Surgical Sciences and Biotechnologies Polo Pontino

The Use of tenofovir disoproxil fumarate in hepatitis B e antigen-positive patients with normal levels of alanine aminotransferase.

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