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Introduction: Laparoscopic devascularization of the upper stomach and splenectomy (Dev+Sp), is technically difficult in patients with portal hypertension because of enlarged collateral vessels and spleen. This report presents the efficacy and safety of hand-assisted laparoscopic (HALS) Dev+Sp., Methods: Ten patients underwent HALS Dev+Sp as a treatment for esophagogastric varices between 2005 and 2012 (HALS group). A vessel-sealing system was used for devascularization of vessels. An autosuture device was applied to dissect the splenic hilum and the left gastric and enlarged short gastric vessels. The operative and postoperative data were compared between patients who previously underwent laparoscopic Dev+Sp (LAP group, n = 9) and conventional Dev+Sp (OP group, n = 10) between 2001 and 2008., Results: The mean operative time was 328, 336, and 245 min (P < 0.05) and the mean blood loss was 1786, 981, and 250 mL (P < 0.05) in the OP, LAP, and HALS groups, respectively. Laparoscopic surgery was converted to HALS in one patient and to open surgery in three patients. There were no conversions in the HALS group. There was no significant difference in the cumulative recurrence rate and bleeding rate in the groups., Conclusion: HALS Dev+Sp is a feasible and effective surgery in patients with portal hypertension., (© 2014 Japan Society for Endoscopic Surgery, Asia Endosurgery Task Force and Wiley Publishing Asia Pty Ltd.)

Purpose: The outcomes of surgery for portal hypertensive patients at a single community hospital in the last two decades were retrospectively examined., Methods: From June 1989 to March 2008, 13 of 848 (1.5%) portal hypertensive patients admitted and treated at the community hospital underwent surgery. The types of surgery performed were a distal splenorenal shunt for 2 patients, gastric devascularization and splenectomy for 8, laparoscopic gastric devascularization and splenectomy for 1, distal gastrectomy for 1, and splenectomy alone for 1. This study reviewed the postoperative records of the endoscopic findings and additional treatments, and the perioperative records., Results: No patient had bleeding from esophagogastric varices during the 75-month mean follow-up period after surgery. Five patients had one or two series of endoscopic treatment for recurrent likely-to-bleed esophageal varices. One patient needed interventional radiology for recurrent gastric varices. No patients died due to upper gastrointestinal bleeding. The survival rates were 87.5% after 5 years and 46.9% after 10 years., Conclusions: Surgery for portal hypertensive patients performed at a single community hospital is still safe and effective, and has been adequately incorporated into the late treatment strategy for portal hypertensive patients.

Background: Small intestinal variceal bleeding is an unusual cause of gastrointestinal hemorrhaging of portal hypertensive patients, but once it occurs it may lead to life-threatening bleeding because this problem is difficult to diagnose and treat. This study investigated the efficacy of balloon occluded retrograde transvenous obliteration (B-RTO) to treat small intestinal variceal bleeding., Methods: From 2003 to 2007, 6 patients with small variceal bleeding were treated by B-RTO. The characteristics of the patients, B-RTO procedures, prognosis, and occurrence of risky esophageal and gastric varices were evaluated according to their medical records., Results: Three-dimensional (3-D) angiography by MD-CT was useful for the diagnosis of small intestinal varices and the draining vessels. In all cases, variceal bleeding was controlled by B-RTO treatment, although rebleeding was recognized in one patient after 30 months (16.6%). All patients were alive throughout the follow-up except 1 patient who died of liver failure (6-44 months). Risky esophageal varices and gastric varices occurred in 2 patients (33.3%) after B-RTO. However, no variceal bleeding occurred., Conclusion: B-RTO was found to be an effective treatment modality which provided good initial hemostasis, thereby eradicating ectopic small intestinal varices., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Portal venous thrombosis (PVT) is a potentially fatal complication following splenectomy. Its mechanisms and risk factors are poorly understood, especially in patients with cirrhosis and portal hypertension. This study investigated risk factors for PVT following splenectomy in such patients., Methods: All consecutive patients with cirrhosis who underwent splenectomy in Kyushu University Hospital between 1998 and 2004 were included in this retrospective study. They were divided into two groups based on the presence or absence of postoperative PVT. Preoperative and operative factors were compared, and the relationships between formation of PVT and its independent variables were analysed. In some cases, portal venous flow was measured before and after splenectomy using duplex Doppler ultrasonography., Results: PVT developed after surgery in 17 (24 per cent) of 70 patients studied. Multivariable analysis showed that increased splenic vein diameter and low white cell count were significant independent risk factors for PVT. Portal venous flow after splenectomy was greatly reduced in the PVT group, but not in patients without PVT., Conclusion: Large splenic vein diameter and low white cell count are independent risk factors for PVT after splenectomy in patients with cirrhosis and portal hypertension.

