Rika Ishii

Potential therapeutic application of intravenous autologous bone marrow infusion in patients with alcoholic liver cirrhosis.

The present study was conducted to evaluate the application and efficacy of autologous bone marrow infusion (ABMi) for improvement of liver function in patients with alcoholic liver cirrhosis (ALC). Five subjects and 5 control patients with ALC who had abstained from alcohol intake for 24 weeks before the study were enrolled. Autologous bone marrow cells were washed and injected intravenously, and the changes in serum liver function parameters, and the level of the type IV collagen 7S domain as a marker of fibrosis, were monitored for 24 weeks. The distribution of activated bone marrow was assessed by indium-111-chloride bone marrow scintigraphy. The number of cells infused was 8.0±7.3×10(9) (mean±standard error). The serum levels of albumin and total protein and the prothrombin time were significantly higher during the follow-up period after ABMi than during the observation period in treated patients, whereas no such changes were observed in the controls. In the patients who received ABMi, the Child-Pugh score decreased in all 3 who were classified as class B; the serum levels of type IV collagen 7S domain improved in 4 of the 5 patients; and bone marrow scintigraphy demonstrated an increase of indium-111-chloride uptake in 3 of the 4 patients tested. ABMi for patients with ALC helps improve liver function parameters in comparison with observation during abstinence and ameliorates the degree of fibrosis in terms of serum markers and bone marrow activation in most cases.

Spontaneous regression of hepatocellular carcinoma and review of literature

A 68‐year‐old man presented with multiple hepatocellular carcinoma, which was considered to be unresectable at the first admission in January 1994. Pathological diagnosis was made by biopsy of the one lesion among them. From January 1994 to December 1997, 10 transarterial chemoembolizations and six percutaneous ethanol injection therapies were performed on the tumours in the cirrhotic liver. In February 1998 the tumour situated in the right lobe began to increase in size. The maximum tumour diameter was 6.3 cm measured by computed tomography (CT). In the beginning of May 1998 moderate ascites was present and mild hepatic encephalopathy was noticed. The patient was in the terminal stage of hepatocellular carcinoma and no further treatment was possible at that time. However, serum α‐fetoprotein and protein induced by vitamin K absence or antagonist II dramatically decreased in June 1998. The CT scan also showed that the tumour had completely regressed without specific treatment. In February 1999 a new biopsy‐proven hepatocellular carcinoma, 2 cm in diameter, developed in the lateral segment of the liver. It was well treated by percutaneous ethanol injection therapy. The patient was alive in good condition without any symptoms or tumour recurrence in June 1999. It was concluded that a rare case of spontaneous regression of hepatocellular carcinoma had occurred.

Impact of metabolic syndrome on elevated serum alanine aminotransferase levels in the Japanese population.

Measurement of the serum alanine aminotransferase (ALT) level is used as an initial test for detection of liver diseases, and recent studies have also highlighted its potential value as a measure of overall health and survival as a marker of an increased risk of metabolic disorder. This study was designed to clarify the prevalence of elevated ALT levels in the Japanese population and to assess factors associated with ALT elevation. The subjects were 2165 individuals aged 40 to 85 years who participated in a Japanese community-based study referred to as the Takahata Study. Serum ALT levels and factors associated with ALT elevation were investigated. Among 2087 subjects who were negative for hepatitis B and C, the rates of elevated ALT greater than 30 U/L in men and greater than 25 U/L in women were 217 (22.7%) of 957 and 239 (21.2%) of 1130, respectively. These ALT cutoff levels had a specificity of more than 80% for exclusion of subjects with none or 1 of 3 metabolic risk factors: hypertension, lipid metabolism abnormality, and hyperglycemia. Multivariate analysis revealed 5 factors with a significant association with ALT elevation in men (n = 957): high gamma-glutamyltranspeptidase, low adiponectin, high low-density lipoprotein cholesterol, high body mass index, and high homeostasis model assessment insulin resistance index. Similarly, 4 factors were significantly associated with ALT elevation in women (n = 1130): high gamma-glutamyltranspeptidase, low adiponectin, high body mass index, and high homeostasis model assessment insulin resistance index. These results suggest that elevated ALT levels in the Japanese population older than 40 years have a strong association with metabolic syndrome-related features including obesity and insulin resistance.

Characteristics of rat bone marrow cells differentiated into a liver cell lineage and dynamics of the transplanted cells in the injured liver

BackgroundBone marrow cells (BMCs) have been shown to differentiate into a liver cell lineage, but little is known about their dynamics following transplantation. BMCs were cultured to investigate the expression of liver-specific genes in vitro and transplanted into in vivo liver-injury models to elucidate their dynamics in the liver.MethodsThe mRNA expression of various liver-specific genes in BMCs cocultured with hepatocytes was analyzed using reverse transcription-polymerase chain reaction. BMCs from transgenic rats expressing green fiuorescent protein were transplanted into the spleen of rat liver-injury models induced with 2-acetylaminofiuorene (2-AAF) or carbon tetrachloride (CCl4). BMCs were also transplanted directly into livers treated with CCl4 to determine which route is better for transplantation.ResultsBMCs differentiated into a liver cell lineage in vitro and expressed mRNAs consistent with mature hepatocytes, including albumin. The transplanted BMCs were found in the liver in the CCl4-induced injury model, but not in the 2-AAF-induced model. The hepatocyte growth factor and fibroblast growth factor mRNA levels in the liver were significantly higher in the CCl4-induced model than in the 2-AAF-induced model. Migration of BMCs to the liver was more effective following injection into the liver, rather than into the spleen.ConclusionsCultured BMCs differentiated into a liver cell lineage are a potential source for cell transplantation. Transplantation is successful in the severely injured liver with a high level of expression of mRNAs for growth factors. Injection of BMCs directly into the liver is the preferred route of administration.

