High Risk Of Liver Cancer Research Articles

Blood Folate Levels and Risk of Liver Damage and Hepatocellular Carcinoma in a Prospective High-Risk Cohort

Studies in experimental animals suggest that low folate levels may play a role in liver damage and hepatocarcinogenesis. To examine this association in humans, folate levels in blood and risk for subsequent liver damage and hepatocellular carcinoma (HCC) were assessed in a population at high risk of liver cancer in China. Four hundred fifteen hepatitis B surface antigen-positive participants of the Haimen City Cohort were prospectively followed between 1998 and 2002. Serum and RBC folate levels were determined at baseline. Alanine aminotransferase (ALT) and hepatitis B virus DNA levels were measured semiannually. Logistic regression modeling was used to examine the presence of hepatitis B virus DNA and HCC, whereas linear regression with a log-link function was used to examine ALT levels. There was a statistically significant inverse association between serum folate level and ALT level. ALT levels decreased with each quartile increase in serum folate (adjusted odds ratio, 0.86; 95% confidence interval, 0.76-0.97 for the highest compared with the lowest quartile; Ptrend = 0.002). After exclusion of three persons with prevalent HCC, 20 (4.9%) of the 412 study participants developed HCC during follow-up, with a median time between enrollment and HCC diagnosis of 2.66 years (interquartile range, 1.8-4.1). When comparing persons in the lowest quartile RBC folate to persons in all other quartiles, the analysis found that higher RBC folate levels were associated with reduced risk of hepatocarcinogenesis (odds ratio, 0.33, 95% confidence interval, 0.13-0.86; P(trend) = 0.02). This study suggests that increased folate levels in humans may be inversely associated with the development of liver damage and HCC.

Porphyria in Sweden

In a brief survey the work of Swedish porphyrinologists through time is presented, from the organic chemist Jakob Berzelius 1840 to the molecular biologists of today. The building up in Stockholm of a Swedish national competence centre for porphyria is touched upon and the emergence of a computerized national register on the porphyria gene carriers in the country described. Figures for the prevalences of the seven different forms of porphyria diagnosed in Sweden are given. The geographical distribution of gene mutation spectra is shown for the most frequent form, acute intermittent porphyria. The organisation at Porphyria Centre Sweden of its diagnostic and consultative services is described, as is the decentralized model for porphyria care applied in the form of a clinical network covering the long and sparsely populated country. The ideas and activities of the Swedish Porphyria Patients' Association are presented. Its focus on protection-by-information of the porphyria gene carrier against maltreatment in health service contacts, and against other exposures to environmental threats to his or her health, is discussed. The combined efforts of the national porphyria centre and the patients' association have resulted in early and accurate diagnosis of most of the porphyria gene carriers in the country. The information to the carriers and to the health service regarding the mechanisms of the diseases and the importance of avoiding exposure to disease triggering environmental factors have greatly reduced porphyric morbidity. In the case of the acute porphyrias, by this programme and after the introduction of heme arginate in the therapy, mortality in the acute phase has become extremely rare in Sweden. In contrast, probably due to greater awareness of the high risk for liver cancer in acute porphyrias the number of hepatoma cases diagnosed has increased. The current research activities at the Porphyria Centre which aim at finding ways to substitute the mutated gene in acute intermittent porphyria for an undamaged one, or to substitute the enzyme deficiency by administration of exogenously produced enzyme, are mentioned, as is the work to establish a reliable drug porphyrinogenicity prediction model for evidence based drug counselling.

Development of an English as a second language curriculum for hepatitis B virus testing in Chinese Americans

Chinese Americans are at disproportionately high risk of liver cancer. A major risk factor for liver cancer in Asia is infection with hepatitis B virus (HBV): Approximately 80% of liver cancers are linked to HBV, and chronic carriers of HBV are > 100 times more likely to develop liver cancer compared with noncarriers. However, many adults, particularly those who have immigrated to the U.S., remain untested and therefore unvaccinated or unmonitored for the disease. Chinese Americans are mostly foreign born, and more recent arrivals face multiple social and health challenges. Many require special attention from public health professionals because of low levels of acculturation and difficulties learning English. It has long been established that an English as a Second Language (ESL) curriculum can teach immigrant adults and their family's important life skills, such as job training and citizenship. The authors report on their plans to develop and pilot test a culturally appropriate curriculum that will motivate Chinese ESL students to obtain a blood test for the detection of the HBV.

