Lowering Portal Pressure Improves Outcomes of Patients With Cirrhosis, With or Without Ascites: A Meta-Analysis.

BACKGROUND & AIMS: In unselected patients with cirrhosis, those with reductions in hepatic venous pressure gradient (HVPG) to below a defined threshold (responders) have a reduced risk of variceal hemorrhage (VH) and death. We performed a meta-analysis to compare this effect in patients with vs without ascites. METHODS: We collected data from 15 studies of primary or secondary prophylaxis of VH that reported data on VH and death in responders vs nonresponders. We included studies in which data on ascites at baseline and on other relevant outcomes during follow-up evaluation were available. We performed separate meta-analyses for patients with vs without ascites. RESULTS: Of the 1113 patients included in the studies, 968 patients (87%) had been treated with nonselective ß-blockers. In 993 patients (89%), HVPG response was defined as a decrease of more than 20% from baseline (>10% in 11% of patients) or to less than 12 mm Hg. In the 661 patients without ascites, responders (n = 329; 50%) had significantly lower odds of events (ascites, VH, or encephalopathy) than nonresponders (odds ratio [OR], 0.35; 95% CI, 0.22-0.56). Odds of death or liver transplantation were also significantly lower among responders than nonresponders (OR, 0.50, 95% CI, 0.32-0.78). In the 452 patients with ascites, responders (n = 188; 42%) had significantly lower odds of events (VH, refractory ascites, spontaneous bacterial peritonitis, or hepatorenal syndrome) than nonresponders (OR, 0.27; 95% CI, 0.16-0.43). Overall, odds of death or liver transplantation were lower among responders (OR, 0.47; 95% CI, 0.29-0.75). No heterogeneity was observed among studies. CONCLUSIONS: In a meta-analysis of clinical trials, we found that patients with cirrhosis with and without ascites who respond to treatment with nonselective ß-blockers (based on reductions in HVPG) have a reduced risk of events, death, or liver transplantation.

Child-Turcotte-Pugh Class is Best at Stratifying Risk in Variceal Hemorrhage: Analysis of a US Multicenter Prospective Study.

GOALS/BACKGROUND: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality. STUDY: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared. RESULTS: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%. CONCLUSIONS: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.

Prevention of portal hypertension: from variceal development to clinical decompensation.

Pharmacological treatment of portal hypertension (PH) has been exclusively devoted to gastroesophageal varices-related events at different frameworks, including prophylactic, emergency, or preventive therapy. The goals of treatment are to avoid the first bleeding episode, stop active bleeding, and prevent bleeding recurrence, respectively. The objective of preprimary prophylaxis (PPP) is to avoid variceal development, and therefore it necessarily deals with patients with cirrhosis at earlier stages of the disease. At these earlier stages, nonselective beta-blockers (NSBBs) have been ineffective in preventing the development of varices and other complications of PH. Therefore, treatment should not rely on NSBB. It is possible that, at these earlier stages, etiological treatment of liver disease itself could prevent progression of PH. This review will focus mainly on early treatment of PH, because, if successful, it may translate into histological-hemodynamic improvements, avoiding not only variceal development, but also other PH-related complications, such as ascites and portosystemic encephalopathy. Moreover, the advent of new therapies may allow not only the prevention of the complications of PH, but also the chance of a substantial degree of regression in the cirrhotic process, with the possible prevention of hepatocellular carcinoma (HCC).

The interpretation of hepatic venous pressure gradient tracings - excellent interobserver agreement unrelated to experience.

