Masashi Yoneda

Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis

The therapeutic efficacy of angiotensin II receptor antagonist, losartan, was studied in patients with nonalcoholic steatohepatitis (NASH). Seven patients with both NASH and hypertension were treated with losartan (50 mg/d) for 48 weeks. Treatment with losartan resulted in a significant decrease in blood markers of hepatic fibrosis, plasma TGF‐β1 and serum ferritin concentration concurrently with an improvement in serum aminotransferase levels. Histological assessment showed improvement of hepatic necroinflammation in five patients, reduction of hepatic fibrosis in four patients, and disappearance of iron deposition in two patients. No side effect of treatment was noted at any time during the study. In conclusion, the present data raise the possibility that an angiotensin II receptor antagonist may be therapeutically efficacious for NASH. (HEPATOLOGY 2004.)

Plasma transforming growth factor‐β1 level and efficacy of α‐tocopherol in patients with non‐alcoholic steatohepatitis: a pilot study

Non‐alcoholic steatohepatitis is a distinct entity, characterized by fatty change, lobular inflammation and fibrosis of the liver. Some cases of non‐alcoholic steatohepatitis progress to cirrhosis, but it is not easy to distinguish this disease from non‐alcoholic fatty liver by non‐invasive examinations. No proven therapy for non‐alcoholic steatohepatitis exists. Transforming growth factor‐β1 is implicated in the development of liver fibrosis, and is inhibited by α‐tocopherol (vitamin E) in the liver. Therefore, in this study, the significance of the measurement of the level of plasma transforming growth factor‐β1 and the effect of α‐tocopherol on the clinical course of non‐alcoholic steatohepatitis were investigated.

Transient elastography in patients with non-alcoholic fatty liver disease (NAFLD)

Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver injury in many countries around the world.1 NAFLD covers a wide spectrum, ranging from simple steatosis—which is generally non-progressive—to non-alcoholic steatohepatitis (NASH). There are no established non-invasive methods of evaluation for patients with NASH, and until recently liver biopsy was the only method for evaluating liver fibrosis. Transient elastography is a new technique that allows rapid, non-invasive measurement of mean tissue stiffness, which has been shown to be useful for accurate estimation of hepatic fibrosis in patients with chronic hepatitis C.2 We carried out a study to determine the value of liver stiffness measurement with the new medical device called the …

Efficacy of ursodeoxycholic acid in Japanese patients with type 1 autoimmune hepatitis

Ursodeoxycholic acid (UDCA) has been shown to have beneficial effects on patients with primary biliary cirrhosis, suggesting that UDCA has immunomodulating effects. We investigated the effect of UDCA in patients with autoimmune hepatitis (AIH) which is characterized by immunological abnormalities. Eight patients with type 1 AIH were treated with 600 mg of UDCA per day for 2 years. Based on the criteria of the International Autoimmune Hepatitis Group, five patients were diagnosed as definite and three as probable type 1 AIH. Liver function tests were performed every 4 weeks, before and during UDCA therapy and the serum levels of anti‐nuclear antibodies (ANA), smooth muscle antibodies (SMA), immunoglobulin G and gamma globulin were determined every 3 months. The levels of serum aspartate aminotransferase and alanine aminotransferase significantly decreased from 154 ± 24 IU/L and 170 ± 17 IU/L before UDCA therapy to 31 ± 3 IU/L and 25 ± 5 IU/L (P < 0.001) after 1 year of treatment and 28 ± 2 IU/L and 23 ± 4 IU/L (P < 0.001) after 2 years of treatment. After 2 years of treatment, the levels of serum immunoglobulin G and gamma globulin significantly decreased (P < 0.05) and ANA titres (5/8 patients) were reduced and SMA (3/5. patients) became negative. Furthermore, hepatic histopathological changes of four patients were assessed after 1 year of treatment, and an improvement of intrahepatic inflammation, but not fibrosis, was observed. In conclusion, these results suggest that UDCA has a beneficial therapeutic effect in patients with type 1 autoimmune hepatitis.

