Lower Incidence Of Hepatocellular Carcinoma Research Articles

Diabetes: One of Few Remarkable Differences in Clinicopathologic Features Between Cirrhotic and Noncirrhotic Swedes With Hepatocellular Carcinoma

The prognosis of hepatocellular carcinoma (HCC) is usually very poor, so increased knowledge of clinicopathologic characteristics and etiologic factors may improve the clinical handling. Because HCC in many patients is unrecognized before death, it is of particular interest to study cases from a period with a high autopsy frequency. The records and liver biopsies from all patients with a diagnosis of primary liver cancer in Göteborg, Sweden, during a 22-year period were scrutinized. Only patients with evaluable non-neoplastic liver tissue were included in the final analysis. The majority (95%) of 478 HCC cases were autopsied and cirrhosis of the liver could be established in 71%. At presentation, general paramalignant symptoms such as malaise, weight loss, anorexia, and hepatomegaly (84%) were common irrespective of cirrhosis. Alcoholism and diabetes mellitus were each significantly more common among cirrhotics (29% and 20%, respectively; P < .001), than among noncirrhotics, in which cholelithiasis was more common (54%; P < .001). The correlation between diabetes and cirrhosis was independent of reported alcoholism. In an unselected population in a low HCC incidence area, there are few differences in clinicopathologic features between cirrhotic and noncirrhotic patients. Diabetes mellitus seems to play an etiologic role in HCC in cirrhotics, and cholelithiasis in noncirrhotics.

Ursodiol Use Is Possibly Associated with Lower Incidence of Hepatocellular Carcinoma in Hepatitis C Virus–Associated Liver Cirrhosis

Abstract In a previous study of patients with hepatitis C virus (HCV)–associated liver cirrhosis (HCV-LC), we showed that increased liver inflammation, as assessed by higher serum alanine aminotransferase (ALT), was associated with increased risk for the development of hepatocellular carcinoma (HCC). This suggested that suppression of inflammation might inhibit HCC development in HCV-LC. Several agents have been suggested to possess chemopreventive potential against the development of HCC in chronic HCV-associated liver disease, including herbal medicines, such as Stronger-Neo-Minophagen C (glycyrrhizin) and Sho-saiko-to (TJ-9). Ursodiol [ursodeoxycholic acid (UDCA)], a bile acid widely used to treat cholestatic liver diseases, also possesses anti-inflammatory properties in liver disease. We hypothesized that suppression of liver inflammation, as assessed by decreases in serum ALT, might inhibit HCC occurrence in patients with HCV-LC. In this study, the preventive effect of UDCA on HCC was examined in patients with early-stage HCV-LC. One hundred two patients with HCV-LC (Child stage A) were treated with anti-inflammatory drugs, Stronger-Neo-Minophagen C,Sho-saiko-to, or UDCA, with the goal of lowering the average serum ALT level to &amp;lt;80 IU. Iftheaverage ALT level did not remain &amp;lt;80 IU after treatment with one agent, multiagent therapy was initiated. The patients were followed up for &amp;gt;5 years and were retrospectively subdivided into two groups: 56 UDCA users (group A) and 46 UDCA nonusers (group B). The mean ± SD dosage of UDCA administered in group A was 473.7 ± 183.0 mg/d. The average duration of UDCA administration in group A was 37.3 ± 15.9 months over the 5-year study period. The cumulative incidence of HCC was recorded. The 5-year incidence of HCC in group A was 17.9% (10 of 56) and was significantly lower than that in group B (39.1%, 18 of 46; P = 0.025). The risk for HCC incidence, calculated by a logistic regression model, showed that the administration of UDCA significantly decreased hepatocarcinogenesis (P = 0.036). The herbal medicines used were comparable in dosage and treatment duration in the UDCA and non-UDCA groups. In conclusion, UDCA might prevent HCC development in HCV-LC. Interestingly, because the serum ALT trends over time were nearly the same in both groups, the chemopreventive effectiveness of UDCA was not accompanied by greater reductions in ALT compared with the UDCA nonusers.

The risk of end stage liver disease and hepatocellular carcinoma among persons infected with hepatitis C virus: publication bias?

