Clinical characteristics and prognosis of non-B non-C hepatocellular carcinoma patients with modest alcohol consumption.

AIM: Alcoholic hepatocellular carcinoma (ALD-HCC) accounts for the majority of non-B non-C HCC (NBNC-HCC) cases. Although alcohol is a potent carcinogen, there have been few reports on the influence of modest alcohol consumption in NBNC-HCC. This study aimed to investigate the clinical characteristics and prognosis of NBNC-HCC patients with modest alcohol consumption. METHODS: From 2007 to 2010, 2283 HCC patients were evaluated at 10 hospitals. We collected detailed etiology data of 588 NBNC-HCC patients and compared the clinical characteristics and prognosis between ALD-HCC and modest alcohol-HCC patients. RESULTS: There were 69 HCC patients with modest alcohol consumption, accounting for 3% of all HCC patients evaluated. This patient group had significantly more women and higher prevalence of Child-Pugh class A, hypertension and advanced disease stage, and were diagnosed with HCC at an older age than the ALD-HCC group (266 patients). Additionally, among the modest alcohol-HCC patients, diabetes was significantly more common in the anti-hepatitis B core (HBc) negative subgroup than in the anti-HBc positive subgroup. However, no significant difference in survival was observed between the two patient groups regardless of significant differences in tumor staging. Alcohol consumption and metabolic factors were not significant independent predictors of survival. CONCLUSION: The clinical characteristics of modest alcohol-HCC included advanced staging, favorable liver reserve capacity and older age at diagnosis. HCC development in patients with modest alcohol consumption may relate to metabolic factors. Although approximately 30% of the evaluated HCC cases were in advanced stages, the prognosis of NBNC-HCC patients with modest alcohol consumption was relatively favorable.

Outcomes of laparoscopic hepatic resection versus percutaneous radiofrequency ablation for hepatocellular carcinoma located at the liver surface: A case-control study with propensity score matching.

AIM: Percutaneous radiofrequency ablation (P-RFA) therapy is a widely applied treatment for small hepatocellular carcinoma (HCC); however, local recurrence is a major issue of HCC located at the surface of the liver (surface HCC). The aim of this study was to compare the outcome of laparoscopic hepatic resection (LH) and P-RFA for surface HCC in case-control patient groups using the propensity score. METHODS: Between 2011 and 2013, 40 and 52 patients underwent LH and P-RFA for surface HCC (≤3 cm, 1-3 nodules). To correct the difference in clinicopathological factors between the two groups, propensity score matching was used at a 1:1 ratio, which resulted in a comparison of 27 patients/group. We compared outcomes between the two groups, with special reference to local recurrence. RESULTS: Clinicopathological variables were well balanced between the two groups. One patient in the LH group was converted to open surgery due to adhesion. The incidence of complications was 0% in the P-RFA group and 15% (four patients) in the LH group (P = 0.11); however, none of these four patients in the LH group sustained severe complications. The duration of hospitalization following treatment was longer in the LH group than in the P-RFA group (12.6 vs 7.6 days, P < 0.01). The incidence of local recurrence was lower in the LH group (0%) than in the P-RFA group (eight patients [30%], P = 0.004). CONCLUSION: LH is an effective treatment for surface HCC with regard to control of local recurrence.

Positioning of 18F-fluorodeoxyglucose-positron emission tomography imaging in the management algorithm of hepatocellular carcinoma.

BACKGROUND AND AIM: (18) F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) may detect primary lesions (PLs) and extrahepatic metastases (EHMs) only in advanced hepatocellular carcinoma (HCC) patients. We investigated the requirement of PET and the optimal timing of PET scanning for accurate staging and treatment planning. METHODS: We conducted a retrospective investigation of 64 HCC patients who underwent PET (median age, 74 years; male/female, 41/23; etiology, 46 hepatitis C virus/4 hepatitis B virus/4 alcoholic/10 others). To determine the best timing for PET examinations, we analyzed PET result-based recommended treatment changes and characteristics of patients with FDG-avid PLs or EHMs. RESULTS: FDG-avid PLs were detected by PET in 22 patients (34%): 18 with hypervascular PL, 11 with serum α-fetoprotein levels ≥ 200 ng/mL, and 11 beyond Milan criteria. EHMs were detected in 21 patients (33%: lymph nodes, 8; lung, 5; abdominal wall, 4; bone, 3; other organs, 4 [including overlapping]). Recommended treatments changed for 16 patients (25%) because of Barcelona Clinic Liver Cancer stage increases based on PET scanning. In multivariate analyses, serum α-fetoprotein levels ≥ 200 ng/mL and beyond Milan criteria were independent factors for FDG-avid PLs and a maximum standardized uptake value (SUVmax) of PLs of ≥ 4.0 was an independent factor for FDG-avid EHMs (P = 0.002, 0.008, and 0.045, respectively). CONCLUSIONS: PET allows detection of HCC spread in patients with elevated serum α-fetoprotein levels or those beyond Milan criteria and detects EHMs in patients with PLs with high SUVmax values. Optimally timed PET scans can complement conventional imaging for accurate staging and treatment strategy determination.

