Malignant Peripheral Nerve Sheath Tumor of the Liver.

Malignant peripheral nerve sheath tumor (MPNST) of the liver is rare. Most cases of MPNST are accompanied by neurofibromatosis 1 (NF-1, von Recklinghausen's disease). We herein report an autopsy case of MPNST without NF-1 and review the pertinent literature. The tumor occupied the entire lobe of the liver, and was 18 cm in maximum diameter. The tumor revealed necrosis and cystic changes with hemorrhage and it had also metastasized to the peritoneum. Microscopically, the tumor was composed of pleomorphic spindle cells with hyperchromatic nuclei and mitogenic figures. The spindle cells stained positive for both S-100 and vimentin antibodies.

Familial clustering and genetic background of primary biliary cirrhosis in Japan.

BACKGROUND: Primary biliary cirrhosis (PBC) is regarded as an autoimmune liver disease and familial clustering of PBC could represent some genetic predisposition to the disease. AIMS: To elucidate the genetic background of PBC by investigating familial cases of PBC. METHODS: Familial cases were picked out from 171 PBC patients who enrolled in this study. We analyzed them and their family members, and compared them clinically and immunogenetically to non-familial cases. RESULTS: Out of 171 PBC patients, ten (5.8%) were identified as familial PBC in five families. The clinical features of familial PBC were almost comparable to those of non-familial PBC. The distribution of human leukocyte antigens (HLA)-A, -B and -DR in familial PBC showed no specificity. Two new PBC patients were identified in one family in addition to the two originally enrolled PBC patients, resulting in four patients with PBC within the same family. The two new PBC patients had an identical HLA haplotype. On the other hand, one HLA-identical sister of a PBC patient in another family did not develop PBC. CONCLUSIONS: Primary biliary cirrhosis can exhibit familial clustering without any HLA predisposition, however, a survey of families for PBC could be useful for identifying new patients with PBC in the asymptomatic stage for earlier diagnosis and treatment.

Overexpression of NK2 promotes liver fibrosis in carbon tetrachloride-induced chronic liver injury.

BACKGROUND/AIMS: Hepatocyte growth factor (HGF) inhibits liver fibrosis induced by carbon tetrachloride (CCl4) in animal models. NK2 is a natural splice variant of HGF, but its in vivo function remains to be elucidated. We investigated the in vivo effects of NK2 on CCl4-induced liver fibrosis. METHODS: NK2 transgenic mice and wild-type (WT) mice were injected intraperitoneally with CCl4 twice a week. The extent of hepatic fibrosis was evaluated by Azan-Mallory staining. Expression levels of mRNAs of transforming growth factor-beta1 (TGF-beta1) and matrix metalloproteinase-13 (MMP-13) were examined by real-time polymerase chain reaction. The protein levels of alpha-smooth muscle actin (alpha-SMA), c-Met and its phosphorylation were determined by Western blot analysis. RESULTS: Liver fibrosis was significantly more severe in NK2 transgenic mice than in WT mice. CCl4 administration increased the expression levels of TGF-beta1 mRNA and alpha-SMA protein, and decreased the expression of MMP-13 mRNA in livers of NK2 transgenic mice compared with those of WT mice. c-Met protein expression in the liver was compatible with the degree of fibrosis. As for c-Met activation, no difference was found between NK2 and WT livers. CONCLUSION: Overexpression of NK2 acts as an antagonist of HGF and promotes liver fibrosis in CCl4-induced chronic liver injury.

Hepatocellular carcinoma with peritoneal dissemination which was regressed during vitamin K2 and vitamin E administration.

A 65-year-old man with positive anti-hepatitis C antibody and chronic renal failure was diagnosed as having a ruptured hepatocellular carcinoma (HCC) based on computed tomography (CT). The patient underwent transcatheter arterial embolization (TAE) for the HCC. After one more session of TAE, the patient underwent surgery. But HCC seeding peritoneally was pointed out. Vitamin K2 and vitamin E were administered as a conservative treatment. Six months after starting vitamins K2 and E, the primary tumor did not increase in size and intraperitoneal dissemination disappeared on CT with a significant decrease of alpha-fetoprotein. Even though this is only one case, combination therapy of vitamin K2 and E may induce growth suppression of HCC.

Preventive effects of vitamin K on recurrent disease in patients with hepatocellular carcinoma arising from hepatitis C viral infection.

