The MELD Score Is Superior to the Maddrey Discriminant Function Score to Predict Short-Term Mortality in Alcohol-Associated Hepatitis: A Global Study.

INTRODUCTION: Several scoring systems predict mortality in alcohol-associated hepatitis (AH), including the Maddrey discriminant function (mDF) and model for end-stage liver disease (MELD) score developed in the United States, Glasgow alcoholic hepatitis score in the United Kingdom, and age, bilirubin, international normalized ratio, and creatinine score in Spain. To date, no global studies have examined the utility of these scores, nor has the MELD-sodium been evaluated for outcome prediction in AH. In this study, we assessed the accuracy of different scores to predict short-term mortality in AH and investigated additional factors to improve mortality prediction. METHODS: Patients admitted to hospital with a definite or probable AH were recruited by 85 tertiary centers in 11 countries and across 3 continents. Baseline demographic and laboratory variables were obtained. The primary outcome was all-cause mortality at 28 and 90 days. RESULTS: In total, 3,101 patients were eligible for inclusion. After exclusions (n = 520), 2,581 patients were enrolled (74.4% male, median age 48 years, interquartile range 40.9-55.0 years). The median MELD score was 23.5 (interquartile range 20.5-27.8). Mortality at 28 and 90 days was 20% and 30.9%, respectively. The area under the receiver operating characteristic curve for 28-day mortality ranged from 0.776 for MELD-sodium to 0.701 for mDF, and for 90-day mortality, it ranged from 0.773 for MELD to 0.709 for mDF. The area under the receiver operating characteristic curve for mDF to predict death was significantly lower than all other scores. Age added to MELD obtained only a small improvement of AUC. DISCUSSION: These results suggest that the mDF score should no longer be used to assess AH's prognosis. The MELD score has the best performance in predicting short-term mortality.

Serum sodium identifies patients with cirrhosis at high risk of hepatorenal syndrome.

BACKGROUND: Although the precipitating events of hepatorenal syndrome (HRS) development have been well characterized, the actual baseline risk of these events resulting in HRS is much less studied. AIM: To assess the predictive value of hyponatremia in the development of HRS. PATIENTS AND METHODS: We performed a retrospective observational cohort study including consecutive patients with decompensated liver cirrhosis and normal creatininemia admitted to tertiary center in Slovakia. Patients were censored at two months, development of renal failure, classified either as HRS or renal failure not fulfilling criteria of HRS, was the main outcome. RESULTS: Out of 202 patients 18 developed HRS and 14 renal failure not fulfilling the HRS criteria. A significant difference was found between patients with and without HRS in serum sodium (135.76 ± 5.01 vs. 130.78 ± 3.574 mmol/l; p < 0.0001), creatinine, (81 ± 20.11 vs. 98.18 ± 25.032 µmol/l; p = 0.006), bilirubin (90.4 ± 104.82 vs.175.42 ± 174.12 µmol/l; p < 0.0001), MELD (15.17 ± 5.52 vs. 21.61 ± 6.0; p < 0.0001) and MELD-Na score (19.96 ± 6.0 vs. 25.89 ± 4.96; p < 0.0001). Sodium, creatinine, bilirubin, MELD, MELD-Na score were found to be significant predictors of HRS in univariate analysis. Multivariate analysis two prediction models (Model 1: Bilirubin, creatinin, sodium and Model 2: Sodium, MELD) showed that sodium together with creatinine are the strongest HRS predictors, followed by bilirubin or MELD score. CONCLUSION: Serum levels of sodium, creatinine and parameters of liver function are important predictors of hepatorenal syndrome.

Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats.

