Journal of Global Infectious Diseases

: 2009  |  Volume : 1  |  Issue : 1  |  Page : 33--37

Association between hepatitis C and hepatocellular carcinoma

Luis Jesuino de Oliveira Andrade1, Argemiro D'Oliveira1, Rosangela Carvalho Melo2, Emmanuel Conrado De Souza2, Carolina Alves Costa Silva1, Raymundo Parana1,  
1 Department of Medicine of Federal University of Bahia, Brazil
2 Faculty of Medicine of State University of Santa Cruz, Bahia, Brazil

Correspondence Address:
Luis Jesuino de Oliveira Andrade
Department of Medicine of Federal University of Bahia


Hepatocellular carcinoma (HCC) is the fifth most common cancer, the third most common cause for cancer death in the world, a major cause of death in patients with chronic hepatitis C virus infection, and responsible for approximately one million deaths each year. Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus (HCV) is a major risk for the development of HCC. The incidence of HCC is expected to increase in the next two decades, largely due to hepatitis C infection and secondary cirrhosis, and detection of HCC at an early stage is critical for a favorable clinical outcome. Potential preventive strategies in the development of HCC are being recognized. The natural history of HCC is highly variable and the clinical management choices for HCC can be complex, hence patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. This review summarizes the inter-relationship between HCV and liver carcinogenesis.

How to cite this article:
Andrade LJ, D'Oliveira A, Melo RC, De Souza EC, Silva CA, Parana R. Association between hepatitis C and hepatocellular carcinoma.J Global Infect Dis 2009;1:33-37

How to cite this URL:
Andrade LJ, D'Oliveira A, Melo RC, De Souza EC, Silva CA, Parana R. Association between hepatitis C and hepatocellular carcinoma. J Global Infect Dis [serial online] 2009 [cited 2020 Feb 28 ];1:33-37
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Hepatocellular carcinoma (HCC) is the fifth most common cancer, the third most common cause for cancer death in the world, [1] the major cause of death in patients with chronic hepatitis C virus infection, [2] and responsible for approximately one million deaths each year. [3] Overwhelming lines of epidemiological evidence have indicated that persistent infection with hepatitis C virus is a major risk for the development of HCC. [4] The incidence of HCC is expected to increase in the next two decades, largely due to hepatitis C infection and secondary cirrhosis, [5] and detection of HCC at an early stage is critical for a favorable clinical outcome. Potential preventive strategies in the development of HCC are being recognized. Novel molecular markers identified may aid in the diagnosis of early HCC in patients with chronic HCV. [6]

Hepatitis C virus is the major causative agent of HCC, mainly through indirect pathways: Chronic inflammation, cell deaths, and proliferation. Clinical research using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis. [7] Recent data has shown that HCV is capable of inducing this active production of free radicals per se, and it is not just through inflammation, a feature peculiar to this virus and the specific activity of its core protein. [8]

A further insight into the pathogenesis of HCC, as to how pathogenesis of an immune-mediated liver cell injury triggers the development of HCC in the absence of viral transactivation, and the molecular pathogenesis that overproduces the virus, largely envelopes the polypeptide and accumulates toxic quantities of the surface antigen within the hepatocyte, develop a severe, prolonged hepatocellular injury that initiates a programmed response within the liver, characterized by inflammation, regenerative hyperplasia, transcriptional deregulation, and aneuploidy progresses to neoplasia. [9]

The natural history of HCC is highly variable, the clinical management choices for HCC can be complex and thus patient assessment and treatment planning have to take the severity of the nonmalignant liver disease into account. The presence of cirrhosis usually places constraints on resection surgery, ablative therapies, and chemotherapy. Therefore, aggressive surgery or liver transplantation may be successful in treating small or slow-growing tumors if they are diagnosed early. Although chemotherapy and radiation treatments are not usually effective, they may be used to shrink large tumors so that surgery has a greater chance of success.

