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Sorafenib, a multikinase inhibitor, is the first and only drug, which improves significantly the overall survival in patients with advanced hepatocellular carcinoma (HCC). However, many patients experience diverse side effects, some of them severe and unexpected. To date, acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib. Here, we report the case of a 43-year-old woman with hepatitis C virus-related advanced HCC. She received sorafenib, and later complained of a sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense. Laboratory examination showed mild elevation of transaminases, biliary enzymes, bilirubin, inflammation markers, and a marked peripheral eosinophilia. Abdominal computed tomography (CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris. Consequently, sorafenib treatment was stopped immediately, and steroid-pulse therapy was performed. Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings, eosinophilia, and liver functions. In summary, we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.

Objective: Pancreatic cancer is a malignant neoplasm with poor prognosis that might be associated with defective immune function. We aimed to determine the influence on survival of circulating myeloid dendritic cells (c-m-DCs), circulating lymphoid DCs (c-l-DCs), and DCs within the tumor tissue in patients with pancreatic cancer., Patients and Methods: Between December 2001 and June 2006, of a total of 110 patients with ductal adenocarcinoma of the pancreas, 42 underwent pancreatectomy, and 68 had unresectable disease. Numbers of c-m-DCs and c-l-DCs were assessed by flow cytometry, and DCs in the tumor tissue by immunohistochemical staining with anti-fascin mAb., Results: The percentage of the c-m-DCs subset in pancreatic cancer patients was significantly lower than in healthy volunteers, and the similar finding was observed between patients who underwent surgical resection and non-resection. Patients with a high percentage of c-m-DCs or with many DCs accumulated in the cancer tissue survived longer than patients with a low percentage or low number in peripheral blood or the tumor, respectively. Moreover, there was a positive correlation between c-m-DCs within peripheral blood mononuclear cells and the number of DCs per field in the cancer tissue., Conclusions: Preoperative c-m-DCs levels in the PBMC of patients with pancreatic cancer and DCs counts in the cancer tissue can be a prognostic factor after surgical resection. Modulating the distribution of DCs may be an effective therapy in pancreatic cancer patients with a dismal prognosis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Objectives: Regulatory T cells (Treg) can inhibit immune responses mediated by T cells. The aim of this study was to evaluate the prevalence of Treg in peripheral blood mononuclear cells from patients with pancreatic cancers in relation to their clinical outcomes., Methods: Among a total of 100 patients with ductal adenocarcinoma of the pancreas, 40 underwent pancreatectomy and 60 had unresectable disease. Their peripheral blood mononuclear cells were evaluated to determine the proportion of CD4CD25 (FoxP3) T cells, as a percentage of the total CD4 cells, by flow cytometric analysis., Results: The percentage of Treg in the patients with pancreatic cancer was significantly lower than that in the healthy volunteers (P = 0.048), and the patients who underwent surgical resection had lower Treg levels than those with unresectable disease (P = 0.040). Patients in the resected group with a higher percentage of Treg survived longer (P = 0.021). Treg in patients who remained disease free at postoperative 12 months significantly decreased compared to that of the postoperative period (P = 0.009)., Conclusion: A relative increase in Treg may be related to immunosuppression and tumor progression in patients with pancreatic cancer. The immunological monitoring of Treg may be useful to predict the prognosis for patients with pancreatic cancer.

An effective therapeutic strategy for suppressing liver fibrosis should improve the overall prognosis of patients with chronic liver diseases. Although enormous efforts are ongoing to develop anti-fibrotic agents, no drugs have yet been approved as anti-fibrotic agents for humans. Insulin resistance (IR) is reportedly involved in the progression of liver fibrosis. The aim of the present study was to evaluate the effect of combination treatment with a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with liver cirrhosis under the condition of IR. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly improved the progression of serum fibrosis markers, whereas single treatment with either BCAA or ACE-I did not exert these inhibitory effects. The plasma level of transforming growth factor-β was significantly attenuated almost in parallel with the suppression of serum fibrosis markers. Furthermore, the combined treatment with BCAA and ACE-I improved the serum albumin level and IR, which was evaluated using the homeostasis model assessment method for IR. Taken together, since both BCAA and ACE-I are widely used with safety in clinical practice, these results indicate that this combination therapy may represent a potential new future strategy against liver fibrosis development in patients with liver cirrhosis under the condition of IR.

Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Since neovascularization plays an important role in hepatocarcinogenesis and IR, an angiostatic therapy may be considered as one of the promising approaches for chemoprevention against HCC. The aim of the current study was to examine the combination effect of a clinically used branched-chain amino acid (BCAA) and an angiotensin-converting enzyme inhibitor (ACE-I), both reportedly possess anti-angiogenic and IR-improving activities, on the cumulative recurrence after curative therapy. BCAA granules (Livact; 12 g/day) and/or ACE-I (perindopril; 4 mg/day) were administered after the curative therapy for HCC, and several indices were analyzed. A 48-month follow-up revealed that the combination treatment with BCAA and ACE-I markedly inhibited the cumulative recurrence of HCC under IR conditions, whereas neither single treatment exerted a significant inhibition. The soluble form of the vascular endothelial growth factor (VEGF; a central angiogenic factor) receptor-2 (sVEGFR2) was significantly decreased only three months after the treatment without recurrence. We also observed that IR, determined by the homeostasis model assessment (HOMA-IR), was significantly improved by this regimen, indicating that an inhibitory effect was achieved, at least partly, by coordinated effects of anti-angiogenesis and IR improvement. In conclusion, since both BCAA and ACE-I are widely used in clinical practice with safety, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC recurrence in the future. Moreover, sVEGFR2 may become a useful clinical predictive marker of this combination treatment.

