Hepatitis Viruses are the Real Cause of "Smoking Related" Liver Cancer

Background: "Research Yields Major Advances in Eradication of HBV -- R. Palmer Beasley, MD: Researcher and Humanitarian." By Michael A. Snyder. Hepatitis Magazine Sep/Oct 2000.

"When R. Palmer Beasley, MD, lived in Taiwan in the mid-1970s, his daily workplace was a US Naval research installation in Taipei. But outside the laboratory, in the communities around him, Dr. Beasley was intrigued by the high rates of two serious liver diseases: hepatitis B (HBV) and liver cancer. Dr. Beasley, then a member of the University of Washington Medical School faculty, began to suspect a correlation between the two, and he set about testing this hypothesis with the same scientific rigor he brought to all his work.

"From the outset, many in the scientific community were skeptical. In the United States, President Richard M. Nixon's 'War on Cancer' reflected a strong focus on environmental causes of cancer; the idea of a link between viruses and cancer had fallen out of favor. In part, this was because previous efforts to establish such a connection had failed. [Sic - notice how this writer goes PC and blames Nixon for the 'War on Cancer' that the Lasker Syndicate got by flagrantly manipulating the public and the government, including Nixon through his "Kitchen Cabinet" advisor Elmer Bobst. Likewise, the Lasker Syndicate controlled the research agenda because they controlled the money, and it is not even clear that Nixon had any opinions of his own on the subject. -cast]

"'When people had thought which cancers might have a viral cause, it was thought that leukemia was a good candidate and a variety of others, but solid tumors of the GI tract were not on anybody's horizon,' Dr. Beasley says. 'When I came along and said viruses again, it was like the door had been shut on that notion.' Best of all, as a result of the vaccination of newborns, "The virus carrier rate among Taiwanese children has declined from about 12 percent to 1 percent. Liver cancer rates are also dropping."

Beasley later collaborated with the Lasker Syndicate in the establishment of the Medicine and Public Health alliance. While the CDC's SAMMEC eventually removed liver cancer from their list of supposed "smoking related diseases," they continue to falsely blame smoking for other diseases that are also really caused by infection.

The IARC declares hepatitis viruses to be human carcinogens

From the International Agency for Research on Cancer, Monograph 59, Hepatitis B Virus (Summary):

5.0 Summary of Data Reported and Evaluation

"... The presence of HBsAg or HBV DNA indicates current HBV infection. The presence of HBeAg indicates a high level of viral replication. Seroconversion to anti-HBe is usually associated with reductions in replication and in disease activity. The presence immunoglobulin M class anti-HBc indicates acute HBV infection; the immunoglobulin G class anti-HBc appears after acute HBV infection and persists during chronic HBV infection.... Infection perinatally and in early childhood is the major risk factor for chronicity, which frequently leads to chronic liver disease and cirrhosis."

5.2 Human carcinogenicity data

"In 15 cohort studies, carrier status for HBV was determined by the presence of HBsAg in serum. In all studies, the risk for hepatocellular carcinoma increased in association with HBsAg seropositivity, with estimates of relative risk ranging from 5.3 to 148. Many case-control studies have been reported on the association between hepatocellular carcinoma and chronic infection with HBV, as determined by HBsAg positivity. Most of the studies were conducted in Asia and in Africa, but some have been reported from Europe and North America. The studies were of variable quality, but the majority showed a strong association, with relative risks between 5 and 30. Potential confounding by aflatoxin, infection with hepatitis C virus, cigarette smoking and alcohol drinking appears to have been excluded in studies in which those factors were evaluated." [Sic - as if the danger is of false risks attributed to HBV due to confounding by smoking, instead of the opposite direction! -cast]

5.5 Evaluation There is sufficient evidence in humans for the carcinogenicity of chronic infection with hepatitis B virus.

Overall evaluation Chronic infection with hepatitis B virus is carcinogenic to humans (Group 1).

The National Toxicology Program of the National Institute of Environmental Health Sciences belatedly classifies HBV as a known human carcinogen. "First listed in the Eleventh Report on Carcinogens (2004)." This is ten years after the IARC did so.

From the International Agency for Research on Cancer, Monograph 59, Hepatitis C Virus (Summary):

5.2 Human carcinogenicity data

"Infection with HCV, as indicated by the presence of antibodies to HCV in serum, appeared to be associated with an increased risk for hepatocellular cancer in two cohorts of patients with chronic liver disease and one cohort of patients from the general population. Over 20 case-control studies have evaluated the association between hepatocellular carcinoma and seropositivity for HCV antibodies, measured either by first- or second-generation tests. Odds ratio estimates ranging from 1.3 to 134 were observed in 17 studies in which first-generation tests were used and were significant in 15 of the studies. In six studies in which second-generation tests were used, the estimated odds ratios ranged from 1.1 to 52 and were significant in three of the studies. In all 11 studies in which it could be evaluated, the risk for hepatocellular carcinoma was greater in subjects who were seropositive for HCV and seronegative for hepatitis B surface antigen than in subjects seronegative for both. In the few studies in which the analysis took into account possible confounding of the effects of HCV by other risk factors for hepatocellular carcinoma, such as smoking [SIC] and alcohol consumption, the association was not materially altered."

"5.5 Evaluation There is sufficient evidence in humans for the carcinogenicity of chronic infection with hepatitis C virus.... Overall evaluation Chronic infection with hepatitis C virus is carcinogenic to humans (Group 1)."

The National Toxicology Program of the National Institute of Environmental Health Sciences belatedly classifies HCV as a known human carcinogen. "First listed in the Eleventh Report on Carcinogens (2004)." This is ten years after the IARC did so.

Review

Human oncogenic viruses: hepatitis B and hepatitis C viruses and their role in hepatocarcinogenesis. VE Gurtsevitch. Biochemistry (Mosc) 2008 May;73(5):504-513.

Diagnosis of hepatitis B virus infection through serological and virological markers. JH Kao. Expert Rev Gastroenterol Hepatol 2008 Aug;2(4):553-562. "The natural history of chronic HBV infection can be divided into four dynamic phases in HBV carriers who acquire the virus early in life. Diagnosis of HBV infection is usually through serological and virological markers. Hepatitis B surface antigen (HBsAg) is the hallmark of HBV infection and is the first serological marker to appear in acute hepatitis B, and persistence of HBsAg for more than 6 months suggests chronic HBV infection. Hepatitis B e antigen (HBeAg) usually indicates active HBV replication and risk of transmission of infection. Recently, occult HBV infection is recognized as the absence of circulating HBsAg in individuals positive for serum or tissue HBV DNA, irrespective of other HBV serological markers. Meanwhile, monitoring the serum HBV DNA level is valuable for assessing liver disease activity, differentiating other etiologies of hepatitis activity in HBV carriers, predicting risk of HCC development or liver-related mortality, deciding to administer antiviral therapy, determination of the response to antiviral treatment, predicting the risk of developing drug resistance, and detecting the emergence of drug-resistant mutants. On the other hand, HBV genotype C, basal core promoter mutant and pre-S deletion mutant are reported to be associated with increased risk of HCC development. The roles of quantitative HBV serology and intrahepatic HBV covalently closed circular (ccc)DNA deserve further studies."

Confounding by hepatitis virus infection is revealed

Since the 1990s, there have been major advances in the detection of hepatitis B virus infection in epidemiologic studies. The old way was to look for hepaitis B surface antigen (HBsAg) alone. Patients without HBsAg were considered HBV negative. It has now been shown to be necessary to look for the core antigen (HBcAg), and attempt to find HBV DNA in tissue samples as well, to more completely determine the presence of HBV infection.

Hepatitis C virus is believed to cause liver cancer also, and studies have found HCV DNA by reverse transcriptase PCR in patients who were negative for antibodies to HCV. Due to the high odds ratios for liver cancer associated with HBV and HCV, and the unequal distribution of exposure between smokers and nonsmokers, failure to fully detect the viruses results in a bogus risk that is associated with smoking due to socioeconomic causes.

Hepatitis B virus DNA in the serum of Sardinian blood donors negative for the hepatitis B surface antigen. ME Lai, P Farci, A Figus, A Balestrieri, M Arnone, GN Vyas. Blood 1989 Jan;73(1):17-19. "Among the 71 subjects positive for serum HBV DNA, 22 (31%) were positive for anti-HBc, while 49 (69%) were negative for all serologic markers of HBV infection." There had been several reports of this, dating back to 1981, including one in the New England Journal of Medicine in 1985.

Detection of hepatitis B virus DNA by polymerase chain reaction in plasma of volunteer blood donors negative for hepatitis B surface antigen. JT Wang, TH Wang, JC Sheu, LN Shih, JT Lin, DS Chen. J Infect Dis 1991 Feb;163(2):397-399. "Plasma samples from 206 volunteer blood donors were tested for hepatitis B virus (HBV) DNA by dot blot hybridization and polymerase chain reaction (PCR). All donors were negative for hepatitis B surface antigen (HBsAg) and had normal serum alanine aminotransferase levels. None of the 206 plasma samples was positive for HBV DNA by dot blot hybridization assay. However, nine samples were positive for HBV DNA by PCR using two primer pairs specific for surface and core regions. Nine persons received the HBV-DNA-positive plasma, and one developed posttransfusion non-A, non-B hepatitis; the others remained well 6 months later."

