Juan G. Abraldes

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

BACKGROUND Patients with cirrhosis in Child-Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. METHODS We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy-EBL group, 31 patients). RESULTS During a median follow-up of 16 months, rebleeding or failure to control bleeding occurred in 14 patients in the pharmacotherapy-EBL group as compared with 1 patient in the early-TIPS group (P=0.001). The 1-year actuarial probability of remaining free of this composite end point was 50% in the pharmacotherapy-EBL group versus 97% in the early-TIPS group (P<0.001). Sixteen patients died (12 in the pharmacotherapy-EBL group and 4 in the early-TIPS group, P=0.01). The 1-year actuarial survival was 61% in the pharmacotherapy-EBL group versus 86% in the early-TIPS group (P<0.001). Seven patients in the pharmacotherapy-EBL group received TIPS as rescue therapy, but four died. The number of days in the intensive care unit and the percentage of time in the hospital during follow-up were significantly higher in the pharmacotherapy-EBL group than in the early-TIPS group. No significant differences were observed between the two treatment groups with respect to serious adverse events. CONCLUSIONS In these patients with cirrhosis who were hospitalized for acute variceal bleeding and at high risk for treatment failure, the early use of TIPS was associated with significant reductions in treatment failure and in mortality. (Current Controlled Trials number, ISRCTN58150114.)

Current management of portal hypertension

The management of portal hypertension should be based on an updated knowledge of its natural history. Portal hypertension is an almost unavoidable complication of cirrhosis, and it is responsible for the more lethal complications of this syndrome: gastro-esophageal varices and massive gastrointestinal bleeding, ascites, hepatorenal syndrome, and hepatic encephalopathy. Appearance of these complications represents the major cause of death and liver transplantation in patients with cirrhosis. The prevalence of esophageal varices is very high: when cirrhosis is diagnosed, varices are present in about 40% of compensated patients and in 60% of those with ascites [1,2]. After initial diagnosis of cirrhosis, the expected incidence of newly developed varices is about 5% per year [3]. Once developed, varices increase in size from small to large at an overall rate of 10–15% per year [3]. Progression of liver failure seems to be the factor with the greatest influence on overall growth [4]. On the other side, improvement in liver function and abstinence from alcohol may result in decrease or even disappearance of varices [5]. Once diagnosed, the overall incidence of variceal bleeding is to the order of 25% at 2 years in non-selected patients [6]. Many efforts have been made to define risk criteria for the development of variceal bleeding. The most important predictive factors related to the risk of bleeding are variceal size,presence of red weal marks in the varices, and severity of liver dysfunction expressed by the Child–Pugh classification. These risk indicators have been combined in the north Italian endoscopic club (NIEC) index [7] which allows to classify patients into different groups with predicted 1-year bleeding risk ranging from 6 to 76%. However, the predictive power of this index is far from satisfactory. In a recent report, variceal size was found to be the best predictor of variceal bleeding, and this is the variable used to decide whether a patient should be given prophylactic therapy or not. The risk of variceal bleeding is about 7% at 2 years in patients with small varices (less than 5 mm), and increases to 30% at 2 years in patients with large varices [6]. Variceal size and red color signs are associated with increased bleeding risk probably because they contribute to marked increase in the tension of the wall of the varices, the decisive factor determining variceal rupture [8]. According to Frank’s modification of Laplace’s law, variceal wall tension is directly proportional to the transmural variceal pressure (the gradient between intravariceal and esophageal luminal pressures) and the radius of the varix, and inversely proportional to the thickness of the variceal wall. While variceal size is a function of variceal radius, red weal marks may represent areas of reduced wall thickness. Hepatic venous pressure gradient (HVPG) may constitute a good surrogate marker of transmural variceal pressure [9]. Indeed, cross-sectional and longitudinal studies demonstrated that variceal bleeding does not occur if HVPG remains below 12 mmHg [5,9–12]. It has been reported that 30–50% of cirrhotic patients with an acute variceal bleeding episode will die within 6 weeks [2], but it is likely that this figure overestimates the current mortality from variceal bleeding [13]. A more accurate, current figure may be a mortality of 20% at 6 weeks. Immediate mortality from uncontrolled bleeding is in the range of 5–8% [2,6]. Active bleeding at endoscopy [14], bacterial infection [15] and HVPG .20 mmHg measured early after admission [16] are significant prognostic indicators of failure to control bleeding. It is important to emphasize that variceal bleeding ceases spontaneously in 40–50% of patients. This is probably influenced by the fact that hypovolemia leads to reflex splanchnic vasoconstriction with reduced portal pressure and blood flow, a beneficial response that is nullified by blood transfusion [17,18]. The incidence of early rebleeding ranges between 30 and 40% within the first 6 weeks [6]. The risk peaks in the first 5 days with 40% of all rebleeding episodes occurring in this very early period [19]. Bleeding gastric varices, active bleeding at emergency endoscopy, low serum albumin levels, renal failure Journal of Hepatology 38 (2003) S54–S68