Cytoglobin is expressed in hepatic stellate cells, but not in myofibroblasts, in normal and fibrotic human liver.

Cytoglobin (CYGB) is ubiquitously expressed in the cytoplasm of fibroblastic cells in many organs, including hepatic stellate cells. As yet, there is no specific marker with which to distinguish stellate cells from myofibroblasts in the human liver. To investigate whether CYGB can be utilized to distinguish hepatic stellate cells from myofibroblasts in normal and fibrotic human liver, human liver tissues damaged by infection with hepatitis C virus (HCV) and at different stages of fibrosis were obtained by liver biopsy. Immunohistochemistry was performed on histological sections of liver tissues using antibodies against CYGB, cellular retinol-binding protein-1 (CRBP-1), α-smooth muscle actin (α-SMA), thymocyte differentiation antigen 1 (Thy-1), and fibulin-2 (FBLN2). CYGB- and CRBP-1-positive cells were counted around fibrotic portal tracts in histological sections of the samples. The expression of several of the proteins listed above was examined in cultured mouse stellate cells. Quiescent stellate cells, but not portal myofibroblasts, expressed both CYGB and CRBP-1 in normal livers. In fibrotic and cirrhotic livers, stellate cells expressed both CYGB and α-SMA, whereas myofibroblasts around the portal vein expressed α-SMA, Thy-1, and FBLN2, but not CYGB. Development of the fibrotic stage was positively correlated with increases in Sirius red-stained, α-SMA-positive, and Thy-1-positive areas, whereas the number of CYGB- and CRBP-1-positive cells decreased with fibrosis development. Primary cultured mouse stellate cells expressed cytoplasmic CYGB at day 1, whereas they began to express α-SMA at the cellular margins at day 4. Thy-1 was undetectable throughout the culture period. In human liver tissues, quiescent stellate cells are CYGB positive. When activated, they also become α-SMA positive; however, they are negative for Thy-1 and FBLN2. Thus, CYGB is a useful marker with which to distinguish stellate cells from portal myofibroblasts in the damaged human liver.

A complete response induced by 21-day sorafenib therapy in a patient with advanced hepatocellular carcinoma.

The response rate and overall survival after sorafenib administration in patients with advanced hepatocellular carcinoma are unsatisfactory. We herein present the case of a 65-year-old man with multiple lung metastases of hepatocellular carcinoma. Because the patient had liver cirrhosis of Child-Pugh B accompanied by pancytopenia, sorafenib administration was initiated at a dose of 400 mg daily. Although he received sorafenib for only 21 days, the patient exhibited complete regression of the tumors. There was no clinical evidence of recurrence without the administration of anticancer treatment. It is unique that short-term sorafenib treatment achieved a complete response.

[Tumor lysis syndrome after transarterial embolization for hepatocellular carcinoma].

A man in his 70's was admitted to our hospital for treatment of a huge hepatocellular carcinoma (HCC) by transcatheter hepatic arterial embolization (TAE). After treatment, anuria occurred, and laboratory examinations revealed a diagnosis of tumor lysis syndrome (TLS). He underwent conservative therapy including hemodialysis, resulting in complete remission of TLS. On the other hand, poor hepatic functional reserve was seen temporarily. After conservative therapy, biochemical markers returned dramatically. TLS is a group of metabolic complications in cancer therapy. It may occur in highly sensitive tumors, resulting from a rapid release of cytoplasmic degradation products of malignant cells. Generally it is rare in the treatment of solid tumors. In the case of TAE for huge HCC, we should keep the possibility of TLS in mind.

