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Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies

Published:November 10, 2005DOI:https://doi.org/10.1016/j.jhep.2005.10.013

      1. Background

      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 [
      • Child C.G.
      • Turcotte J.G.
      Surgery and portal hypertension.
      ] 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 [
      • Kamath P.S.
      • Wiesner R.H.
      • Malinchoc M.
      • Kremers W.
      • Therneau T.M.
      • Kosberg C.L.
      • et al.
      A model to predict survival in patients with end-stage liver disease.
      ]. 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 [
      • Durand F.
      • Valla D.
      Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD.
      ], and both may be unsatisfactory when applied separately to compensated and decompensated patients [

      D'Amico G, Garcia–Tsao G, Abraldes J, Ginès P, Kim WR, Schepis F, et al. Prognostic indicators in cirrhosis. In: de Franchis R, editor. Portal Hypertension IV. Proceedings of the Fourth Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies. Blackwell, 2005.

      ]. 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 [

      D'Amico G, Garcia–Tsao G, Abraldes J, Ginès P, Kim WR, Schepis F, et al. Prognostic indicators in cirrhosis. In: de Franchis R, editor. Portal Hypertension IV. Proceedings of the Fourth Baveno International Consensus Workshop on Definitions, Methodology and Therapeutic Strategies. Blackwell, 2005.

      ].
      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 evaluate whether variables included in the Child–Pugh and MELD scores and other variables have different validity throughout the different stages in the course of cirrhosis.

      2. Natural history of cirrhosis

      Cirrhosis is the end-stage of every chronic liver disease. Its natural history is characterized by an asymptomatic phase, termed ‘compensated’ cirrhosis followed by a rapidly progressive phase marked by the development of complications of portal hypertension and/or liver dysfunction, termed ‘decompensated cirrhosis’ (Fig. 1). In the compensated phase, portal pressure may be normal or below the threshold level identified for the development of varices or ascites (‘clinically significant portal hypertension’) [
      • D'Amico G.
      • Garcia-Tsao G.
      • Cales P.
      • Escorsell A.
      • Nevens F.
      • Cestari R.
      • et al.
      Diagnosis of portal hypertension: how and when.
      ]. As the disease progresses, portal pressure increases and liver function decreases, resulting in the development of ascites, portal hypertensive gastrointestinal (GI) bleeding, encephalopathy and jaundice. The development of any of these complications marks the transition from a compensated to a decompensated phase. Progression may be accelerated by the development of other complications such as (re)bleeding, renal impairment (refractory ascites, hepatorenal syndrome), hepatopulmonary syndrome and sepsis (spontaneous bacterial peritonitis). The development of hepatocellular carcinoma (HCC) may accelerate the course of the disease at any stage.
      Figure thumbnail gr1
      Fig. 1The natural history of cirrhosis and components of prognosis. A simplified view.
      Classification of cirrhosis into a compensated and a decompensated stage is simple and reproducible and identifies patients at a similar rate of disease progression and survival. Decompensated cirrhosis is defined by the presence of ascites, variceal bleeding, encephalopathy and/or jaundice [
      • Saunders J.B.
      • Walters J.R.F.
      • Davies P.
      • Paton A.
      A 20-year prospective study of cirrhosis.
      ,
      • Gines P.
      • Quintero E.
      • Arroyo V.
      Compensated cirrhosis: natural history and prognosis.
      ]. Moreover, since ascites is most frequently the first of these signs to appear [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ], it is usually considered a landmark sign of decompensated cirrhosis. Transition from a compensated to a decompensated stage occurs at a rate of ∼5–7% per year (Fig. 2) [
      • D'Amico G.
      Natural history of compensated cirrhosis and varices.
      ].
      Figure thumbnail gr2
      Fig. 2Cumulative proportion of patients transitioning from a compensated to a decompensated stage. Individual patient data from two prospective studies of the natural history of cirrhosis [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ,
      • D'Amico G.
      • Pasta L.
      • Madonia S.
      • Tarantino G.
      • Mancuso A.
      • Malizia G.
      • et al.
      The incidence of esophageal varices in cirrhosis.
      ].
      Survival of patients with compensated cirrhosis is significantly longer than that of decompensated patients with median survival times of >12 years and ∼2 years, respectively (Fig. 3A). Patients with compensated cirrhosis die mostly after transition to a decompensated stage. Survival while the patient remains in the compensated stage is calculated by censoring data at the first manifestation of decompensation and, as shown in Fig. 3B, is markedly higher than the probability of survival of a given clinical stage at a given point along the course of the disease, e.g. at diagnosis (Fig. 3A).
      Figure thumbnail gr3
      Fig. 3Survival according to decompensation at diagnosis (A) and while remaining in the compensated or decompensated stages (B). Individual patient data from two prospective studies of the natural history of cirrhosis [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ,
      • D'Amico G.
      • Pasta L.
      • Madonia S.
      • Tarantino G.
      • Mancuso A.
      • Malizia G.
      • et al.
      The incidence of esophageal varices in cirrhosis.
      ]. [This figure appears in colour on the web.]
      By combining data from two large natural history studies including 1649 patients [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ,
      • D'Amico G.
      • Pasta L.
      • Madonia S.
      • Tarantino G.
      • Mancuso A.
      • Malizia G.
      • et al.
      The incidence of esophageal varices in cirrhosis.
      ], four clinical stages or status of cirrhosis can be identified, each with distinct clinical features and a markedly different prognosis (Fig. 4). Each stage is defined by the presence or absence of complications of cirrhosis and was agreed upon in the recent Baveno IV consensus conference [
      • de Franchis R.
      Evolving consensus in portal hypertension report of the baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ].
      Figure thumbnail gr4
      Fig. 4Clinical course of cirrhosis: 1-year outcome probabilities according to clinical stages.
      Stage 1 is characterized by the absence of esophageal varices and of ascites. While patients remain in this status, the mortality rate is as low as 1% per year. Patients exit this status at a cumulative rate of 11.4% per year: 7% because of the development of varices and 4.4% because of the development of ascites (with or without varices).
      Stage 2 is characterized by the presence of esophageal varices without ascites and without bleeding. While patients remain in this status, the mortality rate is 3.4% per year. Patients leave this status by developing ascites (6.6% per year) or by developing variceal bleeding before or at the time of development of ascites (rate 4% per year).
      Stage 3 is characterized by ascites with or without esophageal varices in a patient that has never bled. While patients remain in this status, the mortality rate is 20% per year, significantly higher than in the two former states. Patients exit this stage by bleeding (7.6% per year).
      Stage 4 is characterized by GI bleeding with or without ascites. In this stage the one-year mortality rate is 57% (nearly half of these deaths occur within 6 weeks from the initial episode of bleeding).
      Stages 1 and 2 correspond to patients with compensated cirrhosis while stages 3 and 4 refer to decompensated cirrhosis. HCC develops at a fairly constant rate of 3% per year and is associated with a worse outcome at whatever status it develops.
      In the aforementioned consensus conference on portal hypertension it was suggested that this status classification should be adopted in future prognostic studies of cirrhosis and in randomized controlled trials [
      • de Franchis R.
      Evolving consensus in portal hypertension report of the baveno IV consensus workshop on methodology of diagnosis and therapy in portal hypertension.
      ].

      2.1 Predictors of mortality: a systematic review

      2.1.1 (a) Methods

      All prognostic studies of cirrhosis were considered eligible for this review if they fulfilled the following criteria: (a) publication in the English language; (b) inclusion of adult patients with cirrhosis; (c) survival analysis was reported; d) follow-up ≥6 months, and (e) multivariable analysis of prognostic indicators of death risk was performed. Exclusion criteria were: (a) studies that included both cirrhotic and non cirrhotic patients; (b) studies assessing only short term mortality (≤6 months); (c) studies evaluating specific therapies (randomized controlled trials, prospective studies of post-therapeutic course, etc.) or prognosis after procedures (e.g. surgical shunts, transjugular intrahepatic portosystemic shunt), (d) studies including only patients with primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), metabolic or genetic liver diseases.
      Studies were identified by a MEDLINE search using the following terms: (survival [ALL] OR mortality [ALL] OR predictor [ALL] OR prognosis [ALL] OR prognostic [ALL]) AND (multivariate OR Cox OR Cox's OR adjusted OR adjustment OR logistic [ALL]) AND cirrhosis [MESH]. Additional studies were located by manual search using references from retrieved articles.
      The following data were extracted by two independent observers, based on pre-defined criteria: (a) aim of the study, explanatory (i.e. assessing the prognostic value of a specific variable according to a biologically plausible hypothesis) or predictive (assessing many variables without a primary concern for understanding the primary mechanism involved in their prognostic value); (b) design (prospective or retrospective); (c) inception cohort, i.e. whether patients entered the study at a well-defined stage; (d) characteristics of included patients; (d) sample size and follow-up; (e) survival analysis and causes of death; (f) analysis of prognostic factors; (g) study validation. The quality of the included studies was assessed according to widely accepted quality criteria for prognostic studies (marked with an asterisk in Table 1) [
      • Infante-Rivard C.
      • Esnaola S.
      • Villeneuve J.P.
      Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics.
      ,

      Chianciano consensus conference on prognostic studies in hepatology. Ital J Gastroenterol Hepatol 1998; 30: 580-3.

      ,

      Oxford Centre for Evidence Based Medicine. Levels of Evidence and Grades of Recommendation; 2001 [Ref Type: Internet Communication].

