Francesco Salerno

Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis

Hepatorenal syndrome (HRS) is a serious complication of end-stage liver disease, occurring mainly in patients with advanced cirrhosis and ascites, who have marked circulatory dysfunction,1 as well as in patients with acute liver failure.2 In spite of its functional nature, HRS is associated with a poor prognosis,3 4 and the only effective treatment is liver transplantation. During the 56th Meeting of the American Association for the Study of Liver Diseases, the International Ascites Club held a Focused Study Group (FSG) on HRS for the purpose of reporting the results of an international workshop and to reach a consensus on a new definition, criteria for diagnosis and recommendations on HRS treatment. A similar workshop was held in Chicago in 1994 in which standardised nomenclature and diagnostic criteria for refractory ascites and HRS were established.5 The introduction of innovative treatments and improvements in our understanding of the pathogenesis of HRS during the previous decade led to an increasing need to undertake a new consensus meeting. This paper reports the scientific rationale behind the new definitions and recommendations. The international workshop included four issues debated by four panels of experts (see Acknowledgements). The issues were: (1) evidence-based HRS pathogenesis; (2) treatment of HRS using vasoconstrictors; (3) other HRS treatments using transjugular intrahepatic portosystemic stent-shunt (TIPS) and extracorporeal albumin dialysis (ECAD); and (4) new definitions and diagnostic criteria for HRS and recommendations for its treatment.

Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests

The role played by coagulation defects in the occurrence of bleeding in cirrhosis is still unclear. This is partly due to the lack of tests that truly reflect the balance of procoagulant and anticoagulant factors in vivo. Conventional coagulation tests such as prothrombin time and activated partial thromboplastin time are inadequate to explore the physiological mechanism regulating thrombin, because they do not allow full activation of the main anticoagulant factor, protein C, whose levels are considerably reduced in cirrhosis. We used a thrombin generation test to investigate the coagulation function in patients with cirrhosis. Thrombin generation measured without thrombomodulin was impaired, which is consistent with the reduced levels of procoagulant factors typically found in cirrhosis. However, when the test was modified by adding thrombomodulin (i.e., the protein C activator operating in vivo), patients generated as much thrombin as controls. Hence, the reduction of procoagulant factors in patients with cirrhosis is compensated by the reduction of anticoagulant factors, thus leaving the coagulation balance unaltered. These findings help clarify the pathophysiology of hemostasis in cirrhosis, suggesting that bleeding is mainly due to the presence of hemodynamic alterations and that conventional coagulation tests are unlikely to reflect the coagulation status of these patients. In conclusion, generation of thrombin is normal in cirrhosis. For a clinical validation of these findings, a prospective clinical trial is warranted where the results of thrombin generation in the presence of thrombomodulin are related to the occurrence of bleeding. (HEPATOLOGY 2005;41:533–558.)

Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study

AIMS To evaluate the prevalence, incidence and clinical relevance of bacterial infection in predominantly non-alcoholic cirrhotic patients hospitalised for decompensation. PATIENTS/METHODS A total of 405 consecutive admissions in 361 patients (249 males and 112 females; 66 Child-Pugh class B and 295 class C) were analysed. Blood, urine, ascitic and pleural fluid cultures were performed within the first 24 hours, during hospitalisation whenever infection was suspected, and again before discharge. RESULTS Over a one year period, 150 (34%) bacterial infections (89 community- and 61 hospital-acquired) involving urinary tract (41%), ascites (23%), blood (21%) and respiratory tract (17%) were diagnosed. The prevalence of bacterial peritonitis was 12%. Infections were asymptomatic in 69 cases (46%) and 130 (87%) involved a single site. Enteric flora accounted for 62% of infections, Escherichia Coli being the most frequent pathogen (25%). Community-acquired infections were associated with more advanced liver disease (Child-Pugh mean score 10.2+/-2.1 versus 9.5+/-1.9, p<0.05), renal failure (p<0.05), and high white blood cell count (p<0.01). Hospital-acquired infections occurred more frequently in patients admitted for gastrointestinal bleeding (p<0.05). The in-hospital mortality was significantly higher in infected than in non-infected patients (15% versus 7%, p<0.05), and infection emerged as an independent variable affecting survival. Moreover bacterial infection accounted for a significantly prolonged hospital stay. CONCLUSIONS Bacterial infection, regardless of the aetiology, is a severe complication of decompensated cirrhosis, and, although frequently asymptomatic, accounts for both longer hospital stay and increased mortality.