Liver cancer screening in a high-risk population in China fails to reduce mortality

Question Does liver cancer screening reduce mortality from the disease in a high-risk Chinese population? Study design Cluster randomised controlled trial. Main results In people at high risk of liver cancer, screening did not significantly reduce the incidence of primary liver cancer or risk of death compared with no screening (see Table 1), despite earlier detection of the disease (see notes). Table 1 Primary liver cancer incidence and mortality rates in a high-risk Chinese population. Screened ( N=3712) Not screened ( N=1869) p value Number of primary liver cancer cases 257 (7%) 117 (6%) Incidence rate † 1341 1195 0.30 Deaths from primary liver cancer 218 (6%) 109 (6%) Mortality rate † 1138 1113 0.86 †Per 100,000 person years. Authors’ conclusions Liver cancer screening in a high-risk population in China does not reduce mortality from the disease.

Development of aflatoxin B(1)-lysine adduct monoclonal antibody for human exposure studies.

Mouse monoclonal antibodies were developed against a synthetic aflatoxin B(1) (AFB)-lysine-cationized bovine serum albumin conjugate. The isotype of one of these antibodies, IIA4B3, has been classified as immunoglobulin G1(lambda). The affinity and specificity of IIA4B3 were further characterized by a competitive radioimmunoassay. The affinities of IIA4B3 for AFB and its associated adducts and metabolites are ranked as follows: AFB-lysine > 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-AFB > AFB = 8,9-dihydro-8-(N(7)-guanyl)-9-hydroxy-AFB > aflatoxin M(1) > aflatoxin Q(1). IIA4B3 had about a 10-fold higher affinity for binding to AFB-lysine adduct than to AFB when (3)H-AFB-lysine was used as the tracer. The concentration for 50% inhibition for AFB-lysine was 0.610 pmol; that for AFB was 6.85 pmol. IIA4B3 had affinities at least sevenfold and twofold higher than those of 2B11, a previously developed antibody against parent AFB, for the major aflatoxin-DNA adducts 8,9-dihydro-8-(N(7)-guanyl)-9-hydroxy-AFB and 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl formamido)-9-hydroxy-AFB, respectively. An analytical method based on a competitive radioimmunoassay with IIA4B3 and (3)H-AFB-lysine was validated with a limit of detection of 10 fmol of AFB-lysine adduct. The method has been applied to the measurement of AFB-albumin adduct levels in human serum samples collected from the residents of areas at high risk for liver cancer.

Hepatocellular carcinoma despite long‐term survival in chronic tyrosinaemia I

Tyrosinaemia I (fumarylacetoacetate hydrolase deficiency) is an autosomal recessive inborn error of tyrosine metabolism that produces liver failure in infancy or a more chronic course of liver disease with cirrhosis, often complicated by hepatocellular carcinoma, in childhood or early adolescence. We studied a 37-year-old woman with tyrosinaemia I whose severe liver disease in infancy and rickets during childhood resolved with dietary therapy. From 14 years of age she resumed an unrestricted diet with the continued presence of the biochemical features of tyrosinaemia, yet maintained normal liver function. In adult years she accumulated only small amounts of succinylacetone. Despite this evolution to a mild biochemical and clinical phenotype, she eventually developed hepatocellular carcinoma. Her fumarylacetoacetate hydrolase genotype consists of a splice mutation, IVS6-1g>t, and a novel missense mutation, Q279R. Studies of resected liver demonstrated the absence of hydrolytic activity and of immunological expression of fumarylacetoacetate hydrolase in liver tumour. In nontumoral areas, however, 53% of normal hydrolytic activity and immunologically present fumarylacetoacetate hydrolase was found. This case demonstrates the high risk of liver cancer in tyrosinaemia I even in a seemingly favourable biological environment.