      ].
      Table 1Summary of characteristics of 118 studies of predictors of mortality in cirrhosis
      Characteristic of studiesN (%)
      Aim
       Explanatory76 (64)
       Predictive42 (36)
      Design
       Prospective65 (58)
       Retrospective48 (42)
      *Inception cohort17 (15)
      *Patients were included consecutively54 (46)
      *Inclusion and exclusion criteria defined74 (63)
      *Number of excluded patients specified34 (30)
      *Cirrhosis well-defined95 (81)
      *Candidate variables were identified a priori80 (68)
      *Candidate variables included previously identified predictors of survival
      For studies prior to MELD, predictors should have included at a minimum Child (or Child–Pugh) score, Child (or Child–Pugh) class or its components. For studies after MELD, predictors must include Child (or Child–Pugh) or components or MELD or MELD components.
      96 (81)
      *Relevant baseline data shown
      At a minimum the studies should have reported results on age, sex, etiology of cirrhosis and Child or Child–Pugh or all components, or MELD score or all its components.
      74 (63)
      Analysis specific to disease stage41 (35)
      Compensated cirrhosis18 (15)
      Decompensated cirrhosis23 (19)
      Patients not previously included in other similar studies83 (86)
      *Length of followup reported111 (94)
      *Patients lost to followup reported63 (53)
      *Number of deaths reported114 (97)
      Causes of death reported81 (69)
      *Ratio of number of deaths/number of variables >10 (i.e. no overfitting)44 (37)
      *Missing data reported20 (17)
      *Results validated internally or externally17 (15)
      *Quality variables.
      a For studies prior to MELD, predictors should have included at a minimum Child (or Child–Pugh) score, Child (or Child–Pugh) class or its components. For studies after MELD, predictors must include Child (or Child–Pugh) or components or MELD or MELD components.
      b At a minimum the studies should have reported results on age, sex, etiology of cirrhosis and Child or Child–Pugh or all components, or MELD score or all its components.
      The following five major quality criteria were used to select ‘good’ quality studies: (a) inclusion of consecutive patients; (b) relevant baseline patient characteristics were reported (age, gender, etiology of cirrhosis and Child class or components or MELD score); (c) length of follow-up was reported; (d) important variables with a previously established prognostic influence on survival were included in the analysis; (e) number of deaths were reported. Inclusion of patients as an inception cohort was dismissed as a quality criterion because it was reported in only 17 studies.
      In order to achieve a more homogeneous and clinically sound assessment, the studies were grouped according to whether they included patients with compensated or decompensated cirrhosis. Compensated cirrhosis was defined by the absence of ascites, jaundice, portal-systemic encephalopathy or variceal bleeding. Correspondingly, decompensated cirrhosis was defined by the presence of any of these complications. Studies including both compensated and decompensated patients were considered in a separate group of ‘unclassifiable studies’.
      The cumulative proportion of surviving patients after the longest observation period was recorded per each study (observed rates were used if cumulative proportions were not reported). However, since the length of follow-up was very different across studies, 1 and 2-year survival rates were also recorded to obtain more homogeneous estimates.
      To identify the most accurate prognostic indicators, only variables in the first five levels of statistical significance (according to the P value pertinent to each single variable in the final multivariable analysis) were selected from each study as having a prognostic value [
      • Wells C.K.
      • Feinstein A.R.
      • Walter S.D.
      A comparison of multivariable mathematical methods for predicting survival–III. Accuracy of predictions in generating and challenge sets.
      ,
      • Heckerling P.S.
      • Conant R.C.
      • Tape T.G.
      • Wigton R.S.
      Reproducibility of predictor variables from a validated clinical rule.
      ]. To provide a rough measure of the reproducibility of each prognostic variable, we calculated the ratio between the number of studies in which each variable was significant and the number of studies in which it was assessed. To explore the reliability of the prognostic indicators identified in all studies, a sensitivity analysis was performed by analysing only the good quality studies.

