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Background & Aims Although the discriminative ability of the model for end-stage liver disease (MELD) score is generally considered acceptable, its calibration is still unclear. In a validation study, we assessed the discriminative performance and calibration of 3 versions of the model: original MELD-TIPS, used to predict survival after transjugular intrahepatic portosystemic shunt (TIPS); classic MELD-Mayo; and MELD-UNOS, used by the United Network for Organ Sharing (UNOS). We also explored recalibrating and updating the model. Methods In total, 776 patients who underwent elective TIPS (TIPS cohort) and 445 unselected patients (non-TIPS cohort) were included. Three, 6 and 12-month mortality predictions were calculated by the 3 MELD versions: discrimination was assessed by c-statistics and calibration by comparing deciles of predicted and observed risks. Cox and Fine and Grey models were used for recalibration and prognostic analyses. Results In the TIPS/non-TIPS cohorts, the etiology of liver disease was viral in 402/188, alcoholic in 185/130, and non-alcoholic steatohepatitis in 65/33; mean follow-up±SD was 25±9/19±21 months; and the number of deaths at 3-6-12 months was 57-102-142/31-47-99, respectively. C-statistics ranged from 0.66 to 0.72 in TIPS and 0.66 to 0.76 in non-TIPS cohorts across prediction times and scores. A post hoc analysis revealed worse c-statistics in non-viral cirrhosis with more pronounced and significant worsening in the non-TIPS cohort. Calibration was acceptable with MELD-TIPS but largely unsatisfactory with MELD-Mayo and -UNOS whose performance improved much after recalibration. A prognostic analysis showed that age, albumin, and TIPS indication might be used to update the MELD. Conclusions In this validation study, the performance of the MELD score was largely unsatisfactory, particularly in non-viral cirrhosis. MELD recalibration and candidate variables for an update to the MELD score are proposed. Lay summary While the discriminative performance of the model for end-stage liver disease (MELD) score is credited to be fair to good, its calibration, the correspondence of observed to predicted mortality, is still unsettled. We found that application of 3 different versions of the MELD in 2 independent cirrhosis cohorts yielded largely imprecise mortality predictions particularly in non-viral cirrhosis. Thus, we propose a recalibration and suggest candidate variables for an update to the model.

The clinical course of cirrhosis is mostly determined by the progressive increase of portal hypertension, hyperdynamic circulation, bacterial translocation and activation of systemic inflammation. Different disease states, encompassing compensated and decompensated cirrhosis and a late decompensated state, are related to the progression of these mechanisms and may be recognised by haemodynamic or clinical characteristics. While these disease states do not follow a predictable sequence, they correspond to varying mortality risk. Acute-on-chronic liver failure may occur either in decompensated or in compensated cirrhosis and is always associated with a high short-term mortality. The increasing severity of these disease states prompted the concept of clinical states of cirrhosis. A multistate approach has been considered to describe the clinical course of the disease. Such an approach requires the assessment of the probabilities of different outcomes in each state, which compete with each other to occur first and mark the transition towards a different state. This requires the use of competing risks analysis, since the traditional Kaplan-Meier analysis should only be used in two-state settings. Accounting for competing risks also has implications for prognosis and treatment efficacy research. The aim of this review is to summarise relevant clinical states and to show examples of competing risks analysis in multistate models of cirrhosis.

Background & Aims Two randomized controlled studies have evaluated the effect of recombinant Factor VIIa (rFVIIa) on variceal bleeding in cirrhosis without showing significant benefit. The aim of the present study was to perform a meta-analysis of the two trials on individual patient data with special focus on high risk patients. Methods The primary outcome measure was the effect of rFVIIa on a composite five day endpoint: failure to control bleeding, 5-day rebleeding or death. Analysis was based on intention to treat. High risk was defined as active bleeding on endoscopy while under vasoactive drug infusion and Child-Pugh score >8. Results 497 patients were eligible for the meta-analysis; 308 (62%) had active variceal bleeding at endoscopy (oozing or spurting) and 283 of these had a Child-Pugh score >8. Analysis on the composite endpoint in all patients with bleeding from oesophageal varices did not show any beneficial treatment effect. However, failure rate for the primary composite end-point was significantly lower in treated patients with active bleeding at endoscopy (17%) compared to placebo (26%, p =0.049). This difference was highly significant in patients with Child-Pugh score >8 and active bleeding at endoscopy (rFVIIa 16%, placebo 27%; p =0.023). No significant treatment effect was found at 42days. Five thromboembolic events occurred in rFVIIa treated patients compared to none in placebo treated patients. Conclusions The current meta-analysis shows a beneficial effect of rFVIIa on the primary composite endpoint of control of acute bleeding, prevention of rebleeding day 1–5 and 5-day mortality in patients with advanced cirrhosis and active bleeding from oesophageal varices at endoscopy. A major drawback of the treatment is a potential increased risk of arterial thrombo-embolic events. This treatment might be considered in patients with lack of control of bleeding after standard treatment.

