Hironaka Kawasaki

Incidence of hepatitis virus infection and severe liver dysfunction in patients receiving chemotherapy for hematologic malignancies

Abstract: Hepatitis virus infection through virus reactivation has a high risk of mortality in patients with hematological malignancies receiving chemotherapy. We examined the incidence of both hepatitis B virus (HBV) and hepatitis C virus (HCV) infection and severe liver dysfunction (alanine aminotransferase >ten times the normal upper limit and total bilirubin >5 mg/dl) during chemotherapy in 268 patients with hematological malignancies. Eight patients (3.0%) were infected with HBV and 22 patients (8.2%) were infected with HCV. One patient (0.4%) was infected with both HBV and HCV. HBV‐ or HCV‐infected patients showed severe liver dysfunction at a significantly higher incidence than non‐infected patients (11/31 (35.5%) vs. 0/237 (0%), p<0.0001). Furthermore, the incidence of severe liver dysfunction in HBV‐infected patients was significantly higher than in HCV‐infected patients (6/8 (75.0%) vs. 4/22 (18.2%), p<0.01). Three of eight HBV‐infected patients were initially negative for hepatitis B surface antigen (HBsAg) by latex agglutination and became positive for HBsAg during chemotherapy. Furthermore, all three patients developed severe liver dysfunction and two developed fatal fulminant hepatitis. From an examination of the original stock of serum samples before chemotherapy, two patients were found to be positive for HBV‐DNA by polymerase chain reaction (PCR). Although post‐transfusion HBV infection was suspected in the one remaining patient, the cause of HBV infection could not be clarified due to the impossibility of examination in blood donors. Since HBV‐infected patients develop severe liver dysfunction at a higher incidence than either patients not infected with virus or HCV‐infected patients before chemotherapy for hematological malignancies, it is recommended that HBV‐DNA should be tested by PCR to detect HBV marker‐negative carriers and liver function tests should be carefully monitored.

Combination therapy with transcatheter arterial chemoembolization and percutaneous ethanol injection compared with percutaneous ethanol injection alone for patients with small hepatocellular carcinoma

To assess whether the effectiveness of a combination of transcatheter arterial chemoembolization (TACE) and percutaneous ethanol injection (PEI) is superior to PEI alone in the treatment of patients with small hepatocellular carcinoma (HCC), a randomized controlled study was performed.

Diagnostic value of serum type IV collagen test in comparison with platelet count for predicting the fibrotic stage in patients with chronic hepatitis C

Background and Aim: The serum type IV collagen test is now used as a diagnostic aid for the detection of liver fibrosis and cirrhosis. Recently, a platelet count has been reported to be a useful marker for assessing the fibrotic stage in chronic hepatitis C. The aim of this study was to compare the usefulness of the serum type IV collagen test and platelet count for diagnosing the fibrotic stage in chronic hepatitis C patients.

Tissue inhibitor of metalloproteinase-1 in the liver of patients with chronic liver disease.

BACKGROUND/AIMS Tissue inhibitor of metalloproteinase (TIMP)-1 is an important regulator of matrix metalloproteinase activity. To clarify the changes in TIMP-1 in diseased livers, we measured TIMP-1 concentrations in liver tissue samples from patients with chronic liver disease. The relationship between serum and liver levels of TIMP-1 was also examined in some patients. METHODS The subjects were 68 patients who underwent liver biopsy. The liver TIMP-1 concentration was measured using an enzyme immunoassay after the extraction of TIMP-1 with 2 M guanidine. RESULTS As compared with the controls (n=10), the liver TIMP-1 level was increased 2.2-fold in the 24 chronic active hepatitis 2A patients, 2.9-fold in the 10 chronic active hepatitis 2B patients and 4.1-fold in the six liver cirrhosis patients, but no significant increase was observed among the 18 chronic persistent hepatitis patients. The liver TIMP-1 levels were closely correlated with the histological degrees of periportal necrosis, portal inflammation, and liver fibrosis. When the localization of TIMP-1 was examined immunohistochemically, TIMP-1 was stained mainly in hepatocytes, and the intensity was stronger in the livers of chronic active hepatitis and liver cirrhosis patients than in those of the chronic persistent hepatitis patients. The serum TIMP-1 and liver TIMP-1 levels were significantly correlated, indicating that serum TIMP-1 could reflect the change of liver TIMP-1 in patients with chronic liver disease. CONCLUSION Liver TIMP-1 concentration increases with progression of the liver disease, when the degradation of extracellular matrix proteins is decreased, resulting in the development of liver fibrosis.