Nutritional status in relation to lifestyle in patients with compensated viral cirrhosis.

AIM: To assess the nourishment status and lifestyle of non-hospitalized patients with compensated cirrhosis by using noninvasive methods. METHODS: The subjects for this study consisted of 27 healthy volunteers, 59 patients with chronic viral hepatitis, and 74 patients with viral cirrhosis, from urban areas. We assessed the biochemical blood tests, anthropometric parameters, diet, lifestyle and physical activity of the patients. A homeostasis model assessment-insulin resistance (HOMA-IR) value of ≥ 2.5 was considered to indicate insulin resistance. We measured height, weight, waist circumference, arm circumference, triceps skin-fold thickness, and handgrip strength, and calculated body mass index, arm muscle circumference (AMC), and arm muscle area (AMA). We interviewed the subjects about their dietary habits and lifestyle using health assessment computer software. We surveyed daily physical activity using a pedometer. Univariate and multivariate logistic regression modeling were used to identify the relevant factors for insulin resistance. RESULTS: The rate of patients with HOMA-IR ≥ 2.5 (which was considered to indicate insulin resistance) was 14 (35.9%) in the chronic hepatitis and 17 (37.8%) in the cirrhotic patients. AMC (%) (control vs chronic hepatitis, 111.9% ± 10.5% vs 104.9% ± 10.7%, P = 0.021; control vs cirrhosis, 111.9% ± 10.5% vs 102.7% ± 10.8%, P = 0.001) and AMA (%) (control vs chronic hepatitis, 128.2% ± 25.1% vs 112.2% ± 22.9%, P = 0.013; control vs cirrhosis, 128.2% ± 25.1% vs 107.5% ± 22.5%, P = 0.001) in patients with chronic hepatitis and liver cirrhosis were significantly lower than in the control subjects. Handgrip strength (%) in the cirrhosis group was significantly lower than in the controls (control vs cirrhosis, 92.1% ± 16.2% vs 66.9% ± 17.6%, P < 0.001). The results might reflect a decrease in muscle mass. The total nutrition intake and amounts of carbohydrates, protein and fat were not significantly different amongst the groups. Physical activity levels (kcal/d) (control vs cirrhosis, 210 ± 113 kcal/d vs 125 ± 74 kcal/d, P = 0.001), number of steps (step/d) (control vs cirrhosis, 8070 ± 3027 step/d vs 5789 ± 3368 step/d, P = 0.011), and exercise (Ex) (Ex/wk) (control vs cirrhosis, 12.4 ± 9.3 Ex/wk vs 7.0 ± 7.7 Ex/wk, P = 0.013) in the cirrhosis group was significantly lower than the control group. The results indicate that the physical activity level of the chronic hepatitis and cirrhosis groups were low. Univariate and multivariate logistic regression modeling suggested that Ex was associated with insulin resistance (odds ratio, 6.809; 95% CI, 1.288-36.001; P = 0.024). The results seem to point towards decreased physical activity being a relevant factor for insulin resistance. CONCLUSION: Non-hospitalized cirrhotic patients may need to maintain an adequate dietary intake and receive lifestyle guidance to increase their physical activity levels.

Benefits of artificially induced pleural effusion and/or ascites for percutaneous radiofrequency ablation of hepatocellular carcinoma located on the liver surface and in the hepatic dome.

BACKGROUND/AIMS: Radiofrequency ablation (RFA) with artificial pleural effusion and/or artificial ascites has recently been recognized as a useful device for the treatment of hepatocellular carcinoma (HCC). However, the indication of this technique is unclear and its therapeutic efficacy is undetermined. METHODOLOGY: We decided the precise indication for the use of artificial infusion. Artificial pleural effusion was indicated for tumors located on the dorsal side of the liver surface in the right lobe. Artificial ascites were indicated for (i) tumors located on the ventral side of the liver surface in the right lobe; (ii) tumors that could not be completely visualized but located near the liver surface in the right lobe; and (iii) tumors on the liver surface and adjacent to organs. RESULTS: The total local recurrence rates at 1 and 2 years were 4% and 22%, respectively. The estimated survival rates of 32 naïve patients at 1 and 3 years were 90% and 78%, respectively. The local recurrence rates of a tumor size of <3 cm and >3 cm at 2 years were 22% and 17%, respectively. CONCLUSIONS: RFA with artificial pleural effusion and/or ascites is effective for tumors located on the liver surface and in the hepatic dome.