      2.1.2 (b) Results

      A total of 804 references were obtained through a MEDLINE search performed on October 10, 2005; 11 more were obtained outside the search, for a total of 815 references. Of these, 685 were excluded because they were irrelevant or did not meet inclusion criteria by reading title and abstract. Five papers were unobtainable [
      • Buligescu L.
      • Voiculescu M.
      • Costin A.
      • Draghici I.
      Study of the prognosis factors in liver cirrhosis.
      ,
      • Casaril M.
      • Micciolo R.
      • Gabrielli G.B.
      • Bellisola G.
      • Corrocher R.
      Prognostic score in liver cirrhosis developed using the Cox's proportional hazard regression model.
      ,
      • Adler M.
      • Bourgeois N.
      • Van de S.J.
      • Gelin M.
      A Pugh score of 8 adequately selects patients with parenchymal cirrhosis for liver transplantation.
      ,
      • Altman C.
      • Grange J.D.
      • Amiot X.
      • Pelletier G.
      • Lacaine F.
      • Bodin F.
      • et al.
      Survival after a first episode of spontaneous bacterial peritonitis. Prognosis of potential candidates for orthotopic liver transplantation.
      ,
      • Habib A.
      • Mihas A.A.
      • Abou-Assi S.G.
      • Williams L.M.
      • Gavis E.
      • Pandak W.M.
      • et al.
      High-density lipoprotein cholesterol as an indicator of liver function and prognosis in noncholestatic cirrhotics.
      ] and eight more were excluded after reading the paper because they did not meet inclusion criteria [
      • Ekindjian O.G.
      • Devanlay M.
      • Duchassaing D.
      • Leluan G.
      • Kammerer J.
      • Fouet P.
      • et al.
      Multivariate analysis of clinical and biological data in cirrhotic patients: application to prognosis.
      ,
      • Rossi L.
      • Milani A.
      • Marra L.
      • Siciliano M.
      Grading scores and survivorship functions in liver cirrhosis: a comparative statistical analysis of various predictive models.
      ,
      • Pomier-Layrargues G.
      • Huet P.M.
      • Infante-Rivard C.
      • Villeneuve J.P.
      • Marleau D.
      • Duguay L.
      • et al.
      Prognostic value of indocyanine green and lidocaine kinetics for survival and chronic hepatic encephalopathy in cirrhotic patients following elective end-to-side portacaval shunt.
      ,
      • Thomsen B.L.
      • Moller S.
      • Sorensen T.I.
      Optimized analysis of recurrent bleeding and death in patients with cirrhosis and esophageal varices. Copenhagen esophageal varices sclerotherapy project.
      ,
      • Shiomi S.
      • Kuroki T.
      • Ueda T.
      • Takeda T.
      • Ikeoka N.
      • Nishiguchi S.
      • et al.
      Clinical usefulness of evaluation of portal circulation by per rectal portal scintigraphy with technetium-99m pertechnetate.
      ,
      • Borroni G.
      • Maggi A.
      • Sangiovanni A.
      • Cazzaniga M.
      • Salerno F.
      Clinical relevance of hyponatraemia for the hospital outcome of cirrhotic patients.
      ,
      • Zhao C.
      • Chen S.B.
      • Zhou J.P.
      • Xiao W.
      • Fan H.G.
      • Wu X.W.
      • et al.
      Prognosis of hepatic cirrhosis patients with esophageal or gastric variceal hemorrhage: multivariate analysis.
      ,
      • Degre D.
      • Bourgeois N.
      • Boon N.
      • Le Moine O.
      • Louis H.
      • Donckier V.
      • et al.
      Aminopyrine breath test compared to the MELD and Child-Pugh scores for predicting mortality among cirrhotic patients awaiting liver transplantation.
      ]. Therefore, 117 studies met inclusion and exclusion criteria and constitute the basis of this investigation. Of note, one study separately described and analysed two patient populations (decompensated and compensated cirrhosis) [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ] and therefore, this study is considered separately for each of these populations, bringing the total to 118 evaluated studies. Six were published between 1983–1985 [
      • Orrego H.
      • Israel Y.
      • Blake J.E.
      • Medline A.
      Assessment of prognostic factors in alcoholic liver disease: toward a global quantitative expression of severity.
      ,
      • Schlichting P.
      • Christensen E.
      • Andersen P.K.
      • Fauerholdt L.
      • Juhl E.
      • Poulsen H.
      • et al.
      Prognostic factors in cirrhosis identified by Cox's regression model.
      ,
      • Christensen E.
      • Schlichting P.
      • Fauerholdt L.
      • Gluud C.
      • Andersen P.K.
      • Juhl E.
      • et al.
      Prognostic value of Child-Turcotte criteria in medically treated cirrhosis.
      ,
      • Poynard T.
      • Zourabichvili O.
      • Hilpert G.
      • Naveau S.
      • Poitrine A.
      • Benatar C.
      • et al.
      Prognostic value of total serum bilirubin/gamma-glutamyl transpeptidase ratio in cirrhotic patients.
      ,
      • Milani A.
      • Marra L.
      • Siciliano M.
      • Rossi L.
      Prognostic significance of clinical and laboratory parameters in liver cirrhosis. A multivariate statistical approach.
      ,
      • Naveau S.
      • Poynard T.
      • Abella A.
      • Pignon J.P.
      • Poitrine A.
      • Agostini H.
      • et al.
      Prognostic value of serum fibronectin concentration in alcoholic cirrhotic patients.
      ], 19 between 1985–1990 [
      • D'Amico G.
      • Morabito A.
      • Pagliaro L.
      • Marubini E.
      Survival and prognostic indicators in compensated and decompensated cirrhosis.
      ,
      • Infante-Rivard C.
      • Esnaola S.
      • Villeneuve J.P.
      Clinical and statistical validity of conventional prognostic factors in predicting short-term survival among cirrhotics.
      ,
      • Christensen E.
      • Schlichting P.
      • Andersen P.K.
      • Fauerholdt L.
      • Schou G.
      • Pedersen B.V.
      • et al.
      Updating prognosis and therapeutic effect evaluation in cirrhosis with Cox's multiple regression model for time-dependent variables.
      ,
      • Mannes G.A.
      • Thieme C.
      • Stellaard F.
      • Wang T.
      • Sauerbruch T.
      • Paumgartner G.
      Prognostic significance of serum bile acids in cirrhosis.
      ,
      • Villeneuve J.P.
      • Infante-Rivard C.
      • Ampelas M.
      • Pomier-Layrargues G.
      • Huet P.M.
      • Marleau D.
      Prognostic value of the aminopyrine breath test in cirrhotic patients.
      ,
      • Gines P.
      • Quintero E.
      • Arroyo V.
      • Teres J.
      • Bruguera M.
      • Rimola A.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      ,
      • Tanaka R.
      • Itoshima T.
      • Nagashima H.
      Follow-up study of 582 liver cirrhosis patients for 26 years in Japan.
      ,
      • Tsuji Y.
      • Koga S.
      • Ibayashi H.
      • Nose Y.
      • Akazawa K.
      Prediction of the prognosis of liver cirrhosis in Japanese using Cox's proportional hazard model.
      ,
      • Llach J.
      • Gines P.
      • Arroyo V.
      • Rimola A.
      • Tito L.
      • Badalamenti S.
      • et al.
      Prognostic value of arterial pressure, endogenous vasoactive systems, and renal function in cirrhotic patients admitted to the hospital for the treatment of ascites.
      ,
      • Gluud C.
      • Henriksen J.H.
      • Nielsen G.
      Tthe copenhagen study group for liver disease. Prognostic indicators in alcoholic cirrhotic men.
      ,
      • Tage-Jensen U.
      • Henriksen J.H.
      • Christensen E.
      • Widding A.
      • Ring-Larsen H.
      • Christensen N.J.
      Plasma catecholamine level and portal venous pressure as guides to prognosis in patients with cirrhosis.
      ,
      • Albers I.
      • Hartmann H.
      • Bircher J.
      • Creutzfeldt W.
      Superiority of the Child-Pugh classification to quantitative liver function tests for assessing prognosis of liver cirrhosis.
      ,
      • Christensen E.
      • Krintel J.J.
      • Hansen S.M.
      • Johansen J.K.
      • Juhl E.
      Prognosis after the first episode of gastrointestinal bleeding or coma in cirrhosis. Survival and prognostic factors.
      ,
      • Wang J.Y.
      • Liu H.Y.
      • Zhu W.N.
      • Han J.Q.
      • Dong C.Y.
      • Shi Y.J.
      • et al.
      An analysis of prognostic factors in cirrhosis.
      ,
      • Merkel C.
      • Bolognesi M.
      • Angeli P.
      • Noventa F.
      • Caregaro L.
      • Sacerdoti D.
      • et al.
      Prognostic indicators of survival in patients with cirrhosis and esophageal varices, without previous bleeding.
      ,
      • Merkel C.
      • Bolognesi M.
      • Finucci G.F.
      • Angeli P.
      • Caregaro L.
      • Rondana M.
      • et al.
      Indocyanine green intrinsic hepatic clearance as a prognostic index of survival in patients with cirrhosis.
      ,
      • Adler M.
      • Van Laethem J.
      • Glibert A.
      • Gelin M.
      • Bourgeois N.
      • Vereerstraeten P.
      • et al.
      Factors influencing survival at one year in patients with nonbiliary hepatic parenchymal cirrhosis.
      ,
      • Tameda Y.
      • Yoshizawa N.
      • Takase K.
      • Nakano T.
      • Kosaka Y.
      Prognostic value of peritoneoscopic findings in cirrhosis of the liver.
      ]; 27 between 1990–1995 [
      • Bayerdorffer E.
      • Lamerz R.
      • Fliege R.
      • Kopcke W.
      • Mannes G.A.
      Predictive value of serum procollagen-III-peptide for the survival of patients with cirrhosis.
      ,
      • Finucci G.
      • Bellon S.
      • Merkel C.
      • Mormino P.
      • Tirelli M.
      • Gatta A.
      • et al.
      Evaluation of splanchnic angiography as a prognostic index of survival in patients with cirrhosis.
      ,
      • Kleber G.
      • Sauerbruch T.
      • Ansari H.
      • Paumgartner G.
      Prediction of variceal hemorrhage in cirrhosis: a prospective follow-up study.
      ,
      • Merkel C.
      • Gatta A.
      • Zoli M.
      • Bolognesi M.
      • Angeli P.
      • Iervese T.
      • et al.
      Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in patients with cirrhosis. Comparison with the Pugh score.
      ,
      • Oellerich M.
      • Burdelski M.
      • Lautz H.U.
      • Binder L.
      • Pichlmayr R.
      Predictors of one-year pretransplant survival in patients with cirrhosis.
      ,
      • Zoli M.
      • Cordiani M.R.
      • Marchesini G.
      • Iervese T.
      • Labate A.M.
      • Bonazzi C.
      • et al.
      Prognostic indicators in compensated cirrhosis.
      ,
      • de Jongh F.E.
      • Janssen H.L.
      • de Man R.A.
      • Hop W.C.
      • Schalm S.W.
      • van Blankenstein M.
      Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.
      ,
      • Ferro D.
      • Saliola M.
      • Quintarelli C.
      • Alessandri C.
      • Basili S.
      • Cordova C.
      • et al.
      1-year survey of patients with advanced liver cirrhosis. Prognostic value of clinical and laboratory indexes identified by the Cox regression model.
      ,
      • McCormick P.A.
      • Morgan M.Y.
      • Phillips A.
      • Yin T.P.
      • McIntyre N.
      • Burroughs A.K.
      The effects of alcohol use on rebleeding and mortality in patients with alcoholic cirrhosis following variceal haemorrhage.
      ,
      • Merkel C.
      • Bolognesi M.
      • Bellon S.
      • Zuin R.
      • Noventa F.
      • Finucci G.
      • et al.
      Prognostic usefulness of hepatic vein catheterization in patients with cirrhosis and esophageal varices.
      ,
      • Merkel C.
      • Bolognesi M.
      • Bellon S.
      • Bianco S.
      • Honisch B.
      • Lampe H.
      • et al.
      Aminopyrine breath test in the prognostic evaluation of patients with cirrhosis.
      ,
      • Abad-Lacruz A.
      • Cabre E.
      • Gonzalez-Huix F.
      • Fernandez-Banares F.
      • Esteve M.
      • Planas R.
      • et al.
      Routine tests of renal function, alcoholism, and nutrition improve the prognostic accuracy of Child-Pugh score in nonbleeding advanced cirrhotics.
      ,
      • Cabre E.
      • Abad-Lacruz A.
      • Nunez M.C.
      • Gonzalez-Huix F.
      • Fernandez-Banares F.
      • Gil A.
      • et al.
      The relationship of plasma polyunsaturated fatty acid deficiency with survival in advanced liver cirrhosis: multivariate analysis.
      ,
      • Oellerich M.
      • Hartmann H.
      • Ringe B.
      • Burdelski M.
      • Lautz H.U.
      • Pichlmayr R.
      Assessment of prognosis in transplant candidates by use of the Pugh-MEGX score.
      ,
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Badalamenti S.
      • Cassara L.
      • Maggi M.
      • et al.
      Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients.
      ,
      • Zoli M.
      • Iervese T.
      • Merkel C.
      • Bianchi G.
      • Magalotti D.
      • Marchesini G.
      • et al.
      Prognostic significance of portal hemodynamics in patients with compensated cirrhosis.
      ,
      • Arrigoni A.
      • Gindro T.
      • Aimo G.
      • Cappello N.
      • Meloni A.
      • Benedetti P.
      • et al.
      Monoethylglicinexylidide test: a prognostic indicator of survival in cirrhosis.
      ,
      • Bianchi G.
      • Marchesini G.
      • Zoli M.
      • Bugianesi E.
      • Fabbri A.
      • Pisi E.
      Prognostic significance of diabetes in patients with cirrhosis.
      ,
      • Maroto A.
      • Gines A.
      • Salo J.
      • Claria J.
      • Gines P.
      • Anibarro L.
      • et al.
      Diagnosis of functional kidney failure of cirrhosis with Doppler sonography: prognostic value of resistive index.
      ,
      • Moller S.
      • Bendtsen F.
      • Christensen E.
      • Henriksen J.H.
      Prognostic variables in patients with cirrhosis and oesophageal varices without prior bleeding.
      ,
      • Realdi G.
      • Fattovich G.
      • Hadziyannis S.
      • Schalm S.W.
      • Almasio P.
      • Sanchez-Tapias J.
      • et al.
      Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The investigators of the European concerted action on Viral Hepatitis (EUROHEP).
      ,
      • Urbain D.
      • Muls V.
      • Makhoul E.
      • Ham H.R.
      Prognostic value of thallium-201 per rectum scintigraphy in alcoholic cirrhosis.
      ,
      • Sugimura T.
      • Tsuji Y.
      • Sakamoto M.
      • Kotoh K.
      • Fukutomi T.
      • Sakai H.
      • et al.
      Long-term prognosis and prognostic factors of liver cirrhosis in the 1980s.
      ,
      • Homann C.
      • Garred P.
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      • Hasselqvist P.
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      • et al.
      Plasma calprotectin: a new prognostic marker of survival in alcohol-induced cirrhosis.
      ,
      • Ohta M.
      • Hashizume M.
      • Kawanaka H.
      • Akazawa K.
      • Tomikawa M.
      • Higashi H.
      • et al.
      Prognostic significance of hepatic vein waveform by Doppler ultrasonography in cirrhotic patients with portal hypertension.
      ,
      • Urbain D.
      • Muls V.
      • Thys O.
      • Ham H.R.
      Aminopyrine breath test improves long-term prognostic evaluation in patients with alcoholic cirrhosis in Child classes A and B.
      ,
      • Violi F.
      • Ferro D.
