Masaaki Masuhara

Augmenter of liver regeneration (ALR) may promote liver regeneration by reducing natural killer (NK) cell activity in human liver diseases.

Abstract: Cytotoxicity of liver natural killer cells against regenerating hepatocytes has been reported as a possible mechanism of regeneration failure in fulminant hepatitis. An augmenter of liver regeneration (ALR) inhibits liver natural killer cell activity in rats. In this study, we measured hepatic expression of ALR mRNA, blood levels of ALR, and peripheral blood natural killer cell activity in patients with various types of acute liver disease to investigate the relationship between failure of liver regeneration and hepatic natural killer cells. Hepatic ALR mRNA expression was higher in liver disease patients than in non-liver disease controls, and a correlation was found between serum ALR values and hepatic levels of ALR mRNA. In acute liver injury, the serum ALR level also showed a negative correlation with NK activity. ALR was produced by and released from the liver at the time of hepatic injury. Our findings suggest that ALR may protect against failure of regeneration by inhibition of hepatic natural killer cell activity in acute liver injury.

Novel arterial infusion chemotherapy using cisplatin, 5-fluorouracil, and leucovorin for patients with advanced hepatocellular carcinoma

Advanced hepatocelluar carcinoma (HCC) has a poor prognosis. In this study, the authors evaluated the efficacy of chemotherapy using cisplatin (CDDP), 5-fluorouracil (5-FU), and leucovorin (LV), comparing our regimen with chemotherapy using CDDP and 5-FU. Nineteen patients with advanced HCC were treated by arterial infusion of a chemotherapeutic agent via a subcutaneously implanted injection port. In Group A (n=9), one course of chemotherapy consisted of the daily administration of CDDP (10 mg/1 h, on 5 days) and LV (12 mg/10 min, on 5 days) followed by 5-FU (250 mg/5 h, on 5 days). In Group B (n=10), except for the administration of LV, the same regimen was employed. This course was repeated each week for 4 weeks. In Group A, two patients showed a complete response (CR), and the other three showed a partial response (PR). In Group B, two patients showed PR. The response rate (CR+PR/all cases) in Group A was significantly higher than that in Group B (56 vs. 20%; P=0.022). The 1- and 2-year survival rates of Group A (66.7, 44.4%) were significantly higher than those of Group B (10, 0%) (P=0.033). These results suggest that our regimen may be useful in treating patients with advanced HCC.

Expression of hepatocyte growth factor and transforming growth factor β1 mRNA inP. acnes and lipopolysaccharide-treated rats

Hepatocyte growth factor (HGF), a potent hepatocyte mitogen in vitro, triggers hepatocyte regeneration after partial hepatectomy and acute liver cell necrosis induced by chemicals. In contrast, tranforming growth factor β1 inhibits hepatocyte proliferation in vitro and suppresses liver regeneration in vivo. We assessed the expression of HGF and TGF β1 mRNA in an endotoxin-related hepatic cell necrosis model. Intravenous injection of Gram-negative lipopolysaccharide (LPS) into rats previously given heat-killedPropionibacterium acnes induced endotoxinrelated hepatic cell necrosis. In this model, serum ALT began to rise to more than 100 IU as early as 3 h after LPS injection, reaching 300 IU 12 h after injection. HGF mRNA levels in the liver did not increase significantly until 5 h after LPS injection; at 12 h, they had increased about threefold compared with controls. TGF ⨿1 mRNA expression increased threefold afterP. acnes treatment alone and increased further after LPS injection. In the spleen, HGF mRNA levels increased within 3 h, but in the lung no increase in HGF mRNA was observed. Early elevation of liver TGF β1 mRNA levels and delayed elevation of HGF mRNA levels, with low expression of HGF in the lung, may play a role in the pathogenesis of endotoxin-related hepatic necrosis.

Fulminant hepatitis complicated by small intestine infection and massive hemorrhage

Abstract: A 34-year-old man diagnosed with fulminant hepatitis, caused by hepatitis B virus, and acute renal failure was referred to our hospital. After admission to the intensive care unit, the liver and renal failure were ameliorated. Melena requiring transfusion occurred during the course of his illness. Endoscopic examination demonstrated pseudomembranes, erosions, ulcers, and hemorrhage in the duodenum, the upper jejunum, and the terminal ileum, suggesting widespread lesions throughout the small intestine. Pseudomonas putida, Xanthomonas maltophilia, and Candida glabrata were cultured from ileal fluid. Candida glabrata was also detected in sputum, feces, and on an intravenous catheter tip. The patient was treated with amphotericin B and miconazole. The melena was ameliorated, but inflammation of the small intestine persisted. Although we had difficulty in treating the enteritis, the patient survived, and 1 year later colonoscopic examination demonstrated no abnormalities. The small intestine is a difficult site to examine, but endoscopic examination of this site is important when massive hemorrhage develops.

HBV-related fulminant hepatic failure: successful intensive medical therapy in a candidate for liver transplantation

Fulminant hepatic failure (FHF) usually has a fatal prognosis without liver transplantation. We describe the case of a woman who developed FHF, and was evaluated as a candidate for liver transplantation, but who was cured without transplantation through intensive medical care that included glucagon-insulin therapy, methylprednisolone pulse therapy, interferon beta and lamivudine administration, cyclosporine administration, and high-volume hemodiafiltration and plasma exchange. In a patient with FHF who is a candidate for liver transplantation but for whom the transplantation cannot be performed for some reason, intensive medical therapy, including regeneration-promoting therapy, immunosuppressive therapy, antiviral therapy, and vigorous hepatic support, should be carried out.

Detection of hepatitis B virus DNA in liver by polymerase chain reaction for the diagnosis of fulminant hepatitis B

Abstract To assess the involvement of GB virus C (GBV-C) or hepatitis B virus (HBV) infection in fulminant hepatitis of unknown etiology, GBV-C RNA and HBV DNA in serum were retrospectively assayed by polymerase chain reaction (PCR) in six patients with fulminant hepatitis of unknown etiology (group A) and in three patients with fulminant hepatitis B (group B). Additionally, liver specimens were tested for both GBV-C RNA and HBV DNA in two patients and for only HBV DNA in another patient in group A. GBV-C RNA in serum and liver was not detected in any patient. HBV DNA in serum was detected only in patients in group B, while in liver it was detectable in three patients in group A. These results suggest that GBV-C infection is unlikely to be involved in fulminant hepatitis of unknown etiology and that the detection of HBV DNA in liver by PCR is useful for diagnosis of fulminant hepatitis B that shows no serologic evidence of the current infection.

High MDM2 mRNA expression in hepatoblastoma cell-lines

Abstract Both p53 and MDM2 genes are parts of a physiological pathway frequently impaired in human cancer. This is the report on the analysis of p53 and MDM2 genes in a group of four hepatocellular carcinoma cell-lines and one hepatoblastoma cell-line. Four cell-lines were screened for the presence of p53 mutations using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) method. Investigation of the MDM2 gene revealed neither gene amplification nor rearrangement in all cell-lines. However MDM2 mRNA in a hepatoblastoma cell line(HepG2) was elevated to about 2.4 times the level of normal human liver.