Introduction: Budd-Chiari syndrome is a very rare pathological entity that ultimately leads to liver failure. Several therapeutic modalities, including percutaneous transluminal angioplasty, have been attempted to save the life of patients with Budd-Chiari syndrome. Few reports have described a salvage living donor liver transplantation performed after percutaneous transluminal angioplasty in a patient with acute Budd-Chiari syndrome., Case Presentation: A 26-year-old Japanese man developed severe progressive manifestations, such as massive ascites and hematemesis due to rupture of esophageal varices. After making several investigations, we diagnosed the case as Budd-Chiari syndrome. We first performed percutaneous transluminal angioplasty to dilate a short-segment stenosis of his inferior vena cava. The first percutaneous transluminal angioplasty greatly improved the clinical manifestations. However, after a year, re-stenosis was detected, and a second percutaneous transluminal angioplasty failed to open the severe stricture of his inferior vena cava. Since our patient had manifestations of acute liver failure, we decided to perform salvage living donor liver transplantation from his brother. The transplantation was successfully performed and all clinical manifestations were remarkably alleviated., Conclusion: In cases of recurrent Budd-Chiari syndrome, the blocked hepatic venous outflow is not always relieved, even with invasive therapies. We have to take into account the possibility of adopting alternative salvage therapies if the first therapeutic modalities fail. When invasive therapy such as percutaneous transluminal angioplasty fails, liver transplantation should be considered as an alternative option.

The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.

Aim: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH)., Methods: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18-immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated., Results: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18 expression and HOMA-R were significantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization., Conclusion: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH., (2009 The WJG Press and Baishideng. All rights reserved.)

Background/aims: No chemopreventive agent has been approved against hepatocellular carcinoma (HCC) yet. Since neovascularization plays a pivotal role in HCC, an angiostatic agent is considered as one of the promising approaches. The aim of this study was to elucidate the combined effect of the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) on cumulative recurrence after curative treatment on a total of 87 patients, especially in consideration of neovascularization., Methods: VK (menatetrenone; 45 mg/day) and/or ACE-I (perindopril; 4 mg/day) were administered for 36-48 months after curative therapy for HCC. The cumulative recurrence and several indices were analyzed., Results: A 48-month follow-up revealed that the combination treatment with VK and ACE-I markedly inhibited the cumulative recurrence of HCC in association with suppression of the serum level of the vascular endothelial growth factor (VEGF); a central angiogenic factor. The serum level of lectin-reactive alpha-fetoprotein was also suppressed almost in parallel with VEGF. These beneficial effects were not observed with single treatment using VK or ACE-I., Conclusions: The combination treatment of VK and ACE-I may suppress the cumulative recurrence of HCC after the curative therapy, at least partly through suppression of the VEGF-mediated neovascularization.

Background: Although several recent reports have shown that hepatocellular carcinoma (HCC) developed in patients with chronic hepatitis C (CH-C) even after having a sustained virological response (SVR) to interferon (IFN) therapy, it is not common for HCC to develop more than 10 years after SVR., Case Presentation: A 73-year-old Japanese man with CH-C who achieved SVR to IFN therapy 13 years ago was admitted into our hospital because of huge multiple liver tumors along with marked elevation of the tumor markers. Several diagnostic modalities strongly suggested HCC, and we performed histopathological examination. After confirming the diagnosis as well-differentiated HCC, we successfully treated these tumors with intensive combination therapies., Conclusion: Our report highlights the need for careful follow-up for more than 10 years even if the patients with CH-C achieve SVR to IFN therapy.

The objective of this study was to investigate the prevalence of gastric mucosal injury induced by nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA). Upper gastrointestinal endoscopy was performed on 100 RA patients treated with NSAIDs. Patient factors potentially contributing to the development of NSAID-induced gastric mucosal injury were identified by logistic regression analysis; gastric mucosal injury and ulcers were used as objective variables. Gastric mucosal injury was detected in 62 of 100 patients, and eight of these patients had ulcers. Previous history of ulcers, lifestyle, NSAID dosage, and body mass index were associated with the development of gastric mucosal injury,and the use of diclofenac and steroid dose were associated with the development of ulcers. Disease-modifying antirheumatic drugs (DMARDs) did not appear to influence the risk of NSAID-induced gastric mucosal injury. RA patients treated for long periods with NSAIDs for RA symptoms should be controlled with DMARDs, without consideration of increased doses of steroids, in terms of risk for NSAID-induced gastric mucosal injury. Simultaneously, concomitant use of histamine-2 receptor antagonists (H2RA) such as famotidine should be considered.