BACKGROUND AND AIMS: The hepatic venous pressure gradient (HVPG) plays an important role in the diagnosis, prognosis and therapy of patients with cirrhosis and portal hypertension. One barrier to its widespread use is the potential for a low reproducibility. We aimed to evaluate the interobserver agreement in the interpretation of optimally acquired HVPG tracings from patients with cirrhosis and different degrees of portal hypertension. METHODS: Two hundred and fifteen tracings obtained from 51 patients with cirrhosis in a single centre were interpreted independently by two hepatologists: one experienced observer and one inexperienced observer. Correlation was performed by Pearson linear regression and the intraclass correlation coefficient (ICC). A Bland-Altman plot was constructed to visualize how the differences between observers compared across the range of measurements. Logistic regression was used to identify predictors of ≥10% variation between observers' readings. RESULTS: There was a significant linear relationship between observers' readings r = 0.98 (P = 0.001). The ICC between observers (interobserver agreement) was also excellent at 0.991 (P = 0.001). Using the Bland-Altman technique, the mean difference between the observers' readings was 0.2 mmHg (95% CI: -1.2 mmHg to 1.6 mmHg). Thirteen per cent of all readings and 9% of readings with an HVPG of ≥10 mmHg differed by ≥10%. As expected, a lower baseline HVPG was a predictor of this variability. CONCLUSIONS: Interobserver reproducibility in the assessment of optimally acquired HVPG tracings is excellent without differences related to experience. The data provide further support that the HVPG can be used accurately in clinical and research settings.

Evolution in the understanding of the pathophysiological basis of portal hypertension: How changes in paradigm are leading to successful new treatments.

Among the common complication of cirrhosis portal hypertension witnessed a major improvement of prognosis during the past decades. Principally due to the introduction of rational treatments based on new pathophysiological paradigms (concepts of thought) developed in the 1980s. The best example being the use of non-selective beta-blockers and of vasopressin analogs, somatostatin, and its analogs. Further refinement in the knowledge of the molecular mechanisms involved in the regulation of both the splanchnic and hepatic circulation has led to the emergence of new treatments, which are based on evidence that show not only structural but also vasoactive components increase the hepatic vascular resistance, as well as of angiogenesis. This knowledge and future improvements will most likely result in more effective treatment of portal hypertension and effective prevention of its complications in early stages.

Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients.

UNLABELLED: The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day-1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)-1ß (P=0.0052); IL-1R-α (P=0.0085); Fas-R (P=0.0354), and serum VCAM-1 (P=0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFß]; heat shock protein [HSP]-70; at-risk alcohol use; and Child class B) we could exclude HVPG ≥ 12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg. CONCLUSION: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy.

Quantitative histological-hemodynamic correlations in cirrhosis.

UNLABELLED: We have previously shown, in a semiquantitative analysis of liver biopsies showing cirrhosis, that thickness of fibrous septa separating cirrhotic nodules and small size of cirrhotic nodules correlated independently with portal pressure (as determined by the hepatic venous pressure gradient; HVPG) and were independent predictors of the presence of clinically significant portal hypertension (PH). This study aimed to confirm these results using quantitative analysis of these biopsies using digital image analysis. Biopsies of 42 patients with cirrhosis and HVPG measurements within 6 months of the biopsy were included in the study. The following parameters were scored quantitatively and without knowledge of HVPG results: total fibrosis area, septal thickness, nodule size, and number of nodules per millimeter of length of liver biopsy. Fibrosis area was the only parameter that independently correlated with HVPG (r = 0.606; P < 0.0001). Correlation was significant, even among patients with clinically significant PH (r = 0.636; P < 0.005). Fibrosis area and nodule size were both independently predictive of the presence of clinically significant PH (r = 0.57; P = 0.003). CONCLUSIONS: On quantitative analysis, fibrosis area was the parameter that correlated best with HVPG and the presence of clinically significant PH. Beyond pathophysiological implications, this also has methodological implications that are discussed in this article.

Hepatic venous pressure gradient measurement in pre-primary and primary prophylaxis of variceal hemorrhage.

