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Background and Aim: We intended to determine whether laparoscopic splenectomy (Lap-Sp) contributes to treatment with interferon therapy in hepatitis C virus (HCV)-cirrhotic patients with thrombocytopenia caused by hypersplenism., Methods: From December 2004 to August 2008, 100 cirrhotic patients (54 men and 46 women) underwent Lap-Sp for a clinical application of interferon therapy. All the patients were Child-Pugh class A or B with thrombocytopenia (average platelet count, 56 × 10(3) /mm(3)). The HCV genotype was type 1 in 80 patients and type 2 in 20 patients., Results: Pure laparoscopic or hand-assisted laparoscopy was performed in 78 and 22 patients, respectively, without mortality. Conversion to open surgery was not required in any of the patients. The platelet counts improved (mean platelet count 172 × 10(3) /mm(3) 1 month after surgery) and interferon (IFN) therapy was started in 97 patients. In this study period, 36 patients obtained a sustained virologic response. Eight patients discontinued IFN therapy because of depression, neutropenia or other reasons., Conclusions: Lap-Sp permits most patients with HCV cirrhosis and hypersplenism to receive sufficient IFN therapy. Therefore, Lap-Sp can become a strong supportive surgery for cirrhotic patients who require antiviral therapy., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aims: Balloon-occluded retrograde transvenous obliteration (B-RTO) is an effective treatment for gastric varices (GVx), as well as hepatic encephalopathy. The aim of this study was to examine the changes of the hepatic vein pressure gradient (HVPG) after B-RTO and determine the relation between the changes of HVPG and liver function., Patients and Methods: B-RTO was performed in 30 patients with GVx and hepatic encephalopathy. HVPG was measured in 19 of 30 patients both before and after B-RTO., Results: The B-RTO was successful in all patients. The GVx and hepatic encephalopathy were improved, and no recurrence or bleeding was observed within the follow- up period. The serum albumin and prothrombin activity were significantly improved 6 months after B-RTO in all patients. HVPG was elevated 44% above the baseline after B-RTO. Liver function significantly improved 6 months after B-RTO in patients whose HVPG increased ≥ 20% from baseline., Conclusion: An elevated HVPG after B-RTO is one aspect of the effect of liver function, and an HVPG increase of ≥ 20% from baseline is a predictive factor for obtaining an improvement of liver function., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Although the incidence of bleeding from gastric varices is relatively low (10%-36%), the bleeding is massive once it has occurred and it increases the patient's mortality. The management of esophageal variceal bleeding is highly differentiated with several effective treatments available. In contrast, bleeding from gastric varices continues to be a therapeutic challenge. In the last decade, there have been increasing reports regarding the management of gastric varices. In this article we review recent progress in the management of gastric varices and discuss further expected studies., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Background and Aims: To evaluate and compare laparoscopic splenectomy and partial splenic embolization as supportive intervention for cirrhotic patients with hypersplenism to overcome peripheral cytopenia before the initiation of and during interferon therapy or anticancer therapy for hepatocellular carcinoma., Methods: Between December 2000 and April 2008, 43 Japanese cirrhotic patients with hypersplenism underwent either laparoscopic splenectomy or partial splenic embolization as a supportive intervention to facilitate the initiation and completion of either interferon therapy or anticancer therapy for hepatocellular carcinoma. We reviewed the peri- and post-intervention outcomes and details of the subsequent planned main therapies. For interferon therapy, the rate of completion, the rate of treatment cessation and virological responses were evaluated. Anti-cancer therapies for hepatocellular carcinoma included liver resection, ablation therapy, intra-arterial chemotherapy, and transarterial chemoembolization., Results: All patients tolerated the operations well with no significant complications. The platelet count was significantly higher in the laparoscopic splenectomy group than in the partial splenic embolization group at 1 and 2 weeks after the intervention. Interferon therapy was stopped in two patients in the partial splenic embolization group due to recurrent thrombocytopenia whereas all patients in the laparoscopic splenectomy group completed interferon therapy. The planned anticancer therapies were performed in all patients, and were completed in all patients without any problems or major complications., Conclusion: Laparoscopic splenectomy may be superior to partial splenic embolization as a supportive intervention for cirrhotic patients with hypersplenism. Future prospective, randomized controlled patient studies are required to confirm these findings.

