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.

ST Elevation Myocardial Infarction Mortality Among Patients With Liver Cirrhosis: A Nationwide Analysis Across a Decade.

BACKGROUND: Mortality from ST elevation myocardial infarction (STEMI) is decreasing nationwide, but no report to date examined STEMI mortality among patients with cirrhosis. GOALS: Determine mortality rates and investigate possible disparities in cardiovascular interventions for patients with and without cirrhosis admitted with STEMI across a decade using a national database. STUDY: We included all urgent/emergent admissions with STEMI to acute care hospitals across the United States in 1999 and 2009. Exclusion criteria were age less than 18 years or prior liver transplantation. Confounders were accounted for using multivariable regression analyses. RESULTS: A total of 325,857 and 182,491 patients with STEMI were included in 1999 and 2009, respectively, 741 and 541 of whom had cirrhosis, respectively. In-hospital mortality rate was 31% and 11% for patients with and without cirrhosis in 1999, and 17% and 9% in 2009. The adjusted mortality odds ratio was 2.54 (1.52 to 4.24) in 1999 and 1.45 (0.73 to 2.86) in 2009. Stent placement rate was 11% and 26% for patients with and without cirrhosis in 1999, and increased to 47% and 61% in 2009, respectively. Thrombolytic medication injection rate was 3% and 10% for patients with and without cirrhosis in 1999, and 0% and 2% in 2009, respectively. Coronary artery bypass graft surgery rate was 3% and 9% for patients with and without cirrhosis in 1999, and was 6% and 7% in 2009, respectively. CONCLUSIONS: STEMI mortality in patients with cirrhosis is higher compared with patients without cirrhosis. However, this mortality difference declined from 1999 to 2009, likely because of higher coronary artery stent utilization for patients with cirrhosis.

Statin use in patients with cirrhosis: a retrospective cohort study.

BACKGROUND: Statins reduce cardiovascular risk. Patients with cirrhosis have decreased hepatic clearance of statins and potentially increased risk for complications. No studies assess mortality in patients with biopsy-confirmed cirrhosis. AIM: Compare mortality in patients with cirrhosis on statins to those not on statins. METHODS: A retrospective cohort study evaluated patients from 1988 to 2011 at Partners Healthcare Hospitals. The Partners Research Patient Data Registry identified patients with biopsy-proven cirrhosis on statins at biopsy and at least 3 months following. Controls were matched 1:2 by age, gender and Child-Pugh class. Decompensation was defined as ascites, jaundice/bilirubin >2.5 mg/dL, and/or hepatic encephalopathy or variceal hemorrhage. Primary outcome was mortality. Secondary outcome was decompensation in baseline-compensated patients. Chi-square and two-way ANOVA testing compared groups. Cox proportional hazards models for mortality controlled for age, Child-Pugh class, diabetes, coronary artery disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Kaplan-Meier curves graphed mortality. RESULTS: Eighty-one statin users and 162 controls were included. Median follow-up: 36 months in statin users and 30 months in controls. 70.4% of patients were Child-Pugh A. Model for End-Stage Liver Disease (MELD), albumin, varices and beta-blocker use were not significantly different between groups. Statin users had lower mortality on multivariate analysis (HR 0.53, p = 0.01), and Child-Pugh A patients had longer survival on Kaplan-Meier analysis. Cox multivariate analysis for decompensation showed lower risk of decompensation with statins while increased decompensation with low albumin, high MELD score and beta-blocker use. CONCLUSIONS: In patients with cirrhosis, statin therapy is not associated with increased mortality and may delay decompensation.

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.

Hematologic indices improve with eradication of HCV in patients with cirrhosis and predict decompensation.

BACKGROUND: Abnormal hematological indices (HI) are common in cirrhosis from hepatitis C virus (HCV). Eradication of HCV may ameliorate these abnormalities. The objectives of the current study were to assess whether HI improve with HCV eradication and whether they can predict prognosis in patients with cirrhosis during and after completion of antiviral therapy. METHODS: A retrospective cohort study of 153 patients with HCV cirrhosis treated with Peg-interferon and ribavirin was conducted. The primary endpoint was improvement in HI after successful antiviral therapy. The secondary outcome was clinical decompensation during and after completion of antiviral therapy and association with HI. A repeated measures 2-way ANOVA was performed to compare means. Multivariate analysis was used to identify predictors of clinical decompensation. RESULTS: One hundred fifty three patients met study criteria. The rate of sustained virological rate was 26%. Median follow-up was 55 months. Platelet and WBC counts improved with HCV eradication compared to those in whom treatment was unsuccessful (p < 0.05). On univariate analysis, the presence of thrombocytopenia was associated clinical decompensation prior to, on treatment and after completion of therapy. Thrombocytopenia (OR 14.8, p-value <0.001) after completing treatment predicted clinical decompensation when controlled for albumin, MELD and age in multivariate analysis at 6 months after completion of therapy. CONCLUSIONS: Platelet and leukocyte counts improve in patients with cirrhosis who respond to antiviral therapy against HCV. The presence of thrombocytopenia predicts decompensation on treatment and after completion of therapy.

