Hiroyuki Shimomura

Measurement of Spleen Stiffness by Acoustic Radiation Force Impulse Imaging Identifies Cirrhotic Patients With Esophageal Varices

BACKGROUND & AIMS We evaluated whether spleen stiffness (SS), measured by acoustic radiation force impulse imaging, can identify patients who have esophageal varices (EVs); those without EVs would not require endoscopic examination. METHODS In a prospective study, we measured SS and liver stiffness (LS) in 340 patients with cirrhosis undergoing endoscopic screening for EVs and 16 healthy volunteers (controls) at the Kurashiki Central Hospital in Okayama, Japan. The diagnostic accuracy of SS for the presence of EVs was compared with that of other noninvasive parameters (LS, spleen diameter, and platelet count). Optimal cutoff values of SS were chosen to confidently rule out the presence of varices. RESULTS Patients with cirrhosis had significantly higher SS and LS values than controls (P < .0001 and P < .0001, respectively). Levels of SS were higher among patients with EVs (n = 132) than controls, and values were highest among patients with high-risk EVs (n = 87). SS had the greatest diagnostic accuracy for the identification of patients with EVs or high-risk EVs compared with other noninvasive parameters, independent of the etiology of cirrhosis. An SS cutoff value of 3.18 m/s identified patients with EVs with a 98.4% negative predictive value, 98.5% sensitivity, 75.0% accuracy, and 0.025 negative likelihood ratio. An SS cutoff value of 3.30 m/s identified patients with high-risk EVs with a 99.4% negative predictive value, 98.9% sensitivity, 72.1% accuracy, and 0.018 negative likelihood ratio. SS values less than 3.3 m/s ruled out the presence of high-risk varices in patients with compensated or decompensated cirrhosis. SS could not be measured in 16 patients (4.5%). CONCLUSIONS Measurements of SS can be used to identify patients with cirrhosis with EVs or high-risk EVs. A cutoff SS was identified that could rule out the presence of varices and could be used as an initial noninvasive screening test; UMIN Clinical Trials Registry number, UMIN000004363.

Relationship between serum leptin and fatty liver in Japanese male adolescent university students

Relationship between serum leptin and fatty liver in Japanese male adolescent university students

Quantitative detection of hepatitis C virus genome in liver tissue and circulation by competitive reverse transcription-polymerase chain reaction

We quantified hepatitis C virus RNA in 25 Japanese patients with chronic type C liver disease by competitive reverse transcription-polymerase chain reaction. The amount of the viral RNA in the serum (2×105−2×108 copies/ml) correlated with that in the liver tissue (108−1011 copies/g) (N=23,r=0.727,P<0.0001). One gram of the infected liver tissue contained 102−104 (geometric mean, 103,N=23) times as many copies of the viral RNA as did 1 ml of the serum. Liver tissues of chronic aggressive hepatitis contained significantly higher amounts of the viral RNA than those of chronic persistent hepatitis (P<0.05). These observations suggested that this method is useful to evaluate viral amount, and the amount of the circulating hepatitis C virus RNA could be used as a marker of the intrahepatic viral amounts, which might contribute to disease activity.

HBcAg-specific CD8 T cells play an important role in virus suppression, and acute flare-up is associated with the expansion of activated memory T cells

We analyzed the prevalence and longitudinal fluctuation of hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection using an HLA-A2–HBc18-27 tetramer. Thirty-five HLA-A2-positive patients with chronic HBV infection were divided into 17 HBe antigen (HBeAg)-positive and 18 anti-HBe antibody (anti-HBe)-positive patients. Five HLA-A2-positive normal subjects, five HLA-A2-negative patients with chronic HBV infection, and two HLA-A2-positive patients with acute HBV infection were included as controls. HBc18-27-specific CD8 T cells (c18-27-CD8Ts) were detected at a significantly higher prevalence in patients with anti-HBe (6/18) than in those with HBeAg (1/17), and their frequency reached 0.28% of the total CD8 T cells. The prevalence was significantly higher in patients with HBV DNA below 4.0 log genome equivalents (LGE)/ml (5/12) than in those with HBV DNA above 4.0 LGE/ml (2/23). The frequency of c18-27-CD8Ts was consistently higher in liver-infiltrating lymphocytes, ranging from 0.18 to 1.28%, than in autologous peripheral blood lymphocytes. Longitudinal analysis of patients with acute flare-up demonstrated that the elevation of alanine aminotransferase (ALT) was intimately associated with the expansion of c18-27-CD8Ts. Phenotypic analysis revealed that most c18-27-CD8Ts during acute flare-up expressed HLA-DR and CCR5, while those during low-ALT periods showed low expression. Furthermore, most liver-infiltrating c18-27-CD8Ts were positive for HLA-DR and CCR5, suggesting selective recruitment of activated c18-27-CD8Ts into the liver. In conclusion, HBV-specific CD8 T cells play an important role in the suppression of virus replication, and acute flare-up is associated with the expansion and activation of HBV-specific memory cells.

