Metformin exposure, maternal PCOS status and fetal venous liver circulation: A randomized, placebo-controlled study.

BACKGROUND: Metformin is prescribed to women with polycystic ovary syndrome (PCOS) to prevent pregnancy complications. Children exposed to metformin vs. placebo in utero, have increased head circumference at birth and are more overweight and obese at 8 years of age. Also, maternal PCOS-status seems to alter the long-term cardio-metabolic health of offspring. We hypothesized that the long-term effects of metformin-exposure and/or maternal PCOS may be mediated by circulatory adaptations during fetal life. MATERIAL AND METHODS: This is a sub-study of a larger double-blinded, placebo-controlled trial, where women with PCOS were randomized to metformin (2g/day) or placebo in pregnancy, a total of 487 women. A sub-group of participants (N = 58) took part in this sub-study and had an extended ultrasound examination at gestational week 32, including blood flow velocity and diameter measurements of the umbilical vein (UV), the ductus venosus (DV) and the portal vein (PV). Blood flow volume was calculated and adjusted for estimated fetal weight (EFW) (normalized flow). Metformin exposed fetuses were compared to placebo exposed fetuses. Fetuses of mothers with PCOS (metformin [n = 30] and placebo [n = 28]) were compared to a low-risk reference population (N = 160) by z-score statistics. RESULTS: There was no difference in fetal liver flow between metformin vs. placebo-exposed fetuses. Fetuses of mothers with PCOS had higher EFW (0.63 [95% CI 0.44-0.83] p<0.001), lower normalized UV, DV, PV, and lower total venous liver blood flows than the reference population. CONCLUSION: Metformin during pregnancy did not affect fetal liver blood-flow. In our population, maternal PCOS-status was associated with reduced total venous liver blood-flow, which may explain altered growth and metabolism later in life.

Stimulation of the hepatic arterial buffer response using exogenous adenosine: hepatic rest/stress perfusion imaging.

OBJECTIVES: The hepatic arterial buffer response is a mechanism mediated by adenosine whereby hepatic arterial perfusion (HAP) increases when portal flow decreases, and is implicated in liver disease. The first study aim was to measure HAP in patients undergoing myocardial perfusion imaging (MPI), thus developing hepatic arterial rest/stress perfusion imaging (HAPI). The second aim was to compare adenosine-induced changes in splenic perfusion (SP) and HAP with corresponding changes in myocardial blood flow (MBF). METHODS: Patients had MPI with 82Rb PET/CT using adenosine (n = 45) or regadenoson (n = 33) for stressing. SP and HAP were measured using a first-pass technique that gives HAP rather than total hepatic perfusion. Renal perfusion (RP) was also measured. RESULTS: Mean MBF and HAP increased after both adenosine ([stress-rest]/rest 1.1 and 0.8) and regadenoson (1.4 and 0.6), but the respective changes did not correlate. After adenosine, SP (- 0.48) and RP (- 0.26) both decreased. The change in SP correlated positively with the change in MBF (r = 0.36; p = 0.015) but did not correlate with change in HAP. After regadenoson, SP (0.2) and RP (0.2) both increased. The changes in SP correlated with the changes in MBF (r = 0.39; p = 0.025) and HAP (r = 0.39; p = 0.02). Changes in RP correlated with changes in HAP (r = 0.51; p = 0.0008) but not MBF. Resting SP (r = 0.32; p = 0.004), but not resting HAP, correlated with hepatic fat burden. Adenosine-induced change in HAP also correlated with hepatic fat (r = 0.29; p = 0.05). CONCLUSION: HAPI could be a useful new hepatic function test. Neither splenic 'switch-off' nor hepatic arterial 'switch-on' identifies adequacy of stress in MPI. KEY POINTS: • This article describes a new method for assessing arterial perfusion of the liver and its capacity to respond to an infusion of adenosine, a substance that normally 'drives' hepatic arterial flow. • Hepatic arterial flow increased in response to adenosine, sometimes dramatically. Adenosine is already used clinically to stimulate myocardial blood flow in patients with suspected coronary disease, but the increase in flow did not correlate with the corresponding increase in hepatic arterial flow. • Analogous to the use of adenosine in the myocardium, the increase in hepatic arterial flow in response to adenosine has the potential to be a new clinically useful method for the evaluation of hepatic arterial haemodynamics in liver disease.