Pharmacological therapy of portal hypertensión can be accomplished according to different objectives. Among them, pre-primary prophylaxis aims to avoid / delay esophageal varices development while the target of primary prophylaxis is protection against first variceal bleeding. Hepatic venous pressure gradient (HVPG) measurement closely reflects portal pressure in most liver diseases whith predominant sinusoidal network involvement. Clinical-hemodynamic correlations have been demonstrated in both pre-primary and primary prophylatic therapy, allowing to establish HVPG measurement as a predictive parameter, not only regarding variceal growth and bled but also of liver disease evolution and other portal hypertensive related complications.

Intestinal and plasma VEGF levels in cirrhosis: the role of portal pressure.

Increased levels of intestinal VEGF are thought to worsen portal hypertension. The cause of the increase in the level of intestinal VEGF found during cirrhosis is not known. The aim of this study is to demonstrate a relationship between portal pressure (PP) and intestinal/ plasma VEGF levels in different stages of fibrosis/cirrhosis. In this experiment, rats were exposed to carbon tetrachloride (CCl(4) ) for 6, 8 and 12 weeks. At the end of exposure, the three groups of rats exhibited three different stages of pathology: non-cirrhotic, early fibrotic and cirrhotic, respectively. For those rats and their age-matched controls, PP and intestinal/plasma VEGF levels were measured. Rats inhaling CCl(4) for 12 weeks developed portal hypertension (18.02 ± 1.07 mmHg), while those exposed for 6 weeks (7.26 ± 0.58 mmHg) and for 8 weeks (8.55 ± 0.53 mmHg) did not. The rats exposed for 12 weeks also showed a 40% increase in the level of intestinal VEGF compared to the controls (P < 0.05), while those rats exposed to CCl(4) inhalation for 6 and 8 weeks did not. There was a significant positive correlation between PP and intestinal VEGF levels (r(2) = 0.4, P < 0.005). Plasma VEGF levels were significantly elevated in those rats exposed to 12 weeks of CCl(4) inhalation (63.7 pg/ml, P < 0.01), compared to the controls (8.5 pg/ml). However, no correlation was observed between PP and plasma VEGF levels. It is concluded that portal pressure modulates intestinal VEGF levels during the development of cirrhosis.

Reticulon 4B (Nogo-B) is a novel regulator of hepatic fibrosis.

UNLABELLED: Nogo-B, also known as Reticulon 4B, plays important roles in vascular injuries. Its function in the liver is not understood. The aim of this study was to characterize Nogo-B in liver fibrosis and cirrhosis. Nogo-B distribution was assessed in normal and cirrhotic human liver sections. We also determined the levels of liver fibrosis in wild-type (WT) and Nogo-A/B knockout (NGB KO) mice after sham operation or bile duct ligation (BDL). To investigate the mechanisms of Nogo-B's involvement in fibrosis, hepatic stellate cells were isolated from WT and NGB KO mice and transformed into myofibroblasts. Portal pressure was measured to test whether Nogo-B gene deletion could ameliorate portal hypertension. In normal livers, Nogo-B expression was found in nonparenchymal cells, whereas its expression in hepatocytes was minimal. Nogo-B staining was significantly elevated in cirrhotic livers. Fibrosis was significantly increased in WT mice 4 weeks after BDL compared with NGB KO mice. The absence of Nogo-B significantly reduced phosphorylation of Smad2 levels upon transforming growth factor ß (TGF-ß) stimulation. Reconstitution of the Nogo-B gene into NGB KO fibroblasts restored Smad2 phosphorylation. Four weeks after BDL, portal pressure was significantly increased in WT mice by 47%, compared with sham-operated controls (P = 0.03), whereas such an increase in portal pressure was not observed in NGB KO mice (P = NS). CONCLUSION: Nogo-B regulates liver fibrosis, at least in part, by facilitating the TGFß/Smad2 signaling pathway in myofibroblasts. Because absence of Nogo-B ameliorates liver fibrosis and portal hypertension, Nogo-B blockade may be a potential therapeutic target in fibrosis/cirrhosis.

Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.