Accuracy and reproducibility of transient elastography for the diagnosis of fibrosis in pediatric nonalcoholic steatohepatitis

Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in chronic liver disease patients. In this study, we assessed the value of TE for the prediction of fibrosis stage in a cohort of pediatric patients with nonalcoholic steatohepatitis. Furthermore, TE interobserver agreement was evaluated. TE was performed in 52 consecutive biopsy‐proven nonalcoholic steatohepatitis patients (32 males, 20 females, age 13.6 ± 2.44 years). The area under the receiver operating characteristic curves for the prediction of “any” (≥1), significant (≥2), or advanced fibrosis (≥3) were 0.977, 0.992, and 1, respectively. Calculation of multilevel likelihood ratios showed that TE values <5, <7, and <9 kPa, suggest the presence of “any” fibrosis, significant fibrosis, and advanced fibrosis, respectively. TE values between 5 and 7 kPa predict a fibrosis stage of 1, but with some degree of uncertainty. TE values between 7 and 9 kPa predict fibrosis stages 1 or 2, but cannot discriminate between these two stages. TE values of at least 9 kPa are associated with the presence of advanced fibrosis. The intraclass correlation coefficient for absolute agreement was 0.961. Conclusion: TE is an accurate and reproducible methodology to identify pediatric subjects without fibrosis or significant fibrosis, or with advanced fibrosis. In patients in which likelihood ratios are not optimal to provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. (HEPATOLOGY 2008.)

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.

Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C

Background: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease. Aim: To assess the value of TE for predicting the stage of fibrosis. Methods: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated. Results: The areas under the curve for the prediction of significant fibrosis (⩾F2), advanced fibrosis (⩾F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE <6 or ⩾12, <9 or ⩾12, and <12 or ⩾18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis. Conclusions: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.

The management of portal hypertension: Rational basis, available treatments and future options ☆

Variceal bleeding is the last step in a chain of events initiated by an increase in portal pressure, followed by the development and progressive dilation of varices until these finally rupture and bleed. This sequence of events might be prevented - and reversed - by achieving a sufficient decrease in portal pressure. A different approach is the use of local endoscopic treatments at the varices. This article reviews the rationale for the management of patients with cirrhosis and portal hypertension, the current recommendations for the prevention and treatment of variceal bleeding, and outlines the unsolved issues and the perspectives for the future opened by new research developments.

Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis.

