Juan Turnes

Simvastatin Lowers Portal Pressure in Patients With Cirrhosis and Portal Hypertension: A Randomized Controlled Trial

BACKGROUND & AIMS Simvastatin improves liver generation of nitric oxide and hepatic endothelial dysfunction in patients with cirrhosis, so it could be an effective therapy for portal hypertension. This randomized controlled trial evaluated the effects of continuous simvastatin administration on the hepatic venous pressure gradient (HVPG) and its safety in patients with cirrhosis and portal hypertension. METHODS Fifty-nine patients with cirrhosis and portal hypertension (HVPG > or =12 mm Hg) were randomized to groups that were given simvastatin 20 mg/day for 1 month (increased to 40 mg/day at day 15) or placebo in a double-blind clinical trial. Randomization was stratified according to whether the patient was being treated with beta-adrenergic blockers. We studied splanchnic and systemic hemodynamics and variables of liver function and safety before and after 1 month of treatment. RESULTS Simvastatin significantly decreased HVPG (-8.3%) without deleterious effects in systemic hemodynamics. HVPG decreases were observed in patients who were receiving beta-adrenergic blockers (-11.0%; P = .033) and in those who were not (-5.9%; P = .013). Simvastatin improved hepatic, fractional, and intrinsic clearance of indocyanine green, showing an improvement in effective liver perfusion and function. No significant changes in HVPG and liver function were observed in patients receiving placebo. The number of patients with adverse events did not differ significantly between groups. No patient was withdrawn from the study based on adverse events. CONCLUSIONS Simvastatin decreased HVPG and improved liver perfusion in patients with cirrhosis. These effects were additive with those of beta-adrenergic blockers. The beneficial effects of simvastatin should be confirmed in long-term clinical trials for portal hypertension.

Pharmacological Reduction of Portal Pressure and Long-Term Risk of First Variceal Bleeding in Patients with Cirrhosis

OBJECTIVES:A reduction in hepatic venous pressure gradient (HVPG) of ≥20% of baseline or to ≤12 mmHg (responders) is associated with a reduced risk of first variceal bleeding. The aim of this study was to evaluate whether this protective effect is maintained in the long term and if it extends to other portal hypertension complications.METHODS:Seventy-one cirrhotic patients with esophageal varices and without previous variceal bleeding who entered into a program of prophylactic pharmacological therapy and were followed for up to 8 yr were evaluated. All had two separate HVPG measurements, at baseline and after pharmacological therapy with propranolol ± isosorbide mononitrate.RESULTS:Forty-six patients were nonresponders and 25 were responders. Eight-year cumulative probability of being free of first variceal bleeding was higher in responders than in nonresponders (90%vs 45%, P = 0.026). The lack of hemodynamic response and low platelet count were the only independent predictors of first variceal bleeding. Additionally, reduction of HVPG was independently associated with a decreased risk of spontaneous bacterial peritonitis (SBP) or bacteremia. No significant differences in the development of ascites, hepatic encephalopathy, or survival were observed.CONCLUSIONS:The hemodynamic response in cirrhotic patients is associated with a sustained reduction in the risk of first variceal bleeding over a long-term follow-up. Reduction of HVPG also correlate with a reduced risk of SBP or bacteremia.

PTFE-covered stents improve TIPS patency in Budd-Chiari syndrome.

Transjugular intrahepatic portosystemic shunt (TIPS) have been shown to be an efficient portal‐systemic derivative treatment for Budd‐Chiari syndrome (BCS) patients uncontrolled by medical therapy. However, the main drawback of TIPS for this condition is a very high rate of shunt dysfunction. Recently, polytetrafluoroethylene (PTFE)‐covered stents have been shown to reduce the incidence of TIPS dysfunction in patients with cirrhosis. The aim of the study was to assess the incidence of TIPS dysfunction in 2 cohorts of BCS patients treated with bare or PTFE‐covered stents. The study included 25 TIPS procedures (16 bare stents and 9 covered stents) with a median follow‐up period of 20.4 months (range, 3.9‐124.8). Fourteen of 16 patients (87%) receiving bare stents had TIPS dysfunction compared to 3 of the 9 patients (33%) receiving PTFE‐covered stents (P = .005). The actuarial rates of primary patency in the bare‐stent group were 19% at 1 year compared with 67% in the PTFE‐covered stent group (P = .02; log‐rank test). The number of additional interventional procedures to maintain TIPS patency was significantly greater in the bare‐stent than in the PTFE‐covered stent group (1.9 ± 1.2 vs. 0.6 ± 0.9; P = .007). The number of patients with clinical relapses was greater in the bare‐stent group compared to the PTFE‐covered stent group (13 vs. 5 episodes in 9 and 3 patients, respectively). In conclusion, PTFE‐covered stents have a considerable advantage over bare stents for the TIPS treatment of BCS patients, with a lower dysfunction rate, a lower number of reinterventions, and fewer prosthesis requirements. PTFE‐covered stents are preferable in patients with Budd‐Chiari Syndrome. (HEPATOLOGY 2004;40:1197–1202.)

