Elevated Portal Venous Pressure Research Articles

S3168 Sinusoidal Obstruction Syndrome: A Known and Often Missed Complication of Oxaliplatin Therapy

Introduction: Sinusoidal obstruction syndrome (SOS) is caused by sinusoidal endothelial injury due to hematopoietic cell transplantation, liver irradiation or exposure to chemotherapy such as oxaliplatin and may occur days to weeks following exposure. SOS can be a life-threatening complication and its presentation may include jaundice, volume overload or hepatic failure. We present the case of a 32-year-old male with gastroesophageal adenocarcinoma who underwent oxaliplatin-based chemotherapy and developed SOS. Case Description/Methods: A 32-year-old male with no significant medical history presented with dysphagia and weight loss. Esophagogastroduodenoscopy showed a mass at the gastroesophageal junction. He underwent diagnostic laparoscopy which showed peritoneal metastasis. Tissue biopsy was consistent with stage 4 gastroesophageal junction adenocarcinoma. He was started on 5-fluorouracil (5-FU), oxaliplatin and nivolumab. The patient developed thrombocytopenia and moderate aminotransferase elevation after 6 cycles of chemotherapy. An abdominal ultrasound obtained after 10 of 12 cycles of chemotherapy showed portal hypertension. Subsequent abdominal imaging showed worsening ascites (serum ascites to albumin gradient > 1.1), anasarca and splenomegaly. Transjugular liver biopsy showed elevated portal hepatic venous pressure gradient, focal sinusoidal dilatation and centrizonal ischemic changes suggesting drug induced hepatopathy, and a diagnosis of oxaliplatin induced SOS was made. The patient was not a candidate for defibrotide and was treated conservatively. He continued to have worsening ascites with severe direct hyperbilirubinemia and moderately elevated aminotransferases without biliary obstruction (Figure). Discussion: Oxaliplatin-based chemotherapies are known to cause the potentially life-threatening complication of SOS which is oftentimes missed. Our patient developed signs and symptoms suggestive of SOS by cycle 10 of oxaliplatin therapy. These changes included thrombocytopenia, elevated liver associated enzymes, volume overload and portal hypertension. He went on to complete 12 cycles of oxaliplatin with eventual worsening of his portal hypertension related symptoms and worsening of his hepatic function. This case highlights the importance of having a high index of suspicion for the development of SOS with plans to pursue patient-centered discussions regarding alternative chemotherapeutic regimens, instituting prophylactic therapies and timely SOS screening protocols.Figure 1.: Timeline of events leading up to SOS diagnosis.

Nonalcoholic fatty liver disease and portal hypertension.

Nonalcoholic fatty liver disease (NAFLD) is a substantial and growing problem worldwide and has become the second most common indication for liver transplantation as it may progress to cirrhosis and develop complications from portal hypertension primarily caused by advanced fibrosis and erratic tissue remodeling. However, elevated portal venous pressure has also been detected in experimental models of fatty liver and in human NAFLD when fibrosis is far less advanced and cirrhosis is absent. Early increases in intrahepatic vascular resistance may contribute to the progression of liver disease. Specific pathophenotypes linked to the development of portal hypertension in NAFLD include hepatocellular lipid accumulation and ballooning injury, capillarization of liver sinusoidal endothelial cells, enhanced contractility of hepatic stellate cells, activation of Kupffer cells and pro-inflammatory pathways, adhesion and entrapment of recruited leukocytes, microthrombosis, angiogenesis and perisinusoidal fibrosis. These pathological events are amplified in NAFLD by concomitant visceral obesity, insulin resistance, type 2 diabetes and dysbiosis, promoting aberrant interactions with adipose tissue, skeletal muscle and gut microbiota. Measurement of the hepatic venous pressure gradient by retrograde insertion of a balloon-tipped central vein catheter is the current reference method for predicting outcomes of cirrhosis associated with clinically significant portal hypertension and guiding interventions. This invasive technique is rarely considered in the absence of cirrhosis where currently available clinical, imaging and laboratory correlates of portal hypertension may not reflect early changes in liver hemodynamics. Availability of less invasive but sufficiently sensitive methods for the assessment of portal venous pressure in NAFLD remains therefore an unmet need. Recent efforts to develop new biomarkers and endoscopy-based approaches such as endoscopic ultrasound-guided measurement of portal pressure gradient may help achieve this goal. In addition, cellular and molecular targets are being identified to guide emerging therapies in the prevention and management of portal hypertension.