A 69-year-old man was diagnosed as having myasthenia gravis (MG) in September 2004, and treated with thymectomy and prednisolone. He was then diagnosed as having steroid-induced diabetes mellitus, and received sulfonylurea (SU) therapy in May 2005. An alpha-glucosidase inhibitor (alphaGI) was added in March 2006, resulting in good glycemic control. He experienced symptoms of abdominal distention, increased flatus, and constipation in October 2007, and was admitted into our hospital in late November with hematochezia. Plain abdominal radiography revealed small linear radiolucent clusters in the wall of the colon. Computed tomography (CT) showed intramural air in the sigmoid colon. Colonoscopy revealed multiple smooth surfaced hemispherical protrusions in the sigmoid colon. The diagnosis of pneumatosis cystoides intestinalis (PCI) was made on the basis of these findings. As the alphaGI voglibose was suspected as the cause of this patient's PCI, treatment was conservative, ceasing voglibose, with fasting and fluid supplementation. The patient progressed well, and was discharged 2 wk later. Recently, several reports of PCI associated with alphaGI therapy have been published, predominantly in Japan where alphaGIs are commonly used. If the use of alphaGIs becomes more widespread, we can expect more reports of this condition on a global scale. The possibility of PCI should be considered in diabetic patients complaining of gastrointestinal symptoms, and the gastrointestinal tract should be thoroughly investigated in these patients.

Objectives: Pancreaticoduodenectomy (PD) is still associated with high morbidity. To reduce the frequency of postoperative complications, we have made revisions in perioperative managements of pancreaticoduodenectomy., Methods: Subjects were 128 consecutive patients who underwent PD between January 2000 and August 2006. In June 2004, the following new departmental guidelines were introduced: (1) modified Kakita method of pancreaticojejunostomy, (2) omental wrapping, (3) early removal of closed-suction drain, and (4) restrictive use of pancreatic and biliary duct stenting. Operative mortality and morbidity between 77 patients managed conventionally (group A) and 51 patients since 2004 (group B) were compared. Risk factors for postoperative complications were determined., Results: Postoperative morbidity in group B (39%) was significantly lower than in group A (64%; P = 0.019). Occurrence of grade B/C pancreatic fistula (PF) in group B (6%) was significantly lower than in group A (19%; P = 0.0376). Delayed gastric emptying was significantly reduced in group B relative to group A (23% vs 6%; P = 0.0133). Logistic regression analyses showed that the modified Kakita method was a negative independent factor for overall complications, PF, and delayed gastric emptying., Conclusions: The incidence of overall postoperative complications, grade B/C PF, and delayed gastric emptying after PD has been reduced because of the introduction of a new guideline.

Objective: Severe acute pancreatitis (SAP) frequently progresses to pancreatitis-associated multiorgan failure (MOF) with high mortality. Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimers (UL-VWFM) and the formation of platelet thrombi, ultimately leading to MOF. The purpose of the study was to investigate the potential role of ADAMTS13:AC in the severity of SAP., Material and Methods: Plasma ADAMTS13:AC and its related parameters were sequentially determined in 13 SAP patients. ADAMTS13:AC was determined by the chromogenic act-ELISA., Results: Within 1 or 2 days after admission, ADAMTS13:AC was lower in SAP patients (mean 28%) than in healthy controls (99%), and gradually recovered in the 11 survivors but further decreased in the 2 non-survivors. Patients with higher sepsis-related organ failure assessment (SOFA) scores showed lower ADAMTS13:AC than those without these scores. The inhibitor against ADAMTS13 was undetectable. On day 1, von Willebrand factor antigen (VWF:Ag) was higher (402%, p<0.001) in SAP patients than in controls (100%). VWF:Ag gradually decreased in the survivors, except in the 3 patients needing a necrosectomy, but remained high in the non-survivors. ADAMTS13:AC was inversely correlated with the APACHE II score (r=-0.750, p<0.005), and increased plasma concentrations of interleukin 6 (IL-6) and IL-8 at admission. UL-VWFM-positive patients had lower ADAMTS13:AC and decreased serum calcium concentrations, but higher VWF:Ag and IL-8 concentrations than UL-VWFM-negative patients., Conclusions: Plasma ADAMTS13:AC was closely related to the APACHE II score. This intimate relationship may serve as an early prognostic indicator for SAP patients. The imbalance between decreased ADAMTS13:AC and increased UL-VWFM could contribute to SAP pathogenesis through enhanced thrombogenesis.

Although the etiology of eosinophilic cholecystitis is still obscure, the postulated causes include allergies, parasites, hypereosinophilic syndrome, and eosinophilic gastroenteritis. It is sometimes accompanied by several complications, but a simultaneous onset with pericarditis is very rare. A 28-year-old woman complained of acute right hypocondrial pain and dyspnea associated with systemic eruption. Several imaging modalities revealed acute cholecystitis and pericarditis with massive pericardial effusion. A marked peripheral blood eosinophilia was observed, and the eruption was diagnosed as urticaria. Her serum had a high titer of antibody against Ascaris lumbricoides. Treatment with albendazole drastically improved all clinical manifestations along with normalization of the imaging features and eosinophilia. We report herein a rare case of simultaneous onset of acute cholecystitis and pericarditis associated with a marked eosinophilia caused by parasitic infection.