      • Basili S.
      • Cimminiello C.
      • Saliola M.
      • Vezza E.
      • et al.
      Prognostic value of clotting and fibrinolytic systems in a follow-up of 165 liver cirrhotic patients. CALC Group.
      ]; 26 between 1995–2000 [
      • Merkel C.
      • Marchesini G.
      • Fabbri A.
      • Bianco S.
      • Bianchi G.
      • Enzo E.
      • et al.
      The course of galactose elimination capacity in patients with alcoholic cirrhosis: possible use as a surrogate marker for death.
      ,
      • Merli M.
      • Riggio O.
      • Dally L.
      Does malnutrition affect survival in cirrhosis? PINC (Policentrica Italiana Nutrizione Cirrosi).
      ,
      • Salerno F.
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      • et al.
      Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study. AISF Group for the study of liver transplantation. Associazione Italiana per lo Studio del Fegato.
      ,
      • Vorobioff J.
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      • et al.
      Prognostic value of hepatic venous pressure gradient measurements in alcoholic cirrhosis: a 10-year prospective study.
      ,
      • Adler M.
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      • et al.
      Prognostic evaluation of patients with parenchymal cirrhosis. Proposal of a new simple score.
      ,
      • Chan C.C.
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      • Chang F.Y.
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      • et al.
      Prognostic value of plasma endotoxin levels in patients with cirrhosis.
      ,
      • Fattovich G.
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      • Degos F.
      • Tremolada F.
      • Diodati G.
      • Almasio P.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.
      ,
      • Gentilini P.
      • Laffi G.
      • La Villa G.
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      • Buzzelli G.
      • Casini-Raggi V.
      • et al.
      Long course and prognostic factors of virus-induced cirrhosis of the liver.
      ,
      • Homann C.
      • Varming K.
      • Hogasen K.
      • Mollnes T.E.
      • Graudal N.
      • Thomsen A.C.
      • et al.
      Acquired C3 deficiency in patients with alcoholic cirrhosis predisposes to infection and increased mortality.
      ,
      • Jover R.
      • Carnicer F.
      • Sanchez-Paya J.
      • Climent E.
      • Sirvent M.
      • Marco J.L.
      Salivary caffeine clearance predicts survival in patients with liver cirrhosis.
      ,
      • Magliocchetti N.
      • Torchio P.
      • Corrao G.
      • Arico S.
      • Favilli S.
      Prognostic factors for long-term survival in cirrhotic patients after the first episode of liver decompensation.
      ,
      • Caregaro L.
      • Alberino F.
      • Amodio P.
      • Merkel C.
      • Angeli P.
      • Plebani M.
      • et al.
      Nutritional and prognostic significance of serum hypothyroxinemia in hospitalized patients with liver cirrhosis.
      ,
      • Merkel C.
      • Morabito A.
      • Sacerdoti D.
      • Bolognesi M.
      • Angeli P.
      • Gatta A.
      Updating prognosis of cirrhosis by Cox's regression model using Child-Pugh score and aminopyrine breath test as time-dependent covariates.
      ,
      • Serfaty L.
      • Aumaitre H.
      • Chazouilleres O.
      • Bonnand A.M.
      • Rosmorduc O.
      • Poupon R.E.
      • et al.
      Determinants of outcome of compensated hepatitis C virus-related cirrhosis.
      ,
      • Stanley A.J.
      • Robinson I.
      • Forrest E.H.
      • Jones A.L.
      • Hayes P.C.
      Haemodynamic parameters predicting variceal haemorrhage and survival in alcoholic cirrhosis.
      ,
      • Amodio P.
      • DelPiccolo F.
      • Marchetti P.
      • Angeli P.
      • Iemmolo R.
      • Caregaro L.
      • et al.
      Clinical features and survival of cirrhotic patients with subclinical cognitive alterations detected by the number connection test and computerized psychometric tests.
      ,
      • Bustamante J.
      • Rimola A.
      • Ventura P.J.
      • Navasa M.
      • Cirera I.
      • Reggiardo V.
      • et al.
      Prognostic significance of hepatic encephalopathy in patients with cirrhosis.
      ,
      • Hu K.Q.
      • Tong M.J.
      The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States.
      ,
      • Macias-Rodriguez M.A.
      • Rendon-Unceta P.
      • Martinez-Sierra M.C.
      • Teyssiere-Blas I.
      • Diaz-Garcia F.
      • Martin-Herrera L.
      Prognostic usefulness of ultrasonographic signs of portal hypertension in patients with child-pugh stage a liver cirrhosis.
      ,
      • Patch D.
      • Armonis A.
      • Sabin C.
      • Christopoulou K.
      • Greenslade L.
      • McCormick A.
      • et al.
      Single portal pressure measurement predicts survival in cirrhotic patients with recent bleeding.
      ,
      • Testa R.
      • Valente U.
      • Risso D.
      • Caglieris S.
      • Giannini E.
      • Fasoli A.
      • et al.
      Can the MEGX test and serum bile acids improve the prognostic ability of Child-Pugh's score in liver cirrhosis?.
      ,
      • Degos F.
      • Christidis C.
      • Ganne-Carrie N.
      • Farmachidi J.P.
      • Degott C.
      • Guettier C.
      • et al.
      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
      ,
      • del Olmo J.A.
      • Pena A.
      • Serra M.A.
      • Wassel A.H.
      • Benages A.
      • Rodrigo J.M.
      Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis.
      ,
      • Fattovich G.
      • Giustina G.
      • Christensen E.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • et al.
      Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European concerted action on Viral Hepatitis (Eurohep).
      ,
      • Ganne-Carrie N.
      • Christidis C.
      • Chastang C.
      • Ziol M.
      • Chapel F.
      • Imbert-Bismut F.
      • et al.
      Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study.
      ,
      • Guechot J.
      • Serfaty L.
      • Bonnand A.M.
      • Chazouilleres O.
      • Poupon R.E.
      • Poupon R.
      Prognostic value of serum hyaluronan in patients with compensated HCV cirrhosis.
      ]; and 40 between 2000 and October of 2005 [
      • Alberino F.
      • Gatta A.
      • Amodio P.
      • Merkel C.
      • Di Pascoli L.
      • Boffo G.
      • et al.
      Nutrition and survival in patients with liver cirrhosis.
      ,
      • Amodio P.
      • Del Piccolo F.
      • Petteno E.
      • Mapelli D.
      • Angeli P.
      • Iemmolo R.
      • et al.
      Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients.
      ,
      • Fernandez-Esparrach G.
      • Sanchez-Fueyo A.
      • Gines P.
      • Uriz J.
      • Quinto L.
      • Ventura P.J.
      • et al.
      A prognostic model for predicting survival in cirrhosis with ascites.
      ,
      • Fattovich G.
      • Ribero M.L.
      • Pantalena M.
      • Diodati G.
      • Almasio P.
      • Nevens F.
      • et al.
      Hepatitis C virus genotypes: distribution and clinical significance in patients with cirrhosis type C seen at tertiary referral centres in Europe.
      ,
      • Franca A.V.
      • De Souza J.B.
      • Silva C.M.
      • Soares E.C.
      Long-term prognosis of cirrhosis after spontaneous bacterial peritonitis treated with ceftriaxone.
      ,
      • Puthumana L.
      • Chaudhry V.
      • Thuluvath P.J.
      Prolonged QTc interval and its relationship to autonomic cardiovascular reflexes in patients with cirrhosis.
      ,
      • Deltenre P.
      • Rufat P.
      • Hillaire S.
      • Elman A.
      • Moreau R.
      • Valla D.
      • et al.
      Lack of prognostic usefulness of hepatic venous pressures and hemodynamic values in a select group of patients with severe alcoholic cirrhosis.
      ,
      • Fattovich G.
      • Pantalena M.
      • Zagni I.
      • Realdi G.
      • Schalm S.W.
      • Christensen E.
      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
      ,
      • Hui A.Y.
      • Chan H.L.
      • Leung N.W.
      • Hung L.C.
      • Chan F.K.
      • Sung J.J.
      Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation.
      ,
      • Porcel A.
      • Diaz F.
      • Rendon P.
      • Macias M.
      • Martin-Herrera L.
      • Giron-Gonzalez J.A.
      Dilutional hyponatremia in patients with cirrhosis and ascites.
      ,
      • Selberg O.
      • Selberg D.
      Norms and correlates of bioimpedance phase angle in healthy human subjects, hospitalized patients, and patients with liver cirrhosis.
      ,
      • Abraldes J.G.
      • Tarantino I.
      • Turnes J.
      • Garcia-Pagan J.C.
      • Rodes J.
      • Bosch J.
      Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
      ,
      • Bal J.S.
      • Thuluvath P.J.
      Prolongation of QTc interval: relationship with etiology and severity of liver disease, mortality and liver transplantation.
      ,
      • Botta F.
      • Giannini E.
      • Romagnoli P.
      • Fasoli A.
      • Malfatti F.
      • Chiarbonello B.
      • et al.
      MELD scoring system is useful for predicting prognosis in patients with liver cirrhosis and is correlated with residual liver function: a European study.
      ,
      • Hui J.M.
      • Kench J.G.
      • Chitturi S.
      • Sud A.
      • Farrell G.C.
      • Byth K.
      • et al.
      Long-term outcomes of cirrhosis in nonalcoholic steatohepatitis compared with hepatitis C.
      ,
      • Jepsen P.
      • Vilstrup H.
      • Moller J.K.
      • Sorensen H.T.
      Prognosis of patients with liver cirrhosis and spontaneous bacterial peritonitis.
      ,
      • Korner T.
      • Kropf J.
      • Kosche B.
      • Kristahl H.
      • Jaspersen D.
      • Gressner A.M.
      Improvement of prognostic power of the Child-Pugh classification of liver cirrhosis by hyaluronan.
      ,
      • Liangpunsakul S.
      • Ulmer B.J.
      • Chalasani N.
      Predictors and implications of severe hypersplenism in patients with cirrhosis.
      ,
      • Longheval G.
      • Vereerstraeten P.
      • Thiry P.
      • Delhaye M.
      • Le Moine O.
      • Deviere J.
      • et al.
      Predictive models of short- and long-term survival in patients with nonbiliary cirrhosis.
      ,
      • Nidegger D.
      • Ragot S.
      • Berthelemy P.
      • Masliah C.
      • Pilette C.
      • Martin T.
      • et al.
      Cirrhosis and bleeding: the need for very early management.
      ,
      • Pessione F.
      • Ramond M.J.
      • Peters L.
      • Pham B.N.
      • Batel P.
      • Rueff B.
      • et al.
      Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.
      ,
      • Schenk P.
      • Schoniger-Hekele M.
      • Fuhrmann V.
      • Madl C.
      • Silberhumer G.
      • Muller C.
      Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis.
      ,
      • Serra M.A.
      • Escudero A.
      • Rodriguez F.
      • del Olmo J.A.
      • Rodrigo J.M.
      Effect of hepatitis C virus infection and abstinence from alcohol on survival in patients with alcoholic cirrhosis.
      ,
      • Bell H.
      • Jahnsen J.
      • Kittang E.
      • Raknerud N.
      • Sandvik L.
      Long-term prognosis of patients with alcoholic liver cirrhosis: a 15-year follow-up study of 100 Norwegian patients admitted to one unit.
      ,
      • Gildea T.R.
      • Cook W.C.
      • Nelson D.R.
      • Aggarwal A.
      • Carey W.
      • Younossi Z.M.
      • et al.
      Predictors of long-term mortality in patients with cirrhosis of the liver admitted to a medical ICU.
      ,
      • Giron-Gonzalez J.A.
      • Martinez-Sierra C.
      • Rodriguez-Ramos C.
      • Macias M.A.
      • Rendon P.
      • Diaz F.
      • et al.
      Implication of inflammation-related cytokines in the natural history of liver cirrhosis.
      ,
      • Heuman D.M.
      • Abou-Assi S.G.
      • Habib A.
      • Williams L.M.
      • Stravitz R.T.
      • Sanyal A.J.
      • et al.
      Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death.
      ,
      • Moreau R.
      • Delegue P.
      • Pessione F.
      • Hillaire S.
      • Durand F.
      • Lebrec D.
      • et al.
      Clinical characteristics and outcome of patients with cirrhosis and refractory ascites.
      ,
      • Park D.K.
      • Um S.H.
      • Lee J.W.
      • Lee J.B.
      • Kim Y.S.
      • Park C.H.
      • et al.
      Clinical significance of variceal hemorrhage in recent years in patients with liver cirrhosis and esophageal varices.
      ,
      • Romero-Gomez M.
      • Grande L.
      • Camacho I.
      Prognostic value of altered oral glutamine challenge in patients with minimal hepatic encephalopathy.
      ,
      • Yoneyama K.
      • Nebashi Y.
      • Kiuchi Y.
      • Shibata M.
      • Mitamura K.
      Prognostic index of cirrhotic patients with hepatic encephalopathy with and without hepatocellular carcinoma.
      ,
      • Yoneyama K.
      • Taniguchi H.
      • Kiuchi Y.
      • Shibata M.
      • Mitamura K.
      Prognostic index of liver cirrhosis with ascites with and without hepatocellular carcinoma.
      ,
      • Biggins S.W.
      • Rodriguez H.J.
      • Bacchetti P.
      • Bass N.M.
      • Roberts J.P.
      • Terrault N.A.
      Serum sodium predicts mortality in patients listed for liver transplantation.
      ,
      • Giron-Gonzalez J.A.
      • Martinez-Sierra C.
      • Rodriguez-Ramos C.
      • Rendon P.
      • Macias M.A.
      • Fernandez-Gutierrez C.
      • et al.
      Adhesion molecules as a prognostic marker of liver cirrhosis.
      ,
      • Huo T.I.
      • Wu J.C.
      • Lin H.C.
      • Lee F.Y.
      • Hou M.C.
      • Lee P.C.
      • Chang F.Y.
      • Lee S.D.
      Evaluation of the increase in model for end-stage liver disease (DeltaMELD) score over time as a prognostic predictor in patients with advanced cirrhosis: risk factor analysis and comparison with initial MELD and Child-Turcotte-Pugh score.
      ,
      • Kayali Z.
      • Ranguelov R.
      • Mitros F.
      • Shufelt C.
      • Elmi F.
      • Rayhill S.C.
      • et al.
      Hemosiderosis is associated with accelerated decompensation and decreased survival in patients with cirrhosis.
      ,
      • Papatheodoridis G.V.
      • Cholongitas E.
      • Dimitriadou E.
      • Touloumi G.
      • Sevastianos V.
      • Archimandritis A.J.
      MELD vs Child-Pugh and creatinine-modified Child-Pugh score for predicting survival in patients with decompensated cirrhosis.
      ,
      • Pineda J.A.
      • Romero-Gomez M.
      • Diaz-Garcia F.
      • Giron-Gonzalez J.A.
      • Montero J.L.
      • Torre-Cisneros J.
      • et al.
      HIV coinfection shortens the survival of patients with hepatitis C virus-related decompensated cirrhosis.
      ,
      • Ruf A.E.
      • Kremers W.K.
      • Chavez L.L.
      • Descalzi V.I.
      • Podesta L.G.
      • Villamil F.G.
      Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.
      ,
      • Nahon P.
      • Ganne-Carrie N.
      • Degos F.
      • Nahon K.
      • Paries J.
      • Grando V.
      • et al.
      Serum albumin and platelet count but not portal pressure are predictive of death in patients with Child-Pugh A hepatitis C virus-related cirrhosis.
      ].

