Topical application of glycyrrhizin preparation ameliorates experimentally induced colitis in rats

AIM:To examine the efficacy of glycyrrhizin preparation(GL-p) in the treatment of a rat model of ulcerative colitis(UC).METHODS:Experimental colitis was induced by oral administration of dextran sodium sulfate.Rats with colitis were intrarectally administered GL-p or saline.The extent of colitis was evaluated based on body weight gain,colon wet weight,and macroscopic damage score.The expression levels of pro-inflammatory cytokines and chemokines in the inflamed mucosa were measured by cytokine antibody array analysis.The effect of GL-p on myeloperoxidase(MPO) activity in the inflamed mucosa and purified enzyme was assayed.RESULTS:GL-p treatment significantly ameliorated the extent of colitis compared to sham treatment with saline.Cytokine antibody array analysis showed that GL-p treatment significantly decreased the expression levels of pro-inflammatory cytokines and chemokines,including interleukin(IL)-1β,IL-6,tumor necrosis factor-α,cytokine-induced neutrophil chemoattractant-2,and monocyte chemoattractant protein-1 in the inflamed mucosa.Furthermore,GL-p inhibited the oxidative activity of mucosal and purified MPO.CONCLUSION:GL-p enema has a therapeutic effect on experimental colitis in rats and may be useful in the treatment of UC.

Autoimmune thrombocytopenia in response to splenectomy in cirrhotic patients with accompanying hepatitis C

AIM： To estimate the contribution of autoimmune thrombocytopenia to hepatitis C virus-related liver cirrhosis （type C cirrhosis）, we evaluated the influence of splenectomy upon platelet-associated immunoglobulin G （PAIgG） levels and platelet numbers. METHODS： PAIgG titers and immune markers were determined in 24 type C cirrhotic patients with an intact spleen, 17 type C cirrhotic patients submitted to splenectomy, and 21 non-C cirrhosis with an intact spleen. RESULTS： Thrombocytopenia （PLT〈15×10^4/μL） in type C cirrhosis was diagnosed in all patients with an intact spleen, 8 patients submitted to splenectomy, and in 19 non-C cirrhosis with intact spleen. Elevated titers of PAIgG at more than 25.0 ng/107cells were detected in all cirrhotic patients except for one splenectomized patient. PAIgG titers （ng/10^7cells） were significantly higher in the type C cirrhosis with an intact spleen （247.9 ± 197.0） compared with the splenectomized patients （125.6±87.8） or non-C cirrhosis （152.4± 127.4）. PAIgG titers were negatively correlated with platelet counts in type C cirrhotic patients with an intact spleen. In comparison with the type C cirrhosis with an intact spleen, the splenectomized patients had a reduced CD4/CD8 ratio and serum neopterin levels. The spleen index （cm^2） was negatively correlated with platelet counts in the non-C cirrhosis, but not in the type C cirrhosis. CONCLUSION： Our data indicate that the autoimmune mechanism plays an important role in thrombocytosis complicated by HCV-positive cirrhosis. In addition, splenectomy may impair T cells function through, at least in part, a reduction of CD4/CD8 ratio, consequently suppressing PAIgG production.

Spontaneous regression of hepatic inflammatory pseudotumor with primary biliary cirrhosis:Case report and literature review

Hepatic inflammatory pseudotumor （IPT） is a rare benign non-neoplastic lesion characterized by proliferating fibrous tissue infiltrated by inflammatory cells. The exact etiology of IPT remains unclear. Although the association of IPT with systemic inflammatory disorders has been well established, a specific relationship with cholangitis is distinctly rare. We report a case of spontaneous regression of hepatic IPT with primary biliary cirrhosis （PBC）. To date, only two cases of IPT with PBC have been reported. In our case, however, IPT developed during the course of improvement of cholangitis of PBC induced by effective treatment, differing from two previously reported cases. Our case indicates that the development of IPT does not also relate to the activity of cholangitis and/or hyper gamma-globulinemia, since our case was confirmed radiologically to be free of IPT when biliary enzymes and immunoglobulins were much higher than the corresponding values on admission. Comparison of our case with the two previously reported cases suggests that IPT occurring with PBC does not represent the same disease entity or be a bystander for PBC.

