Liver cell cancer — Intervention studies

Summary The field studies leading to possible intervention procedures are reviewed. Currently the most promising form of intervention is the prevention of aflatoxin contamination of foodstuffs. It is essential that these are monitored and their efficacy in lowering the incidence of liver cancer measured. The association of liver cancer with hepatitis B infection may be a confounding factor and the impact of this on the study population must also be considered. The imminent production of vaccines for hepatitis B infection may provide an alternative or additional mode of intervention. The possibilities for intervention in liver cell cancer appear one of the brighter prospects for primary prevention of a cancer.     

Prevention of hepatocellular carcinoma: progress and challenges

Hepatocellular carcinoma (HCC) is a lethal cancer for both men and women and is caused by multiple risk factors. Most patients with HCC have an underlying liver disease caused by either chronic viral infection due to hepatitis B or hepatitis C virus or non-viral etiologic risk factors such as alcohol, fatty liver disease, dietary aflatoxin exposure, smoking and diabetes mellitus. While these risk factors are progressively and persistently damaging the liver, the majority of patients show very few symptoms of HCC. By the time symptoms appear the cancer is typically at a very advanced stage with limited options for treatment. In order to prevent death from HCC, it is therefore critically important to reduce the prevalence of the major risk factors, identify and treat those at high risk for development of HCC, and institute effective surveillance strategies for early diagnosis and treatment of HCC. This article reviews the recent progress and current challenges to the prevention of HCC.     

The role of aflatoxins and hepatitis viruses in the etiopathogenesis of hepatocellular carcinoma: A basis for primary prevention in Guinea–Conakry,West Africa

Abstract Aflatoxins and hepatitis B virus (HBV) are major risk factors for hepatocellular carcinoma (HCC) in South‐east Asia and Africa, parts of the world where this cancer is most prevalent. Exposure to both factors is endemic, occurring from early in life. There is evidence from both epidemiological studies and animal models that the two factors can act synergistically to increase the risk of HCC, but the underlying cellular and molecular mechanisms of interaction are as yet undefined. One possiblity suggested by studies in HBV transgenic mice is that chronic liver injury alters the expression of carcinogen metabolizing enzymes, thus modulating the level of binding of aflatoxin to DNA. Primary prevention of HCC in high incidence areas of the world should primarily be focused on provision of the safe, effective vaccine against HBV. However, measures to reduce the high levels of aflatoxin exposure, where chronic HBV infection is currently epidemic, would also significantly contribute to reducing HCC incidence. In Guinea–Conakry, West Africa, surveys of HBV infection and aflatoxin exposure have established baseline data for the implementation of a community‐based intervention study. This study will evaluate the effectiveness of improving the post‐harvest processing and storage of the groundnut crop, a major source of aflatoxins, using aflatoxin‐albumin adducts as the outcome measurement. © 2002 Blackwell Publishing Asia Pty Ltd     

Zebrafish as a disease model for studying human hepatocellular carcinoma

Liver cancer is one of the world's most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma(HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel smallmolecule inhibitors. This review will focus on illustrativeexamples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts,drug discovery, and drug-induced toxic liver injury.     

Epidemiology and natural history of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major contributor to cancer incidence and mortality. There is a wide variation, however, in the global distribution of HCC. Eighty percent of the burden is borne by countries in Asia and sub-Saharan Africa. In most high-risk countries, principal risk factors include infection with hepatitis B virus and dietary exposure to aflatoxin B(1). In contrast, hepatitis C virus and alcohol consumption are more important risk factors in low-risk countries. In recent years, the incidence of HCC has decreased in some high-risk countries and increased in some low-risk countries. Reasons for both trends are not completely understood, but are likely related to public health efforts in Asia and the increase in hepatitis C virus infection in low-risk countries. Vaccination programs against hepatitis B virus will likely decrease the HCC rate even further in decades to come.     