Nonselective ß-Blockers May Progress the Thrombosis of Portal Venous System in Cirrhotic Patients: A Retrospective Observational Study.

INTRODUCTION: Occlusive portal venous system thrombosis (PVT) is significantly associated with poor outcomes in cirrhotic patients. Nonselective ß-blockers (NSBBs) may be associated with the development of PVT. However, the role of NSBBs in progressing thrombosis remains unclear. METHODS: Forty-three patients on whom contrast-enhanced computed tomography or magnetic resonance imaging was performed twice, and for whom there was detailed information regarding NSBBs, were eligible in this study, including 16 in the NSBBs group and 27 in the no NSBBs group. A composite endpoint of progressing thrombosis included the development of PVT in patients without PVT and aggravation of PVT in patients with PVT. Logistic regression analysis was employed to identify the effect of NSBBs on the progression of PVT. RESULTS: At the last admission, 13 patients had progressing thrombosis. The incidence of progressing thrombosis was significantly higher in the NSBBs group than in the no NSBBs group [50.0% (8/16) vs. 18.5% (5/27), P = 0.030]. The use of NSBBs (odds ratio 4.400, 95% confidence interval 1.107-17.482, P = 0.035) was significantly associated with progressing thrombosis in univariate logistic regression analyses, but not significant (odds ratio 4.084, 95% confidence interval 0.488-34.158, P = 0.194) in multivariate logistic regression analyses. CONCLUSIONS: NSBBs may play a role in the progression of PVT in liver cirrhosis. The benefits and risks of NSBBs in the management of liver cirrhosis should be fully weighed.

Effect of terlipressin infusion therapy on recipient's hepatic and renal functions in living donor liver transplantations: Experience from a tertiary hospital.

BACKGROUND: Patients with end-stage liver disease are prone to hemodynamic disturbances which may be aggravated with liver transplantation. Blood pooling in splanchnic area and portal hypertension cause reduction in central blood volume. Terlipressin reduces mesenteric and hepatic blood flow, causing vasoconstriction in the smooth muscles of the arteries in the splanchnic region. OBJECTIVE: We investigated the efficacy of perioperative terlipressin infusion in patients who received living donor liver transplantation (LDLT) on hepatic and renal functions. DESIGN: Retrospective. SETTING: University hospital. METHOD: The study included 86 adult patients who received LDLT, due to end-stage hepatic disease, between April 2014 and July 2016 in our institute. Data were collected by searching the medical archives of patients. A standard anesthesia protocol was administered to all patients. In a selected group of patients, terlipressin infusion was initiated at 3 µg/kg/h, immediately after anesthesia was induced. The dose was halved following arterial anastomosis and was continued at this dose for the subsequent 3 days. Patients who received terlipressin infusion were compared with patients who did not receive it. MAIN OUTCOME MEASURES: There is no evidence in this trial to show evidence of effectiveness as a result of terlipressin infusion. RESULTS: Patients in the terlipressin group were statistically significantly older. Central venous pressure, cardiac index, global end diastolic volume, and extravascular lung volume did not show significant differences between the groups. Urine output was similar in both groups; however, regarding the use of packed red blood cells and fresh frozen plasma, terlipressin group patients needed more packs. Perioperative liver function tests were similar between the groups except for aspartate aminotransferase and alanine aminotransferase values on the first and third postoperative days. CONCLUSION: Terlipressin infusion was not found to be significantly effective among the liver and kidney function tests. LIMITATIONS: This may be a result of randomization defect of our retrospective study design. Many prospective randomized studies should be planned to reach more accurate results.

The effects of terlipressin and direct portacaval shunting on liver hemodynamics following 80% hepatectomy in the pig.