      2.2 Description of studies

      The characteristics of the 118 studies evaluating predictors of long-term survival (>6 months) in patients with cirrhosis are summarized in Table 1. Almost two-thirds of the studies were explanatory, only 58% were prospective and 51% included consecutive patients. The most commonly met quality criteria included the reporting of inclusion and exclusion criteria, diagnosis of cirrhosis, number of deaths, length of follow-up, and inclusion of relevant prognostic variables. However, only a minority of studies fulfilled several other important quality criteria such as inclusion of an inception cohort (14%), reporting of missing data (17%) and validation (internal or external) (15%). Also, the adequate proportion of deaths/variables (>10) was only fulfilled in 37% while the rest demonstrated overfitting (Fig. 5). Only one study fulfilled all quality criteria [
      • Gines P.
      • Quintero E.
      • Arroyo V.
      • Teres J.
      • Bruguera M.
      • Rimola A.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      ]. Thirty-one studies met our criteria for a ‘good’ quality study [
      • Christensen E.
      • Schlichting P.
      • Fauerholdt L.
      • Gluud C.
      • Andersen P.K.
      • Juhl E.
      • et al.
      Prognostic value of Child-Turcotte criteria in medically treated cirrhosis.
      ,
      • Mannes G.A.
      • Thieme C.
      • Stellaard F.
      • Wang T.
      • Sauerbruch T.
      • Paumgartner G.
      Prognostic significance of serum bile acids in cirrhosis.
      ,
      • Gines P.
      • Quintero E.
      • Arroyo V.
      • Teres J.
      • Bruguera M.
      • Rimola A.
      • et al.
      Compensated cirrhosis: natural history and prognostic factors.
      ,
      • Wang J.Y.
      • Liu H.Y.
      • Zhu W.N.
      • Han J.Q.
      • Dong C.Y.
      • Shi Y.J.
      • et al.
      An analysis of prognostic factors in cirrhosis.
      ,
      • Merkel C.
      • Gatta A.
      • Zoli M.
      • Bolognesi M.
      • Angeli P.
      • Iervese T.
      • et al.
      Prognostic value of galactose elimination capacity, aminopyrine breath test, and ICG clearance in patients with cirrhosis. Comparison with the Pugh score.
      ,
      • Zoli M.
      • Cordiani M.R.
      • Marchesini G.
      • Iervese T.
      • Labate A.M.
      • Bonazzi C.
      • et al.
      Prognostic indicators in compensated cirrhosis.
      ,
      • McCormick P.A.
      • Morgan M.Y.
      • Phillips A.
      • Yin T.P.
      • McIntyre N.
      • Burroughs A.K.
      The effects of alcohol use on rebleeding and mortality in patients with alcoholic cirrhosis following variceal haemorrhage.
      ,
      • Merkel C.
      • Bolognesi M.
      • Bellon S.
      • Bianco S.
      • Honisch B.
      • Lampe H.
      • et al.
      Aminopyrine breath test in the prognostic evaluation of patients with cirrhosis.
      ,
      • Abad-Lacruz A.
      • Cabre E.
      • Gonzalez-Huix F.
      • Fernandez-Banares F.
      • Esteve M.
      • Planas R.
      • et al.
      Routine tests of renal function, alcoholism, and nutrition improve the prognostic accuracy of Child-Pugh score in nonbleeding advanced cirrhotics.
      ,
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Badalamenti S.
      • Cassara L.
      • Maggi M.
      • et al.
      Survival and prognostic factors of cirrhotic patients with ascites: a study of 134 outpatients.
      ,
      • Ohta M.
      • Hashizume M.
      • Kawanaka H.
      • Akazawa K.
      • Tomikawa M.
      • Higashi H.
      • et al.
      Prognostic significance of hepatic vein waveform by Doppler ultrasonography in cirrhotic patients with portal hypertension.
      ,
      • Salerno F.
      • Borroni G.
      • Moser P.
      • Sangiovanni A.
      • Almasio P.
      • Budillon G.
      • et al.
      Prognostic value of the galactose test in predicting survival of patients with cirrhosis evaluated for liver transplantation. A prospective multicenter Italian study. AISF Group for the study of liver transplantation. Associazione Italiana per lo Studio del Fegato.
      ,
      • Fattovich G.
      • Giustina G.
      • Degos F.
      • Tremolada F.
      • Diodati G.
      • Almasio P.
      • et al.
      Morbidity and mortality in compensated cirrhosis type C: a retrospective follow-up study of 384 patients.
      ,
      • Magliocchetti N.
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      Prognostic factors for long-term survival in cirrhotic patients after the first episode of liver decompensation.
      ,
      • Serfaty L.
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      Determinants of outcome of compensated hepatitis C virus-related cirrhosis.
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      • Bustamante J.
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      • et al.
      Prognostic significance of hepatic encephalopathy in patients with cirrhosis.
      ,
      • Hu K.Q.
      • Tong M.J.
      The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States.
      ,
      • Macias-Rodriguez M.A.
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      Prognostic usefulness of ultrasonographic signs of portal hypertension in patients with child-pugh stage a liver cirrhosis.
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      • Degos F.
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      Hepatitis C virus related cirrhosis: time to occurrence of hepatocellular carcinoma and death.
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      Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow up study.
      ,
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      • Chazouilleres O.
      • Poupon R.E.
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      Prognostic value of serum hyaluronan in patients with compensated HCV cirrhosis.
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      • Fattovich G.
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      Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.
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      Hemodynamic response to pharmacological treatment of portal hypertension and long-term prognosis of cirrhosis.
      ,
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      Prolongation of QTc interval: relationship with etiology and severity of liver disease, mortality and liver transplantation.
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      Long-term prognosis of patients with alcoholic liver cirrhosis: a 15-year follow-up study of 100 Norwegian patients admitted to one unit.
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      Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone.
      ].
      Figure thumbnail gr5
      Fig. 5Number of variables included in the multivariable analysis as related to the number of observed deaths in 114 studies reporting this information. Each study is represented by a dot. The diagonal line represents the points where the ratio of deaths:variables is equal to 10. In the studies above the diagonal line, the ratio is <10 and there is a considerable risk of overfitting the data, and therefore of false-positive results. In studies below the diagonal line, the risk of overfitting is acceptably low.

