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Microvesicles (MVs) are extracellular vesicles released by cells following activation or apoptosis. Some MV subpopulations augment with cirrhosis severity and contribute to portal hypertension. This study aimed at determining if plasma MV levels can estimate the presence of hepatic venous pressure gradient (HVPG) ≥10 mm Hg and predict mortality in patients with advanced chronic liver disease. All patients with severe fibrosis or cirrhosis undergoing liver catheterization between 2013 and 2015 at two centers were prospectively included. We measured circulating levels of annexin V + , platelet, leukocyte, endothelial, and hepatocyte MVs. The test cohort included 139 patients. Hepatocyte MV levels were 4.0-fold and 2.2-fold higher in patients with Child-Pugh C than in those with Child-Pugh A or B liver disease, respectively. Levels of other MV subpopulations were not influenced by liver disease severity. Hepatocyte MV levels correlated with HVPG but could not identify patients with HVPG ≥10 mm Hg. Hepatocyte MV level >65 U/L predicted 6-month mortality independently of Child-Pugh score and of Model for End-Stage Liver Disease (MELD). Patients with hepatocyte MV levels >65 U/L and MELD >15 had a higher 6-month mortality than other patients (23% versus 3%; P = 0.001). These findings were confirmed in a validation cohort including 103 patients., Conclusion: Circulating MV levels cannot identify patients with HVPG ≥10 mm Hg; by contrast, hepatocyte MV levels strongly improve prediction of 6-month mortality in patients with advanced chronic liver disease; therapies associated with decreased levels of circulating hepatocyte MV might be attractive strategies in patients with severe cirrhosis. (Hepatology 2018)., (© 2018 by the American Association for the Study of Liver Diseases.)

Purpose: To prospectively compare the technical success rate and accuracy of shear-wave elastography (SWE) and transient elastography (TE) for the detection of clinically significant portal hypertension (PH) in patients with advanced cirrhosis who are undergoing hepatic vein pressure gradient (HVPG) measurements., Materials and Methods: The institutional ethics committee approved the study, and written informed consent was obtained. Seventy-nine consecutive patients with cirrhosis who were undergoing SWE and TE at the time of HVPG measurement were studied. The technical success rate of SWE and TE was compared with the diagnostic value of liver stiffness (LS) and spleen stiffness (SS) measurements and composite scores (LS spleen-diameter-to-platelet-ratio score [LSPS] and PH risk score) by using SWE and TE to detect clinically significant PH (HVPG ≥ 10 mm Hg) and esophageal varices at high risk of bleeding. Areas under the receiver operating characteristic curve and the DeLong test were used., Results: The technical success rate of SWE was significantly better than that of TE for both LS and SS (97% and 97% vs 44% and 42%, respectively; P < .001). LS of more than 24.6 kPa with SWE had a sensitivity, specificity, and accuracy for clinically significant PH of 81%, 88%, and 82%, respectively. Diagnostic performance of LS by using SWE was significantly better than that for SS for the diagnosis of clinically significant PH (area under the receiver operating characteristic curve of 0.87 vs 0.64, P = .003). LS, SS, LSPS, and PH risk score (according to SWE or TE) did not differ between patients with and those without high-risk esophageal varices (P = .09-.42)., Conclusion: In patients with advanced cirrhosis who are undergoing HVPG measurements, LS measurements obtained by using SWE have a higher technical success rate and a better diagnostic value than TE for clinically significant PH., ((©) RSNA, 2014)