Objectives In persons infected with hepatitis C virus (HCV), the incidence of cirrhosis and hepatocellular carcinoma (HCC) can be estimated by examining over time entire cohorts with known onset of HCV infection. We performed a systematic review of the literature to identify and to analyze studies that examine such cohorts. Methods A search of all articles from 1980 to 2001 was performed. Published studies were included in which chronic HCV infection was defined by elevation of liver enzymes or persistent RNA. We excluded studies in which cohorts were selected from patients with prevalent liver disease or in whom the onset of infection could not be estimated. Two investigators abstracted the data. The incidences of cirrhosis and HCC were analyzed in all studies and in categories based on study design, mode of HCV acquisition, sample size and duration of follow-up, age at the onset of infection, and the quality of estimating the onset of HCV infection. Results Of the articles, 21 fulfilled the selection criteria. Studies varied in sample size (17–1,680), duration of follow-up (8–45 yr), total person-years (157–34,098), and the mean age at onset of HCV (5–58 yr). The mean time to end stage liver disease (ESLD) was 4–23 yr and to HCC was 9–31 yr. A funnel plot showed a possible publication bias against studies with low incidence of ESLD and HCC. The pooled weighted incidence rates for ESLD and HCC based on infection mode were as follows: community-acquired HCV, 1.9 and 0 per 1,000 person-years; transfusion associated, 4.5 and 0.7; hemophilia patients, 7.9 and 1.0; anti-D IgG, 0.7 and 0 per 1,000 person-years. Poisson regression modeling showed that the incidence of ESLD is increased in studies with a low quality estimate of the onset of HCV infection, in community-acquired and transfusion-associated HCV, and in studies with prospective design. Conclusions We found large variation in the incidence estimates of cirrhosis and HCC. Short duration of follow-up, small sample size, and possible publication bias may explain some of this variation. Low quality estimates of the onset of HCV infection, a prospective study design, and a transfusion- or hemophilia-related mode of acquisition were independent predictors of high reported incidence of ESLD.

Sustained biochemical remission after interferon treatment may closely be related to the end of treatment biochemical response and associated with a lower incidence of hepatocarcinogenesis.

Clinical background and incidence of hepatocellular carcinoma (HCC) of patients with chronic hepatitis C who obtained biochemical remission without eradication of virus (biochemical response) after interferon (IFN) treatment was retrospectively analyzed for 755 patients. Annual incidence of HCC was significantly lower in the patients with biochemical response and sustained response than that of the patients that did not show these responses. Logistic regression analysis showed that only the normalization of alanine aminotransferase (ALT) value at the end of IFN treatment was a significant factor for biochemical response. Annual incidence of HCC was significantly lower in the patients who obtained normalization of ALT values at the end of treatment than those who did not. Patients who were younger, who had a lower level of activity and fibrosis indices in histology, higher platelet count, and who were given more higher total dose of IFN were more likely to attain normalization of ALT levels at the end of treatment, and this was related to biochemical response. Low incidence of HCC in patients who obtained normalization of ALT values at the end of treatment was likely because they were in the earlier stage of chronic hepatitis. Active treatment of chronic hepatitis C with interferon in the early phase of the disease may bring about a biochemical response in some patients, even if sustained virological response is not obtained.

Why treat chronic hepatitis B in childhood with interferon α?

See article on page 715 Advances in the understanding of hepatitis B viral infection are a major accomplishment in modern hepatology. In three decades we have progressed from rather vague...