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/aims: Laparoscopic splenectomy is now increasingly being performed. However, controversy remains regarding the effectiveness of a laparoscopic splenectomy for patients with portal hypertension., Methodology: Seventy-three patients with portal hypertension who underwent a laparoscopic splenectomy from February 1992 until October 2000 were reviewed and the effectiveness of the procedures for portal hypertension was evaluated. Forty-two patients had esophagogastric varices and twenty had a concomitant hepatocellular carcinoma. The indications for surgery were bleeding tendency due to thrombocytopenia (n = 40), difficulty in receiving treatment for hepatocellular carcinoma due to thrombocytopenia (n = 18), and sclerotherapy-resistant esophagogastric varices (n = 15)., Results: A laparoscopic splenectomy was successfully performed in all the patients. The rate of conversion to conventional open surgery was 9.6% (7/73). The mean operative time was 210.1 +/- 101.9 minutes, and the estimated blood loss was 374.7 +/- 352.4 mL. There were no cases of mortality, and morbidity was encountered in 11.0% of patients. The increase in the platelet count correlated significantly to the spleen weight (P < 0.001). The platelet count had been maintained at over 10 x 10(4)/mm3 for over three years. Eighteen patients with hepatocellular carcinoma successfully underwent treatment for hepatocellular carcinoma after surgery and no recurrence of esophagogastric varices was encountered., Conclusions: A laparoscopic splenectomy resulted in the successful secondary treatment of hepatocellular carcinoma and esophagogastric varices. Portal hypertension was not a contraindication. A laparoscopic approach is therefore the procedure of choice for a splenectomy in portal hypertension.

Background/aims: This study investigates the effect of prostacyclin, which is thought to be involved in the hemodynamic circulation, on the gastric mucosa of rats with portal hypertension., Methodology: Various gastric functions were evaluated in portal vein ligated rats after the intraperitoneal administration of either a placebo or prostacyclin for 7 days., Results: The gastric mucosal damage induced by the instillation of 90% ethanol was significantly greater in the prostacyclin-treated group than in placebo-treated group. The portal pressure was similar in both groups. There was no significant difference between the two groups in plasma concentration of 6-keto-PGF1a (a stable metabolite of prostacyclin), whereas the mucosal content of 6-keto-PGF1a was significantly higher in the prostacyclin-treated group than in the placebo-treated group. Prostacyclin pretreatment significantly increased the gastric mucosal blood flow, estimated by laser-Doppler flowmetry, and the hemoglobin content of the gastric mucosa, measured by reflectance spectrophotometry, whereas the oxygen content remained unchanged., Conclusions: We speculate that the increased gastric mucosal perfusion induced by a high content of prostacyclin in the portal hypertensive gastric mucosa may play a role in the pathogenesis of ethanol-induced gastric mucosal damage.

Portal hypertensive gastropathy (PHG) is recognized as a clinical entity in portal hypertension, but the pathogenesis of PHG is still unclear. Therefore, we reviewed the current state of knowledge concerning the portal hypertensive gastric mucosa and hypothesized the pathogenesis of PHG. Elevated portal pressure can induce changes of local hemodynamics, thus causing congestion in the upper stomach and gastric tissue damage. These changes may then activate cytokines and growth factors, such as tumor necrosis factor alpha, which are substances that activate endothelial constitutive nitric oxide synthase and endothelin 1 in the portal hypertensive gastric mucosa. Overexpressed nitric oxide synthase produces an excess of nitric oxide, which induces hyperdynamic circulation and peroxynitrite overproduction. The overproduction of peroxynitrite, together with endothelin overproduction may cause an increased susceptibility of gastric mucosa to damage. When combined with the characteristics of impaired mucosal defense and healing, these factors may together produce PHG in patients with portal hypertension.