Efficacy of balloon-occluded retrograde transvenous obliteration, percutaneous transhepatic obliteration and combined techniques for the management of gastric fundal varices

AIM： To evaluate the effect of three interventional treatments involving transvenous obliteration for the treatment of gastric varices, and to compare the efficacy and adverse effects of these methods, METHODS： From 1995 to 2004, 93 patients with gastric fundal varices underwent interventional radiologic embolotherapy at our hospital. Of the 93 patients, 75 were treated with the balloon-occluded retrograde transvenous obliteration （BRTO） procedure; 8 were with the percutaneous transhepatic obliteration （PTO） procedure; and 10 were with the combined BRTO and PTO therapy. A follow-up evaluation examined the rates of survival, recurrence and rebleeding of the gastric varices, worsening of esophageal varices and complications in each group. RESULTS： The BRTO, PTO, and combined therapy were technically successful in 81% （75/93）, 44% （8/18）, and 100% （10/10） patients, respectively. Recurrence of gastric varices was found in 3 patients in the BRTO group and in 3 patients in the PTO group. Rebleeding was observed in 1 patient in the BRTO group and in 1 patient in the PTO group. The 1- and 3-year survival rates were 98% and 87% in the patients without hepatocellular carcinoma （HCC） in the BRTO group, 100% and 100% in the PTO group, and 90% and 75% in the combined therapy group, respectively. CONCLUSION： Combined BRTO and PTO therapy may rescue cases with uncontrollable gastric fundal varices that remained even after treatment with BRTO and/or PTO, though there were limitations of our study, including retrospective nature and discrepancy in sample size between the BRTO, PTO and combined therapy groups.

Analysis of colonoscopic perforations at a local clinic and a tertiary hospital

AIM： To define the clinical characteristics, and to as- sess the management of colonoscopic complications at a local clinic. METHODS： A retrospective review of the medical re- cords was performed for the patients with iatrogenic colon perforations after endoscopy at a local clinic be- tween April 2006 and December 2010. Data obtained from a tertiary hospital in the same region were also analyzed. The underlying conditions, clinical presenta- tions, perforation locations, treatment types （operative or conservative） and outcome data for patients at the local clinic and the tertiary hospital were compared. RESULTS： A total of 10 826 colonoscopies, and 2625 therapeutic procedures were performed at a local clinic and 32 148 colonoscopies, and 7787 therapeutic proce-dures were performed at the tertiary hospital. The clinic had no perforations during diagnostic colonoscopy and 8 （0.3%） perforations were determined to be related to therapeutic procedures. The perforation rates in each therapeutic procedure were 0.06% （1/1609） in polyp- ectomy, 0.2% （2/885） in endoscopic mucosal resection （EMR）, and 3.8% （5/131） in endoscopic submucosal dis- section （ESD）. Perforation rates for ESD were significantly higher than those for polypectomy or EMR （P 〈 0.01）. All of these patients were treated conservatively. On the oth- er hand, three （0.01%） perforation cases were observed among the 24 361 diagnostic procedures performed, and these cases were treated with surgery in a tertiary hospi- tal. Six perforations occurred with therapeutic endoscopy （perforation rate, 0.08%; 1 per 1298 procedures）. Perfo- ration rates for specific procedure types were 0.02% （1 per 5500） for polypectomy, 0.17% （1 per 561） for EMR, 2.3% （1 per 43） for ESD in the tertiary hospital. There were no differences in the perforation rates for each therapeutic procedure between the clinic and the tertiary hospital. The incidence of iatrogenic perforation requiring surgical treatment was quite low in both the clinic and the tertiary hospital. No procedure-related mortalities occurred. Performing closure with endoscopic clipping reduced the C-reactive protein （CRP） titers. The mean maximum CRP titer was 2.9：1：1.6 mg/dL with clipping and 9.7 ＋ 6.2 mg/dL without clipping, respectively （P 〈 0.05）. An operation is indicated in the presence of a large perforation, and in the setting of generalized peritonitis or ongoing sepsis. Although we did not experience such case in the clinic, patients with large perforations should be immediately transferred to a tertiary hospital. Good relationships between local clinics and nearby tertiary hospitals should therefore be maintained. CONCLUSION： It was therefore found to be possible to perform endoscopic treatment at a local clinic when sufficient back up was available at a nearby tertiary hospital.