Portosystemic shunt surgery has played a major role in the evolution of management of portal hypertension. Prophylactic shunts were abandoned in the early 1970s after 4 RCTs showed increased encephalopathy and mortality in operated patients, although bleeding was virtually abolished. The increase in mortality and portal systemic encephalopathy was attributed to the progressive liver function deterioration, induced by the blood diversion from the portal to the systemic circulation [1]. Selective variceal decompression by the distal splenorenal shunt (DSRS) was ideated in the late 1960s to maintain a sufficient portal hepatopetal flow, and therefore preserving liver function, while reducing the risk of variceal bleeding. However, since RCTs and meta-analyses showed no advantage of DSRS over total shunt and sclerotherapy [2], it was confined to the role of rescue therapy for failure of endoscopic therapy for the prevention of rebleeding in patients with relatively well preserved liver function. More recently the trans-jugular intra-hepatic portal systemic shunt (TIPS) has been added to the therapeutic options for portal hypertension and it is currently widely used as a rescue therapy after failure of combined medical and endoscopic therapy for the prevention of recurrent variceal bleeding. In fact, since two meta-analyses showed that TIPS is effective in reducing the risk of variceal rebleeding, but also increases the risk of portal hepatic encephalopathy and does not improve survival, it is not recommended as a first-line treatment for the prevention of recurrent variceal bleeding [3]. Besides the lack of clinical advantage, bare stent TIPS has also the disadvantage of requiring a strict surveillance program with ultrasonography and repeated reinterventions for preserving its patency, with a marked increase of the overall cost over that of the initial procedure. However, the rates of stent dysfunction and reinterventions have been significantly reduced by the use of covered stents. Current AASLD guidelines for the prevention of variceal hemorrhage in cirrhosis recommend that TIPS

Liver transplantation significantly improves the survival and quality of life of patients with end-stage cirrhosis. However, a large proportion of cirrhotic patients still die while on the transplant list because of an insufficient number of donors and because of the lack of an accurate prediction of life expectancy. Although many prognostic models have been proposed in the last two decades to predict mortality in cirrhosis, the Child–Pugh score [1] is by far the most largely used both in clinical practice and in clinical research. Recently, the model for end stage liver disease (MELD) has replaced the Child–Pugh score in the United States for prioritizing liver donor allocation [2]. MELD is considered more reproducible than the Child– Pugh score because it does not include subjective variables such as ascites and encephalopathy. However, obtaining the score requires computing and it is, therefore, much less practical than the Child–Pugh score for individual estimates at the bedside. Moreover, the MELD score has not been proven to be superior to the Child–Pugh score in terms of predictive accuracy [3], and both may be unsatisfactory when applied separately to compensated and decompensated patients [4]. It is in fact well known that life expectancies in compensated and decompensated cirrhosis are strikingly different and it is, therefore, conceivable that prognostic indicators may be different or may have a different weight according to the disease stage [4]. In this article we outline the natural history of cirrhosis and report on a systematic review of the literature regarding predictors of mortality in cirrhosis in order to