Portal hypertensive (PHT) gastropathy is a frequent, serious complication of liver cirrhosis. PHT gastric mucosa has numerous abnormalities such as reduced mucosal potential differences, reduced surface oxygenation, and increased susceptibility to injury caused by alcohol, aspirin, and other noxious factors. Because such mucosal injury is initially mediated by oxygen free radicals, and because mitogen-activated protein (MAP) kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we show that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from the underlying and continual oxidative state associated with portal hypertension, and is ameliorated by inhibiting MKP-1. Furthermore, we found that supplementing vitamin E, a free radical scavenger, reduces the oxidative state in PHT gastric mucosa, normalizes MKP-1 expression, and thereby reverses impairment of oxidative stress-induced ERK2 activation. Finally, we show that orally administered vitamin E completely reverses the increased susceptibility of PHT gastric mucosa to alcohol injury. Our findings point to a new molecular and mechanistic basis for PHT gastropathy and provide a new therapeutic modality for protection of PHT gastric mucosa.

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.

Portal hypertensive (PHT) gastric mucosa has increased susceptibility to injury and impaired mucosal healing. Because our previous study showed that ulcer-induced activation of mitogen-activated protein (MAP) kinase (ERK) plays a pivotal role in gastric mucosal healing, we investigated whether ERK activation is altered in PHT gastric mucosa following alcohol injury. We studied ERK2 phosphorylation and activity and expression of MAP kinase phosphatase-1 (MKP-1) in gastric mucosa of PHT and sham-operated (SO) normal rats both at baseline and following alcohol injury. In SO gastric mucosa, ERK2 phosphorylation and activity were significantly increased time-dependently following alcohol injury: by 221% and 137%, respectively at 24 h vs. baseline. In contrast, in PHT gastric mucosa following alcohol injury, neither ERK2 phosphorylation nor activity was increased versus baseline. In PHT gastric mucosa, MKP-1 mRNA and protein expression were increased at baseline versus SO rats and were increased further following alcohol injury with values higher by 20%-40% at each study time versus SO rats. Because ERK2 is crucial for mucosal healing, reduced ERK2 activation resulting from the overexpression of MKP-1 might be the basis for the impaired mucosal healing in PHT gastric mucosa.

Background: Portal hypertension is often accompanied by a hyperdynamic circulation state. Some reports have suggested that nitric oxide (NO) plays an important role in this hyperdynamic state. On the other hand, although endothelin (ET)-1, a powerful vasoconstrictor, was recently identified, little is known about its role in portal hypertension or about the interaction between NO and ET-1. The aim of this study was therefore to investigate whether or not the inhibitor of NO synthase (NOS) might improve portal hypertension, and also to clarify the relationship between NO and ET-1., Methods: Portal hypertensive (PHT) rats, in which hypertension was induced by a two-step ligation of the portal vein (PVL), were used. The mean arterial pressure (MAP), portal pressure (PP), visceral blood flow volume (BFV), and serum levels of NO and ET-1 were determined in PVL rats treated with two NOS inhibitors with different functions: N(G)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG). Control (CTR) rats. treated by a sham operation (SO), were also studied., Results: Two-step PVL treatment induced a significant increase in the serum level of NO3-and ET-1 in the portal vein. L-NAME and AG administration significantly decreased PP at doses of 50 mg/kg in PHT rats after 60 min administration, while no inhibitor effected any modification in the CTBR rats. Both NOS inhibitors increased MAP and decreased PP and BFV in the portal vein, gastric mucosa, and spleen, in addition to decreasing the serum levels of NO3- and ET-1 in the PHT rats, while neither blockade modified any parameters in the CTR rats. In PHT rats, L-arginine, a NO substance, reversed the effect of L-NAME, while it did not induce any recovery from the AG effect., Conclusions: In PHT rats, NO seems to contribute to portal hypertension. PVL increases not only the serum level of NO3-, but also that of ET-1 in the portal vein. Both L-NAME and AG reduce PP and BFV of the portal vein, spleen, gastric mucosa. and liver. In addition, the inhibition of NOS diminishes the serum level not only of NO, but also of ET-1. Use of an appropriate NOS inhibitor may therefore positively affect the hyperdynamic state in portal hypertension.