Hepatocellular carcinoma： Epidemiology, risk factors and pathogenesis

Hepatocellular carcinoma （HCC） is the commonest primary malignant cancer of the liver in the world. Given that the burden of chronic liver disease is expected to rise owing to increasing rates of alcoholism, hepatitis B and C prevalence and obesity-related fatty liver disease, it is expected that the incidence of HCC will also increase in the foreseeable future. This article summarizes the international epidemiology, the risk factors and the pathogenesis of HCC, including the roles of viral hepatitis, toxins, such as alcohol and aflatoxin, and insulin resistance.     

Environmental Exposures and Hepatocellular Carcinoma

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC.     

The role of the hepatitis viruses in cholangiocarcinoma

Cholangiocarcinoma is the second most common liver cancer in the world. The aetiology of the disease is diverse incorporating a variety of conditions leading to biliary stasis, biliary and liver inflammation, but a large number of cases still occur in the absence of established risk factors. Its incidence and mortality is increasing, which has intensified the search for alternative aetiological agents and pathogenetic mechanisms. Chronic infection with hepatitis B and hepatitis C viruses are the primary risk factor for hepatocellular cancer. This review focuses on the epidemiological evidence of a role for these viruses in cholangiocarcinoma and the pathogenetic mechanisms that might be involved.     

Hepatocellular carcinoma: risk factors other than HBV.

The putative risk factors for hepatocellular carcinoma (HCC) are several, even in countries endemic for hepatitis B virus (HBV) infection. Cirrhosis characterizes more than 90% of HCC cases. The phases of inflammation, necrosis and regeneration, present for long periods in cirrhosis, might be most relevant in hepatocarcinogenesis. It is not clear what role is played by sex hormones while alcohol probably has a promoter role. Aflatoxins are known carcinogenins in the experimental animal: however it is difficult to evaluate the impact in human carcinogenesis due to the lack of reliable methods of measuring aflatoxin exposure in population studies. In conclusion, the aetiology of HCC is multifactorial and the main risk factor resides in the presence of underlying chronic liver disease.     

Aflatoxin levels in chronic hepatitis B patients with cirrhosis or hepatocellular carcinoma in Balıkesir,Turkey

Aflatoxins, the secondary metabolites produced by species of naturally occurring Aspergilli, are commonly found in food such as cereals, dried fruits and juice, wine, beer and spices. They are hepatotoxic and are well known human carcinogens based on evidence from human studies. Aflatoxins are an environmental risk factor for the development of hepatocellular carcinoma (HCC). Chronic hepatitis B‐infected patients are at increased risk of cirrhosis, hepatic failure and liver cancer. This study was designed to determine the serum aflatoxin B₁ (AFB₁), aflatoxin B₂ (AFB₂), aflatoxin G₁ (AFG₁) and aflatoxin G₂ (AFG₂) concentrations using high‐pressure liquid chromatography (HPLC) in hepatitis B‐infected patients with or without cirrhosis and liver cancer, alongside healthy controls in Bal?kesir, Turkey. The mean AFB₁ and total AF levels in patients without liver cancer and cirrhosis were significantly higher than healthy controls. The mean AFB₁ and total AF levels in patients with chronic hepatitis B and HCC were significantly higher than infected patients with or without cirrhosis. These results suggest that patients with chronic hepatitis B who are exposed to AFs are at increased risk for developing HCC, which might be prevented by reducing consumption of contaminated foods.     

Non-viral factors contributing to hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide, accounting for over half a million deaths per year. The geographic pattern of HCC incidence is parallel to exposure to viral etiologic factors. Its incidence is increasing, ranging between 3% and 9% annually depending on the geographical location, and variability in the incidence rates correspond closely to the prevalence and pattern of the primary etiologic factors. Chronic infections with hepatitis B viruses or hepatitis C viruses have both been recognized as human liver carcinogens with a combined attributable fraction of at least 75% of all HCC cases. Multiple non-viral factors have been implicated in the development of HCC. Increased body mass index and diabetes with subsequent development of non-alcoholic steatohepatitis represent significant risk factors for HCC. Other non-viral causes of HCC include iron overload syndromes, alcohol use, tobacco, oral contraceptive, aflatoxin, pesticides exposure and betel quid chewing, a prevalent habit in the developing world. Wilson disease, α-₁ antitrypsin deficiency, Porphyrias, autoimmune hepatitis, Schistosoma japonicum associated with positive hepatitis B surface antigen, and thorotrast-ray are also contributing hepatocellualar carcinoma. In addition, primary biliary cirrhosis, congestive liver disease and family history of liver cancer increase the risk of HCC incident. In conclusion, clarification of relevant non-viral causes of HCC will help to focus clinicians on those risk factors that are modifiable. The multilevel preventative approach will hopefully lead to a reduction in incidence of non-viral HCC, and a decrease in the patient morbidity and mortality as well as the societal economic burden associated with HCC.     

