Hepatocellular carcinomas, development

Benv nn, L., Noventa, F., Bernardinello, E., Pontisso, P., Gatta, A., Alberti, A. Evidence for an association between the aetiology of cirrhosis and pattern of hepatocellular carcinoma development. Gut 2001 48 110-115... 

Hepatocellular carcinomas developed in female Sherman rats fed an estimated dose of 5 mg/kg/day Aroclor 1260 (purity not reported) for 21 months (Kimbrough et al. 1975). Almost all treated rats (170 of 184) exhibited a few to multiple tan nodules on the surface of the liver and more upon sectioning. 

Liver neoplastic nodules and hepatocellular carcinomas developed in 50% (63 of 126) and 48.4% (61 of 126) of male Wistar rats, respectively, that were fed Clophen A60 (60% chlorine by weight) at an estimated dosage of 5 mg/kg/day for up to 832 days (Schaeffer et al. 1984). The incidences of these lesions were significantly (p<0.05) higher than control values of 3.8% (5 of 131) and 0.8% (1 of 131), respectively. Combined incidences of neoplastic nodules and hepatocellular carcinomas were 98.4% (124 of 126) and 4.5% (6 of 131) in the treated and control groups, respectively. Time-dependent progression from altered foci to neoplastic nodules to hepatocellular carcinoma was observed. The Clophen A60 mixture was reported to be free of CDFs, but it is not certain whether these contaminants... 

In another study of Aroclor 1254 (purity not reported), no neoplastic nodules or hepatocellular carcinomas developed in small groups of Sherman rats (10 per sex) treated with estimated dietary doses as high as 72.4 mg/kg/day for 8 months (Kimbrough et al. 1972). Increased incidences of adenofibrosis of the liver were observed, but this lesion was not considered precancerous by the investigators. Sensitivity of this study is limited by the small number of animals, and the short duration may be insufficient to express possible carcinogenicity and to draw any negative conclusions. 

Meyer, K., Lee, J. S., Dyck, P. A., Cao, W. Q., Rao, M. S., Thorgeirsson, S. S., and Reddy, J. K. (2003). Molecular profiling of hepatocellular carcinomas developing spontaneously in acyl-CoA oxidase deficient mice comparison with Uver tumors induced in wild-type mice by a peroxisome proliferator and a genotoxic carcinogen. Carcinogenesis 24, 975-984. 

Symptoms appear in the 4th or 5th decade of life and include hepato-splenomegaly, liver cirrhosis, diabetes mellitus, cardiomyopathy, hyperpigmentation and hypogonadism. Hepatocellular carcinoma develops in approximately one third of the patients and leads to death [20, 21]. 

HBV infection remains a major worldwide public health problem. The World Health Organization estimates that there are still 350 million chronic carriers of the vims, who are at risk of developing chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. The success of IFN-a treatment - mainly performed as combined treatment with adenine-arabinoside - has been measured by the normalization of liver enzymes, loss of HBe antigen and of detectable viral DNA in the serum of patients. It has been estimated from several clinical trials that as many as 40% of treated HBV patients would respond to therapy with IFN-a or combined treatment with nucleoside analogues and IFN-a. 

Persistent activation of PPARa can induce the development of hepatocellular carcinoma in susceptible rodent species by a nongenotoxic mechanism, i.e., one that does not involve direct DNA damage by peroxisome proliferator chemicals or their metabolites. This hepatocarcinogenic response is abolished in mice deficient in PPARa, underscoring the central role of PPARa, as opposed to that of two other mammalian PPAR forms (PPARy and PPAR5), in peroxisome proliferator chemical-induced hepatocarcinogenesis. Other toxic responses, such as kidney and testicular toxicities caused by exposure to certain phthalate... 

Hepatocellular carcinoma (HCC) develops in patients with chronic liver diseases associated with hepatitis B and hepatitis C vims infections with high incidences. Here, an acyclic retinoid has been shown to suppress the posttherapeutic recurrence after interferon-y or glycerrhicin treatment in cirrhotic patients who underwent curative treatment of preceding tumors. The retinoid induced the disappearance of serum lectin-reactive a-fetoprotein (AFP-L3), a tumor marker indicating the presence of unrecognizable tumors in the remnant liver, suggesting a deletion of such minute (pre)malignant clones (clonal deletion). As a molecular mechanism of the clonal deletion, a novel mechanism of... 