 Hepatitis C

Hepatitis C virus infection was first suspected in the 1970s, when most blood transfusion infections were associated with either hepatitis A or hepatitis B virus. This new type of hepatitis transmitted by blood was then called "non-A, non-B" hepatitis. The genome of HCV was identified in 1989, and the name hepatitis C was subsequently applied to the human infection caused by this single-strand ribonucleic acid (RNA) virus of positive polarity. [10] Hepatitis C virus belongs to the Hepacivirus genus, Flaviviridae family, and has six major genotypes, and more than 70 subtypes. [11]

Hepatitis C virus has a major impact on public health, infects around 170 million people in the world, with an estimated global incidence of three to four million new infections per year. [12] Most patients infected with HCV are unaware of their exposure and remain asymptomatic during the initial stages of the infection; making early diagnosis during the acute phase (first six months after infection) is unlikely. While some of these infections will have a spontaneous resolution, the majority will progress to chronic HCV. [13] The infection by HCV may be unresolved in approximately 85% of the infected individuals, representing an important cause of liver cirrhosis and hepatocellular carcinoma.

The knowledge of the natural history of hepatitis C is still incomplete, because the acute infection is often asymptomatic in many individuals, as demonstrated in the epidemiological studies involving HCV infection and hemotherapy centers. [14] Moreover, this clinical form of HCV infection may present different geographical characteristics, which may be associated with ethnical / race and environmental factors such as HCV genotype and coinfection with other pathogenic agents. [15] The estimated mortality due to acute hepatitis C is very low (≤0.1%), contrasting with that verified for chronic HCV infection.

The transmission of HCV is mainly caused by infected blood or its products. However, other risks have been demonstrated for HCV infection, which are mainly represented by the intravenous use of illicit drugs, transplantation of HCV contaminated organs, and hemodialysis. Less frequent HCV infection has been documented as being due to occupational exposure to contaminated blood. Sporadic reports of HCV infection due to household exposure, vertical transmission, unsafe sex, and intranasal cocaine use, have also been published [16] However, the use of both third generation anti-HCV immunoassays and polymerase chain reaction to detect HCV-RNA in blood donors provoked an important fall in HCV infection, which has today an estimated incidence ratio of 1 : 500,000-2,000,000 transfusions. [17]

HCV is the most common cause of chronic liver disease and cirrhosis in the world, and represents the main cause of liver transplantation in the United States of America, Australia, and Europe. The chronic infection is evidenced by the demonstration of HCV-RNA in the blood for at least six months after virus contamination. [14] Patients who exhibit clinical or laboratory signs of chronic liver disease must be diagnosed for chronic HCV infection through the demonstration of both anti-HCV antibodies and HCV-RNA. [18]

Besides hepatocytes, HCV infects different cells, including leukocytes and epithelial cells of different organs. However, it does not cause cytotoxicity, suggesting that both the hepatic injury and the extra-hepatic clinical manifestations caused by HCV infection are probably mediated by the immune events of cryoglobulinemia, immune complex persistence, and autoimmune recognition. [19] Thus, the pathogenesis of HCV infection involves a complex virus / host interaction.

 Relation Between Hepatitis C and Hepatocellular Carcinoma

Hepatocellular carcinoma accounts for 85 to 90% of the cases of primary liver cancer. Chronic hepatitis and cirrhosis constitute the major preneoplastic conditions in the majority of HCC. The risk of developing HCC for a patient with HCV-related cirrhosis is approximately 2-6% per year. [20] HCC risk increases to 17-fold in HCV-infected patients compared to HCV-negative subjects. [21] In general, HCC develops only after two or more decades of HCV infection and the increased risk is restricted largely to patients with cirrhosis or advanced fibrosis. [22]

Multiple steps are required in the induction of all cancers; it would be mandatory for hepatocarcinogenesis that genetic mutations accumulate in the hepatocytes. In HCV infection, however, some of these steps might be skipped in the development of HCC, in presence of the core protein. The overall effects achieved by the expression of the core protein would be the induction of HCC, even in the absence of a complete set of genetic aberrations, required for carcinogenesis. By considering such a non-Vogelstein type process for the induction of HCC, a plausible explanation might be given for many unusual events happening in HCV carriers. [23]

It is well known that the incidence of HCC in patients with HCV correlates with the progression of liver fibrosis. The degree of liver fibrosis and the time of acquisition of the infection modify the risk of HCC occurrence and are different in all HCV patients. [24] HCC without cirrhosis in HCV-infected patients, though rare, has been reported. The relation of the virus to the development of HCC is through chronic hepatitis and cirrhosis.

