M. Cazzaniga

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.

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.

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.

Nadolol is superior to isosorbide mononitrate for the prevention of the first variceal bleeding in cirrhotic patients with ascites.

BACKGROUND/AIMS beta-blockers effectively prevent first variceal bleeding (FVB) in cirrhotic patients. In patients with ascites, however, their use might be precluded by a high rate of contraindications and side effects. We compared the efficacy and applicability of nadolol and isosorbide-mononitrate (IsMn) in preventing FVB in a population of cirrhotic patients at high risk of variceal bleeding with ascites, who can be frequently intolerant to beta-blockers. METHODS A total of 80 consecutive cirrhotic patients with ascites and esophageal varices (25% average risk of bleeding at 1 year) were considered, 28 were excluded due to contraindications and 52 were randomly assigned to receive nadolol (n=25) or IsMn (n=27). RESULTS Frequency of contraindications was greater for beta-blockers than IsMn (35 versus 0%, P=0.001). During 21.3+/-11.6 months of follow-up, side effects forced six patients taking nadolol and four taking IsMn to stop treatment. Bleeding occurred in two patients taking nadolol and ten taking IsMn. The probability of bleeding was significantly lower in the nadolol group (P<0.05), whereas overall survival was similar (seven patients on IsMn and eight on nadolol died, P=0.3). CONCLUSIONS In patients with ascites IsMn is tolerated but ineffective while nadolol is effective but less tolerated.

Diagnosis, treatment and survival of patients with hepatorenal syndrome: A survey on daily medical practice

BACKGROUND & AIMS Hepatorenal syndrome (HRS) is a severe complication of cirrhosis with ascites. The International Ascites Club recommended strict diagnostic criteria and treatment with vasoconstrictors and albumin. Aim of this prospective cohort study was to investigate the prevalence of HRS, diagnostic criteria, treatment and 3-month outcome in the daily-clinical-practice. METHODS Two-hundred-fifty-three patients with cirrhosis and renal failure consecutively admitted to 21 Italian hospitals were recruited. RESULTS The prevalence of HRS was 45.8% (30% type-1 and 15.8% type-2). In 36% of cases HRS was presumed because not all diagnostic criteria could be fulfilled. In 8% of cases HRS was superimposed on an organic nephropathy. Patients with HRS type-1 were younger and showed higher leukocyte count, higher respiratory rates, and worse liver function scores. Sixty-four patients with HRS type-1 received vasoconstrictors (40 terlipressin and 24 midodrine/octreotide). A complete response was obtained in 19 cases (30%) and a partial response in 13 (20%). Age was the only independent predictor of response (p=0.033). Three-month survival of patients with HRS type-1 was 19.7%. Survival was better in patients who responded to therapy. Age (p=0.017), bilirubin (p=0.012), and creatinine increase after diagnostic volume expansion (p=0.02) independently predicted death. The mortality rate was 97% among patients with at least two negative predictors. CONCLUSIONS The diagnostic criteria of HRS in our daily-clinical-practice could not be completely fulfilled in one third of cases. The treatment with vasoconstrictors and albumin was widely implemented. Mortality was strongly predicted by simple baseline variables.

Point-of-care coagulation monitors calibrated for the international normalized ratio for cirrhosis (INRliver) can help to implement the INRliver for the calculation of the MELD score

BACKGROUND/AIMS The MELD defines a score used to prioritize patients awaiting liver transplantation and includes results for bilirubin, creatinine and PT expressed as INR. It is assumed that the MELD for individual patients is the same regardless of the laboratory method used for testing, thus ensuring parity of organ allocation. Previous studies showed that the INR calibrated for patients on vitamin K antagonists (INR(vka)) does not normalize results across thromboplastins, whereas an alternative calibration called INR(liver) does. However, implementation of INR(liver) calibration for thromboplastins is difficult in practice. This study aimed to assess whether easy-to-run whole-blood coagulation monitors (widely used for patients on VKA) can be calibrated to measure efficiently the INR(liver) and minimize the interlaboratory variability. METHODS PT values for 61 cirrhotic patients were measured on native-blood with 2 monitors calibrated in terms of INR(vka). PTs for these subjects were also measured with a WHO-standard for thromboplastin. Paired-PTs with the monitors and the standard were subsequently used to calibrate the monitors in terms of INR(liver). INR(vka) and INR(liver) were then compared to assess for statistical significance. RESULTS The mean INR(vka) obtained with the monitors and the standard were significantly different (p<0.001). Conversely, the corresponding INR(liver) were not. CONCLUSIONS The INR(liver) calibration as previously described for thromboplastins works also for the easy-to-run whole-blood coagulation monitors. Once the monitors are calibrated by the manufacturer in terms of INR(liver) they could be used as near-patient-testing devices directly by the personnel of liver units making the determination of the INR for patients awaiting liver transplantation much easier and standardized.

Increased flow‐mediated vasodilation in cirrhotic patients with ascites: relationship with renal resistive index

Background: Peripheral vasodilation is the key factor in the development of hyperdynamic circulation, sodium retention and functional renal failure in patients with cirrhosis. Brachial artery flow‐mediated dilation (FMD) after transient vascular occlusion is a non‐invasive method to assess the shear stress‐induced arterial vasodilation.