I-Fang Hsin

Cannabinoid receptor 2 agonist ameliorates mesenteric angiogenesis and portosystemic collaterals in cirrhotic rats.

Angiogenesis in liver cirrhosis leads to splanchnic hyperemia, increased portal inflow, and portosystemic collaterals formation, which may induce lethal complications, such as gastroesophageal variceal hemorrhage and hepatic encephalopathy. Cannabinoids (CBs) inhibit angiogenesis, but the relevant influences in cirrhosis are unknown. In this study, Spraque‐Dawley rats received common bile duct ligation (BDL) to induce cirrhosis. BDL rats received vehicle, arachidonyl‐2‐chloroethylamide (cannabinoid receptor type 1 [CB1] agonist), JWH‐015 (cannabinoid receptor type 2 [CB2] agonist), and AM630 (CB2 antagonist) from days 35 to 42 days after BDL. On the 43rd day, hemodynamics, presence of CB receptors, severity of portosystemic shunting, mesenteric vascular density, vascular endothelial growth factor (VEGF), VEGFR‐1, VEGFR‐2, phospho‐VEGFR‐2, cyclooxygenase (COX)‐1, COX‐2, and endothelial nitric oxide synthase (eNOS) expressions as well as plasma VEGF levels were evaluated. Results showed that CB1 and CB2 receptors were present in left adrenal veins of sham rats, splenorenal shunts (the most prominent intra‐abdominal shunts) of BDL rats, and mesentery of sham and BDL rats. CB2 receptor was up‐regulated in splenorenal shunts of BDL rats. Both acute and chronic JWH‐015 treatment reduced portal pressure and superior mesenteric arterial blood flow. Compared with vehicle, JWH‐015 significantly alleviated portosystemic shunting and mesenteric vascular density in BDL rats, but not in sham rats. The concomitant use of JWH‐015 and AM630 abolished JWH‐015 effects. JWH‐133, another CB2 agonist, mimicked the JWH‐015 effects. JWH‐015 decreased mesenteric COX‐1, COX‐2 messenger RNA expressions, and COX‐1, COX‐2, eNOS protein expressions. Furthermore, JWH‐015 decreased intrahepatic angiogenesis and fibrosis. Conclusions: CB2 agonist alleviates portal hypertension (PH), severity of portosystemic collaterals and mesenteric angiogenesis, intrahepatic angiogenesis, and fibrosis in cirrhotic rats. The mechanism is, at least partly, through COX and NOS down‐regulation. CBs may be targeted in the control of PH and portosystemic collaterals. (HEPATOLOGY 2012;56:248–258)

Caffeine ameliorates hemodynamic derangements and portosystemic collaterals in cirrhotic rats

Portal hypertension (PH), a pathophysiological derangement of liver cirrhosis, is characterized by hyperdynamic circulation, angiogenesis, and portosystemic collaterals. These may lead to lethal complications, such as variceal bleeding. Caffeine has been noted for its effects on liver inflammation, fibrogenesis, and vasoreactiveness. However, the relevant influences of caffeine in cirrhosis and PH have not been addressed. Spraque‐Dawley rats with common bile duct ligation–induced cirrhosis or sham operation received prophylactic or therapeutic caffeine treatment (50 mg/kg/day, the first or 15th day since operation, respectively) for 28 days. Compared to vehicle (distilled water), caffeine decreased cardiac index, increased systemic vascular resistance, reduced portal pressure (PP), superior mesenteric artery flow, mesenteric vascular density, portosystemic shunting (PSS), intrahepatic angiogenesis, and fibrosis without affecting liver and renal biochemistry. The beneficial effects were reversed by selective adenosine A1 agonist N6‐cyclopentyladenosine (CPA) or A2A agonist GCS21680. Both prophylactic and therapeutic caffeine treatment decreased portal resistance and PP in thioacetamide (200mg/kg, thrice‐weekly for 8 weeks)‐induced cirrhotic rats. Caffeine down‐regulated endothelial nitric oxide synthase, vascular endothelial growth factor (VEGF), phospho‐VEGFR2, and phospho–Akt mesenteric protein expression. Caffeine adversely affected viability of hepatic stellate and sinusoidal endothelial cells, which was reversed by CPA and GCS21680. On the other hand, caffeine did not modify vascular response to vasoconstrictors in splanchnic, hepatic, and collateral vascular beds. Conclusions: Caffeine decreased PP, ameliorated hyperdynamic circulation, PSS, mesenteric angiogenesis, hepatic angiogenesis, and fibrosis in cirrhotic rats. Caffeine may be a feasible candidate to ameliorate PH‐related complications in cirrhosis. (Hepatology 2015;61:1672‐1684)

Liver failure after transarterial chemoembolization for patients with hepatocellular carcinoma and ascites: incidence, risk factors, and prognostic prediction.