Impaired mitochondrial β-oxidation in patients with chronic hepatitis C: relation with viral load and insulin resistance

BackgroundHepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.MethodsThis study consisted of thirty patients with CH-C. Serum levels of insulin and hepatitis C virus (HCV) core protein were measured by chemiluminescence enzyme immunoassay. The subjects were then fasted, and venous blood samples were drawn 12 h and 15 h after the start of fasting. The levels of blood ketone bodies were measured by an enzymatic cycling method. The rate of change in total ketone body concentration was compared with that in eight healthy volunteers.ResultsThe rate of change in total ketone body concentration between 12 h and 15 h after the start of fasting was significantly lower in CH-C patients than in healthy volunteers (129.9% (8.5-577.3%) vs. 321.6% (139.6-405.4%); P <0.01). The rate of change in total ketone body concentration in patients with a serum level of HCV core protein of 10000 fmol/L or higher was significantly lower than in patients with a level of less than 10000 fmol/L (54.8% (8.5-304.3%) vs. 153.6% (17.1-577.3%); P <0.05). The rate of change in total ketone body concentration in patients with a homeostasis model assessment of insulin resistance (HOMA-IR) of 2.5 or higher was significantly lower than in patients with a HOMA-IR of less than 2.5 (56.7% (8.5-186.7%) vs. 156.4% (33.3-577.3%); P <0.01).ConclusionsThese results suggest that mitochondrial β-oxidation is impaired, possibly due to HCV infection in patients with CH-C.

Secondary structure of the amino-terminal region of HCV NS3 and virological response to pegylated interferon plus ribavirin therapy for chronic hepatitis C

The aim of the study was to identify a predictive marker for the virological response in hepatitis C virus 1b (HCV‐1b)‐infected patients treated with pegylated interferon plus ribavirin therapy. A total of 139 patients with chronic hepatitis C who received therapy for 48 weeks were enrolled. The secondary structure of the 120 residues of the amino‐terminal HCV‐1b non‐structural region 3 (NS3) deduced from the amino acid sequence was classified into two major groups: A and B. The association between HCV NS3 protein polymorphism and virological response was analyzed in patients infected with group A (n = 28) and B (n = 40) isolates who had good adherence to both pegylated interferon and ribavirin administration (>95% of the scheduled dosage) for 48 weeks. A sustained virological response (SVR) representing successful HCV eradication occurred in 33 (49%) in the 68 patients. Of the 28 patients infected with the group A isolate, 18 (64%) were SVR, whereas of the 40 patients infected with the group B isolate only 15 (38%) were SVR. The proportion of virological responses differed significantly between the two groups (P < 0.05). These results suggest that polymorphism in the secondary structure of the HCV‐1b NS3 amino‐terminal region influences the virological response to pegylated interferon plus ribavirin therapy, and that virus grouping based on this polymorphism can contribute to prediction of the outcome of this therapy. J. Med. Virol. 82:1364–1370, 2010.

Serum prolactin levels and prolactin mRNA expression in peripheral blood mononuclear cells in hepatitis C virus infection

Prolactin is not only a pituitary hormone but an immunoregulatory hormone secreted from lymphocytes. Prolactin induction in relation to hepatitis C virus (HCV) infection has not been elucidated. The serum levels of prolactin were examined in 232 HCV‐infected subjects positive for anti‐HCV antibody and 65 healthy controls negative for it, who were recruited in the cohort study. The prolactin mRNAs were measured in peripheral blood mononuclear cells (PBMCs) of eleven healthy volunteers including five men and six women before and after stimulation by HCV in vitro. The serum level of prolactin and prolactin mRNA in PBMCs were measured by chemiluminescence immunoassay and real‐time PCR, respectively. The serum levels of prolactin were significantly higher in the HCV‐infected subjects (median: 7.5, IQR: 5.7–10.9 ng/ml) than in the controls (median: 5.6, IQR: 4.4–8.3 ng/ml) (P < 0.01). They were significantly higher in HCV‐infected males (median: 8.0, IQR: 5.9–11.8 ng/ml) than in the controls (median: 4.8, IQR: 4.2–5.9 ng/ml) (P < 0.001), however, the difference was not significant between HCV‐infected females (median: 7.3, IQR: 5.6–10.5 ng/ml) and the controls (median: 6.4, IQR: 5.3–9.8 ng/ml). The mRNA expression of prolactin was induced in PBMCs of all males, but it was induced in PBMCs of the two of six females examined in vitro. These results suggest that the serum level of prolactin is higher in HCV‐infected males than in healthy males, and that HCV infection induces the mRNA expression of prolactin in PBMCs that is more apparent in male than in females. J. Med. Virol. 85:1199–1205, 2013.