Aim: This study investigated the relationship between portal hypertensive gastropathy (PHG) and splenomegaly, and the effect of laparoscopic splenectomy on PHG in cirrhotic patients with portal hypertension., Methods: Seventy patients with liver cirrhosis and portal hypertension were prospectively studied. Indication for laparoscopic splenectomy was bleeding tendency in 10 patients, induction of interferon in 45, treatment of hepatocellular carcinoma in seven, and treatment for endoscopic injection sclerotherapy-resistant esophagogastric varices in eight. The severity of PHG was classified into none, mild, or severe according to the classification by McCormack et al. The severity of liver disease was classified using the Child-Pugh score. All patients underwent upper gastrointestinal endoscopy before and 1 month after the operation., Results: The prevalence of PHG was significantly correlated with the severity of liver disease using the Child-Pugh score. The severity of PHG was significantly correlated with the resected spleen volume. One month after the operation, PHG was improved in 16 of 17 patients with severe PHG and in 12 of 32 with mild PHG. The Child-Pugh score showed a significant improvement (6.8 +/- 1.4 to 6.2 +/- 1.2) at 3 months after laparoscopic splenectomy (P < 0.0001)., Conclusions: PHG may be associated with splenomegaly, and laparoscopic splenectomy may have a beneficial effect on PHG, at least for a short time.

Background and Aim: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a new alternative treatment for gastric varices (GVx), but the long-term efficacy is not known. We investigated the long-term effects of B-RTO on rebleeding, prevention of first bleeding, mortality and occurrence of risky esophageal varices (EVx)., Methods: B-RTO was performed in 68 cirrhotic patients with GVx. Twenty patients had recent bleeding, transiently treated by endoscopic Histoacryl injection or balloon tamponade. Forty-eight patients had varices likely to bleed, but no bleeding. After B-RTO, the recurrent bleeding, occurrence of EVx and mortality over the long-term were evaluated., Results: B-RTO was successfully performed in 63 of 68 patients (92.6%). Varices eradication was confirmed by endoscopy in 61 of 63 patients (96.6%). During follow up, GVx bleeding occurred in two patients (3.2%). The 8-year cumulative rebleeding rates of patients with bleeding and risky GVx were 14% and 0%, respectively. Risky EVx occurred in 10 patients (17%) and the cumulative occurrence rate was 22% in 8 years. The cumulative occurrence rate of risky EVx was higher in GVx with EVx (GOV2-GVx) compared to GVx without EVx (IGV1, P < 0.05). No ectopic variceal bleeding occurred. No patients died from variceal bleeding. Hepatocellular carcinoma was the only significant prognostic factor (P < 0.05)., Conclusion: B-RTO is beneficial over the long-term, despite worsening EVx in some patients, because of excellent treatment efficacy and improved mortality. We believe that B-RTO can become a first-choice radical treatment following hemostasis for gastric variceal bleeding and prophylactic treatment for risky GVx.

Background and Aim: We investigated the prognostic significance of changes in the Doppler hepatic vein (HV) waveforms in cirrhotic patients with portal hypertension and the mechanisms of these changes., Methods: A total of 103 consecutive patients were included in this study and their HV waveforms were classified into four types: type I, triphasic waveform; type II, biphasic waveform; type III, biphasic waveform with reduced phasic oscillations; and type IV, a flat waveform., Results: Type I was observed in 34, type II in 40, type III in 23, and type IV in six patients. The 5-year survival rates were 90%, 89%, 41%, and 0% in type I, II, III, and IV, respectively. Five variables including the Child-Pugh score, albumin, bilirubin, ascites, and HV waveform significantly correlated with the survival in a univariate analysis. A multivariate analysis only identified the HV waveform (type III and IV) to be an independent prognostic value. Even in Child-Pugh class B patients, the 5-year survival rate for type III or IV was as poor as 26% in comparison to 92% for type I or II. In contrast, in Child-Pugh class C patients, the 5-year survival rate for type I or II was as good as 63% in comparison to 25% for type III or IV. Furthermore, the changes in HV waveforms correlated with the extent of hepatic fibrosis, the increase in portal perfusion per liver volume, or the decrease in portal vascular resistance., Conclusions: Analyzing the HV waveforms was thus found to be a simple method for accurately assessing the prognosis in cirrhotic patients with portal hypertension.

Background and Aim: In Japan, endoscopic injection sclerotherapy (EIS) is widely used to prevent first esophageal variceal bleeding, in contrast to pharmacological therapy which is the main treatment used in the rest of the world. The present study investigated if propranolol alone is acceptable to prevent first esophageal variceal bleeding in Japanese cirrhotic patients. This was compared with EIS., Methods: Twenty-five Japanese cirrhotic patients with endoscopically proven, likely to bleed esophageal varices were randomly assigned for propranolol administration (12 patients; group A) and EIS (13 patients; group B) to prevent first esophageal variceal bleeding. Complications, non-recurrence rate, bleeding rate and probability of survival were compared between the two groups., Results: One patient in group A had severe bradycardia with loss of consciousness that seriously worsened his quality of life. The cumulative non-recurrence rate of group A was significantly lower compared with that of group B (P < 0.05). In group A, 2 of the 12 patients requested to discontinue taking propranolol and were excluded from the trial. The EIS treatment (group B) showed excellent results. No patient in group A or group B bled from esophageal varices throughout this study. The two groups showed no statistically significant differences in probability of survival., Conclusions: Propranolol alone may not be acceptable to prevent first esophageal variceal bleeding in Japanese cirrhotic patients.