The Role of Magnetic Resonance Elastography in the Diagnosis of Noncirrhotic Portal Hypertension

Portal hypertension (PH) is defined as abnormal elevation of portal venous pressure with cirrhosis accounting for 90% of cases and 10% of cases classified as noncirrhotic PH (NCPH).1,2 The differentiation of cirrhotic PH (CPH) from NCPH is difficult (Supplementary Figure1), with recent research efforts focusing on noninvasive evidence of increased hepatic stiffness.3,4 Magnetic resonance elastography (MRE) is an established imaging technique in the assessment of hepatic stiffness, and is now the most efficacious, noninvasive method to assess for hepatic fibrosis.5-8 The aim of this study was to assess the ability of magnetic resonance imaging (MRI) and MRE to differentiate between CPH and NCPH.

Effect of Proximal Splenorenal Shunt on Intraoperative Portal Venous Pressure and Its Correlation with Clinical Outcomes

Proximal splenorenal shunt (PSRS), commonly performed for non-cirrhotic portal hypertension (NCPH), diminishes elevated portal venous pressure (PP) and prevents its sequelae. The change in PP after PSRS and its correlation with clinical outcome is largely unknown. Twenty-four patients who underwent PSRS for NCPH were evaluated prospectively. PP was measured after completion of splenectomy and after PSRS. Follow-up for 3 months was done to assess shunt patency and other relevant clinical variables. Change in PP and shunt patency were correlated with clinical outcome. Seventeen patients had extrahepatic portal vein obstruction (EHPVO) and seven had non-cirrhotic portal fibrosis (NCPF). There was a significant decrease in PP (median10 mmHg) after PSRS (p 0.05). Shunt patency showed significant correlation with splenic vein diameter (p = 0.018), shunt diameter (p = 0.024), blood flow across shunt (p = 0.023), change in variceal grade (p = 0.032), and need for endotherapy (p = 0.002). PP decreases after PSRS in patients with NCPH. However, this does not correlate with clinical outcome. A patent shunt at 3 months correlated with most of these variables.

Is Portal Venous Pressure or Porto-systemic Gradient Really A Harbinger of Poor Outcomes After Living Donor Liver Transplantation?

Portal hyperperfusion as a cause of small for size syndrome (SFSS) after living donor liver transplantation (LDLT) remains controversial. Portal venous pressure (PVP) is often measured indirectly and may be confounded by central venous pressure (CVP). In 42 adult cirrhotics undergoing elective LDLT, PVP was measured by direct canulation of portal vein and porto systemic gradient (PSG) was obtained after subtracting CVP from PVP. None underwent portal inflow modulation. SFSS was looked in 27 patients after excluding 15 with technical complications. Clinical features of SFSS found in 6 patients, 5 with graft recipient weight ratio (GRWR)>0.8% and PVP<20mm of Hg. One with GRWR<0.8% could truly be labeled as SFSS. Incidence of SFSS was not higher in patients with elevated PVP>20mm of Hg (14.3% vs 0%, P=0.259) or PSG>13mm of Hg (33.3% vs 0%, P=0.111). Intensive care unit (ICU) stay was longer in patients with elevated PVP (14.55 vs 9.13 days, P=0.007) and PSG (16.8 vs 9.72 days, P=0.009). There was no difference in graft functions, post-operative complications and mortality in first month post-LDLT. Elevated PVP or PSG increased morbidity but neither predicted SFSS nor affected survival.

Portal Vein Pressure Change Predicts Posthepatectomy Liver Failure Following Right Lobectomy

