Juan C. García-Pagán

Noninvasive Prediction of Clinically Significant Portal Hypertension and Esophageal Varices in Patients With Compensated Liver Cirrhosis

OBJECTIVES:We aimed to develop a model based on noninvasive variables for the prediction of clinically significant portal hypertension (CSPH) and of esophageal varices (EV) in patients with compensated liver disease.METHODS:Sixty patients with compensated liver cirrhosis diagnosed by histology were included in the training set. All patients had physical examination, laboratory tests, abdominal color-Doppler ultrasound, upper digestive tract endoscopy, and measurement of hepatic venous pressure gradient. Predictive models for the presence of CSPH and of EV were calculated. The models were validated in an independent series of 74 patients with compensated liver disease.RESULTS:Clinical and laboratory variables were selected in the final models, while ultrasonography did not add statistical power for the prediction of CSPH and EV. The model for prediction of CSPH included albumin, INR, and ALT. The best cutoff had 93% sensitivity and 61% specificity in the training set, and correctly classified 77% of patients in the validation set. Spider angiomas, ALT, and albumin predicted EV. The best cutoff of the model in the training set had a sensitivity of 93% and a specificity of 37% and correctly classified 72% of cases in the validation set.CONCLUSIONS:Noninvasive prediction of EV in well-compensated cirrhotic patients is not accurate. However, a model obtained by combining simple laboratory variables has a high sensitivity to predict CSPH in this population and may be useful to select the subset of patients requiring screening endoscopy. By this method, endoscopic screening could be obviated in about 40% of patients.

Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

Patients with cirrhosis show intrahepatic endothelial dysfunction, characterized by an impaired flow‐dependent vasorelaxation. This alteration is responsible for the marked postprandial increase in portal pressure and is attributed to an insufficient release of nitric oxide (NO). Ascorbic acid reverts endothelial dysfunction in other vascular disorders, via the increase of NO bioavailability through the neutralization of superoxide anions, thus preventing the scavenging of NO by superoxide. This study examined whether acute ascorbic acid administration might improve endothelial dysfunction in cirrhosis. Thirty‐seven portal hypertensive patients with cirrhosis had measurements of hepatic and systemic hemodynamics, ascorbic acid, and malondialdehyde (MDA). Patients were randomly allocated to receive ascorbic acid (3 g, intravenously, n = 15) or placebo (n = 12) followed by a liquid meal. A third group received ascorbic acid followed by a sham meal (n = 10). Measurements were repeated after 30 minutes (hepatic venous pressure gradient at 15 and 30 minutes). Patients with cirrhosis had significantly lower ascorbic acid levels and higher MDA than healthy controls. Ascorbic acid significantly reduced MDA levels and markedly attenuated the postprandial increase in the hepatic venous pressure gradient (4% ± 7% vs. 18% ± 10% in placebo at 30 minutes, P < .001). Ascorbic acid followed by sham meal did not modify hepatic or systemic hemodynamics. In conclusion, patients with cirrhosis exhibited intrahepatic endothelial dysfunction, associated with decreased levels of ascorbic acid and increased levels of MDA. Ascorbic acid improved intrahepatic endothelial dysfunction, blunting the postprandial increase in portal pressure. These results encourage the performance of further studies testing antioxidants as adjunctive therapy in the treatment of portal hypertension. (HEPATOLOGY 2006;43:485–491.)

Glucagon hinders the effects of somatostatin on portal hypertension: A study in rats with partial portal vein ligation

Whether the decrease of portal venous inflow and portal pressure induced by somatostatin is related to the effects of somatostatin in inhibiting the secretion of glucagon and other vasodilatory peptides that are increased in portal hypertension was investigated in the current study. Splanchnic vascular resistance and splanchnic blood flow were determined using radioactive microspheres in rats with portal hypertension caused by partial portal vein ligation. Somatostatin infusion significantly decreased portal pressure (from 13.1 +/- 1.9 to 12.1 +/- 2.2 mm Hg; P less than 0.05). This was associated with a significant decrease in portal venous inflow caused by splanchnic vasoconstriction, as evidenced by increased splanchnic vascular resistance, and with a marked suppression of glucagon secretion. The simultaneous infusion of somatostatin and glucagon (2.8 ng/min, a dose that prevented any decrease in circulating glucagon levels) abolished all the hemodynamic effects of somatostatin. This effect seems to be specific because no hemodynamic changes were noted in portal hypertensive rats receiving only the glucagon infusion.

Review article: the modern management of portal hypertension--primary and secondary prophylaxis of variceal bleeding in cirrhotic patients.

Backgroundu2002 Variceal bleeding is a life–threatening complication of liver cirrhosis with a high probability of recurrence. Treatment to prevent first bleeding or rebleeding is mandatory.

Esophageal balloon tamponade versus esophageal stent in controlling acute refractory variceal bleeding: A multicenter randomized, controlled trial