Close correlation of liver stiffness with collagen deposition and presence of myofibroblasts in non-alcoholic fatty liver disease.

AIM: Transient elastography is known as a rapid, objective, and highly reliable technique for staging hepatic fibrosis caused by hepatitis C virus infection; however, the relationship between degree of fibrosis and the collagen deposition or the accumulation of myofibroblasts in non-alcoholic fatty liver disease (NAFLD) remains to be further elucidated. METHODS: The subjects were 36 patients with NAFLD who received liver biopsy and liver stiffness measurement using transient elastography. Their clinical data and laboratory values were collected. Morphometric analyses of liver fibrosis indicated by collagen deposition and the relative numbers of myofibroblasts were performed. RESULTS: Liver stiffness measured by transient elastography correlated with histopathological fibrosis staging of NAFLD determined by Brunt's scoring system (P = 0.000149). The fibrosis staging correlated with the ratios of the Sirius red-positive area (P = 0.000032) and α-smooth muscle actin-positive area (P = 0.000898). Finally, liver stiffness significantly correlated with the ratios of the Sirius red-positive area (r = 0.390, P = 0.0184) and α-smooth muscle actin-positive area (r = 0.333, P = 0.0471). CONCLUSIONS: Liver stiffness measurement by transient elastography is valuable for evaluating fibrotic progression in NAFLD.

Real-time tissue elastography as a tool for the noninvasive assessment of liver stiffness in patients with chronic hepatitis C.

BACKGROUND: Although histopathological examination by "invasive" liver biopsy remains the gold standard for evaluating disease progression in chronic liver disease, noninvasive tools have appeared and have led to great progress in diagnosing the stage of hepatic fibrosis. The aim of this study was to assess the value of real-time tissue elastography, using an instrument made in Japan, for the visible measurement of liver elasticity; in particular, comparing the results with those of transient elastography (Fibroscan). METHODS: Real-time tissue elastography (RTE), transient elastography (Fibroscan), liver biopsy, and routine laboratory analyses were performed in 101 patients with chronic hepatitis C. The values for tissue elasticity obtained using novel software (Elasto_ver 1.5.1) connected to RTE were transferred to four image features, Mean, Standard Deviation (SD), Area, and Complexity. Their association with the stage of fibrosis at biopsy and with liver stiffness (kPa) obtained by Fibroscan was analyzed. RESULTS: Colored images obtained by RTE were classified into diffuse soft, intermediate, and patchy hard patterns and the calculated elasticity differed significantly between patients according to and correlated with the stages of fibrosis (p < 0.0001). Mean, SD, Area, and Complexity showed significant differences between the stages of fibrosis (Tukey-Kramer test, p < 0.05). In discriminating patients with cirrhosis, the areas under the receiver operating characteristic curves (AUC) were 0.91 for Mean, 0.84 for SD, 0.91 for Area, 0.93 for Complexity, and 0.95 for Fibroscan. CONCLUSIONS: RTE is a noninvasive instrument for the colored visualization of liver elasticity in patients with chronic liver disease.

Usefulness of transient elastography for assessment of liver fibrosis in chronic hepatitis B: Regression of liver stiffness during entecavir therapy.