Ultrasensitive and specific detection methods for exocylic DNA adducts: Markers for lipid peroxidation and oxidative stress

Among exocyclic DNA adducts, etheno ( ε) bases ( εdA, εdC, N 2,3- εdG) are generated by reactions of DNA bases with lipid peroxidation (LPO) products derived from endogenous sources and from the carcinogens vinyl chloride or urethane. The recent development of ultrasensitive methods has made it possible to detect these ε-adducts in vivo and to study their formation and role in experimental and human carcinogenesis. The promutagenic ε-DNA modifications can be detected by immunoaffinity/ 32P-postlabelling or by immunohistochemistry. When ε-adducts are excised from tissue DNA, the modified nucleosides can be quantified in urine by an immunoaffinity-HPLC-fluorescence method. Highly variable background levels of ε-adducts were detected in tissues from unexposed humans and rodents, suggesting an endogenous pathway of formation from reaction of trans-4-hydroxy-2-nonenal (via its 2,3-epoxide) with DNA bases. Several known cancer risk factors increased the level of these DNA lesions: Elevated ε-adducts were found in hepatic DNA from patients with excess metal storage (haemochromatosis, Wilson's disease), resulting in oxidative stress and high risk of liver cancer. Reactive O/N-intermediates generated during inflammatory processes, for example in patients with inflammatory bowel disease (IBD) and familial adenomatous polyposis (FAP) led to the formation of ε-adducts likely through peroxynitrite-mediated LPO and/or increased oxidative arachidonic acid metabolism. A high ω-6-polyunsaturated fatty acid (PUFA) diet increased ε-DNA adducts in white blood cells (WBC), particularly in female subjects (about 40-fold), while the level of adducted malondialdehyde in deoxyguanosine of WBC-DNA was only moderately elevated. In conclusion, there is now growing evidence that ε-adducts were elevated in cancer-prone patients and in rodents (liver, pancreas, colon, skin), suggesting that promutagenic ε-adducts, when formed as a consequence of persistent oxidative stress, can drive cells to malignancy. Therefore, biomonitoring of exocyclic DNA adducts offers useful tools: (i) to evaluate the etiological contributions of dietary fats, oxidative stress, and chronic inflammatory/infectious processes; (ii) to verify the efficacy of chemopreventive agents on endogenous DNA damage and cancer risk; and (iii) to gain mechanistic insights into the role of oxidative stress/LPO-derived lesions in the initiation and progression of human cancer.

HPLC based method for the measurement of the reduction of aflatoxin B1 by bacterial cultures isolated from different African foods

The consumption of fermented foods contaminated with aflatoxin B1 is linked to aflatoxicosis. Aflatoxicosis is a serious problem in developing countries with environmental conditions appropriate for the biosynthesis of AFB1 byAspergillus flavus andAspergillus parasiticus. In Africa, especially in Ghana and Nigeria, there is a very high risk of liver cancer which is caused by the consumption of AFB1-intoxicated, traditionally fermented maize and sorghum products. It is suggested that one way to diminish this health risk might be the reduction of the AFB1 concentration in foods by bacteria. Especially bacteria used for food fermentation processes are of great importance, with a special emphasis on lactic acid bacteria which are involved in traditionally fermented African foods based on maize and sorghum.Most publications dealing with aflatoxin degradation by microorganisms describe a phosphate buffer test system for the performance of degradation experiments. In contrast to that, a test system based on physiological active bacterial and yeast cells has been developed, to assess food fermentation organisms for their ability to reduce the AFB1 concentration in vitro. The aflatoxin B1 concentration in test samples was quatitatively determined by HPLC.The assessment of lactic acid bacteria originating from different German and other European culture collections only showed a very slight reduction of the AFB1 concentration from 3% to 12%. Screening experiments in which other bacterial genera and lactic acid bacteria, isolated from different African foods have been assessed, in most cases showed the same results. However, some bacterial strains, e.g. strains of the genusBacillus derived from European culture collections and strains of the genusLactobacillus isolated from African foods, caused a release of AFB1 which was chemically bound before to components of the test medium and which therefore could not be extracted with chloroform.A process quite similar to that may happen during food fermentations. Different experiments showed that e.g. cellulose can bind AFB1 very effectively. Cellulose and different other food components are well known to absorb AFB1. During fermentation the cellulose and other AFB1-absorbing components may be degraded and the AFB1 will be released again.The only bacterial strain known as yet which is able to reduce the AFB1 concentration in vitro and in different food comodities isNocardia corynebacteroides (formerFlavobacterium aurantiacum). Nevertheless the mechanism of this AFB1 reduction is actually not well understood, it still has to be investigated. In the meantime several other bacterial strains, presumably from the taxonomic group of theActinomycetes could be proved to be effective reducers of the AFB1 concentration in our in vitro test system. Because as yet no food relevant microorganism could be found, which is able to degrade AFB1, these new strains in general offer the possibility for a genetic modification of food relevant microorganisms. This seems to be the way to come to starter cultures which are able to degrade AFB1 during food fermentations.