Chronic hepatitis cirrhosis adenoma hepatocellular carcinoma

Hepatocyte necrosis and mitosis of chronic hepatitis favor nodular regeneration, which in appropriate circumstances, is followed by hepatocyte dysplasia and carcinoma. [25]

In many parts of the world HCC is among the leading causes of cancer-related mortality, and the third most common cause of cancer death in the world. [1],[7] Japan, for example, unlike other Asian countries, also has a high proportion of HCC caused by HCV infection accounting for 80 to 90% of all cases, [26] while in the western world hepatocellular carcinoma is known to complicate cirrhosis secondary to hepatitis C in 2-6% per year. [20]

There is currently no evidence that HCV by itself is oncogenic; however, HCC may rarely develop in non-cirrhotic HCV-infected individuals, so a direct oncogenic effect cannot be excluded. [27] However, in the pathogenesis of HCC associated with HCV, it remains controversial whether the virus plays a direct or indirect role. Recent studies using transgenic mouse models, in which the core protein of HCV has an oncogenic potential, indicate that HCV is directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with inflammation would also play a role. [7],[28]

HCV causes HCC via an indirect pathway by causing chronic inflammation, cell death, proliferation, and cirrhosis. [7],[29] HCV genomes can be detected in the tumor and surrounding liver tissue. [30] As for an association with the genotype of HCV and HCC, the incidence of genotype 1b is markedly high among the patients where it is associated with a more rapid deterioration of the liver histology in chronic hepatitis, although some studies have argued against this. [31]

A prospective study performed to establish whether infection with specific HCV genotypes was associated with an increased risk of development of HCC in cirrhosis, shows that cirrhotic patients infected with HCV type 1b carry a significantly higher risk of developing HCC than patients infected by other HCV types. [32]

There are suggestions that the presence of hepatitis B virus (HBV) gene in patients with chronic HCV-associated liver injury appears to promote hepatocarcinogenesis. [33] Similar to most types of cancer, hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to the malignant transformation of the hepatocyte. [34]

In most patients with HCV-related HCC, the tumors are more likely to be solitary, smaller sized, and encapsulated, whereas, HBV-related HCC are more commonly infiltrative and multinodular. [35] The imaging diagnosis using ultrasound, computed tomography (CT), magnetic resonance, and hepatic angiography with or without CT is extremely useful for the detection of small HCC. Imaging diagnosis clearly indicates localization of the HCC inside the liver. However, confirmed diagnosis of a lesion is only available by the histological study of a biopsied specimen. [36]

Tumor markers are often used for screening of HCC. hepatoma tissues can synthesize various tumor-related proteins, polypeptides, and isoenzymes, such as alpha-fetoprotein (AFP), hepatoma-specific gamma-glutamyl transpeptidase (HS-GGT), and so on, and then secrete them into the blood. The valuable early diagnostic and prognostic biomarkers can predict the development and metastases of HCC. Recent researches have confirmed that circulating hepatoma-specific AFP subfractions, transforming growth factors (TGF)-β1, HS-GGT, and free insulin-like growth factors (IGF)-β1 may be more specific markers than the total AFP level for early diagnosis of HCC. Circulating genetic markers such as AFP-mRNA, TGF-β1-mRNA, IGF-II-mRNA, and so on, from the peripheral blood mononuclear cells of HCC patients have been most extensively used in monitoring distal metastasis or postoperative recurrence of HCC. [37]

Almost all HCC occurs in the liver of patients with chronic hepatitis and liver cirrhosis, caused by HBV and HCV. Consequently, eradication of these hepatitis viruses with anti-viral agents and chemoprevention methods may decrease the risk of HCC. [38]

Studies that have reported that Interferon (IFN) therapy, even after curative treatment for HCV-related HCC, could prevent HCC recurrence and improve survival, [39],[40] despite the mechanisms by which IFN suppresses HCC recurrence, including possible direct anti-tumor and anti-inflammatory effects, remain uncertain.

Treatment options for HCC: Hepatectomy remains the standard treatment for HCC, but sufficient hepatic functional reserve is necessary. [41] Liver transplantation is the treatment of choice for patients with early HCC and decompensated cirrhosis; recent data have suggested that a modest expansion of tumor size limits could still preserve an acceptable, long-term, recurrence-free survival. [42] Local ablative therapy with percutaneous ethanol injection and radiofrequency ablation are most commonly used to destroy unresectable hepatic tumors. [43] Transarterial chemoembolization has been used for the majority with advanced disease. There is some evidence for survival benefit, but only in very carefully selected patients. [44] The systemic therapy using chemotherapy, immunotherapy, hormonal therapy or somatostatin analog have been disappointing in patients with advanced HCC. [45] Since HCC is a hypervascular cancer, gene therapy may be used for anti-angiogenesis to reduce tumor growth, and is a promising approach to treat HCC. [46]

HCC is a disease that requires multidisciplinary management: Gastroenterology / hepatology, surgery, transplant surgery, interventional and conventional radiology, medical oncology, radiation oncology, and nuclear medicine. Moreover, early diagnosis, correct treatment and referral to specialized services require a degree of high alert and an integration of all health services.