Expected developments in hepatology

It is very difficult to predict new developments in hepatology so we have decided to analyse the most important issues related to three clinical conditions in hepatology. The first is chronic hepatitis. Here, we discuss the relevance of occult forms of hepatitis B virus infection in the development of cryptogenic liver disease and hepatocellular carcinoma. In addition, the role of genotyping in hepatitis B is analysed, indicating that patients with genotype A have a better prognosis than those with genotype D. The treatment of hepatitis B virus infection is also reviewed, and it has been suggested that research should be directed towards the development of new anti-viral agents to suppress virus replication. The natural history of hepatitis C virus infection is considered, emphasizing the need to know the progression of fibrosis in these patients. The chapter also suggests that treatment of hepatitis C virus infection with pegilated interferon and ribavirin is currently relatively effective. New therapeutic strategies will be required in the future, the most important challenge being the development of a hepatitis C virus vaccine. The second section is on chronic cholestasis. The role of anti-mitochondrial antibodies in primary biliary cirrhosis is considered. The possible infectious agents implicated as potential triggers of primary biliary cirrhosis are also discussed, suggesting that several infections may play a role in the pathogenesis of this condition. Other aetiopathogenic factors, for example organic compounds, drugs and chemicals, are indicated. It is possible that, in the near future, the precise sequence and molecular basis by which infectious agents or xenobiotics may initiate the cascade of the autoimmune response will be defined. One of the most important challenges in primary sclerosing cholangitis concerns the mechanisms that may induce the development of this disease. Up until now, genetic factors have been suggested, recent data reporting a clear-cut association between primary sclerosing cholangitis and the tumour necrosis factor-alpha(2) allele. The third part of this chapter includes recent progress achieved in hepatocellular carcinoma, discussing developments in the knowledge of hepatocellular carcinogenesis. Hepatocellular carcinomas appear so far to be genetically heterogeneous neoplasms, and this heterogeneity may correlate with the variety of aetiological factors involved. The risk factors and primary, secondary and tertiary prevention of the condition are also analysed. Finally, the development of new therapeutic strategies for hepatocellular carcinoma is evaluated by evidence-based studies.     

Transposon mouse models to elucidate the genetic mechanisms of hepatitis B viral induced hepatocellular carcinoma

The major type of human liver cancer is hepatocellular carcinoma(HCC), and there are currently many risk factors that contribute to this deadly disease. The majority of HCC occurrences are associated with chronic hepatitis viral infection, and hepatitis B viral(HBV) infection is currently a major health problem in Eastern Asia. Elucidating the genetic mechanisms associated with HBV-induced HCC has been difficult due to the heterogeneity and genetic complexity associated with this disease. A repertoire of animal models has been broadly used to study the pathophysiology and to develop potential treatment regimens for HBVassociated HCC. The use of these animal models has provided valuable genetic information and has been an important contributor to uncovering the factors involved in liver malignant transformation, invasion and metastasis. Recently, transposon-based mouse models are becoming more widely used in liver cancer research to interrogate the genome by forward genetics and also used to validate genes rapidly in a reverse genetic manner. Importantly, these transposon-based rapid reverse genetic mouse models could become crucial in testing potential therapeutic agents before proceeding to clinical trials in human. Therefore, this review will cover the use of transposon-based mouse models toaddress the problems of liver cancer, especially HBVassociated HCC occurrences in Asia.     