AIM: The usefulness of transient elastography remains to be validated in chronic hepatitis B, particularly as a tool for monitoring the degree of liver fibrosis during treatment. METHODS: The subjects were 50 patients with chronic hepatitis B virus infection. Liver biopsy was performed in 38 patients, and in 12 patients with platelet counts of 50 × 10(9)/L or less, cirrhosis was clinically diagnosed on the basis of specific signs of portal hypertension. Liver stiffness was measured by transient elastography at baseline and after 12 months of treatment in 20 nucleos(t)ide-naïve patients who started entecavir within 3 months after study entry. RESULTS: Twenty (40%) patients were classified as F1, 10 (20%) as F2, 5 (10%) as F3, and 15 (30%) as F4 (cirrhosis). Median liver stiffness (interquartile range) was 7.0 kPa (5.6-9.4), 9.8 kPa (5.6-14.7), 9.8 kPa (7.6-12.9), and 17.3 kPa (8.2-27.6) in fibrosis stages F1 to F4, respectively. Liver stiffness significantly correlated with fibrosis stage (r = 0.46; P = 0.0014). Of the patients who started entecavir, median liver stiffness significantly decreased from 11.2 kPa (7.0-15.2) to 7.8 kPa (5.1-11.9; P = 0.0090) during 12 months of treatment. Median levels of amino-terminal peptide of type III procollagen and type IV collagen 7S domain in serum significantly decreased from 0.9 (0.6-1.3) to 0.6 (0.5-0.7) U/mL (P = 0.0010) and from 5.0 (4.4-6.7) to 3.9 (3.2-4.4) ng/mL (P = 0.015), respectively. CONCLUSION: Liver stiffness measurement can be useful for monitoring regression of liver fibrosis during entecavir treatment in patients with chronic hepatitis B virus infection.

Two cases of hepatocellular adenomatosis treated with transcatheter arterial embolization.

Hepatocellular adenoma is a rare benign tumor of the liver. However, some complications, such as hemorrhage, rupture, and malignant transformation, have been reported previously. Surgical resection is considered to be the best choice of treatment, when adenomas are increasing in size, while resection is difficult to perform when multiple adenomas develop throughout the liver. Here, we report two cases of multiple hepatocellular adenomatosis. One patient had a history of aplastic anemia and the other had glycogen storage disease. We treated them with transcatheter arterial embolization (TAE) to prevent hemorrhage and rupture. After TAE, most parts of the adenomas showed necrotic change. These cases suggest that TAE is an effective treatment of hepatocellular adenomatosis.

Frequent detection of hepatitis B virus DNA in hepatocellular carcinoma of patients with sustained virologic response for hepatitis C virus.

Hepatocellular carcinoma (HCC) develops several years after the eradication of hepatitis C virus (HCV) by interferon therapy. Risk factors for the development of HCC are only partly understood. To elucidate the role of occult hepatitis B virus (HBV) infection in hepatocarcinogenesis in patients with sustained virologic response, the prevalences of HBV-related makers were examined. Study group comprised 16 patients with sustained virologic response (group A) and 50 with HCV (group B). Anti-HBc and anti-HBs in serum were examined by enzyme-linked immunoassay. HBV DNA in liver was examined by nested polymerase chain reaction, using primers specific for genes encoding for HBx, HBsAg, HBcAg, and HBV cccDNA. Sequence of the amplified HBV DNA for 'a' determinant of HBsAg was determined in HCC. Anti-HBc was positive in 10 of 16 in group A and 25 of 50 in group B. HBV DNA in liver was detected in 12 of 16 in group A and 21 of 50 in group B (P = 0.044). In group A, HBV DNA in liver was detected frequently in patients without cirrhosis and in those with a longer period from the time of HCV eradication to the development of HCC. Mutation in 'a' determinant of HBsAg was found in three HCC of group A. Occult HBV infection may be one of the most important risk factors in hepatocarcinogenesis of Japanese patients with sustained virologic response.

Noninvasive laboratory tests proposed for predicting cirrhosis in patients with chronic hepatitis C are also useful in patients with non-alcoholic steatohepatitis.

BACKGROUND: Several noninvasive tests have been proposed to predict cirrhosis in patients with chronic hepatitis C, but not in patients with non-alcoholic steatohepatitis (NASH). We assessed whether noninvasive laboratory tests designed to predict the risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection could be used in patients with NASH. METHODS: The subjects were 50 patients with biopsy-proved NASH and 100 age- and sex-matched patients with HCV. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio (AAR), age-platelet (AP) index, AST-to-platelet ratio index (APRI), cirrhosis discriminant score (CDS), and the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) model were calculated. RESULTS: The areas under the receiver-operating characteristic curves of the AAR, AP index, APRI, CDS, and HALT-C model for predicting cirrhosis were respectively 0.813, 0.877, 0.786, 0.949, and 0.908 in patients with NASH and 0.555, 0.652, 0.761, 0.782, and 0.782 in patients with HCV. A CDS cutoff value of less than 5 misclassified none of the 9 patients with NASH who had cirrhosis, while a value of more than 8 misclassified none of the 41 patients with NASH without cirrhosis. With the HALT-C model, a cutoff value of less than 0.6 classified non-cirrhotic NASH, while a cutoff value of 0.97 or higher classified cirrhotic NASH. The use of CDS and HALT-C model could avoid liver biopsy for predicting cirrhosis in 60 and 48% of the patients with NASH, respectively. CONCLUSIONS: Noninvasive laboratory tests designed to predict cirrhosis in patients with HCV are also useful in patients with NASH.