Worldwide, 15 million HBsAg carriers are also infected with hepatitis D/delta virus (HDV) (Gaeta et al. 2000). This situation represents a major therapentic challenge, as most of these patients have advanced liver disease, inclnding cirrhosis in 60-70% of cases, and hepatocellular carcinoma (Fattovich et al. 2000 Saracco et al. 1987). No specific HDV inhibitors have been developed, and IFN-a-based treatment is more difficnlt in HBV-HDV infection than in HBV monoinfection. HDV RNA levels in sernm can be nsed to monitor treatment efficacy. The endpoint of therapy is HDV RNA clearance and ALT normalization, and this is sometimes achieved after the end of treatment. A snstained response can lead to HBsAg clearance from serum. 

Individuals with chronic hepatitis B have a high risk to develop cirrhosis and, once cirrhosis is present, the 5-year cumulative risk to develop hepatocellular carcinoma is about 10-15% (Fattovich et al. 2004). 

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis. 

Only 10% to 15% of patients have acute hepatitis C that resolves without any further sequelae.10 In more than 85% of cases, hepatitis C develops into a chronic disease. Approximately 70% of chronic HCV cases progress to mild, moderate, or severe hepatitis. While the natural history of the progression to cirrhosis is not clear, it is estimated that 10% to 20% of cases may take up to 20 to 40 years from the time of exposure to advance from fibrosis to cirrhosis.10 Fifteen to twenty percent of patients infected with HCV develop complications associated with cirrhosis. Once cirrhosis is confirmed, the rate of developing hepatocellular carcinoma increases to 1% to 4% per year.10 The estimated death rate from HCV infection is 1.8 deaths per 100,000 persons per year.12,15... 

Hepatitis B virus is a blood-borne or sexually transmitted virus. Most acute infections occur in adults, while chronic infections usually occur in individuals infected as infants or children. However, about 10% of adults who contract hepatitis B virus will fail to clear their infection and develop chronic hepatitis B infection. Individuals with chronic hepatitis B infection are at risk for cirrhosis or hepatocellular carcinoma. Vaccination with hepatitis B vaccine is the most effective way to prevent hepatitis B infection.6... 

Approximately 20% of patients with chronic HBV infection develop complications of decompensated cirrhosis, including hepatic insufficiency and portal hypertension. HBV is a risk factor for development of hepatocellular carcinoma. 

The most common symptom of chronic HCV infection is persistent fatigue. An estimated 20% of patients with chronic HCV infection will develop cirrhosis and half of those patients will progress to decompensated cirrhosis or hepatocellular carcinoma. 

Yet another SET domain protein, which is directly related to cancers, is SMYD3 that gets upregulated in colorectal cancer and hepatocellular carcinoma, a leading cause of death in developed countries (Hamamoto et al, 2004). 

At dosages above 30mg/kg in the diet, chlordane interfered with reproduction in rats and mice, but this effect was reversible after exposure ceased." Pre- and postnatal exposures to chlordane altered the development of the immune system in rodents. A dose-related increase in the incidence of hepatocellular carcinomas was found in male and female mice fed approximately 60mg/k chlordane for 80 weeks. In rats, increases in the incidences of thyroid follicular cell neoplasms were observed. ... 

The hepatocarcinogenicity of DDT by the oral route has been demonstrated and confirmed in several strains of mice. Liver cell tumors have been produced in both sexes and in CE mice were found to have metastasized to the lungs. However, the tumorigenic potential of DDT was negligible in monkeys after dosing for 15-22 years. Of 35 monkeys administered 20mgDDT/kg, 5 days/week for 130 months, only 1 developed hepatocellular carcinoma after a latency period of 20 years. Despite numerous studies, there is no conclusive, unequivocal, or consistent evidence linking... 

Rats exposed to 207 ppm daily for 6 months developed hepatic neoplasms hepatocellular hyperplasia and necrosis occurred after 3 months of exposure at this concentration. In another series of inhalation experiments on rats, 200 ppm produced hepatocellular carcinomas in both sexes 100 ppm resulted in liver tumors in males after 12 months of exposure... 

Hepatotoxicity Prolonged use of high doses of androgens has been associated with the development of potentially life-threatening peliosis hepatis, hepatic neoplasms, and hepatocellular carcinoma. Cholestatic hepatitis and jaundice occur with fluoxymesterone and methyltestosterone at relatively low doses. Drug-induced jaundice is reversible when the medication is discontinued. 

Because woodchuck hepatitis virus is similar to human hepatitis B, that rodent is a good animal model for the infection. McKenzie et al. followed the development in woodchucks of hepatocellular carcinoma arising from the infection over 6 months using P 2D MRSI. They attributed the increased ratio of PME/(3-NTP to increased cellular proliferation of the liver tumour. 

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