Background : Increased prevalence of cirrhosis in cirrhotics' families in previous studies. Aims : To compare the prevalence of cirrhosis in cirrhotics' families with that in families of patients with non-hepatic diseases. Methods : Case-control study including 500 index cases with cirrhosis and 500 pair-matched controls with chronic non-hepatic diseases, interviewed about cirrhosis in first-degree relatives and spouses using standardized forms. Results : Ninety-three index cases (88% anti-hepatitis C virus (HCV)-positive) and 13 controls had one or more cirrhotics among first-degree relatives and/or spouses (odds ratio (OR) 7.38, 95% confidence interval (CI) 4.21–12.9); cirrhosis was found in 123/4485 first-degree relatives of the index cases and in 16/4086 of controls (OR 7.17 95% CI 4.25–12.09), in 14/467 spouses of the index cases and in 1/416 spouses of controls (OR 12.8, 95% CI 1.67–97.96). The percentage of secondary cases in the families of 440 anti-HCV-positive and 60 anti-HCV-negative index cases was similar (18.8 and 21.6%, respectively). Almost all the secondary cases in families of anti-HCV-positive index cases and none in families of anti-HCV-negative index cases were anti-HCV-positive. Conclusions : Cirrhosis is significantly more frequent among first-degree relatives and spouses of patients with cirrhosis, mostly HCV-related, than among first-degree relatives and spouses of controls.

Between 1988 and 1990 an unblinded, randomized trial of terlipressin or vasopressin plus transdermal nitroglycerin, as part of a treatment strategy including emergency sclerotherapy for actively bleeding varices, was conducted during 165 admissions in 137 patients with cirrhosis and upper digestive bleeding. Eighty-four patient admissions were assigned to terlipressin (2 mg every 6 h) and 81 to vasopressin (0.4 to 0.8 unit per min) plus transdermal nitroglycerin (20 to 80 mg). The two groups were comparable for relevant clinical data, but there were slightly more patients with hepatocellular carcinoma or terminal conditions in the terlipressin group. After the 24-h study period, failure to control bleeding was 20/84 (25%) in the vasopressin and 14/81 (17%) in the terlipressin group ( p =0.19). Corresponding figures for patients bleeding from varices (emergency sclerotherapy in 43 and 45, respectively) were 13/55 (24%) and 5/56 (9%; p =0.035), from other sources 5/16 (31%) and 2/15 (13%; p =0.23), from undefined sources 2/10 (20%) and 7/13 (54%; p =0.1). In a logistic multivariate regression model the odds ratio for terlipressin adjusted for prognostic factors was 0.45 ( p =0.07). There were seven major side effects requiring treatment discontinuation in the vasopressin and one in the terlipressin group. These results suggest that terlipressin alone is as effective as vasopressin plus transdermal nitroglycerin, with less severe side effects, in 24-h control of upper gastrointestinal bleeding in patients with cirrhosis.

Background & Aims To evaluate renal failure (RF) in cirrhosis to determine and quantify its prognostic significance. Methods Studies were identified by MEDLINE, EMBASE, Cochrane, ISI Web of Science (1977–2010); search terms included renal failure, mortality, and cirrhosis. Included studies (n=74) reported >10 patients and mortality data (8088 patients). Mortality at 1, 3, and 12months was evaluated with respect to Child-Pugh score, serum creatinine, ascites, ICU status or sepsis, prospective study design, and publication year. Pooled odds ratio (POR) for death was compared for RF vs . non-RF (5668 patients). Results Overall median mortality for RF patients was 67%: 58% at 1month and 63% (IQR 54–79) at 12months. POR for death RF vs. non-RF patients was 7.6 (95%CI 5.4–10.8). Overall mortality before 2005 (1264 patients) was 74% and after 2005 (2833 patients) was 63% with a marked reduction only at 30days (71% vs. 52%). Conclusions This study provides a measure of the increased risk of death in cirrhosis with renal failure. RF increases mortality 7-fold, with 50% of patients dying within one month. Preventative strategies for RF are needed.