Background: An increase in gastric mucosal lesions due to nonsteroidal antiinflammatory drugs (NSAIDs) has been reported along with the aging of society; even orthopedic surgeons can no longer remain unconcerned about this disease. However, no study has accurately examined the incidence of gastric mucosal lesions; therefore, adequate evidence has not been established. In this study, endoscopic examinations were performed to determine the status of gastric mucosal lesions in patients receiving long-term NSAID therapy., Methods: In 261 patients receiving NSAIDs other than aspirin for more than 28 days, excluding external application, upper gastrointestinal endoscopy was performed regardless of any subjective symptoms after obtaining the patient's medical history. The severity of the gastric mucosal lesions was evaluated using the modified Lanza score. Patient factors involved in the development of lesions were examined using a logistic regression analysis with criterion variables of gastric mucosal lesions and ulcers and the factors of sex, age, Helicobacter pylori infection, and type of NSAID as candidates for the explanatory variable., Results: Gastric mucosal lesions were observed in 164 patients (62.8%); 27 (10.3%) had ulcers. The use of diclofenac, subjective symptoms, irregular lifestyle, and increased body mass index (BMI) were four factors associated with the development of gastric mucosal lesions; the odds ratios were 2.99, 1.92, 1.80, and 1.09, respectively. Also, the use of diclofenac, presence of H. pylori, irregular lifestyle, alcohol consumption, and aging were five factors associated with the development of ulcers; the odds ratios were 6.40, 6.07, 2.62, 2.06, and 1.05, respectively., Conclusions: Diclofenac can cause gastric mucosal lesions, including ulcers, more easily than other NSAIDs. H. pylori infection is a high-risk factor for ulcers in patients receiving long-term NSAIDs therapy. In NSAID-treated patients, subjective symptoms are not grounds for a diagnosis of gastric mucosal lesions, especially ulcers.

Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor (ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodule in the liver detected by enhanced computed tomography along with elevation of the tumor markers, namely, alpha-fetoprotein (AFP) and lectin-reactive demarcation (AFP-L3), suggesting the presence of latent HCC. After oral administration of VK and ACE-I, the serum levels of both AFP and AFP-L3 gradually decreased without any marked alteration of the serum aminotransferase activity. After one-year treatment, not only the serum levels of AFP and AFP-L3 returned to the normal ranges, but also the dysplastic nodule disappeared. Since both VK and ACE-I are widely used without serious side effects, this combined regimen may become a new strategy for chemoprevention against HCC.

Aim: To evaluate the effect of combination treatment with the interferon (IFN) and angiotensin-converting enzyme inhibitor (ACE-I) on several fibrotic indices in patients with refractory chronic hepatitis C (CHC)., Methods: Perindopril (an ACE-I; 4 mg/d) and/or natural IFN (3 MU/L; 3 times a week) were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed., Results: ACE-I decreased the serum fibrosis markers, whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-I, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-beta was significantly attenuated almost in parallel with suppression of the serum fibrosis markers., Conclusion: The combination therapy of an ACE-I and IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

Background: Many Japanese patients with hepatic disorders confirmed on diagnostic imaging and coexisting upper gastrointestinal (GI) peptic lesions receive treatment with proton pump inhibitors. Some pharmacotherapies used to treat peptic ulcers have been associated with adverse drug reactions (ADRs), including elevated liver enzyme levels., Objective: The aim of this study was to determine the tolerability and effectiveness of rabeprazole sodium in treating peptic lesions in patients with coexisting hepatic disorders., Methods: This open-label, practice-based, postmarketing surveillance investigation was conducted at 15 centers across Japan. Male and female patients aged ≥18 years with peptic lesions confirmed on upper GI endoscopy and with underlying hepatic disease were enrolled. Patients were randomly assigned to receive rabeprazole 10 or 20 mg PO (tablet) QD after a meal for up to 8 weeks. Tolerability was assessed using monitoring of the incidence of ADRs determined by direct patient questioning, spontaneous reporting, and laboratory assessment. All patients who received at least 1 dose of study drug were included in the tolerability assessment. Effectiveness was assessed at baseline and study end using the rates of achievement of improvement on endoscopy, relief of subjective/objective symptoms (rates of improvement in epigastric pain and heartburn), and global improvement. The effectiveness analysis included all patients with complete data before and after treatment. Subanalyses were conducted to determine the effectiveness of drug by identification of the proportion of patients with coexisting hepatic disorders (cirrhosis, chronic hepatitis, and other hepatic diseases [eg, alcoholic hepatitis, fatty liver]) and by peptic lesion (gastric ulcer, duodenal ulcer, stomal ulcer, and reflux esophagitis) who achieved improvement., Results: A total of 114 patients were enrolled; 108 patients were included in the tolerability analysis (81 men, 27 women; mean age, 59.9 years; 10-mg dose, 90 patients; 20-mg dose, 18 patients) and 98 patients were included in the analysis of effectiveness. Twenty-one ADRs occurred in 11 (10.2%) patients. Serious ADRs occurred in 2 patients (elevated bilirubin level and hepatic encephalopathy, 1 patient each). Administration of rabeprazole was discontinued in 5 patients due to the occurrence of the following ADRs: constipation (1 patient); epigastric pain (1); dyslalia, disorientation, tremor, sleep disorder, and hepatic encephalopathy (1); diarrhea (1); and elevated alkaline phosphatase and y-glutamyl transpeptidase levels (1). On endoscopy, the proportion of patients achieving improvement with either dose was 30/33 (90.9%). The relief rates assessed using subjective symptoms were 47/55 (85.5%) and 47/56 (83.9%) for epigastric pain and heartburn, respectively. The proportion of patients achieving global improvement with either dose was 80/98 (81.6%) patients (49/62 [79.0%] for cirrhosis, 11/16 [68.8%] for chronic hepatitis, and 20/20 [100.0%] for other hepatic diseases [alcoholic hepatitis, fatty liver])., Conclusion: In this study in Japanese patients with hepatic disorders, rabeprazole was well tolerated and appeared effective for the treatment of upper GI peptic lesions.