UNLABELLED: Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta-blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow-up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P=0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P=0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01-1.12), P=0.02] was an independent predictor of decompensation, together with HVPG and albumin. CONCLUSION: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population.

Portal hypertension in children: expert pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology of Diagnosis and Therapy in Portal Hypertension.

Complications of portal hypertension in children lead to significant morbidity and are a leading indication for consideration of liver transplantation. Approaches to the management of sequelae of portal hypertension are well described for adults and evidence-based approaches have been summarized in numerous meta-analyses and conferences. In contrast, there is a paucity of data to guide the management of complications of portal hypertension in children. An international panel of experts was convened on April 8, 2011 at The Children's Hospital of Pittsburgh of UPMC to review and adapt the recent report of the Baveno V Consensus Workshop on the Methodology of Diagnosis and Therapy in Portal Hypertension to the care of children. The opinions of that expert panel are reported.

Sildenafil has no effect on portal pressure but lowers arterial pressure in patients with compensated cirrhosis.

BACKGROUND & AIMS: The reduction of portal pressure in patients with early compensated cirrhosis may be more responsive to drugs increasing intrahepatic vasodilatation than those reducing portal venous inflow. The phosphodiesterase-5 (PDE-V) inhibitor sildenafil can potentially reduce portal pressure by decreasing intrahepatic resistance, but its systemic vasodilatory effects may be deleterious. The aim of this study was to evaluate the effect of sildenafil on systemic and portal hemodynamics in an open-label pilot study. METHODS: Twelve patients with compensated cirrhosis and baseline hepatic venous pressure gradient (HVPG) >5 mm Hg received 25 mg of oral sildenafil. Mean arterial pressure (MAP), heart rate (HR), and HVPG were repeated after 30 and 60 minutes in 9/12 patients at 90 minutes (after an additional 25 mg of sildenafil). HVPG tracings were read by 3 blinded observers. RESULTS: All 12 patients were Child A with median MAP of 92 mm Hg (interquartile range, 83-94) and HVPG 10.4 mm Hg (interquartile range, 6.6-13.0). While MAP decreased significantly at all time points, sildenafil had no effect on HVPG. CONCLUSIONS: As shown with other vasodilators in compensated cirrhotic patients, sildenafil at therapeutic doses for erectile dysfunction reduces MAP without reducing portal pressure. The search should continue for specific intrahepatic vasodilators.

Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition.

The Rho/ROCK pathway is activated in differentiated hepatic stellate cells (HSCs) and is necessary for assembly of actin stress fibers, contractility, and chemotaxis. Despite the importance of this pathway in HSC biology, physiological inhibitors of the Rho/ROCK pathway in HSCs are not known. We demonstrate that adenosine induces loss of actin stress fibers in the LX-2 cell line and primary HSCs in a manner indistinguishable from Rho/ROCK inhibition. Loss of actin stress fibers occurs via the A2a receptor at adenosine concentrations above 10 muM, which are present during tissue injury. We further demonstrate that loss of actin stress fibers is due to a cyclic adenosine monophosphate, protein kinase A-mediated pathway that results in Rho inhibition. Furthermore, a constitutively active Rho construct can inhibit the ability of adenosine to induce loss of actin stress fibers. Actin stress fibers are required for HSC contraction, and we demonstrate that adenosine inhibits endothelin-1 and lysophosphatidic acid-mediated HSC contraction. We propose that adenosine is a physiological inhibitor of the Rho pathway in HSCs with functional consequences, including loss of HSC contraction.

A distinct nitric oxide and adenosine A1 receptor dependent hepatic artery vasodilatatory response in the CCl-cirrhotic liver.

