Unidirectional arginine transport in reconstituted plasma-membrane vesicles from yeast overexpressing CAN1

BACKGROUND: In hepatocellular carcinoma (HCC), a high prevalence of hepatitis C virus antibody (anti-HCV) has been reported, indicating that it may be an important etiologic factor in the pathogenesis of HCC. In this study, the authors investigated the prevalence of anti-HCV in HCC patients, as well as the same prevalence in patients with cholangiocarcinoma (CC) and combined hepatocellular-cholangiocarcinoma (combined HCC-CC), to study the clinicopathologic features of anti-HCV-positive cases. METHODS: The authors examined 141 patients with primary liver cancer who were pathologically diagnosed as having HCC (121 cases), CC (13 cases), or combined HCC-CC (7 cases). Hepatitis B surface antigen (HBsAg) and anti-HCV were measured in these patients. RESULTS: Of 121 HCC cases, 85 (70.3%) were found to be anti-HCV positive, 16 (13.2%) were HBsAg positive, and 5 (4.1%) were both anti-HCV and HBsAg positive. In 13 cases with CC and in 7 with combined HCC-CC examined, 4 (30.8%) and 5 (71.4%), respectively, were anti-HCV positive. CONCLUSIONS: The anti-HCV-positive rate was high in combined HCC-CC as well as in HCC. These three types of primary liver cancer, which were anti-HCV positive, shared two common features: male dominance and high incidences of complication with liver cirrhosis.     

Chronic lithium treatment decreases brain phospholipase A2 activity

BACKGROUND/AIMS: The hepatitis C virus (HCV) genome consists of quasispecies populations of heterogeneous variants, especially in the hypervariable region. To assess the profiles of viral quasispecies in HCV-related hepatocellular carcinoma, we studied the viral population patterns in serum and liver tissues of 13 HCV-positive patients with hepatocellular carcinoma developed on cirrhotic and non-cirrhotic livers (5 and 8 cases, respectively). METHODS: HCV genome heterogeneity was analyzed by polymerase chain reaction-mediated single-strand conformation polymorphism analysis, which showed multiple DNA bands representing different hypervariable region sequences. RESULTS: The HCV populations were different between tumorous and nontumorous tissues in 3/5 hepatocellular carcinomas with cirrhosis and in 6/8 without cirrhosis. At least one or more than one common band was detected in both compartments in all but one case. No significant differences in the complexity of HCV quasispecies were found in hepatocellular carcinoma with or without underlying cirrhosis. Comparison of the HCV quasispecies profiles in serum and liver tissues showed a different distribution of HCV variants between these two compartments in 6/7 patients. In four cases, both common and compartmentalized sequences were detected, whereas in two cases, both without cirrhosis, the HCV population in serum was completely different from that found in the liver. CONCLUSIONS: These results suggest that the complexity of HCV populations is influenced by the presence of hepatocellular carcinoma rather than by the severity of the underlying chronic liver disease. The different quasispecies patterns found in serum and liver may reflect different biological properties of circulating and intrahepatic HCV particles or the existence of extrahepatic sites of replication.     

Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM

An 81-year-old woman in whom liver dysfunction had been pointed out 3 years previously was diagnosed as having liver cirrhosis due to lupoid hepatitis. Considering the poor prognosis of cirrhosis and her age, immunosuppressive therapy was not adopted. Nine months later, a small liver tumor was found by ultrasonography and was diagnosed as hepatocellular carcinoma (HCC). The tumor was treated with transcatheter arterial embolization, but grew continuously. She also developed gingival lymphoma that was successfully treated. Three years after initial diagnosis of lupoid hepatitis, she died of hepatic failure. An autopsy was performed and confirmed the clinical diagnosis, liver cirrhosis with HCC. HCC is regarded as a rare complication of lupoid hepatitis, but cases of HCC complicating lupoid hepatitis may increase with progress in treatment methods and elongation of survival. The present case suggests that any malignancy can be developed in long-term surviving patients with lupoid hepatitis.     