Impact of HBV, HCV and GBV-C/HGV on hepatocellular carcinomas in Europe: results of a European concerted action. C Brechot, F Jaffredo, D Lagorce, G Gerken, K Meyer zum Buschenfelde, A Papakonstontinou, S Hadziyannis, R Romeo, M Colombo, J Rodes, J Bruix, R Williams, N Naoumov. J Hepatol 1998 Aug;29(2):173-183. HBV DNA was detected in the serum and liver of 33% and 47% of HBsAg negative patients, and in the serum of 25.1% who were "without any HBV marker." They also found HCV RNA by R-PCR in 7% of anti-HCV negatives. "It also stresses the need to use genome detection in epidemiological studies when serological tests are negative."

High prevalence of infection with hepatitis B and C viruses in patients with hepatocellular carcinoma in Japan. S Kubo, S Nishiguchi, K Hirohashi, H Tanaka, T Tsukamoto, H Hamba, T Shuto, T Okuda, A Tamori, T Kuroki, H Kinoshita. Hepatogastroenterology 1999 Jan-Feb;46(25):357-359. "Hepatitis B virus genes were detected in 13 patients with anti-surface antibody, in 21 of 30 patients with anti-core antibody, and in 9 of 22 patients without hepatitis B antibodies. Viral genes were detected in tumor tissue in 5 of 11 patients with neither B nor C virus markers in their sera; viral markers were found in either serum or tumor tissue in 324 of 330 patients (98.2%)."

[Prevalence of HCV and HBV infection in patients with primary hepatocellular carcinoma in Shanxi Province]. J Wang, H Zhao, S Zhao. Chung Hua Liu Hsing Ping Hsueh Tsa Chih 1999 Aug;20(4):215-217. In a regression analysis on 98 patients assessing numerous serological markers, Wang et al. found odds ratios for antibodies to HCV of 55.06; for HBsAg of 10.8; for anti-HBc of 9.85; and for both anti-HCV and HBsAg of 61.37. These high ORs have a high potential to produce spurious results due to confounding.

High prevalence of anti-hepatitis B virus serological markers in patients with hepatitis C related chronic liver disease in Japan. H Marusawa, Y Osaki, T Kimura, K Ito, Y Yamashita, T Eguchi, M Kudo, Y Yamamoto, H Kojima, H Seno, F Moriyasu, T Chiba. Gut 1999 Aug;45(2):284-288. A large proportion (49.9%) of patients with HCV-related chronic liver disease were also positive for antibodies to HBc. "Notably, anti-HBc was the only serological marker for HBV infection in a significant number of patients with HCV-related chronic liver disease (24.1%), and especially those with hepatocellular carcinoma."

Etiology of hepatocellular carcinoma in Italian patients with and without cirrhosis. R Chiesa, F Donato, A Tagger, M Favret, ML Rivero, G Nardi, U Gelatti, E Bucella, E Tomasi, N Portolani, M Bonetti, L Bettini, G Pelizzari, A Salmi, A Savio, M Garatti, F Callea. Cancer Epidemiol Biomarkers Prev 2000 Feb;9(2):213-216. In 174 newly-diagnosed liver cancer patients, according to positivity for HCV RNA, HBsAg and/or HBV DNA, and alcohol intake >80g/day, the odds ratios with 95% confidence intervals, with and without cirrhosis, were HCV RNA 33.5 (17.7-63.4) and 19.7 (6-64.8); HBsAg 17.6 (9.0-34.4) and 20.3 (5.7-72.6); alcohol 5.5 (3.1-9.7) and 4.6 (1.5-13.8). And, "No association was found with HGV or TT virus infections or tobacco."

Virologic analysis of non-B, non-C hepatocellular carcinoma in Japan: frequent involvement of hepatitis virus. H Yotsuyanagi, Y Shintani, K Moriya, H Fujie, T Tsutsumi, T Kato, K Nishioka, T Takayama, M Makuuchi, S Iino, S Kimura, K Koike. J Infect Dis 2000 Jun;181(6):1920-1928. HBV DNA was found by PCR in the sera of 47.6% of liver cancer patients with supposedly "non-B, non-C" hepatitis. In twelve with liver tissues available, HBV DNA detection was 67%.

Occult hepatitis B virus infection in HBs antigen-negative hepatocellular carcinoma in a Japanese population: involvement of HBx and p53. G Shiota, K Oyama, A Udagawa, K Tanaka, T Nomi, A Kitamura, A Tsutsumi, N Noguchi, Y Takano, K Yashima, Y Kishimoto, T Suou, H Kawasaki. J Med Virol. 2000 Oct;62(2):151-158. "Serum DNA was amplified by nested PCR by using specific primers of surface (S), core (C) and X regions in 26 patients negative for HBsAg and anti-HCV. Eighteen (69%) patients were positive for either S, C, or X region and the results of PCR were confirmed by Southern blotting."

Correlation of clinical characteristics with detection of hepatitis B virus X gene in liver tissue in HBsAg-negative, and HCV-negative hepatocellular carcinoma patients. Y Higashi, S Tada, S Miyase, K Hirota, H Imamura, T Kamio, H Suko. Liver. 2002 Oct;22(5):374-379. About half of non-B non-C hepatocellular carcinoma patients were seronegative for HBsAg but positive for the HBV-X gene in liver tissue.

Dominant role of hepatitis B virus and cofactor role of aflatoxin in hepatocarcinogenesis in Qidong, China. L Ming, SS Thorgeirsson, MH Gail, P Lu, CC Harris, N Wang, Y Shao, Z Wu, G Liu, X Wang, Z Sun. Hepatology 2002 Nov;36(5):1046-1049. 100% of 181 incident HCCs had markers for HBV (HBsAg, anti-HBc, or HBV X gene sequence). Six were co-infected with HCV.

Geographic Characterization of Hepatitis Virus Infections, Genotyping of Hepatitis B Virus, and p53 Mutation in Hepatocellular Carcinoma Analyzed by In Situ Detection of Viral Genomes from Carcinoma Tissues: Comparison among Six Different Countries. X Ding, YN Park, TC Taltavull, SN Thung, X Jin, Y Jin, NS Trung, Y Edamoto, T Sata, K Abe. Jpn J Infect Dis 2003 Feb;56(1):12-18. 449 patients with HCC. "HBV was the most prevalent in Korea (69.1%), China (66.1%), Vietnam (60.5%), and Spain (38.6%). In contrast, HCV was the most prevalent in Japan (59.8%) and in the United States (41.5%). Type C of HBV was the most common genotype (78.6%) encountered in HCC in these countries. Importantly, among 125 intrahepatic HBV DNA-positive patients, 44 (35.2%) were serologically negative for HBsAg (occult hepatitis B). Furthermore, 15.5% of HCC patients (9/58) who were negative for all HBV markers had intrahepatic HBV DNA." "Based on PCR, immunohistochemical, serological, and clinical findings, 4.8% of HCC patients were diagnosed with non-B, non-C." Markers of hepatitis viruses B and C were not found in only 6.2% of American cases, and about 5% overall. "Histological findings of non-B, non-C HCC showed that 81% of cases were accompanied by liver cirrhosis and 62.5% had chronic inflammatory cell infiltration in the portal tracts of nontumorous regions, which findings suggested persistent infection by unknown virus(es)."

Molecular and serological aspects of HBsAg-negative hepatitis B virus infections in North America. CC Hsia, CH Scudamore, AM Di Bisceglie, E Tabor. J Med Virol 2003 May;70(1):20-26. In 31 HBsAg-negative HCC patients, "HBV DNA was detected in HCC and/or in adjacent nontumorous liver tissue using nested polymerase chain reaction (PCR) in 5/9 (56%) patients from the United States and in 12/22 (55%) from Canada. The 17 HBV DNA-positive/HBsAg-negative patients from the United States and Canada included 9 without any serological markers for HBV and 8 with detectable antibodies to hepatitis B core antigen. In these patients, HBV genotype C was the most prevalent genotype (11/17; 64%). HBV genotypes have not been previously reported in HCC patients from North America." Due to undetected evidence of HBV infection, "those with antibody to hepatitis C virus (HCV) would otherwise have been designated 'HCV-associated HCCs' based on serological tests alone."

Prevalence of HBV precore/core promoter variants in the United States. CJ Chu, EB Keeffe, SH Han, RP Perrillo, AD Min, C Soldevila-Pico, W Carey, RS Brown Jr., VA Luketic, N Terrault, AS Lok, U.S. HBV Epidemiology Study Group. Hepatology 2003 Sep;38(3):619-628. "Precore and core promoter variants were more common in hepatitis B e antigen (HBeAg)-negative than in HBeAg-positive patients (precore, 38% vs 9%; core promoter, 51% vs 36%, respectively, P <.001).... Physicians should be aware of the existence of precore and core promoter variants and the clinical condition of 'HBeAg-negative chronic hepatitis.'"

Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection. T Pollicino, G Squadrito, G Cerenzia, I Cacciola, G Raffa, A Crax, F Farinati, G Missale, A Smedile, C Tiribelli, E Villa, G Raimondo. Gastroenterology. 2004 Jan;126(1):102-10. "We tested tumor tissues from 107 patients with HCC and the corresponding nontumor liver tissue from 72 of these patients for HBV DNA. We also examined liver specimens from 192 patients with chronic hepatitis. All cases were hepatitis B surface antigen negative... Viral DNA was detected in 68 of 107 cases of HCC (63.5%) and in 63 of 192 cases of chronic hepatitis (32.8%) (P < 0.0001; odds ratio, 3.6; 95% confidence interval, 2.2-5.9)... CONCLUSIONS: Our findings provide clear evidence that occult HBV is a risk factor for development of HCC and show that the potential mechanisms whereby overt HBV might induce tumor formation are mostly maintained in cases of occult infection."