Low doses of sorafenib have been shown to decrease portal pressure (PP), portal-systemic shunts, and liver fibrosis in cirrhotic rats. Nonselective beta blockers (NSBB) are the only drugs recommended for the treatment of portal hypertension. The aim of our study was to explore whether the combination of propranolol and sorafenib might show an additive effect reducing PP in cirrhotic rats. Groups of common bile duct-ligated cirrhotic rats (CBDL) and sham-operated control rats were treated by gavage with vehicle, propranolol (30 mg·kg(-1)·day(-1)), sorafenib (1 mg·kg(-1)·day(-1)), or propranolol+sorafenib. Treatment began 2 wk after the CBDL or sham operation. Hemodynamic evaluation was performed after 2 wk of treatment. In cirrhotic rats, propranolol and sorafenib produced a significant (P < 0.001) and similar reduction in PP (-19 and -15%, respectively). This was achieved through different mechanisms: whereas propranolol decreased PP by reducing portal blood flow (-35%; P = 0.03), sorafenib decreased PP without decreasing portal flow indicating decreased hepatic resistance. After propranolol+sorafenib, the fall in PP was significantly greater (-30%; P < 0.001) than with either drug alone, demonstrating an additive effect. However, the reduction in portal flow (-39%) under combined therapy was not significantly greater than after propranolol alone. Sorafenib, alone or in combination with propranolol, produced significant reduction in portal-systemic shunting (-25 and -33%, respectively), splanchnic vascularization (-37 and -41%, respectively), liver fibrosis (38%), and hepatic neovascularization (-42 and -51%, respectively). These effects were not observed after propranolol alone. In conclusion, the combination of propranolol+sorafenib causes a greater reduction in PP than either drug alone and decreases markedly the extent of portal-systemic shunting, splanchnic and hepatic neovascularization, and liver fibrosis, suggesting that this drug combination is a potentially useful strategy in the treatment of portal hypertension.

Nadolol plus isosorbide mononitrate alone or associated with band ligation in the prevention of recurrent bleeding: a multicentre randomised controlled trial.

BACKGROUND AND AIMS: Previous clinical trials suggest that adding non-selective beta-blockers improves the efficacy of endoscopic band ligation (EBL) in the prevention of recurrent bleeding, but no study has evaluated whether EBL improves the efficacy of beta-blockers + isosorbide-5-mononitrate. The present study was aimed at evaluating this issue in a multicentre randomised controlled trial (RCT) and to correlate changes in hepatic venous pressure gradient (HVPG) during treatment with clinical outcomes METHODS: 158 patients with cirrhosis, admitted because of variceal bleeding, were randomised to receive nadolol+isosorbide-5-mononitrate alone (Drug: n = 78) or combined with EBL (Drug+EBL; n = 80). HVPG measurements were performed at randomisation and after 4-6 weeks on medical therapy. RESULTS: Median follow-up was 15 months. One-year probability of recurrent bleeding was similar in both groups (33% vs 26%: p = 0.3). There were no significant differences in survival or need of rescue shunts. Overall adverse events or those requiring hospital admission were significantly more frequent in the Drug+EBL group. Recurrent bleeding was significantly more frequent in HVPG non-responders than in responders (HVPG reduction >or=20% or

Liver failure complicating segmental hepatic ischaemia induced by a PTFE-coated TIPS stent.

The use of polytetrafluoroethylene (PTFE)-covered prostheses improves trans-jugular intrahepatic porto-systemic shunt (TIPS) patency and decreases the incidence of clinical relapses and re-interventions. Therefore, the improvement provided by covered stents might expand the currently accepted recommendations for TIPS use. Stent-related occlusion of the hepatic vein with consequent ischaemia of the corresponding liver parenchyma emerges as a novel complication reported in at least 5% of patients implanted with coated stents. However, this complication was reported to be mild, without signs or symptoms of liver failure, and self-limiting. We report a case of segmental liver ischaemia following PTFE-covered stent placement resulting in a marked impairment in liver function in a patient with hepatitis C virus cirrhosis implanted because of refractory oesophageal bleeding, thus expanding the severity range of this new procedural complication. Moreover, we discuss the possible involvement of additional pathogenetic mechanisms other than out-flow obstruction in the onset of coated-stent induced congestive liver ischaemia.

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 (> or = F2), advanced fibrosis (> or = F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE < 6 or > or = 12, < 9 or > or = 12, and < 12 or > 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.

Primary prophylaxis of esophageal variceal bleeding in cirrhosis.

Variceal bleeding is a common and severe complication of liver cirrhosis. The risk of bleeding increases with the size of varices, red wheal marks and disease severity. Noninvasive tests are not accurate enough for the diagnosis of varices, so all patients with cirrhosis should be screened by endoscopy. Nonselective beta-blockers (propranolol, nadolol) are indicated for primary prophylaxis in patients with medium/large varices, and for those with small varices and red signs or advanced liver failure (Child C). In such patients, beta-blockers have been shown to reduce the risk of bleeding from 25 to 15%. There is no evidence to support using beta-blockers with nitrates or spironolactone. In patients with contraindication or intolerance to beta-blockers, endoscopic band ligations are indicated.