Risk Factors for the Development of Hepatocellular Carcinoma in Thailand

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. The incidence of HCC is on the rise in Thailand, where it has become the most common malignancy in males and the third most common in females. Here, we review some of the risk factors that have contributed to this increase in HCC incidence in the Thai population. Hepatitis B virus (HBV) is the main etiologic risk factor for HCC, followed by hepatitis C virus (HCV). Patients with HBV genotype C have a higher positive rate of hepatitis B early antigen (HBeAg) and progress to cirrhosis and HCC earlier than genotype B. For HCV patients, 16% developed HCC associated cirrhosis by year 5 after diagnosis, and the cumulative risk for death from HCC at year 10 was 60%. Dietary exposure to the fungal hepatocarcinogen aflatoxin B1 has been shown to interact synergistically with HBV infection to increase the risk of early onset HCC. Chronic alcohol abuse remains an important risk factor for malignant transformation of hepatocytes, frequently in association with alcohol-induced cirrhosis. In recent years, obesity and metabolic syndrome have markedly increased the incidence of HCC and are important causes of HCC in some resource-rich regions.     

Epidemiology of hepatocellular carcinoma

Year 2000 estimates of the incidence of cancer indicate that primary liver cancer remains the fifth most common malignancy in men and the eighth in women. The number of new cases has been predicted as 564,000, corresponding to 398,000 in men and 166,000 in women. The geographic areas at highest risk are located in Eastern Asia, Middle Africa, and some countries of Western Africa. Changes in incidence among migrant populations underline the predominant role of environmental factors in the etiology of primary liver cancer. In high-risk countries, the early cases of primary liver cancer occur already at ages 20 and above, underlying the impact of viral exposures early in life. In countries at low risk, primary liver cancer is rare before the 50s, translating the impact of late exposures with moderate risks and long latency intervals. Sex ratios are typically between 2 and 4. The incidence of primary liver cancer is increasing in several developed countries including the United States, and the increase will likely continue for several decades. The trend has a dominant cohort effect related to exposures to hepatitis B and C viruses. The variability of primary liver cancer incidence is largely explained by the distribution and the natural history of the hepatitis B and C viruses. The attributable risk estimates for the combined effects of these infections account for well over 80% of liver cancer cases worldwide. Primary liver cancer is the first human cancer largely amenable to prevention using hepatitis B virus vaccines and screening of blood and blood products for hepatitis B and C viruses.     

Risk factors for the rising rates of primary liver cancer in the United States

BACKGROUND: A recent increase in the incidence of hepatocellular carcinoma was reported in the United States. The cause of this witnessed rise remains unknown. METHODS: We examined the temporal changes in both age-specific and age-standardized hospitalization rates of primary liver cancer associated with hepatitis C, hepatitis B, and alcoholic cirrhosis in the Department of Veterans Affairs Medical Center's Patient Treatment File. RESULTS: A total of 1605 patients were diagnosed with primary liver cancer between 1993 and 1998. The overall age-adjusted proportional hospitalization rate for primary liver cancer increased from 36.4 per 100,000 (95% confidence interval [CI], 34.0-38.9) between 1993 and 1995 to 47.5 per 100,000 (95% CI, 44.6-50.1) between 1996 and 1998. There was a 3-fold increase in the age-adjusted rates for primary liver cancer associated with hepatitis C virus, from 2.3 per 100,000 (95% CI, 1. 8-3.0) between 1993 and 1995 to 7.0 per 100,000 (95% CI, 5.9-8.1) between 1996 and 1998. Concomitant with this rise, the age-specific rates for primary liver cancer associated with hepatitis C also shifted toward younger patients. During the same periods, the age-adjusted rates for primary liver cancer associated with either hepatitis B virus (2.2 vs 3.1 per 100,000) or alcoholic cirrhosis (8. 4 vs 9.1 per 100,000) remained stable. The rates for primary liver cancer without risk factors also remained without a statistically significant change, from 17.5 (95% CI, 15.8-19.1) between 1993 and 1995 to 19.0 per 100,000 (95% CI, 17.3-20.7) between 1996 and 1998. CONCLUSIONS: Hepatitis C virus infection accounts for most of the increase in the number of cases of primary liver cancer among US veterans. The rates of primary liver cancer associated with alcoholic cirrhosis and hepatitis B virus infection have remained stable. Arch Intern Med. 2000;160:3227-3230.     