BACKGROUND & AIMS Noninvasive methods are needed to identify clinically significant portal hypertension (CSPH) and esophageal varices (EVs) in patients with compensated cirrhosis. We looked for markers of the presence of CSPH and EVs in patients with cirrhosis. METHODS We performed a cross-sectional study that included a training set of 117 patients with compensated cirrhosis, confirmed by histology, from a tertiary referral center. Spleen diameter was measured by ultrasound, and liver stiffness (LS) was measured by transient elastography; endoscopy was used as the standard for detection of EVs, and measurements of hepatic venous pressure gradient were used as the standard for identifying CSPH. We assessed the ability of platelet count, spleen diameter, LS, and combinations of these factors (ie, ratio of platelet count to spleen size, and LS × spleen size/platelet count [LSPS]) to identify patients with CSPH and EV. The analysis included 2 new statistical models: the PH risk score and the varices risk score. Results were validated using an independent series of 56 patients with compensated patients from another center. RESULTS LS was the best single noninvasive variable for identifying patients with CSPH (area under the receiver operating characteristic, 0.883; 95% confidence interval [CI], 0.824-0.943; P < .0001). The area under the receiver operating characteristic value increased when LS was combined with platelet count and spleen size, either as LSPS (0.918; 95% CI, 0.872-0.965; P < .0001) or PH risk score (0.935; 95% CI, 0.893-0.977; P < .0001). More than 80% of patients were accurately classified using LSPS and PH risk score. Analyses of the varices risk score and LSPS were superior to all other noninvasive tests for identifying patients with EVs (area under the receiver operating characteristic, 0.909; 95% CI, 0.841-0.954 and 0.882; 95% CI, 0.810-0.935, respectively); they correctly classified 85% of patients in the training set and 75% in the validation set. CONCLUSIONS Combined data on LS, spleen diameter, and platelet count can be used to identify patients with compensated cirrhosis most likely to have CSPH and EV.

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.

Efficacy and Safety of Anticoagulation on Patients With Cirrhosis and Portal Vein Thrombosis

BACKGROUND & AIMS Portal vein thrombosis (PVT) is a frequent event in patients with cirrhosis; it can be treated with anticoagulants, but there are limited data regarding safety and efficacy of this approach. We evaluated this therapy in a large series of patients with cirrhosis and non-neoplastic PVT. METHODS We analyzed data from 55 patients with cirrhosis and PVT, diagnosed from June 2003 to September 2010, who received anticoagulant therapy for acute or subacute thrombosis (n = 31) or progression of previously known PVT (n = 24). Patients with cavernomatous transformation were excluded. Thrombosis was diagnosed, and recanalization was evaluated by using Doppler ultrasound, angio-computed tomography, and/or angio-magnetic resonance imaging analyses. RESULTS Partial or complete recanalization was achieved in 33 patients (60%; complete in 25). Early initiation of anticoagulation was the only factor significantly associated with recanalization. Rethrombosis after complete recanalization occurred in 38.5% of patients after anticoagulation therapy was stopped. Despite similar baseline characteristics, patients who achieved recanalization developed less frequent liver-related events (portal hypertension-related bleeding, ascites, or hepatic encephalopathy) during the follow-up period, but this difference was not statistically significant (P = .1). Five patients developed bleeding complications that were probably related to anticoagulation. A platelet count <50 × 109/L was the only factor significantly associated with higher risk for experiencing a bleeding complication. There were no deaths related to anticoagulation therapy. CONCLUSIONS Anticoagulation is a relatively safe treatment that leads to partial or complete recanalization of the portal venous axis in 60% of patients with cirrhosis and PVT; it should be maintained indefinitely to prevent rethrombosis.

Portal hypertensive bleeding in cirrhosis: Risk stratification, diagnosis, and management: 2016 practice guidance by the American Association for the study of liver diseases.

This guidance provides a data-supported approach to risk stratification, diagnosis, and management of patients with cirrhosis and portal hypertension (PH). A guidance document is different from a guideline. Guidelines are developed by a multidisciplinary panel of experts who rate the quality (level) of the evidence and the strength of each recommendation using the Grading of Recommendations Assessment, Development, and Evaluation system. A guidance document is developed by a panel of experts in the topic, and guidance statements, not recommendations, are put forward to help clinicians understand and implement the most recent evidence. This guidance focuses on PH, varices, and variceal hemorrhage (VH), and statements are based on the following: (1) review of the recent literature using PubMed, giving more weight to large, well-designed, prospective trials and well-performed meta-analyses; (2) several consensus conferences among experts; and (3) the authors’ years of experience caring for patients with cirrhosis and varices. Management of ascites and encephalopathy is addressed in other documents.