Oltipraz, a novel inhibitor of hepatitis B virus transcription through elevation of p53 protein.

Molecular epidemiological studies of populations at high risk for liver cancer have shown that hepatitis B virus (HBV) and aflatoxin B1 exposures are two major risk factors for this disease. Oltipraz is currently being considered for clinical trial to protect against aflatoxin B1-induced hepatocarcinogenesis based on its proven protective effect in many different animal models. In addition, oltipraz inhibits human immunodeficiency virus (HIV) replication. The inactivation of reverse transcriptase of HIV appears to be the antiviral mechanism. It has been demonstrated that a number of compounds that inhibit HIV replication also inhibit HBV replication in vitro. Therefore, we tested the possibility of oltipraz blocking HBV replication in 2.2.15 cells (clonal cells derived from HepG2 cells that were transfected with a plasmid containing HBV DNA) in vitro. Results of the experiments indicate that oltipraz has a dose-dependent inhibitory effect on HBV replication and specifically blocks HBV transcription in 2.2.15 cells. In addition, oltipraz induces endogenous wild-type p53 protein in a dose- and time-course-dependent manner. Taken together, we speculate that the effects of oltipraz against replication of HBV and specific blocking of HBV transcription may be through the induction of p53-mediated pathway in 2.2.15 cells. In addition to its known chemopreventive action on aflatoxin B1 hepatocarcinogenesis, oltipraz was shown here to inhibit HBV replication. These dual effects put oltipraz as the excellent candidate for the chemopreventive agent of human hepatocellular carcinoma.

Ultrasonographic mass survey of subjects at high risk for liver cancer selected based on the results of health examinations mandated by elderly health act

Ultrasonographic mass survey of subjects at high risk for liver cancer selected based on the results of health examinations mandated by elderly health act

Primary liver cancer death and occupation in Texas.

A death certificate case-control study of primary liver cancer and occupation was conducted to determine if the high risk of liver cancer in Mexican-Americans can be explained by farmworker exposures to pesticides. The association of liver cancer with the petroleum and chemical industry and with other potentially high-risk occupations was also examined. For the years 1969 to 1980, 1,742 deaths from primary liver cancer were identified for Texas males. Controls were randomly selected from other causes of deaths among males excluding all neoplasms, liver and gallbladder diseases, infectious hepatitis, and alcoholism, and were frequency matched to cases by age, race, ethnicity, and year of death. Risk for farmworkers based on age, race, and ethnicity-adjusted odds ratios (ORs) was not excessive (OR = 1.4, 95% confidence limits [C.L.] 0.8-2.2) but was larger than the risk for farmers (OR = 1.0, 95% C.L. 0.8-1.2). Excess risk in the petroleum and chemical manufacturing industries was confined to oil refinery workers (OR = 2.0, 95% C.L. 1.1-3.5). Other occupations with twofold risk or greater were plumbers and pipefitters (OR = 2.0, 95% C.L. 1.0-3.8), butchers and meat cutters (OR = 2.6, 95% C.L. 1.1-6.6), textile workers (OR = 3.1, 95% C.L. 1.2-7.8), cooks (OR = 2.2, 95% C.L. 1.1-4.5), and longshoremen (OR = 2.2, 95% C.L. 0.6-7.4).

