Salvador Augustin

A Histologic Scoring System for Prognosis of Patients With Alcoholic Hepatitis

BACKGROUND & AIMS There is no histologic classification system to determine prognoses of patients with alcoholic hepatitis (AH). We identified histologic features associated with disease severity and created a histologic scoring system to predict short-term (90-day) mortality. METHODS We analyzed data from 121 patients admitted to the Liver Unit (Hospital Clinic, Barcelona, Spain) from January 2000 to January 2008 with features of AH and developed a histologic scoring system to determine the risk of death using logistic regression. The system was tested and updated in a test set of 96 patients from 5 academic centers in the United States and Europe, and a semiquantitative scoring system called the Alcoholic Hepatitis Histologic Score (AHHS) was developed. The system was validated in an independent set of 109 patients. Interobserver agreement was evaluated by weighted κ statistical analysis. RESULTS The degree of fibrosis, degree of neutrophil infiltration, type of bilirubinostasis, and presence of megamitochondria were independently associated with 90-day mortality. We used these 4 parameters to develop the AHHS to identify patients with a low (0-3 points), moderate (4-5 points), or high (6-9 points) risk of death within 90 days (3%, 19%, and 51%, respectively; P < .0001). The AHHS estimated 90-day mortality in the training and test sets with an area under the receiver operating characteristic value of 0.77 (95% confidence interval, 0.71-0.83). Interrater agreement values were 0.65 for fibrosis, 0.86 for bilirubinostasis, 0.60 for neutrophil infiltration, and 0.46 for megamitochondria. Interestingly, the type of bilirubinostasis predicted the development of bacterial infections. CONCLUSIONS We identified histologic features associated with the severity of AH and developed a patient classification system that might be used in clinical decision making.

Predicting Early Mortality After Acute Variceal Hemorrhage Based on Classification and Regression Tree Analysis

BACKGROUND & AIMS Available prognostic models for mortality after an acute variceal hemorrhage have limitations that restrict their clinical value. We assessed the performance of a novel prognostic approach based on classification and regression tree (CART) analysis. METHODS Logistic regression (LR) and CART analyses were performed to identify prognostic models for mortality at 6 weeks in a single-center cohort of 267 consecutive patients with acute variceal bleeding. Receiver operating characteristic (ROC) curves were constructed to assess the performance of the models. Prognostic models were fitted and validated by split-sample technique (training set, 164 patients, 2001-2005; test set, 103 patients, 2006-2008). RESULTS After 6 weeks, 21% of patients experienced rebleeding and 24% died. The best LR model was based on Child-Pugh score, creatinine level, bacterial infection, and hepatocellular carcinoma. CART analysis provided a simple algorithm based on the combined use of just 3 variables (Child-Pugh score, creatinine level, and bacterial infection), allowing accurate early discrimination of 3 distinct prognostic subgroups with 8% (low risk), 17% (intermediate), and 50% to 73% (high) mortality. Its accuracy was similar to the LR model (area under the ROC curves, 0.81 vs 0.84; P = .17) and better than that of Child-Pugh (0.75; P = .05) and model for end-stage liver disease (0.74; P = .05). The prognostic accuracy of both LR and CART models was validated in the test set (area under the ROC curve values, 0.81 and 0.83, respectively). CONCLUSIONS A simple CART algorithm based on Child-Pugh score, creatinine level, and infection allowed an accurate predictive assessment of 6-week mortality after acute variceal bleeding.

A MELD-Based Model to Determine Risk of Mortality Among Patients With Acute Variceal Bleeding

BACKGROUND & AIMS Patients with cirrhosis with acute variceal bleeding (AVB) have high mortality rates (15%-20%). Previously described models are seldom used to determine prognoses of these patients, partially because they have not been validated externally and because they include subjective variables, such as bleeding during endoscopy and Child-Pugh score, which are evaluated inconsistently. We aimed to improve determination of risk for patients with AVB. METHODS We analyzed data collected from 178 patients with cirrhosis (Child-Pugh scores of A, B, and C: 15%, 57%, and 28%, respectively) and esophageal AVB who received standard therapy from 2007 through 2010. We tested the performance (discrimination and calibration) of previously described models, including the model for end-stage liver disease (MELD), and developed a new MELD calibration to predict the mortality of patients within 6 weeks of presentation with AVB. MELD-based predictions were validated in cohorts of patients from Canada (n = 240) and Spain (n = 221). RESULTS Among study subjects, the 6-week mortality rate was 16%. MELD was the best model in terms of discrimination; it was recalibrated to predict the 6-week mortality rate with logistic regression (logit, -5.312 + 0.207 • MELD; bootstrapped R(2), 0.3295). MELD values of 19 or greater predicted 20% or greater mortality, whereas MELD scores less than 11 predicted less than 5% mortality. The model performed well for patients from Canada at all risk levels. In the Spanish validation set, in which all patients were treated with banding ligation, MELD predictions were accurate up to the 20% risk threshold. CONCLUSIONS We developed a MELD-based model that accurately predicts mortality among patients with AVB, based on objective variables available at admission. This model could be useful to evaluate the efficacy of new therapies and stratify patients in randomized trials.