Portal Hypertension–Related Complications After Acute Portal Vein Thrombosis: Impact of Early Anticoagulation

BACKGROUND & AIMS Acute portal vein thrombosis (APVT) is a rare disorder that causes chronic portal hypertension if recanalization is not obtained. However, response to anticoagulation and long-term prognosis of APVT are not well-defined. METHODS Thirty-eight patients diagnosed with APVT between 1995 and 2003 from 5 Spanish referral hospitals, in whom cirrhosis and malignancy were specifically excluded, were included in this retrospective study. The response to anticoagulation therapy and development of portal hypertension-related complications during follow-up were evaluated. RESULTS Mean follow-up was 43 months (range, 6-112 months). Recanalization occurred in 12 of 27 patients receiving anticoagulation versus 0 of 11 patients who did not receive anticoagulation (P = .008). Rates of recanalization were influenced by the precocity of heparin administration and the number of underlying prothrombotic conditions. Follow-up upper endoscopy performed in 29 patients disclosed gastroesophageal varices in 16 (55%). Varices appeared as early as 1 month after APVT. However, in most patients varices were detected in successive endoscopies, mainly during the first year. Two-year actuarial probability of variceal bleeding was 12% and for ascites 16%. Five-year survival was 87%. Mortality was related to the APVT episode in 2 cases and to an underlying hematologic disorder in one. CONCLUSIONS Anticoagulation achieved recanalization in about 40% of patients. Most patients not achieving recanalization will develop gastroesophageal varices during follow-up. However, development of variceal bleeding and ascites is infrequent, and survival is satisfactory.

Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy.

Hepatic encephalopathy can arise from portal‐systemic shunting in the absence of intrinsic liver disease. However, there are few descriptions of this form of encephalopathy. Portal vein thrombosis is an infrequent disease that causes portal‐systemic shunting. Episodic hepatic encephalopathy has been described in patients with portal vein thrombosis, but it is not known if these patients develop minimal hepatic encephalopathy. We designed a study to investigate the neurological consequences of portal vein thrombosis in patients without cirrhosis and no clinical signs of encephalopathy. For this purpose, 10 patients underwent neuropsychological tests, an oral glutamine challenge test, and brain magnetic resonance (MR) imaging. The results were compared with those obtained in 10 healthy controls. Patients with portal vein thrombosis exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and MR similar to those described in hepatic encephalopathy associated with cirrhosis. MR spectroscopy revealed a decrease in myo‐inositol and an increase in glutamine. The increase in glutamine correlated with an increase in ammonia following the oral glutamine challenge test, signs of increased brain water (decrease in magnetization transfer ratio), and impairment of attention tests. In conclusion, patients with noncirrhotic portal vein thrombosis develop subclinical neurological abnormalities compatible with minimal hepatic encephalopathy. These disturbances, which include signs of increase in brain water and a compensatory osmotic response (decrease in brain myo‐inositol), appear to be secondary to brain exposure to ammonia induced by portal‐systemic shunting. (HEPATOLOGY 2006;43:707–714.)

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.)

Effectiveness, safety and clinical outcomes of direct-acting antiviral therapy in HCV genotype 1 infection: results from a Spanish real world cohort.

BACKGROUND & AIMS Clinical trials evaluating second-generation direct-acting antiviral agents (DAAs) have shown excellent rates of sustained virologic response (SVR) and good safety profiles in patients with chronic hepatitis C virus (HCV) genotype 1 infection. We aimed to investigate the effectiveness and safety of two oral DAA combination regimens, ombitasvir/paritaprevir/ritonavir plus dasabuvir (OMV/PTV/r+DSV) and ledipasvir/sofosbuvir (LDV/SOF), in a real-world clinical practice. METHODS Data from HCV genotype 1 patients treated with either OMV/PTV/r+DSV±ribavirin (RBV) (n=1567) or LDV/SOF±RBV (n=1758) in 35 centers across Spain between April 1, 2015 and February 28, 2016 were recorded in a large national database. Demographic, clinical and virological data were analyzed. Details of serious adverse events (SAEs) were recorded. RESULTS The two cohorts were not matched with respect to baseline characteristics and could not be compared directly. The SVR12 rate was 96.8% with OMV/PTVr/DSV±RBV and 95.8% with LDV/SOF±RBV. No significant differences were observed in SVR according to HCV subgenotype (p=0.321 [OMV/PTV/r+DSV±RBV] and p=0.174 [LDV/SOF]) or degree of fibrosis (c0.548 [OMV/PTV/r/DSV±RBV] and p=0.085 [LDV/SOF]). Only baseline albumin level was significantly associated with failure to achieve SVR (p<0.05) on multivariate analysis. Rates of SAEs and SAE-associated treatment discontinuation were 5.4% and 1.7%, in the OMV/PTV/r+DSV subcohort and 5.5% and 1.5% in the LDV/SOF subcohort, respectively. Hepatocellular carcinoma (HCC) recurred in 30% of patients with a complete response to therapy for previous HCC. Incident HCC was reported in 0.93%. CONCLUSIONS In this large cohort of patients managed in the real-world setting in Spain, OMV/PTV/r+DSV and LDV/SOF achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with similarly good safety profiles. LAY SUMMARY In clinical trials, second-generation direct-acting antiviral agents (DAAs) have been shown to cure over 90% of patients chronically infected with the genotype 1 hepatitis C virus and have been better tolerated than previous treatment regimens. However, patients enrolled in clinical trials do not reflect the real patient population encountered in routine practice. The current study, which includes almost 4,000 patients, demonstrates comparable rates of cure with two increasingly used DAA combinations as those observed in the clinical trial environment, confirming that clinical trial findings with DAAs translate into the real-world setting, where patient populations are more diverse and complex.