Background: Several previous studies have shown that hepatic regeneration after partial hepatic resection accelerates over time once a splenectomy has been performed. This was a retrospective study investigating whether a splenectomy has some beneficial effects for cirrhotic patients with esophageal varices., Methods: Ninety-three patients underwent either esophageal transection, including splenectomy (splenectomy group), or endoscopic injection sclerotherapy (controls) for esophageal varices. No patient had hepatocellular carcinoma and the grades of their hepatic function were from mild to moderate. The changes in hepatic and splenic functions and liver volume were evaluated, as well as the probability of survival., Results and Conclusions: Both plasma white blood cell and platelet counts significantly increased in the splenectomy group compared to the controls (P < 0.05). The proportion of liver volume 1 year after the treatments compared to the volume before the treatments (which was 100%) was 96.4% in splenectomy group and 94.4% in controls. No patient had serious complications, such as severe infection caused by the splenectomy. The two groups showed no statistically significant differences in survival rates throughout this study. Although hypersplenism significantly was improved by splenectomy, no difference in changes in liver volume nor survival probability between the two groups was found. Further studies, such as those with a large number of patients, long-term volumetric analysis, or histopathological examination, are needed to clarify fully the effects of splenectomy on cirrhotic patients.

Background: The effect of the spleen on the cirrhotic liver is unknown. Transforming growth factor-beta 1 (TGF-beta 1), which plays a crucial role in the matrix production during liver fibrosis, is an inhibitory factor regarding the regeneration of hepatocytes. In this study, we investigated the TGF-beta 1 production in the spleen of cirrhotic rats and the effects of a splenectomy on the healing process from liver fibrosis., Methods: Thirty-six Wistar male rats were used. Thioacetamide (TAA) was administered intraperitoneally for 24 weeks. The rats underwent either a sham operation (TAA + Sham) or a splenectomy (TAA + SPL). The improvements in liver fibrosis and liver regeneration were investigated 10, 30 and 60 days after the operations in each group. The effect of a splenectomy on the plasma concentration of TGF-beta 1 in the portal vein was investigated by ELISA. The TGF-beta 1 expressions in the spleen were measured using immunohistochemical staining and the degree of such expression was measured using RT-PCR. The activity of TGF-beta 1 in the portal vein of TAA + Sham and TAA + SPL was assessed by the inhibiting effect of rat parenchymal hepatocyte proliferation in primary culture., Results: Liver regeneration (PCNA-labeling index) in the TAA + SPL rats was stimulated more at 10 and 30 days after the operation (P < 0.05) than in the TAA + Sham rats, and the improvement of liver fibrosis (fibrosis rate) in the TAA + SPL rats was higher at 60 days (P < 0.05) than in the TAA + Sham rats. The plasma concentration of TGF-beta1 of the portal vein in TAA + SPL rats was significantly lower than in the TAA + Sham rats for each period. Immunohistochemically, TGF-beta1-positive stained cells were recognized in the spleen macrophages in the red pulp of cirrhotic rats. The plasma of the TAA + Sham rats at 10 and 30 days after the operation was significantly stronger than that of the TAA + SPL rats in inhibiting the proliferation of rat hepatocytes of primary culture. Inhibitory effects were then dose-dependently neutralized by monoclonal TGF-beta 1 antibody., Conclusion: Spleen-derived TGF-beta 1 may thus play an inhibitory role in the healing of liver cirrhosis by inhibiting the regeneration of the damaged liver.