Tight association of hepatocellular carcinoma with HBV infection in North China. JD Gao, YF Shao, Y Xu, LH Ming, ZY Wu, GT Liu, XH Wang, WH Gao, YT Sun, XL Feng, LM Liang, YH Zhang, ZT Sun. Hepatobiliary Pancreat Dis Int 2005 Feb;4(1):46-49. "RESULTS: In the 119 HCC patients, 82.4% (98/119) were HBsAg seropositive. When a comprehensive set of HBV markers were detected, the HBV infection rate in these HCC patients was 99.2% (118/119). Of the patients, 11.8% (14/119) were found to be anti-HCV positive. But all the anti-HCV positive HCC patients were co-infected with HBV. CONCLUSIONS: HBV infection is virtually ubiquitous in HCC patients in North China. The tight association of HBV with HCC strongly suggests the dominant role of HBV infection in causing hepatocellular carcinoma. About 11.8% of HCC patients being HCV-related are co-infected with HBV."

HBsAg-negative hepatitis B virus infections in hepatitis C virus-associated hepatocellular carcinoma. S Momosaki, Y Nakashima, M Kojiro, E Tabor. J Viral Hepat 2005 May;12(3):325-329. "Thirty newly diagnosed HCC patients from Kurume, Japan, with antibody to the hepatitis C virus (anti-HCV) were studied. None of the 30 had HBsAg detectable in their serum. Of 22 for whom test results for antibodies to the hepatitis B core antigen (anti-HBc) and antibodies to HBsAg (anti-HBs) were available, 14 (64%) had anti-HBc and anti-HBs, four (18%) had anti-HBc alone, and four (18%) had no HBV markers. Nested polymerase chain reaction was used to detect the HBV surface (S), core (C), polymerase (P) and core promoter gene sequences in the HCC tissues and in the adjacent nontumorous liver tissues. HBV DNA was detected in HCC and/or adjacent nontumorous liver in 22 of 30 (73%) patients [detected in both HCC and nontumorous liver in 19/30 patients (63%)]. Among the 22 patients with detectable HBV DNA, more than one HBV gene was detected in 10 (46%). Among the four patients whose sera were negative for all HBV markers, three had HBV DNA in either HCC and nontumorous liver (two cases) or only in the nontumorous liver (one case); HBV DNA could not be detected in tissues from the fourth patient. In 18 of 21 (86%) patients with detectable HBV core promoter sequences, mutations at both nucleotides 1762 (A-GT) and 1764 (G-A) in the core promoter region were found... Thus, HBV DNA was detectable in 22 (73%) HBsAg-negative, anti-HCV-positive HCCs, including three (10%) who were also negative for anti-HBc and anti-HBs."

Significance of HBV DNA in the hepatic parenchyma from patients with non-B, non-C hepatocellular carcinoma. T Nakai, O Shiraishi, T Kawabe, H Ota, H Nagano, H Shiozaki. World J Surg 2006 Jul;30(7):1338-1343. "Nonneoplastic liver tissue from 46 patients with non-B, non-C HCC were examined for hepatitis B virus (HBV) DNA and HCV RNA using in situ hybridization.... HBV DNA was detected in nonneoplastic liver specimens from 35 patents (76.1%), whereas HCV RNA was not detected in any case." Patients with higher HBV DNA expression had a worse outcome.

Lengths of hepatitis B viremia and antigenemia in blood donors: preliminary evidence of occult (hepatitis B surface antigen-negative) infection in the acute stage. A Yoshikawa, Y Gotanda, K Minegishi, R Taira, S Hino, K Tadokoro, H Ohnuma, K Miyakawa, K Tachibana, H Mizoguchi; Japanese Red Cross NAT Screening Research Group. Transfusion 2007 Jul;47(7):1162-1171. "The Japanese Red Cross (JRC) implemented a fully automated pooling and nucleic acid amplification test (NAT) system for testing seronegative donations. The JRC sample repository and repeat blood donations allowed for lookback and follow-up studies of hepatitis B virus (HBV) DNA-positive donors, who tested negative for hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antigen in the JRC screening system.... 328 HBV DNA-positive donations were found. From 26 of these donors, sequential samples were available at short intervals.... Six of the 26 donors were infected with mutant viruses, and 3 of these 6 donors did not develop detectable HBsAg during the entire observation period, despite a moderately high viral load of 10(4) to 10(5) HBV DNA copies per mL."

Hepatitis B virus DNA in liver tissue and risk for hepatocarcinogenesis in patients with hepatitis C virus-related chronic liver disease. A prospective study. M Obika, T Shinji, S Fujioka, R Terada, H Ryuko, AA Lwin, H Shiraha, N Koide. Intervirology 2008;51(1):59-68. 167 patients with HCV-related chronic liver disease without HBV surface antigen (HBsAg). "HBV DNA was detected in 9 of 167 patients (5.4%) by single PCR and in 25 patients (15.0%) by nested PCR. HCC developed in 12 of 167 patients (7.2%). Ten of 142 HBV DNA-negative patients (7.0%) and 2 of 9 patients with a high HBV copy number (22.2%) developed HCC, whereas none of 16 patients with a low HBV copy number developed HCC."

A case-control study of the relationship between hepatitis B virus DNA level and risk of hepatocellular carcinoma in Qidong, China. TT Liu, Y Fang, H Xiong, TY Chen, ZP Ni, JF Luo, NQ Zhao, XZ Shen. World J Gastroenterol 2008 May 21;14(19):3059-3063. Prospective study of 2387 participants who were seropositive for HBsAg and confirmed to be free of HCC by AFP level and abdominal ultrasonography were followed up with abdominal ultrasonography and serological tests including ALT, AFP, HBV serological markers (HBsAg) and anti-Hepatitis C virus (HCV) antibody until February 2006. 186/276 (67.4%) samples of control subjects had undetectable levels of serum HBV DNA. 73/243 HCC cases who were diagnosed with HCC within two years were excluded, leaving 170 cases. "Compared with those with undetectable levels of serum HBV DNA, the adjusted odds ratios of HCC for subjects with increasing HBV DNA level were 0.465 (95% CI 0.172-1.259), 2.834 (1.237-6.492), 48.403 (14.392-162.789), 42.252 (14.784-120.750), and 14.819 (6.992-31.411)."

Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus. S Adachi, A Shibuya, Y Miura, A Takeuchi, T Nakazawa, K Saigenji. Scand J Gastroenterol 2008;43(7):849-856. 123 patients with LC due to HCV, and negative for HBsAg. "Serum HBV DNA was detectable in 14 patients (11.4%) and serum anti-HBc in 96 (78.0%). During the follow-up period (mean 53.3 months), 80 patients (65.0%) developed HCC. The cumulative HCC development rate was significantly higher in the anti-HBc-positive group than in the anti-HBc-negative group (p=0.0039), but did not differ between the serum HBV DNA-positive and -negative groups (p=0.8570)."

Survival and hepatitis status among Asian Americans with hepatocellular carcinoma treated without liver transplantation. JP Hwang, MM Hassan. BMC Cancer 2009 Feb 4;9:46. Of 82 patients, "94% had positive anti-HBc and 61% had positive HBsAg. 20% had positive anti-HCV. There were no significant changes in the rates of HBV and HCV over time." [Hassan perpetrated a fraudulent study that ignored HBV in order to falsely blame smoking.]

Frequent detection of hepatitis B virus DNA in hepatocellular carcinoma of patients with sustained virologic response for hepatitis C virus. A Tamori, T Hayashi, M Shinzaki, S Kobayashi, S Iwai, M Enomoto, H Morikawa, H Sakaguchi, S Shiomi, S Takemura, S Kubo, N Kawada. J Med Virol 2009 Jun;81(6):1009-1014. "Study group comprised 16 patients with sustained virologic response (group A) and 50 with HCV (group B). Anti-HBc and anti-HBs in serum were examined by enzyme-linked immunoassay. HBV DNA in liver was examined by nested polymerase chain reaction, using primers specific for genes encoding for HBx, HBsAg, HBcAg, and HBV cccDNA. Sequence of the amplified HBV DNA for 'a' determinant of HBsAg was determined in HCC. Anti-HBc was positive in 10 of 16 in group A and 25 of 50 in group B. HBV DNA in liver was detected in 12 of 16 in group A and 21 of 50 in group B (P = 0.044)."

Occult hepatitis B virus infection increases hepatocellular carcinogenesis by eight times in patients with non-B, non-C liver cirrhosis: a cohort study. K Ikeda, M Kobayashi, T Someya, S Saitoh, T Hosaka, N Akuta, F Suzuki, Y Suzuki, Y Arase, H Kumada. J Viral Hepat 2009 Jun;16(6):437-443. In 82 consecutive Japanese patients observed for a median of 5.8 years, "The carcinogenesis rates in the patients with positive DNA group and negative DNA group were 27.0% and 11.8% at the end of the 5th year, and 100% and 17.6% at the 10th year, respectively (P = 0.0078)."