The aim of this study was to evaluate the usefulness of intraoperative portal venous pressure (PVP) as a predictor of posthepatectomy liver failure (PHLF). Hepatic functional reserve is typically evaluated by using parameters such as albumin level, platelet count, prothrombin activity level, or indocyanine green retention rate at 15 minutes. Low hepatic functional reserve can enhance the risk of PHLF. We retrospectively analyzed the outcomes of 35 patients who underwent right lobectomy and intraoperative PVP measurements between April 2004 and August 2012. According to preoperative prediction scores, all patients were within a safe limit for right lobectomy. The patients were grouped into uncomplicated (n = 22) and PHLF (n = 13) groups by postoperative course. PHLF was defined as grade B or C according to International Study Group of Liver Surgery criteria. Patient background, intraoperative bleeding, operative time, and PVP elevation after hepatectomy (ΔPVP) grade were compared between the groups. No cases of in-hospital death occurred. Univariate analysis revealed significant differences in preoperative white blood counts, intraoperative bleeding, and ΔPVP between the groups (P &amp;lt; 0.05). The ΔPVP was an independent risk factor on multivariate analysis. A ΔPVP &amp;gt;3 cmH2O was associated with PHLF at 69.2% sensitivity and 90.9% specificity. Following right lobectomy, a ΔPVP &amp;gt;3 cmH2O indicates a risk of PHLF and warrants careful postoperative management.

Elevated Liver Regeneration in Response to Pharmacological Reduction of Elevated Portal Venous Pressure by Terlipressin After Partial Hepatectomy

Liver regeneration is of crucial importance for patients undergoing living liver transplantations or extended liver resections and can be associated with elevated portal venous pressure, impaired hepatic regeneration, and postoperative morbidity. The aim of this study was to assess whether reduction of portal venous pressure by terlipressin improves postoperative liver regeneration in normal and steatotic livers after partial hepatectomy in a rodent model. Portal venous pressure was assessed after minor (30%), standard (60%), or extended (80%) partial hepatectomy (PH) in mice with and without liver steatosis. Liver regeneration was assessed by BrdU incorporation and Ki-67 immunostaining. Portal venous pressure was significantly elevated post-PH in mice with normal and steatotic livers compared to sham-operated mice. Reduction of elevated portal pressure after 80% PH by terlipressin was associated with an increase of hepatocellular proliferation. In steatotic livers, animals treated with terlipressin had an increase in liver regeneration after 30% PH and increased survival after 60% PH. Mechanistically, terlipressin alleviated IL-6 mRNA expression following PH and down-regulated p21 and GADD45 mRNA suggesting a reduction of cell cycle inhibition and cellular stress. Reduction of elevated portal pressure post-PH by the use of terlipressin improves liver regeneration after PH in lean and steatotic mouse livers.

Endothelin-1 Activation of the Endothelin B Receptor Modulates Pulmonary Endothelial CX3CL1 and Contributes to Pulmonary Angiogenesis in Experimental Hepatopulmonary Syndrome

Hepatic production and release of endothelin-1 (ET-1) binding to endothelin B (ETB) receptors, overexpressed in the lung microvasculature, is associated with accumulation of pro-angiogenic monocytes and vascular remodeling in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). We have recently found that lung vascular monocyte adhesion and angiogenesis in HPS involve interaction of endothelial C-X3-C motif ligand 1 (CX3CL1) with monocyte CX3C chemokine receptor 1 (CX3CR1), although whether ET-1/ETB receptor activation influences these events is unknown. Our aim was to define if ET-1/ETB receptor activation modulates CX3CL1/CX3CR1 signaling and lung angiogenesis in experimental HPS. A selective ETB receptor antagonist, BQ788, was given for 2 weeks to 1-week CBDL rats. ET-1 (±BQ788) was given to cultured rat pulmonary microvascular endothelial cells overexpressing ETB receptors. BQ788 treatment significantly decreased lung angiogenesis, monocyte accumulation, and CX3CL1 levels after CBDL. ET-1 treatment significantly induced CX3CL1 production in lung microvascular endothelial cells, which was blocked by inhibitors of Ca(2+) and mitogen-activated protein kinase (MEK)/ERK pathways. ET-1-induced ERK activation was Ca(2+) independent. ET-1 administration also increased endothelial tube formation in vitro, which was inhibited by BQ788 or by blocking Ca(2+) and MEK/ERK activation. CX3CR1 neutralizing antibody partially inhibited ET-1 effects on tube formation. These findings identify a novel mechanistic interaction between the ET-1/ETB receptor axis and CX3CL1/CX3CR1 in mediating pulmonary angiogenesis and vascular monocyte accumulation in experimental HPS.