Background & Aims: Circulating membrane-shed microparticles (MPs) participate in regulation of vascular tone. We investigated the cellular origins of MPs in plasma from patients with cirrhosis and assessed the contribution of MPs to arterial vasodilation, a mechanism that contributes to portal hypertension., Methods: We analyzed MPs from blood samples of 91 patients with cirrhosis and 30 healthy individuals (controls) using flow cytometry; their effects on the vascular response to vasoconstrictors were examined in vitro and in vivo., Results: Circulating levels of leuko-endothelial (CD31(+)/41(-)), pan-leukocyte (CD11a(+)), lymphocyte (CD4(+)), and erythrocyte (CD235a(+)) MPs were higher in patients with cirrhosis than in controls. Plasma of patients with cirrhosis contained hepatocyte-derived MPs (cytokeratin-18(+)), whereas plasma from controls did not. The severity of cirrhosis and systemic inflammation were major determinants of the levels of leuko-endothelial and hepatocyte MPs. MPs from patients with advanced cirrhosis significantly impaired contraction of vessels in response to phenylephrine, whereas MPs from healthy controls or from patients of Child-Pugh class A did not. This effect depended on cyclooxygenase type 1 and required phosphatidylserine on the surface of MPs. Intravenous injection of MPs from patients with cirrhosis into BALB/C mice decreased mean arterial blood pressure., Conclusions: Cirrhosis is associated with increases in circulating subpopulations of MPs, likely resulting from systemic inflammation and liver cell damage. The overall pool of circulating MPs from patients with advanced cirrhosis impairs vasoconstrictor responses and decreases blood pressure, contributing to the arterial vasodilation associated with portal hypertension., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Purpose: To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated., Methods: The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2-3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein., Results: Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group., Conclusion: In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.

Severe portal hypertension is responsible for complications and death. Although measurement of the hepatic venous pressure gradient is the most accurate method for evaluating the presence and severity of portal hypertension, this technique is considered invasive and is not routinely performed in all centers. Several noninvasive techniques have been proposed to measure portal hypertension. Certain methods evaluate elements related to the pathogenesis of portal hypertension through the measurement of hyperkinetic syndrome, for example, or they investigate the development of hepatic fibrosis through the measurement of increased intrahepatic vascular resistance. Other methods evaluate the clinical consequences of portal hypertension, such as the presence of esophageal varices or the development of portosystemic shunts. Methods evaluating increased hepatic vascular resistance are fairly accurate and mainly involve the detection of hepatic fibrosis by serum markers and transient elastography. The radiological assessment of hyperkinetic syndrome probably has value but is still under investigation. The assessment of severe portal hypertension by the presence of varices may be performed with simple tools such as biological assays, computed tomography, and esophageal capsules. More sophisticated procedures seem promising but are still under development. Screening tools for large populations must be simple, whereas more complicated procedures could help in the follow-up of already diagnosed patients. Although most of these noninvasive methods effectively identify severe portal hypertension, methods for diagnosing moderate portal hypertension need to be developed; this shows that further investigation is needed in this field., (Copyright © 2010 American Association for the Study of Liver Diseases.)

Rationale: Portopulmonary hypertension (PoPH) can be defined as elevation of pulmonary arterial pressure and pulmonary vascular resistance in the setting of portal hypertension. Survival results in PoPH are contrasting, and prognostic factors need to be identified., Objectives: To analyze long-term survival in a large cohort of patients with PoPH with the aim of determining the independent variables affecting survival., Methods: We retrospectively analyzed charts of all patients referred to the French Referral Center for pulmonary arterial hypertension with the diagnosis of PoPH between 1984 and 2004., Measurements and Main Results: The study population comprised 154 patients; 57% male. Mean age at diagnosis was 49 +/- 11 years, 60% of patients were in New York Heart Association functional class III-IV, and mean 6-minute walk distance was 326 +/- 116 m. Hemodynamic measurements showed a mean pulmonary arterial pressure of 53 +/- 13 mm Hg, cardiac index of 2.9 +/- 0.9 L/min/m(2), and pulmonary vascular resistance of 752 +/- 377 dyn/s/cm(5). Portal hypertension was related to cirrhosis in 136 patients, with a severity assessed as follows: Child-Pugh class A 51%, Child-Pugh class B 38%, Child-Pugh class C 11%. Overall survival rates at 1, 3, and 5 yr were 88, 75, and 68%, respectively. Multivariate regression analysis individualized the presence and severity of cirrhosis and cardiac index as major independent prognostic factors., Conclusions: Prognosis in PoPH is mainly related to the presence and severity of cirrhosis and to cardiac function. The place of pulmonary arterial hypertension-specific therapies remains to be determined in the setting of PoPH.