Hepatocellular carcinoma in extremely elderly patients:An analysis of clinical characteristics,prognosis and patient survival

AIM： To identify the clinical and prognostic features of patients with hepatocellular carcinoma （HCC） aged 80 years or more. METHODS： A total of 1310 patients with HCC were included in this study. Ninety-one patients aged 80 years or more at the time of diagnosis of HCC were defined as the extremely elderly group. Two hundred and thirty-four patients aged 〉/ 50 years but less than 60 years were regarded as the non-elderly group. RESULTS： The sex ratio （male to female） was significantly lower in the extremely elderly group （0.90：1） than in the non-elderly group （3.9：1, P〈 0.001）. The positive rate for HBsAg was significantly lower in the extremely elderly group and the proportion of patients negative for HBsAg and HCVAb obviously increased in the extremely elderly group （P〈 0.001）. There were no significant differences in the following parameters： diameter and number of tumors, Child-Pugh grading, tumor staging, presence of portal thrombosis or ascites, and positive rate for HCVAb. Extremely elderly patients did not often receive surgical treatment （P 〈 0.001） and they were more likely to receive conservative treatment （P〈 0.01）. There were no significant differences in survival curves based on the Kaplan-Meier methods in comparison with the overall patients between the two groups. However, the survival curves were significantly worse in the extremely elderly patients with stage Ⅰ/Ⅱ, stage Ⅰ/Ⅱ and Child-Pugh grade A cirrhosis in comparison with the non-elderly group. The causes of death did not differ among the patients, and most cases died of liverrelated diseases even in the extremely elderly patients. CONCLUSION： In the patients with good liver functions and good performance status, aggressive treatment for HCC might improve the survival rate, even in extremely elderly patients.

MK-0626,a selective DPP-4 inhibitor,attenuates hepatic steatosis in ob/ob mice

AIM: To investigate the mechanism and in vivo effects of MK-0626, a dipeptidyl peptidase-4 inhibitor, on hepatic steatosis using ob/ob mice.

Reduction of virus burden-induced splenectomy in patients with liver cirrhosis related to hepatitis C virus infection

AIM： To examine the hepatitis C virus （HCV） levels and immunological markers in cirrhotic patients after splenectomy. METHODS： HCV RNA titers as well as cellular and humoral immune markers were determined in 20 cirrhotic patients after splenectomy and in 32 cirrhotic controls with an intact spleen. RESULTS： Serum HCV RNA titers were lower in the splenectomized patients than in the controls （186 ± 225 × 10^3 copies/mL vs 541 ± 417×10^3 copies/mL, P〈0.01）. HCV RNA was judged to have been spontaneously eradicated in 4 splenectomized patients, but in none of the controls. Natural killer cell activity was higher in the splenectomized patients than in the controls （41.2 ± 19.3% vs 24.7 ± 15.3%, P〈 0.01）, and natural killer cell activity was negatively correlated to HCV RNA titers in the splenectomized patients except in those with serotype 2-related infection. The CEH/CD8 ratio was significantly lower in the splenectomized patients than in the controls. CONCLUSION： The findings suggest that splenectomy may diminish virus burden in cirrhotic patients with HCV infection at least in part, through augmentation of natural killer cell activity.