A Case of Adult Type 1 Gaucher Disease Complicated by Temporal Intestinal Hemorrhage

A 21-year-old man with a history of sudden rectal hemorrhage was referred to our hospital. Examination disclosed thrombocytopenia and hepatosplenomegaly. A liver biopsy specimen demonstrated Gaucher cells in Glissons capsule. Additional investigations revealed a low level of leukocyte β-glucosidase activity and common mutations of the glucocerebrosidase gene, L444P/D409H. We diagnosed the patient with Gaucher disease type 1. He underwent enzyme replacement therapy. Thrombocytopenia and hepatosplenomegaly improved at a rate of approximately 50 and 20%, respectively, within 6 months. This case suggests that we must pay attention to adult Gaucher disease as a differential diagnosis for cryptogenic thrombocytopenia.

Su1232 The Serum Level of B-FGF and Scf in Hepatitis C Patients and Its Prognosis With Hepatocelluler Carcinoma

[Background/Aim] In spite of intraductal papillary mucinous neoplasm of the bile duct (IPMNB) has been recently recognized, the clinicopathological features of IPMNB still remains unclear. The aim of this study is to resolve this problem by comparing IPMNB and intraductal papillary mucinous neoplasm of the pancreas (IPMNP). [Patients]Medical records of 7 patients with IPMNB, 12 patients with intraductal papillary non-mucinous neoplasm of the bile duct (IPNB) and 51 patients with IPMNP operated on between 2000 and 2010 at our department were reviewed retrospectively. [Results] As for the difference with IPMNB and IPNB, IPMNB had more immunohistochemical staining positive cases of MUC2 and longer for the illness than IPNB. There were no differences between IPMNB and IPNB about Age, gender and tumormarkers. As for the comparison between IPMNB and IPMNP, the malignant frequency, tumor-cell type and immunohistochemical positive staining of MUC2 of IPMNB was equal with main-duct type of IPMNP. [Conclusion]Our data suggested that IPMNB had similar clinicopathological characteristics compared with main-duct type of IPMNP, not branch-type of IPMNP. IPMNB have been proposed as the biliary counterpart of main-duct type of IPMNP. There are similarities and differences between IPMNB and IPNB.

Mo1903 Transition in Hepatitis B Virus Genotypes Responsible for Acute Hepatitis B in a Hyperendemic Area for Genotype B Infection – 20 Years Follow-up Study in Japan

Background/Aims: Hepatitis B virus (HBV) genotypes B and C are common in Japan and have been demonstrated as one of the predictive factors associated with the progression of liver diseases. The aim of this study was to examine the changes over time in genotypes of HBV carriers in the hyperendemic area for HBV genotype B infection in Japan as well as in genotypes responsible for acute hepatitis B. Methods: We evaluated HBV genotypes in 430 HBsAg-positive HBV carriers and 34 patients with acute hepatitis B who had a medical examination at our university hospital between 1990 and 2010. The subjects were divided into two time-period groups (1990-1999 and 2000-2010) and analyzed the distribution of genotypes. In addition, the clinical and virological characteristics; ALT value, HBeAg, antiHBe antibody, IgM-HBc antibody, HBVDNA, were compared between subjects with genotype A infection and those with non-genotype A infection. Results: Of the 430 HBsAg-positive carriers, 45% had genotype B and 35% had genotype C in both time-period groups, indicating no changes in genotypes over time. Among 34 acute hepatitis B patients, the prevalence of genotype B was lower in the 2000-2009 group (1/17; 5.9%) than in the 1990-1999 group (10/17; 58.8%, p=0.012), while that of genotype A tended to have increased from 11.8% (2/17) to 29.4% (5/17) in the last 10 years. One of 7 patients with acute HBV genotype A infection did not clear HBsAg and developed to chronic infection. When Kaplan-Meier analysis was used to compare HBsAg clearance phase between the patients with or without genotype A infection, the phase was significantly longer in the genotype A patients (49 wks vs. 8 wks; p < 0.05). HBV DNA negative phase was also significantly longer in the genotype A patients (45 wks vs. 4.9 wks; p < 0.05), while the both groups showed no difference in HBeAg negative phase, anti-HBe positive phase, IgM-HBc antibody negative phase, and ALT normalization period. Conclusion: In a hyperendemic area for HBV genotype B infection in Japan, there was no large change of HBV genotypic distribution in carriers, while genotype A infection was increased in acute hepatitis B in the last 10 years. Compared to patients with acute HBV non-genotype A infection, patients with genotype A infection took a longer duration for HBsAg clearance and for achievement of HBV DNA negative status. Infection became chronic in some of the patients with infected with genotype A, suggesting that genotype distribution in HBV carriers will change in Japan in the future. It is necessary to re-examine the nation-wide study of clinical course of acute hepatitis B patients, especially infected with genotype A.