Beta-blockers in hospitalised patients with cirrhosis and ascites: mortality and factors determining discontinuation and reinitiation.

BACKGROUND: It has been suggested that beta-blockers may increase mortality in patients with cirrhosis and refractory ascites but the effect of beta-blockers discontinuation or reinitiation has not been examined. AIMS: To compare, in hospitalised patients with cirrhosis and ascites, the effect of BB on survival and to examine the effect/predictors of beta-blockers discontinuation and reinitiation. METHODS: Sub-analysis of NACSELD (North American consortium for the study of end-stage liver disease, database containing prospective data on hospitalised patients with cirrhosis) data from 7 centres enrolling >100 patients with ascites. Data on BB discontinuation and reinitiation were collected by chart review. RESULTS: Seven hundred and sixteen patients, 307 (43%) on beta-blockers at admission and 366 (51%) with refractory ascites, were followed to death or hospital discharge. Beta-blocker use was associated with a lower white blood cell count at admission. Beta-blocker use in hospitalised patients with ascites was not associated with a higher mortality, even in those with refractory ascites. No significant changes in mean arterial pressure (MAP) were observed between groups. Discontinuation of beta-blockers (49%) was driven by low MAP, infection and acute kidney injury at time of discontinuation but was not associated with a higher mortality. Beta-blocker reinitiation occurred in 40% prior to discharge and was mainly driven by an increase in MAP. CONCLUSIONS: Beta-blocker use is safe in patients with cirrhosis and ascites (including those with refractory ascites) provided beta-blockers are discontinued in the presence of a low MAP and reinitiated once MAP reincreases. A potentially beneficial anti-inflammatory effect of beta-blockers is suggested.

[Animal models for the study of portal hypertension]. / Modelos animales en el estudio de la hipertensión portal.

Animal models allow detailed study of the hemodynamic alterations in portal hypertension syndrome and of the molecular mechanisms involved in the abnormalities in splenic and systemic circulation associated with this syndrome. Models of prehepatic portal hypertension can be used to study alterations in the splenic circulation and the physiopathology of hyperdynamic circulation. Moreover, models of cirrhosis allow the alterations in intrahepatic microcirculation that lead to increased resistance to portal flow to be studied. The present review summarizes currently available animal models of portal hypertension and analyzes their relative utility in investigating the distinct disorders associated with this entity. The criteria for the choice of a particular model, depending on the specific objectives of the study, are also discussed.

The impact of delayed biliary decompression and anti-microbial therapy in 260 patients with cholangitis-associated septic shock.

BACKGROUND: Cholangitis-associated septic shock carries significant mortality. There is uncertainty regarding the most appropriate time to achieve biliary decompression. AIM: To determine whether the timing of biliary decompression and anti-microbial therapy affect the survival in cholangitis patients with septic shock. METHODS: Nested retrospective cohort study of all cholangitis-associated septic shock patients (hypotension requiring vasopressors) from an international, multi-centre database between 1996 and 2011. RESULTS: Among 260 patients (mean age 69 years, 57% male), overall mortality was 37%. Compared to nonsurvivors (n = 96), survivors (n = 164) had lower mean admission Acute Physiology And Chronic Health Evaluation (APACHE) II (22 vs. 28, P < 0.001) and lower median serum lactate on admission (3.4 vs. 4.6 mmol/L, P < 0.001). Survivors were more likely to receive appropriate anti-microbial therapy earlier (median 2.6 vs. 6.8 h from shock, P < 0.001). Survivors were also more likely to undergo successful biliary decompression earlier (median 8.8 vs. 22 h, P < 0.001). After adjusting for co-variates, APACHE II (odds ratio, OR 1.21 per increment (1.11-1.32), time delay to appropriate anti-microbial therapy [OR 1.15 per hour (1.07-1.25)] and delayed biliary decompression >12 h [OR 3.40 (1.12-10.31)] were all significantly associated with increased mortality (P < 0.04 for all; c-statistic 0.896). CONCLUSIONS: Patients with septic shock secondary to acute cholangitis have significant mortality. Endoscopic biliary decompression >12 h after the onset of shock and delayed receipt of appropriate anti-microbial therapy were both significantly associated with adverse hospital outcome. This might suggest that early initiation of anti-microbial therapy and urgent biliary decompression (within 12 h) could potentially improve outcomes in this high-risk patient population.