Hepatic Cavernous Hemangioma in Patients at High Risk for Liver Cancer

Cavernous hemangioma of the liver occurring in patients at high risk for liver cancer has been reviewed. Twenty-four patients with hemangioma were encountered during the past 4 years. Five lesions over 3 cm in diameter were correctly diagnosed with enhanced CT alone. Definite CT findings were however obtained in only 6 out of 19 lesions smaller than 3 cm in diameter. Ultrasonography was the most sensitive method for picking up small liver tumors even when compared with angiography, but the findings were non-specific (an echogenic mass was noted in 14 of the 19 lesions). Magnetic resonance imaging (MRI) had almost the same sensitivity as ultrasound in detecting small hemangiomas, and a prolonged T2 was highly suggestive of the diagnosis (T2 over 80 ms in 8 of 11 lesions). The results suggest that combined use of non-invasive diagnostic modalities has sufficient reliability to make a diagnosis of cavernous hemangioma even in small hepatic lesions, in patients at high risk for liver cancer.

Hepatic Cavernous Hemangioma in Patients at High Risk for Liver Cancer

Hepatic Cavernous Hemangioma in Patients at High Risk for Liver Cancer

Hemochromatosis: Precirrhotic therapy restores normal life expectancy

We analyzed survival and causes of death among 163 patients with primary hemochromatosis diagnosed between 1959 and 1983. The mean follow-up period was 10.5 ± 5.6 years (±S.D.). Cu- mulative survival was 92 per cent at 5 years, 76 per cent at 10 years, 59 per cent at 15 years, and 49 per cent at 20 years. Life expectancy was re- duced in patients with cirrhosis of the liver as compared with those without cirrhosis (P≤0.05), in patients with diabetes mellitus as compared with those without diabetes (P≤0.002), and in pa- tients who could not be depleted of iron during the first 18 months of venesection therapy as com- pared with those who could be depleted (P≤0.001). Prognosis was not influenced by sex (P>0.5). Pa- tients without cirrhosis had a life expectancy that was not different from that expected in an age- and sex-matched normal population. Analysis of the causes of death in 53 patients, as compared with the normal population, showed that liver can- cer was 219 times more frequent among the pa- tients (16 patients), cardiomyopathy was 306 times more frequent (3 patients), liver cirrhosis was 13 times more frequent (10 patients), and diabetes mellitus was 7 times more frequent (3 patients). Death rates for other causes, including extrahepatic carcinomas (seven patients), were not different from the rates expected. We conclude that patients with hemochromatosis diagnosed in the precirrhotic stage and treated by venesection have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.

Survival and Causes of Death in Cirrhotic and in Noncirrhotic Patients with Primary Hemochromatosis

We analyzed survival and causes of death among 163 patients with primary hemochromatosis diagnosed between 1959 and 1983. The mean follow-up period was 10.5 +/- 5.6 years (+/- S.D.). Cumulative survival was 92 per cent at 5 years, 76 per cent at 10 years, 59 per cent at 15 years, and 49 per cent at 20 years. Life expectancy was reduced in patients with cirrhosis of the liver as compared with those without cirrhosis (P less than or equal to 0.05), in patients with diabetes mellitus as compared with those without diabetes (P less than or equal to 0.002), and in patients who could not be depleted of iron during the first 18 months of venesection therapy as compared with those who could be depleted (P less than or equal to 0.001). Prognosis was not influenced by sex (P less than or equal to 0.5). Patients without cirrhosis had a life expectancy that was not different from that expected in an age- and sex-matched normal population. Analysis of the causes of death in 53 patients, as compared with the normal population, showed that liver cancer was 219 times more frequent among the patients (16 patients), cardiomyopathy was 306 times more frequent (3 patients), liver cirrhosis was 13 times more frequent (10 patients), and diabetes mellitus was 7 times more frequent (3 patients). Death rates for other causes, including extrahepatic carcinomas (seven patients), were not different from the rates expected. We conclude that patients with hemochromatosis diagnosed in the precirrhotic stage and treated by venesection have a normal life expectancy, whereas cirrhotic patients have a shortened life expectancy and a high risk of liver cancer even when complete iron depletion has been achieved.