Degradation of annexin I in bronchoalveolar lavage fluid from patients with cystic fibrosis

BACKGROUND/AIMS: The number of perisinusoidal myofibroblasts has been shown to be increased in hepatocellular carcinoma, as compared to cirrhosis. This increase might suggest a cooperative relationship between tumour cells and myofibroblasts. To assess this relationship, we undertook: (a) an immunohistochemical study to confirm the existence of an increased number of perisinusoidal myofibroblasts in human hepatocellular carcinoma, as compared to cirrhosis with or without liver cell dysplasia, (b) an in vitro study testing the role of normal or tumoral human hepatocytes in myofibroblast proliferation. METHODS: Forty explanted cirrhotic livers, including 14 with hepatocellular carcinoma and 24 with liver cell dysplasia, were studied. Myofibroblasts were detected by immunohistochemistry using an antibody directed against alpha-smooth muscle actin. Hepatic myofibroblasts in culture were obtained by outgrowth from human liver explants. RESULTS: There was a progressive increase in the number of perisinusoidal myofibroblasts, from cirrhotic nodules without dysplasia to liver cell dysplasia and hepatocellular carcinoma. Conditioned medium from isolated normal human hepatocytes had only minor mitogenic effects on myofibroblasts, as assessed by measuring DNA synthesis and cell growth. In contrast, conditioned medium from a human hepatoma cell line (HepG2 cells) markedly stimulated the proliferation of human myofibroblasts. This mitogenic activity was stored in HepG2 cells and secreted in the extracellular medium rather than being simply released following cell lysis. CONCLUSIONS: These results suggest that the increased number of myofibroblasts in hepatocellular carcinoma might be due to a paracrine mechanism involving soluble mitogenic factor(s) secreted by tumour cells.     

Immunohistochemical localization of metallothionein in hepatocellular carcinoma: preferential expression in non-cancerous cirrhotic nodules

Metallothionein (MT), an oncofocal gene product was strongly expressed in 35%-95% of hepatocytes in hepatocellular carcinoma (HCC) and MT-positive hepatocytes were localized mainly in the non-cancerous cirrhotic nodules but not in malignant hepatocytes. On the other hand, <10% hepatocytes showed weak staining for MT in chronic hepatitis and cirrhosis of liver. Strong expressions of MT in non-cancerous cirrhotic nodule in HCC and low expressions in liver cirrhosis without HCC indicate a relationship between malignant transformation of hepatocytes and the expression of MT.     

The natural course of hepatitis B and hepatitis C virus infection

Chronic hepatitis B and hepatitis C virus infections maintain a significant risk for the development of liver cirrhosis and hepatocellular carcinoma and cause a considerable morbidity in the population. Among patients with chronic HBV infection and histologically confirmed hepatitis the annual incidence of liver cirrhosis is 2%. The risk for hepatocellular carcinoma in chronic HBsAg carriers is elevated about 40-230 fold. 20-30% of patients with chronic HCV infection will develop cirrhosis over 20-30 years. Hepatocellular carcinoma evolves yearly in about 3% of patients with chronic HCV infection and cirrhosis, whereas HCV-carriers without cirrhosis usually do not develop hepatocellular carcinoma. The high incidence of serious sequelae warrants a regular surveillance of chronic virus carriers.     