Clearance of hepatitis B surface antigen and risk of hepatocellular carcinoma in a cohort chronically infected with hepatitis B virus. J Simonetti, L Bulkow, BJ McMahon, C Homan, M Snowball, S Negus, J Williams, SE Livingston. Hepatology 2010 May;51(5):1531-1537. A prospective population-based cohort study in 1,271 Alaska Native persons with chronic HBV infection followed for an average of 19.6 years. "Six patients, two with cirrhosis and four without, developed HCC a mean of 7.3 years after HBsAg clearance (range, 2.0-15.5 years). The incidence of HCC after clearance of HBsAg was 36.8 per 100,000 per year (95% CI 13.5-80.0) which was significantly lower than the rate in those who remained HBsAg-positive (195.7 cases per 100,000 person-years of follow-up [95% CI 141.1-264.5; P < 0.001]). After loss of HBsAg, HBV DNA was detected in the sera of 28 (18%) of those who cleared a median of 3.6 years after clearance."

Examples: False Smoking Risks Are Generated by Defective Studies

Risk factors for hepatocellular carcinoma among patients with chronic liver disease. H Tsukuma, T Hiyama, S Tanaka, M Nakao, T Yabuuchi, T Kitamura, K Nakanishi, I Fujimoto, A Inoue, H Yamazaki, et al. N Engl J Med 1993 Jun 24;328(25):1797-1801. The only markers considered were HBsAg, anti-HBc, and anti-HCV.

The role of previous hepatitis B virus infection and heavy smoking in hepatitis C virus-related hepatocellular carcinoma. T. Chiba, Y Matsuzaki, M Abei, J Shoda, N Tanaka, T Osuga, T Aikawa. Am J Gastroenterol 1996 Jun;91(6):1195-1203. The investigators state that "We prospectively observed 412 patients with anti-HCV-positive CLD but without co-infection of hepatitis B virus [emphasis added] (232 patients with chronic hepatitis and 180 with liver cirrhosis) for between 0.5 and 15.8 yr (median: 4.9 yr)." Then, they claim to have founds risks "2-fold in patients with positive antibodies against hepatitis B surface antigen and/or antibodies against hepatitis B core antigen (risk ratio, 2.14; 95% confidence interval, 1.13-4.07, p = 0.0201), and 2.5-fold in heavy smokers (risk ratio, 2.46; 95% confidence interval, 1.11-5.49, p = 0.0276)." First, the two statements obviously contradict each other. Second, they must have failed to detect some cases of HBV infection because they did not look for HBV DNA. A substantial proportion of patients with no HBV markers in serum nevertheless have HBV DNA; and given the high odds ratios associated with HBV, small odds ratios of 2-3 are easily created by confounding. Nevertheless, this is one of the favorite pieces of "evidence" among anti-smokers for claiming that smoking causes liver cancer.

This is a classic example of confounding, as demonstrated by Phillips & Smith (Cigarette smoking as a potential cause of cervical cancer: Has confounding been controlled? Int J Epidemiol 1994 Feb;23:42-49). That purported "stronger association" in ostensibly HBV- and HCV-negative patients is the result of speciously blaming smoking for HCC in false negatives, due to the different rates of exposure between smokers and nonsmokers. They did not look at positivity by HBcAg or PCR! And their vaunted "significant dose-response, positive association" with smoking overall is a bogus risk generated from residual confounding by the statistical calculation itself, as Phillips & Smith showed.

Yet here is a disgraceful statement in a review by FX Bosch (who ought to know better), et al. (Epidemiology of primary liver cancer. Semin Liver Dis 1999;19(3):271-285): "Other documented risk factors such as... cigarette smoking... may explain the residual variation between and within countries." These are not legitimate claims, because the studies were defective.

Has Bosch already forgotten his own confirmation of Phillips & Smith's model of how smoking is falsely blamed for another disease actually caused by viral infection (Int J Epidemiol 1994;23:1100-1101)? Or does he fail to understand that their model is just as applicable to hepatitis viruses as to human papillomaviruses?

The ORs claimed for smoking and liver cancer are similar to those falsely claimed for smoking and cervical cancer, while the ORs for hepatitis viruses are far higher than the OR of 10 assumed in Phillips & Smith's model. The conventional methods of detection of HBV and HCV used in epidemiologic studies have been shown to be incomplete, thus the existence of confounding is a certainty.

Othrwise, according to this review, "The role of chronic infection with the hepatitis B and hepatitis C viruses (HBV and HCV) in the etiology of LC is well established. The attributable risk estimates for LC for each of these hepatotropic viruses varies among countries but the combined effects of persistent HBV or HCV infections account for well over 80% of LC cases worldwide." (And this is by those inadequate methods that miss many cases and falsely blame them on smoking.)

They acknowledge that "New laboratory techniques and biological markers such as polymerase chain reaction detection of HBV DNA and HCV RNA, as well as specific mutations related to aflatoxin exposure may help to provide quantitative estimates of the risks related to each of these factors." However, the same purveyors of anti-smoking junk science, such as those in the National Cancer Institute and the Centers for Disease Control, who have ignored and concealed the incontrovertible caveats relating to cervical cancer, can be counted on to do the same concerning liver cancer. And only the objections of an informed public can quash them.

Chronic liver diseases for the risk of hepatocellular carcinoma: a case-control study in Japan. Etiologic association of alcohol consumption, cigarette smoking and the development of chronic liver diseases. M Mukaiya, M Nishi, H Miyake, K Hirata. Hepatogastroenterology 1998 Nov-Dec;45(24):2328-2332. The biomarkers used are not given in the abstract. According to IARC 83, they considered only HBsAg and anti-HCV.

A long-term follow-up study on risk factors for hepatocellular carcinoma among Japanese patients with liver cirrhosis. K Tanaka, H Sakai, M Hashizume, T Hirohata. Jpn J Cancer Res 1998 Dec;89(12):1241-1250. Only HBsAg, anti-HCV, and HCV-RNA titer were considered.

HBV/HCV Infection, Alcohol, Tobacco and Genetic Polymorphisms for Hepatocellular Carcinoma in Nagoya, Japan. T Koide, T Ohno, XE Huang, Y Iijima, K Sugihara, M Mizokami, J Xiang, S Tokudome. Asian Pac J Cancer Prev 2000;1(3):237-243. The biomarlers used are not stated in the abstract. The OR for hepatitis B virus was 5.14 (95%CI=2.29-11.6) and hepatitis C virus 32.00 (95%CI=7.83-130.7), while a history of blood transfusion was 5.25 (95%CI=1.80-15.29), and habitual smoking 2.36 (95%CI=1.17-4.78). Both of the later were likely confounded by undetected infection; after all, blood transfusions can only cause liver cancer via infection, so it can be inferred that insufficient biomarkerts were used.

Prospective study on the relation of cigarette smoking with cancer of the liver and stomach in an endemic region. T Mizoue, N Tokui, K Nishisaka, S Nishisaka, I Ogimoto, M Ikeda, T Yoshimura. Int J Epidemiol 2000 Apr;29(2):232-237. This study considered no biomarkers whatsoever for either hepatitis viruses or stomach infections, and its mere publication reflects the dishonesty of the editors of the journal, who in 2006 include George Davey-Smith, co-author of a paper demonstrating how confounding occurs in exactly such circumstances.

Risk of hepatocellular carcinoma and habits of alcohol drinking, betel quid chewing and cigarette smoking: a cohort of 2416 HBsAg-seropositive and 9421 HBsAg-seronegative male residents in Taiwan. LY Wang, SL You, SN Lu, HC Ho, MH Wu, CA Sun, HI Yang, C Chien-Jen. Cancer Causes Control. 2003 Apr;14(3):241-250. Again, they tested only for HBsAg and anti-HCV, and fraudulently claimed to have found a risk associated with smoking.

Incidence and cofactors of hepatitis C virus-related hepatocellular carcinoma: a prospective study of 12,008 men in Taiwan. CA Sun, DM Wu, CC Lin, SN Lu, SL You, LY Wang, MH Wu, CJ Chen. Am J Epidemiol 2003 Apr 15;157(8):674-682. These data appear to be the same as Wang 2003. Likwise, the only infection markers evaluated were HCV antibody (anti-HCV) and hepatitis B surface antigen (HBsAg).

Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. JM Yuan, S Govindarajan, K Arakawa, MC Yu. Cancer 2004 Sep 1;101(5):1009-1017. In 295 cases, "Seropositivity for antibodies to HCV was associated with an odds ratio (OR) of 125 (95% confidence interval [95% CI], 17-909) for HCC, whereas seropositivity for antibodies to the hepatitis B core antigen was related to an OR of 2.9 (95% CI, 1.7-5.0). Heavy alcohol consumption and cigarette smoking were found to be independently associated with a statistically significant two to threefold increase in risk of HCC after adjustment for hepatitis B and C serology." This study is defective because of the large proportion of cases which are negative for HBV by serology, but positive by DNA.

The effect of interaction between hepatitis C virus and cigarette smoking on the risk of hepatocellular carcinoma. Y Fujita, A Shibata, I Ogimoto, Y Kurozawa, T Nose, T Yoshimura, H Suzuki, N Iwai, R Sakata, S Ichikawa, A Tamakoshi. Br J Cancer 2006 Mar 13;94(5):737-739. This defective study considered only HCV infection and ignored HBV in order to lie that "The odds ratio of death from HCC for smoking was 9.60 (1.50-61.35) and 1.71(0.58-5.08) among anti-HCV positive and negative individuals, respectively."