Transient responses of inflammatory cytokines in acute stress

It has been demonstrated that concentrations of pro-inflammatory cytokines such as interleukin-1beta (IL-1beta) and interleukin-6 (IL-6) are elevated by acute stress. Although several studies confirmed robust changes in IL-6, how acute stress affects other cytokines was less clear. Therefore, the present study simultaneously examined the effects of acute stress on several pro-inflammatory cytokines. Sixteen male participants were given the Trier Social Stress Test (TSST). Blood samples were collected at baseline, immediately after, and 30, 60, and 90min after the TSST. IL-1beta significantly increased immediately after the TSST and returned to the baseline level after 30min. Additionally, this elevation of IL-1beta was correlated with the perceived intensity of stress. These results showed that the concentration of IL-1beta is rapidly regulated, and that elevation of the IL-1beta level could possibly be attributed to transient mobilization of monocytes caused by sympathetic nervous activation. Moreover, a transient increase of IL-1beta might be conveyed to the brain and play a role in forming negative emotional states.

High, but not low, molecular weight hyaluronan prevents T-cell-mediated liver injury by reducing proinflammatory cytokines in mice

BackgroundThe extracellular matrix component hyaluronan (HA) modulates the production of various cytokines and chemokines by activated inflammatory cells. In this study, we investigated whether exogenous administration of HA influences T-cell-mediated liver injury and cytokine production.MethodsLiver injury was induced by administration of concanavalin A (Con A) or D-galactosamine/lipopolysaccharide (GalN/LPS), and 0.05%–0.35% (v/v) HA (MW 250, 470, 780, 900, and 1200 kDa) was administered intravenously 18 h before Con A or GalN/LPS injection. Plasma ALT level was determined enzymatically and plasma cytokine levels were determined by ELISA.ResultsThe elevated plasma levels of ALT at 8 h after Con A and at 7 h after GalN/LPS injection were significantly decreased by pretreatment with high molecular weight HAs (780, 900, and 1200 kDa) but not low molecular weight HAs (250 and 470 kDa). High molecular weight HA (900 kDa) significantly reduced plasma tumor necrosis factor-alpha, interferon gamma, macrophage inflammatory protein 2, and interleukin 4 levels after Con A injection. However, this inhibitory effect on plasma cytokines was not observed with low molecular weight HA (250 kDa) pretreatment.ConclusionsThe present results suggest that high molecular weight but not low molecular weight HA prevents liver injury by reducing proinflammatory cytokines in a T-cell-mediated liver injury model.

Macrophage inflammatory protein-2 induced by TNF-α plays a pivotal role in concanavalin A-induced liver injury in mice

Abstract Background/Aims : Macrophage inflammatory protein-2 (MIP-2), one of the CXC chemokines, is involved in the recruitment of neutrophils in several tissue injuries. In this study, we investigated the role of MIP-2 in concanavalin A (Con A)-induced liver injury in mice. Methods : Liver injury was induced by intravenous injection of Con A (15 mg/kg) and plasma alanine aminotransferase (ALT), MIP-2 levels were determined and histological assessment of the liver was performed. Anti-mouse MIP-2 antibody was intravenously administered 30 min before Con A injection. Results : The plasma ALT level significantly elevated and reached a maximum at 8 h after Con A injection. The plasma MIP-2 level was also elevated and reached a peak value at 2 h after Con A injection. The elevated ALT level by Con A injection was significantly inhibited by the MIP-2 antibody. The elevated plasma MIP-2 level after Con A injection was significantly reduced by the tumor necrosis factor alpha (TNF- α ) antibody, and MIP-2 was induced in plasma after recombinant TNF- α injection. Hepatic necrosis and infiltration of neutrophils were observed after Con A injection, and these histological changes were attenuated by the MIP-2 antibody. Conclusions : These findings suggest that Con A induces TNF- α release, and this TNF- α stimulates MIP-2 induction, at least partially contributing to the liver injury mediated through the recruitment of neutrophils.