Background Transarterial chemoembolization (TACE) is widely used in patients with hepatocellular carcinoma (HCC). Post-TACE liver failure may occur, especially in patients with poor hepatic reserve. Ascites is often present in patients with HCC with coexisting cirrhosis. This study investigated the incidence, risk factors, and prognostic predictors in patients with HCC and ascites receiving TACE. Methods A total of 614 patients with HCC were enrolled and analyzed. Liver failure was defined as an increase of serum bilirubin level (≥2.0 mg/dL), increasing or newly developed ascites, or hepatic encephalopathy within 2 weeks of TACE. Results Ascitesthat were present in 100 (16.2%) patients at study entry, independently predicted a poor prognosis in the Cox proportional hazard model [relative risk (RR)=1.75, P=0.004]. Post-TACE liver failure occurred in 17 (17.3%) of 98 patients with HCC who had ascites and long-term follow-up. Child-Turcotte-Pugh class B (odds ratio=10.1, P=0.038) and post-TACE gastrointestinal bleeding (odds ratio=10.86, P=0.006) were independent risk factors associated with liver failure in the multivariate analysis. Of the 17 patients with post-TACE liver failure, 16 (94%) died within the first year of treatment. Liver failure (RR: 2.13, P=0.029), serum &agr;-fetoprotein level >51 ng/mL (RR=2.0, P=0.013) and poor performance status (RR: 2.17, P=0.003) independently predicted a poor prognosis in patients with ascites receiving TACE. Conclusions Preexisting ascites increases the mortality in patients with HCC receiving TACE. In patients with HCC and ascites, Child-Turcotte-Pugh class B and gastrointestinal bleeding are associated with liver failure after TACE. Post-TACE liver failure is a common event and predicts a decreased survival in patients with HCC and ascites.

Portosystemic collaterals are not prerequisites for the development of hepatic encephalopathy in cirrhotic rats

Background: Liver functions and portosystemic collaterals influence the development and severity of hepatic encephalopathy (HE) in cirrhosis. However, it has not been examined which factor has a greater influence or if shunts can be used to determine the presence and severity of HE. The expression of tumor necrosis factor‐α (TNF‐α) is increased in cirrhosis, and its role in HE deserves further evaluation. Methods: Portal hypertension was induced by portal vein ligation (PVL; a model of high‐degree portosystemic shunting without significant liver damage) and liver cirrhosis was induced by bile duct ligation (BDL; a model of low‐degree shunting with liver cirrhosis) in male Spraque‐Dawley rats. Sham‐operated rats were used as controls. Motor activity counts, hemodynamic parameters, plasma levels, liver biochemistry parameters, TNF‐α, and a flow‐pressure curve study of portosystemic collaterals (where a higher slope indicates fewer portosystemic collaterals) were performed on Day 7 after PVL and Week 5 after BDL. Results: Portal pressure was significantly higher in the PVL and BDL groups than in controls. The liver biochemistry parameters, TNF‐α, and motor activities were not significantly different between the PVL and PVL‐control groups. In the BDL group, TNF‐α, AST, and total bilirubin levels were significantly higher and the motor activity counts were lower than in the BDL‐control group. Moreover, in the BDL rats, TNF‐α (p = 0.037, R = ‐0.490), AST (p = 0.007, R = ‐0.595) and total bilirubin (P = 0.001, R = −0.692) levels, but not the slopes of the flow‐pressure curves, were significantly and negatively correlated with the motor activity counts. Conclusion: The presence of a high degree of portosystemic shunting without significant liver damage may not be adequate for the development of HE.

The influence of sorafenib on hepatic encephalopathy and the mechanistic survey in cirrhotic rats

Eur J Clin Invest 2012; 42 (12): 1309–1316

Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats

Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin‐1 (ET‐1), an endothelium‐derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension.