Effect of Portal Haemodynamics on Liver Graft and Intestinal Mucosa after Small-for-Size Liver Transplantation in Swine

Background: After small-for-size graft (SFSG) transplantation, elevated portal venous pressure (PVP) may lead to postoperative liver damage. Herein we evaluated the impact of portocaval shunt (PCS) to control PVP on liver grafts and intestine following SFSG transplantation. Methods: Nineteen SFSG transplantations were performed with 30% of native liver in swine. Swine were divided into 3 groups: a high-flow shunt group (HS: n = 7), in which portal venous flow (PVF) was reduced with a 10-mm diameter PCS; a low-flow shunt group (LS: n = 6), in which PVF was reduced with a 5-mm diameter PCS, and a no-shunt group (NS: n = 6), in which no PCS was placed. Results: Seven-day survivals were 83.3% in NS, 100% in LS and 0% in HS (p = 0.0088). PVP was significantly higher in the NS group (p = 0.0001; mean ± SEM NS/LS/HS: 20.5 ± 0.7/14.0 ± 1.2/11.6 ± 0.5 mm Hg). The LS group exhibited the highest compliance (PVF/PVP; NS/LS/HS 42.7 ± 10.9/44.6 ± 4.9/37.7 ± 8.3 ml/min/mm Hg; p = 0.009), the lowest aspartate aminotransferase (NS/LS/HS 562 ± 18/370 ± 55/720 ± 130 IU/l; p = 0.0493), and suppressed deleterious alternations of the hepatic parenchyma and intestinal mucosa. Conclusions: Portal hypertension after SFSG transplantation impaired liver and intestinal mucosa; however, inadequate portal flow impaired not only the liver, but also survival.

Portal venous pressure in biliary atresia

Biliary atresia (BA) is characterized by a variable degree of fibrosis within the liver, causing portal hypertension sometimes evident at the time of presentation. AimThe aims of this study are to measure portal venous pressure (PVP) at time of Kasai portoenterostomy (KP) and to investigate the value of surrogate indices. MethodsAt the time of KP and before any liver manipulation, an attempt was made to recanalize the umbilical vein, allowing a catheter to be sited. Preoperative noninvasive variables included maximum splenic diameter (on ultrasound); platelet count, aspartate aminotransferase, and bilirubin; and the aspartate aminotransferase/platelet index ratio (APRi). Clearance of jaundice was defined as achieving a bilirubin of less than 20 μmol/L. Data are quoted as median (range). Nonparametric statistical tests were used, and P < .05 was regarded as significant. ResultsPortal venous pressure measurements were available in 61 infants, who underwent a KP during the period February 2007 to October 2010. Median age at KP was 52 (19-151) days. Median PVP was 9 (3-26) mm Hg and was significantly lower in those with isolated (n = 47) BA vs cytomegalovirus-associated BA (n = 6) (8 vs 17 mm Hg; P = .02). Overall, PVP correlated with spleen size (rs = 0.38; P < .0001), APRi (rs = 0.5; P < .0001), bilirubin (rs = 0.38; P = .001), and age at KP (rs = 0.33; P = .0004).Thirty-three infants (56%) cleared their jaundice (to <20 μmol/L). There was no significant difference in median PVP (7 vs 9.5 mm Hg; P = .1) between these groups. To date, 6 children have undergone endoscopy, with 2 requiring intervention for significant varices. Neither infant at time of KP had elevated PVP (3 and 9 mm Hg). ConclusionsPortal venous pressure is a key variable in the assessment of the BA liver, and differences can be shown depending on underlying cause (eg, cytomegalovirus status). Furthermore, it has modest correlation with noninvasive indices (eg, spleen size and APRi) but appears of limited use when used as prognostic index of outcome and indeed in the later development of varices.

Differences in portal hemodynamics between whole liver transplantation and living donor liver transplantation