[Drug-induced liver injury caused by an herbal medicine, bofu-tsu-sho-san].

A 37-year-old woman was admitted to a hospital with jaundice. Within a couple of weeks, her liver function improved with only symptomatic therapy. About 30 to 60 days before admission, she had taken a herbal medicine, bofu-tsu-sho-san. A diagnosis of drug-induced liver injury was made according to the diagnostic scale proposed at the Digestive Disease Week-Japan 2004. A drug-lymphocyte stimulation test for each ingredient of bofu-tsu-sho-san; the results were positive for Cnidii Rhizoma, Angelicae Radix and Menthae Herba. The liver biopsy specimen revealed features of acute hepatitis. Physicians should be aware that bofu-tsu-sho-san can cause liver injury, as this drug is commonly used as an over-the-counter medicine.

A case of primary small cell carcinoma of the liver that was treated with chemotherapy.

Primary small cell carcinoma (SSC) of the liver is very rare in Japan and only ten cases have been reported worldwide. We report herein the case of a 77-year-old man with primary SCC of the liver. He had a tumor over 10 cm in diameter which was localized in the right lobe of the liver and had invaded the right diaphragm. In laboratory tests, high serum levels of lactate dehydrase and neuron-specific enolase were observed. A biopsy specimen showed that the tumor cells were similar in cytology to a pulmonary SCC. The patient was first treated with carboplatin and etoposide according to the therapy protocol for pulmonary SCC and then with a regimen using etoposid and cisplatinum, resulting in an unfavorable outcome. We discuss the clinical course and therapy of extra-pulmonary SCC and review the literature of the cases previously reported.

Thiopurine S-methyltransferase gene polymorphism in Japanese patients with autoimmune liver diseases.

BACKGROUND AND AIM: Thiopurine S-methyltransferase (TPMT) genotypes or phenotypes may be a predictive factor for azathioprine-induced toxicities. We investigated the genotypic status of TPMT to evaluate the risk of azathioprine-related adverse effects in Japanese patients with different liver diseases, including autoimmune hepatitis (AIH). METHODS: 49 patients with AIH, 67 with primary biliary cirrhosis (PBC), and 120 with hepatitis C virus (HCV) were examined. TPMT genotypes were determined by PCR-restriction fragment length polymorphism-based assays. RESULTS: The distribution of TPMT genotypes was 90% TPMT*1/TPMT*1, 8% TPMT*1/TPMT*3C, and 2% TPMT*3C/TPMT*3C in AIH, and 94% TPMT*1/TPMT*1, 4.5% TPMT*1/TPMT*3C, and 1.5% TPMT*3C/TPMT*3C in PBC. All except 1 patient with HCV had the TPMT*1/TPMT*1 genotype. Severe myelosuppression occurred in two of nine patients with AIH who received azathioprine, one of whom was homozygous for TPMT*3C. CONCLUSIONS: TPMT*3C variants are more frequent in patients with AIH or PBC than in patients with viral hepatitis or healthy volunteers in Japan. Pharmacogenetic screening for TPMT polymorphisms before commencing azathioprine therapy may help to prevent severe hematotoxicity in patients with TPMT deficiency.

High sensitivity of fatty liver Shionogi (FLS) mice to diethylnitrosamine hepatocarcinogenesis: comparison to C3H and C57 mice.