Portal hypertension (PHT) increases susceptibility of the gastric mucosa to injury. The aim of this study was to investigate whether PHT affects rat gastric mucosal defense mechanisms in vivo at the pre-epithelial, epithelial, and/or post-epithelial levels. PHT was produced in rats by staged portal vein ligation and sham-operated (SO) rats served as controls. The gastric mucosa was exposed, chambered, and continuously superfused with buffers under in vivo microscopy. We measured gastric mucosal gel layer thickness, surface epithelial cell intracellular pH (pHi), mucosal blood flow, and mucosal/serosal oxygenation. In PHT rats, gastric mucosal gel layer thickness was significantly reduced (88 +/- 16 microm in PHT rats vs. 135 +/- 25 microm in SO rats; P <0.0001), and the surface epithelial cell pHi was significantly decreased (6.80 +/- 0.11 in PHT rats vs. 7.09 +/- 0.21 in SO rats; P <0.01). Although total gastric mucosal blood flow was significantly increased in PHT rats by 72% (P <0.05), the oxygenation of the gastric mucosal surface was decreased by 42% (P <0.05) compared with SO rats. PHT impairs pre-epithelial (mucosal gel layer thickness), epithelial (pHi), and post-epithelial (maldistribution of blood flow) components of the gastric mucosal barrier. These findings can explain the increased susceptibility of portal hypertensive gastric mucosa to injury.

Background and Aims: Portal hypertensive gastropathy (PHG) is now recognized as a distinct entity; however, the angiogenesis in the portal hypertensive gastric mucosa has yet to be elucidated. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor involved in both physiological and pathological angiogenesis. The aim of this study was thus to examine the function of VEGF in the portal hypertensive and non-portal hypertensive gastric mucosa., Method: Forty-five cirrhotic patients were divided into 3 groups as follows. Group I included 15 patients without PHG who were treated with 1.5 g teprenone/day for 8 weeks: PHG(-)-t. Group II included 15 patients with PHG who were not treated with teprenone: PHG(+)-n. Group III included 15 patients with PHG who were treated with teprenone for 8 weeks: PGH(+)-t. The gastric mucosal blood flow (GMBF), the concentration of gastric mucosal VEGF and hexosamine and the endoscopic findings were studied both before and after medication., Results: Before teprenone treatment, the GMBF in the antrum, fundus, fornix were significantly higher in PHG(+)-n than PHG(-)-t. After treatment, the GMBF in the fundus and fornix significantly decreased more than before treatment in the PHG(+)-t. After treatment, the GMBF in the antrum increased significantly more than before treatment in PHG(-)-t. The gastric VEGF and hexoxamine concentration in the antrum were significantly higher in PHG(+)-n than in PHG(-)-t. After treatment, the gastric VEGF and hexosamine concentration in the antrum significantly decreased in PHG(+)-t while no change in concentration was recognized in PHG(+)-n. In the endoscopic findings, a decrease in the PHG score was recognized in 2 patients in PHG(+)-t., Conclusion: Portal hypertensive gastric mucosal change was thus found to trigger a high concentration of VEGF and hexosamine. Such increased activity of VEGF and hexosamine may thus account for the presence of active congestion in PHG., (Copyright 2000 S. Karger AG, Basel)

Objective: To determine the expression and localization of adrenomedullin (AM) and its receptor (AM-R) in portal hypertensive (PHT) gastric mucosa after intragastric ethanol administration., Summary Background Data: The repair of gastric mucosal injury requires reestablishment of the microvascular network. The authors previously demonstrated impaired angiogenesis of PHT gastric mucosa after ethanol-induced injury. Because AM, a potent vasodilatory peptide, is also a novel growth and angiogenic factor, the authors hypothesized that AM is involved in the impaired repair of PHT gastric mucosa and its microvasculature after damage., Methods: Either PHT or sham-operated rats received intragastrically 100% ethanol, and the stomachs were excised at 1, 6, and 24 hours later. Expression and localization of AM and AM-R mRNA were examined by competitive reverse transcription-polymerase chain reaction and in situ hybridization. AM protein expression was examined by Western blot analysis., Results: One hour after ethanol administration, AM mRNA expression in PHT gastric mucosa was significantly decreased by 81%, especially in the superficial mucosa, compared with the gastric mucosa in sham-operated rats. The significant decrease lasted for 24 hours. AM protein expression was significantly decreased by 43% compared with the sham-operated gastric mucosa. Although AM-R mRNA expression in both groups was significantly increased 1 hour after ethanol administration and lasted for 24 hours compared with baseline, there were no differences between the two groups., Conclusions: The expression of AM in PHT gastric mucosa after ethanol-induced injury is significantly decreased compared with controls. This finding could explain one mechanism for the impaired angiogenesis after injury of PHT gastric mucosa.