Analysis of ABC (D) stratification for screening patients with gastric cancer

AIM:To evaluate the value of ABC(D) stratification [combination of serum pepsinogen and Helicobacter pylori(H.pylori) antibody]of patients with gastric cancer.METHODS:Ninety-five consecutive patients with gastric cancer were enrolled into the study.The serum pepsinogenⅠ(PGⅠ) /pepsinogenⅡ(PGⅡ) and H.pylori antibody levels were measured.Patients were classified into five groups of ABC(D) stratification according to their serological status.Endoscopic findings of atrophic gastritis and histological differentiation were also analyzed in relation to the ABC(D) stratification.RESULTS:The mean patient age was(67.9±8.9) years.Three patients(3.2%) were classified into group A,7 patients(7.4%) into group A',27 patients(28.4%) into group B,54 patients(56.8%) into group C,and 4patients(4.2%) into group D,respectively.There were only three cases in group A when the patients taking acid proton pump inhibitors and those who had undergone eradication therapy for H.pylori(group A') were excluded.These three cases had mucosal atrophy in the grey zone according to the diagnostic manual of ABC(D) stratification.Histologically,the mean age of the patients with well differentiated adenocarcinoma was significantly higher than that of the patients with poorly differentiated adenocarcinoma(P<0.05) .There were no differences in the pattern of atrophy in the endoscopies between the well differentiated and poorly differentiated groups.CONCLUSION:ABC(D) stratification is a good method for screening patients with gastric cancers.Endoscopy is needed for grey zone cases to check the extent of mucosal atrophy.

Overexpression of NK2 inhibits liver regeneration after partial hepatectomy in mice

AIM： To investigate the in vivo effects of NK2 on liver regeneration after partial hepatectomy （PH）. METHODS： Survival after PH was observed with 21 NK2 transgenic mice and 23 wild-type （WT） mice over 10 d. Liver regeneration was analyzed using histology and immunohistochemistry. Expressions of genes were analyzed using Northern blot analysis, immunoprecipitation and immunoblotting, and reverse transcriptase polymerase chain reaction assay. Kaplan Meier method and the log-rank test were used for analyzing the survival after PH. Differences in the results of immunohistochemistry and percentage of liver regeneration was determined by the Student＇s t-test. RESULTS： More than half of NK2 transgenic mice died within 48 h after PH. After PH, increased deposition of small lipid droplets in hepatocytes was evident and hepatic proliferation was inhibited in NK2 transgenic mice. The hepatic expression and kinase activity of HGF receptor, c-Met, were unchanged among WT mice and NK2 transgenic mice after PH. The expression of tumor necrosis factor-co （TNF-c0 and interleukin-6 （IL-6） in liver tissues were prolonged in NK2 transgenic mice that died after PH. CONCLUSION： Our findings indicate that overexpression of NK2 inhibits liver regeneration after PH.

Clinical characteristics of null responders to Peg-IFNα2b/ ribavirin therapy for chronic hepatitis C