Background & Aims The definition of failure to control bleeding agreed upon at the Baveno IV consensus meeting, included the Adjusted Blood Requirement Index [ABRI: number of blood units/(final−initial hematocrit+0.01)]. ABRI ⩾0.75 denotes failure. However, timing for hematocrit measurements was not defined. The aims of this study were: (1) to assess the Baveno IV criteria performance to classify treatment success or failure to control bleeding at 5days, (2) to determine the appropriate timing for hematocrit. Methods Two hundred and forty-two cirrhotic patients with gastrointestinal bleeding were independently classified by three clinical experts according to the Baveno IV criteria, by analysis of the database of a randomized trial. ABRI was calculated by using the closest hematocrit to the 5day time point from the first trial product administration (ABRI-1) or after the latest transfusion within the 5-day period (ABRI-2). The gold standard for success/failure for 5-day control of bleeding was the clinical judgment of the three independent observers based on all the clinical and follow-up data. Results Inter-observer agreement for the final outcome assessment was 0.82 and a final consensus was obtained in 236/242 patients. Inter-observer agreement on patient classification with Baveno IV criteria was 0.70 with ABRI-1 and 0.84 with ABRI-2. c-statistics for correct patients classification were 0.86 for ABRI-1, 0.84 for ABRI-2, and 0.88 for Baveno IV criteria without ABRI. ABRI-1 caused misclassification of 27 patients and ABRI-2 of 39. Conclusions Baveno IV criteria are accurate to assess outcome of patients with variceal bleeding. There is a substantial observer variability linked to timing of hematocrits for ABRI calculation. With the current definition ABRI does not add to the performance of the other criteria.

Our aims were to develop a noninvasive predictive tool to identify cirrhotic patients with esophageal varices and to evaluate whether portal Doppler ultrasonographic parameters may improve the value of other predictors. One hundred forty-three consecutive compensated cirrhotic patients underwent upper gastrointestinal endoscopy. Fourteen clinical, biochemical, ultrasonographic, and Doppler ultrasonographic parameters of each patient were also recorded. Esophageal varices were detected in 63 of the 143 patients examined (44%; 95% confidence interval [CI] 36.2-52.6). Medium and large esophageal varices were observed in 28 subjects (44%; 95% CI 31.4-58.4). Using stepwise logistic regression, presence of esophageal varices was independently predicted by prothrombin activity less than 70% (odds ratio [OR]: 5.83; 95% CI: 2.6-12.8), ultrasonographic portal vein diameter greater than 13 mm (OR: 2.92; 95% CI: 1.3-6.4), and platelet count less than 100 3 109/L (OR: 2.83; 95% CI: 1.27-6.28). Variables included in the model were used to generate a simple incremental rule to evaluate each individual patient. The discriminating ability of the prediction rule was relevant (area under the curve: 0.80) and did not change by replacing ultrasonographic portal vein diameter with congestion index of portal vein. We concluded that compensated cirrhotic patients should be screened by upper gastrointestinal endoscopy when prothrombin activity less than 70%, platelet count less than 100 3 109/L, and ultrasonographic portal vein diameter greater than13 mm are observed, whereas those without any of these predictors should not undergo endoscopy. The contribution provided by portal Doppler ultrasonographic parameters does not appear of practical utility. (HEPATOLOGY 2001;33:333-338.)

level of MHC class II antigens but very few adhesion and co-stimulatory molecules (particularly CD86) whilst have good phagocytosis. Mature DC are not contained adherent fraction and show an opposite pattern. PBL CD 80 and CD86 staining was much weaker maybe indicating more immature DC. Conclusion: Isolation of LAL from liver graft perfusate is a reliable and convenient method to study donor cell lines (allowing donor-recipient immunological studies).

Summary In order to evaluate the reliability of the endoscopic assessment of variceal features, 6 skilled endoscopists separately examined 28 patients with liver cirrhosis and varices. Definitions of variceal features were set up on the basis of the classification of the Japanese Research Society for Portal Hypertension. A new item, i.e. oesophageal lumen occupancy, and a semiquantitative rating system of endoscopic findings were introduced. Beyond chance agreement (Kappa index) was poor on the assessment of the extension of blue colour (0.33) and prevalence of cherry red spots or red weal marking (0.17) whereas was fair to good (0.40–0.66; P −5 ) on the following: location, size, lumen occupancy, presence of blue colour, presence and extension of red colour sign, haematocystic spot. We conclude that the endoscopic assessment of oesophageal varices based on these features is reliable; their prognostic value as predictors of bleeding risk should be prospectively assessed.