The aim of this study was to investigate the differences in portal hemodynamics between whole liver transplantation and living donor liver transplantation (LDLT). Twenty patients who underwent LDLT (the L group) and 42 patients who underwent whole liver transplantation (the W group) were enrolled, and colored Doppler ultrasonography was performed preoperatively and on postoperative days (PODs) 1, 3, 5, 7, 30, and 90. The changes in the portal blood flow velocity (PBV) and portal blood flow volume (PBF) were monitored. The graft and spleen sizes were measured with angiographic computed tomography, and upper endoscopy was used to measure esophageal varices on PODs 14, 30, and 90. Although the portal venous pressure (PVP) decreased after graft implantation, it was higher in the L group with a smaller graft size ratio (25.7 ± 5.1 cm H₂O for the L group and 18.5 ± 4.6 cm H₂O for the W group, P < 0.05). PBF and PBV increased in both the W and L groups on POD 1 after transplantation; however, the PBF and PBV peaks were significantly higher in the W group. The postoperative PVP and graft volume were greatly related to PBF on POD 1. Grafts in the L group regenerated rapidly after the operation, and the volume increased from 704 ± 115 to 1524 ± 281 mL as early as 1 month after transplantation. A rapid improvement in splenomegaly was observed in both groups. An improvement in esophageal varices was observed in the W group on POD 14 after transplantation, whereas no change was observed in the L group. The portal venous flow in patients with portal hypertension showed a high perfusion state after LDLT, but in contrast to whole liver transplantation, the PVP elevation after LDLT postponed the closing time of the collateral circulation and affected the recovery from splenomegaly.

Management of ascites due to gastrointestinal malignancy

Ascites is the pathological accumulation of fluid within the abdominal cavity. The most common cancers associated with ascites are adenocarcinomas of the ovary, breast, colon, stomach and pancreas. Symptoms include abdominal distension, nausea, vomiting, early satiety, dyspnea, lower extremity edema, weight gain and reduced mobility. There are many potential causes of ascites in cancer patients, including peritoneal carcinomatosis, malignant obstruction of draining lymphatics, portal vein thrombosis, elevated portal venous pressure from cirrhosis, congestive heart failure, constrictive pericarditis, nephrotic syndrome and peritoneal infections. Depending on the clinical presentation and expected survival, a diagnostic evaluation is usually indicated as it will impact both prognosis and the treatment approach. Key tests include serum albumin and protein and a simultaneous diagnostic paracentesis, checking ascitic fluid, WBCs, albumin, protein and cytology. Median survival after diagnosis of malignant ascites is in the range of 1 to 4 months; survival is apt to be longer for ovarian and breast cancers if systemic anti-cancer treatments are available.

Hyperdynamic Circulation in Patients with Liver Cirrhosis and Portal Hypertension

Hyperdynamic circulation in patients with liver cirrhosis is characterized by increased cardiac output and heart rate, and decreased systemic vascular resistance with low arterial blood pressure and currently focused on understanding the pathogenesis because of possibility of developing novel treatment modality. Basically, these hemodynamic alternations arise from portal hypertension. Portosystemic collaterals develop to counterbalance the increased intrahepatic vascular resistance to portal blood flow and induce an increase in venous return to heart. Increased shear stress in vascular endothelial cell related high blood flow by portosystemic shunting contributes to this upregulation of eNOS resulting in NO overproduction. Additionally, bypassing through portosystemic collaterals and escaping degradation of over-produced circulating vasodilators in the diseased liver can promote the peripheral arterial vasodilation. Vasodilation of the systemic and splanchnic circulations lead to a reduced systemic vascular resistance, and increased cardiac output and splanchnic blood flow. Furthermore, neurohumoral vasoconstrictive systems including systemic nervous system, rennin angiotensin aldosterone system, and vasopressin are intensively activated secondary to vasodilation. However, hyperdynamic circulation would be more aggravated by the activated vasoconstrictive systems. With the progression of the cirrhotic process, hyperdynamic alternations can be more profound due to hyporesponsiveness to vasoconstrictors and increased shunt formation in conjunction with autonomic neuropathy. Eventually, splanchnic arterial vasodilation results in an increase portal venous inflow, maintaining the elevated portal venous pressure. Hyperdynamic circulation is intimately involved in portal hypertension with liver cirrhosis, therefore it is reasonable to have an interest in complete understanding of the pathogenesis of hyperdynamic circulation to develop novel treatment modality.