Hepatitis viruses, alcohol, and tobacco in the etiology of hepatocellular carcinoma in Italy. S Franceschi, M Montella, J Polesel, C La Vecchia, A Crispo, L Dal Maso, P Casarin, F Izzo, LG Tommasi, I Chemin, C Trepo, M Crovatto, R Talamini. Cancer Epidemiol Biomarkers Prev 2006 Apr;15(4):683-689. "ORs for hepatitis B surface antigen (HBsAg) positive versus HBsAg negative and for anti-HCV antibody positive versus anti-HCV antibody negative were 20.2 and 15.6, respectively. Positivity for both markers was associated with an OR of 51.6... Tobacco smoking was unrelated to HCC risk overall but seemed to enhance HCC risk among virus carriers." In other words, they failed to find an increased risk from smoking despite using a study which is defective because it only evaluated HBsAg, but they attempted to chisel one out anyway.

Alcohol, cofactors and the genetics of hepatocellular carcinoma. MC Yu, JM Yuan, SC Lu. J Gastroenterol Hepatol 2008 Mar;23 Suppl 1:S92-97. This study does not state which markers for HBV and HCV were used. Supposedly, 109 were negative for HBV and/or HCV, versus 136 who were positive, which is a suspiciously low rate of positivity. Funded by the US National Institutes of Health.

Independent and additive interactive effects among tumor necrosis factor-alpha polymorphisms, substance use habits, and chronic hepatitis B and hepatitis C virus infection on risk for hepatocellular carcinoma. JE Jeng, HR Tsai, LY Chuang, JF Tsai, ZY Lin, MY Hsieh, SC Chen, WL Chuang, LY Wang, ML Yu, CY Dai, JG Chang. Medicine (Baltimore) 2009 Nov;88(6):349-357. Only serum hepatitis B surface antigen (HBsAg) and antibodies to HCV (anti-HCV) were detected.

Flagrant scientific fraud by the health fascists

Note that Jonathan M. Samet was Chairman of the IARC committee which produced the fraudulent Monograph 83, as well as the Senior Scientific Editor of the 2004 Surgeon General report. He has been a ringleader in every major anti-smoking offensive since the 1980s, including the Surgeon General reports, the corrupt EPA ETS report, and committing perjury in the Minnesota and federal tobacco lawsuits.

The fraud of IARC Monograph 83 (Tobacco smoke and involuntary smoking. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans). IARC Monograph 83. Lyon: International Agency for Research on Cancer; 2004.)

"In the previous IARC Monograph on tobacco smoking, a causal relation between liver cancer and smoking could not be established, chiefly due to possible confounding from alcohol intake and hepatitis B and hepaitis C viral infections. Many cohort studies and case-control studies have provided additional information on smoking and liver cancer since then. Most of the cohort studies and the case-control studies (most notably those that included community controls) showed a moderate association between tobacco smoking and risk of liver cancer. In many studies, the risk for liver cancer increased with the duration of smoking or the number cigarettes smoked daily. Former smokers who had stopped smoking for more than 10 years showed a decline in liver cancer risk. Confounding from alcohol can be ruled out, at least in the best case-control studies, by means of careful adjustment for drinking habits. An association with smoking has also been demonstrated among non-drinkers. Many studies, most notably from Asia, have shown no attenuation of the association between smoking and liver cancer after adjustment/stratification for markers of hepatitis B/hepatitis C virus infection. There is now sufficient evidence to judge the association between tobacco smoking and liver cancer as causal."

Of the studies cited in this report to justify their pretense that smoking causes liver cancer, the majority had no information on HBV status (Hammond 1968; Basa 1977; Williams & Horn, 1977; Hirayama 1981; Steinhagen 1983; Tu 1983; Yu 1983; Hardell 1984; Carstensen 1987; Kono 1987; La Vecchia 1988; Ferraroni 1989; Akiba & Hirayama 1990; Hirayama 1990; Hsing 1990; Kew 1990; Olubuyide & Bamgboye 1990; Shibata 1990; Tsukuma 1990; Chen 1991; Lin 1991; Yu MC 1991; Kato 1992; Tanaka 1992; Doll 1994; Peters 1994; Pyong 1994; Goodman 1995; McLaughlin 1995; Siemiatycki 1995; Murata 1996; Shin 1996; Yuan 1996; Chen 1997; Lam 1997; Nordlund 1997; Liu 1998; Gao 1999; Lam 2001; Chen 2003; Mizoue 2000; Lam 2001; Evans 2002; Chen 2003).

Of those which did, few evaluated any markers of HBV infection except HBsAg, which is insufficient (Trichopoulos 1980; Lam 1982; Tu 1985; Austin 1986; Hiyama 1990; Vall Mayans 1990; Choi & Kahyo 1991; Kato 1992, HBV ["Status known No adjustment No stratification"]; Mohamed 1992; Ross 1992; Tanaka 1995; Liaw & Chen 1998).

Only a few considered HCV as well as HBsAg (Tzonou 1991; Yu & Chen 1993; London 1993, "no adjustment no stratification;" Chang 1994; Pyong 1994; Shin 1996; Mukaiya 1998; Sun 1999; Kuper 2000; Mori 2000; Yang 2002). Peters 1994 included HBc, but the "controls" and 90% of cases had cirrhosis. In Chiba 1996, all were HBsAg-negative patients with HCV, evaluated for antibodies to HBsAg and HBc. Yu MW 1991 included HCV, HBsAg, and HBeAg.

The studies cited for adjustment and/or stratification for infection and smoking actually numbered only four (Yu MC 1991; Yu MW 1991; Liaw & Chen 1998; Kuper 2000). None of them was equal in quality to the at least seven studies appearing before 2001 which demonstrated the inadequacy of evaluating only HBsAg.

The abstract of the study by MC Yu made no mention of any such adjustments (Nonviral risk factors for hepatocellular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. Yu MC, Tong MJ, Govindarajan S, Henderson BE. J Natl Cancer Inst 1991 Dec 18;83(24):1820-1826).

Association between hepatitis C virus antibodies and hepatocellular carcinoma in Taiwan. MW Yu, SL You, AS Chang, SN Lu, YF Liaw, CJ Chen. Cancer Res 1991 Oct 15;51(20):5621-5625. Multivariate-adjusted odds ratio of 24.8 for carriers of HBsAg alone, 33.5 for carriers of both HBsAg and HBeAg, and 23.7 for those who were positive for anti-HCV. Note that these high odds ratios easily cause confounding from undetected infection, and undetected infection is a certainty because of their failure to look for all markers.

The only hepatitis virus infection marker mentioned in Liaw & Chen is hepatitis B virus surface antigen. (Mortality attributable to cigarette smoking in Taiwan: a 12-year follow-up study. KM Liaw, CJ Chen. Tob Control 1998 Summer;7(2):141-148.)

Tobacco smoking, alcohol consumption and their interaction in the causation of hepatocellular carcinoma. H Kuper, A Tzonou, E Kaklamani, CC Hsieh, P Lagiou, HO Adami, D Trichopoulos, SO Stuvor. Int J Cancer 2000 Feb 15;85(4):498-502). Note that co-author Dimitrios Trichopoulos is famed for his ETS studies. They tested sera only for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C, and triumphantly crowed that "We found a significant dose-response, positive association between smoking and HCC risk [>/= 2 packs per day, odds ratio (OR) = 2.5]. This association was stronger in individuals without chronic infection with either HBV or HCV (>/= 2 packs per day, OR = 2.8)."

And so their "many studies" which supposedly "have shown no attenuation of the association between smoking and liver cancer after adjustment/stratification for markers of hepatitis B/hepatitis C virus infection" may actually amount to only two.

The Fraud of the 2004 Surgeon General Report

The 2004 Surgeon General report used essentially the same body of inadequate and defective "evidence" as if their designs were of equal merit. They did not cite the smoking results of Chiesa 2000, nor discuss the other studies relating to occult HBV infection. "Evidence Synthesis: A substantial body of epidemiologic evidence supports a relationship between smoking and liver cancer, but a positive association was not found in all studies considered." [This obfuscates the fact that there is no substantial body of quality evidence supporting this claim.] "The metabolism in the liver of the many carcinogens from tobacco smoke leads to an exposure of hepatocytes to these carcinogens." [Which omits the fact that there are far more alleged carcinogens in ordinary food, and in higher quantities, e.g., benzo(a)pyrene.] "The strength of an association between cigarette smoking and liver cancer varies according to HBV infection status, with stronger associations among those who are negative for HBV." [Which is in fact an indicator of confounding, as explicitly confirmed by the studies of occult HBV they failed to discuss.] "In many of the studies, risk increases with the number of cigarettes smoked per day." [Which is a worthless point when the smoking results are confounded in the first place.] "Although confounding by alcohol and HBV infection status may bias the findings of some studies, controlling for these causes does not remove the strong association between smoking and liver cancer seen in several of the studies summarized in this report." [In all of the studies, evaluation of HBV infection is deficient, and the vast majority ignored HCV, so it cannot be pretended that they "controlled" in fact, as opposed to performing a statistical ritual.] "Finally, in 2002, IARC concluded that there is now sufficient evidence for a causal association between cigarette smoking and cancer of the liver (IARC 2002)." In other words, this politically-connected gang of charlatans made a big pile of junk studies to look impressive by the unexacting standards of anti-smoker politicians and the media.