Effectiveness of Combined Pharmacologic and Ligation Therapy in High-Risk Patients With Acute Esophageal Variceal Bleeding

OBJECTIVES:After an acute variceal bleeding, early decision for aggressive management of patients with worse prognosis may improve outcomes. The effectiveness of currently recommended standard therapy (drugs plus endoscopic ligation) for different risk subgroups and the validity of available risk criteria in clinical practice are unknown.METHODS:We analyzed data of 301 consecutive cirrhotic patients admitted with esophageal variceal bleeding. All patients received antibiotics, somatostatin, and in 263 early endoscopic therapy. A stratified 6-week mortality assessment according to risk (low-risk: Child-Pugh B without active bleeding or Child-Pugh A; high-risk: Child-Pugh B with active bleeding or Child-Pugh C) was performed. A multivariate analysis was conducted to elaborate a new risk classification rule.RESULTS:Among the 162 patients receiving emergency ligation, 14% rebled and 16% died. Standard therapy was very effective in all risk strata, even in high-risk patients, specially if eligible for therapeutic trials (child <14, age ≤75 years, creatinine ≤3.0 mg/dl, no hepatocellular carcinoma, or portal thrombosis), showing this stratum a 10% mortality. In patients receiving ligation, Child-Pugh C patients with baseline creatinine <1.0 mg/dl showed similar mortality to Child-Pugh A or B patients (8% vs. 7%, respectively). Only Child-Pugh C patients with creatinine ≥1.0 were at a significant higher risk (Child-Pugh C: 46% mortality if creatinine ≥1.0 vs. 8% if creatinine <1.0, P=0.006).CONCLUSIONS:The combination of somatostatin, antibiotics, and endoscopic ligation after an acute variceal bleeding in a real-life situation is associated with very low mortality. Child-Pugh C patients with baseline creatinine ≥1.0 mg/dl should be considered high-risk patients in this setting.

Effects of intravenous albumin in patients with cirrhosis and episodic hepatic encephalopathy: A randomized double-blind study

BACKGROUND & AIMS Episodic hepatic encephalopathy is frequently precipitated by factors that induce circulatory dysfunction, cause oxidative stress-mediated damage or enhance astrocyte swelling. The administration of albumin could modify these factors and improve the outcome of hepatic encephalopathy. The aim of this study is to assess the efficacy of albumin in a multicenter, prospective, double-blind, controlled trial (ClinicalTrials.gov number, NCT00886925). METHODS Cirrhotic patients with an acute episode of hepatic encephalopathy (grade II-IV) were randomized to receive albumin (1.5g/kg on day 1 and 1.0g/kg on day 3) or isotonic saline, in addition to the usual treatment (laxatives, rifaximin 1200mg per day). The primary end point was the proportion of patients in which encephalopathy was resolved on day 4. The secondary end points included survival, length of hospital stay, and biochemical parameters. RESULTS Fifty-six patients were randomly assigned to albumin (n=26) or saline (n=30) stratified by the severity of HE. Both groups were comparable regarding to demographic data, liver function, and precipitating factors. The percentage of patients without hepatic encephalopathy at day 4 did not differ between both groups (albumin: 57.7% vs. saline: 53.3%; p>0.05). However, significant differences in survival were found at day 90 (albumin: 69.2% vs. saline: 40.0%; p=0.02). CONCLUSIONS Albumin does not improve the resolution of hepatic encephalopathy during hospitalization. However, differences in survival after hospitalization suggest that the development of encephalopathy may identify a subgroup of patients with advanced cirrhosis that may benefit from the administration of albumin.