In vivo electroporetic transfer ofbcl-2 antisense oligonucleotide inhibits the development of hepatocellular carcinoma in rats

To investigate the potential use of a bcl-2 antisense oligonucleotide for therapy against hepatocellular carcinoma, we examined the effects of the electroporetic transfer of a bcl-2 antisense oligonucleotide on rat hepatocarcinogenesis induced by N-nitrosomorpholine (NNM). Sprague–Dawley rats were given water containing 175 mg/l NNM for 8 weeks and received intraperitoneal injections of a bcl-2 antisense phosphorothioate oligonucleotide, a sense oligonucleotide or a scrambled sequence oligonucleotide encapsulated in empty liposomes, at a dose of 150 μg oligonucleotide/kg body weight, every 4 weeks. One hour after injection, in vivo electroporation was performed on the liver to achieve selective transfer of the oligonucleotides. By week 16, the rats that had received the bcl-2 antisense oligonucleotide had significantly fewer and smaller precancerous liver lesions positive for glutathione-S-transferase (placental type), and a significantly lower incidence of hepatocellular carcinoma in the electroporation zone than rats that had received the sense or the scrambled oligonucleotides. Moreover, the bcl-2 antisense oligonucleotide significantly increased the apoptotic indices in foci, neoplastic nodules and in hepatocellular carcinomas. The expression of bcl-2 mRNA also decreased, and 3′-fragments of bcl-2mRNA produced by cleavage at the antisense target site were detected in rat liver. Mean cellular fluorescence in the liver increased with higher doses of fluorescein-isothiocyanate-labeled antisense or sense oligonucleotides. Our results show that the electroporetic transfer of bcl-2 antisense oligonucleotide can inhibit rat hepatocarcinogenesis. Int. J. Cancer 85:260–266, 2000. ©2000 Wiley-Liss, Inc.

In vivo electroporetic transfer ofbcl-2 antisense oligonucleotide inhibits the development of hepatocellular carcinoma in rats

To investigate the potential use of a bcl-2 antisense oligonucleotide for therapy against hepatocellular carcinoma, we examined the effects of the electroporetic transfer of a bcl-2 antisense oligonucleotide on rat hepatocarcinogenesis induced by N-nitrosomorpholine (NNM). Sprague-Dawley rats were given water containing 175 mg/l NNM for 8 weeks and received intraperitoneal injections of a bcl-2 antisense phosphorothioate oligonucleotide, a sense oligonucleotide or a scrambled sequence oligonucleotide encapsulated in empty liposomes, at a dose of 150 microg oligonucleotide/kg body weight, every 4 weeks. One hour after injection, in vivo electroporation was performed on the liver to achieve selective transfer of the oligonucleotides. By week 16, the rats that had received the bcl-2 antisense oligonucleotide had significantly fewer and smaller precancerous liver lesions positive for glutathione-S-transferase (placental type), and a significantly lower incidence of hepatocellular carcinoma in the electroporation zone than rats that had received the sense or the scrambled oligonucleotides. Moreover, the bcl-2 antisense oligonucleotide significantly increased the apoptotic indices in foci, neoplastic nodules and in hepatocellular carcinomas. The expression of bcl-2 mRNA also decreased, and 3'-fragments of bcl-2mRNA produced by cleavage at the antisense target site were detected in rat liver. Mean cellular fluorescence in the liver increased with higher doses of fluorescein-isothiocyanate-labeled antisense or sense oligonucleotides. Our results show that the electroporetic transfer of bcl-2 antisense oligonucleotide can inhibit rat hepatocarcinogenesis.

Risk factors and the effect of interferon therapy in the development of hepatocellular carcinoma: a multivariate analysis in 343 patients.

The aims of the present study were to clarify the risk factors for the development of hepatocellular carcinoma (HCC) in chronic hepatitis C virus (HCV) infection and to investigate the effectiveness of interferon (IFN) therapy. We retrospectively studied 343 patients who had been admitted to our hospital; 161 with chronic hepatitis, 49 with liver cirrhosis, 42 with chronic hepatitis bearing HCC and 91 with liver cirrhosis bearing HCC. The mean (+/- SD) observation period was 41.6 +/- 31.1 months. The mean age of HCC and non-HCC patients was 63.5 +/- 7.6 and 56.9 +/- 12.5 years, respectively (P < 0.001). The HCV genotype II (1b) was the most prevalent genotype (92.5%) in HCC patients and the mean age was higher among patients with this genotype (63.6 +/- 7.7 years). Multivariate analysis identified age (P < 0.001), the male gender (P < 0.01), HCV genotype II (1b) (P < 0.05) and excessive alcohol intake (P < 0.05) as independent factors associated with the development of HCC. There was no relationship between the development of HCC and serum HCV levels as quantified by branched DNA assay or competitive reverse transcription polymerase chain reaction. The incidence of HCC in patients who had not received IFN therapy was 10.4/100 person-year, while that of patients who had received IFN therapy was 1.2/100 person-year (P < 0.01) by the person-year method. The low incidence of HCC in patients treated with IFN suggests that IFN may prevent the development of HCC.