At present, early diagnosis of HCC is critical for its effective treatment. The prognosis of untreated HCC is extremely poor, while therapeutic interventions are generally ineffective in advanced stages. [47] This review summarizes the inter-relationship between HCV and liver carcinogenesis.


1Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74-108.
2Alberti A, Chemello L, Benvegnu L. Natural history of hepatitis C. J Hepatol 1999;31:17-24.
3Mitra AK. Hepatitis C-related Hepatocellular Carcinoma: Prevalence Around the World, Factors Interacting, and Role of Genotypes. Epidemiologic Reviews 1999;21:180-7.
4Koike K, Tsutsumi T, Miyoshi H, Shinzawa S, Shintani Y, Fujie H, et al . Molecular basis for the synergy between alcohol and hepatitis C virus in hepatocarcinogenesis. J Gastroenterol Hepatol 2008;23:S87-91.
5Willatt JM, Hussain HK, Adusumilli S, Marrero JA. MR Imaging of hepatocellular carcinoma in the cirrhotic liver: Challenges and controversies. Radiology 2008;247:311-30.
6Walzer N, Kulik LM. Hepatocellular carcinoma: Latest developments. Curr Opin Gastroenterol 2008;24:312-9.
7Koike K. Hepatitis C virus contributes to hepatocarcinogenesis by modulating metabolic and intracellular signaling pathways. J Gastroenterol Hepatol 2007;22:S108-11.
8Farinati F, Cardin R, Bortolami M, Burra P, Russo FP, Rugge M, et al . Hepatitis C virus: From oxygen free radicals to hepatocellular carcinoma. J Viral Hepat 2007;14:821-9.
9Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, et al . Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 1989;59:1145-56.
10Choo QL, Kou G, Weiner AJ, Overby LR, Bladley DW, Houghton M. Isolation of cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359-62.
11Lindenbach BD, Thiel HJ, Rice CM. Flaviviridae: The Viruses and Their Replication. In: Knipe DM, Howley PM, editors. Fields Virology. 5 th ed. Philadelphia: Lippincott-Raven; 2007.
12World Health Organization. Hepatitis C-global prevalence (update). Weekly Epidemiological Record 1999;74:425.
13Kamal SM. Acute hepatitis C: A systematic review. Am J Gastroenterol 2008;103:1283-97.
14Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001;194:1395-406.
15Farrell G. Hepatitis C. Other liver disorders, and liver health: A practical guide. Sydney: MacLennan and Petty; 2002.
16Chen SL, Morgan TR. The Natural History of Hepatitis C Virus (HCV) Infection. Int J Med Sci 2006;3:47-52.
17Dodd RY, Notari EP 4 th , Stramer SL. Current prevalence and incidence of infectious disease markers and estimated window-period risk in the American Red Cross blood donor population. Transfusion 2002;42:975-9.
18EASL International Consensus Conference on Hepatitis C. Paris, 26-28, February 1999, Consensus Statement. European Association for the Study of the Liver. J Hepatol 1999;30:956-61.
19Hoofnagle J. Course and outcomes of hepatitis C. Hepatology 2004;36:S21-9.
20Sangiovanni A, Del Ninno E, Fasani P, De Fazio C, Ronchi G, Romeo R, et al . Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance. Gastroenterology 2004;126:1005-14.
21Donato F, Tagger A, Gelatti U, Parrinello G, Boffetta P, Albertini A, et al . Alcohol and hepatocellular carcinoma: The effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155:323-31.
22El-Serag HB. Hepatocellular Carcinoma and Hepatitis C in the United States. Hepatology 2002;36:S74-83.
23Blonski W, Reddy KR. Hepatitis C virus infection and hepatocellular carcinoma. Clin Liver Dis 2008;12:661-74.
24Kiyosawa K. Trend of liver cirrhosis as precancerous lesions. Hepatol Res 2002;24:40-5.
25Takayama T, Makuuchi S, Hirohashi M, Sakamoto M, Okazaki N, Takayasu K, et al . Malignant transformation of adenomatous hyperplasia to hepatocellular carcinoma. Lancet 1990;336:1150-3.