Liver failure is the major cause of death following liver resection. Post-resection portal venous pressure (PVP) predicts liver failure, is implicated in its pathogenesis, and when PVP is reduced, rates of liver dysfunction decrease. The aim of the present study was to characterize the hemodynamic, biochemical, and histological changes induced by 80% hepatectomy in non-cirrhotic pigs and determine if terlipressin or direct portacaval shunting can modulate these effects. Pigs were randomized (n=8/group) to undergo 80% hepatectomy alone (control); terlipressin (2 mg bolus + 0.5-1 mg/h) + 80% hepatectomy; or portacaval shunt (PCS) + 80% hepatectomy, and were maintained under terminal anesthesia for 8 h. The primary outcome was changed in PVP. Secondary outcomes included portal venous flow (PVF), hepatic arterial flow (HAF), and biochemical and histological markers of liver injury. Hepatectomy increased PVP (9.3 ± 0.4 mmHg pre-hepatectomy compared with 13.0 ± 0.8 mmHg post-hepatectomy, P<0.0001) and PVF/g liver (1.2 ± 0.2 compared with 6.0 ± 0.6 ml/min/g, P<0.0001) and decreased HAF (70.8 ± 5.0 compared with 41.8 ± 5.7 ml/min, P=0.002). Terlipressin and PCS reduced PVP (terlipressin = 10.4 ± 0.8 mmHg, P=0.046 and PCS = 8.3 ± 1.2 mmHg, P=0.025) and PVF (control = 869.0 ± 36.1 ml/min compared with terlipressin = 565.6 ± 25.7 ml/min, P<0.0001 and PCS = 488.4 ± 106.4 ml/min, P=0.002) compared with control. Treatment with terlipressin increased HAF (73.2 ± 11.3 ml/min) compared with control (40.3 ± 6.3 ml/min, P=0.026). The results of the present study suggest that terlipressin and PCS may have a role in the prevention and treatment of post-resection liver failure.

Catheter-Directed Thrombolysis for Portal Vein Thrombosis in Children: A Case Series.

PURPOSE: To describe safety and efficacy of catheter-directed thrombolysis (CDT) for portal vein thrombosis (PVT) in children. MATERIALS AND METHODS: Retrospective review was performed of 10 consecutive patients (7 girls, 3 boys; mean age 11.9 y; range, 3-17 y) with PVT undergoing CDT at a single tertiary children's hospital between August 2005 and March 2016. PVT was categorized by etiology and extent (intrahepatic, extrahepatic, or both). CDT was performed with infusion catheters placed via percutaneous transhepatic (PTH) and/or transjugular intrahepatic (TJ) approaches, with or without the use of adjunctive maneuvers, including balloon maceration and suction and rheolytic thrombectomy. Degree of thrombolysis on portal venography, presence of portal vein thrombus on available follow-up imaging, and complication rates were recorded. RESULTS: In 10 patients, 13 CDT procedures were performed for PVT, with 3 patients requiring repeat CDT. Portal access was achieved with PTH (n = 6), TJ (n = 2), or combined (n = 2) approaches. All cases were successful in re-establishing patency and hepatopetal flow on portal venography with complete thrombolysis achieved in 10 of 13 cases (77%). Two major complications (20%) occurred, both with PTH access. Mean follow-up time for 9 patients was 2.6 years (range, 51-1,902 d) with long-term patency achieved in 6 (67%). CONCLUSIONS: CDT can be safe and effective for PVT in children. Portal access considerations and early initiation of thrombolysis may further increase safety and efficacy.

Simvastatin Prevents Progression of Acute on Chronic Liver Failure in Rats With Cirrhosis and Portal Hypertension.