The Surgeon General Reports are all deliberate, flagrant frauds, designed to manufacture bogus anti-smoking "evidence" for the health fascists' political agenda of outlawing smoking. Their despicable media prostitutes breathlessly announced that "The list of diseases linked to smoking grew longer Thursday" - as if this is a triumph instead of a disgrace! The scum triumphantly proclaimed that smoking causes a laundry list of diseases, including even ulcers and cervical cancer - all based on the deliberate fraud of confounding by infection! With regard to liver cancer, the vermin smarmily said that "current evidence is not conclusive enough to say smoking causes colorectal cancer, liver cancer, prostate cancer or erectile disfunction. Some research has associated those diseases with smoking, but Carmona said more proof is needed." To them, "proof" actually consists merely of saturation-bombing the people with BIG LIES repeated over and over again, just like the Nazis! (More Diseases Linked To Smoking. By Nancy Zuckerbrod. AP, May 27, 2004. CBS News HealthWatch.)

Cigarette Smoking, Alcohol Drinking, Hepatitis B, and Risk for Hepatocellular Carcinoma in Korea. SH Jee, H Ohrr, JW Sull, JM Samet. J Natl Cancer Inst 2004 Dec 15;96(24):1851-1856. Jonathan M. Samet is the author in the "Herr Professor" position. Here, he gloats that tobacco "was recently classified as causal by the International Agency for Research on Cancer (IARC)," concerning which they fail to note that Jonathan M. Samet himself was the chairman! (List of Participants, p. 3. International Agency for Research on Cancer (IARC). Tobacco smoke and involuntary smoking. IARC Monograph 83. Lyon, France: IARC; 2004.) "All participants reported their smoking and alcohol consumption, and hepatitis B surface antigen (HBsAg) status was documented for 47.2% of the participants... Current smoking was associated with increased risk of mortality from hepatocellular carcinoma in men (RR = 1.4; 95% CI = 1.3 to 1.6) but not women (RR = 1.1; CI = 0.8 to1.7). The relative risk of mortality from hepatocellular carcinoma for male HBsAg carriers was 24.3 (95% CI = 21.9 to 26.9) times that in HBsAg-negative males; the relative risk for HBsAg-positive women was 54.4 (95% CI = 24.8 to119.5)." They fraudulently pretend that because the association with smoking didn't change after performing adjustment rituals including stratification, it demonstrates the absence of confounding, while ignoring hepatitis C virus infection!

Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma (liver cancer). Jorge A. Marrero, Robert J. Fontana, Sherry Fu, Hari S. Conjeevaram, Grace L. Su, Anna S. Lok. Division of Gastroenterology, University of Michigan, 3912 Taubman Center, Ann Arbor, MI 48109-0362, USA. Journal of Hepatology 2005 Feb;42(2):218-224. This study did not even consider the possibility that hepatitis viruses of any kind cause liver cancer. It consisted of nothing but a lifestyle questionnaire, upon the basis of which they made specious proclamations that "alcohol, tobacco and obesity are independent risk factors for HCC with a dose-dependent effect." The study was approved by the University of Michigan Institutional Review Board.

An incompetent meta-analysis, for which there is no excuse

Cigarette smoking and liver cancer risk: an evaluation based on a systematic review of epidemiologic evidence among Japanese. K Tanaka, I Tsuji, K Wakai, C Nagata, T Mizoue, M Inoue, S Tsugane; Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan. Jpn J Clin Oncol 2006 Jul;36(7):445-456. They treat the issue of occult infection as if it is of only trivial importance: "However, potential confounding by chronic HBV and HCV infections was not addressed in most studies. Since, in Japan, individuals with either or both infections may have more than 100 times higher risk than those without either (3,31), only a slight change in smoking habit among such infected individuals could result in a substantial distortion of associated RRs." This is false. It is not "change in smoking habits" which causes confounding, it is a higher proportion of smokers among those who are infected, which results also in a higher proportion of smokers among those infection was not detected, which results in a fraudulent claim of risk from smoking. "Chronic infections with both HCV and HBV were taken into account in only three studies, all of which followed patients with chronic liver disease" (which were Tsukuma 1993, Chiba 1996, and Tanaka 1998). "In only two case–control studies, both HCV and HBV infections were controlled for" (which were Mukaiya 1998 and Koide 2000). But these were in fact were NOT adequately controlled for, because each of these studies missed a substantial proportion of cases. Nevertheless, 12 cohort studies and 11 case-control studies were thrown together regardless of their lack of quality, and a fraudulent claim against smoking issued.

Political Corruption of Science: The CDC's Bogus Estimate of the Role of HBV and HCV

The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. JF Perz, GL Armstrong, LA Farrington, YJ Hutin, BP Bell. J Hepatol 2006 Oct;45(4):529-538. They make the ridiculous claim that only 78% of HCC was attributable to HBV (53%) or HCV (25%). They claim to have based this upon "representative samples of published reports." Presumably this means that they grabbed a handful of studies and averaged their results, without regard to the quality of the work, as in the Incompetent Meta-Analysis above. This exploits the multitude of trashy studies which are funded to serve the political agenda of the anti-smoking movement! And it contradicts the high-quality studies which found a far greater role of HBV and HCV, including the study of six countries which found that markers of hepatitis viruses B and C were not found in only about 5% of cases (Ding et al., Jpn J Infect Dis 2003). Obviously, the CDC has concocted a fraudulent estimate for political purposes, in order to "make room" to falsely blame smoking.

The Fraud Continues

Effect of different types of smoking and synergism with hepatitis C virus on risk of hepatocellular carcinoma in American men and women: case-control study. MM Hassan, MR Spitz, MB Thomas, AS El-Deeb, KY Glover, NT Nguyen, W Chan, A Kaseb, SA Curley, JN Vauthey, LM Ellis, E Abdalla, RD Lozano, YZ Patt, TD Brown, JL Abbruzzese, D Li. Int J Cancer 2008 Oct 15;123(8):1883-1891. THERE IS NO MENTION OF HBV IN THIS ACT OF FRAUD, which was funded by the National Institutes of Health and the Texas Tobacco Settlement.

The incidence of liver cancer is increasing in the U.S.

The Continuing Increase in the Incidence of Hepatocellular Carcinoma in the United States: An Update. HB El-Serag, JA Davila, NJ Petersen, KA McGlynn. Ann Intern Med 2003 Nov 18;139(10):817-823. In data from the SEER registry, "The overall age-adjusted incidence rates of hepatocellular carcinoma increased from 1.4 per 100 000 in 1975 to 1977 to 3.0 per 100 000 in 1996 to 1998. There was a 25% increase during the last 3 years of the study compared with the preceding 3 years (1993 to 1995). The increase affected most age groups above 40 years, with the greatest increase in the 45- to 49-year-old age group. White men had the greatest increase (31%) in the last time period (1996 to 1998) compared with 1993 to 1995. The Poisson regression model confirmed an almost 2-fold increase in the incidence rate ratio for hepatocellular carcinoma between 1975 to 1978 and 1996 to 1998... These findings are consistent with a true increase and could be explained by consequences of hepatitis C virus acquired during the 1960s and 1970s."

"A study from the Centers for Disease Control and Prevention that used mathematical modeling estimated that the HCV epidemic started in the 1960s and peaked in the 1980s. Risk factors for transmitting HCV were rampant during this period (for example, injection drug use, needle sharing, and transfusion of unscreened blood and blood products). A recent study examined the constant evolutionary rate of HCV over time ("the molecular clock") in retrospectively collected serum samples of HCV carriers in Japan and the United States. The study concluded that HCV first appeared in Japan around 1882 and in the United States around 1910, whereas widespread dissemination occurred in the 1930s in Japan and in the 1960s in the United States. These findings suggest that hepatocellular carcinoma in the United States will continue to increase for the near future. Currently, the highest prevalence HCV infection rate is among 40- to 50-year-old persons who have been infected for 1 to 2 decades and are expected to live for another 2 to 3 decades with the increased potential for developing HCV-related complications."

Hepatocellular Carcinoma Incidence, Mortality, and Survival Trends in the United States From 1975 to 2005. SF Altekruse, KA McGlynn, ME Reichman. J Clin Oncol 2009 Mar 20;27(9):1485-1491. From the Surveillance, Epidemiology, and End Results (SEER) registries from 1975 to 2005. "Age-adjusted HCC incidence rates tripled between 1975 and 2005. Incidence rates increased in each 10-year birth cohort from 1900 through the 1950s," especially among men.

Aging of hepatitis C virus (HCV)-infected persons in the United States: a multiple cohort model of HCV prevalence and disease progression. GL Davis, MJ Alter, H El-Serag, T Poynard, LW Jennings. Gastroenterology 2010 Feb;138(2):513-521. "Hepatic decompensation and liver cancer will continue to increase for another 10 to 13 years. Treatment of all infected patients in 2010 could reduce risk of cirrhosis, decompensation, cancer, and liver-related deaths by 16%, 42%, 31%, and 36% by 2020, given current response rates to antiviral therapy."