      2.3 Description of patients included in prognostic studies

      Overall, 23,797 patients were included in 118 studies. Their characteristics are reported in Table 2. The median number of patients per study was 129 but the range was wide (from 23 to 1217). The median age was 54 and two-thirds were male. Almost half of the patients had an alcoholic etiology of cirrhosis and, although not reported in all studies, only a minority (29%) corresponded to Child(–Pugh) class A. MELD score was only reported in nine studies with a median score of 12.
      Table 2Characteristics of cirrhotic patients included in 118 studies evaluating predictors of mortality
      VariableN of studies with available informationMedianRange (IQR
      Interquartile range.
      )
      Sample size (patients included/study)11812923–1217
      Age1115444–67
      % Male10867%23–100
      Etiology of cirrhosis (All)115
      Alcohol10946%0–100 (22–71)
      Hepatitis C4735%0–100 (22–68)
      Hepatitis B6611%0–100 (1–23)
      Other
      Includes cryptogenic, non-alcoholic steatohepatitis, autoimmune, PBC, PSC.
      7612%0–100 (0–21)
      Cirrhosis stage41
      Compensated1844%
      Decompensated2356%
      Child(–Pugh) score3385.3–10
      Child(–Pugh) class
      A7329%0–100 (18–50)
      B6838%0–68 (30–46)
      C7128%0–79 (14–39)
      MELD score9127–18
      Varices present2978%0–100 (46–100)
      Followup period (months)11131.06–168 (15–60)
      Mortality11436%11–100 (23–54)
      Causes of death
      HCC585%0–25 (1–9)
      Variceal hemorrhage6810%0–40 (5–13)
      Liver failure
      Includes encephalopathy, hepatorenal syndrome, sepsis.
      7417%4–48 (11–25)
      OLT1218%5–36 (8–27)
      Median survival time (months)32331–186 (21–63)
      One-year cumulative survival6478%24–100 (62–92)
      Child(-Pugh) class A2395%75–100 (90–98)
      Child(-Pugh) class B2080%63–99 (73–88)
      Child(-Pugh) class C2245%15–95 (33–68)
      Compensated2495%62–100 (91–98)
      Decompensated2661%26–85 (56–70)
      Two-year cumulative survival4275%44–100 (53–90)
      Child(-Pugh) class A2090%70–100 (85–96)
      Child(-Pugh) class B1670%50–96 (58–82)
      Child(-Pugh) class C1838%8–90 (21–52)
      Compensated1990%70–100 (87–97)
      Decompensated1654%45–77 (48–72)
      Final cumulative survival11461%0–89 (40–75)
      N variables considered
      Total number of assessed variables
      100152–162 (10–21)
      N deaths114496–486 (26–82)
      N variables entered on multivariable analysis10492–46 (6–12)
      N variables independently predictive of death11330–12 (2–4)
      a Interquartile range.
      b Includes cryptogenic, non-alcoholic steatohepatitis, autoimmune, PBC, PSC.
      c Includes encephalopathy, hepatorenal syndrome, sepsis.
      Total number of assessed variables

      2.4 Survival in prognostic studies

      As shown in Table 1, median followup time was 31 months with a median mortality rate of 36%. Median survival time, reported in only 32 studies, was 33 months. One-year, 2-year and final cumulative survivals were 78, 75 and 61%, respectively. One- and two-year survival times by Child class and by stage (compensated vs. decompensated) are depicted in Fig. 6, Fig. 7, respectively. The most commonly reported cause of death was liver failure (including hepatorenal syndrome and sepsis), followed by variceal hemorrhage and HCC.
      Figure thumbnail gr6
      Fig. 6Box plots of one and two-year survival rates in Child–Pugh (or variants) class A, B and C in the studies reporting this information. The number of studies providing the relevant information is reported in .
      Figure thumbnail gr7
      Fig. 7Box plots of one and two-year survival rate in studies including only compensated (n=18 studies) or decompensated (n=23 studies) patients.