BACKGROUND & AIMS: Cirrhosis and its clinical consequences can be aggravated by bacterial infections, ultimately leading to the development of acute on chronic liver failure (ACLF), characterized by acute decompensation, organ failure, and high mortality within 28 days. Little is known about cellular and molecular mechanisms of ACLF in patients with cirrhosis, so no therapeutic options are available. We developed a sepsis-associated preclinical model of ACLF to facilitate studies of pathogenesis and evaluate the protective effects of simvastatin. METHODS: Male Wistar rats inhaled CCl4 until they developed cirrhosis (at 10 weeks) or cirrhosis with ascites (at 15-16 weeks). Male Sprague-Dawley rats received bile-duct ligation for 28 days or intraperitoneal thioacetamide for 10 weeks to induce cirrhosis. After induction of cirrhosis, some rats received a single injection of lipopolysaccharide (LPS) to induce ACLF; some were given simvastatin or vehicle (control) 4 hours or 24 hours before induction of ACLF. We collected data on changes in hepatic and systemic hemodynamics, hepatic microvascular phenotype and function, and survival times. Liver tissues and plasma were collected and analyzed by immunoblots, quantitative polymerase chain reaction, immuno(fluoro)histochemistry and immunoassays. RESULTS: Administration of LPS aggravated portal hypertension in rats with cirrhosis by increasing the severity of intrahepatic microvascular dysfunction, exacerbating hepatic inflammation, increasing oxidative stress, and recruiting hepatic stellate cells and neutrophils. Rats with cirrhosis given LPS had significantly shorter survival times than rats with cirrhosis given the control. Simvastatin prevented most of ACLF-derived complications and increased survival times. Simvastatin appeared to increase hepatic sinusoidal function and reduce portal hypertension and markers of inflammation and oxidation. The drug significantly reduced levels of transaminases, total bilirubin, and ammonia, as well as LPS-mediated activation of hepatic stellate cells in liver tissues of rats with cirrhosis. CONCLUSIONS: In studies of rats with cirrhosis, we found administration of LPS to promote development of ACLF, aggravating the complications of chronic liver disease and decreasing survival times. Simvastatin reduced LPS-induced inflammation and liver damage in rats with ACLF, supporting its use in treatment of patients with advanced chronic liver disease.

Beneficial Effects of the Peroxisome Proliferator-Activated Receptor α/γ Agonist Aleglitazar on Progressive Hepatic and Splanchnic Abnormalities in Cirrhotic Rats with Portal Hypertension.

Recent studies have reported that peroxisome proliferator-activated receptor α (PPARα) agonist decreases intrahepatic resistance, whereas PPARγ agonist reduces portosystemic shunts (PSSs) and splanchnic angiogenesis in cirrhotic rats. The present study investigated the effects of a 21-day treatment with the dual PPARα/γ agonist aleglitazar (Ale) on progressive abnormalities in bile-duct-ligated and thioacetamide-induced cirrhotic rats with portal hypertension (PH). In vivo and in vitro effects were evaluated. Chronic Ale treatment significantly up-regulated PPARα/PPARγ receptors and down-regulated tumor necrosis factor-α (TNF-α) and NF-κB expression in the liver, splanchnic tissues, collateral vessels, and intestines of cirrhotic rats with PH. Notably, Ale improved PH by the suppression of systemic/tissue inflammation, hepatic fibrosis, hepatic Rho-kinase-mediated endothelin-1 hyperresponsiveness, intrahepatic/mesenteric angiogenesis, vascular endothelial growth factor expression, PSS, intestinal mucosal injury, and hyperpermeability in cirrhotic rats. Acute Ale treatment inhibited TNF-α-enhanced endothelin-1-induced contraction of primary hepatic stellate cells, vascular endothelial growth factor-induced migration/angiogenesis of liver sinusoidal endothelial cells, and TNF-α-induced disruption of Caco-2 cell monolayer-epithelial barrier. The present study suggested that Ale can potentially treat relevant abnormalities through the inhibition of inflammatory, vasoconstrictive, angiogenic, and mucosal-disrupted pathogenic markers in cirrhosis. Overall, chronic Ale treatment ameliorated PH syndrome by the suppression of hepatic fibrogenesis, neoangiogenesis, vasoconstrictor hyperresponsiveness, splanchnic vasodilatation, and PSS; and decreased intestinal mucosal injury and hyperpermeability in cirrhotic rats.