Exogenous Superoxide Dismutase Prevents Peroxynitrite-Induced Apoptosis in Non-Heart-Beating Donor Livers

Objective: To investigate the role of oxygen free radicals in the induction of apoptosis in non-heart-beating donor (NHBD) livers, and if superoxide dismutase (SOD) ameliorates these alterations. Methods: Rat livers were perfused via the portal vein with histidine/tryptophan/α-ketoglutarate solution from heart-beating donors (HBD) or 60-min warm ischemia from NHBD, with or without the addition of SOD. After 24 h, cold storage livers were evaluated by isolated reperfusion. Results: NHBD showed significantly higher enzyme leakage and elevated portal venous pressure (PVP) versus HBD. Bile and total adenine nucleotides (TAN) were significantly decreased. Apoptosis was prominent in sinusoidal lining cells, coupled with strong nitrotyrosine staining (NTR). The concentrations of nitric oxide and lipoperoxides were largely increased. SOD medication reduced hepatic enzyme release by 30% and lipoperoxides by nearly 50%. Apoptosis and NTR were significantly decreased, and PVP was strikingly reduced to normal values. A 3-fold enhancement in bile production and 1.5-fold increase in TAN of the liver tissue were also observed. Conclusion: NHBD livers are prone to severe reoxygenation injury promoted by oxygen free radicals, massive nitrite oxide production and peroxynitrite-induced apoptosis within the sinusoids. Antioxidant medication with SOD should be considered as a useful means of preserving NHBD livers.

Improvement of Morphological Changes after 70% Hepatectomy with Portocaval Shunt: Preclinical Study in Porcine Model

After extensive hepatectomy, excessive portal venous flow (PVF) and elevated portal venous pressure (PVP) may lead to postoperative liver damage. We have evaluated the use of portocaval shunt (PCS) to control PVF and PVP following partial hepatectomy (PH) to reduce the postoperative liver damage. Twenty-four pigs were divided into two Groups: Group C (n = 10) underwent 70% PH alone and Group S (n = 14) underwent 70% PH with PCS. The changes in PVF, PVP, serum liver function tests, and histology were evaluated. PVP and PVF per unit of remnant liver weight and serum total bilirubin levels in Group S were significantly lower than those in Group C postoperatively (P < 0.05). Histology showed that there were significant differences in hepatocyte ballooning, necrosis, and neutrophil aggregation between the two groups (P < 0.05). In particular, hepatic necrosis was observed in zone 3 of Group C as centrilobular necrosis. These results suggest that hepatic and sinusoidal damage after 70% PH were more severe in Group C than in Group S, with the latter group maintaining an almost normal ultrastructural appearance. Hepatocyte apoptotic index differed significantly between the two groups (P < 0.0001). After 70% PH, extensive centrolobular necrosis and neutrophil aggregation were present and may have caused liver damage, manifested as hyperbilirubinemia and coagulopathy. The delayed liver regeneration with PCS may reduce the postoperative liver damages rather than the rapid liver hypertrophy. The diversion of PVF with PCS to maintain adequate PVP is a very effective procedure for avoiding the postoperative liver failure after extensive hepatectomy.

Selective Embolization of the Splenic Vein in Patients with Hepatic Encephalopathy and Splenorenal Shunt

Obliteration of portal-systemic shunts is effective for portosystemic encephalopathy but is often associated with complications such as retention of ascites and worsening of esophageal varices. Selective embolization of the splenic vein was performed on six patients with hepatic encephalopathy and splenorenal shunts. Hepatic encephalopathy was not observed in four patients after the procedure. Neither retention of ascites nor rupture of esophageal varices was observed because postoperative elevation of portal venous pressure was not as great as that seen when shunt obliteration is performed. This procedure can be an effective and safe treatment option for hepatic encephalopathy with a splenorenal shunt.

Small-for-size graft in liver transplantation.

Controversies on small-for-size (SFS) graft in liver transplantation have evolved in parallel with the history of living donor liver transplantation for adults. It is true that the liver regenerates rapidly within a limited threshold. But 'normal' liver weight itself is variable and the influences of variable liver graft and extrahepatic factors are not negligible in pathological condition. Clinical features of 'SFS syndrome' are neither specific nor inevitable in low-weight liver and many other factors than actual graft weight contribute to their occurrence. Among them, early elevation of portal venous pressure highly probably plays a key role. In the clinical trials of surgical modification and local pharmacological manipulation targeting portal hemodynamics and tissue congestion, it may be the time to discard an excessive fear for SFS grafts and to minimize unnecessary withdrawal from the opportunity of transplantation.