Type 1 hepatorenal syndrome (HRS) is prerenal failure specific to decompensated cirrhosis. In patients with HRS, there is marked splanchnic/systemic vasodilation resulting in arterial hypotension, arterial baroreceptor unloading, overstimulation of the sympathetic nervous and renin-angiotensin systems. This reflex neurohumoral hyperactivity via endogenous vasoconstrictors/vasopressors such as angiotensin II and noradrenaline induces arterial vasoconstriction in different extrasplanchnic vascular beds (including preglomerular arteries in the kidneys). Decreased arterial pressure (i.e. low renal perfusion pressure) and preglomerular vasoconstriction are thought to play a major role in the decline of the glomerular filtration rate (GFR). Nonrandomized studies in patients with HRS have shown that the administration of a splanchnic vasoconstrictor (vasopressin analogue or alpha(1)-adrenoceptor agonist), usually combined with intravenous albumin, causes increases in arterial pressure, arterial baroreceptor uploading, decreased neurohumoral activity, decreased renal vascular resistance, and increased GFR. Randomized clinical trials have shown that treatment with a combination of the vasopressin analogue terlipressin and intravenous albumin improves renal function in patients with type 1 HRS. Vasopressor therapy with terlipressin plus intravenous albumin is the medical treatment of choice for type 1 HRS., (Copyright 2008 S. Karger AG, Basel.)

Increased understanding of the hyperdynamic circulation syndrome has resulted in novel therapeutic approaches, some of which have already reached clinical practice. Central to the hyperdynamic circulation syndrome is an imbalance between the increase in different vasodilators (foremost among which is nitric oxide) and the compensatory increase in vasoconstrictors--usually accompanied by a blunted response. This chapter discusses the role of endothelin in the pathogenesis of the syndrome and in future treatment approaches. A relatively new area of research in this field is the role of infection and inflammation in the initiation and maintenance of the hyperdynamic circulation syndrome. The use of antibiotics in the setting of acute variceal bleeding is standard practice. Studies have suggested that chronic manipulation of the intestinal flora could have beneficial effects in the treatment of portal hypertension. The bile salts are another novel and interesting target. Although their vasoactive properties have been known for some time, recent data demonstrate that their effects could be central in the pathogenesis of the hyperdynamic circulation syndrome, and that manipulation of the composition of the bile acid pool could be a therapeutic approach to portal hypertension. Finally, hypoxia and angiogenesis play a role in the development of portal hypertension and the formation of collaterals. This role needs to be further defined but it appears likely that this phenomenon is yet another target for therapeutic intervention.

Background/aim: Spontaneous bacterial peritonitis (SBP) is a severe complication of cirrhosis but its exact pathogenesis has not yet been elucidated and the role of portal hypertension in the development of SBP has been suggested. The aim of this study was to test the hypothesis that an association exists between the degree of portal hypertension and the occurrence of SBP., Methods: 292 patients with cirrhosis who underwent a measurement of the hepatic venous pressure gradient (HVPG) were retrospectively studied. Following their ascites profile, patients were classified in three groups: patients with ascites who suffered from SBP, patients with sterile ascites, and patients who had no ascites., Results: Among the 137 patients with ascites, 24 patients suffered from SBP (17.5%). The mean HVPG was significantly different: 20.7 +/- 6.2 mm Hg in the SBP group, 17.5 +/- 5.1 mm Hg in the sterile ascites group and 14.7 +/- 5.6 mm Hg in the group without ascites (p < 0.05). Patients with the most severe portal hypertension (HVPG > or =30 mm Hg) had the highest risk to suffer from SBP (50%). Using the multivariate analysis, only the serum albumin level (p = 0.004) and the HVPG (p = 0.02) were independently correlated with the occurrence of ascites infection., Conclusions: This study suggests that in patients with SBP the degree of portal hypertension is greater than in the non infected patients. Ascites infection is independently associated with a low serum albumin level and a high HVPG.