Utility of color Doppler ultrasonography predicting tips dysfunction.

OBJECTIVES:Color Doppler ultrasonography (CDUS) has been proposed as an alternative to portal pressure gradient (PPG) measurement to detect transjugular intrahepatic portosystemic shunt (TIPS) dysfunction but with inconsistent results. This study aimed at developing and validating CDUS criteria to assess TIPS dysfunction.METHODS:A total of 117 consecutive follow-up simultaneous CDUS and hemodynamic evaluations in 34 patients with TIPS were analyzed. TIPS dysfunction was defined as a PPG >12 mmHg. A predictive model was obtained with logistic regression and was validated in an independent, prospective sample of 119 consecutive paired CDUS/hemodynamic evaluations in 55 patients.RESULTS:TIPS dysfunction was present in 57 of the 117 studies in the retrospective series. At multivariate analysis, mean maximum flow velocity at the portal vein (mVPmax) and direction of flow in the intrahepatic portal vein branches (FD) were the only independent predictors of TIPS dysfunction. The prediction rule for TIPS dysfunction derived from the model (mVPmax <28 cm/s when flow is hepatofugal or mVPmax <39 cm/s when flow is hepatopetal) had 90% sensitivity, 45% specificity, and negative likelihood ratio of 0.23. This prediction rule was validated both in patients with bare stents and in patients with polytetra fluoroethylene (PTFE)-covered stents, showing an overall 87% sensitivity, 57% specificity, and 0.23 negative likelihood ratio.CONCLUSIONS:The combination of two CDUS parameters correlate with TIPS dysfunction with high sensitivity and low specificity but with a good negative likelihood ratio. TIPS catheterization can be safely avoided in half of the patients using this predictive rule.

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.)

Treatment of hepatitis C virus infection in patients with cirrhosis and predictive value of model for end‐stage liver disease: Analysis of data from the Hepa‐C registry

Direct‐acting antiviral agents (DAAs) are highly effective and well tolerated in patients with chronic hepatitis C virus infection, including those with compensated cirrhosis. However, fewer data are available in patients with more advanced liver disease. Our retrospective, noninterventional, national, multicenter study in patients from the Spanish Hepa‐C registry investigated the effectiveness and safety of interferon‐free DAA regimens in patients with advanced liver disease, including those with decompensated cirrhosis, in routine practice (all currently approved regimens were registered). Patients transplanted during treatment or within 12 weeks of completing treatment were excluded. Among 843 patients with cirrhosis (Child‐Turcotte‐Pugh [CTP] class A, n = 564; CTP class B/C, n = 175), 90% achieved sustained virologic response 12 weeks after treatment (SVR12). Significant differences in SVR12 and relapse rates were observed between CTP class A and CTP class B/C patients (94% versus 78%, and 4% versus 14%, respectively; both P < 0.001). Serious adverse events (SAEs) were more common in CTP class B/C versus CTP class A patients (50% versus 12%, respectively; P < 0.001). Incident decompensation was the most common serious adverse event (7% overall). Death rate during the study period was 16/843 (2%), significantly higher among CTP class B/C versus CTP class A patients (6.4% versus 0.9%; P < 0.001). Baseline Model for End‐Stage Liver Disease (MELD) score alone (cut‐off 18) was the best predictor of survival. Conclusion: Patients with decompensated cirrhosis receiving DAAs present lower response rates and experience more SAEs. In this setting, a MELD score ≥18 may help clinicians to identify those patients with a higher risk of complications and to individualize treatment decisions. (Hepatology 2017;65:1810‐1822).