Vasopressin and nitroglycerin decrease portal and hepatic venous pressure and hepato-splanchnic blood flow.

BACKGROUND: Various methods are used to reduce venous blood pressure in the hepato-splanchnic circulation, and hence minimise blood loss during liver surgery. Previous studies show that combination of vasopressin and nitroglycerin reduces portal pressure and flow in patients with portal hypertension, and in this study we investigated this combination in patients with normal portal pressure. METHOD: In all, 13 patients were studied. Measurements were made twice to confirm baseline (C1 and BL), during vasopressin infusion 4.8 U/h (V), and during vasopressin infusion combined with nitroglycerin infusion (V + N). Portal venous pressure (PVP), hepatic venous pressure (HVP), central haemodynamics and arterial and venous blood gases were obtained at each measuring point, and portal (splanchnic) and hepato-splanchnic blood flow changes were calculated. RESULTS: Vasopressin alone did not affect PVP, whereas HVP increased slightly. In combination with nitroglycerin, PVP decreased from 10.1 ± 1.6 to 8.9 ± 1.3 mmHg (P < 0.0001), and HVP decreased from 7.9 ± 1.9 to 6.2 ± 1.3 mmHg (P = 0.001). Vasopressin reduced portal blood flow by 47 ± 19% and hepatic venous flow by 11 ± 18%, respectively. Addition of nitroglycerin further reduced portal- and hepatic flow by 55 ± 13% and 30 ± 13%, respectively. Vasopressin alone had minor effects on central haemodynamics, whereas addition of nitroglycerin reduced cardiac index (3.2 ± 0.7 to 2.7 ± 0.5; P < 0.0001). The arterial-portal vein lactate gradient was unaffected. CONCLUSION: The combination of vasopressin and nitroglycerin decreases portal pressure and hepato-splanchnic blood flow, and could be a potential treatment to reduce bleeding in liver resection surgery.

Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis.

BACKGROUND & AIMS: Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. METHODS: Cirrhosis was induced in male Sprague-Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL ), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH ). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium- and fibrosis-related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. RESULTS: Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL-6 levels or survival in rats with CCl4ORAL or BDL-induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. CONCLUSIONS: Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease-related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis.

Terlipressin: Current and emerging indications in chronic liver disease.

Terlipressin is an analogue of vasopressin that has potent vasoactive properties and has been available for use in most countries for nearly two decades. It has both established roles and emerging indications in the management of complications of decompensated chronic liver disease. We explore historic and emerging literature regarding the use of terlipressin for a range of indications including hepatorenal syndrome, portal hypertensive bleeding, and disruptions in sodium homeostasis. Novel methods of infusion-based terlipressin administration including the beneficial effect in reduction of adverse events are explored, in addition to new indications for the use of terlipressin in decompensated cirrhosis in an outpatient setting.

MicroRNA-21-Regulated Activation of the Akt Pathway Participates in the Protective Effects of H2S against Liver Ischemia-Reperfusion Injury.

Maintaining a certain level of hydrogen sulfide (H2S) in ischemia-reperfusion (I/R) is essential for limiting injury to the liver. Exogenous H2S exerts protective effects against this injury, but the mechanisms remain unclear. Liver injury was induced in Wistar rats undergoing hepatic I/R for 30 min, followed by a 3-h reperfusion. Administration of GYY4137 (a slow-releasing H2S donor) significantly attenuated the severity of liver injury and was reflected by reduced inflammatory cytokine production and cell apoptosis, the levels of which were elevated by I/R, while DL-propargylglycine (PAG, an inhibitor of cystathionine γ-lyase [CSE]) aggravated liver injury. Delivery of GYY4137 significantly elevated the plasma levels of H2S and upregulated the expression of microRNA-21 (miR-21), leading to the activation of the Akt pathway, in rat livers subjected to I/R. To further investigate the protective mechanisms of H2S during liver I/R injury, we established a cell model of hypoxia/reoxygenation (H/R) by incubating Buffalo rat liver (BRL) cells under hypoxia for 4 h followed by normoxia for 10 h. The regulatory effect of miR-21 on the Akt pathway by downregulating phosphatase and tensin homolog (PTEN) was validated by luciferase assays. Incubation of sodium hydrosulfide (NaHS), an H2S donor, increased the expression of miR-21, attenuated the reduced cell viability and the increased apoptosis by H/R, in BRL cells. Anti-miR-21 abolished the protective effects of NaHS by inactivating the Akt pathway. In conclusion, the present results indicate the activation of the Akt pathway regulated by miR-21 participates in the protective effects of H2S against I/R-induced liver injury.