Diagnostic value of serum markers of connective tissue turnover for predicting histological staging and grading in patients with chronic hepatitis C.

Purpose. Chronic hepatitis C is an insidiously progressive disease, in which repeated assessment of liver histology is required. Various serum fibrotic markers have now been introduced. Our present aim was to assess, by receiver operating characteristic analysis, the usefulness of serum fibrotic markers for diagnosing fibrotic staging and necroinflammatory grading in chronic hepatitis C. Methods. Serum levels of procollagen type III N-terminal peptide (PIIINP), 7S fragment of type IV collagen (PIVNP), hyaluronan (HA), matrix metalloproteinase (MMP)-1, MMP-2, and tissue inhibitor of metalloproteinases (TIMP)-1 were measured in 169 patients with chronic hepatitis C. Results. The accuracy of these tests for discriminating stages greater than F2 from stages less than F1 was superior to that for discriminating stage F3 from stages less than F2. The most useful test for predicting stages greater than F2 was the serum HA test (cutoff value, 50 ng/ml; sensitivity, 75%; specificity, 80%), and the next-most useful was the serum MMP-2 test (cutoff value, 550 ng/ml; sensitivity, 75%; specificity, 70%). The usefulness of these tests for discriminating moderate grade from grades less than mild was superior to that for discriminating grades more than mild from minimal grade. The most useful test for predicting moderate grade was the serum HA test (cutoff value, 60 ng/ml; sensitivity, 77%; specificity, 74%), and the second-most useful was the serum PIVNP test (cutoff value, 6.5 ng/ml; sensitivity, 74%; specificity, 75%). The combination of the most useful and next-most useful test results increased the accuracy of the diagnosis of staging and grading. Conclusions. These serum fibrotic markers, especially the serum HA test, would be clinically useful for assessing staging and grading in patients with chronic hepatitis C.

Occult hepatitis B virus infection in HBs antigen-negative hepatocellular carcinoma in a Japanese population: involvement of HBx and p53.

Hepatitis B virus (HBV) genome was reported to be detected in serum or liver tissues in hepatocellular carcinoma (HCC) patients negative for hepatitis B surface antigen (HBsAg). Hepatitis B × (HBx) and p53 protein were reported to play an important role in HBV‐related hepatocarcinogenesis. To clarify latent HBV infection in HBsAg‐ and anti‐hepatitis C virus (anti‐HCV)‐negative HCC in a Japanese population and involvement of HBx and p53 protein in these patients, we performed the sensitive and specific nested polymerase chain reaction (PCR) and immunohistochemical analysis. Of 1,024 HCC patients we saw between 1974 and 1998, 66 (6.4%) were negative for HBsAg and anti‐HCV. Serum DNA was amplified by nested PCR by using specific primers of surface (S), core (C) and X regions in 26 patients negative for HBsAg and anti‐HCV. Eighteen (69%) patients were positive for either S, C, or X region and the results of PCR were confirmed by Southern blotting. Of 18 PCR‐positive patients, 3 were positive for anti‐HBs and 9 were positive for anti‐HBc, however, one was negative for any HBV markers. In HBsAg‐negative and PCR‐positive patients, the positive rates of expression of HBx and p53 were 8/13 (62%) and 7/13 (54%), being comparable to those in HBsAg‐positive HCC patients. The results of the present study suggest that high prevalence of HBV infection is observed in HBsAg‐negative HCC in a Japanese population and expression of HBx and p53 is consistent with a role, in these patients, for the transforming ability of these proteins. J. Med. Virol. 62:151–158, 2000.