Hepatocellular Carcinoma --- United States, 2001--2006. MMWR 2010 May 7;59(17):517-520. "[T]he average annual incidence rate of HCC for 2001--2006 was 3.0 per 100,000 persons and increased significantly from 2.7 per 100,000 persons in 2001 to 3.2 in 2006, with an average annual percentage change in incidence rate (APC) of 3.5%. The largest increases in HCC incidence rates were among whites (APC = 3.8), blacks (APC = 4.8), and persons aged 50--59 years (APC = 9.1). "

Clinical Practice

Hopefully, better testing will be done in clinical practice as well. "Liver transplanted from HBsAg-negative donors can harbor and transmit hepatitis B infection to recipients, according to a report in the December Journal of Medical Virology. Previous studies have suggested the possibility of transmission of hepatitis B from liver donor to recipient despite the absence of HBV viremia in the donor, the authors explain, but no genetic analysis has been conducted to confirm these cases." (Orthotopic liver transplantation transmits hepatitis B. Medscape - Reuters Medical News 2000 Dec 20 http://id.medscape.com/31574.rhtml link died); De novo infection of hepatitis B in patients with orthotopic liver transplantation: analysis by determining complete sequence of the genome. A Rokuhara, E Tanaka, S Yagi, H Mizokami, Y Hashikura, S Kawasaki, K Kiyosawa. J Med Virol 2000 Dec;62(4):62(4):471-478.)

Strains vary by geography

Hepatitis B virus genotypes in the United States: results of a nationwide study. CJ Chu, EB Keeffe, SH Han, RP Perrillo, AD Min, C Soldevila-Pico, W Carey, RS Brown Jr., VA Luketic, N Terrault, AS Lok. Gastroenterology 2003 Aug;125(2):444-451. "The prevalence of HBV genotypes was different in different regions of the United States. A strong correlation was found between HBV genotypes and ethnicity...."

Novel hepatitis B virus genotype A subtyping assay that distinguishes subtype Aa from Ae and its application in epidemiological studies. I Hasegawa, Y Tanaka, A Kramvis, T Kato, F Sugauchi, SK Acharya, E Orito, R Ueda, MC Kew, M Mizokami. J Virol 2004 July;78(14):7575-7581. African-Americans, Caucasians and Hispanics had HBV/Ae, whereas Asians had mainly HBV/Aa, "suggesting that the HBV/Aa isolates may have been imported by recent immigration from Asia."

Hepatitis C Virus Genotypes in Clinical Specimens Tested at a National Reference Testing Laboratory in the United States. JJ Germer, JN Mandrekar, JL Bendel, PS Mitchell, JD Yao. J Clin Microbiol 2011 May 25 [Epub ahead of print]. "Hepatitis C virus (HCV) genotype (GT) distribution and frequency were studied among 22,407 unique specimens tested at a national reference testing laboratory. Subjects with HCV GT 3 were younger (P<0.0001) than those with GT 1, 2, or 4, and regional frequency of HCV GT 2/3 ranged from 19.9% to 29.2%."

Hepatitis viruses as a cause of cancer: mechanisms

Hepatitis B virus has been accepted as a cause of liver cancer for decades. However, because it has not been found to cause any distinctive mutation(s), it has been thought that HBV did so purely as a result of the increased proliferation of liver cells resulting from their destruction by the virus.

But evidence is building that the X protein of HBV may cause cancer by interfering with the cellular repair mechanisms under the control of the crucial p53 tumor suppressor protein, much as the E6 protein of human papillomavirus is known to do.

1) Early in the process of cell repair and division, p53 activates the cellular genes WAF1 (also called p21) and GADD45.

2) WAF1 protein inhibits cyclin dependent kinases (cdks), which prevents them from phosphorylating the Rb protein. The unphosphorylated Rb keeps the cell arrested at the G1 stage.

3) GADD45 repairs damaged DNA. When the DNA has been repaired, p53 levels decline, which lowers the WAF1 levels and releases the cdks, which phosphorylate the Rb so the cell is free to progress from the G1 to the S stage. Alternatively, if the DNA is not repaired, p53 causes the cell to die (apoptosis).

4) The activity of p53 is blocked, however, if cells contain the polyoma virus large T antigen, human papillomavirus E6 protein, or adenovirus E1B 55KD protein. Now, there is evidence that the X protein of HBV (HBx) binds to p53 in the cytoplasm, which prevents it from entering the nucleus and causing the death of the cell if the DNA has not been repaired.

Mutations occur during practically every cell division. High levels of p53 occur after widespread cell damage such as caused by ultraviolet light. So, these viruses can cause cancer by interfering with the normal protective mechanisms that guard against mutations.

Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis. LW Elmore, AR Hancock, S-F Chang, XW Wang, S Chang, CP Callahan, DA Geller, H Will, CC Harris. Proc Natl Acad Sci USA 1997 Dec;94(26):14707-14712.

Hepatitis B virus X protein interferes with cellular DNA repair. SA Becker, T-H Lee, JS Butel, BL Slagle. J Virol 1998 Jan;72(1):266-272.

Hepatitis viruses: their role in human cancer. DW Bradley. Proc Assoc Am Physicians 1999 Nov-Dec;111(6):588-593.

Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. M Forgues, MJ Difilippantonio, SP Linke, T Ried, K Nagashima, J Feden, K Valerie, K Fukasawa, XW Wang. Mol Cell Biol 2003 Aug;23(15):5282-5292. "Hepatitis B virus (HBV) includes an X gene (HBx gene) that plays a critical role in liver carcinogenesis. Because centrosome abnormalities are associated with genomic instability in most human cancer cells, we examined the effect of HBx on centrosomes. We found that HBx induced supernumerary centrosomes and multipolar spindles. This effect was independent of mutations in the p21 gene. Furthermore, the ability of HBV to induce supernumerary centrosomes was dependent on the presence of physiological HBx expression."

Pathogenesis of hepatitis B virus-related hepatocellular carcinoma: old and new paradigms. C Brechot. Gastroenterology. 2004 Nov;127(5 Suppl 1):S56-S61. "Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of hepatocellular carcinoma (HCC). The pathogenesis of cancer in HBV infection has been extensively analyzed, and multiple factors appear to play a role. A major factor is chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation. Also important is the role of integration of HBV DNA into host cellular DNA, which, in some situations, acts to disrupt or promote expression of cellular genes that are important in cell growth and differentiation. In addition, expression of HBV proteins may have a direct effect on cellular functions, and some of these gene products can favor malignant transformation. Several HBV genes have been found in infected tissues more frequently than others, including truncated pre-S2/S, hepatitis B X gene, and a novel spliced transcript of HBV, referred to as the hepatitis B spliced protein. The proteins expressed from these integrated genes have been shown to have intracellular activities that may account for their association with HCC, including effects on cellular growth and apoptosis. Finally, some patients with HCC have no detectable hepatitis B surface antigen in serum but do have low levels of HBV DNA in serum and integrated molecules of HBV DNA in tissue. Occult HBV infection may account for a proportion of cases of HCC that occur in patients without serologic markers for hepatitis B and C and may be a cofactor in HCC in patients with chronic hepatitis C who have coexistent occult HBV infection."

Specific mutations of hepatitis B virus in plasma predict liver cancer development. Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, Kensler TW, Groopman JD. Proc Natl Acad Sci U S A 2004 Mar 9;101(10):3575-3580. 74% of liver carcinomas were positive for a 1762^T/1764^A mutation of HBV. "67 of 70 (95.7%) tumors contained detectable levels of either the HBV double mutation or integrated WT HBV DNA or both. Fifty-two of the specimens (74.3%) contained the 1762T/1764A HBV mutation." In over 53% of cases from a prospective study, the mutation was found in plasma samples up to eight years before diagnosis.

Association of p16INK4A hypermethylation with hepatitis B virus X protein expression in the early stage of HBV-associated hepatocarcinogenesis. R Zhu, BZ Li, H Li, YQ Ling, XQ Hu, WR Zhai, HG Zhu. Pathol Int 2007 Jun;57(6):328-36. "The data indicate that p16(INK4A) promoter hypermethylation correlated closely with higher HBx expression in the precancerous lesions, suggesting that HBx may play an important role in the early stage of HBV-associated hepatocarcinogenesis via induction of hypermethylation of p16(INK4A) promoter."

Regulation of hepatitis B virus replication by the phosphatidylinositol 3-kinase-akt signal transduction pathway. H Guo, T Zhou, D Jiang, A Cuconati, GH Xiao, TM Block, JT Guo. J Virol 2007 Sep;81(18):10072-10080. "Consistent with previous reports showing that the HCV NS5A protein could bind to the p85 subunit of PI3K and activate the PI3K-Akt signal transduction pathway, our results showed that expression of this protein could inhibit HBV RNA transcription and reduce HBV DNA replication in HepG2 cells. Taken together, our results suggest that the activation of the PI3K-Akt pathway during liver oncogenesis may be at least partially responsible for the elimination of HBV replication from tumor cells and may also provide an explanation for the observed suppression of HBV replication by HCV coinfection."

The Size of the Viral Inoculum Contributes to the Outcome of Hepatitis B Virus Infection. S Asabe, SF Wieland, PK Chattopadhyay, M Roederer, RE Engle, RH Purcell, FV Chisari. J Virol 2009 Oct;83(19):9652-9662. Both high-dose and low-dose inocula allowed infection of 100% of hepatocytes resulting in prolonged immunopathology before clearance occurred. In contrast, intermediate nocula primed the T-cell response before detectable logarithmic spread and were abruptly terminated with minimal immunopathology before 0.1% of hepatocytes were infected.