Role of acute elevation of portal venous pressure by exogenous glucagon on gastric mucosal injury in rats with portal hypertension

Time-course studies revealed the increased susceptibility of the gastric mucosa to noxious injury in portal hypertension correlates with the level of elevated portal venous pressure and hyperglucagonemia. Whether acute elevation of portal venous pressure by exogenous glucagon aggravates such injury is not known. We tested the hypothesis that glucagon in a dose sufficient to acutely elevate portal venous pressure aggravates noxious injury of the gastric mucosa in rats with portal hypertension. Infusion of a portal hypotensive dose of somatostatin should reverse these changes. In anesthetized rats with portal vein ligation, glucagon, somatostatin or the combination was administered intravenously in a randomized, coded fashion. Acidified ethanol-induced gastric mucosal injury was determined. Portal venous pressure and gastric mucosal perfusion and oxygenation (reflectance spectrophotometry) were monitored to confirm the effects of the respective intravenous treatments. Exogenous glucagon exacerbated acidified ethanol-induced gastric mucosal injury. The exacerbation was attenuated by somatostatin. These changes paralleled the portal hypertensive and hypotensive effects of glucagon and somatostatin, respectively. Our data suggest that a unique mechanism is triggered with the onset of portal hypertension. In an antagonistic manner, glucagon and somatostatin modulate this novel mechanism that controls portal venous pressure and susceptibility of the gastric mucosa to noxious injury.

Dynamics of Portal and Peripheral Endothelin-1 in Hepatic Resection and Its Implication

Background. The liver and portal circulation contribute to production and clearance of endothelin-1 (ET-1). This study was undertaken to investigate what variables relate to the dynamics of ET-1 in hepatic resection and its clinical implication.Patients and Methods. On 20 patients with (n = 8) or without (n = 12) chronic liver disease who underwent hepatic resection, peripheral arterial and portal venous ET-1 were serially measured to determine a correlation with pre-, intra-, and postoperative variables.Results. The preoperative factors with which the portal ET-1 showed a positive correlation were the indocyanine green retention rate at 15 min (ICG R15) and portal venous pressure. The ET-1 clearance, as calculated from the difference between the portal and the peripheral ET-1 concentrations, was also correlated with the ICG R15. The peripheral ET-1 elevated significantly in the patients with increasing intraoperative blood loss or hepatic inflow occlusion. An increase in the portal ET-1 was correlated with an elevation of portal venous pressure after hepatectomy. Postoperative increase in serum bilirubin was closely correlated with the peripheral ET-1 at closure.Conclusion. The peripheral and portal ET-1 are correlated with not only preoperative hepatic reserve and portal venous pressure but also invasiveness of hepatectomy and postoperative course.

Reduction in nonparenchymal cell injury and vascular endothelial dysfunction after cold preservation of the liver by gaseous oxygen.

Reintroduction of oxygen to previously anoxic tissue may result in severe cell injury (oxygen paradox) and contribute to the so-called reperfusion damage of ischemic organs. Our study investigated the influence of simple gaseous oxygen supply during ischemia on nonparenchymal cell alterations upon reperfusion of the liver. Livers from male Wistar rats were isolated, rinsed blood-free and stored for 48 h at 4 degrees C in UW-preservation solution (group 1; n = 6). Gaseous oxygen was insufflated into a second group of livers (group 2; n = 6) during the storage period via the inferior caval vein at a pressure limited to 18 mmHg. To simulate the period of slow rewarming of the organ during surgical implantation in vivo, all livers were incubated at 25 degrees C in saline solution for 30 min prior to reperfusion. Reperfusion was carried out in vitro in a recirculating system with Krebs-Henseleit buffer. A control group was perfused immediately after harvest. The technique of aerobic storage (group 2) resulted in normal vascular perfusion characteristics without elevation of portal venous pressure (PVP) above control values, in contrast to group 1 livers which showed a significantly elevated PVP, averaging between 1.5 and 2 times the values of the control. Hepatic efflux of NO (nmol/ml) after 10 min of reperfusion was massively increased in group 1, while only low concentrations were found in group 2 and in control livers. Kupffer cell activation after ischemia was shown by a huge increase in acid phosphate release upon reperfusion compared with the control, with significantly lower values in group 2 after 10 min of reperfusion than in group 1. Thus, aerobic ischemia by gaseous oxygen persufflation seems an appropriate tool for long-term organ preservation, preventing vascular and parenchymal dysfunction upon reperfusion.