Clinical significance of serum hyaluronan in patients with chronic viral liver disease

In order to elucidate the clinical significance of serum hyaluronan in chronic viral hepatitis, serum hyaluronan concentrations were measured using a sandwich enzyme binding assay in 115 patients with chronic viral hepatitis. These findings were examined in relation to the results of laboratory liver tests, levels of serum markers for fibrosis and liver histological findings. Serum hyaluronan levels increased with the progress of liver disease, particularly in liver cirrhosis. There were no significant differences in serum hyaluronan levels among the cirrhotic patients according to Childs grade. Multivariate analysis showed that the significant independent predictors of serum hyaluronan were serum aspartate aminotransferase (P= 0.020), serum alanine aminotransferase (P= 0.008), serum cholinesterase (P< 0.001), particularly serum type IV collagen 7S domain (P< 0.0001), and the histological degree of liver fibrosis (P< 0.0001). These findings suggest that elevated serum hyaluronan levels are closely related to the severity of liver fibrosis. We assessed the predictive value of serum hyaluronan in differentiating cirrhosis from chronic hepatitis, constructing receiver operating curves; we found that serum hyaluronan was a better test for diagnosing cirrhosis than serum type IV collagen 7S domain and laboratory liver tests.

Serum matrix metalloproteinase‐1 in patients with chronic viral hepatitis

Background and Aims: Previously we found that serum matrix metalloproteinase (MMP)‐1 activity decreased with progression of chronic liver disease. Our objectives in the present study were to observe the change in the serum MMP‐1 protein concentration using recently developed specific enzyme immunoassays for MMP‐1 and MMP‐1 complexed with tissue inhibitor of metalloproteinases (TIMP)‐1 and to elucidate the clinical usefulness of the serum MMP‐1 test in chronic viral hepatitis. We measured the serum concentrations of MMP‐1 and MMP‐1/TIMP‐1 complex using these immunoassays in 64 patients with histologically characterized chronic viral hepatitis.

Serum tissue inhibitor of metalloproteinases in patients with chronic liver disease and with hepatocellular carcinoma.

To examine the clinical significance of serum level of tissue inhibitor of metalloproteinases (TIMP) in chronic liver disease and in hepatocellular carcinoma, we measured serum TIMP concentration by a sandwich enzyme immunoassay in 79 patients with chronic liver disease and 49 patients with hepatocellular carcinoma. Serum TIMP concentration was 164 +/- 20 ng/ml in healthy controls, and was 10% higher than control in chronic persistent hepatitis, 36% higher in chronic active hepatitis, 62% higher in liver cirrhosis and 30% higher in primary biliary cirrhosis. Serum TIMP level was closely correlated with serum level of type IV collagen 75 domain and with the histological degree of liver fibrosis in chronic liver disease. Serum TIMP level in hepatocellular carcinoma was increased 2.3-fold compared with that in controls, and was significantly higher than in liver cirrhosis. Serum TIMP level increased with tumor size, and significantly correlated with serum alpha-fetoprotein level. Gel filtration on Sephadex G-75 showed that the TIMP in serum was present as an enzyme-complexed form. These results suggest that the measurement of serum TIMP concentration is useful in the clinical assessment of liver fibrosis in chronic liver disease and of the development of hepatocellular carcinoma.

Clinical significance of c-met oncogene alterations in human colorectal cancer.

Abnormalities of the c-met oncogene have been studied in cancers of many organs including thyroid, lung, pancreas, and stomach. However, little is known about the clinical significance of c-met oncogene abnormalities in colorectal cancer. We investigated the amplification and overexpression of the c-met gene in surgically resected samples from 43 patients with colorectal cancer using Southern blot analysis and reverse transcription-polymerase chain reaction (RT-PCR). Four of 33 (12%) samples of colorectal cancer showed amplification of the c-met gene. Twelve of 43 (30%) exhibited overexpression of the c-met gene. The patients with c-met overexpression showed greater tumor size, compared to those without c-met overexpression (p < 0.05). However, there were no differences in clinical stage, histological differentiation, tumor markers, or overall survival between two groups. The findings of the present study suggest that overexpression of c-met gene plays an important role in growth of colorectal cancer.