Vagal regulation of gastric function involves thyrotropin-releasing hormone in the medullary raphe nuclei and dorsal vagal complex.

There is convincing electrophysiological, neuroanatomical and functional data in support of an excitatory action of thyrotropin-releasing hormone (TRH) on the dorsal motor nucleus of the vagus neurons leading to stimulation of vagal outflow to the stomach and to a vagal cholinergic-dependent stimulation of gastric secretory and motor function and alterations of mucosal integrity in rats and cats. The raphe pallidus and obscurus have become important medullary nuclei regulating vagal function through their TRH and serotonin projections to the dorsal vagal complex. However, still little is known about the transmitters and conditions which influence the activity of these TRH-containing medullary raphe neurons. Existing knowledge points out a possible physiological role of TRH in mediating vagal reflex and the cephalic phase of digestion.

Evidence-based clinical practice guidelines for nonalcoholic fatty liver disease/nonalcoholic steatohepatitis*

Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in industrialized countries worldwide, and has become a serious public health issue not only in Western countries but also in many Asian countries including Japan. Within the wide spectrum of NAFLD, non‐alcoholic steatohepatitis (NASH) is a progressive form of disease, which often develops into liver cirrhosis and increases the risk of hepatocellular carcinoma. In turn, a large proportion of NAFLD/NASH is the liver manifestation of metabolic syndrome, suggesting that NAFLD/NASH plays a key role in the pathogenesis of systemic atherosclerotic diseases. Currently, a definite diagnosis of NASH requires liver biopsy, though various non‐invasive measures are under development. The mainstays of prevention and treatment of NAFLD/NASH include dietary restriction and exercise; however, pharmacological approaches are often necessary. Currently, vitamin E and thiazolidinedione derivatives are the most evidence‐based therapeutic options, although the clinical evidence for long‐term efficacy and safety is limited. This practice guideline for NAFLD/NASH, established by the Japanese Society of Gastroenterology in cooperation with The Japan Society of Hepatology, covers lines of clinical evidence reported internationally in the period starting from 1983 through January 2012, and each clinical question was evaluated using the GRADE system. Based on the primary release of the full version in Japanese, this English summary provides the core essentials of this clinical practice guideline comprising the definition, diagnosis, and current therapeutic recommendations for NAFLD/NASH in Japan.

Comparison between endoscopic papillary balloon dilatation and endoscopic sphincterotomy for the treatment of common bile duct stones

BackgroundThis study was designed to evaluate the therapeutic outcome and early postoperative complications, especially pancreatitis, of endoscopic papillary balloon dilation (EPBD) and endoscopic sphincterotomy (EST) in patients with common bile duct stones in our department.MethodsOne hundred eighty patients with common bile duct stones were randomized to undergo EPBD or EST. An 8-mm dilatation balloon was used for EPBD. Modified Cotton’s criteria, in which relatively mild pancreatitis is also included as a complication, were used to determine the incidence of postoperative complications.ResultsThe rate of complete removal of stones was significantly higher in the EST group (95.6%) than in the EPBD group (86.6%); for stones less than 10 mm in diameter, however, the rate with EPBD (93.8%) was almost equivalent to that with EST (98.1%). According to modified Cotton’s criteria, the incidence of postoperative pancreatitis was significantly higher in the EPBD group (16.7%) than in the EST group (6.7%). Bleeding was encountered in one patient (1.1%) in the EST group, but in none in the EPBD group. No fatal complication occurred in either the EPBD or the EST group.ConclusionsAlthough EPBD appears to be comparable to EST for removal of small common bile duct stones, mild postoperative pancreatitis is more likely to occur with EPBD than with EST.