Portal hypertension is a complication of diseases that obstruct portal blood flow, such as cirrhosis or portal vein thrombosis. In these diseases, increased vascular resistance to portal blood flow is the primary mechanism that increases portal pressure. In cirrhosis, increased intrahepatic vascular resistance is a result of both intrahepatic vasoconstriction and surrounding mechanical factors including collagen deposition and regenerative nodules. This article summarizes recent progress in the understanding of molecular mechanisms underlying the portal hypertension-associated arterial alterations in splanchnic systemic territories and those involved in the development of portal-systemic collateral circulation.

Background & Aims: It has been suggested that beta-blockers might be harmful in pulmonary arterial hypertension. However, no study has evaluated the effect of beta-blockers in these patients. The aim of this study was to investigate the effect of beta-blockers on exercise capacity and pulmonary hemodynamics in patients with portopulmonary hypertension receiving beta-blockers for the prophylaxis of variceal bleeding., Methods: Ten consecutive patients with moderate to severe portopulmonary hypertension (mean pulmonary artery pressure of 52 [10] mm Hg) underwent a 6-minute walk test and a right heart catheterization at baseline and 2 (1) months after beta-blocker withdrawal., Results: Following beta-blocker withdrawal, 9 of 10 patients increased their 6-minute walked distance with a mean increase in the whole group of 79 (78) meters (P = .01). Cardiac output increased by 28% (P < .01) with no change in mean pulmonary artery pressure, resulting in a 19% decrease in pulmonary vascular resistance (P < .01). Increases in cardiac output were related to a 25% increase in heart rate (P < .01), whereas stroke volume was unchanged (P = .65). The improvements in exercise tolerance were associated with increases in chronotropic response (maximal heart rate minus resting heart rate) from 18 (9) to 34 (12) beats/min (P < .01) during the 6-minute walk test., Conclusions: In patients with moderate to severe portopulmonary hypertension, beta-blockers are associated with significant worsening in exercise capacity and pulmonary hemodynamics. These deleterious effects support the contraindication of beta-blockers in patients with portopulmonary hypertension.

Portal hypertension is responsible for different severe complications such as variceal bleeding, ascites and pulmonary disorders. Different pharmacological and endoscopic treatments have been proposed but some recommendations may differ. The conclusions of a French consensus conference on the prevention and treatments of the main complications of portal hypertension in adults are reported.

Portopulmonary hypertension represents a major risk factor for transplantation; therefore, preoperative detection is crucial. The aims of this study were to determine (1) whether Doppler echocardiography performed at evaluation is a reliable tool for detecting portopulmonary hypertension and (2) the incidence of acquired portopulmonary hypertension profile after evaluation. One hundred sixty-five patients had Doppler echocardiography and right heart catheterization at evaluation over a 9-year period. All patients had a prospective follow-up, and the results of catheterization at evaluation were compared with those obtained at the time of transplantation. Seventeen of 165 patients met the criteria for portopulmonary hypertension on Doppler echocardiography. Portopulmonary hypertension was confirmed by catheterization in 10 patients and ruled out in 7. There were no false negatives for echocardiography. Mean pulmonary artery pressure was significantly higher during the initial phase of transplantation than at evaluation (17.8 +/- 4.3 vs. 20.3 +/- 5.5 mm Hg, respectively, P <.0001), and there was no significant correlation between values obtained at these 2 time points. Three patients showed to have acquired portopulmonary hypertension profile while waiting for a graft within time intervals ranging from 2.5 to 5 months. In conclusion, Doppler echocardiography is a highly sensitive tool for detecting portopulmonary hypertension. However, because this technique has a poor positive predictive value, right heart catheterization is recommended for confirming portopulmonary hypertension. In addition, the absence of portopulmonary hypertension at evaluation does not exclude the occasional occurrence of acquired portopulmonary hypertension profile after listing.