Tomomi Shibuya

Differentiation of liver epithelial (stem-like) cells into hepatocytes induced by coculture with hepatic stellate cells.

The liver is believed to contain stem cells that can differentiate into either hepatocytes or biliary epithelial cells. In the present study, we established a nonhepatocytic epithelial cell line from the normal livers of adult rats. The established cells, designated HSL cells, were immunoreactive against alpha-fetoprotein, but neither albumin nor cytokeratin 19. To demonstrate the differentiation potential of HSL cells in vitro, the cells were cocultured with hepatic stellate cells as a mixture or separately using insert wells. Consequently, although coculture with hepatic stellate cells rendered HSL cells able to produce albumin, the mixed coculture system mimicking the hepatic environment elicited this phenomenon more effectively than the separated coculture system. In conclusion, HSL cells have immature properties and the potential to differentiate into mature cells. Not only the extracellular matrices but also soluble factors, which are produced by hepatic stellate cells, induce this maturation, demonstrating the importance of the hepatic environment for hepatocyte differentiation.

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats

BackgroundPortal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats.MethodsPHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6 N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups.ResultsPortal venous pressure was significantly higher in cirrhotic rats compared with control rats (P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress.ConclusionsThese findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.

Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

Background and Aims:  Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L‐carnosine, an anti‐ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG.

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats.

BackgroundGabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats.MethodsAcute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague–Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats.ResultsGabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%.ConclusionsGabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.

Distribution and isoforms of epimorphin in carbon tetrachloride-induced acute liver injury in mice.

Background and Aim:  Epimorphin, a morphoregulatory factor essential to organ development, is believed to direct normal morphogenesis in tissue repair. We examined the dynamics and the roles of epimorphin, a cell surface‐associated molecule detected on mesenchymal cells, in hepatic tissue repair from acute liver injury.

Mao (Ephedra sinica Stapf) protects against D-galactosamine and lipopolysaccharide-induced hepatic failure.

Mao is one component of various traditional herbal medicines. We examined the effects of Mao on an acute liver failure model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). The lethality of mice administrated Mao with GalN/LPS was significantly decreased compared with that in mice without Mao. Hepatic apoptosis and inflammatory cell infiltration were slight in Mao-treated mice. Serum alanine aminotransferase (ALT) and total bilirubin (T.Bil) activity, tumor necrosis factor alpha (TNF-alpha) levels and caspase 8, 9, and 3 activity in the liver were significantly lower in mice administrated Mao. But, Serum interleukin-6 (IL-6), IL-10 levels and signal transducers and activators of transcription 3 (STAT3) activity in the liver were significantly higher in mice administrated Mao. To investigate the effect of STAT3, we used AG490, which selectively inhibits the activation of Janus kinase (JAK) family tyrosine kinase and inhibits the constitutive activation of STAT3. There was significant aggravation in hepatic apoptosis treated with Mao and AG490 compared with Mao alone. In conclusions, Mao significantly suppressed hepatic apoptosis by inhibition of TNF-alpha production and caspase activity. Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glissons capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patients prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Efficacy of combined balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic injection sclerotherapy.

OBJECTIVE We evaluated the efficacy and safety of balloon-occluded retrograde transvenous obliteration (B-RTO) performed using absolute ethanol with iodized oil (ET+LPD) and simultaneous endoscopic injection sclerotherapy (EIS) with cyanoacrylate (CA) for gastric varices (GVs). METHODS A total of 16 patients with endoscopically proven high-risk GVs treated using combined B-RTO with ET+LPD and EIS with CA between January 2007 and July 2012 were enrolled. RESULTS Twelve cases included GVs involving both the cardia and fundus, two cases included fundal varices and two cases included cardiac varices. In terms of the form of GVs, 10 cases involved F2 lesions and six cases involved F3 lesions. The flow vein was the left gastric vein in 13 cases and the posterior gastric vein in three cases. The drainage route was a splenorenal shunt in all cases. The average dose of ET+LPD was 12.0 mL, while that of CA was 2.45 mL. All complications were transient, and no major complications occurred after the procedures. None of the patients experienced bleeding or recurrence of gastric varices after the combined B-RTO and EIS procedures during an average follow-up period of 38.3 months. CONCLUSION Combined B-RTO with ET+LPD and simultaneous EIS with CA is considered to be an effective and safe procedure for treating GVs.

Su1471 Noninvasive Evaluation of the Risk of Hepatocellular Carcinoma Oncogenesis in Chronic Hepatic Disease by Measuring Shear Wave Velocity

Partially Hydrolyzed Guar Gum (PHGG) Attenuates Nonalcoholic Steatohepatitis (NASH) in Mice Through the Gut-Liver Axis Kazuhiro Katada, Yuji Naito, Tomohisa Takagi, Katsura Mizushima, Yasuki Higashimura, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiko Uchiyama, Ishikawa Takeshi, Osamu Handa, Hideyuki Konishi, Nobuaki Yagi, Hiroshi Ichikawa, Zenta Yasukawa, Makoto Tokunaga, Tsutomu Okubo, Lekh R. Juneja, Yoshito Itoh

Three Patients with Viral Breakthrough During Pegylated Interferon Alpha-2b and Ribavirin Therapy: A Case Series

Introduction A viral breakthrough occurs when a patient achieves a response while on interferon (IFN) therapy and then loses the response despite continued IFN therapy. The cause of viral breakthroughs is not well understood. We encountered three cases with viral breakthrough during treatment with pegylated interferon (PEG-IFN) and ribavirin (RBV). Case presentation The three cases were all late virological responders. They did not express anti-IFN alpha-2b antibodies after PEG-IFN and RBV therapy. We analyzed amino acid substitutions of core 70, core 91, and interferon sensitivity-determining region (ISDR), which significantly influence sustained virological response (SVR). Their amino acid substitutions of core 91 were mutant in two cases. Amino acid substitutions of ISDR were wild pattern in two cases. PEG-IFN adherence was above 80% in three cases, and RBV adherence was below 80% in two cases. Conclusion During PEG-IFN and RBV therapy, we should watch for viral breakthrough in late virological responders with mutant type of amino acid substitutions of core 91, wild pattern of amino acid substitution of ISDR, and decrease of RBV adherence. Viral breakthrough is an important problem in PEG-IFN and RBV therapy for chronic hepatitis C. Therefore, it should be investigated more thoroughly in more cases.