26El-Serag HB, Rudolph KL. Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology 2007;132:2557-76.
27Leong TY, Leong AS. Epidemiology and carcinogenesis of hepatocellular carcinoma. HPB (Oxford). 2005; 7:5-15.
28Tsutsumi T, Suzuki T, Moriya K, Shintani Y, Fujie H, Miyoshi H, et al . Hepatitis C virus core protein activates ERK and p38 MAPK in cooperation with ethanol in transgenic mice. Hepatology 2003;38:820-8.
29But DY, Lai CL, Yuen MF. Natural history of hepatitis-related hepatocellular carcinoma. World J Gastroenterol 2008;14:1652-6.
30Gerber MA, Shieh YS, Shim KS, Thung SN, Demetris AJ, Schwartz M, et al . Detection of replicative hepatitis C virus sequences in hepatocellular carcinoma. AmJ Pathol 1992;141:1271-7.
31Lee CM, Hung CH, Lu SN, Changchien CS. Hepatitis C virus genotypes: Clinical relevance and therapeutic implications. Chang Gung Med J 2008;31:16-25.
32Bruno S, Crosignani A, Maisonneuve P, Rossi S, Silini E, Mondelli MU. Hepatitis C virus genotype 1b as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis: A seventeen-year prospective cohort study. Hepatology 2007;46:1350-6.
33Fujioka S, Shimomura H, Iwasaki Y, Fujio K, Nakagawa H, Onishi Y, et al . Hepatitis B virus gene in liver tissue promotes hepatocellular carcinoma development in chronic hepatitis C patients. Dig Dis Sci 2003;48:1920-4.
34Tan A, Yeh SH, Liu CJ, Cheung C, Chen PJ. Viral hepatocarcinogenesis: From infection to cancer. Liver Int 2008;28:175-88.
35Okuda H, Obata H, Motoike Y, Hisamitsu T. Clinicopa-thological features of hepatocellular carcinoma-comparison of hepatitis B seropositive and seronegative patients. Hepatogastroenterology 1984;31:64-8.
36Kenmochi K, Sugihara S, Kojiro M. Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grade in single HCC. Liver 1987;7:18-26.
37Yao DF, Dong ZZ, Yao M. Specific molecular markers in hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2007;6:241-7.
38Yoshida H, Shiratori Y, Moriyama M, Arakawa Y, Ide T, Sata M, et al . Interferon therapy reduces the risk for hepatocellular carcinoma: National surveillance program of cirrhotic and noncirrhotic patients with chronic hepatitis C in Japan. IHIT Study Group. Ann Intern Med 1999;131:174-81.
39Shiratori Y, Shiina S, Teratani T, Imamura M, Obi S, Sato S, et al . Interferon therapy after tumor ablation improves prognosis in patients with hepatocellular carcinoma associated with hepatitis C virus. Ann Intern Med 2003;138:299-306.
40Nishiguchi S, Tamori A, Kubo S. Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma. Intervirology 2005;48:71-5.
41Nanashima A, Masuda J, Miuma S, Sumida Y, Nonaka T, Tanaka K, et al . Selection of treatment modality for hepatocellular carcinoma according to the modified Japan Integrated Staging score. World J Gastroenterol 2008;14:58-63.
42Hanje AJ, Yao FY. Current approach to down-staging of hepatocellular carcinoma prior to liver transplantation. Curr Opin Organ Transplant 2008;13:234-40.
43Howard JH, Tzeng CW, Smith JK, Eckhoff DE, Bynon JS, Wang T, et al . Radiofrequency ablation for unresectable tumors of the liver. Am Surg 2008;74:594-600.
44Williams S, Palmer D, Johnson P. New medical options for liver tumors. Clin Med 2007;7:351-6.
45Romano O, Truant S, Sergent-Baudson G, Comet B, Pruvot FR, Hebbar M. Docetaxel therapy for advanced hepatocellular carcinoma developed in healthy liver: Report of three cases. J Chemother 2008;20:518-20.
46Goto T, Ishikawa H, Matsumoto K, Nishimura D, Kusaba M, Taura N, et al . Tum-1, a tumstatin fragment, gene delivery into hepatocellular carcinoma suppresses tumor growth through inhibiting angiogenesis. Int J Oncol 2008;33:33-40.
47Okuda K. Hepatocellular carcinoma. J Hepatol 2000;32:225-37.