Biomedical subjects
Publications and source records attributed to M Ohto.
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Hepatocellular carcinoma (HCC) is considered to develop either on a background of preneoplastic lesions as multistep carcinogenesis or on a liver without such a lesion as de novo. The latter course can be assumed by our clinical experience of imaging diagnosis and by follow up studies of alpha fetoprotein (AFP) producing HCCs. Although serial checkup of AFP is important, serological or genetic approach is little use for early detection of HCC. At present, imaging diagnosis especially ultrasound is the best modality for detecting early developing HCC. The most reliable way for the final diagnosis of the detected mass is done by aspiration histology using a 21G needle with ultrasound guidance. Recent new imaging modalities such as contrast enhanced ultrasound using CO2 microbubbles or CTAP are not so reliable as aspiration histology, especially in tumors less than 15 mm in diameter.
The effect of ursodeoxycholic acid on liver function tests and on bile acid metabolism was investigated in a multi-center randomized controlled dose study for chronic hepatitis C. Twenty, 18 and 19 patients were administered 150, 600 and 900 mg/day, respectively of ursodeoxycholic acid every day for 16 wk. Serum liver parameters and bile acid composition in the treatment groups were compared with 17 control patients. A similarly significant decrease of serum alanine aminotransferase and serum gamma-glutamyltransferase was observed in patients administered 600 and 900 mg of ursodeoxycholic acid. Serum bile acid composition was determined by high-performance liquid chromatography. At entry, the relative proportions of major bile acids were similar to those observed in normal individuals. Maximal concentrations of total ursodeoxycholic acid were 0.30 mumol/L, 5.59 mumol/L, 21.42 mumol/L and 14.73 mumol/L in the control, 150, 600 and 900 mg/day groups, respectively. The fraction of the total ursodeoxycholic acid increased in a dose-dependent manner, and it was significantly higher than in controls (p < 0.001). The hydrophobicity index of bile acids was calculated by the method of Heuman, and its correlation with serum parameter levels was analyzed. In the 600 and 900 mg/day dose groups, serum alanine aminotransferase decreased in the cases in which hydrophobicity index significantly decreased during treatment. The same correlation was observed between the hydrophobicity index and serum gamma = glutamyltransferase in these two groups. There was no correlation between these parameters in the control and 150-mg groups. There was no correlation between reduction rate of serum alanine aminotransferase and initial liver histology.(ABSTRACT TRUNCATED AT 250 WORDS)
We performed periodical examinations by ultrasonography (US) and serum alpha-fetoprotein in 272 patients with liver cirrhosis (male, 167; female, 105) over long follow-up periods (1985. 1-1992.9). The average period was 1934 days, and we prospectively studied the early detection of hepatocellular carcinoma (HCC). HCC was detected in 78 patients during the periods, with the average cumulative incidence rate being per year 7%. Tumor size at detection was 15mm or less in diameter in 37.2% HCC patients and 30mm or less in 89.7%. In spite of frequent ultrasonic examinations, it was difficult to detect small sized HCCs in blind spots of US or in the liver with the rough parenchymal echo pattern. Predictive factors important for development of HCC were analyzed using Cox's proportional hazards model. It showed that significant factors were serum AFP level, liver parenchymal echo pattern and small mass lesions (ultrasonic appearance) of the liver.
Seventy-one patients with untreated hepatocellular carcinoma (111 tumors) were studied angiographically to investigate the pathological features of multiple carcinoma. The 111 tumors comprised 23 lesions resected from 14 patients and 88 lesions measuring 3 cm or less in diameter detected in 57 patients who did not undergo resection. Hemodynamically, major lesions exhibited an increase in frequency of tumor angiogenesis and intensity of tumor stain with an increase in diameter. Analysis of angiographic features of tumors measuring 2 cm or less in diameter revealed a greater vascularity in intrahepatic metastatic foci than in primary foci, demonstrating a difference between them. When multiple tumors were classified into the isolated, concentric or disseminated type in terms of the pattern of their distribution, their angiographic findings suggested that min or lesions of the concentric or disseminated type might represent local metastases spread from the primary focus, and that those of the isolated type might represent multicentric occurrence in the liver.
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The clinicopathological characteristics of the diffuse gastric mucosal redness were studied in 235 patients with liver cirrhosis. Moreover, in 96 patients in whom percutaneous transhepatic portal catheterization was carried out, the relationship was studied between gastric mucosal lesions and portal hemodynamic aspect with reference to portal vein pressure and extrahepatic collaterals. Extrahepatic collaterals were divided into three groups, which related either of cephalad, caudal and peri-abdominal as the most prevalent extrahepatic collateral on portographic findings. The frequency of the diffuse gastric mucosal redness was increased with the elevation of portal vein pressure, and it was seen more frequently in patients with cephalad collaterals than in caudal. However, the diffuse gastric mucosal redness was seen less frequently in patients with cephalad collateral accompanied with the development of renal shunts. Multiple logistic model analysis showed significant correlation between the diffuse gastric mucosal redness and the development of cephalad collaterals. These results suggest that the gastric mucosal circulation in liver cirrhosis is strongly affected by the development of portosystemic collaterals in portal hypertension.