Hepatocellular carcinoma with and without cirrhosis: A comparison in southern African blacks

Hepatocellular carcinoma and cirrhosis frequently coexist. In populations with a low incidence of hepatocellular carcinoma, the tumor often arises as a complication of long-standing symptomatic cirrhosis, which may be micronodular or macronodular and which is usually alcoholic in origin, and cirrhosis per se is the major etiologic association of the tumor. The relation between these two pathologic conditions in populations with a high incidence of hepatocellular carcinoma has not hitherto been analyzed. In this study the association was examined in 463 southern African black men with hepatocellular carcinoma. Cirrhosis, almost always macronodular and rarely showing features of alcoholic toxicity, was present in 63.1% of the patients. No differences were found in the age structure, clinical features, hepatic function, serum α-fetoprotein concentrations, or hepatitis B virus status between patients with hepatocellular carcinoma with and without cirrhosis. Patients with cirrhosis survived slightly longer, but the difference was not biologically significant. It is concluded that the relation between hepatocellular carcinoma and cirrhosis in southern African blacks differs substantially from that in low incidence regions of the tumor.

Monitoring hepatocellular carcinoma by using a monoclonal immunoenzymometric assay for alpha-fetoprotein.

A monoclonal immunoenzymometric assay for alpha-fetoprotein (M-AFP) was evaluated with respect to its utility in monitoring hepatocellular carcinoma (HCC) patients. Earlier (Clin Chem 1986;32:1318-22), we found this immunoassay to demonstrate abilities similar to polyclonal AFP assays, and we suggested that changes in M-AFP correlated with changes in intrahepatic tumor volume in most HCC patients. In the present study, 107 HCC patients were evaluated between 1978 and 1986. Patient demographics characterized this study population as being similar to those seen in regions with low incidence of HCC. Changes in serum M-AFP concentration correlated moderately (r = 0.55) with changes in intrahepatic tumor volume. The AFP concentration in serum was found to be a statistically significant independent predictor of survival; patients with above-normal M-AFP (AFP[+]) at presentation demonstrated a median survival time of 10 months, compared with 16 months for patients with "normal" values for M-AFP (AFP[-]) (P = 0.008). This prognostic pattern persisted when adjusted for serum bilirubin concentration (AFP[+] 12 months vs AFP[-] 29 months, P = 0.01).

Dynamics of serum alpha-fetoprotein during spontaneous hepatocellular carcinoma development in mice

C3H-A vyfB mice have been studied over their normal life span and 69% developed hepatocellular carcinoma (HCC). Forty-seven mice were bled at monthly intervals, and individual serum alpha-fetoprotein (AFP) profiles are presented for 36 animals. Most of these profiles are quite irregular. Sixty percent of the 15 male mice had a transient serum AFP elevation at 5 months, reaching a mean of 289 ng/ml, compared to a mean of 208 ng/ml for those male mice without a transient AFP elevation and a mean of 185 ng/ml in male mice at 2–4 months of age. All of these male mice and others were tested for murine hepatitis virus and found to be negative. Mice with this early AFP peak tended to have a lower incidence of HCC and much lower AFP values later in life than those not having an early peak, but this difference was not statistically significant. Of the mice whose serum AFP concentration exceeded 300 ng/ml beyond 6 months of age, 23% (9/39) experienced a subsequent pronounced decline in AFP, averaging 74% of previous peak values for males and 44% for females. Of the 39 mice evaluated, 35 were autopsied and 50% (4/8) of these “serum AFP regressors” had minicroscopic evidence of lymphocytic infiltration their livers, as compared to 15% (4/27) of the “non-regressors” that had a similar change.