BACKGROUND: Despite the progression of therapeutic approaches, a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma (HCC). In this study, the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated. METHODS: Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were randomly assigned to either the vitamin K2 group (n = 30 patients) or the control group (n = 30 patients). All patients were positive for the hepatitis C virus (HCV) antibody and hepatitis B surface antigen positive patients were excluded from this study. Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day. Disease recurrence and the survival rates were analyzed in patients with HCC. RESULTS: The cumulative recurrence-free rates in the vitamin K2 group were 92.3% at 12 months, 48.6% at 24 months and 38.8% at 36 months; and those in the control group were 71.7%, 35.9% and 9.9%, respectively (P = 0.045). The cumulative survival rates in the vitamin K2 group were 100% at 12 months, 95.0% at 24 months and 77.5% at 36 months; and those in the control group were 95.8%, 90.2% and 66.4%, respectively (P = 0.70). CONCLUSIONS: Vitamin K2 may have a suppressive effect on the recurrence of HCC and a beneficial effect on tumor recurrence. However, there was no significant difference in the survival rates. The chemopreventive effects of vitamin K2 are not sufficient. The development of a further regimen such as combination therapy is required.

HGF ameliorates a high-fat diet-induced fatty liver.

Hepatocyte growth factor (HGF) has various effects especially on epithelial cells. However, the precise role of HGF on lipogenesis is still not fully understood. A high-fat diet was administered to HGF transgenic mice and wild-type control mice in vivo. Furthermore, recombinant human HGF (rhHGF) was administered to HepG2 cell line in vitro. We performed an analysis regarding the factors relating to lipid metabolism. An overexpression of HGF dramatically ameliorates a high-fat diet-induced fatty liver. HGF transgenic mice showed an apparently reduced lipid accumulation in the liver. The activation of microsomal triglyceride transfer protein (MTP) and apolipoprotein B (ApoB) accompanying higher triglyceride levels in the serum were found in HGF transgenic mice on a normal diet. Interestingly, this upregulation of the MTP activation became more apparent in the high-fat diet. In addition, the administration of rhHGF stimulated MTP and ApoB expression while reducing reduced the intracellular lipid content in HepG2 cell line. However, this induction of MTP and ApoB by HGF was clearly inhibited by PD98059 (MAPK inhibitor). In conclusion, the data presented in this study indicated that HGF ameliorates a high-fat diet-induced fatty liver via the activation of MTP and ApoB.

Lack of macrophage migration inhibitory factor protects mice against concanavalin A-induced liver injury.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in inflammatory and immune-mediated diseases but the role of MIF in liver injury has not yet been elucidated. METHODS: We investigated biochemically, histologically and immunologically the character of MIF in concanavalin A (Con A)-induced T-cell-mediated liver injury using MIF knockout (KO) mice and wild-type (WT) mice. RESULTS: MIF KO mice showed significantly decreased serum alanine aminotransferase values and suppressed histological change with massive necrosis of the hepatic parenchymal cells and infiltration of inflammatory cells compared with their WT counterparts. This protection was not mediated by either tumor necrosis factor-alpha or interferon-gamma, which are critical mediators of Con A-induced liver injury, as their serum concentrations were shown to be similar in MIF KO and WT mice. On the other hand, a flow cytometric analysis demonstrated that the number of activated hepatic leukocytes decreased more in the MIF KO mice than in the WT mice. CONCLUSIONS: A lack of MIF protected the mice from Con A-induced liver injury. Controlling the MIF activity may be a useful therapeutic strategy for treating such T-cell activation-associated liver diseases as autoimmune hepatitis and viral hepatitis.

Randomized controlled trial of consensus interferon with or without zinc for chronic hepatitis C patients with genotype 2.

AIM: The beneficial effect of zinc supplementation on the efficacy of interferon as a treatment for chronic hepatitis C had been demonstrated in hepatitis virus genotype 1b of high viral load. This study focused on patients with genotype 2, which is more sensitive to interferon than genotype 1b, and used consensus interferon (CIFN) with or without zinc. METHODS: We randomized 83 patients with chronic hepatitis C to CIFN at 18 MIU six times/wk for 4 wk, followed by CIFN at 18 MIU six times/wk for another 20 wk, in combination with polaprezinc 300 mg (regimen A, n=41) or as monotherapy (regimen B, n=42). Thirty-one patients in regimen A and 33 patients in regimen B completed the clinical trial; the remaining patients withdrew because of side effects or a transfer to another hospital. RESULTS: Sustained biochemical response, defined as a normal aminotransferase level at the end of the 6-mo post-treatment observation, was 68% and 69%, and sustained virological response, defined as undetectable HCV-RNA at the end of the 6-mo post-treatment observation, was 54% and 67% for regimens A and B, respectively. CONCLUSION: CIFN treatment combined with zinc did not enhance the effect of CIFN as shown by biochemical, virological criteria. No side effects related to polaprezinc were noted.

Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival.