Comparison of BQ123, Epoprostenol, and Verapamil as Vasodilators During Normothermic Ex Vivo Liver Machine Perfusion.

BACKGROUND: The optimal vasodilator to avoid hepatic artery vasospasm during normothermic ex vivo liver perfusion (NEVLP) is yet to be determined. We compared safety and efficacy of BQ123 (endothelin1 antagonist), epoprostenol (prostacyclin analogue), and verapamil (calcium channel antagonist). METHODS: Livers from porcine heart beating donors were perfused for 3 hours and transplanted into recipient pigs. Four groups were compared: group 1, livers perfused with a dose of 1.25 mg of BQ123 at baseline and at 2 hours of perfusion; group 2, epoprostenol at a continuous infusion of 4 mg/h; group 3, verapamil 2.5 mg at baseline and at 2 hours of perfusion; group 4, no vasodilator used during ex vivo perfusion. Liver injury and function were assessed during perfusion, and daily posttransplantation until postoperative day (POD) 3. All groups were compared with a cold storage group for postoperative graft function. RESULTS: Hepatic artery flow during NEVLP was significantly higher in BQ123 compared with verapamil, epoprostenol, and no vasodilator-treated livers. Aspartate aminotransferase levels were significantly lower with BQ123 and verapamil compared with epoprostenol and control group during perfusion. Peak aspartate aminotransferase levels were lower in pigs receiving BQ123 and verapamil perfused grafts compared with epoprostenol and control group. International Normalized Ratio, alkaline phosphatase, and total bilirubin levels were lower in the BQ123 and verapamil groups compared to epoprostenol group. Cold storage group had increased markers of ischemia reperfusion injury and slower graft function recovery compared to machine perfused grafts. CONCLUSION: The use of BQ123, epoprostenol, and verapamil during NEVLP is safe. Livers perfused with BQ123 and verapamil have higher hepatic artery flow and reduced hepatocyte injury during perfusion compared with epoprostenol. Hepatic artery flow is significantly reduced in the absence of vasodilators during NEVLP.

Changes of liver hemodynamic and elastography parameters in patients with colorectal liver metastases receiving preoperative chemotherapy: "a note of caution".

BACKGROUND: New systemic chemotherapy agents have improved prognosis in patients with colorectal liver metastases (CLM), but some of them damage the liver parenchyma and ultimately increase postoperative morbidity and mortality after liver resection. The aims of our study were to determine the degree of hemodynamic and pathological liver injury in CLM patients receiving preoperative chemotherapy and to identify an association between these injuries and postoperative complications after liver resection. METHODS: This is a prospective descriptive study of patients with CLM receiving preoperative chemotherapy before curative liver resection from November 2013 to June 2014. All patients had preoperative elastography and hepatic hemodynamic evaluation. We analyzed clinical preoperative data and postoperative outcomes after grouping the patients by chemotherapy type, development of sinusoidal obstructive syndrome (SOS), and development of major complications. RESULTS: Eleven from the 20 patients included in the study received preoperative oxaliplatin-based chemotherapy (OBC). Nine patients had SOS at pathological analysis and five patients developed major complications. Patients receiving preoperative OBC had higher values of hepatic venous pressure gradient (HVPG) and developed more SOS and major complications. Patients developing SOS had higher values of HVPG and developed more major complications. Patients with major complications had higher values of HVPG, and patients with a HVPG of 5 mmHg or greater had more major complications than those under 5 mmHg (20 vs 80%, p = 0.005). CONCLUSIONS: OBC and SOS impair liver hemodynamics in CLM patients. An increase in major complications after liver resection in these patients develops at subclinical HVPG levels.