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 examined the expression and localization of adrenomedullin (AM) mRNA, AM receptor (AM-R) mRNA and AM protein in normal and portal hypertensive (PHT) rat gastric mucosa. Methods included competitive reverse transcription-polymerase chain reaction (RT/PCR), in situ hybridization and Western blot analysis. Both AM mRNA and AM-R mRNA were strongly expressed not only in normal rat gastric mucosa but also PHT rat gastric mucosa. While total AM and AM-R mRNA abundance was similar in both normal and PHT stomachs, in the superficial mucosa-where major defense mechanisms are located-their expression was significantly reduced in PHT rats by 33% (AM mRNA) and 25% (AM-R mRNA) (both p .0.05). AM protein was also expressed similarly in both normal and PHT gastric mucosa. We conclude that AM and its receptor play a role in regulation of gastric mucosal microcirculation and thus gastric mucosal defense.

Anti-tumor necrosis factor alpha (TNF-alpha) treatment decreases nitric oxide (NO) synthesis and ameliorates the hyperdynamic circulation in portal hypertensive rats. We have recently demonstrated that nitric oxide synthase isoform 3 (NOS3) is overexpressed in portal hypertensive gastric mucosa and that resultant NO overproduction probably is responsible for the increased susceptibility of the mucosa to damage. In the present study, we examined whether TNF-alpha is overexpressed in portal hypertensive gastric mucosa and whether anti-TNF-alpha treatment affects gastric NOS3 messenger RNA (mRNA) and protein expression. We examined plasma concentrations of TNF-alpha and its protein expression in gastric specimens from portal hypertensive and sham-operated rats using Western blotting and immunohistochemistry. We also measured gastric mucosal blood flow, gastric expression of NOS3 mRNA and protein, and NOS3 enzyme activity in rats with and without TNF-alpha-neutralizing antibody treatment. The TNF-alpha protein levels in portal hypertensive stomachs were significantly increased by 57% compared with levels in sham-operated controls. TNF-alpha antibody treatment normalized gastric mucosal blood flow in portal hypertensive stomachs and significantly reversed overexpression of gastric NOS3 mRNA, protein, and its enzyme activity in portal hypertensive rats by 48%, 45%, and 33%, respectively. These results suggest that TNF-alpha may regulate NOS3 expression in the portal hypertensive stomach and that anti-TNF-alpha treatment may ameliorate the pathophysiological abnormalities of portal hypertensive gastric mucosa.

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.

Objective: We prospectively evaluated the prognostic value of the flat hepatic vein waveform, measured by Doppler ultrasound, in cirrhotic patients with portal hypertension., Methods: The Doppler pattern of right and left hepatic veins in a series of 120 consecutive cirrhotic patients with portal hypertension but without hepatocellular carcinoma was examined, together with clinical and biochemical parameters., Results: Flat waveform of the right hepatic vein was recognized in nine patients and that of the left hepatic vein was seen in 13. After a mean follow-up of 13.6 +/- 9.7 months, 17 patients died, all from liver failure. In the univariate analysis, variable significantly associated with the duration of survival were age, etiology of the liver cirrhosis, upper gastrointestinal bleeding after start of the study, Child-Pugh score, ascites, encephalopathy, prothrombin index, bilirubin, albumin, and flat Doppler waveform in the right and left hepatic veins. Multivariate analysis showed that flat Doppler waveform in the right hepatic vein, bilirubin, and prothrombin index were independently related to survival., Conclusions: The prognostic accuracy in cases of cirrhosis with portal hypertension is significantly improved with acquisition of information obtained from hepatic vein waveform by Doppler ultrasound.

Plasma levels and gastric mucosal contents of prostaglandin (PG) E2 and prostacyclin were determined in cirrhotic patients with portal hypertensive gastropathy (PHG), in cirrhotic patients without PHG and in healthy controls. PGE2 and 6-keto-PGF1 alpha (a stable metabolite of prostacyclin) levels were measured in 30 cirrhotic patients and 10 controls, using radioimmunoassay. Of 30 cirrhotics, 13 had PHG of the fundus and the corpus. Plasma concentrations of 6-keto-PGF1 alpha in the cirrhotic patients were significantly higher than in the controls (p < 0.01), but there was no significant difference between cirrhotics and controls with regard to plasma levels of PGE2. The gastric mucosal contents of 6-keto-PGF1 alpha in the fundus was significantly higher in cirrhotics with PHG than those without PHG (p < 0.05) and controls (p < 0.01). However, the gastric mucosal contents of PGE2 in the fundus were not significantly different in cirrhotics with and without PHG. The gastric mucosal contents of 6-keto-PGF1 alpha significantly correlated to the plasma levels (r = 0.37, p < 0.05), but there was no significant correlation between plasma levels and gastric mucosal contents of PGE2. Since prostacyclin has vasodilator and gastric acid inhibitory effects, we speculate that high contents of prostacyclin in the gastric mucosa may have some role in the pathogenesis of PHG.