Hepatocellular carcinoma and the risk of occupational exposure

Hepatocellular carcinoma(HCC)is the most common type of liver cancer.The main risk factors for HCC are alcoholism,hepatitis B virus,hepatitis C virus,nonalcoholic steatohepatitis,obesity,type 2 diabetes,cirrhosis,aflatoxin,hemochromatosis,Wilson’s disease and hemophilia.Occupational exposure to chemicals is another risk factor for HCC.Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent.This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.     

慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型

HBV感染是肝硬化和肝癌的主要病因之一。抗病毒药物的使用明显降低了慢性乙型肝炎患者肝癌的发生风险,但部分长期服用抗病毒药物患者,最终仍发生肝癌。因此,有必要对此类患者发生肝癌的风险进行早期识别和预测。当前根据肝硬化、年龄、性别、肝硬度、病毒学、血清学指标、饮酒情况、糖尿病病史等危险因素,形成了一些慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型,这些预测模型包括mREACH-B、PAGE-B、mPAGE-B、APA-B、CAMD、AASL、REAL-B等。综述了慢性乙型肝炎患者抗病毒治疗过程中发生肝癌的风险预测模型研究进展。     

Aflatoxin and p53 abnormality in duck hepatocellular carcinoma

Recent studies have revealed that a point mutation at codon 249 in the p53 gene predominates in hepatocellular carcinoma (HCC) cases from Southern Africa and China, where infection with hepatitis B virus (HBV) and contamination of aflatoxin B₁ in food are risk factors for HCC. This unique mutation from G to T at the third base in codon 249 observed in human HCC cases is suggested to be linked to aflatoxin exposure. Six ducks with HCC, five of which were fed a diet containing aflatoxin B₁ for 1–2 years, were analysed for the presence of point mutations at this codon of the p53 gene by polymerase chain reaction and direct nucleotide sequencing. None of the six ducks with HCC showed the change at this codon regardless of duck hepatitis B virus infection. This suggests that aflatoxin B₁ itself might not be involved in the unique mutation at codon 249 in hepatocar-cinogenesis, or that other factors coincident with aflatoxin may be responsible for this unique mutation.     

The role of hepatitis B virus in the development of primary hepatocellular carcinoma: Part I

Chronic infections with hepatitis B virus (HBV) of humans and animal hepadnavirus infections in their natural hosts are strongly associated with primary hepatocellular carcinoma (HCC). Although viral integrations are found in cells of many HCC, no general viral-specific hepatocarcinogenic mechanism for hepadnaviruses has been identified. In approximately one half of HCC in woodchuck hepatitis virus (WHV) infected woodchucks, viral integrations near the c-myc or N-myc genes have been reported which result in enhanced expression of the respective gene. Such host gene-specific insertional mutagenesis has not been found in HCC of other hepadnavirus infected hosts. Thus in humans, ground squirrels and ducks hepadnaviral integrations appear to be at different host chromosomal DNA sites in each HCC and few integrations have been found within or near any cellular gene. Other possible hepadnavirus-specific carcinogenic mechanisms that are being investigated include transactivation of cellular gene expression by an hepadnavirus gene product (e.g. the X-gene), and mutation of host genes by unknown hepadnavirus-specific mechanisms. It should be noted, however, that chronic hepadnavirus infection is associated with chronic necroinflammatory liver disease with hepatocellular necrosis and regeneration (sometimes leading to cirrhosis in humans), a pathological process that is common to numerous other risk factors for HCC. This suggests the possibility that this pathological process is hepatocarcinogenic irrespective of the inciting agent and the role of hepadnavirus infection is no different from that of other risk factors in causing chronic necroinflammatory liver disease.