In vivo inhibitory activity of andrographolide derivative ADN-9 against liver cancer and its mechanisms involved in inhibition of tumor angiogenesis.

It is well known that liver cancer is a highly aggressive malignancy with poor prognosis. Andrographolide (AD), a major bioactive component of Andrographis paniculata (Burm. F.), is a potential anti-cancer pharmacophore and the synthesis of AD derivatives with better cytotoxicity to cancer cells has attracted considerable attentions. In the present study, we evaluated the in vivo inhibitory effects of ADN-9, a 15-benzylidene substituted derivative of AD, on the growth and metastasis of murine hepatoma H22 using an orthotopic xenograft model and a subcutaneous xenograft model, and we further studied the anti-angiogenic action and the related mechanisms of ADN-9 in vivo and in vitro. Importantly, ADN-9 remarkably suppressed the growth and metastasis of both orthotopic and subcutaneous xenograft tumors, and the serum AFP level in orthotopic hepatoma-bearing mice treated with 100mg/kg ADN-9 (ig.) was decreased to the normal level. We also found that ADN-9 showed stronger abilities than AD in shrinking tumors, suppressing the invasion and metastasis of H22 cells, decreasing the MVD and promoting tumor cell apoptosis in subcutaneous xenograft of mice. Additionally, ADN-9 exhibited stronger inhibitory activity than AD against the migration and VEGF-induced capillary-like tube formation in HUVECs, which was further proved to be associated with attenuating VEGF/VEGFR2/AKT signaling pathway. The present research provides the first evidence that a 15-substituted AD derivative is more promising than the parent compound in therapeutic treatment of liver cancer.

Response to Sildenafil in a Patient With Coexisting Post-Liver Transplant Portopulmonary Hypertension and Hepatopulmonary Syndrome.

Hepatopulmonary syndrome and portopulmonary hypertension are complications of portal hypertension with opposing mechanisms that can coexist. Moderate portopulmonary hypertension, which is a contraindication to a liver transplant, must be managed with pulmonary vasodilators to normalize pulmonary arterial pressures before a transplant listing. Concomitant hepatopulmonary syndrome complicates the management of portopulmonary hypertension, as pulmonary vasodilators can theoretically exacerbate the intrapulmonary dilatation believed to cause hepatopulmonary syndrome. We describe a case of a post-liver transplant patient with concomitant hepatopulmonary syndrome and portopulmonary hypertension safely treated with sildenafil.

The impact of microbubble-enhanced therapeutic ultrasound combined with prothrombin on microwave ablation in the rabbit liver.

AIM: This study aimed to investigate the effect of microbubble-enhanced ultrasound (MEUS) combined with prothrombin on regional hepatic circulation and microwave ablation (MWA) in rabbit livers. MATERIALS AND METHODS: High-pressureamplitude therapeutic ultrasound (TUS) was used to treat 52 surgically exposed livers of healthy New Zealand rabbits: 13 livers were treated with MEUS alone, 13 with MEUS and prothrombin (PMEUS), 13 with ultrasound plus normal saline and 13 with ultrasound plus prothrombin as controls. Contrast-enhanced ultrasound (CEUS) imaging was performed on the exposed livers before and after treatment, and acoustic quantification was done to assess liver perfusion. Then, the liver was divided into two parts, one was used for pathologic examination and the other was ablated with microwave (MWA) and then processedfor pathologic examination. RESULTS: The CEUS images and Peak value after treatment in the PMEUS group were significantly reduced as compared to the remaining 3 groups (p<0.05). Occasional piecemeal hemorrhage was evidenced in the pathological examination in the MEUS group. Obvious cellular degeneration and necrosis with thrombosis were observed in the PMEUS group. Electron microscopy showed endothelial damage in both the MEUS group and PMEUS group. After MWA, coagulated volumes (V) in the PMEUS group were larger than in the remaining 3 groups (p<0.05). The cell ultrastructure disorder wasmore severe in the PMEUS group than in remaining 3 groups. CONCLUSION: PMEUS promotes endothelial injury and produces more obvious thrombotic occlusion, improving the therapeutic effect of MWA on the rabbit liver.