UNLABELLED: Increase of portal venous vascular resistance is counteracted by decrease of hepatic arterial vascular resistance (hepatic arterial buffer response). This process is mediated by adenosine in normal livers. In cirrhosis, hepatic arterial vascular resistance is decreased but the involvement of adenosine in this process is unknown. The aim of our study was to identify the signalling pathway responsible for the decreased hepatic arterial resistance in cirrhotic livers. METHODS: Cirrhosis was induced by CCl(4). Using a bivascular liver perfusion dose-response curves to adenosine of the HA were performed in the presence and the absence of pan-adenosine blocker (8-SPT), A1 blocker (caffeine) or nitric oxide synthase-blocker (l-NMMA) after preconstriction with an alpha1-agonist (methoxamine). Western blot of the HA were used to measure the density of the A1 and A2a receptors. RESULTS: Adenosine caused a dose dependent relaxation of the hepatic artery of both cirrhotic and control animals that were blocked in both groups by 8-SPT (P<0.02). The response to adenosine was greater in cirrhotic rats (P=0.016). Both l-NMMA (P=0.003) and caffeine reduced the response to adenosine in cirrhotic but not in control animals. Western blot analysis showed a higher density of A1 and a lower density of A2a receptor in cirrhotic animals (P<0.05). CONCLUSION: The adenosine-induced vasodilatation of the HA is increased in cirrhotic rats suggesting a role for adenosine-NO in the decreased hepatic arterial vascular resistance found in cirrhosis. This significantly greater response in cirrhosis by the A1 receptor follows the same pathway that is seen in hypoxic conditions in extra-hepatic tissues.

Hepatic venous pressure gradient predicts development of hepatocellular carcinoma independently of severity of cirrhosis.

BACKGROUND/AIMS: A total of 213 patients with compensated cirrhosis, portal hypertension and no varices were included in a trial evaluating beta-blockers in preventing varices. Predictors of the development of hepatocellular carcinoma (HCC), including hepatic venous pressure gradient (HVPG) were analyzed. METHODS: Baseline laboratory tests, ultrasound and HVPG measurements were performed. Patients were followed prospectively every three months until development of varices or variceal bleeding or end of the study in 09/02. The endpoint was HCC development according to standard diagnostic criteria. Univariate and multivariate Cox regression models were developed to identify predictors of HCC. RESULTS: In a median follow-up of 58 months 26/213 (12.2%) patients developed HCC. Eight patients were transplanted and 28 patients died without HCC. Twenty-one (84%) HCC developed in patients with HCV. On multivariate analysis HVPG (HR 1.18; 95%CI 1.08-1.29), albumin (HR 0.34; 95%CI 0.14-0.83) and viral etiology (HR 4.59; 95%CI 1.51-13.92) were independent predictors of HCC development. ROC curves identified 10 mmHg of HVPG as the best cut-off; those who had an HVPG above this value had a 6-fold increase in the HCC incidence. CONCLUSIONS: Portal hypertension is an independent predictor of HCC development. An HVPG >10 mmHg is associated with a 6-fold increase of HCC risk.

Incidence, prevalence, and clinical significance of abnormal hematologic indices in compensated cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis develop abnormal hematologic indices (HI) from multiple factors, including hypersplenism. We aimed to analyze the sequence of events and determine whether abnormal HI has prognostic significance. METHODS: We analyzed a database of 213 subjects with compensated cirrhosis without esophageal varices. Subjects were followed for approximately 9 years until the development of varices or variceal bleeding or completion of the study; 84 subjects developed varices. Abnormal HI was defined as anemia at baseline (hemoglobin, < or =13.5 g/dL for men and 11.5 g/dL for women), leukopenia (white blood cell counts, < or =4000/mm3), or thrombocytopenia (platelet counts, < or =150,000/mm3). The primary end points were death or transplant surgery. RESULTS: Most subjects had thrombocytopenia at baseline. Kaplan-Meier analysis showed that leukopenia occurred by 30 months (95% confidence interval, 18.5-53.6), and anemia occurred by 39.6 months (95% confidence interval, 24.1-49.9). Baseline thrombocytopenia (P = .0191) and leukopenia (P = .0383) were predictors of death or transplant, after adjusting for baseline hepatic venous pressure gradient (HVPG), and Child-Pugh scores. After a median of 5 years, a significant difference in death or transplant, mortality, and clinical decompensation was observed in patients who had leukopenia combined with thrombocytopenia at baseline compared with patients with normal HI (P < .0001). HVPG correlated with hemoglobin and white blood cell count (hemoglobin, r = -0.35, P < .0001; white blood cell count, r = -0.31, P < .0001). CONCLUSIONS: Thrombocytopenia is the most common and first abnormal HI to occur in patients with cirrhosis, followed by leukopenia and anemia. A combination of leukopenia and thrombocytopenia at baseline predicted increased morbidity and mortality.