Balloon tamponade is recommended only as a “bridge” to definitive therapy in patients with cirrhosis and massive or refractory esophageal variceal bleeding (EVB), but is frequently associated with rebleeding and severe complications. Preliminary, noncontrolled data suggest that a self‐expandable, esophageal covered metal stent (SX‐ELLA Danis; Ella‐CS, Hradec Kralove, Czech Republic) may be an effective and safer alternative to balloon tamponade. We conducted a randomized, controlled trial aimed at comparing esophageal stent versus balloon tamponade in patients with cirrhosis and EVB refractory to medical and endoscopic treatment. Primary endpoint was success of therapy, defined as survival at day 15 with control of bleeding and without serious adverse events (SAEs). Twenty‐eight patients were randomized to Sengstaken‐Blakemore tube (n = 15) or SX‐ELLA Danis stent (n = 13). Patients were comparable in severity of liver failure, active bleeding at endoscopy, and initial therapy. Success of therapy was more frequent in the esophageal stent than in balloon tamponade group (66% vs. 20%; P = 0.025). Moreover, control of bleeding was higher (85% vs. 47%; Pu2009=u20090.037) and transfusional requirements (2 vs 6 PRBC; P = 0.08) and SAEs lower (15% vs. 47%; P = 0.077) in the esophageal stent group. TIPS was used more frequently in the tamponade group (4 vs. 10; P = 0.12). There were no significant differences in 6‐week survival (54% vs. 40%; P = 0.46). Conclusion: Esophageal stents have greater efficacy with less SAEs than balloon tamponade in the control of EVB in treatment failures. Our findings favor the use of esophageal stents in patients with EVB uncontrolled with medical and endoscopic treatment. (Hepatology 2016;63:1957‐1967)

Systemic hemodynamics, vasoactive systems, and plasma volume in patients with severe Budd‐Chiari syndrome

Budd‐Chiari syndrome (BCS) causes postsinusoidal portal hypertension, which leads to complications similar to those observed in cirrhosis. However, no studies have investigated whether patients with BCS develop the hyperdynamic circulatory syndrome present in patients with cirrhosis who have portal hypertension. We evaluated systemic and cardiopulmonary hemodynamics, plasma renin activity, aldosterone and norepinephrine levels, and plasma volume in patients with BCS admitted for complications of portal hypertension. BCS patients had mean systemic and cardiopulmonary pressures and cardiac indices that were within the normal range but were significantly different from those of a group of patients with cirrhosis matched by sex, body surface, and liver function (cardiac index 3.1 ± 0.7 vs. 4.9 ± 1.2 L · min−1 · m−2; P < .001; systemic vascular resistance [SVR] index, 2,189 ± 736 vs. 1,377 ± 422 dyne · s · cm−5 · m−2, P < .001). Despite normal systemic vascular resistance, BCS patients had activation of the neurohumoral vasoactive systems, as evidenced by increased plasma renin activity, aldosterone and norepinephrine levels (15.0 ± 21.5 ng/mL · h, 76.7 ± 106.8 ng/dL, 586 ± 868 pg/mL; respectively) and plasma volume expansion. The analysis of individual BCS patients identified that 7 of the 21 patients actually had reduced SVR index. These patients had the greatest plasma volume expansion. A significant inverse correlation between plasma volume and SVR index was observed. In conclusion, patients with BCS had activation of vasoactive neurohumoral systems and expanded plasma volume. This outcome was observed even though most of these patients did not exhibit systemic vasodilation and cardiac output was not increased, in marked contrast with what is observed in patients with cirrhosis. (HEPATOLOGY 2006;43:27–33.)

New approaches in the pharmacologic treatment of portal hypertension

To alleviate the risk of variceal bleeding, the portal pressure gradient--usually evaluated as the hepatic venous pressure gradient (HVPG)--must be reduced to < or = 12 mmHg. Although beta-blocking agents are accepted therapy for preventing first or subsequent bleeding episodes, propranolol therapy decreases final HVPG to < or = 12 mmHg in only 12% of patients, while only 24% of patients have a > or = 20% reduction in HVPG and nearly 40% show no reduction in HVPG. This has stimulated research on alternative or additional treatments. Nitrates such as isosorbide dinitrate reduce portal pressure by decreasing resistance to portal and collateral blood flow and by promoting reflex splanchnic vasoconstriction. However, while nitrates are effective in the acute situation, tolerance leading to refractoriness develops over the long term unless they are combined with diuretics or other agents in the treatment of portal hypertension. Propranolol and isosorbide-5-mononitrate combined cause a substantially greater reduction in HVPG than monotherapy with either drug in both acute and long-term use. Presumably concomitant isosorbide-5-mononitrate administration opposes the increase in portal resistance induced by propranolol. Spironolactone, which has been shown to lower HVPG in patients with cirrhosis, produces a reduction in plasma volume that attenuates the increased cardiac output associated with cirrhosis and triggers vasoactive mechanisms that decrease splanchnic blood flow. Potentially, spironolactone may maintain and enhance the decrease in portal pressure achieved by nitrates or propranolol. Triple therapy with a beta-blocker, a nitrate and spironolactone may be feasible.(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of deep sedation on the accuracy of hepatic and portal venous pressure measurements in patients with cirrhosis.

Measurement of the hepatic venous pressure gradient (HVPG) offers valuable prognostic information in patients with cirrhosis. In specific circumstances, (children, agitated patients, TIPS placement) deep sedation is required. This study aims to assess the impact of deep sedation on the accuracy of hepatic/portal pressure measurements.

Role of gap junctions modulating hepatic vascular tone in cirrhosis

Gap junctions are formed by connexins (Cx), a family of proteins that couple endothelial and smooth muscle cells in systemic vessels. In this context, Cx allow the transmission of signals modulating vascular tone. Recently, vascular Cx have been observed in liver cells implicated in liver blood flow regulation. Here, we investigated the role of Cx in the regulation of intrahepatic vascular tone in cirrhosis.

Effects of end-to-side portacaval shunt and distal splenorenal shunt on systemic and pulmonary haemodynamics in patients with cirrhosis

Background : Patients with cirrhosis exhibit splanchnic, peripheral and pulmonary vasodilation, which are thought to play a role in increasing portal pressure, promoting sodium retention and determining arterial hypoxaemia. The present study investigated whether these abnormalities are influenced by portal hypertension or by portal systemic shunting.