AIM: To identify the clinical and prognostic features of patients with hepatocellular carcinoma (HCC) aged 80 years or more. METHODS: A total of 1310 patients with HCC were included in this study. Ninety-one patients aged 80 years or more at the time of diagnosis of HCC were defined as the extremely elderly group. Two hundred and thirty-four patients aged > or = 50 years but less than 60 years were regarded as the non-elderly group. RESULTS: The sex ratio (male to female) was significantly lower in the extremely elderly group (0.90:1) than in the non-elderly group (3.9:1, P < 0.001). The positive rate for HBsAg was significantly lower in the extremely elderly group and the proportion of patients negative for HBsAg and HCVAb obviously increased in the extremely elderly group (P < 0.001). There were no significant differences in the following parameters: diameter and number of tumors, Child-Pugh grading, tumor staging, presence of portal thrombosis or ascites, and positive rate for HCVAb. Extremely elderly patients did not often receive surgical treatment (P < 0.001) and they were more likely to receive conservative treatment (P < 0.01). There were no significant differences in survival curves based on the Kaplan-Meier methods in comparison with the overall patients between the two groups. However, the survival curves were significantly worse in the extremely elderly patients with stage I/II, stage I/II and Child-Pugh grade A cirrhosis in comparison with the non-elderly group. The causes of death did not differ among the patients, and most cases died of liver-related diseases even in the extremely elderly patients. CONCLUSION: In the patients with good liver functions and good performance status, aggressive treatment for HCC might improve the survival rate, even in the extremely elderly patients.

Long-term outcome of interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C.

BACKGROUND: Autoimmune thyroid disorders are among the well-known adverse effects of interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis C. However, there are few reports regarding the long-term outcome of this complication. We aimed to evaluate the natural history of IFN-alpha-induced autoimmune thyroid disorders with long-term follow-up. METHODS: Four hundred and thirty-nine patients with chronic hepatitis C were treated with IFN-alpha for 24 weeks between March 1993 and April 1998. Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders including nine cases of hyperthyroidism and eight cases of hypothyroidism. The patients with hypothyroidism were all women. These 17 patients were followed up for 71.1 +/- 17.8 months (48-120 months) and were evaluated for long-term outcome. RESULTS: Eight patients could discontinue the thyroid medication (2-36 months, median 10 months). Nine patients needed the thyroid medication at the follow-up period. The patients with hyperthyroidism who needed long-term thyroid medication had a significantly high titer of TSH receptor antibody on onset compared with the patients who could discontinue the thyroid medication. There were no significant differences in age, type of IFN, duration from IFN administration to onset, cessation of IFN, genotype of hepatitis C virus and thyroid hormone levels on onset between the patients who needed long-term thyroid medication and the patients who could discontinue the thyroid medication. CONCLUSION: All patients with IFN-alpha-induced thyroid disorders could be controlled with medication. However, the IFN-alpha-induced thyroid disorders are not always reversible. One must be careful about not only the development of autoimmune thyroid disorders during IFN-alpha therapy but also the outcome of the thyroid disease.

Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice.

AIM: To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy (PH). METHODS: Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type (WT) mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. Kaplan-Meier method and the log-rank test were used for analyzing the survival after PH. Differences in the results of immunohistochemistry and percentage of liver regeneration was determined by the Student's t-test. RESULTS: More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) in liver tissues were prolonged in NK2 transgenic mice that died after PH. CONCLUSION: Our findings indicate that over-expression of NK2 inhibits liver regeneration after PH.

Metastasis of hepatocellular carcinoma to the supramaxillary gingiva and right ventricle.

We describe a rare double metastasis of hepatocellular carcinoma to the supramaxillary gingiva and papillary muscle of the right ventricle. The patient was a 72-year-old woman who underwent three sessions of transcatheter arterial embolization for the primary lesions. Control of bleeding from the supramaxillary gingival metastasis was difficult by conservative treatment such as compression with gauze soaked in epinephrine. Therefore, radiotherapy was performed, but it failed to control the bleeding. The patient subsequently died due to hepatic failure. Autopsy revealed metastases of hepatocellular carcinoma to the papillary muscle of the right ventricle and paraaortic lymph node in the abdomen in addition to the supramaxillary gingival metastasis. Histopathological examination showed moderately differentiated hepatocellular carcinoma of both the primary site and metastatic sites to the gingiva and the heart and poorly differentiated in the paraaortic lymph node.

CCl4-induced acute liver injury in mice is inhibited by hepatocyte growth factor overexpression but stimulated by NK2 overexpression.