Follow-up study of HBs Ag-positive blood donors with special reference to effect of drinking and smoking on development of liver cancer.

In order to confirm the close association between chronic hepatitis B virus (HBV) infection and primary hepatocellular carcinoma (PHC) in Japan, 8,646 male hepatitis B surface antigen (HBs Ag)-positive blood donors (GPT less than or equal to 35 Karmen units) were followed up. Twenty liver cancer cases were observed during the follow-up period (average 6.2 years), the expected number calculated on the basis of age-specific incidence rates among the general population being 3.03. Therefore, the observed to expected ratio of liver cancer was 6.60, that is significantly higher than 1.0. During the same follow-up period, a total of 76 deaths were observed, of which 20 were due to liver cancers and 9 to liver cirrhoses, meaning that nearly 40% of deaths among the study subjects due to chronic liver diseases. Drinking and smoking habits in the liver cancer cases were compared with those observed in healthy male HBV carriers. A strong positive association between drinking habits and liver cancer was observed and there was a significant dose-response relationship after adjustment for cigarette smoking habits. A high risk of liver cancer was also observed among heavy smokers, but a significant dose-response relationship could not be found between smoking habits and liver cancer, partly because of the limited number of the study subjects. These findings suggest that HBV is a major etiologic agent of PHC in Japan where the HBs Ag prevalence rate is about 2%, and alcohol drinking and cigarette smoking may promote the process of HB viral hepato-carcinogenesis.

Risk of cancer deaths among agricultural households in kanto area I.

Agriculture, as an occupation, differs from other occupations in the following respects. First, agricultural works often involve not only farmers but their family members such as wives, children and their old parents even. Secondly, agricultural labor is out-door and seasonal, using a variety of chemicals for agricultural purposes. Their life-style is somewhat conservative and different from others in many respects including their eating habits (Ministry of Health and Welfare, 1977). Thirdly, agriculture is mostly a hereditary occupation, and thus they are very likely natural-born people of their resident districts. It may be important to disclose the cancer incidence or mortality of farmers and their families, who can be regarded to be a characterized population as described above. The importance of this study can be emphasized not only by the fact that agricultural households occupied one-sixth of Japanese total population, but also by the promising possibility of finding some important clues to the study of causes and/or prevention of human cancers. In fact, some cancers have been found to be agriculture-associated; e.g., positive association of stomach cancer (Hirayama, 1971), gallbladder and bile ducts cancer (Tominaga et al., 1979); negative one of colon cancer (Haenszel et al., 1980). Additionally, recent studies in Saitama prefecture revealed that liver (Sasaba and Kubo, 1982) and esophageal cancers showed high odds ratios in farmers and their families. Here the high risk of liver cancer was observed in a restricted area of Saitama. The purpose of the present study is then to analyze the cancer deaths among agricultural households (farming families) in comparison with non-agricultural ones, and to offer useful information and/or suggestion for the research of cancer-related factors in agricultural environments. This study is focused on the farming families of about four million population living in Kanto area, where the climate, geology and soil are rather uniform. The results on Kanto area is compared with those obtained for the whole of Japan, and hence the characteristics of Kanto farming families in cancer deaths will be remarked. In the analysis of cancer deaths, we consider a number of cancer sites and estimated the risk of agricultural life-style for each site, since the agricultural life is characterized not only in an occupational aspect but in many other aspects of living circumstances. We have to examine or confirm the association of those cancers with agriculture which have been suggested so. The examination on many other cancers may also add a new aspect to the traditional concept on this association. It is also meaningful to analyze the agespecific cancer risks of agricultural households. This further analysis answers the two questions: which age group of agricultural households shows a specially high or low risk of cancer; in which ages of the agricultural households the agriculture-linked factor(s) causing a high or low risk of cancer affects on them. The latter is estimated in terms of so-called multistage theory using some reasonable assumptions.