A New Chemical Compound, NecroX-7, Acts as a Necrosis Modulator by Inhibiting High-Mobility Group Box 1 Protein Release During Massive Ischemia-Reperfusion Injury.

BACKGROUND: Necrotic cell death is common in a wide variety of pathologic conditions, including ischemia-reperfusion (IR) injury. The aim of this study was to develop an IR injury-induced hepatic necrosis model in dogs by means of selective left hepatic inflow occlusion and to test the efficacy of a new chemical compound, NecroX-7, against the IR injury-induced hepatic damage. METHODS: A group of male Beagle dogs received intravenous infusions of either vehicle or different doses of NecroX-7 (1.5, 4.5, or 13 mg/kg) for a 20-minute period before a 90-minute left hepatic inflow occlusion followed by reperfusion. RESULTS: The gross morphology in the NecroX-7-treated groups after occlusion appeared to be less congested and less swollen than that in vehicle-treated control group. Circulating alanine transaminase and aspartate transaminase levels in the control group were elevated during the course of IR, and were effectively blocked in the 4.5 and 13 mg/kg NecroX-7-treated groups. The serum levels of high-mobility group box 1 protein showed a peak at 8 hours after occlusion in control group, and this elevation was significantly blunted by 4.5 mg/kg NecroX-7 treatment. Histologic analysis showed a marked ischemia or IR injury-induced hepatocytic degenerations, sinusoidal and portal vein congestions, and inflammatory cell infiltrations in the control group, whereas the treatment groups showed significantly diminished histopathology in a dose-dependent manner. CONCLUSIONS: These results demonstrated that NecroX-7 attenuated the hepatocyte lethality caused by hepatic IR injury in a large animal setting. We conclude that NecroX-7 may provide a wide variety of therapeutic options for IR injury in human patients.

Rapid Infusion of Hydroxyethyl Starch 70/0.5 but not Acetate Ringer's Solution Decreases the Plasma Concentration of Propofol during Target-controlled Infusion.

BACKGROUND: Rapid fluid infusion resulting in increased hepatic blood flow may decrease the propofol plasma concentration (Cp) because propofol is a high hepatic extraction drug. The authors investigated the effects of rapid colloid and crystalloid infusions on the propofol Cp during target-controlled infusion. METHODS: Thirty-six patients were randomly assigned to 1 of 3 interventions (12 patients per group). At least 30 min after the start of propofol infusion, patients received either a 6% hydroxyethyl starch (HES) solution at 24 ml·kg·h or acetated Ringer's solution at 24 or 2 ml·kg·h during the first 20 min. In all groups, acetated Ringer's solution was infused at 2 ml·kg·h during the next 20 min. The propofol Cp was measured every 2.5 min as the primary outcome. Cardiac output, blood volume, and indocyanine green disappearance rate were determined using a pulse dye densitogram analyzer before and after the start of fluid administration. Effective hepatic blood flow was calculated as the blood volume multiplied by the indocyanine green disappearance rate. RESULTS: The rapid HES infusion significantly decreased the propofol Cp by 22 to 37%, compared to the Cp at 0 min, whereas the rapid or maintenance infusion of acetate Ringer's solution did not decrease the propofol Cp. Rapid HES infusion, but not acetate Ringer's solution infusion, increased the effective hepatic blood flow. CONCLUSIONS: Rapid HES infusion increased the effective hepatic blood flow, resulting in a decreased propofol Cp during target-controlled infusion. Rapid HES infusion should be used cautiously as it may decrease the depth of anesthesia.