Percutaneous ethanol injection (PEI) was performed on 183 tumors in 147 patients with small hepatocellular carcinoma (HCC), of no larger than 3 cm in size and less than three in number, during 9 years and 4 months between August 1983 and December 1992. The 1-, 3- and 5-year survival rates of all 147 patients calculated by the Kaplan-Meier method were 96.3%, 62.5% and 40.7% respectively. Multivariate analysis (Cox's proportional hazard model) demonstrated that the most significant factor contributing to the prognosis of the patients was the severity of liver dysfunction (clinical stage) before treatment. Recurrence was seen in different areas of the liver from the original lesion in 26.9% in one year and 61.5% in three years. Multivariate analysis demonstrated that the most significant factor contributing to the recurrence was the number of tumors before treatment. Regrowth of the original tumor occurred in two patients (1.4%). There was no serious complication due to PEI. To evaluate the therapeutic effect of PEI, contrast-enhanced CT with intravenous bolus injection was considered to be indispensable. We conclude that PEI can be indicated in most patients with small HCC and is also effective.
Ultrasound is now widely used in the diagnosis of liver diseases. Applications of ultrasound in the diagnosis of liver cirrhosis are reviewed in this paper. Characteristic findings of liver cirrhosis in ultrasound are nodular liver surface, round edge, and hypoechoic nodules in liver parenchyma which represent regenerative nodules of cirrhotic liver. Detection of hypoechoic nodule more than 10 mm is important in the early diagnosis of hepatocellular carcinoma. Detection of splenomegaly, ascites, and portosystemic collaterals is possible by ultrasound. Evaluation of portosystemic collaterals is beneficial in the management of esophagogastric varices and portosystemic encephalopathy. Ultrasound is useful in the non-invasive diagnosis and long-term management of cirrhotic patients.
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BACKGROUND: p53 gene mutations at codon 249 have been reported in hepatocellular carcinoma (HCC) from China and South Africa, a phenomenon shown to be closely associated with food contamination by aflatoxin. There have been few reports, however, in regard to p53 gene mutations in HCC from other geographic areas. METHODS: The authors analyzed 20 HCC from Japan for alteration of the p53 gene by restriction fragment length polymorphisms and for nucleic acid mutations by polymerase chain reaction with direct sequencing. RESULTS: Alterations associated with the p53 gene were found in 6 of 20 HCC (30%). Allelic loss of chromosome 17p occurred in 5 of 14 informative (heterozygous) cases (36%). Mutations in the p53 gene were detected in three cases (15%), at codons 176 (exon 5), 236 (exon 7), and 294 (exon 8). These cases were different from the HCC cases from China and South Africa, where point mutations in the p53 gene were reported at the same codon 249 in half of the cases and where aflatoxin food contamination and hepatitis B virus infection are recognized risk factors of HCC. No p53 gene alterations were found in smaller HCC (< 3 cm) or at earlier stages. CONCLUSIONS: In Japan, p53 gene alterations seem to be a late event in the progression of hepatocarcinogenesis, which is often associated with persistent infection by the hepatitis C or B virus, but not usually with exposure to aflatoxin.
Pancreatic adenocarcinomas are known to have a high incidence of K-ras gene mutations. Differential diagnosis of pancreatic cancer and chronic pancreatitis sometimes presents a clinical dilemma. We recently developed a highly sensitive and specific polymerase chain reaction capable of detecting 3-30 copies of mutant K-ras genes harboring codon 12 single base changes in the presence of 300,000 normal copies. Mutant ras genes were detected in DNA purified from pancreatic juice from all 6 cases of pancreatic adenocarcinoma and 1 case of intraductal papillary neoplasms of the pancreas. In 2 of 6 other cases with pancreatic adenocarcinoma, circulating metastatic cells were detected in DNA purified from peripheral blood. Activated ras genes were not found in pancreatic juice of three control cases (chronic pancreatitis and choledocholithiasis) or in the peripheral blood of two patients with insulinomas. Notable conclusions of this study are that there can be significant levels of shed tumor cells in peripheral blood and an even higher number in pancreatic juice. In addition, two different K-ras mutations were found in some patients.
The presence of hepatitis C virus RNA was examined in the sera of 32 patients with acute non-A, non-B hepatitis. Hepatitis C virus RNA was extracted from serum, reverse transcribed to cDNA and amplified by two rounds of polymerase chain reaction. Hepatitis C virus RNA was detected in all patients who developed anti-C100-3 as well as 79% who did not. These data suggest that hepatitis C virus accounts for most cases of acute non-A, non-B hepatitis whether anti-C100-3-positive or not. In addition, hepatitis C virus RNA was detected in the earliest serum samples, 9 +/- 11 weeks before anti-C100-3, and thus may be valuable as a diagnostic marker for acute hepatitis C.