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.

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.

Hepatic venous pressure gradient supplements liver biopsy in the diagnosis of cirrhosis.

BACKGROUND: Liver biopsy is the gold standard for establishing cirrhosis, but may provide inadequate tissue for interpretation in some patients. GOALS: The aim of this study was to determine whether the hepatic venous pressure gradient predicts the presence of cirrhosis. STUDY: Patients with liver disease who had undergone hepatic venous pressure gradient measurements were identified. Clinical, laboratory, and hepatic venous pressure gradient data were collected and biopsies were staged for fibrosis. Univariable logistic regression was used to identify potential predictors of cirrhosis. Multivariable logistic regression was applied to determine adjusted odds ratios. RESULTS: Thirty-two patients were included. The hepatic venous pressure gradient was an independent predictor of cirrhosis. On multivariable analysis, the hepatic venous pressure gradient predicted cirrhosis, with an odds ratio of 1.46 (95% confidence interval 1.05-2.02, P=0.023). Using a cutoff of >or=6.5 mm Hg, the hepatic venous pressure gradient was 86% sensitive and 80% specific for diagnosing cirrhosis. CONCLUSIONS: The hepatic venous pressure gradient measurement predicts the presence of cirrhosis in patients with liver disease. Therefore, when the diagnosis of cirrhosis is in question, an elevated hepatic venous pressure gradient can support the diagnosis.

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.

Pharmacologic therapy of portal hypertension.

Portal hypertension is a progressively debilitating complication of cirrhosis and a principal cause of mortality in patients who have hepatic decompensation. During the last few decades, significant clinical advances in the prevention of initial variceal hemorrhage, the management of acute variceal hemorrhage, and the prevention of recurrent variceal hemorrhage have reduced the morbidity and mortality of this lethal complication of cirrhosis. This article discusses the pharmacologic treatment of portal hypertension, including preprimary prophylaxis, prevention of a first variceal hemorrhage, treatment of acute variceal hemorrhage, and secondary prophylaxis of a variceal hemorrhage.

A study of low dose peginterferon alpha-2b with ribavirin for the initial treatment of chronic hepatitis C.

PURPOSE: A prospective randomized trial was undertaken to test the efficacy of low and standard doses of pegylated interferon alpha-2b in combination with ribavirin for the initial treatment of chronic hepatitis C. By nature of its design the study also provided data on response to therapy over a spectrum of doses of both pegylated interferon alpha-2b and ribavirin calculated on a body weight basis. SUBJECTS AND METHODS: Fifty micrograms of pegylated interferon alpha-2b or 100 microg for patients weighing<75 kg or 150 microg for patients>or=75 kg were administered weekly with 1000 mg ribavirin daily for 48 wk if serum hepatitis C virus (HCV) RNA was undetectable after the first 24 wk of therapy. RESULTS: Overall sustained viral response (SVR) was 45% for standard dose and 33% for low dose, p=0.02. For genotypes 2 and 3 SVR was 65% for standard dose, and 56% for low dose, p=0.51. For genotype 1 SVR was 38% for standard dose, and 24% for low dose, p=0.03. For genotype 1 patients whose doses exceeded the 1-2-5 threshold, that is >or=1.25 microg/kg body weight pegylated interferon alpha-2b weekly and >or=12.5 mg/kg body weight ribavirin daily, SVR was 51%. CONCLUSION: The results of this study underscore the importance of adequate dosing of ribavirin as well as pegylated interferons in achieving an SVR when treating genotype 1 chronic hepatitis C patients with combination therapy.

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.)

Liver imaging. A hepatologist's perspective.

Numerous diagnostic modalities may be employed in the assessment of liver disease. In this article we outline radiologic approaches to several clinical problems including the evaluation of abnormal liver function tests and jaundice, evaluation of liver masses, and management of the patient with cirrhosis and portal hypertension.