Enhancement of HBsAg detection in serum of patients with chronic liver disease following removal of circulating immune complexes

Patients with chronic liver disease and hepatocellular carcinoma may lack serological evidence of previous hepatitis B virus infection. The purpose of the present study was to test the hypothesis that circulating immune complexes may interfere with the detection of low levels of HBsAg in such patients. Sera from 190 patients were initially screened for the presence of circulating immune complexes. Patients belonged to three clinical categories: asymptomatic HBsAg carriers (50 patients), chronic liver disease (30 patients) and hepatocellular carcinoma (110 patients). Forty-one of the group of 190 patients (21%) were positive for circulating immune complexes. Sera from 21 patients were selected for further evaluation. The sera of 13 chronic liver disease or hepatocellular carcinoma patients (HBsAg negative, hepatitis B virus-DNA negative, with or without evidence of previous hepatitis B virus infection) and eight HBsAg positive carriers (four asymptomatic, three with chronic liver disease and one with hepatocellular carcinoma) were passed through a Clq affinity column (first column) to remove circulating immune complexes. Unbound material was then passed through a monoclonal IgG2a anti-HBs affinity column (second column). Unbound material (following both columns) contained free HBsAg, as determined by monocolonal radio-immunoassay, in eight patients in whom HBsAg had been undetectable in the original serum. Removal of circulating immune complexes from the serum of the three HBsAg positive patients with chronic liver disease also caused a significant increase in measurable circulating HBsAg compared with the original serum.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disseminated cutaneous sporotrichosis as the initial manifestation of acquired immunodeficiency syndrome--case report

Two patients with ectopic liver are described. In one patient, a small ectopic liver attached to the gastric serosa developed hepatocellular carcinoma (HCC). The preoperative diagnosis was an alpha-fetoprotein (AFP)-producing carcinoma and a malignant ulcer of the stomach. Total gastrectomy and esophago-jejunostomy were performed. The tumor that measured 4 x 2 x 2 cm contained an AFP-producing HCC and normal liver tissue. In another patient who had alcoholic cirrhosis, ectopic liver on the serosa of the gallbladder was found to have the same histological changes as the mother liver. A survey of the literature disclosed more than 20 cases in which HCC developed outside the liver; the liver did not have HCC. By contrast, there was only one report on HCC occurring in the liver in the presence of a noncancerous, relatively large accessory liver lobe. Because ectopic liver does not have a complete vascular and ductal system as a normal liver, it is perhaps functionally handicapped and more prone to hepatocarcinogenesis.     

Outcome of hepatitis C patients with and without hepatocellular carcinoma undergoing liver transplant

OBJECTIVE: Hepatitis C virus (HCV) infection is associated with development of hepatocellular carcinoma (HCC). The aim of this study was to examine clinical characteristics and outcome of patients with HCV with or without HCC undergoing liver transplant. METHODS: We reviewed the charts of all 55 patients transplanted between November 1990 and December 1996 for HCV cirrhosis with HCC and compared them with a control group of HCV patients without HCC. Patients with a history of alcohol abuse or HBsAg positivity were excluded. There were 37 men and 18 women, with a mean age of 57.6 yr (range, 19-70 yr) in the HCC group. RESULTS: There was no significant difference between the HCC and nonHCC groups regarding Child's class or United Network for Organ Sharing (UNOS) status at the time of transplant. Twenty-six (45%) patients were diagnosed or suspected of having HCC before transplant. Twenty-five patients (45.5%) had a single focus of HCC. Fourteen percent (seven of 50) of the patients with HCC had been treated with interferon, whereas 12% (six of 52) of patients in the nonHCC group had received interferon. Duration of interferon therapy ranged from 1 to 9 months. All interferon treatment occurred within 5 yr of transplant. A history of intravenous drug use or transfusion was identified in 37 (67%) of HCC patients. Thirty-two patients (58%) without HCC had a parenteral exposure. There was no significant difference in patient or graft survival rates between the patients with and without HCC. CONCLUSION: Approximately one-half of HCC was not detected before liver transplant. There was no significant difference in the mode of transmission, clinical status at the time of transplant, or outcome between the HCV patients with and without HCC.     