The fatty liver Shionogi (FLS) mouse is a new inbred strain that spontaneously develops fatty liver with infiltration of mononuclear cells. Moreover, this mouse is known to frequently develop spontaneous hepatic cancers. Recently, human non-alcholic steatohepatitis (NASH) has been focused of attention regarding hepatocellular carcinoma. Therefore, this mouse has potential as a model for human hepatic cancer due to steatosis. It is of interest therefore, whether it exhibits elevated susceptibility not only regarding spontaneous tumor development but also to chemical hepatocarcinogens. To examine this concern, we examined diethylnitrosamine (DEN) hepatocarcinogenesis in FLS mice with 30ppm in drinking water for 26 weeks in comparison to two other strains of mice, C3H and C57. The induction of spontaneous and DEN-induced hepatic tumors was clearly increased in the FLS case, along with levels of 8-hydroxy-2'-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, as compared to the other strains, with or without DEN treatment. These results indicate that the oxidative DNA stress is intimately involved in hepatocarcinogenesis in FLS mice and provide further support for use of this mouse as a useful model for investigating hepatocarcinogenesis due to human hepatic steatosis.

A clinicopathological study of inflammatory pseudotumors of the liver with special reference to vessels.

BACKGROUND/AIMS: Inflammatory pseudotumor of the liver is rare, and patients with inflammatory pseudotumor frequently undergo unnecessary surgical resection as a result of misdiagnosis of malignancy. In this study, we therefore investigated inflammatory pseudotumor clinicopathologically to clarify its characteristics. METHODOLOGY: Twenty patients including 3 with inflammatory pseudotumor and 17 with various malignant liver tumors were studied. We further investigated tumor vessels by means of immunohistochemistry using monoclonal antibodies against CD34, factor VIII-related antigen and alpha-smooth muscle actin. RESULTS: Although serum levels of alkaline phosphatase were significantly higher in inflammatory pseudotumor patients than in other patients, the laboratory data alone could not precisely distinguish inflammatory pseudotumor from other hepatic tumors. On imaging studies such as ultrasonography and computed tomography, significant changes in tumor size, especially size reduction, during relatively short follow-up periods were often observed in inflammatory pseudotumor but not in other liver tumors. An enhancement of the peripheral regions of inflammatory pseudotumor was frequently observed in the early phase of contrast-medium dynamic computed tomography. This might be due to abnormal vessels located in the peripheral regions of inflammatory pseudotumor which might result from obliteration of some pre-existing vessels in portal tracts within inflammatory pseudotumor. Immunohistochemical analysis further revealed that abnormal vessels in the peripheral regions of inflammatory pseudotumor were positively stained with CD34, factor VIII-related antigen and alpha-smooth muscle actin as were tumor sinusoids within hepatocellular carcinoma and tumor capillaries in other malignant liver tumors. CONCLUSIONS: Although inflammatory pseudotumor seems to have some features in imaging studies, a biopsy is needed for a correct diagnosis of inflammatory pseudotumor.

Immunohistochemical detection of Fas and apoptosis in type-1 autoimmune hepatitis.

BACKGROUND/AIMS: Although Fas expression has been reported in liver with chronic viral hepatitis and primary biliary cirrhosis, little is known about Fas expression and apoptosis in type-1 autoimmune hepatitis. The aim of this study was to investigate whether the expression of Fas and apoptosis are found in liver with autoimmune hepatitis. The relationship between Fas expression and clinicopathological findings including the occurrence of apoptosis was also investigated. METHODOLOGY: Fas expression and apoptosis were immunohistochemically examined in liver tissues from 20 patients with autoimmune hepatitis and five control subjects using specific antibodies against Fas and single-stranded DNA. The grade of expression of Fas and apoptosis was evaluated and compared with histological findings and the results of liver function tests in each patient. RESULTS: Fas expression in hepatocytes was detected in all patients with autoimmune hepatitis, while Fas expression was not detected in control livers. The Fas-positive hepatocytes were particularly abundant in those areas facing piecemeal and confluent necrosis. In 30% of autoimmune hepatitis cases, bile-duct cells were faintly stained for Fas. A few hepatocytes positive for single-stranded DNA were found in the areas facing piecemeal necrosis and confluent necrosis. In 95% cases, many bile-duct cells were positive for single-stranded DNA. No relationship between the expression of Fas and single-stranded DNA was found in hepatocytes or bile-duct cells. However, the degree of Fas expression in hepatocytes significantly correlated with serum transaminase concentrations and was increased in parallel with the grade of activity but not with the stage of fibrosis. CONCLUSIONS: We have demonstrated that Fas expression is detected in hepatocytes of the liver with autoimmune hepatitis and that the level of Fas expression reflects the severity of inflammation in autoimmune hepatitis.