Background: The pathogenesis of alcoholic hepatitis (AH) remains unclear and the prognosis of severe alcoholic hepatitis (SAH) is very poor. Deficiency of von Willebrand factor (VWF)-cleaving protease (VWF-CP/ADAMTS13) results in an increase of the plasma unusually large VWF multimer and leads to platelet clumping, which causes microcirculatory disturbance and finally multiorgan failure. The aim of this study was to explore the potential role of ADAMTS13 on the development of liver disturbance and multiorgan failure in AH., Methods: The activity of plasma ADAMTS13 and its clinical correlation were determined in 14 patients with AH, 4 with SAH (Maddrey score, mean 62), and 10 with alcoholic liver cirrhosis (LC)., Results: The activity of the plasma ADAMTS13 significantly decreased in patients with AH (mean 59%, p < 0.001), SAH (17%, p < 0.001) and LC (76%, p < 0.02) as compared with the healthy subjects (102%, n = 60). The activity was markedly lower in SAH than in AH (p < 0.02) and LC (p < 0.02). In three nonsurvivors with SAH who had multiorgan failure, it was extremely low (4.5%, 5.0%, and 16.0%, respectively), but in a survivor with SAH it remained mild decrease (44%). In AH, the protease activity increased at the recovery stage (42% --> 75%, p < 0.05). In the univariate analysis, the activity correlated with 10 clinical variables including functional liver capacity, inflammation signs, renal function, and platelet count in patients with AH and SAH. Among these, multivariate analysis showed that serum total bilirubin and C-reactive protein independently correlated with the protease activity., Conclusion: The activity of plasma ADAMTS13 markedly decreased in SAH in addition to AH. The activity was closely related to hyperbilirubinemia and inflammation signs, and was extremely low in nonsurvivors with SAH and multiorgan failure. The marked decrease of plasma ADAMTS13 may, in part, contribute to not only the progression of liver disturbance in AH, but also the development of multiorgan failure in SAH through microcirculatory disturbance.

Background: Abstinence is a prerequisite for the treatment of alcoholic chronic pancreatitis, but there are patients who have repeated attacks because of their inability to abstain and the consequent congestive effects of the continued alcohol intake on pancreatic juice. Bromhexine hydrochloride, a bronchial mucolytic, has an affinity for acinar cells and causes them to secrete pancreatic juice of low viscosity., Methods: Twelve patients with alcoholic chronic pancreatitis, who were unable to abstain from drinking, were administered bromhexine hydrochloride for 6 months to assess its therapeutic efficacy., Results: Of 12 patients administered bromhexine, 8 (67%) reported symptomatic improvement, and all patients showed improvement in the levels of pancreatic enzymes. Pancreatic exocrine function also tended to improve, but no improvement of pancreatic endocrine function was detected. Although none of the pancreatic stones present in some patients disappeared, a protein plug present in one patient disappeared, accompanied by improvement in the irregular outline of the lumen of the main pancreatic duct., Conclusion: Bromhexine hydrochloride may be a new for the morbidity of chronic pancreatitis, in which there is increased viscosity of the pancreatic juice and formation of a protein plug.

Although several diagnostic imaging modalities have been significantly improved in the recent years, the definitive diagnosis of intrahepatic cholangiocarcinoma (IHC) is still sometimes difficult because of the versatile features of IHC with each imaging. A 68-year-old Japanese man with alcoholic liver cirrhosis developed an intrahepatic tumor. Several imaging modalities demonstrated various features, such as central calcification and arterio-portal (A-P) shunt. Since we could not reach a final diagnosis and the tumor size gradually increased, partial hepatectomy was done after obtaining written informed consent from the patient. The postoperative histopathological examination revealed a cholangiocarcinoma. Herein, we report this case of IHC that was very difficult to diagnose due to the simultaneous association with central calcification and A-P shunt.

We report the case of a 21-yr-old female with Turner syndrome associated with cerebral hemorrhage (CH). She was transferred to our hospital for loss of consciousness and was diagnosed with right putaminal hemorrhage. Following surgical removal of the hematoma, she regained consciousness, and her left hemiplegia gradually improved after surgery. Angiography revealed absence of vascular abnormality of the cerebral artery, aorta, and renal arteries. Hypertension was noted on arrival at the hospital and persisted after surgery. A slight hypertensive change was observed in her retinas. Plasma renin activity was elevated (20 ng/ml/h) and renovascular hypertension was suspected. In this patient, CH was suspected to have occurred due to hypertension. This case emphasizes the necessity to carefully monitor the blood pressure in Turner syndrome cases, even during childhood.