Background and Aims: Portal hypertensive gastropathy (PHG) is now recognized to be a distinct entity. Recently, angiogenesis has been noticed as a key factor in clarifying the pathophysiology of various diseases. Angiogenesis in the PHT of explored gastric mucosa has yet to be explored. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. The aim of the present study was thus to investigate whether the hypoxic state exists in PHG, and whether VEGF appears more strongly in PHG than in normal gastric mucosa and, if so, what exactly is the role of the hypoxic state and VEGF in PHG., Methods: At 1, 3, 7 and 14 days after either a portal ligation or sham operation, the portal venous pressure, the gastric mucosal blood flow volume and the blood gas were measured and, the expression of VEGF and antiproliferating cell nuclear antigen (PCNA) in gastric mucosal specimens was immunohistochemically assessed., Results: The portal pressure (PP) and the gastric mucosal blood flow (GMBF) in the PHT rats were significantly greater than in the control (CTR). Both the SaO2 and PaO2 of the arterial blood gas were lower in the PHT rats than in the control rats. The percentage of VEGF expression in the PHG was found to be higher than that in the control gastric mucosa. The percentage of PCNA expression in the PHG was higher than that in the control gastric mucosa., Conclusion: The levels of SaO2 and PaO2 were lower in the PHT rats. There is a possibility that a kind of portal hypertensive gastric change may trigger an enhanced histochemical expression of VEGF. The increased activity of VEGF may have a possibility of the hypoxic gastric mucosal state caused by the presence of active congestion. This damaged mucosal state 'PHG' may thus facilitate the fragility in PHG and such lesions may be slow and insidious, which may therefore lead to sudden and severe anemia, thus causing massive and sometimes fatal hemorrhaging.

Background and Aims: Prostacyclin has been shown to play a role in hyperdynamic circulation in portal hypertension. Recently, a new subtype of cyclo-oxygenase (COX), COX-2, which acts as an inducible synthase in response to various stimuli. The aim of this study was to investigate whether COX-2 contributes to portal hypertension and whether a COX-2 blockade induces the same sort of gastric mucosal injury as a COX-1 blockade., Methods: Portal hypertension (PHT) in rats was induced by a two-step ligation of the portal vein. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), serum levels of 6-keto-prostaglandin F1alpha (PGF1alpha), thromboxane B2 (TXB2) and gastric mucosal injury induced by pure ethanol were all measured in PHT rats receiving different inhibitors (indomethacin, a highly selective COX-1 inhibitor; NS-398, a highly selective COX-2 inhibitor). Control rats treated by a sham operation were also studied., Results: The NS-398 administration significantly decreased PP to the same extent as indomethacin at doses of 5 and 10 mg/kg in PHT rats after a 60 min administration, while neither inhibitor affected the control rats. Both inhibitors significantly increased PP after a 30 min administration in the PHT and control rats at a dose of 5 mg/kg while both inhibitors significantly decreased PP after 60 min administration only in the PHT rats. Portal vein ligation treatment induced a significant increase in PP and BFV of the portal vein, gastric mucosa, oesophageal mucosa and the serum levels of 6-keto-PGF1alpha and TXB2, while portal vein ligation treatment induced a significant decrease in BFV of the liver. Both blockades increased MAP and decreased PP and BFV in the splanchnic area and decreased the serum level of 6-keto-PGF1alpha and TXB2 in the PHT rats, while neither blockade modified any parameters in the control rats, except that indomethacin administration significantly decreased the BFV of the gastric mucosa. Indomethacin administration significantly increased the ulcer index (UI). The NS-398 had no effect on UI in either the PHT or control rats. Only indomethacin significantly increased the number of rats demonstrating gastric mucosal long lesions (> 2 cm) in the PHT rats., Conclusion: In the PHT rats, prostaglandin seemed to contribute to portal hypertension. Both COX blockades reduced PP and BFV of the portal vein and gastric mucosa. NS-398, a selective COX-2 inhibitor, may, therefore, improve portal hypertension without inducing gastric mucosal injury.

We report here complications of percutaneous transhepatic catheterization of the portal venous system in 170 Japanese patients with portal hypertension. All patients underwent percutaneous transhepatic portography and percutaneous transhepatic obliteration of oesophagogastric varices was also performed in 29 patients. After retraction of the catheter, the puncture canal was plugged with gelatin sponge in 150 subjects and with one steel coil in 20 others. The overall complication rate was 16.5%. Intraperitoneal bleeding occurred in 10.6% of patients and 2.9% required blood transfusion. In these patients with intraperitoneal bleeding, the gelatin sponge was used for plugging after retraction of the catheter, while in the 20 patients with a steel coil plug, haemoperitoneum never occurred. Right pleural effusion was recognized in 3.5% of patients, intraperitoneal bile leakage in 1.8% and deterioration of liver function due to arteriovenous fistula in 0.6%. By univariate and multivariate analyses, female gender was the only risk factor for intraperitoneal bleeding among 150 patients investigated by percutaneous transhepatic catheterization of the portal venous system with gelatin sponge plugging. Intraperitoneal bleeding is the most important complication in patients with portal hypertension; it is difficult to predict intraperitoneal bleeding before retraction of the catheter in patients for whom gelatin sponge is used. Thus, for patients undergoing percutaneous transhepatic catheterization of the portal venous system, close follow up is recommended.