Hepatocyte growth factor (HGF) inhibits acute liver injury. NK2 acts as an antagonist to HGF in vitro, but its in vivo function has reached no consensus conclusions. We have investigated in vivo effects of HGF and NK2 on CCl4-induced acute liver injury. Elevation of the serum alanine aminotransferase level and extension of centrilobular necrosis were inhibited in HGF transgenic mice but were promoted in NK2 transgenic mice. Hepatocyte proliferation after liver injury was not inhibited in NK2 transgenic mice. Thus, this study indicates that HGF inhibits liver injury, and NK2 antagonizes HGF on liver injury, however, NK2 may not antagonize HGF on hepatocyte proliferation.

Early diagnosis and radical surgical treatment of Budd-Chiari syndrome.

We report a 26-year-old woman who was diagnosed with Budd-Chiari syndrome following consultation for a skin nodule in the lower extremity. Histopathological examination of a biopsy specimen showed features of erythema induratum. As part of the diagnostic work-up, chest roentgenography performed to rule out possible tuberculosis showed enlarged right lower mediastinum. Computed tomography identified a dilated azygos vein and obstruction of the inferior vena cava near the liver. Liver function tests and blood cell counts were all within normal limit and no sign of portal hypertension was noted except for mild splenomegaly. Although angioplasty by balloon catheter resulted in recanalization of the obstructed inferior vena cava, obstruction of the inferior vena cava appeared again 2 months later. One-stage surgical reconstruction of the vascular abnormalities affecting inferior vena cava and hepatic vein using autologous pericardial patch was performed 11 months after angioplasty, which resulted in normalization of blood flow. Examination of a liver biopsy obtained intraoperatively revealed hepatic fibrosis compatible with early-stage Budd-Chiari syndrome. No complications were noted postoperatively and the nodular lesion in the lower extremity disappeared after surgery.

Synergism between INK4a/ARF inactivation and aberrant HGF/SF signaling in rhabdomyosarcomagenesis.

Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in children, yet molecular events associated with the genesis and progression of this potentially fatal disease are largely unknown. For the molecules and pathways that have been implicated, genetic validation has been impeded by lack of a mouse model of RMS. Here we show that simultaneous loss of Ink4a/Arf function and disruption of c-Met signaling in Ink4a/Arf(-/-) mice transgenic for hepatocyte growth factor/scatter factor (HGF/SF) induces RMS with extremely high penetrance and short latency. In cultured myoblasts, c-Met activation and Ink4a/Arf loss suppress myogenesis in an additive fashion. Our data indicate that human c-MET and INK4a/ARF, situated at the nexus of pathways regulating myogenic growth and differentiation, represent critical targets in RMS pathogenesis. The marked synergism in mice between aberrant c-Met signaling and Ink4a/Arf inactivation, lesions individually implicated in human RMS, suggests a therapeutic combination to combat this devastating childhood cancer.

Severe manifestation of acute hepatitis A recently found in Gunma, Japan.

BACKGROUND: The incidence of acute hepatitis A infection in Japan peaked 10 years ago and has been decreasing since then. However, an increase in severe cases of the disease has been documented recently. We experienced an outbreak in 1998-1999, and compared the clinical features of the disease in 1998-1999 (recent outbreak) and in 1987-1988 (past outbreak) in our prefecture (Gunma). METHODS: Forty patients with acute hepatitis A were admitted to nine Gunma hospitals from October 1998 to September 1999. Their clinical features were compared with those of 100 patients with acute hepatitis A admitted to the same hospitals in 1987-1988. RESULTS: Both outbreaks occurred mostly during the winter-spring season. Secondary familial infection was significantly decreased in the recent outbreak. Patients in the recent outbreak were 7 years older than those in the past outbreak. Laboratory findings, such as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels and prothrombin time, were worse in the recent than in the past outbreak. Severe-type hepatitis and fulminant hepatitis occurred in 5 patients (12.5%) in the recent outbreak but in only 2 patients (2.0%) in the past outbreak. CONCLUSIONS: Clinical data and manifestations were more severe in the recent outbreak than in the past outbreak of acute hepatitis A. It is important to be aware of hepatitis A virus infection and to take into account the available vaccination against hepatitis A virus in Japan.

Transforming growth factor alpha protects against Fas-mediated liver apoptosis in mice.

The Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti-Fas antibody to mice causes massive hepatic apoptosis and fulminant hepatic failure. Several growth factors have recently been found to function in preventing apoptosis. In this study, we demonstrated that overexpression of transforming growth factor alpha (TGFalpha) has a dramatic protective effect on Fas-mediated hepatic apoptosis at the biochemical and histological levels. Moreover, 85.7% (six out of seven) of TGFalpha transgenic mice survived the lethal liver damage, whereas all wild-type mice died. Expression of Bcl-xL, an anti-apoptotic protein, was greatly increased in the transgenic mice. Taken together, our findings suggest that TGFalpha protects against Fas-mediated liver apoptosis in vivo and up-regulation of Bcl-xL may participate in protective effect of TGFalpha.