Effects of simvastatin on the portal-systemic collateral vascular response to endothelin-1 and shunting degree in portal hypertensive rats

Abstract Objective. Endothelin-1 (ET-1) exerts vasoconstrictive effect on portal-systemic collateral vascular bed of portal hypertensive rats. Statins are lipid-lowering agents with nitric oxide (NO)-related vasodilatory effects. Considering NO-associated vascular hyporesponsiveness to vasoconstrictors and shunting formation in portal hypertension, this study investigated the effects of simvastatin on 1) the portal-systemic collateral vascular responsiveness to ET-1 and 2) the portal-systemic shunting degree. Materials/methods. Portal hypertension was induced by partial portal vein ligation (PVL) in Sprague-Dawley rats. Simvastatin (20 mg/kg/day) or distilled water (control) was randomly administered by oral gavage since 2 days prior to until 7 days after PVL. Systemic and portal hemodynamics were measured on the 8th day. In another series, collateral perfusion with Krebs solution at different flow rates was performed to get flow–pressure curves which serve as an index of shunting degree. To survey the direct vascular effect, PVL rats randomly underwent preincubation with 1) Krebs solution, that is, the control group; or Krebs solution plus 2) simvastatin; 3) simvastatin + N ω-nitro-l-arginine (NNA, a NO synthase inhibitor); 4) simvastatin + indomethacin (a cyclooxygenase inhibitor), followed by ET-1 to evaluate the collateral vascular responsiveness. Results. Chronic simvastatin treatment significantly reduced portal pressure. The flow–pressure curves were similar between two groups. Simvastatin preincubation reduced collateral perfusion pressure changes to ET-1 (p < 0.05), which were partially reversed by NNA (p < 0.05), but not by indomethacin. Conclusions. Chronic simvastatin treatment significantly improved portal hypertension. The effect was at least partially exerted by decreased portal-systemic collateral vascular resistance through NO-mediated vascular hyporesponsiveness. The severity of portal-systemic collaterals was not influenced by simvastatin.

Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats

ABSTRACT Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal‐systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)‐induced cirrhotic rats. The female Sprague‐Dawley rats received BDL plus ovariectomy or sham‐operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10 mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up‐regulated hepatic endothelin‐1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin‐1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin‐1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism.

2'‐hydroxyflavanone ameliorates mesenteric angiogenesis and portal‐systemic collaterals in rats with liver fibrosis

Portal‐systemic collaterals lead to dreadful consequences in patients with cirrhosis. Angiogenesis participates in the development of liver fibrosis, hyperdynamic circulation, and portal‐systemic collaterals. 2′‐Hydroxyflavanone (2′‐HF), one of the citrus fruits flavonoids, is known to have antiangiogenesis effect without adverse response. However, the relevant effects in liver fibrosis have not been surveyed.

Clinical Outcomes and Complications of Endoscopic Submucosal Dissection for Superficial Gastric Neoplasms in the Elderly

AbstractThe number of elderly people with superficial gastric neoplasms is increasing, but the clinical outcome of endoscopic submucosal dissection (ESD) for treating elderly people with superficial gastric neoplasms remains unclear. We aimed to compare the efficacy and safety of ESD for patients with early gastric cancer (EGC) and precancerous lesions in elderly (≥75 years of age) and nonelderly (<75 years of age) patients.From October 2005 to December 2014, 83 consecutive patients with EGC and precancerous lesions (86 lesions) who were treated using ESD in our hospital were retrospectively reviewed. There were 44 lesions in 42 elderly patients who were at least 75-years old. The following parameters were compared between the 2 groups: preexisting comorbidities, performance status (PS), lesion inclusion criteria, lesion characteristics, treatment outcomes, surgery time, duration of hospitalization, complications, and intraoperative hemodynamic changes.Elderly patients had significantly higher preexisting comorbidity rates (90.9% vs 59.5%, P = 0.001), expanded lesion criteria rates (43.2% vs 19.0%, P = 0.016), and lower best PS rates (38.6% vs 81.0%, P < 0.001) than nonelderly patients. Lesion characteristics were similar in the 2 groups. The elderly had higher intraoperative hypotension rates (47.7% vs 21.4%, P = 0.011) and oxygen desaturation rates (9.1% vs 0.0%, P = 0.045) than nonelderly patients. In addition, the elderly also had a longer surgery time (107.0 ± 51.4 vs 91.5 ± 66.2 minutes, P = 0.049) and duration of hospitalization (7.5 ± 3.8 vs 5.9 ± 2.0 days, P = 0.016) than nonelderly patients. There were no differences in the prevalence rates of en-bloc resection, complete resection, bleeding, perforation, pneumonia, or intraabdominal free air between the 2 groups.Although elderly patients who underwent ESD for superficial gastric neoplasms had an increasing risk of intraoperative hypotension and oxygen desaturation, all patients were treated appropriately without postoperative sequelae. ESD is a safe and feasible intervention for elderly patients who have more comorbidity, a worse PS and more expanded lesions.