Working Party proposal for a revised classification system of renal dysfunction in patients with cirrhosis

Objectives To propose an improvement on the current classification of renal dysfunction in cirrhosis. Clinicians caring for patients with cirrhosis recognize that the development of renal dysfunction is associated with significant morbidity and mortality. While most cases of renal dysfunction in cirrhosis are functional in nature, developed as a result of changes in haemodynamics, cardiac function, and renal auto-regulation, there is an increasing number of patients with cirrhosis and structural changes in their kidney as a cause of renal dysfunction. Therefore, there is a need for a newer classification to include both functional and structural renal diseases. Design A working party consisting of specialists from multiple disciplines conducted literature search and developed summary statements, incorporating the renal dysfunction classification used in nephrology. These were discussed and revised to produce this proposal. Setting Multi-disciplinary international meeting. Patients None. Interventions Literature search using keywords of cirrhosis, renal dysfunction, acute kidney injury (AKI), chronic kidney injury (CKD), and hepatorenal syndrome. Results Acute kidney injury will include all causes of acute deterioration of renal function as indicated by an increase in serum creatinine of >50% from baseline, or a rise in serum creatinine of ≥26.4µmol/L (≥0.3mg/dL) in <48hours. Chronic renal disease will be defined as an estimated glomerular filtration rate (GFR) of <60ml/min calculated using the Modification of Diet in Renal Disease 6 (MDRD6) formula, recognising that the MDRD6 formula is not perfect for the cirrhotic patients and this may change as improved means of estimating GFR becomes available. Acute on chronic kidney disease will be defined as AKI superimposed on existing chronic renal disease using the above definitions for AKI and CKD. Conclusions Accepting this new classification will allow studies into the epidemiology, incidence, prevalence, natural history and the development of new treatments for these subtypes of renal dysfunction in cirrhosis.

Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites

The transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be effective in the control of refractory or recidivant ascites. However, the effect of TIPS on survival as compared with that of large‐volume paracentesis plus albumin is uncertain. A multicenter, prospective, clinical trial was performed in 66 patients with cirrhosis and refractory or recidivant ascites (16 Child‐Turcotte‐Pugh class B and 50 Child‐Turcotte‐Pugh class C) randomly assigned to treatment with TIPS (n = 33) or with large‐volume paracentesis plus human albumin (n = 33). The primary endpoint was survival without liver transplantation. Secondary endpoints were treatment failure, rehospitalization, and occurrence of complications. Thirteen patients treated with TIPS and 20 patients treated with paracentesis died during the study period, 4 patients in each group underwent liver transplantation. The probability of survival without transplantation was 77% at 1 year and 59% at 2 years in the TIPS group as compared with 52% and 29% in the paracentesis group (P = .021). In a multivariate analysis, treatment with paracentesis and higher MELD score showed to independently predict death. Treatment failure was more frequent in patients assigned to paracentesis, whereas severe episodes of hepatic encephalopathy occurred more frequently in patients assigned to TIPS. The number and duration of rehospitalizations were similar in the two groups. In conclusion, compared to large‐volume paracentesis plus albumin, TIPS improves survival without liver transplantation in patients with refractory or recidivant ascites. (HEPATOLOGY 2004;40:629–635.)

MELD score is better than Child-Pugh score in predicting 3-month survival of patients undergoing transjugular intrahepatic portosystemic shunt

BACKGROUND/AIMS Patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) are at risk of early death due to end-stage liver failure. The aim of this study was to compare model of end-stage liver disease (MELD) and Child-Pugh scores as predictors of survival after TIPS. METHODS We studied 140 cirrhotic patients treated with elective TIPS. Concordance (c)-statistic was used to assess the ability of MELD or Child-Pugh scores to predict 3-month survival. The prediction of overall survivals was estimated by comparing actuarial curves of subgroups of patients stratified according to either Child-Pugh scores or MELD risk scores. RESULTS During a median follow-up of 23.7 months, 55 patients died, 14 underwent liver transplantation and seven were lost to follow-up. For 3-month survival, the discrimination power of MELD score was superior to Child-Pugh score (0.84 vs. 0.70, z=2.07; P=0.038). Unlike Pugh score, MELD score identified two subgroups of Child C patients with different overall survivals (P=0.027). The comparison between observed and predicted survivals showed that MELD score overrates death risk. CONCLUSIONS MELD score is superior to Child-Pugh score as predictor of short-term outcome after TIPS. Its accuracy, however, decreases for long-term predictions.