AIM: To predict which chronic hepatitis C patients are likely to be late-responders, we herein investigated the clinical characteristics of null-responders at 36 wk with hepatitis C virus (HCV) genotype Ib and a high viral load during the course of pegylated interferon (Peg-IFN)/ ribavirin ther apy. METHODS: One hundred forty-two patients with genotype Ib HCV and a high viral load were included in this study. Peg-IFNα2b (1.5 μg/kg once a week) and ribavirin (600-1000 mg per day according to body weight) were administered for 48 wk. We def ined nullresponders as the cases that never cleared serum HCV RNA as determined using RT-PCR until 36 wk. Other patients were def ined as responders. We compared the clinical characteristics (age, gender, body mass index, previous treatment) and HCV RNA titer during the therapy between null-responders and responders.RESULTS: The HCV RNA clearance rate was 17.9% (24/134), 46.3% (62/134), 60.6% (86/142), 86.6% (123/142), and 88.0% (125/142) at 4, 8, 12, 24, and 36 wk, respectively. There were 17 patients (12.0%) who were still null-responders at 36 wk. There were no differences in the clinical characteristics between the responders and null-responders except for the titer and decline rates of HCV RNA at 1 wk and 4 wk. The HCV RNA titers at 1 wk and after 4 wk of treatment were significantly higher in the null-responders in comp arison to the responders (P <0.01). The serum HCV RNA titers of the responders decreased by 1.3 log after 1 wk of treatment, and 1.6 log after 4 wk of treatm ent, respectively. On the other hand, the titers of the null responders decreased by only 0.5 log after 1 wk, and 0.7 log after 4 wk of treatment, respectively. The decrease rates of HCV RNA after 1 and 4 wk of treatm ent were signif icantly worse for null responders than for the responders (P <0.01). CONCLUSION: The HCV RNA titer at 1 wk and 4 wk after initiating treatment may be useful for predicting null-responders to Peg-IFNα2b/ribavirin therapy. However, further investigation is needed to determine the optimal time at which the decision to discontinue the Peg-IFNα2b/ribavirin therapy for null-responders can be made.

Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

AIM： To investigate the precise roles of CAR in CCI4- induced acute hepatotoxicity. METHODS： To prepare an acute liver injury model, CCI4 was intraperitoneally injected in CAR＋/＋ and CAR-/- mice. RESULTS： Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR＋/＋ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR＋/＋ mice. On the other hand, androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR＋/＋ but not in CAR./. mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR＋/＋ and CAR./. mice. However, the expression of other CCI4-metabolizing enzymes, such as CYP2B10 and 3All, was induced by PB in CAR＋/＋ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3All in the presence of activator or inhibitor. CONCLUSION： The nuclear receptor CAR modulates CCl4- induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drug- drug interaction even though such drugs themselves are not hepatotoxic.

Living-related liver transplantation for multiple liver metastases from rectal carcinoid tumor: A case report

A 42-year-old woman was admitted to our hospital because of multiple liver tumors detected by ultrasonography. Colonoscopy revealed submucosal tumor in the rectum, which was considered the primary lesion. Endoscopic mucosal resection followed by histopathological examination revealed that the tumor was carcinoid. The resected margin of the tumor was positive for malignant cells. Two courses to transcatheter arterial chemotherapy for liver metastasis were ineffective. Accordingly, the rectal tumor and metastatic lymph nodes were surgically resected. One month after the operation, she received liver transplantation （left lateral segment and caudate lobe） from her son. No recurrent lesion has been observed at two years after the liver transplantation. Liver transplantation should be considered as a treatment option even in advanced case of carcinoid metastasis to the liver. We also discuss the literature on liver transplantation for metastatic carcinoid tumor.

Fulminant hepatic failure resulting from small-cell lung cancer and dramatic response of chemotherapy

Prompt treatment in tumor-associated encephalopathy may prolong survival. We describe a 69-year-old male patient who was presented with fulminant hepatic failure, secondary to small-cell lung carcinoma with rapidly progressing encephalopathy. Both symptoms remitted following chemotherapy, suggesting swift diagnosis and administration of chemotherapy to be effective in treatment of fulminant hepatic failure and encephalopathy.

Extended therapy duration for therapy-refractory hepatitis C patients with genotype 2

We devised an extended 72-wk peginterferon--2a/ribavirin therapy regimen for the retreatment of highly intractable cases,i.e.,48-wk peginterferon--2b/ribavirin therapy-intractable cases.Although 2 cases achieved a rapid virological response to 72-wk peginterferon--2a/ribavirin therapy,1 case failed to achieve a sustained virological response.Although the reason for this difference in the effectiveness of 72-wk peginterferon--2a/ribavirin therapy between the cases was unclear,the rebound phenomenon of serum transaminase after48-wk peginterferon--2b/ribavirin therapy and the resultant lower viral load compared to that before 48-wk peginterferon--2b/ribavirin therapy might have influenced the treatment outcome.Thus,it may be beneficial to consider the rebound phenomenon of serum transaminase and the changes in viral load resulting from previous interferon-based therapy and then cau-tiously determine the indication and the timing of the administration of 72-wk peginterferon--2a/ribavirin in highly intractable cases.Further studies should be performed to confirm this strategy.