Detection of early portal hypertension with routine data and liver stiffness in patients with asymptomatic liver disease: A prospective study

BACKGROUND & AIMS Detecting portal hypertension (PH) before the development of varices is important for prognosis and for designing interventional studies. None of the available strategies is used in practice. We evaluated a sequential screening-diagnostic strategy based on clinical data and transient elastography (TE) to detect PH in asymptomatic outpatients with liver disease. METHODS Consecutive patients with chronic liver disease and no previous diagnosis of PH were screened by TE. Patients with liver stiffness (LS) ⩾ 13.6 kPa were further evaluated by endoscopy and hepatic venous pressure gradient (HVPG). For analysis, patients were classified in 3 groups: group A, platelets ⩾ 150,000/mm(3), normal abdominal ultrasound; group B, platelets <150,000/mm(3), normal ultrasound; group C, platelets <150,000/mm(3), abnormal ultrasound (splenomegaly, nodular liver surface). RESULTS 250 patients were evaluated (69% group A, 20% group B, 11% group C). In 9% elastography was non-valid. LS ⩾ 13.6 was found in 54 patients (8% A, 43% B, and 81% C, p<0.001). Endoscopy was performed in 49 of these: 20% had small varices, 0% high-risk varices. No patients from group A had varices, and 90% with varices belonged to group C. HVPG was obtained in 40 patients: 93% had PH (HVPG >5 mmHg) and 65% clinically significant PH (CSPH, HVPG ⩾ 10). Only 3 patients, all from group A, had HVPG <5. All patients from groups B and C with LS ⩾ 13.6 had PH. The LS 25 cut-off was excellent at ruling-in CSPH. CONCLUSIONS A simple strategy based on routine clinical data and TE could be useful to detect early PH among asymptomatic patients with chronic liver disease.

Hemodynamic Response-Guided Therapy for Prevention of Variceal Rebleeding: An Uncontrolled Pilot Study

The clinical usefulness of assessing hemodynamic response to drug therapy in the prophylaxis of variceal rebleeding is unknown. An open‐labeled, uncontrolled pilot trial was performed to evaluate the feasibility and efficacy of using the hemodynamic response to pharmacological treatment to guide therapy in this setting. Fifty patients with acute variceal bleeding underwent a hepatic venous pressure gradient (HVPG) measurement 5 days after the episode. Nadolol and nitrates were initiated, and a second HVPG was measured 15 days later. Responder patients (≥20% decrease in HVPG from baseline) were maintained on drugs, partial responders (≥10% and <20%) had banding ligation added to the drugs, and nonresponders (<10%) received a transjugular intrahepatic portal‐systemic shunt (TIPS). Mean follow‐up was 22 months. Eight patients (16%) did not receive the second HVPG, 6 of them because of early variceal rebleeding. Of the other 42 patients, 24 were classified as responders (57%); 10 as partial responders (24%), who had banding added; and 8 as nonresponders (19%), who received a TIPS. Patients with cirrhosis of viral etiology compared to alcoholic cirrhosis tended to present more early rebleedings, less response to drugs and needed more TIPS. Variceal rebleeding occurred in 22% of all patients but only in 12% of patients whose hemodynamic response was assessed. The 3 therapeutic groups were not different. In conclusion, using hemodynamic response to pharmacological treatment to guide therapy in secondary prophylaxis to prevent variceal bleeding is feasible and effectively protects patients from rebleeding. In this context, viral cirrhosis seems to present a worse outcome than alcoholic cirrhosis. (HEPATOLOGY 2006;44:806–812.)

Development of hyperdynamic circulation and response to β-blockers in compensated cirrhosis with portal hypertension.