Alpha feto-protein and albumin in ascitic fluid in hepatocellular carcinoma patients

Alpha-feto-protein (AFP) is the most popular tumor marker for hepatocellular carcinoma (HCC). It is used in diagnosis and follow up of cases by estimating its rise in the serum. The aim of this work is to study the value of estimating AFP in ascitic fluid of HCC patients with ascites. This work is a case control study on 32 patients, including 22 cases with ascites and HCC and 10 control group with ascites due to liver cirrhosis without HCC. The level of AFP was estimated in serum and in ascitic fluid by Radio-immuno assay RIA. The serum ascites albumin gradient (SAAG) was assessed by measuring albumin in all samples using bromocresole green dye binding. Guided aspiration liver biopsy and ascitic fluid cytology was done, stained with H & E. It was found that, AFP level in serum was elevated in 72.7% of HCC patients, and in ascitic fluid was elevated 63.6% HCC patients. Also, there was a highly significant, direct positive correlation between elevation of AFP in serum and in ascitic fluid (r = 0.778). No elevation of AFP in serum and in ascitic fluid was detected in control group. Ascitic fluid cytology showed malignant cells in one case only. SAAG was significantly lower in the HCC group 0.83 gm/dl than the control group 2.43 gm/dl (p-value < 0.001). Elevation of AFP in ascitic fluid is of high importance in evaluation of HCC, and is as significant as serum and runs parallel to it. Estimation of AFP in ascitic fluid is much more significant in evaluation of HCC cases than ascitic fluid cytology.     

Prevention of hepatitis B and C virus infection for prevention of cirrhosis and hepatocellular carcinoma

In Taiwan, cirrhosis and hepatocellular carcinoma (HCC) have been common in medical practice since the 1960s. In 1969, Taiwan was shown to be a hyperendemic area of hepatitis B virus (HBV) infection with a high rate of hepatitis B surface antigen (HBsAg) positivity, 19% of the population being infected before the fourth decade of life. There is evidence indicating that more than 80% of chronic hepatitis, cirrhosis and HCC are the sequelae of chronic HBV infection. In 1984, after 3 years of preparation, a programme to control cirrhosis and HCC began. All neonates born to HBsAg+ mothers were given Pasteur plasma-derived vaccine 5 micrograms i.m. at 1, 5 and 9 weeks with a booster at 12 months. In 1986, all neonates were included in this programme. In addition, beginning in 1987, all non-vaccinated preschool children were also immunized and susceptible medical personnel and people from HBsAg+ households were recommended to receive the vaccine. Using data obtained from the 7-year evaluation study on the efficacy of this vaccine and some historical data, the HBsAg positivity rate in people born in the first few years after 1986 was estimated to be 2.6%. This rate is expected to decrease to 0.2% in those born after around 1990. In July 1992, an anti-hepatitis C virus (HCV) test was included in blood donor screening tests. This was followed by a decrease in the incidence of post-transfusion hepatitis (PTH) from 13 to 2.5% and there have been no anti-HCV+ PTH cases since. However, without immunization, the prevalence of HBsAg decreased among children in Taipei in 1989. This coincided with the widespread use of disposable syringes and needles and an improvement in the sterilization of medical instruments. Therefore, it is likely that HCV infection may also decrease as a result of these practices. Through the use of immunization and improved medical procedures, chronic hepatitis, cirrhosis and HCC may decrease in Taiwan by around 95%.     

Pathomorphological study of HCV antibody-positive liver cirrhosis

A morphological investigation was carried out to study the pathological features of liver cirrhosis caused by hepatitis C virus (HCV) infection. The materials consisted of liver specimens taken from 47 cases of anti-HCV antibody-positive liver cirrhosis (37 by surgery for hepatocellular carcinoma and 10 by autopsy), and from 21 cases of hepatitis B surface antigen-positive liver cirrhosis as the control. Liver specimens containing more than 10 regenerative nodules were examined. In addition, a histometric study was conducted to determine the degree of fibrosis and the size of regenerative nodule using a computer image-analysis system. The results showed that the histological characteristics of HCV antibody-positive liver cirrhosis are: (i) broadly expanded fibrous septa and small regenerative nodules; (ii) relatively strong inflammatory reaction and prominent lymphoid aggretation in the fibrous septum; and (iii) mild regenerative activity of the liver parenchyma, and infrequent liver cell dysplasia. These findings may facilitate better understanding of the pathology of HCV antibody-positive liver cirrhosis and more accurate pathological diagnosis by needle biopsy.     

