[Show abstract][Hide abstract] ABSTRACT: α-fetoprotein (AFP) is a tumor marker of hepatocellular carcinoma (HCC) and has also been reported to reflect the effectiveness of long-term low-dose interferon (IFN) therapy in hepatitis C virus (HCV)-infected patients with chronic liver disease. The correlation between AFP levels and the incidence of HCC has been discussed over a long period. We investigated whether high levels of AFP at the time of diagnosis were associated with an increased incidence of HCC in patients with HCV. A total of 107 HCV patients with liver cirrhosis without other risks were evaluated for the predictive value of non-invasive risk factors for HCC, including age, gender, alcohol intake, aspartate and alanine aminotransferase levels, bilirubin, albumin, platelet count and AFP levels at study entry, as well as the IFN therapy received. During the follow-up period, HCC developed in 68 (63.6%) patients. Kaplan-Meier estimates were made to assess the cumulative risk of HCC. The 10-year cumulative incidence rate of HCC was 80%. Cox regression analysis was performed on several variables, including age, gender, alcohol consumption, experience of IFN therapy and biochemical parameters. The following factors were identified as exhibiting an increased risk of HCC by univariate analysis: aspartate transaminase (AST) ≥71 IU/l, alanine transaminase (ALT) ≥60 IU/l, AFP ≥6 ng/ml and IFN therapy. Multivariate analysis identified that the AFP level [6-19 ng/ml: hazard ratio (HR), 2.22; P=0.006 and ≥20 ng/ml: HR, 2.09; P=0.003] was an independent and significant risk factor for the development of HCC. A slightly elevated (6-19 ng/ml) AFP level may be a risk factor for HCC in certain cases. By contrast, AFP levels <6 ng/ml indicate a low risk of HCC development in HCV patients with liver cirrhosis.
Experimental and therapeutic medicine 12/2012; 4(6):972-976. DOI:10.3892/etm.2012.709 · 1.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The number and ratio of both HBsAg- and HCV Ab-negative hepatocellular carcinoma (HCC-nonBC) cases have been steadily increasing in Japan. The aim of this study was to examine the frequency of detection of HCC-nonBC by screening methods and to elucidate the clinical characteristics of HCC-nonBC compared with those of hepatitis C and/or B virus-associated HCC (HCC-virus). We recruited 624 patients with HCC who were diagnosed between 1982 and 2007 at the Department of Gastroenterology and Hepatology, Nagasaki University Hospital. They were categorized into 2 groups as follows: i) 550 were included in the HCC-virus group: positive for HBsAg and/or positive for HCV Ab, and ii) 74 were included in the HCC-nonBC group: negative for both HBsAg and HCV Ab. The follow-up patterns until the initial detection of HCC and the survival rates were analyzed and compared between the 2 groups. Multivariate analysis identified follow-up, alcohol consumption, albumin level, total bilirubin level, alpha-fetoprotein (AFP) level, and tumor-node-metastasis (TNM) stage as independent and significant risk factors for prognosis. Among the 397 patients with HCC in TNM stage I or II, multivariate analysis identified the cause of liver disease, gender, Child-Pugh score, serum albumin level and TNM stage as independent and significant risk factors for prognosis. We reported that the poor prognoses of patients with HCC-nonBC were attributable to its late detection in an advanced condition due to the absence of a surveillance system for the early detection of HCC. However, in early-stage patients, patients with HCC-nonBC showed significantly better prognosis than those in the HCC-virus group.
[Show abstract][Hide abstract] ABSTRACT: A 52-year-old man was admitted to our hospital for fever, jaundice, and general malaise. Laboratory data revealed elevated serum liver enzyme levels (AST 2377IU/L, ALT 2756IU/L) and bilirubin (T-Bil 3.7 mg/dl). Blood count showed a marked decrease of platelets (2.0 x 10(4)/microl). Serological and virological analysis showed positive results for HEV IgM and HEV RNA, indicating a diagnosis of acute hepatitis E. The serum ferritin level was also markedly elevated (23200 ng/ml). A diagnosis of virus associated hemophagocytic syndrome (VAHS) was strongly suggested. This is the first report of hepatitis E most likely accompanied by VAHS.
Nippon Shokakibyo Gakkai zasshi The Japanese journal of gastro-enterology 06/2008; 105(6):841-6.