A 49-year-old man, who had a 30-year history of drinking the equivalent of 80 g of ethanol per day, underwent a detailed medical examination for cough and dyspnea. Chest-abdominal computed tomography and endoscopic retrograde pancreatography led to the diagnosis of a mediastinal pancreatic pseudocyst resulting from obstruction of the pancreatic duct by a protein plug. The pseudocyst rapidly improved with conservative treatment with camostat mesilate, H2-receptor antagonist and digestive enzymes. Although the patient abstained from alcohol for approximately 6 months, he resumed drinking, leading to recurrent attacks of pancreatitis. Bromhexine hydrochloride was then administered for 6 months, with the expectation that it would have a mucolytic effect on the pancreatic juice, resulting in improvement in the clinical symptoms, pancreatic enzymes and pancreatic exocrine function, as well as elimination of the protein plug. Bromhexine hydrochloride may be a new therapy for pathological states, such as alcoholic chronic pancreatitis, in which there is increased viscosity of the pancreatic juice because of elevated protein concentration, leading to protein plug formation and temporary blockage of the pancreatic duct.

Background: It is suggested that endotoxin and proinflammatory cytokines play an important role in the development and progression of alcoholic liver disease. Recently, a prostaglandin receptor subtype EP4 agonist with cytoprotective effect has been developed. We examined the efficacy of an EP4 agonist ONO-AE1-437 on tumor necrosis factor-alpha (TNF-alpha) secretion of Kupffer cells, splenic macrophages, and alveolar macrophages in acute ethanol-loaded rats., Methods: Kupffer cells, splenic macrophages, and alveolar macrophages were isolated from control and acute ethanol-loaded rats (5 mg/g body weight of ethanol, intraperitoneally). After the preculture in the medium that containing 0, 0.1, 1, 10, or 100 nmol/liter of ONO-AE1-437, TNF-alpha secretion of these cells stimulated by 100 ng/ml of endotoxin was determined for 3 hr., Results: The amount of TNF-alpha secreted from alveolar macrophages was largest in both the control and the acute ethanol-loaded rats. Acute ethanol load enhances TNF-alpha secretion of splenic macrophages. The addition of ONO-AE1-437 significantly inhibited TNF-alpha secretion of Kupffer cells and splenic macrophages in both the control and the acute ethanol-loaded rats. Alveolar macrophages were less affected., Conclusions: An EP4 agonist ONO-AE1-437 suppresses excess TNF-alpha secretion from macrophages and seems promising for future trial in patients with severe alcoholic hepatitis.

Our patient was a 71-year-old man who presented with lower abdominal pain, and bloody and white mucosal stools. He purchased by mail-order an electrical muscle stimulation (EMS) device, which he strapped onto his lower abdomen, and for 2 consecutive days he underwent muscle stimulation comprising 600 contractions at 2.40 mA and 1.20 V over a 10 minute period. He experienced the onset of lower abdominal pain immediately following muscle stimulation on the second day, and then passed stools containing blood and white mucus. The cause was thought to be electrical and mechanical stimulation of the lower abdomen by the EMS equipment, either inducing colonic or vascular spasm, or dislodging thrombi associated with atrial fibrillation or atherosclerosis. This is the first known report of ischemic colitis associated with the use of EMS exercise equipment. We report this case in the belief that this condition is likely to become more common with increasing use of such devices.

Mouse embryonic stem (ES) cells are clonal cell lines derived from the inner cell mass of developing blastocysts and have multi-lineage differentiation ability. We previously reported that ES cells can be made to differentiate into hepatocytes possessing high metabolic activities by transfection of hepatocyte nuclear factor-3beta (HNF-3beta). In the present study, we investigated the expression of hepatobiliary organic anion transporters and bilirubin uridine diphosphate glucuronosyltransferase (ugt1a1) in undifferentiated and differentiating HNF-3beta-transfected ES (HNF-3beta-ES) cells. The expression of organic anion transporting polypeptide 1 (oatp1), multidrug resistance-associated protein 1 (mrp1), mrp2, mrp3, and ugt1a1 was not seen in the undifferentiated HNF-3beta-ES cells by RT-PCR, whereas all were expressed in differentiating HNF-3beta-ES cells. Protein expression for oatp1, mrp1, mrp2, mrp3, and ugt1a1 was also observed in the differentiating HNF-3beta-ES cells by Western blotting. An immunofluorescence examination revealed that oatp1 was co-located with desmoplakin, a marker for the basolateral (sinusoidal) membrane, and mrp2 was co-localized with CD26, a marker for the apical (canalicular) membrane, though they were both expressed throughout most of the cell membranes.