Chemolipiodolization and prostaglandin E1 administration with use of hepatic arterial infusion port for the treatment of hepatocellular carcinoma and liver cirrhosis

Frequent chemolipiodolization and prostaglandin E1 (PGE1) administered through a hepatic arterial infusion port were used for treatment in 2 cases of hepatocellular carcinoma (HCC) with liver cirrhosis. Chemolipiodolization was performed every 4 weeks with 6 ml lipiodol, 3 ml Optilay and 30 mg Epirubicin or 10 mg Mytomycin C. PGE1 (10 ug) was administrated to the hepatic artery once every week after the first 7 days administration. The treatment resulted in a decrease of the AFP level, an arrest of HCC growth and a reduction in ascites with an improvement of clinical and biochemical parameters in both cases. These encouraging preliminary results show that frequent lipiodolization is effective for unresectable HCC and frequent PGE1 administration via the hepatic artery is a safe and efficient treatment for liver cirrhosis.     

The putative tumor suppressor gene on chromosome 5q for hepatocellular carcinoma is distinct from the MCC and APC genes

We have previously shown that the tumor suppressor gene for hepatocellular carcinoma (HCC) without cirrhosis may be located on chromosome 5q35-qter. In this study, we analyzed nine cases of primary HCC without cirrhosis using probes from the MCC and APC genes, which are in the region 5q21-22. None of the informative cases had allele loss detected by these probes, whereas the probe lambda MS8 for the region 5q35-qter showed allele loss in six out of six informative cases. The results confirm that the putative tumor suppressor gene for HCC without cirrhosis on chromosome 5q is distinct from the MCC and APC genes.     

Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is estimated to have an annual worldwide incidence of 0.25 to 1.2 million new cases per year. Both the prevalence and incidence of HCC vary markedly as a function of geography and the local prevalence of chronic viral hepatitis. Both chronic hepatitis B and chronic hepatitis C are recognized as risk factors for HCC. The prevalence of cirrhosis in individuals with HCC and chronic hepatitis B or C is reported to be 80.9% and 75.8%, respectively. HCC occurs at a lower rate in chronic viral hepatitis in the absence of cirrhosis. Moreover, hepatitis C virus (HCV) rather than hepatitis B virus (HBV) is associated with the majority of non-cirrhotic cases of HCC. It is probable that the ongoing process of hepatocyte necrosis and liver cell renewal coupled with inflammation, which is characteristic of chronic viral hepatitis, causes not only nodular regeneration and cirrhosis but also progressive genomic errors in hepatocytes as well as unregulated growth and repair mechanisms leading to hepatocyte dysplasia and, in some cases, hepatic carcinoma. Current concepts concerning virus-induced HCC are reported and discussed in the following review.     

Hepatocellular carcinoma in an orthotopic mouse model metastasizes intrahepatically in cirrhotic but not in normal liver

Prognosis of hepatocellular carcinoma (HCC) still remains poor mainly because of intrahepatic metastasis. In the majority of cases, HCC is found in conjunction with liver cirrhosis. It is, therefore, of great importance to investigate the invasive and metastatic behavior of HCC in cirrhotic liver. To examine this, a liver cirrhosis model was produced by injecting thioacetamide i.p. into mice. Murine HCC cells were labeled with the fluorescent carbocyanine dye, DiI, and implanted directly under the capsule of cirrhotic and normal livers of syngeneic mice. DiI-labeled HCC cells in the liver were observed under fluorescent and confocal microscopy. Histological analysis of cirrhotic and normal livers revealed that implanted HCC cells migrated to and invaded the adjacent periportal regions, but not the adjacent centrolobular areas. This characteristic behavior of HCC was more evident in cirrhotic liver than in normal liver. Furthermore, intrahepatic metastasis to unimplanted hepatic lobes was observed in cirrhotic liver as early as 7 days after implantation, while it was not detected in normal liver even 4 weeks later. Thus, an orthotopic animal model for HCC with cirrhosis described here may be suitable for investigating the invasive and metastatic behavior of HCC. Importantly, labeling tumor cells with a fluorescent dye before orthotopic implantation may be a convenient and useful method to investigate the invasive and metastatic behavior of various types of cancer.     