[Show abstract][Hide abstract] ABSTRACT: Hepatopulmonary syndrome (HPS) is a complication of liver disease that is characterized by hypoxemia and intrapulmonary vascular dilatations. The only established therapy for this disorder is liver transplantation. Here, we report two patients (a 63-year-old woman and a 72-year-old man) with HPS associated with hepatitis C virus-related cirrhosis. We gave the patients low-dose oxygen supplementation to improve their respiratory symptoms. Surprisingly, their liver function improved from Child Pugh class C to class A, and ascites disappeared after a year of oxygen supplementation. We believe that long-term oxygen therapy contributed to the improvement of liver function in these two cases. Long-term oxygen therapy might offer a new therapeutic approach to improve liver function in patients with cirrhosis with hypoxemia.
Journal of Gastroenterology 03/2007; 42(2):176-80. DOI:10.1007/s00535-006-1965-0 · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the pathogenesis of non-alcoholic steatohepatitis (NASH) remains poorly understood, proinflammatory cytokines seem to play an important role in the process of NASH. We have undertaken this study in order to elucidate the role of proinflammatory cytokines and their soluble receptors in NASH patients.
Serum cytokines and soluble cytokine receptors levels were determined using an enzyme-linked immunosorbent assay kit in 23 patients with NASH, 21 patients with simple steatosis, and 18 healthy volunteers.
Patients with NASH had significantly higher serum tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) levels than did the simple steatosis patients. Similarly, when compared with simple steatosis, NASH was associated with higher soluble TNF receptor 1 (sTNFR1) and soluble IL-6 receptor (sIL-6R) levels, and a significant positive correlation was seen between the levels of sTNFR1 and aminotranferases in NASH patients.
This study shows that circulating TNF-alpha/sTNFR1 and IL-6/sIL-6R levels are significantly increased in NASH patients as compared with simple steatosis patients and healthy volunteers, and that these increased levels may be implicated in the pathogenesis of NASH.
Liver international: official journal of the International Association for the Study of the Liver 03/2006; 26(1):39-45. DOI:10.1111/j.1478-3231.2005.01191.x · 4.85 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the study was to determine the epidemiological trends in HCC mortality in Japan.
We reviewed the medical records of all patients whose death was caused by liver disease between 1981 and 2000 at two hospitals. The courses of death were separated based on presence or absence of HCC when death ensued. Additionally, cohorts of patients with HCC were analyzed in 5-year time periods.
The number of deaths from hepatitis C virus (HCV)-associated HCC steadily increased 2.6 times from 49 to 128 during observation period. The mean age at death from HCV-associated HCC from 1996 to 2000 was significantly higher than that in the period from 1981 to 1985 (p<0.0001).
Deaths from HCV-associated HCC increased from 1981 to 2000, consistent with the aging of the population in Japan.
Hepatology Research 03/2006; 34(2):130-4. DOI:10.1016/j.hepres.2005.11.007 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The pathogenesis of primary biliary cirrhosis (PBC) remains enigmatic. In order to address this issue, we analyzed by laser capture microdissection and real-time reverse transcription-polymerase chain reaction the site-specific expression of messenger RNA (mRNA) for cytokines (interferon (IFN)-alpha, -beta, -gamma, interleukin (IL)-1beta, -4, -6, -10, -12p40, -18, tumor necrosis factor-alpha) and toll-like receptors (TLRs) (TLR-2, -3, -4, -7, -9) in portal tract and liver parenchyma from patients with early-stage PBC. Expression of IFN-alpha, -beta and TLR-3 proteins was also studied by immunohistochemistry. Autoimmune hepatitis (AIH) and chronic hepatitis C (CHC) served as disease controls. The expression levels of type I IFN (IFN-alpha, -beta) and TLR-3 mRNAs, which are known to induce type I IFN, were significantly higher in portal tract and liver parenchyma as compared to AIH and CHC. A strong positive correlation between the mRNA levels of type I IFN and TLR-3 was also seen in both areas. Immunohistologically, IFN-alpha is present in the mononuclear cells in portal tract and sinusoidal cells. Macrophages in portal tract and hepatocytes expressed IFN-beta and TLR-3. Furthermore, the level of IFN-alpha mRNA in the portal tract was positively correlated with serum alkaline phosphatase. In conclusion, these data indicate that TLR-3 and type I IFN signaling pathways are active in both the portal tract and liver parenchyma of early-stage PBC, and form the basis for our hypothesis that these signaling pathways are involved in the pathophysiology of PBC.