Hepatitis B Viral Replication Induces Methylation of Both Host and Viral DNA. P Vivekanandan, HD Daniel, R Kannangai, F Martinez-Murillo, M Torbenson. J Virol 2010 May;84(9):4321-4329. "[H]epatocytes respond to HBV infection by up-regulating DNMTs. The DNMTs methylate viral DNA leading to decreased viral gene expression and decreased viral replication. However, viral induced over expression of DNMTs also leads to methylation of host CpG islands."

Hepatitis C Virus

Hepatitis C virus core protein promotes immortalization of primary human hepatocytes. RB Ray, K Meyer, R Ray. Virology 2000 May 25;271(1):197-204. Core-transfected primary human hepatocytes displayed altered cell morphology resembling that of low-differentiated epithelial cells. Those cells retained an immortalized phenotype and exhibited continuous growth after more than 50 passages over 2 years. Stable hepatocyte transfectants exhibited albumin secretion and HCV core protein expression. Telomerase activity, a characteristic of immortalized or transformed cells, was evident in the transfected hepatocytes immediately after senescence. Anchorage-independent growth of the immortalized hepatocytes provided further evidence for a transformed phenotype. Results from these studies suggest that the HCV core protein promotes primary human hepatocytes to an immortalized phenotype, which may predispose cells over an extended period of time to undergo a transforming event. Thus, HCV core protein appears to contribute to virus-mediated pathogenesis in a persistently infected host."

Molecular cytogentic profiles of hepatitis C infection in patients at Sharkia Governorate, Egypt. E el-Sobky, AM Mangoud, S Mahrous, MH Eissa, EI Sabee, IA Ibrahem, A Ismail, TA Morsy, E Nor Edin, I el-Naggar, Y Mostafa, Y Abuel-Magd, AF Afefy, E el-Shorbagy, M el-Sadawy, H Ragab, A el-Far, MI Hassan, K Lakouz, K Abdel-Aziz M Saber, G el-Hady. J Egypt Soc Parasitol 2004 Apr;34(1 Suppl):401-415. 40 paraffin blocks from HBV-seronegative, HCV-positive patients, by FISH. "The results showed high percentage of S-phase fraction in cases of G2S2 and G3S3 with DNA diploidy. Only two cases of G3S3 showed DNA aneuploidy with severe amplification of chromosome 20q 13.2." HCV amplifies the aggressive tumor behavior oncogene LSIZNF 217 at chromosome 20q 13.2.

Hepatitis C virus core protein inhibits tumor suppressor protein promyelocytic leukemia function in human hepatoma cells. K Herzer, S Weyer, PH Krammer, PR Galle, TG Hofmann. Cancer Res 2005 Dec 1;65(23):10830-10837. "Importantly, we show that HCV core protein inhibits PML-IV-induced apoptosis and interferes with the coactivator function of PML-IV for proapoptotic p53 target genes including CD95 (Fas/APO-1). In particular, we found that the HCV core inhibits p53-mediated target gene expression by predominantly targeting the coactivator function of PML-IV because HCV core-mediated p53 target gene repression was absent in PML-ablated cells. HCV core expression abrogated both p53 serine 15 phosphorylation and lysine 382 acetylation, two p53-activating posttranslational modifications which were previously linked to an increased PML-NB formation. Taken together, our results suggest a potential mechanism for HCV-associated development of hepatocellular carcinoma through HCV core-mediated inactivation of the PML tumor suppressor pathway."

Hepatitis C Virus Induces E6AP-Dependent Degradation of the Retinoblastoma Protein. T Munakata, Y Liang, DR McGivern, J Huibregtse, A Nomoto, SM Lemon. PLoS Pathogens 2007;3(9):e139. "Persons infected with hepatitis C virus (HCV) are at increased risk for liver cancer. This is remarkable because HCV is an RNA virus with replication confined to the cytoplasm and no potential for integration of its genome into host cell DNA. While it is likely that chronic inflammation contributes to liver cancer, prior studies with HCV transgenic mice indicate that the viral proteins are intrinsically carcinogenic. In this study, we have examined the interaction of one of these, the RNA-dependent RNA polymerase nonstructural protein 5B, with an important cellular tumor suppressor protein, the retinoblastoma protein (pRb). pRb is a master regulator of the cell cycle, and altered expression of some of the many genes it regulates may lead to cancer. We show that the abundance of pRb is strongly downregulated in cells infected with HCV, and that nonstructural protein 5B targets pRb for destruction via the cell's normal protein degradation machinery. The E6-associated protein appears to play a role in this process, which is interesting as it also mediates the degradation of another tumor suppressor, p53, by papillomaviruses. The loss of pRb function in HCV-infected cells likely promotes hepatocellular proliferation as well chromosomal instability, factors important for the development of liver cancer."

Hepatitis C virus core protein downregulates E-cadherin expression via activation of DNA methyltransferase 1 and 3b. P Arora, EO Kim, JK Jung, KL Jang. Cancer Lett 2008 Mar 18;261(2):244-252. "Here, we report that hepatitis C virus Core downregulates E-cadherin expression at the transcription level. This effect was abolished after treatment of 5'-Aza-2'dC, a specific inhibitor of DNA methyltransferase (DNMT). In addition, this repression was strongly correlated with hypermethylation of CpG islands of E-cadherin promoter via concerted action of both DNMT1 and 3b in Core-expressing cells. The decreased E-cadherin expression results in dramatic morphological changes in Core-expressing cells. In addition, Core-expressing cells aggregate poorly in suspension culture, reflecting their altered cell-cell interactions. The biological significance was further demonstrated by the increased collagen invasion ability of Core-expressing cells."

Hepatitis C Virus Causes Uncoupling of Mitotic Checkpoint and Chromosomal Polyploidy through the Rb Pathway. K Machida, JC Liu, G McNamara, A Levine, L Duan, MM Lai. J Virol 2009 Dec;83(23):12590-12600. "[P]eripheral blood mononuclear cells (PBMC) obtained from hepatitis C patients and hepatocytes infected with HCV in vitro showed frequent chromosomal polyploidy. HCV infection or the expression of viral core protein alone in hepatocyte culture or transgenic mice inhibited mitotic spindle checkpoint function because of reduced Rb transcription, and enhanced E2F-1 and Mad2 expression."

Hepatitis C virus inhibits DNA damage repair through reactive oxygen and nitrogen species and by interfering with the ATM-NBS1/Mre11/Rad50 DNA repair pathway in monocytes and hepatocytes. K Machida, G McNamara, KT Cheng, J Huang, CH Wang, L Comai, JH Ou, MM Lai. J Immunol 2010 Dec 1;185(11):6985-6998. "The viral core and nonstructural protein 3 proteins were shown to be responsible for the inhibition of DNA repair, mediated by NO and reactive oxygen species. Stable expression of core protein induced frequent chromosome translocations in cultured cells and in transgenic mice. HCV core protein binds to the NBS1 protein and inhibits the formation of the Mre11/NBS1/Rad50 complex, thereby affecting ATM activation and inhibiting DNA binding of repair enzymes."

New methods find occult virus

Quantitative detection of hepadnavirus-infected lymphoid cells by in situ PCR combined with flow cytometry: implications for the study of occult virus persistence. PM Mulroney, TM Michalak. J Virol 2003 Jan;77(2):970-979. "The detection of small amounts of viral pathogens in infected cells by classical PCR is hampered by a partial loss of virus nucleic acid due to extraction and by difficulties in discriminating between truly intracellular virus genome material and that possibly adhered to the cell surface... In this study, hepadnavirus-specific in situ PCR combined with the enzymatic elimination of extracellular virus and flow cytometry permitted detection of viral genomes in lymphoid cells without nucleic acid isolation and allowed quantification of infected cells during the course of persistent infection with woodchuck hepatitis virus (WHV)... The data obtained provide further evidence that WHV infection continues indefinitely in the lymphatic system independently of whether it is symptomatic or concealed."

Detection of hepatitis B and C viruses in almost all hepatocytes by modified PCR-based in situ hybridization. H Nuriya, K Inoue, T Tanaka, Y Hayashi, T Hishima, N Funata, K Kaji, S Hayashi, S Kaneko, M Kohara. J Clin Microbiol 2010 Nov;48(11):3843-3851. "HBV-genomic DNA was detected in almost all hepatocytes, whereas HBV-RNA or protein was differentially distributed only in a subset of the HBV-DNA-positive region. Further, HCV-genomic RNA was detected in almost all hepatocytes and was localized to the cytoplasm. HCV-RNA was also detected in the epithelium of the large bile duct but not in endothelial cells, portal tracts, or sinusoidal lymphocytes. In patients with HBV and HCV coinfection, HCV-RNA was localized to the noncancerous tissue whereas HBV-DNA was found only in the cancerous tissue. Using this novel PCR-ISH method, we could visualize the staining pattern of HBV and HCV in liver sections, and obtained results consistent with those of real-time detection (RTD)-PCR analysis. In conclusion, almost all hepatocytes are infected with HBV or HCV in chronic liver disease; this finding implies that the viruses spreads throughout the liver in the chronic stage."

See also:

cast 07-31-11