To elucidate the temporal relationship between liver damage and mutation(s) in hepatitis B virus core gene, serial sera from a progressive liver disease patient and an asymptomatic carrier were studied. By direct sequencing, missense mutations in the core gene were only found in serum from the progressive liver disease patient during the period with frequent exacerbation. Using methods of cloning and sequencing, missense mutations were also found in clones derived from the progressive liver disease patient at a relatively early phase, but strains with a missense mutation from earlier sera did not exist in sera of a later period. Furthermore, there was a tendency of concentrating missense mutations in clones derived from the progressive liver disease patient. These data suggested that missense mutations in the core gene that occurred at an earlier phase might evoke an immune response to eliminate mutated virus and that concentrating missense mutations during a phase of exacerbation might be a result of adaptive mutation.
Putative hepatitis C virus core sequence was amplified from a serum sample positive for anti-C-100-3 and expressed in Escherichia coli. Approximately 62 kDa fusion protein with maltose binding protein containing 20 kDa hepatitis C core protein was obtained. The antibody to this protein was detected in 53 of 54 (98%) sera from hepatitis C virus ribonucleic acid-positive patients including 40 sera positive for anti-C-100-3 and 13 sera negative for anti-C-100-3. The antibody was also detected in all of 12 patients with acute hepatitis C showing the earlier detectability of the antibody than anti-C-100-3. Thus, the protein expressed from the amplified hepatitis C core sequence by the polymerase chain reaction would be useful for the diagnosis of hepatitis C.
Putative hepatitis C virus E2 protein was applied for detection of anti-E2 antibody in patients with type C hepatitis. The Putative E2 sequence was expressed in E. coli and approximately 38 KDa hepatitis C E2 protein fused with 42 KDa maltose binding protein was obtained. The HCV E2 antibody was detected in 2 of 7 acute hepatitis cases, in 8 of 12 chronic persistent hepatitis, in 17 of 25 chronic active hepatitis, and in 2 of 4 cirrhosis. It was not detected in 10 normal subjects. Anti-E2 antibody became undetectable after successful interferon treatment in patients with type C hepatitis. The High detection rate of E2 antibody in chronic hepatitis C and disappearance of the antibody after the interferon treatment indicate that the E2 antibody is related to viral replication and is unlikely to be a neutralizing antibody.
Since November 1989, the Japan Red Cross has been screening blood donors for hepatitis C virus antibody (anti-HCV) with 1st generation assay and high-titer antibody to hepatitis B virus core antigen (HBcAb). To clarify the effectiveness of the new screening tests for the prevention of post-transfusion hepatitis, the incidence of post-transfusion hepatitis after the introduction of new tests (December 1989 to September 1990) was compared with the incidence before the in introduction (January 1982 to December 1987). The incidence of "definite" post-transfusion hepatitis was 10.3% (205/1991) with a mean transfusion volume of 10.2 units before the screening, and 3.9% (11/282) with a mean transfusion volume of 14.6 units after the introduction of the new screening tests. Statistical analysis revealed a significant decrease of post-transfusion non-A, non-B hepatitis after the introduction of new tests (chi 2 = 10.9, P < 0.01). The incidence of "probable" post-transfusion hepatitis was 12.4% (246/1991) and 11.7% (33/282) respectively. No significant change was observed between the rates of "probable" post-transfusion hepatitis before and after the introduction of the new tests. It was concluded that anti-HCV and high-titer anti-HBc screening of volunteer blood donors could contribute to the prevention of the post-transfusion non-A, non-B hepatitis in Japan.
To assess the effects of interferon treatment on chronic hepatitis C, histological changes long after treatment were compared with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. Twenty one histologically proven chronic hepatitis C patients received alpha-interferon, 3 million units 3 times weekly for 12 months. Hepatitis C virus RNA was detected by reverse transcription/polymerase chain reaction method. Follow-up liver biopsies were performed 3 to 5 years after treatment. Fourteen of 21 (67%) patients showed normal aminotransferases for 3 to 5 years after treatment. HCV RNA seroconversion was observed in 12 of these patients. These responders showed improvement in histological activity indices and in histological findings. Two patients improved from chronic active hepatitis 2a to nonspecific changes, 1 from chronic active hepatitis 2a to portal fibrosis, 1 from chronic active hepatitis 2a to chronic persistent hepatitis and 1 from chronic active hepatitis 2b to chronic persistent hepatitis. Histological improvement of the liver correlated well with normalization of aminotransferases and seroconversion of hepatitis C virus RNA. These data indicate that complete histological resolution of chronic hepatitis C can be achieved by elimination of the virus with interferon treatment.