      2.5 Prognostic variables

      A total of 174 different variables were evaluated in these studies. Table 3 shows the grouping of these variables according to their purported clinical and pathophysiological role in cirrhosis. As shown in Table 4 the variable that was found to be the most common independent predictor of death was the Child(–Pugh) score, having been introduced in a multivariable analysis in 67 studies and having been among the first five significant predictors in 42 (63%) of them. This was followed by all components of the Child–Pugh score (albumin, bilirubin, ascites, encephalopathy, prothrombin time). Age is the only variable found to be predictive of survival in more than 10 studies that is not part of the Child–Pugh score. Variables found to be independently predictive of survival in at least one study are shown in Table 5 and of these, HVPG, MELD and the presence of HCC are remarkable because they were found to be predictive of death in over two-thirds of the 8–9 studies in which they were evaluated. Almost half of the variables evaluated were not significant in any study (Table 6) and remarkably ALT has been non-predictive of death in 31 studies in which it was evaluated. When restricting the analysis to the 31 studies that met criteria for ‘good’ quality (Table 7), the same most common prognostic variables were confirmed, that is, Child–Pugh score or its components and age.
      Table 3Variables (n=174) evaluated in 118 studies
      Patient demographics (n=2)
      Age, gender
      Hepatic insufficiency (n=28)
      ChildPugh score/class, albumin, bilirubin, encephalopathy, prothrombin time
      Including prothrombin activity, INR.
      , MELD, MELD change, aminopyrine breath test, pseudocholinesterase, factor V, factor VII, ICG clearance, caffeine clearance, pre-kallikrein, GEC, fibronectin, arachidonic acid, complement, cholesterol, nutrition, midarm circumference, phase angle
      Total serum protein, fibrinogen, OGC, bilirubin/GGT ratio, gynecomastia, skinfold thickness
      Portal hypertension (n=26)
      Ascites, varices, UGI hemorrhage, platelets, HVPG, HVPG change, γ-globulins, spleen size, hypersplenism, PV diameter, PV flow velocity, liver perfusion
      Abdominal collaterals, portosystemic shunting (scintigraphy), portosystemic shunting (angiography), hepatic blood flow, portal blood flow, splenic vein diameter, azygos blood flow, post-sinusoidal resistance, hepatic vein O2 saturation, liver O2 extraction, portal vein resistive index, hepatic artery caliber, mesenteric vein caliber, FHVP
      Hyperdynamic circulation/volume abnormalities (n=32)
      BUN/azotemia, creatinine, serum sodium/hyponatremia, blood pressure, TNF, ICAM, bile acids, vascular spiders, norepinephrine, ADH, plasma renin activity, urinary sodium
      Edema, aldosterone, urinary potassium, diuretic use, heart rate, cardiac output, systemic vascular resistance, glomerular filtration rate, palmar erythema, urine volume, urine osmolarity, endotoxin, diastolic pressure, circulation time, plasma volume, renal resistance, plasma osmolarity, renal blood flow, creatinine clearance, right atrial pressure
      Liver inflammation/necrosis/fibrosis/cholestasis/histology (n=17)
      AST, hyaluronic acid, liver iron, histological score, lactic dehydrogenase, liver size, GGT, nodule size,lymphatic cyst, efferent vessels, calprotectin, alkaline phosphatase, flat Doppler waveform HV
      ALT, procollagen III, AST/ALT ratio, laparoscopic abnormalities
      Complications related to cirrhosis and their markers (n=32)
      HCC, decompensated cirrhosis, SBP/infection, WBC, AFP, PIVKA-II, PV tumoral thrombosis, alcoholic hepatitis, hemoglobin, UGI hemorrhage+PSE, time since UGI bleed, autonomic neuropathy, HPS, Apache score, time in ICU, use of pressors in ICU
      Ascites protein, QTc interval, pulmonary pressure, O2 saturation, AaDO2, ascites WBC count, ascites PMN count, number of decompensating events, IgG, IgM, IgA, fibrin split products, hemoccult, opsonins, temperature, constipation
      Etiologic factors (n=16)
      Alcohol abstinence, alcoholic etiology, viral load, time since diagnosis, MCV, HBsAg, etiology
      Hepatitis C etiology, route of viral exposure, HCV genotype, active viral infection, intravenous drug use, CD4 count, duration of HCV infection, anti-HDV, HBeAg
      Co-morbidities and other factors (n=18)
      T4, smoking, diabetes, serum potassium, HIV
      Cholelithiasis, cardiac disease, glycemia, hypertension, any co-morbidity, serum chloride, serum iron, triglycerides, incapacity index, diet, symptoms, asthenia, anorexia
      Treatment (n=3)
      IFN, endoscopic treatment
      Non-specified treatment/prednisolone
      Variables in italics are those that were significant on multivariable analysis in at least one study. ICG, indocyanine green; GEC, galactose elimination capacity; OGC, oral glutamine challenge; HVPG, hepatic venous pressure gradient; PV, portal vein; FHVP, free hepatic venous pressure; HV, hepatic vein; SBP, spontaneous bacterial peritonitis; WBC, white blood cell count; PIVKA-II, serum protein induced by vitamin K absence or antagonist II; AFP, alfa-fetoprotein; ICU, intensive care unit; HIV, human immunodeficiency virus; IFN, interferon.
      a Including prothrombin activity, INR.
      Table 4Variables that were most commonly found to be significant predictors of death in cirrhosis in 118 studies (n=7)
      VariableN of studies in which variable was among the first 5 significant variablesN of studies evaluating the variable% of studies in which variable was among first 5/total of studies
      CPS/class426763
      Albumin317939
      Bilirubin298136
      Age278034
      Ascites246239
      Encephalopathy247034
      Prothrombin time197525
      In more than 10 studies.
      Table 5Variables that were found to be significant in 1–10 studies (n=84)
      Variables significant among the first 5 in 2–10 studies divided by the total studies in which the variable was tested (%)Variables significant among the first 5 in only one study divided by the total studies in which the variable was tested (%)Variables significant among the first 5 and tested in only one study
      Varices9/36 (25%)Factor V1/2 (50%)Complement
      C3, C4, CH50, alternative and classical pathways, PIVK, protein induced by vitamin K or antagonist II, PIVK, serum protein induced by vitamin K absence or antagonist II (PIVKA-II).
      Gender9/68 (13%)Midarm circumference1/2 (50%)MELD change
      UGI hemorrhage8/32 (25%)PIVKA-II1/2 (50%)Caffeine clearance
      Platelets7/33 (21%)Portal vein tumoral thrombosis1/2 (50%)Arachidonic acid
      MELD6/8 (75%)Viral load1/2 (50%)Fibronectin
      HVPG6/9 (67%)Smoking1/2 (50%)Phase angle
      HCC6/9 (67%)Histological score1/3 (33%)PV flow velocity
      BUN/Azotemia5/13 (38%)Alcoholic hepatitis1/3 (33%)HVPG change
      γ-globulins5/23 (22%)Time since diagnosis1/3 (33%)Hypersplenism
      Creatinine5/32 (16%)MCV1/3 (33%)Liver perfusion
      Alkaline phosphatase5/33 (15%)Portal vein diameter1/4 (25%)ICAM
      Aminopyrine BT4/8 (50%)Norepinephrine1/4 (25%)Calprotectin
      Pseudocholinesterase4/9 (44%)Lactic dehydrogenase1/4 (25%)Flat Doppler wave HV
      Sodium/hyponatremia4/19 (21%)Etiology1/4 (25%)Efferent vessels
      AST4/40 (10%)Antidiuretic hormone1/5 (25%)Nodule size
      Factor VII3/5 (60%)Diabetes1/5 (20%)Lymphatic cyst
      ICG clearance3/11 (27%)Urinary sodium1/6 (17%)UGIH+PSE
      Nutrition3/13 (23%)Renin1/7 (14%)Time in ICU
      Blood pressure3/13 (23%)AFP1/9 (11%)HIV
      Pre-kallikrein2/2 (100%)Potassium1/9 (11%)Apache score
      TNF2/2 (100%)Hemoglobin1/11 (9%)Autonomic neuropathy
      Hyaluronic acid2/2 (100%)Liver size1/16 (6%)Time since bleed
      Liver iron2/2 (100%)HbsAg1/20 (5%)HPS
      Decompensated cirrh2/2 (100%)GGT1/25 (4%)Pressors in ICU
      T42/2 (100%)Alcoholic etiology1/48 (2%)Endoscopic treatment
      Bile acids2/4 (50%)
      IFN treatment2/6 (33%)
      SBP/infection2/7 (29%)
      Galactose elimination2/8 (25%)
      WBC2/11 (18%)
      Vascular spiders2/12 (17%)
      Alcohol abstinence2/12 (17%)
      Cholesterol2/13 (15%)
      Spleen size2/17 (12%)
      a C3, C4, CH50, alternative and classical pathways, PIVK, protein induced by vitamin K or antagonist II, PIVK, serum protein induced by vitamin K absence or antagonist II (PIVKA-II).
      Table 6Non-significant variables (n=83)
      VariableN of studies in which the variable was testedVariableN studies in which the variable was testedVariableN studies in which the variable was tested
      ALT31Splenic vein diameter2Renal blood flow1
      HCV etiology9Azygos blood flow2Renal resistance1
      Treatment
      Non-specified or prednisolone.
      9Plasma volume2Creatinine clearance1
      Edema8Urinary osmolarity2R atrial pressure1
      Aldosterone5Diastolic pressure2Laparoscopic abn1
      Urine potassium5AST/ALT ratio2Endotoxin1
      Diuretic use5Procollagen III2Opsonins1
      Cholelithiasis5Ascites protein2Ascites WBC1
      Abdo collaterals4Pulmonary pressure2Ascites PMN1
      Heart rate4O2 saturation2FSP1
      Total protein3QTc interval2IgG1
      Skinfold thickness3Constipation2IgA1
      PSS (scintigraphy)
      By scintigraphy.
      3HCV genotype2IgM1
      Cardiac output3Viral exposure route2CD41
      SVR3Serum chloride2Co-morbidity1
      GFR3Anorexia2N decompensating events1
      Palmar erythema3OGC1AaDO21
      Urine volume3Hepatic artery caliber1Temperature1
      Cardiac disease3Mesenteric vein caliber1Hemoccult1
      Active infection3PSS (angiography)1IVDU1
      Anti-HDV3Portal blood flow1Duration of HCV inf1
      HbeAg3PV resistive index1Incapacity index1
      Asthenia3Post-sinusoidal resistance1Diet1
      Glycemia3Hepatic vein O2 sat1Triglycerides1
      Fibrinogen2Liver O2 extraction1Serum iron1
      Bilirubin/GGT rat2FHVP1Symptoms1
      Gynecomastia2Circulation time1Hypertension1
      Hepatic blood flow2Plasma osmolarity1
      OGC, oral glutamine clearance.
      a Non-specified or prednisolone.
      b By scintigraphy.
      Table 7Variables that were most commonly found to be significant predictors of death assessed in 31 ‘good’ studies
      VariableN of good studies in which variable was among first 5 significant onesN of good studies evaluating variable% of studies in which variable was among first 5/total of studies
      CPS/class132065
      Bilirubin112348
      Albumin112348
      Age112839
      Prothrombin time82138
      Encephalopathy71450
      Ascites41429
      Gender52322
      BUN3475
      Platelets31030
      When the analysis is performed separately for studies that included only compensated or only decompensated cirrhotic patients, the most common prognostic variables in each group are different (Table 8), with variables related to portal hypertension (platelet count, varices, spleen size) appearing in the compensated group, and variables related to renal insufficiency or HCC appearing in the decompensated group.
      Table 8Variables significant in studies including or analyzing compensated (n=18) and decompensated cirrhosis (n=23) separately
      Compensated cirrhosis (n=18 studies)Decompensated cirrhosis (n=23 studies)
      VariableN of sign studiesN of studies eval%VariableN of sign studiesN of studies eval%
      Age101471Child–Pugh91656
      Albumin101759Encephalopathy61250
      Bilirubin81553HCC4666
      Platelet count61346Bleeding41136
      Gender41429Creatinine41527
      Prothrombin time31030Prothrombin time41625
      Child–Pugh22100Albumin41625
      Vascular spiders22100BUN/Azotemia3933
      Spleen size2633Ascites31127
      Varices2729Bilirubin31718
      γ-globulins2729Age31817

      3. Discussion

      Prognosis is an essential part of the baseline assessment of any disease. It is not only the basis for the information that a physician provides to the patient, but is also the basis for any decision-making process. However, the applicability of the available prognostic information to the individual patient is frequently unsatisfactory because individual patients are different from the average patient population on which a prognostic estimation is based. Apart from the individual biologic variability, a very important source of this diversity is the specific disease stage of the individual patient. In order to provide prognostic information, a physician needs to recognize in his/her patient a specific pattern of clinical characteristics from patients included in predictive studies. The bulk of the methodology for prognostic studies has been developed from these concepts and its application to cirrhosis has been discussed in detail elsewhere [

      Chianciano consensus conference on prognostic studies in hepatology. Ital J Gastroenterol Hepatol 1998; 30: 580-3.