Appropriate and timely antimicrobial therapy in cirrhotic patients with spontaneous bacterial peritonitis-associated septic shock: a retrospective cohort study.

BACKGROUND: Spontaneous bacterial peritonitis (SBP)-associated septic shock carries significant mortality in cirrhosis. AIM: To determine whether practice-related aspects of antimicrobial therapy contribute to high mortality. METHODS: Retrospective cohort study of all (n = 126) cirrhotics with spontaneous bacterial peritonitis (neutrophil count >250 or positive ascitic culture)-associated septic shock (1996-2011) from an international, multicenter database. Appropriate antimicrobial therapy implied either in vitro activity against a subsequently isolated pathogen (culture positive) or empiric management consistent with broadly accepted norms (culture negative). RESULTS: Overall hospital mortality was 81.8%. Comparing survivors (n = 23) with non-survivors (n = 103), survivors had lower Acute Physiology and Chronic Health Evaluation (APACHEII) (mean ± s.d.; 22 ± 7 vs. 32 ± 8) and model for end-stage liver disease (MELD) (24 ± 9 vs. 34 ± 11) scores and serum lactate on admission (4.9 ± 3.1 vs. 8.9  ± 5.3), P < 0.001 for all. Survivors were less likely to receive inappropriate initial antimicrobial therapy (0% vs. 25%, P = 0.013) and received appropriate antimicrobial therapy earlier [median 1.8 (1.1-5.2) vs. 9.5 (3.9-14.3) h, P < 0.001]. After adjusting for covariates, APACHEII [OR, odds ratio 1.45 (1.04-2.02) per 1 unit increment, P = 0.03], lactate [OR 2.34 (1.04-5.29) per unit increment, P = 0.04] and time delay to appropriate antimicrobials [OR 1.86 (1.10-3.14) per hour increment, P = 0.02] were significantly associated with increased mortality. CONCLUSIONS: Cirrhotic patients with septic shock secondary to spontaneous bacterial peritonitis have high mortality (>80%). Each hour of delay in appropriate antimicrobial therapy was associated with a 1.86 times increased hospital mortality. Admission APACHEII and serum lactate also significantly impacted hospital mortality. Earlier initiation of appropriate antimicrobial therapy could substantially improve outcome.

Portal hypertension: pre-primary and primary prophylaxis of variceal bleeding.

In liver cirrhosis, variceal bleeding is the last in a chain of events initiated by the increase in portal pressure (estimated in clinical practice by the hepatic venous pressure gradient). When hepatic venous pressure gradient goes above 10 mmHg the patient is at risk of developing varices, and when hepatic venous pressure gradient reaches 12 mmHg variceal bleeding might develop. Currently, there is not any effective therapy for the prevention of the development of varices. When varices are small, beta-adrenergic blockers might prevent the enlargement of the varices, and may reduce the risk of variceal bleeding. In patients with medium to large varices, beta-blockers are clearly effective in reducing the risk of variceal bleeding. Endoscopic band ligation might be more effective than beta-blockers, but available evidence is still very weak.

Acute propranolol administration effectively decreases portal pressure in patients with TIPS dysfunction. Transjugular intrahepatic portosystemic shunt.

BACKGROUND AND AIMS: Up to 60% of patients treated with transjugular intrahepatic portosystemic shunt (TIPS) require angioplasty or restenting during the first year of follow up because of TIPS dysfunction (stenosis of the intrahepatic shunt increasing the portal pressure gradient above the 12 mm Hg threshold). We hypothesised that in patients with TIPS stenosis, propranolol administration, by decreasing portal inflow, would markedly decrease portal pressure. PATIENTS AND METHODS: Eighteen patients with TIPS dysfunction were investigated by measuring portal pressure gradient before and after acute propranolol administration (0.2 mg/kg intravenously; n=18). RESULTS: Propranolol markedly reduced the portal pressure gradient (from 16.6 (3.5) to 11.9 (4.8) mm Hg; p<0.0001), cardiac index (-26 (7)%), and heart rate (-18 (7)%) (p<0.0001). Portal pressure gradient decreased to less than 12 mm Hg in nine patients, more frequently in those with moderate dysfunction (portal pressure gradient 16 mm Hg) than in patients with severe dysfunction (portal pressure gradient >16 mm Hg) (8/10 v 1/8; p=0.015). CONCLUSIONS: Propranolol therapy may delay the increase in portal pressure and reduce the need for reintervention in patients with TIPS dysfunction.