Cloning of a cDNA associated with acute and chronic hepatitis C infection generated from patients serum RNA

SummaryIn order to clone hepatitis C (blood-borne non-A, non-B hepatitis) virus, lambda gt11cDNA library was constructed from RNA extracted from 100 liters serum collected from 1,047 donors with elevated ALT levels and negative for hepatitis B virus-DNA. The library was immunoscreened on Y1090 cells with pooled serum obtained from patients with acute hepatitis C or chronic hepatitis C. By screening 29 clones specific for Japanese hepatitis C infection were isolated. The specificity of these clones for hepatitis C infection was determined by panels constructed in 3 laboratories. Of these, 12 clones were specific for American hepatitis C infection as well. The nucleotide sequence (201 bp) of one of them was determined to be unique compared to known human viruses including hepatitis A virus, hepatitits B virus and hepatitis D virus. Southern blot analysis showed the absence of the sequence of the human genome in the clone. The predicted amino acid sequence is rich in residues of lysine, arginine, glutamic acid and asparagine, while lacking leucine, cysteine and methionine.

Long-term monitoring of platelet count, as a non-invasive marker of hepatic fibrosis progression and/or regression in patients with chronic hepatitis C after interferon therapy.

Background:  Platelet count has been shown to correlate with the hepatic fibrosis stage in chronic hepatitis C (CHC). The aim of the present study was to assess hepatic fibrosis progression or regression of CHC patients by long‐term monitoring of the platelet count.

Lamivudine and glycyrrhizin for treatment of chemotherapy-induced hepatitis B virus (HBV) hepatitis in a chronic HBV carrier with non-Hodgkin lymphoma.

We report a chronic hepatitis B virus (HBV) carrier with non-Hodgkin lymphoma (NHL) who developed HBV hepatitis following conventional dose chemotherapy and was successfully treated with lamivudine and glycyrrhizin. A 55 year-old male patient with primary testicular NHL (diffuse large B-cell type) relapsed. During the salvage chemotherapy, the patient showed elevated serum levels of transaminase and HBV-DNA due to HBV reactivation. Treatment with lamivudine, an antiviral nucleoside analog, was started at a dose of 100mg/day. Shortly after the treatment the HBV-DNA level was suppressed, and sustained elevation of transaminase levels were normalized after additional treatment with glycyrrhizin. This experience suggests that lamivudine combined with glycyrrhizin may be effective for controlling HBV replication and treating chemotherapy-induced HBV hepatitis in chronic HBV carriers with NHL.

Outcomes after curative treatment for cryptogenic cirrhosis-associated hepatocellular carcinoma satisfying the Milan criteria.

Background and Aim:  The prognosis of cryptogenic cirrhosis‐associated hepatocellular carcinoma (CC‐HCC) was reported to be poor because many of them were discovered at the advanced stage. The aim of this study is to reveal the clinical features of early CC‐HCC.

Regulation of circulating immune complexes by complement receptor type 1 on erythrocytes in chronic viral liver diseases.

Background and aim: Complement receptor type 1 (CR1) is a transmembrane protein, and human erythrocyte CR1 (E-CR1) is involved in the transport of circulating immune complexes (IC) from the circulation to the reticuloendothelial system, including the liver and spleen. In chronic viral hepatitis, increased levels of IC containing viral particles and an association with various extrahepatic manifestations have been reported. However, regulatory mechanisms for IC levels are not fully understood. Patients/subjects and methods: We analysed IC, E-CR1, and quantitative polymorphism of the CR1 gene in 149 patients with chronic viral liver diseases and in 64 normal blood donors using an enzyme linked immunosorbent assay, radioimmunoassay, and polymerase chain reaction-restriction fragment length polymorphism, respectively. We also analysed the effect of CR1 gene polymorphism on IC binding to E-CR1 using molecular methods. Results: E-CR1 levels in patients with chronic hepatitis and chronic viral liver diseases as a whole correlated inversely with increased levels of IC. Moreover, significantly high levels of IC were observed in patients with chronic hepatitis C (CH-C) who were homozygous for the E-CR1 low density allele. We also found low levels of E-CR1 in liver cirrhosis and CH-C but not in CH-B. Low levels of E-CR1 in CH-C were observed, even after considering the polymorphism of the CR1 gene. Finally, we demonstrated CR1 gene polymorphism dependent binding of hepatitis virus containing IC. Conclusions: Our results emphasise the important role of E-CR1 in clearance of IC from the circulation and the acquired, rather than inherited, decrease in E-CR1 in chronic viral liver diseases, especially of type C.

High prevalence of TT virus in human bile juice samples: importance of secretion through bile into feces.

TT virus (TTV) is much more prevalent than we once imagined. With the use of primers designed from the noncoding regions, a more than 90% rate of TTV infection in the general population by polymerase chain reaction (PCR) has been reported, showing that nonparenteral transmission must play an important role to its epidemiology. We considered that TTV may be secreted through bile juice into feces to establish nonparenteral infection. Paired bile juice and serum samples were obtained from 26 patients who were receiving bile drainage. Feces were also recovered after the drainage tube was removed. TTV DNA was detected from 22 patients in serum (84.6%), and they were all TTV DNA positive in bile juice. Most feces samples recovered from TTV-positive patients were also TTV DNA positive. Secretion of TTV into bile juice appears to be common, and this could play an important role to its transmission and its epidemiology.