Nonselective β‐blockers are useful to prevent bleeding in patients with cirrhosis and large varices but not to prevent the development of varices in those with compensated cirrhosis and portal hypertension (PHT). This suggests that the evolutionary stage of PHT may influence the response to β‐blockers. To characterize the hemodynamic profile of each stage of PHT in compensated cirrhosis and the response to β‐blockers according to stage, we performed a prospective, multicenter (tertiary care setting), cross‐sectional study. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured in 273 patients with compensated cirrhosis before and after intravenous propranolol (0.15 mg/kg): 194 patients had an HVPG ≥10 mm Hg (clinically significant PHT [CSPH]), with either no varices (n = 80) or small varices (n = 114), and 79 had an HVPG >5 and <10 mm Hg (subclinical PHT). Patients with CSPH had higher liver stiffness (P < 0.001), worse Model for End‐Stage Liver Disease score (P < 0.001), more portosystemic collaterals (P = 0.01) and splenomegaly (P = 0.01) on ultrasound, and lower platelet count (P < 0.001) than those with subclinical PHT. Patients with CSPH had lower systemic vascular resistance (1336 ± 423 versus 1469 ± 335 dyne · s · cm‐5, P < 0.05) and higher cardiac index (3.3 ± 0.9 versus 2.8 ± 0.4 L/min/m2, P < 0.01). After propranolol, the HVPG decreased significantly in both groups, although the reduction was greater in those with CSPH (‐16 ± 12% versus ‐8 ± 9%, P < 0.01). The HVPG decreased ≥10% from baseline in 69% of patients with CSPH versus 35% with subclinical PHT (P < 0.001) and decreased ≥20% in 40% versus 13%, respectively (P = 0.001). Conclusion: Patients with subclinical PHT have less hyperdynamic circulation and significantly lower portal pressure reduction after acute β‐blockade than those with CSPH, suggesting that β‐blockers are more suitable to prevent decompensation of cirrhosis in patients with CSPH than in earlier stages. (Hepatology 2016;63:197–206)

Noninvasive tools and risk of clinically significant portal hypertension and varices in compensated cirrhosis: The “Anticipate” study

In patients with compensated advanced chronic liver disease (cACLD), the presence of clinically significant portal hypertension (CSPH) and varices needing treatment (VNT) bears prognostic and therapeutic implications. Our aim was to develop noninvasive tests‐based risk prediction models to provide a point‐of‐care risk assessment of cACLD patients. We analyzed 518 patients with cACLD from five centers in Europe/Canada with paired noninvasive tests (liver stiffness measurement [LSM] by transient elastography, platelet count, and spleen diameter with calculation of liver stiffness to spleen/platelet score [LSPS] score and platelet‐spleen ratio [PSR]) and endoscopy/hepatic venous pressure gradient measurement. Risk of CSPH, varices, and VNT was modeled with logistic regression. All noninvasive tests reliably identified patients with high risk of CSPH, and LSPS had the highest discrimination. LSPS values above 2.65 were associated with risks of CSPH above 80%. None of the tests identified patients with very low risk of all‐size varices, but both LSPS and a model combining TE and platelet count identified patients with very low risk (<5%) risk of VNT, suggesting that they could be used to triage patients requiring screening endoscopy. LSPS values of <1.33 were associated with a <5% risk of VNT, and 26% of patients had values below this threshold. LSM combined with platelet count predicted a risk <5% of VNT in 30% of the patients. Nomograms were developed to facilitate point‐of‐care risk assessment. Conclusion: A significant proportion of patients with a very high risk of CSPH, and a population with a very low risk of VNT can be identified with simple, noninvasive tests, suggesting that these can be used to individualize medical care. (Hepatology 2016;64:2173‐2184).

Impact of anticoagulation on upper-gastrointestinal bleeding in cirrhosis. A retrospective multicenter study.

Recent studies have shown that liver cirrhosis (LC) behaves as an acquired hypercoagulable state with increased thrombotic risk. This is why anticoagulation therapy (AT) is now frequently used in these patients. Variceal bleeding is a severe complication of LC. It is unknown whether AT may impact the outcome of bleeding in these patients. Fifty‐two patients on AT with upper gastrointestinal bleeding (UGIB) were evaluated. Portal vein thrombosis (PVT) and different cardiovascular disorders (CVDs) were the indication for AT in 14 and 38 patients, respectively. Overall, 104 patients with LC and UGIB not under AT matched for severity of LC, age, sex, source of bleeding, and Sequential Organ Failure Assessment (SOFA) score served as controls. UGIB was attributed to portal hypertension (PH) in 99 (63%) patients and peptic/vascular lesions in 57 (37%). Twenty‐six (17%) patients experienced 5‐day failure; SOFA, source of UGIB, and PVT, but not AT, were independent predictors of 5‐day failure. In addition, independent predictors of 6‐week mortality, which was observed in 26 (11%) patients, were SOFA, Charlson Comorbidity index, and use of AT for a CVD. There were no differences between patients with/without AT in needs for rescue therapies, intensive care unit admission, transfusions, and hospital stay. Conclusions: Factors that impact the outcome of UGIB in patients under AT are degree of multiorgan failure and comorbidity, but not AT itself. (Hepatology 2015;62:575–583