Background: It is suggested that endotoxin, proinflammatory cytokines, and lipopolysaccharide-binding protein (LBP) play an important role in the development of alcoholic liver disease. Our previous study showed that splenic macrophages were important for endotoxin uptake and excessive production of tumor necrosis factor (TNF) in rats given large amounts of alcohol. To determine the pathophysiological roles of macrophages in alcoholic liver disease, we examined the effect of ethanol on TNF-alpha secretion of rat Kupffer cells, alveolar macrophages, and peritoneal macrophages in the presence or absence of LBP., Methods: Kupffer cells, alveolar macrophages, and peritoneal macrophages were isolated from male Sprague Dawley rats. After the preculture in the medium containing 0, 10, 50, and 100 mmol/liter of ethanol, TNF-alpha secretion by these cells incubated with 100 ng/ml of endotoxin in the presence or absence of LBP (1% rat serum) was determined., Results: In the absence of LBP, an addition of ethanol to the medium suppressed TNF-alpha secretion of alveolar macrophages. Kupffer cells and peritoneal macrophages were less affected. Addition of LBP led to marked enhancement (7- to 24-fold) of TNF-alpha secretion of macrophages either with or without ethanol in the medium. Although ethanol tended to suppress TNF-alpha secretion of these cells, alveolar macrophages were less affected in the presence of LBP., Conclusions: Serum LBP enhances the secretion of TNF-alpha by macrophages. Alveolar macrophages may be important for excessive production of TNF-alpha in chronic alcoholics with endotoxemia.

Ursodeoxycholic acid (UDCA) has been recognized as a therapeutic drug for primary biliary cirrhosis (PBC) and chronic viral hepatitis. As one of the mechanisms by which UDCA improves liver function tests in those patients, its immunomodulatory effect is currently considered important. Although the suppressive effects of UDCA on some cytokine productions, T-cell mediated cytotoxicity and immunoglobulin production were observed from in vitro studies, the immunomodulation in vivo by UDCA remains unclear. In the present study, we investigated the effect of UDCA administration on the number of immunoglobulin secreting cells in liver, peripheral blood, spleen and Peyer's patches in mice using the enzyme linked immunospot assay and assessed whether the UDCA-mediated immunomodulation is liver-specific. It was demonstrated that intragastric administration of UDCA reduced immunoglobulin secretion by lymphocytes from liver, but not from peripheral blood, spleen, or Peyer's patches. However, immunoglobulin production of those lymphocytes cultured in the presence of UDCA was suppressed, irrespective of their distribution sites, in a UDCA dose-dependent manner. When the concentrations of UDCA in portal and peripheral blood were measured using high performance liquid chromatography, UDCA was detectable in the portal blood in UDCA-treated mice, but not in peripheral blood, suggesting that the concentrations of UDCA in the environment surrounding lymphocytes may be an important factor for the modulation of lymphocyte functions.

Background and Study Aims: Intraductal ultrasonography (IDUS) is a useful method for the diagnosis of pancreatobiliary diseases, but the images obtained using the presently available ultrasonic probes are limited by their two-dimensional nature and are sometimes difficult to interpret. The possible application of three-dimensional intraductal ultrasonography (3 D-IDUS) to facilitate the diagnosis of pancreatobiliary disease was therefore studied using a newly developed system., Patients and Methods: 3 D-IDUS of the biliary system was performed on 26 patients with benign (n = 100) or malignant pancreatobiliary diseases (n = 16), via percutaneous transhepatic or peroral approaches. Three-dimensional diagnoses were made using both radial and linear images generated on the monitor of this system along with a comparison with conventional IDUS (2 D-IDUS) findings., Results: The courses of vessels surrounding the bile duct could be easily imaged in all cases, and accurate assessment of tumor extension and the relationship with surrounding organs could be achieved for all the malignancies. In four of six cases of bile duct cancers the whole outline of the tumor could be visualized so that the tumor volumes could be measured., Conclusions: These preliminary results of 3 D-IDUS in the pancreatobiliary system, the first to be reported in the English literature, indicate that this new system has clear advantages over the 2 D-IDUS approach for diagnostic purposes. Further technical improvements can be expected which will ensure a clinical role for 3 D-IDUS.

Intravenous administration of glycyrrhizin is known to decrease elevated plasma transaminase levels in patients with chronic viral hepatitis, in which immune-mediated cytotoxicity by cytotoxic T lymphocytes and tumour necrosis factor (TNF)-alpha is considered to play an important pathogenic role. However, the immunological interpretation of the transaminase-lowering action of glycyrrhizin is not known. Studies were performed to elucidate this action immunologically by assessing the effects of glycyrrhizin on immune-mediated cytotoxicity using an antigen-specific murine CD4+ T hybridoma line, which exhibits cytotoxicity against antigen-presenting cells after stimulation with specific antigen, and a murine TNF-alpha-sensitive fibroblast line. Glycyrrhizin inhibited the cytotoxic activity of the T cells against antigen-presenting cells and also suppressed TNF-alpha-induced cytotoxicity in the TNF-alpha-sensitive cell line in vitro. These results suggest that the decrease of elevated transaminase levels by glycyrrhizin in patients with chronic viral hepatitis is mediated in part by inhibition of immune-mediated cytotoxicity against hepatocytes.