      ,
      • Infante-Rivard C.
      • Villeneuve J.P.
      • Esnaola S.
      A framework for evaluating and conducting prognostic studies: an application to cirrhosis of the liver.
      ] and recommendations on how to perform and how to interpret prognostic studies have been developed [

      Oxford Centre for Evidence Based Medicine. Levels of Evidence and Grades of Recommendation; 2001 [Ref Type: Internet Communication].

      ,
      • Diamond G.A.
      Future imperfect: the limitations of clinical prediction models and the limits of clinical prediction.
      ,
      • Laupacis A.
      • Sekar N.
      • Stiell I.G.
      Clinical prediction rules. A review and suggested modifications of methodological standards.
      ,
      • Justice A.C.
      • Covinsky K.E.
      • Berlin J.A.
      Assessing the generalizability of prognostic information.
      ]. We have based this systematic review on these recommendations as indicated by the evaluation of quality items reported in Table 1.
      A remarkable finding of this systematic review is the very large number of prognostic studies of cirrhosis performed in 23 years, at least 118 studies including a total of 23,797 patients. The fact that the number of studies has been increasing over time (40 in the past 5 years) indicates uncertainty and dissatisfaction with available prognostic models. Methodological problems in these studies leading poor reproducibility may partly explain this dissatisfaction. In fact, only 1 of the 117 reviewed studies fulfilled all the considered quality criteria and only 17 provided a validation of the results, of which only five based the validation on an independent patient sample. The major problems, however, lie in the inclusion of non-consecutive patients, incomplete reporting of inclusion/exclusion criteria, incompleteness of follow-up and the inclusion of patients at differing disease stages without a separate analysis. These deficiencies, particularly the inclusion in the same study of patients at different disease stages, lead to irreparable and yet non-measurable biases and render the results non-applicable to clinical practice.
      In addition to the clinical aspects of methodology, the statistical methodology plays a key role in the assessment of predictors of survival. In the majority of the studies the number of variables included in the final analysis did not allow for controlling the risk of overfitting the data, i.e. the ratio of the number of deaths to the number of variables was <10:1 [
      • Laupacis A.
      • Sekar N.
      • Stiell I.G.
      Clinical prediction rules. A review and suggested modifications of methodological standards.
      ,
      • Harrell Jr, F.E.
      • Lee K.L.
      • Matchar D.B.
      • Reichert T.A.
      Regression models for prognostic prediction: advantages, problems, and suggested solutions.
      ,
      • Concato J.
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      The risk of determining risk with multivariable models.
      ] (Fig. 5). Overfitting of data translates in a high risk of false positive results, which may well be a further explanation of the low reproducibility of the results for most studies.
      A second major consideration from this systematic review is the wide range of reported survival rates (Table 2). While the variability of the final survival was obviously expected on the basis of the wide range of observation times across the studies, the variability of survival at fixed follow-up times (1 and 2 years, Table 2) should be interpreted, at least in part, as an expression of the heterogeneity of the included patients. In fact, this variability was appreciably reduced when the survival rates were assessed by Child(–Pugh) class or by stage (decompensated vs. decompensated) (Fig. 6, Fig. 7). It is notable that, while there is obvious overlap among survival times across the different Child–Pugh classes (Fig. 6), this overlap is almost negligible when analyzed by compensation stage (Fig. 7). However, even considering the compensated (or decompensated) stage of cirrhosis, there is still an appreciable variability of the 1 or 2-years survival rate across studies. This residual variability may be further explained, at least in part, by the inclusion of patients at different times along the course of their compensated or decompensated disease stage. Although somewhat intriguing, this concept may be easily understood if one considers the differences between a patient with compensated cirrhosis and different degrees of portal hypertension (e.g. with and without varices) and if one considers a patient with decompensated cirrhosis with ascites at different time intervals since the development of ascites (e.g. newly developed vs. ascites developed 2 years before). The prognosis of the compensated patient without varices will be better than that of the patient with varices and the prognosis of the decompensated patient with newly diagnosed ascites will be better than the one from ascites that developed two years ago. This stresses the importance of including inception cohorts in prognostic studies. Unfortunately this inclusion criterion was met in only 17 of the 117 reviewed studies.
      However, despite methodological problems in the evaluated studies, this systematic review allowed for the identification of ‘robust’ predictors of death in cirrhosis. Not only was this evident in the total number of studies in which these variables were significant, but also by calculating a ratio between the number of studies in which each variable was significant and the number of studies in which it was assessed. With larger number of studies, a large ratio is an indirect measure of validity as each study that confirms the predictive value of a variable, provides indirect proof of its validity. This robustness is, therefore, independent of the quality of the studies. Of note, we only report on predictors that were statistically significant at the first five levels of multivariable analysis, as this yields more reproducible and powerful results by omitting variables that may be statistically significant at a lower level [
      • Wells C.K.
      • Feinstein A.R.
      • Walter S.D.
      A comparison of multivariable mathematical methods for predicting survival–III. Accuracy of predictions in generating and challenge sets.
      ,
      • Heckerling P.S.
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      Reproducibility of predictor variables from a validated clinical rule.
      ].
      By far, the most consistent and ‘robust’ predictor of death in cirrhosis is the Child–Pugh score and/or its components (albumin, bilirubin, ascites, encephalopathy and prothrombin time). This was the variable most commonly introduced in multivariable analyses in the 118 studies (57%) and the one most commonly found to be an independent predictor of survival (63% of the time): importantly, exactly the same parameters (Child–Pugh score, bilirubin, albumin, prothrombin time, encephalopathy and ascites) were the most frequent significant variables when only the ‘good’ quality studies were analyzed. A first important conclusion from this review is that the Child–Pugh score and/or its parameters as well as another important and powerful predictor of death, the patient's age, must be included in any future prognostic studies in cirrhosis, independent of disease stage. This includes studies in which parameters, such as the MELD score and the HVPG, that have been less frequently studied but that nevertheless were found to be predictive of death in over two-thirds of a reasonable number of studies, should be evaluated. On the other hand, our results also demonstrate that other parameters, such as the ALT, should no longer be incorporated into prognostic models as it has been consistently and repeatedly found to be non-predictive of death.
      Another important finding of this large systematic review is that, as hypothesized and as shown earlier [
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      • Pulco A.
      • Politi F.
      • Vizzini G.
      Natural history of cirrhosis: predictors of death risk; overview of published studies and validation in a new test set.
      ], prognostic markers differ depending on the stage of cirrhosis. In studies that included only patients with compensated cirrhosis, the Child(–Pugh) score was still among the most frequent significant predictors of death despite the absence of ascites, encephalopathy and jaundice, because its laboratory components, bilirubin, albumin and prothrombin time continued to be among the most frequent predictors, indicating that even subtle abnormalities in these laboratory parameters are predictive of death. In addition to these markers of liver insufficiency, in the compensated stage, significant predictors that come to light are those related to portal hypertension, such as the presence of varices, splenomegaly and platelet count as well as γ-globulin levels (as hyper γ-globulinemia is an indirect marker of portosystemic shunting). This probably indicates that, in a compensated stage, measurements of portal pressure will be of important prognostic value. This is strengthened by a recent study that showed that in patients with no varices and no ascites (stage 1 of our classification system) the most important predictor of the development of varices was an HVPG of >10 mmHg [

      Groszmann RJ, Garcia-Tsao G, Bosch J, Grace ND, Burroughs AK, Planas R, et al. Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis. N Engl J Med, in press.

      ]. Conversely, the set of significant prognostic variables in the group of patients with decompensated cirrhosis reflect a more advanced stage, as bleeding and HCC become predictive of death. It is in this group that the Child–Pugh score (and its components) has the most important prognostic value. In addition to the Child–Pugh score, parameters that reflect a further deterioration of the circulatory status of the cirrhotic patient, such as parameters of renal dysfunction (creatinine and blood urea nitrogen/azotemia) arise as powerful prognostic indicators in this setting and, therefore, it is not surprising that the MELD score (which incorporates creatinine in addition to markers of liver dysfunction) has become a valuable method to allocate organs. On the contrary, it is predictable that the MELD score would not be useful to predict survival in patients with compensated cirrhosis.
      Lessons learned from this large systematic review should allow us to make suggestions for future studies on prognostic indicators of cirrhosis so that the information can be used in clinical practice. Regarding methodological issues, it will be of major importance to (a) include patients at a well-defined stage in the course of cirrhosis (inception cohort) thereby homogenizing the study population and (b) to avoid the error of overfitting, observed in a significant proportion of studies. From the clinical point of view, it will be important to assess prognostic variables separately for the different stages of cirrhosis, at a minimum, separating those with compensated and those with decompensated cirrhosis. Better still, and as recently concluded in the Baveno IV consensus conference, prognostic indicators should be targeted at the four specific subgroups of patients with cirrhosis that have a different risk of dying (Fig. 4). In patients with decompensated cirrhosis, any study of predictors of death should include important variables identified by the majority of studies, such as the Child–Pugh score (or its components) and age. In patients with compensated cirrhosis (or status 1 and 2), particularly in those who remain at a compensated stage, the risk of dying is low and in this group of patients it would be more useful to look at predictors of decompensation rather than at predictors of mortality.
      In clinical practice, our results strengthen the current use of the Child–Pugh score in cirrhotic patients at large and the use of the MELD score in decompensated cirrhotic patients.

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