The systemic inflammatory response syndrome in cirrhotic patients: Relationship with their in-hospital outcome ☆

BACKGROUND/AIMS Some evidence suggests that the systemic inflammatory response syndrome (SIRS) contributes to the poor outcome of cirrhotic patients. We studied 141 cirrhotic patients consecutively admitted to a tertiary referral centre assessing prevalence of SIRS and its relationship with in-hospital outcome. METHODS Presence of SIRS was assessed on admission and during hospital stay. Main clinical outcomes were death and development of portal hypertension-related complications. RESULTS Thirty-nine patients met SIRS criteria. SIRS was present on admission in 20 of 141 patients (14.1%), whereas it occurred during hospital stay in 19 of 121 (15.7%). SIRS was correlated with bacterial infection at admission (p=0.02), jaundice (p=0.011), high serum creatinine levels (p=0.04), high serum bilirubin levels (p=0.002), high international normalized ratio (p=0.046), high model of end-stage liver disease (MELD) score (p=0.001), and high SOFA score (p=0.003). During a follow-up of 14+/-8 days, 16 patients died (11%), 7 developed portal hypertension-related bleeding (5%), 16 hepatic encephalopathy (11%), and 5 hepatorenal syndrome type-1 (3.5%). SIRS was correlated both to death (p<0.001) and to portal hypertension-related complications (p<0.001). On multivariate analysis, SIRS and MELD were independently associated with death. CONCLUSIONS SIRS frequently occurs in patients with advanced cirrhosis and is associated with a poor outcome.

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites

Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised consensus recommendations of the International Club of Ascites Paolo Angeli1,⇑, Pere Ginès, Florence Wong, Mauro Bernardi, Thomas D. Boyer, Alexander Gerbes, Richard Moreau, Rajiv Jalan, Shiv K. Sarin, Salvatore Piano, Kevin Moore, Samuel S. Lee, Francois Durand, Francesco Salerno, Paolo Caraceni, W. Ray Kim, Vicente Arroyo, Guadalupe Garcia-Tsao

Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt

Background: Transjugular intrahepatic portosystemic shunt (TIPS) is a treatment for portal hypertension-related complications. Accurate prediction of the outcome of patients treated with TIPS is important, because some patients have very short survival. Diastolic dysfunction is frequently observed in patients with cirrhosis. Aim: To investigate whether or not diastolic dysfunction can predict the outcome after TIPS. Methods: Echocardiography with Doppler exploration was performed before and 28 days after TIPS insertion in 32 patients with cirrhosis. Several echocardiographic measures, including the early maximal ventricular filling velocity/late filling velocity (E/A) ratio as indicative of diastolic function, as well as laboratory, clinical and demographic variables were evaluated as predictors of survival. Results: Univariate analysis revealed that the presence of diastolic dysfunction observed 28 days after TIPS (E/A ratio ⩽1) and baseline model of end-stage liver disease score were related to survival. Multivariate analysis identified diastolic dysfunction as an independent predictor of death (RR 8.9, 95% CI 1.9 to 41.5, p = 0.005). During the first year of follow–up, six out of 10 patients with an E/A ratio ⩽1 died, whereas all 22 patients with E/A ratio >1 survived. Conclusions: Diastolic dysfunction estimated using E/A ratio is a promising predictor of death in patients with cirrhosis who are treated with TIPS.

The Use of E/A Ratio as a Predictor of Outcome in Cirrhotic Patients Treated With Transjugular Intrahepatic Portosystemic Shunt

OBJECTIVES:The clinical significance of diastolic dysfunction in cirrhosis, a feature of cirrhotic cardiomyopathy, is unclear. The aim of this study was to assess the utility of E/A ratio, an indicator of diastolic dysfunction, to predict ascites clearance and mortality after transjugular intrahepatic portosystemic stent shunt (TIPS) insertion.METHODS:A total of 101 cirrhotic patients who received TIPS had pre-TIPS assessments of demographics, severity of liver dysfunction (Child–Pugh and Model for End-Stage Liver Disease (MELD) scores), renal function, hemodynamics, and cardiac function (two-dimensional echocardiography). An E/A ratio of ≤1 was used to indicate diastolic dysfunction. Patients were followed-up for a mean period of 24.6±2.4 months post TIPS.RESULTS:A total of 41 patients with an E/A ratio of ≤1 (group A), and 60 patients with an E/A ratio of >1 (group B) were studied. Group A had significantly higher MELD scores (14.0±1.0 vs. 11.4±0.8; P=0.03), because of higher serum creatinine levels (107±5 vs. 86±6 μmol/l; P<0.01). There was no difference in pre-TIPS systemic hemodynamics, systolic function, or portal pressure between the two groups. After TIPS, more patients in group B had ascites clearance (log rank, P=0.038), and the same patients had a higher probability of survival (log rank, P=0.046). There were three post-TIPS cardiac deaths in group A only. A multivariate analysis showed that an E/A of ratio ≤1 was predictive of slow ascites clearance (hazard ratio=7.3, 95% confidence interval=1.3–40.7, P=0.021) and death after TIPS (hazard ratio=4.7, 95% confidence interval=1.1–20.2, P=0.035).CONCLUSIONS:Diastolic dysfunction, indicated by reduced E/A ratio, is prevalent in advanced cirrhosis and is associated with reduced ascites clearance and increased mortality post TIPS, possibly related to worsening of hemodynamic dysfunction in the post-TIPS period.