Platelet count is not a predictor of the presence or development of gastroesophageal varices in cirrhosis.

UNLABELLED: Current guidelines recommend esophagogastroduodenoscopy (EGD) in patients with cirrhosis to screen for gastroesophageal varices (GEV). Thrombocytopenia has been proposed as a noninvasive test to predict the presence of GEV. There is no agreement regarding a specific platelet count (PLT) that can reliably predict GEV. The present longitudinal study aims to (1) further investigate the relationship between varices and PLT at the time of endoscopy, (2) investigate whether changes in PLT from the baseline over time can predict the development of GEV, and (3) investigate whether changes in PLT correlate with the hepatic venous pressure gradient (HVPG). A secondary analysis was conducted for 213 subjects with compensated cirrhosis with portal hypertension but without GEV enrolled in a randomized, placebo-controlled, double-blind trial of a nonselective beta-blocker used to prevent GEV. PLTs were obtained every 3 months, and HVPG measurements and EGD were done annually. The PLTs were compared between subjects who did and did not develop GEV. In a median follow-up of 54.9 months, 84 patients developed GEV. PLT was greater than 150,000 in 15% of patients at the development of GEV. A receiver operating curve did not show any PLT with high sensitivity or specificity for the presence of GEV. Subjects with clinically insignificant portal hypertension (HVPG < 10 mm Hg) whose PLT remained greater than 100,000 had a 2-fold reduction in the occurrence of GEV (P = 0.0374). A significant correlation was found between HVPG and PLT at the baseline, year 1, and year 5 (P < 0.0001). CONCLUSION: Cross-sectional or longitudinal evaluations of PLTs are inadequate noninvasive markers for GEV. Patients with mild portal hypertension whose PLT remains greater than 100,000 have significantly less risk of GEV. Although HVPG correlates somewhat with PLT, changes in PLT cannot be used as a surrogate for HVPG changes.

Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis.

BACKGROUND: Nonselective beta-adrenergic blockers decrease portal pressure and prevent variceal hemorrhage. Their effectiveness in preventing varices is unknown. METHODS: We randomly assigned 213 patients with cirrhosis and portal hypertension (minimal hepatic venous pressure gradient [HVPG] of 6 mm Hg) to receive timolol, a nonselective beta-blocker (108 patients), or placebo (105 patients). The primary end point was the development of gastroesophageal varices or variceal hemorrhage. Endoscopy and HVPG measurements were repeated yearly. RESULTS: During a median follow-up of 54.9 months, the rate of the primary end point did not differ significantly between the timolol group and the placebo group (39 percent and 40 percent, respectively; P=0.89), nor were there significant differences in the rates of ascites, encephalopathy, liver transplantation, or death. Serious adverse events were more common among patients in the timolol group than among those in the placebo group (18 percent vs. 6 percent, P=0.006). Varices developed less frequently among patients with a baseline HVPG of less than 10 mm Hg and among those in whom the HVPG decreased by more than 10 percent at one year and more frequently among those in whom the HVPG increased by more than 10 percent at one year. CONCLUSIONS: Nonselective beta-blockers are ineffective in preventing varices in unselected patients with cirrhosis and portal hypertension and are associated with an increased number of adverse events. (ClinicalTrials.gov number, NCT00006398.)