[Show abstract][Hide abstract] ABSTRACT: In this study, we determined the frequencies of the genotypes associated with the polymorphism of the cytokines genes, and investigated their association with the risk of hepatocellular carcinoma (HCC) in hepatitis B virus (HBV) carriers.
Genetic polymorphism in the cytokines TNF-alpha, IFN-gamma, TGF-beta1, IL-6, and IL-10 were studied in 236 Japanese patients with HBV infection. The genetic polymorphisms of these cytokines were analyzed by polymerase chain reaction-sequence-specific primer (SSP).
There was no statistically significant difference in the genetic polymorphisms of TNF-alpha, IFN-gamma, and IL-10 genes between HBV carriers with HCC and those without HCC. However, the TGF-beta1+29 (codon 10) C/C genotype was lower in HBV carriers with HCC than in those without HCC (HCC 14.6% vs non-HCC 31.9%). The association of HCC was significantly lower in HBV carriers with C/C genotype than in those with T/C or T/T genotype in position +29 of the TGF-beta1 gene.
Our findings suggest that the genetic polymorphism in codon 10 of the TGF-beta1 gene may play a role in HCC development in patients with chronic HBV infection.
Journal of Hepatology 05/2005; 42(4):505-10. DOI:10.1016/j.jhep.2004.11.026 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presence of antibodies to the 210-kDa glycoprotein of the nuclear pore complex (gp210) is highly indicative of primary biliary cirrhosis (PBC). However, the significance of anti-gp210 antibody titers for monitoring PBC remains unresolved.
We used an ELISA with a gp210 C-terminal peptide as an antigen to assess serum antibody titers in 71 patients with PBC.
Patients were classified into three groups: Group A in whom anti-gp210 titers were sustained at a high level, Group B in whom anti-gp210 status changed from positive to negative under ursodeoxycholic acid (UDCA) therapy, Group C in whom anti-gp210 antibodies were negative at the time of diagnosis. The rate of progression to end-stage hepatic failure was significantly higher in group A (60%) as compared to groups B (0%) and C (4.2%). The sustained antibody response to gp210 was closely associated with the severity of interface hepatitis. The significance of anti-gp210 antibody was confirmed by National Hospital Organization Study Group for Liver Disease in Japan.
The serial quantitation of serum anti-gp210-C-terminal peptide antibodies is useful for monitoring the effect of UDCA and for the early identification of patients at high risk for end-stage hepatic failure.
Journal of Hepatology 04/2005; 42(3):386-92. DOI:10.1016/j.jhep.2004.11.016 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Des-gamma-carboxy prothrombin (DCP) has been reported to be an important prognostic factor in patients with hepatocellular carcinoma (HCC). Recently, a monoclonal antibody, 19B7, which recognizes the Gla domain of DCP, has been identified. The 19B7 antibody recognizes an epitope different from that recognized by MU-3, which is another antibody against DCP. In this study, the authors investigated the measurement of DCP using the antibodies MU-3 and 19B7, respectively, as a prognostic factor for patients with HCC who had solitary, small tumors and or Child Stage A HCC.
One hundred four patients with HCC who had solitary, small tumors or Child Stage A tumors were enrolled in the study between 1991 and 2001. All patients were treated and were followed for a mean of 3.2 years. The authors analyzed the correlation between the DCP Index (DCP measured by MU-3 and DCP measured by 19B7) and patient prognosis. The patients were classified into 3 groups based on their DCP Index: 1) DCP negative (DCP < 40 milli arbitrary unit (mAU)/mL)); 2) low DCP Index (DCP > or = 40 mAU/mL; MU-3:19B7 ratio, < 3.0; and 3) high DCP Index (DCP > or = 40 mAU/mL; MU-3:19B7 ratio, > or = 3.0).
The survival rate for patients in the high DCP Index group was lower compared with the survival rate for patients in the DCP-negative group and was significantly lower compared with the survival rate for patients in the low DCP Index group. In a univariate Cox proportional hazards model, the positive factors were high DCP Index and low DCP Index. Among the positive predictive factors that were analyzed using a multivariate Cox proportional hazards model were age (hazard ratio, 3.27; P = 0.006), low DCP Index (hazard ratio, 2.87; P = 0.012), and high DCP Index (hazard ratio, 12.3; P < 0.0001).