Triple therapy of interferon and ribavirin with zinc supplementation for patients with chronic hepatitis C:A randomized controlled clinical trial

AIM： To study the therapeutic effect of interferon （IFN） and ribavirin with zinc supplement on patients with chronic hepatitis C viral （HCV） infection. METHODS： A total of 102 patients confirmed histologically to have chronic HCV infection with genotype lb and more than 100 KIU/mL of HCV were randomly assigned to each arm of the study and each received 10 million units of pegylated interferon （IFN- alpha-2b） daily for 4 wk followed by the same dose every other day for 20 wk plus ribavirin （600 or 800 mg/d depending on body weight）, with or without polaprezinc （150 mg/d） orally for 24 wk. The primary endpoint was sustained virological response （SVR） defined as negative HCV-RNA in the serum 6 mo after treatment. RESULTS： There were no differences in the clinical background between the two groups except for more females in the dual therapy group than in the other group （P〈 0.05）. SVR was observed in 33.3% of the triple therapy group and 33.3% of the dual therapy group. The side effects were almost the same in both groups except for gastrointestinal symptoms, which were less in the triple therapy group （P= 0.019）. CONCLUSION： Considered together, triple therapy of zinc plus IFN and ribavirin for HCV infection patients with genotype lb and high viral load is not better than dual therapy except for lower incidence of gastrointestinal side effects.

Concordance of ulcerative colitis in monozygotic twin sisters

The etiology of inflammatory bowel disease is multifacto rial and appears to combine both genetic and environmental factors. We experienced here a rare occurrence of woman monozygotic twins with ulcerative colitis (UC). A 45-year-old woman (the elder monozygotic twin) was admitted to our hospital because of bloody diarrhea occurring over 10 times per day, abdominal pain and fever. She was diagnosed as UC at the age of 22, and repeated the relapse and remission. She was diagnosed as relapse of UC and total colitis type. Her younger monozygotic twin sister also suffered from UC at the age of 22. Human leukocyte antigen was examined serologically with DNA type in both patients. DRB1*1502, which was previously shown to be dominant in Japanese patients with UC, was not observed in this case. Although the concordance in monozygotic twin in UC is reported to be 6.3-18.8%, the concordant case like this is relatively rare. We report this rare case of UC and the previously reported cases are also discussed.

Different outcomes of nosocomial infection with hepatitis C virus from the same origin

The outcome of infection with hepatitis C virus （HCV） varies substantially from self-limiting infection to chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma among the individuals. The mechanisms that determine the clearance or the persistence of HCV have not yet been clarified. Here, we experienced two cases of hospital-related infection with HCV from the same origin but with quite different outcomes. One case resolved after an episode of acute hepatitis, while the other case developed a chronic hepatitis although they were infected with HCV of the same origin. Although infected with the virus of the same origin, the clinical and virological courses were completely different. This suggests that host factors play a major role in conditioning the outcome of acute HCV infection.

Solitary pituitary metastasis resulting from pulmonary large cell neuroendocrine carcinoma

Solitary pituitary metastasis is a rare phenomenon in human neoplasms. We report a case of lung cancer with the initial manifestation of endocrinopathy resulting from pituitary metastasis. The patient's initial diagnosis was a poorly differentiated carcinoma, however, morbid anatomy revealed a definite diagnosis of large cell neuroendocrine carcinoma(LCNEC). Clinical physicians should be aware of potential initial manifestations such as endocrine abnormalities including panhypopituitarism and diabetes insipidus due to solitary pituitary metastasis. This case demonstrates that an endocrine abnormality such as panhypopituitarism could be an initial manifestation of LCNEC.