Emerging mechanisms of eukaryotic DNA replication initiation

One hundred sixty-four consecutive cases of primary liver carcinoma were evaluated for tumor type, (i.e., hepatocellular carcinoma [HCC], cholangiocarcinoma [CC], and combined hepatocholangiocarcinoma [CHCC]), and for signs of alpha-1-antitrypsin deficiency (AATD) in the surrounding liver tissue. Hepatocellular globular alpha-1-antitrypsin deposits, as detected by a monoclonal antibody to the mutant PiZ alpha-1-antitrypsin (AAT), were seen in 13 cases (7.9%). With regard to tumor type, 4 of 111 HCC cases (3.5%), but 4 of 37 CC cases (10.5%), and even 5 of 16 CHCC cases (30%) were positive for this antitrypsin variant. In all but 1 of 13 cases of alpha-1-antitrypsin deficiency, the carcinoma developed in noncirrhotic liver tissue of elderly people (mean age, 62.9 years). In three patients, a heterozygous state of ATT (PiMZ) could be revealed using isoelectric focusing or direct genetic analysis. We conclude from our findings that CHCC and CC especially might be associated with PiZ alpha-1-antitrypsin deficiency. Primary liver carcinoma might develop even in a heterozygote state of PiZ alpha-1-antitrypsin deficiency without concurrent liver disease. Furthermore, liver cirrhosis is not a precondition for these tumors.     

High serum alpha-fetoprotein concentration associated with pseudoinfarction of a cirrhotic liver: report of a case

We report herein the case of a 65-year-old man with cirrhosis of the liver in whom a portal vein thrombus was found to be the cause of a marked elevation in serum alpha-fetoprotein (AFP). The patient presented with fever and abdominal pain, and a diagnostic work-up revealed a liver mass and an increased serum AFP concentration of 91,000 ng/ml. The mass gradually regressed, and the AFP concentration simultaneously decreased to 163 ng/ml. However, because hepatocellular carcinoma (HCC) could not be ruled out, a partial hepatectomy was performed. Histological examination of the resected specimen revealed a thrombus of the portal vein surrounded by the fibrosis associated with liver cirrhosis, but no neoplastic lesion was found. Thus, portal thrombus associated with liver cirrhosis might induce an extremely high level of AFP production.     

Seroepidemiological study of hepatitis delta virus infection in Okinawa, Japan

A seroepidemiological study on hepatitis delta virus (HDV) infection was conducted in the Okinawan islands, the area of Japan where hepatitis B virus infection is most prevalent. The subjects of this study included 116 asymptomatic hepatitis B surface antigen (HBsAg) carriers, 48 patients with chronic hepatitis (CH), 19 with liver cirrhosis (LC), and 11 with hepatocellular carcinoma (HCC). Among the 194 serum samples examined, a total of 10 (5.2%) were anti-HDV seropositive. Anti-HDV was detected in 2 (1.7%) of the 116 asymptomatic HBsAg carriers, in 3 (6.3%) of the 48 patients with CH, and in 5 (26.3%) of the 19 with LC. However, none of the patients with HCC had detectable anti-HDV. Eight of the 10 were born in the Miyako island group and the remaining 2 on the main island of Okinawa. Since the subjects included 34 individuals who were living and/or born in the Miyako islands, the positive rate of anti-HDV in the islands was 23.5%. This study demonstrates the existence of an endemic area of HDV infection in Japan.