Seven patients with chronic hepatitis C, six hemophiliacs and a patient with von Willebrand's disease, were treated with interferon-alpha (IFN-alpha). Either 9 MU of recombinant IFN-alpha 2a or 3 MU of lymphoblastoid alpha-IFN was administered daily for 2 weeks and then three times a week for 22 weeks. Liver histology, hepatitis C virus (HCV) genotypes, and HCV-RNA levels in sera were investigated in all of the patients before IFN therapy was instituted. Liver histology was classified by the European classification. HCV genotyping conformed to the so-called Okamoto's classification. HCV-RNA levels in sera were quantitated by competitive polymerase chain reaction, using mutant RNA. Liver histology, HCV genotype, and serum HCV-RNA level (copies/ml) in each patient were: patient 1, chronic persistent hepatitis, type II, 3 x 10(3) respectively; patient 2, chronic active hepatitis (CAH) 2a, type III, 6 x 10(4); patient 3, CAH2a, type IV, 2 x 10(5); patient 4, CAH2b, type I, 2 x 10(7); patient 5, CAH2b, type II, 8 x 10(4); patient 6, CAH2b, type III, 7 x 10(6); and patient 7, CAH2b, type IV, 1 x 10(7). Sustained elimination of HCV was achieved in patient 3 and temporary elimination was achieved in patients 1 and 2. The other patients showed persistent HCV-RNA positivity in sera both during and after IFN treatment. Poor responsiveness to IFN was observed in patients with relatively progressive liver histology and high levels of HCV viremia.

We investigated the relation between gastric mucosal lesions and substance P (SP) in 64 patients with rheumatoid arthritis (RA) taking nonsteroidal antiinflammatory drugs (NSAIDs). In these patients, the incidence of gastric mucosal lesions was as high as 53.1%. Serum SP levels were significantly higher in patients with gastric mucosal lesions than in those without gastric lesions. Erythrocyte sedimentation rate, serum C-reactive protein and rheumatoid factor (RF) levels were also higher in patients with gastric mucosal lesions. A positive correlation between serum SP and RF levels was found in patients with RA. Experimental gastric mucosal lesions induced by an oral administration of indomethacin in rats were significantly enhanced by an additional intraperitoneal injection of SP. From these observations, it is suggested that, in addition to the effect of NSAIDs, SP elevation in blood has a role in the development of gastric mucosal lesion in patients with RA.

We report a 34-year-old man with chronic hepatitis C who showed exacerbation of ulcerative colitis during alpha-interferon (IFN alpha) therapy. Discontinuance of the IFN alpha therapy improved his symptoms, suggesting that IFN alpha administration might worsen ulcerative colitis. The administration of sulfasalazine allowed the patient to receive IFN alpha again without flare-up of ulcerative colitis. This case suggests the possible efficacy of sulfasalazine therapy in patients with ulcerative colitis complicated by some other diseases requiring IFN alpha administration.

Ursodeoxycholic acid was recently recognized as an effective agent in the treatment of primary biliary cirrhosis. Experimental evidence supporting the usefulness of ursodeoxycholic acid as a potentially beneficial therapeutic agent for primary biliary cirrhosis has been reported from the biochemical and physiological aspects. In this study, we investigated the direct effects of ursodeoxycholic acid on immunoglobulin and cytokine production in vitro using plaque-forming cell assay and enzyme-linked immunosorbent assay. It was demonstrated that ursodeoxycholic acid suppressed the production of IgM, IgG and IgA induced by Staphylococcus aureus Cowan I in peripheral blood mononuclear cells derived from healthy subjects and patients with primary biliary cirrhosis and also in human B lymphoma cell lines. Furthermore, ursodeoxycholic acid suppressed interleukin-2 and interleukin-4 production induced by concanavalin A and interferon-gamma production induced by polyinosinic-polycytidylic acid, but it did not affect interleukin-1 and interleukin-6 production induced by lipopolysaccharide in peripheral blood mononuclear cells. In addition, ursodeoxycholic acid suppressed the concanavalin A-induced thymocyte proliferation mediated by interleukin-1. Cytotoxicity against lymphocytes was not observed at the concentrations of ursodeoxycholic acid used. These results suggest that the beneficial effect of ursodeoxycholic acid in primary biliary cirrhosis is mediated in part by immunosuppression.

Percent changes in serum total bile acid level after IV administration of 1 mg glucagon were measured in 61 cirrhotics. Thirty-three of 38 cases with Child's grade A disease showed a reduction of total bile acid level at 15 minutes; this level was maintained in the majority of them until 120 minutes. A similar mode of serial changes in total bile acid level was also shown in the cases with Child's grade B disease. On the other hand, only 2 of 10 cases with Child's grade C showed a reduction of total bile acid level at 15 minutes. Reduction of total bile acid level at 15 minutes after glucagon administration was mimicked by infusion of dibutyryl cyclic adenosine monophosphate. However, in 3 of 6 cases with elevated total bile acid level at 15 minutes after glucagon administration, dibutyryl cyclic adenosine monophosphate induced a reduction of total bile acid level. Also, it was confirmed that glucagon enhances the uptake of taurocholate into freshly isolated rat hepatocytes by activating Na(+)-dependent, carrier-mediated membrane transport system and observed that its effect is associated with elevation of Vmax (0.6114 nmol.min-1 x 10(6) cells-1 without glucagon; 0.975 nmol.min-1 x 10(6) cells-1 in glucagon added) but not with affecting Km (13.58 mumol/L without glucagon; 13.71 mumol/L with glucagon) or protein synthesis which is inhibited by cycloheximide. These observations suggest that glucagon enhances Na(+)-coupled membrane transport of bile acids in the liver and causes the reduction of serum total bile acid level and that a lack of this response may be indicative of membrane dysfunction in the liver.