Tissue distribution of 2,4-dinitrotoluene and its metabolites in male and female Fischer-344 rats

The hepatocarcinogen, dinitrotoluene (DNT), produces a lower incidence of hepatocellular carcinoma in female rats than in male rats. This study compares the elimination of radiolabeled 2,4-DNT in male rats at three dosages and the elimination of 2,4-DNT in male and female rats at a dose of 100 mg/kg. Terminal half-lives of total radioactivity in various tissues were similar after doses of 10 or 35 mg/kg in male rats, but were shorter after a dose of 100 mg/kg in plasma, red blood cells, liver, and kidney. Although terminal half-lives for total radioactivity were similar in male and female rats after a dose of 100 mg/kg, female liver contained concentrations of radioactivity which were one-half those found in males. The tissues of both sexes contained parent compound, 2,4-dinitrobenzoic acid, and 2-amino-4-nitrobenzoic acid. No evidence for the presence of the hepatocarcinogen, 2,4-diaminotoluene, was found. The difference between nanomole equivalents of 2,4-DNT and its metabolites found by specific assay and nanomole equivalents found by radioactivity measurements was two to five times larger in female rats than in males. The data suggest that dose-dependent changes occur in the elimination and distribution of 2,4-DNT at high doses and that female rats metabolize 2,4-DNT to unidentified metabolites to a greater extent than males. Furthermore, the lack of evidence for the formation of 2,4-diaminotoluene from 2,4-DNT suggests that the hepatocarcinogenicity of 2,4-DNT is not due to its conversion to 2,4-diaminotoluene.

Comparison of an Avian Osteopetrosis Virus with an Avian Lymphomatosis Virus by RNA-DNA Hybridization

Myeloblastosis-associated virus (MAV)-2(0), a virus which was derived from avian myeloblastosis virus and induced a high incidence of osteopetrosis, was compared with avian lymphomatosis virus 5938, a recent field isolate which induced a high incidence of lymphomatosis. The following information was obtained. (i) MAV-2(0) induced osteopetrosis, nephroblastoma, and a very low incidence of hepatocellular carcinoma. No difference was seen in the oncogenic spectrum of end point and plaque-purified MAV-2(0). (ii) 125I-labeled RNA sequences from MAV-2(0) formed hybrids with DNA extracted from osteopetrotic bone at a rate suggesting five proviral copies per haploid cell genome. The extent of hybridization of MAV-2(0) RNA with DNA from osteopetrotic tissue was more extensive (87%) than was observed in reactions with DNA from uninfected chicken embryos (52%). (iii) Competition of unlabeled viral RNA in hybridization reactions between the radioactive RNA from the two viruses and their respective proviral sequences present in tumor tissues showed that 15 to 20% of the viral sequences detected in these reactions were unshared. In contrast, no differences were detected in competition analyses of RNA sequences from the two viruses detected in DNA of normal chicken cells. (iv) MAV-2(0) 35S RNA was indistinguishable in size from avian lymphomatosis virus 5938 35S RNA by polyacrylamide gel electrophoresis.

Role of injury and hyperplasia in the induction of hepatocellular carcinoma.

THE INDUCTION of hepatocellular carcinoma is not dependent on continuous feeding of carcinogen. Short periods of exposure to carcinogen may result in tumors many weeks or months after drug withdrawal.¹Nevertheless, hepatocellular injury and hyperplasia apparently precede the development of hepatomas. The persistence, regression, or alteration of early hepatocellular injury and hyperplasia were studied in rats after withdrawal of 3'-methyl-4-dimethylamino azobenzene (methyl butter yellow, MeBY), a potent carcinogen. Since 26 days of drug feeding causes a low incidence of hepatocellular carcinoma and 40 days a high incidence of hepatomas,²2 groups of rats fed the drug for these intervals were compared. Morphologic changes that were more prominent in the second group might be associated with hepatoma induction. The formation and persistence of nodules of hydropic, weakly basophilic cells, deficient in glucose-6-phosphatase (G-6-P' ase) that are closely associated with hepatocellular carcinoma will be described. <h3>Materials and Methods</h3> Sprague-Dawley male