The effects of metoclopramide on blood flow in portal and left gastric veins and cardiovascular haemodynamic variables were studied in 30 patients with both liver cirrhosis and oesophageal varices. Measurements were made under baseline conditions and after the intravenous administration of saline, metoclopramide 10 mg, and metoclopramide 20 mg. Portal haemodynamics, including portal and left gastric veins were studied using pulsed Doppler ultrasound. In all groups, the blood flow and the maximal diameter of portal and left gastric veins, and heart rate remained unchanged. However, metoclopramide 10 mg significantly decreased the mean arterial pressure 15 minutes after administration while metoclopramide 20 mg decreased it 30, 45 and 60 minutes after administration. Therefore, metoclopramide apparently does not alter the blood flow of the portal venous system in these patients.

Controversy exists as to the nature of gastric perfusion in portal-hypertensive gastropathy. To investigate portal hemodynamics and gastric mucosal perfusion in cirrhotic patients with and without portal-hypertensive gastropathy, we subjected 56 cirrhotic patients with portal hypertension to portal vein catheterization, pneumatic pressure sensor technique, duplex sonography and laser Doppler flowmetry. Thirteen patients had portal-hypertensive gastropathy: In 10 it was mild, and in 3 it was severe. The presence of portal-hypertensive gastropathy seemed to be independent of age, sex, cause of cirrhosis or grade of esophageal varices. Portal venous pressure, esophageal variceal pressure, portal venous flow and congestion index in patients with portal-hypertensive gastropathy were not significantly different from the values in those without portal-hypertensive gastropathy. However, portal-variceal pressure gradient (subtracting esophageal variceal pressure from portal venous pressure) (p < 0.01) and the incidence of palisading-type esophageal varices on portography (p < 0.05) was increased in patients with portal-hypertensive gastropathy significantly more than in those without portal-hypertensive gastropathy. In the fundus, gastric mucosal blood flow was significantly higher in patients with portal-hypertensive gastropathy than in those without portal-hypertensive gastropathy, whereas in the corpus and the antrum the values were not significantly different. We suggest that the mucosa of the upper stomach in patients with portal-hypertensive gastropathy is congestive and highly perfused. The pathogenesis of portal-hypertensive gastropathy may be related to both congestion and hyperemia in the upper stomach.

Objectives: We classified the Doppler waveform seen in patients with portal hypertension and examined the associations of the waveform type with the diagnosis of Budd-Chiari syndrome and severity of the liver cirrhosis., Methods: The Doppler pattern of right and left hepatic veins in 100 consecutive Japanese patients with portal hypertension and esophagogastric varices was classified into six types: I, triphasic waveform; II, biphasic waveform without reversed flow; III, decreased amplitude of phasic oscillations; IV, flat waveform with fluttering; V, completely flat waveform with fluttering; VI, no waveform. All patients underwent computed tomography and magnetic resonance imaging. Patients in whom hepatic vein waveform showed type IV, type V, or type VI, positively underwent hepatic venography and inferior vena cavography., Results: Type I was seen in 31 of 100 patients, type II in 35, type III in 17, type IV in eight, type V in four, and type VI in five. Types I-IV waveform indicated no lesion in hepatic veins and inferior vena cava, type V indicated stenosis of hepatic veins or occlusion of inferior vena cava, and type VI, occlusion of hepatic veins. For one patient with type V hepatic veins, balloon angioplasty was done, and the waveform changed from type V to type II. Examining the relationship between hepatic vein waveform and the Child-Pugh score, liver function of type IV cases was worse than that of type I cases in 66 cirrhotic patients without hepatocellular carcinoma (p < 0.05). There was no clear relationship between hepatic vein waveform and portal venous perfusion, as based on Nordlinger's grade., Conclusions: Our classification of hepatic vein waveform in Doppler ultrasonography is useful in diagnosing Budd-Chiari syndrome, in judging the efficiency of treatment for hepatic vein lesions, and in assessing severe liver function in cirrhotic patients.