The prognosis of patients who had a high DCP Index score was poorer compared with patients who had a low DCP Index score and patients who were classified as DCP negative. The authors concluded that the DCP Index is a prognostic indicator for patients with HCC.
Cancer 12/2003; 98(12):2671-7. DOI:10.1002/cncr.11839 · 4.89 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recently, a novel DNA virus was isolated from the serum of a patient with post-transfusion non-A-G hepatitis and named TT virus. The aim of this study was to determine the prevalence and clinical characteristics of TT virus infection in patients with sporadic acute hepatitis of unknown etiology.
TT virus was investigated in the serum of 66 patients with sporadic acute hepatitis non-A-G and 50 healthy controls by semi-nested PCR with previously published primers.
TT virus was detected in 17 (26%) of the 66 patients with sporadic acute hepatitis non-A-G and in a slightly higher rate (34%,17/50) in the control group. No significant differences in alanine aminotransferase or bilirubin concentrations were observed between the groups of patients with or without TT virus infection. Eighty per cent (12/15) of patients for whom follow up was possible had persistent viremia from 4 to 36 months, and 67% (8/12) of these patients had already normalized their levels of alanine aminotransferase. A phylogenetic tree constructed by the Neighbor Joining Method revealed that all isolates in this study were grouped within genotype 1a and 1b, without showing any association between genetic type and development of hepatic disease.
Our results suggest that TT virus DNA is present not only in patients with sporadic acute hepatitis non-A-G but also in a large proportion of the general population. This virus was not likely to be the causative agent of hepatitis among the patients in this study.
Journal of Hepatology 01/2000; 31(6):985-9. DOI:10.1016/S0168-8278(99)80309-2 · 11.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The presence of α-fetoprotein (AFP) mRNA in mononuclear cells of the peripheral blood was examined in patients with hepatocellular carcinoma (HCC), liver cirrhosis, chronic hepatitis and normal volunteers using nested reverse transcription polymerase chain reaction (RT-PCR). Then, the AFP mRNA levels were quantitatively analyzed in AFP mRNA-positive patients with HCC. AFP mRNA was detected in 23 of 38 (60.5%) cases with HCC, 2 of 12 (16.7%) cases with cirrhosis, and 1 of 9 (11.1%) cases with chronic hepatitis, respectively. AFP mRNA was not demonstrated in six healthy volunteers. The frequency of positive cases in TNM stage III–IV (16/21, 76.2%) was significantly higher than that in stage I–II (7/17, 41.2%)(P
Hepatology Research 01/1999; 14(1):1-12. DOI:10.1016/S1386-6346(98)00098-9 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The polymerase chain reaction (PCR) is a rapid and very sensitive method to detect viral genomes. In the present study, the efficacy of immunization against hepatitis B virus (HBV) of high-risk infants was evaluated by PCR. Twenty-nine infants born to 24 HBeAg-positive carrier mothers were given hepatitis B immune globulin (HBIG) at birth and thereafter received repeated inoculations of plasma-derived vaccine or HBIG, or both, within 1 year. Serum samples at 1 year following immunization were stored at -40 degrees C for later analysis using PCR to detect HBV-DNA. When HBV genomes were detected in infants, the DNA sequences in the S gene of HBV were determined. Of 29 infants, 2 were positive for HBV-DNA at the 1 year following immunization; one had the HBV containing only the wild-type sequence in the S gene and became negative for HBV-DNA during the follow-up period. In contrast, another had the HBV, which contained nucleotide substitutions that altered the expression of the common group-specific determinant "a" of the S gene and resulted in clinical hepatitis with viral persistence. PCR analysis suggests that immunization against HBV prevents effectively high-risk infants from mother-to-child transmission. Even then, however, it is possible that amino acid substitutions in the "a" determinant of the S gene are associated with failure of conventional immunization against HBV.
Journal of Medical Virology 12/1997; 53(3):255-60. DOI:10.1002/(SICI)1096-9071(199711)53:3<255::AID-JMV13>3.0.CO;2-G · 2.35 Impact Factor